Two presentations at the June 2004 meeting of the American Society of Clinical Oncology (ASCO) have confirmed the benefit of adjuvant chemotherapy for early stage non-small cell lung cancer (NSCLC).  A randomized clinical trial performed by the National Cancer Institute of Canada showed that adjuvant vinorelbine (Navelbine®) and cisplatin (Platinol®) improved 5-year overall survival from 54% in the surgery alone arm to 69% in patients with stage IB and II disease.[1]  The second randomized trial (CALGB 9633) compared surgery alone to adjuvant paclitaxel (Taxol®) and carboplatin (Paraplatin®) in patients with stage IB NSCLC.[2]  This trial showed that the 3-year overall survival was increased from 69% to 82% with adjuvant chemotherapy.

Patients with stage I-III NSCLC who have all tumor resected have a high rate of local and distant recurrences. There have been many trials of adjuvant and neoadjuvant chemotherapy and radiation therapy with conflicting results. Randomized controlled trials of patients with stage I-IIIA NSCLC suggest that adjuvant radiation therapy can decrease the frequency of local recurrences but does not significantly increase survival. However, prevention of local recurrences can be of significant palliative benefit and is probably the reason that adjuvant radiation therapy has become a relatively standard approach for the treatment of patients with stage I-IIIA NSCLC. However, high dose of radiation therapy in the adjuvant setting can lead to excess deaths which should be avoidable by newer radiation techniques and lower doses.

The role of adjuvant chemotherapy for stage I-IIIA NSCLC has not been determined with certainty. Some studies showing benefit for the patients at lesser risk, while others show benefit for the high-risk patients. A large meta-analysis suggested that adjuvant chemotherapy improves survival by approximately 5% at 5 years. The role of neo-adjuvant chemotherapy followed by adjuvant chemotherapy for stage IIIA NSCLC appears to be well established, as a result of an MD Anderson clinical trial. One French randomized trial suggests that patients with stage I and II NSCLC also benefit from neo-adjuvant and adjuvant chemotherapy.

Phase III randomized trials continue to be performed to more clearly define the role of adjuvant and neo-adjuvant therapies. One adjuvant chemotherapy study presented by French researchers at ASCO in 2003 involved over 1,800 patients with stage I-III resected lung cancer treated in 43 countries at 148 institutions.[3]  Results adjuvant Platinol®-based chemotherapy resulted in a 4.1% improvement in OS and a 5.1% improvement in DFS at 5 years. Overall survival at 5 years was 44.5% for the adjuvant group and 40.4% for the control group. DFS was 39.4% for the adjuvant group and 34.3% for the control group. This trial suggested that adjuvant treatment would save approximately 7,000 lives world wide per year.

The Canadian trial enrolled 482 patients with stage IB and II NSCLC from 1994 to 2001.[4]  The average age was 61 years, two thirds were male, 56% had adenocarcinoma, and 70% underwent lobectomy.  These authors reported that 65% of patients received 3 or more courses of planned chemotherapy (Navelbine® plus Platinol®) and 12% stopped therapy because of toxicity. This trial demonstrated a 13% improvement in 5-year disease free survival and a 14% improvement in overall survival with chemotherapy compared to surgery alone (see table 1).

Table 1 Canadian trial of adjuvant Navelbine® plus Platinol® in stageIB and II NSCLC

The presenter made clear that these patients were “tightly” selected in terms of staging and general condition.  Thus, this study may not reflect the “average” patient population with stage IB-II NSCLC who frequently are older and have co-morbidities. The cutoff of age was 75 years but no data were presented on the effect of age on outcome.  The presenter stated that the therapeutic effect was greater for stage II than for stage IB disease.

The CALGB evaluated a regimen of Taxol® and Paraplatin® in 344 patients with stage IB surgically resected NSCLC.  This study was stopped early because statistical analysis showed positive benefit from adjuvant chemotherapy.  The median age of patients in this study was 61 years and two thirds were male. It was reported that 85% received all scheduled chemotherapy with the main side effect being neutropenia.  Lobectomy was performed on 89% of patients in this trial. The main findings of this trial showed an improvement in overall survival for surgery plus chemotherapy (see table 2).

Table 2 CALGB trial of Adjuvant Taxol® and Paraplatin® in stage IB NSCLC

All these results were reported to be improved when patients not receiving chemotherapy as per protocol were excluded from the analysis.  In multivariate analyses the p-value for adjuvant chemotherapy was 0.03.

Comments: These two studies plus the less restrictive study presented last year by the French suggest that there is benefit from adjuvant chemotherapy without radiation therapy in early stage NSCLC.  Japanese researchers also presented a meta-analysis of over 2000 patients randomized to receive or not receive adjuvant UFT.[5]  This study suggested that oral UFT improved 5-year survival by approximately 5%.  The reason other studies may have failed was possibly the inclusion of poor-risk patients who were actually harmed by chemotherapy.  Thus, one cannot say that adjuvant chemotherapy is of benefit for all patients with stage I-III NSCLC.

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