Sinn et al. (1) report the results of a multicenter trial comparing the combination of gemcitabine and erlotinib with gemcitabine alone for adjuvant therapy in 436 patients who underwent R0 resection for pancreatic ductal carcinoma (PDAC).
PDAC is a devastating disease as less than 10% of patients are still living 5 years after the diagnosis. Surgery offers the single chance of cure, but no more than 15% of patients may achieve a curative-intent resection and most of them relapse within 2 years (2). Adjuvant chemotherapy after surgery is needed to treat an undetectable concomitant micrometastatic disease often present, explaining why 71–76% of patients relapse 1 year after surgery and no more than 20% to 30% are still living at 5 years (2).
Since 2001, adjuvant chemotherapy with 5-fluorouracil (5-FU) and leucovorin (LV) after curative-intent pancreatic resection has been the standard of care for all tumor stages, while the role of adjuvant radiation therapy is still undefined (3,4). The ESPAC 1 trial provided the first robust evidence that 6 months of adjuvant chemotherapy with these drugs improved survival compared to simple observation [median overall survival (OS): 20.1 months in the chemotherapy arm vs. 15.5 months in the observation arm, P=0.009] and the chemoradiation arm. The German CONKO-001 trial showed that gemcitabine administration was better than simple observation whether the resected tumor was R0/R1 or N0/N1, doubling disease-free survival (DFS) (13.4 vs. 6.9 months, P=0.001) and resulting in longer median OS (22.8 vs. 20.2 months, P=0.005 for an estimated 5-year survival of 21% vs. 9% (5). Thereafter, the ESPAC 3 trial compared gemcitabine and 5FU/LV, initially with an observation arm that was closed when the mature results of ESPAC-1 were available. Results obtained were similar, with a median OS of 23.6 vs. 23 months with gemcitabine and 5-FU/LV [hazard ratio (HR) 0.94, P=0.7], respectively. Grade 3–4 hematological toxicity was higher in the gemcitabine arm (P<0.003) (6). Intra-tumoral expression of the hENT-1 protein was then evaluated as a potential predictive marker for gemcitabine efficacy (7), but this marker is not yet recommended in routine practice due to discordant results and the lack of a validated anti-hENT1 antibody (8).
In the next step, the ESPAC 4 trial has tested the combination of gemcitabine and capecitabine vs. gemcitabine alone (9). Grade 3–4 toxicity (neutropenia and hand-foot syndrome) was higher in the combination arm compared to gemcitabine alone (38% vs. 24% and a 7% vs. 0%, respectively; P<0.001). OS was 28 months in the experimental arm and 25.5 months in single-gemcitabine arm (HR 0.82; 95% CI, 0.68–0.98, P=0.032). Despite certain limitations [lack of postoperative computed tomography (CT), inclusion of patients with high CA 19.9 serum levels and similar DFS between the two arms], due to the benefit in estimated 5-year OS, i.e., 28.8% (22.9–35.2%) vs. 16.3% (10.2–23.7%), gemcitabine plus capecitabine could was considered a new standard in this setting. Meanwhile, the Japanese non-inferiority trial JASPAC-01 reported impressive results in 385 patients with the S-1 compound compared to gemcitabine [5-year OS 44.1% (36.9–51.1%) in the S-1 group vs. 24.4% (18.6–30.8%)] (10). However, the S-1 compound has not been tested in Western countries. Finally, the CONKO-006 trial (11) compared the combination of gemcitabine plus sorafenib to placebo in 122 patients who underwent R1 resection and found no difference in disease free survival (DFS) (9.6 vs. 10.7 months, P=0.89).
Erlotinib is an oral quinazoline derivative, a potent inhibitor of epidermal growth factor receptor (EGFR) related tyrosine kinase. In 2006, Moore et al. (12) reported that gemcitabine plus oral erlotinib 100 or 150 mg daily was weakly but significantly better than gemcitabine alone in patients with advanced PDAC (HR 0.82; 95% CI, 0.69–0.99, P=0.038). These results prompted Sinn et al. (1) to test this drug in adjuvant setting. Four hundred and thirty-six patients were randomized between April 2008 and July 2013 in this open-label phase III trial performed in 57 centers in Germany. Patients were stratified according to the usual criteria [surgery, lymph node involvement (N0/N1), and centers] and were randomly assigned (1:1) to receive gemcitabine 1,000 mg/m2 and daily oral erlotinib 100 mg, or gemcitabine alone. In this study, R0 resection was a major criteria for eligibility, although there was no central review for pathology. Chemotherapy began from 2 to 8 weeks after surgery, for 6 months. The size of the study population was calculated to detect an improvement in DFS at 4 months (endpoint). The characteristics of both arms were well balanced in terms of clinical characteristics, tumor status and surgical procedures. Both DFS [11.4 months in the gemcitabine plus erlotinib arm vs. 11.4 months in the control arm (HR 0.94; 95% CI, 0.76–1.15, P=0.26] and OS were not different between the two arms or in the different subgroups according to stratification (24.5 vs. 26.2 months). Rash occurred in 77% of patients (Grade 1: 31%, Grade 2: 28%, Grade 3–4: 8%) in the experimental arm and its severity did not influence OS. This was discordant with two studies showing that patients with skin rash had a better tumor control (12,13). Dose escalation of erlotinib increased the rate of patients with rash and did not improve OS.
Fourteen percent of the patients in the Sinn study had postoperative serum CA 19.9 levels >100 kU/L in both arms and they had a significantly reduced median DFS and OS compared to those with values below this level. Similarly, 17% of patients in the ESPAC-4 trial had a postoperative serum level >92 kU/L with a median survival of 13.1 (10.8–16.2) months vs. a median survival of 29.6 (26.6–32.1) months in patients with lower values. In the Sinn study, full adjuvant treatment (six cycles) was completed in 145 patients (66%) in the combination arm and 160 patients (74%) in the gemcitabine arm.
Treatment started more than 7 weeks after surgery in 139 patients (66%) in the combination arm and only 105 patients (49%) in the gemcitabine arm. A delay of more than 6 weeks was associated with a worse DFS (10.9 vs. 12.2 months, P=0.026), but did not influence OS, possibly due to insufficient power in the study. The authors suggest that the longer delay in the combination arm was probably due to a desire to limit adverse effects. In view of ESPAC3 results, Valle et al. (14) suggested that the delay to the start of adjuvant chemotherapy did not influence OS (HR 0.985; 95% CI, 0.956–1.015), but OS was increased in patients who completed the full treatment compared to those who did not (HR 0.156; 95% CI, 0.443–0.601).
Sinn et al. (1) mention certain limitations to their study. First, this was an open label study and no placebo was given to the patients in the gemcitabine arm. Also, the lines of treatment after tumor progression were not standardized, thus two thirds of patients received an undefined chemotherapy, while a small percentage received radiation therapy (7%), and even second a surgical procedure (2%). It cannot be excluded that second line treatments following gemcitabine based-chemotherapy (i.e., FOLFIRINOX combination) could influence OS. Moreover, quality of life was not defined as a secondary end point. Finally, there was no central review of imaging even though defining tumor relapse can be difficult, particularly when it is locoregional.
The study by Sinn et al. (1) provides further evidence on the value of erlotinib in PDAC, as other negative studies in both metastatic or locally advanced forms of this cancer have been published (15,16).
The results of the PRODIGE 24 study comparing gemcitabine to the combination FOLFIRINOX in adjuvant setting were presented at the ASCO meeting 2018 (17). Four hundred and ninety-three patients were randomized in two well balanced arms. Resection was R1 in 40.1%/45.7% of cases in FOLFIRINOX and gemcitabine arms, respectively. Despite the rate of relative dose-intensity >70% was more reduced in the FOLFIRINOX arm than the gemcitabine one (48.7% and 91.4%, respectively), the DFS, main objective of the study, was clearly higher with FOLFIRINOX [21.6 months (95% CI, 17.7–27.6)] vs. than with gemcitabine [12.8 months (95% CI, 11.7–15.2)]; in addition, OS was better in the FOLFIRINOX arm [54.4 (95% CI, 41.8–not reached) months] than in the gemcitabine arm [35.0 (95% CI, 28.7–43.9) months]. This combination will be a new standard of care in the adjuvant setting, at least in Western countries. Finally, the results of the APACT study (NCT01964430) comparing gemcitabine plus nab-paclitaxel vs. gemcitabine are pending.
In conclusion, the combination of erlotinib and gemcitabine did not improve survival in patients who underwent R0 surgical resection for PDAC in the study by Sinn et al. (1). Twelve years after the publication by Moore et al. (12) erlotinib seems to have a very limited impact on the management of this cancer, whatever the stage of development.
Thanks to Mrs. Dale Roche-Lebrec for her help in the edition of this manuscript.
Conflicts of Interest: The authors have no conflicts of interest to declare.
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