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Kirk Woodard Non Small Cell Lung Cancer Diagnosis, Treatment, Diary, Oncology, Taxol, Carboplatin, Research, Chemotherapy, Anderson, Malignant, Cat Scan, Tomography,  Pet,  Radioactive, Bronchoscopy,  Fine Needle Aspiration,  Pathophysiology, Mortality, Morbidity, Locoregional, Respiratory, Cardiovascular, Cardiac, Smoking, Asbestos, Hydrocarbons, Dietary, Large Cell, Pleomorphic, Stage, Occult, Treatment, Endoscopic, Photodynamic Therapy, NSCLC, Sulcus Tumor, Metastisis, Primary, Regional, Lymph nodes
1935-2002

Kirk Woodward's
Non Small Cell Lung Cancer Diagnosis & Treatment Diary

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Welcome to my compendium website about Kirk Woodward's Fight with

Non Small Cell Lung Cancer
Diagnosis & Treatment Diary

I learned a lot Kirks Website when I searched for information about a medical procedure I was about to go through called Thoracentisis  Lung Procedure as a part of a Pleural Effusion. You may learn something here as I have.  You can find my cancer journal at www.IamFightingCancer.com

Like Kirk I too have  NON-SMALL CELL CARCINOMA.  You will see a lot of information below on this.  On my journal  www.IamFightingCancer.com  You will see it on the 10-9-06 entry.  Below I have put in 36 pt font the following statements from 3 different articles on Non-Small Cell Cancer.

1. "For most patients with non-small cell lung cancer, current treatments do NOT  cure the cancer."

 2. "About 85% of all lung cancers are of the non-small cell type. There are 3 sub-types of NSCLC. The cells in these sub-types differ in size, shape, and chemical make-up."

 3. "Because treatment is NOT satisfactory for almost all patients with NSCLC, eligible patients should be considered for clinical trials."

THIS IS NOT WHAT BRIAN WOULD CALL POSITIVE MOTIVATING ENCOURAGEMENT BUT IT IS REALITY WHICH IS WHAT WE HAVE TO LIVE WITH.


  • Important words found on this site. Kirk Woodard Non Small Cell Lung Cancer Diagnosis, Treatment, Diary, Oncology, Taxol, Carboplatin, Research, Chemotherapy, Anderson, Malignant, Cat Scan, Tomography,  Pet,  Radioactive, Bronchoscopy,  Fine Needle Aspiration,  Pathophysiology, Mortality, Morbidity, Locoregional, Respiratory, Cardiovascular, Cardiac, Smoking, Asbestos, Hydrocarbons, Dietary, Large Cell, Pleomorphic, Stage, Occult, Treatment, Endoscopic, Photodynamic Therapy, NSCLC, Sulcus Tumor, Metastisis, Primary, Regional, Lymph nodes
  •  
  • Contact information for this Website:
    Brian Nelson
    Webpage Marketing Consultant 

    31 Gessner Rd. ,  Houston, TX 77024
    713-467-3025  Fax 713-4
    67-3192
    Click: E-mail me

Misspelled Words on this site. based on : Non Small Cell Lung Cancer Diagnosis, Treatment, Diary, Oncology, Taxol, Carboplatin, Research, Chemotherapy, Anderson, Malignant, Cat Scan, Tomography,  Pet,  Radioactive, Bronchoscopy,  Fine Needle Aspiration,  Pathophysiology, Mortality, Morbidity, Locoregional, Respiratory, Cardiovascular, Cardiac, Smoking, Asbestos, Hydrocarbons, Dietary, Large Cell, Pleomorphic, Stage, Occult, Treatment, Endoscopic, Photodynamic Therapy, NSCLC, Sulcus Tumor, Metastisis, Primary, Regional, Lymph nodes

You can find this site again  by typing in the  Google search engine  the unique word " 1drawdooWkriK "  which is  OR " KirkWoodward1 " backwards.

Article Word Count 29,115

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4525 Misspelled words used to find this page 1 of 14
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You are at: http://www.IamFightingCancer.com/Kirk-Woodward-Diary/Non-Small-Cell-Lung-Cancer.html    ud 06/19/2007 08:10 AM -0500  Bookmark this page now!

Misspelled words used to find this page 1 of 3.  KIrk Woodward Non Small Cell Lung Cancer Diagnosis, Treatment, Diary, Oncology, Taxol, Carboplatin, Research, Chemotherapy, Anderson, Malignant, Cat Scan, Tomography,  Pet,  Radioactive, Bronchoscopy,  Fine Needle Aspiration,  Pathophysiology, Mortality, Morbidity, Locoregional, Respiratory, Cardiovascular, Cardiac, Smoking, Asbestos, Hydrocarbons, Dietary, Large Cell, Pleomorphic, Stage, Occult, Treatment, Endoscopic, Photodynamic Therapy, NSCLC, Sulcus Tumor, Metastisis, Primary, Regional, Lymph nodes
Misspelled words used to find this page 2 of 14. cenght, ceignte, ceignght, ciegnte, ciegnght, cemter, cenetr, cetner, cneter, ecnter, centr, cener, ceter, cnter, carcinoma, carsinoma, calsinoma, carkinoma, carcinoa, carcnoma, carcinma, carcioma, carinoma, cacinoma, crcinoma, calcinoma, carc1nomas, carcinomas, carcimomas, carcinomsa, carcinoams, carcinmoas, carcionmas, carcniomas, caricnomas, cacrinomas, cracinomas, acrcinomas, carcinoms, carcinoas, carcinmas, carciomas, carcnomas, carinomas, cacinomas, crcinomas, arcinomas, sarcoma, srcoma, sacoma, saroma, sarcma, sarcoa, sarkoma, salcoma, salcomas, sarcomas, srcomas, sacomas, saromas, sarcmas, sarcoas, sarcoms, sarkomas, sarconas, sarcomsa, sarcoams, sarcmoas, sarocmas, sacromas, sracomas, asrcomas, arcomas, eukmias, leukemias, leukeias, leukemais, leukemas, elukemias, leukemis, elukemais, reukemias, reukemais, lukemias, lekemias, leuemias, 1euk1en1as, leuk1en1as, leukienias, leukiemisa, leukiemais, leukieimas, leukimeias, leukeimias, leuikemias, lekuiemias, luekiemias, elukiemias, leukiemia, leukiemis, leukiemas, leukieias, leukimias, leuiemias, lekiemias, lukiemias, eukiemias, leukiemias, 1ynphommas, lynphommas, lymphommas, lymphonmsa, lymphonams, lymphomnas, lymphnomas, lympohnmas, lymhponmas, lypmhonmas, lmyphonmas, ylmphonmas, lymphonma, lymphonms, lymphonas, lymphomas, lymphnmas, lymponmas, lymhonmas, lyphonmas, lmphonmas, ymphonmas, lymphonmas, cause, caws, cawse, cases, causes, cawses, causse, cauess, casues, cuases, acuses, causs, caues, cuses, auses, environmental, enviromental, environmenal, envirnmentel, enviromentar, environmentl, envirnmantel, enviromantal, evironmental, enviromantar, envirmental, enironmental, enviromentel, envirmentar, envronmental, enviromantel, envirmantal, envionmental, envirnmental, envirmantar, environental, envirnmentar, envirmentel, environmntal, envirnmantal, envirmantel, environmetal, envirnmantar, envilonmentel, environmantel, environmentar, envilonmantel, envilonmental, envilonmentar, environmantal, environmantar, envilonmantal, envilonmantar, environmentel, iegnviromentel, iegnvirnmantal, iegnvilonmentar, eignvironmentel, eignvirmental, eignvironmiegntal, iegnviromental, iegnvironmantal, eignvilonmentel, eignvirmentar, eignvironmiegntar, iegnviromentar, iegnvironmantar, eignvironmantel, eignvirmantal, eignvironmental, eignvilonmiegntal, iegnviromantal, iegnvilonmantal, eignvirmentel, eignvirnmental, eignvironmentar, eignvirmiegntal, iegnvironmentel, iegnvirmental, eignvirnmentel, eignvirnmentar, eignvilonmental, eignvirnmiegntal, iegnvilonmentel, iegnvirmentar, eignviromentel, eignvirnmantal, eignvilonmentar, eignviromiegntal, iegnvironmantel, iegnvirmantal, iegnvironmental, eignviromental, eignvironmantal, eignvironmiegntel, iegnvirmentel, iegnvirnmental, iegnvironmentar, eignviromentar, eignvironmantar, iegnvirnmentel, iegnvirnmentar, iegnvilonmental, eignviromantal, eignvilonmantal, env1ronmenta1, env1ronmental,
Page Updated: 2/13/2002
 
Kirk Woodard Non Small Cell Lung Cancer Diagnosis, Treatment, Diary, Oncology, Taxol, Carboplatin, Research, Chemotherapy, Anderson, Malignant, Cat Scan, Tomography,  Pet,  Radioactive, Bronchoscopy,  Fine Needle Aspiration,  Pathophysiology, Mortality, Morbidity, Locoregional, Respiratory, Cardiovascular, Cardiac, Smoking, Asbestos, Hydrocarbons, Dietary, Large Cell, Pleomorphic, Stage, Occult, Treatment, Endoscopic, Photodynamic Therapy, NSCLC, Sulcus Tumor, Metastisis, Primary, Regional, Lymph nodes
1935-2002

Kirk Woodward

Non Small Cell Lung Cancer
Diagnosis & Treatment Diary

Page Updated: 2/13/2002

July 30, 2001 Regular six month check with primary care physician. I mentioned that for the past two weeks I'd had trouble finishing my stationary bike routine because I became short of breath. A stress test was scheduled and two chest x-rays were taken before I left the office.

August 1, 2001 The chest x-ray is abnormal. I'm referred for CT Scan.
August 2, 2001 The CT scan is also abnormal. The stress test is cancelled in favor of seeing a pulmonologist.
August 8, 2001 Pulmonologist drains two liters of fluid from my right lung . . . an immediate improvement in breathing and an instant 5 pound weight loss. Samples of the fluid are sent to pathologist for examination.
August 13, 2001 There are Non Small Cell Lung Cancer cells in the fluid. Dr. Washington (the pulmonoloigst) strongly recommends beginning treatment because of my high functionality (i.e., still walking around). Without treatment he estimates my survival at between 6 and 18 months. With treatment the 5 year survival rate is 10%. Not much of a chance, but none the less a chance. My tumor is staged at IIIB. I am referred to Texas Oncology, a subsidiary of U.S. Oncology.
August 15, 2001 Dr. Singh, Texas Oncology, discusses treatment options. Mentions a Clinical Trial for my particular cancer and suggests I visit with the Research Nurse, Jayne Mettahale. Jayne explains that there are two arms of this particular Trial. Arm 1 receives Taxol and Carboplatin - two standard chemicals for treatment of my cancer. Arm 2 receives Taxol, Carboplatin and a third Investigational drug. The Arm assignment is made by random assignment.
August 17, 2001 I agree to participate in the clinical trial. Lab samples are gathered and an additional CT scan of my head is done to insure that the cancer has not spread to distant sites.
August 24, 2001 I have been randomized to Arm 1 of the clinical trial . . . the standard treatment. Arm 2 calls for a degree of poking and prodding that I've come to wonder if I could handle it. I take my first chemotherapy treatment of 4 hours, 45 minutes duration with no major difficulty.
August 27, 2001 Surgical Associates implants a Triumph-1 Vascular Access System. A port just beneath the skin of my right collar bone that facilitates drawing blood samples, chemotherapy, etc. It is the most unpleasant experience of my treatment to date. Not the surgery. I was asleep. The preparation. Nothing, not even water, for the twelve hours prior to the surgery. The chemo effect - flu like aching, etc., is just kicking in and I spend an uncomfortable half day waiting for the implant. Perhaps the undertaker removes the port . . . I wouldn't want to repeat the 'get ready' of the surgical process.
August 31, 2001 First follow-up appointment with Michelle, Dr. Singh's nurse. Billed as a Lab appointment, blood is drawn and then we discuss the findings. Michelle is very upbeat . . . great numbers. The major concern is white cell and red cell counts. They are triple what they would need to be to continue chemo and nearly normal. Normal being a very slippery term the past month or so. We also spend some time discussing/adjusting medication. My pain pills have been hitting too hard, so we will break them in half. Michelle phones in another prescription for sleep medication. Sleep would not have been possible without the pain pills during the week and because I disliked the stoned feeling of a full pain pill, I've been tolerating considerable discomfort during the day.
September 15, 2001
Second cycle of chemotherapy went fine yesterday. Hair is starting to loosen up so I got a crew cut to cut down on the mess. On the upside: The beard also stops growing. Doc did a more complete description of my tumor. Staging is really somewhat more than IIIB in that fluid containing cancer cells covers my right lung and heart, there is a 'questionable involvement' on the 5th rib, lymph notes at the base of the my neck are 'suspiciously enlarged.' Yet no spread to abdomen or brain. There is a five year 10% survival rate for IIIB, 'rare' for IV. Glad to be betwix and between. At diagnosis the tumor was irregular in shape, 5cm wide, 3cm high. The first measurement of what chemotherapy may have accomplished comes up October 2nd when they repeat the CT scan of my chest. 'Tumor shrinking' and 'No change' are the hoped for results, 'tumor growing' gets me off the chemo cycling but with a pretty grim prognosis. In the absence of any treatment the best guess is that I would die in January, 2002. With treatment? Well, stay tuned. Anything beyond January, 2002 will be gravy.

My son-in-law had a heart valve replaced earlier in the week and is doing fine. That has had the effect of shifting focus from me. Not much fun to be in this spotlight.

 

Some links I've found good information in . . .
Lung Cancer
National Cancer
M.D. Anderson, Houston
National Institutes of Health

The medicines I'm currently taking . ..
Taxol
Carboplatin

 
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September 24, 2001
Over the past weekend the billing summary from Medicare arrived. Yikes! ALL the numbers are in the hundreds and my first chemo session totals out at $18,465.00!! The 'plan' is for six. $110,790.00!! And my memory is clear on one point. We are not after a cure. Only 10% of people with my condition survive 5 years. We are just seeking an extension of life. And these treatments are no day at the beach. Plan on REALLY punk for the week following infusion. I leave a message on Jayne's voice mail . . . 'Has a decimal point been misplaced?' She returns my call to report that - somehow - they made a $7,000 billing error in my favor. Gasp. The treatments are $11,000.00 each. $66,000 for the planned cycle. A considerable saving, but, gee, why mine for gold when there is cancer out there? It is tough to tell right off how much of this tab I'll be expected to pay. Medicare pays, then United Health Care pays, then me. Looks like a max of 30% of the grand total. Gulp.

September 28, 2001
This is the regular Friday lab check and hand hold with the nurse, Jayne. My white cell blood count is way down. Down far enough that if this were chemo day, they would postpone the infusion. The 'down' is to be expected at this stage of the cycle (known as the nadir) but it does turn on some caution lights. No leafy greens, no fruits or vegetables unless they are peeled. Avoid crowds, people with colds, anyone with a recent immunization, etc. Low white cells means you are pretty much a sitting duck for an infection. Also I'm to watch temperature VERY closely. Anything over 100 degrees means to contact the clinic 24/7. They don't want a bug to get any sort of head start.
October 4, 2001
They did a follow-up CAT Scan of my chest and abdomen Tuesday, October 2, 2001. While I hoped for yes/no, black/white, bigger/smaller, on the tumor, it was not to be. CAT scan was distorted by a return of the fluid that was present in my right lung back in August. Terribly discouraging in that so much of my future is linked to the tumor's reaction to the chemo. After much thought, I've decided not to take the third cycle of chemo scheduled for Friday, October 5, 2001, until something more definite is known about what the first two cycles have or have not accomplished. Given my really desperate situation, I can't imagine a delay of a week or so is going to mean much. There IS consensus that the fluid must come out, and the CAT scan repeated so if I take the chemo scheduled for October 5, I'll be in the midst of those painful side effects when the fluid is drawn. Not a happy combination. Jayne told me that Dr. Sing wants to talk to me about the scan and I for SURE want more information. Has there been a spread into the abdomen (drank 32 ozs of barium sulfate before the scan)? Does the 'involvement' of the 5th rib seem more definite? How about the 'suspicious' enlargement of lymph nodes in my neck? Other than a really joyful visit from my son Ted, this hasn't been a good week.
October 5, 2001
Met with Dr. Sing. He contacted the pulmonologist, Dr. Washington, and made arrangements to withdraw the fluid from the right lung tomorrow morning. The 5th rib thing and neck glands are issues for later examination . . . bigger fish to fry right now. White cell count is now back up to a level that would permit chemotherapy and eating leafy vegetables and other fruits and vegetables without having to peel them. Got a copy of the CT scan report. Lots of big words but, happily, there is no metastasis to abdomen and the fluid has distended the lung enough to make an accurate reading of the tumor impossible. I look forward to drawing the fluid. In August it resulted in an immediate improvement in breathing which has been difficult the past two weeks.
October 6, 2001
Dr. Washington drew three liters of really awful looking fluid from my right lung. A pathologist will look at a sample of the fluid. Likely it will still be Non Small Cell Lung Cancer, but one does hope, you know. For now: Immediate improvement in breathing. I can come up stairs without having to sit down. Slept better last night. Also 7.5 lb weight loss . . . although I can't recommend this as a weight control program. We'll check fluid again in three weeks time. If it is back in this volume, we'll do an additional procedure to drain ALL fluid and inhibit its return.
October 8, 2001
Long, very frank visit with Dr. Singh (the oncologist) today. Whatever another CT scan would show in the absence of the fluid, Singh believes the tumor is larger. Maybe as much as 20%, perhaps less. Not worth another $800 to get a precise measurement. It certainly is not smaller or the same size as when I started treatment. Singh discussed other chemical combinations, treatment protocols etc,. but I said that having received $25,000 of treatment and become worse, I now wanted a referral to the M. D. Anderson Cancer Center in Houston, TX. Anderson, along with Sloan-Kettering in New York lead the cancer treatment field. In fact, Singh was at Sloan for a time. Singh graciously acceded to my decision and said he would expedite the referral in every way possible. Dr. Washington was equally supportive of my decision on Saturday. I am maintaining future appointments with both Singh and Washington. Certainly not interested in burning any of the bridges so painstakingly built over the past two months. Good news in all this? Well, Dr. Singh who guessed I would die in January, 2002 without any treatment, now sees me functional through June, 2002. It is kind of like the insurance tables . . . if you make it to here, there is a good chance you'll make it to here + x years. Having survived two months since diagnosis, I get some more months tacked on to the January date. I'll take all I can get. It will take some time to actually get an appointment at M.D.Anderson. They want all the materials developed since my diagnosis AND a basic summary from my primary care physician. Those things are spread over four offices and two cities and I'm totally dependent on the 'providers' to locate what Anderson wants and get it off to Houston. I've got their phone numbers in my speed dialer. Stay tuned.

Later in the day, Dr. Singh ordered a Doppler Test. I'd call it a sonogram of the heart. It produces a picture like you see of babies in the womb, only LOTS more movement/action. Incredible to see a little valve open, then close over and over and over and over. It has been doing that little job without trouble or complaint for 66 years. Wow. The test was done because all the CT scans have showed the fluid around my lung also around the heart and Dr. Singh wanted to know how it is affecting heart function. It could put the squeeze on the heart that it does on the lung, impairing function.

October 10, 2001
Firm appointment at M. D. Anderson Cancer Center in Houston, TX, Tuesday, October 16, 2001, at noon. Frank Fossella, MD. His cv. sounds encouraging. And I'm encouraged by the fast 'turn.' Generally you don't expect an appointment this quickly. Obviously the front running on the part of favorite son, Ted et al, has speeded things up dramatically. I've been successful in locating everything they want at MDA (shorthand for M. D. Anderson Cancer Center) but still need to get the pathology slides FedExed to them and get the CAT scans into my hands for taking with me to Houston on Tuesday. Apparently they have enough info in hand to do the initial appointment, but it would be nice to have the base line CAT film and avoid gathering another fluid sample. MDA's FAQ section says to plan on being in Houston 3-5 days. American Airline's price of $65 round trip beats cost of gas to drive it . . . 270 miles one way. Still shopping for hotel/motel space.
October 12, 2001
Whew! Everything has been pulled together. In fact, Michelle, Dr. Singh's nurse, advises that the report on the Dopper scan of my heart is also available to go to MDA along with the CT scan films. Confirmed airline and hotel as well. The $65 fare on American was based on 14 day advance purchase. I explained that I didn't know about the appointment until Wednesday and asked - in view of the nature of the trip - for 'compassionate' waiver to no avail. Southwest's Senior fare for the round trip is $109 . . . so I booked that. Nothing to do now but wait . . . the hardest part, no?
October 16, 17, 2001
Long awaited visit to M. D. Anderson Cancer Center in Houston, TX. Saw Dr. Fossella in the afternoon and trotted around for blood draw and x-rays following. Declining Clinical Trial participation effectively reduced the trip to a 'second opinion.' Which is: This type of tumor is notoriously unresponsive to chemotherapy. We need to move on to other combinations. Specifically: Chemo every week for four weeks, then two weeks of 'rest.' Then repeat, then a CT scan to see how things are going. Then? Well, looks like there are about a dozen bullets to shoot. I'd be delighted to be around for the year or so it would take to work through them all. Happily the treatment regime can be carried out locally rather than in Houston. MDA also suggested the Denver Catheter. A 'permanent' tube placed inside the chest to make it possible for a person to do their own thoracentisis - drain the fluid that accumulates. They showed me a video of the process and it seemed to me to be something I shouldn't attempt. Really the type of thing a doctor rather than a patient should be doing. I have an appointment with the pulmonologist, Dr. Washington, next week and it seems likely that we will proceed with an in-patient procedure - 3-5 days hospitalization - that will drain all the fluid and inhibit further formation. X-rays at MDA suggested that another liter of fluid has collected since the three liters were drawn October 6. At that pace, thoracentisis (no day at the beach by itself) would become a weekly chore.
October 20, 21, 22, 2001
Delightful visit from big brother Tom and his wife Sara from Pittsburgh, PA. They wax enthusiastic about everything we suggest, making entertaining them super easy. We'll see a preview production of The Front Page and they hitch hike nicely with Granddaughter Heather's 11th birthday. This being sick isn't unrelenting bad news!
October 23,2001
Dr. Washington says the rapid accumulation of fluid in the right lung suggests a 'tube and talc' procedure. I'm admitted to Baylor Hospital in Grapevine and Dr. inserts the tube a little after 7pm. Immediate improvement in breathing as before. We hit 10 on the pain scale several times during the insertion process.
October 24, 2001
The chest tube almost immediately re-inflates the upper lobe of the right lung. The lower part of the lung remains partially collapsed even though the fluid is now gone. Allowing for a week in the hospital makes sure we get all the fluid that comes . . . . so we'll just wait and see what develops. They are taking x-rays every morning to see where we stand.
October 28, 2001
Day light savings ends with the earlier sunrise this morning. Dr. Turner is not optimistic that further drainage will re-inflate the middle of the right lung. This leaves 3 options. #1. Transfer to H.E.B. (they have the necessary equipment) as an in patient for 5 weeks of radiation treatment. Chest tube remains in place until radiation is completed or the lung reinflates. #2. Remove chest tube . . . do radiation as an out patient . . . deal with fluid build up as needed. #3. Chest tube might remain in place while doing radiation . . . this would be more Dr. Washington's call than mine or Dr. Turner.
October 31, 2001
Dr. Herman . . . a colleague of Dr. Washington . . . explains clearly and concisely the options from this point. Pem and I decide on radiation treatment of the lung section that has not re-inflated while leaving my chest tube in place to facilitate removal of any fluid build up. The major draw back: has to be done on an in patient basis because of the chest tube, ergo, a transfer to Harris Methodist HEB where they have radiation equipment needed. Also the transfer will be done in an ambulance which seems sizeable overkill given how good I feel. Sigh.
November 1, 2001
Transfer to Methodist H.E.B. for access to radiation equipment. Visit with radiation doc who paints a less than glowing picture of what radiation might be able to do. Best case: The lung, cleared of the blockage, re-inflates to the chest wall, thus making the 'talc' part of 'tube and talc' a possible 'permanent' solution to the fluid collection. Worst case: Lung does not inflate. Radiation course is of no avail. Looks like a two week time frame to see any sort of indication of how the radiation can help the situation. In both cases, of course, the treatment is carried out on an inpatient basis. These hospitals are not much fun and very expensive. The major annoyance is being away from home for the many, many hours of 'custodial care.' Although I doubt that fierce pain of this first night could have been dealt with at home.
November 2, 2001
First radiation treatment . . . about 5 minutes with much whirring, clicking and cranking of enormous equipment at the Edwards Cancer Center associated with HEB Hospital. Later first chemo with docetaxel lasted about an hour and was done in my room.
November 3, 2001
A Saturday, cancer only fought 5 days a week.
Sunday, November 4, 2001
Early this morning the chest tube pulls out. Odd sound from the suction machine is the first clue. The doc covering for Dr. Washington stops in and suggests re-inserting the tube. I went 'in patient' just to avoid such a occurrence, so request discharge from the Hospital and switch to outpatient treatment for radiation and chemotherapy. Dr. agrees and we leave the hospital shortly before noon.
Monday, November 5, 2001
Being home is wonderful but triggers two very bad days. Terrible constipation is followed by near catastrophic diahareaa. The radiation appt is shifted to 1PM, but I am unable to make it. If not for wife Pem's constant ministrations and encouragement, I would have totally collapsed before the end of the day, totally unable to care for myself. A close call.
Tuesday, November 6, 2001
Get radiation at 1PM but in very shaky condition and need to be moved around in a wheel chair. Consult with Dr. re G.I. track troubles and get additional medication for nausea and drug induced constipation. Go across the street to Texas Oncology for bag of fluids which helps a lot.
Wednesday, November 7, 2001
What a difference two days has made! Carefully following Pem's and Dr's instructions regarding diet, rest, medication, I'm feel nearly normal, have resumed daily radiation treatments and can look forward to visit from Ted, Sheri, Helen and Miriam on Fall school break from New Jersey. It is a joy to see them.
Friday, November 9, 2001
Two months of treatment, legally bald and still vertical I close out this roller coaster week with a radiation and chemo session. We finally get real Fall weather, rain, cool, wind, but my outlook is much brighter than it has been for many weeks. It seems we've gotten a 'balance' between medications. We have lots of people around to sing Happy Birthday for Pemmie. She says she is joining Margot in calling a halt to birthdays. She plans to hold right here, which suits her well.
Friday, November 16, 2001
8:00AM
Dr. Dubay is not able to tell definitely what progress the radiation treatments have made (9 treatments) because the fluid has returned to the degree that it obscures the middle lobe of right lung which has been the focus of the treatment. He plans to 'confer' with Dr. Turner on Monday and I mentioned bringing Dr. Washington 'in loop' in that if anything is done about the fluid, he'd likely be the guy to do it.
1:15PM
Dr. Singh has returned from vacation and has set my next chemo for December 14, 2001. Joy! The nausea following this new juice has been profound. Two weeks off seems a marvelous gift. Singh is also pleased at the 'sound' of my right lung . . . less fluid than in the past.
Wednesday, November 21, 2001
Dr. Washington does my third thorencentisis and drains 2.5 liters of fluid. The usual immediate improvement in breathing and comfort is most welcome over the long Thanksgiving weekend. Dr's opinion now is that a more 'permanent' solution must be employed on the recurring fluid. The Denver Catheter is such a device and would enable me to draw fluid at home every day if necessary.
Friday, November 28, 2001
Completed with some delight the radiation portion of my current treatment protocol. In that I'm 'on break' from Chemo, I've got two whole weeks of 'rest.' I need it. Nausea and vomiting has become more difficult to 'manage.' On Wednesday, December 5th, I have an appointment with Dr. Washington. If fluid is back, we'll install the Denver Catheter.
Monday, December 17, 2001
Sometimes up, sometimes down. We 'make' the schedule of doc appointments and do install the Denver Catheter. Pemmie can now - under visiting nurse's guidance - drain the fluid from the right lung. A major improvement over having to have a daily thoracentisis. Much more comfortable. Dr. Washington also prescribes a derivative of marijuana for the nausea - which, this morning was continuous. The food didn't even go to body temperature before coming back up. Between these new pills and daily draining of fluid, there is hope for some comfort from side effects.
Monday, February 4, 2002
From son-in-law, John: After going into the hospital to be treated for dehydration and disorientation on January 23, 2002, Kirk was admitted today to hospice care at All Saints Hospital in Fort Worth. The personnel there are doing a fine job of "making him as comfortable as possible." Pam has requested that any cards be sent to the house -- 2024 Heatherbrook, Grapevine, TX, 76051. When scheduled, we will be posting memorial service details. Thank you all for your continuing thoughts and prayers.
Monday, February 11, 2002
Obituary Kirk Woodward A memorial service for Kirk Woodward of Grapevine, TX, will be held at 11:00 AM, Friday, February 15th, at the Martin Thompson Carriage House Chapel, 224 E. College, Grapevine. Kirk Woodward was born to Thomas A. and Jessie G. Woodward in Beatrice, Nebraska, March 25, 1935. He attended the University of Nebraska and was inducted into the Army in 1955, where he served in Korea, and received an honorable discharge in 1957. He married Pearl (Pam) Bremer on August 16, 1958. They moved to West Lafayette, Indiana, and then on to Peoria, Illinois, where he worked for Radio Station WIRL. While in Peoria, a son, Ted, and a daughter, Margot, were born to them. They moved to Abilene, Texas, in 1965, where he and Pam raised their two children. Kirk was associated with Radio Station KRBC for twelve years in various capacities including Sales Manager, then became Vice President-Marketing for First Security Savings and Loan, and finally served as Vice President-Membership Director of West Texas Chamber of Commerce before forming his own company, People Centered Programs. From his company, he provided various professional services, including public speaking, seminars, and training manuals. While in Abliene, Kirk was active in community theater groups, Rotary Club, and an avid sailor in the Fort Phantom Yacht Club. After founding People Centered Programs, they moved to Grapevine, Texas, in 1987. In Grapevine, he served as a Mutual Fund Representative for Fidelity Investments. Once more drawing upon his entrepreneurial skills, in 1994 he formed a marketing, publishing, and video production corporation, HHJM, Inc. A motorcycle enthusiast, he founded the annual Motorcycle Mother Road Ride/Rally for Historic Route 66, which is now in its 8th year. Following a six month battle with lung cancer he succumbed to the disease at All Saints Hospital, Fort Worth. He is survived by his wife of 43 years, Pam; son, Ted Kirk Woodward, Ph.D., and wife, Sheri Woodward, Ph.D., of Holmdel, NJ; daughter, Mrs. Margot Quinn, CPA, and husband, John Quinn, of Irving, TX; brother Thomas A. Woodward, Attorney, and wife, Sara Woodward, of Pittsburgh, PA; four grandchildren, Helen Woodward, Miriam Woodward, Heather Quinn, Jacob Quinn; an aunt, Mrs. Mollie Hungate and husband, Dr. Frank Hungate, of Seattle, WA; sister-in-law Mrs. Flo Havens and husband, Dick Havens, of Fremont, NE; sister-in-law Mrs. Nancy Bremer of Stanton, NE; 5 nephews; and 3 nieces.

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Misspelled words used to find this page 5 of 14.diagnoestik, diagnostc, daignostic, dyagnostic, d1agnost1c, diagmostic, diagnostci, diagnositc, diagnotsic, diagnsotic, diagonstic, diangostic, diganostic, idagnostic, diagnosti, iagnostic, staging, saging, stging, staing, stagng, stagig, stageing, stageint, stagint, stag1ng, stagimg, stagign, stagnig, staigng, stgaing, satging, tsaging, stagin, taging,curative, crative, cuative, curtive, curaive, curatve, curatie, culative, curat1ve, curatiev, curatvie, curaitve, curtaive, cuartive, cruative, ucrative, curativ, urative, supporive, supportive, supportve, supportie, spportive, supprtive, suppotive, suportive, suppertive, supertive, suppoltive, supoltive, suport1v3, suport1ve, supportiev, supportvie, supporitve, suppotrive, supprotive, supoprtive, spuportive, uspportive,restortive, restorative, restoraive, restoratve, restoratie, resterative, rstorative, lesterative, retorative, resorative, restrative, restoative, lestorative, restolative, lestolative, restorat1ve, restoratiev, restoratvie, restoraitve, restortaive, restoartive, restroative, resotrative, retsorative, rsetorative, erstorative, restorativ, estorative, palliative, pallative, pallitive, palliaive, palliatve, palliatie, pawliative, pawlaitive, plliative, pallaitive, paliative, palaitive, parliative, parlaitive, pariative, paraitive, pa11at1v3, pa11at1ve, pal1at1ve, palliatiev, palliatvie, palliaitve, pallitaive, palilative, plaliative, aplliative,intlavenos, intravenous, intlavenus, intravenos, intlavenoos, intravenus, intravenius, ingravenous, ingravenius, ingravenos, intlavenius, ingravenus, intravenoos, ingravenoos, intlavenous, intrvenous, iegngravenoos, ingraviegnoos, eigntravanoos, iegntraveignoos, eigntlavenos, eigngraveignous, eigntravenius, intlaveignius, intravanois, ingraveignoos, iegntraviegnius, intravanos, iegntravanoos, eigntraviegnoos, intraveniis, iegntlavenos, intlaviegnos, intraenous, iegntravenius, intraviegnius, eigntravanius, iegntraveignius, eigntlavenus, eigntraveignoos, eigngravenius, intlaveignos, ingravanois, intraveignius, iegntraviegnos, ingravanos, iegntravanius, eigntraviegnius, ingraveniis, iegntlavenus, intlaviegnus, intravnous, iegngravenius, ingraviegnius, eigntravanos, iegntraveignos, eigntravenois, eigntraveignius, eigntravenos, intlaveignus, intravaniis, ingraveignius, iegntraviegnus, intravanus, iegntravanos, eigntraviegnos, intlaveniis, iegntravenois, intraviegnois, intraveous, iegntravenos, intraviegnos, eigntravanus, iegntraveignus, eigngravenois, eigntraveignos, eigngravenos, intraveignois, intravanis, intraveignos, iegntlaviegnous, ingravanus, iegntravanus, eigntraviegnus, intravanous, iegngravenois, ingraviegnois, intravenois, iegngravenos, ingraviegnos, eigntlavanous, iegntlaveignous, eigntraveniis, eigntraveignus, eigntravenus, ingraveignois, intlavanois, ingraveignos, iegntraviegnois, intlavanous, oral, aural, orar, olal, olar, roal, roar, loal, loar, ora1, orla, oarl, injection, injecion, injectin, injectiom, ijection, inection, injction, injetion, eignjecshun, iegnjectiom, eignjecsion, iegnjecton, eignjectiom, eignjecton, injecchon, iegnjection, injecchun, iegnjecchon, eignjection, iegnjecchun, eignjecchon, iegnjecshon, eignjecchun, iegnjecshun, eignjecshon, iegnjecsion, injecton, injecshun, injecshon, injecsion, injectons, injecshuns, injecshons, injecsions, injections, iegnjecchuns, eignjecchons, injctions, iegnjecshons, eignjecchuns, injetions, iegnjecshuns, eignjecshons, injecions, iegnjecsions, eignjecshuns, injectins, iegnjectioms, eignjecsions, injectios, iegnjectons,
Misspelled words used to find this page 6 of 14.eignjectioms, injectioms, eignjectons, injecchons, iegnjections, injecchuns, ijections, iegnjecchons, eignjections, inections, 1nject1ons, imjections, injectiosn, injectinos, injectoins, injecitons, injetcions, injcetions, inejctions, ijnections, nijections, njections, eternal, external, eteral, eternl, etornal, etornar, eernal, etrnal, etenal, eturnal, eternar, eturnar, etelnal, etelnar, exernal, extrnal, extenal, exteral, externl, extornal, extornar, exturnal, externar, exturnar, extelnal, extelnar, exerna, extrna, extena, extera, externa, exturna, extelna, extorna, eterna, externa1, extermal, externla, exteranl, extenral, extrenal, exetrnal, etxernal, xeternal, xternal, internal, internl, enternal, enternar, intenral, intornal, intenrar, intornar, iternal, entornal, inernal, entornar, intrnal, enturnal, intenal, enturnar, interal, intelnar, ingelnar, ingernal, inturnal, internar, ingernar, inturnar, intelnal, ingelnal, iegntelna, enturna, interna, intera, iegngerna, eignterna, intelna, iegngelna, eigntelna, ingerna, iegntenra, eigngerna, ingelna, iegntorna, eigngelna, enterna, iegnturna, eigntenra, intenra, iterna, eigntorna, intorna, inerna, eignturna, entorna, intrna, iegnterna, inturna, intena, 1nterna1, 1nternal, imternal, internla, interanl, intrenal, inetrnal, itnernal, niternal, nternal,bean, beam, biam, bam, bem, beem, bein, bin, bian, biin, bien, ban, ben, been, bema, baem, ebam, ingerns, inturns, intelns, ingelns, interns, intenrs, intens, inters, enterns, intorns, entorns, iterns, inerns, intrns, enturns, intrs, intlos, ingrs, intros, ingros, ingrns, itrons, inrons, introns, intons, ingrons, intls, intlons, intlns, 1nterons, interons, imterons, interosn, internos, inteorns, intreons, inetrons, itnerons, niterons, interon, interos, inteons, inerons, iterons, nterons,intrleukin, entorleuken, ingerleukins, iegngerleukins, ingelelukin, intelleukan, eignturleukeyn, entorleukeigns, interleukin, intelleuken, intorelukeyn, eignterleukeyns, enturleukiegn, ingerleukeyn, intorelukeyns, enterleukiegn, iegntelleukan, ingerleukeyns, entorleukeign, eigntorleuken, interlukins, eignterleukiegns, eigntelleukin, inturelukan, intorleukins, iegnterelukeyns, inteleukin, intoreluken, ingerelukins, iegngelleukins, enterleukin, ingerleukan, iegnterleukeyn, eigntorleukeyns, interelukin, ingerleuken, inturleukeyn, eigntelleukeyns, iegnturelukin, ingelleukeyn, inturleukeyns, iegnterelukin, iegngerleukan, ingelleukeyns, eigntorelukin, eigntorleukan, interlekins, eigntelleukiegns, eigngerleukin, eignterleuken, intorelukins, iegntorleukins, intereukin, intorleukan, inturleukins, enterleukiegns, enterelukin, ingelleukan, iegntelleukeyn, eigntorelukins, ingerleukin, ingelleuken, enturleukeyn, eigngerleukeyns, eignterleukiegn, enterleukeyn, enturleukeyns, iegntelelukin, iegnterelukan, enterleukeyns, eignturleukin, eignturleuken, interleuins, eigngerleukiegns, eigngelleukin, eigntelleuken, entorleukins, entorleukiegns, interlukin, entorleukan, inturelukins, iegnterleukeyns, intorleukin, enterleukan, iegngerleukeyn, eignturleukins, ingerelukin, enterleuken, inturelukeyn, eignterelukins, eigntelleukiegn, interelukeyn, inturelukeyns, iegngerelukin, iegntorleuken,
 
 
General Information About Non-Small Cell Lung Cancer
Key Points for This Section

 

Non-small cell lung cancer is a disease in which malignant (cancer) cells form in the tissues of the lung.

The lungs are a pair of cone-shaped breathing organs in the chest. The lungs bring oxygen into the body as you breathe in. They release carbon dioxide, a waste product of the body’s cells, as you breathe out. Each lung has sections called lobes. The left lung has two lobes. The right lung is slightly larger and has three lobes. Two tubes called bronchi lead from the trachea (windpipe) to the right and left lungs. The bronchi are sometimes also involved in lung cancer. Tiny air sacs called alveoli and small tubes called bronchioles make up the inside of the lungs.

Enlarge
Anatomy of the respiratory system, showing the trachea and both lungs and their lobes and airways. Lymph nodes and the diaphragm are also shown. Oxygen is inhaled into the lungs and passes through the thin membranes of the alveoli and into the bloodstream (see inset).

A thin membrane called the pleura covers the outside of each lung and lines the inside wall of the chest cavity. This creates a sac called the pleural cavity. The pleural cavity normally contains a small amount of fluid that helps the lungs move smoothly in the chest when you breathe.

There are two main types of lung cancer: non-small cell lung cancer and small cell lung cancer. (See the PDQ summary on Small Cell Lung Cancer Treatment for more information.)

There are several types of non-small cell lung cancer.

Each type of non-small cell lung cancer has different kinds of cancer cells. The cancer cells of each type grow and spread in different ways. The types of non-small cell lung cancer are named for the kinds of cells found in the cancer and how the cells look under a microscope:

Other less common types of non-small cell lung cancer are: pleomorphic, carcinoid tumor, salivary gland carcinoma, and unclassified carcinoma.

Smoking can increase the risk of developing non-small cell lung cancer.

Smoking cigarettes or cigars is the most common cause of lung cancer. The more years a person smokes, the greater the risk. If a person has stopped smoking, the risk becomes lower as the years pass, but is never completely gone.

Anything that increases a person's chance of developing a disease is called a risk factor. Risk factors for lung cancer include the following:

  • Smoking cigarettes or cigars, now or in the past.
  • Being exposed to second-hand smoke.
  • Being treated with radiation therapy to the breast or chest.
  • Being exposed to asbestos, radon, chromium, arsenic, soot, or tar.
  • Living where there is air pollution.

When smoking is combined with other risk factors, the risk of developing lung cancer is increased.

Possible signs of non-small cell lung cancer include a cough that doesn't go away and shortness of breath.

Sometimes lung cancer does not cause any symptoms and is found during a routine chest x-ray. Symptoms may be caused by lung cancer or by other conditions. A doctor should be consulted if any of the following problems occur:

  • A cough that doesn’t go away.
  • Trouble breathing.
  • Chest discomfort.
  • Wheezing.
  • Streaks of blood in sputum (mucus coughed up from the lungs).
  • Hoarseness.
  • Loss of appetite.
  • Weight loss for no known reason.
  • Feeling very tired.

Tests that examine the lungs are used to detect (find), diagnose, and stage non-small cell lung cancer.

Tests and procedures to detect, diagnose, and stage non-small cell lung cancer are often done at the same time. The following tests and procedures may be used:

  • Physical exam and history: An exam of the body to check general signs of health, including checking for signs of disease, such as lumps or anything else that seems unusual. A history of the patient’s health habits, including smoking, and past jobs, illnesses, and treatments will also be taken.
  • Chest x-ray: An x-ray of the organs and bones inside the chest. An x-ray is a type of energy beam that can go through the body and onto film, making a picture of areas inside the body.
    Enlarge
    X-ray of the chest. X-rays are used to take pictures of organs and bones of the chest. X-rays pass through the patient onto film.
  • CT scan (CAT scan): A procedure that makes a series of detailed pictures of areas inside the body, such as the chest, taken from different angles. The pictures are made by a computer linked to an x-ray machine. A dye may be injected into a vein or swallowed to help the organs or tissues show up more clearly. This procedure is also called computed tomography, computerized tomography, or computerized axial tomography.
  • PET scan (positron emission tomography scan): A procedure to find malignant tumor cells in the body. A small amount of radioactive glucose (sugar) is injected into a vein. The PET scanner rotates around the body and makes a picture of where glucose is being used in the body. Malignant tumor cells show up brighter in the picture because they are more active and take up more glucose than normal cells do.
    Enlarge
    PET (positron emission tomography) scan. The patient lies on a table that slides through the PET machine. The head rest and white strap help the patient lie still. A small amount of radioactive glucose (sugar) is injected into the patient's vein, and a scanner makes a picture of where the glucose is being used in the body. Cancer cells show up brighter in the picture because they take up more glucose than normal cells do.
  • Sputum cytology: A procedure in which a pathologist views a sample of sputum (mucus coughed up from the lungs) under a microscope, to check for cancer cells.
  • Fine-needle aspiration biopsy of the lung: The removal of part of a lump, suspicious tissue, or fluid from the lung, using a thin needle. This procedure is also called needle biopsy. Ultrasound or another imaging procedure is used to locate the abnormal tissue or fluid in the lung. A small incision may be made in the skin where the biopsy needle is inserted into the abnormal tissue or fluid. A sample is removed with the needle and sent to the laboratory. A pathologist then views the sample under a microscope to look for cancer cells. A chest x-ray is done after the procedure to make sure no air is leaking from the lung.
  • Bronchoscopy: A procedure to look inside the trachea and large airways in the lung for abnormal areas. A bronchoscope (a thin, lighted tube) is inserted through the nose or mouth into the trachea and lungs. Tissue samples may be taken for biopsy.
    Enlarge
    Bronchoscopy. A bronchoscope is inserted through the mouth, trachea, and major bronchi into the lung, to look for abnormal areas. A bronchoscope is a thin, tube-like instrument with a light and a lens for viewing. It may also have a cutting tool. Tissue samples may be taken to be checked under a microscope for signs of disease.
  • Thoracoscopy: A surgical procedure to look at the organs inside the chest to check for abnormal areas. An incision (cut) is made between two ribs, and a thoracoscope (a thin, lighted tube) is inserted into the chest. Tissue samples and lymph nodes may be removed for biopsy. This procedure may be used to remove parts of the esophagus or lung. If certain tissues, organs, or lymph nodes can’t be reached, a thoracotomy may be done. In this procedure, a larger incision is made between the ribs and the chest is opened.
  • Thoracentesis: The removal of fluid from the space between the lining of the chest and the lung, using a needle. A pathologist views the fluid under a microscope to look for cancer cells.

Certain factors affect prognosis (chance of recovery)
and treatment options.

The prognosis (chance of recovery) and treatment options depend on the following:

  • The stage of the cancer (the size of the tumor and whether it is in the lung only or has spread to other places in the body).
  • The type of lung cancer.
  • Whether there are symptoms such as coughing or trouble breathing.
  • The patient’s general health.

For most patients with non-small cell lung cancer, current treatments do not cure the cancer.

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Overview: Lung Cancer - Non-small Cell
What Is Non-small Cell Lung Cancer?
The lungs are 2 sponge-like organs found in the chest. The right lung has 3 sections, called lobes. The left lung has 2 lobes. The left lung is smaller because the heart takes up more room on that side of the body. The lungs bring air in and out of the body, taking in oxygen and getting rid of carbon dioxide gas, a waste product.

The lining around the lungs, called the pleura, helps to protect the lungs and allows them to move during breathing. The windpipe (trachea) brings air down into the lungs. It divides into tubes called bronchi (or just one, bronchus) which divide into smaller branches called bronchioles. At the end of these small branches are tiny air sacs known as alveoli.

Lung Cancer

Most lung cancer starts in the lining of the bronchi, although it can also start in other parts of the lung.

Lung cancer often takes many years to develop. First, there may be areas of pre-cancerous changes in the lung. These changes are not a mass or tumor. They can’t be seen on an x-ray and they don’t cause symptoms. But these changes can be found by special tests of cells in the lining of the airways of lungs damaged by smoke.

As these pre-cancerous areas go on to become true cancer, they may make chemicals that cause new blood vessels to form nearby. These new blood vessels nourish the cancer cells and allow a tumor to form. Finally, the tumor becomes large enough to show up on an x-ray.

Once lung cancer occurs, cancer cells can break away and spread to other parts of the body in a process called metastasis. Lung cancer is a life-threatening disease because it often spreads in this way before it is found.

Types of Lung Cancer

There are 2 main types of lung cancer
and they are treated differently.

  • small cell lung cancer (SCLC)
  • non-small cell lung cancer (NSCLC)

If the cancer has features of both types, it is called mixed small cell/large cell cancer. The information here only covers non- small cell lung cancer. Small cell lung cancer is covered in a separate document.

Other types of tumors can grow in the lungs as well. Some of these are not cancer and others are cancerous. Carcinoid tumors, for example, are slow-growing and usually cured by surgery. The American Cancer Society has more information about lung carcinoid tumors. To learn about these tumors, see our document “Lung Carcinoid Tumor.”

Non-small Cell Lung Cancer (NSCLC)

About 85% of all lung cancers are of the non-small cell type. There are 3 sub-types of NSCLC. The cells in these sub-types differ in size, shape, and chemical make-up.

  • squamous cell carcinoma: about 25% to 30% of all lung cancers are of this kind. They are linked to smoking and tend to be found near the bronchus.
  • adenocarcinoma: this type accounts for about 40% of lung cancers. It is usually found in the outer part of the lung.
  • large-cell undifferentiated carcinoma: about 10% to 15% of lung cancers are this type. It can start in any part of the lung. It tends to grow and spread quickly.
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Lung Cancer, Non-Small Cell

Last Updated: December 13, 2005

Synonyms and related keywords: bronchogenic carcinoma, NSCLC, non-small cell lung cancer, non-small-cell lung cancer, nonsmall cell lung cancer, adenocarcinoma, squamous cell carcinoma, SCC, lung SCC, large cell carcinoma, bronchoalveolar carcinoma, broncho-alveolar carcinoma, lung carcinoma, lung malignancy, tobacco, smoking, asbestos, radon, secondhand smoke, passive smoking, second-hand smoke, smoking-related cancer, lung cancer, acinar adenocarcinoma, papillary adenocarcinoma, bronchoalveolar adenocarcinoma, mucus-secreting adenocarcinoma, large cell neuroendocrine carcinoma, lobectomy, pneumonectomy, ras oncogene, H-ras, K-ras, N-ras, c-myc, c-raf, ectopic hormone production, atelectasis, postobstructive pneumonia, wheezing, hemoptysis, pleural effusion, superior vena cava obstruction, superior vena cava syndrome, paralysis of recurrent laryngeal nerve, phrenic nerve palsy, paralysis of the diaphragm, Horner syndrome, dysphagia, esophageal compression, pericardial effusion, Pancoast tumor, paraneoplastic syndromes, hypercalcemia, clubbing, hypertrophic pulmonary osteoarthropathy, Trousseau syndrome of hypercoagulability, scar carcinoma, gynecomastia, galactorrhea, spinal cord compression, silicate type of asbestos, HIV infection, diesel exhaust

Author: Irfan Maghfoor, MD, Consulting Oncologist, Department of Oncology, King Faisal Specialist Hospital and Research Center, Saudi Arabia

Coauthor(s): Michael Perry, MD, Professor, Department of Internal Medicine, Nellie B Smith Chair of Oncology, Director, Division of Hematology and Oncology, University of Missouri at Columbia/Ellis Fischel Cancer Center

Irfan Maghfoor, MD, is a member of the following medical societies: American Society of Clinical Oncology, American Society of Hematology, and European Society for Medical Oncology
Editor(s): Antoni Ribas, MD, Assistant Professor of Medicine, Department of Medicine, Division of Hematology-Oncology, University of California at Los Angeles Medical Center; Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine; Benjamin Movsas, MD, Vice-Chairman, Department of Radiation Oncology, Fox Chase Cancer Center; Rajalaxmi McKenna, MD, FACP, Consulting Staff, Department of Medicine, Southwest Medical Consultants, SC, Good Samaritan Hospital, Advocate Health Systems; and John S Macdonald, MD, Professor of Medicine, New York Medical College; Chief, Division of Medical Oncology, St Vincent's Hospital and Medical Center; Medical Director, Saint Vincent's Comprehensive Cancer Center

Background: Lung cancer is the leading cause of cancer-related mortality in both men and women. The prevalence of lung cancer is second only to that of prostate cancer in men and breast cancer in women. Lung cancer recently surpassed heart disease as the leading cause of smoking-related mortality. Most lung carcinomas are diagnosed at an advanced stage, conferring a poor prognosis. The need to diagnose lung cancer at an early and potentially curable stage is obvious. In addition, most patients who develop lung cancer smoke and have smoking-related damage to the heart and lungs, making aggressive surgical or multimodality therapies less viable options.

Pathophysiology: Non–small cell lung cancer (NSCLC) accounts for approximately 75% of all lung cancers. NSCLC is divided further into adenocarcinoma, squamous cell carcinoma, and large cell carcinoma. All share similar treatment approaches and prognoses but have distinct histologic and clinical characteristics.

Recently, advanced molecular techniques have identified amplification of oncogenes and inactivation of tumor suppressor genes in NSCLC. The most important abnormalities detected are mutations involving the ras family of oncogenes. The ras oncogene family has 3 members: H-ras, K-ras, and N-ras. These genes encode a protein on the inner surface of the cell membrane with GTPase activity and may be involved in signal transduction.

Animal studies performed on mice suggest the involvement of ras mutations in the molecular pathogenesis of NSCLC. Studies in humans suggest that ras activation contributes to tumor progression in persons with lung cancer. The ras gene mutations occur almost exclusively in adenocarcinomas and are found in 30% of such cases. These mutations are not identified in adenocarcinomas that develop in persons who do not smoke. The K-ras mutation appears to be an independent prognostic factor. Studies are ongoing to develop management plans according to the presence or absence of ras gene mutations.

Other molecular abnormalities with less clear roles in tumor pathogenesis and progression include c-myc and c-raf among oncogenes and retinoblastoma (Rb) and p53 among tumor suppressor genes.

Frequency:
 

  • In the US: Lung cancer is the second most common malignancy after prostate cancer in men and breast cancer in women. Lung cancer is the leading cause of smoking- and cancer-related mortality in both sexes. An estimated 164,100 new lung cancer cases will occur this year in the United States (89,500 in men and 74,600 in women).
  • Internationally: Lung cancer remains the most common malignancy, with an estimated 1.04 million new cases each year worldwide, which accounts for 12.8% of new cancer cases. Fifty-eight percent of new lung cancer cases occur in the developing world. Lung cancer is the most common cancer among men, with an incidence of approximately 37.5 new cases per 1 million population. The incidence is lower in women, at 10.8 cases per 1 million population.

Mortality/Morbidity:

  • Lung cancer is the cause of 921,000 deaths each year worldwide, accounting for 17.8% of cancer-related deaths.
  • Lung cancer is highly lethal, with the highest recorded 5-year patient survival rates (14%) observed in the United States. In Europe, the 5-year overall survival rate is 8%, similar to that of the developing world.
  • Estimates suggest that approximately 156,900 lung cancer–related deaths will occur this year in the United States (89,300 in men and 67,600 in women).

Sex:

  • Lung cancer is more common in men than in women. In the United States, northern Europe, and western Europe, the prevalence of lung cancer has been decreasing in men. In eastern and southern European countries, the incidence of lung cancer has been rapidly increasing. Most Western countries have encountered a disturbing trend of increasing prevalence in women and younger patients.

History: Lung cancers manifest with symptoms produced by the primary tumor, locoregional spread, metastatic disease, or ectopic hormone production. See Image 1 for a summary of all signs and symptoms. Approximately 7-10% of patients with lung cancer are asymptomatic and their cancers are diagnosed incidentally after a chest radiograph (CXR) performed for other reasons. The symptoms produced by the primary tumor depend on its location (ie, central, peripheral).

    • Central tumors are generally squamous cell carcinomas and produce symptoms of cough, dyspnea, atelectasis, postobstructive pneumonia, wheezing, and hemoptysis.
    • Most peripheral tumors are adenocarcinomas or large cell carcinomas and, in addition to causing cough and dyspnea, can cause symptoms due to pleural effusion and severe pain as a result of infiltration of parietal pleura and the chest wall.
  • Symptoms due to locoregional spread
    • These symptoms can include superior vena cava obstruction, paralysis of the recurrent laryngeal nerve, and phrenic nerve palsy, causing hoarseness and paralysis of the diaphragm; pressure on the sympathetic plexus, causing Horner syndrome; dysphagia resulting from esophageal compression; and pericardial effusion (ie, Pancoast tumor).
    • Superior sulcus tumors can cause compression of the brachial plexus roots as they exit the neural foramina, resulting in intense, radiating neuropathic pain in the ipsilateral upper extremity.
  • Paraneoplastic syndromes
    • Squamous cell carcinomas are more likely to be associated with hypercalcemia due to parathyroidlike hormone production.
    • Clubbing and hypertrophic pulmonary osteoarthropathy and the Trousseau syndrome of hypercoagulability are caused more frequently by adenocarcinomas.
  • Summary of clinical characteristics by histologic subtype
    • Adenocarcinoma is the most frequent NSCLC in the United States, representing 35-40% of all lung cancers, usually occurring in a peripheral location within the lung and arising from bronchial mucosal glands. Adenocarcinoma is the most common histologic subtype, manifesting as a scar carcinoma. This is the subtype observed most commonly in persons who do not smoke. This type may manifest as multifocal tumors in a bronchoalveolar form.
    • Bronchoalveolar carcinoma is a distinct subtype of adenocarcinoma with the classic manifestation as an interstitial lung disease on a CXR. Bronchoalveolar carcinoma arises from type II pneumocytes and grows along alveolar septa. This subtype may manifest as a solitary peripheral nodule, multifocal disease, or a rapidly progressing pneumonic form. A characteristic finding in persons with advanced disease is voluminous watery sputum.
    • Squamous cell carcinoma accounts for 25-30% of all lung cancers. The classic manifestation is a cavitary lesion in a proximal bronchus. This type is characterized histologically by the presence of keratin pearls and can be detected based on results from cytologic studies because it has a tendency to exfoliate. It is the type most often associated with hypercalcemia.
    • Large cell carcinoma accounts for 10-15% of lung cancers, typically manifesting as a large peripheral mass on a CXR. Histologically, this type has sheets of highly atypical cells with focal necrosis, with no evidence of keratinization (typical of squamous cell carcinoma) or gland formation (typical of adenocarcinomas). Patients with large cell carcinoma are more likely to develop gynecomastia and galactorrhea.

Physical: See Image 1 for a summary of all signs and symptoms.

  • In approximately two thirds to three fourths of patients, the cancer is diagnosed at an advanced stage; patients may have lost weight and may have obvious respiratory distress.
  • Head and neck
    • Commonly, no signs are found upon examination of the head and neck regions, but when the cancer has spread to the supraclavicular lymph nodes, careful examination may reveal enlargement of involved nodes, which helps in the clinical staging process.
    • Superior sulcus tumors, because of their presence at the apex of the lung, can compress the cervical sympathetic plexus, causing classic Horner syndrome (for more information, see Horner Syndrome). Findings include ipsilateral ptosis, miosis, and anhidrosis (ie, lack of sweating).
    • Superior vena cava syndrome is commonly caused by small cell carcinomas, but any centrally located tumor or mediastinal spread can give rise to superior vena cava syndrome. This results from obstruction of blood flow to the heart from the head and neck regions and upper extremities due to tumor compression of the superior vena cava. Patients have facial edema, dusky skin coloration, and, possibly, conjunctival edema. Edema of the upper extremities and prominent veins on the upper thoracic wall with retrograde flow may be present.
  • Respiratory system
    • Findings are variable and depend on location and spread.
    • Centrally located obstructing tumors can cause collapse of the entire lung with an absence of breath sounds on the side of the lesion.
    • Peripheral lesions can cause individual segments or lobes to collapse, leading to findings of dullness to percussion and/or decreased breath sounds.
    • Pleural effusions give rise to characteristic findings of dullness and decreased breath sounds, depending on the size.
  • Cardiovascular system: Cardiac findings are usually noted when the tumor causes an effusion. Findings can range from simple effusion to tamponade.
  • Gastrointestinal system: The most common site of metastatic spread is the liver, which may manifest as tender hepatomegaly.

     

  • Musculoskeletal system
    • Bone is another common site of spread for lung carcinomas.

       

    • Patients may report bone pain, and tender spots may be found during the examination.

       

    • The examination should include fist percussion of the spine to look for tender spots, which may suggest vertebral column metastases.
  • Central nervous system: A neurologic examination should be performed to look for focal neurological deficits caused by brain metastases and/or signs of spinal cord compression.

Causes:

  • Smoking
    • Unlike many other malignancies, whose causes are largely unknown, the cause of lung cancer is tobacco smoking in as many as 90% of patients (78% in men, 90% in women).
    • For a person who currently smokes, the risk of developing lung cancer is 13.3 times that of a person who has never smoked. The risk also varies with the number of cigarettes smoked. The risk ranges from 10 times higher than controls for those smoking 20 or fewer cigarettes per day to 20 times higher than controls for those smoking more than 20 cigarettes per day.
    • Because not all persons who smoke develop lung cancer and because not all patients with lung cancer have a history of smoking, other factors, including genetic susceptibility, also play roles.
    • Once a person quits smoking, the risk of lung cancer increases for the first 2 years and then gradually decreases, but it never returns to the same level as that of a person who has never smoked.
  • Passive smoking
    • As many as 15% of the lung cancers in persons who do not smoke are believed to be caused by secondhand smoke. The US Environmental Protection Agency recently recognized passive smoking as a potential carcinogen.
    • Cigarette smoke contains N-nitrosamines and aromatic polycyclic hydrocarbons, which act as carcinogens. The N-nitrosamines are hydroxylated by the P-450 enzyme system, leading to the formation of carcinogens that cause formation of DNA adducts.
  • Asbestos
    • Asbestos exposure has been shown to be strongly associated with the causation of lung cancer, malignant pleural mesothelioma, and pulmonary fibrosis.

       

    • The silicate type of asbestos fiber is an important carcinogen.

       

    • Asbestos exposure increases the risk of developing lung cancer by as much as 5 times.

       

    • Tobacco smoke and asbestos exposure act synergistically, and the risk of developing lung cancer for persons who currently smoke tobacco and have a history of asbestos exposure approaches 80-90 times that of control populations.
  • Radon
    • Radon is an inert gas produced as a result of uranium decay. Radon exposure is a well-established risk factor for lung cancer in uranium miners. Approximately 2-3% of lung cancers annually are estimated to be caused by radon exposure.
    • The US National Research Council's report of the Sixth Committee on Biological Effects of Ionizing Radiation has estimated that radon exposure causes 2100 new lung cancers each year, while it contributes to lung cancer causation in approximately 9100 persons who smoke.
    • Household exposure to radon has never been clearly shown to cause lung cancer.
  • HIV infection: A recent report from the State of Texas Health Department suggested a 6.5-fold increase in lung cancer in patients infected with HIV. Other large series do not support an increased prevalence of lung cancers in subjects with HIV infection.

     

  • Other environmental agents
    • Aromatic polycyclic hydrocarbons, beryllium, nickel, copper, chromium, cadmium, and diesel exhaust all have been implicated in causing lung cancer.
    • Dietary fiber and vegetables have been suggested as protective from lung cancer.
    • In a recent study, alpha-tocopherol and carotenoids have been found to be harmful rather than beneficial in decreasing the mortality from lung cancer.

 

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Non-Small Cell Lung Cancer


General Information
Cellular Classification
Stage Information
Treatment Option Overview
Occult Non-Small Cell Lung Cancer
Stage 0 Non-Small Cell Lung Cancer
Stage I Non-Small Cell Lung Cancer
Stage II Non-Small Cell Lung Cancer
Stage IIIA Non-Small Cell Lung Cancer
Stage IIIB Non-Small Cell Lung Cancer
Stage IV Non-Small Cell Lung Cancer
Recurrent Non-Small Cell Lung Cancer
Changes to This Summary (05/17/2006)
More Information


General Information

 

Note: Estimated new cases and deaths from lung cancer (non-small cell and small cell combined) in the United States in 2006: [1]

  • New cases: 174,470.
  • Deaths: 162,460.

Non-small cell lung cancer (NSCLC) is a heterogeneous aggregate of histologies. The most common histologies are epidermoid or squamous carcinoma, adenocarcinoma, and large cell carcinoma. These histologies are often classified together because approaches to diagnosis, staging, prognosis, and treatment are similar. Patients with resectable disease may be cured by surgery or surgery with adjuvant chemotherapy. Local control can be achieved with radiation therapy in a large number of patients with unresectable disease, but cure is seen only in a small number of patients. Patients with locally advanced, unresectable disease may have long-term survival with radiation therapy combined with chemotherapy. Patients with advanced metastatic disease may achieve improved survival and palliation of symptoms with chemotherapy.

At diagnosis, patients with NSCLC can be divided into 3 groups that reflect both the extent of the disease and the treatment approach. The first group of patients has tumors that are surgically resectable (generally stage I, stage II, and selected stage III patients). This group has the best prognosis, which depends on a variety of tumor and host factors. Patients with resectable disease who have medical contraindications to surgery are candidates for curative radiation therapy. Adjuvant cisplatin-based combination chemotherapy may provide a survival advantage to patients with resected stage IB, stage II, or stage IIIA NSCLC.

The second group includes patients with either locally (T3-T4) and/or regionally (N2-N3) advanced lung cancer. This group has a diverse natural history. Selected patients with locally advanced tumors may benefit from combined modality treatments. Patients with unresectable or N2-N3 disease are treated with radiation therapy in combination with chemotherapy. Selected patients with T3 or N2 disease can be treated effectively with surgical resection and either preoperative or postoperative chemotherapy or chemoradiation therapy.

The final group includes patients with distant metastases (M1) that were found at the time of diagnosis. This group can be treated with radiation therapy or chemotherapy for palliation of symptoms from the primary tumor. Patients with good performance status (PS), women, and patients with distant metastases confined to a single site live longer than others. [2] Platinum-based chemotherapy has been associated with short-term palliation of symptoms and with a survival advantage. Currently, no single chemotherapy regimen can be recommended for routine use. Patients previously treated with platinum combination chemotherapy may derive symptom control and survival benefit from docetaxel, pemetrexed, or epidermal growth factor receptor inhibitor.

Multiple studies have attempted to identify prognostic determinants after surgery and have yielded conflicting evidence as to the prognostic importance of a variety of clinicopathologic factors. [2] [3] [4] [5] [6] Factors that have correlated with adverse prognosis include the following:

  • Presence of pulmonary symptoms.
  • Large tumor size (>3 cm).
  • Nonsquamous histology.
  • Metastases to multiple lymph nodes within a TNM-defined nodal station. [7] [8] [9] [10] [11] [12] [13] [14] [15] [16] [17]
  • Vascular invasion. [3] [18] [19] [20]
  • Increased numbers of tumor blood vessels in the tumor specimen.

Similarly, conflicting results regarding the prognostic importance of aberrant expression of a number of proteins within lung cancers have been reported. For patients with inoperable disease, prognosis is adversely affected by poor PS and weight loss of >10%. These patients have been excluded from clinical trials evaluating aggressive multimodality interventions. In multiple retrospective analyses of clinical trial data, advanced age alone has not been shown to influence response or survival with therapy. [21]

Because treatment is not satisfactory for almost all patients with NSCLC, eligible patients should be considered for clinical trials.

Cellular Classification

Before a patient begins lung cancer treatment, an experienced lung cancer pathologist must review the pathologic material. This is critical because small cell lung cancer, which responds well to chemotherapy and is generally not treated surgically, can be confused on microscopic examination with non-small cell carcinoma. [1]

In 1999, the World Health Organization (WHO) classification of lung tumors was updated. [1] Major changes in the revised classification as compared with the previous one (WHO 1981) include the addition of 2 preinvasive lesions to squamous dysplasia and carcinoma in situ: atypical adenomatous hyperplasia and diffuse idiopathic pulmonary neuroendocrine cell hyperplasia. Another significant change is the subclassification of adenocarcinoma: the definition of bronchioalveolar carcinoma has been restricted to noninvasive tumors. A substantial evolution of concepts in neuroendocrine lung tumour classification has occurred. Large cell neuroendocrine carcinoma (LCNEC) is now recognized as a histologically high-grade non-small cell carcinoma showing histopathological features of neuroendocrine differentiation as well as immunohistochemical neuroendocrine markers. The large-cell carcinoma class now includes several variants, including the LCNEC and the basaloid carcinoma, both with a dismal prognosis. Finally, a new class was defined called carcinoma with pleomorphic, sarcomatoid, or sarcomatous elements that are characterized by a spectrum of epithelial to mesenchymal differentiation. Immunohistochemistry and electron microscopy are invaluable techniques for diagnosis and subclassification, but most lung tumors can be classified by light microscopic criteria.

Malignant non-small epithelial tumors of
the lung are detailed in the following list.

The changes in the WHO classification are described in greater detail in the following sections.

    THE NEW WHO/INTERNATIONAL ASSOCIATION FOR THE STUDY OF LUNG CANCER HISTOLOGIC CLASSIFICATION OF NON-SMALL CELL LUNG CARCINOMAS (NSCLC)

  1. Squamous cell carcinoma.
    • Papillary.
    • Clear cell.
    • Small cell.
    • Basaloid.
  2. Adenocarcinoma.
    • Acinar.
    • Papillary.
    • Bronchioloalveolar carcinoma.
      • Nonmucinous.
      • Mucinous.
      • Mixed mucinous and nonmucinous or indeterminate cell type.
    • Solid adenocarcinoma with mucin.
    • Adenocarcinoma with mixed subtypes.
    • Variants.
      • Well-differentiated fetal adenocarcinoma.
      • Mucinous (colloid) adenocarcinoma.
      • Mucinous cystadenocarcinoma.
      • Signet ring adenocarcinoma.
      • Clear cell adenocarcinoma.
  3. Large cell carcinoma.
    • Variants.
      • Large-cell neuroendocrine carcinoma.
      • Combined large-cell neuroendocrine carcinoma.
      • Basaloid carcinoma.
      • Lymphoepithelioma-like carcinoma.
      • Clear cell carcinoma.
      • Large-cell carcinoma with rhabdoid phenotype.
  4. Adenosquamous carcinoma.
     
  5. Carcinomas with pleomorphic, sarcomatoid or sarcomatous elements.
    • Carcinomas with spindle and/or giant cells.
    • Spindle cell carcinoma.
    • Giant cell carcinoma.
    • Carcinosarcoma.
    • Pulmonary blastoma.
  6. Carcinoid tumor.
    • Typical carcinoid.
    • Atypical carcinoid.
  7. Carcinomas of salivary-gland type.
    • Mucoepidermoid carcinoma.
    • Adenoid cystic carcinoma.
    • Others.
  8. Unclassified carcinoma.
     

Adenocarcinoma

Adenocarcinoma is now the predominant histologic subtype in many countries, and issues relating to subclassification of adenocarcinoma are very important. One of the biggest problems with lung adenocarcinomas is the frequent histologic heterogeneity. In fact, mixtures of adenocarcinoma histologic subtypes are more common than tumors consisting purely of a single pattern of acinar, papillary, bronchioloalveolar, and solid adenocarcinoma with mucin formation. Criteria for the diagnosis of bronchioloalveolar carcinoma have varied widely in the past. The current WHO/International Association for the Study of Lung Cancer (IASLC) definition is much more restrictive than that previously used by many pathologists because it is limited to only noninvasive tumors. If stromal, vascular, or pleural invasion are identified in an adenocarcinoma that has an extensive bronchioloalveolar carcinoma component, the classification would be an adenocarcinoma of mixed subtype with predominant bronchioloalveolar pattern and either a focal acinar, solid, or papillary pattern, depending on which pattern is seen in the invasive component. Several variants of adenocarcinoma are recognized in the new classification, including well-differentiated fetal adenocarcinoma, mucinous (colloid) adenocarcinoma, mucinous cystadenocarcinoma, signet ring adenocarcinoma, and clear cell adenocarcinoma.

Neuroendocrine tumors

Since 1981, a substantial evolution of concepts of neuroendocrine lung tumor classification has occurred. LCNEC is now recognized as a histologically high-grade non-small cell carcinoma. It has a very poor prognosis similar to that of small cell lung cancer (SCLC). Atypical carcinoid is recognized as an intermediate-grade neuroendocrine tumor with a prognosis that falls between typical carcinoid and the high-grade SCLC and LCNEC. In addition, it has become well recognized that neuroendocrine differentiation can be demonstrated by immunohistochemistry or electron microscopy in 10% to 20% of common NSCLC that do not have any neuroendocrine morphology. These tumors are not formally recognized within the WHO/IASLC classification scheme since the clinical and therapeutic significance of neuroendocrine differentiation in NSCLC is not firmly established. These tumors are referred to collectively as NSCLC with neuroendocrine differentiation.

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Large cell carcinoma

In addition to the general category of large cell carcinoma, several uncommon variants are recognized, including LCNEC, basaloid carcinoma, lymphoepithelioma-like carcinoma, clear cell carcinoma, and large cell carcinoma with rhabdoid phenotype. Basaloid carcinoma is also recognized as a variant of squamous cell carcinoma and, rarely, adenocarcinomas may have a basaloid pattern; however, in tumors without either of these features, they are regarded as a variant of large cell carcinoma.

Carcinomas with pleomorphic,
sarcomatoid or sarcomatous elements

This is a group of rare tumors. Spindle and giant cell carcinomas and carcinosarcomas comprise only 0.4% and 0.1% of all lung malignancies, respectively. In addition, this group of tumors reflects a continuum in histologic heterogeneity as well as epithelial and mesenchymal differentiation. Biphasic pulmonary blastoma is regarded as part of the spectrum of carcinomas with pleomorphic, sarcomatoid, or sarcomatous elements based on clinical and molecular data.

Stage Information

Determination of stage is important in terms of therapeutic and prognostic implications. Careful initial diagnostic evaluation to define the location and to determine the extent of primary and metastatic tumor involvement is critical for the appropriate care of patients.

Stage has a critical role in the selection of therapy. The stage of disease is based on a combination of clinical factors (i.e., physical examination, radiology, and laboratory studies) and pathological factors (i.e., biopsy of lymph nodes, bronchoscopy, mediastinoscopy, or anterior mediastinotomy). [1] The distinction between clinical stage and pathologic stage should be considered when evaluating reports of survival outcome.

Staging procedures include history, physical examination, routine laboratory evaluations, chest x-ray, and chest computed tomography (CT) scan with infusion of contrast material. The CT scan should extend inferiorly to include the liver and adrenal glands. Magnetic resonance imaging (MRI) scans of the thorax and upper abdomen do not appear to yield advantages over CT scans. [2] In general, symptoms, physical signs, laboratory findings, or perceived risk of distant metastasis lead to an evaluation for distant metastatic disease. Additional tests such as bone scans and CT/MRI of the brain may be performed if initial assessments suggest metastases, or for patients with stage III disease who are under consideration for aggressive local and combined modality treatments. Surgical staging of the mediastinum is considered standard if accurate evaluation of the nodal status is needed to determine therapy. The wider availability and use of fluorodeoxyglucose positron emission tomography (FDG-PET) for staging has modified this approach to staging mediastinal lymph nodes and distant metastases.

If there is no evidence of distant metastatic disease on CT scan, FDG-PET scanning complements CT scan staging of the mediastinum. The combination of CT scanning and PET scanning has greater sensitivity and specificity than CT scanning alone. [3] Numerous nonrandomized studies of FDG-PET have evaluated mediastinal lymph nodes using surgery (i.e., mediastinoscopy and/or thoracotomy with mediastinal lymph node dissection) as the gold standard of comparison. A prospective trial studied the impact of FDG-PET on the staging of 102 patients with NSCLC and found that the sensitivity, specificity, negative predictive value and positive predictive value of FDG-PET alone for detection of mediastinal metastases were 91%, 86%, 95%, and 74%, respectively, as compared with CT scan alone, which had a sensitivity of 75% and a specificity of 66%. [4] False-negative results from FDG-PET were seen in small tumors and when FDG-PET was unable to distinguish the primary lesion from contiguous lymphadenopathy. False-positive results were often caused by the presence of benign inflammatory disease. These results have been corroborated by other studies. [5] [6] For patients with clinically operable NSCLC, biopsy of mediastinal lymph nodes, found on chest CT scan to be >1.0 cm in shortest transverse axis or positive on FDG-PET scanning, is recommended. Negative FDG-PET scanning does not preclude biopsy of radiographically enlarged mediastinal lymph nodes. Mediastinoscopy is necessary for the detection of cancer in mediastinal lymph nodes when the results of the CT scan and FDG-PET do not corroborate each other.

Numerous nonrandomized, prospective and retrospective studies have demonstrated that FDG-PET seems to offer diagnostic advantages over conventional imaging in staging distant metastatic disease; however, standard FDG-PET scans have limitations. FDG-PET scans may not extend below the pelvis and may not detect bone metastases in the long bones of the lower extremities. Because the metabolic tracer used in FDG-PET scanning accumulates in the brain and urinary tract, FDG-PET is not reliable for detection of metastases in these sites. [7]

Decision analyses demonstrate that FDG-PET may reduce the overall costs of medical care by identifying patients with falsely negative CT scans in the mediastinum or otherwise undetected sites of metastases. [8] [9] [10] Studies concluded that the money saved by forgoing mediastinoscopy in FDG-PET–positive mediastinal lesions was not justified because of the unacceptably high number of false-positive results. [8] [9] [10] A randomized trial evaluating the impact of PET on clinical management found that PET provided additional information regarding appropriate stage but did not lead to significantly fewer thoracotomies. [11]

Patients at risk for brain metastases may be staged with CT or MRI scans. One study randomized 332 patients with potentially operable NSCLC, but without neurological symptoms, to brain CT or MRI imaging to detect occult brain metastasis before lung surgery. MRI showed a trend toward a higher preoperative detection rate than CT (P = .069), with an overall detection rate of approximately 7% from pretreatment to 12 months after surgery. [7] Patients with stage I or stage II disease had a detection rate of 4% (i.e., 8 detections out of 200 patients), while for individuals with stage III disease, the rate was 11.4% (i.e., 15 detections out of 132 patients). The mean maximal diameter of the brain metastases was significantly smaller in the MRI group. Whether the improved detection rate of MRI translates into improved outcome remains unknown. Not all patients are able to tolerate MRI, and for these patients, contrast-enhanced CT scan is a reasonable substitute.

The Revised International Staging System for Lung Cancer

The Revised International System for Staging Lung Cancer, based on information from a clinical database of more than 5,000 patients, was adopted in 1997 by the American Joint Committee on Cancer (AJCC) and the Union Internationale Contre le Cancer. [12] [13] These revisions provide greater prognostic specificity for patient groups; however, the correlation between stage and prognosis predates the widespread availability of PET imaging. Stage I is divided into 2 categories by the size of the tumor: IA (T1, N0, M0) and IB (T2, N0, M0). Stage II is divided into 2 categories by the size of the tumor and by the nodal status: IIA (T1, N1, M0) and IIB (T2, N1, M0). T3, N0 has been moved from stage IIIA in the 1986 version of the staging system to stage IIB in the latest version. This change reflects the slightly superior prognosis of these patients and shows that many patients with invasion of the parietal pleura or chest wall caused by pleural-based or superior sulcus tumors (T3), but with negative lymph nodes (N0), are often treated with surgery, sometimes combined with radiation therapy or chemoradiation therapy, and the results are similar to those of patients with resected stage II disease. Another change clarifies the classification of multiple tumor nodules. Satellite tumor nodules located in the same lobe as the primary lesion, which are not lymph nodes, should be classified as T4 lesions. Intrapulmonary ipsilateral metastasis in a lobe other than the lobe containing the primary lesions should be classified as an M1 lesion (stage IV).

The AJCC has designated staging by TNM classification. [13]

TNM definitions

    Primary tumor (T)

  • TX: Primary tumor cannot be assessed, or tumor is proven by the presence of malignant cells in sputum or bronchial washings but is not visualized by imaging or bronchoscopy
     
  • T0: No evidence of primary tumor
     
  • Tis: Carcinoma in situ
     
  • T1: A tumor that is ≤3 cm in greatest dimension, is surrounded by lung or visceral pleura, and is without bronchoscopic evidence of invasion more proximal than the lobar bronchus (i.e., not in the main bronchus). The uncommon superficial tumor of any size with its invasive component limited to the bronchial wall, which may extend proximal to the main bronchus, is also classified as T1.
     
  • T2: A tumor with any of the following features of size or extent:
    • >3 cm in greatest dimension
    • Involves the main bronchus and is ≥2 cm distal to the carina
    • Invades the visceral pleura
    • Associated with atelectasis or obstructive pneumonitis that extends to the hilar region but does not involve the entire lung

     

  • T3: A tumor of any size that directly invades any of the following: chest wall (including superior sulcus tumors), diaphragm, mediastinal pleura, parietal pericardium; or, tumor in the main bronchus <2 cm distal to the carina but without involvement of the carina; or, associated atelectasis or obstructive pneumonitis of the entire lung
     
  • T4: A tumor of any size that invades any of the following: mediastinum, heart, great vessels, trachea, esophagus, vertebral body, carina; or, separate tumor nodules in the same lobe; or, tumor with a malignant pleural effusion. Most pleural effusions associated with lung cancer are due to tumor; however, in a few patients multiple cytopathologic examinations of pleural fluid are negative for tumor. In these cases, fluid is nonbloody and is not an exudate. Such patients may be further evaluated by videothoracoscopy and direct pleural biopsies. When these elements and clinical judgment dictate that the effusion is not related to the tumor, the effusion should be excluded as a staging element, and the patient should be staged as T1, T2, or T3.
     

    Regional lymph nodes (N)

  • NX: Regional lymph nodes cannot be assessed
  • N0: No regional lymph node metastasis
  • N1: Metastasis to ipsilateral peribronchial and/or ipsilateral hilar lymph nodes, and intrapulmonary nodes including involvement by direct extension of the primary tumor
  • N2: Metastasis to ipsilateral mediastinal and/or subcarinal lymph node(s)
  • N3: Metastasis to contralateral mediastinal, contralateral hilar, ipsilateral or contralateral scalene, or supraclavicular lymph node(s)

    Distant metastasis (M)

  • MX: Distant metastasis cannot be assessed
  • M0: No distant metastasis
  • M1: Distant metastasis present. M1 includes separate tumor nodule(s) in a different lobe (ipsilateral or contralateral).

Specify sites according to the following notations:

Notation Key for Tumor Sites

BRA = brain EYE = eye HEP = hepatic
LYM = lymph nodes MAR = bone marrow OSS = osseous
OTH = other OVR = ovary PER = peritoneal
PLE = pleura PUL = pulmonary SKI = skin

AJCC stage groupings

    Occult carcinoma

  • TX, N0, M0

    Stage 0

  • Tis, N0, M0

    Stage IA

  • T1, N0, M0

    Stage IB

  • T2, N0, M0

    Stage IIA

  • T1, N1, M0

    Stage IIB

  • T2, N1, M0
  • T3, N0, M0

    Stage IIIA

  • T1, N2, M0
  • T2, N2, M0
  • T3, N1, M0
  • T3, N2, M0

    Stage IIIB

  • Any T, N3, M0
  • T4, any N, M0

    Stage IV

  • Any T, any N, M1

Treatment Option Overview

In non-small cell lung cancer (NSCLC), results of standard treatment are poor except for the most localized cancers. All newly diagnosed patients with NSCLC are potential candidates for studies evaluating new forms of treatment. Surgery is the most potentially curative therapeutic option for this disease; radiation therapy can produce a cure in a small number of patients and can provide palliation in most patients. Adjuvant chemotherapy may provide an additional benefit to patients with resected NSCLC. In advanced-stage disease, chemotherapy offers modest improvements in median survival, though overall survival is poor. [1] [2] Chemotherapy has produced short-term improvement in disease-related symptoms. Several clinical trials have attempted to assess the impact of chemotherapy on tumor-related symptoms and quality of life. In total, these studies suggest that tumor-related symptoms may be controlled by chemotherapy without adversely affecting overall quality of life; [3] [4] [5] however, the impact of chemotherapy on quality of life requires more study.

Current areas under evaluation include combining local treatment (surgery), regional treatment (radiation therapy), and systemic treatments (chemotherapy, immunotherapy, and targeted agents) and developing more effective systemic therapy. Several agents, including cisplatin, carboplatin, paclitaxel (Taxol), docetaxel (Taxotere), topotecan, irinotecan, vinorelbine, and gemcitabine are active in the treatment of advanced NSCLC. Chemoprevention of second primary cancers of the upper aerodigestive tract is undergoing clinical evaluation in patients with early stage lung cancer.

The designations in PDQ that treatments are “standard” or “under clinical evaluation” are not to be used as a basis for reimbursement determinations.

Occult Non-Small Cell Lung Cancer

    Occult non-small cell lung cancer (NSCLC) is defined by the following clinical stage grouping:

  • TX, N0, M0

In occult lung cancer, a diagnostic evaluation often includes chest x-ray and selective bronchoscopy with close follow-up (e.g., computed tomographic scan), when needed, to define the site and nature of the primary tumor; tumors discovered in this fashion are generally early stage and curable by surgery. After discovery of the primary tumor, treatment involves establishing the stage of the patient’s tumor. Therapy is identical to that recommended for other NSCLC patients with similar stage disease.

Stage 0 Non-Small Cell Lung Cancer

    Stage 0 non-small cell lung cancer (NSCLC) is defined by the following clinical stage grouping:

  • Tis, N0, M0

Stage 0 NSCLC is the same as carcinoma in situ of the lung. Because these tumors are by definition noninvasive and incapable of metastasizing, they should be curable with surgical resection; however, a high incidence of second primary cancers, many of which are unresectable, exists. Endoscopic phototherapy with a hematoporphyrin derivative has been described as an alternative to surgical resection in carefully selected patients. [1] [2] [3] This treatment, which is under clinical evaluation, seems to be most effective for very early central tumors that extend <1 cm within the bronchus. [2] Efficacy of this treatment modality in the management of early NSCLC remains to be proven.

Standard treatment options:

  1. Surgical resection using the least extensive technique possible (segmentectomy or wedge resection) to preserve maximum normal pulmonary tissue because these patients are at high risk for second lung cancers.
     
  2. Endoscopic photodynamic therapy. [2] [3]
     

Stage I Non-Small Cell Lung Cancer

Note: Some citations in the text of this section are followed by a level of evidence. The PDQ editorial boards use a formal ranking system to help the reader judge the strength of evidence linked to the reported results of a therapeutic strategy. (Refer to the PDQ summary on Levels of Evidence for more information.)

    Stage I non-small cell lung cancer (NSCLC) is defined by the following clinical stage groupings:

  • T1, N0, M0
  • T2, N0, M0

Surgery is the treatment of choice for patients with stage I NSCLC. Careful preoperative assessment of the patient’s overall medical condition, especially the patient’s pulmonary reserve, is critical in considering the benefits of surgery. The immediate postoperative mortality rate is age-related, but 3% mortality to 5% mortality with lobectomy can be expected. [1] Patients with impaired pulmonary function are candidates for segmental or wedge resection of the primary tumor. The Lung Cancer Study Group conducted a randomized study [2] to compare lobectomy with limited resection for patients with stage I lung cancer. The study's results showed a reduction in local recurrence for patients treated with lobectomy compared with those treated with limited excision, but the outcome showed no significant difference in overall survival. [3] Similar results have been reported from a nonrandomized comparison of anatomic segmentectomy and lobectomy. [4] A survival advantage was noted with lobectomy for patients with tumors >3 cm but not for those with tumors <3 cm; however, the rate of locoregional recurrence was significantly less after lobectomy, regardless of primary tumor size.

Another study of stage I patients showed that those treated with wedge or segment resections had a local recurrence rate of 50% (i.e., 31 recurrences out of 62 patients) despite having undergone complete resections. [5] Exercise testing may aid in the selection of patients with impaired pulmonary function who can tolerate lung resection. [6] The availability of video-assisted thoracoscopic wedge resection permits limited resections in patients with poor pulmonary function who are not usually candidates for lobectomy. [7]

Patients with inoperable stage I disease and with sufficient pulmonary reserve may be candidates for radiation therapy with curative intent. In a single report of patients >70 years who had resectable lesions <4 cm, but who had medically inoperable disease or who refused surgery, survival at 5 years after radiation therapy with curative intent was comparable with an historical control group of patients of similar age who were resected with curative intent. [8] In the 2 largest retrospective radiation therapy series, patients with inoperable disease treated with definitive radiation therapy achieved 5-year survival rates of 10% and 27%. [9] [10] Both series found that patients with T1, N0 tumors had better outcomes, and 5-year survival rates of 60% and 32% were found in this subgroup.

Primary radiation therapy should consist of approximately 6,000 cGy delivered with megavoltage equipment to the midplane of the known tumor volume using conventional fractionation. A boost to the cone down field of the primary tumor is frequently used to enhance local control. Careful treatment planning with precise definition of target volume and avoidance of critical normal structures to the extent possible is needed for optimal results; this requires the use of a simulator.

Many patients treated surgically subsequently develop regional or distant metastases. [5] Such patients are candidates for entry into clinical trials evaluating adjuvant treatment with chemotherapy or radiation therapy following surgery. A meta-analysis of 9 randomized trials evaluating postoperative radiation versus surgery alone showed a 7% reduction in overall survival with adjuvant radiation in patients with stage I or stage II disease. [11][Level of evidence: 1iiA] Whether these outcomes can potentially be modified with technical improvements, better definitions of target volumes, and limitation of cardiac volume in the radiation portals is important to determine.

Patients with stage IB disease may benefit from adjuvant platinum-based combination chemotherapy. [12] [13] [14] [15] [16] A meta-analysis of adjuvant chemotherapy trials reported in 1995 showed a hazard ratio (HR) for death of 0.87 for patients treated with cisplatin-based chemotherapy; [17] however, this result was not statistically significant. Since the 1995 publication, 4 large randomized trials and an additional meta-analysis evaluating the benefit of adjuvant cisplatin combination chemotherapy have been reported. Three of the trials and the meta-analysis have shown that adjuvant cisplatin-based chemotherapy improves overall survival in selected NSCLC patients.

In the largest trial, the International Adjuvant Lung Cancer Trial (IALT), 1,867 patients with resected stage I, stage II, or stage III NSCLC underwent randomization to cisplatin combination chemotherapy or follow-up. [13] Patients assigned to chemotherapy had a significantly higher survival rate than those assigned to observation (5-year survival, 44.5% vs. 40.4%; HR for death = 0.86; 95% confidence interval [CI], 0.76-0.98; P < .03). [13][Level of evidence: 1iiA] Seven patients (0.8%) died of chemotherapy-induced toxic effects.

In the second trial, 482 patients with completely resected stage I (T2N0) or stage II (excluding T3N0) NSCLC were randomized to receive 4 cycles of vinorelbine and cisplatin or observation. [12] Overall survival was significantly prolonged for patients receiving chemotherapy (median survival, 94 months vs. 73 months; HR = 0.69; P = .011). [12][Level of evidence: 1iiA] Two patients died of drug-related toxicity.

In the third trial, 344 patients with stage IB (T2N0M0) NSCLC were randomized to 4 cycles of paclitaxel and carboplatin or observation. [14] There were no chemotherapy-related toxic deaths. The hazard ratio for death was significantly lower among patients receiving adjuvant chemotherapy (HR = 0.62; 95% CI, 0.41-0.95; P = .028). [14][Level of evidence: 1iiA] Overall survival at 4 years was 71% (95% CI, 62%-81%) in the chemotherapy group and 59% (95% CI, 50%-69%) in the observation group.

In the fourth trial, the Adjuvant Lung Project Italy (ALPI) trial, 1,209 patients with stage I, stage II, or stage IIIA NSCLC were randomly assigned to receive mitomycin C, vindesine, and cisplatin every 3 weeks or no treatment after complete resection. [15][Level of evidence: 1iiA] After a median follow-up time of 64.5 months, there was no statistically significant difference between the 2 patient groups in overall survival (HR = 0.96; 95% CI, 0.81-1.13; P = .589) or progression-free survival (HR = 0.89; 95% CI, 0.76-1.03; P = .128).

The recent literature-based meta-analysis of randomized trials, which was reported after the publication of the 1995 meta-analysis, identified 11 trials conducted with a total of 5,716 patients. This analysis includes the IALT and ALPI trials noted above. In this analysis, HR estimates suggested that adjuvant chemotherapy yielded a survival advantage over surgery alone (HR = 0.872; 95% CI, 0.805-0.944; P = .001). In a subset analysis, both cisplatin-based chemotherapy (HR = 0.891; 95% CI, 0.815-0.975; P = .012) and single-agent therapy with tegafur and uracil (UFT) (HR = 0.799; 95% CI, 0.668-0.957; P = .015) were found to yield a significant survival benefit. [16] [18]

In summary, the preponderance of evidence indicates that adjuvant cisplatin combination chemotherapy provides a significant survival advantage to patients with resected NSCLC. The optimal sequence of surgery and chemotherapy and the benefits and risks of adjuvant radiation therapy in patients with resectable NSCLC remain to be determined.

A significant number of patients cured of their smoking-related lung cancer may develop a second malignancy. In the Lung Cancer Study Group trial of 907 stage T1, N0 resected patients, the rate was 1.8% per year for nonpulmonary second cancers and 1.6% per year for new lung cancers. [19] Others have reported even higher risks of second tumors in long-term survivors, including rates of 10% for second lung cancers and 20% for all second cancers. [5] A randomized trial of vitamin A versus observation in patients with resected stage I disease showed a trend toward decreased second primary cancers in the vitamin A arm, with no difference in overall survival rates; [20] however, a large randomized study of β-carotene and retinol supplements used in the primary prevention of lung cancer showed an increase in mortality and lung cancer incidence. [21][Level of evidence: 1iA]

An intergroup trial evaluated the role of isotretinoin in the chemoprevention of second cancers in patients with resected stage I NSCLC. In the trial, 1,116 patients were randomly assigned to receive isotretinoin (30 mg/day) for 3 years or a placebo. [22][Level of evidence: 1iiA] (Refer to the PDQ summary on Prevention of Lung Cancer for more information.) After a median follow-up of 3.5 years, no differences existed between the arms in time to development of second primary tumors, disease recurrence, or survival.

Treatment options:

  1. Lobectomy or segmental, wedge, or sleeve resection as appropriate.
     
  2. Radiation therapy with curative intent (for potentially resectable patients who have medical contraindications to surgery).
     
  3. Adjuvant chemotherapy after resection.
     
  4. Clinical trials of adjuvant chemoprevention. [23]
     
  5. Endoscopic photodynamic therapy (under clinical evaluation in highly selected T1, N0, M0 patients). [24]
     

Stage II Non-Small Cell Lung Cancer

Note: Some citations in the text of this section are followed by a level of evidence. The PDQ editorial boards use a formal ranking system to help the reader judge the strength of evidence linked to the reported results of a therapeutic strategy. (Refer to the PDQ summary on Levels of Evidence for more information.)

    Stage II non-small cell lung cancer (NSCLC) is defined by the following clinical stage groupings:

  • T1, N1, M0
  • T2, N1, M0
  • T3, N0, M0

Surgery is the treatment of choice for patients with stage II NSCLC. Careful preoperative assessment of the patient’s overall medical condition, especially the patient’s pulmonary reserve, is critical in considering the benefits of surgery. Despite the immediate and age-related postoperative mortality rate, a 5% to 8% mortality rate with pneumonectomy or a 3% to 5% mortality rate with lobectomy can be expected.

Patients with inoperable stage II disease and with sufficient pulmonary reserve are candidates for radiation therapy with curative intent. [1] Among patients with excellent performance status, a 3-year survival rate to 20% may be expected if a course of radiation therapy with curative intent can be completed. In the largest retrospective series reported to date, 152 patients with medically inoperable NSCLC, who were treated with definitive radiation therapy, achieved a 5-year overall survival rate of 10%; however, the 44 patients with T1 tumors achieved an actuarial disease-free survival rate of 60%. This retrospective study also suggested that improved disease-free survival was obtained with radiation therapy doses >6,000 cGy. [2] Primary radiation therapy should consist of approximately 6,000 cGy delivered with megavoltage equipment to the midplane of the volume of the known tumor using conventional fractionation. A boost to the cone down field of the primary tumor is frequently used to enhance local control. Careful treatment planning with precise definition of target volume and avoidance of critical normal structures, to the extent possible, is needed for optimal results; this requires the use of a simulator.

After surgery, many patients develop regional or distant metastases. [3] Prospective randomized trials evaluating the role of postoperative adjuvant chemotherapy in patients with NSCLC have been performed since the 1960s. A meta-analysis of adjuvant chemotherapy trials reported in 1995 showed a hazard ratio (HR) for death of 0.87 for patients treated with cisplatin-based chemotherapy; [4] however, this result was not statistically significant. Since the 1995 publication, 4 large randomized trials and an additional meta-analysis evaluating the benefit of adjuvant cisplatin combination chemotherapy have been reported. Three of the trials and the meta-analysis have shown that adjuvant cisplatin-based chemotherapy improves overall survival in selected NSCLC patients.

In the largest trial, the International Adjuvant Lung Cancer Trial (IALT), 1,867 patients with resected stage I, stage II, or stage III NSCLC underwent randomization to cisplatin combination chemotherapy or follow-up. [5] Patients assigned to chemotherapy had a significantly higher survival rate than those assigned to observation (5-year survival 44.5% vs. 40.4%, HR for death = 0.86; 95% confidence interval [CI], 0.76-0.98; P < .03). [5][Level of evidence: 1iiA] Seven patients (0.8%) died of chemotherapy-induced toxic effects.

In the second trial, 482 patients with completely resected stage I (T2N0) or stage II (excluding T3N0) NSCLC were randomized to receive 4 cycles of vinorelbine and cisplatin or observation. [6] Overall survival was significantly prolonged for patients receiving chemotherapy (median 94 months vs. 73 months; HR = 0.69; P = .011). [6][Level of evidence: 1iiA] Two patients died of drug-related toxic effects.

In the third trial, 344 patients with stage IB (T2N0M0) NSCLC were randomized to 4 cycles of paclitaxel and carboplatin or observation. [7] There were no chemotherapy-related toxic deaths. The hazard ratio for death was significantly lower among patients receiving adjuvant chemotherapy (HR = 0.62; 95% CI, 0.41-0.95; P = .028). [7][Level of evidence: 1iiA] Overall survival at 4 years was 71% (95% CI, 62%-81%) in the chemotherapy group and 59% (95% CI, 50%-69%) in the observation group.

In the fourth trial, the Adjuvant Lung Project Italy trial (ALPI), 1,209 patients with stage I, stage II, or stage IIIA NSCLC were randomly assigned to receive mitomycin C, vindesine, and cisplatin every 3 weeks, or no treatment after complete resection. [8][Level of evidence: 1iiA] After a median follow-up time of 64.5 months, there was no statistically significant difference between the 2 patient groups in overall survival (HR = 0.96; 95% CI, 0.81-1.13; P = .589) or progression-free survival (HR = 0.89; 95% CI, 0.76-1.03; P = .128).

The recent literature-based meta-analysis of randomized trials reported after the publication of the 1995 meta-analysis identified 11 trials conducted on a total of 5,716 patients. This analysis includes the IALT and ALPI trials noted above. In this analysis, HR estimates suggested that adjuvant chemotherapy yielded a survival advantage over surgery alone (HR = 0.872; 95% CI, 0.805-0.944; P = .001). In a subset analysis, both cisplatin-based chemotherapy (HR = 0.891; 95% CI, 0.815-0.975; P = .012) and single-agent therapy with tegafur and uracil (UFT) (HR = 0.799; 95% CI, 0.668-0.957; P = .015) were found to yield a significant survival benefit. [9] [10]

In summary, the preponderance of evidence indicates that adjuvant cisplatin combination chemotherapy provides a significant survival advantage to patients with resected NSCLC. The optimal sequence of surgery and chemotherapy and the benefits and risks of adjuvant radiation therapy in patients with resectable NSCLC remain to be determined.

Treatment options:

  1. Lobectomy; pneumonectomy; or segmental, wedge, or sleeve resection as appropriate.
     
  2. Radiation therapy with curative intent (for potentially operable patients who have medical contraindications to surgery).
     
  3. Adjuvant chemotherapy with or without other modalities after curative surgery. [5] [6] [7] [8] [9] [10]
     
  4. Clinical trials of radiation therapy after curative surgery. [11]
     

Stage IIIA Non-Small Cell Lung Cancer

Note: Some citations in the text of this section are followed by a level of evidence. The PDQ editorial boards use a formal ranking system to help the reader judge the strength of evidence linked to the reported results of a therapeutic strategy. (Refer to the PDQ summary on Levels of Evidence for more information.)

    Stage IIIA non-small cell lung cancer (NSCLC) is defined by the following clinical stage groupings:

  • T1, N2, M0
  • T2, N2, M0
  • T3, N1, M0
  • T3, N2, M0

Patients with clinical stage IIIA N2 disease have a 5-year survival rate of 10% to 15% overall; however, patients with bulky mediastinal involvement (i.e., visible on chest radiograph) have a 5-year survival rate of 2% to 5%. Depending on clinical circumstances, the principal forms of treatment that are considered for patients with stage IIIA NSCLC are radiation therapy, chemotherapy, surgery, and combinations of these modalities. Although most patients do not achieve a complete response to radiation therapy, a reproducible long-term survival benefit in 5% to 10% of patients treated with standard fractionation to 6,000 cGy occurs, and significant palliation often results. Patients with excellent performance status (PS) and those who require a thoracotomy to prove that a surgically unresectable tumor is present are most likely to benefit from radiation therapy. [1]

Because of the poor long-term results, all patients with stage IIIA NSCLC are candidates for treatment on clinical trials. Trials examining fractionation schedules, brachytherapy, and combined modality approaches may lead to improvement in the control of this disease. [2] One prospective randomized clinical study showed that radiation therapy given as 3 daily fractions improved overall survival compared with radiation therapy given as one daily fraction. [3][Level of evidence: 1iiA]

The addition of chemotherapy to radiation therapy has been reported to improve survival in prospective clinical studies that have used modern cisplatin-based chemotherapy regimens. [4] [5] [6] [7] A meta-analysis of patient data from 11 randomized clinical trials showed that cisplatin-based combinations plus radiation therapy resulted in a 10% reduction in the risk of death compared with radiation therapy alone. [8] The optimal sequencing of modalities and schedule of drug administration is yet to be determined and is under study in ongoing clinical trials. [9]

The use of preoperative (i.e., neoadjuvant) chemotherapy has been effective in 2 small randomized studies of a total of 120 patients with stage IIIA NSCLC. [10] [11] In both studies, the 58 patients randomized to 3 cycles of cisplatin-based chemotherapy before surgery had a median survival more than 3 times as long as patients treated with surgery but no chemotherapy. Two additional single-arm studies have evaluated either 2 to 4 cycles of combination chemotherapy or combination chemotherapy plus chest radiation therapy for 211 patients with histologically confirmed N2 stage IIIA NSCLC. [12] In these studies, 65% to 75% of patients had a resection of their cancers, and 27% to 28% of patients were alive 3 years later. These results are encouraging, and combined-modality therapy with neoadjuvant chemotherapy with surgery and/or chest radiation therapy should be considered for patients with good PS who have stage IIIA NSCLC.

After surgery, many patients develop regional or distant metastases. [13] Patients with resected stage IIIA NSCLC may benefit from adjuvant cisplatin combination chemotherapy. [14] [15] [16] [17] [18] [19] Prospective randomized trials evaluating the role of postoperative adjuvant chemotherapy in patients with NSCLC have been performed since the 1960s. A meta-analysis of adjuvant chemotherapy trials reported in 1995 showed a hazard ratio (HR) for death of 0.87 for patients treated with cisplatin-based chemotherapy; [8] however, this result was not statistically significant. Since the 1995 publication, 4 large randomized trials and an additional meta-analysis evaluating the benefit of adjuvant cisplatin combination chemotherapy have been reported. Three of the trials and the meta-analysis have shown that adjuvant cisplatin-based chemotherapy improves overall survival in selected NSCLC patients.

In the largest trial, the International Adjuvant Lung Cancer Trial (IALT), 1,867 patients with resected stage I, stage II, or stage III NSCLC underwent randomization to cisplatin combination chemotherapy or follow-up. [14] Patients assigned to chemotherapy had a significantly higher survival rate than those assigned to observation (5-year survival 44.5% vs. 40.4%, HR for death = 0.86; 95% confidence interval [CI], 0.76-0.98; P < .03). [14][Level of evidence: 1iiA] Seven patients (0.8%) died of chemotherapy-induced toxic effects.

In the second trial, 482 patients with completely resected stage I (T2N0) or stage II (excluding T3N0) NSCLC were randomized to receive 4 cycles of vinorelbine and cisplatin or observation. [15] Overall survival was significantly prolonged for patients receiving chemotherapy (median 94 months vs. 73 months; HR 0.69; P = .011). [15][Level of evidence: 1iiA] Two patients died of drug-related toxic effects.

In the third trial, 344 patients with stage IB (T2N0M0) NSCLC were randomized to 4 cycles of paclitaxel and carboplatin or observation. [16] There were no chemotherapy-related toxic deaths. The hazard ratio for death was significantly lower among patients receiving adjuvant chemotherapy (HR = 0.62; 95% CI, 0.41-0.95; P = .028). [16][Level of evidence: 1iiA] Overall survival at 4 years was 71% (95% CI, 62%-81%) in the chemotherapy group and 59% (95% CI, 50%-69%) in the observation group.

In the fourth trial, the Adjuvant Lung Project Italy (ALPI) trial, 1,209 patients with stage I, stage II, or stage IIIA NSCLC were randomly assigned to receive mitomycin C, vindesine, and cisplatin every 3 weeks or no treatment after complete resection. [17][Level of evidence: 1iiA] After a median follow-up time of 64.5 months, there was no statistically significant difference between the 2 patient groups in overall survival (HR = 0.96; 95% CI, 0.81-1.13; P = .589) or progression-free survival (HR = 0.89; 95% CI, 0.76-1.03; P = .128).

The recent literature-based meta-analysis of randomized trials reported after the publication of the 1995 meta-analysis identified 11 trials conducted on a total of 5,716 patients. This analysis includes the IALT and ALPI trials noted above. In this analysis, HR estimates suggested that adjuvant chemotherapy yielded a survival advantage over surgery alone (HR = 0.872; 95% CI, 0.805-0.944; P = .001). In a subset analysis, both cisplatin-based chemotherapy (HR = 0.891; 95% CI, 0.815-0.975; P = .012) and single-agent therapy with tegafur and uracil (UFT) (HR = 0.799; 95% CI, 0.668-0.957; P =.015) were found to yield a significant survival benefit. [18] [19]

In summary, the preponderance of evidence indicates that adjuvant cisplatin combination chemotherapy provides a significant survival advantage to patients with resected NSCLC. The optimal sequence of surgery and chemotherapy and the benefits and risks of adjuvant radiation therapy in patients with resectable NSCLC remain to be determined.

Although most retrospective studies suggest that postoperative radiation therapy can improve local control for node-positive patients whose tumors were resected, it remains controversial whether it can improve survival. [20] [21] One controlled trial of patients with completely resected stage II or stage III squamous cell lung cancer failed to demonstrate a survival benefit for patients who received postoperative radiation therapy, but local recurrences were significantly reduced. [22] In a trial conducted from 1986 to 1994, patients with completely resected stage I, stage II, or stage IIIA lung cancers were randomly assigned to resection alone or to resection plus postoperative radiation therapy. The addition of postoperative radiation therapy did not improve overall survival or local recurrence either for the whole group or for the subset of patients with stage IIIA disease. [23][Level of evidence: 1iiA] An intergroup trial comparing postoperative radiation therapy alone to postoperative radiation therapy with concurrent cisplatin and etoposide did not demonstrate either a disease-free survival or overall survival advantage with the combined therapy. [24][Level of evidence: 1iiA] A meta-analysis of 9 randomized trials that evaluated postoperative radiation therapy versus surgery alone showed no difference in overall survival for the entire postoperative radiation therapy group or for the subset of N2 patients. [25][Level of evidence: 1iiA] Whether these outcomes can be modified with technical improvements, better definitions of target volumes, and limitation of cardiac volume in the radiation portals is important to determine.

No consistent benefit from any form of immunotherapy has been demonstrated thus far in the treatment of NSCLC.

Treatment options:

  1. Surgery alone in operable patients without bulky lymphadenopathy. [26] [27] [28]
     
  2. Radiation therapy alone, for patients who are not suitable for neoadjuvant chemotherapy plus surgery. [1] [2] [29]
     
  3. Chemotherapy combined with other modalities. [4] [5] [6] [12]
     

Superior sulcus tumor (T3, N0 or N1, M0)

A special approach is also merited for treatment of superior sulcus tumors. They are a locally invasive problem and usually have a reduced tendency for distant metastases. Consequently, local therapy has curative potential, especially for patients with T3, N0 disease. Radiation therapy alone, radiation therapy preceded or followed by surgery, or surgery alone (in highly selected cases) may be curative in some patients, with a 5-year survival rate of >20% in some studies. [30] Patients with more invasive tumors of this area, or true Pancoast tumors, have a worse prognosis and generally do not benefit from primary surgical management. Follow-up surgery may be used to verify complete response in the radiation therapy field and to resect necrotic tissue. Concurrent chemotherapy and radiation therapy followed by surgery may provide the best outcome, particularly for patients with T4, N0 or N1 disease. [31][Level of evidence: 3iiiDi]

Treatment options:

  1. Radiation therapy and surgery.
     
  2. Radiation therapy alone.
     
  3. Surgery alone (selected cases).
     
  4. Chemotherapy combined with other modalities.
     
  5. Clinical trials of combined modality therapy.
     

Chest wall tumor (T3, N0 or N1, M0)

Selected patients with bulky primary tumors that directly invade the chest wall can obtain long-term survival with surgical management provided that their tumor is completely resected.

Treatment options:

  1. Surgery. [28] [32]
     
  2. Surgery and radiation therapy.
     
  3. Radiation therapy alone.
     
  4. Chemotherapy combined with other modalities.
     

Stage IIIB Non-Small Cell Lung Cancer

    Stage IIIB non-small cell lung cancer (NSCLC) is defined by the following clinical stage groupings:

  • Any T, N3, M0
  • T4, any N, M0

Note: Some citations in the text of this section are followed by a level of evidence. The PDQ editorial boards use a formal ranking system to help the reader judge the strength of evidence linked to the reported results of a therapeutic strategy. (Refer to the PDQ summary on Levels of Evidence for more information.)

Patients with stage IIIB NSCLC do not benefit from surgery alone and are best managed by initial chemotherapy, chemotherapy plus radiation therapy, or radiation therapy alone, depending on the sites of tumor involvement and their performance status (PS). Most patients with excellent PS are candidates for combined modality therapy; however, patients with malignant pleural effusion are rarely candidates for radiation therapy and should generally be treated similarly to stage IV patients. Many randomized studies of patients with unresectable stage III NSCLC show that treatment with neoadjuvant or concurrent cisplatin-based chemotherapy and chest irradiation is associated with improved survival compared with treatment that uses radiation therapy alone. [1] [2] [3] [4] [5] A meta-analysis of patient data from 11 randomized clinical trials showed that cisplatin-based combinations plus radiation therapy resulted in a 10% reduction in the risk of death compared with radiation therapy alone. [6]

Patients with stage IIIB disease with poor PS are candidates for chest radiation therapy to palliate pulmonary symptoms (e.g., cough, shortness of breath, hemoptysis, or pain). [7][Level of evidence: 3iiiC]

T4 or N3, M0

An occasional patient with supraclavicular node involvement, who is otherwise a good candidate for radiation therapy with curative intent, will survive 3 years. Although most of these patients do not achieve a complete response to radiation therapy, significant palliation often results. Patients with excellent PS and those who are found to have advanced-stage disease at the time of resection are most likely to benefit from radiation therapy. [8] Adjuvant systemic chemotherapy with radiation therapy has been tested in randomized trials for patients with inoperable or unresectable locoregional NSCLC. [1] [2] [3] [9] Some patients have shown a modest survival advantage with adjuvant chemotherapy. The addition of chemotherapy to radiation therapy has been reported to improve long-term survival in some, [1] [3] [4] but not all, [10] prospective clinical studies. A meta-analysis of patient data from 54 randomized clinical trials showed an absolute survival benefit of 4% at 2 years with the addition of cisplatin-based chemotherapy to radiation therapy. [11] The optimal sequencing of modalities is yet to be determined and is under study in clinical trials. [12]

Because of the poor overall results, these patients are candidates for clinical trials that examine new fractionation schedules, radiosensitizers, and combined modality approaches, which may lead to improvement in the control of disease. Information about ongoing clinical trials is available from the NCI Web site.

Patients with NSCLC can present with superior vena cava syndrome. (Refer to the PDQ summary on Cardiopulmonary Syndromes for more information.) Regardless of the clinical stage, this problem should generally be managed with radiation therapy with or without chemotherapy.

Treatment options:

  1. Radiation therapy alone. [7] [13]
     
  2. Chemotherapy combined with radiation therapy. [1] [2] [3] [9]
     
  3. Chemotherapy and concurrent radiation therapy followed by resection. [14] [15]
     
  4. Chemotherapy alone.
     

Stage IV Non-Small Cell Lung Cancer

Note: Some citations in the text of this section are followed by a level of evidence. The PDQ editorial boards use a formal ranking system to help the reader judge the strength of evidence linked to the reported results of a therapeutic strategy. (Refer to the PDQ summary on Levels of Evidence for more information.)

    Stage IV non-small cell lung cancer (NSCLC) is defined by the following clinical stage grouping:

  • Any T, any N, M1

Palliative chemotherapy with a cisplatin-based or carboplatin-based regimen has been associated with objective and subjective responses for patients with metastatic NSCLC. Randomized trials have shown that cisplatin-based chemotherapy produces modest benefits in short-term survival compared with supportive care alone in patients with inoperable stage IIIB or IV disease. Although toxic effects may vary, outcomes are similar with most platinum-containing regimens. A prospective randomized trial comparing 5 older cisplatin-containing regimens showed no significant difference in response, duration of response, or survival among the different cisplatin-based regimens. [1][Level of evidence: 1iiA] Patients with good performance status (PS) and a limited number of sites of distant metastases have superior response and survival when given chemotherapy and compared with other patients. [2] A prospective randomized comparison of vinorelbine plus cisplatin versus vindesine plus cisplatin versus single-agent vinorelbine has reported an improved response rate of 30% and a median survival time of 40 weeks with the vinorelbine plus cisplatin regimen when compared with the other 2 regimens. [3][Level of evidence: 1iiA]

Reports of taxane and platinum combinations have shown relatively high response rates, significant 1-year survival, and palliation of lung cancer symptoms. [4] In a multicenter phase III study, the combination of cisplatin and paclitaxel showed a higher response rate than the older combination of cisplatin and etoposide. [5][Level of evidence: 1iiDi] Results from clinical trials indicate that platinum-doublet combinations are superior to both platinum and other single agents. [6]

Cisplatin-containing combination chemotherapy regimens provide clinical benefit when compared with supportive care alone; however, treatment may be contraindicated in some older patients because of the age-related reduction in the functional reserve of many organs and/or comorbid conditions. Often patients in this subgroup are not offered cytotoxic treatment because of concerns about tolerability. Several studies have demonstrated similar response rates, survival, and quality-of-life outcomes for patients ≥70 years as compared with patients <70 years despite a greater frequency of leukopenia, weight loss, and neuropsychiatric toxic effects among the older population. [7] [8] In a randomized trial of patients >70 years with NSCLC, single-agent vinorelbine resulted in superior survival when compared with supportive care alone (median survival of 28 weeks vs. 21 weeks). [9][Level of evidence: 1iiA] A multicenter Italian group conducted a randomized study of 698 older patients that compared both single-agent vinorelbine and single-agent gemcitabine with the combination of vinorelbine and gemcitabine. [10] Compared with each single drug, the combination treatment did not improve survival. [10][Level of evidence: 1iiA]. The hazard ratio of death for patients receiving the combination treatment was 1.17 (95% confidence interval [CI], 0.95-1.44) compared with single-agent vinorelbine and 1.06 (95% CI, 0.86-1.29) compared with single-agent gemcitabine. Studies to date suggest that fit elderly patients can receive the same benefit from platinum combination chemotherapy as younger patients, with acceptable toxic effects. [11] In patients with contraindications to platinum compounds, no evidence indicates that nonplatinum combinations are superior to single-agent vinorelbine or single-agent gemcitabine. The use of single agent versus combination chemotherapy should be based on PS and comorbid conditions rather than age. [12]

A prospective randomized study compared 4 commonly used platinum-based chemotherapy regimens for patients with stage IIIB or stage IV NSCLC: cisplatin plus paclitaxel, gemcitabine plus cisplatin, cisplatin plus docetaxel, and carboplatin plus paclitaxel. [13] No regimen was found to have a significantly better response rate or survival time. [13][Level of evidence: 1iiA] The response rate for all 1,158 of the eligible patients was 19%, and the median survival time was 7.9 months (95% CI, 7.3-8.5 months). Patients with a PS of 2 had significantly worse toxic effects and survival compared with patients who had a PS of 0 to 1. [13] Another prospective randomized study compared the combination of carboplatin plus paclitaxel with vinorelbine plus cisplatin. This study also found no significant difference in efficacy between the 2 standard regimens. [14][Level of evidence: 1iiDi] A prospective randomized trial compared chemotherapy with carboplatin and paclitaxel with or without bevacizumab in patients with nonsquamous NSCLC. Patients with squamous cell histology were excluded because previous studies demonstrated significant bleeding complications in that group. A second planned interim analysis has been reported in abstract form. [15] Of the 842 patients entered, the response rates (10% vs. 27%, P < .001), progression-free survival (4.5 months vs. 6.4 months, P < .001), and median survival (10.2 months vs. 12.5 months, P = .075) were superior in the bevacizumab arm. The 5 deaths that occurred were on the bevacizumab arm and were the result of hemoptysis.

The results support further evaluation of chemotherapeutic approaches for both metastatic and locally advanced NSCLC; however, the efficacy of current platinum-based chemotherapy combinations is such that no specific regimen can be regarded as standard therapy. Appropriate patients are candidates for clinical trials that evaluate the role of platinum-based and nonplatinum-based chemotherapy. Outside of a clinical trial setting, chemotherapy should be given only to patients with good PS and evaluable tumor lesions, who desire such treatment after being fully informed of its anticipated risks and limited benefits.

Radiation therapy may be effective in palliating symptomatic local involvement with NSCLC, such as tracheal, esophageal, or bronchial compression; bone or brain metastases; pain; vocal cord paralysis; hemoptysis; or superior vena cava syndrome. In some cases, endobronchial laser therapy and/or brachytherapy has been used to alleviate proximal obstructing lesions. [16] In the rare patient with synchronous presentation of a resectable primary tumor in the lung and a single brain metastasis, surgical resection of the solitary brain lesion is indicated with resection of the primary tumor. Appropriate postoperative chemotherapy and/or radiation therapy of the primary tumor site (and with postoperative whole-brain radiation therapy delivered in daily fractions of 180 cGy to 200 cGy) is used to avoid long-term toxic effects to normal brain tissue. [17] [18]

Thoracic radiation therapy is an effective treatment modality to relieve symptoms from intrathoracic disease, either after disease progression during chemotherapy or in patients who are not candidates for, or decline, chemotherapy. Most of these patients will have symptoms from the primary tumor and local regional metastases, including dyspnea, cough, and hemoptysis; however, there is still no consensus on which fractionation scheme should be used. Although different multifraction regimens appear to provide similar symptom relief, [19] [20] single-fraction radiation may be insufficient for symptom relief compared to hypofractionated or standard regimens. [21] Evidence is available of a modest increase in survival for patients with better PS given high-dose radiation therapy. [19] [20]

In closely observed asymptomatic patients, treatment may often be appropriately deferred until symptoms or signs of a progressive tumor develop.

Treatment options:

  1. External-beam radiation therapy, primarily for palliative relief of local symptomatic tumor growth. [19] [20] [21]
     
  2. Chemotherapy. The following regimens are associated with similar survival outcomes:
    • Cisplatin plus vinblastine plus mitomycin. [19] [22] [23] [24] [25]
    • Cisplatin plus vinorelbine. [3] [14]
    • Cisplatin plus paclitaxel. [5] [13]
    • Cisplatin plus docetaxel. [13] [26] [27]
    • Cisplatin plus gemcitabine. [13] [28]
    • Carboplatin plus paclitaxel. [13] [14] [29]
  3. Clinical trials evaluating the role of new chemotherapy regimens and other systemic agents. Initial results suggest newer nonplatinum-based chemotherapy regimens produce response and survival results like those produced by standard platinum-based regimens. [30] Further trials comparing platinum-based and nonplatinum-based regimens are ongoing. .
     
  4. Endobronchial laser therapy and/or brachytherapy for obstructing lesions. [16]
     

Recurrent Non-Small Cell Lung Cancer

Note: Some citations in the text of this section are followed by a level of evidence. The PDQ editorial boards use a formal ranking system to help the reader judge the strength of evidence linked to the reported results of a therapeutic strategy. (Refer to the PDQ summary on Levels of Evidence for more information.)

Many patients with recurrent non-small cell lung cancer (NSCLC) are eligible for clinical trials. Radiation therapy may provide excellent palliation of symptoms from a localized tumor mass.

Patients who present with a solitary cerebral metastasis after resection of a primary NSCLC lesion and who have no evidence of extracranial tumor can achieve prolonged disease-free survival with surgical excision of the brain metastasis and postoperative whole-brain radiation therapy. [1] [2] Unresectable brain metastases in this setting may be treated radiosurgically. [3] Because of the small potential for long-term survival, radiation therapy should be delivered by conventional methods in daily doses of 180 cGy to 200 cGy. Because of the high risk of toxic effects observed with such treatments, higher daily doses over a shorter period of time (i.e., hypofractionated schemes) should be avoided because of the high risk of toxic effects observed with such treatments. [4] Most patients who are not suitable for surgical resection should receive conventional whole-brain radiation therapy. Selected patients with good performance status (PS) and small metastases can be considered for stereotactic radiosurgery. [5]

Approximately 50% of patients treated with resection and postoperative radiation therapy will develop recurrence in the brain; some of these patients will be suitable for additional treatment. [6] In those selected patients with good PS and without progressive metastases outside of the brain, treatment options include reoperation or stereotactic radiosurgery. [3] [6] For most patients, additional radiation therapy can be considered; however, the palliative benefit of this treatment is limited. [7][Level of evidence: 3iiiDii]

A solitary pulmonary metastasis from an initially resected bronchogenic carcinoma is unusual. The lung is frequently the site of second primary malignancies in patients with primary lung cancers. Whether the new lesion is a new primary cancer or a metastasis may be difficult to determine. Studies have indicated that in most patients the new lesion is a second primary tumor, and after its resection some patients may achieve long-term survival. Thus, if the first primary tumor has been controlled, the second primary tumor should be resected, if possible. [8] [9]

The use of chemotherapy has produced objective responses and small improvement in survival for patients with metastatic disease. [10][Level of evidence: 1iiA] In studies that have examined symptomatic response, improvement in subjective symptoms has been reported to occur more frequently than objective response. [11] [12] Informed patients with good PS and symptomatic recurrence can be offered treatment with a platinum-based chemotherapy regimen for palliation of symptoms. For patients who have relapsed after platinum-based chemotherapy, second-line therapy can be considered. Two prospective randomized studies have shown an improvement in survival with the use of docetaxel compared with vinorelbine, ifosfamide, or best supportive care; [13] [14] however, criteria for the selection of appropriate patients for second-line treatment are not well defined. [15] A randomized phase III trial of 571 patients designed to demonstrate the noninferiority of pemetrexed compared with docetaxel showed no difference in response rates, progression-free survival, or overall survival. [16][Level of evidence: 1iiA]

A phase II study of erlotinib (i.e., 150 mg orally, daily) in patients with epidermal growth factor receptor (EGFR)-expressing NSCLC previously treated with platinum-based chemotherapy reported an objective response rate of 12.3% (95% confidence interval [CI], 5.1%-23.7%). [17][Level of evidence: 3iiiDiii] Drug-related cutaneous rash and diarrhea were observed in 75% and 56% of patients, respectively. A preliminary report of a randomized, placebo-controlled trial indicated that erlotinib prolongs survival in NSCLC patients after first-line or second-line chemotherapy compared with placebo. [18] In this trial of 731 patients, the median overall survival was 6.7 months versus 4.7 months (hazard ratio [HR] = 0.73; 95% CI, 0.6-0.87; P = .001). The median progression-free survival was 2.23 months versus 1.84 months (HR = 0.6; 95% CI, 0.51-0.73; P < .001). [18][Level of evidence: 1iiA] When used in combination with carboplatin/paclitaxel [19] or cisplatin/gemcitabine, [20] erlotinib was not found to improve response rates, progression-free survival, or overall survival in previously untreated patients with advanced or metastatic NSCLC. [19] [20][Level of evidence: 1iiA]

Gefitinib induces responses in 9.6% to 19% of NSCLC patients treated previously with platinum and taxane chemotherapy. [21] [22][Level of evidence: 3iiiDiii] Additionally, it has been reported that a randomized phase III trial evaluating gefitinib versus placebo in 1,692 previously treated NSCLC patients showed that gefitinib does not improve overall survival (HR = 0.89; P = .11; median 5.6 vs. 5.1 months for gefitnib and placebo, respectively). [23][Level of evidence: 1iiA] In addition, in 2 randomized trials comparing the addition of gefitinib with standard platinum combination chemotherapy, no improvement in response rates, progression-free survival, or overall survival was shown. [24] [25][Level of evidence: 1iiA]

Objective response rates to erlotinib and gefitinib are higher in patients who have never smoked, in females, and in patients with adenocarcinoma and bronchioloalveolar carcinoma. [26] [27] [28] [29] [30] Responses may be associated with mutations around the tyrosine kinase domain of the EGFR receptor [27] [28] [29] and with the absence of K-RAS mutations. [30][Level of evidence: 3iiiDii]

Treatment options:

  1. Palliative radiation therapy. [31]
     
  2. Chemotherapy alone.

    For patients who have not received chemotherapy previously, the following regimens are associated with similar survival outcomes:

    • Cisplatin plus vinblastine plus mitomycin. [32]
    • Cisplatin plus vinorelbine. [33]
    • Cisplatin plus paclitaxel. [34] [35]
    • Cisplatin plus gemcitabine. [35] [36]
    • Carboplatin plus paclitaxel. [35] [37] [38]
    • Cisplatin plus docetaxel. [35] [39]

    For patients who have received platinum chemotherapy previously:

    • Docetaxel. [14] [16]
    • Pemetrexed. [16]
    • Erlotinib after failure of both platinum-based and docetaxel chemotherapies. [18]
  3. Surgical resection of isolated cerebral metastasis (highly selected patients). [6]
     
  4. Laser therapy or interstitial radiation therapy for endobronchial lesions. [40]
     
  5. Stereotactic radiosurgery (highly selected patients). [3] [5]
     
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GENERAL INFORMATION

Non-small cell lung cancer (NSCLC) is a heterogeneous aggregate of at least 3 distinct histologies of lung cancer including epidermoid or squamous carcinoma, adenocarcinoma, and large cell carcinoma. These histologies are often classified together because, when localized, all have the potential for cure with surgical resection. Systemic chemotherapy can produce objective partial responses and palliation of symptoms for short durations in patients with advanced disease. Local control can be achieved with radiation in a large number of patients with unresectable disease, but cure is seen only in a small minority of patients.

At diagnosis, patients with NSCLC can be divided into 3 groups that reflect the extent of disease and treatment approach. The first group of patients has tumors that are surgically resectable (generally stages I and II). This is the group with the best prognosis, depending on a variety of tumor and host factors. Patients with resectable disease who have medical contraindications to surgery can be considered for curative radiation therapy. The second group includes patients with either locally (T3-T4) or regionally (N2-N3) advanced lung cancer who have a diverse natural history. This group is treated with radiation therapy or, more commonly, with radiation therapy in combination with chemotherapy or other therapy modalities. Selected patients with T3 or N2 disease can be treated effectively with surgical resection alone. The final group of patients have distant metastases (M1) found at the time of diagnosis. This group can be treated with radiation therapy or chemotherapy for palliation of symptoms from the primary tumor. Patients with good performance status, women, and patients with distant metastases confined to a single site appear to live longer than others.[1] Cisplatin-based chemotherapy has been associated with short-term palliation of symptoms and a small survival advantage. Currently no single chemotherapy regimen can be recommended for routine use.

For operable patients, prognosis is adversely influenced by the presence of pulmonary symptoms, large tumor size (>3 centimeters), and presence of the erbB-2 oncoprotein.[1-6] Other factors that have been identified as adverse prognostic factors in some series of patients with resectable non-small cell lung cancer include mutation of the K-ras gene, vascular invasion, and increased numbers of blood vessels in the tumor specimen.[3,7,8]

Since treatment is not satisfactory for almost all patients with NSCLC, with the possible exception of a subset of pathologic stage I (T1, N0, M0) patients treated surgically, eligible patients should be considered for clinical trials.

CELLULAR CLASSIFICATION

Prior to initiating treatment of any patient with lung cancer, a review of pathologic material by an experienced lung cancer pathologist is critical since some cases of small cell lung cancer (which responds well to chemotherapy) can be confused on microscopic examination with non-small cell carcinoma.[1] Nonsquamous cell cancers may be more likely to recur after surgical resection of early stage I tumors than other types of non-small cell lung cancers.[2] Bronchoalveolar carcinoma represents 10% to 25% of adenocarcinomas and sometimes has a distinct presentation and biologic behavior.[3-5] Bronchoalveolar cancer may present as a more diffuse lesion than other types of cancer; 30% to 40% of patients undergoing an attempt at surgical resection present with an infiltrate on their chest radiograph. Bronchoalveolar cancer is more common in women and in patients who do not smoke cigarettes than other histologic types of lung cancer.

Histologic classification of non-small cell lung cancer:
 

  • squamous cell (epidermoid) carcinoma
    • spindle cell variant
  • adenocarcinoma
    • acinar
    • papillary
    • bronchoalveolar [4,5]
    • solid tumor with mucin
  • large cell carcinoma
    • giant cell
    • clear cell
  • adenosquamous carcinoma
  • undifferentiated carcinoma

STAGE INFORMATION

Since determination of stage has important therapeutic and prognostic implications, careful initial diagnostic evaluation to define location and extent of primary and metastatic tumor involvement is critical for the appropriate care of patients.

Stage has a critical role in the selection of therapy. The stage of disease is based on a combination of clinical (physical examination, radiologic, and laboratory studies) and pathologic (biopsy of lymph nodes, bronchoscopy, mediastinoscopy, or anterior mediastinotomy.[1] The distinction between clinical stage and pathologic stage should be considered when evaluating reports of survival outcome. Surgical staging of the mediastinum is considered standard if accurate evaluation of the nodal status is needed to determine therapy. The Radiology Diagnostic Oncology Group reported that the sensitivity and specificity of computed tomographic (CT) scanning is only 52% and 69%, respectively.[2] Magnetic resonance imaging does not appear to improve the accuracy of staging.[2] Early evaluation of the role of positron emission tomography (PET) suggests that the combination of CT and PET may have greater sensitivity and specificity than CT alone.[3] A report evaluating the staging of 1,400 patients undergoing tumor resection found that clinical staging by radiologic studies accurately assessed the T stage in 78% of patients and the N stage in only 47% of patients. Errors in clinical staging were equally divided between overstaging and understaging.[4]


The Revised International Staging System for Lung Cancer

The Revised International System for Staging Lung Cancer was adopted in 1997 by the American Joint Committee on Cancer and the Union Internationale Contre le Cancer.[5] These revisions were made to provide greater specificity for patient groups. Stage I is divided into 2 categories by the size of the tumor; IA, T1N0M0 and IB, T2N0M0. Stage II is divided into 2 categories by the size of the tumor and by the nodal status; IIA, T1N1M0 and IIB, T2N1M0. T3N0 has been moved from stage IIIA in the 1986 version of the staging system to stage IIB. The other change has been to clarify the classification of multiple tumor nodules. Satellite tumor nodules in the same lobe as the primary lesion that are not lymph nodes should be classified as T4 lesions. Intrapulmonary ipsilateral metastasis in a lobe other than the lobe containing the primary lesions should be classified as an M1 lesion (stage IV).

The American Joint Committee on Cancer (AJCC) has designated staging by TNM classification.[6]

Misspelled words used to find this page 12 of 14. prmary, primurie, priary, plimurie, primry, primay, primarie, primery, plimarie, plimery, primalie, primury, plimahie, primahie, plimahy, primahy, plimary, primaly, plimaly, pr1nary, prinary, primayr, primray, priamry, prmiary, pirmary, rpimary, primar, rimary, risk, risque, lisque, risch, lisch, lisk, r1sk, riks, rsik, irsk, menopausel, menopausal, mnopausal, menopawsal, meopausal, menopawsar, menpausal, menopawsel, menoausal, menopusal, menopasal, menopaual, menopausl, menopausar, nemopausa1, nemopausal, memopausal, menopausla, menopauasl, menopasual, menopuasal, menoapusal, menpoausal, meonpausal, mneopausal, emnopausal, menopausa, enopausal,amenorhe, ameignorhea, ameignolrha, amenorrhea, ameignorrhea, aminerreia, aminerhea, amiegnorhee, aminolrhea, amiegnorrea, amenerhee, amiegnorrhee, amenolrhe, ameignorha, ameignolrhe, ameignorrha, amenolreia, aminorrea, amiegnerhea, aminolhea, amiegnerrea, aminorrhea, amiegnerrhea, amenolhe, ameignorhe, ameignolrhee, ameignorrhe, aminolreia, amenerrea, amiegnorea, aminolrha, amiegnolrea, aminorhea, amiegnerrha, amenerrhea, ameignorhee, amenorrea, ameignorrea, ameignorrhee, amenorea, aminerrea, amiegnoreia, aminolrhe, amiegnorreia, aminorrha, amiegnerrhe, amenerhea, ameignerhea, amenrrhea, ameignerrea, ameignerrhea, aminorea, amenolrea, aminolrhee, amiegnerreia, aminorha, amiegnerrhee, amenerrha, ameignorea, ameorrhea, ameignolrea, ameignerrha, amenerea, aminolrea, aminerrhea, amiegnolreia, aminorrhe, amiegnolrhea, amenerha, ameignoreia, amnorrhea, ameignorreia, ameignerrhe, amenoreia, amenorreia, aminerrha, amiegnorhea, aminorhe, amiegnolrha, amenerrhe, amiegnorrhea, aenorrhea, ameignerreia, ameignerrhee, aminoreia, aminorreia, aminerrhe, amiegnorha, aminorrhee, amiegnolrhe, amenerhe, amiegnorrha, amenorrhe, ameignolreia, ameignolrhea, amenereia, amenerreia, aminerrhee, amiegnorhe, aminorhee, hot, hto, oht, flashes, frashes, fashes, flshes, flahes, flases, flashs, rashes, lashes, phashes, f1ashes, flashse, flasehs, flahses, flsahes, falshes, lfashes, flashe, vagina, vaginal, vagiegna, vahgina, vahgeigna, vahgiegna, vageigna, vahgeignar, vaginl, vahgiegnal, vahgiegnar, vageignal, vageignar, vagiegnal, vagiegnar, vginal, vahginal, vainal, vahginar, vagnal, vahgeignal, vagial, vaginar, vag1na1, vag1nal, vagimal, vaginla, vagianl, vagnial, vaignal, vgainal, avginal, aginal, atrophy, atlofi, atophy, arophy, atrophie, atrofie, atlophie, atlofie, atrophi, atropy, atlophi, atrohy, atrofi, atrphy, atrofy, atlophy, atlofy, trophi, tlophi, trophy, trofi, tlofi, trophie, trofie, tlophie, tlofie, trofy, tlophy, tlofy, atropyh, atrohpy, atrpohy, atorphy, artophy, tarophy, atroph, osteoporosis, osteoporosys, osteoperosis, osteoperosys, osteopolosis, osteopolosys, osteoporocis, oseoporosis, osteoperocis, ostoporosis, osteopolocis, osteporosis, osteoporocys, osteoorosis, osteoperocys, osteoprosis, osteopolocys, osteopoosis, osteoporsis, osteoporois, osteopoross, oteoporosis, osteoporosee, osteoperosee, osteopolosee, osteoporocee, osteoperocee, osteopolocee, osteoporocus, osteoporosus, osteoperocus, osteoperosus, osteopolocus, osteopolosus, oesteoperosus, ousteopolosis, oesteoporosis, oesteoporosys, oesteoperocis, ousteoperosis, ousteopolosee, oesteoporosee, oesteopolosys, ousteoperocis, ousteoperosee, ousteopolosus, oesteoporosus, ousteoporosys, oesteoporocys, ousteoperosus, oesteoporousis, oesteopolosis, ousteopolosys, oesteopolocys, oesteoperousis, oesteoporousee, oesteopolosee, oesteoporousys, ousteoporocys, oesteoporocis, oesteoporousus, oesteopolosus, oesteoperosys, ousteopolocys, oesteopolocis, oesteopolousis, ousteoporosis, ousteoperosys, oesteoporoucys, ousteoporocis, oesteoperosis, ousteoporosee, oesteoperocys, ousteopolocis, oesteoperosee, ousteoporosus, ousteoperocys, oesteoporoucis, osteoporos1s, osteoporossi, osteoporoiss, osteoporsois, osteopoorsis, osteoproosis, osteooprosis, ostepoorosis, ostoeporosis, osetoporosis, otseoporosis, soteoporosis, osteoporosi, steoporosis, cardiovascular, cadiovascular, cardiovascuar, cartiovahscurar, cardiovahscular, crdiovascular, cardiovasclar, cardyovahscurar, caldiovahscular, cartiovascular, cardiovasular, carrediovahscurar, cartiovahscular, cartyovascular, cardiovacular, cardyovahscular, cartiovascurar, cardiovscular, caldyovahscular, cartyovascurar, cardioascular, carrediovahscular, carrediovascular, cardivascular, carredyovahscular, carredyovascular, cardovascular, cardiovahscurar, carrediovascurar, cariovascular, cardiovasculr, caldiovahscurar, carredyovascurar, cardyovascular, caldiovascular, caldyovascular, cardiovascurar, cardyovascurar, caldiovascurar, caldyovascurar, card1ovascu1ar, card1ovascular, cardiovasculra, cardiovascualr, cardiovascluar, cardiovasuclar, cardiovacsular, cardiovsacular, cardioavscular, cardivoascular, cardoivascular, caridovascular, cadriovascular, cradiovascular, acrdiovascular, cardiovascula, ardiovascular, thyroid, tyroid, throid, thyoid, thyrid, thyrod, thiroid, thyro1d, thyrodi, thyriod, thyorid, thryoid, tyhroid, htyroid, thyroi, hyroid, breast, beast, bleest, brest, breest, bleast, blest, breaist, brheast, brheaist, briast, bliast, bast, best, beest, biast, brast, blast, blias, breas, breais, bleas, brheas, bras, brheais, blas, bres, bles, brees, blees, brias, breats, bresat, braest, berast, rbeast, breat, reast, disease, dsease, diease, diseae, dizease, dizese, dizeese, disase, disese, diseese, dysease, dysase, dysese, dyseese, dicease, dicese, diceese, disiase, dysiase, d1sease, diseaes, disesae, disaese, diesase, dsiease, idsease, diseas, isease, metal, mental, mentel, mantel, mentar, mantal, mantar, mital, mitar, mitel, mettle, metar, metel, ental, entel, entar, menta, manta, meignta, miegnta, nemta1, nemtal, memtal, mentla, menatl, metnal, mnetal, emntal, mentl, menal, mntal,

TNM definitions

Primary tumor (T)

TX: Primary tumor cannot be assessed, or tumor proven by the presence of
malignant cells in sputum or bronchial washings but not visualized by imaging or bronchoscopy

T0: No evidence of primary tumor
Tis: Carcinoma in situ
T1: A tumor that is 3 cm or less in greatest dimension, surrounded by lung

or visceral pleura, and without bronchoscopic evidence of invasion more proximal than the lobar bronchus (i.e., not in the main bronchus)*

T2: A tumor with any of the following features of size or extent:

More than 3 cm in greatest dimension
Involves the main bronchus, 2 cm or more distal to the carina Invades the visceral pleura
Associated with atelectasis or obstructive pneumonitis that extends
o the hilar region but does not involve the entire lung

T3: A tumor of any size that directly invades any of the following: chest

wall (including superior sulcus tumors), diaphragm, mediastinal pleura, parietal pericardium; or tumor in the main bronchus less than 2 cm distal to the carina but without involvement of the carina; or associated atelectasis or obstructive pneumonitis of the entire lung

T4: A tumor of any size that invades any of the following: mediastinum,

heart, great vessels, trachea, esophagus, vertebral body, carina; or separate tumor nodules in the same lobe; or tumor with a malignant pleural effusion **

*Note: The uncommon superficial tumor of any size with its invasive component limited to the bronchial wall, which may extend proximal to the main bronchus, is also classified as T1.

**Note: Most pleural effusions associated with lung cancer are due to tumor. However, there are a few patients in whom multiple cytopathologic examinations of pleural fluid are negative for tumor. In these cases, fluid is non-bloody and is not an exudate. When these elements and clinical judgement dictate that the effusion is not related to the tumor, the effusion should be excluded as a staging element and the patient should be staged as T1, T2, or T3.

Regional lymph nodes (N)

NX: Regional lymph nodes cannot be assessed
N0: No regional lymph node metastasis
N1: Metastasis to ipsilateral peribronchial and/or ipsilateral hilar lymph
nodes, and intrapulmonary nodes including involvement by direct extension of the primary tumor

N2: Metastasis to ipsilateral mediastinal and/or subcarinal lymph node(s) N3: Metastasis to contralateral mediastinal, contralateral hilar,

ipsilateral or contralateral scalene, or supraclavicular lymph node(s)

Distant metastasis (M)

MX: Distant metastasis cannot be assessed
M0: No distant metastasis
M1: Distant metastasis present

Note: M1 includes separate tumor nodule(s) in a different lobe (ipsilateral or contralateral).


Specify sites according to the following notations:

        BRA = brain             EYE = eye                HEP = hepatic
        LYM = lymph nodes       MAR = bone marrow        OSS = osseous
        OTH = other             OVR = ovary              PER = peritoneal
        PLE = pleura            PUL = pulmonary          SKI = skin

TREATMENT OPTION OVERVIEW

In non-small cell lung cancer (NSCLC), results of standard treatment are poor in all but the most localized cancers. All newly diagnosed patients with NSCLC are potential candidates for studies evaluating new forms of treatment. Surgery is the major potentially curative therapeutic option for this disease; radiation therapy can produce cure in a small minority and palliation in the majority of patients. In advanced-stage disease, chemotherapy offers modest improvements in median survival although overall survival is poor.[1,2] Where studied, chemotherapy has been reported to produce short-term improvement in disease-related symptoms. In a single study, symptomatic relief with combination chemotherapy was significant but independent of objective response.[3,4] The impact of chemotherapy on quality of life requires more study.

Current areas under evaluation include combining local (surgery), regional (radiation therapy), and systemic (chemotherapy and immunotherapy) treatments and developing more effective systemic therapy. Several new agents, including paclitaxel (Taxol), docetaxel (Taxotere), topotecan, irinotecan, vinorelbine, and gemcitabine have been shown to be active in the treatment of advanced NSCLC. Chemoprevention of second primary cancers of the upper aerodigestive tract is also under active investigation in early-stage lung cancer.[5]

The designations in PDQ that treatments are "standard" or "under clinical evaluation" are not to be used as a basis for reimbursement determinations.

OCCULT NON-SMALL CELL LUNG CANCER

TX, N0, M0

In occult lung cancer, a diagnostic evaluation often includes chest x-ray and selective bronchoscopy with close follow-up (e.g., computed tomographic scan), when needed, to define the site and nature of the primary tumor; tumors discovered in this fashion are generally early stage and curable by surgery. After discovery of the primary tumor, treatment is determined by establishing the stage of the patient's tumor. Therapy is identical to that recommended for other non-small cell lung cancer patients with similar stage disease.

STAGE 0 NON-SMALL CELL LUNG CANCER

Tis, N0, M0

Stage 0 non-small cell lung cancer (NSCLC) is the same as carcinoma in situ of the lung. Because these tumors are by definition noninvasive and incapable of metastasizing, they should be curable with surgical resection; however, there is a high incidence of second primary cancers, many of which are unresectable. Endoscopic phototherapy with a hematoporphyrin derivative has been described as an alternative to surgical resection in carefully selected patients.[1-3] This investigational treatment seems to be most effective for very early central tumors that extend less than 1 centimeter within the bronchus.[2] Efficacy of this treatment modality in the management of early NSCLC remains to be proven.

Treatment options:

1. Surgical resection using the least extensive technique possible (segmentectomy or wedge resection) to preserve maximum normal pulmonary tissue since these patients are at high risk for second lung cancers.

2. Endoscopic photodynamic therapy.[2,3]


STAGE I NON-SMALL CELL LUNG CANCER

Some citations in the text of this section are followed by a level of evidence. The PDQ editorial boards use a formal ranking system to help the reader judge the strength of evidence linked to the reported results of a therapeutic strategy. Refer to the PDQ levels of evidence summary for more information.

T1, N0, M0 or T2, N0, M0

Surgery is the treatment of choice for patients with stage I non-small cell lung cancer (NSCLC). Careful preoperative assessment of the patient's overall medical condition, especially the patient's pulmonary reserve, is critical in considering the benefits of surgery. The immediate postoperative mortality rate is age-related, but 3% to 5% with lobectomy can be expected.[1] Patients with impaired pulmonary function may be considered for segmental or wedge resection of the primary tumor; the Lung Cancer Study Group has conducted a randomized study (LCSG-821) to compare lobectomy with limited resection for patients with stage I cancer of the lung. The results of this study show a reduction in local recurrence for patients treated with lobectomy compared with those treated with limited excision but no significant difference in overall survival.[2] Similar results have been reported from a nonrandomized comparison of anatomic segmentectomy and lobectomy.[3] A survival advantage was noted with lobectomy for patients with tumors greater than 3 centimeters, but not for those with tumors smaller than 3 centimeters. However, the rate of local/regional recurrence was significantly less after lobectomy, regardless of primary tumor size. Another study of stage I patients showed that those treated with wedge or segment resections had a local recurrence rate of 50% (31 of 62) despite having undergone complete resections.[4] Exercise testing may aid in the selection of patients with impaired pulmonary function who can tolerate lung resection.[5] The availability of video-assisted thoracoscopic wedge resection permits limited resections in patients with poor pulmonary function who are not usually considered candidates for lobectomy.[6]

Inoperable patients with stage I disease and with sufficient pulmonary reserve may be considered for radiation therapy with curative intent. In a single report of patients older than 70 years of age who had resectable lesions smaller than 4 centimeters but who were medically inoperable or who refused surgery, survival at 5 years following radiation therapy with curative intent was comparable to a historical control group of patients of similar age resected with curative intent.[7] In the 2 largest retrospective radiation therapy series, inoperable patients treated with definitive radiation therapy achieved 5-year survival rates of 10% and 27%. Both series found that patients with T1, N0 tumors had better outcomes, with 5-year survival rates of 60% and 32% in this subgroup.[8,9]

Primary radiation therapy should consist of approximately 6,000 cGy delivered with megavoltage equipment to the midplane of the known tumor volume using conventional fractionation. A boost to the cone-down field of the primary tumor is frequently used to further enhance local control. Careful treatment planning with precise definition of target volume and avoidance of critical normal structures to the extent possible is needed for optimal results and requires the use of a simulator.

Many patients treated surgically subsequently develop regional or distant metastases.[10] Therefore, patients should be considered for entry into clinical trials evaluating adjuvant treatment with chemotherapy or radiation therapy following surgery. A meta-analysis of 9 randomized trials evaluating postoperative radiation versus surgery alone showed a 7% reduction in overall survival with adjuvant radiation in patients with stage I or II disease.[11][Level of evidence: 1iiA] It will be important to determine whether these outcomes can potentially be modified with technical improvements, better definitions of target volumes, and limitation of cardiac volume in the radiation portals. Trials of adjuvant chemotherapy regimens have failed to demonstrate a consistent benefit. Smokers who undergo complete resection of stage I NSCLC are also at risk for second malignant tumors. In the Lung Cancer Study Group trial of 907 stage T1, N0 resected patients, the rate of nonpulmonary second cancers was 1.8% per year and 1.6% per year for new lung cancers.[12] Others have reported even higher risks of second tumors in long-term survivors, including rates of 10% for second lung cancers and 20% for all second cancers.[4] A randomized trial of vitamin A versus observation in resected stage I patients showed a trend toward decreased second primary cancers in the vitamin A arm with no difference in overall survival rates.[13] An ongoing intergroup clinical trial will evaluate the role of isotretinoin in the chemoprevention of second cancers in patients resected for stage I NSCLC.[14]

Treatment options:

1. Lobectomy or segmental, wedge, or sleeve resection as appropriate.

2. Radiation therapy with curative intent (for potentially resectable patients who have medical contraindications to surgery).

3. Clinical trials of adjuvant chemotherapy following resection.[15,16]

4. Adjuvant chemoprevention trials.[13,14]

5. Endoscopic photodynamic therapy (under clinical evaluation in highly selected T1, N0, M0 patients).[17]


STAGE II NON-SMALL CELL LUNG CANCER

Some citations in the text of this section are followed by a level of evidence. The PDQ editorial boards use a formal ranking system to help the reader judge the strength of evidence linked to the reported results of a therapeutic strategy. Refer to the PDQ levels of evidence summary for more information.


T1, N1, M0 or T2, N1, M0 or T3, N0, M0

Surgery is the treatment of choice for patients with stage II non-small cell lung cancer (NSCLC). Careful preoperative assessment of the patient's overall medical condition, especially the patient's pulmonary reserve, is critical in considering the benefits of surgery. The immediate postoperative mortality rate is age-related, but up to 5% to 8% with pneumonectomy or 3% to 5% with lobectomy can be expected.

Inoperable patients with stage II disease and with sufficient pulmonary reserve may be considered for radiation therapy with curative intent.[1] Among patients with excellent performance status, up to a 20% 3-year survival rate may be expected if a course of radiation therapy with curative intent can be completed. In the largest retrospective series reported to date, 152 patients with medically inoperable NSCLC treated with definitive radiation therapy achieved a 5-year overall survival rate of 10%; however, the 44 patients with T1 tumors achieved an actuarial disease-free survival rate of 60%. This retrospective study also suggested that improved disease-free survival was obtained with radiation therapy doses greater than 6,000 cGy.[2] Primary radiation therapy should consist of approximately 6,000 cGy delivered with megavoltage equipment to the midplane of the volume of known tumor using conventional fractionation. A boost to the cone-down field of the primary tumor is frequently used to further enhance local control. Careful treatment planning with precise definition of target volume and avoidance of critical normal structures to the extent possible is needed for optimal results and requires the use of a simulator.

Many patients treated surgically subsequently develop regional or distant metastases.[3] Therefore, patients should be considered for entry into clinical trials evaluating the use of adjuvant treatment with chemotherapy or radiation therapy following surgery. One controlled trial has failed to demonstrate an overall survival benefit for patients with carefully staged squamous cell carcinoma receiving postoperative irradiation, although local recurrences were significantly reduced.[4] A meta-analysis of 9 randomized trials evaluating postoperative radiation versus surgery alone showed a 7% reduction in overall survival with adjuvant radiation in patients with stage I or II disease.[5][Level of evidence: 1iiA] It will be important to determine whether these outcomes can potentially be modified with technical improvements, better definitions of target volumes, and limitation of cardiac volume in the radiation portals. In 2 controlled trials in carefully staged, surgically resected patients, adjuvant combination chemotherapy with cisplatin, doxorubicin, and cyclophosphamide produced modestly increased disease-free survival and a trend toward improved overall survival, especially in the first year after surgery.[6,7] Based on these data, participation in clinical trials evaluating adjuvant therapy after surgical resection should be encouraged.

Treatment options:

1. Lobectomy, pneumonectomy, or segmental, wedge, or sleeve resection as appropriate.

2. Radiation therapy with curative intent (for potentially operable patients who have medical contraindications to surgery).

3. Clinical trials of adjuvant chemotherapy with or without other modalities following curative surgery.[6-8]

4. Clinical trials of radiation therapy following curative surgery.[8]


STAGE IIIA NON-SMALL CELL LUNG CANCER

Some citations in the text of this section are followed by a level of evidence. The PDQ editorial boards use a formal ranking system to help the reader judge the strength of evidence linked to the reported results of a therapeutic strategy. Refer to the PDQ levels of evidence summary for more information.


T1, N2, M0 or T2, N2, M0 or T3, N1, M0 or T3, N2, M0

Depending on clinical circumstances, the principal forms of treatment that are considered for patients with stage III non-small cell lung cancer (NSCLC) are radiation therapy, chemotherapy, surgery, and combinations of these modalities. Although the majority of these patients do not achieve a complete response to radiation therapy, there is a reproducible long-term survival benefit in 5% to 10% of patients treated with standard fractionation to 6,000 cGy, and significant palliation often results. Patients with excellent performance status and those who require a thoracotomy to prove that surgically unresectable tumor is present are most likely to benefit from radiation therapy.[1] Because of the poor long-term results, these patients should be considered for clinical trials. Trials examining fractionation schedules, endobronchial laser therapy, brachytherapy, and combined modality approaches may lead to improvement in the control of this regional disease.[2] One prospective randomized clinical study showed that radiation therapy given as 3 daily fractions improved overall survival compared to radiation therapy given as 1 daily fraction.[3][Level of evidence: 1iiA]

The addition of chemotherapy to radiation therapy has been reported to improve survival in prospective clinical studies that have used modern cisplatin-based chemotherapy regimens.[4-7] A meta-analysis of patient data from 11 randomized clinical trials showed that cisplatin-based combinations plus radiation therapy resulted in 10% reduction in the risk of death compared with radiation therapy alone.[8] The optimal sequencing of modalities and schedule of drug administration remains to be determined and is under study in ongoing clinical trials.[9]

Patients with N2 disease apparent on chest radiograph and documented by biopsy or discovered by prethoracotomy exploration have a 5-year survival rate of only about 2%. The use of preoperative (neoadjuvant) chemotherapy has been shown to be effective in these clinical situations in 2 small randomized studies of a total of 120 patients with stage IIIa NSCLC.[10,11] The 58 patients randomized to 3 cycles of cisplatin-based chemotherapy followed by surgery had a median survival more than 3 times as long as patients treated with surgery but no chemotherapy in both these studies. Two additional single-arm studies have evaluated either 2 to 4 cycles of combination chemotherapy or combination chemotherapy plus chest irradiation for 211 patients with histologically confirmed N2 stage IIIa NSCLC.[12] Sixty-five percent to 75% of patients were able to have a resection of their cancer, and 27% to 28% were alive at 3 years. These results are encouraging, and combined-modality therapy with neoadjuvant chemotherapy with surgery and/or chest radiation therapy should be considered for patients with good performance status who have stage IIIa NSCLC.

Although most retrospective studies suggest that postoperative radiation therapy can improve local control for node-positive patients whose tumors were resected, it remains controversial whether it can improve survival.[13,14] One controlled trial in patients with completely resected stage II or III squamous cell lung cancer failed to demonstrate a survival benefit for patients who received postoperative irradiation, although local recurrences were significantly reduced.[15] A meta-analysis of 9 randomized trials evaluating postoperative radiation versus surgery alone showed no difference in overall survival with adjuvant radiation in patients with stage III disease.[16][Level of evidence: 1iiA] It will be important to determine whether these outcomes can potentially be modified with technical improvements, better definitions of target volumes, and limitation of cardiac volume in the radiation portals. In 2 controlled trials with carefully staged surgically resected patients, adjuvant combination chemotherapy with cisplatin, doxorubicin, and cyclophosphamide produced modestly increased disease-free survival and a trend toward improved survival, especially in the first year after surgery.[17-19] Based on these data, participation in clinical trials evaluating adjuvant therapy after surgical resection should be encouraged.

No consistent benefit from any form of immunotherapy has been demonstrated thus far in the treatment of NSCLC.

Treatment options:

1. Surgery alone in highly selected cases.[20-22]

2. Chemotherapy combined with other modalities.[4-6,12,17-19]

3. Surgery with postoperative radiation therapy.[13,15]

4. Radiation therapy alone.[1,2]


Superior sulcus tumor (T3, N0 or N1, M0)

Another category that merits a special approach is that of superior sulcus tumors, a locally invasive problem usually with a reduced tendency for distant metastases. Consequently, local therapy has curative potential, especially for T3, N0 disease. Radiation therapy alone, radiation therapy preceded or followed by surgery, or surgery alone (in highly selected cases) may be curative in some patients, with a 5-year survival rate of 20% or more in some studies.[23] Patients with more invasive tumors of this area, or true Pancoast tumors, have a worse prognosis and generally do not benefit from primary surgical management. Follow-up surgery may be used to verify complete response in the radiation therapy field and to resect necrotic tissue.

Treatment options:

1. Radiation therapy and surgery.

2. Radiation therapy alone.

3. Surgery alone (selected cases).

4. Chemotherapy combined with other modalities.

5. Brachytherapy.[24]

6. Clinical trials of combined modality therapy.


Chest wall tumor (T3, N0 or N1, M0)

Selected patients with bulky primary tumors that directly invade the chest wall can obtain long-term survival with surgical management provided that their tumor is completely resected.

Treatment options:

1. Surgery.[22,25]

2. Surgery and radiation therapy.

3. Radiation therapy alone.

4. Chemotherapy combined with other modalities.


STAGE IIIB NON-SMALL CELL LUNG CANCER

Patients with stage IIIb non-small cell lung cancer (NSCLC) do not benefit from surgery alone and are best managed by initial chemotherapy, chemotherapy plus radiation therapy, or radiation therapy alone, depending on sites of tumor involvement and performance status. Most patients with excellent performance status should be considered for combined modality therapy. However, patients with malignant pleural effusion are rarely candidates for radiation therapy, and should generally be treated similarly to stage IV patients (see separate section of this summary on treatment of stage IV disease). Many randomized studies of unresectable patients with stage III NSCLC show that treatment with neoadjuvant or concurrent cisplatin-based chemotherapy and chest irradiation is associated with improved survival compared to treatment with radiation therapy alone.[1-5] A meta-analysis of patient data from 11 randomized clinical trials showed that cisplatin-based combinations plus radiation therapy resulted in 10% reduction in the risk of death compared with radiation therapy alone.[6]

Patients with stage IIIb disease with poor performance status are candidates for chest irradiation to palliate pulmonary symptoms (e.g., cough, shortness of breath, or local chest pain). No consistent benefit from any form of immunotherapy has been demonstrated thus far.


T4 or N3, M0

An occasional patient with supraclavicular node involvement who is otherwise a good candidate for irradiation with curative intent will survive 3 years. Although the majority of these patients do not achieve a complete response to radiation therapy, significant palliation often results. Patients with excellent performance status and those who are found to have advanced-stage disease at the time of resection are most likely to benefit from radiation therapy.[7] Adjuvant systemic chemotherapy with radiation therapy has been tested in randomized trials for patients with inoperable or unresectable locoregional NSCLC.[1-3,8] Some patients have shown a modest survival advantage with adjuvant chemotherapy. The addition of chemotherapy to radiation therapy has been reported to improve long-term survival in some,[1,3,4] but not all,[9] prospective clinical studies. A meta-analysis of patient data from 54 randomized clinical trials showed an absolute survival benefit of 4% at 2 years with the addition of cisplatin-based chemotherapy to radiation therapy.[10] The optimal sequencing of modalities remains to be determined and is under study in ongoing clinical trials.[11]

Because of the poor overall results, these patients should be considered for clinical trials; trials examining fractionation schedules, radiosensitizers, radiolabeled antibodies, and combined modality approaches may lead to improvement in the control of regional disease.

Patients with NSCLC can present with superior vena cava syndrome. Refer to the PDQ supportive care summary on superior vena cava syndrome for more information. Regardless of stage, this problem should generally be managed with radiation therapy with or without chemotherapy.

Treatment options:

1. Radiation therapy alone.

2. Chemotherapy combined with radiation therapy.[1-3,8]

3. Chemotherapy and concurrent radiation therapy followed by resection.[12,13]

4. Chemotherapy alone.


STAGE IV NON-SMALL CELL LUNG CANCER


Any T, any N, M1

Cisplatin-containing and carboplatin-containing combination chemotherapy regimens produce objective response rates (including a few complete responses) that are higher than those achieved with single-agent chemotherapy. Although toxic effects may vary, outcome is similar with most cisplatin-containing regimens; a randomized trial comparing 5 cisplatin-containing regimens showed no significant difference in response, duration of response, or survival.[1] Patients with good performance status and a limited number of sites of distant metastases have superior response and survival when given chemotherapy when compared to other patients.[2] A prospective randomized comparison of vinorelbine plus cisplatin versus vindesine plus cisplatin versus single agent vinorelbine has reported improved response rate (30%) and median survival (40 weeks) with the vinorelbine plus cisplatin regimen.[3] Two small phase II studies reported that paclitaxel (Taxol) has single-agent activity in stage IV patients, with response rates in the range of 21% to 24%.[4,5] Reports of paclitaxel combinations have shown relatively high response rates, significant 1 year survival, and palliation of lung cancer symptoms.[6] With the paclitaxel plus carboplatin regimen, response rates have been in the range of 27% to 53% with 1-year survival rates of 32% to 54%.[6,7] The combination of cisplatin and paclitaxel was shown to have a higher response rate than the combination of cisplatin and etoposide.[8] Additional clinical studies should better define the role of these newer combination chemotherapy regimens in the treatment of advanced non-small cell lung cancer.[8] Meta-analyses have shown that chemotherapy produces modest benefits in short-term survival compared to supportive care alone in patients with inoperable stages IIIb and IV disease.[9-11]

Although these results support further evaluation of chemotherapeutic approaches for both metastatic and locally advanced non-small cell lung cancer (NSCLC), efficacy of current programs is such that no specific regimen can be regarded as standard therapy. Appropriate patients should be encouraged to participate in clinical trials. Outside of a clinical trial setting, chemotherapy should be given only to patients with good performance status and evaluable tumor lesions who desire such treatment after being fully informed of its anticipated risks and limited benefits.

Radiation therapy may be effective in palliating symptomatic local involvement with NSCLC such as tracheal, esophageal, or bronchial compression, bone or brain metastases, pain, vocal cord paralysis, hemoptysis, or superior vena cava syndrome. In some cases, endobronchial laser therapy and/or brachytherapy has been used to alleviate proximal obstructing lesions.[12] Such therapeutic intervention may be critical in the prolongation of an acceptable lifestyle in an otherwise functional patient. In the rare patient with synchronous presentation of a resectable primary tumor in the lung and a single brain metastasis, surgical resection of the solitary brain lesion is indicated with resection of the primary tumor and appropriate postoperative chemotherapy and/or irradiation of the primary tumor site and with postoperative whole-brain irradiation delivered in daily fractions of 180-200 cGy to avoid long-term toxic effects to normal brain tissue.[13,14]

In asymptomatic patients kept under close observation, treatment may often be appropriately deferred until symptoms or signs of progressive tumor develop.

Treatment options:

1. External-beam radiation therapy, primarily for palliative relief of local symptomatic tumor growth.

2. Chemotherapy. The following regimens are associated with similar survival outcomes:

cisplatin plus vinblastine plus mitomycin [15]
cisplatin plus vinorelbine [3]
cisplatin plus paclitaxel [8]
cisplatin plus gemcitabine [16]
carboplatin plus paclitaxel [6,7]

3. Clinical trials evaluating the role of new chemotherapy regimens. Refer to the clinical trials section of PDQ for a list of clinical trials. The clinical trials in PDQ are also available on CancerNet (http://cancernet.nci.nih.gov).

4. Endobronchial laser therapy and/or brachytherapy for obstructing lesions.[12]


RECURRENT NON-SMALL CELL LUNG CANCER

Many patients with recurrent non-small cell lung cancer (NSCLC) are eligible for clinical trials. Radiation therapy may provide excellent palliation of symptoms from a localized tumor mass.

Patients who present with a solitary cerebral metastasis after resection of a primary NSCLC lesion and who have no evidence of extracranial tumor can achieve prolonged disease-free survival with surgical excision of the brain metastasis and postoperative whole-brain irradiation.[1,2] Unresectable brain metastases in this setting may be treated radiosurgically.[3] Because of the small potential for long-term survival, radiation therapy should be delivered by conventional methods in daily doses of 180 to 200 cGy, while higher daily doses over a shorter period of time (hypofractionated schemes) should be avoided because of the high risk of toxic effects observed with such treatments.[4] Most patients not suitable for surgical resection should receive conventional whole-brain radiation therapy. Selected patients with good performance status and small metastases can be considered for stereotactic radiosurgery.[5]

Approximately one half of patients treated with resection and postoperative radiation therapy will develop recurrence in the brain; some of these patients will be suitable for additional treatment.[6] In those selected patients with good performance status and without progressive metastases outside of the brain, treatment options include reoperation or stereotactic radiosurgery.[3,6] For most patients, conventional radiation therapy can be considered; however, the palliative benefit of this treatment is limited.[7]

A solitary pulmonary metastasis from an initially resected bronchogenic carcinoma is unusual. The lung is frequently the site of second primary malignancies in patients with primary lung cancers. Determining whether the new lesion is a new primary cancer or a metastasis may be difficult. Studies have indicated that in the majority of patients the new lesion is a second primary tumor, and following resection some patients may achieve long-term survival. Thus, if the first primary tumor has been controlled, the second primary tumor should be resected if possible.[8,9]

The use of chemotherapy has produced objective responses and small improvement in survival for patients with metastatic disease.[10] In studies that have examined symptomatic response, improvement in subjective symptoms has been reported to occur more frequently than objective response.[11,12] Informed patients with good performance status and symptomatic recurrence can be offered treatment with a cisplatin-based chemotherapy regimen for palliation of symptoms.

Treatment options:

1. Palliative radiation therapy.

2. Chemotherapy alone. For patients who have not received prior chemotherapy, the following regimens are associated with similar survival outcomes:

cisplatin plus vinblastine plus mitomycin