Taxanes in Gastric Cancer
abstract & Commentary
Synopsis: The use of docetaxel as a single agent for the frontline treatment of advanced gastric cancer was investigated. Using 100 mg/m2 every three weeks, and supported by G-CSF, the regimen was found to be well tolerated and effective.
Source: Mavroudis D, et al. Am J Clin Oncol 2000; 23:341-344.
Most of the currently available chemotherapy regimens for gastric cancer are limited by either low response rates or significant toxicity. To further the search for active drugs in stomach cancer, Mavroudis and colleagues evaluated the frontline treatment of advanced gastric cancer with docetaxel and G-CSF.
In this study from Greece, 30 patients with advanced, measurable gastric cancer were treated with docetaxel at 100 mg/m2 every three weeks supported by G-CSF 5 mcg/kg on days two through eight. These patients did not have favorable characteristics. For example, the tumors were either poorly differentiated or undifferentiated in 76% of the cases. Furthermore, of the six patients who received adjuvant chemotherapy, four developed recurrent disease during the postoperative chemotherapy.
Nevertheless, the response rate to docetaxel was 20% including one complete response (3.3%). An additional seven patients (23%) had stable disease. The duration of response was measured from the first documented response rather than from onset of therapy. The median duration of response was 4.5 months (range, 2-12). The median time to progression, measured from initiation of treatment, was six months (range, 2-14). The median survival in this study was seven months and the one-year probability of survival was 28%.
Of the 127 courses of docetaxel given (median 3.5 courses/patient), only five were delayed because of toxicity. Although 37% of the patients experienced grade III-IV neutropenia, there were only three episodes of neutropenic fever. No other grade IV toxicity was observed, with six patients experiencing grade III toxicity consisting of either anemia, nausea/vomiting, diarrhea, or fatigue.
COMMENT by Kenneth W. Kotz, MD
Now that 5-FU and leucovorin have proven successful in the adjuvant setting,1 the investigation of other agents in the metastatic setting may ultimately lead to improved adjuvant options. In the study by Mavroudis et al, docetaxel as a single agent was both well tolerated and had a response rate of 20%, with an additional 23% demonstrating stable disease. Other researchers using lower doses of docetaxel without G-CSF support have reported similar response rates in the frontline treatment of gastric cancer. For example, Mai and colleagues from Japan found that responses occurred in 23.7% of the 72 patients treated with docetaxel 60 mg/m2 given every 3-4 weeks.2
As is well known, higher response rates can be achieved by using the combination of active drugs. As predicted, Roth and Colleagues observed a response rate of 56% when docetaxel 85 mg/m2 was combined with cisplatin 75 mg/m2 on an every three-week schedule.3 Cisplatin has also been combined with paclitaxel, leucovorin, and a 24-hour continuous infusion of 5-FU. This four-drug regimen was given to 45 patients in whom 11% had a complete response and 40% had a partial response.4 Similarly, paclitaxel and 5-FU have been combined resulting in a response rate of 65.5%, with a remarkable 24.1% complete response rate. These previously untreated patients received paclitaxel 175 mg/m2 as a three-hour infusion on day 1 and 5-FU 1.5 g/m2 as a three-hour infusion on day two.5
Taxanes may also have a role in the second-line therapy of gastric cancer. In the study by Mavroudis et al, the potential for noncross resistance with docetaxel was demonstrated by two partial responses among the six patients with primary refractory disease. Another study found that patients failing a regimen of 5-FU, leucovorin, cisplatin and epirubicin had a response rate of 22.2% when treated with paclitaxel 225 mg/m2 over three hours every three weeks.6
Most oncologists have experience combining taxanes with radiation for diseases such as lung cancer. It is likely that taxanes can be safely combined with radiation when treating gastric cancer with important implications for the adjuvant setting. One report of chemoradiotherapy as primary treatment of gastric cancer demonstrated substantial local-regional activity. Twenty-seven patients received paclitaxel 50 mg/m2 weekly and concurrent radiation to 45.0 Gy (50.4 Gy if inoperable). A response rate of 56% with a two-year progression-free survival rate of 29% was noted.7
In conclusion, docetaxel at 100 mg/m2 every three weeks supported by G-CSF was found to have activity in advanced gastric cancer. It is hoped that improvements in the treatment of advanced gastric cancer will eventually lead to more beneficial adjuvant options.
References
1. MacDonald J, et al. PASCO 2000;19:1a.
2. Mai M, et al. Gan To Kagaku Ryoho 1999;26:487-496.
3. Roth A, et al. Ann Oncol 2000;11:301-306.
4. Kollmannsberger C, et al. Br J Cancer 2000;83:
458-462.
5. Murad A, et al. Am J Clin Oncol 1999;22:580-586.
6. Cascinu S, et al. Anticancer Drugs 1998;9:307-310.
7. Safran H, et al. Int J Radiat Oncol Biol Phys 2000;
46:889-894.
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