Five-year Results of the Phase III Intergroup Trial (RTOG 97-04) of Adjuvant Pre- and Postchemoradiation (CRT) 5-FU vs. Gemcitabine (G) For Resected Pancreatic Adenocarcinoma: Implications for Future International Trial Design

Reviewer: Charles B. Simone, II, MD
Abramson Cancer Center of the University of Pennsylvania
Last Modified: November 9, 2009

Presenter: William F. Regine, MD
Presenter's Affiliation: University of Maryland Medical Center, Baltimore, MD
Type of Session: Scientific


  • Due to the often advanced stage of presentation among patients with pancreatic adenocarcinoma, only 15-20% with head of the pancreas lesions and fewer with body and tail lesions are optimal candidates for a potentially curative resection. Even with such a surgery, patterns of failure analyses demonstrate that 50-85% of patients have a local alone or a combination of local and distant disease relapse. Therefore, the combination of adjuvant postoperative chemotherapy and radiation therapy are considered standard of care in this patient population. 
  • The efficacy of Gemcitabine in comparison to fluorouracil (5-FU) was initially demonstrated in a randomized trial in patients with advanced or metastatic adenocarcinoma of the pancreas. Since its US Food and Drug Administration approval in 1996, Gemcitabine has also been studied in combination with 5-FU-based chemoradiation for patients with resectable pancreatic adenocarcinoma.
  • The addition of Gemcitabine to 5-FU chemoradiation was recently demonstrated to improve the median survival and 3-year overall survival in patients with resected pancreatic head adenocarcinoma (p = 0.05 on multivariate analysis) [Regine WF, et al. JAMA. 2008;299(9):1019-26.].
  • The current study investigated whether this overall survival advantage remained with longer follow-up out to five years.

Materials and Methods

  • An intergroup trial lead by the RadiationTherapy Oncology Group (RTOG) with the trialdesignation RTOG 97-04 was conducted to assess if the addition of Gemcitabine to adjuvant 5-FU chemoradiation improves survival for patients with resected pancreatic adenocarcinoma.
  • Eligibility criteria included histologically confirmed pancreatic adenocarcinoma with gross total tumor resection, confirmed bycentral review of operative and pathology reports and postoperative computed tomographic imaging. Patients with pT1-T4, N0-N1 disease were enrolled, while patients with any prior radiation therapy or chemotherapywere ineligible.
  • Protocol therapy was initiated three to eight weeks after resection and within five days of randomization.  Following resection, patients were randomized to receive either 5-FU (250 mg/m2 per day for 3 weeks) or Gemcitabine (30-minuteinfusion of 1000 mg/m2 of Gemcitabine once weekly for 3 weeks). 
  • Between one and two weeks after the completion of chemotherapy, chemoradiationwas initiated. Both groups received concurrent continuous infusion of 250 mg/m2 of 5-FU daily throughoutradiation therapy. Radiation therapy was delivered in 28 fractions, with 45 Gy delivered to the tumor bed and regional nodes, followed by a boost to the tumor bed with margin to a total dose of 50.4 Gy. Prospective central quality assurance review of radiation therapy films and approval was required prior to beginning radiotherapy.
  • Three to five weeks following chemoradiation, patients in the 5-FU arm received an additional 3 monthsof continuous infusion of 5-FU daily, while patients in the Gemcitabine arm received an additional 3 monthsof Gemcitabine.
  • Patients underwent follow-up with physicalexamination, complete blood cell count, liver function testing,chest x-ray, and CT scanning 2 to 4 weeks after the completionof chemoradiation and prior to the start of the second phaseof chemotherapy, followed by 3-month intervals for 1 year, then at 6-month intervalsfor 3 years, and then yearly thereafter.
  • Patients were stratified by nodal status, primary tumor diameter, and surgical margins. The primary endpoints of the study were overall survival for all patients and for patients with pancreatic head tumors. Secondary endpoints included pattern of relapse.


  • Between July 1998 and July 2002, 538 patients were entered onto the study, with 451 eligible and analyzable patients.  Patients were most often ineligible due to no measurement of CA-19-9 (28 patients) and treatment starting greater than eight weeks postoperatively (19 patients).
  • When assessing margin status, 42% of patients had negative surgical margins, 34% had positive margins, and 25% had an unknown marginal status. Sixty-seven percent of patients had node-positive disease, 59% had primary tumor diameter ≥ 3 cm, and 75% had T3 or T4 tumors. There was no imbalance in treatment arms other than for T-Stage, with more patients in the Gemcitabine arm having T3 or T4 disease (81% vs. 70%, p = 0.013).
  • At three years, the median survival (20.5 months vs. 16.9 months) and a 3-year overall survival (31% vs. 22%) were higher in the Gemcitabine arm than the 5-FU arm ([95% confidence interval, 0.65-1.03]; p = 0.09). The treatment effect was strengthened on multivariate analysis [95% confidence interval, 0.63-1.00]; p = 0.05).
  • With this update at five years, there was no difference in overall survival between the two arms on univariate analysis. On multivariate analysis, patients with pancreatic head tumors (388 patients) had only a trend toward improved overall survival (20.5 months vs. 17.2 months, p = 0.076) and disease-free survival. The 5-year overall survival rates were 22% for the Gemcitabine arm and 18% for the 5-FU arm.
  • Grade 4 hematologic toxicity was 1% in the 5-FU arm and 14% in the Gemcitabine group (p < 0.001), with no difference in febrile neutropenia, infection, or the ability to complete chemotherapy or radiation therapy (≥87%).
  • Among all patients, the site of first relapse was local in 28% (30% in the 5-FU arm and 25% in the Gemcitabine arm) and distant in 73%. Of the 230 patients assigned to the 5-FU arm, 46% received salvage therapy. Of these patients, 80% were salvaged with Gemcitabine.

Author's Conclusions

  • The sequencing of 5-FU based chemoradiation with Gemcitabine performed in this trial was not associated with a statistically significant improvement in overall survival with five years of follow-up.
  • Despite higher rates of patients with T3 or T4 disease, involved lymph nodes, and positive surgical margins, the local recurrence rate of 28% demonstrated in this trial is approximately half of that reported in previous Phase III adjuvant chemoradiation trials. However, distant disease relapse still occurs in >70% of patients.
  • Although the percentage of patients with an unknownmargin status is higher than that reported in previous trials, there was no difference in survival observed among patientswith unknown or negative surgical margin status.  
  • Although Gemcitabine was associated with increased grade 3 or 4 hematologic toxicity,therewere no differences in the ability to complete therapy.
  • Based on this trial and the recently reported 5-year results of the CONKO-001 phase III adjuvant trial showing a significant improvement in overall survival with Gemcitabine alone (Oettle H, et al. JAMA. 2007;297(3):267-77; Neuhaus P, et al. ASCO 2008), these findings serve as the basis for US Intergroup (RTOG 08-48)/EORTC Phase III adjuvant trial awaiting activation with a plan to enroll 950 patients to assess the impact of chemoradiation after the completion of a full course of Gemcitabine.

Clinical/Scientific Implications

  • In this trial, the high rate of salvage therapy with Gemcitabineadministered at relapse may have reduced any potential overall survival benefit for patients randomized to the Gemcitabine arm. Additionally, patients randomized to the Gemcitabine arm had a break from this agent prior to, during, and after chemoradiation, for a total of 10 to 13 weeks without Gemcitabine therapy. While this likely allowed for the high rate of patients able to complete their prescribed course of therapy, this break may also have limited the ability of the study to demonstrate a survival advantage for Gemcitabine. Despite this, a trend towards an improvement in survival among patients in the Gemcitabine arm was identified. 
  • This study is the first phase III trial requiring prospectivequality assurance of radiation therapy. This quality assurance may account for the improved local control with modest toxicity demonstrated in this study, in comparison to other recent phase III trials.
  • The European Study Group for PancreaticCancer 1 (ESPAC-1) phase III adjuvant trial has questioned the roleof adjuvant chemoradiation. Despite numerous critiques of that trial, including the lack of specification of radiation therapy guidelines,lack of radiation therapy quality assurance, and wide variability of radiation therapy doses used, many practitioners, particularly in Europe, do not routinely administer radiation therapy in the adjuvant setting for patients with pancreatic adenocarcinoma. Although RTOG 97-04 was not designed to assess the utilization of adjuvant radiation therapy since each arm received identical chemoradiation, the results of this trial compare favorably with those from the CONKO-001 trial. This is likely due to the high rate of patients with resected pancreatic adenocarcinoma developing bothsystemic and local recurrence, with systemic therapieshaving only modest activity.  
  • Laboratory correlative studies from RTOG 97-04 are ongoing in an attempt to determine molecular genetic alterations that may predict for localand systemic relapse.  Future trials should assess novelsystemic treatments to reduce systemic metastases. We will await the results of RTOG 08-48 that will be activated in the near future. We also await the results of the EORTC phase II/III trialevaluating the feasibility and potential benefit of combiningconcurrent Gemcitabine with radiation therapy in the adjuvantsetting. In the interim, Gemcitabine has been demonstrated to be safely administered in patients with pancreatic adenocarcinoma following resection and should be considered a standard systemic agent in the adjuvant setting.