The 5-year results of this study demonstrate that the previously observed improvement in 3-year OS with the addition of G to adjuvant fluorouracil based CRT for patients with pancreatic head adenocarcinoma is no longer seen at 5 years.
While the OS curves remain separated throughout 5 years () only a trend towards statistical significance is now seen. Thus, in the context of this study design, any improvement in survival associated with the use of G appears to be temporary and marginal at best.
Although the 5-year results in this study did not reach statistical significance, the observed marginal difference in survival between study arms favoring the G arm deserves further comments in the context of the conduct and design of this trial. First, 41% of the patients on the 5-FU arm received salvage chemotherapy after any recurrence, of which 81% of patients received G. This ‘cross-over’ like occurrence may have diluted differences in survival between the two study arms. Secondly, a greater proportion of patients on the G arm had T3/T4 disease (81% vs. 70%, p=0.013).
In addition and perhaps most importantly, is the associated potential negative impact on the survival benefit which could be seen with G due to the prolonged interruption of G related to the fundamental design of this study. In the G arm, patients were given a single cycle of G, followed by a required 1 – 2 weeks break before initiation of 5.5 weeks of 5-FU based CRT. This was then followed by a required 3 – 5 week break to allow for recovery from acute toxicity and restaging before resumption of G given in three additional cycles. Thus, between the first cycle of G and resumption of the final three cycles of G, patients were without G therapy for at least 9.5 weeks and for as long as 12.5 weeks. Given the known exponential rate of tumor recurrence associated with this disease, this prolonged interruption of G therapy may well have been a significant factor contributing to the temporary and eventually marginal survival benefit seen with use of G in this study.
The 5-year results from this study must also be reviewed in the context of the recently updated Phase III CONKO-001 trial and the recently reported Phase III ESPAC-3 trial (2
). The CONKO trial randomized patients with completely resected pancreatic cancer to six
total cycles of G versus surgery alone. Patient selection and eligibility requirements clearly differed between RTOG 9704 and the CONKO trial (23
), including frequency of R0 resections (42% - RTOG vs. 83% - CONKO) and the CONKO requirement for CA19-9 to be < 2.5 x upper limit of normal (~ 90). RTOG 97-04 did not exclude patients by CA19-9, with 21% having values > 90. CONKO-001 initially demonstrated only a statistically significant improvement in disease-free survival without an improvement in overall survival (1
). However, the recently reported 5-year results in now demonstrate a statistically significant improvement in overall survival with a median and 5-year survival rate of 22.8 months and 21% in the G arm and 20.2 months and 9% in the surgery alone arm (p=0.005) (2
). The use of 6 total cycles of G in the CONKO trial should be viewed in contrast to our study, which in addition to the prolonged interruption of G therapy, made use of only four total cycles of G.
While the CONKO trial evaluated the impact of adjuvant G compared to surgery alone, the recently reported ESPAC-3 trial was a direct comparison of G to 5-FU in the adjuvant setting. This trial randomized patients with completely resected pancreatic carcinoma to six cycles of G versus six cycles of 5-FU. In this adjuvant trial where patients did not receive RT by design, direct comparison of G versus 5-FU demonstrated no significant difference in survival. (3
) While RTOG 9704 represents the only other phase III trial making a direct comparison of G to 5-FU in the adjuvant setting, all patients received CRT by design.
When viewed in total, the findings from RTOG 9704, CONKO-001, and ESPAC-3, as well as previously reported phase III postoperative adjuvant therapy trials for pancreatic adenocarcinoma, would suggest the following: 1) the survival benefit associated with G is observed with use of 6 cycles; 2) the survival benefit seen with G in comparison to 5-FU appears to be temporary/marginal at best and seen only with the inclusion of CRT; 3) while the local recurrence rate of 28% seen in RTOG 9704, which made use of central RT QA (22
), is the lowest reported to date and is approximately half of that reported in previous phase III adjuvant CRT trials (10
), distant disease relapse remains the primary mode of failure occurring in greater than 70% of patients. These fundamental observations based on level one evidence serve as the basis of the international EORTC/US Intergroup/RTOG 0848 which is a phase III trial evaluating adjuvant therapy in patients with resected pancreatic adenocarcinoma, the schema of which is shown in . Patient stratification will include CA19-9 level ( < 90 vs. > 90 – 180). By design this trial will have two randomizations. The first randomization will evaluate the impact of the addition of erlotinib to G. The testing of erlotinib is based on results in the locally advanced and metastatic setting demonstrating a survival benefit with use of erlotinib in combination with G (25
Schema for RTOG 0848: A Phase III Trial Evaluating Both Erlotinib and Chemoradiation as Adjuvant Treatment for Patients with Resected Head of Pancreas Adenocarcinoma
After five cycles of G based therapy patients will undergo re-imaging and those who have no evidence of disease progression will undergo a second randomization evaluating the impact of CRT. CRT will be given after completion of the sixth and final cycle of G. During this sixth and final cycle central RT QA will be performed. This trial will also allow the use of intensity modulated radiation therapy (IMRT) in addition to Trans-Atlantic central RT QA. Quality of life, patient reported outcomes, and correlative molecular science analyses are also planned.