Induction Chemotherapy for Resectable Non–Small-Cell Lung Cancer

Recent advances in molecular classification and the advent of noncytotoxic molecularly targeted therapies have offered increased hope of improving the diagnosis, treatment, and prognosis for patients with non-small-cell lung cancer (NSCLC).[1] Yet the use of che motherapy in NSCLC has continued to evolve over recent years with the appearance of newer cytotoxic agents that have improved the outcome for patients. Doublet combination chemotherapy has become the standard of care for patients with advanced disease and good performance status. Prolongation of survival has also been shown with second-line chemotherapy for patients whose tumors are refractory to first-line agents.[1] The value of combined-modality therapy in locally advanced stage IIIB disease has been unquestionably proven despite the limitation that concurrent therapy imposes on the doses of systemic agents used in the combined concurrent setting.[2] Recent evidence indicates that systemic therapy added to a definitive surgical approach offers a modest increase in survival in patients with resectable disease.[3] These modest advances seen with the use of cytotoxic therapy force a reexamina reexamination of the role of systemic therapy in resectable disease, ultimately redefining optimal care for the minority of patients presenting with resectable clinical stage I, II, and IIIA disease. Adjuvant Chemotherapy
Patients with stage I to IIIA NSCLC treated with lobectomy or pneumonectomy and node sampling have a 5-year survival ranging between 67% for stage IA to as low as 23% for resected stage IIIA disease.[4] Previous meta-analysis showed that postoperative cisplatin(Drug information on cisplatin)-based chemotherapy may improve the absolute survival at 5 years by 5%.[5] The sample sizes in the individual trials were too small, however, to draw any firm conclusions. Since then, a number of larger adjuvant chemotherapy trials have been completed. The Adjuvant Lung Project Italy (ALPI) trial randomized 1,209 stage I to IIIA patients to adjuvant systemic therapy with MVP (mitomycin [Mutamycin], vindesine(Drug information on vindesine), cisplatin). The time to progression favored the chemotherapy arm with a nonsignificant difference.[ 6] The UK trial assigned the same group of patients to one of four cisplatin- based chemotherapy regimens after a complete resection. The study was underpowered and showed no difference in survival.[7] The International Adjuvant Lung Cancer Trial (IALT) was a larger similarly designed study that enrolled 1,867 patients. It showed a statistically significant absolute increase of 4.1% in the 5-year survival rate (P = .03).[3] The National Cancer Institute of Canada (NCIC) and Cancer and Leukemia Group B (CALGB) trials used more up-to-date chemotherapy combinations and helped clarify the degree to which toxicity from systemic therapy contributed to increased death in the previous trials, providing survival benefits of 5% to 10% with combinations of vinorelbine (Navelbine) and cisplatin,[8] or paclitaxel(Drug information on paclitaxel) and carboplatin(Drug information on carboplatin) (Paraplatin).[9] Both studies showed a survival advantage of 5% to 10% for adjuvant chemotherapy. Value of Induction Therapy
Extrapolating from data in breast and colon cancer, it seems appropriate to offer systemic adjuvant therapy to patients with resected stages I to IIIA NSCLC with good performance status. The appropriate sequencing of chemotherapy with surgery and the role of induction therapy in resectable NSCLC patients is the topic of review in the paper by Patel et al. The value of induction therapy has been extensively studied in other malignancies including breast and colorectal cancer. In breast cancer, the beneficial role of induction therapy has clearly been shown in terms of organ preservation.[10] However, investigators have yet to show evidence of improved outcome measured in terms of survival for patients receiving this modality vs the more standard adjuvant approach. To a certain extent, the same applies to rectal cancer.[11] It appears reasonable to examine the question of induction chemotherapy and its potential benefits in lung cancer, as a large proportion of recurrences after surgical resection of stages I to IIIA are extrathoracic. Potential advantages of induction therapy would include the targeting of micrometastatic sites.[12] In addition, as argued by Patel et al, decreasing tumor size may improve the chance and ease of adequate resection. Higher responses and resectability rates have been noted with induction therapy in patients with stage IIIA/IIIB disease,[13] and overall survival was improved and maintained with chemotherapy for patients with stage IIIA disease.[14,15] Study Results
Based on the successes observed in stage IIIA disease, numerous phase II trials evaluating the role of induction chemotherapy in earlier stages (IB and II) as well as in stage IIIA were initiated. These trials showed some increase in postoperative morbidity in the combined arms with no difference in local recurrence rates, yet a low incidence of distant metastatic sites favoring chemotherapy.[16] The phase III French study comparing induction with mitomycin(Drug information on mitomycin), ifosfamide(Drug information on ifosfamide) (Ifex), and cisplatin to surgery alone for patients with stage IB, II, or IIIA disease had a median survival favoring chemotherapy (37 vs 26 months, P = .15) with a significant prolongation in disease-free survival (P = .033).[17] Of note in this study are the apparent inaccuracies in clinical staging despite the use of mediastinoscopy and CT scanning, as there was only a 16% correlation between clinical and postsurgical pathologic stage, and 36% more extensive disease than predicted, raising the question of whether a more elaborate staging approach is needed. There was no significant difference in the rate of resectability and survival. The Intergroup randomized trial comparing three cycles of induction paclitaxel and carboplatin (Southwest Oncology Group [SWOG] 9900) to surgery alone in stages T2, N0; T1/2, N1; and T3, N0/1 NSCLC is expected to randomize 600 patients, and its results are anxiously awaited. Conclusions
Can induction therapy be recommended for patients with resectable NSCLC? Similar uncertainties exist when the question of adjuvant therapy in NSCLC is raised. First and foremost is the need to define which patients would clearly benefit from such therapy. It seems more appropriate to reserve it for those with good performance status. The appropriate choice of induction regimens and their duration is also an area that needs clarification. A plethora of cytotoxic agent combinations is available without proven superiority in advanced disease. Any doublet of active agents (eg, paclitaxel, docetaxel(Drug information on docetaxel), vinorelbine, gemcitabine(Drug information on gemcitabine) [Gemzar]) could be considered for further investigation. Prolonged therapies of more than four cycles have not produced increased benefit in more advanced disease,[18] which makes two to four cycles of therapy seem appropriate in the induction phase. Will the inclusion of additional adjuvant chemotherapy lead to better survival? Is the addition of radiation therapy beneficial, or does it lead to increased morbidity and complications, and who should receive it? More studies are obviously needed to clarify all these issues. Finally, one could not tackle the question of adjuvant or induction therapy in NSCLC without a closer look at the area of most active research in lung cancer today-that is, molecularly targeted therapies, used alone, in combination with cytotoxics, or with other targeted agents. One challenge in this area is the need to define the most appropriate subset of patients for a certain targeted therapy. The time when the choice of induction or adjuvant therapy is dictated by a genotype of a certain tumor may not be very far off. Until this is achieved, a better definition of the role of induction and adjuvant therapy should be better answered by the next generation of clinical trials in NSCLC.