**5. Current status of the role of non-operative management in rectal cancer for patients with a complete clinical response**

Neoadjuvant chemoradiation for the management of patients with stage II and III rectal cancer results in a clinical complete response (cCR), which is defined as the absence of detectable rectal tumor with diagnostic modalities [i.e. endorectal ultrasound (EUS), magnetic resonance imaging (MRI), digital rectal exam (DRE), or proctoscopy] in 10-40% of patients [33]. Can these patients be followed non-operatively?

There have been three sentinel papers that have addressed this issue: one in 2004 published by Habr-Gama's group [34], the second was a reproduction of these results by a Dutch group in 2011 [35], which was followed by a systematic review by Glynne-Jones in 2012 [2]. An editorial summarizes the main aspects of these seminal events [36].

The first manuscript to document a possible approach in observing patients that achieve a cCR was published by Harb-Gama's group in 2004. In this study, 71 patients who had a cCR were compared to 22 patients that had an initial incomplete response, but after surgery, they were found to have no microscopic evidence of tumor in the resected specimen (pCR). Patients who underwent surgery had a 5-year overall survival of 88% compared to the cCR group, which was 100%. Disease free survival was 83% in the surgery group and 92% in the cCR group [34].

Mass et al. documented similar observations in 2011 [34]. This study compared 21 patients who had a cCR and compared them to 20 patients from another observational study that had documented pCR. Only one patient developed a recurrence at a 2-year follow up and they were all alive at this point in time. Comparatively, the 2-year disease free survival for patients in the surgery group was 93% with an overall survival of 91%.

A number of small institutional studies have documented similar observations in small cohort of patients such as in the United States [37] and in the United Kingdom [38] in 2012. A few other papers that demonstrated similar findings was summarized by a systematic review by Glynne-Jones in 2012 [2].

In this systematic review, 30 papers were included that met the primary end point of cCR with secondary end points of local recurrence, overall survival and disease free survival. This analysis demonstrated that 361 patients (56%) were from a single group (Habr-Gama) and the rest (n=289) were from eight different groups. cCR ranged from 11% - 39%. Results of secondary outcomes showed low local recurrence in Habr-Gama studies (~5%), but higher in all other series 33.8% (range 23%-83%). Habr-Gama reported salvage surgery to be possible in most cases, whereas only one quarter of patients could be salvaged surgically in all other groups. Long-term outcomes (DFS, and OS) in other groups were similar to Habr-Gama's and suggested that patients who achieve cCR have similar outcomes to patients who undergo surgery and are found to have pCR.

Integration of systemic therapy both during this time period as well as during the induction phase (prior to chemoradiation) remain active areas of clinical interest. In addition, determin‐ ing which patients are made candidates for sphincter-preserving surgery also remains an imprecise practice. Improvements in imaging technologies and possible use of pre-treatment

**5. Current status of the role of non-operative management in rectal cancer**

Neoadjuvant chemoradiation for the management of patients with stage II and III rectal cancer results in a clinical complete response (cCR), which is defined as the absence of detectable rectal tumor with diagnostic modalities [i.e. endorectal ultrasound (EUS), magnetic resonance imaging (MRI), digital rectal exam (DRE), or proctoscopy] in 10-40% of patients [33]. Can these

There have been three sentinel papers that have addressed this issue: one in 2004 published by Habr-Gama's group [34], the second was a reproduction of these results by a Dutch group in 2011 [35], which was followed by a systematic review by Glynne-Jones in 2012 [2]. An

The first manuscript to document a possible approach in observing patients that achieve a cCR was published by Harb-Gama's group in 2004. In this study, 71 patients who had a cCR were compared to 22 patients that had an initial incomplete response, but after surgery, they were found to have no microscopic evidence of tumor in the resected specimen (pCR). Patients who underwent surgery had a 5-year overall survival of 88% compared to the cCR group, which was 100%. Disease free survival was 83% in the surgery group and 92% in the cCR group [34]. Mass et al. documented similar observations in 2011 [34]. This study compared 21 patients who had a cCR and compared them to 20 patients from another observational study that had documented pCR. Only one patient developed a recurrence at a 2-year follow up and they were all alive at this point in time. Comparatively, the 2-year disease free survival for patients

A number of small institutional studies have documented similar observations in small cohort of patients such as in the United States [37] and in the United Kingdom [38] in 2012. A few other papers that demonstrated similar findings was summarized by a systematic review by

In this systematic review, 30 papers were included that met the primary end point of cCR with secondary end points of local recurrence, overall survival and disease free survival. This analysis demonstrated that 361 patients (56%) were from a single group (Habr-Gama) and the rest (n=289) were from eight different groups. cCR ranged from 11% - 39%. Results of secondary outcomes showed low local recurrence in Habr-Gama studies (~5%), but higher in all other series 33.8% (range 23%-83%). Habr-Gama reported salvage surgery to be possible in most cases, whereas only one quarter of patients could be salvaged surgically in all other groups.

biomarkers may improve on patient selection for low anterior resection.

**for patients with a complete clinical response**

editorial summarizes the main aspects of these seminal events [36].

in the surgery group was 93% with an overall survival of 91%.

patients be followed non-operatively?

266 Updates on Cancer Treatment

Glynne-Jones in 2012 [2].

The authors of the meta-analysis suggested that there is not enough evidence at this time to support observation in patients who have a cCR [2]. The inability to propose non-operative management for patients with a cCR primarily emanates from an inability to clearly define cCR. However, it is likely that a group of patients with a cCR can be observed without surgery; who those patients are and how we can monitor them closely is a difficult issue in the management of rectal cancer.
