CME/CNE/CPE

Expert Perspectives on Contemporary Management of Pancreatic Malignancies: Weighing the Latest Clinical Evidence

Eileen M. O'Reilly, MD

Memorial Sloan-Kettering Cancer Center
Weill Medical College of Cornell University
New York, New York

The questions below were submitted by your peers based on a recent CME/CNE/CPE activity.
The Course Director, Dr. Eileen M. O'Reilly, provides her answers below.

Question 1: For locally advanced pancreatic cancer, how many cycles of induction chemotherapy with gemcitabine would you recommend prior to chemoradiation?

Question 2: What is your preferred regimen for first-line metastatic pancreatic cancer in a patient with PS 1?

Question 3: Is 5-FU/leucovorin, irinotecan, and oxaliplatin now the new standard of care for metastatic pancreatic cancer based upon the recent abstract of the phase 3 trial presented at ASCO (Conroy T et al. ASCO 2010. Abstract 4010)?

For locally advanced pancreatic cancer, how many cycles of induction chemotherapy with gemcitabine would you recommend prior to chemoradiation?

In the setting of locally advanced pancreas cancer, there is currently no consensus on the optimal number of cycles/months of systemic therapy prior to administering combined chemoradiation therapy.

Retrospective data from Huguet and colleagues noted that for patients who had not progressed after at least 3 months of systemic therapy, survival was improved by the addition of chemoradiation (Huguet F et al. J Clin Oncol. 2007;25:326-331). This topic is now being prospectively addressed in a European GERCOR/AIO randomized phase 3 trial.

Extrapolating from these and other single-institution data, a reasonable time period would seem to be about 3 to 4 months. A strategy of upfront systemic therapy offers the opportunity to select patients who are destined to develop early metastatic disease and hence would not benefit from the inclusion of chemoradiotherapy in their treatment plan.

What is your preferred regimen for first-line metastatic pancreatic cancer in a patient with PS 1?

Outside of a clinical trial for front-line treatment of metastatic pancreas cancer, I favor combination cytotoxic therapy. To date, randomized phase 3 trials have not discerned a survival benefit for doublet cytotoxic combinations. However, pooled and meta-analysis data (Sultana A et al. BMC Cancer. 2008;8:192; Heinemann V et al. BMC Cancer. 2008;8:82) suggest that gemcitabine combined with either a platinum analog (cisplatin or oxaliplatin) or a fluoropyrimidine are reasonable options for a PS 1 patient.

A phase 3 trial of FOLFIRINOX compared to gemcitabine alone as initial treatment for metastatic pancreas cancer, presented at the 46th Annual Meeting of the American Society of Clinical Oncology (ASCO 2010), demonstrated a statistically significant improvement in response rate, progression-free and overall survival in PS 0-1 patients for FOLFIRINOX (Conroy T et al. ASCO 2010. Abstract 4010). The magnitude of the survival benefit was nearly 4 months (6.9 mo for gemcitabine vs 10.5 mo for FOLFIRINOX) and represents the largest survival increment ever observed in a phase 3 trial in advanced pancreas cancer. The FOLFIRINOX combination did expectedly result in higher rates of myelosuppression, febrile neutropenia, fatigue, neuropathy, nausea, vomiting, and diarrhea compared to gemcitabine. The FOLFIRINOX combination (which includes bolus and infusional 5-FU/leucovorin and full-dose biweekly oxaliplatin and irinotecan) could be considered for such a patient with careful consideration of the risk-benefit equation in a PS 1 patient.

Is 5-FU/leucovorin, irinotecan, and oxaliplatin now the new standard of care for metastatic pancreatic cancer based upon the recent abstract of the phase 3 trial presented at ASCO (Conroy T et al. ASCO 2010. Abstract 4010)?

The phase 3 trial discussed in Question 2 (ie, FOLFIRINOX compared to gemcitabine in metastatic pancreas cancer), which showed a significant survival benefit for FOLFIRINOX in PS 0-1 patients, offers a new treatment option for this patient group.

Much discussion has taken place regarding whether or not this represents the new standard of care, and the consensus to date is that it represents a standard option rather than the standard option.

The major discussion points include the efficacy benefit traded against the higher rates of hematologic, neurologic, and gastrointestinal toxicities. There is considerable interest in a possible US-based randomized phase 2 trial of the FOLFIRINOX regimen with other reference arms to be finalized, but potentially to include FOLFOX (and hence evaluate the contribution of irinotecan) and possibly gemcitabine and nanoparticle albumin-bound (nab)-paclitaxel. Such a study would provide some estimates of the comparative efficacy and toxicity balance of these regimens.

For now, gemcitabine as a single agent, or in combination, remains a standard consideration for front-line treatment. It is also worth remembering that a high proportion of patients, probably around 50%, will never be candidates for the FOLFIRINOX regimen due to poor performance status, comorbidities, etc.