CHAPTER TWENTY ONE : SMALL CELL LUNG CANCER

21.0 OVERVIEW


Small cell is a quick-moving cancer, rapidly spreading to lymph nodes and other organs. Characterized by rapid cell division, SCLC long-term survival can be low because many patients have widespread disease at the time of diagnosis. “The biologic nature of small cell lung cancer causes dissemination to regional lymph nodes and/or distant metastatic sites in {most} patients at the time of initial presentation.” NCI (1). Metastasises can be in the bone, liver, brain, or pleura.
Chemotherapy is the standard treatment for small cell lung cancer in the United States. In well more than half of the cases, small cell initially responds well to chemotherapy which reduces the tumor by half or completely eliminates any evidence of tumor on x-ray. Sadly, the tumors frequently return, and the phenomenon of multi-drug resistance (MDR) means the tumor system develops ways to resist the chemotherapy.
Radiation may be used to target specific areas of the tumor in the lung or areas of metastasises. Surgery remains controversial, and is used more frequently outside the United States. Some studies indicate a favorable prognosis for surgically treated patients with limited disease at the time of diagnosis. New forms of gene therapy have shown good results on non-small cell patients and are being evaluated with small cell.
21.1 SMALL CELL STAGING

 
21.11 The Limited Extensive Demarcation
NCI states, “Staging procedures are important in distinguishing patients who have disease limited to their thorax from those who have distant metastasises. Determining the stage of cancer by nonsurgical means allows a better assessment of prognosis and identifies sites of tumor that can be evaluated for response. Also, the choice of treatment is usually influenced by stage, particularly when chest irradiation or surgical excision is added to chemotherapy for patients with limited stage disease.”
Exactly how small cell should be staged is somewhat controversial, with different approaches to staging indicating different approaches to treatment. Recall that non-small cell cancer is divided into four stages (seven, if we count 1 A and 1 B, 2A...) based on the involvement of lymph nodes and other organs.
In contrast, most United States physicians divide small cell into but two categories: limited and extensive. Our National Cancer Institute explains,
“Because occult or overt metastatic disease is present at diagnosis in most patients, survival is usually not affected by small differences in the amount of locoregional tumor involvement. Therefore, the detailed TNM staging system developed for lung cancer by the American Joint Committee on Cancer (AJCC) is not commonly employed in patients with small cell carcinoma. A simple 2-stage system developed by the Veterans Administration Lung Cancer Study Group is more commonly used for staging small cell lung cancer patients.” NCI (1).

Non small cell is divided into stages because the determination of whether to perform surgery depends upon stage. If surgery is not generally recommended for small cell patients, a four stage demarcation is unnecessary.
21.11 Countries Utilizing A Four Stage Categorization for Small Cell
In contrast, Japan employs the four step staging of non small cell cancer to small cell and surgery is a more frequent option in Japan. Japan has an extensive system of screening for lung cancer which means that more early tumors are more frequently seen, allowing for surgery. Indeed, some physicians have admired and written about the Japanese approach. Sandler (12). Given the difficult prognosis of small cell patients, the use of surgery must be considered One can argue the two step staging system contains an implicit bias against surgery, since surgical decisions need to utilize accurate information about tumor status that the simplified two stage analysis may not always provide.“
21.12 How is Stage Determined
The basic aim of staging procedures is to determine and measure the extent of metastasises to lymph nodes and other organs. Staging procedures commonly used to document distant metastasises include bone marrow examination, computed topographic or magnetic resonance imaging scans of the brain, computerized topographic scans of the chest and the abdomen, and radio nuclide bone scans.
21.13 Limited stage
Limited stage small cell lung cancer means tumor confined to the hemothorax, mediastinum, and supraclavicular nodes, and which can be encompassed within a radiation therapy port. There is no universally accepted definition of the term limited stage, and patients with pleural effusion, large tumors, and positive contralateral supraclavicular nodes have been both included within and excluded from limited stage categorization.
21.14 Extensive stage
Extensive stage small cell lung cancer means tumor that is too widespread to be included within the definition of limited stage disease above. Patients with distant metastasises (M1) are always considered to have extensive stage disease.[1,2]
21.15 Cellular Classification
The current classification of subtypes of small cell lung cancer are:[1]
* small cell carcinoma
* mixed small cell/large cell carcinoma
* combined small cell carcinoma (small cell lung cancer combined with neoplastic squamous and/or glandular components.
Since the treatment of small cell is different from non small cell, identifying the correct type is important and generally done through pathology, examination of tissue.
 

21.2 CHEMOTHERAPY AS THE PRIMARY FORM OF TREATMENT
In the United States, chemotherapy is the primary form of treatment for small cell lung cancer. Initial results are usually promising but the cancer frequently returns.
“(Chemotherapy) regimens will result in response rates of 85-95% in limited disease and 65-85 percent in extensive disease patients. Complete responses, prerequisite for potential cure, can be achieved in about 50 per cent limited disease patients and in about a quarter of extensive disease patients. Depending on the addition of radiotherapy, in limited disease patients about a third will have disease-free survival in excess of 2 years.” Carney (1) at 157.

21.22 Recurrence and Drug Resistance
While the initial success of chemotherapy for small cell cancer is indeed promising, the propensity for recurrence and difficulties combating that are troubling. “Chemotherapy is the main treatment modality for small cell lung cancer. The disease is highly chemoresponsive and around 50 per cent of patients receive complete response. In the great majority of these, however, the disease recurs within a few months and is progressively chemoresistant.” “A primary cause of treatment failure in SCLC (Small Cell Lung Cancer) is the emergence of drug-resistant cell clones during chemotherapy.” Carney, (1) at 158.
21.31 Second-Line Chemotherapy
Second-line chemotherapy (after the initial administration has failed) has been debated. A proponent explains,
“numerous clinical trials demonstrate that some patients benefit from treatment, achieving prolonged survival, symptom palliation, improved quality of life, and the opportunity, albeit rare, for durable remission. Additionally, several novel chemotherapeutics are available that alone or in combination help patients lead an improved quality of life. Finally, alternative routes and schedules--oral formulations, weekly administration, and prolonged treatment vacations--have been developed to deliver chemotherapy to patients with poor performance status or multiple comorbidities.” Eckhardt (12)

21.4 TREATMENT FOR LIMITED STAGE SMALL CELL LUNG CANCER
22.41 Surgery and the Stage 1 or Limited Stage Patient
Even if we assume that at least 90% of small cell patients have advanced disease, that leaves a critical 10% with timely diagnosed tumors confined to part of a single lung. That subgroup has a excellent prognosis perhaps almost equivalent to stage 1 non-small cell patients. One text states,
“Shields analysis of patients with small cell carcinomas in the VASOG trials also demonstrated the importance of TNM (tumor, node, metastasis) staging for tumors of this cell type. Sixty percent of patients with T1, No, Mo tumors were alive at 5 years, whereas there were almost no 5-year survivors among the patients who presented either with T2--3 tumors or with mediastinal lymph node involvement. Patients with T1 tumors with only hilar or bronchopulmonary nodes involved had an intermediate survival of approximately 30%. In fact, these survival results are similar to those of patients who have undergone complete surgical resection for non-small cell lung cancer of equivalent stage.” Aisner (11)

22.42 Impressive Japanese Results with Surgery and Stage 1 and 2 Small Cell Patients
A Japanese study found good results with surgery for small cell patients. “The 4 year survival rate of the patients in stage I was 50%, and that of those in stage II and IIIA was 50% and 37.5%.” The authors boldly conclude, “Surgical resection for limited SCLC should be recommended in patients with stage I, II and T3NoMo or T3N1Mo disease. Ohkubo, (5).
Aisner concludes, “Although there was general acceptance by the 1970's that surgical resection was inappropriate for the majority of patients with small cell lung cancer, the observations of Shields and his colleagues suggested that there might be a subpopulation of patients with small cell cancers for whom a surgical approach could be considered.” Id. at 441. The notion that small cell treatment is comparable to non-small cell treatment would be rejected by most American physicians and investigators. However, at least at early stage 1, there are significant similarities and the same favorable prognosis. In many areas surgery is not performed upon small cell patients, even in earlier stages. The small cell patient will want to carefully review his options and review his options. If surgeon is a realistic option, this highlights the need for early detection. As I discuss later in the book, neither the American Cancer Society nor the National Cancer Institute recommend screening as a means to assure timely diagnosis and improved long term survival.
Thus, even if we consider surgery, there are certain limitations. Patients with poor performance status, limited breathing capacity or other health problems may not be candidates for surgery.
21.23 Chemotherapy and Radiation for Limited Stage Patients
A combination of chemotherapy and radiation is standard treatment for even limited stage patients in the United States. Radiation is used to reduce the size of the tumor while chemotherapy is designed to address the areas of metastasis as well as the tumor itself.
“It is useful to identify patients with limited- stage disease as several randomized controlled trials employing combined modality therapy (chemotherapy and thoracic irradiation in this group have demonstrated survival advantage over treatment with chemotherapy alone.” Richardson & in Carney (3), at 114.
NCI states “In patients with small cell lung cancer, combination chemotherapy produces results that are clearly superior to single-agent treatment, and moderately intensive doses of drugs are superior to doses that produce only minimal or mild hematologic toxicity. Current programs yield overall objective response rates of 65%-90% and complete response rates of 45%-75%. Because of the frequent presence of occult metastatic disease, chemotherapy is the cornerstone of treatment of limited stage small cell lung cancer. Combinations containing two or more drugs are needed for maximal effect.
Mature results of prospective randomized trials suggest that combined modality therapy produces a modest but significant improvement in survival compared with chemotherapy alone. Two meta-analyses showed an improvement in 3-year survival rates of about 5% for those receiving chemotherapy and radiation therapy compared to those receiving chemotherapy alone. Most of the benefit occurred in patients less than 65 years of age. Combined modality treatment is associated with increased morbidity and, in some trials, increased treatment-related mortality from pulmonary and hematologic toxic effects; proper administration requires close collaboration between medical and radiation oncologist.” NCI (1) Another study combining radiation with two chemotherapy drugs showed 5 year survival rates of at least 15% of limited stage patients. (12)
21.23 Particular Chemotherapy Drugs Used
As with non-small cell, defining combinations of drugs, maximum doses, and other variables is a continuing process with sometimes conflicting results. “Clinical trials have failed to show superiority of 1 chemotherapeutic regimen over another.” Reddy (4). Cisplatin/etopiside is a frequently used combination, though physicians continue to examine Carboplatin instead of Cisplatin because of its lesser tendency towards nausea. Cyclophosphamide, Iritocecan and Ifosamide are also used, and physicians are now looking at Taxol and other drugs used for non-small cell tumors.
21.54 Chemotherapy and Radiation
Reddy also suggests that combining chemotherapy with radiation improves results:
Combined modality therapy appears to result in improved complete response rates, but with increased toxicity. There is a benefit associated with the addition of radiation therapy to multiagent chemotherapy, compared with chemotherapy alone. Recent Intergroup data published in the New England Journal of Medicine reported improved overall survival with the use of concurrent twice-daily fractionated radiotherapy and cisplatin/etopiside.[17] Patients with limited-stage SCLC (N = 417) were randomized to once-daily (45 Gy/25 fractions/5 weeks) or twice-daily (45 Gy/30 fractions/3 weeks) radiotherapy given concurrently with cycle 1 of cisplatin/etopiside. The median survival for all patients was 20 months, with a 40% 2-year survival rate. Overall survival was significantly better in the twice-daily arm compared with the standard fractionation arm (26% vs 16%, respectively). An increase in transient grade-3 esophagitis was seen in the twice-daily arm. Reddy, (4) at 1.

21.55 Gene therapies

Most of the clinical trials with gene therapies have dealt with non-small cell lung cancer. However, many of the same rationales for treatment apply to small cell, and we can expect gene therapies like Iressa to be tested on small cell patients, alone and in conjunction with chemotherapy and radiation.
 

21.7 EXTENSIVE STAGE SMALL CELL LUNG CANCER
NCI states, (1) “As in limited stage small cell carcinoma, chemotherapy should be given as multiple agents in doses associated with at least moderate toxicity in order to produce the best results in extensive stage disease. Doses and schedules used in current programs yield overall response rates of 70%-85% and complete response rates of 20%-30% in extensive stage disease. Since overt disseminated disease is present, combination chemotherapy is the cornerstone of treatment of this stage of small cell lung cancer. Combinations containing two or more drugs are needed for maximal benefit.
The relative effectiveness of many 2- to 4-drug combination programs appears similar, and there are a large number of potential combinations. Optimal duration of chemotherapy is not clearly defined, but there is no obvious improvement in survival when the duration of drug administration exceeds 6 months.
Combination chemotherapy plus chest irradiation does not appear to improve survival compared with chemotherapy alone in extensive stage small cell lung cancer. However, radiation therapy plays an extremely important role in palliation of symptoms of the primary tumor and of metastatic disease, particularly brain, epidural, and bone metastasises...
Patients with small cell lung cancer treated with chemotherapy with or without chest irradiation who have achieved a complete remission can be considered for administration of prophylactic cranial irradiation (PCI). Patients whose cancer can be controlled outside the brain have a 60% actuarial risk of developing central nervous system metastasises within 2-3 years after starting treatment.
Retrospective studies have shown that long-term survivors of small cell lung cancer (>2 years from the start of treatment) have a high incidence of central nervous system impairment. However, prospective studies have shown that patients treated with PCI do not have detectably different neuropsychological function than patients not treated. Therefore, additional neuropsychologic testing of patients beyond 2 years from the start of treatment will be needed before concluding that PCI does not contribute to the decline in intellectual function.
Many more patients with extensive stage small cell carcinoma have greatly impaired performance status at the time of diagnosis when compared to patients with limited stage disease. Such patients have a poor prognosis and tolerate aggressive chemotherapy or combined modality therapy poorly. Single-agent intravenous, oral, and low-dose biweekly regimens have been developed for these patients. However, prospective randomized studies have shown that patients with a poor prognosis who are treated with conventional regimens live longer than those treated with the single-agent or low-dose regimens.
NCI lists these chemotherapy options:
1. cyclophosphamide + doxorubicin + vincristine
2. cyclophosphamide + doxorubicin + etopiside

3. etopiside + cisplatin or carboplatin

4. ifosfamide + carboplatin + etopiside

There are certainly a number of other combinations and drugs used for Sclc throughout the world.
21.71 The Controversy Over Prophylactic Cranial Radiation
One of the sad sequalae of small cell cancer are metastasises to the head. Given their frequently, would it make sense to irradiate the patient before the tumor metastasises are seen on x-ray. Radiation may stem a metastasises while arguably causing only limited discomfort to the patient. At least this is what some scientists have suggested, with prophylactic cranial radiation an important and controversial topic in current treatment of small cell lung cancer. Many patients and their families would reject the notion of applying a potentially toxic substance to the brain where disease was not even identified in that area.
Here is the argument in favor of PCI from the New England Journal of Medicine:
A major cause of morbidity and mortality in patients with small-cell lung cancer is brain metastasis, which in most patients results in multiple tumors. At the time of initial diagnosis, brain metastasises can be detected in up to 10 percent of patients, and 1 to 2 percent of these patients have metastasises only in the brain. However, among patients who complete chemotherapy, an additional 30 to 70 percent subsequently have clinically apparent brain metastasises, and even more have such metastasises at autopsy. Moreover, among patients who have a complete remission with chemotherapy, approximately 15 percent have brain metastasises as the initial or sole manifestation of recurrence. As the length of survival after diagnosis increases, the risk of metastasises to the brain increases. Thus, as chemotherapy with concurrent thoracic irradiation becomes more effective for patients with limited small-cell lung cancer, the frequency of brain metastasises later in the course of the disease may continue to rise.

For many years, prophylactic cranial irradiation has been used in patients with small-cell lung cancer in the belief that the treatment of microscopic or subclinical metastasises would prevent or delay the onset of symptomatic brain metastasises, but its efficacy for this purpose has been uncertain. Those who advocate prophylactic cranial irradiation point out that it is a safe way to reduce the overall incidence of brain metastasises, even if only a small number of patients benefit.... Others argue against routine prophylactic cranial irradiation. They point out that the brain is rarely the sole site of recurrence, that radiation can be neurotoxic, and that radiation therapy does not prolong survival. In this issue of the Journal, Auperin et al. report the results of a detailed meta-analysis of the efficacy of prophylactic cranial irradiation in 987 patients (847 patients with limited disease and 140 patients with extensive disease) who took part in seven trials and who had complete remission with chemotherapy, with or without thoracic irradiation. Prophylactic cranial irradiation was associated with an absolute decrease of 25.3 percent in the cumulative incidence of brain metastasis at three years, from 58.6 percent in the control group to 33.3 percent in the treatment group. More important, prophylactic cranial irradiation was also associated with an absolute increase in overall survival of 5.4 percent at three years, from 15.3 percent in the control group to 20.7 percent in the treatment group. Prophylactic cranial irradiation was beneficial in patients with either limited or extensive disease....

We still do not know how best to integrate prophylactic cranial irradiation with chemotherapy in patients with small-cell lung cancer. The optimal dose of radiation, volume of tissue to be irradiated, and duration and timing of prophylactic cranial irradiation have not been determined. Also, questions remain regarding the safety and long-term neuropsychological consequences of prophylactic cranial irradiation. The study found a significant survival benefit, but it should be noted that four of the trials included in the meta-analysis had fewer than 100 patients, which suggests that there may have been some selection bias.

There are ongoing studies and we cannot expect this question to be quickly or conclusively resolved.
 

21.8 SMALL CELL LUNG CANCER AND GENE THERAPY
21.81 Overview
Scientists have also looked to gene therapy for both patients with limited and extensive disease. Given the apparent success of drugs like Iressa in prolonging the lives of non-small patients with even metastatic disease, scientists are looking for comparable treatments for the small cell patient. “Recent clinical trials of gene therapy for patients with thoracic cancers have shown that these treatments were well tolerated with minimal side effects and that we need to further enhance specificity as well as efficiency of gene transfer to target cancer cells.” (9) Gene therapy is a broad category encompassing drugs which seeks to frustrate the cancer process in many different ways.
When some laboratory studies have documented favorable response on cells, there have been few clinical trials showing favorable results for small cell, though this may have changed at the time of publication.
21.82 The Role of P-53
One method is to restore the body’s natural tumor suppressor genes which may have been damaged during the carcinogenic process. One of the most important tumor-suppresor genes is P-53, the subject of a separate chapter.
“The protein is recognized as an important cell regulatory element that arrests the growth of cells containing damaged DNA. A reversible arrest in the G1 phase of the cell cycle allows DNA repair before DNA synthesis. When optimal repair is impossible, p53 expression may trigger apoptosis, an irreversible process culminating in cell death. Thus, loss of wild type p53 function may result in relative resistance to treatment as a consequence of abrogation of p53-dependent apoptosis....
Reports show the frequency of p53 mutations in SCLC cell lines and tumors (about 70-100% in different series). The alterations in the p53 gene are common and perhaps critical events in lung carcinogenesis, but probably they are not the first, although these alterations are essential for the maintenance of malignant phenotypes in the progression of SCLC on the relationship between p53 status and clinical outcome. The available data in the literature results controversial. Iggo et al.performed immunohistochemical p53 study and p53 gene secuentiation in 47 lung tumors, and found p53 altered expression in all SCLC: nine samples, in all of these cases it was correlated with mis-sense mutations in p53 gene (G toT transversions), finally they suggests that the presence of p53 mutations in SCLC implies a poor prognosis while D'Amico analyzed p53 mutations in 16 cell lines and in 20 tumors, and found p53 gene abnormalities in 100% cell lines and in 80% tumors, but they did not find correlation between location or type of mutations and clinical characteristics, stage, response to therapy or survival.” Salas (7),
Salas found a strong correlation between P53 expression and response to chemotherapy. “In 15 of the 20 patients who had complete response p53 expression was considered negative (<15% of positive nuclei area) (P=0.0212, Fisher's exact test). The mean p53 staining in these 15 patients was much lower.” (Salas, (7). Interestingly Salas did not find an association between P53 expression and other clinical data such as stage and disease stage.
21.83 2 Herpes Simplex Viral Treatment
A Japanese group is investigating treatments designed to attack the myc oncogene implicated in small cell cancer:
“We previously reported that myc-overexpressing SCLC cell lines became selectively sensitive to ganciclovir (GCV) by transducing the herpes simplex virus thymidine kinase (HSV-TK) gene under the control of the Myc-Max response elements (a core nucleotide sequence, CACGTG) and that this construct (MycTK) could be utilized to develop a novel treatment against chemo-radio-resistant SCLC. We report here in vivo antitumor effects and safety of a replication-deficient adenoviral vector containing the Myc-Max binding motif (AdMycTK) on SCLC cells. In vitro infection with AdMycTK selectively rendered myc-overexpressing SCLC cell lines 63- to 307-fold more sensitive to GCV. In vivo injections with AdMycTK followed by GCV administration markedly suppressed the growth of myc-overexpressing tumors established in the subcutis or in the peritoneal cavity of athymic mice. On the other hand, infection with AdMycTK did not significantly affect either in vitro GCV sensitivity of the cells expressing very low levels of the myc genes or the growth of their subcutaneous tumors. Moreover, we observed no apparent side effects of this treatment including body weight loss or biochemical abnormalities in contrast to the treatment with AdCATK that conferred strong but nonspecific expression of the HSV-TK gene. These results suggested that AdMycTK/GCV therapy is effective on SCLC patients whose tumors overexpress myc family oncogenes.” Nusino (9)
Results have been mixed. Another researcher states,
“Replication-incompetent adenoviruses (Ad) carrying the herpes simplex thymidine kinase (HSVtk) gene have been used in a number of human cancer gene therapy trials, however transduction has generally been limited to a small minority of tumor cells....Our results indicate that addition of HSVtk to a replicating Ad virus will not likely be useful in augmenting antitumor effects.” (10)

REFERENCES
1. NCI.net. The NCI publishes its analysis and recommended protocols from which these excerpts have been taken. Since the NCI frequently revises its materials and excerpts have been taken from the Internet, precise quotations may be missing or changed in the latest version.
2. Twentyman, Mechanism of Drug Resistance in Lung Cancer Cells, in Carney, Lung Cancer (Arnold Publ. Co. 1995).
3. Carney Chemotherapy of Small Cell Lung Cancer, 157, in , Lung Cancer (Arnold Publ Co. 1995).
4. Reddy, Small Cell Lung Cancer: Improving Outcomes,Presentation, American Society for Therapeutic Radiology and Oncology 42nd Annual Meeting, excerpted on medscape.
5. Ohkubo, (4) Surgical Analysis for Small Cell Lung Cancer of the Lung, Kyobu Geka 1999 Dec; 52 (13) 1061-6.
7. Salas, Correlation of p53 oncoprotein expression with chemotherapy response in small cell lung cancer, Lung Cancer, Vol. 34 (1) (2001) pp. 67 - 74
8. Carney, Prophylactic Cranial Irradiation and Small-Cell Lung Cancer, The New England Journal of Medicine Vol. 341, No. 7 (August 12, 1999).
9. Nushino, Adenovirus-mediated gene therapy specific for small cell lung cancer cells using a Myc-Max binding motif,. Int J Cancer 2001 Mar 15;91(6):851-6
10. Lambright, Inclusion of the herpes simplex thymidine kinase gene in a replicating adenovirus does not augment antitumor efficacy, Gene Ther 2001 Jun;8(12):946-53.
11. Aisner, et. al., Comprehensive Textbook of Thoracic Oncology 441 (Williams & Wilkins 1996).
12. Eckhardt, Second-line treatment of small-cell lung cancer. The case for systemic chemotherapy.Oncology (Huntingt) 2003 Feb;17(2):181-8, 191; discussion 191-2.
13.Sandler, Extending Survival in SCLC with Irinotecan: Building on the Japanese Experience, http://www.medscape.com/viewarticle/429347_7

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