Surgery in limited-disease small-cell lung cancer.

Small cell carcinoma of lung (SCLC) constitutes about 15% of the lung cancers and due to its clinical and biologic characteristics is considered distinct from other lung carcinomas, collectively termed as non-small-cell lung carcinomas (NSCLC). SCLC exhibits an aggressive behavior that is characterized by rapid growth, early metastasis to distant sites, and exquisite sensitivity to chemotherapeutic agents and radiation. Currently combined chemotherapy and thoracic radiation therapy is the standard treatment for patients with limited-stage disease SCLC (LD): the combination of platinum and etoposide with thoracic radiation therapy being the most widely used regimen with clinical trials consistently having achieved median survivals of 18 to 24 months and 40% to 50% 2-year survival rates with less than a 3% treatment-related mortality.[1-3]

Generally unresectable at presentation due to local spread or dissemination, the role of surgery in SCLC, especially in the early stages, has remained a subject of considerable interest in recent years. In this issue of the journal, Arturo and Daniel present successful 2-year follow up of a patient with LD-SCLC who presented as a solitary pulmonary nodule and was managed with multimodality treatment including surgical resection. The authors recommend that surgical resection should be considered in the management of patients with LD-SCLC.

Although surgery was initially regarded as the treatment of choice for all types of lung cancer, it was abandoned for SCLC almost 30 years ago after the results of the Medical Research Council randomized trial revealed a significant survival difference between surgery and radiotherapy, a 4-year survival of 3% and 7%, respectively, and a 5-year survival of 5% in the radiotherapy arm.[4] After this study radiation therapy became the favored treatment for SCLC till the introduction and advancements in chemotherapy. After the introduction of TNM classification, investigators proposed that surgery was postulated to be indicated in LD-SCLC, particularly stage T1, N0, with 5-year survival rates of as high as 57.1% for stage 1 disease.[5-7] Ankaru and Waddell,[8] reviewed the rationale of surgery in SCLC and supported its utilization arguing that with current chemoradiotherapy protocols demonstrating local failure rates up to 50%,[9] surgical resection for T1-2, N0, M0 SCLC, could offer better local control of the disease compared to chemotherapy alone. Further, surgical resection after induction chemoradiotherapy demonstrated a control of local relapse in almost 100% of the patients and 5 and 10 year survival rates for patients with stage IIB to IIA were 39% and 35%, respectively, for all patients (resected or not) and 44% and 41% for patients treated with a trimodality approach including adjuvant surgery.[10] They also argued that the final histology of SCLC might reveal a component of NSCLC in 11-25% cases[11] and other histological subtypes might be misdiagnosed as SCLC prior to surgical resection,[812] and that it would be more logical to offer surgery in mixed or combined small-cell tumors. Salvage surgery could also be preferable to second line chemotherapy in cases of SCLC where after an initial response to chemoradiotherapy, a chemotherapy resistant tumor or a local recurrence of the disease is incident or in patients with mixed histology.[8]

Although no prospective randomized control trials comparing combined adjuvant surgery to chemotherapy or chemoradiotherapy alone are reported, accumulated data have shown that surgery can contribute to both prognosis and local recurrence control. Granetzny et al,[13] in a retrospective trial studied the effect of surgery in a trimodality treatment in 95 patients with SCLC and reported that patients with stage I and II SCLC can be treated with promising results using a combination of primary surgery and adjuvant chemotherapy as well as thoracic and cranial irradiation. Reviewing 2442 patients with SCLC in Norway, 38 of whom underwent surgical resection in conjunction with the routine therapy, Rostad et al,[14] concluded that more patients with peripherally located tumors stage 1A and 1B should have been referred for surgery because the 5-year survival rate for stage-1 patients improved from 11.3% for conventional treatment to 44.9% with the addition of surgery. Other investigators[15-17] too have supported adjuvant surgery in early stage SCLC whereas in stages II and III it is proposed to be planned in a multidisciplinary basis, in the context of controlled trials.[15] In a report by investigators from the Imperial College, UK, lung resection and mediastinal lymph node dissection used as primary therapy for SCLC in either pure (73%) or in mixed histological types was associated with a surprisingly 5- year survival for the total cohort of stage I-III patients of 52% independently of the tumor's T, N, and UICC stage.[17] This report strongly suggested that selected patients with SCLC, even in more advanced stage disease may benefit from surgery if complete tumor resection is achieved. In yet another recent study, Yu et al,[18] reported a 5-year survival of 50.3% amongst 205 patients with stage 1 SCLC who underwent surgical resection (lobectomy only) and they concluded that surgery without radiotherapy appears to offer reasonable survival outcomes in patients with stage I SCLC.

Hence, despite lack of randomized trials time has come to accept that surgery has to play an important role in management of LD-SCLC, either as a primary treatment or as adjuvant therapy. Thus, patients with early-stage SCLC (T1–2 N0 and perhaps even stage II) or “very limited” (to use a phrase coined by the University of Toronto Thoracic Oncology Group)[12] may benefit from a combined modality approach that includes surgery. In stage II disease induction concurrent chemotherapy and radiotherapy should be given and radical resection should follow with intent to curative therapy only if there has been a definite initial response to the induction treatment. In stage IIIA, if adjuvant surgery is planned, a mediastinoscopy should always precede the surgical treatment. If mediastinal clearance has not been achieved it is doubtable that surgery will contribute to survival. Finally surgery should be considered in mixed tumors, as a salvage therapy or in the rare cases of a second NSCLC tumor.[19] All investigators have emphasized the importance of precise staging for careful selection of patients. Pathologists also need to be cautious to rule out any coexisting NSCLC component or a mixed tumor. If SCLC is revealed at frozen section analysis in the operating room, and frozen sections suggest the absence of hilar or mediastinal nodal involvement, a radical resection has been proposed, which may be combined with lymph node dissection in N2 disease.[19] If the procedure can easily be tolerated. The case by Arturo and Daniel et al,[20] is another admonition that must prompt physicians dealing with lung cancer to strongly consider surgery in patients with LD-SCLC, mostly in tandem with other modalities of management. Since very few patients fall into this category, a randomized international collaborative study is the need of the hour to carve recommendations based on robust statistical numbers.