EPIDEMIOLOGY
In 2008, about 28,000 new cases of SCLC were estimated to occur in the United States. The incidence of SCLC decreased from 17.26% in 1986 to 12.95% in 2002. The incidence among females increased over the same period from 28% in 1973 to 50% in 2002, reflecting cigarette consumption patterns in this group. The proportion of patients presenting over the age of 70 has also increased from 31.6% in 1985 to 44.9% in 2000.
SCLC is strongly associated with cigarette smoking. It is exceptionally rare among nonsmokers. Exposure to ionizing radiation, uranium, radon, and chloromethyl ethers has also been implicated in its etiology.
PATHOLOGY
Small cell carcinoma is characterized on light microscopy by small, round, “blue” malignant cells with scant cytoplasm, finely granular chromatin, and without distinct nucleoli. The mitotic count is high and individual cell necrosis may be seen.
The 1999 WHOInternational Association for the Study of Lung Cancer (IASLC) classification characterizes SCLC in three groups:
- Classical small cell carcinoma
- Large cell neuroendocrine cancer
- Combined small cell carcinoma, composed largely of SCLC with areas of non-small cell lung cancer (NSCLC).
Up to 30% of autopsies of SCLC demonstrate areas of differentiation into non-small cell carcinoma. This differentiation is rare in untreated specimens leading to the hypothesis that pulmonary carcinogenesis may occur in a pluripotent stem cell capable of differentiation along a variety of pathways.
A majority of SCLCs are positive on immunohistochemistry for keratin, thyroid transcription factor 1 (TTF-1), and epithelial membrane antigen. Markers of neuroendocrine differentiation such as neuron-specific enolase, chromogranin A, and synaptophysin are also commonly present. However, as these may also be present on up to 10% of NSCLC they may not be used to distinguish between these two malignancies.
GENETIC ABNORMALITIES
Cumulative exposure to tobacco smoke and other mutagens lead to carcinogenesis over a period of years. The most commonly observed mutations in SCLC include:
- P53 mutations are present in 75% to 95% of SCLCs.
- Loss of heterozygosity of 10q (PTEN site) and 9p are present on most tumors.
- Tumor suppressor gene loss due to deletion of 3p may play an important role in tumorigenesis. These include FHIT (fragile histidine triad) gene, RASSF1A, and TGFBR2 (transforming growth factor 2 receptor)
- Loss of the retinoblastoma gene occurs in 60% of SCLC, the remaining 40% having abnormal gene products.
- Telomerase enzyme activity, which is responsible for stabilization of telomerase length and cellular immortality, is present in 90% of SCLCs. This is undetectable in normal somatic cells with the exception of those with the capacity to divide indefinitely, such as basal epidermal cells and hematopoietic cells.
- C-kit and phosphorylated c-kit are present in 80% to 90% of SCLCs, which may represent a growth factor loop. Imatinib has not been useful in phase 2 trials.
- Unlike NSCLC, K-ras and p16 mutations are uncommon.
CLINICAL PRESENTATION
SCLC is a disease of the central airways, typically presenting with a large hilar mass and bulky mediastinal adenopathy. Clinical symptoms of local disease include cough, dyspnoea and postobstructive pneumonia. Seventy percent of patients present with metastatic disease causing symptoms such as weight loss, debility, neurological compromise, or bone pain. SCLC commonly metastasizes to liver, adrenals, bone marrow, bone, and brain.
Presentation as a peripheral nodule in the absence of mediastinal adenopathy is uncommon. In this situation, fine-needle aspiration of the lesion may not be adequate to differentiate SCLC from typical or atypical carcinoid tumor or from large cell neuroendocrine carcinoma, and surgical resection followed by mediastinal staging is recommended.
SCLC may also present as endocrine or neurological paraneoplastic phenomena. Lambert-Eaton syndrome presents as a proximal myopathy caused by antibodies against voltage gated calcium channels. Anti-Hu antibodies which cross-react with small cell carcinoma antigen and human neuronal components may result in paraneoplastic encephalomyelitis or a sensory neuropathy. Endocrine paraneoplastic manifestations include Cushing’s syndrome or hyponatremia due to ectopic ACTH and ADH hormone production respectively.
STAGING OF SCLC
The Veteran’s Administration Lung Group (VALG) two-stage classification scheme is routinely used to stage SCLC.
Limited stage disease is defined as disease limited to the ipsilateral hemithorax, which may be encompassed safely within a tolerable radiation field. Contralateral mediastinal and ipsilateral supraclavicular adenopathy are included within the definition of limited stage disease. Approximately one-third of patients present with limited stage disease. The clinical relevance of this observation lies with the fact that those with limited stage disease are treated with combined modality therapy with curative intent and those with extensive stage disease are treated with palliative chemotherapy alone.
Extensive stage disease is designated as that which has spread beyond the ipsilateral hemithorax including both contralateral hilar or supraclavicular adenopathy and cytologically malignant pleural or pericardial effusions, in addition to overt distant hematogenous metastases.
Alternative Staging Systems
The IASLC advocates the use of the more complex TNM staging system for SCLC. An overlap exists between prognosis and therapy for stage groupings within this classification, limiting its clinical utility. This system defines any patient without distant metastatic disease as limited stage.
Staging Workup
All patients with SCLC should be considered for systemic chemotherapy. The significance of the staging workup lies in guiding the use of chest radiotherapy, which will be necessary for limited stage disease only. Staging will require a history and physical examination, followed by computed tomography (CT) of chest liver and adrenal glands, head CT or magnetic resonance imaging (MRI) (preferred), and a bone scan.
Bone marrow aspirate and biopsy may be recommended in the presence of neutropenia, thrombocytopenia, or nucleated red blood cells on a peripheral smear, and no other indication of metastatic disease. Bone marrow is involved in up to 30% of patients at presentation but is the solitary site of metastatic disease in less than 5% of cases. This invasive test has a low yield in the presence of a normal serum lactate dehydrogenase (LDH) level.
SCLC is a high-grade, metabolically active tumor, and positron emission tomography (PET) is likely to be useful in the future for initial staging evaluation. However, this modality has not yet been widely studied in this disease. A PET scan is therefore optional, but may be used in addition to the other recommended investigations as part of the initial evaluation.
It is recommended that thoracocentesis be attempted on all pleural effusions that are large enough to be seen by chest radiograph. If cytological analysis does not document malignant cells, thoracoscopy may be considered to document pleural involvement and thus extensive stage disease.
A nonmalignant effusion must be documented to have repeated negative cytological examinations, be nonbloody and a nonexudatative, be considered clinically to be not directly related to the cancer or be so small as not to allow image-guided sampling.
Comprehensive staging should be performed from the outset due to the high incidence of clinically occult metastatic disease. Bone scan may be positive in up to 30% of patients without bone pain or an elevated alkaline phosphatase. CT brain or MRI document disease in 10% to 15% of patients, and 5% to 8% of these are asymptomatic. Early treatment of brain metastases will lead to lower levels of subsequent neurological morbidity.
Current NCCN guidelines recommend that staging should not delay treatment by more than 1 week. Due to the rapidly progressive nature of the disease, patients may become seriously ill within that interval.
PROGNOSTIC FACTORS
The most important adverse prognostic factors are poor performance status (PS 3-4), weight loss, and markers related to high disease burden such as LDH. In limited stage disease, female gender, age <70, normal LDH and stage I disease have a favorable prognosis. In extensive stage, a single metastatic site and normal LDH are favorable prognostic markers.
SURVIVAL
Median survival for early-stage (ES) SCLC is 8 to 13 months, and 15 to 20 months for limited stage disease. Two-year survival is 20% to 40% for late-stage (LS) SCLC and <5% for ES-SCLC. Recent SEER (survival, epidemiology, and end results) program data have demonstrated a small increase in survival: for limited-stage disease the median survival has increased by 6.4 months and the 5-year survival increased by a factor of 2 (12.1% vs. 5.2%), when the period covering 1972 to 1981 is compared to that of 1982 to 1992. For patients with ES-SCLC, progress has been limited to a 2-month gain in survival (from 7 to 9 months) over the same time frame.
CHEMOTHERAPY FOR SCLC
Chemotherapy is essential in the treatment of SCLC. For LS-SCLC with good PS (<2), recommendations are for chemotherapy with concurrent radiotherapy. For ES-SCLC, chemotherapy alone is recommended. For those who have undergone surgical resection, adjuvant chemotherapy is recommended.
SCLC is exceptionally chemosensitive, and chemotherapy substantially prolongs survival versus best supportive care. This benefit to palliative chemotherapy may even be seen in patients with severe organ dysfunction.
LS-SCLC has shown response rates of 80% to 90% with concurrent chemoradiation, with 50% to 60% CR rates. ES-SCLCs show response rates of 60% to 80%, with one-quarter of these having a CR. The median duration of response is 6 to 8 months. Median survival after recurrence is 4 months.
The chemotherapeutic agents commonly used in the treatment of SCLC are as follows:
- Platinum compounds (cisplatin, carboplatin)
- Podophyllotoxins (etoposide, tenoposide)
- Camptothecins (irinotecan, topotecan)
- Alkylating agents (ifosfamide, cyclophosphamide)
- Anthracyclines (doxorubicin, epirubicin)
- Taxanes (paclitaxel, docetaxel)
- Vinca alkaloids (vincristine)
Platinum-based regimens appear to be more effective than non-platinum-based regimens. The cisplatin-plus-etoposide (PE or EP) regimen demonstrated preclinical synergism and is now the most frequently used combination in the limited stage setting, based on activity and toxicity profiles. Due to the limited risk of pneumonitis and manageable hematologic toxicity profile, this is the recommended regimen in conjunction with radiotherapy for LS-SCLC.
Clinically, carboplatin is often substituted for cisplatin due to the decreased risk of emesis, nephropathy, and neuropathy. Carboplatin use involves a higher risk of myelosuppression. Substitution of carboplatin for cisplatin in LS-SCLC has not been extensively evaluated and is recommended only if cisplatin is poorly tolerated or contraindicated. It is more acceptable in extensive stage disease as chemotherapy for these patients is not curative.
Irinotecan-Based Regimens
Multiple trials are evaluating whether the substitution of irinotecan for etoposide in ES-SCLC can improve on current outcomes. A phase 3 Japanese trial showed a higher response rate (84% vs. 66%) and longer median survival (12.8 vs. 9.4 months) and 2-year survival (19.5 vs. 5.4 months) when compared with the etoposide regimen. Hematological toxicity was less pronounced with the irinotecan regimen but diarrhea was more common.
A larger trial with a similar but not identical design conducted in the United States failed to replicate these results. An ongoing SWOG trial (SWOG 0124) is currently underway, using identical regimens to the original Japanese design. Recent initial pharmocogenomic and toxicity data were presented at the American Society of Clinical Oncology Meeting (ASCO) 2007, which showed significant differences in the toxicity between American and Japanese populations, in addition to differences in single nucleotide polymorphisms (SNPs) related to irinotecan metabolism. Whether these genetic differences account for differences in toxicities and efficacy will require further investigation.
Further evidence relating to the efficacy of irinotecan in ES-SCLC is seen in the results of a multicenter Scandinavian IRIS trial where patients were randomized to carboplatin and either irinotecan or etoposide. At a minimum 1-year follow-up presented at ASCO 2007 the irinotecan arm showed a higher response rate, longer median (8.5 vs. 7.1 months), and 1-year survival (34% vs. 24%).
Chemotherapy in the Elderly
Individuals over the age of 70 currently represent more than 40% of those diagnosed with SCLC, a figure that is likely to increase. Lower organ reserves may lead to increased toxicity due to chemotherapy. Despite this, elderly patients have similar survival rates when compared to younger patients.
Less intensive treatment is associated with decreased toxicity but inferior survival in those with a good PS (0-2) in this age group. Therefore, it is functional status rather than chronological age that must inform clinical decision making. Those who are functionally independent in their activities of daily living should undergo the recommended combination chemotherapy and radiotherapy as clinically indicated.
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Less intensive treatment is associated with decreased toxicity but inferior survival in those with a good PS (0-2) in this age group. Therefore, it is functional status rather than chronological age that must inform clinical decision making. Those who are functionally independent in their activities of daily living should undergo the recommended combination chemotherapy and radiotherapy as clinically indicated.
EXPERIMENTAL THERAPIES
Strategies to improve on standard two-drug regimens include addition of a third agent, maintenance or consolidation therapy, alternating or sequential combination therapies, and higher-dose therapies. Overall these approaches have failed to deliver significant improvements on the results yielded by standard approaches.
Additional Agents
Despite promising phase 2 data, the addition of paclitaxel to EP in ES-SCLC has shown no benefit in two phase-3 trials. In the larger trial, median survival and 1-year survival were comparable, but there was an excess of treatment-related mortality (6.5% vs. 2.4%) in the paclitaxel-containing arm. The addition of ifosfamide has been shown in one trial to be associated with a modest survival advantage, but this effect has not been uniformly observed. Multidrug regimens such as EP plus cyclophosphamide and epirubicin have shown statistically significant small increases in response rate, median survival and 1-year survival, at the expense of significantly increased hematological toxicity, including rates of febrile neutropenia and blood product transfusion.
Maintenance therapy or consolidation therapy beyond the standard 4 to 6 cycles of treatment carries a minor prolongation of response with no subsequent increase in survival and is associated with increased cumulative toxicity. Recently, maintenance therapy with bevacizumab was associated with the development of tracheoesophageal fistulae in patients with LS-SCLC receiving bevacizumab, carboplatin, and irinotecan as part of a phase 2 trial. Bevacizumab is not recommended for the treatment of SCLC.
Dose Escalation and Dose-Dense Therapy
Increased tumor cell exposure to chemotherapeutic agents can be achieved by increasing the drug dose or by decreasing the interval between cycles. This is facilitated by the use of myeloid growth factors. Numerous trials have demonstrated a higher response rate in patients receiving higher doses of chemotherapy. Most have not demonstrated a comparable increase in survival, but have documented increased toxicity. The only trial to demonstrate a survival benefit randomized 100 patients with LS-SCLC to conventional-dose cisplatin, cyclophosphamide, doxorubicin, and etoposide (CD-PCDE) or high-dose PCDE (HD-PDCE) that used 20% higher doses on the first cycle. Rates of complete response were higher with HD-PDCE (67% vs. 54%) as were survival rates at 2 and 5 years (42% vs. 20% and 26% vs. 8%, respectively).
Higher chemotherapy dose levels may be achieved using hematopoietic growth factory support (e.g., G-CSF or GM-CSF). Increasing dose intensity using these drugs has not improved survival when compared to the maximum tolerated standard chemotherapy doses without their use. Use of CSFs has been documented in two reports to be associated with increased toxicity and decreased survival. Meta-analysis of dose intensity in trials using a CAV-CAE-EP regimen and its relationship to survival showed a small and insignificant increase in median survival in patients with ES-SCLC when increased dose intensity was used.
Despite initial promising reports, the use of early or late intensification of chemotherapy with hematopoietic cell transplantation with either bone marrow or peripheral blood precursor cells has not been shown to be of benefit.
Targeted Agents
Advances in SCLC with cytotoxic chemotherapy have been small, and new approaches to treatment are required. Newer biologically targeted agents that have been investigated include bevacizumab,
temosirolimus, matrix metalloproteinase inhibitors, the tyrosine kinase inhibitors imatinib and vandetanib, and the antisense oligonucleotide olibmerson. As yet, none have demonstrated significant activity in vivo, and phase 2 and 3 trials are ongoing.
temosirolimus, matrix metalloproteinase inhibitors, the tyrosine kinase inhibitors imatinib and vandetanib, and the antisense oligonucleotide olibmerson. As yet, none have demonstrated significant activity in vivo, and phase 2 and 3 trials are ongoing.
THORACIC RADIOTHERAPY FOR LS-SCLC
Local recurrence or tumor progression occurs in up to 80% of those with LS-SCLC treated by chemotherapy alone. This high recurrence rate and overall survival may be improved by the addition of thoracic radiation therapy (TRT). Meta-analysis suggests that TRT is associated with an increase in local control of 23% (24% to 47%) and a 5% absolute gain in overall survival at 2 years (20.5% vs. 15%). Survival benefit is gained at an increase in toxicity.
Radiation Fields
The use of limited-field TRT is currently the gold standard. This includes all gross disease present at the time of planning (postchemotherapy volume) and all nodal regions at the time of diagnosis (prechemotherapy volume). Treatment with smaller treatment fields is associated with a reduction in toxicity from combined-modality therapy without diminishing local control rates.
Fractionation Schedule
Standard schedules consist of single daily treatments of 1.8 to 2.0 Gy 5 days per week over 6 weeks. Accelerated hyperfractionation implies treatment delivery over a shorter period of time (acceleration) with an increased number of fractions (hyperfractionation). Radiation treatment occurs two to three times daily with smaller fraction sizes. These treatment regimens are associated with more acute toxicity, increased daily treatment time, and are more complex in terms of treatment delivery. Superior survival outcomes in recent trials using hyperfractionated TRT of 45 Gy over 3 weeks of twice-daily treatment have led to the establishment of this regimen as a standard of care within the field. The CALGB 30610 trial aims to compare directly twice-daily short-course TRT (45 Gy b.i.d) to longer traditional schedules.
Integration With Chemotherapy
Concurrent, sequential, and alternating patterns of delivery have been investigated. Concurrent or alternating regimens allow uninterrupted delivery of chemotherapy—essential due to the systemic nature of SCLC. These methods have been associated with increased toxicity (esophagitis, pneumonitis, and myelosupression), but improved survival when compared to sequential treatment.
Conflicting evidence exists regarding the optimal timing of TRT relative to chemotherapy, possibly due to the heterogeneity of the chemotherapy regimens and chemotherapy dose intensity between the trials involved. Studies that showed a significant survival advantage for early TRT (given with the first cycle of chemotherapy) used cisplatin-based drug regimens and had high rates of dose delivery. Those that did not show a benefit to early TRT did not use cisplatin-based regimens and/or showed a lower rate of dose delivery in the early arms.
Despite this conflicting data regarding the optimal timing of TRT delivery, the studies using standard EP chemotherapy delivery with minimal dose reductions all showed a clear benefit to early TRT. To this end, early TRT integrated with cycle one or two of chemotherapy is the standard of care for LS-SCLC.
TREATMENT OF RELAPSED AND REFRACTORY SCLC
Despite initial chemosensitivity, most patients with SCLC will eventually relapse and require salvage chemotherapy. Disease that occurs more than 3 months after completion of first-line chemotherapy
referred to as relapsed SCLC. The term refractory disease refers to disease that has progressed through first-line chemotherapy or recurred within 3 months of treatment completion. In general, relapsed disease is more sensitive to salvage chemotherapy than refractory disease, with response rates of 25% versus 10%, respectively. Median survival of relapsed SCLC is 2 to 6 months. Prognostic indicators include disease burden (limited or extensive stage), performance status, and whether the disease is relapsed or refractory. Response rates to second-line therapy relate to time to relapse from initial treatment, response to initial treatment, first-line chemotherapy regimen used, and performance status.
referred to as relapsed SCLC. The term refractory disease refers to disease that has progressed through first-line chemotherapy or recurred within 3 months of treatment completion. In general, relapsed disease is more sensitive to salvage chemotherapy than refractory disease, with response rates of 25% versus 10%, respectively. Median survival of relapsed SCLC is 2 to 6 months. Prognostic indicators include disease burden (limited or extensive stage), performance status, and whether the disease is relapsed or refractory. Response rates to second-line therapy relate to time to relapse from initial treatment, response to initial treatment, first-line chemotherapy regimen used, and performance status.
Single-agent chemotherapies that have documented activity in relapsed or refractory SCLC include camptothecin derivatives toptecan and irinotecan, taxanes, oral etoposide, vinorelbine, and gemcitabine. Phase 3 trial data comparing CAV to IV topotecan in patients who had relapsed more than 2 months after completing therapy (mostly EP) showed similar response rates (18% vs. 24%) and median survival (25 vs. 24.7 weeks). The topotecan group reported better control of symptoms including dyspnea, anorexia and fatigue, and less neutropenia than the CAV group, but significantly more thrombocytopenia and anemia. This led to topotecan being recommended as the second-line agent for SCLC that has relapsed within 2 to 3 months of treatment. The efficacy and toxicity of oral topotecan is similar to the IV formulation, which is not yet commercially available in the United States.
Combination chemotherapies may have slightly higher response rates in second-line therapy, but are also more toxic. For those with relapsed disease and a long relapse-free interval, it may be feasible to reintroduce the initial induction chemotherapy.
ROLE OF SURGERY IN SCLC
SCLC is a disseminated disease at presentation, including those with apparently limited stage disease. The futility of surgery as the primary treatment modality has been documented by the historical cohort of clinical trials. Early-stage SCLC (ES-SCLC) is diagnosed in less than 5% of patients. Most data relating to resection of SCLC are uncontrolled. However, when SCLC presents as a solitary pulmonary nodule and is resected, 5-year survival ranged from 43% to 53%.
Patients with clinical stage I disease (T1-2, N0) may undergo surgical resection following standard staging and evaluation of the mediastinum by mediastinoscopy or other surgical staging to outrule occult nodal disease. Those who undergo full resection with lobectomy and mediastinal nodal dissection should be treated with postoperative chemotherapy if there is no evidence of nodal metastases and with concurrent chemotherapy and radiation to the mediastinum in the presence of positive lymph nodes. In addition, those with presumed complete remission following surgery and adjuvant chemotherapy should undergo prophylactic cranial irradiation (PCI).
PROPHYLACTIC CRANIAL IRRADIATION FOR PATIENTS WITH SCLC
The brain represents a sanctuary site for SCLC due to the relative impermeability of the blood-brain barrier to commonly used chemotherapeutic agents. This leads to a significant rate of intracerebral metastasis as a site of relapse or failure following complete response to systemic therapy. The incidence of brain metastases at 2 years is 80% leading to significant morbidity and mortality. Previously, concerns existed regarding the late neurologic toxicity of PCI—especially in LS-SCLC. This predominantly occurred in studies using high doses per fraction (>3.0 Gy), high total dose, and concurrent chemotherapy. There is less neurotoxicity when given sequentially following completion of chemotherapy and when lower doses per fraction are used.
Two meta-analyses suggest a benefit to PCI with a decrease of 25% in the cumulative 3-year incidence of brain metastases from 58% to 23% and small increase in the overall 3-year survival in the PCI group (from 15.3% to 20.1%). A recent trial of the European Organisation for Research and Treatment of Cancer (EORTC) assessed the role of PCI in the ES-SCLC population. Those
who were deemed by the treating physician to have responded to 4 to 6 cycles of standard chemotherapy were randomized to PCI or observation. Radiation doses varied depending on the institution. Those who underwent PCI had a significantly decreased incidence of symptomatic brain metastases at 1 year (15% vs. 40%) and a significantly higher 1-year survival rate (27% vs. 13%). Treatment with PCI was well tolerated with most common toxicities being mild headache (42%), nausea (36%), and fatigue (10%).
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who were deemed by the treating physician to have responded to 4 to 6 cycles of standard chemotherapy were randomized to PCI or observation. Radiation doses varied depending on the institution. Those who underwent PCI had a significantly decreased incidence of symptomatic brain metastases at 1 year (15% vs. 40%) and a significantly higher 1-year survival rate (27% vs. 13%). Treatment with PCI was well tolerated with most common toxicities being mild headache (42%), nausea (36%), and fatigue (10%).
PCI is currently recommended for patients with limited stage disease and ES-SCLC who achieve a complete response, who have only radiation scarring or a decrease in the tumor mass to less than 10% of the original volume on CT following induction chemoradiation. It may be considered for those with a partial response to initial treatment. It is not recommended for those with multiple co-morbidities, poor PS (3-4), or impaired cognition. It should not be given concurrently with chemotherapy due to the additive neurotoxic effects.
REGIMENS
The most important factors that predict a favorable outcome are extent of disease, good performance status, biology of the small cell tumor, and smoking cessation. Several combinations have been used successfully (Table 3.1).
TABLE 3.1. Summary of commonly used chemotherapeutic regimens | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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