Just as in recent years attitudes and treatment therapies have changed regarding non–small-cell lung cancer (NSCLC), it is time that the same occur for its small-cell counterpart. Although treatment for advanced-stage small-cell lung cancer (SCLC) is fairly standardized, there remain a number of controversies that have yet to be clarified by evidence-based data.
In this issue, Ganti and colleagues present an overview of the histologic diagnosis, role of surgery, and chemotherapeutic options for patients with SCLC. Noticeably missing is any discussion of the role of radiation therapy—especially discussion of the controversial topics of radiation dose, the timing of radiation vis à vis chemotherapy (concurrent versus sequential), radiation modalities (hyperfractioning versus standard), and the use of cranial radiation (since the latter may not be beneficial in all stages of disease).
However, the authors do join a number of recent publications in revisiting the role of surgery, especially for earlier-stage disease. As they point out, the biology and presentation of SCLC has changed over the past several decades. Thus, one should refrain from referring to old data that predate the platinum-based chemotherapy era, as well as the negative data from the Lung Cancer Study Group from the 1970s and 80s; these studies were criticized for their small numbers and inadequate staging. We should no longer equate the diagnosis of SCLC with inoperability.
Why revisit surgery as a definite option for resectable disease? There are a number of reasons. The published data are largely retrospective and still may include data from patients treated before platinum drugs were introduced. There is limited information on the site of relapse for stage I disease, due to the unavailability of such details in large national databases (such as the Surveillance, Epidemiology, and End Results [SEER] database). Just as with NSCLC, few patients present with stage II SCLC; thus, there are no definite data for this stage of the disease. In some of the prospective trials, up to one-third of the patients included in the study had stage III disease. Newer imaging modalities, such as PET scanning and endoscopic bronchial ultrasound, have not been used to improve disease staging and to correlate with clinical and surgical findings. Finally, surgeons are increasingly being asked to provide “salvage surgery,” probably as a consequence of the better induction therapies now available; unfortunately, these requests fall outside the safe radiation window (6 to 8 weeks), and complying with them presents technical challenges.
Unfortunately, the Ganti review omitted two important studies involving the SEER database that complete the discussion on the role of surgery for SCLC. The study by Yu and colleagues[1] and that by Schreiber and colleagues,[2], both of which were published in the past year, concluded that surgery should be offered to select patients with limited-stage SCLC, with lobectomy as the procedure of choice. This approach conferred a survival benefit across all nodal stages. Surgery without radiotherapy offers reasonable survival outcomes in early-stage disease. The addition of surgery results in a significant survival benefit for both localized and regional disease, even if chemoradiation was used as the initial definitive therapy.
Future therapies will likely involve the use of novel biologic agents and be influenced by further elucidation of the molecular biology of SCLC. Although a review of these molecular markers is beyond the scope of this commentary, there are proteins whose expression has been correlated with therapeutic resistance or poorer survival in SCLC; these include bcl-2, fragile histidine triad complex (FHIT), and c-kit. Other signature SCLC tumor markers that correlate with chemotherapy response are similar to those seen in NSCLC and include excision repair cross-complementation group 1 (ERCC1), myc, and p16.
Given that very few patients fall into the category of early-stage disease, a randomized trial comparing surgery to the best oncologic treatment may never be conducted. Currently, trials in Europe are addressing the issue of induction chemoradiation therapy and the role of surgical resection for advanced-stage disease.
To address the limitations of prior surgical studies, the American College of Surgeons’ Oncology Group (ACOSOG) has proposed a prospective trial to verify the role of surgery plus adjuvant chemotherapy for early-stage (Ia-IIb) SCLC. This trial will include patients who either are found after resection to have limited disease or who have biopsy-proven SCLC. The primary endpoint will be 3-year survival and recurrence patterns. However, the exciting part of the trial will be the collection of tissue and serum for biomarker study and proteomics, since to date there have been no basic science correlative studies using surgical specimens. Hopefully this trial will be activated at the end of the current year.
Despite all the negative past data, a new focus of research on SCLC is warranted, both clinically and from a basic science perspective. Because of the likelihood that the biology of the disease is changing, it is unclear now which clinical and biologic factors may predict long-term survival. The correlative science data that may be obtained from resected surgical samples may hold the key to unfolding novel treatment strategies for advanced-stage disease. It is time to reverse the negative stigma of surgery for SCLC.
Financial Disclosure: The authors have no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.
