Radical excision of the rectum and mesorectal envelope, also known as total mesorectal excision (TME), has been the mainstay of rectal cancer treatment for more than a century. Prospective studies demonstrated that preoperative or neoadjuvant radiation with or without sensitizing chemotherapy reduced local recurrence risk and may increase the proportion of patients who benefit from a sphincter-saving procedure (SSP).1,2 Because distant metastasis is the most common form of treatment failure in patients with locally advanced rectal cancer (LARC), patients with this disease have received postoperative systemic chemotherapy, borrowing data from patients with colon cancer.3
However, the benefit of adjuvant chemotherapy remains the subject of controversy.4 A meta-analysis of prospective randomized trials suggests that fluorouracil-based systemic chemotherapy does not improve survival in patients with resectable LARC treated with preoperative chemoradiotherapy.5 These studies have been criticized because the proportion of patients receiving the intended doses of chemotherapy was low as a result of postoperative morbidity. To overcome compliance issues, there is increasing interest in delivering systemic chemotherapy preoperatively, either before or after chemoradiation (CRT).1 Proponents of total neoadjuvant therapy (TNT) argue that delivering all of the chemotherapy before surgery treats micrometastatic disease earlier, increases the proportion of patients receiving the entire chemotherapy dose without reductions or delays, and reduces time to ileostomy closure in patients undergoing SSPs.6
Trimodal treatment for rectal cancer provides excellent local tumor control and long-term survival but is associated with significant morbidity that permanently impairs quality of life (QoL).1 Although each treatment modality contributes to overall morbidity, most of the long-term sequelae are attributable to surgery, particularly in patients with distal tumors requiring low anastomoses or a permanent colostomy.
Of note, a proportion of LARCs seem to be fully eradicated with neoadjuvant therapy (NAT) (see Figures 1A–B). Rectal cancer patients with a pathological complete response (pCR) have lower local recurrence and improved survival rates versus nonpCR patients.7 Thus, the added value of radical surgery in these patients is debatable. Because most of the mortality, morbidity, and long-term sequelae from trimodal therapy are related to proctectomy, avoiding TME selectively in those patients who obtain a sustained clinical complete response (cCR) to NAT will improve their QoL.
Figure 1A. Distal rectal cancer baseline
Figure 1B. Distal rectal cancer after TNT
Evidence supporting watch-and-wait approach
Habr-Gama and colleagues were the first to show that rectal cancer patients with a cCR to neoadjuvant CRT who were observed with deferral of immediate surgery had similar long-term survival to patients who underwent TME and were found to have a pCR.8 Some cCR patients in the watch-and-wait (WW) cohort ultimately experienced tumor regrowth, but most were salvaged by TME. Recent pooled analysis of 880 rectal cancer patients entered into WW protocols at 47 institutions further supports this deferral of surgery in select patients with a cCR to NAT.9 The two-year regrowth rate in this series was 25 percent, most of them salvageable, through TME surgery, and five-year overall survival was 85 percent.
The data supporting WW are thus based on small, institutional series of heterogenous groups of patients who were staged using different imaging modalities, treated according to diverse CRT regimens over a 25-year period, evaluated at different times after NAT completion, selected for WW using different response criteria, and followed for relatively short periods of time. Additionally, most of the published series do not provide the total number of rectal cancer patients treated during the study period; therefore, the proportion of patients who could benefit from WW is unknown. Hence, before WW is widely incorporated as standard practice in rectal cancer, prospective data are needed.
A prospective study integrating WW
The ideal study design incorporating WW in rectal cancer treatment would randomize patients with cCR to either WW or TME. This randomization probably would be unacceptable to patients; thus, a more practical and less conventional study design is needed. The organ preservation in rectal adenocarcinoma (OPRA) trial is a multi-institutional phase II study testing the hypothesis that a treatment paradigm incorporating WW for LARC patients with a cCR to NAT should provide equivalent oncological outcomes to LARC treated with CRT, TME, and adjuvant therapy (historical controls).10 All patients in the trial receive TNT. Patients are re-staged eight to 12 weeks after TNT completion with digital rectal exam, flexible sigmoidoscopy, and rectal magnetic resonance imaging. cCR patients are offered WW and those without cCR undergo TME. To determine the best organ preservation method, patients are randomized to one of two TNT arms—chemotherapy before CRT or CRT before chemotherapy (see Figure 2). This National Institutes of Health-sponsored and funded study (5R01-CA182551 [JGA]) had an accrual target of 222 patients over four years and completed accrual one year ahead of schedule. Study results will be available in 12 months.
Figure 2. OPRA protocol schema
- Funding: 5R01-CA182551-04 (Principal Investigator, J. Garcia-Aguilar)
- ClinicalTrials.gov Identifier: NCT02008656
- Role of funders: The funding sources had no role in this manuscript and had no role in the collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; or decision to submit the manuscript for publication.
- Conflicts of interest: Dr. Smith has received travel support from Intuitive Surgical Inc. for fellow education and has served as a clinical advisor for Guardant Health Inc. Dr. Garcia-Aguilar has received honoraria from Medtronic, Johnson & Johnson, and Intuitive Surgical Inc.
- Author contributions: Drs. Smith and Garcia-Aguilar conceived, wrote, edited, and finalized the manuscript, and constructed and edited the figures.
- Contacts: J. Garcia-Aguilar: firstname.lastname@example.org. J. Joshua Smith: email@example.com.
- Smith JJ, Garcia-Aguilar J. Advances and challenges in treatment of locally advanced rectal cancer. J Clin Oncol. 2015;33(16):1797-1808.
- Sauer R, Becker H, Hohenberger W, et al. Preoperative versus postoperative chemoradiotherapy for rectal cancer. N Engl J Med. 2004;351(17):1731-1740.
- National Comprehensive Cancer Network. Clinical Practice Guidelines in Oncology Rectal Cancer Version 1. 2019. Available at: www.nccn.org/professionals/physician_gls/pdf/rectal.pdf. Accessed May 6, 2019. [Subscription required for viewing.]
- Xu Z, Mohile SG, Tejani MA, et al. Poor compliance with adjuvant chemotherapy use associated with poorer survival in patients with rectal cancer: An NCDB analysis. Cancer. 2017;123(1):52-61.
- Breugom AJ, Swets M, Bosset JF, et al. Adjuvant chemotherapy after preoperative (chemo)radiotherapy and surgery for patients with rectal cancer: A systematic review and meta-analysis of individual patient data. Lancet Oncol. 2015;16(2):200-207.
- Cercek A, Roxburgh CSD, Strombom P, et al. Adoption of total neoadjuvant therapy for locally advanced rectal cancer. JAMA Oncol. 2018;4(6):e180071.
- Park IJ, You YN, Agarwal A, et al. Neoadjuvant treatment response as an early response indicator for patients with rectal cancer. J Clin Oncol. 2012;30(15):1770-1776.
- Habr-Gama A, Perez RO, Nadalin W, et al. Operative versus nonoperative treatment for stage 0 distal rectal cancer following chemoradiation therapy: Long-term results. Ann Surg. 2004;240(4):711-717.
- Van der Valk MJM, Hilling DE, Bastiaannet E, et al. Long-term outcomes of clinical complete responders after neoadjuvant treatment for rectal cancer in the International Watch & Wait Database (IWWD): An international multicentre registry study. Lancet. 2018;391(10139):2537-2545.
- Smith JJ, Chow OS, Gollub MJ, et al. Organ Preservation in Rectal Adenocarcinoma: a phase II randomized controlled trial evaluating 3-year disease-free survival in patients with locally advanced rectal cancer treated with chemoradiation plus induction or consolidation chemotherapy, and total. BMC Cancer. 2015;15(1):767.