Total Mesorectal Neglect in the Age of Total Mesorectal Excision

Total mesorectal excision (TME) has been firmly established as the standard of care for rectal cancer. Its principles include precise anatomic resection of the rectum and its mesentery to ensure negative circumferential resection margins and central vascular ligation to ensure removal of all relevant regional lymph nodes. While TME is variably combined with radiation and chemotherapy for locally advanced tumors, surgery alone is indicated for stage I tumors. For these early tumors, expert surgeons can achieve local control rates of approximately 95% and 5-year overall survival rates in excess of 90%. Given these excellent outcomes, why meddle? But surprisingly, as reported in the article that accompanies this editorial, Stitzenberg et al demonstrate that the rates of non-TME, local resection for stage I rectal cancer have risen between 1998 and 2010: for T1 cancers, from 39.8% to 62%, and for T2 cancers from 12.2 to 21.4%. These findings show that the trend identified in a previous study from 2007 has continued unabated. That study, like the present one, utilized the National Cancer Data Base to document a rise in local excision rates between 1989 and 2003 from 26.6 to 43.7% for T1 and from 5.8% to 16.8% for T2 cancers. It also showed a near tripling of the risk of local recurrence following local therapy compared with radical surgery, and decrease in disease-specific but not overall survival. Thus, given the excellent results achievable with TME, can the widespread use of local excision be justified? Local excision of early rectal cancer gained acceptance as a treatment option after Morson et al’s 1977 publication of the St Mark’s Hospital (London, United Kingdom) 25-year experience with the technique. The authors, noting a local recurrence rate of 3% following excision with negative resection margins, 14% following excision with doubtful margins, and 36% following excision with positive margins, emphasized the importance of thorough histological examination of the excised specimen, which they considered to be an excisional biopsy. Incomplete resection, transmural extension, and poor histologic differentiation were all considered to be indications for radical resection. Enthusiasm for local excision was dampened with publication of a series of sobering retrospective case series from major centers showing local recurrence rates of 15% to 29% for T1% and 26% to 47% for T2 cancers, only a minority of which received chemoradiotherapy. Equally alarming was the realization that salvage therapy after failed local resection is far from ideal. Recurrent cancers invariably present at a more advanced stage than the original tumor—hardly a surprising result given that locoregional recurrence occurs either in the full-thickness resection bed or in undetected or inadequately treated metastatic disease in the mesorectum. Patients with recurrent cancers also generally require chemoradiotherapy before radical resection, often require multivisceral resections, and frequently end up with permanent stomas. Yet, despite this aggressive treatment, local recurrence is fatal in almost 50% of patients—individuals who would have had a high likelihood of cure had they undergone radical resection when they first presented. There are several reasons why local excision might lead to treatment failure. First, despite the advantages of transanal endoscopic microsurgery (TEM) over conventional transanal excision, both approaches create a raw surface in the mesorectum where tumor cells can at least theoretically implant. More importantly, because the mesorectum is left largely or entirely untouched in local excision, success of the approach is critically dependent on proper patient selection. Undiagnosed metastases in regional lymph nodes are not treated and serve as the nidus for eventual locoregional recurrence. Unfortunately, even in the most skilled hands, imaging to detect nodal disease is imperfect: meta-analyses show sensitivities and specificities for detecting metastatic lymph nodes of 73.2% and 75.8% for endorectal ultrasound (ERUS) and 77% and 71% for magnetic resonance imaging (MRI). One is left with surrogate markers, the most useful of which is T stage: nodal positivity is approximately 10% to 13% in T1% and 17% to 22% in T2 cancers. But other factors play a role. Tumor grade and the presence of angiolymphatic invasion are important. For T1 cancers, deep invasion into the submucosal layer is a predictor of nodal positivity. One report suggests that female sex significantly increases the risk of nodal metastases. Tumor budding and poor differentiation at the invasive front appear to be particularly important predictors of nodal disease in early rectal cancers, and numerous additional histopathological factors have been suggested. The best evidence supporting local excision of early rectal cancers emerged from Cancer and Leukemia Group B (CALGB) 8984, a multi-institutional prospective trial. In this study, T1 cancers were treated by local excision alone, and T2 by local excision with adjuvant chemoradiotherapy. At a median follow-up of 7 years, local recurrence rates were 8% for T1% and 18% for T2 tumors; corresponding disease-free survival rates were 75% and 64%, respectively. One critical weakness of this study is that it is not based on an intention-totreat analysis. Excised tumors underwent pathologic review that lead to exclusion of almost one third of patients who met initial eligibility JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 31 NUMBER 34 DECEMBER 1 2013