Minimally Invasive Therapy. 2014;23:63–69
REVIEW ARTICLE
Minim Invasive Ther Allied Technol Downloaded from informahealthcare.com by University of Connecticut on 10/10/14 For personal use only.
Pitfalls of transanal endoscopic microsurgery for rectal cancer following neoadjuvant chemoradiation therapy
ANGELITA HABR-GAMA1,2, GUILHERME PAGIN SÃO JULIÃO1, RODRIGO OLIVA PEREZ1,3,4 1
Angelita & Joaquim Gama Institute/Hospital Alemão Oswaldo Cruz, São Paulo, Brazil, 2University of São Paulo School of Medicine, São Paulo, Brazil, 3University of São Paulo School of Medicine, Colorectal Surgery Division, São Paulo, Brazil, and 4Ludwig Institute for Cancer Research – São Paulo Branch, São Paulo, Brazil
Abstract Transanal endoscopic microsurgery has become a very useful surgical tool for the management of selected cases of rectal cancer. However, the considerably high local recurrence rates led to the introduction of neoadjuvant therapies including radiation with or without chemotherapy. This treatment strategy may result in significant rates of tumor regression allowing the procedure to be offered to a significant proportion of cases. On the other hand, neoadjuvant chemoradiation (CRT) may also determine wound-healing difficulties with significant postoperative pain. In addition, salvage total mesorectal excision in the case of local recurrence may also be a challenging task. Finally, accurate selection criteria for this minimally invasive approach are still lacking and may be influenced by baseline staging, post-treatment staging and final pathology information. Ultimately, selection of patients for this treatment modality remains a significant challenge for the colorectal surgeon who should be aware of the pitfalls of this procedure in the setting of neoadjuvant CRT.
Key words: Rectal cancer, neoadjuvant chemoradiation therapy, transanal endoscopic microsurgery
Background Transanal endoscopic microsurgery (TEM) has made a major impact on the surgical management of rectal tumors (1). This revolutionary approach incorporating laparoscopic and endoscopic techniques to standard transanal procedures allowed surgeons to overcome significant hurdles associated with standard transanal resection of rectal tumors (2). This approach allows excellent visualization of the surgical field, precise margin clearance and tissue hemostasia and proper closure of defects created. In fact, these advantages led to immediate incorporation of this technique for the resection of benign tumors of the rectum (3,4). Particularly useful in large adenomas and higher locations in the rectum, often requiring piece-meal resection by the colonoscope (5), TEM offered the opportunity of providing the pathologist with a single oriented specimen with all layers or
submucosal resection of the rectum and occasionally with perirectal nodes attached (4). Not only the audit of the surgical specimen was superior to standard transanal techniques, but also allowed much easier teaching of other training surgeons in the technique (6). Finally, post-operative recovery was almost always uneventful, presenting few and simple complications. Even in cases of entry into the peritoneal cavity, hermetic closure led to an uncomplicated postoperative course in most situations (3). These observations led to the interest in using the technique for selected rectal cancers (7). However, even though TEM could provide a superior quality specimen for the pathologist with minimal postoperative complications, local recurrence was still considered a major limitation of any type of full-thickness local excision (FTLE) (8,9). In fact, local recurrence rates among patients undergoing local excision are still considered to be associated with the risk of lymph
Correspondence: A. Habr-Gama, Rua Manoel da Nóbrega 1564, São Paulo – SP, ZIP 04001-005, Brazil, Fax: +55 11 3884 8845; E-mail: [email protected] ISSN 1364-5706 print/ISSN 1365-2931 online 2014 Informa Healthcare DOI: 10.3109/13645706.2014.893891
Minim Invasive Ther Allied Technol Downloaded from informahealthcare.com by University of Connecticut on 10/10/14 For personal use only.
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node metastases rather than with the quality of the resected specimen. Series of patients with T1 and T2 rectal cancer managed by full-thickness local excision (FTLE) showing local recurrence rates of 10% and 25%, respectively, were a major drawback for this procedure in this setting. In fact, even when TEM was performed for selected T1 cancers, local recurrence was quite significant (10–14). The risk of local recurrence after FTLE raised another relevant issue in the management of these patients. The possibility of salvage resection and its impact on survival became a relevant aspect of FTLE (regardless of the technique) for rectal cancer. The observation of poor survival among patients undergoing salvage resection for recurrent disease after TEM for T1 rectal cancer was quite disappointing (15). Therefore, in order to avoid local recurrence and/or the unfavorable outcomes of salvage after a local recurrence, two alternatives were suggested. First, early or immediate salvage could be offered to patients with “unfavorable” pathological findings (including lymphovascular invasion, poor differentiation, tumor size >3 cm, ‡pT2) after a FTLE/TEM. Second, adjuvant or neoadjuvant therapy could also help to minimize the risk of local recurrence (16). Immediate or early salvage of patients with unfavorable pathological findings was less appealing since it would require the need for radical surgery in a considerable amount of patients leading to stomas, urinary, sexual dysfunctions and significant morbidity rates. The use of additional therapy including radiation with or without chemotherapy seemed to provide a better chance of performing FTLE with TEM as the sole surgical procedure, minimizing functional disorders, need for stomas and major surgical morbidity (17,18). Even though postoperative (adjuvant) therapy would have the benefit of offering patients treatment after confirmation of “unfavorable” pathological findings, the observation of decreased toxicity and improved local disease control in prospective randomized trials of rectal cancer in the setting of radical surgery led to the utilization of radiation and chemotherapy in the pre-operative period (neoadjuvant) (19–21). In addition, the exposure of healthy and well-oxygenated tissue, as opposed to post-operative fibrotic tissue, to radiation would theoretically improve its anti-neoplastic effects. Finally, perhaps one of the most beneficial aspects of offering patients preoperative neoadjuvant therapy would be the effect on tumor shrinkage. The decrease in tumor size (downsizing) and shifts in tumor stage (downstaging) have been well documented after neoadjuvant therapies with radiation and chemoradiation (CRT) (22–25). In fact, the addition of chemotherapy to
radiation has been shown to significantly increase the effects on tumor size and stage when delivered preoperatively (22). Also, this downsizing and downstaging seem to be time-dependent and therefore, at least six, eight or even 12 weeks may be required to obtain maximal results for tumor regression (26–28). It appeared that neoadjuvant therapy, particularly CRT, was the answer to all prayers for TEM in rectal cancer: Improve local disease control, minimize toxicity, decrease tumor size, downstage cancers and allow a minimally invasive approach without all the downsides of radical total mesorectal excision (TME). However, the expected benefits of this strategy came at a significant cost in terms of wound healing and salvage possibilities. Also, local recurrences may still be a concern depending on baseline and post-treatment characteristics.
Wound healing One of the most significant benefits of TEM after the resection of rectal tumors was the minimal associated postoperative morbidity. Postoperative complications are minimal and usually do not require readmission or reintervention. However, when preoperative CRT is delivered, TEM resection leads to a rectal wound that allows primary suturing without any technical difficulty, unless the proximal margin is very close to the anal canal/verge. In this situation, even though the upper border of the wound may retain its considerable elasticity, the lower border of the wound of the anal canal is rather fixed and with little mobility. If the resection is wide enough to result in significant separation of the proximal and distal borders, significant tension will be present, a known feature to contribute to wound dehiscence. Also, the anal canal has ectodermic as opposed to endodermic nerve supply to the rectum. Therefore, wound separation and mucosal discontinuity in this region may be quite painful. Finally, regardless of the level of suturing (rectal or anal canal), the borders to be sutured after a TEM resection in a previously irradiated rectum will necessarily put together two previously irradiated borders. This is actually quite different from a coloanal anastomosis following neoadjuvant CRT, where the proximal colon is never included in the radiation field and therefore a normal colon is sutured to an abnormal analcanalpreviouslytreated with a significant amount of RT (29). In fact, even after a coloanal anastomosis is constructed, the risk of dehiscence is so significant that a loop ileostomy is almost always recommended (30). One can imagine the risk of wound dehiscence after suturing together two previously irradiated borders of
Minim Invasive Ther Allied Technol Downloaded from informahealthcare.com by University of Connecticut on 10/10/14 For personal use only.
Pitfalls of TEM for rectal CA after CRT rectum or anus, sometimes with significant tension depending on the level of the suture. In fact, few studies compared the risk of wound separation and its consequences with or without previous exposure to CRT. However, retrospective studies have suggested that the risk of wound dehiscence was significantly higher when CRT was delivered preoperatively. In one of these studies, diagnosis of wound dehiscence was made after more than one week following TEM and healing of the dehiscence took an average of more than eight weeks to complete. An operation that otherwise would almost never require a stoma, in this situation diversion is occasionally required (31). In another study, even though none of the dehiscences required stomas, pain management was quite significant requiring readmission for analgesia in a considerable proportion of patients (32). Ultimately, these findings raised the issue whether any attempt to close the wound defect created by TEM should even be performed. Leaving the wound open could potentially avoid the complication of wound dehiscence and minimize its consequences. However logical this may seem, there is no good evidence to support this idea from any study and the author’s clinical experience with unclosed wounds showed no significant differences in pain control after TEM following neoadjuvant CRT for rectal cancers.
Salvage In any patient with a rectal cancer treated by neoadjuvant CRT and TEM, the only possible salvage after recurrent disease or unfavorable pathological findings would be a total mesorectal excision (TME). Also, tumors that are candidates for TEM should ideally be restricted to the rectal wall (ycT2N0) regardless of the baseline staging features. Therefore, in theory and unless the patient is already incontinent, these tumors are candidates for sphincter-saving procedures such as low coloanal or even partial/total intersphincteric resections. Therefore, one would expect that any salvage resection here would allow a safe TME and at least the possibility of sphincter preservation. However, TEM for the management of rectal cancers should preferably include a significant amount of perirectal fat, often reaching the mesorectal fascia for oncological purposes. Considering the fact that wound dehiscence is frequent, scarring and fibrotic changes may be quite significant leading inevitably to perforation or violation of the mesorectal fascia during TME attempt for salvage. This may be crucial in the setting of local tumor recurrence and its clinical consequences are yet to be reported.
65
Even when TME can be safely performed, sphincter preservation may also be compromised. In a study where patients treated by neoadjuvant RT or CRT were managed by FTLE (including TEM), the presence of unfavorable pathology recommended subsequent TME. None of these patients salvaged could avoid an abdominal perineal resection. Interestingly, a few of these patients could have been originally offered a sphincter preserving operation with TME as an alternative to FTLE (33). In another recently reported study offering TEM after CRT and salvage for patients with unfavorable pathology, patients undergoing radical TME were able to undergo sphincter preservation. Curiously however, five out of seven patients (>71%) undergoing sphincter preservation developed anastomotic dehiscence and two out of 11 (18%) required emergency reoperations (34). Therefore, sphincter preservation after previous CRT & TEM may be quite technically challenging and associated with significant postoperative morbidity. Functional outcomes of these patients are yet to be known.
Local recurrence Few studies have addressed the use of TEM after neoadjuvant CRT. Most of the studies have included FTLE, grouping together transanal standard resections and TEM. There is no study in rectal cancer showing TEM superiority in oncological outcomes as compared to standard technique. However, considering that TEM has shown to provide a better quality of the specimen, one could assume that TEM may offer better results when compared to standard FTLE. As mentioned earlier, local recurrence rates have historically paralleled the risk of lymph node metastases in patients treated by FTLE for rectal cancer. pT status is one of the most relevant determinants of the risk of perirectal nodal metastases both with or without chemoradiation (10–12,14). In fact, studies have suggested that the risk of lymph node metastases is
REVIEW ARTICLE
Minim Invasive Ther Allied Technol Downloaded from informahealthcare.com by University of Connecticut on 10/10/14 For personal use only.
Pitfalls of transanal endoscopic microsurgery for rectal cancer following neoadjuvant chemoradiation therapy
ANGELITA HABR-GAMA1,2, GUILHERME PAGIN SÃO JULIÃO1, RODRIGO OLIVA PEREZ1,3,4 1
Angelita & Joaquim Gama Institute/Hospital Alemão Oswaldo Cruz, São Paulo, Brazil, 2University of São Paulo School of Medicine, São Paulo, Brazil, 3University of São Paulo School of Medicine, Colorectal Surgery Division, São Paulo, Brazil, and 4Ludwig Institute for Cancer Research – São Paulo Branch, São Paulo, Brazil
Abstract Transanal endoscopic microsurgery has become a very useful surgical tool for the management of selected cases of rectal cancer. However, the considerably high local recurrence rates led to the introduction of neoadjuvant therapies including radiation with or without chemotherapy. This treatment strategy may result in significant rates of tumor regression allowing the procedure to be offered to a significant proportion of cases. On the other hand, neoadjuvant chemoradiation (CRT) may also determine wound-healing difficulties with significant postoperative pain. In addition, salvage total mesorectal excision in the case of local recurrence may also be a challenging task. Finally, accurate selection criteria for this minimally invasive approach are still lacking and may be influenced by baseline staging, post-treatment staging and final pathology information. Ultimately, selection of patients for this treatment modality remains a significant challenge for the colorectal surgeon who should be aware of the pitfalls of this procedure in the setting of neoadjuvant CRT.
Key words: Rectal cancer, neoadjuvant chemoradiation therapy, transanal endoscopic microsurgery
Background Transanal endoscopic microsurgery (TEM) has made a major impact on the surgical management of rectal tumors (1). This revolutionary approach incorporating laparoscopic and endoscopic techniques to standard transanal procedures allowed surgeons to overcome significant hurdles associated with standard transanal resection of rectal tumors (2). This approach allows excellent visualization of the surgical field, precise margin clearance and tissue hemostasia and proper closure of defects created. In fact, these advantages led to immediate incorporation of this technique for the resection of benign tumors of the rectum (3,4). Particularly useful in large adenomas and higher locations in the rectum, often requiring piece-meal resection by the colonoscope (5), TEM offered the opportunity of providing the pathologist with a single oriented specimen with all layers or
submucosal resection of the rectum and occasionally with perirectal nodes attached (4). Not only the audit of the surgical specimen was superior to standard transanal techniques, but also allowed much easier teaching of other training surgeons in the technique (6). Finally, post-operative recovery was almost always uneventful, presenting few and simple complications. Even in cases of entry into the peritoneal cavity, hermetic closure led to an uncomplicated postoperative course in most situations (3). These observations led to the interest in using the technique for selected rectal cancers (7). However, even though TEM could provide a superior quality specimen for the pathologist with minimal postoperative complications, local recurrence was still considered a major limitation of any type of full-thickness local excision (FTLE) (8,9). In fact, local recurrence rates among patients undergoing local excision are still considered to be associated with the risk of lymph
Correspondence: A. Habr-Gama, Rua Manoel da Nóbrega 1564, São Paulo – SP, ZIP 04001-005, Brazil, Fax: +55 11 3884 8845; E-mail: [email protected] ISSN 1364-5706 print/ISSN 1365-2931 online 2014 Informa Healthcare DOI: 10.3109/13645706.2014.893891
Minim Invasive Ther Allied Technol Downloaded from informahealthcare.com by University of Connecticut on 10/10/14 For personal use only.
64
A. Habr-Gama et al.
node metastases rather than with the quality of the resected specimen. Series of patients with T1 and T2 rectal cancer managed by full-thickness local excision (FTLE) showing local recurrence rates of 10% and 25%, respectively, were a major drawback for this procedure in this setting. In fact, even when TEM was performed for selected T1 cancers, local recurrence was quite significant (10–14). The risk of local recurrence after FTLE raised another relevant issue in the management of these patients. The possibility of salvage resection and its impact on survival became a relevant aspect of FTLE (regardless of the technique) for rectal cancer. The observation of poor survival among patients undergoing salvage resection for recurrent disease after TEM for T1 rectal cancer was quite disappointing (15). Therefore, in order to avoid local recurrence and/or the unfavorable outcomes of salvage after a local recurrence, two alternatives were suggested. First, early or immediate salvage could be offered to patients with “unfavorable” pathological findings (including lymphovascular invasion, poor differentiation, tumor size >3 cm, ‡pT2) after a FTLE/TEM. Second, adjuvant or neoadjuvant therapy could also help to minimize the risk of local recurrence (16). Immediate or early salvage of patients with unfavorable pathological findings was less appealing since it would require the need for radical surgery in a considerable amount of patients leading to stomas, urinary, sexual dysfunctions and significant morbidity rates. The use of additional therapy including radiation with or without chemotherapy seemed to provide a better chance of performing FTLE with TEM as the sole surgical procedure, minimizing functional disorders, need for stomas and major surgical morbidity (17,18). Even though postoperative (adjuvant) therapy would have the benefit of offering patients treatment after confirmation of “unfavorable” pathological findings, the observation of decreased toxicity and improved local disease control in prospective randomized trials of rectal cancer in the setting of radical surgery led to the utilization of radiation and chemotherapy in the pre-operative period (neoadjuvant) (19–21). In addition, the exposure of healthy and well-oxygenated tissue, as opposed to post-operative fibrotic tissue, to radiation would theoretically improve its anti-neoplastic effects. Finally, perhaps one of the most beneficial aspects of offering patients preoperative neoadjuvant therapy would be the effect on tumor shrinkage. The decrease in tumor size (downsizing) and shifts in tumor stage (downstaging) have been well documented after neoadjuvant therapies with radiation and chemoradiation (CRT) (22–25). In fact, the addition of chemotherapy to
radiation has been shown to significantly increase the effects on tumor size and stage when delivered preoperatively (22). Also, this downsizing and downstaging seem to be time-dependent and therefore, at least six, eight or even 12 weeks may be required to obtain maximal results for tumor regression (26–28). It appeared that neoadjuvant therapy, particularly CRT, was the answer to all prayers for TEM in rectal cancer: Improve local disease control, minimize toxicity, decrease tumor size, downstage cancers and allow a minimally invasive approach without all the downsides of radical total mesorectal excision (TME). However, the expected benefits of this strategy came at a significant cost in terms of wound healing and salvage possibilities. Also, local recurrences may still be a concern depending on baseline and post-treatment characteristics.
Wound healing One of the most significant benefits of TEM after the resection of rectal tumors was the minimal associated postoperative morbidity. Postoperative complications are minimal and usually do not require readmission or reintervention. However, when preoperative CRT is delivered, TEM resection leads to a rectal wound that allows primary suturing without any technical difficulty, unless the proximal margin is very close to the anal canal/verge. In this situation, even though the upper border of the wound may retain its considerable elasticity, the lower border of the wound of the anal canal is rather fixed and with little mobility. If the resection is wide enough to result in significant separation of the proximal and distal borders, significant tension will be present, a known feature to contribute to wound dehiscence. Also, the anal canal has ectodermic as opposed to endodermic nerve supply to the rectum. Therefore, wound separation and mucosal discontinuity in this region may be quite painful. Finally, regardless of the level of suturing (rectal or anal canal), the borders to be sutured after a TEM resection in a previously irradiated rectum will necessarily put together two previously irradiated borders. This is actually quite different from a coloanal anastomosis following neoadjuvant CRT, where the proximal colon is never included in the radiation field and therefore a normal colon is sutured to an abnormal analcanalpreviouslytreated with a significant amount of RT (29). In fact, even after a coloanal anastomosis is constructed, the risk of dehiscence is so significant that a loop ileostomy is almost always recommended (30). One can imagine the risk of wound dehiscence after suturing together two previously irradiated borders of
Minim Invasive Ther Allied Technol Downloaded from informahealthcare.com by University of Connecticut on 10/10/14 For personal use only.
Pitfalls of TEM for rectal CA after CRT rectum or anus, sometimes with significant tension depending on the level of the suture. In fact, few studies compared the risk of wound separation and its consequences with or without previous exposure to CRT. However, retrospective studies have suggested that the risk of wound dehiscence was significantly higher when CRT was delivered preoperatively. In one of these studies, diagnosis of wound dehiscence was made after more than one week following TEM and healing of the dehiscence took an average of more than eight weeks to complete. An operation that otherwise would almost never require a stoma, in this situation diversion is occasionally required (31). In another study, even though none of the dehiscences required stomas, pain management was quite significant requiring readmission for analgesia in a considerable proportion of patients (32). Ultimately, these findings raised the issue whether any attempt to close the wound defect created by TEM should even be performed. Leaving the wound open could potentially avoid the complication of wound dehiscence and minimize its consequences. However logical this may seem, there is no good evidence to support this idea from any study and the author’s clinical experience with unclosed wounds showed no significant differences in pain control after TEM following neoadjuvant CRT for rectal cancers.
Salvage In any patient with a rectal cancer treated by neoadjuvant CRT and TEM, the only possible salvage after recurrent disease or unfavorable pathological findings would be a total mesorectal excision (TME). Also, tumors that are candidates for TEM should ideally be restricted to the rectal wall (ycT2N0) regardless of the baseline staging features. Therefore, in theory and unless the patient is already incontinent, these tumors are candidates for sphincter-saving procedures such as low coloanal or even partial/total intersphincteric resections. Therefore, one would expect that any salvage resection here would allow a safe TME and at least the possibility of sphincter preservation. However, TEM for the management of rectal cancers should preferably include a significant amount of perirectal fat, often reaching the mesorectal fascia for oncological purposes. Considering the fact that wound dehiscence is frequent, scarring and fibrotic changes may be quite significant leading inevitably to perforation or violation of the mesorectal fascia during TME attempt for salvage. This may be crucial in the setting of local tumor recurrence and its clinical consequences are yet to be reported.
65
Even when TME can be safely performed, sphincter preservation may also be compromised. In a study where patients treated by neoadjuvant RT or CRT were managed by FTLE (including TEM), the presence of unfavorable pathology recommended subsequent TME. None of these patients salvaged could avoid an abdominal perineal resection. Interestingly, a few of these patients could have been originally offered a sphincter preserving operation with TME as an alternative to FTLE (33). In another recently reported study offering TEM after CRT and salvage for patients with unfavorable pathology, patients undergoing radical TME were able to undergo sphincter preservation. Curiously however, five out of seven patients (>71%) undergoing sphincter preservation developed anastomotic dehiscence and two out of 11 (18%) required emergency reoperations (34). Therefore, sphincter preservation after previous CRT & TEM may be quite technically challenging and associated with significant postoperative morbidity. Functional outcomes of these patients are yet to be known.
Local recurrence Few studies have addressed the use of TEM after neoadjuvant CRT. Most of the studies have included FTLE, grouping together transanal standard resections and TEM. There is no study in rectal cancer showing TEM superiority in oncological outcomes as compared to standard technique. However, considering that TEM has shown to provide a better quality of the specimen, one could assume that TEM may offer better results when compared to standard FTLE. As mentioned earlier, local recurrence rates have historically paralleled the risk of lymph node metastases in patients treated by FTLE for rectal cancer. pT status is one of the most relevant determinants of the risk of perirectal nodal metastases both with or without chemoradiation (10–12,14). In fact, studies have suggested that the risk of lymph node metastases is
