The Oncologist, Vol. 4, No. 3, 252-255,
June 1999
© 1999 AlphaMed Press
Commentary on "Gemcitabine: Single-Agent and Combination Therapy in Non-Small Cell Lung Cancer"
The Oncologist 1999;4:241-251
Martin J. Edelman
Correspondence:
Martin J. Edelman, M.D., Veterans Administration, Northern California Healthcare System, 150 Muir Road, Mail Code 111H, Martinez, California 94553-4612, USA. Telephone: 925-372-2062; Fax: 925-228-4686; e-mail: mjedelman{at}ucdavis.edu
Dr. Sandler has presented an important summary of the rationale and utilization of gemcitabine in non-small cell lung cancer (NSCLC) [1]. In this commentary, I will endeavor to place this summary in the context of recent developments in NSCLC, more fully explore some of the significant toxicity issues raised by Dr. Sandler with regard to platinum/gemcitabine combinations, and describe potential future trials utilizing this important drug.
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Current Status of NSCLC Therapy
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Recent trials and analyses allow three major points to be made:- Chemotherapy and, specifically, platinum-based chemotherapy, is superior to "best supportive care" (i.e., analgesics, radiotherapy, etc.) in terms of survival and/or quality of life [2, 3].
- Currently, there is no clear "standard" chemotherapy. Phase III trials have unequivocally demonstrated that platinum-new agents (i.e., paclitaxel, gemcitabine, vinorelbine, irinotecan) are superior to cisplatinum alone or to cisplatinum-older agent combinations (e.g., etoposide, vindesine, etc.) [4]. Of note, the only trial yet presented which compares the newer chemotherapy regimens (SWOG 9509, carboplatin/paclitaxel versus cisplatin/vinorelbine) was a dead heat in terms of response and survival, with some toxicity and tolerance parameters favoring the carboplatin/paclitaxel arm, while economic analysis favored the cisplatin/vinorelbine arm [5].
- Prognostic variables predict survival and response to chemotherapy [2].
These three points raise the question of what to do in day-to-day practice. It is clear that many patients with advanced NSCLC should be treated. However, which patients should be treated requires careful assessment of the individual patient. Most clinical trials exclude poor performance status patients (PS >2) and, in some cases, the elderly. These exclusions are frequently ignored in practice with undesirable results, i.e., toxicity, expense, and lack of patient benefit. The surprising progress in this disease in recent years should not result in over-treatment. Other patients who probably will not benefit from therapy with the current two-drug regimens are those with substantial weight loss (>10%) or with severe co-morbid illness.
On the other hand, there are patients, particularly the elderly, who are frail and may not tolerate a platinum-based regimen, but who otherwise might benefit from treatment. These patients are appropriate candidates for single-agent chemotherapy. As Dr. Sandler indicates, gemcitabine, with its favorable toxicity profile is an excellent choice in this setting and has demonstrated its value as a single agent in a trial versus "best supportive care" [6]. Vinorelbine has also shown utility in this setting, demonstrating superiority over "best supportive care" in terms of both survival and quality of life [7].
If one of the current two-agent regimens are to be utilized, which one? This is a decision which should be individualized. In the United States, the regimen of carboplatin and paclitaxel is unquestionably the most commonly employed. It is convenient, requiring therapy only once every three weeks. However, it has no clear advantage in terms of survival over other regimens. Though well tolerated overall, neuropathy is common and cumulative with paclitaxel-based therapy. Patients with underlying neuropathy or those who are likely to have subclinical neuropathy (e.g., diabetics, alcoholics) may benefit from alternative regimens. Unfortunately, most of the larger comparative trials of new agents and platinum have employed cisplatin rather than carboplatin. The well-known toxicities and inconvenience of cisplatin make it difficult to utilize these regimens. However, the closely related drug, carboplatin, has activity similar to cisplatin in terms of survival. The ECOG demonstrated that carboplatin as a single agent was superior to cisplatin-based therapy in terms of survival [8]. There are phase I and II data elucidating dose and schedule for carboplatin and gemcitabine (v.i.) as well as for carboplatin and vinorelbine.
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The Tale of Two Schedules—Platelet Toxicity and Platinum Gemcitabine Combinations
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Dr. Sandler has noted the frequent incidence of significant platelet toxicity associated with platinum and gemcitabine combinations. This toxicity was felt to be so significant by the Hoosier Oncology Group when they evaluated the combination of carboplatin/gemcitabine that they abandoned the trial [9]. Many concluded, based on that trial, that the drugs could not be combined. Subsequent studies have demonstrated that this conclusion was premature and the two drugs can be combined without difficulty. Careful evaluation and comparison of these trials highlight several important points: First, gemcitabine combined with either platinum will result in thrombocytopenia. Second, this thrombocytopenia may be significant (i.e., grade IV), but is usually brief and without clinical bleeding. Third, dose intensity may be maintained by altering the schedule to eliminate day-15 administration of gemcitabine and recycling on a 21-day instead of a day-28 schedule. Alternatively, a 28-day schedule may be utilized if gemcitabine is administered only on days 1 and 8 [10].
Table 1 compares the incidence of grade 4 thrombocytopenia, with 95% confidence intervals for a representative sampling of cisplatin/gemcitabine and carboplatin/gemcitabine regimens [9, 11-16]. Clearly, there is little difference in terms of thrombocytopenia between cisplatin/gemcitabine and carboplatin/gemcitabine if a 21-day schedule for carboplatin/gemcitabine is employed. Notably, a similar adjustment in the schedule of cisplatin/gemcitabine also mitigated platelet toxicity [12]. The most dramatic demonstration of the importance of schedule comes from the work of Carrato et al. who evaluated both 21- and 28-day regimens. Substantially less thrombocytopenia was noted utilizing the 21-day regimen. In the United States, the largest trial utilizing this regimen was performed at the University of California, Davis and demonstrated that the combination was well tolerated and effective. In that study gemcitabine/carboplatin was employed for three cycles followed by three cycles of paclitaxel as part of an evaluation of planned sequential therapy. Platelet toxicity from gemcitabine and carboplatin was brief, self-limited, rarely required prophylactic platelet transfusion, and was not cumulative.
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Three-Drug Regimens
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A logical extension of the success of platinum-gemcitabine regimens is to add a third active agent. The most logical choice is paclitaxel. Several groups have piloted combinations of these three drugs with good reports of activity and tolerance. Interestingly, severe thrombocytopenia has not been a problem and one can speculate on the potential platelet-sparing influence of paclitaxel. Another approach to adding drugs is to utilize them in sequence. This strategy, in which paclitaxel follows carboplatin and gemcitabine is supported by mathematical modeling, biological considerations, and some clinical data [17, 18]. In breast cancer, the use of paclitaxel following adriamycin/cyclophosphamide resulted in superior outcomes [19]. The sequential regimen described above serves as one arm of the current SWOG trial in NSCLC (9806).
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Non-Platinum Regimens
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The introduction of non-platinum regimens, many containing gemcitabine, represents a paradigm shift in the chemotherapeutic management of NSCLC. Since the mid-1980s virtually all regimens have contained a platinum backbone. In a SWOG evaluation of over 2,000 patients, cisplatin was the only intervention which favorably affected outcome [2]. Unfortunately, cisplatin and, to a lesser extent carboplatin, have substantial toxicity. Furthermore, while there has unquestionably been improvement in the management of NSCLC attributable to cisplatin and carboplatin, these benefits are clearly modest. The introduction of new agents at effective doses may be compromised by continued employment of the platinums.
Both gemcitabine and vinorelbine as single agents have demonstrated improvement over best supportive care alone in terms of quality of life and vinorelbine in terms of survival. These were benefits previously seen only with the platinums and are in marked contrast to the experience with alkylating agents, etoposide or the older vinca alkaloids. Several combinations with these two drugs are now undergoing study. An EORTC trial will compare gemcitabine and paclitaxel to two platinum-containing regimens (gemcitabine/cisplatin, paclitaxel/cisplatin). The use of sequential therapy also offers the possibility of retaining the benefits of the platinums, allowing more aggressive utilization of new drugs and enhancement of drug diversity.
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Gemcitabine in Previously Treated NSCLC
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Although there have clearly been improvements in the management of both stage III and IV NSCLC, the vast majority of stage III and all of stage IV patients will experience progressive disease. Many of these patients will still have good functional status and desire additional treatment. To date only the taxanes and specifically, docetaxel, have demonstrated reproducible activity and proven value in Phase III trials in this setting [20, 21].
Several trials have evaluated gemcitabine in patients with previous chemotherapy treatment, with mixed results. Table 2 summarizes these studies [22-25]. The data are conflicting, with some studies demonstrating significant response rates, while in others response rates were low, but survival unexpectedly prolonged. These differences may be the result of varying definitions of resistance to prior therapy as well as the possibility that patients entered onto some of these studies had inherently more indolent disease. The role of gemcitabine in this setting remains to be defined.
Overall, as Dr. Sandler concludes, gemcitabine represents a valuable addition to the armamentarium in the treatment of NSCLC. Unfortunately, even with an expanding number of reasonably well-tolerated drugs, the vast majority of patients will die from this largely preventable disease.
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Acknowledgments
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Partially supported by CA 63265.
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References
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accepted for publication June 1, 1999.
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Current Status of NSCLC...
The Tale of Two...
