Compliance with Recommended Adjuvant Chemotherapy for Rectal Cancer: Room for Improvement

Abstract & Commentary

By William B. Ershler, MD

Synopsis: In examining the National Comprehensive Cancer Network Colorectal Database, reasons for not completing the recommended postsurgical chemotherapy were examined. Although only 17% of patients for whom adjuvant therapy was recommended failed to receive treatment, the decision to not proceed was based on a number of factors, most notably the existence of comorbidities. In comparison to this cohort of patients treated at academic centers, the percent of patients not treated with adjuvant chemotherapy is likely to be greater in the community setting.

Source: Khirzman P, et al. Postoperative adjuvant chemotherapy use in patients with stage II/III rectal cancer treated with neoadjuvant therapy: A National Comprehensive Cancer Network analysis. J Clin Oncol 2013;31:30-38.

Current recommendations call for the administration of neoadjuvant chemoradiotherapy and postsurgical adjuvant chemotherapy for patients with stage II/III rectal cancer. Yet, there is a concern that these guidelines are not uniformly administered, particularly with regard to the postsurgical adjuvant chemotherapy. To address this issue, National Comprehensive Cancer Network (NCCN) investigators examined their database, which includes treatment and outcomes for patients registered at any of the participating eight comprehensive cancer centers participating in the NCCN Colorectal Cancer Database.

For the purposes of this investigation, the database was used to evaluate how frequently patients with rectal cancer who were treated with neoadjuvant chemotherapy also received postoperative systemic chemotherapy. Patient and tumor characteristics were examined in a multivariable logistic regression model.

Between September 2005 and December 2010, 2073 patients with stage II/III rectal cancer were enrolled in the database. Of these, 1193 patients receiving neoadjuvant chemoradiotherapy were in the analysis, including 203 patients not receiving any adjuvant chemotherapy. For those seen by a medical oncologist, the most frequent reason chemotherapy was not recommended was comorbid illness (25 of 50, 50%); the most frequent reason chemotherapy was not received, even though it was recommended or discussed, was patient refusal (54 of 74, 73%).

After controlling for NCCN Cancer Center and clinical TNM stage in a multivariable logistic model, factors significantly associated with not receiving adjuvant chemotherapy were age, Eastern Cooperative Oncology Group performance status ≥ 1, on Medicaid or indigent compared with private insurance, complete pathologic response, presence of reoperation/wound infection, and no closure of ileostomy/colostomy.

Commentary

Approximately 50% of patients with rectal cancer present with locally advanced disease, and for these patients current recommendations include preoperative (neoadjuvant) combined chemotherapy/radiation therapy (CRT) followed by total mesorectal excision and subsequent (adjuvant) chemotherapy.1,2 Data are quite clear that neoadjuvant CRT improves local control; however, approximately 35% of patients will develop metastatic disease.3,4 Accordingly, current recommendations suggest an additional 6-month course of chemotherapy administered postoperatively.5,6

This recommendation, however, is difficult for some, particularly those who experienced difficulty with neoadjuvant therapy or who had prolonged recovery from surgery. In this regard, it is quite remarkable that only 17% of patients in the NCCN Colorectal Database did not receive the third phase of treatment (adjuvant chemotherapy). And, of these, 20% had not been seen by medical oncology, and of the remainder, approximately 50% for whom adjuvant therapy was recommended made the decision to not proceed with additional therapy. This high rate of adjuvant therapy compliance is in distinct contrast to other reports. For example, a cross-sectional study from the Veteran’s Medical Center in Houston found that only 42.5% of patients with stage II/III rectal cancer received all three phases (i.e., neoadjuvant CRT, surgery, and adjuvant chemotherapy).7 In that population, the reasons for non-pursuit of recommended therapy were accounted to comorbidities (36%), early death (31%), physician choice (18%), or patient choice (15%). Although comparable data for community-managed patients (i.e., distinct from academic centers or the VA) are not available, they likely would resemble the experience within the VA. But, for all settings, factors that relate include insurance coverage, physician involvement, and a variety of patient issues including comorbidities, functional status, postsurgical recovery, and willingness to continue arduous treatment. As an additional note, overall enthusiasm for postsurgical treatment for individuals who had received neoadjuvant CRT would be bolstered by additional studies demonstrating the efficacy of such therapy. In this regard, in a sub-analysis of the EORTC 22921 study, patients who responded best to neoadjuvant CRT (i.e., downstaged) benefited from adjuvant chemotherapy, whereas those with residual T3/4 disease did not.8

In summary, even at specialty cancer centers, a sizeable minority of patients with rectal cancer treated with curative-intent neoadjuvant chemoradiotherapy do not complete postoperative chemotherapy. Likely, in the community this subset is larger, perhaps on the order of 50%. Strategies to improve the completion of this third phase of curative intent management of rectal cancer are necessary.

References

1. Bosset JF, et al. Chemotherapy with preoperative radiotherapy in rectal cancer. N Engl J Med 2006;355:1114-1123.

2. Gerard JP, et al. Preoperative radiotherapy with or without concurrent fluorouracil and leucovorin in T3-4 rectal cancers: Results of FFCD 9203. J Clin Oncol 2006;24:4620-4625.

3. Bonnetain F, et al. What is the clinical benefit of preoperative chemoradiotherapy with 5FU/leucovorin for T3-4 rectal cancer in a pooled analysis of EORTC 22921 and FFCD 9203 trials: Surrogacy in question? Eur J Cancer 2012;48:1781-1790.

4. Sauer R, et al. Preoperative versus postoperative chemoradiotherapy for rectal cancer. N Engl J Med 2004;351:1731-1740.

5. Benson AB 3rd, et al. NCCN Guidelines Version 3. 2012.

6. Romanus D, et al. Concordance with NCCN Colorectal Cancer Guidelines and ASCO/NCCN Quality Measures: An NCCN institutional analysis. J Natl Compr Canc Netw 2009;7:895-904.

7. Abraham NS, et al. Receipt of recommended therapy by patients with advanced colorectal cancer. Am J Gastroenterol 2006;101:1320-1328.

8. Janjan NA, et al. Improved overall survival among responders to preoperative chemoradiation for locally advanced rectal cancer. Am J Clin Oncol 2001;24:107-112.