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Seidenfeld J, Bonnell C, Ziegler KM, et al. Management of Small Cell Lung Cancer. Rockville (MD): Agency for Healthcare Research and Quality (US); 2006 Jul. (Evidence Reports/Technology Assessments, No. 143.)

  • This publication is provided for historical reference only and the information may be out of date.

This publication is provided for historical reference only and the information may be out of date.

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Management of Small Cell Lung Cancer.

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1Introduction

This systematic review summarizes and analyzes evidence on selected aspects of managing patients diagnosed with small cell lung cancer (SCLC). This section outlines the review's clinical scope, highlights relevant aspects of the disease's epidemiology and public health impact, describes briefly current treatment guidelines and uncertainties, and overviews key questions to be addressed.

Objective of Systematic Review

The American College of Chest Physicians (ACCP) is preparing to update its 2003 evidence-based guideline on diagnosis and management of lung cancer. To support this effort, the ACCP nominated SCLC as a topic for systematic review by one of the Agency for Healthcare Research and Quality's (AHRQ) Evidence-based Practice Centers (EPC). Consultation with technical experts, some nominated by ACCP, identified key issues in need of systematic review.

Epidemiology and Public Health Impact of Small Cell Lung Cancer

Small cell lung cancer (SCLC) accounts for 13–20 percent of the estimated 172,570 new cases and 163,510 deaths from lung cancer expected in the U.S. in 2005 (American Cancer Society, 2005; Murren, Glatstein, and Pass 2001; Simon and Wagner, 2003; Physicians Data Query 2005; Chua, Steer, and Yip, 2004; Ettinger 2004; Stupp, Monnerat, Turrisi, et al., 2004). Untreated SCLC has the most aggressive clinical course of any lung tumor, with a median survival of only 2 to 4 months after diagnosis (Physicians Data Query, 2005). Since it metastasizes rapidly, SCLC is present outside the hemithorax of origin in most patients at diagnosis (Physicians Data Query, 2005).

Current Staging and Treatment Strategies for Small Cell Lung Cancer

Staging and Classification

SCLC is also known as “oat cell” carcinoma or small cell undifferentiated carcinoma (American Cancer Society, 2004). SCLC can be subtyped according to cellular classification as 1) small cell carcinoma; 2) mixed small cell/large cell carcinoma; or 3) combined small cell carcinoma (i.e., small cell lung cancer combined with neoplastic squamous and/or glandular components) (Physician Data Query, 2005).

Although the TNM classification scheme used for non-SCLC is applicable to SCLC staging (Cameron and Schwartz, 2005), most clinicians use a simplified two-stage scheme developed by the Veterans Administration Lung Cancer Study Group (Simon and Wagner, 2003; Physician Data Query, 2005). Limited-stage SCLC (approximately 30 percent of patients at diagnosis) includes those with tumor confined to the hemithorax of origin, the mediastinum, or the supraclavicular lymph nodes (Simon and Wagner, 2003; Physicians Data Query, 2005). In extensive-stage SCLC, tumor has spread outside these limits; patients with distant metastases are always considered to have extensive disease (Physician Data Query, 2005). At the time of diagnosis, 60–65 percent of SCLC patients have extensive disease (Osterlind, 2001). Estimates of median survival with current therapies are 16–24 months for those with limited-stage disease, and 6–12 months for those with extensive-stage disease (Physician Data Query, 2005).

Diagnostic procedures commonly used to establish the presence of distant metastases include bone marrow aspiration, brain scans using computed tomography (CT) or magnetic resonance imaging, chest and abdomen scans using CT, and radionuclide bone scans (Physician Data Query, 2005; Murren, Turrisi, and Pass, 2005). Whether positron emission tomography (PET) metabolic scanning using 18-fluorodeoxyglucose (18-FDG) provides any additional information to current staging techniques is uncertain (Murren, Turrisi, and Pass, 2005; Simon and Wagner, 2003).

Treatment Strategies

Treatments for SCLC are selected by stage and other features of disease extent (Physician Data Query, 2005). Few patients with extensive SCLC currently attain long-term survival. Their survival at 2 years after diagnosis is approximately 5 percent and at 5 years is less than 1 percent (Murren, Turrisi, and Pass, 2005).

Over time, there has been better success in the management of patients with limited disease. The proportion of long-term survivors among these patients has doubled from the 1970s to the 1990s (Janne, Freidlin, Saxman, et al., 2002; Murren, Turrisi, and Pass, 2005). While this may be due in part to stage migration, it is probably more associated with the change in practice of using platinum-based, rather than cyclophosphamide-based, combination chemotherapy regimens (Murren, Turrisi, and Pass, 2005). Attempts to improve on those results, either by adding a third drug or by substituting newer drugs have not yielded more long-term survivors thus far. It appears that further improvement requires both more and more complete responses to primary therapy (i.e., chemotherapy and radiation). Absent that, other interventions seem to largely alter the pattern of relapse, but not overall survival.

Chemotherapy. Chemotherapy is used for most patients, either as adjuvant therapy for the few patients eligible for surgery, or as primary therapy for patients with inoperable tumors. Preferred regimens have evolved over time (Murren, Turrisi, and Pass, 2005). Current guidelines recommend platinum-etoposide combinations in patients with limited-stage disease and platinum-based regimens in patients with extensive-stage disease (Simon and Wagner, 2003; Osterlind, 2001). According to the 2003 ACCP guidelines, there is no evidence on the benefit of maintenance chemotherapy in any patient achieving a partial or complete remission, and maintenance therapy is not recommended outside of a clinical trial (Simon and Wagner, 2003).

Surgery. Surgery is usually limited to patients with smaller tumors (T1 or T2) and no evidence of nodal involvement or spread outside the hemithorax of origin (Physician Data Query, 2005). Whether surgery added to chemotherapy for patients with limited-stage disease improves survival is currently uncertain.

Thoracic Radiotherapy. Meta-analyses published in the 1990s demonstrated the benefit of adding thoracic radiotherapy (TRTx) to chemotherapy in patients with limited-stage disease (Warde and Payne, 1992; Pignon, Arrigada, Ihde, et al., 1992). Addition of TRTx to chemotherapy increased 2- to 3-year overall survival by an absolute 5.4 percent over chemotherapy alone (Warde and Payne, 1992; Pignon, Arrigada, Ihde, et al., 1992; Carney, 1999). Addition of TRTx to chemotherapy in patients with limited-stage SCLC is now the recommended course of therapy (Simon and Wagner, 2003). However, uncertainties remain with respect to optimal timing, sequencing, and radiation regimens (i.e., dosages and fractionation schemes) (Turrisi, 1994; Osterlind, 2001). Table 1 summarizes factors that might influence how chemotherapy and radiation may interact when used for primary treatment of limited stage SCLC.

Table 1. Alternatives for Combined Chemotherapy and Radiation to Treat Limited SCLC.

Table 1

Alternatives for Combined Chemotherapy and Radiation to Treat Limited SCLC.

Meta-analyses using different study inclusion criteria have addressed the timing of TRTx given with chemotherapy for limited-stage SCLC. Cancer Care Ontario (2003) included 5-year survival data for 4 studies involving 777 patients, finding no difference between early and late TRTx. Huncharek and McGarry compared the impact of early (i.e., given with the first or second course of systemic therapy) versus delayed (i.e., with the final courses) TRTx in patents with limited disease (Huncharek and McGarry, 2004). The analysis pooled data from 8 randomized, controlled trials enrolling over 1,500 patients and found that early, concurrent TRTx (i.e., administered during the same time period as chemotherapy) improved 1, 2, and 3-year overall survival relative to delayed TRTx, and that TRTx with etoposide/cisplatin regimens performed better compared with non-etoposide/cisplatin regimens. This meta-analysis was flawed by double-counting data from one study (i.e., Goto, Nishiwaki, Takada, et al. 1999 and Takada, Fukuoka, Kawahara, et al., 2002).

A meta-analysis by the Cochrane Collaboration (Pijls-Johannesma, De Ruysscher, Lambin, et al. 2004), included 7 studies, 6 of which overlapped with those in the Huncharek and McGarry meta-analysis, and found that the 2–3 year survival difference as a function of timing was less certain. The Cochrane meta-analysis identified patient selection issues and differences in systemic regimens as potential confounders. Fried, Morris, Poole, et al. (2004) included 7 studies with 1,500 patients and found that 2-year survival was significantly improved by early TRTx, but the pooled result was not significant at 3 years. Two-year subgroup analysis showed that using hyperfractionation and platinum chemotherapy were associated with significant advantages favoring early TRTx, but significant results were not obtained in studies using conventional fractionation and non-platinum chemotherapy.

The role of radiation therapy in extensive disease is less established than in patients with limited-stage disease (Murren, Turrisi, and Pass, 2005). Several large studies reported in the 1980s by the Southwest Oncology Group (SWOG) and that did not randomize patients to TRTx versus no TRTx, suggested that, although thoracic radiation reduced initial relapse at the primary tumor site, there was no effect on overall survival (Murren, Turrisi, and Pass, 2005; Livingston, Mira, Chen, et al., 1984; Livingston, Schulman, Mira, et al., 1986).

Prophylactic Cranial Irradiation. The frequency of brain metastasis in SCLC patients led to the hypothesis that subclinical metastases are commonly present in the brain at diagnosis. Thus, clinicians often add prophylactic cranial irradiation (PCI), particularly for patients achieving a complete remission (CR) after primary therapy. Without PCI, patients who achieve an extracranial CR have a 50–80 percent actuarial risk of developing CNS metastases within 2–3 years (Simon and Wagner, 2003; Murren, Turrisi, and Pass, 2005; Carney, 1999). In addition, among patients who achieve a CR with chemotherapy, approximately 15 percent have brain metastases as the initial or only manifestation of recurrence (Carney, 1999). A patient-level meta-analysis of almost 1,000 patients in complete remission from 7 randomized, controlled trials showed the addition of PCI can reduce the risk of CNS metastases by over half and significantly improves survival (Auperin, Arriagada, Pignon, et al. 1999; Prophylactic Cranial Irradiation Overview Collaborative Group, 2000; Carney, 1999).

Definitive recommendations regarding optimal timing of PCI and radiation dosage issues (e.g., optimizing dose to balance efficacy and toxicity, fractionation) still require additional study (Prophylactic Cranial Irradiation Overview Collaborative Group, 2000; Boher and Wenz, 2002). According to one of the PCI meta-analyses, “Establishing the optimal dose and timing of treatment so as to reduce further the incidence of brain metastases with minimal and acceptable toxicity should be the aim of future clinical trials” (Prophylactic Cranial Irradiation Overview Collaborative Group, 2000).

Data on the adverse effects of PCI, both acute (e.g., skin burns, headaches) and late-developing (e.g., neurocognitive impairment, overt cerebral necrosis) are also not well characterized from analyses of controlled trials (Boher and Wenz, 2002). Although many retrospective studies describe an association between PCI and neurotoxicity, evidence from prospective, controlled trials does not appear to support that association (Bohrer and Wenz, 2002).

Second-Line Therapy. Most patients respond to primary therapy, but relapse after remissions of varying duration (Murren, Turrisi, and Pass, 2005). Second-line therapy is offered to most patients if the first remission has lasted 3–6 months; relapse after 3 months or more is also known as “sensitive relapse” (Murren, Turrisi, and Pass, 2005). Evidence of benefit is lacking from second-line therapy for refractory SCLC (i.e., no remission after primary therapy). Response to second-line therapy appears to be related to the chemotherapy agents given in both the induction and second-line regimens (Murren, Turrisi, and Pass, 2005). It is also unknown whether third or subsequent lines of therapy for relapsed or progressive SCLC improve outcomes compared with best supportive care.

Key Questions for this Systematic Review

As stated previously, consultation with experts has identified critical concerns deserving of inquiry to support the ACCP update to guidelines on the diagnosis and management of lung cancer. Thus, this systematic review of the literature will address the following questions regarding managing patients with small cell lung cancer:

1.

For limited-stage SCLC, what are the relative benefits and harms (survival, toxicity, and quality of life) of TRTx combined with chemotherapy either in alternating fashion, concurrently or sequentially?

2.

For limited-stage SCLC, do outcomes (survival, toxicity, or quality of life) differ if concurrent TRTx is given in early versus late chemotherapy cycles?

3.

For limited-stage SCLC, do outcomes (survival, toxicity, quality of life) of primary therapy differ if one varies dose rate, treatment interval, or fractionation scheme for delivering TRTx? Comparisons of interest include:

  • accelerated regimens (>10 Gy per week completed over a short interval) versus standard duration regimens (<10 Gy per week) versus split courses delivered over the standard interval; and
  • single daily fractions versus hyperfractionated (two or more daily fractions or concomitant boost).

4.

What are the relative benefits and harms (survival, toxicity, and quality of life) of adding TRTx to chemotherapy for primary treatment of extensive-stage SCLC?

5.

What are the benefits and harms (survival, toxicity and quality of life) of prophylactic cranial irradiation (PCI)?

6.

Does the addition of PET scanning improve the accuracy of staging for patients diagnosed with SCLC, over the use of other techniques, including CT and MRI, without PET?

7.

What are the outcomes (survival, toxicity and quality of life) of treatments used to manage patients with mixed small cell/non-small cell lung cancers?

8.

What is the role of surgery and what is its impact on survival in patients with early stage SCLC? How do available studies define early stage SCLC?

9.

What are the outcomes of second- or subsequent-line therapy in patients with relapsed or progressive SCLC? Where available data permit, patients with limited- and extensive-stage disease will be addressed separately, as will those with refractory disease (relapse or progression within 3 months of primary treatment).

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