The treatment of advanced non-small-cell lung cancer has undergone incremental improvement over the last three decades of investigation. When this incremental history is reviewed, three distinct subdivisions emerge: (1) the minimal-activity era
The treatment of advanced non-small-cell lung cancer has undergone incremental improvement over the last three decades of investigation. When this incremental history is reviewed, three distinct subdivisions emerge: (1) the minimal-activity era (chemotherapy based on alkylating agents), (2) the consistent low-level-activity era (based on cisplatin [Platinol]), and (3) the moderate-activity era (newer agents combined with cisplatin). Studies in the first era were associated with an almost complete lack of interinstitutional reproducibility and little or no effect on survival. The second era was characterized by more reproducibility and a demonstrable but meager impact on survival, as reviewed by Dr. Vokes. Finally, the third era has yet to completely unfold.
The most exciting aspect of the current period of chemotherapeutic treatment of non-small-cell lung cancer is the availability of new agents, many of which possess unique mechanisms of action. These reagents include the taxanes, topoisomerase I inhibitors, and gemcitabine (Gemzar), an antimetabolite that has distinct pharmacologic properties. Two additional reagents that have been employed are analogs of existing compounds: edatrexate, a methotrexate analog, and vinorelbine (Navelbine), a vinca analog that is the topic of Dr. Vokes' timely and thorough review. Both of these agents have been studied in large randomized trials, the results of which have been reported. The addition of edatrexate to existing drug combinations has not proven beneficial, whereas vinorelbine has been successfully integrated in combination with cisplatin.
The vinca alkaloids have played a significant role in the development of the second era described above, as components of cisplatin-based regimens. In addition to having a small, but detectable impact on the survival of patients with metastatic disease [1,2], combined-modality programs have shown an increasingly consistent impact on survival of patients with intrathoracic disease [3,4].
Vinorelbine is the newest of the vinca alkaloids to enter clinical trials. This compound was developed by a modification of the basic vinca structure. Early clinical trials confirmed the drug's activity in a variety of diseases, including breast and lung carcinomas, and delineated a toxicity profile dominated by myelosuppression. The specificity of vinorelbine for non-axonal microtubules predicted the reduced neurotoxicity that was noted in these studies.
Randomized Trials of Vinorelbine
Dr. Vokes' review summarizes the phase I and II studies that ultimately led to the two randomized trials supporting the FDA approval for vinorelbine in the treatment of advanced non-small-cell lung cancer. In the first of these trials, O'Rourke et al compared vinorelbine as a single agent to a "control" arm consisting of fluorouracil plus leucovorin . Vinorelbine provided a significant improvement in survival over fluorouracil/leucovorin (30 vs 22 weeks, P = 0.03), whereas the latter regimen yielded survival characteristics comparable to many of the "best supportive care" arms from previous randomized trials.
In a second large randomized study, Le Chevalier et al evaluated vinorelbine/cisplatin vs single-agent vinorelbine and the established combination of vindesine (Eldisine) plus cisplatin.6 Vinorelbine/cisplatin resulted in significantly longer survival than vinorelbine alone or vindesine/cisplatin (40 weeks vs 32 and 31 weeks, respectively; P < 0.05). The survival characteristics of the vindesine/cisplatin arm were virtually identical to the equivalent arm in the National Cancer Institute of Canada's randomized study of cisplatin-based chemotherapy vs best supportive care (32.6 weeks) .
Interestingly, in the study by Le Chevalier et al, only 71% of the planned dose of vinorelbine could be administered in the vinorelbine/cisplatin treatment arm as a result of dose reduction for toxicity. It should be noted that treatment was administered without hematopoietic growth factors in this study. Ironically, vinorelbine is approved for use in lung cancer, whereas cisplatin, which has been the most important building block in non-small-cell lung cancer therapeutics to date, has not won approval as a single agent in this setting. At least the entry of vinorelbine into the sanctum sanctorum of approved agents has provided the opportunity for cisplatin to receive a circumspect approval.
In summary, the data on vinorelbine in advanced non-small-cell lung cancer, both as a single agent and in combination with cisplatin, are encouraging. This agent would be expected to be active in this setting based on the long experience with other vinca alkaloids in this disease. Future explorations are focusing on moving active combinations such as vinorelbine/cisplatin to the more chemotherapy-sensitive setting of locally advanced non-small-cell lung cancer, in which other platinum-based regimens have improved the survival of selected patients treated with combined-modality programs.
New Agents With Novel Mechanisms of Action
Even more compelling data are accumulating relative to the group of new agents with novel mechanisms of action, such as the taxanes, topoisomerase I inhibitors, and gemcitabine. Initial phase II studies [7-10] indicate that single-agent therapy with either paclitaxel (Taxol) or docetaxel (Taxotere) yields a med- ian survival duration of over 40 weeks, with 1-year survival rates approaching 40%. Phase II studies combining the taxanes with platinum agents have produced even more encouraging results.
Although there is some cause for optimism as a result of the progress made in the chemotherapy of non-small-cell lung cancer, the greatest advances in therapy will almost certainly arise from our emerging understanding of the biology of this disease. When these two arenas of knowledge are integrated, we may truly hope to improve treatment outcomes for these patients.
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