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role of adjuvant chemotherapy. Dis Colon Rectum 2005; 48: 218–26. Lee JH, Jang HS, Kim JG et al. Lymphovascular invasion is a significant prognosticator in rectal cancer patients who receive preoperative chemoradiotherapy followed by total mesorectal excision. Ann Surg Oncol 2012; 19: 1213–21. Du CZ, Xue WC, Cai Y et al. Lymphovascular invasion in rectal cancer following neoadjuvant radiotherapy: a retrospective cohort study. World J Gastroenterol 2009; 15: 3793–8. Ptok H, Meyer F, Steinert R et al. No prognostic impact of isolated lymphovascular invasion after radical resection of rectal cancer–results of a multicenter observational study. Int J Colorectal Dis 2007; 22: 749–56. Engelen SM, Beets GL, Beets-Tan RG. Role of preoperative local and distant staging in rectal cancer. Onkologie 2007; 30: 141–5. Epub 2007 Feb 16. Torricelli P. Rectal cancer staging. Surg Oncol 2007; 16 (Suppl 1): S49–50. Epub 2007 Nov 26. Beets-Tan RG, Beets GL. Rectal cancer: review with emphasis on MR imaging. Radiology 2004; 232: 773–83. Giusti S, Buccianti P, Castagna M et al. Preoperative rectal cancer staging with phased-array MR. Radiat Oncol 2012; 7: 29. Bianchi PP, Ceriani C, Rottoli M et al. Endoscopic ultrasonography and magnetic resonance in preoperative staging of rectal cancer: comparison with histologic findings. J Gastrointest Surg 2005; 9: 1222–7; discussion 1227-8. Halefoglu AM, Yildirim S, Avlanmis O et al. Endorectal ultrasonography versus phased-array magnetic resonance imaging for preoperative staging of rectal cancer. World J Gastroenterol 2008; 14: 3504–10. Janjan NA, Crane C, Feig BW et al. Improved overall survival among responders to preoperative chemoradiation
Commentary on Wibe et al. The paper by Wibe et al. in this issue of the journal invites the reader to consider tailoring treatment for rectal cancer rather than accepting recommended guidelines alone and I resonate with this principle. The authors’ aim is to highlight features, apart from tumour stage, that are known to be prognostic in rectal cancer but are not currently incorporated in treatment guidelines and to advocate that individually tailored treatment should take account of these features as well as tumour stage. The authors specifically refer to two separate matters: (i) circumferential resection margin involvement by tumour (CRMI) and (ii) histopathological features of the resected specimen, namely depth of invasion beyond the muscularis propria, histological grade, and venous, perineural and
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for locally advanced rectal cancer. Am J Clin Oncol 2001; 24: 107–12. Sanghera P, Wong DW, McConkey CC et al. Chemoradiotherapy for rectal cancer: an updated analysis of factors affecting pathological response. Clin Oncol (R Coll Radiol), 2008; 20: 176–83. Park JH, Kim JH, Ahn SD et al. Prospective phase II study of preoperative chemoradiation with capecitabine in locally advanced rectal cancer. Cancer Res Treat 2004; 36: 354–9. Chari RS, Tyler DS, Anscher MS et al. Preoperative radiation and chemotherapy in the treatment of adenocarcinoma of the rectum. Ann Surg 1995; 221: 778–86. Yu CS, Kim TW, Kim JH et al. Optimal time interval between capecitabine intake and radiotherapy in preoperative chemoradiation for locally advanced rectal cancer. Int J Radiat Oncol Biol Phys 2007; 67: 1020–6. Read TE, McNevin MS, Gross EK et al. Neoadjuvant therapy for adenocarcinoma of the rectum: tumour response and acute toxicity. Dis Colon Rectum 2001; 44: 513–22. Habr-Gama A, Oliva Perez R. The strategy “wait and watch” in patients with a cancer of bottom stocking rectum with a complete clinical answer after neoadjuvant radiochemotherapy. J Chir (Paris) 2009; 146: 237–9. Hiotis SH, 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. Nakagawa WT, Rossi BM, de O Ferreira F et al. Chemoradiation instead of surgery to treat mid and low rectal tumours: is it safe? Ann Surg Oncol, 2002; 9: 568–73. Chang GJ, You YN, Park IJ et al. Pretreatment high-resolution rectal MRI and treatment response to neoadjuvant chemoradiation. Dis Colon Rectum 2012; 55: 371–7.
doi:10.1111/codi.12409
lymphovascular invasion. It is important to acknowledge that the latter are prognostic features but, as will be argued below, they may not be able to predict the outcome of treatment. A further aim of the paper was to concentrate on literature describing the prognostic impact of these features in T3 rectal tumours. However, many of the references cited by the authors are not specific to T3 tumours and it appears that many of the prognostic findings described may not necessarily apply to these tumours. To achieve a tighter focus on their stated aim it would have been more appropriate if the authors had limited the range of citations to those specifically about independent prognostic features in T3 rectal tumours.
Colorectal Disease ª 2013 The Association of Coloproctology of Great Britain and Ireland. 15, 1333–1344
A. Wibe et al.
The importance of CRMI has been known since 1986 and the ability of MRI to predict CRMI and the possibility of reducing its likelihood by preoperative radiotherapy are now widely accepted and incorporated into guidelines such as those to which the authors refer. Indeed their sections on MRI in preoperative staging, margin involvement and neoadjuvant therapy all serve to show how widely implemented these have become as part of tailored treatment. It is noteworthy that CRMI is fundamentally different from the other prognostic features which the authors emphasize, all of which exist before treatment commences, whereas an involved versus a clear margin is actually a consequence of treatment (whether by surgery or chemoradiotherapy). Potential CRMI can be predicted from MRI and hopefully avoided but actual CRMI becomes known only postoperatively from the pathology of the resected specimen. In both situations it is very clear that contemporary preoperative, intra-operative and postoperative treatment are closely tailored by information on potential or actual CRMI. Depth of invasion beyond the muscularis propria, histological grade, and venous, perineural and lymphovascular invasion are all prognostic tumour markers; that is, they are inherent biological characteristics of the tumour (or tumour plus host) which have repeatedly been shown to have independent prognostic power in relation to recurrence or overall survival or some surrogate outcome such as recurrence-free survival. However, to assert that these markers can help in selecting patients for tailored treatment strategies would require evidence that they are not simply prognostic but can also predict response to treatment. These markers can only be ascertained by histopathology of the specimen after surgery and thus can only be used to tailor treatment after the operation. It is important to acknowledge that, although these are recognized independent prognostic features, almost none of the literature cited in the article had a research design which was capable of predicting the outcome of treatment and hence supporting the use of these factors in tailored management. A necessary requirement in such a study would be random allocation of patients with data on these features to a treated group versus an untreated group so that the possible effects of selection bias are negated. The well established design and statistical methods for studies capable of demonstrating the predictive power of tumour markers are nicely summarized by Lee et al. [1] and exemplified in Ribic et al. [2]. However, the elephant in the room is that many contemporary guidelines recommend particular treatments, making it ethically difficult to allocate patients randomly, thus
Tailored rectal cancer treatment
undermining the possibility of conducting a study truly capable of demonstrating a predictive effect of a marker on treatment outcome. It is unfortunate that the good intention of guidelines may have stifled the very research which is needed to identify useful predictive markers. The management of rectal cancer depends on patient factors (gender, age, weight etc.); factors relating to the position of the tumour (distance from the anal verge, anterior location, clinically evident local invasion); factors relating to surgical technique and volume of the surgeon’s experience; and the interpretation of diagnostic tools which measure the extent of local invasion, the presence of lymph node invasion and the extent of distant metastasis. The outcomes of treatment depend upon these factors but, in addition, the prognosis is significantly affected by histopathological factors. At the time of presentation the surgeon has no influence over either patient factors or histopathology, but can influence surgical technique and, to a certain extent, may utilize various imaging modalities to decide on the appropriateness of preoperative radiotherapy or chemotherapy. This paper alludes to this broader objective but tends to concentrate on MRI and its use in predicting an involved circumferential margin. In essence, apart from surgical technique, the only modality which has been shown to influence local recurrence is neoadjuvant therapy, and the interpretation of MRI is crucial to its judicious use. However, it must be acknowledged that the interpretation of MRI is operator dependent and there is evidence to suggest that it can either over- or under-stage the depth of invasion [3]. Furthermore, the accuracy of MRI in diagnosing involved lymph nodes is not infallible and the finding of a circumferential resection margin on MRI should be interpreted with some caution [3]. This critique of MRI is not to deny its importance but is intended to draw attention to its judicious use in patient selection because, although preoperative adjuvant therapy has been shown to diminish local recurrence, there is a significant associated short- and longterm morbidity and its effect on overall survival has not been proven. The literature cited by the authors does not support the contention that well established histopathological prognostic factors can be used for implementing treatment protocols. However, there is no doubt that MRI has an important role in planning treatment. The concept of tailored treatment is highly desirable but, until specific predictive markers have been identified, the surgeon must rely on each patient’s individual circumstances rather than blindly following one-size-fits-all or off-the-shelf guidelines.
Colorectal Disease ª 2013 The Association of Coloproctology of Great Britain and Ireland. 15, 1333–1344
1343
A. Wibe et al.
Tailored rectal cancer treatment
Les Bokey Clinical Dean, Professor of Colon and Rectal Surgery at Liverpool Hospital, University of Western Sydney, New South Wales, Australia. E-mail: [email protected]
References
2 Ribic CM, Sargent DJ, Moore NJ et al. Tumor microsatellite-instability status as a predictor of benefit from fluorouracil-based adjuvant chemotherapy for colon cancer. N Engl J Med 2003; 349: 247–57. 3 Fleming FJ, P ahlman L, Monson JRT. Neoadjuvant therapy in rectal cancer. Dis Colon Rectum 2011; 54: 901–12.
1 Lee CK, Lord SJ, Coates AS, Simes RJ. Molecular biomarkers to individualise treatment: assessing the evidence. Med J Aust 2009; 190: 631–6.
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Colorectal Disease ª 2013 The Association of Coloproctology of Great Britain and Ireland. 15, 1333–1344
Copyright of Colorectal Disease is the property of Wiley-Blackwell and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use.
Tailored rectal cancer treatment
56
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60 61 62
63
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65
role of adjuvant chemotherapy. Dis Colon Rectum 2005; 48: 218–26. Lee JH, Jang HS, Kim JG et al. Lymphovascular invasion is a significant prognosticator in rectal cancer patients who receive preoperative chemoradiotherapy followed by total mesorectal excision. Ann Surg Oncol 2012; 19: 1213–21. Du CZ, Xue WC, Cai Y et al. Lymphovascular invasion in rectal cancer following neoadjuvant radiotherapy: a retrospective cohort study. World J Gastroenterol 2009; 15: 3793–8. Ptok H, Meyer F, Steinert R et al. No prognostic impact of isolated lymphovascular invasion after radical resection of rectal cancer–results of a multicenter observational study. Int J Colorectal Dis 2007; 22: 749–56. Engelen SM, Beets GL, Beets-Tan RG. Role of preoperative local and distant staging in rectal cancer. Onkologie 2007; 30: 141–5. Epub 2007 Feb 16. Torricelli P. Rectal cancer staging. Surg Oncol 2007; 16 (Suppl 1): S49–50. Epub 2007 Nov 26. Beets-Tan RG, Beets GL. Rectal cancer: review with emphasis on MR imaging. Radiology 2004; 232: 773–83. Giusti S, Buccianti P, Castagna M et al. Preoperative rectal cancer staging with phased-array MR. Radiat Oncol 2012; 7: 29. Bianchi PP, Ceriani C, Rottoli M et al. Endoscopic ultrasonography and magnetic resonance in preoperative staging of rectal cancer: comparison with histologic findings. J Gastrointest Surg 2005; 9: 1222–7; discussion 1227-8. Halefoglu AM, Yildirim S, Avlanmis O et al. Endorectal ultrasonography versus phased-array magnetic resonance imaging for preoperative staging of rectal cancer. World J Gastroenterol 2008; 14: 3504–10. Janjan NA, Crane C, Feig BW et al. Improved overall survival among responders to preoperative chemoradiation
Commentary on Wibe et al. The paper by Wibe et al. in this issue of the journal invites the reader to consider tailoring treatment for rectal cancer rather than accepting recommended guidelines alone and I resonate with this principle. The authors’ aim is to highlight features, apart from tumour stage, that are known to be prognostic in rectal cancer but are not currently incorporated in treatment guidelines and to advocate that individually tailored treatment should take account of these features as well as tumour stage. The authors specifically refer to two separate matters: (i) circumferential resection margin involvement by tumour (CRMI) and (ii) histopathological features of the resected specimen, namely depth of invasion beyond the muscularis propria, histological grade, and venous, perineural and
1342
66
67
68
69
70
71
72
73
74
for locally advanced rectal cancer. Am J Clin Oncol 2001; 24: 107–12. Sanghera P, Wong DW, McConkey CC et al. Chemoradiotherapy for rectal cancer: an updated analysis of factors affecting pathological response. Clin Oncol (R Coll Radiol), 2008; 20: 176–83. Park JH, Kim JH, Ahn SD et al. Prospective phase II study of preoperative chemoradiation with capecitabine in locally advanced rectal cancer. Cancer Res Treat 2004; 36: 354–9. Chari RS, Tyler DS, Anscher MS et al. Preoperative radiation and chemotherapy in the treatment of adenocarcinoma of the rectum. Ann Surg 1995; 221: 778–86. Yu CS, Kim TW, Kim JH et al. Optimal time interval between capecitabine intake and radiotherapy in preoperative chemoradiation for locally advanced rectal cancer. Int J Radiat Oncol Biol Phys 2007; 67: 1020–6. Read TE, McNevin MS, Gross EK et al. Neoadjuvant therapy for adenocarcinoma of the rectum: tumour response and acute toxicity. Dis Colon Rectum 2001; 44: 513–22. Habr-Gama A, Oliva Perez R. The strategy “wait and watch” in patients with a cancer of bottom stocking rectum with a complete clinical answer after neoadjuvant radiochemotherapy. J Chir (Paris) 2009; 146: 237–9. Hiotis SH, 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. Nakagawa WT, Rossi BM, de O Ferreira F et al. Chemoradiation instead of surgery to treat mid and low rectal tumours: is it safe? Ann Surg Oncol, 2002; 9: 568–73. Chang GJ, You YN, Park IJ et al. Pretreatment high-resolution rectal MRI and treatment response to neoadjuvant chemoradiation. Dis Colon Rectum 2012; 55: 371–7.
doi:10.1111/codi.12409
lymphovascular invasion. It is important to acknowledge that the latter are prognostic features but, as will be argued below, they may not be able to predict the outcome of treatment. A further aim of the paper was to concentrate on literature describing the prognostic impact of these features in T3 rectal tumours. However, many of the references cited by the authors are not specific to T3 tumours and it appears that many of the prognostic findings described may not necessarily apply to these tumours. To achieve a tighter focus on their stated aim it would have been more appropriate if the authors had limited the range of citations to those specifically about independent prognostic features in T3 rectal tumours.
Colorectal Disease ª 2013 The Association of Coloproctology of Great Britain and Ireland. 15, 1333–1344
A. Wibe et al.
The importance of CRMI has been known since 1986 and the ability of MRI to predict CRMI and the possibility of reducing its likelihood by preoperative radiotherapy are now widely accepted and incorporated into guidelines such as those to which the authors refer. Indeed their sections on MRI in preoperative staging, margin involvement and neoadjuvant therapy all serve to show how widely implemented these have become as part of tailored treatment. It is noteworthy that CRMI is fundamentally different from the other prognostic features which the authors emphasize, all of which exist before treatment commences, whereas an involved versus a clear margin is actually a consequence of treatment (whether by surgery or chemoradiotherapy). Potential CRMI can be predicted from MRI and hopefully avoided but actual CRMI becomes known only postoperatively from the pathology of the resected specimen. In both situations it is very clear that contemporary preoperative, intra-operative and postoperative treatment are closely tailored by information on potential or actual CRMI. Depth of invasion beyond the muscularis propria, histological grade, and venous, perineural and lymphovascular invasion are all prognostic tumour markers; that is, they are inherent biological characteristics of the tumour (or tumour plus host) which have repeatedly been shown to have independent prognostic power in relation to recurrence or overall survival or some surrogate outcome such as recurrence-free survival. However, to assert that these markers can help in selecting patients for tailored treatment strategies would require evidence that they are not simply prognostic but can also predict response to treatment. These markers can only be ascertained by histopathology of the specimen after surgery and thus can only be used to tailor treatment after the operation. It is important to acknowledge that, although these are recognized independent prognostic features, almost none of the literature cited in the article had a research design which was capable of predicting the outcome of treatment and hence supporting the use of these factors in tailored management. A necessary requirement in such a study would be random allocation of patients with data on these features to a treated group versus an untreated group so that the possible effects of selection bias are negated. The well established design and statistical methods for studies capable of demonstrating the predictive power of tumour markers are nicely summarized by Lee et al. [1] and exemplified in Ribic et al. [2]. However, the elephant in the room is that many contemporary guidelines recommend particular treatments, making it ethically difficult to allocate patients randomly, thus
Tailored rectal cancer treatment
undermining the possibility of conducting a study truly capable of demonstrating a predictive effect of a marker on treatment outcome. It is unfortunate that the good intention of guidelines may have stifled the very research which is needed to identify useful predictive markers. The management of rectal cancer depends on patient factors (gender, age, weight etc.); factors relating to the position of the tumour (distance from the anal verge, anterior location, clinically evident local invasion); factors relating to surgical technique and volume of the surgeon’s experience; and the interpretation of diagnostic tools which measure the extent of local invasion, the presence of lymph node invasion and the extent of distant metastasis. The outcomes of treatment depend upon these factors but, in addition, the prognosis is significantly affected by histopathological factors. At the time of presentation the surgeon has no influence over either patient factors or histopathology, but can influence surgical technique and, to a certain extent, may utilize various imaging modalities to decide on the appropriateness of preoperative radiotherapy or chemotherapy. This paper alludes to this broader objective but tends to concentrate on MRI and its use in predicting an involved circumferential margin. In essence, apart from surgical technique, the only modality which has been shown to influence local recurrence is neoadjuvant therapy, and the interpretation of MRI is crucial to its judicious use. However, it must be acknowledged that the interpretation of MRI is operator dependent and there is evidence to suggest that it can either over- or under-stage the depth of invasion [3]. Furthermore, the accuracy of MRI in diagnosing involved lymph nodes is not infallible and the finding of a circumferential resection margin on MRI should be interpreted with some caution [3]. This critique of MRI is not to deny its importance but is intended to draw attention to its judicious use in patient selection because, although preoperative adjuvant therapy has been shown to diminish local recurrence, there is a significant associated short- and longterm morbidity and its effect on overall survival has not been proven. The literature cited by the authors does not support the contention that well established histopathological prognostic factors can be used for implementing treatment protocols. However, there is no doubt that MRI has an important role in planning treatment. The concept of tailored treatment is highly desirable but, until specific predictive markers have been identified, the surgeon must rely on each patient’s individual circumstances rather than blindly following one-size-fits-all or off-the-shelf guidelines.
Colorectal Disease ª 2013 The Association of Coloproctology of Great Britain and Ireland. 15, 1333–1344
1343
A. Wibe et al.
Tailored rectal cancer treatment
Les Bokey Clinical Dean, Professor of Colon and Rectal Surgery at Liverpool Hospital, University of Western Sydney, New South Wales, Australia. E-mail: [email protected]
References
2 Ribic CM, Sargent DJ, Moore NJ et al. Tumor microsatellite-instability status as a predictor of benefit from fluorouracil-based adjuvant chemotherapy for colon cancer. N Engl J Med 2003; 349: 247–57. 3 Fleming FJ, P ahlman L, Monson JRT. Neoadjuvant therapy in rectal cancer. Dis Colon Rectum 2011; 54: 901–12.
1 Lee CK, Lord SJ, Coates AS, Simes RJ. Molecular biomarkers to individualise treatment: assessing the evidence. Med J Aust 2009; 190: 631–6.
1344
Colorectal Disease ª 2013 The Association of Coloproctology of Great Britain and Ireland. 15, 1333–1344
Copyright of Colorectal Disease is the property of Wiley-Blackwell and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use.
