Advances in the Management of Lung Cancer

In October 1999, 40 leading experts from Europe, the United States, and the Far East met in St. Julians, Malta, to discuss recent progress in the management of lung cancer. Emphasis was placed on novel treatment strategies for non–small-cell tumors, including combination chemotherapy and combined-modality treatment.

Gemcitabine (Gemzar) is approved as primary therapy for advanced non–small-cell lung cancer (NSCLC) in several countries worldwide. Expanded use of gemcitabine and the evolving role of Alimta—a multitargeted antifolate (MTA)—were the major focal points for data review and discussion. Other agents with appealing activity, such as oxaliplatin, were also discussed.

Both gemcitabine and Alimta offer substantial single-agent activity in NSCLC. Several new gemcita-bine doublets are being widely tested, and randomized phase II and phase III trials involving these gemcitabine regimens are also now underway. Preliminary results of some of these trials, as well as their implications, were presented and considered at this conference. The developing combination of gemcitabine and Alimta—a regimen with preclinical evidence of synergy—was of particular interest.

Gemcitabine

Multiple-induction chemotherapy studies report excellent response rates for gemcitabine and cisplatin (Platinol) as initial therapy in patients with stage III NSCLC.[1] Now, a multicenter trial in Italy is comparing induction therapy with this combination followed by surgery vs surgery alone. A similar design in the United States will study induction therapy with carboplatin (Paraplatin) and paclitaxel (Taxol) followed by surgery vs immediate surgical resection. In Spain, a three-arm trial is currently underway, comparing surgery alone vs induction chemotherapy followed by resection vs resection followed by adjuvant chemotherapy.

The radiosensitizing potential of gemcitabine is well recognized. Initial attempts to combine full doses of weekly gemcitabine with curative radiotherapy for patients with locally advanced NSCLC were associated with unacceptable in-field toxicity. However, additional studies using different treatment volumes, fractionation schedules, and chemotherapy doses are needed to define a safe and beneficial interaction between these two active modalities. For example, Vokes et al recently completed a Cancer and Leukemia Group B trial in patients with stage III NSCLC. Results of this study demonstrate the feasibility and tolerability of induction chemotherapy with a standard gemcitabine/cisplatin combination followed by concurrent radiation plus a reduced dose and less frequent schedule of gemcitabine.[2]

Alimta

Data from several studies of Alimta were also presented, and the future development of this agent was discussed. Alimta offers substantial single-agent activity in lung cancer. It also offers theoretical appeal in terms of overcoming de novo or developing drug resistance, because of its multiple sites of cellular action.

Conference members also reviewed the status of the development of Alimta combinations and suggested further studies. In particular, the evaluation of gemcitabine/Alimta combinations as first-line therapy was considered a priority. The potential for Alimta as second-line therapy for previously treated patients with NSCLC was also of interest.

Regional Differences

Different treatment approaches in Europe, the United States, and the Far East were articulated by conference participants. “Standard care” approaches in the United States and Europe were also discussed. Of debate was whether there is a well-defined “standard chemotherapy” for locally advanced or metastatic NSCLC. Clearly, in the United States, the dominant combination is carboplatin/paclitaxel, despite the absence of randomized data to suggest this combination is more efficacious than numerous other available regimens. In Europe and Canada, gemcitabine/cisplatin and vinorelbine (Navelbine)/cisplatin are widely used, with country by country differences quite evident.

Based on the completed studies of the North American cooperative groups, treating physicians in the United States often use an induction strategy of concurrent chemoradiation followed either by surgery or additional radiation in appropriate patients with stage III disease. Response rates are high with the use of concurrent chemoradiation, but acute toxicity is increased and surgical and postoperative care may be rendered more challenging.

In much of Europe, induction chemotherapy alone followed by definitive locoregional treatment is the more common approach. However, the addition of a component of concurrent chemoradiation is certainly being tested. Conference members debated the relative values of these strategies and opportunities for additional testing to optimize the overall approach.

We look forward to continuing this dialogue with an expanding circle of colleagues. At this time, we are pleased to provide you with this Oncology supplement. It contains several reports that highlight much of the information that was presented at our conference.

References:

1. van Zandwijk N, Crino L, Kramer GW, et al: Phase II study of gemcitabine plus cisplatin as induction regimen for patients with stage IIIA non–small-cell lung cancer by the EORTC Lung Cancer Cooperative Group (EORTC 08955) (abstract). Proc Am Soc Clin Oncol 1799:468a, 1998.

2. Vokes EE, Leopold KA, Herndon JE, et al: A randomized phase II study of gemcitabine or paclitaxel or vinorelbine with cisplatin as induction chemotherapy and concomitant chemoradiotherapy for unresectable stage III non–small-cell lung cancer (CALGB study 9431) (abstract). Proc Am Soc Clin Oncol 18(1771):459a, 1999.