ABSTRACT: Lung cancer generally has an unfavorable prognosis. For those with resectable disease, the use of neoadjuvant chemotherapy has the potential to reduce tumor volume, address micrometastatic disease early, and improve outcomes. Randomized trials comparing neoadjuvant platinum-based regimens with surgery alone were able to demonstrate the feasibility and safety of this modality. These trials supported evidence found in phase II trials that utilized third-generation chemotherapies. Still, limitations to these studies exist, such as the inclusion of various disease stages in one study, inter- and intratrial variability of the chemotherapy regimens used, and lack of phase III data comparing neoadjuvant to adjuvant chemotherapy. These heterogeneous factors make it difficult to offer firm recommendations about neoadjuvant chemotherapy. Other matters of contention include the role of postoperative radiation and the concern for increased postoperative complications, especially when a right pneumonectomy is being considered after neoadjuvant chemotherapy. To clarify these issues, well-structured phase III trials comparing adjuvant to neoadjuvant chemotherapy are needed.
Lung cancer is the most common cancer diagnosed in men and women in the United States, and is the leading cause of cancer death.
AJCC Staging of Non-Small Cell Lung Cancer
Over 160,000 individuals died as a result of lung cancer in 2008.[1] This number amounted to more than the number of deaths from colon, breast, and prostate cancers combined. The majority of lung cancer cases are non–small-cell lung cancer (NSCLC), and the poor outcomes are attributed to the high rate of metastases associated with this disease. Most patients diagnosed with NSCLC present with stage IIIB or IV (Table 1). These late stages are unresectable and have grave prognoses (1%–5% 5-year survival).[2,3] Even those with early-stage (stage I–IIIA), resectable disease are likely to succumb to recurrent disease. The rates of recurrence and death at 5 years for patients with stages IB, II, and IIIA NSCLC are high.[4-6]
To reduce the rate of distant metastases, adjuvant platinum-based chemotherapy is now considered the standard of care for patients with stages IIA to IIIA NSCLC and may be considered an option for select patients with stage IB disease. This article will review the neoadjuvant chemotherapy data and explore what role, if any, neoadjuvant chemotherapy plays in patients with resectable NSCLC.
Adjuvant Chemotherapy
Prior to discussing neoadjuvant chemotherapy, a brief review of adjuvant NSCLC chemotherapy is needed. Three large trials and two meta-analyses have demonstrated that platinum-based chemotherapy can result in a survival benefit when given in the adjuvant setting. Before these studies were published, adjuvant chemotherapy was not considered a standard therapy. In 1995, a meta-analysis of 52 randomized trials evaluating cytotoxic chemotherapy in patients with NSCLC was reported. Of these trials, 14 were randomized, pooling together over 4,000 patients. This subset analysis demonstrated that platinum-based regimens (8 studies) vs non–platinum-based regimens (6 studies) did improve survival following surgical resection.[7] Survival was improved by 4% at 2 years, with a 13% reduction in death.
Further platinum-based trials were then developed based on this promising information, and these findings were confirmed in another meta-analysis.[8] The modern trials included the International Adjuvant Lung Trial (IALT), Adjuvant Navelbine International Trialist Association (ANITA), and the National Cancer Institute of Canada Clinical Trials Group JBR.10. The IALT randomized 1,867 participants with stage I to III NSCLC to adjuvant cisplatin(Drug information on cisplatin)-based chemotherapy vs observation and demonstrated an improved overall survival (44.5% vs 40.4%, P < .03) and disease-free survival (39.4% vs 34.3%, P < .003) in the treatment arm at 5 years.[4] The ANITA trial randomized 407 vs 433 patients with stage IB to IIIA NSCLC to cisplatin plus vinorelbine chemotherapy vs observation following surgical resection. At the 7-year follow-up, the ANITA trial demonstrated that overall survival was improved by 8.4% (P = .017).[9] In the JBR.10 trial, cisplatin plus vinorelbine was once again the chemotherapy of choice; this trial randomized 482 patients with stage IB or II NSCLC to adjuvant chemotherapy vs observation. The 5-year survival was 69% vs 54% (P = .03).[6] Results from all three trials changed the outlook and treatment algorithms for patients with early-stage NSCLC.
Both the American Society of Clinical Oncology and National Comprehensive Cancer Network guidelines recommend the use of adjuvant chemotherapy for patients with resectable stage IIA to IIIA NSCLC.
Neoadjuvant Chemotherapy
The role of neoadjuvant chemotherapy has also been explored in patients with early-stage NSCLC. The rationale for further investigations was the hope of decreasing micrometastases at distant sites and tumor burden preoperatively to increase resectability rates and overall survival.
Randomized Trials of Induction Chemotherapy Compared With Surgery Alone in NSCLC
In the 1990s, two small randomized trials sparked further interest in neoadjuvant chemotherapy in patients with resectable NSCLC because they demonstrated a survival benefit to platinum-based therapy (Table 2).[10,11] These trials had their limitations, which included relatively small patient numbers, unexpectedly poor outcome in the control arm, and inhomogeneous study populations.
In 2006, a meta-analysis evaluating seven neoadjuvant randomized trials involving 988 patients demonstrated an overall survival improvement of 20% in the treatment group compared with 14% (P = .02) in the observation group.[12] Three of the largest studies included in this meta-analysis were responsible for most of the observed affect. The Depierre et al study randomized 355 patients with stage IB to IIIA to two cycles of preoperative cisplatin, ifosfamide(Drug information on ifosfamide), and mitomycin(Drug information on mitomycin) compared with primary surgery.[13] Patients who responded to chemotherapy (64%) received an additional two cycles postoperatively. Overall survival for patients in the treatment arm was increased compared with those in the nontreatment arm (8.6% vs 3.8% at 1 year). This study also provided evidence regarding the safety of preoperative chemotherapy. No excess deaths were found in the preoperative chemotherapy arm compared with the primary surgical arm (6.7% vs 4.5%, P = .38).
Gilligan et al developed a randomized trial that compared neoadjuvant cisplatin-based chemotherapy to surgery alone. This study, which spanned four countries and randomized 588 participants with resectable stage I to III disease, failed to demonstrate a statistically significant improvement in overall survival at 5 years (44% vs 45%, hazard ratio = 1.02). Although 31% of the patients in the chemotherapy arm were downstaged, there was no change in the planned surgery.[14] The investigators found no increase in surgical morbidity in the chemotherapy group. Factors that may have contributed to the negative results included the fact that six different chemotherapy regimens were allowed in this study and the majority of study participants had stage I disease (61%), thus making it more difficult for the study to reach statistical significance.
Phase II Neoadjuvant Trials in Non–Small-Cell Lung Cancer
At the 2007 annual meeting of the American Society of Clinical Oncology (ASCO), the results of the Southwest Oncology Group (SWOG) 9900 trial were updated. The trial randomized 388 participants to surgery alone vs three cycles of preoperative carboplatin(Drug information on carboplatin) and paclitaxel(Drug information on paclitaxel). A statistically nonsignificant trend toward improved 5-year survival was observed in the experimental arm (43% vs 50%, hazard ratio = 0.81).[15] Phase II studies evaluating cisplatin/vindesine (Eldisine)/ifosfamide,[16] cisplatin/vinblastine,[17] cisplatin/docetaxel (Taxotere),[18] and cisplatin/gemcitabine (Gemzar)[19] combinations have further demonstrated a role for third-generation drugs in the neoadjuvant setting (Table 3). These studies suggest a role for induction chemotherapy for patients with stage II or IIIA NSCLC who are operable candidates.
