‘Watch-and-Wait’ for Rectal Cancer: What's the Way Forward?

For over a century, surgical resection has remained the cornerstone of curative treatment for rectal cancer. The principles of treatment include complete resection of the tumor-bearing rectum and mesorectum with clear margins. For patients without high-risk features on initial evaluation, high-quality surgery alone provides definitive therapy and avoids potential radiotherapy-related toxicity.[1] For patients with locally advanced tumors, preoperative radiotherapy with concurrent chemotherapy (chemoradiotherapy [CRT]) is administered to improve local control. Following completion of CRT, up to 50% of patients will experience a clinical complete response (cCR) and 10% to 20% of patients will have a pathologic complete response (pCR) with no evidence of residual tumor.[2,3] Thus, surgeons and patients are often faced with the sometimes unsettling discussion of the good news of a pCR coupled with the reality that the rectum had to be removed and a permanent ostomy was required.

There is now ample evidence, however, that tumor response to neoadjuvant CRT is a surrogate marker for long-term outcome. Among patients who have a pCR, the risk of local failure is negligible and the risk of distant relapse may be less than 10%.[4] As Sabbaga and colleagues point out in this issue of ONCOLOGY, however, it is not known whether omission of surgery (the “watch-and-wait” strategy) in these patients can achieve a similarly excellent oncologic outcome.[5] Moreover, there are a number of challenges in using clinical examination to determine which patients have achieved a pCR; for example, residual disease may exist not in the bowel wall but within the lymph node basin, which is more difficult to evaluate.[6] Building upon the pioneering work by Habr-Gama, colorectal surgeons from many cancer centers have reported preliminary experiences with watch-and-wait strategies that provide reason for optimism, and several other trials are underway.[7]

It is clear that a strict monitoring protocol with a detailed process for informed consent is required before surgery can be avoided. The Habr-Gama group has reported that two experienced surgeons perform clinical assessment for cCR following neoadjuvant CRT, and patient follow-up with clinical and radiological assessment occurs every 1 to 2 months.[2] Using this approach, they reported a 5-year local recurrence rate of 31%, although the majority could be salvaged with surgery. The Maastricht University group utilized strict selection criteria requiring evidence of cCR, such as via post-treatment high-resolution magnetic resonance imaging (MRI) and then MRI-based follow-up every 3 months for the first year and biannually thereafter. With their approach, 75% of the pCR patients who had undergone resection were classified by MRI as incomplete responders. After a relatively short median follow-up of 15 months, only one patient had developed a local recurrence.[3] Local treatment failure can occur even beyond 5 years after CRT, however, raising questions about the durability of the treatment response and the appropriate duration of intensive follow-up.[2] With either approach, assessment of cCR alone seems to be an inadequate means of determining who should be managed with a nonsurgical strategy. A pragmatic approach may be “deferral” of surgery and close follow-up as a treatment strategy for patients with cCR, as has been proposed by the group at the Royal Marsden Hospital in London. Patients for whom abdominoperineal resection may be required are treated with CRT, then eligible patients are identified by MRI-based tumor regression criteria and observed with serial MRI, with the expectation of subsequent definitive surgery for patients who demonstrate residual or recurrent disease.[8]

While Sabbaga and colleagues note that local excision of the tumor bed may seem to be an attractive alternative to watch-and-wait initially, local excision is subject to the same limitations; demonstration of long-term oncologic efficacy is lacking and this approach cannot address the problem of the unexamined mesorectum. Furthermore, in cases of distal rectal cancer involving the anal sphincter in which a rectum-preserving strategy may have the greatest role, it may not be possible to perform local excision without sphincter compromise. The long-term oncologic efficacy of the watch-and-wait approach still needs to be validated, especially given the high cure potential associated with definitive surgery in this patient population. Also needed is confirmation that deferral of surgery via serial observation does not result in a lost window of opportunity for curative surgery. Finally, we still need more accurate methods for assessing treatment response after CRT.

So how do we move forward? Rectal cancer management is becoming increasingly complex. There is increasing recognition of the potential to avoid routine CRT, as excellent results can be achieved with a more selective approach even in node-positive patients, as long as a high-quality resection is performed.[9] We also continue to learn about the role of neoadjuvant chemotherapy alone for treatment of intermediate-risk midrectal cancers. Thus, patients with intermediate-risk distal rectal cancers may be the optimal candidates in whom to study this approach. Only a few years ago, most surgeons would have been reluctant to consider a nonoperative approach for rectal cancer, but the increasing emergence of encouraging data has turned the tide.[10] For now, radical surgery should remain standard treatment for rectal cancer, but through rigorous protocol-based treatment we now have an opportunity to make true progress towards individualization of rectal cancer management.

Financial Disclosure:The author has no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.

References:

1. Taylor FG, Quirke P, Heald RJ, et al. Magnetic Resonance Imaging in Rectal Cancer European Equivalence Study Study Group. Preoperative magnetic resonance imaging assessment of circumferential resection margin predicts disease-free survival and local recurrence: 5-year follow-up results of the MERCURY study. J Clin Oncol. 2014;32:34-43.

2. Habr-Gama A, Gama-Rodrigues J, São Julião GP, et al. Local recurrence after complete clinical response and watch and wait in rectal cancer after neoadjuvant chemoradiation: impact of salvage therapy on local disease control. Int J Radiat Oncol Biol Phys. 2014;88:822-8.

3. Maas M, Nelemans PJ, Valentini V, et al. Long-term outcome in patients with a pathological complete response after chemoradiation for rectal cancer: a pooled analysis of individual patient data. Lancet Oncol. 2010;11:835-44.

4. 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;30:1770-6.

5. Sabbaga J, Braghiroli MI, Hoff PM. Is surgery always necessary in rectal cancer? Oncology (Williston Park). 2014;28:607-11.

6. Park IJ, You YN, Skibber JM, et al. Comparative analysis of lymph node metastases in patients with ypT0-2 rectal cancers after neoadjuvant chemoradiotherapy. Dis Colon Rectum. 2013;56:135-41.

7. 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;240:711-7.

8. Yu SK, Tait D, Chau I, Brown G. MRI predictive factors for tumor response in rectal cancer following neoadjuvant chemoradiation therapy-implications for induction chemotherapy? Int J Radiat Oncol Biol Phys. 2013;87:505-11.

9. Quirke P, Steele R, Monson J, et al; MRC CR07/NCIC-CTG CO16 Trial Investigators, NCRI Colorectal Cancer Study Group. Effect of the plane of surgery achieved on local recurrence in patients with operable rectal cancer: a prospective study using data from the MRC CR07 and NCIC-CTG CO16 randomised clinical trial. Lancet 2009;373(9666):821-8.

10. São Julião GP, Smith FM, Macklin CP, et al. Opinions have changed on the management of rectal cancer with a complete clinical response to neoadjuvant chemoradiotherapy. Colorectal Dis. 2014;16:392-4.