Expert Point of View: Hedy Lee Kindler, MD


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Hedy Lee Kindler, MD, Associate Professor of Medicine at the University of Chicago, the invited discussant of three of these presentations, emphasized the persistent lethality of advanced pancreatic cancer. She predicted that within this decade, pancreatic cancer will become the second leading cause of cancer death in the United States. “It still has the briefest survival of any solid tumor. Five-year survival is just 6%,” she noted.

“There has been a long-standing, well-deserved therapeutic nihilism regarding chemotherapy for advanced pancreatic cancer. In countless trials over several decades, many drugs and combinations have been tested, with minimal to no activity observed,” she said.

Nab-paclitaxel/Gemcitabine Offers New Option

One of the few milestones has now come in the form of nab-paclitaxel, she said, which, in combination with gemcitabine, improved overall survival over gemcitabine alone in the MPACT trial. Response rate, disease control rate, and median progression-free survival were all superior to the single agent, though “this came at the cost of increased grade 3 and 4 toxicity,” including neutropenia (38% vs 27%), thrombocytopenia (13% vs 9%), and neuropathy (17% vs < 1%).

“This is an important practice-changing study. It is the first randomized trial to demonstrate that a cytotoxic agent added to gemcitabine prolongs survival in pancreatic cancer,” she emphasized. “This is wonderful. We are not accustomed to having good treatment choices in advanced pancreatic cancer.”

Dr. Kindler acknowledged, however, that while the results achieved with nab-paclitaxel plus gemcitabine are certainly better than with gemcitabine alone, they are not as good as those for FOLFIRINOX (leucovorin, fluorouracil, irinotecan, oxaliplatin), as illustrated in Table 1.1,2 ­FOLFIRINOX is “superior in all metrics” to nab-paclitaxel/gemcitabine, and was shown to improve quality of life and to be cost-effective; for nab-paclitaxel/gemcitabine, these data are still lacking.

In the absence of a head-to-head comparison of the two effective regimens, she suggested, “We need to understand the data that we have.” Clinicians may simply need to accept that “it’s nice to finally have choices,” she concluded.

Chemoradiotherapy, Current Immunotherapy Less Promising

The results of LAP 07 may also “change practice,” she said, by showing a lack of benefit for the addition of radiation to chemotherapy in patients who respond to induction. “The authors conclude that the standard of care should remain chemotherapy, though chemoradiation is an option, and I agree,” she said.

Among the potential explanations for “these somewhat surprising results” is that the treatment may have been inadequate, she suggested. “Could we do better with intensity-modulated radiotherapy or stereotactic body radiation therapy? Could we do better with induction ­FOLFIRINOX or nab-paclitaxel/gemcitabine? Can we use better radiosensitizers?” Dr. Kindler questioned.

Two upcoming cooperative group trials may help answer these questions: the three-arm randomized phase II RTOG 1201 study, which is evaluating standard vs intensified local or systemic therapy, and the proposed ­ALLIANCE/ECOG randomized phase II trial evaluating induction ­FOLFIRINOX followed by either chemoradiotherapy (with capecitabine) or additional ­FOLFIRINOX.

Also disappointing were the “clearly negative” results of TeloVac, one of the largest studies ever conducted in pancreatic cancer. While TeloVac is “one of a long line of negative phase III trials in pancreatic cancer,” Dr. Kindler maintained that the immune system does play a critical role in the development, progression, and eradication of pancreatic tumors. She suggested that the optimal pancreatic immunotherapy will incorporate the best possible antigen and optimal adjuvant agent, and will aim to uncouple the tolerance mechanism by blocking immune checkpoints or manipulating the tumor microenvironment. ■

Disclosure: Dr. Kindler has served as a consultant or advisor for Abraxis Bioscience, Amgen, AstraZeneca, Bristol-Myers Oncology, Clovis Oncology, Genentech, GlaxoSmithKline, Merck, Otsuka, Roche, and Verastem, and has received research funding from AB Science, Aduro Biotech, Astellas/OSI, CanBas, Genentech, Infinity, Lilly, Merck, and Morphotek.

References

1. Conroy T, Desseigne F, Ychou M, et al: FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. N Engl J Med 364:1817-1825, 2011.

2. Von Hoff DD, Ervin TJ, Arena FP, et al: Results of a randomized phase III trial (MPACT) of weekly nab-paclitaxel plus gemcitabine versus gemcitabine alone for patients with metastatic adenocarcinoma of the pancreas with PET and CA 19-9 correlates. 2013 ASCO Annual Meeting. Abstract 4005. Presented June 3, 2013.


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