XELOX for Second-Line Pancreatic Cancer

Abstract & Commentary

By William B. Ershler, MD

Synopsis: Capecitabine and oxaliplatin were used in combination for patients with advanced pancreatic cancer refractory to first-line gemcitabine. The combination was well tolerated and, although only one patient met criteria for partial response, stable disease was seen in approximately 25% and overall survival was 23 weeks. The combination appears active in this setting and may be well suited for those with good performance status, particularly if they initially responded to first-line treatment.

Source: Xiong HQ, et al. Phase II trial of oxaliplatin plus Capecitabine (XELOX) as second-line therapy for patients with advanced pancreatic cancer. Cancer. 2008;113: 2046-2052.

For almost a decade, gemcitabine has been considered the standard chemotherapeutic approach to advanced pancreatic cancer.1 Several combinations have been tested, but none have added clinically significant improvements to this drug used alone. Furthermore, few studies have demonstrated, or even addressed, treatment options for those who have become refractory to gemcitabine. In previous studies, both capecitabine and oxaliplatin have been used as components of front-line therapy for advanced pancreatic cancer. For patients with good performance status, capecitabine added to gemcitabine significantly improved median overall survival as first-line therapy, compared to gemcitabine alone.2 (This was not true for the entire treatment cohort; just for those with good performance status.) Similarly, oxaliplatin, when used in combination with gemcitabine, was shown to improve progression-free, but not overall survival when compared to gemcitabine alone.3 Thus, there was rationale to test the combination of capecitabine and oxaliplatin as second-line treatment for gemcitabine-resistant pancreatic cancer. Accordingly, Xiong et al conducted a Phase II trial designed to evaluate the efficacy of oxaliplatin in combination with capecitabine (XELOX) in gemcitabine-pretreated patients with advanced pancreatic cancer.

For this, patients aged 65 years or younger who had an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1 received oxaliplatin at a dose of 130 mg/m2 given on Day 1 and capecitabine at a dose of 1000 mg/m2 twice daily for 14 days. For patients who were over 65 years of age or who had an ECOG PS of 2, the oxaliplatin dose was 110 mg/m2 on Day 1 and the capecitabine dose was 750 mg/m2 twice daily for 14 days on 21-day cycles. The primary outcome measure was survival at six months.

The study enrolled 41 patients. Of the 39 evaluable patients, one patient had a partial response and 10 patients demonstrated stable disease. The Kaplan-Meier estimate of the overall median survival was 23 weeks (95% confidence interval [95% CI], 17.0-31.0 weeks). Progression-free survival was 9.9 weeks (95% CI, 9.6-14.5 weeks). The six-month and one-year survival rates were 44% (95% CI, 31%-62%) and 21% (95% CI, 11%-38%), respectively. The most common grade 3-4 non-hematologic toxicity was fatigue (toxicity was graded using the National Cancer Institute Common Toxicity Criteria [version 2.0]).

Commentary

Thus, the combination of capecitabine and oxaliplatin is active in gemcitabine-pretreated patients with advanced pancreatic cancer. Typically, survival after patients become refractory to gemcitabine therapy is approximately eight weeks,4 and thus, the observed overall survival of those second-line XELOX-treated patients of 23 weeks suggests potential for significant improvement in outlook.

Other second-line regimens have also been tested; some with comparable results. Regimens tested included irinotecan plus raltitrexed,5 irinotecan plus oxaliplatin,6 5-fluorouracil and leucovorin plus oxaliplatin,7 and capecitabine plus erlotinib.8 In this regard, the value of XELOX may also relate to ease of administration and low toxicity profile.

Advances in imaging technology allow the recognition of patients with smaller volume of tumor, many of whom will have well maintained performance status. Thus, clinicians are likely to encounter patients refractory to gemcitabine but functionally capable, and desiring, second-line treatment, with the goal of maximizing survival. The capecitabine/oxaliplatin regimen seems a reasonable choice in that setting. For those with good performance status, it is probable that such treatment would provide survival advantage compared with supportive care alone. However, whether this doublet is superior to the others that have been reported could only be determined by randomized clinical trial.

References

1. Burris HA, 3rd, et al. Improvements in survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced pancreas cancer: a randomized trial. J Clin Oncol. 1997;15:2403-2413.

2. Herrmann R, et al. Gemcitabine plus capecitabine compared with gemcitabine alone in advanced pancreatic cancer: a randomized, multicenter, phase III trial of the Swiss Group for Clinical Cancer Research and the Central European Cooperative Oncology Group. J Clin Oncol. 2007;25:2212-2217.

3. Louvet C, et al. Gemcitabine in combination with oxaliplatin compared with gemcitabine alone in locally advanced or metastatic pancreatic cancer: results of a GERCOR and GISCAD phase III trial. J Clin Oncol. 2005;23:3509-3516.

4. Nakachi K, et al. Prognostic factors in patients with gemcitabine-refractory pancreatic cancer. Jpn J Clin Oncol. 2007;37:114-120.

5. Ulrich-Pur H, et al. Irinotecan plus raltitrexed vs raltitrexed alone in patients with gemcitabine-pretreated advanced pancreatic adenocarcinoma. Br J Cancer. 2003;88:1180-1184.

6. Cantore M, et al. Combined irinotecan and oxaliplatin in patients with advanced pre-treated pancreatic cancer. Oncology. 2004;67:93-97.

7. Tsavaris N, et al. Second-line treatment with oxaliplatin, leucovorin and 5-fluorouracil in gemcitabine-pretreated advanced pancreatic cancer: A phase II study. Invest New Drugs. 2005;23:369-375.

8. Kulke MH, et al. Capecitabine plus erlotinib in gemcitabine-refractory advanced pancreatic cancer. J Clin Oncol. 2007;25:4787-4792.