Results after change of treatment policy for rectal cancer – report from a single hospital in China

Results Three hundred and seventy-seven patients with rectal cancer were enrolled in our study, with 175 patients in the TME group and 202 as controls. Mortality and morbidity rates were 1% and 14% in TME patients and 1% and 31% in controls, respectively. The TME group had a shorter operation time and hospital stay, and less bleeding, wound and urinary complications. The local recurrence (LR) rate was 6% and 12% in the TME and the control groups, respectively ( P < 0.05). With a median follow-up of 35 months, the actuarial 5-year survival rate was 66%. Consistent with the univariate analysis result, multivariate analysis demonstrated that TNM stage, tumor grade, age, and surgeons were independent prognostic factors. TME was not an independent prognostic factor for patients' survival. Conclusions TME is a safe and efficient option in reducing LR. However, it is not an independent predictor for patients' survival. In addition to the standardized usage of TME, further knowledge on the molecular mechanism of cancer is needed. Keywords Rectal cancer Treatment Total mesorectal excision Abbreviations TME total mesorectal excision LR local recurrence APR abdominoperineal resection LAR low anterior resection BMI body mass index TNM tumor-node-metastasis staging system ß coefficient S.E standard error Wald Wald statistic df degrees of freedom Sig level of significance Exp(ß) relative risk Introduction The introduction of total mesorectal excision (TME) into clinical practice for colorectal cancer surgery in recent years is of significant importance. 1,2 With meticulous dissection of the avascular plane between the mesorectum and parietal fascia, the envelope of the mesorectum (which encompasses tumor cells) is kept intact, thereby preventing the dissemination of cancerous cells. Data from clinically controlled trials have demonstrated that TME has reduced the recurrence rate of rectal cancer from 30% down to less than 10%. 3–5 This has pointed the current post-operative management with radiotherapy and chemotherapy in the direction of surgical treatment with TME – either without radiotherapy or chemotherapy, or with toned-down radiotherapy and chemotherapy. 6,7 Although surgical treatment with TME has reduced local recurrence (LR) rate and cancer-specific deaths significantly, the role of TME as a prognostic factor remains controversial. 8,9 In China, colorectal cancer is among the first five in incidence among all cancers according to recent epidemiological data. 10,11 In one report, the overall survival and LR rates of rectal cancer patients after curative resection were approximately 50% and 30%, respectively. 12 Even though TME for rectal cancer was introduced into clinical practice in China in the 1990s, very few results of China-based studies have been published in the English language literature. 13 The procedure is routinely used in clinical practice in many Chinese institutions, including School of Oncology, Peking University. 14 Rectal cancer tends to present at more advanced stages, and 75% of the time it is found in the middle or lower part of the rectum. In this report of a retrospective study, we summarize the clinical outcome of rectal cancer patients treated with or without TME in our institution and suggest its routine use in all clinical practices. Materials and methods Patients and methods Histopathological diagnosis and surgical procedures associated with TME were standardized at our institution under the vigilant supervision of Dr. RJ Heald (North Hampshire Hospital, Basingstoke, UK) and Dr. P Quirke (University of Leeds, Leeds, UK). Rectal cancer patients who received TME performed by three senior colorectal surgeons from January 2000 to August 2004 were enrolled in this study. Autonomic nerve function was also carefully preserved. Patients who received surgical resection for rectal cancer between January 1996 and December 1999 with adequate data for this study were chosen as controls. All surgeries in the control group were performed by highly experienced surgeons. The surgical procedures included modified Bacon, Swenson, or trans-sacral (Kraske) rectal cancer resection. Data on patients' characteristics, tumor location, TNM (tumor-node-metastasis) staging, surgical procedure, histological grading, postoperative complications, and follow-up were tabulated. The indications for TME were as follows: tumors not more advanced than TNM stage III; histopathologically proven adenocarcinomas of the rectum; complete clinical records and histopathological data; intent to curative resection; distance from the anal verge (3–10 cm); and no contraindications for surgery. TME – surgical techniques All patients except those with obstructive lesions underwent preoperative bowel preparation. Informed consent for the surgery was obtained after thorough discussion with the patients and/or their relatives. The stomal site was marked prior to surgery. The Lloyd Davis position was adopted. Precise dissection of the “holy plane” was made between the mesorectum and parietal fascia down to the pelvic floor. The autonomic nerves, including the inferior hypogastric nerve plexuses and the sacral plexuses posterior to the Denonvilliers' fascia, were carefully preserved. The mesorectum of at least 5 cm around the tumor and a 2-cm tumor-free margin of the large bowel were excised. If there were signs of tumor invasion into adjacent organs such as ovaries or uterus in females and seminal vesicles in males, an en bloc resection was performed. The double-stapling method was used for colorectal or coloanal anastomosis, after a thorough irrigation of the pelvic cavity. For patients with inferior margins of the tumors positioned 4 cm or less proximal to the anal verge, abdominoperineal resection (APR) was performed. Prophylactic ileostomy or colostomy was not performed routinely, except when the surgeons were dissatisfied with the anastomosis. Pre/postoperative management and follow-up Pelvic drainage was performed on all patients after surgery until they voided formed feces following a regular diet. Six courses of postoperative chemotherapy were performed for those in the TNM stages II, III and stage I with high risk. The regimens included 5-fluoracil, such as leucovorin plus 5-fluoracil (Mayo clinic regimen 15 ) with or without oxaliplatin (FOLFOX regimens 16 ). Some patients received a short course of preoperative chemoradiation (30 Gy/10 fractions/14 days) or intra-arterial chemotherapy. The operations were carried out 10–14 days following the neoadjuvant treatment. The patients were followed up every 3 months in the first 2 years, every 6 months in the next 3 years, and then once a year until the tumor recurred or metastasized, or until the patient's death. The routine follow-up protocol included digital rectal examination, chest X-ray, abdominal and/or pelvic ultrasonography and serum carcinoembryonic antigen levels in all patients every three months. CT or magnetic resonance imaging was performed when indicated. LR was defined as a tumor recurrence in the field of surgery with radiological or pathological evidence. Metastasis was defined as the reappearance of tumor in distant sites or organs from the field of surgery with radiological or pathological confirmation. The endpoint of follow-up included death caused by cancer or other causes, missing, or the date of last follow-up. Statistical analysis The differences between the TME and control groups were calculated with χ 2 or Fisher's exact test for categorical variables. For continuous variables, the Mann–Whitney U -test was used. Univariate analysis for patients' survival was performed using the Kaplan–Meier method. Multivariate analysis of survival and LR was performed with the Cox proportional hazard model and logistic regression, respectively. Statistical significance was considered when the P value was <0.05. Results General characteristics of the patients Three hundred and seventy-seven patients with rectal cancer were enrolled in our study – 175 patients in the TME group and 202 in the control group. The general characteristics of these patients are outlined in Table 1 ; there were no statistically significant differences between the two groups except tumor grade and neoadjuvant therapy. Short-term outcome of TME for rectal cancer patients The mortality rates (death within 30 days after the surgery) in the TME and control groups were 1% (2/175) and 1% (2/202), respectively; the morbidity rates were 14% (25/175) and 31% (63/202), respectively. The intra-operative and postoperative complications included excessive hemorrhage, spleen injury, anastomotic leakage, embolism in large vessels, intestinal obstruction, incision complications including infection or dehiscence, and urinary retention or infection. Compared with the controls, the TME group had a shorter operation time and hospital stay, less bleeding, and also had lesser incision complications. The drainage time following the operation was also shorter. Patients in the TME group tended to suffer from less urinary complications – either urinary tract infection or urinary retention, although this was of no statistical significance. However, the TME group had a higher rate of secondary diversion (6%), either for anastomotic leakage or other causes. Other complications such as intestinal obstruction and large vessel embolism were relatively rare and demonstrated no statistically significant difference between the two groups. We also found that some of the surgical procedures, such as modified Bacon, Swenson, or trans-sacral (Kraske) rectal cancer resection, had seldom been performed in the later stage. In the TME group, LAR was performed more frequently than APR (LAR vs APR = 2.5 vs 1.8). With TME, more lymph nodes could be found (14 vs 9), in spite of similar positive lymph node numbers between the two groups ( Table 1 ). Long-term outcome of TME for rectal cancer patients Among the 377 rectal cancer patients, 36 cases developed LR. The recurrence rates were 6% and 12% in the TME and control groups, respectively ( P < 0.05). The results of the univariate analysis of risk factors are shown in Table 2 . We included factors such as age, gender, body mass index, distance of the cancerous lesion from the anal verge, neoadjuvant therapy, surgeon, gross type of the tumor, tumor grade, TNM stage, lymphovascular invasion and TME into logistic regression analysis to demonstrate the risk factors for LR and metastasis. Statistical significant or marginal significant factors were introduced into the Cox proportional hazard model for multivariate analysis. The results showed that TME (HR: 0.23, 95%CI: 0.06–0.83) and gender (HR: 3.66, 95%CI: 1.29–10.41) were independent predictors of tumor recurrence. The common sites of metastasis were liver, abdominal-pelvic cavity, lung, bone, supraclavicular lymph nodes, and brain (data not shown). Until the endpoint of follow-up, 22 patients in the TME group developed metastasis compared with 78 in the control group. Survival analysis The median survival was 35 months with a follow-up period of 1–103 months. The data for 12 patients were missing (3%). The actuarial 5-year survival rate was 65%. Both univariate and multivariate analyses demonstrated that TNM stage, tumor grade, and age were independent prognostic factors. The survival curves of both groups with or without TME are shown in Fig. 1 . Discussion TME and recurrence Tumor recurrence and metastasis are generally the preface of cancer-related deaths. 17 For rectal cancer, especially those in the middle and distal rectum, LR rates are generally high, varying from 5% to 32%. 3,4 Adjuvant chemotherapy has not played an important role in reducing the recurrence rate until now. 18,19 However, since the introduction of TME in 1982, 20 the rate of recurrence has sharply decreased to less than 10% and it has now been widely accepted as a standard procedure for rectal cancer surgery. 21 Meticulous dissection along the natural plane between the mesorectum and pelvic visceral fascia is required in order to keep the mesorectum intact, thereby preventing the spillage of tumor cells into the wound. This is considered to be the key advantage of TME, since any breach of the mesorectum might be propitious, leading to local recurrence. Therefore, the standardization of TME should not be neglected. 22,23 An imprecise surgical maneuver might tear the mesorectum exposing the muscularis propria, where the tumors generally reside. In a recent paper, Quirke had reaffirmed that it is crucial that the integrity between these two compartments should not be breached. We carefully chose patients treated by three colorectal surgeons and have presented the data in comparison with conventional surgery. In our series, the LR rate was approximately 6%. This relatively good result was largely due to good quality control. Most of the specimens were classified as grade 3 by gross appearances upon evaluation right after the surgery. The chances of LR dropping from 15% to 9% during a grade 3 operation (by gross appearance) are lower than those of grade 1 or 2 operations. 24–26 This again proved the importance of quality control of the surgery, and strongly supported the routine use of audit following TME. It has been demonstrated that preoperative chemoradiation is useful to reduce LR and to improve patient survival. 6,7 In our series, there was no difference between the TME group and the control in view of the preoperative treatment, perhaps because radiotherapy and/or chemotherapy, intra-arterial chemotherapy have been performed either alone or in combination in this group of patients. Inconsistent with reports from other centers larger sample size and/or longer period of follow-up may be necessary to draw definite conclusion. TME and patients' survival No consensus on whether TME improves patients' survival or not can be derived from the published data. 5,27–32 A well-organized, controlled trial by the Dutch Colorectal Group demonstrated that the LR rate at 2 years was roughly half of the previously published record, and 2-year overall survival was improved. 32 Unfortunately, no long-term survival data was available. In this study, our TME patients had a better outcome than the control group patients, but there was a crossing of two survival curves at about 40 months following surgery ( P = 0.08). These results are consistent with reports from Italy 33 and Germany. 34 TME is safe and effective in reducing the LR of rectal cancer, but why it does not influence survival should be investigated further. Patients with mere LR could have a good outcome with or without treatment. Overall survival of rectal cancer patients with pelvic recurrences who received surgical resection was 31% at 5 years with a median survival time of 32 months. 35 On the contrary, only 9% of patients with distant metastasis may survive 5 years. 35 The ultimate cause of death of these patients was distant metastasis, i.e. it is generally not the LR but the metastasis that leads to cancer death. As mentioned by Heald, 20 in TME, the emphasis is on the “en bloc” removal of the tumor with a clear margin. However, the confirmation of a complete negative margin could be done based on the gross appearance and pathological evidence. Current methods may have a sampling error. Tepper et al. reported that the outcome of cancer patients was directly correlated with the number of lymph nodes examined and it suggested a tendency to miss occult tumor cells if not enough lymph nodes are examined. 9 Micrometastasis that eventually causes metastasis or local recurrence can be missed when tumor margins are detected during surgery or even by histopathological means. 36 It is reported that most neoplasmas, including rectal cancer, represent a systemic disease, and even in its early stage, micrometastasis can be found in the lymph nodes, peripheral blood, and bone marrow. 37 Our data show that rectal cancers containing lymphovascular invasion have a relative risk of more than three times that of those without. Our data prove that TNM staging and grade are the final decision-makers – even after the intervention of TME – are also good predictors of LR and even metastasis. We also find that TME group has a less likelihood of metastasis. Possible explanation may be less squeezing of tumor cells into the circulation during the operation, and less massive bleeding (more than 1000 ml per operation) which makes transfusion necessary. In Fig. 1 , the TME group has a higher cumulative survival rate than non-TME group in the first three years, then a crossing between the two survival curves. Since it is a retrospective study comparing outcomes of rectal cancer patients in different periods, TME group has a shorter time of follow-up. Further follow-up is necessitated. On the other side, TNM staging and tumor grade remain the significant prognostic factors indicating deeper understanding of the molecular mechanisms involved in the development and spread of colorectal cancers is crucial to the management of the spread of colorectal cancer and perhaps even to the ultimate treatment of cancer. Conclusion In conclusion, TME is safer and more efficient than conventional surgery for the treatment of rectal cancer and the reduction of the high rate of LR and metastasis. We have not found the prognostic significance of TME for rectal cancer patients in this study, indicating further follow-up should be awaited. Besides the use of TME for the removal of cancerous growths in rectal cancers, it is important to better understand the molecular mechanisms involved in the development, growth and spread of cancer, so that it can be treated before it develops into an unmanageable condition or prevented from spreading into local or distant sites. 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