20.11 Overview

Stage 4 means the tumor has metastasized to another organ and the common feature among stage 4 patients is that surgery is not an alternative.

Removal of a tumor in the lung will not eradicate the cancer, and is not worth the risk such surgery entails. The focus in stage 4 treatment is on chemotherapy, radiation to diminish tumor size in the lung and improve quality of life, and newer forms of gene therapy such as Iressa.

At stage 4, treatment is generally not curative, though there are periodic reports of complete remissions or long-term survival at stage 4. Palliation, preventing pain and maintaining quality of life becomes significant. See Bianco (4) (improvement in quality of life of elderly patients seen after three cycles of Gemcitabine chemotherapy).

Radiation is designed to reduce tumors and may provide pain and symptom relief as well as extend life. Since radiation provides few side effects and only limited discomfort, it is a standard treatment for stage 4 patients. Most oncologists would not regard radiation as curative since they cannot eliminate the entire tumor nor prevent metastasis. Since a substantial amount of tumor is eliminated through radiation, survival

should be improved, though that is difficult to establish since there are relatively few clinical trials comparing radiation to best supportive care with the absence of any radiation or chemotherapy.

Current forms of chemotherapy are also not curative though they have the potential to reach different parts of the body including areas of metastasis. Since they have that potential, there are periodic reports of patients with 3 and 5 year survivals after chemotherapy, and many clinical trials will report instances of complete response, absence of any tumor appearing on x-ray or ST Scan. A typical clinical trial report of 200-300 people will report an individual with a complete response. Thus, there is reason for hope, though these reports are not the norm. Studies show a modest or reasonable increase in survival times from chemotherapy though one year survival rates are less than 50% even in favorable studies. The colloquial six months to survival can represent a rough average.

Many studies report pain relief and improvement of quality of life from chemotherapy. Some patients or family members may focus on hair loss, stomach discomfort, and immune issues, which are a part of most forms of chemotherapy. One must be careful is generalizing about chemotherapy or using another patient’s experience as a guide; the drugs have gotten better and are causing fewer side effects. Additionally, there is a greater sensitivity to chemotherapy side effects, with many physicians recommending other drugs to reduce stomach discomfort or other side effects.

20.12 Gene Therapy for Stage 4

Stage 4 has been where new drugs are being intensively tested with various forms of gene therapy showing limited promise in stabilizing disease.

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. Some have suggested that the nonsmall cell cancer category is too large and encompasses forms of lung cancer which might respond slightly differently to forms of chemotherapy. For example, some studies have shown that squamous cell cancer metastasises more slowly than adenocarcinoma so the prognosis for squamous cell patients is a little better. Thus, if we tried the same drug in two clinical trials of non-small cell patients at the same stage but with different proportions of patients with adenocarcinoma, we could expect different results with the same drug.

Additionally how each patient is doing may vary. 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 careful with general assessments of stage 4 patients.

20.14 The Wide Gap in Survival Statistics for Stage 4

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 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. Scientifically, perhaps we need further definition to stage 4.

20.15 Recategorizing Stage 4

Stages 1, 2, and 3 each have separate subcategories. Perhaps it is time to do the same for stage 4. Subcategorizing stage 4 would provide more precision in clinical trials. In some clinical trials, better or worse results may be attributable to variations in the patient’s status, not the treatment proposed. (In fairness, some clinical trials do classify patients based upon performance status, a measure of the patient’s overall health).

Many clinicians would agree that stage 4 should be divided; the problem is how. In stages 1-3, we created divisions based upon the nature of the spread of the lung cancer itself. In stage 4, we might be asked to undertake a tougher job, distinguishing among metastases. What type of cranial metastases are more serious; how does a liver metastases compare with bone. It is clear that further demarcation would be helpful, but determining precisely how to do it presents an imposing task. In the interim we should recognize that some assessments including those of predicting survival will be inaccurate.

20.16 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.

20.21 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 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

20.21 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.

20.22 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.

20.23 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.

20.24 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.

20.241 Quality of Life Benefits from 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.

20.25 Multi-modal Chemotherapy

Studies have shown that combinations of drugs improve response. Taxol and Carboplatin are the most widely used combination, though any number of combinations have been tried including Cisplatin and Gemcitabine, Carboplatin and Gemcitabine, Cisplatin and Vinorelbine. A recent study tested three drugs together and found in a preliminary trial that "a 28-day cycle of topotecan (1.75 mg/m(2) days 1, 8, 15), cisplatin (20 mg/m(2) days 1, 8, 15), and gemcitabine (1,000 mg/m(2) days 1, 15) was a safe and well-tolerated outpatient treatment for advanced non-small cell lung cancer. " Guarino (5)

Scientists hope that one day, perhaps fortuitously, they will find a combination which dramatically increases response. Today they know there is a modest increase in effectiveness with combination chemotherapy.

If the patient is in otherwise good health and can withstand a combination without untoward side effects, that will be tried, though generally after a careful explanation of the benefits and concerns with such treatment.

With multi-modal chemotherapy, white blood cell counts and other side effects would be monitored perhaps even more carefully.

Chemotherapy along with gene therapy is being tested in clinical trials too. We know from laboratory tests that some types of radiation and gene therapy improve cell responsiveness but the results remain to be duplicated on actual patients.

20.26 Second Line Chemotherapy

Platinum drugs like Carboplatin and Cisplatin are the most frequently used for initial chemotherapy. Unfortunately, the tumor develops ways of circumventing the chemotherapy drugs which generally lose their effectiveness other time. That is why complete cures are generally rare (though not unknown) with stage 4 non-small cell lung cancer. Second-line chemotherapy involves using other drugs with different mechanisms after initial chemotherapy becomes ineffective.

Gemcitabine and Taxol are drugs used as second-line chemotherapy though they are increasingly used as initial chemotherapy.

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.

We have discussions specific forms of gene therapy such as Iressa and P53 in particular chapters.

20.41 Iressa

Iressa has shown good results in stabilizing disease, and is an important treatment alternative for stage 4 patients, particularly those whose cancer has recurred despite chemotherapy. Indeed, given the consistent results of Iressa, the absence of side effects, a plausible argument can be made for its use before chemotherapy fails

20.411 Limited Side Effects of Iressa

Unlike chemotherapy which can affect all dividing cells, Iressa targets a specific area, the epidermal growth factor receptor. s a designer drug, created to target the epidermal growth factor receptor. Iressa has caused minimal side effects.

20.412 Iressa and Chemotherapy

Iressa’s best use may be to compliment chemotherapy with studies finding the combination of chemotherapy and Iressa more effective than either alone.

20.32 P-53

P53 treatments to try to re-create the tumor-suppression role of P-53 have been tested and shown some success. As with Iressa, the best results may come with chemotherapy, and scientists will test potent combinations, hoping to achieve the maximum cancer-fighting efficiency without intolerable side effects.

The primary danger of stage 4 cancer is the propensity to metastasize, and attention to 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. In the late 80's, drugs like Angiostatin were being hailed as the new cures. Unfortunately, clinical trials have not been able to duplicate the promise shown in cell and animal studies. While some modest results have been reported, more attention is being focused on gene therapy. We have reviewed different forms of anti-angiogenic therapy is our chapter on that subject.

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 of 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 nonsmall 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

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 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.

20.61 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 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)