Key Questions for Perioperative Chemotherapy in Resectable Lung Cancer

In this issue of ONCOLOGY, Drs. Benjamin Besse and Thierry Le Chevalier have written a clear and concise review of the recent trials of adjuvant (postoperative) and neoadjuvant (preoperative) cisplatin-based chemotherapy for early-stage non–small-cell lung cancer (NSCLC). Their review of historical data highlights how far we have come with these modalities, but it is sobering to realize that with current approaches, we are at best having an impact on only 5% to 10% of patients who receive these therapies, and relapse rates remain over 30% even for completely resected stage I tumors.

Also disconcerting is the loss of an overall survival benefit with long-term follow-up on the International Adjuvant Lung Cancer Trial (IALT). However, it is important to put this in context with the other large positive cisplatin-based adjuvant trials. The long-term survival benefit with adjuvant chemotherapy was maintained on the Adjuvant Navelbine International Trialist Association (ANITA) trial-8.6% at 5 years, persisting to 8.4% at 7 years.[1] Thus, while the long-term IALT results are discouraging, they are not necessarily reproduced in other studies. Nevertheless, they do highlight the importance of long-term follow-up for the ongoing adjuvant trials. Long-term results of the JBR.10 trial are eagerly awaited, and presentation of these data at the 2009 annual meeting of the American Society of Clinical Oncology (ASCO) may shed further light on adjuvant treatment for NSCLC.

Stage I Disease
Another aspect of adjuvant therapy to be highlighted is the controversy over benefit in stage I disease. To properly discuss this issue, it is important to bring in Cancer and Leukemia Group B (CALGB) 9633, the largest stage IB–focused trial to date. This trial randomized 344 patients to observation or four cycles of carboplatin/paclitaxel after resection of stage IB disease. In the final publication of results, with 74 months of follow-up, an overall survival hazard ratio (HR) of 0.83 (90% confidence interval [CI] = 0.64–1.08; P = .12) was reported.[2] On the surface, this negative trial therefore supports the results of the other investigations, which in subset analysis failed to find any benefit to adjuvant chemotherapy for patients without nodal involvement.

An unplanned subset analysis of CALGB 9633, however, showed that patients with tumors larger than 4 cm did have a significant improvement in overall survival (HR = 0.69; 95% CI = 0.48–0.99; P = .043) with adjuvant chemotherapy. Analyses of benefit by size of tumor in stage I patients in the other large adjuvant trials have not yet been presented, but for those without nodal involvement, the size of the tumor is likely of high significance. The new staging system proposed to go into effect later this year reflects our understanding that tumor size is important for prognosis, with multiple subdivisions now based on the size of the primary tumor (although the 4-cm cutpoint is between the 3- and 5-cm marks used in the new guidelines).[3]

How Critical Is Timing of Chemotherapy?
Drs. Besse and Le Chevalier have rightly emphasized meta-analyses that focused on individual patient data. However, in looking at the question of preoperative vs postoperative chemotherapy, it is worth noting a poster presented at ASCO 2008, which reported an indirect-comparison meta-analysis of published trials involving preoperative vs postoperative chemotherapy. Of 112 possible trials identified, 31 fulfilled inclusion criteria, and hazard ratios for postoeprative compared to preoperative chemotherapy were reported for overall survival (HR = 0.99; CI = 0.81–1.21; P = .9) and progression-free survival (HR = 0.96; CI = 0.74–1.26; P = .77), supporting the view that perioperative timing of chemotherapy may not be critical.[4]

A more direct answer to the question will possibly be found in the Neoadjuvant/Adjuvant Taxol Carboplatin Hope (NATCH) study, which compares pre- vs postoperative carboplatin and paclitaxel in resected NSCLC and is due to be presented at ASCO 2009. Other trials looking directly at the pre- vs postoperative approach are ongoing in Asia, but a similar effort in North America failed due to lack of accrual. Although the jury is still out, the question of pre- vs postoperative is likely not the most important question to ask as we attempt to maximize benefit for our patients with early-stage NSCLC.

Patient Selection
The bigger question, which Drs. Besse and Le Chevalier mention at the end of their excellent article, is who should be receiving therapy at all. Selection of patients based on markers that are predictive of chemotherapy benefit is critical and the basis for multiple ongoing trials. In a retrospective analysis from IALT, expression of the excision repair cross-complementation group 1 (ERCC1) protein, as measured by immunohistochemical (IHC) analysis, correlated with outcome. Patients with less expression of ERCC1 (“ERCC1-negative”) had a much more impressive benefit from adjuvant chemotherapy (HR = 0.76; 95% CI = 0.59–0.98), than those with high levels of the protein (HR = 1.20; 95% CI = 0.91–1.59), who may not benefit at all.[5]

The reduced capacity of individuals with low levels of ERCC1 to repair DNA damage caused by chemotherapy may explain this difference, and it is noteworthy that patients with high ERCC1 levels tend to do better overall, although without additional benefit from adjuvant chemotherapy. RRM1 predicts for response to gemcitabine (Gemzar), thymidylate synthetase (TS) levels are likely predictive of benefit from pemetrexed (Alimta), and the BRCA1/RAP80 complex indicates sensitivity to platinum and taxanes. These observations have led to multiple ongoing trials outlined in Table 1, designed to better select particular drugs for specific patients in the adjuvant setting. Genomic approaches are also being explored, most notably CALGB 30506, which is based on the prognostic lung metagene analysis.[6]

Drug Development
The development of newer drugs that have shown promise in later stages of NSCLC is also an important step. Many compounds are under investigation in this setting, including pazopanib and bevacizumab (Avastin), as mentioned in the review. These compounds will also likely work best for patients whose tumors are more “sensitive” to the drug.

We are still learning how to select patients who benefit from the antiangiogenic drugs, but progress has been made with epidermal growth factor receptor (EGFR) inhibitors such as erlotinib (Tarceva). The ongoing Randomized Double-Blind Trial in Adjuvant NSCLC with Tarceva (­RADIANT) only allows for enrollment of patients with resected early-stage NSCLC whose tumors show evidence of EGFR overexpression. More detailed studies of preferential benefit by EGFR mutational status and other factors are also underway. The large ongoing MAGRIT trial uses a vaccine against the tumor antigen MAGE-A3 in stage IB–IIIA MAGE-A3–positive, completely resected NSCLC. Only the approximately 35% to 50% of early-stage NSCLC patients with expression of MAGE-A3 antigen are eligible.

Conclusions
Although the question of when to give perioperative chemotherapy is important, as nicely outlined in this review by Drs. Besse and Le Chevalier, it is only through better targeting of therapy that we are likely to make real progress. The promise of the future is personalized medicine, and the ongoing trials summarized in Table 1 offer great hope, highlighting the exciting work in this field.

References:

1. Douillard JY, Rosell R, De Lena M, et al: Adjuvant vinorelbine plus cisplatin versus observation in patients with completely resected stage IB-IIIA non-small-cell lung cancer (Adjuvant Navelbine International Trialist Association [ANITA]): A randomised controlled trial. Lancet Oncol 7:719-727, 2006.2. Strauss GM, Herndon JE 2nd, Maddaus MA, et al: Adjuvant paclitaxel plus carboplatin compared with observation in stage IB non-small-cell lung cancer: CALGB 9633 with the Cancer and Leukemia Group B, Radiation Therapy Oncology Group, and North Central Cancer Treatment Group Study Groups. J Clin Oncol 26:5043-5051, 2008.3. Goldstraw P, Crowley J, Chansky K, et al: The IASLC Lung Cancer Staging Project: Proposals for the revision of the TNM stage groupings in the forthcoming (seventh) edition of the TNM Classification of malignant tumours. J Thorac Oncol 2:706-714, 2007.4. Lim E, Harris G, Patel A, et al: Preoperative versus postoperative chemotherapy in patients with resectable non-small cell lung cancer: Systematic review and indirect comparison meta-analysis of randomized trials (abstract 7546). J Clin Oncol 26(15S):408s, 2008.5. Olaussen KA, Dunant A, Fouret P, et al: DNA repair by ERCC1 in non-small-cell lung cancer and cisplatin-based adjuvant chemotherapy. N Engl J Med 355:983-991, 2006.6. Potti A, Mukherjee S, Petersen R, et al: A genomic strategy to refine prognosis in early-stage non-small-cell lung cancer. N Engl J Med 355:570-580, 2006.