The Paradox of the Efficacy of Local Treatment for Small-Cell Lung Cancer

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Introduction

Although small-cell lung cancer (SCLC) is a systemic disease all or nearly all of the time, advances in treatment of this systemic disease have come from radiotherapy innovations over the past 20 years. The best results in long-term survival for limited SCLC have been achieved by the addition of thoracic irradiation to systemic chemotherapy, and more intense thoracic irradiation, with early integration of thoracic irradiation and concurrent chemotherapy. The addition of prophylactic cranial irradiation (PCI) adds to survival in complete responders as proven by meta-analytic data. To the surprise of many, a recent trial proves that extensive stage SCLC benefits from PCI after any response to systemic therapy provided for 4 to 6 cycles.

Findings from the American Society of Clinical Oncology as well as a broader review of small-cell lung cancer therapy are summarized in a Journal of Thoracic Oncology overview coauthored with Nevin Murray.¹ This E-Update relates the advances in local therapy, particularly radiotherapy, that have made a profound, although often ignored, difference in this systemic disease.

Incidence and Outlook

Small-cell lung cancer (SCLC) appears to be declining in frequency.² This reduced incidence of SCLC seems to have curtailed interest and investigation as well. The tempo of SCLC investigation does not match the public health problem since SCLC still accounts for 4% of all cancer mortality.³

Untreated SCLC has a dismal outlook, with a median survival of 2 months for extensive small-cell lung cancer (ESCLC) and 3 months for limited small-cell lung cancer (LSCLC).⁴ Despite high initial responses to chemotherapy, SCLC proves ultimately resistant in most cases. Median survivals of 20 months and 5-year survival of 25% to 30% for patients treated with chemoradiation are very similar for LSCLC and stage III non-small-cell lung cancer (NSCLC).^5,6 (See Table 1.)The interval from diagnosis to emergence of resistant clones, and then fatal outcome also seems comparable in SCLC and NSCLC.

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Although distant metastasis dominate, local and brain relapse remain problems, and disease control appears to plateau with 5-year survival of 20% to 30% in patients treated with combined modalities. While it appears that we are able to remove the visible cells, therapy seems to select for resistant clones. The patient with either limited or extensive SCLC has no chance once a resistant genotypic cell leaves the site of origin and establishes itself and grows distantly.

It may be that the small cells mimic primitive progenitor cells, especially those committed to forming the embryonic lung.⁷ With stem cells, the ability to migrate or circulate seems critical to their function during organogenesis. Since this also characterizes the metastatic phenotype in general and particularly in lung cancer; we need to identify characteristics and genes related to these functions. We are very able to eliminate the clusters of developed small cells, but the stem cells or progenitors are elusive, and the resistant clones return to doom the patient.

Although a truly effective chemotherapy combination has never become evident, the combination of cisplatin and etoposide is the internationally accepted standard for limited and extensive SCLC, except in Japan where irinotecan (CPT-11, Campath) is used instead of etoposide.⁸ Somewhat disconcerting and harkening back to the past, the CAV or CAE regimen (cyclophosphamide, doxorubicin [Adriamycin], vincristine and/or etoposide) has persisted in use for more than 30 years, including use in one of the few limited SCLC trials published this century.⁹

Interest in the combination of etoposide and cisplatin (EP)¹⁰ moved forward after this combination produced tumor regression in patients whose cancers had progressed following a cyclophosphamide-based regimen.¹¹ The consistent performance of EP (or acceptably, carboplatin and etoposide) in clinical trials and its compatibility with thoracic radiotherapy allowed both to be used at doses that are known to be systemically active. EP is better than alkylator-based or anthracycline-based regimens,¹² and it is possible that alkylator and anthracycline use is detrimental to survival.