Adjuvant Gemcitabine and Nab-Paclitaxel Misses the Target in Pancreas Adenocarcinoma: Or Did an Effective Therapy Fall to the Definition of Recurrence?

Interpreting Primary End Points in Randomized Trials of Pancreatic Cancer

“…Manji 1 proposes that GnP should be restricted to a narrow subset of patients who meet all four criteria-(1) those who are not appropriate for modified folinic acid, 5-fluorouracil, irinotecan, and oxaliplatin (mFOLFIRINOX), which remains the preferred regimen in this setting; (2) those expected to require significant dose/schedule modifications of gemcitabine 1 capecitabine (GEM-CAP) such that the doses of capecitabine are well below those tested in ESPAC-4; (3) those who have adequate performance status to tolerate therapies in addition to gemcitabine alone such that the addition of nab-paclitaxel will not result in significant dose reduction of gemcitabine; and (4) those who acknowledge understanding regarding the regimens' unproven limited benefit in DFS.…”

“…The median dose intensity was 93% of the planned protocol for the gemcitabine group and 83% for gemcitabine and 78% for capecitabine in the GEMCAP group. 4 The median cumulative dose of gemcitabine was 16,750 mg/m 2 in the gemcitabine group (1000 mg/m 2 dose given as an intravenous infusion once a week for 3 of every Manji 1 states that "frequent dose/schedule adjustments are required for patients treated in the United States given the poor tolerability with unknown consequence to efficacy," but there is no evidence that US patients behave any differently in this respect than patients from Europe. Indeed, lower capecitabine doses may be equally effective, and side effects from capecitabine may predict longer survival.…”

Reply to C. Springfeld et al

“…1 In the editorial, the answer to the question as to whether there is a role for Nab-paclitaxel 1 gemcitabine in the adjuvant setting was "not for most." 2 However, Springfeld et al 3 contend with the author's assessment that this regimen may play a role in a narrow subset of patients in whom four criteria are to be met. These criteria represent a subset of patients who are not infrequently encountered by oncologists within the United States.…”

“…One of the major points of contention was criterion (2), those expected to require significant dose/schedule modifications of gemcitabine 1 capecitabine such that the doses of capecitabine are well below those tested in ESPAC-4. Springfeld et al 3 are of the opinion that this criterion is speculative as it is highly doubtful that not more than a tiny handful of patients who do not tolerate capecitabine may tolerate full-dose nab-paclitaxel.…”

“…The justification of the restricted recommendations in a defined subset of patients for the use of Nab-paclitaxel 1 gemcitabine was not solely based on its established efficacy in the metastatic setting, but in addition, its "favored investigator-assessed disease-free survival with combination therapy, which likely more accurately reflects recurrence (albeit not statistically powered) and (3) median OS (41.8 v 37.7 months) and 5-year OS rate (38% v 31%) favoring the combination regimen." 2 The themes raised by Springfeld et al 3 point to opportunities in the design and execution of future clinical trials where standardization of inclusion and exclusion criteria would allow for better interpretation of clinical trial results and informing oncologists when selecting treatment regimens for patients. In addition, caution in generalizing initial results regarding tolerance to treatment and efficacy from clinical trials performed in a relative homogenous population, when incongruent observations emerge.…”