Wait-and-See Policy for Clinical Complete Responders After Chemoradiation for Rectal Cancer

Abstract & Commentary

By Samir P. Kanani, MD, Associate Clinical Professor of Neurosurgery and Radiation Oncology, George Washington University; Radiation Oncology, Inova Fairfax Hospital, Falls Church, VA. Dr. Kanani reports no financial relationships relevant to this field of study.

Synopsis: In a prospective trial conducted from 2004-2010, 21 patients (median age 65 years) with a clinical complete response after chemoradiotherapy were followed closely per a stringent wait-and-see policy consisting of MRI, endosopies, and CT scans. These patients were compared to 20 patients prospectively who underwent surgery and were found to have a pathologic complete response. Two-year disease-free survival was not statistically different among the two groups — 89% in the wait-and-see cohort and 93% in the surgery cohort. Two-year overall survival also was similar at 100% in the wait-and-see group and 91% in the immediate surgery group. Bowel function and incontinence were superior in the wait-and-see group.

Source: Maas M, et al. Wait-and-see policy for clinical complete responders after chemoradiation for rectal cancer. J Clin Oncol 2011;29:4633-4640.

Approximately 15-20% of patients who undergo neoadjuvant chemoradiotherapy (CRT) for advanced rectal cancer are found to have a pathologic complete response (pCR) at the time of surgery. Recently, escalating neoadjuvant CRT regimens have tried to improve on this pCR rate. While total mesorectal excision (TME) remains the standard of care after neoadjuvant CRT for rectal cancer, in other gastrointestinal tumor sites, such as esophageal and anal carcinoma, CRT alone has demonstrated equivocal survival when compared to surgically treated patients. A previous trial published by Habr-Gama et al reported 5-year overall survival (OS) of 93% and a disease-free survival (DFS) of 85% in patients,1 using a watch-and-see policy after clinical complete response (cCR). The current study was done with the hope to validate the watch-and-see policy and to evaluate a selection process and follow-up schedule with modern imaging incorporating MRI.

The study cohort consisted of 21 patients who were staged using standard T2 weighted MRI sequences that were enhanced with nanoparticles of iron oxide and/or gadofosvent and diffusion weighted images. These advanced MRI techniques are not readily available in the United States. CRT was given in patients with locally advanced rectal cancers, which was specifically defined as patients with T4 tumors or a T3 tumor with a threatened or involved mesorectal fascia and/or more than three involved nodes and/or a distal tumor with one to three involved nodes. CRT consisted of 50.4 Gy of radiation along with 2 x 825 mg/m2 capecitabine. The investigators waited 6-8 weeks after completing therapy before re-evaluating for response with a repeat MRI and endoscopy with biopsy. Patients were considered cCR if they had a negative MRI, negative endoscopy, negative digital rectal exam, and a negative biopsy. An MRI showing only fibrosis or edema was considered negative. A small residual erythematous ulcer or scar on endoscopy was considered negative if the biopsy was negative. Of 192 patients treated in that time frame with locally advanced rectal cancer, only 21 patients (11%) met the above strict criteria for a cCR, and these patients were enrolled on the wait-and-see protocol.

The wait-and-see follow-up protocol was rigorous and included DRE, MRI, endoscopy, biopsy, CT scan of chest and abdomen, and CEA. Patients who were node positive at the time of diagnosis were treated with adjuvant XELOX chemotherapy. The results of patents treated with the wait-and-see protocol were compared to a group of 20 patients who underwent CRT, who had a TME, and who were found to have a pCR (ypT0N0).

The patients in the wait-and-see cohort and the patients in the pCR cohort were evenly balanced. Mean age was 65 years and 64 years, respectively, and approximately two-thirds of the patients were male. Approximately two-thirds of the patients in both arms received adjuvant chemotherapy. Mean time between completing CRT and evaluating for CR was 6 weeks and mean follow-up was 35 months. One patient in the wait-and-see arm required an anterior sigmoid resection above the site of tumor because of complications from radiation therapy 14 months after completing CRT. The surgery was complicated by an anastomotic leak that eventually healed. Nine of the patients in the pCR group required a permanent colostomy and 11 required a temporary colostomy. There was a 35% rate of major surgical complications such as anastomotic leakage, abscess, or respiratory failure. The MSKCC bowel function score and Wexner incontinence scores were superior in patients treated with a wait-and-see policy vs immediate surgery. With long-term follow-up, one of 21 patients in the wait-and-see arm required surgery for a T1 local recurrence. The patient declined TME and underwent transanal excision 22 months after completing CRT. None of the patients in the pCR arm had a local failure, but one patient in the pCR group was diagnosed with metastatic disease and eventually died and another patient died from surgical complications. The 2-year DFS and OS in the wait-and-see vs the immediate surgery group was 89% vs 93% and 100% vs 91%.

Commentary

The authors conclude that a wait-and-see policy is feasible, appears safe, and improves functional outcome. These conclusions should be taken with significant caution. It is important to point out that the authors used highly selective criteria and rigorous follow-up with advanced imaging. Although MRI scanners are widely available in the majority of community centers across the United States, MRI scans are not routinely done for staging rectal cancer; thus, a learning curve in interpreting scans to determine a complete radiographic response is definitely an issue. In addition, most centers do not use gadofosveset contrast agent. Gadofsveset improves sensitivity and specificity over standard contrast agents.2 This study does validate a previous experience from Habr-Gama et al, but there are important differences that should be pointed out. In the series from Habr-Gama et al, cCR was defined by a negative CT scan, DRE, and endoscopy, which was less rigorous than the current study that used an MRI instead of a CT scan and insisted on a negative biopsy; thus 28% were defined as a cCR in the report from Habr-Gama et al compared to 11% in the current study. This "selection bias" led to more patients undergoing surgical resection with a pCR (ypT0N0).

In an era where the concept of personalized medicine has become a marketing tool, it is refreshing to see that an institution is taking a prospective multidisciplinary approach and actually delivering on what is often discussed conceptually. This groundbreaking experience will hopefully open the door for Phase 2 studies that individualize treatment for a diverse group of patients who are lumped into the bucket of "locally advanced rectal cancer." Previous experiences in patients refusing surgery have demonstrated that patients can be cured with radical radiotherapy.3 However, studies questioning the benefit of radiation therapy in all locally advanced rectal cancers also have been reported.4 Perhaps incorporating genomic evaluation of tumor tissue, similar to the treatment of breast cancer, we can now begin a new era in actually individualizing the management of advanced rectal cancer and improving control without sacrificing quality of life. Maas et al have provided evidence that not all patients with locally advanced rectal cancer need surgery, but longer follow-up and more patients in a multicenter trial are needed to validate this paradigm.

References

1. Habr-Gama A, et al. Operative versus nonoperative treatment for stage 0 distal rectal cancer following chemoradiation therapy: Long-term results. Ann Surg 2004;240:711-717.

2. Lambregts DM, et al. Accuracy of gadofosveset-enhanced MRI for nodal staing and restaging in rectal cancer. Ann Surg 2011;253:559-545.

3. Brierley JD, et al. Adenocarcinoma of the rectum treated with radical external radiation therapy. Int J Radiat Oncol Biol Phys 1995;31:255-259.

4. Shrag D, et al. Neoadjuvant FOLFOX-bev, without radiation, for locally advanced rectal cancer. J Clin Oncol 2010;28:263s.