doi:10.1111/codi.12902
Original article
Regional lymph node status after neoadjuvant chemoradiation of rectal cancer producing a complete or near complete rectal wall response C. Shwaartz*, N. Haim*, D. Rosin*, Y. Lawrence†, M. Gutman* and O. Zmora* *Department of Surgery, Sheba Medical Center, Sackler School of Medicine, Tel Aviv, Israel and †Department of Radiotherapy, Sheba Medical Center, Sackler School of Medicine, Tel Aviv, Israel Received 5 August 2014; accepted 19 November 2014; Accepted Article online 20 January 2015
Abstract Aim Transanal excision of the tumour site after complete response to chemoradiotherapy can determine the rectal wall response to treatment. This study was designed to assess whether the absence of tumour in the rectal wall corresponds to the absence of tumour in the mesorectum (true pathological complete response). Method A retrospective review identified patients who underwent preoperative chemoradiation therapy for advanced mid and low rectal cancer followed by routine pre-planned radical surgery with total mesorectal excision. Patients in whom the pathology specimen showed no residual tumour in the rectal wall (ypT0) or a ypT1 lesion were assessed for tumour involvement in the mesorectum. Results Seventy-eight patients who underwent pelvic chemoradiation followed by radical surgery were reviewed. The rectal wall tumour disappeared in eight (ypT0). Of these, residual tumour was found in the mesorectum (ypT0N1) in one (12%) patient. Eleven patients were found to have ypT1 residual tumour. Of these, two (18%) had a final post-surgical staging of ypT1N1.
Introduction Neoadjuvant chemoradiation treatment (CRT) for mid and low rectal cancer improves local control, reduces the risk of pelvic recurrence and may increase the chance of Correspondence to: Oded Zmora, MD, Department of Surgery and Transplantation, Sheba Medical Center, Tel Hashomer 52621, Israel. E-mail: [email protected] Presented as a poster at the 8th Annual Meeting of the European Society of Coloproctology, 25–27 September 2013, Belgrade, Serbia.
Conclusion Complete rectal wall tumour eradication was achieved in 10% of the patients, and downstaging to ypT1 was achieved in 14%. In 15% (12% in ypT0 and 18% in ypT1) of these patients, residual tumour cells were evident in the mesorectum. This would probably have rendered these patients with residual disease had a nonradical approach of transanal excision of the original tumour site been employed. Caution should be taken when considering the avoidance of radical surgery. Keywords Rectal cancer, chemoradiation, complete response, lymph nodes What does this paper add to the literature? Some patients have a pathological complete response following neoadjuvant chemoradiation treatment and could potentially avoid radical surgery. There is poor correlation between clinical complete response and pathological complete response. This study adds validity to previous studies suggesting that positive lymph nodes or tumour deposits may be found in the mesorectum of patients with a complete response in the rectal wall. Caution should be taken using transanal excision of the tumour site, in patients who clinically appear to have had a complete response and selected for nonradical approach.
anal sphincter preservation [1]. Some patients may have a pathological complete response with no residual tumour found in the postoperative pathological specimen [2]. It has been shown, however, that the identification of a clinical complete response as assessed by digital rectal examination, rigid rectoscopy or imaging may be inaccurate. Approximately three-quarters of patients who were assessed to have clinical complete response harboured tumour cells in the pathological specimen following surgery [3,4]. For this reason, radical surgery, including total mesorectal excision (TME), is still consid-
Colorectal Disease ª 2015 The Association of Coloproctology of Great Britain and Ireland. 17, 595–599
595
C. Shwaartz et al.
Mesorectal status in rectal wall complete response
ered the gold standard, regardless of the clinical assessment of the effect of neoadjuvant CRT. In some cases, post neoadjuvant therapy clinical assessment reveals scar tissue or normal appearing rectal wall on endoscopic assessment of the rectum. In these cases, the pathological response of the rectal wall can be assessed by transanal excision of the scar or recorded pretreatment tumour site. If this specimen does not reveal tumour cells, rectal wall complete response (ypT0) can be determined with a high level of confidence. This still renders the status of the mesentery uncertain, however. The aim of this study was to assess whether the absence of tumour in the rectal wall following neoadjuvant chemoradiation (ypT0, y stands for pathological staging after radiation therapy) corresponds to the absence of tumour in the mesorectum (ypT0N0), which may be considered as a true pathological complete response. Additionally, the status of the mesorectum in patients with ypT1 is assessed.
Method A retrospective chart review of patients who underwent neoadjuvant CRT for mid and low rectal cancer between the years 1998 and 2012 followed by radical surgery using TME was performed. The study was approved by the local Institutional Review Board committee. Routine pretreatment evaluation, including digital rectal examination, rigid rectoscopy and transrectal ultrasound, was made before the decision on neoadjuvant CRT to evaluate the precise location of the tumour, the depth of invasion of the rectal wall (T staging) and mesenteric lymph node status. All patients underwent full colonoscopy to clear the rest of the colon, and patients with synchronous tumours were excluded from the study. A biopsy from the rectal tumour was obtained in all cases to confirm the diagnosis of adenocarcinoma. All patients were systemically evaluated using CT scan to exclude metastatic disease, and MRI was used selectively to assess T staging, mesorectum lymph nodes and mesorectal margins at risk. In general, any uT3 or uN1 tumour was considered an indication for neoadjuvant chemoradiation. In selected cases, low lying uT2 cases in which the ability to perform sphincter saving surgery was questionable were also assigned to neoadjuvant therapy. Patients with pretreatment T4 staging were excluded from the study as nearby organs may not be included in the surgical margins of the specimen. The neoadjuvant CRT regimen included long-course radiation therapy of 50.4 Gy over 5–6 weeks, combined
596
(in most patients) with 5-fluorouracil based chemosensitization. Surgery was scheduled 6–8 weeks after the completion of CRT. In most cases, patients were clinically re-evaluated by a colorectal surgeon before surgery. All patients included in the study underwent radical surgery with total mesorectal excision under the supervision of a trained colorectal surgeon to ascertain adherence to the accepted colorectal guidelines for rectal cancer surgery. Our unit policy at the time that the study was undertaken was that resection margins of a minimum of 2 cm were considered appropriate for sphincter preserving procedures. If this margin could not be met, abdominoperineal resection was performed. The fresh specimen was evaluated in the operating room to measure the distance of the tumour from the distal margin. The mesorectal fascia was evaluated by the surgical team to ensure the TME quality, which has been recorded in the operative report. The deep perirectal margin was inked and sent for light microscopy evaluation. Lymph nodes were dissected from the mesorectal tissue and separated. The remaining tissue was then placed in paraffin blocks for staining with haematoxylin and eosin. For the purpose of this study, the pathology reports of the surgical specimens were reviewed and the following data were retrieved: (1) presence or absence of residual carcinoma cells in the entire TME specimen; (2) tumour grade; (3) perineural and perivascular invasion by tumour cells; (4) ypT and ypN stage; and (5) tumour deposits in the perirectal tissue. A complete response in the rectal wall was defined as no residual tumour throughout its entire thickness. Positive lymph nodes were defined as tumour cells seen in lymphatic tissue and mesorectal tumour deposits were defined as tumour cells seen in the mesorectal fat without adjacent lymphatic tissue. Finally the recorded evaluation of clinical complete response before surgery was compared with the pathological result following surgery.
Results Seventy-eight patients in our database were diagnosed with uT2–uT3 mid (6–12 cm) to low (< 5 cm) rectal adenocarcinoma between the years 1998 and 2012 and had neoadjuvant CRT followed by radical surgery with TME. There were 45 males and 33 females with a mean age of 63 years. The average distance of the lower edge of the tumour from the anal verge was 6.8 cm (Table 1). Pre-CRT staging showed 12 patients with a low rectal tumour invading the muscularis propria (uT2) and 52 patients with tumour invading into the perirectal fat (uT3). In 14 patients referred from other hospitals, reliable pre-CRT clinical and imaging evalua-
Colorectal Disease ª 2015 The Association of Coloproctology of Great Britain and Ireland. 17, 595–599
C. Shwaartz et al.
Mesorectal status in rectal wall complete response
Table 1 Demographic and clinical characteristics. N Gender (M/F) Mean age Mean distance of the tumour from anal verge Pre CRT imaging T2 T3 T data not retrieved N+ Type of surgical procedure Low anterior resection Abdominoperineal excision of the rectum
Discussion
78 45/33 63 6.8 cm (2–15)
12 52 14 25 58 20
tion could not be retrieved retrospectively from the charts (marked ‘not recorded’). Twenty-five patients had positive mesorectal lymph nodes on pre-CRT rectal ultrasound or MRI. Records were obtained retrospectively of 41 clinical assessments of patients awaiting surgery. Clinical assessment of response to therapy was based on digital rectal examination and rigid rectoscopy. Table 2 shows the clinical response assessment done at outpatient followup. Eleven patients were assessed as being clinical complete responders, with no evidence of tumour on digital rectal examination or rigid rectoscopy or transrectal ultrasound. Sixteen were assessed to have had a partial response, and 14 had no response. In 37 patients the assessment of response could not be retrieved. There was poor correlation between the surgeon’s post CRT evaluation and the histopathology report, with only one of the 11 patients with a clinically complete response having a histopathological complete response. Patients underwent surgery at a median interval of 6 (2–24) weeks following CRT. Table 1 shows the surgical procedures performed and Fig. 1 shows the final histopathological results. A median of 8.9 (6–28) lymph nodes was found in the TME specimen. Of eight assessed clinically to be ypT0, one (12%) had malignant cells in the mesorectal lymph nodes. Of the 11 ypT1 patients, two (18%) had malignant cells in the mesorectum, one in lymph nodes and one in the mesorectal fat. Table 2 Clinical assessment following neoadjuvant chemoradiotherapy. Complete response Partial response No response Not retrieved
11 16 14 37
(14%) (21%) (18%) (47%)
TME is associated with a low rate of local recurrence and improved disease-free survival [5–8]. Preoperative radiotherapy further reduces local recurrence but without improving survival [9,10]. It may be given by a short course including five fractions of 5 Gy followed by surgery 1 week later or by a long course of approximately 50.4 Gy with chemotherapy followed by surgery at 6–12 weeks. In the latter case, the tumour may completely disappear giving an apparent ‘complete response’. True complete response can only be determined by histopathological examination of the resected specimen. If it were possible to predict a histopathological complete response without radical resection, this would enable radical surgery to be avoided, but the clinical assessment of response to neoadjuvant treatment correlates poorly with the subsequent histopathological findings [3,4]. Hiotis et al. [3] showed that up to 75% of the patients assessed to have a clinical complete response had residual tumour on histopathological examination of the resected rectum. Endoanal local excision of the scar at the site of the tumour after neoadjuvant chemoradiotherapy has been advocated to improve the assessment of response; although a surgical procedure, it involves minimal risk and is clearly less traumatic than radical rectal resection [11,12]. It may be assumed that if there is a complete response in the rectal wall (ypT0) a true pathological complete response (ypT0N0) is likely. The present study demonstrated that this was not the case in the eight tumours found to be ypT0, with one patient having a ypT0N1 tumour. Equally important was the observation of lymph node positivity in the 11 patients whose tumour was found to be yT1, where two were actually N+. Habr Gama et al. [13] followed patients with clinical complete response by clinical examination alone. Of 122 patients who were clinically assessed to have had complete response at 8 weeks from the completion of radiation therapy, 19% had recurrence within 1 year and 99 (81%) remained clinically tumour free. In the latter group, five (5%) subsequently experienced isolated locoregional recurrence at a mean follow-up of 52 months. The results of the present study, showing positive mesorectum in 12–18% of patients with pathologically proven ypT0 and ypT1, show that caution should be exercised when adopting a wait-and-watch approach. Furthermore, the results of the study show poor correlation between clinically complete and pathological response. According to our findings, a wait-and-watch policy would have resulted in 10 of the patients reported by Habr Gama et al. having residual tumour.
Colorectal Disease ª 2015 The Association of Coloproctology of Great Britain and Ireland. 17, 595–599
597
C. Shwaartz et al.
Mesorectal status in rectal wall complete response
78 Patients
T0
T1
T2
T3
8
11
16
43
N–
N+
N–
N+
N–
N+
N–
N+
7
1
9
2
15
1
23
20
Pelvic MRI and other modern imaging techniques may potentially detect residual tumour and improve the clinical assessment of response, but they will only detect sizable lymph node or tumour deposits. This study has several limitations. Being retrospective, there was no predefined uniform protocol for pretreatment staging, radiation therapy, post radiation assessment and interval to surgery. In addition, a portion of the data could not be reliably retrieved retrospectively. There was no record of the size of positive lymph nodes or mesorectal deposits. The routine practice at the time included transrectal ultrasound evaluation for tumour staging followed by long-course radiotherapy with assessment of response at 6–8 weeks by physical examination. Garcia-Aguilar et al. [14] showed that extending the time interval between completion of CRT and surgery from 6 to 11 weeks increased the rate of a pathological complete response from 18% to 25%. It may be possible that a longer interval would have increased the response rates in the present study. Several retrospective studies with small numbers of patients have previously suggested that positive lymph nodes or mesorectal tumour deposits may be present in patients with a complete response in the rectal wall [5– 16]. The current study adds validity to these findings, whereby a complete ypT0 response or downstaging to ypT1 does not imply a true complete pathological response. Caution should therefore be used when interpreting the histopathological examination of a local excision specimen in patients demonstrated to have had a complete or nearly complete T-stage response.
Author contributions Shwaartz Chaya: data collection, database management, data analysis and writing a draft of the manuscript.
598
Figure 1 Histopathology reports of the resected specimen after neoadjuvant chemoradiotherapy.
Haim Nadav: data collection, database management, data analysis and writing a draft of the manuscript. Rosin Danny: data interpretation and revision of the manuscript. Lawrence Yaacov: data collection. Gutman Mordechai: data interpretation and revision of the manuscript. Zmora Oded: conception and design of the work, supervising data collection and analysis, final manuscript.
References 1 Sauer R, Becker H, Hohenberger W et al. Preoperative versus postoperative chemoradiotherapy for rectal cancer. N Engl J Med 2004; 351: 1731–40. 2 Huh JW, Kim HR, Kim YJ. Clinical prediction of pathological complete response after preoperative chemoradiotherapy for rectal cancer. Dis Colon Rectum 2013; 56: 698–703. 3 Hiotis SP, Weber SM, Cohen AM et al. Assessing the predictive value of clinical complete response to neoadjuvant therapy for rectal cancer: an analysis of 488 patients. J Am Coll Surg 2002; 194: 131–5. 4 Smith FM, Wiland H, Mace A, Pai RK, Kalady MF. Clinical criteria underestimate complete pathological response in rectal cancer treated with neoadjuvant chemoradiotherapy. Dis Colon Rectum 2014; 57: 311–5. 5 Heald RJ, Moran BJ, Ryall RD, Sexton R, MacFarlane JK. Rectal cancer: the Basingstoke experience of total mesorectal excision, 1978–1997. Arch Surg 1998; 133: 894–9. 6 Tocchi A, Mazzoni G, Lepre L et al. Total mesorectal excision and low rectal anastomosis for the treatment of rectal cancer and prevention of pelvic recurrences. Arch Surg 2001; 136: 216–20. 7 Heald RJ, Husband EM, Ryall RD. The mesorectum in rectal cancer surgery: the clue to pelvic recurrence? Br J Surg 1982; 69: 613–6. 8 Cecil TD, Sexton R, Moran BJ, Heald RJ. Total mesorectal excision results in low local recurrence rates in lymph nodepositive rectal cancer. Dis Colon Rectum 2004; 47: 1145–9.
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9 Kapiteijn E, Marijnen CA, Nagtegaal ID et al. Preoperative radiotherapy combined with total mesorectal excision for resectable rectal cancer. N Engl J Med 2001; 345: 638–46. 10 Peeters KC, Marijnen CA, Nagtegaal ID et al. The TME trial after a median follow-up of 6 years: increased local control but no survival benefit in irradiated patients with resectable rectal carcinoma. Ann Surg 2007; 246: 693– 701. 11 Nair RM, Siegel EM, Chen DT et al. Long-term results of transanal excision after neoadjuvant chemoradiation for T2 and T3 adenocarcinomas of the rectum. J Gastrointest Surg 2008; 12: 1797–805. 12 Issa N, Murninkas A, Powsner E, Dreznick Z. Long-term outcome of local excision after complete pathological response to neoadjuvant chemoradiation therapy for rectal cancer. World J Surg 2012; 36: 2481–7.
Mesorectal status in rectal wall complete response
13 Habr-Gama A1, Perez RO, Proscurshim I et al. Patterns of failure and survival for nonoperative treatment of stage c0 distal rectal cancer following neoadjuvant chemoradiation therapy. J Gastrointest Surg 2006; 10: 1319–28. 14 Garcia-Aguilar J, Smith DD, Avila K, Bergsland EK, Chu P, Krieg RM. Optimal timing of surgery after chemoradiation for advanced rectal cancer: preliminary results of a multicenter, nonrandomized phase II prospective trial. Ann Surg 2011; 254: 97–102. 15 Zmora O, Dasilva GM, Gurland B et al. Does rectal wall tumor eradication with preoperative chemoradiation permit a change in the operative strategy? Dis Colon Rectum 2004; 47: 1607–12. 16 Tulchinsky H, Rabau M, Shacham-Shemueli E et al. Can rectal cancers with pathologic T0 after neoadjuvant chemoradiation (ypT0) be treated by transanal excision alone? Ann Surg Oncol 2006; 13: 347–52.
Colorectal Disease ª 2015 The Association of Coloproctology of Great Britain and Ireland. 17, 595–599
599
Original article
Regional lymph node status after neoadjuvant chemoradiation of rectal cancer producing a complete or near complete rectal wall response C. Shwaartz*, N. Haim*, D. Rosin*, Y. Lawrence†, M. Gutman* and O. Zmora* *Department of Surgery, Sheba Medical Center, Sackler School of Medicine, Tel Aviv, Israel and †Department of Radiotherapy, Sheba Medical Center, Sackler School of Medicine, Tel Aviv, Israel Received 5 August 2014; accepted 19 November 2014; Accepted Article online 20 January 2015
Abstract Aim Transanal excision of the tumour site after complete response to chemoradiotherapy can determine the rectal wall response to treatment. This study was designed to assess whether the absence of tumour in the rectal wall corresponds to the absence of tumour in the mesorectum (true pathological complete response). Method A retrospective review identified patients who underwent preoperative chemoradiation therapy for advanced mid and low rectal cancer followed by routine pre-planned radical surgery with total mesorectal excision. Patients in whom the pathology specimen showed no residual tumour in the rectal wall (ypT0) or a ypT1 lesion were assessed for tumour involvement in the mesorectum. Results Seventy-eight patients who underwent pelvic chemoradiation followed by radical surgery were reviewed. The rectal wall tumour disappeared in eight (ypT0). Of these, residual tumour was found in the mesorectum (ypT0N1) in one (12%) patient. Eleven patients were found to have ypT1 residual tumour. Of these, two (18%) had a final post-surgical staging of ypT1N1.
Introduction Neoadjuvant chemoradiation treatment (CRT) for mid and low rectal cancer improves local control, reduces the risk of pelvic recurrence and may increase the chance of Correspondence to: Oded Zmora, MD, Department of Surgery and Transplantation, Sheba Medical Center, Tel Hashomer 52621, Israel. E-mail: [email protected] Presented as a poster at the 8th Annual Meeting of the European Society of Coloproctology, 25–27 September 2013, Belgrade, Serbia.
Conclusion Complete rectal wall tumour eradication was achieved in 10% of the patients, and downstaging to ypT1 was achieved in 14%. In 15% (12% in ypT0 and 18% in ypT1) of these patients, residual tumour cells were evident in the mesorectum. This would probably have rendered these patients with residual disease had a nonradical approach of transanal excision of the original tumour site been employed. Caution should be taken when considering the avoidance of radical surgery. Keywords Rectal cancer, chemoradiation, complete response, lymph nodes What does this paper add to the literature? Some patients have a pathological complete response following neoadjuvant chemoradiation treatment and could potentially avoid radical surgery. There is poor correlation between clinical complete response and pathological complete response. This study adds validity to previous studies suggesting that positive lymph nodes or tumour deposits may be found in the mesorectum of patients with a complete response in the rectal wall. Caution should be taken using transanal excision of the tumour site, in patients who clinically appear to have had a complete response and selected for nonradical approach.
anal sphincter preservation [1]. Some patients may have a pathological complete response with no residual tumour found in the postoperative pathological specimen [2]. It has been shown, however, that the identification of a clinical complete response as assessed by digital rectal examination, rigid rectoscopy or imaging may be inaccurate. Approximately three-quarters of patients who were assessed to have clinical complete response harboured tumour cells in the pathological specimen following surgery [3,4]. For this reason, radical surgery, including total mesorectal excision (TME), is still consid-
Colorectal Disease ª 2015 The Association of Coloproctology of Great Britain and Ireland. 17, 595–599
595
C. Shwaartz et al.
Mesorectal status in rectal wall complete response
ered the gold standard, regardless of the clinical assessment of the effect of neoadjuvant CRT. In some cases, post neoadjuvant therapy clinical assessment reveals scar tissue or normal appearing rectal wall on endoscopic assessment of the rectum. In these cases, the pathological response of the rectal wall can be assessed by transanal excision of the scar or recorded pretreatment tumour site. If this specimen does not reveal tumour cells, rectal wall complete response (ypT0) can be determined with a high level of confidence. This still renders the status of the mesentery uncertain, however. The aim of this study was to assess whether the absence of tumour in the rectal wall following neoadjuvant chemoradiation (ypT0, y stands for pathological staging after radiation therapy) corresponds to the absence of tumour in the mesorectum (ypT0N0), which may be considered as a true pathological complete response. Additionally, the status of the mesorectum in patients with ypT1 is assessed.
Method A retrospective chart review of patients who underwent neoadjuvant CRT for mid and low rectal cancer between the years 1998 and 2012 followed by radical surgery using TME was performed. The study was approved by the local Institutional Review Board committee. Routine pretreatment evaluation, including digital rectal examination, rigid rectoscopy and transrectal ultrasound, was made before the decision on neoadjuvant CRT to evaluate the precise location of the tumour, the depth of invasion of the rectal wall (T staging) and mesenteric lymph node status. All patients underwent full colonoscopy to clear the rest of the colon, and patients with synchronous tumours were excluded from the study. A biopsy from the rectal tumour was obtained in all cases to confirm the diagnosis of adenocarcinoma. All patients were systemically evaluated using CT scan to exclude metastatic disease, and MRI was used selectively to assess T staging, mesorectum lymph nodes and mesorectal margins at risk. In general, any uT3 or uN1 tumour was considered an indication for neoadjuvant chemoradiation. In selected cases, low lying uT2 cases in which the ability to perform sphincter saving surgery was questionable were also assigned to neoadjuvant therapy. Patients with pretreatment T4 staging were excluded from the study as nearby organs may not be included in the surgical margins of the specimen. The neoadjuvant CRT regimen included long-course radiation therapy of 50.4 Gy over 5–6 weeks, combined
596
(in most patients) with 5-fluorouracil based chemosensitization. Surgery was scheduled 6–8 weeks after the completion of CRT. In most cases, patients were clinically re-evaluated by a colorectal surgeon before surgery. All patients included in the study underwent radical surgery with total mesorectal excision under the supervision of a trained colorectal surgeon to ascertain adherence to the accepted colorectal guidelines for rectal cancer surgery. Our unit policy at the time that the study was undertaken was that resection margins of a minimum of 2 cm were considered appropriate for sphincter preserving procedures. If this margin could not be met, abdominoperineal resection was performed. The fresh specimen was evaluated in the operating room to measure the distance of the tumour from the distal margin. The mesorectal fascia was evaluated by the surgical team to ensure the TME quality, which has been recorded in the operative report. The deep perirectal margin was inked and sent for light microscopy evaluation. Lymph nodes were dissected from the mesorectal tissue and separated. The remaining tissue was then placed in paraffin blocks for staining with haematoxylin and eosin. For the purpose of this study, the pathology reports of the surgical specimens were reviewed and the following data were retrieved: (1) presence or absence of residual carcinoma cells in the entire TME specimen; (2) tumour grade; (3) perineural and perivascular invasion by tumour cells; (4) ypT and ypN stage; and (5) tumour deposits in the perirectal tissue. A complete response in the rectal wall was defined as no residual tumour throughout its entire thickness. Positive lymph nodes were defined as tumour cells seen in lymphatic tissue and mesorectal tumour deposits were defined as tumour cells seen in the mesorectal fat without adjacent lymphatic tissue. Finally the recorded evaluation of clinical complete response before surgery was compared with the pathological result following surgery.
Results Seventy-eight patients in our database were diagnosed with uT2–uT3 mid (6–12 cm) to low (< 5 cm) rectal adenocarcinoma between the years 1998 and 2012 and had neoadjuvant CRT followed by radical surgery with TME. There were 45 males and 33 females with a mean age of 63 years. The average distance of the lower edge of the tumour from the anal verge was 6.8 cm (Table 1). Pre-CRT staging showed 12 patients with a low rectal tumour invading the muscularis propria (uT2) and 52 patients with tumour invading into the perirectal fat (uT3). In 14 patients referred from other hospitals, reliable pre-CRT clinical and imaging evalua-
Colorectal Disease ª 2015 The Association of Coloproctology of Great Britain and Ireland. 17, 595–599
C. Shwaartz et al.
Mesorectal status in rectal wall complete response
Table 1 Demographic and clinical characteristics. N Gender (M/F) Mean age Mean distance of the tumour from anal verge Pre CRT imaging T2 T3 T data not retrieved N+ Type of surgical procedure Low anterior resection Abdominoperineal excision of the rectum
Discussion
78 45/33 63 6.8 cm (2–15)
12 52 14 25 58 20
tion could not be retrieved retrospectively from the charts (marked ‘not recorded’). Twenty-five patients had positive mesorectal lymph nodes on pre-CRT rectal ultrasound or MRI. Records were obtained retrospectively of 41 clinical assessments of patients awaiting surgery. Clinical assessment of response to therapy was based on digital rectal examination and rigid rectoscopy. Table 2 shows the clinical response assessment done at outpatient followup. Eleven patients were assessed as being clinical complete responders, with no evidence of tumour on digital rectal examination or rigid rectoscopy or transrectal ultrasound. Sixteen were assessed to have had a partial response, and 14 had no response. In 37 patients the assessment of response could not be retrieved. There was poor correlation between the surgeon’s post CRT evaluation and the histopathology report, with only one of the 11 patients with a clinically complete response having a histopathological complete response. Patients underwent surgery at a median interval of 6 (2–24) weeks following CRT. Table 1 shows the surgical procedures performed and Fig. 1 shows the final histopathological results. A median of 8.9 (6–28) lymph nodes was found in the TME specimen. Of eight assessed clinically to be ypT0, one (12%) had malignant cells in the mesorectal lymph nodes. Of the 11 ypT1 patients, two (18%) had malignant cells in the mesorectum, one in lymph nodes and one in the mesorectal fat. Table 2 Clinical assessment following neoadjuvant chemoradiotherapy. Complete response Partial response No response Not retrieved
11 16 14 37
(14%) (21%) (18%) (47%)
TME is associated with a low rate of local recurrence and improved disease-free survival [5–8]. Preoperative radiotherapy further reduces local recurrence but without improving survival [9,10]. It may be given by a short course including five fractions of 5 Gy followed by surgery 1 week later or by a long course of approximately 50.4 Gy with chemotherapy followed by surgery at 6–12 weeks. In the latter case, the tumour may completely disappear giving an apparent ‘complete response’. True complete response can only be determined by histopathological examination of the resected specimen. If it were possible to predict a histopathological complete response without radical resection, this would enable radical surgery to be avoided, but the clinical assessment of response to neoadjuvant treatment correlates poorly with the subsequent histopathological findings [3,4]. Hiotis et al. [3] showed that up to 75% of the patients assessed to have a clinical complete response had residual tumour on histopathological examination of the resected rectum. Endoanal local excision of the scar at the site of the tumour after neoadjuvant chemoradiotherapy has been advocated to improve the assessment of response; although a surgical procedure, it involves minimal risk and is clearly less traumatic than radical rectal resection [11,12]. It may be assumed that if there is a complete response in the rectal wall (ypT0) a true pathological complete response (ypT0N0) is likely. The present study demonstrated that this was not the case in the eight tumours found to be ypT0, with one patient having a ypT0N1 tumour. Equally important was the observation of lymph node positivity in the 11 patients whose tumour was found to be yT1, where two were actually N+. Habr Gama et al. [13] followed patients with clinical complete response by clinical examination alone. Of 122 patients who were clinically assessed to have had complete response at 8 weeks from the completion of radiation therapy, 19% had recurrence within 1 year and 99 (81%) remained clinically tumour free. In the latter group, five (5%) subsequently experienced isolated locoregional recurrence at a mean follow-up of 52 months. The results of the present study, showing positive mesorectum in 12–18% of patients with pathologically proven ypT0 and ypT1, show that caution should be exercised when adopting a wait-and-watch approach. Furthermore, the results of the study show poor correlation between clinically complete and pathological response. According to our findings, a wait-and-watch policy would have resulted in 10 of the patients reported by Habr Gama et al. having residual tumour.
Colorectal Disease ª 2015 The Association of Coloproctology of Great Britain and Ireland. 17, 595–599
597
C. Shwaartz et al.
Mesorectal status in rectal wall complete response
78 Patients
T0
T1
T2
T3
8
11
16
43
N–
N+
N–
N+
N–
N+
N–
N+
7
1
9
2
15
1
23
20
Pelvic MRI and other modern imaging techniques may potentially detect residual tumour and improve the clinical assessment of response, but they will only detect sizable lymph node or tumour deposits. This study has several limitations. Being retrospective, there was no predefined uniform protocol for pretreatment staging, radiation therapy, post radiation assessment and interval to surgery. In addition, a portion of the data could not be reliably retrieved retrospectively. There was no record of the size of positive lymph nodes or mesorectal deposits. The routine practice at the time included transrectal ultrasound evaluation for tumour staging followed by long-course radiotherapy with assessment of response at 6–8 weeks by physical examination. Garcia-Aguilar et al. [14] showed that extending the time interval between completion of CRT and surgery from 6 to 11 weeks increased the rate of a pathological complete response from 18% to 25%. It may be possible that a longer interval would have increased the response rates in the present study. Several retrospective studies with small numbers of patients have previously suggested that positive lymph nodes or mesorectal tumour deposits may be present in patients with a complete response in the rectal wall [5– 16]. The current study adds validity to these findings, whereby a complete ypT0 response or downstaging to ypT1 does not imply a true complete pathological response. Caution should therefore be used when interpreting the histopathological examination of a local excision specimen in patients demonstrated to have had a complete or nearly complete T-stage response.
Author contributions Shwaartz Chaya: data collection, database management, data analysis and writing a draft of the manuscript.
598
Figure 1 Histopathology reports of the resected specimen after neoadjuvant chemoradiotherapy.
Haim Nadav: data collection, database management, data analysis and writing a draft of the manuscript. Rosin Danny: data interpretation and revision of the manuscript. Lawrence Yaacov: data collection. Gutman Mordechai: data interpretation and revision of the manuscript. Zmora Oded: conception and design of the work, supervising data collection and analysis, final manuscript.
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Mesorectal status in rectal wall complete response
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