Anna F. Farago, Rebecca Suk Heist
EPIDEMIOLOGY
Lung cancer is the leading cause of cancer-related mortality in the United States with over 172,000 new cases and over 163,000 deaths in 2005 with over 225,000 new cases and 160,000 deaths in 2013. Approximately 14% of lung cancers diagnosed between 2005 and 2009 were small cell lung cancer (SCLC), with the remainder being various subtypes of non-small cell lung cancer (NSCLC) such as adenocarcinoma, squamous cell, and large cell, among others. The proportion of new lung cancers diagnosed that are SCLC has been declining over the past few decades. The reasons for this are unclear but may relate at least in part to the changing composition of cigarettes and inhalation patterns.
SCLC is associated with cigarette smoking in the vast majority of cases. Both duration of smoking and number of cigarettes per day are directly correlated with lung cancer risk. Patients who quit smoking decrease their lung cancer risk, although not to never-smoking levels (1).
PATHOLOGY
SCLC is a type of high-grade neuroendocrine lung cancer. The neuroendocrine lung tumors encompass a diverse spectrum that ranges widely in prognosis, from low-grade typical carcinoids and intermediate-grade atypical carcinoids to the higher-grade cancers including large cell neuroendocrine cancer and SCLC. SCLC and large cell neuroendocrine cancer behave similarly and have similar prognoses.
Pathologically, SCLC is defined as “a proliferation of small cells (<4 lymphocytes in diameter) with unique and strict morphologic features, scant cytoplasm, ill-defined borders, finely granular salt and pepper chromatin, absent or inconspicuous nucleoli, frequent nuclear molding, and a high mitotic count” (2). Immunohistochemical staining is generally positive for epithelial cell markers such as keratin and epithelial membrane antigen. In addition, neuroendocrine markers such as chromogranin A and synaptophysin are positive in the majority of SCLCs.
CLINICAL PRESENTATION
Most patients present with symptoms that are related to the intrathoracic bulk of disease or widespread dissemination. Cough, dyspnea, weight loss, and weakness are the most common presenting symptoms (3).
In addition, a variety of paraneoplastic syndromes are observed with SCLC. The ectopic production of hormones is a common culprit for the endocrine paraneoplastic disorders, which include hyponatremia (due to ectopic production of antidiuretic hormone), Cushing’s syndrome (ectopic corticotropin production), and acromegaly (ectopic growth hormone releasing hormone). Neurologic paraneoplastic syndromes such as Lambert-Eaton myasthenic syndrome are caused by autoantibody-mediated damage to the nervous system. Treatment of the underlying tumor can help control these paraneoplastic syndromes; in addition, medical management of symptoms may be indicated (see Table 52-1).
TABLE 52-1 CLINICAL PRESENTATION
DIAGNOSIS AND STAGING
Radiographically, SCLCs tend to present as central hilar masses with bulky mediastinal lymphadenopathy. Given the central location of most SCLCs, the diagnosis is usually made by pathologic analysis of a bronchoscopic or endoscopic biopsy sample. Alternatively, percutaneous CT-guided biopsies provide another means of obtaining tissue for diagnosis.
Once the diagnosis of SCLC is made, accurate staging is important for treatment planning. SCLC is traditionally categorized into either limited stage or extensive stage disease, as described by the Veteran’s Administration Lung Group. Limited stage is typically defined as disease that involves one hemithorax or disease that is encompassable within one radiotherapy port; using the TNM staging system, this corresponds to T any, N any, M0, excluding T3-4 due to multiple nodules that do not fit within a tolerable radiation field. Extensive stage is any disease that extends beyond these parameters. The majority of patients present with extensive stage disease.
The staging workup is designed to establish whether a patient has meta-static disease, since this will substantially alter both the prognosis and treatment plan. The workup should include a CT of the chest with extension into the abdomen to evaluate the liver and adrenals, which are common sites of metastasis. Brain imaging should be performed since the CNS is a frequent site of spread. Both head CT and brain MRI are commonly used, but MRI is preferred for its greater sensitivity for detecting metastatic disease. Bone scan should be performed to assess for bony metastases. PET scans are increasingly being used for staging purposes, but its exact role is not yet clearly defined.
TREATMENT FOR LIMITED STAGE SCLC
Limited stage SCLC is treated with a combination of chemotherapy and radiation, which typically yields a response rate of greater than 80% (complete response 40%–60%) and median survival of 14–20 months. Surgery is not typically attempted due to the high early dissemination rate and poor overall survival at 5 years. Occasionally, patients present with a T1-2N0M0 cancer that is surgically resected on the presumption of NSCLC. These patients still need adjuvant chemotherapy after resection with appropriate SCLC regimens.
Combination chemotherapy and radiation remain the standard of care for limited stage SCLC. In terms of chemotherapy, cisplatin and etoposide is the standard regimen used. A randomized phase III trial demonstrated better survival among limited stage SCLC patients treated with cisplatin and etoposide in combination with radiation compared with the regimen of cyclophosphamide, epirubicin, and vincristine with radiation (4). As the cisplatin/etoposide regimen is easily combined with radiation, with little mucosal toxicity and less hematologic toxicity than other regimens, it remains the standard of care.
The addition of radiation to chemotherapy improves survival, and approximately 5% more patients are alive at 2 and 3 years when treated with combination chemoradiation versus chemotherapy alone (5). The early incorporation of radiation appears to yield better results than waiting until later in the treatment course. Several trials have addressed the timing of thoracic radiation. The National Cancer Institute of Canada randomized 308 patients receiving chemotherapy to early thoracic radiation (starting with the second cycle of chemotherapy) versus late thoracic radiation (starting with the sixth cycle). There was no difference in the total cumulative chemotherapy dose delivered between the two arms, but both progression-free survival and overall survival were improved in the early radiation arm (6). Multiple meta-analyses have also examined the benefits of early versus late thoracic radiation, and most favor early radiation (7–12). There is a suggestion that completing radiation within 30 days of starting any therapy, without compromising chemotherapy dosing, may be most beneficial.
Hyperfractionated radiation also appears to improve outcomes. Turrisi et al. randomized 417 patients with limited SCLC to cisplatin/etoposide given with either daily (qd) radiation (45 Gy total, 1.8 Gy fractions) or twice-daily (bid) radiation (45 Gy total, 1.5 Gy fractions). Patients on the bid dose schedule had better median survival (23 months for bid, vs. 19 months for qd) and 5-year survival (26% vs. 16%). Significantly worse toxicities were noted with the bid regimen, including grade III esophagitis, which occurred in 27% of this population versus 11% of the qd dosed population (13).
Not all centers have adopted the hyperfractionated dosing, however, and the question of whether hyperfractionation or total dose of radiation is more important remains debated. Choi et al. tested escalating radiation doses in both the qd and bid schedules. The bid total dose was limited to 55 Gy while the qd dose went up to 70 Gy. In long-term follow-up, both median survival (24 months vs. 29.8 months) and 5-year survival (20% vs. 36%) favored qd dosing (14).
Current NCCN guidelines recommend that radiation be delivered concurrently with chemotherapy in limited stage SCLC, starting within the first two cycles of chemotherapy. Either twice-daily dosing of radiation (to a total dose of 45 Gy in 1.5 Gy fractions) or once-daily dosing (to a total dose of 60-70 Gy) is acceptable (15).
PROPHYLACTIC CRANIAL IRRADIATION
Prophylactic cranial irradiation (PCI) should be considered in both limited and extensive stage disease where there has been response.
PCI has been shown to improve overall survival at 3 years by approximately 5% (from 15.3% to 20.7%). In addition, PCI decreases the incidence of future brain metastases by approximately 25% (from 58.6% without PCI to 33.3% with PCI) (16). Slotman et al. have examined PCI in patients with extensive stage disease who had a response to chemotherapy. PCI reduced the risk of brain metastases at 1 year from 40.4% to 14.6%, and improved median overall survival from 5.4 to 6.7 months (17). Typical doses range from 24 to 30 Gy. High-dose (36-Gy) PCI resulted in no significant reduction in brain metastases and a significant increase in mortality compared to standard dose (25 Gy) in patients with limited stage disease (18).
TREATMENT FOR EXTENSIVE STAGE SCLC
Chemotherapy is the mainstay of treatment for extensive stage SCLC. As in limited stage SCLC, the combination of cisplatin and etoposide is one of the most widely used regimens in the United States. Response rates range from 60% to 70%, but the overall survival remains poor, with less than 5% of extensive SCLC patients alive at 2 years. Median survival is between 9 and 11 months.
A phase III trial in Japan raised a great deal of interest in a new combination of cisplatin and irinotecan for treatment of extensive SCLC, showing a significant improvement in median survival among patients treated with cisplatin/CPT11 versus cisplatin/etoposide (12.8 months vs. 9.4 months) (19). However, a follow-up U.S. study failed to show a significant difference in response or survival between the two regimens (20).
Numerous studies have attempted to alternate chemotherapy regimens or add a third agent, but none of these strategies have proven more effective than the doublet of cisplatin/etoposide. In addition, attempts to administer high-dose therapy with autologous bone-marrow transplantation have not shown a significant benefit in the phase III setting.
Therefore, cisplatin/etoposide remains the standard regimen in extensive SCLC. A total of four to six cycles are usually delivered, as prolonged maintenance chemotherapy has not shown any significant survival benefit and increases the toxicity risk. Since chemotherapy in the extensive stage setting is palliative in nature, carboplatin is often substituted for cisplatin to minimize toxicity. A meta-analysis of four trials comparing cisplatin- and carboplatin-based chemotherapy in first-line treatment found no differences in overall survival, progression-free survival, or response rate, although there were differences in the toxicity profiles (21).
TREATMENT FOR REFRACTORY OR RELAPSED SCLC
Patients whose disease recurs within 3 months of completing initial chemotherapy or who have progressive disease during treatment are considered to have “refractory” disease. Patients whose disease recurs beyond 3 months of initial therapy are considered to have “relapsed” disease. Although refractory and relapsed patients are generally treated with similar second-line regimens, their prognoses are significantly different: patients with refractory disease have much poorer response to additional therapies.
Median survival after SCLC recurrence ranges from 2 to 6 months. Therefore, the goals of salvage chemotherapy and a focus on palliation must be carefully discussed with patients and families.
For patients who have failed carboplatin/etoposide or cisplatin/etoposide, topotecan is commonly used as second-line therapy. In a phase II trial administering single-agent topotecan to patients who progressed after first-line chemotherapy, overall response rate was 22%. Patients who had relapsed disease had higher complete and partial response rates (13% CR, 24% PR) compared with patients who had refractory disease (2% CR, 4% PR) (22). In a phase III trial administering single-agent oral topotecan or best supportive care to patients with recurrent disease after first-line chemotherapy, survival was prolonged in the topotecan group (25.9 weeks vs. 13.9 weeks) and quality of life deterioration was slowed (23). Furthermore, oral and IV topotecan offer similar response rates, survival, and tolerability among patients with relapsed disease (24). Other agents with activity include irinotecan, taxanes, and gemcitabine. Single-agent therapy is generally preferred over combination therapies, as minimizing toxicities in this palliative setting is important. Enrollment on clinical trials is encouraged, as none of the above regimens are extremely successful.
MOLECULAR FEATURES OF SCLC
Recently, the molecular alterations underlying SCLC are becoming better understood. Loss of the tumor suppressor genes TP53 and RB1 is nearly universal among SCLC tumors and cell lines (25–29). Amplification of at least one MYC family member (most commonly MYCL1 and N-MYC) also occurs in the majority of tumors (30–32). Altered expression of bcl-2 and c-kit has also been reported in SCLC (33–35), with c-kit mutations reported in a small minority (36). Multiple bcl-2 inhibitors and the c-kit inhibitor imatinib have been tested in SCLC, but have not shown significant activity to date; it is possible that the clinical trials have not pinpointed the optimal subset of patients to treat or the optimal combination of agents (37–39). Heterozygous loss of PTEN is also commonly seen (40), but homozygous deletions and point mutations are less common (28, 41). Although not yet tested clinically, it is possible that PI3K inhibitors may be useful in targeting this subset of patients. While beta-specific inhibitors may be of particular interest for PTEN-deficient tumors (42), there are also reports of p110-alpha inhibition being important to impairing growth of SCLC (43), and clinical testing in genetically defined subsets of patients may be informative.
More recent whole genome and whole exome sequencing efforts have confirmed what has been known historically and identified a variety of other gene mutations that occur in SCLC tumors and/or cell lines, including alterations predicted to influence signaling pathways and histone modifications (28–29). The clinical significance of such alterations is not yet clear, but is an area of active investigation (44–45).
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