Chapter 41 Small Cell Lung Cancer
During 2009, lung cancer was diagnosed in an estimated 219,440 patients and caused an estimated 159,390 deaths in the United States.1 About 15% of patients with lung cancer have SCLC, and of these, 30% have L-SCLC.2 Very few SCLC patients have stage I disease. Lung cancer is a disease of the elderly, with a median age of 71 years at diagnosis.3
The natural history of untreated SCLC included rapid tumor progression, with a median survival time of only 2 to 4 months.4 Until the late 1960s, physicians did not differentiate the management of SCLC from that of NSCLC, and clinical trials in the 1970s continued to include both major histologic types. Investigators recognized that most patients with SCLC had poor survival times following resection and/or thoracic radiotherapy, with little apparent survival benefit from either treatment. A major change in management occurred in the late 1960s and was linked to the recognition that SCLC was far more responsive to chemotherapy than NSCLC.5
Pathologic Findings And Pathways Of Spread
The 2004 World Health Organization (WHO) classification defined SCLC as “a malignant epithelial tumor consisting of small cells with scant cytoplasm, ill-defined cell borders, finely granular nuclear chromatin, and absent or inconspicuous nucleoli.” The cells are round, oval, and spindle shaped. Nuclear molding is prominent. Necrosis is extensive, and the mitotic count is high. SCLC occurs in two variant forms: small cell carcinoma and combined small cell carcinoma. The latter type includes SCLC cells and any of the histologic types of NSCLC.6
Biologic And Molecular Biologic Characteristics
Cigarette smoke is a powerful mutagen that is strongly associated with the development of SCLC. Acquired hypermethylation of the promoter region of key genes has become a common mechanism that tumors use to inactivate tumor suppressor genes. A number of genetic mutations are frequently observed in SCLC tumors, which frequently involve tumor suppressor genes. The mutations lead to dysfunction of these suppressor molecules and then to unrestricted tumor growth. The most common mutations are deletions in the short arm of chromosome 3 in the 3p14-23 region (>80% of SCLC cases), inactivation of the retinoblastoma (RB) gene on chromosome 13 (90%), and mutations of the TP53 tumor suppressor gene on the short arm of chromosome 17 (>80%) (Table 41-1). There has been substantial progress in understanding the relationship of the molecular abnormalities that cause normal bronchial epithelium to become carcinoma. However, there has not yet been much progress in preventing these events or reversing them once they have taken place.
| Molecular Abnormality | SCLC (%) | NSCLC (%) |
|---|---|---|
| RAS mutation | <1 | 30-40 |
| MYC amplification | 30 | 10 |
| EGFR expression | NR | 40-80 |
| ERBB2 (HER2) overexpression | 10 | 30 |
| KIT (SCFR) coexpression | 70 | 15 |
| BCL2 expression | 95 | 35 |
| TP53 mutation | 75-100 | 50 |
| RB1 deletion (loss of RB1 protein) | 90 | 20 |
| CDKN2A (pl6) inactivation | <1 | 70 |
| COX-2 expression | NR | 70 |
| 3p deletion | 90 | 50 |
| VEGF expression | >100-fold variation | |
| Matrix metalloproteinase (gelatinase) | 50 | 65 |
| Neuropeptides | 90 | NR |
BCL2, B-cell lymphoma 2; CDKN2A, cyclin-dependent kinase inhibitor 2A gene (formerly designated pl6); cKit, tyrosine-protein kinase Kit; COX-2, cyclooxygenase-2; EGFR, epidermal growth factor receptor; ERBB (HER2), human epidermal growth factor receptor 2; NR, not reported; NSCLC, non–small cell lung cancer; RAS, rat sarcoma; RB1, retinoblastoma gene; SCFR, stem cell factor receptor; SCLC, small cell lung cancer; TP53, tumor protein 53; VEGF, vascular endothelial growth factor; 3p deletion, deletion in the short arm of chromosome 3 in the 3p14-23 region.
Adapted from Dye GK, Adjei AA: Novel targets for lung cancer therapy. Part I. J Clin Oncol 20:2881-2894, 2002.
The chromosome 3 genetic deletions have been observed in both dysplastic and preneoplastic changes and have been demonstrated as the genetic mutations associated with the transformation of precancerous lesions into carcinoma. Recently emerged evidence has shown that the critical deletion in SCLC and many other malignant diseases may be in a fragile portion of chromosome 3 known as the fragile histidine triad gene (FHIT gene).7,8 Mutations in the FHIT gene are found in many different cancers, suggesting that defects in these genes may have a role in tumor development. Inactivation of the RB gene most likely results in a loss of control of cell growth. It is thought that a functional RB gene keeps the G1/S cell cycle boundary in check and that its inactivation will result in uncontrolled growth.9 The TP53 mutations specific to SCLC have also been observed in preneoplastic lesions and appear to most closely resemble TP53 mutations observed in other malignant diseases for which tobacco is a known carcinogen. It is likely that the TP53 mutations in SCLC impair the ability of tumor cells to undergo apoptosis in response to various therapies.10 Another growth regulator, which is overexpressed in 95% of SCLC tumors, is BCL2. This overexpression may prevent the tumor’s apoptotic response to therapy.11
Amplification or overexpression of the myc family of oncogenes is often observed, most notably, c-myc, N-myc, and L-myc. It appears that abnormalities are more often observed in recurrent tumors, tumors with variant rather than classic SCLC, or tumors with a more aggressive and unfavorable prognosis. This has led to the concept that the overexpression of the myc oncogenes is a relatively late event in the pathogenesis of SCLC.12
Another biologic feature that distinguishes SCLC from NSCLC is the more common expression of neuroendocrine markers in SCLC. These neuroendocrine markers include enzymes such as neuron-specific enolase and L-dopa decarboxylase, peptide hormones such as gastrin-releasing peptide and arginine vasopressin, and surface markers such as neural cell adhesion molecule. The two peptide hormones meet the criteria of autocrine growth factors, which require the production of a growth-promoting protein for which the producing cell has functional receptors. In the case of gastrin-releasing peptide, there is clear evidence that it is produced and secreted by many SCLC cells and then attaches to its cellular membrane receptors, stimulating tumor growth.13
Clinical Manifestations, Patient Evaluation, And Staging
SCLC is the most common solid tumor to have a number of associated paraneoplastic syndromes. Several of these are endocrinologic and neurologic syndromes. The most common endocrinologic abnormality is the syndrome of inappropriate secretion of antidiuretic hormone (SIADH). This condition results from the excessive secretion of antidiuretic hormone from tumor tissue, leading to severe hyponatremia with resultant hypo-osmolality. SIADH occurs in 11% to 46% of SCLC patients and typically resolves after response to anticancer therapy. Restriction of free water intake is critical to maintaining proper sodium concentrations before SIADH improves secondary to cancer therapy.14 Table 41-2 lists paraneoplastic syndromes associated with SCLC.15
The neurologic syndromes associated with SCLC include Lambert-Eaton syndrome, cerebellar degeneration syndrome, encephalomyelitis, sensory neuropathy, and cancer-associated retinopathy. Each of these is observed in well under 5% of SCLC patients. Lambert-Eaton syndrome is an autoimmune disorder that affects calcium channels of the neuromuscular junction. Antibodies are directed against the calcium channels responsible for the presynaptic release of acetylcholine. These antibodies prevent the opening of calcium channels and, therefore, the release of acetylcholine. Patients with Lambert-Eaton syndrome present with myasthenia gravis–like symptoms of proximal myopathy, autonomic dysfunction, and hyporeflexia. Like many paraneoplastic syndromes, this condition generally improves with response to anticancer therapy, although there can also be symptomatic responses to antimyasthenia therapies.16 The other neurologic syndromes are thought to be primarily autoimmune phenomena and usually respond poorly to cancer therapy.17,18
The Veterans Administration Lung Cancer Study Group staging system, which distinguishes between L-SCLC and E-SCLC is most commonly used.19 The initial definition of limited disease was an extent of intrathoracic disease that could be encompassed within a “reasonable” radiation field. Investigators in recent years have recognized the dangers of variable interpretations, and recent cooperative group trials require the staging of SCLC patients with the standard TNM system. However, the categorization of SCLC lesions as limited-stage versus extensive-stage disease has been extremely helpful for making rational treatment choices and designing trials.
Approximately two thirds of SCLC patients have extensive-stage, or stage IV, disease at presentation. Staging evaluation would traditionally include a history and physical examination, complete blood cell count, chemistry panel, contrast-enhanced CT scanning of the thorax and upper abdomen, pulmonary function testing, and CT or magnetic resonance imaging (MRI) scanning of the brain. Positron emission tomography (PET) scans are quite accurate for the staging of this SCLC. PET scans can aid with the choice of appropriate therapy and with radiation therapy planning by better identifying the tumor.20 PET/CT scanning can replace the traditional radiographic staging studies for SCLC with the exception of CT or MRI of the brain because uptake of the tracer is high in the brain and metastases are difficult to distinguish from normal brain tissue.
There have been several efforts to identify prognostic factors other than staging as a means of better selecting patients for specific therapies. As with many malignant diseases, good performance status, young age, and female gender are associated with a better prognosis, and these factors have been verified in large multivariate analyses.21,22,23,24 The Mayo Clinic/North Central Cancer Treatment Group (NCCTG) recently evaluated 1598 patients with SCLC to determine prognostic factors. Multivariate analysis revealed that performance status, age, gender, number of metastatic sites, and baseline creatinine levels were all associated with survival rates of E-SCLC patients. Among L-SCLC patients, only age and gender were associated with survival rates.24 One critical reason for determining prognostic factors is to help in selecting and stratifying patients for well-designed trials, so that investigators can decrease the possibility that uncontrolled biases will cloud the results.
Treatment
Thoracic Radiotherapy
After the demonstration in the late 1960s of the activity of several chemotherapeutic agents and the poor prognosis of patients treated with surgery and/or radiation alone, chemotherapy became the primary therapy for SCLC.25,26 Unfortunately, recurrence inevitably followed the response to chemotherapy, and the relapses were most frequently in areas of previous disease. This pattern of failure led investigators to reexamine the use of thoracic radiation therapy for L-SCLC. Today, both radiation therapy and chemotherapy have central roles in the treatment of SCLC.27,28 A series of randomized trials were performed comparing chemotherapy alone with chemotherapy with thoracic radiation therapy.29–31,32 In 1992, two meta-analyses were published regarding the role of thoracic radiation therapy in addition to chemotherapy.2,32 Pignon and colleagues32 reported a 3-year survival rate of 14.3% with combined-modality therapy compared with 8.9% with chemotherapy alone (p = .001). This 5.4% absolute difference in 3-year survival rates was identical to the 5.4% difference in 2-year survival rates (p <.001) reported by Warde and Payne.2 Although this 5.4% difference appears rather small, it represented a 61% increase in the 3-year survival rate of 8.9% achieved with chemotherapy alone.32 In addition, the intrathoracic tumor control rate was improved by 25% with thoracic radiation therapy.2
Sequencing and Timing of Thoracic Radiation Therapy and Chemotherapy
Chemotherapy and thoracic radiation therapy can be delivered concurrently, sequentially, or in an alternating manner. Potential advantages of concurrent delivery include the shorter overall treatment time, an increase in treatment intensity, and potential anticancer synergism between the various therapies. Disadvantages include the heightened toxicity and the inability to assess the antitumor response rate of the chemotherapy alone. The Japanese Clinical Oncology Group performed a phase III trial in which L-SCLC patients were randomized to sequential or concurrent therapy. All 231 patients received four cycles of etoposide-cisplatin therapy every 3 weeks (sequential arm) or 4 weeks (concurrent arm) and were randomized to receive thoracic radiation therapy during the first cycle of chemotherapy in the concurrent arm or after the fourth cycle in the sequential arm. Thoracic radiation therapy included 45 Gy (1.5 Gy twice daily) over 3 weeks. Concurrent therapy yielded a trend toward better survival times than sequential therapy (p = .097). The median survival time was 19.7 months in the sequential arm versus 27.2 months in the concurrent arm. The 5-year survival rate for patients treated sequentially was 18.3% versus 23.7% for those treated concurrently. Hematologic toxicity was more severe in the concurrent arm, as was esophagitis, which occurred in 9% in the concurrent arm and 4% in the sequential arm. The authors concluded that the findings strongly suggested that concurrent therapy was more effective for L-SCLC.33
There have been conflicting results from the randomized trials that have addressed the issue of timing of thoracic radiation therapy during chemotherapy. However, recent meta-analyses help make sense of the contradictory data. One study analyzed randomized trials published after 1985 addressing the timing of thoracic radiotherapy relative to chemotherapy in L-SCLC. Early thoracic radiation therapy was defined as radiation therapy initiated less than 9 weeks after the start of chemotherapy, and late thoracic radiation therapy as radiation therapy initiated ≥9 weeks or longer after the start of chemotherapy. Seven trials (n = 1524 patients) met the inclusion criteria and were included in the analysis. The relative risk of survival for early thoracic radiation therapy compared with late thoracic radiation therapy for all studies was 1.17 (p = .03), indicating an increased 2-year survival rate for early-therapy patients. This translated to a 5.2% (p = .03) improvement in the 2-year survival rate for early-therapy patients.34 A subsequent meta-analysis investigated the influence of the time interval between the start of any treatment until the end of thoracic radiation therapy (SER) on rates of local tumor control, survival, and esophagitis. There was a significantly higher 5-year survival rate in the shorter SER arms (relative risk [RR] = 0.62; p = .0003), which was more than 20% when the SER was less than 30 days. A low SER was also associated with a higher incidence of severe esophagitis (RR = 0.55; p <.0001). Each week of extension of the SER beyond that of the study arm with the shortest SER resulted in an overall absolute decrease in the 5-year survival rate of 1.83%. Therefore, earlier, shorter, more intense thoracic radiation therapy programs improved survival rates.35
Thoracic Radiation Therapy Doses
SCLC is considered a radioresponsive malignant tumor because low doses of thoracic radiation therapy, previously used, produced encouraging responses. Total thoracic radiation therapy doses for L-SCLC have ranged from 25 to 30 Gy in 10 fractions in the 1970s to up to 70 Gy in 35 fractions in recent years. Doses in the lower end of this range were acceptable when chemotherapy was less effective and disseminated disease occurred earlier in the disease course. Improvements in systemic therapy have increased the need for aggressive thoracic radiation therapy regimens that produce more durable responses. Choi and Carey36 estimated that the risk of intrathoracic tumor failure at total doses of 40 Gy or less was 80%, and this was confirmed in a National Cancer Institute of Canada (NCIC) L-SCLC trial in which patients were randomized between 25 Gy in 10 fractions versus 37.5 Gy in 15 fractions.37 The 2-year actuarial rates of local failure were 80% and 69%, respectively.
The most commonly administered doses of thoracic radiation therapy range from 45 to 70 Gy in 1.8- to 2-Gy daily fractions. Most trials estimated the local control rates in this dose range to be between 58% and 85%.38 The Cancer and Leukemia Group B (CALGB) found a dose of 70 Gy in 35 daily fractions to be both tolerable and effective. Eligible patients received two cycles of induction paclitaxel and topotecan with granulocyte colony-stimulating factor support, followed by three cycles of carboplatin and etoposide. Thoracic radiation therapy was initiated with the first cycle of carboplatin and etoposide. Prophylactic cranial irradiation was offered to patients achieving a favorable response. Nonhematologic grade 3 to 4 toxicities affecting more than 10% of patients, during or after thoracic radiation therapy, were dysphagia (16% and 5%) and febrile neutropenia (12% and 4%), respectively. The median overall survival time was 22 months. The researchers concluded that 70 Gy daily of thoracic radiation therapy could be delivered safely. They hypothesized that high-dose once-daily therapy resulted in comparable or improved survival rates compared with twice-daily therapy and that the theory warranted testing in a phase III trial.39
Altered Fractionation in Thoracic Radiation Therapy
Several encouraging pilot studies led to the development of a phase III trial led by the Eastern Cooperative Group (ECOG) testing the concept that accelerated hyperfractionation would improve the outcome for L-SCLC patients. The experimental regimen was 45 Gy in 1.5-Gy twice-daily fractions beginning on day 1 of a four-cycle regimen of etoposide plus cisplatin. The interfraction interval was 6 to 8 hours, and the elapsed treatment time was 19 to 21 days. A total of 419 patients were randomized between the thoracic radiation therapy regimens of 45 Gy in 1.8-Gy once-daily fractions versus 45 Gy in 30 1.5-Gy twice-daily fractions. Of these, eight treatments were often given with oblique fields off the spinal cord to limit the dose to the spinal cord to 36 Gy. In both arms, the thoracic radiation therapy began on day 1 of a four-cycle course of etoposide plus cisplatin. There was a significant survival advantage for the patients who received twice-daily therapy as compared with those who received once-daily therapy, with 5-year survival rates of 26% versus 16%, respectively (p = .04). The median survival time was 19 months for the once-daily therapy group and 23 months for the twice-daily therapy group. The intrathoracic tumor failure rate was 36% for the twice-daily therapy arm and 52% for the once-daily therapy arm (p = .06). The principal difference in toxicity was a higher rate of grade 3 esophagitis in the twice-daily therapy arm (27% vs. 11%; p <.001).40 This study confirms the principle that intensification of thoracic radiation therapy beyond the relatively low dose once-daily regimen can improve rates of both local control and survival. This trial has altered the standard of care of L-SCLC patients because the twice-daily fractionation program is now considered to be the standard against which all other programs are measured.
The North Central Cancer Treatment Group (NCCTG) performed a trial (89-20-52) that has been misinterpreted as contradicting the findings of Intergroup Trial 0096. This trial included 310 patients with L-SCLC initially treated with three cycles of etoposide-cisplatin therapy.41
