In this study of a large epidemiologic database from the American College of Surgeons and American Cancer Society, we identified a large proportion of patients with locally advanced rectal cancer who continue to undergo chemoradiotherapy with single-agent chemotherapy. Those who received single-agent chemotherapy had worse overall survival compared to those who received multiple-agent chemotherapy after adjusting for covariates such as patient characteristics, tumor variables, radiation dose, and type of surgery. Interestingly, even though we observed a significant difference in overall survival, we did not find any difference in positive resection margins, nor any clinically significant difference in pathologic complete response rates with additional chemotherapeutic agents.
Single versus multiple-agent chemotherapy has been widely debated in rectal cancer clinical practice [9]. In the ACCORD 12/0405 PRODIGE 2 randomized controlled trial a total of 598 patients were randomized into two arms; chemoradiotherapy with capecitabine versus chemoradiotherapy with capecitabine and oxaliplatin [10, 11]. At 3 years the investigators identified no significant difference between the two groups in terms of local recurrence, overall survival, or disease-free survival. As a result, they concluded against the addition of oxaliplatin to the chemotherapy treatment protocols. The authors did mention that the follow-up was short and that the study was not adequately powered to detect differences <10%. Other studies have investigated different aspects such as chemotherapy-related toxicity following the addition of chemotherapeutic agents. Aschele and colleagues published the STAR-01 randomized phase 3 trial in 2011 [8]. They randomized a total of 747 patients with resectable, locally advanced (cT3-4 and or cN1-2) rectal adenocarcinoma into two groups. The first group (379 patients) was randomized to receive pelvic radiation and fluorouracil alone and the second group (368 patients) was assigned to receive the above with the addition of oxaliplatin. They demonstrated a statistically significant increase in the incidence of toxicity in the oxaliplatin group, without a significant impact on pathologic complete response. Thus, they also recommended against the addition of oxaliplatin to the chemoradiotherapy regimen. The above findings were corroborated by the results of the NSABP R04 trial, which concluded that adding oxaliplatin to neoadjuvant capecitabine did not improve locoregional control or survival but did add considerable toxicity [12].
In contrast, the German CAO/ARO/AIO-04 study was a phase III, multicenter, randomized controlled trial published in 2015 [6, 7]. The authors enrolled 1,236 patients with Stage II or Stage III rectal adenocarcinoma, of whom 623 received preoperative radiotherapy and fluorouracil followed by surgery and adjuvant fluorouracil (control group) and the remaining 613 received preoperative radiotherapy plus fluorouracil and oxaliplatin followed by surgery and adjuvant fluorouracil, leucovorin, and oxaliplatin (investigational group). The authors found a significant improvement in disease-free survival for patients in the investigational group and recommended the addition of oxaliplatin to the classic fluorouracil-based neoadjuvant chemotherapy protocols. The results of this study are supported by our findings that multiple-agent chemoradiotherapy regimens lead to improved overall survival in patients with locally advanced rectal adenocarcinoma.
Our study provides important data with its main strength being the very large sample size that the NCDB offers with more that 31,000 patients, a large cohort of patients with locally advanced rectal cancer that received treatment in the United States from 01/2006 through 12/2016. This sample size enabled us to detect a statistically significant difference in long-term outcomes between patients receiving single as compared to those receiving multiple-agent chemoradiotherapy. We identified a difference in overall survival favoring the multiple-agent chemotherapy group even after adjusting for clinically important variables including baseline comorbidities, radiation dose, and surgical procedure. The NCDB unfortunately does not provide data on important factors such as disease-free survival, locoregional recurrence or distant metastases, and systemic toxicity, however the results of our study imply that randomized controlled trials with longer follow-up or potentially larger sample size might be needed to identify significant statistical and clinical differences in outcomes.
The addition of oxaliplatin has been shown to have radiation-sensitizing properties and enhance the activity of 5-FU, ultimately leading to improved survival in patients with rectal cancer when offered in the adjuvant setting [13, 14]. The results of our study show that there may also be an advantage to using multiple-agent chemoradiotherapy in the neoadjuvant setting. If it is not simply a matter of sample size, perhaps we should turn our attention and research efforts to identifying subsets of patients with locally advanced rectal cancer that could benefit the most from multiple-agent chemotherapy. For instance, a post-hoc analysis of the CAO/ARO/AIO-04 study revealed that the addition of oxaliplatin significantly improved disease free-and overall survival in patients with rectal cancer younger than 60, however did not confer a survival benefit in patients older than 70 [15]. In our study the patients who received multiple-agent chemotherapy were more frequently diagnosed with poorly differentiated tumors or Stage III disease. It is possible that such patients with more advanced disease have a survival benefit with additional chemotherapeutic agents.
Our study has a few limitations that warrant discussion. The main limitation is the potential bias secondary to its retrospective nature. As a result, there are potential confounding variables that have not been completely accounted for. In addition, the NCDB only includes patients who were treated at one of the CoC centers many of which are academic or comprehensive cancer centers, hence the generalizability of our results is somewhat limited. Furthermore, the NCDB does not capture several outcomes of interest including local or distant recurrence, disease-specific survival, and surgical complications such as leak rates etc. Lastly, the NCDB does not provide any details about the specific chemotherapy regimens such as the exact drugs that were used and dosing/administration schedules, hence there is inevitably a degree of bias that cannot be accounted for in the analysis. However, the strength of the NCDB is in its large population of patients, approximately 70% of all cancer diagnoses in the USA and the standard data collection. For these reasons, we maintain the value of these data in clinical decision making.