Post-resectional CA 19-9 Values >90 are Associated With Significantly Worse Survival in Patients With Pancreatic Carcinoma Treated With Adjuvant Therapy on RTOG 9704 - Implications for Current and Future Trials
Reviewer: Charles B. Simone, II, MD
Abramson Cancer Center of the University of Pennsylvania
Last Modified: October 29, 2007
Presenter: William F. Regine, MD Presenter's Affiliation: University of Maryland Medical Center, Radiation Therapy Oncology Group Type of Session: Scientific
The CONKO-001 phase III trial (Oettle H, et al. JAMA. 2007;297(3):267-77) recently reported that adjuvant Gemcitabine without radiation resulted in improved disease free survival but no change in overall survival among patients with pancreatic adenocarcinoma.
These findings have been used to question the need for adjuvant radiation in the treatment of pancreatic malignancies.
The US Intergroup/RTOG 9704 trial (Regine WF, et al. IJROBP. 2006;66(3):S23(#42)) randomized 538 patients with pancreatic andeocarcinoma following resection to Gemcitabine followed by chemoradiation followed by Gemcitabine or 5-FU followed by chemoradiation followed by 5-FU.
Although RTOG 9704 cannot be directly compared to CONKO-001, these two trials can allow for a debate of the role for radiation therapy in patients with pancreatic cancer, provided differences in patient characteristics of the two trials are examined. Specifically, the CONKO-001 trial required post-resection CA 19-9 levels to be less than 2.5 times the upper limit of normal (approximately 90 U/ml), while RTOG did not have an exclusion criteria based on CA 19-9.
An RTOG 9704 secondary endpoint included the prospective evaluation of the ability of post-resectional CA 19-9 to predict overall survival. This study analysis evaluates the impact on survival of CA 19-9 values ≤ 90 U/ml versus >90 U/ml.
Materials and Methods
RTOG 9704 was analyzed with CA 19-9 as a dichotomized variable, separating values ≤90 U/ml and values >90.
CA 19-9 was examined with regards to its impact on overall survival.
538 patients were enrolled in RTOG 9704, 385 of which had an analyzable CA 19-9. Among these patients, 132 were Lewis Antigen negative and were without expression for CA 19-9.
Among the 253 patients with analyzable CA 19-9 levels and who were Lewis Antigen positive, 200 (79%) had CA 19-9 values ≤ 90 U/ml, while 53 (21%) had values > 90 U/ml.
Among RTOG 9704 adjuvant therapy arms, baseline characteristics were statistically balanced.
Overall survival was found to be statistically decreased for patients with CA 19-9 levels >90 U/ml by univariate (HR = 3.4, p<0.0001) and multivariate (HR = 3.34, p<0.0001) analyses.
Subset analyses confirmed decreased survival for higher CA 19-9 levels among patients with pancreatic head and non-head tumors, with significant results holding after adjusting for RTQA score.
RTQA score was also shown to be predictive for a decrease in overall survival when given substandard to the protocol (p = 0.02).
Median survival for patients with CA 19-9 <90 U/ml was 22.8 months, significantly higher than the 9.6 months for patients with levels >90 U/ml (p<0.0001).
Three-year overall survival for patients with CA 19-9 <90U/ml was 33%, significantly higher than the 2% for patients with levels >90 U/ml (p<0.0001).
For comparison, the median and 3-year overall survival reported in the CONKO-001 trial among patients in the gemcitabine arm were 22.1 months and 34%, respectively, while the median and 3-year overall survival seen in the RTOG 9704 trial among patients in the Gemcitabine arm with pancreatic head tumors, a CA 19-9 ≤90 U/ml, and a RTQA score per protocol were 25.2 months and 46%, respectively.
RTOG 9704 analysis demonstrates that post-resectional CA 19-9 values of >90 U/ml are associated with a significant decrease in survival among patients treated with adjuvant therapy.
CA 19-9 levels were found to be the most important predictor of survival, while nodal involvement and RTQA score were also demonstrated to influence survival. No other factors significantly impacted survival.
RTOG 9704 supports the continued administration of adjuvant radiation among patients with pancreatic adenocarcinoma in future trials, especially among patients with elevated post-resectional CA19-9 values.
The RTOG trial supports the continued administration of radiation therapy in the adjuvant setting for patients with pancreatic adenocarcinoma. CA 19-9 in this study was clearly demonstrated to be an important prognostic factor among these patients, with post-resection values >90 U/ml correlating with significantly worse survival. This is not surprising as high CA 19-9 level after resection signifies either residual disease in the pancreatic bed and nodal region or subclinical metastatic disease. These results indicated that future adjuvant therapy trials for patients with pancreatic adenocarcinoma should stratify patients according to post-resectional CA 19-9 levels.
Partially funded by an unrestricted educational grant from Bristol-Myers Squibb.