Commentary (Miller): Adjuvant Chemotherapy for Resected Non–Small-Cell Lung Cancer

Lung cancer continues to be the most common cause of cancer deaths in the United States for both men and women. Unfortunately, the majority of patients present with local or distant disease at the time of diagnosis. Surgical resection continues to offer the best chance for long-term survival; however, less than 25% of patients have surgically resectable disease. Even after surgical resection for early-stage disease a significant number of patients will develop recurrent disease, with the majority being distant in nature. Development of distant disease usually proves to be the terminal event in most patients. Multiple treatment modalities have been investigated as adjuvant therapy to decrease the incidence of distant disease after complete surgical resection. Until recently, no modality has shown a survival advantage in patients after resection for non-small-cell lung cancer (NSCLC). Drs. Solomon, Mitchell, and Bunn from the University of Colorado Health Sciences Center have compiled an extensive review of the recent adjuvant treatment trials that have shown improved survival in patients who have undergone complete surgical resection for NSCLC. The following will be my comments on their conclusions. Over the past 2 years, three large, prospective randomized adjuvant chemotherapy trials have shown a survival advantage of 4% to 15% in patients who have undergone complete resection for stage IB, II, and selected IIIA disease.[1-3] Multiple issues are present within these studies as well as unanswered questions, ones that need to be addressed before every patient is subjected to the risks of adjuvant treatment when only a small percentage of patients will benefit. These issues include ascertaining who the ideal candidate for adjuvant chemotherapy is, what agents should be used, whether every patient no matter what stage (IA, IB, IIA, IIB, IIIA) of NSCLC should receive chemotherapy, and whether the agents should be delivered preoperatively, postoperatively, or both. Patient and Chemotherapy Agent Selection
As our population continues to age more patients will be asked to undergo adjuvant chemotherapy for less than a 15% survival advantage. In the two North American trials (National Cancer Institute of Canada [NCIC] JBR10 and Cancer and Leukemia Group B [CALGB] 9633), median patient age was 60 years, which usually correlates to being able to tolerate a more harsh chemotherapy regimen after resection than older individuals. Further analysis is indicated to determine if this survival advantage is seen in our older patients as well, in order to avoid subjecting them to unnecessary adjuvant treatment. The chemotherapy used in the three trials (International Adjuvant Lung Cancer Trial [IALT], NCIC JBR10, and CALGB 9633) was a platinumbased system. Cisplatin and carboplatin have their advantages and disadvantages, depending on the setting and the patient's performance status. As an adjuvant agent carboplatin has less toxicity, thus possibly increasing the number of patients completing the adjuvant treatment; cisplatin seems better suited in the neoadjuvant setting. Combination therapy (dual agents) is better than single or triple agents: less risk with greater benefit. Further work is needed to determine tumor resistance and to help tailor the treatment to the patients that will respond to adjuvant chemotherapy. In the IALT study all surgically resected patients were included except stage IA patients. The overall survival improvement in the IALT was 4%. The greatest survival advantage was found in the patients with stage IIIA (N2) disease, whereas in the NCIC and CALGB trials survival was almost three times higher in patients with earlier-stage disease. Radiation therapy used in these trials may have worsened survival, especially in the higher-staged patients. As we continue to understand the biology of these smaller tumors, there may even be a role for adjuvant therapy for stage IA disease, especially if we can determine tumor response and reduce the risks of current therapy. Chemotherapy: Preoperative, Postoperative, or Both?
The final dilemma is should chemotherapy be delivered preoperatively, postoperatively, or both? Preoperative therapy usually results in greater than 90% of patients completing both modalities whereas only 50% to 70% complete postoperative therapy. As more patients undergo minimally invasive procedures (ie, video-assisted thoracic surgery [VATS] lobectomy), hopefully a higher percentage of patients can complete the adjuvant treatment post-operatively. A large randomized trial is needed to evaluate neoadjuvant vs adjuvant vs surgery alone, especially in stage IA patients. However, it may be hard to enroll patients into the surgery-only arm because of the exponential use of adjuvant chemotherapy after resection. A similar situation occurred in the multiple-modality treatment of esophageal cancer. Conclusions
In the past, surgical treatment was felt to be the only modality that could achieve long-term success; unfortunately, a significant number of patients would develop late metastatic disease. The paradigm has shifted to a multimodality approach, even in early-stage disease, in which surgery and systemic chemotherapy are warranted. As chemotherapy agents improve with less toxicity and more specificity, hopefully we can improve the dismal survival that awaits most Americans with NSCLC. And finally, as screening studies identify more patients with earlier-stage disease, a greater percentage of patients may be candidates for curative rather than palliative therapy. I congratulate the authors on an excellent review.

Disclosures:

The author has no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.

References:

1. The International Adjuvant Lung Cancer Trial Collaborative Group: Cisplatin-based adjuvant chemotherapy in patients completely resected NSCLC. N Engl J Med 350:351-360, 2004.
2. Winton TL, Livingston R, Johnson D, et al: A prospective randomized trial of adjuvant vinorelbine (VIN) and cisplatin (CIS) in completely resected stage IB and II non-small cell lung cancer (NSCLC) Intergroup JBR.10 (abstract 7018). J Clin Oncol 22(14S):621s, 2004.
3. Strauss GM, Herndon J, Maddaus MA, et al: Randomized clinical trial of adjuvant chemotherapy with paclitaxel and carboplatin following resection in stage IB non-small cell lung cancer (NSCLC): Report of Cancer and Leukemia Group B (CALGB) Protocol 9633 (abstract 7019). J Clin Oncol 22(14S):621s, 2004.