Combined Modality Therapy for Limited-disease Small Cell Lung Cancer Luis Raez, MD Michael Samuels, MD Rogerio Lilenbaum, MD* Address *Mount Sinai Comprehensive Cancer Center, 4306 Alton Road Miami Beach, FL 33140, USA. E-mail:
[email protected] Current Treatment Options in Oncology 2005, 6:69–74 Current Science Inc. ISSN 1527–2729 Copyright © 2005 by Current Science Inc.
Opinion statement Small Cell Lung Cancer (SCLC) is highly sensitive to chemotherapy and radiotherapy. However, despite initial responses, relapses are common and most patients eventually succumb to this disease. Patients with limited-disease SCLC represent approximately 30% of all patients with SCLC, and are potentially curable when treated with combined chemotherapy and thoracic radiotherapy (TRT). Chemotherapy consists of four cycles of the combination of cisplatin and etoposide (PE). Thoracic radiotherapy should be started with the first or second cycle of chemotherapy, and preferably administered twice daily for 3 weeks. Prophylactic cranial irradiation (PCI) is recommended for patients who achieve a complete response. Surgery is of limited value in SCLC, except in patients who present with a solitary pulmonary nodule. Approximately 20% to 25% of patients with limited disease (LD)-SCLC can be cured with this aggressive approach. Newer treatment modalities are currently under investigation.
Introduction An estimated 174,000 new lung cancer patients will be diagnosed in the United States in 2004 [1]. Historically, 20% to 25% of lung cancer patients had small cell lung cancer (SCLC), but more recent reports indicate that SCLC has decreased in incidence, and currently constitutes no more than 15% of all lung cancers [2]. The reasons for this decline remain unclear, but may be related to pathology issues and patterns of smoking. Indeed, of all subtypes of lung cancer, SCLC is the most strongly associated with tobacco exposure, with greater than 95% of the patients having a history of cigarette smoking. The staging of SCLC is based on the old Veterans Administration system and comprises limited or extensive disease. Limited-stage SCLC (LD-SCLC) is defined as disease that can be encompassed within a radiation field. This includes the primary tumor and the regional lymph nodes, including contralateral hilar and medi-
astinal lymph nodes, and ipsilateral supraclavicular lymph nodes. Extensive-disease SCLC (ED-SCLC) is defined as disease outside of these borders. Patients with pleural effusions, pleural nodules, bilateral supraclavicular involvement, and multiple ipsilateral lung nodules should be treated as ED-SCLC. The basic work-up for patients with SCLC includes history, physical examination, pathology review, a full set of laboratory tests, computed tomography (CT) scans of the chest and upper abdomen, magnetic resonance imaging (MRI) of the brain, bone scan, and pulmonary function tests. The use of positron emission tomography (PET) scans in SCLC has not yet been validated. A study [3] from Spain showed no improvement of PET scanning over conventional staging in patients with SCLC. Bone marrow aspirates and biopsies are no longer routine.
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Approximately one-third of patients with SCLC present with limited-disease. Besides stage, performance status, and gender are also important prognostic factors. Age is not a significant prognostic variable in LD-SCLC patients, but may affect toxicity patterns. Continuation
of smoking will adversely affect the outcome. Other adverse prognostic factors in both LD- and ED-SCLC include elevated lactate dehydrogenase (LDH) and alkaline phosphatase, low sodium, and the presence of paraneoplastic syndromes [4].
Treatment Chemotherapy • The standard chemotherapy for patients with LD-SCLC is the combination of cisplatin and etoposide (PE), which is less toxic when combined with thoracic radiotherapy (TRT). The most commonly used doses are cisplatin at 60 mg/m2, administered on day 1, and etoposide, at 100 to 120 mg/m2, given daily for 3 consecutive days [5••]. The cycle is repeated every 21 days, for a total of four cycles. Response rates of PE chemotherapy, along with TRT, range from 70% to 90% in LD-SCLC patients, with approximately 50% achieving a complete response. • Investigators have attempted to replace cisplatin with carboplatin, which has a more favorable toxicity profile and it is easier to administer. A phase III study [6] conducted by the Hellenic Cooperative Oncology Group (HCOG) showed comparable complete response rates and median survival times between the two platinum analogs given in combination with etoposide. However, while this substitution has been widely adopted for patients with ED-SCLC, most cooperative group protocols in the United States still recommend cisplatin for patients with LD-SCLC. • There have been several attempts to add a third agent, such as ifosfamide or paclitaxel, to the PE doublet, but none has yet led to an improvement in survival or quality of life [7,8]. In ED-SCLC, a large intergroup phase III trial [9] in the United States showed that the addition of paclitaxel to PE resulted in increased toxicity and no improvement in survival. • Other strategies designed to improve survival in patients with LD-SCLC include maintenance or high-dose chemotherapy, neither of which led to an improvement in outcome. In fact, maintenance or “consolidation” topotecan was recently tested in a phase III trial [10] in patients with ED-SCLC with no significant impact on survival. • Other new agents have been tested in SCLC. The most promising results were reported in a randomized trial [11•] from Japan, which compared PE versus cisplatin/irinotecan (PI) in patients with ED-SCLC. There was a significant survival advantage for the PI arm (1-year survival, 58% vs 38%; P=0.002). A higher incidence of moderate to severe diarrhea was observed in the PI arm, whereas more severe hematological toxicity was reported in the PE arm. There are two confirmatory randomized trials ongoing in the United States. Further, investigators from Radiation Therapy Oncology Group (RTOG) and Cancer and Leukemia Group B (CALGB) are testing the combination of prolonged infusion (PI) with TRT in LD-SCLC (see below).
Cisplatin Standard dosage Contraindications Mechanism of action Main drug interactions
60 to 80 mg/m2 IV on day 1, repeated every 21 days. Poor renal function, hearing problems; hypersensitivity; neurotoxicity Damage of DNA with cross-links. Avoid other drugs that cause renal damage.
Modality Therapy for Small Cell Lung Cancer
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Etoposide Standard dosage 100 mg or 120 mg/m2 IV on days 1 to 3, repeated every 21 days. Contraindications Hypersensitivity; bone marrow suppression (leukopenia, neutropenia, and thrombocytopenia). Mechanism of action Topoisomerase-2 inhibitor. Main drug interactions Avoid using with other drugs that cause bone marrow suppression if possible.
Carboplatin Standard dosage Area under the curve (AUC) of 5 to 6 on day 1, repeated every 21 days. Contraindications Bone marrow suppression (leukopenia, neutropenia, and thrombocytopenia) Mechanism of action Carboplatin, like cisplatin, produces predominantly interstrand DNA cross-links rather than DNA-protein cross-links. This effect is apparently cell-cycle nonspecific. Main drug interactions Avoid using with other drugs that cause bone marrow suppression if possible.
Thoracic radiotherapy • Thoracic radiotherapy has been demonstrated in a meta-analyses by Pignon et al. [12] to improve local control and prolong survival compared to chemotherapy alone in patients with LD-SCLC. Overall survival at 3 years was improved by 5%, with younger patients benefiting the most. However, long-term local control remains relatively poor, and issues such as total dose, fractionation schedule, field design, and sequencing of radiation therapy with chemotherapy have been subject to intense investigation in recent years. • Randomized data from Murray et al. [13] demonstrated that TRT given early (with the second cycle of chemotherapy) was superior to delaying TRT until the final cycle of chemotherapy. Twice-daily TRT was subsequently tested in a phase III trial led by Turrisi [5••], which randomized 417 patients with LD-SCLC to 45 Gy delivered in 25 fractions once daily over 5 weeks versus 45 Gy delivered in 30 fractions twice daily over 3 weeks. Chemotherapy consisted of four cycles of PE, and TRT was started on the first day of therapy (Fig. 1). Five-year survival was significantly improved in the BID arm, at 26% versus 16% (P=0.04). Local failure was also reduced in the BID arm (36% versus 52%, P=0.06), but acute grade-3 esophagitis was increased (27% versus 11%; P
