A prospective trial needs to be done in order to create a safe and responsible environment in which to offer patients the watch-and-wait option for rectal cancer.
The article by Drs. Das and Minsky in this issue of ONCOLOGY represents a valuable starting point in the discussion of rapidly evolving treatment options for rectal cancer. Because this is a review article, there is no methodology to critique or conclusion to debate, so I will confine my commentary to a discussion of the clinical issues related to this topic, from a surgeon’s perspective.
All of us who evaluate and treat rectal cancer are simultaneously encouraged by the advances in its management and anxious about how to properly advise our patients with this disease. While optimal treatment of this malignancy already represents one of the most complicated preoperative discussions that a surgeon will have with a patient and his or her family, the possibility of avoiding surgery altogether has added another deep layer to this conversation. The absence, in the medical literature, of clear guidelines on options and on how to proceed in the setting of rectal cancer makes this discussion and the appropriate weighing of risks and benefits virtually impossible. There is an accumulating body of evidence, however, that a certain percentage of patients whose rectal cancer is treated with chemoradiation are cured without the need for surgery. The obvious challenge is to accurately identify these patients and determine how best to monitor them. The current standard of care for patients receiving chemoradiation for rectal cancer is to proceed with definitive resection regardless of the magnitude of the response to such therapy. Yet all of us are increasingly making exceptions to this standard based on dramatic responses to chemoradiation in some patients. The requirement to responsibly tailor a patient’s surgical care based on his or her response to chemoradiation therapy depends on several factors, including: (1) identification of the preoperative staging and biologic features of rectal cancers that are likely to respond favorably to chemoradiation; (2) accurate post-treatment assessment of treatment response; and (3) adequate follow-up measures to promptly identify locally recurrent or metastatic disease so that salvage therapy may be employed to maximum advantage.
As Drs. Das and Minsky point out, in the existing literature there is significant variability in patient selection for observation-only after chemoradiation; in the nature of the components of both the radiation therapy and chemotherapy administered to the patient; and in the methods used for follow-up. All of these factors must be standardized in order for clarity to emerge, and this standardization can only be accomplished by a prospective multicenter trial.
The motivation to minimize the proportion of patients requiring major surgical resection for rectal cancer after chemoradiation is based on the morbidity of the surgery and the often unsatisfying functional outcomes after major resection in a significant number of patients. Bowel function difficulties after low resections for rectal cancer that are preceded by chemoradiation are well documented. Patients often have difficulties, including frequent bowel function, difficulty in emptying the neorectum, feelings of incomplete evacuation, and overall compromise in activity and lifestyle.[2,3]
To determine whether a given patient can safely be spared this surgery, one should start with assessment of the patient’s response to chemoradiation. While it is important to first identify patients with a complete clinical response, it is then necessary to confirm that the patient has had a complete biologic response. The first decision concerns how long after completion of chemoradiation this assessment can be made. There are no solid data yet to answer this question, but the timeframe of 8 to 12 weeks after completion of therapy has emerged as a reasonable one for response evaluation.
The means of assessment are clinical examination, endoscopy with biopsies, and imaging studies. The clinical assessment is confined to digital examination of the tumor site if possible (distal rectum), followed by endoscopy and, usually, biopsies. MRI or CT scanning with or without PET is then performed, and this may be supplemented with endorectal ultrasound. Digital rectal examination may reveal no palpable abnormality, or fibrosis, or a residual ulcer. Endoscopy with biopsy should then be performed. But how reassuring is a negative biopsy? A multicenter study recently evaluated the pathology of the residual tumor bed after chemoradiation followed by surgical resection, and found that of those specimens with a residual focus of carcinoma, only 13% had malignant cells in the mucosa, with the remaining specimens having malignant cells at deeper levels only. Endoscopic biopsies usually sample only to the depth of the mucosa. A residual ulcer or palpable firmness can be more definitely assessed for residual malignancy with a full-thickness local excision, either by a simple transanal approach or by transanal endoscopic microsurgery (TEM) for lesions more than 7 to 8 cm from the anal verge. Following a negative full-thickness excision, further assessment of perirectal nodal status is required. As mentioned in this study, a small percentage of patients (10%–15%) with no residual carcinoma at the time of resection will have positive mesorectal lymph nodes.
Results of imaging studies of the rectum after chemoradiation are not reassuring. Imaging studies rely on enlarged lymph node size as an indicator of the presence of metastasis. Perez et al examined lymph nodes in resected specimens after chemoradiation and found that 95% of nodes were less than 5 mm in size, and that individual lymph node size was not a good predictor of nodal metastases. Kristiansen et al evaluated the rectum in patients with locally advanced rectal cancer 7 weeks after they had completed chemoradiation with PET/CT, and reported a false-negative rate of nearly 50% (interpreted as no residual tumor when, in fact, tumor was present on resected specimen). MRI differentiation between fibrosis and residual tumor is also not sufficiently accurate for clinical decision making.
The aforementioned considerations leave us with many challenges, all of which need to be acknowledged. A prospective trial needs to be done in order to create a safe and responsible environment in which to offer patients the watch-and-wait option. The existing data are too uncontrolled and the current investigations are still too small to allow us to adequately advise patients on the best approach to rectal cancer management. Drs. Das and Minsky are to be congratulated for developing this review article. Their effort clearly identifies the many components of rectal cancer treatment that require further investigation and clarification. All of us who treat this disease look forward to participating in the studies to come.
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.
1. Das P, Minsky BD: A watch-and-wait approach to the management of rectal cancer. Oncology (Williston Park). 2013;27:962-8.
2. Hassan I, Larson DW, Cima RR, et al. Long-term functional and quality of life outcomes after coloanal anastomosis for distal rectal cancer. Dis Colon Rectum. 2006;49:1266-74.
3. Parc Y, Zutshi M, Zalinski S, et al. Pre-operative radiotherapy is associated with worse functional results after coloanal anastomosis for rectal cancer. Dis Colon Rectum 2009;52:2004-15.
4. Duldulao MP, Lee W, Streja L, et al. Distribution of residual cancer cells in the bowel wall after neoadjuvant chemoradiation in patients with rectal cancer. Dis Colon Rectum. 2013;56:142-9.
5. Perez RO, Pereira DD, Proscurshim I, et al. Lymph node size in rectal cancer following neoadjuvant chemoradiation-can we rely on radiologic nodal staging after chemoradiation ? Dis Colon Rectum. 2009;52:1278-84.
6. Kristiansen C, Loft A, Berthelsen AK, et al. PET/CT and histopathologic response to preoperative chemoradiation therapy in locally advanced rectal cancer. Dis Colon Rectum. 2008;51:21-5.