Following the results of the last generation of randomized trials, adjuvant chemotherapy is now a standard treatment in non-small-cell lung cancer (NSCLC), confirming the findings of the individual patient data meta-analysis published in 1995.[1] It took more than 25 years to demonstrate the effect of chemotherapy in this setting, long after similar demonstrations in colon and breast cancer. Thus, the question is no longer "should adjuvant chemotherapy be given in resected NSCLC?" but rather, "how long will the medical community need to standardize, optimize, and individualize this approach?" The current debate concerns which patients benefit from this treatment and which drugs should be used.

Key Trials

The available high-quality evidence comes first from trials of cisplatin(Drug information on cisplatin)-based chemotherapy for 3 months, which were evaluated mostly in Western countries in stage IB, II, and IIIA NSCLC,[2-8] and second, from trials of oral uracil/tegafur (UFT) for at least 1 year, performed in Japan on a population including 96% patients with stage I disease and more than 80% with adenocarcinoma.[9]

The Lung Adjuvant Cisplatin Evaluation (LACE) study is a pooled analysis of the individual data of the five largest trials on adjuvant cisplatin-based chemotherapy,[2-6] which aimed to identify trials or patient characteristics linked to chemotherapy effects. Based on its results, the effect of cisplatin-based chemotherapy in stage II and IIIA NSCLC is clearly shown.[8] The number of patients treated with stage IA disease was too small to draw any conclusions. The effect of chemotherapy in the subgroup with stage IB was not significant, which argues against an effect. Nevertheless, the test of interaction between stage IB, II, and III is not significant (although powerful) in a population of more than 4,500 patients—a strong argument in favor of an effect in stage IB disease.[8]

Of note, the updated results of the Cancer and Leukemia Group B (CALGB) trial 9633[7] are fully compatible with stage IB findings in the LACE study, as the confidence intervals of the corresponding hazard ratios of death largely overlap. To evaluate treatment effect in subgroups of patients, the recommended method is to compare results between the different subgroups using an interaction test and not to perform an analysis in each subgroup.[10,11] The limitation of the test of interaction is its lack of power, but this is not an issue in a large population such as in LACE. Since P values are more dependent on the size of subgroups or trials, overemphasis on P value should be avoided, and estimates of treatment effect with confidence intervals (indicating precision) should be reported.[12]

The question about chemotherapy effect in early-stage NSCLC is similar to the ongoing debate in the setting of stage II colon cancer.[13] Inclusion of stage IB patients in trials by those not convinced of an effect in this group as well as the search for prognostic factors of high risk of recurrence in this population will help to clarify this issue. The updated results of the NSCLC meta-analysis (NSCLC-MA) in approximately 10,000 patients and more than 30 trials should settle this issue when they become available in 2007.[1,14]

Concerning the choice of cisplatin-based chemotherapy, the LACE results did not favor a triplet with mitomycin(Drug information on mitomycin); the doublet vinorelbine/cisplatin offered more promising results.[8] But we should be careful in interpreting the comparison of the results between cisplatin/vinca alkaloid/etoposide and cisplatin/vinorelbine doublets. The population included in the different trials may be different. The different doses of cisplatin may also explain the difference in results between the doublets.[8] Can we extrapolate the results of third-generation chemotherapy in metastatic disease to the adjuvant setting? Our opinion is that new trials are needed to demonstrate any benefit of these drugs, including gemcitabine(Drug information on gemcitabine) (Gemzar), docetaxel (Taxotere), and pemetrexed(Drug information on pemetrexed) (Alimta).

Role of UFT

The individual patient data meta-analysis on UFT included 2,003 patients, but its power is limited, as only 477 deaths occurred.[9] A treatment effect has been demonstrated for the drug in both stage IA and IB NSCLC, and the absence of difference in the treatment effect between adenocarcinoma and squamous cell carcinoma needs to be confirmed. UFT is not available in Europe and the United States for adjuvant treatment. It would be important to confirm the benefit of UFT in the adjuvant setting in non-Japanese populations before it is introduced in adjuvant regimens elsewhere. Randomized trials in squamous cell carcinoma would also be helpful.