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.
- Multivariate analyses examined treatment, nodal involvement, tumor diameter, tumor stage, RT quality assurance (RTQA) score, and margin status.
- 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.
Partially funded by an unrestricted educational grant from Bristol-Myers Squibb.