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Commentary |
Ochsner Cancer Institute, Alton Ochsner Medical Foundation, New Orleans, Louisiana, USA
Correspondence: Richard J. Gralla, M.D., Ochsner Cancer Institute, Alton Ochsner Medical Foundation, 1514 Jefferson Highway, New Orleans, Louisiana 70121-2483, USA. Telephone: 504-842-3261; Fax: 504-842-4533; e-mail: rgralla{at}ochsner.org
In most instances, it would be disappointing to conclude a 444-patient randomized study designed to detect a four-month advantage for one regimen, and to find instead identical therapeutic results for both treatment groups. But thanks to the thoughtful design of the Southwest Oncology Group (SWOG) trial in advanced non-small cell lung cancer (9509) just presented at ASCO [1], we have a great deal to discuss about treating lung cancer and the design of clinical studies. This discussion concerns not only response and survival, but quality of life and cost of treatment, as well.
The trial pitted two newer "doublets" against each other. The SWOG standard of vinorelbine plus cisplatin was compared with the often-used paclitaxel plus carboplatin. A total of 201 patients received the vinorelbine plus cisplatin regimen, while 207 patients received paclitaxel plus carboplatin. The results concerning the typical endpoints were surprising. Survival, whether measured at the median or at the one-year points (eight months and 37%, respectively) were the same for both regimens. As clearly presented by Dr. Karen Kelly of the University of Colorado, the survival figures for the vinorelbine combination were similar to those from prior SWOG trials (and similar to the eight- to nine-month median survivals reported in numerous phase III studies) [2]. However, the results from the paclitaxel-carboplatin regimen fell well below those expected, based on phase II reports of 10- to 12-month median survival. It should be noted that the survival results with paclitaxel-carboplatin were similar to the 7.7 months reported when this combination yielded results close to those seen with etoposide plus cisplatin in its only prior phase III test [3].
Supporting the identical survival results were response rates of 27% in both arms of this SWOG trial. Again, the results closely resembled those from prior vinorelbine-cisplatin trials, but were well below the phase II results, which popularized the paclitaxel combination.
Serious adverse reactions occurred at a relatively low rate in both arms but differed depending on the regimen used. Grade III/IV peripheral neuropathy was more frequent with the paclitaxel regimen, while nausea was more common with the vinorelbine combination (both occurring about 10% more often with the regimen inducing more toxicity). Myelosuppression occurred with both regimens, was more frequent with the vinorelbine arm, but reportedly rarely resulted in febrile neutropenia. The relative frequency of alopecia was not discussed in the ASCO presentation until a question was asked. Most would assume that this side effect was universal with paclitaxel and occasional with vinorelbine. The questioner objected to this omission, perhaps reflecting that recent reports have shown this toxicity to be a leading concern for patients receiving chemotherapy [4].
It is always difficult to assess which side effect is more disturbing to patients, especially in a comparative trial. SWOG deserves great credit for having built in a quality-of-life evaluation (using the FACT-L instrument). Although few details were given in either the abstract or the presentation, nearly two-thirds of patients completed a six-month follow-up evaluation, making this one of the largest trials with reasonable follow-up data. Of marked importance was the fact that quality-of-life improvement was slightly greater on the vinorelbine arm, while improvement plus stability of quality of life was similar for both arms. This would appear to support that patients did not detect an overall subjective advantage or disadvantage for either regimen.
Dose delivery in comparison studies serves as a means to an end, not as an important endpoint in itself. A lower percentage of vinorelbine compared with paclitaxel was given. This raises the point that perhaps better results with the former combination could be achieved if the dosing employed by Le Chevalier and colleagues had been used [2] (which delivered about 20% more drug and 15% better survival), or if other suggested methods of giving dose-dense vinorelbine had been followed [5]. The paclitaxel-carboplatin regimen employed the highest dosing scheme commonly given (225 mg/M2, an AUC of 6), although a prior randomized study with paclitaxel failed to indicate a dose-response benefit [6].
The most unique feature of this trial and its report was the cost analysis. As with the quality-of-life evaluation, this trial may represent the largest randomized study that prospectively examines the cost of treating patients with non-small cell lung cancer. Unlike the similar therapeutic results, striking differences in costs occurred. Both costs of the chemotherapy, and, more importantly, total costs of treatment were reported. The per-patient drug costs of the vinorelbine combination were about $4,000, compared with nearly $20,000 for the paclitaxel regimen. Total costs were $18,000 and $35,000 per patient with the respective regimens. While all these differences were statistically significant, the financial impact may be more meaningful.
It is important to put the therapeutic, quality-of-life, and cost results in perspective. SWOG has not yet reported on its analysis of the context of these findings. In terms of response and survival, both regimens performed nearly identically. While toxicities differed between the regimens, these results had no impact on the patient-reported quality-of-life results. The marked cost differences are notable. As an example, a busy practice that sees two new patients with lung cancer per week would spend nearly $1,700,000 more per year if the more expensive regimen were selected, without achieving better survival or quality of life. Treating lung cancer has been previously shown to be cost effective in several analyses in the 1990s, especially when vinca alkaloid plus cisplatin regimens are compared with "best" supportive care [7-9]. Conservative estimates of cost effectiveness of the two regimens (the cost of adding one year of life) when compared with supportive care only, reveal major differences. The less costly regimen costs about $20,000 per added year of life (± $10,000) contrasted with $80,000 (± $20,000) for the more costly chemotherapy. The ranges reflect different hypotheses concerning survival and costs associated with supportive care (four to five months median survival based on recent randomized trials, and a cost of $10,000 to $15,000 per patient for supportive care). Thus, one regimen is clearly cost effective without risking survival or quality of life, while the other regimen is not.
SWOG is to be commended for performing such a broad and thorough evaluation of two important regimens for patients with advanced non-small cell lung cancer. This design should become a model for future randomized studies. The question remains as to whether the community will react to the only difference documented by this study—the cost. If so, it will demonstrate that oncologists will respond to well-documented cost analyses when patient survival and quality of life are not jeopardized.
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