Stage 4 lung cancer treatment

CHAPTER 20: STAGE 4 NON‑SMALL CELL LUNG CANCER

excerpted from the book Cancer and Mesothelioma

keywords, stage 4 lung cancer, treatment, clinical trial, stage 4 lung cancer, clinical trial, experimental treatment, stage 4 treatment.

20.1 CURRENT STAGE 4 TREATMENT

20.11 Overview

Stage 4 means the tumor has metastasized to another organ. Surgery would entail operation on the lung and other structures where the metastasis are located and current science reasons the risk and complexity of such surgery is not worth the reward since it would be difficult to successfully remove the entire cancer. That supposition, while sensible, has not really been confirmed in clinical trials. While respect for the years of training and experience of oncologists is appropriate, investigation of options is also appropriate. Here, and at other junctions, the patient or family member cancer can research new medical developments on databases like Medline, and ask about new treatments.
The current focus in stage 4 treatment is on chemotherapy to kill the disseminated cancer cells. Chemotherapy has the potential to reverse the cancer, and there are reports of partial response, diminution of at least 50% of the tumor in response to chemotherapy. The response rate of chemotherapy is in the 20-25% range, with multimodal therapy providing a modest increase in response. Many tumors do unfortunately develop resistance.

      The precise survival rate and efficacy of cancer drugs is difficult to determine because many of the statistics come from clinical trials upon seriously ill patients for whom other drugs have been unsuccessful.   Patients in support group not infrequently report success rates better than those in published clinical trial reports. One patient was given a dim prognosis and distributed his assets, and sued when he was still alive 18 months later but without the means to support himself. Whether the physician should present an optimistic approach or disclose treatment limitations as he sees them is an ongoing debate. Even in the literature, there are reports of patients with 3 and 5 year survivals after chemotherapy, but most physicians do not regard chemotherapy as fully curative because of the relatively low rate of response and subsequent development of drug resistance.
      Thus there is an ongoing search for more effective drugs. I use the term chemotherapy to refer to those drugs which basically work by and killing certain dividing cells. A chemotherapy drug like Cisplatin may limit duplication of various types of dividing cells and cause hair loss because hair growth requires cell growth.
    A more targeted approach is gene therapy. Here, a drug targets a specific gene involved with the cancer process. If we can target the right gene, we could limit cancer processes but have limited impact on other cells and maintain overall quality of life. The goal makes sense but implementation remains difficult. Lung cancer may involve many types of genetic mutations, which do we target and how do we deliver the corrective gene correction to the particular area.
      The major success in lung cancer research has been primarily with non-smokers. Many non-smokers have a small mutation in the EGFR (epidermal growth factor receptor) and an anti-EGFR drug has shown response rates of about 60% for those with the mutation. Test the patient for the mutation, and apply the drug has been a simple but promising strategy. Unfortunately resistance can arise, but the model of identifying offending growth factors may well be the way of the future. Thus, patients may want to monitor medical developments to determine if particular growth factors can be identified, tested, and applied. Clinical trials can be promising for those with the growth factor. Quality of life is a concern. Since it diminishes the impact of the cancer, studies frequently report chemotherapy increases quality of life. See Bianco (4) (Improvement in quality of life of elderly patients seen after three cycles of Gemcitabine chemotherapy). Radiation also provides pain and symptom relief. Radiation is generally not curative since it does not cannot eliminate the entire tumor nor prevent metastasis.

20.12 The Broad Scope of the Stage 4 Category

Stage 4 has many variations since the various types of cancer with different types and areas of metastasis are all grouped in the same category. Given the variation in disease type, patient status, and extent of metastasis, one must be cautious with broad-based assessments and predictions for stage 4 patients. Evolving research is showing that patients respond differently based upon their subtype. Adenocarcinoma and BAC patients who were EGFR positive had over 60% response rates to Tarceva in several recent studies, while the response rates for EGFR negative patients, primarily smokers, was 10%. One study found little benefit from Cox-2 inhibitors except for patients with Cox-2 positive tumors. Today patients may wish to ask their oncologists:

       1) what growth factors are moving or influencing my cancer,

       2) is testing of my genetic profile to determine the impact of various growth factors possible or recommended,

       3) can you prescribe drugs based upon the particular genetic characteristics of my tumor rather than a general assessment of my stage and type.

20.13 The role of Multi-modal chemotherapy

Multi-modal forms of treatment utilizing different drug combinations are standard for those who can tolerate aggressive therapy. One evolving is tailoring chemotherapy to the patient's profile. Are there particular drugs which provide a better or worse response to particular types of cancers or genetic profiles. Getting better information about which growth factors are stimulating the cancer and selecting particular drugs to address them is an important goal.

20.14 Gene Therapy Concepts

While most chemotherapy drugs generally target dividing cells, newer forms of gene therapy such as tyrosine kinase inhibitors target specific components of particular genes. This may provide fewer side effects with less impact to the body as a whole and possibly better results if the particular growth factor driving the cancer can be identified and its aberrant signaling stopped. The idea of subgroups with these new drugs is shown through various studies. For example, while the overall response rate to the anti-EGFR drug Tarceva is a disappointing 10%, EGFR positive patients show an impressive 60% response rate, more than double that of conventional chemotherapy. Identify particular growth factors, measuring them, categorizing patients, and prescribing the drugs to targeted subgroups who may benefit is one goal.
There are limitations and hurdles. The Tarceva studies with EGFR positive involved non-smokers whose cancer may be simpler than the smoker who was exposed to multiple carcinogens and therefore may have multiple aberrant growth factors. Pharmaceutical companies may find it more profitable to market a drug as providing a modest benefit to the large group of cancer patients, rather than a substantial benefit to a small subgroup and construct clinical trials with that goal. Physicians now seeing 25-30 patients per day may find the task of individualizing treatment based upon cellular characteristics difficult and time-consuming. Nonetheless, despite these limitations, patients, particularly those at major research institutions will be seeing more treatment based upon pathology and individualized genetic profiles in the upcoming years.

20.15 Varying Survival Statistics for Stage 4

Chemotherapy is the primary form of treatment for stage 4 and serves to extend life and frequently reduce cancer-related symptomology. While there is general agreement that chemotherapy is beneficial, the extent of that benefit is unclear as is which drugs are best. 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 an emerging consensus that multi-modal chemotherapy is preferable to single agent, though scientists struggle to limit 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. ... 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

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 stomach discomfort and nausea. Carboplatin and Cisplatin are both platinum-based chemotherapy drugs but Carboplatin has fewer side effects and essentially the same impact, so it is used more often. The chemotherapy chapter reviews various drugs with Taxol and Carboplatin the most widely used combination, with Gemcitabine a second line therapy.

20.23 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).

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:

Tarceva has shown impressive results upon EGFR positive patients, with response rates of approximately 60%. Tarceva seems to work well on the small subgroup of patients with a mutated EGFR.

Most non-smokers are EGFR positive, though some smokers who quit after less than 15 pack years (packs a day x years smoked) are EGFR positive, and a few smokers are also. Most EGFR positive patients have adenocarcinoma or BAC cancers. Testing makes more sense than guessing, with testing costs less than $1,000 and less intrusive methods of testing such as sputum being tested. With FDA approval of Tarceva, coverage under insurance is becoming more widespread. Given the dramatic difference in response between EGFR positive patients (60% +) and EGFR negative patients, (10%) testing makes sense and is likely to determine at least initial success of the drug.

Originally the FDA approved Tarceva for third line treatment, looking at its impact upon the overall group of patients rather than just EGFR positive ones. This impact was mild though the FDA approved Tarceva for third line treatment- after two other chemotherapy treatments were no longer effective. Most physicians will follow these recommendation though use of an FDA approved drug in other contexts, off-label, is permitted.

20.42 Tarceva resistance

While Tarceva has impressive initial response among EGFR positive patients, many later develop resistance. Scientists have identified a mutation at T790M as the primary cause of resistance, with a mutation in the MET gene also examined. In cell studies, experimental pan-inhibitors showed success in suppressing the T790M mutation, but further testing is needed for approval.

20.42 EGFR Negative Patients

The role of EGFR in EGFR negative patients is debated. The 10% response rate is modest though Tarceva is still used for third line treatment based upon the original FDA approval.
Many smokers have K-Ras mutations and studies found that K-Ras EGFR mutations were generally mutually exclusive, and that K-Ras positive patients did not respond to EGFR inhibitors.

20.43 Cox2

Cox-2 is a protein and growth factor produced in response to cellular stress which can contribute to the abnormal reproduction of cells we call cancer. Celebrex is a Cox-2 inhibitor and approved FDA approved in connection with prevention of certain colon tumors, and an argument has been made to suggest its use with cancer patients. A recent study provided important findings.
In that study, while Celebrex provided no benefit to the overall study grouip, it did help the patients high levels of Cox-2. Patients with moderate to high expression of COX-2 had a worse overall survival than did those who did not. However, if patients with moderate to high COX-2 expression received the COX-2 inhibitor Celebrex, the outcome was dramatically improved. Patients receiving Celebrex who had moderate to high expression of COX-2 had a superior outcome in terms of overall survival compared with patients with moderate to high expression who did not receive celecoxib. That study found that the greater the degree of COX-2 expression, the greater the benefit from Celebrex. More study is needed to test the hypothesis that Cox-2 positive patients will benefit from Celebrex and determine whether there the drug helps others.

20.5 ANTI-ANGIOGENIC THERAPY

Anti-angiogenic drugs with Avastin FDA approved. Initial studies found Avastin when combined with chemotherapy extended life-span, but another study found more modest results.

20.51 Targeting Subgroups

Perhaps the lesson of the 21^st century here is that not all lung cancers are alike, and the term lung cancer encompasses a wide variety of tumors with differing causes, characteristics, locations, and growth factors. Thus, the question should be what subgroups will Avastin show the most effectiveness.

Vascular growth factor and its receptor are associated with lung cancer metastatic behavior. Can either be tested and do positive findings predict higher response rates to the drug.

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 metastases were the bone, brain, liver and adrenal glands. Hanigiri, (6).ADVANCE \d4

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 metastases 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 CLINICAL TRIALS

     There is experimental and there’s experimental. A completely new drug can be called fully experimental and the chances of success are limited. Sometimes however, the history of the drug provides promise and an educated chance of success.
      Typically a prospective drug will be tested in cell studies. These studies may segregate results by cell characteristics and impressive results there may predict success. For example, EGFR positive patients appear to have the EGFR as a primary growth factor, have a high rate of response to EGFR drugs, but frequently develop a new mutation at position T790M. Studies now test pan-inhibitors which have fully or partly inhibited T790M signaling in cell studies.
       A clinical trial of such a drug for the EGFR positive patient with the T790M mutation would be a promising clinical trial. In contrast, a new study testing heat waves or a new drug, without resort to the client’s genetic profile may appear unpromising. Thus the patient evaluating a clinical trial may wish to evaluate:

1. Can my particular offending growth factor be identified.

2. Has the prospective new drug shown promise in suppressing this growth factor’s signaling.

20.8 PSYCHOLOGICAL ISSUES AND THE PHYSICIAN

20.81 Performance Status as the Best Indicator of Survival

While stage and extent of metastasis are important, performance status continues to be the critical factor. Performance status is a medical term which evaluates a patient=s mobility and overall condition. An ambulatory patient conducting his usual activities has a high performance status, a bed-ridden fatigued patient would have a low one.

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). and enjoying some reasonable quality of life in the process.

Contrariwise, an ability to perform most of the activities of life generally shows no immediate danger.

20.82 Selection of a physician

Results vary for stage 4 patients. The diversity of this group with different areas of metastases, subtypes, age, performance status, and genetic profile 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. Support groups encourage this group providing inspiring stories of patients surviving 2, 3 and even 5 years after diagnosis,

      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. Others believe the patient is owed a stark candor.
      Select a physician based in part upon his attitude and feel free to make a change. Family members may have to push some doctors to be aggressive. Advanced age may periodically play a role, and older patients and family may need to search for an physician if they believe aggressive treatment is the best approach.
      Recognize that patience and understanding do not necessarily correlate with skill. We know of one family upset with an oncologist seeming lack of concern and empathy. However this same physician recognized that non-smokers were doing unusually well on the EGFR drug Iressa, well before s before published data revealed that fact. Some of the leading researchers may be curt.

As medical data accumulates, many patients will be seeking individualized treatment involving assessment of the particular growth factors in their tumor and larger research hospitals may be best able to provide that approach. On the other hand, having chemotherapy at a local hospital near family may be preferable. Patients and family members should monitor drugs for side effects and ask for help when needed. Do recognize that in a age of HMO’s and reduced reimbursement, doctors can be busy. Organize, symptoms and , and questions beforehand and bring up important issues first.

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) 63-5.

2. Naruke, Implications of staging in lung cancer, Chest 1997 Oct;112(4 Suppl):242S-248S.

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.

for Celecoxib Chemotherapy—Cancer and Leukemia Group B Trial 30203, Volume 26, Number 6, February 20, 2008.

REVIEWS

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