Expert Point of View: Jiping Wang, MD, PhD

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Jiping Wang, MD, PhD

Jiping Wang, MD, PhD

“The jury is still out,” said APACT’s invited discussant, Jiping Wang, MD, PhD, a biostatistician and hepatobiliary pancreas surgical oncologist at Dana-Farber Cancer Institute and Brigham and Women’s Hospital, Boston. “The final overall survival analysis is needed to know the real benefit from nab-paclitaxel combined with gemcitabine. Nevertheless, the APACT trial gives us another option for adjuvant chemotherapy for resected pancreatic cancer, especially in patients who cannot tolerate modified FOLFIRINOX [fluorouracil, leucovorin, irinotecan, oxaliplatin].”

As suggested by Dr. Tempero, the choice of independent central review is responsible for the negative outcome and may have been unwise, Dr. Wang maintained. “It was believed this was essential to avoid the bias that can be introduced by local investigators’ belief about a therapy. However, as we all know, local/regional recurrence is difficult to determine in pancreatic cancer,” he said. “The independent reviewer usually doesn’t have access to critical and relevant information such as surgical details and tumor marker changes to make this call, and this may be a major reason for the discrepancy between the independent review and the investigators’ evaluations.”

Further exploration for this discrepancy would be informative, added Dr. Wang, and without it, he would question whether this endpoint is a good surrogate for overall survival in future pancreatic cancer trial design.

Choices of Combination Regimens in Adjuvant Setting

With three chemotherapy combinations in the adjuvant setting, Dr. Wang showed the overall survival data and hazard ratios to support his recommendations for clinicians. “Modified -FOLFIRINOX offered a 20-month median overall survival improvement, whereas the improvement with nab-paclitaxel plus gemcitabine, and capecitabine plus gemcitabine, was 4.3 and 2.5 months, respectively,” he noted.

Single-agent gemcitabine yielded much worse survival in -ESPACT-4 than in the other trials, likely due to the fact that this study included more patients who did not undergo complete resection. Hazard ratios, therefore, are a better means of comparing the efficacy of the three regimens, he said, with modified -FOLFIRINOX still coming out on top and gemcitabine/capecitabine and nab-paclitaxel/gemcitabine demonstrating similar risk reduction.

By resection status, capecitabine/gemcitabine had its impact primarily in patients with R0 resection, whereas those with R1 resection derived no real benefit from this combination. With modified FOLFIRINOX, risk reductions were significant for both the R0 and R1 resection groups. And for nab-paclitaxel/gemcitabine, such conclusions cannot yet be drawn, he said.

The toxicity profile appears to be the most favorable with capecitabine/gemcitabine, “moderate” with nab-paclitaxel/gemcitabine, and the worst with modified FOLFIRINOX, which is associated with a many-fold–higher incidence of nausea, vomiting, diarrhea, and fatigue vs gemcitabine, he noted.

A Matter of Tolerability

“In short, modified FOLFIRINOX is the most effective adjuvant chemotherapy but it has the worst toxicity profile. It is a treatment choice for the patient who can tolerate it. If a patient cannot tolerate it, then capecitabine/gemcitabine is a good choice…. However, clinicians should disclose to patients that it might not benefit those with R1 resection,” Dr. Wang said.

Pending the overall survival results of the APACT trial, it appears that, for now, the role of nab-paclitaxel/gemcitabine is primarily as “an alternative treatment, especially for patients with R1 resection who cannot tolerate modified FOLFIRINOX,” he offered. 

DISCLOSURE: Dr. Wang owns stock in; has consulted for; and has received honoraria, research funding, and travel expenses from GenomiCare.

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