Clinical Investigation
Failure to Adhere to Protocol Specified Radiation Therapy Guidelines Was Associated With Decreased Survival in RTOG 9704—A Phase III Trial of Adjuvant Chemotherapy and Chemoradiotherapy for Patients With Resected Adenocarcinoma of the Pancreas

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Purpose

In Radiation Therapy Oncology Group 9704, as previously published, patients with resected pancreatic adenocarcinoma received continuous infusion 5-FU and concurrent radiotherapy (5FU-RT). 5FU-RT treatment was preceded and followed by randomly assigned chemotherapy, either 5-FU or gemcitabine. This analysis explored whether failure to adhere to specified RT guidelines influenced survival and/or toxicity.

Methods and Materials

RT requirements were protocol specified. Adherence was scored as per protocol (PP) or less than per protocol (<PP). Scoring occurred after therapy but before trial analysis and without knowledge of individual patient treatment outcomes. Scoring was done for all tumor locations and for the subset of pancreatic head location.

Results

RT was scored for 416 patients: 216 PP and 200 <PP. For all pancreatic sites (head, body/tail) median survival (MS) for PP vs. <PP was 1.74 vs. 1.46 years (log–rank p = 0.0077). In multivariate analysis, PP vs. <PP score correlated more strongly with MS than assigned treatment arm (p = 0.014, p = NS, respectively); for patients with pancreatic head tumors, both PP score and gemcitabine treatment correlated with improved MS (p = 0.016, p = 0.043, respectively). For all tumor locations, PP score was associated with decreased risk of failure (p = 0.016) and, for gemcitabine patients, a trend toward reduced Grade 4/5 nonhematologic toxicity (p = 0.065).

Conclusions

This is the first Phase III, multicenter, adjuvant protocol for pancreatic adenocarcinoma to evaluate the impact of adherence to specified RT protocol guidelines on protocol outcomes. Failure to adhere to specified RT guidelines was associated with reduced survival and, for patients receiving gemcitabine, trend toward increased nonhematologic toxicity.

Introduction

Radiotherapy (RT) combined with chemotherapy and surgery is efficacious in the management of gastrointestinal carcinoma, especially of the rectum and stomach 1, 2, 3, 4. However, whether an adjuvant paradigm involving both RT and chemotherapy, or chemotherapy alone, represents the best option for patients with curatively resected pancreatic adenocarcinoma is controversial 5, 6, 7, 8, 9. Randomized trials have demonstrated an advantage to surgery followed by gemcitabine chemotherapy as compared with surgery alone (6) and have also raised the question that RT, rather than being helpful, might actually be detrimental (5).

The administration of RT involves numerous clinical and technical details and the extent to which adherence to protocol specified guidelines influences treatment outcomes has not been well studied. MacDonald et al. (4) have reported that in Intergroup 0116, an adjuvant trial for resected gastric adenocarcinoma, initially submitted RT fields were judged inappropriate because of inadequate coverage of at risk areas for subclinical tumor or because of unacceptable toxicity risk in 35% of patients. Moreover, deviations from protocol specified RT guidelines are known to occur in cooperative group trials during protocol management 10, 11.

Because deviations from established quality assurance (QA) guidelines had been shown to impact on survival in a number of nononcologic clinical contexts 12, 13, 14, 15 and because of the existing controversy regarding the role of RT in the adjuvant management of pancreatic adenocarcinoma, the following secondary analysis of Radiation Therapy Oncology Group (RTOG) 9704 was undertaken.

Section snippets

RTOG 9704

The details of this protocol have been previously published (16). Eligibility included adenocarcinoma of the pancreas and gross total tumor resection with curative intent. All patients gave written, protocol specific, informed consent according to institutional and federal guidelines.

Treatment

Patients were randomly assigned to pre- and post-chemoradiotherapy (CRT) 5-FU (arm 1) or gemcitabine (arm 2). Randomization was performed at registration and was stratified for tumor diameter (<3 cm vs. ≥3 cm),

Enrollment and eligibility

RTOG 9704 accrual opened and closed on July 20, 1998, and July 26, 2002, respectively, with 538 patients enrolled; 270 on the 5-FU arm and 268 on the gemcitabine arm. Of these, 451 were eligible and analyzable (16). Figure 1B charts patient numbers for each step of this analysis.

Final RT QA review

Thirty-five patients had incomplete or inevaluable RT data, 19 in the 5-FU arm and 16 in the gemcitabine arm. Reasons for being incomplete/inevaluable included: death after enrollment but before the completion of RT, 2

Discussion

The Agency for Healthcare Quality Research has defined quality in health care as “….. doing the right thing, at the right time, in the right way, for the right person—and having the best possible results” (18). In this secondary analysis from RTOG 9704, we have observed that RT was not always administered in the prospectively defined “right” way, and when it was not, the treatment administered was associated with inferior survival (Fig. 2B, 2D) and was more likely to result in the occurrence of

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    • Cited by (0)

    Supported by the following grants for the RTOG: CA21661, CA37422, and 32115 Clinicaltrials.gov Identifier: NCT00003216

    Conflict of interest: none.

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