The War on Pancreatic Cancer: We Are Not There Yet

In this issue of ONCOLOGY, Dr. Thota and colleagues[1] provide a comprehensive review of first-line therapy options for patients with metastatic pancreatic adenocarcinoma (mPAC). They discuss toxicities of and outcomes data for the approved regimens, including single-agent gemcitabine, gemcitabine plus erlotinib, FOLFIRINOX (leucovorin, fluorouracil, irinotecan, and oxaliplatin), and the combination used in the recently published Metastatic Pancreatic Adenocarcinoma Clinical Trial (MPACT)-gemcitabine plus nab-paclitaxel. After 2 decades of disappointing phase III trials and years of single-agent gemcitabine therapy, the pancreatic cancer community is relieved to expand the front-line armamentarium in patients with mPAC. Here we evaluate the current landscape and ask some provocative questions about response rate, dosing, and predictive markers.

Back in the era of single-agent gemcitabine, experts suggested we should stop our fixation on response rate and focus on clinical benefit. Experience with gemcitabine/nab-paclitaxel and FOLFIRINOX demonstrates that higher response rates are obtainable; both regimens have a response rate of more than 20%-with the rate of FOLFIRINOX exceeding 30%-which appears to translate into improved survival. This is analogous to the experience with colon cancer, in which the FOLFIRI (leucovorin, fluorouracil, and irinotecan) and FOLFOX (leucovorin, fluorouracil, and oxaliplatin) regimens, with response rates of more than 40%, clearly improved overall survival (OS).

It is also clear that patients who are exposed to the full range of available drugs have the best survival (eg, patients with breast and colon cancers). This is probably due in some part to the biology of the disease and to the performance status of the patients, in that the latter live long enough and are healthy enough to receive and tolerate the range of therapies. We believe the same considerations will apply to mPAC. The authors allude to the dilemma in selecting appropriate first-line therapy, especially choosing between FOLFIRINOX and gemcitabine/nab-paclitaxel. Cross-trial comparisons of progression-free survival and OS are not helpful, although there are some differences between FOLFIRINOX and gemcitabine/nab-paclitaxel that have practical implications when choosing between the two for first-line therapy. The study that evaluated FOLFIRINOX excluded patients older than 75 years of age and included only those with an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1.[2] In MPACT, 10% of patients were > 75 years of age and ~ 7% to 8% of patients had a poor PS, corresponding to an ECOG PS of 2 (the study allowed a Karnofsky PS of ≥ 70).[3] The FOLFIRINOX study had more patients with carcinomatosis compared with the gemcitabine/nab-paclitaxel trial (19% vs 4%), which could suggest more aggressive disease biology. A randomized trial may (or may not) select a “better” front-line regimen, but without predictive biomarkers, we are far from the promise of personalized medicine and the ability to match the right combination with the right patient.

Let us discuss the status of predictive markers. To date, erlotinib remains the only biologic agent approved by the US Food and Drug Administration (FDA) for the treatment of mPAC, although given its marginal clinical benefit, it has limited use in the community. In the PA.3 study, grade ≥ 2 rash was strongly correlated with OS (hazard ratio = 0.47; P < .001); the median OS in patients with such a rash (35%) was 10.5 months, on par with other regimens.[4] “Dosing to rash” is an interesting concept, and studies have evaluated dose escalation in several settings, including non–small-cell lung cancer and colorectal and head and neck cancers, although a clear verdict on the strategy is pending at this time.[5] Also, it is possible that the benefit of erlotinib in mPAC is noted mainly in the small group of patients with KRAS wild-type tumors. Retrospective analysis of the tissue from the PA.3 study showed that KRAS testing was completed in samples from only 117 patients (out of 569) and only 25 patients had KRAS wild-type tumors-small numbers from which to draw conclusions.[4] Prospective studies are warranted to evaluate the predictive role of KRAS, to identify patients in whom rash is most likely to develop, and to determine whether dose escalation to induce rash can improve efficacy.

Nab-paclitaxel was approved by the FDA for use in mPAC in September 2013 after the MPACT results demonstrated that the gemcitabine/nab-paclitaxel combination was superior to single-agent gemcitabine. As mentioned by Thota and colleagues, nab-paclitaxel has been shown to improve intratumoral concentration of gemcitabine in murine models of pancreatic cancer, either through stromal depletion or by decreasing the primary gemcitabine-metabolizing enzyme, cytidine deaminase. In the study of gemcitabine/nab-paclitaxel, secreted protein acidic and rich in cysteine (SPARC) was evaluated in 36 patients.[6] A significant increase in OS was observed for patients in the high-SPARC group (n = 19) compared with those in the low-SPARC group (n = 17); median OS was 17.8 vs 8.1 months, respectively (P = .0431). The SPARC level remained a significant predictor of OS in a multivariate Cox regression model after adjusting for clinical covariates, including sex, race, age, treatment, and baseline CA19-9 level (P = .041). In addition, stromal SPARC was significantly correlated with OS (P = .013) but SPARC in tumor cells was not (P = .15). At this time, we eagerly await tissue correlative data from the MPACT study, and the role of stromal vs tumor SPARC remains to be evaluated.

Lastly, we need to examine the doses of cytotoxic chemotherapy. Gemcitabine/nab-paclitaxel and FOLFIRINOX are active regimens but not without toxicity (especially FOLFIRINOX), and there are few data to support a clear dose-response relationship with these regimens. We believe it is important that oncologists consider the role of “minimally effective dose” instead of “maximum tolerated dose” for aggressive cytotoxic regimens. For example, in the community, the use of dose-modified FOLFIRINOX (which amounts to ~ an 18%–20% dose reduction of one to three drugs) does not compromise efficacy and has better tolerability.[7] Unfortunately, studies to identify the minimally effective dose are difficult to conduct, and the data are not easily available. Nonetheless, we owe it to our patients to challenge the norm, given the side effects (and expense) of the various combinations that may not work for a patient and that may negatively affect quality of life.

Financial Disclosure:Dr. Varadhachary serves on the advisory board of and receives honoraria from Celgene, and he serves as a consultant to Rexahn Pharmaceuticals. Dr. Wolff has no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.

References:

1. Thota R, Pauff JM, Berlin JD. Treatment of metastatic pancreatic adenocarcinoma: a review. Oncology (Williston Park). 2014;28:70-4.

2. Conroy T, Desseigne F, Ychou M, et al. FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. N Engl J Med. 2011;364:1817-25.

3. Von Hoff D, Ervin T, Arena F, et al. Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine. N Engl J Med. 2013;369:1691-1703.

4. da Cunha Santos G, Dhani N, Tu D, et al. Molecular predictors of outcome in a phase 3 study of gemcitabine and erlotinib therapy in patients with advanced pancreatic cancer: National Cancer Institute of Canada Clinical Trials Group Study PA.3. Cancer. 2010;116:5599-607.

5. Brahmer JR, Lee JW, Traynor AM, et al. Dosing to rash: a phase II trial of the first-line erlotinib for patients with advanced non-small-cell lung cancer an Eastern Cooperative Oncology Group Study (E3503). Eur J Cancer. 2013 Nov 15. [Epub ahead of print]

6. Von Hoff DD, Ramanathan RK, Borad MJ, et al. Gemcitabine plus nab-paclitaxel is an active regimen in patients with advanced pancreatic cancer: a phase I/II trial. J Clin Oncol. 2011;29:4548-54.

7. Peddi PF, Lubner S, McWilliams R, et al. Multi-institutional experience with FOLFIRINOX in pancreatic adenocarcinoma. JOP. 2012;13:497-501.