“Although gemcitabine/capecitabine may absolutely represent the most appropriate choice for select patients with resected pancreatic cancer at present, it may not remain the reference standard for long.”— Andrew H. Ko, MD
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THE PAST YEAR has undoubtedly been a disappointing one as far as clinical advances in pancreatic cancer go. No fewer than five high-profile randomized phase II or III trials in this setting reported negative results in 2016, ranging from next-generation cytotoxic agents1 to novel immunotherapeutic approaches2,3 to molecularly targeted therapies.4,5 Thus, one could certainly not be faulted for feeling a jolt of enthusiasm upon hearing the positive study outcomes from ESPAC-4, reported by Neoptolemos and colleagues in The Lancet6 and reviewed in this issue of The ASCO Post. However, while we should justifiably welcome any positive news in this arena—especially when it comes from a large, well-designed randomized phase III trial performed by a highly respected group—it is also necessary to take a step back to place the study results in appropriate clinical context.
Benefit Reconsidered
FIRST OF ALL , the authors conclude that results of this trial establish the combination of gemcitabine and capecitabine as “the new standard of care” following pancreatic cancer resection. Is this a fair claim? The median overall survival for combination therapy was 28.0 months compared with 25.5 months for gemcitabine monotherapy, translating to a statistically significant but relatively modest hazard ratio of 0.82 (P = .032). The 2-year survival difference of less than 2% between the two arms is even less impressive.
However, when looking exclusively at the subset of patients with R0 resections, the addition of gemcitabine to capecitabine seemed to confer a much greater benefit, with an almost 12-month absolute improvement in median survival over single-agent chemotherapy (39.5 vs 27.9 months). Moreover, in the overall study population, relapse-free survival at 5 years—reflecting, somewhat optimistically, the proportion of patients who may be cured of their disease—favors the gemcitabine/capecitabine combination by almost 7% (18.6% vs 11.9%). To provide some perspective, this represents a similar incremental benefit in 5-year relapse-free survival as that conferred by FOLFOX (oxaliplatin, leucovorin, fluorouracil [5-FU]), the widely accepted standard of care, used for the adjuvant treatment of stage III colon cancer.7
So, should we consider these efficacy results, on balance, clinically meaningful enough to justify routinely adding capecitabine to gemcitabine in the postoperative adjuvant setting? Furthermore, in an era of cost-containment, when we are constantly reminded to consider the value of any therapeutic intervention, does this “positive” study—absent formal cost-benefit analysis—measure up?
Toxicity Concerns
AS IS ALWAYS THE CASE, a careful weighing of the risk:benefit balance must also take into account toxicity concerns and the adverse impact that more-aggressive therapy may have on patients’ quality of life. First of all, combination therapy did not seem to place patients at greater risk of treatment-related death; this is of paramount importance and should always represent the number one priority for any novel therapeutic approach in a potentially curative setting.
Second, the incidence of grade 3 to 4 adverse events was predictably higher for patients treated with gemcitabine plus capecitabine in terms of hand-foot syndrome, cytopenias, and diarrhea. However, this was counterbalanced to some degree (somewhat surprisingly) by a higher overall and serious infection rate in the gemcitabine monotherapy arm.
Finally, from a global quality-of-life standpoint, serial questionnaires embedded into the ESPAC-4 study showed no significant effect in the longitudinal estimate of quality of life according to treatment group. So, on the whole, safety and quality-of-life issues appear to be acceptable with this combination strategy.
Patient Selection Issues
THE NEXT QUESTION we have to ask is whether the addition of capecitabine to gemcitabine truly represents the best option for all patients in this postoperative setting. There are certain subpopulations we may very well wish to avoid exposing to capecitabine: for example, elderly individuals in whom metabolism of this drug is notoriously unpredictable (although there was no stated upper age cutoff in ESPAC-4); patients concurrently receiving warfarin, due to drug-drug interactions; and those with impaired renal function. From a purely practical standpoint, one might also choose to adopt a “less-is-more” approach for individuals who have a difficult time with the ingestion of large tablets or oral medication compliance, as well as those who are struggling with irregular bowel function after a Whipple procedure.
Moreover, one must recognize that ESPAC-4 was performed in an exclusively European, predominantly white, population, and so the generalizability of these study results to other ethnicities and geographic regions remains uncertain, given the interethnic variability that might produce differences in both efficacy and toxicity. We should also remind ourselves of the strikingly positive results of the phase III JASPAC 01 trial reported this past year in The Lancet,8 in which the oral fluoropyrimidine S-1, as monotherapy, demonstrated unequivocal superiority to gemcitabine for Japanese patients following pancreatic cancer surgery. Thus, we should not automatically assume that the doublet therapy from ESPAC-4 will translate into a change of practice in other parts of the world, where an alternative standard of care has already been established.
A recurring theme in the realm of pancreatic cancer therapy has been our need to be more selective in deciding which patients are most (or least) likely to benefit from specific therapies, beyond just clinical and demographic characteristics. Adjuvant studies such as ESPAC-4 should, in theory, be able to provide access to sufficient quantities of tumor material for either biomarker-specific or multiomic analyses that may, in the future, help better inform selection of treatment. While no correlative findings were described in the current report in The Lancet, we eagerly await any follow-up studies from this data set that may provide further insight into which patients may benefit most from capecitabine as part of their adjuvant therapy.
Looking to the Future
FINALLY, it is worth noting other ongoing or recently completed studies of other combination chemotherapy regimens being evaluated in the adjuvant setting, including FOLFIRINOX (oxaliplatin, leucovorin, irinotecan, 5-FU)9 and gemcitabine/nab-paclitaxel (Abraxane),10 as well as a current cooperative group trial (RTOG 0848)11 that hopefully will definitively address the question of whether radiation confers any survival benefit in this postoperative setting.
Thus, although gemcitabine/capecitabine may absolutely represent the most appropriate choice for select patients with resected pancreatic cancer at present, it may not remain the reference standard for long. Ideally, we may soon be faced with an expanded array of options in this clinical context that makes it all the more imperative for us to be smarter in using all the genomic and molecular tools at our disposal to identify the right selection of treatment for any given patient. ■
DISCLOSURE: Dr. Ko has received clinical research support from Celgene, paid directly to his institution. He reported no other conflicts of interest.
REFERENCES
1. Van Cutsem E, Lenz H, Furuse J, et al: Evofosfamide (TH-302) in combination with gemcitabine in previously untreated patients with metastatic or locally advanced unresectable pancreatic ductal adenocarcinoma: Primary analysis of the randomized, double-blind phase III MAESTRO study. 2016 Gastrointestinal Cancers Symposium. Abstract 193. Presented January 21, 2016.
2. Le D, Ko A, Wainberg Z, et al: Results from a phase 2b, randomized, multicenter study of GVAX pancreas and CRS-207 compared to chemotherapy in adults with previously-treated metastatic pancreatic adenocarcinoma (ECLIPSE Study). 2017 Gastrointestinal Cancers Symposium. Abstract 345. Presented January 19, 2017.
3. NewLink Genetics announces results from phase 3 IMPRESS trial of algenpantucel-L for patients with resected pancreatic cancer. Press release, May 9, 2016. Available at http://investors.linkp.com/releasedetail.cfm?ReleaseID=969978. Accessed March 3, 2017.
4. Incyte announces decision to discontinue JANUS studies of ruxolitinib plus capecitabine in patients with advanced or metastatic pancreatic cancer. Press release, February 11, 2016. Available at http://www.incyte.com/ir/press-releases.aspx. Accessed March 3, 207.
5. OncoMed provides update on tarextumab phase 2 pancreatic cancer ALPINE trial. Press release, January 25, 2016. Available at http://investor.shareholder. com/oncomed/releasedetail.cfm?ReleaseID=951460. Accessed March 3, 2017.
6. Neoptolemos JP, Palmer DH, Ghaneh P, et al: Comparison of adjuvant gemcitabine and capecitabine with gemcitabine monotherapy in patients with resected pancreatic cancer (ESPAC-4): A multicentre, open-label, randomised, phase 3 trial. Lancet 389:1011-1024, 2017.
7. Andre T, Boni C, Navarro M, et al: Improved overall survival with oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment in stage II or III colon cancer in the MOSAIC trial. J Clin Oncol 27:3109-3116, 2009.
8. Uesaka K, Boku N, Fukutomi A, et al: Adjuvant chemotherapy of S-1 versus gemcitabine for resected pancreatic cancer: A phase 3, open-label, randomised, non-inferiority trial (JASPAC 01). Lancet 388:248-257, 2016.
9. Trial comparing adjuvant chemotherapy with gemcitabine versus mFolfirinox to treat resected pancreatic adenocarcinoma. Available at https://clinicaltrials.gov/ct2/show/NCT01526135. Accessed March 3, 2017.
10. Nab-paclitaxel and gemcitabine vs gemcitabine alone as adjuvant therapy for patients with resected pancreatic cancer (the “Apact” study). Available at https://clinicaltrials.gov/ct2/show/NCT01964430. Accessed March 3, 2017.
11. Gemcitabine hydrochloride with or without erlotinib hydrochloride followed by the same chemotherapy regimen with or without radiation therapy and capecitabine or fluorouracil in treating patients with pancreatic cancer that has been removed by surgery. Available at https://clinicaltrials.gov/ct2/ show/NCT01013649. Accessed March 3, 2017.
