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Capecitabine shows promise in pancreatic cancer
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Capecitabine demonstrated encouraging efficacy and toxicity outcomes compared with gemcitabine in a cohort of patients with locally advanced pancreatic cancer, according to phase 2 results of the SCALOP trial.
Researchers conducted the open-label, randomized, two-arm investigation to assess gemcitabine-based and capecitabine-based chemoradiotherapy after induction chemotherapy in a cohort of 114 patients with histologically proven, locally advanced disease.
All patients were aged at least 18 years and had a tumor diameter of 7 cm or less.
Patients were recruited from 28 centers in the United Kingdom between Dec. 24, 2009, and Oct. 25, 2011.
The induction regimen consisted of 12 weeks of gemcitabine and capecitabine (Xeloda, Hoffmann-La Roche) — three cycles of gemcitabine 1,000 mg/m2 on days 1, 8, 15 of a 28-day cycle; and capecitabine 830 mg/m2 twice daily on days 1 to 21 of a 28-day cycle.
A further cycle of gemcitabine and capecitabine was assigned to patients with stable or responding disease, a tumor diameter of 6 cm or less and WHO performance status 0-1. This was followed by a regimen of gemcitabine 300 mg/m2 once per week or capecitabine 830 mg/m2 twice daily, Monday to Friday only.
Patients in both the gemcitabine and capecitabine cohorts received 50.4 Gy radiation in 28 fractions.
Nine-month PFS in an intention-to-treat analysis served as the primary endpoint.
The final analysis included 36 patients receiving capecitabine and 38 patients in the gemcitabine cohort.
Results at 9 months indicated that 62.9% (80% CI, 50.6-73.9) of 35 evaluable patients in the capecitabine group and 51.4% (80% CI, 39.4-63.4) in the gemcitabine group did not progress.
Capecitabine was associated with an OS of 15.2 months (95% CI, 13.9-19.2) compared with 13.4 months for gemcitabine (95% CI, 11.0-15.7; adjusted HR=0.39; 95% CI, 0.18-0.81).
At 12 months, the OS was 79.2% (95% CI, 61.1-89.5) for capecitabine and 64.2% (95% CI, 46.4-77.5) for gemcitabine.
Median PFS was 12 months (95% CI, 10.2-14.6) for capecitabine and 10.4 months (95% CI, 8.9-12.5; adjusted HR=0.60, 95% CI, 0.32-1.12) for gemcitabine.
An objective response at 26 weeks was reported in eight patients in the capecitabine group and seven in the gemcitabine group.
Gemcitabine was linked to higher rates of grade 3 to 4 toxic effects (18% vs. 0%; P=.008) and non-hematological toxic effects (26% vs. 12%; P=.12).
Leucopenia, neutropenia and fatigue were the most frequently reported events.
Progression occurred in two patients in the capecitabine arm during the fourth cycle of induction therapy.
The full protocol dose of radiotherapy was administered to 74% of the capecitabine group and 68% of the gemcitabine group.
Similar quality-of-life scores were observed between the two arms.
“Will the results of the SCALOP trial change medical practice? The answer could be yes, if the concomitant improvement in progression-free survival and overall survival with decreased toxicity of the capecitabine regimen can be reproduced in a larger number of patients,” Markus K. Diener, MD, of the department of general, visceral and transplantation surgery at the University of Heidelberg in Germany, and colleagues wrote an accompanying editorial.
“The SCALOP investigators acknowledge the fairly small sample size of their trial and the non-significant difference in primary endpoint, which impairs the interpretative power of the results. We therefore agree with their conclusion that these findings have to be interpreted with caution, especially with respect to the efficacy endpoints such as survival.”
For more information:
Diener MK. Lancet Oncol. 2013;14:269-270.
Mukherjee S. Lancet Oncol. 2013;14:317-326.
Perspective
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Laura Williams Goff, MD
In patients with pancreas cancer that is locally advanced without distant metastases, chemoradiation is used to potentially improve survival and symptoms. Previous studies have suggested a small improvement in survival with gemcitabine-based radiation when compared with fluorouracil-based radiation, but high rates of toxicity have limited its use. In this study, all patients were treated with 12 weeks of induction chemotherapy with the combination of capecitabine and gemcitabine. Patients who had not progressed were then randomly assigned to either capecitabine with radiation or gemcitabine with radiation.
There was a suggestion that PFS was better with capecitabine-based radiation than with gemcitabine-based radiation and also was associated with fewer side effects. Although these results did not reach statistical significance, the trend toward better outcomes with less toxicity is reassuring to practitioners who have been reluctant to use gemcitabine-based chemotherapy due to toxicity concerns. I will continue to use fluoropyrimidines for radiation sensitization in my patients undergoing chemoradiation for pancreas cancer.
Perspective
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May Abdel- Wahab, MD
This trial was a multicenter, open-label, randomized phase 2 trial for locally advanced pancreatic cancer that compared capecitabine vs. gemcitabine when given both in the induction and concomitant setting with radiation. Although this is a very interesting randomized study that suggests that — in this setting — capecitabine may have advantages with regard to survival and toxicity, there are many areas of concern that lead to caution before any change in practice occurs.
Although the actual radiotherapy quality assurance process must be commended, there were issues with the fact that the technique allowed was not standardized. For example, 3-D or intensity-modulated radiotherapy were allowed. The same technique should have been used for all patients because this can affect toxicity.
With regard to the chemotherapy given, the low concomitant gemcitabine dose was significantly lower than that used in some of the positive studies. Moreover, the primary endpoint, PFS at 9 months, was not significantly different. Data for second-line treatment after disease progression were not obtained and could be a significant factor that determines OS, leading to a significant bias.
If the effect of gemcitabine as a radiosensitizer is important in terms of control, the low dose used in this study would adversely affect results with gemcitabine and is an important drawback. Perhaps a combination of capecitabine for induction and gemcitabine for concurrent treatment may be considered in the future.
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