STAGE 4 NON-SMALL CELL LUNG CANCER
                                                                        
(Excerpted from Lung Cancer and Mesothelioma)
 

keywords, stage 4 treatment, clinical trials,  stage 4 treatment, advanced lung cancer, treatment,  stage 4 treatment alternatives.

20.1 SUMMARY OF STAGE 4 TREATMENT

20.11 Overview

Stage 4 means the tumor has metastasized to another organ.  Surgery is generally not an option with scientists reasoning that removal of a lung tumor while leaving visible or microscopic metastases will not effect a cure.  Current science reasons the benefit is questionable and the procedure carries significant risk. Clinical trials to confirm this have been limited.  

Chemotherapy is the standard treatment for these disseminated tumors.  Response rates for particular drugs are in the 20-25%, with rates a alittle higher or multi-drug regimens.  There are periodic reports of patients with 3 and 5 year survivals after chemotherapy, and clinical trials occasionally report complete responses.  Many patients do not respond to chemotherapy and other develop resistance after response.  Thus second line treatment after initial response is part of lung cancer treatment.  chemotherapy may also improve quality of life by reducing disease-related consequences, and side effects like nausea are less than in the past.

Radiation in the lung area is designed to reduce pain or discomfort. 

Cancer is started by abnormal growth factors.  One such growth factor is the epidermal growth factor receptor (EGFR).  Patients who are EGFR positive have response rates of an astronomical 60% using Tarceva and EGFR inhibitor, almost triple that of conventional chemotherapy.  EGFR patients are primarily non-smokers with adenocarcinoma, but that is not exclusive.  Some light and even an occasional heavy smoker is EGFR positive and some non-smokers are not EGFR positive.  Testing the patient for the mutation and contouring treatment based upon that makes sense.

Only about 10% of patients are EGFR positive. However, the lessons of testing are expanding.  Rather than simply generalize about treatment, why not conduct specialized testing and prescribe drugs specifically designed to address the offending growth factor.  There are difficulties.  Non-smokers lung cancer  non-smokers lung cancer  is probably simpler with one or perhaps few growth factors, while smoker's cancer appears to  involve multiple growth factors.   Nonetheless, to test for particular growth factors and treat based upon the test makes logical sense with clinical trials needed to confirm the theory's efficacy with particular drugs.  Cox-2 is being evaluated with a recent study showing Celebrex a Cox-2 inhibitor showing some promise with Cox-2 patients.  

Keywords,   cancer lung,  stage 4 treatment cancer lung,  stage 4  survival statistics,  fatigue, symptoms, Stage 4 lung cancer,  lung non small.
cancer lung stage, cancer lung symptom,  lung treatment, alternative treatment, small cell lung cancer, fatigue, symptoms, Stage 4 lung cancer,  lung non small.
cancer lung stage, asbestos cancer lung, lung cancer cause cancer, survival rate, information, cancer lung type, statistics, lung cancer stage 4,
      

 


20.12 The Broad Scope of the Stage 4 Category

Stage 4 has many variations since the number of organs, the extent of metastasis, and other factors impact the period of survival and chances for cure. Stage 4 would include an elderly patient with extensive COPD (chronic obstructive pulmonary disorder) and extensive metastasises as well as a middle-aged patient with a single metastasis and otherwise good health. Given the variation in disease type, patient status, and extent of metastasis, one must be careful with general assessments of stage 4 patients.

New research is showing that patients respond differently based upon their subtype. Adenocarcinoma and BAC patients who did not smoke or smoked little had over 65% response rates to Iressa and Tarceva in several recent studies. (A separate chapter is devoted to epidermal growth factor inhibitors so I will only summarize findings here.)

20.13 Varying Survival Statistics for Stage 4

Survival reports differ. Some are favorable: “The 5-year cumulative survival rate was 88.0% for patients in stage IA, 53.9% in stage IB, 33.5% in stage II, 14.7% in stage IIIA, 5.5% in stage IIIB and 7.0% in stage IV.” Wu (1). “The 5-year survival rates for these patients were as follows: stage I, 68.5%; stage II, 46.9%; stage IIIA, 26.1%; stage IIIB, 9.0%; and stage IV, 11.2%.” Naruke (2). Others are dim, reporting survival rates of 20-30 weeks in clinical trials, even those receiving chemotherapy.

It may well be the status of the patient, since we know that the overall health or performance status, as well as the number of lymph nodes involved and other factors influence survival. A 45 year patient with a small area of metastasis in otherwise good health should do better than an older patient with COPD and multiple metastases. Those looking for hope can legitimately find it, not in bizarre reports from other countries, but legitimate clinical trials. Those looking for stark reality may find that the prospects of overall cure are limited.

20.14 Mental Attitude

Some would suggest attitude can play a role and that the willingness to fight and undergo treatment can extend life. The author of The Cancer Patients Handbook wrote the book while 3 years post-diagnosis for stage 4 NSCLC.
A patient in a support group wrote:

“I was diagnosed 7/99 with stage 4 NSCLC and chose to have chemo (taxol and carboplatin). Over three years later I am in remission and still enjoying life. I grant you that it is not life as I knew it before, but it is still quite enjoyable. So please, everyone who has lung cancer, don't think there isn't any use to fight it. I am living proof that for some, the outcome is NOT always the same and there is a possibility of living much longer than the statistics say.” Acor.org support group.


20.2 CHEMOTHERAPY

20.21 Chemotherapy Is Standard

Chemotherapy is the primary form of treatment for stage 4 and serves to extend life and frequently reduce cancer-related symptomology. While there is near agreement that chemotherapy is beneficial, the exact form of chemotherapy which should be used remains unclear, though the combination of Taxol and Carboplatin is generally given today (March, 2002). Carboplatin, vinorelbine, taxol, gemcitabine and other forms of chemotherapy have displayed benefits, but the optimal mix of drugs remains unclear since clinical trials have reached varying results. There is detailed information on the Internet about clinical trials with different chemotherapy combinations. One must be careful not to place undue emphasis on the result of a single trial, for it is only consistent results which can create a standard of care. There is an emerging consensus that multi-modal chemotherapy is preferable to single agent, though scientists may struggle to minimize side effects.

The National Cancer Institute states,

“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... 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%- 24%. Reports of paclitaxel combinations have shown relatively high response rates, significant 1 year survival, and palliation of lung cancer symptoms. With the paclitaxel plus carboplatin regimen, response rates have been in the range of 27%-53% with 1-year survival rates of 32%-54%. The combination of cisplatin and paclitaxel was shown to have a higher response rate than the combination of cisplatin and etopiside. [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. 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.” www.nci.net.

20.22 Carboplatin Compared with Cisplatin

Carboplatin and Cisplatin are both platinum-based chemotherapy drugs. Carboplatin has fewer side effects and essentially the same impact, so it is used more often.

20.23 Physician’s Attitudes and Chemotherapy

Many physicians will be familiar with recent favorable developments in treatment for advanced lung cancer. Some may be negative and one writer explains why:

“Early trials in NSCLC (non small cell lung cancer) did not show the improvements in survival with SCLC. Indeed, the earliest regimens, based upon alkylating agents rather than cisplatin, appeared detrimental. Physicians attitudes to chemotherapy for NSCLC were therefore profoundly negative, and have tended to remain so. Subsequent combination chemotherapies have yielded some improvements in survival, as well as symptom relief as described above. Unfortunately, attitudes have not changed despite the now-abundant evidence that chemotherapy is superior to supportive care.” Pass (1), at 998.

20.24 The Creation of Multi-Drug Resistance

Chemotherapy has served to extend life and reduce symptoms, but it has unfortunately not served as a cure for most stage 4 lung cancer patients. Even those patients who respond initially to chemotherapy frequently develop multi-drug resistance (MDR). For this reason, attention has focused on gene and other therapies for stage 4 patients.

20.25 Chemotherapy as Improving Quality of Life

There is significant evidence that chemotherapy improves quality of life.
“There is evidence that most patients either improve or preserve their performance status during treatment. In one report on the MIC (mitomycin C, ifosfamide, cisplatin) regimen, only 9% of patients experienced deterioration in quality of life on treatment, and 30% improved. It is also well documented that improvements in symptoms are not confined to patients with an objective response.” Pass (1), at 909.

Devita’s well-known cancer treatise states:

“Disease-related symptoms will improve after chemotherapy, sometimes even in the absence of a measurable tumor response. QOL scores improved with chemotherapy, whereas they declined over the first 6 weeks with best supportive care....Improved survival and QOL were also demonstrated with single agent chemotherapy in a population of patients exceeding the age of 70 years.” (Devita 3) at 969.

See Bianco (4) (improvement in quality of life of elderly patients seen after Gemcitabine chemotherapy). However, each individual will need to make determinations of the type of treatment based not only upon statistics but an individualized assessment of the patient’s condition.

20.251 Substituting Other Drugs for Cisplatin

Cisplatin was one of the most widely-used chemotherapy for a number of years, and its efficacy has been shown in clinical trials. However, it has been associated with nausea and vomiting. Other drugs are being used to replace Cisplatin with similar effectiveness but without these side effects. Taxol, Carboplatin, and Gemcitabine are three widely used substitutes.

20.26 Multi-Modal Chemotherapy

Combining drugs improve response. Taxol and Carboplatin is the most widely used combination, though any number of combinations have been tried including Cisplatin and Gemcitabine, Carboplatin and Gemcitabine, Cisplatin and Vinorelbine. Whether three drug combinations further improve response is unclear.

20.3 RADIATION

20.31 Local Control and Palliation

Radiation is used to diminish tumor size, reduce pain, and improve breathing ability. Radiation will generally not eradicate the entire tumor, putting aside the areas of metastasis.

20.4 GENE THERAPY



20.41 Egfr Treatment  

Tarceva and Iressa have shown substantial effectiveness for a narrow group of EGFR positive patients.  Since Tarceva and Iressa are tyrosine kinase, EGFR inhibitors, it is not surprising they are effective with EGFR patients.   The Harvard Gene Laboratory contacts a genetic test which generally finds that non-smokers and very light former smokers who have quit are EGFR positive.

Tarceva and Iressa's benefits outside this target group is unclear.  Because the drugs impact only a limited number of cells, their side effects are limited and the drugs continue to be evaluated. 
 

20.5 ANTI-ANGIOGENIC THERAPY

The primary danger of stage 4 cancer is the propensity to metastasize, and attention is paid to anti-angiogenic drugs which attempt to inhibit angiogenesis, the process by which tumors form new blood vessels and pathways through which the tumor can metastasize.

20.51 Avastin

Avastin has received FDA approval for certain non-small cell patients, and is designed to inhibit VEGF.  "Preliminary results from a large, randomized clinical trial for patients with previously untreated advanced non-squamous, non-small cell lung cancer show that those patients who received bevacizumab (Avastin™) in combination with standard chemotherapy lived longer than patients who received the same chemotherapy without bevacizumab." 

A total of 878 patients with advanced non-squamous, non-small cell lung cancer (NSCLC) who had not previously received systemic chemotherapy were enrolled in this study between July 2001 and April 2004. Patients were randomized to one of the two treatment arms. One patient group received standard treatment -- six cycles of paclitaxel and carboplatin. The second group received the same six-cycle chemotherapy regimen with the addition of bevacizumab, followed by bevacizumab alone until disease progression.  See the manufacturer's website.   www.anti-vegf.com

20.52 How Avastin Works

The vascular endothelial growth factor (VEGF)  is associated with metastasis.  Angiogeneis is the process by which new blood vessels and related sources of blood supply are developed in cancer patients.  The process occurs in healthy people; we need to develop sources of blood supply for growth, repair of damaged tissue.  In cancer patients, angiogenesis facilitates metastasis, spread of cancerous cells to other organs.  VEGF is a growth factor which prompts this process.  Inhibition of VEGF and with it angiogenesis holds forth the prospect of limiting metastasis  and improving survival.   More technically:

VEGF is essential for establishing a functional vascular system during embryogenesis and early postnatal development, but has limited physiological activities in adults. Studies in mice have shown that: targeted disruption of one of the two copies of the VEGF gene results in embryo death (Figure 1) VEGF inactivation during early postnatal development is also lethal VEGF and angiogenesis are also required for endochondral bone formation, the mechanism by which bone grows longitudinally in vertebrate development, and therefore VEGF inhibition in young animals causes growth restriction. See Sandler (7) (8)

20.53 Avastin Side Effects

Blood related side effects were found:

"The most significant adverse event observed in this study was life-threatening or fatal bleeding, primarily from the lungs. This occurred infrequently, but was more common in the patient group that received bevacizumab in combination with chemotherapy than in the patient group that received only chemotherapy. A fuller description of side effects observed in this trial were presented at the ASCO press briefing as well. These included information that both treatment regimens were well-tolerated, with the most common side-effects being low white blood cell counts (24 percent on bevacizumab vs. 16 percent on standard chemotherapy), blood clots (3.8 percent vs. 3.0 percent)and bleeding (4.1 percent vs. 1.0 percent).

Certainly the side effects would indicate awareness and monitoring by physician and patient.  Whether certain subgroups should not take the combination remains to be seen.  

20.6 SITES OF METASTASIS FOR LUNG CANCER

20.61 The Variability of Metastatic Behavior in Lung Cancer

Exactly where and when a tumor will metastasize is difficult to determine:

“It has been known that the biological behavior of NSCLC is heterogeneous; for example, distant metastasises occur early in most patients, but late in others, and there are also significant differences in responsiveness to irradiation or chemotherapy, even in patients with the same histological type.” Fu, (5).

The frequent sites for distant metastasises were the bone, brain, liver and adrenal glands. Hanigiri, (6).
20.62 Brain

Approximately 10% of non-small cell patients will have some type of brain metastasis at time of presentation and by time of death, some 30% of patients will display some evidence of cranial metastasis. Pass (6) at 1011, (Quantin, (7), Rodriqus(8). Family members need to be alert to significant changes in personality or functioning. Single metastasises account for 30-50% of metastases. Pass (6) at 1011.
Radiation is the primary treatment though surgery may also be utilized. Some have advocated stereotactic radiosurgery, the use of computerized techniques to identify targets and focus large single doses of radiation on specific areas, while attempting to minimize exposure to adjoining tissues. Chemotherapy is used to generally combat metastatic cancer, while radiation and surgery are directed to specific areas.

20.63 Bone

A study found that 13% of non-small cell patients had bone metastasis. Hanigiri, (7). Bone scanning is a sensitive examination to detect bone metastases. A standard x-ray is also possible but,

“Fifty per cent of bone material content must be lost before changes are apparent on plain radiographs.... [Thus] plain radiograph is an insensitive method of investigating localized bone pain. Radiopharmaceutical bone scans are, in contrast, highly sensitive though non-specific. Bone scanning is thus only indicated in those patients who have bone pain, elevated alkaline phosphatase levels, or recent exacerbation of bone pain... MRI may be useful to assess localized areas of persistent bone pain which appear normal on bone scan and plain radiographs.” Carney (10) at 65-66.

20.7 PSYCHOLOGICAL ISSUES AND THE PHYSICIAN

Results vary for stage 4 patients. While most will pass away within a year, some will survive longer. Again, the large number of people with different areas of metastases, subtypes, age, and performance status makes prediction difficult.
Many patients and their families will want to be fighters, searching for the best treatment, and maintaining a positive approach in the face of adversity. Not every physician will have this approach. Some doctors worry that if they predict or suggest success, they will be blamed for failure, the patient reasoning that the doctor’s lack of skill or knowledge was the cause. Thus, some doctors will present a pessimistic approach. Other physicians may present a positive and optimistic, and sometimes be blamed for subjecting a patient to difficult chemotherapy when the chance of a cure was small.
It is therefore important to carefully select a physician and, if need be, make a change. Family members may have to push some doctors to be aggressive. On an aggregate basis extensive chemotherapy may not be cost-effective for a 75 year old man when measured against the time period that life is extended. However, no family member would want such cost considerations to infringe upon decisions for his or her family member.
So beware of the negativity which may be present in some circumstances. Countering it may not be accepting undocumented claims of cure, it is aggressively seeking prompt diagnosis and the best treatments. Where a particular drug does not appear to be working the aggressive patient will ask to have its impact evaluated and be willing to test another drug regimen.

20.71 Performance Status as the Best Indicator of Survival

While stage and extent of metastasis are important, performance status continues to be the critical factor in determining the patient’s status. Performance status is a medical term which evaluates a patient’s mobility and status. An ambulatory patient conducting his usual activities has a high performance status, a bed-ridden fatigued patient would have a low performance status. The fact that a patient is bed-ridden, severely fatigued, or immobile is likely to be the most reliable indicator of poor prognosis:

“Three studies that have included large numbers of patients with cancer at all stages found that functional or performance status was the accurate predictor of survival. Decline in activities of daily living including bathing, continence, dressing and transfer, were very strongly associated with decreased survival.” (Devita 6).



REFERENCES


1. Wu, Post-operative staging and survival based on the revised TNM staging system for non-small cell lung cancer, Zhonghua Zhong Liu Za Zhi 1999 Sep;21(5):363-5.
2. Naruke, Implications of staging in lung cancer, Chest 1997 Oct;112(4 Suppl):242S-248S.
3. Devita, Principles and practice of Oncolology (6th Ed. 2001).
4. Bianco, Gemcitabine as single agent chemotherapy in elderly patients with stages III-IV non-small cell lung cancer (NSCLC): a phase II study. Anticancer Res 2002 Sep-Oct;22(5):3053-6.
5. Guarino, A dose-escalation study of weekly topotecan, cisplatin, and gemcitabine front-line therapy in patients with inoperable non-small cell lung cancer, Oncologist 2002;7(6):509-15.
6. Devita, Cancer Principles and Practice of Oncology 3078 (Lippincott 2001).
7. Sandler, Randomized phase II/III Trial of paclitaxel (P) plus carboplatin (C) with or without bevacizumab (NSC # 704865) in patients with advanced non-squamous non-small cell lung cancer (NSCLC): An Eastern Cooperative Oncology Group (ECOG) Trial – E4599. J Clin Oncol 2005; 23 (June 1 Suppl.): 2s (Abstract LBA4)
8
. Lung Cancer Highlights from ASCO 2005, The Oncologist, Vol. 11, No. 1, 39-50, January 2006; doi:10.1634/theoncologist.11-1-39
 

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OTHER BOOK EXCERPTS  

Lung cancer and Mesothelioma ( The book Lung Cancer and Mesothelioma in Word format, formatting varies from published version)
What is cancer   basic concepts of cancer development, growth factors, oncogenes. 
cancer terminology partial and complete response, methods of evaluating drugs, causation,
how lung cancer develops concepts of genetic damage and alteration,
screening and identification of tumors
diagnostic tools and their accuracy Chest x-ray, Ct Scan, Pet Scan,
Types of lung cancer
Small cell and non-small cell distinctions

Iressa
Analysis of Iressa and epidermal growth factor inhibitors. 
Cancer weight loss and fatigue   Cachexia, lung cancer pain and fatigue.
Anti-angiogenic drug overview discussion of drugs to limit cancer metastasis.
Small cell lung cancer staging and treatment standard and other staging methods,
surgical options, chemotherapy and drug resistance. 
health insurance issues
Overview of Mesothelioma 
surgery and radiation for mesothelioma 
chemotherapy for mesothelioma

Standard of care for diagnosis of lung cancer
Resource sources
Lung cancer family history and diet 
  
Other books on Lung Cancer


BOOK REVIEWS                                                 
Lung Cancer and Mesothelioma 

  
 
Quality Books "This book provides an invaluable resource for anyone who has or who is caring others with Mesothelioma or other Lung cancers. It provides a wealth of relevant and useful information on various types of lung cancers, medical trials, treatments and medications. This well researched and comprehensive book is quite unique on the subject. This book also contains a detailed discussion on the emotional burden of Lung Cancer upon the patient and their families and ways to manage it."
                    
 
Lorraine Kember. Author of "Lean on Me - Cancer through a Carer's Eyes", "The very mention of the word Cancer, strikes fear into all of us.... From personal experience I know that knowledge is the key to providing a better "quality of life" for the cancer patient. Better understanding of the stages of the disease and of methods and medications available to treat the pain and symptoms caused by it, allow for the patient and those who care for them, to make informed decisions regarding their care. In this way, they are able to regain some control over their lives. Rarely does one find all the information they need in one book, however I believe Howard's well researched and comprehensive book "Lung Cancer & Mesothelioma", is quite unique. It provides a wealth of relevant and useful information including; how various types of cancer are formed, medical trials, available treatments and medications, insight and discussion regarding the emotional burden of cancer upon the patient and their families and ways by which to manage grief. I believe this book will provide an invaluable resource for anyone who has or who is caring for someone with cancer.

 

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Howard Gutman is a New Jersey attorney based in Parsippany, New Jersey who has handled numerous legal claims involving pulmonary tumors.   A member of the board of directors of a leading cancer support group and a caregiver, he is the author of the new book Lung Cancer and Mesothelioma.   In his legal capacity, he has appeared on Good Day New York, spoken at the National Press Club  and been interviewed by NBC Nightly News.

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Howard A. Gutman, Esq.
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Howian@aol.com Comments about this site or other questions are welcome.


 

Keywords,   cancer lung,  stage 4 treatment cancer lung,  stage4 3 year survival statistics, atigue, symptoms, Stage 4 lung cancer,  lung non small.
cancer lung stage, cancer lung symptom,  lung treatment, alternative treatment, small cell lung cancer, fatigue, symptoms, Stage 4 lung cancer,  lung non small.
cancer lung stage, asbestos cancer lung, lung cancer cause cancer, survival rate, information, cancer lung type, statistics, lung cancer stage 4,
      
                    

Disclaimer This page is not intended to provide medical advice or treatment.  Some of the information on this site may not be relevant to your condition, and all advice should be obtained from a physician.  The materials herein are intended to provide general information and no representation or made as to its completeness or accuracy.

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