Early studies1–5 with small samples from specialized centers report success with nonoperative management (NOM) or the watch-and-wait approach after neoadjuvant chemoradiotherapy for rectal adenocarcinoma. However, it is unknown whether the results are generalizable to the broader population of patients with rectal cancer.1–5 Still, use of chemoradiotherapy without surgery has doubled among individuals with nonmetastatic rectal adenocarcinoma.6 The highest use is observed among those who typically have lower access to innovative care: black patients, uninsured or Medicaid insured patients, and individuals treated at low-volume centers.6 We suspected that this treatment approach in the community setting may often represent a disparity in appropriate care rather than an innovative and intentional treatment strategy. The outcomes for patients who receive chemoradiotherapy only outside a clinical trial are unknown. We hypothesized that this approach is associated with worse overall survival (OS).
Methods |
The National Cancer Database, a hospital-based cancer registry, was used to identify incident cases of clinical stage II/III rectal adenocarcinoma from January 1, 2004, through December 31, 2008. The cohort was divided into 2 groups: chemoradiotherapy only and chemoradiotherapy plus proctectomy. To construct the cohort in such a way as to maximize the chance that patients in the chemoradiotherapy-only group would have been candidates for surgery, we restricted this group to only patients for whom it was reported that surgery was “not part of the planned first course of treatment.” We calculated OS in months from date of diagnosis to last contact or confirmed death.
We compared OS by treatment group using Kaplan-Meier survival curves and adjusted Cox proportional hazards models, controlling for patient, tumor, and facility characteristics. To account for immortal time bias, we excluded deaths that occurred in the year of diagnosis. The National Cancer Database analyses were each approved by and the need for informed consent waived by the University of North Carolina Institutional Review Board. All data were deidentified.
Results |
Throughout the entire follow-up period, individuals receiving chemoradiotherapy only had poorer OS than those receiving chemoradiotherapy and proctectomy (hazard ratio, 1.90; 95% CI, 1.75–2.04) (Figure). These differences persisted after adjusting for race, insurance status, and other factors independently associated with OS (adjusted hazard ratio, 1.69; 95% CI, 1.59–1.84) (Table).
Figure.
Unadjusted Overall Survival of Patients With Rectal Cancer by Treatment Type and Stage of Disease
Table.
Adjusted Overall Survival for Patients With Rectal Cancer Diagnosed From 2004 to 2008a
| Characteristic | Overall Survival, No. (%) | Hazard Ratio (95% Cl) |
|---|---|---|
| Treatment | ||
| Chemoradiotherapy and proctectomy | 14 207 (89.6) | 1 [Reference] |
| Chemoradiotherapy only | 1655 (10.4) | 1.69 (1.59–1.84) |
| Sex | ||
| Male | 9954 (62.8) | 1 [Reference] |
| Female | 5908 (37.3) | 0.89 (0.83–0.94) |
| Age, y | ||
| 18–29 | 152 (1.0) | 1 [Reference] |
| 30–39 | 736 (4.6) | 0.59 (0.42–0.83) |
| 40–49 | 2587 (16.3) | 0.59 (0.44–0.81) |
| 50–59 | 4552 (28.7) | 0.66 (0.49–0.90) |
| 60–69 | 4264 (26.9) | 0.79 (0.59–1.08) |
| 70–79 | 2741 (17.3) | 1.08 (0.79–1.47) |
| ≥80 | 830 (5.2) | 1.81 (1.32–2.45) |
| Race | ||
| White | 13 689 (86.3) | 1 [Reference] |
| Black | 1220 (7.7) | 1.31 (1.18–1.45) |
| Other | 953 (6.0) | 0.94 (0.82–1.07) |
| Comorbidity score | ||
| 0 | 13 251 (83.5) | 1 [Reference] |
| 1 | 2181 (13.8) | 1.27 (1.17–1.37) |
| ≥2 | 430 (2.7) | 1.88 (1.63–2.16) |
| Clinical stage | ||
| II | 7965 (50.2) | 1 [Reference] |
| III | 7897 (49.8) | 1.12 (1.06–1.19) |
| Insurance status | ||
| Private | 8488 (54.8) | 1 [Reference] |
| Uninsured | 724 (4.7) | 1.45 (1.26–1.67) |
| Medicaid | 1101 (7.1) | 1.53 (1.37 1.72) |
| Medicare | 5172 (33.4) | 1.28 (1.17–1.40) |
| Tumor grade | ||
| Well differentiated | 1143 (7.2) | 1 [Reference] |
| Moderately differentiated | 10 323 (65.1) | 1.04 (0.92–1.16) |
| Poorly differentiated | 2095 (13.2) | 1.67 (1.46–1.90) |
| Unknown | 2301 (14.5) | 1.06 (0.93–1.21) |
| Facility volume: total No. of facilities (range of annual cases) | ||
| High: 142 (32–167) | 4741 (29.9) | 1 [Reference] |
| Medium: 302 (17–31) | 5185 (32.7) | 1.14 (1.06–1.22) |
| Low: 781 (1–16) | 5936 (37.4) | 1.17 (1.09–1.26) |
The estimated overall survival was 88.29% (95% CI, 87.73%−88.81%) at 36 mo from diagnosis and 77.12% (95% CI, 76.40%−77.82%) at 60 mo from diagnosis for patients undergoing chemoradiotherapy and proctectomy and 71.34% (95% CI, 69.04%−73.52%) at 36 mo after diagnosis and 58.21% (95% CI, 55.69%−60.63%) at 60 mo after diagnosis for patients undergoing chemoradiotherapy only.
Discussion |
Among a national sample of patients with clinical stage II/III rectal adenocarcinoma, patients treated with chemoradiotherapy only had inferior survival compared with conventional treatment. This finding is contrary to results of previously published single-institution and clinical trial reports on NOM.1–5 This finding is likely because chemoradiotherapy only can be viewed at once as both an innovative treatment paradigm in some settings and low-quality care in others. Although NOM is an intentional approach for some patients, it is likely that many individuals forgoing surgery in the community are doing so as a result of systematic barriers. Our results point to disparities in the process of rectal cancer care where historically disadvantaged groups receive suboptimal care and experience worse outcomes.
The finding that NOM is noninferior to conventional treatment for patients who have a complete response has received much attention. However, intensive follow-up is required for these patients. Although this type of surveillance is feasible with motivated patients in the context of a trial, substantial barriers may exist to ongoing follow-up in real-world settings.
Our study found inferior survival for patients treated with chemoradiotherapy only. From these data, we cannot know whether patients were receiving NOM and had a complete response to chemoradiotherapy or whether patients failed to receive surgery for other reasons. However, the results are concerning. As NOM becomes an increasingly accepted treatment approach, more comparative effectiveness studies evaluating outcomes in the real-world setting will be needed.
Funding/Support:
This research was partially supported by grant T32-HS000032 from a National Research Service Award Pre-doctoral/Post-doctoral Traineeship from the Agency for Healthcare Research and Quality sponsored by The Cecil G. Sheps Center for Health Services Research, The University of North Carolina at Chapel Hill.
Role of the Funder/Sponsor: The funding organizations had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.
Conflict of Interest Disclosures: Dr Sanoff reported receiving research funding from Novartis, Bayer, and Merck. No other disclosures were reported.
Footnotes
Publisher's Disclaimer: Disclaimer: The American College of Surgeons and the Commission on Cancer have not verified and are not responsible for the analytic or statistical methods used or the conclusions drawn from these data by the investigator.
Contributor Information
C. Tyler Ellis, Department of Surgery, University of North Carolina at Chapel Hill, Chapel Hill.
Stacie B. Dusetzina, Eshelman School of Pharmacy, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill.
Hanna Sanoff, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill.
Karyn B. Stitzenberg, Division of Surgical Oncology, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill.
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