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A multimodality approach to localized rectal cancer
Annals of Oncology 17 (Supplement 10): x129–x134, 2006 doi:10.1093/annonc/mdl250
A multimodality approach to localized rectal cancer A. Cervantes1, I. Chirivella1, E. Rodriguez-Braun1, S. Campos2, S. Navarro3 & E. Garcı´a Granero4 1
Depertment Hematology and Medical Oncology, 2Department Radiology, 3Department Pathology, 4Colorectal Unit, Department Surgery, Hospital Clı´nico Universitario, University of Valencia, Spain
introduction
staging The prognosis of rectal cancer is related to the anatomic disease extension determined on pathologic examination of the resection specimen. ª 2006 European Society for Medical Oncology
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Group 1: rectal tumors with good prognostic features and potentially negative CRM, including patients with T1 and T2 or T3 tumors with an extramural spread of less than 5 mm and less than 4 involved lymph nodes and no extramural vascular invasion. Group 2: rectal tumors with potentially negative CRM but with some poor prognostic factors such as peritoneal involvement (T4), or T3 tumors with an extramural invasion of 5 mm or more, extramural vascular invasion or 4 or more involved lymph nodes.
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The first years of the 21st century are witnessing many and important changes in the treatment of rectal cancer. The disease has moved from a surgically managed condition with contributions of other disciplines to management by a highly skilled multidisciplinary team (MDT). The management of all patients with colorectal cancer should be by such a MDT and it is recommended that any patient with a diagnosis of rectal cancer is referred to such a team. The participation of all members of the MDT in the discussion on all details of staging and other characteristics before any therapeutic intervention is essential. All MDTs who are treating patients with rectal cancer would benefit from a coordinated training program. The MDT should consist of a core team of members with a particular interest and expertise in rectal cancer with the commitment to continuous medical education, and associates. The core MDT is composed of specialist surgeons, medical and radiation oncologists, radiologists, pathologists, gastro-enterologists and stoma therapist nurses. The MDT should implement a treatment strategy based on national guidelines with the aim of standardization and improvement of outcome [1]. Although there is so far no proof to support the key role of the MDT in improvement of treatment outcome, it is difficult to understand how the quality of care could be improved otherwise since so many different specialists are involved in cancer care. Team discussions should be efficient, allowing all patients to be presented before any therapeutic intervention and should have an educational value stimulating interactions among team members and reinforcing clinical judgment in junior members. Treatment of rectal cancer may range from simple local excision to radical surgery after chemoradiation taking into account functional results and the risk of recurrence. The outcome will be the best when patients’ preferences are understood and expertise of multiple specialists is routinely provided [2]. This article deals with several issues that should be considered in a MDT approach in patients with rectal cancer: staging, quality of surgery and pathology assessment, and the integration of radiation and chemotherapy.
The TNM staging system is universally recommended and describes the anatomical extention of rectal tumors that have not been previously treated. Its prognostic value is based on data derived from the outcome of patients after complete surgical resection. However, information derived from conventional surgical TNM staging should be complemented with two other parameters: the macroscopic quality of the mesorectum in the surgical specimen and the involvement of the circumferential margin (CRM) [3–5]. Both parameters may reflect the adequacy of the surgical technique and the aggressiveness of the tumor, and are excellent predictors of outcome. Complete surgical resection with curative intent may be improved not only by adequate surgical training, but also with better staging. When rectal cancer is diagnosed, the surgical approach may vary from transanal local excision, primary total mesorectal excision (TME) or primary chemoradiation followed by TME. To select the most appropriate, treatment locoregional staging is becoming more important. Endorectal ultrasonography (EUS) and magnetic resonance imaging (MRI) are the most useful techniques for preoperative evaluation [6–9]. EUS is very accurate for assessing invasion of tumors within the bowel wall but less accurate for staging tumors beyond the bowel wall. EUS it is not able to visualize the mesorectal fascia, an important structure to assess involvement of the CRM. EUS is of little value in stenotic tumors causing bowel obstruction or when the proctoscope it is not able to pass the tumor. High resolution MRI predicts with high accuracy the CRM involvement and T2-weighted sequences are recommended. With the development of MRI, it is now possible to accurately predict tumor stage and other prognostic features such as nodal disease, depth of extramural spread and the presence of extramural vascular invasion. According to some expert centres using a MDT approach, MRI may classify rectal cancer patients into three subcategories [10]:
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Group 3: rectal tumors with potential involvement of CRM, with full thickness T2 or more at the level of puborectal muscles or tumor extending within 1 mm or beyond the mesorectal fascia, which forms the surgical resection margin in TME surgery.
Patients of Group 1 should be considered for local excision or surgery; those of group 2 or 3 are candidates for preoperative chemoradiation. This approach may reduce the rate of positive CRM. MRI is also a valuable tool for patient selection in clinical trials and should be used in clinical practice to assess the risk of CRM involvement and decide the optimal MDT approach.
surgery
pathology Two pathological assessments are critical in judging the standard quality of surgery: CRM involvement and the gross appearance of the surgically resected specimen.
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The main goals of rectal cancer surgery are locoregional control and a high cure rate. Locoregional tumor control in rectal cancer surgery has improved significantly over the last fifteen years after the introduction of TME. A national TME training program in several countries as Norway, Sweden and The Netherlands resulted in lower local relapse rates and significant improvement in overall survival [11–13]. TME involves removal of the mesorectum in the mesorectal plane by sharp dissection or careful diathermy. TME leads to the complete removal of the intact mesorectum including the lymphatics, lymph nodes, nerves, and vascular supply. Evidence of the superiority of TME over other methods of surgery is overwhelming and recognized not only by surgeons, but also by pathologists, oncologists, and radiotherapists. However, variations in surgery may have profound effects on quality of life and cause permanent stoma formation, faecal and urinary incontinence, impotence, and impaired sexual activity [14]. Although TME is an excellent approach for removing lymphatic, vascular, and neural ways of metastasis, it is not indicated for local resection of very low primary rectal tumours (less than 4 cm from the anal verge) for which an abdominoperineal excision still is required. Currently used approaches frequently lead to high rates of involvement in the CRM and local recurrence and the outcome of surgery has been shown to be worse for low rectal tumours [3]. Local radical excision of low rectal cancers may be compromised due to the natural ‘coning in’ of the mesorectum above the puborectal muscles. The standard abdominoperineal resection follows the mesorectal fascia onto the sphincters and with the predominantly abdominal approach, the most important area of resection, which around the tumor itself, is located at the floor of the pelvis where good visualization and access are limited. These difficulties lead to a high intraoperative perforation rate in patients with a low rectal cancer and a high level of CRM involvement [15].
The CRM is an extensive surgically created plane of dissection produced during the removal of the rectum from its surroundings. The largest area is posterior and a full 360 circumferential margin appears below the peritoneal reflection. The frequency of histological involvement of the CRM is strongly associated with local recurrence and poor survival [4–5, 16]. Tumors within 1 mm of the surgically created margin greatly increase the risk of recurrence. One study showed that the risk is lesser, but still high at 2 mm, but other investigators have not confirmed this finding. With standard surgery, 36% of all patients and 25% of those undergoing a curative operation showed CRM involvement [14]. In studies where TME has been taught and adopted, the CRM involvement rate has fallen: in a Norwegian study [5] with 686 patients, this rate fell to 9.4%, and in the Dutch study [4, 13], in which 656 patients were treated by TME this number was 18.3%. A number of audits have demonstrated the poor quality of routine pathology reports in daily practice. To try to improve this finding, educational programmes are important. National or International guidelines for the dissection and reporting of colorectal cancer, that contain the minimum required information for the management of patients are also critical. In 1998, the Royal College of Pathologists in the United Kingdom made available on the web dissection guidelines and a colorectal minimum data set that may help as an ‘aide me´moire’ to pathologists as well as recording the absence of features that otherwise might not be recorded [17]. This minimum data set may also be used as an audit tool and allow monitoring of standards of reporting. Major improvements in the frequency of recorded information, the number of examined lymph nodes, peritoneal involvement and extramural vascular invasion have all been found [18]. Another important role for the pathologist is the careful assessment of rectal specimens after preoperative chemoradiation. There is good evidence from retrospective and also randomized trials indicating that preoperative chemoradiation downstages rectal tumors, leading to a complete regression of around 10%. Pathological regression has been evaluated by several methods [19–21]. Some tumors may exhibit excellent response with no residual tumor cells or the presence of microscopically difficult to find tumor cells, while other may show poor response or no response at all. It is a common finding that patients with excellent or complete pathological responses have a better disease-free survival (DFS) then those lacking any pathological effect of chemoradiation. In the experience of the German Rectal Cancer Study Group complete regression of the primary tumor was associated with better control of disease in lymph nodes, and finally resulted in sustained local control and a minor risk to develop distant metastases with an estimated DFS of 86% at 5 years. Patients with tumors showing intermediate tumor regression also had an intermediate risk of lymph node involvement, and yielded an intermediate prognosis (DFS 75%). Poor tumor regression was associated with adverse pathological features, such as more advanced pT categories, higher incidence of nodal involvement, and predicted for an unfavorable outcome (DFS 63%). These findings are in accordance with observations in other malignancies such as esophageal, gastric, bladder, and head and
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neck cancer, treated with preoperative radiotherapy or chemotherapy. Overall, in these series, a higher grade of tumor regression predicted better survival [22]. Another important aim of chemoradiation for locally advanced rectal tumors is to achieve a clear margin in the resected specimen. Some studies suggest that this may be more important than achieving a pathological complete response. In a recently published British study, patients with a negative CRM had a 7% local relapse rate and 22% developed distant metastases. However, those patients with a CRM involved with tumor, relapse rate went up to 43% and distant metastases occurred in 57% [23].
radiation
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the integration of chemotherapy Despite important advances in local therapy for rectal cancer, metastases will appear in a significant number of patients, especially in those with locally advanced tumors, nodal involvement or positive CRM. Chemotherapy has been used aiming to eradicate micro-metastases and therefore reducing distant relapses. Chemotherapy has also been integrated in radiation schedules trying to enhance the effect of radiotherapy and resulting in better local control. In a pooled analysis of 5 randomized American trials conducted before the introduction of TME with more than 3700 patients, surgery alone and adjuvant postoperative radiation alone had inferior survival when compared with the addition of fluorouracil-based chemotherapy (P < 0.001) [35]. However, only those arms containing radiation presented better local control. After the results of the randomized trial performed by the German Rectal Cancer Study Group it is clear that preoperative fluorouracil-based chemoradiation administered in the conventional way over 5 weeks is more effective in local control than when the same treatment is given postoperatively [36]. Local relapse rate estimates at 5 years were 13% for the postoperatively treated patients and only 6% for the preoperative treated group (P = 0.006). The incidence of acute and long-term toxicity, mainly gastrointestinal, also favors the group with preoperative treatment. No differences in distant metastases or survival were observed. Therefore, preoperative chemoradiation with its better tolerability and improved local control may be considered as the new standard treatment of rectal cancer. However, some questions about the role of chemotherapy remain: is chemotherapy needed as a part of preoperative radiation and does it influence local control and overall survival? Is chemotherapy, as systemic treatment, able to reduce
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Radiation has been used for many years to palliate symptoms of patients with unresectable or with pelvic relapses of rectal cancer. Its combination with surgery was based on the ability to reduce local relapse rates. A systematic review of 131 scientific papers, including three meta-analysis and 42 randomized trials involving more than 25 000 patients underlines several important features [24]. Local relapses after rectal cancer surgery in centers that have adopted the TME technique went down from about 28% to 10%. There is strong evidence that preoperative radiotherapy significantly reduces local relapses and prolongs survival in patients with resectable rectal cancer. Also, preoperative radiation is superior to postoperative radiotherapy. However, the improvement in survival by preoperative radiation was seen mainly in a trial conducted by Swedish investigators, in which non-TME surgery was performed [25]. Radiotherapy was given in five daily fractions of 5 Gray (Gy) followed by immediate surgery. Although long-term survival and local control benefits have been confirmed in irradiated patients [26], a very high local relapse rate was observed in the control arm, even in initial stages, indicating overall poor quality of surgery. A trial with a similar design was carried out by Dutch investigators, integrating TME into surgery and including an extensive quality assurance program to assess surgery and radiotherapy [13]. This trial was not able to detect differences in survival among patients allocated to surgery alone or to preoperative radiation and no down-staging was observed in irradiated patients [27]. However, preoperative radiation was able to significantly reduce local relapse rate at five years from 12% in the surgery alone arm to 6% in the group of irradiated patients [28]. Another finding of this trial is that CRM involvement is a relevant negative prognostic indicator and supports the concept that preoperative treatment is better, because even if patients with CRM positive patients receive postoperative radiation, this compensates not for positive margins [29]. The impact of short-term preoperative radiotherapy on acute and late toxicity as well as on quality of life aspects and sexual functioning was also analysed in the Dutch trial [30–32]. Patients receiving preoperative radiation had more acute postoperative complications than patients allocated to surgery alone (48% versus 41%, P = 0.008). This difference may be attributable to problems related to perineal wound healing (29% versus 18%). Irradiated patients recovered more slowly from
defecation problems than TME-only patients and had a negative effect on sexual functioning in males and in females. However, these side effects were reported not to affect health-related quality of life seriously. The analysis of long-term effects in the Swedish trial, involving the same type of preoperative radiation, showed that gastrointestinal disorders resulting in hospitalizations seem to be the most common adverse effect. Bowel obstruction was the most important complication and was more frequently observed in irradiated than in nonirradiated patients [33]. Only one randomized trial has addressed the issue of comparing short-term radiation versus conventional chemoradiation [34]. In the conventional chemoradiation arm, radiotherapy was given in daily fraction of 1.8 Gy for 5–6 consecutive days to a total dose of 45–50.4 Gy. No differences in sphincter-saving surgery were detected between the two arms, but local control or survival data have not yet been reported. Short-term preoperative radiation trials were conducted when staging with MRI was not routinely used in localized rectal cancer. This makes that patients populations might be heterogeneous and consist of T2 and limited extension T3 tumors as well as locally advanced cancers. For patients with locally advanced tumors this strategy cannot be recommended due to the absence of down-staging.
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For locally advanced rectal cancer, current evidence suggests that preoperative chemoradiation provides optimal locoregional control. However, distant failure remains common. The role of adjuvant chemotherapy either before or following chemoradiation in improving disease-free or overall survival has yet to be established, despite evidence that response to induction chemotherapy may predict response to subsequent radiotherapy. Preoperative chemoradiation again resulted in lower local recurrence without any survival benefit. Interestingly, in three recent randomized studies [36, 38–39], no impact was seen on distant metastasis with preoperative chemoradiation. Two possible explanations for this observation were that the chemotherapeutic agents used in these studies (5-fluorouracil and folinic acid) were administered at doses adequate only for radiosensitizing but not adequate to have a systemic effect and that those drugs were suboptimal chemotherapeutic agents. A novel and investigational strategy suggests that starting treatment with neoadjuvant chemotherapy, followed by chemoradiation before surgery and postoperative chemotherapy may be beneficial. A recently published pilot trial by investigators at the Royal Marsden [46] showed that is was possible to administer four courses of capecitabine and oxaliplatin before radiotherapy. Radiation was given concomitant with capecitabine and after surgery twelve more weeks of adjuvant capecitabine were given. Neoadjuvant treatment was extremely active in this serie with an objective response rate of 88% assessed by MRI. A rapid symptomatic improvement was also seen in a similar proportion of treated patients and most of them went to surgery, where a clear CRM was seen in all except one patient. Another striking feature was that pathological complete remissions were observed after chemoradiation in 23% of patients with an additional 48% of patients having only microscopic tumor foci in the resection specimen. This approach, although promising, should yet be considered as experimental and its application should be restricted to clinical trials [47].
conclusion There is now evidence that the treatment of rectal cancer requires a multidisciplinary approach with a focus on achievement of clear circumferential, mesorectal and levator, surgical margins. The use of MRI to predict potentially involved margins preoperatively enables treatment teams to shrink or destroy the tumor with neoadjuvant multimodality therapy before an attempt at curative surgery is made. The selection of patients with high-risk features for preoperative chemoradiation is a critical point. Optimal surgical techniques after preoperative treatment will enable clearance of CRM and histopathology will assess the effect of neoadjuvant therapy, confirm complete surgical removal and provide quality control for both the radiologist and surgeon. Thus, the team work of the surgeon, radiologist, pathologist, radiotherapist and medical oncologist can reduce recurrence rates and improve survival in patients with rectal cancer.
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the risk of distant metastases? Is the early initiation of chemotherapy beneficial in patients with locally advanced rectal cancer? Two large randomized trials of the EORTC [37–38] and the French FFCD [39] group addressed the issue of the addition of chemotherapy to conventional radiation (25 fractions over 5 weeks). In two arms of the 2 · 2 factorial EORTC trial and in both arms of the FFCD study, systemic 5-fluorouracil with folinic acid was given as adjuvant treatment. The addition of chemotherapy resulted in significant higher rates of complete tumor eradication in pathological analysis of the surgical specimen (11–16% for chemoradiation versus 3–5% for radiation alone). Systemic chemotherapy not only induced down-staging and downsizing of treated tumors, but also reduced the rate of tumor vascular and lymphatic invasion. Local failure rate for radiation alone arms was 17.1% and 16.5%, but went down to 7.6% and 8.6% in patients treated in the combined modality arms. However, although the addition of chemotherapy was able to increase local control, no effect was observed in distant metastases or overall survival. These observations underline the importance of improving systemic therapy to get better results in the treatment for localized rectal cancer. With an optimal local control obtained by current standards and local relapse rates of 6–8%, distant metastases will still occur in 30–40% of patients. Chemotherapy for colon cancer is changing and modulated 5-fluorouracil is not any more the standard approach. Combinations of drugs, such as oxaliplatin or irinotecan with 5-fluorouracil, or oral fluoropyrimidines, sometimes with the addition of bevacizumab or cetuximab, are sequentially used in the palliative treatment of patients with advanced disease. In the adjuvant setting for colon cancer, capecitabine and oxaliplatin have been shown to be equivalent or superior in disease-free survival compared to classical schedules of 5-fluorouracil [40–41]. The combination of oxaliplatin and capecitabine has shown significant anti-tumor activity in a similar range of combinations of oxaliplatin and leucovorin-modulated 5-fluorouracil [42]. In addition, twice-daily dosing of oral capecitabine obviates the drawbacks of prolonged infusions of 5-fluorouracil and makes therapy more convenient for patients. For those reasons, the integration of capecitabine and oxaliplatin in concomitant administration with radiation has been extensively evaluated in patients with locally advanced rectal cancer [43–45]. Single-agent phase I studies identified a recommended dose of capecitabine of 825 mg/m2, administered twice daily without interruption, plus standard radiotherapy for neo-adjuvant treatment of rectal cancer. Phase I studies in combination with oxaliplatin have also shown that full doses of this agent can be administered concomitant with pelvic radiation. Phase II evaluation of the recommended regimen has confirmed the high activity and favorable safety profile. Chemoradiation incorporating capecitabine in place of infusional 5-fluorouracil is more convenient, with potential to enhance quality of life and reduce medical resource use. Based on this rationale, the National Surgical Adjuvant Breast and Bowel Project (NSABP) is evaluating neo-adjuvant, capecitabine-based chemoradiation in a randomized, phase III trial (NSABP R-04).
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acknowledgements There was no grant or other financial support for this article.
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Volume 17 | Supplement 10 | September 2006
A multimodality approach to localized rectal cancer A. Cervantes1, I. Chirivella1, E. Rodriguez-Braun1, S. Campos2, S. Navarro3 & E. Garcı´a Granero4 1
Depertment Hematology and Medical Oncology, 2Department Radiology, 3Department Pathology, 4Colorectal Unit, Department Surgery, Hospital Clı´nico Universitario, University of Valencia, Spain
introduction
staging The prognosis of rectal cancer is related to the anatomic disease extension determined on pathologic examination of the resection specimen. ª 2006 European Society for Medical Oncology
•
•
Group 1: rectal tumors with good prognostic features and potentially negative CRM, including patients with T1 and T2 or T3 tumors with an extramural spread of less than 5 mm and less than 4 involved lymph nodes and no extramural vascular invasion. Group 2: rectal tumors with potentially negative CRM but with some poor prognostic factors such as peritoneal involvement (T4), or T3 tumors with an extramural invasion of 5 mm or more, extramural vascular invasion or 4 or more involved lymph nodes.
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The first years of the 21st century are witnessing many and important changes in the treatment of rectal cancer. The disease has moved from a surgically managed condition with contributions of other disciplines to management by a highly skilled multidisciplinary team (MDT). The management of all patients with colorectal cancer should be by such a MDT and it is recommended that any patient with a diagnosis of rectal cancer is referred to such a team. The participation of all members of the MDT in the discussion on all details of staging and other characteristics before any therapeutic intervention is essential. All MDTs who are treating patients with rectal cancer would benefit from a coordinated training program. The MDT should consist of a core team of members with a particular interest and expertise in rectal cancer with the commitment to continuous medical education, and associates. The core MDT is composed of specialist surgeons, medical and radiation oncologists, radiologists, pathologists, gastro-enterologists and stoma therapist nurses. The MDT should implement a treatment strategy based on national guidelines with the aim of standardization and improvement of outcome [1]. Although there is so far no proof to support the key role of the MDT in improvement of treatment outcome, it is difficult to understand how the quality of care could be improved otherwise since so many different specialists are involved in cancer care. Team discussions should be efficient, allowing all patients to be presented before any therapeutic intervention and should have an educational value stimulating interactions among team members and reinforcing clinical judgment in junior members. Treatment of rectal cancer may range from simple local excision to radical surgery after chemoradiation taking into account functional results and the risk of recurrence. The outcome will be the best when patients’ preferences are understood and expertise of multiple specialists is routinely provided [2]. This article deals with several issues that should be considered in a MDT approach in patients with rectal cancer: staging, quality of surgery and pathology assessment, and the integration of radiation and chemotherapy.
The TNM staging system is universally recommended and describes the anatomical extention of rectal tumors that have not been previously treated. Its prognostic value is based on data derived from the outcome of patients after complete surgical resection. However, information derived from conventional surgical TNM staging should be complemented with two other parameters: the macroscopic quality of the mesorectum in the surgical specimen and the involvement of the circumferential margin (CRM) [3–5]. Both parameters may reflect the adequacy of the surgical technique and the aggressiveness of the tumor, and are excellent predictors of outcome. Complete surgical resection with curative intent may be improved not only by adequate surgical training, but also with better staging. When rectal cancer is diagnosed, the surgical approach may vary from transanal local excision, primary total mesorectal excision (TME) or primary chemoradiation followed by TME. To select the most appropriate, treatment locoregional staging is becoming more important. Endorectal ultrasonography (EUS) and magnetic resonance imaging (MRI) are the most useful techniques for preoperative evaluation [6–9]. EUS is very accurate for assessing invasion of tumors within the bowel wall but less accurate for staging tumors beyond the bowel wall. EUS it is not able to visualize the mesorectal fascia, an important structure to assess involvement of the CRM. EUS is of little value in stenotic tumors causing bowel obstruction or when the proctoscope it is not able to pass the tumor. High resolution MRI predicts with high accuracy the CRM involvement and T2-weighted sequences are recommended. With the development of MRI, it is now possible to accurately predict tumor stage and other prognostic features such as nodal disease, depth of extramural spread and the presence of extramural vascular invasion. According to some expert centres using a MDT approach, MRI may classify rectal cancer patients into three subcategories [10]:
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Group 3: rectal tumors with potential involvement of CRM, with full thickness T2 or more at the level of puborectal muscles or tumor extending within 1 mm or beyond the mesorectal fascia, which forms the surgical resection margin in TME surgery.
Patients of Group 1 should be considered for local excision or surgery; those of group 2 or 3 are candidates for preoperative chemoradiation. This approach may reduce the rate of positive CRM. MRI is also a valuable tool for patient selection in clinical trials and should be used in clinical practice to assess the risk of CRM involvement and decide the optimal MDT approach.
surgery
pathology Two pathological assessments are critical in judging the standard quality of surgery: CRM involvement and the gross appearance of the surgically resected specimen.
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The main goals of rectal cancer surgery are locoregional control and a high cure rate. Locoregional tumor control in rectal cancer surgery has improved significantly over the last fifteen years after the introduction of TME. A national TME training program in several countries as Norway, Sweden and The Netherlands resulted in lower local relapse rates and significant improvement in overall survival [11–13]. TME involves removal of the mesorectum in the mesorectal plane by sharp dissection or careful diathermy. TME leads to the complete removal of the intact mesorectum including the lymphatics, lymph nodes, nerves, and vascular supply. Evidence of the superiority of TME over other methods of surgery is overwhelming and recognized not only by surgeons, but also by pathologists, oncologists, and radiotherapists. However, variations in surgery may have profound effects on quality of life and cause permanent stoma formation, faecal and urinary incontinence, impotence, and impaired sexual activity [14]. Although TME is an excellent approach for removing lymphatic, vascular, and neural ways of metastasis, it is not indicated for local resection of very low primary rectal tumours (less than 4 cm from the anal verge) for which an abdominoperineal excision still is required. Currently used approaches frequently lead to high rates of involvement in the CRM and local recurrence and the outcome of surgery has been shown to be worse for low rectal tumours [3]. Local radical excision of low rectal cancers may be compromised due to the natural ‘coning in’ of the mesorectum above the puborectal muscles. The standard abdominoperineal resection follows the mesorectal fascia onto the sphincters and with the predominantly abdominal approach, the most important area of resection, which around the tumor itself, is located at the floor of the pelvis where good visualization and access are limited. These difficulties lead to a high intraoperative perforation rate in patients with a low rectal cancer and a high level of CRM involvement [15].
The CRM is an extensive surgically created plane of dissection produced during the removal of the rectum from its surroundings. The largest area is posterior and a full 360 circumferential margin appears below the peritoneal reflection. The frequency of histological involvement of the CRM is strongly associated with local recurrence and poor survival [4–5, 16]. Tumors within 1 mm of the surgically created margin greatly increase the risk of recurrence. One study showed that the risk is lesser, but still high at 2 mm, but other investigators have not confirmed this finding. With standard surgery, 36% of all patients and 25% of those undergoing a curative operation showed CRM involvement [14]. In studies where TME has been taught and adopted, the CRM involvement rate has fallen: in a Norwegian study [5] with 686 patients, this rate fell to 9.4%, and in the Dutch study [4, 13], in which 656 patients were treated by TME this number was 18.3%. A number of audits have demonstrated the poor quality of routine pathology reports in daily practice. To try to improve this finding, educational programmes are important. National or International guidelines for the dissection and reporting of colorectal cancer, that contain the minimum required information for the management of patients are also critical. In 1998, the Royal College of Pathologists in the United Kingdom made available on the web dissection guidelines and a colorectal minimum data set that may help as an ‘aide me´moire’ to pathologists as well as recording the absence of features that otherwise might not be recorded [17]. This minimum data set may also be used as an audit tool and allow monitoring of standards of reporting. Major improvements in the frequency of recorded information, the number of examined lymph nodes, peritoneal involvement and extramural vascular invasion have all been found [18]. Another important role for the pathologist is the careful assessment of rectal specimens after preoperative chemoradiation. There is good evidence from retrospective and also randomized trials indicating that preoperative chemoradiation downstages rectal tumors, leading to a complete regression of around 10%. Pathological regression has been evaluated by several methods [19–21]. Some tumors may exhibit excellent response with no residual tumor cells or the presence of microscopically difficult to find tumor cells, while other may show poor response or no response at all. It is a common finding that patients with excellent or complete pathological responses have a better disease-free survival (DFS) then those lacking any pathological effect of chemoradiation. In the experience of the German Rectal Cancer Study Group complete regression of the primary tumor was associated with better control of disease in lymph nodes, and finally resulted in sustained local control and a minor risk to develop distant metastases with an estimated DFS of 86% at 5 years. Patients with tumors showing intermediate tumor regression also had an intermediate risk of lymph node involvement, and yielded an intermediate prognosis (DFS 75%). Poor tumor regression was associated with adverse pathological features, such as more advanced pT categories, higher incidence of nodal involvement, and predicted for an unfavorable outcome (DFS 63%). These findings are in accordance with observations in other malignancies such as esophageal, gastric, bladder, and head and
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neck cancer, treated with preoperative radiotherapy or chemotherapy. Overall, in these series, a higher grade of tumor regression predicted better survival [22]. Another important aim of chemoradiation for locally advanced rectal tumors is to achieve a clear margin in the resected specimen. Some studies suggest that this may be more important than achieving a pathological complete response. In a recently published British study, patients with a negative CRM had a 7% local relapse rate and 22% developed distant metastases. However, those patients with a CRM involved with tumor, relapse rate went up to 43% and distant metastases occurred in 57% [23].
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the integration of chemotherapy Despite important advances in local therapy for rectal cancer, metastases will appear in a significant number of patients, especially in those with locally advanced tumors, nodal involvement or positive CRM. Chemotherapy has been used aiming to eradicate micro-metastases and therefore reducing distant relapses. Chemotherapy has also been integrated in radiation schedules trying to enhance the effect of radiotherapy and resulting in better local control. In a pooled analysis of 5 randomized American trials conducted before the introduction of TME with more than 3700 patients, surgery alone and adjuvant postoperative radiation alone had inferior survival when compared with the addition of fluorouracil-based chemotherapy (P < 0.001) [35]. However, only those arms containing radiation presented better local control. After the results of the randomized trial performed by the German Rectal Cancer Study Group it is clear that preoperative fluorouracil-based chemoradiation administered in the conventional way over 5 weeks is more effective in local control than when the same treatment is given postoperatively [36]. Local relapse rate estimates at 5 years were 13% for the postoperatively treated patients and only 6% for the preoperative treated group (P = 0.006). The incidence of acute and long-term toxicity, mainly gastrointestinal, also favors the group with preoperative treatment. No differences in distant metastases or survival were observed. Therefore, preoperative chemoradiation with its better tolerability and improved local control may be considered as the new standard treatment of rectal cancer. However, some questions about the role of chemotherapy remain: is chemotherapy needed as a part of preoperative radiation and does it influence local control and overall survival? Is chemotherapy, as systemic treatment, able to reduce
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Radiation has been used for many years to palliate symptoms of patients with unresectable or with pelvic relapses of rectal cancer. Its combination with surgery was based on the ability to reduce local relapse rates. A systematic review of 131 scientific papers, including three meta-analysis and 42 randomized trials involving more than 25 000 patients underlines several important features [24]. Local relapses after rectal cancer surgery in centers that have adopted the TME technique went down from about 28% to 10%. There is strong evidence that preoperative radiotherapy significantly reduces local relapses and prolongs survival in patients with resectable rectal cancer. Also, preoperative radiation is superior to postoperative radiotherapy. However, the improvement in survival by preoperative radiation was seen mainly in a trial conducted by Swedish investigators, in which non-TME surgery was performed [25]. Radiotherapy was given in five daily fractions of 5 Gray (Gy) followed by immediate surgery. Although long-term survival and local control benefits have been confirmed in irradiated patients [26], a very high local relapse rate was observed in the control arm, even in initial stages, indicating overall poor quality of surgery. A trial with a similar design was carried out by Dutch investigators, integrating TME into surgery and including an extensive quality assurance program to assess surgery and radiotherapy [13]. This trial was not able to detect differences in survival among patients allocated to surgery alone or to preoperative radiation and no down-staging was observed in irradiated patients [27]. However, preoperative radiation was able to significantly reduce local relapse rate at five years from 12% in the surgery alone arm to 6% in the group of irradiated patients [28]. Another finding of this trial is that CRM involvement is a relevant negative prognostic indicator and supports the concept that preoperative treatment is better, because even if patients with CRM positive patients receive postoperative radiation, this compensates not for positive margins [29]. The impact of short-term preoperative radiotherapy on acute and late toxicity as well as on quality of life aspects and sexual functioning was also analysed in the Dutch trial [30–32]. Patients receiving preoperative radiation had more acute postoperative complications than patients allocated to surgery alone (48% versus 41%, P = 0.008). This difference may be attributable to problems related to perineal wound healing (29% versus 18%). Irradiated patients recovered more slowly from
defecation problems than TME-only patients and had a negative effect on sexual functioning in males and in females. However, these side effects were reported not to affect health-related quality of life seriously. The analysis of long-term effects in the Swedish trial, involving the same type of preoperative radiation, showed that gastrointestinal disorders resulting in hospitalizations seem to be the most common adverse effect. Bowel obstruction was the most important complication and was more frequently observed in irradiated than in nonirradiated patients [33]. Only one randomized trial has addressed the issue of comparing short-term radiation versus conventional chemoradiation [34]. In the conventional chemoradiation arm, radiotherapy was given in daily fraction of 1.8 Gy for 5–6 consecutive days to a total dose of 45–50.4 Gy. No differences in sphincter-saving surgery were detected between the two arms, but local control or survival data have not yet been reported. Short-term preoperative radiation trials were conducted when staging with MRI was not routinely used in localized rectal cancer. This makes that patients populations might be heterogeneous and consist of T2 and limited extension T3 tumors as well as locally advanced cancers. For patients with locally advanced tumors this strategy cannot be recommended due to the absence of down-staging.
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For locally advanced rectal cancer, current evidence suggests that preoperative chemoradiation provides optimal locoregional control. However, distant failure remains common. The role of adjuvant chemotherapy either before or following chemoradiation in improving disease-free or overall survival has yet to be established, despite evidence that response to induction chemotherapy may predict response to subsequent radiotherapy. Preoperative chemoradiation again resulted in lower local recurrence without any survival benefit. Interestingly, in three recent randomized studies [36, 38–39], no impact was seen on distant metastasis with preoperative chemoradiation. Two possible explanations for this observation were that the chemotherapeutic agents used in these studies (5-fluorouracil and folinic acid) were administered at doses adequate only for radiosensitizing but not adequate to have a systemic effect and that those drugs were suboptimal chemotherapeutic agents. A novel and investigational strategy suggests that starting treatment with neoadjuvant chemotherapy, followed by chemoradiation before surgery and postoperative chemotherapy may be beneficial. A recently published pilot trial by investigators at the Royal Marsden [46] showed that is was possible to administer four courses of capecitabine and oxaliplatin before radiotherapy. Radiation was given concomitant with capecitabine and after surgery twelve more weeks of adjuvant capecitabine were given. Neoadjuvant treatment was extremely active in this serie with an objective response rate of 88% assessed by MRI. A rapid symptomatic improvement was also seen in a similar proportion of treated patients and most of them went to surgery, where a clear CRM was seen in all except one patient. Another striking feature was that pathological complete remissions were observed after chemoradiation in 23% of patients with an additional 48% of patients having only microscopic tumor foci in the resection specimen. This approach, although promising, should yet be considered as experimental and its application should be restricted to clinical trials [47].
conclusion There is now evidence that the treatment of rectal cancer requires a multidisciplinary approach with a focus on achievement of clear circumferential, mesorectal and levator, surgical margins. The use of MRI to predict potentially involved margins preoperatively enables treatment teams to shrink or destroy the tumor with neoadjuvant multimodality therapy before an attempt at curative surgery is made. The selection of patients with high-risk features for preoperative chemoradiation is a critical point. Optimal surgical techniques after preoperative treatment will enable clearance of CRM and histopathology will assess the effect of neoadjuvant therapy, confirm complete surgical removal and provide quality control for both the radiologist and surgeon. Thus, the team work of the surgeon, radiologist, pathologist, radiotherapist and medical oncologist can reduce recurrence rates and improve survival in patients with rectal cancer.
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the risk of distant metastases? Is the early initiation of chemotherapy beneficial in patients with locally advanced rectal cancer? Two large randomized trials of the EORTC [37–38] and the French FFCD [39] group addressed the issue of the addition of chemotherapy to conventional radiation (25 fractions over 5 weeks). In two arms of the 2 · 2 factorial EORTC trial and in both arms of the FFCD study, systemic 5-fluorouracil with folinic acid was given as adjuvant treatment. The addition of chemotherapy resulted in significant higher rates of complete tumor eradication in pathological analysis of the surgical specimen (11–16% for chemoradiation versus 3–5% for radiation alone). Systemic chemotherapy not only induced down-staging and downsizing of treated tumors, but also reduced the rate of tumor vascular and lymphatic invasion. Local failure rate for radiation alone arms was 17.1% and 16.5%, but went down to 7.6% and 8.6% in patients treated in the combined modality arms. However, although the addition of chemotherapy was able to increase local control, no effect was observed in distant metastases or overall survival. These observations underline the importance of improving systemic therapy to get better results in the treatment for localized rectal cancer. With an optimal local control obtained by current standards and local relapse rates of 6–8%, distant metastases will still occur in 30–40% of patients. Chemotherapy for colon cancer is changing and modulated 5-fluorouracil is not any more the standard approach. Combinations of drugs, such as oxaliplatin or irinotecan with 5-fluorouracil, or oral fluoropyrimidines, sometimes with the addition of bevacizumab or cetuximab, are sequentially used in the palliative treatment of patients with advanced disease. In the adjuvant setting for colon cancer, capecitabine and oxaliplatin have been shown to be equivalent or superior in disease-free survival compared to classical schedules of 5-fluorouracil [40–41]. The combination of oxaliplatin and capecitabine has shown significant anti-tumor activity in a similar range of combinations of oxaliplatin and leucovorin-modulated 5-fluorouracil [42]. In addition, twice-daily dosing of oral capecitabine obviates the drawbacks of prolonged infusions of 5-fluorouracil and makes therapy more convenient for patients. For those reasons, the integration of capecitabine and oxaliplatin in concomitant administration with radiation has been extensively evaluated in patients with locally advanced rectal cancer [43–45]. Single-agent phase I studies identified a recommended dose of capecitabine of 825 mg/m2, administered twice daily without interruption, plus standard radiotherapy for neo-adjuvant treatment of rectal cancer. Phase I studies in combination with oxaliplatin have also shown that full doses of this agent can be administered concomitant with pelvic radiation. Phase II evaluation of the recommended regimen has confirmed the high activity and favorable safety profile. Chemoradiation incorporating capecitabine in place of infusional 5-fluorouracil is more convenient, with potential to enhance quality of life and reduce medical resource use. Based on this rationale, the National Surgical Adjuvant Breast and Bowel Project (NSABP) is evaluating neo-adjuvant, capecitabine-based chemoradiation in a randomized, phase III trial (NSABP R-04).
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acknowledgements There was no grant or other financial support for this article.
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