**4. What is the appropriate length of the "waiting period" between completion of neoadjuvant chemoradiation and surgery?**

Initially, the waiting period following CRT was based on sufficient time to allow the acute radiation reaction to subside. Thus, an interval between 3-5 weeks was selected based on empirical experience. Favorable outcomes in patients who achieve a pCR and the desire to obtain a cCR have led to an increase of the radiation dose to the tumor center, increased intervals between CRT and TME, addition of chemotherapy during the waiting time, or starting with induction chemotherapy [24].

Allowing for a "waiting period" without active treatment of many weeks between the completion of neoadjuvant long-course therapy and surgery is common in the management of rectal cancer. Delaying surgery may allow for continued volume reduction of the treated tumor, potentially increasing the ultimate likelihood of a sphincter-preserving surgery for lowlying tumors and facilitating ease of the operation. However, too long of a delay in proceeding to surgery, especially in patients with poor response to neoadjuvant treatment, may allow for growth of the primary tumor with an increased risk of margin-positive surgery and increased risk of distant dissemination of cancer [25]. Further, there is a perception that waiting too long after the end of CRT (> 12 weeks) might lead to radiation fibrosis, making surgical intervention more difficult. However, this has not been substantiated in the literature [24].

The Lyon R90-01 trial randomized patients with T2-3 (N-any) rectal carcinoma to treatment with preoperative radiation (39 Gy in 13 fractions, without concurrent chemotherapy) followed by either a "short interval" to surgery (surgery performed within 2 weeks of completion of radiation) or a "long interval" to surgery (surgery performed within 6-8 weeks of completion of radiation) [26]. Tumors had to be low enough in the rectum to be palpable on digital examination. The primary endpoint of the study was the rate of sphincter-preserving surgery. The decision regarding the type of surgery was made by the surgeon at the time of the operation. Of the enrolled patients, 201 were assessable. Patients in the long-interval group had improved clinical and pathologic responses compared to the short-interval group. Twenty-six percent of the patients in the long-interval group had either a complete or nearcomplete pathologic response compared to 10.3% in the short-interval group, likely a reflection of the increased amount of time for lethally injured tumor cells to manifest their injury as death. Ultimately, however, 75.5% of the patients in the long-interval group as opposed to 67.7% in the short-interval group underwent a sphincter-preserving operation, a difference that was not statistically significant. There were no differences in the post-operative toxicity and mortality rates between the two groups. There were also no differences in overall survival or local control rates to a median follow-up of 33 months.

Integrating systemic therapy during the waiting period may have potential benefits for patients with rectal cancer, including improved downstaging of the primary tumor as well as potentially more effective treatment (relative to delayed postoperative treatment) of distant micrometastatic disease, a major cause of the poor disease-free survival rates seen in patients with locally advanced rectal cancer. Garcia-Aguilar and colleagues performed a phased II nonrandomized trial investigating the use of chemotherapy with modified FOLFOX-6 delivered during the waiting period following standard long-course chemoradiotherapy, with succes‐ sively more administrations of chemotherapy (and thus longer overall waiting periods) [27]. In a preliminary analysis of patients treated with two cycles of mFOLFOX-6 during the waiting period, with a mean time of 11 weeks from completion of neoadjuvant therapy to surgery, the pathologic complete response was 25%. In a comparison group of patients treated with neoadjuvant chemoradiation and no intervening systemic therapy, with a mean time to surgery of 6 weeks, the pCR was 18%. There was no substantial difference between the two arms with respect to postoperative complication rates.

**4. What is the appropriate length of the "waiting period" between**

Initially, the waiting period following CRT was based on sufficient time to allow the acute radiation reaction to subside. Thus, an interval between 3-5 weeks was selected based on empirical experience. Favorable outcomes in patients who achieve a pCR and the desire to obtain a cCR have led to an increase of the radiation dose to the tumor center, increased intervals between CRT and TME, addition of chemotherapy during the waiting time, or

Allowing for a "waiting period" without active treatment of many weeks between the completion of neoadjuvant long-course therapy and surgery is common in the management of rectal cancer. Delaying surgery may allow for continued volume reduction of the treated tumor, potentially increasing the ultimate likelihood of a sphincter-preserving surgery for lowlying tumors and facilitating ease of the operation. However, too long of a delay in proceeding to surgery, especially in patients with poor response to neoadjuvant treatment, may allow for growth of the primary tumor with an increased risk of margin-positive surgery and increased risk of distant dissemination of cancer [25]. Further, there is a perception that waiting too long after the end of CRT (> 12 weeks) might lead to radiation fibrosis, making surgical intervention

The Lyon R90-01 trial randomized patients with T2-3 (N-any) rectal carcinoma to treatment with preoperative radiation (39 Gy in 13 fractions, without concurrent chemotherapy) followed by either a "short interval" to surgery (surgery performed within 2 weeks of completion of radiation) or a "long interval" to surgery (surgery performed within 6-8 weeks of completion of radiation) [26]. Tumors had to be low enough in the rectum to be palpable on digital examination. The primary endpoint of the study was the rate of sphincter-preserving surgery. The decision regarding the type of surgery was made by the surgeon at the time of the operation. Of the enrolled patients, 201 were assessable. Patients in the long-interval group had improved clinical and pathologic responses compared to the short-interval group. Twenty-six percent of the patients in the long-interval group had either a complete or nearcomplete pathologic response compared to 10.3% in the short-interval group, likely a reflection of the increased amount of time for lethally injured tumor cells to manifest their injury as death. Ultimately, however, 75.5% of the patients in the long-interval group as opposed to 67.7% in the short-interval group underwent a sphincter-preserving operation, a difference that was not statistically significant. There were no differences in the post-operative toxicity and mortality rates between the two groups. There were also no differences in overall survival or

Integrating systemic therapy during the waiting period may have potential benefits for patients with rectal cancer, including improved downstaging of the primary tumor as well as potentially more effective treatment (relative to delayed postoperative treatment) of distant micrometastatic disease, a major cause of the poor disease-free survival rates seen in patients with locally advanced rectal cancer. Garcia-Aguilar and colleagues performed a phased II nonrandomized trial investigating the use of chemotherapy with modified FOLFOX-6 delivered

more difficult. However, this has not been substantiated in the literature [24].

local control rates to a median follow-up of 33 months.

**completion of neoadjuvant chemoradiation and surgery?**

starting with induction chemotherapy [24].

264 Updates on Cancer Treatment

In the large Dutch Surgical Colorectal Audit study including 1593 patients, patients were divided into three groups in terms of interval from the start of CRT to TME: < 13, 13-14, and 15-16 weeks. The largest pCR (18%) was observed in patients in the 15-16 week group (median time at the end of CRT = 9-10 weeks) [28].

A meta-analysis was conducted that compared two groups of patients: (1) less or equal to the conventional 6-8 week period from CRT to surgery and (2) longer than 6-8 weeks. pCR was the primary end point and was increased from 13.7 to 19.5% in the more than 8 week group [29]. This study included 13 trials inclusive of 3584 patients. Secondary end points (OS, DFS, R0 resection rates, sphincter preservation, and complication rates) were similar in both groups [29]. However, in patients who had a short interval (< 1 week), the rate of perineal wound complication and anastomotic leak was higher [29].

The question of appropriate waiting time periods has also emerged in the context of short course radiation therapy (5 Gy X 5 fractions without concurrent chemotherapy). In the original clinical trials of short-course neoadjuvant therapy, surgery was mandated to be performed within one week of completion of radiation [30]. This regimen has been associated with lower pCR rates relative to long-course neoadjuvant treatment, possibly as a result of the decreased interval between radiation and surgery. In the more recent Stockholm III trial, patients were randomized to one of three arms: short-course radiation followed by surgery within 1 week, short-course radiation followed by surgery at 4-8 weeks, or long-course radiation (2 Gy X 25 fractions, without concurrent chemotherapy) followed by surgery at 4-8 weeks [31]. Interest‐ ingly, pCR rates were highest in the short-course radiation group with the extended interval to surgery (12.5%, versus 0.8% in the short interval group and 5% in the long-course radiation group). Patients treated with short-course radiation and delayed surgery had postoperative complication rates that were similar to the two other groups. In an analysis of actual time to surgery, patients treated with short-course radiation followed by surgery at an interval of 11-17 days had the highest rates of postoperative complications.

Many questions remain regarding the appropriate duration of the waiting period in patients undergoing neoadjuvant therapy. Most of the data regarding CRT-TME gap emanate from retrospective studies. Thus, the recommendations of the length of time are largely observa‐ tional and empirically-driven. However, cCR and pCR has been observed in three randomized controlled trials when the gap is about 8-12 weeks [26;31;32]. Surgery within 3-4 weeks in the long CRT modality should not be performed secondary to radiation reaction. There is currently limited experience in waiting over 12 weeks.

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 biomarkers may improve on patient selection for low anterior resection.
