Randomized study on preoperative radiotherapy in rectal carcinoma

Background: A population based prospective randomized trial on preoperative radiotherapy in operable rectal cancer was conducted in Stockholm, Sweden. Five hundred fifty-seven patients from 12 institutions were included with histologically proven, clinically resectable rectal adenocarcinoma. Patients planned for local excision or previously irradiated to the pelvis were excluded. Methods: A total of 272 patients were allocated to preoperative irradiation with 25 Gy in five cycles during 5–7 days to the rectum and the pararectal tissues (RT+ group) and 285 patients were allocated to surgery only (RT? group). The median follow-up time was 50 months. No patient was lost to follow-up. Surgery was considered curative in 479 patients (86%). Results: Locoregional recurrence occurred in 10% of the patients in the RT+ group versus 21% in the RT? group (p<0.01). Among the curatively operated patients, distant metastases occurred in 19% in the RT+ group versus 26% in the RT? group (p=0.02). The overall survival was improved in the irradiated patients (p=0.02). Postoperative complications were more common after irradiation but were usually mild. The postoperative mortality was low in both groups. Conclusion: Preoperative short-term, high-dose radiotherapy as given in this trial reduces the risk of local and distant recurrence and improves survival after curative surgery for rectal carcinoma.     

Histopathology of residual rectal carcinoma following preoperative radiochemotherapy

Preoperative radiotherapy with (CRT) or without chemotherapy (RT) in the management of patients with locally advanced rectal carcinoma is increasingly accepted as therapeutic modality to reduce local recurrence and improve survival, decrease tumor size and/or stage, has less toxicity compared to postoperative therapy, improves sphincter preservation and the ability to perform a curative resection. In a brief review of literature we discussed the possible prognostic role of most important pathologic parameters and their clinical implications. At present, predictive value of tumor response to neoadjuvant therapy remains uncertain, whether evaluated as five-point histological tumor regression grade (TRG) or recently proposed three-point rectal cancer regression grade (RCRG). However, most reports emphasize reduced local reccurence rates and disease-free survival advantage in patients with complete tumour regression or tumour down-staging, occuring in up to 20% and 60% of cases, respectively. Patients with advanced post-treatment tumour stage (ypT3/4), positive lymph nodes (ypN1/2), vascular invasion, positive circumferential resection margin, clearance < 2mm, or absence of tumor regression are shown to have poor clinical outcome. Among CRT-induced morphological features, only "fibrotic-type" stromal response with minimal inflammatory infiltrates and absence of surface ulceration are correlated to recurrence-free survival. Preliminary unpublished results of a pilot study from our multidisciplinary prospective trial relate to correlation of histopathologic parameters and morphologic changes to rectal cancer regression grade (RCRG). Therefore, we studied 22 consecutive patients, mean age 56 (range 23-69) years, with transmural cT3/4 stage and were subgrouped as follows: RCRG-1 (7 patients, 31.8%), RCRG-2 (9 patients, 40.,9%) and RCRG-3 (6 patients, 27,2%). In addition, 14 patients (63%) showed tumour downstaging and only 1 patient (4.5%) nodal down-staging after ypTNM restaging. There was the predominance of fibrotic-type stroma (16 patients, 72.8%) versus fibro-inflammatory response (6 patients, 27.2%), frequent tumoral necrosis (13 patients, 59%) but infrequent surface ulceration (5 patients, 22.7%) and peritumoural eosinophylic infiltration as well as endocrine cell differentiation (4 patients, 18%). The second aim of our study was to investigate determinants of radiosensitivity, i.e. the relationship between proliferative activity indices (Ki-67 and PCNA) as well as the induction of apoptosis (p53) and the tumour regression (RCRG) after neoadjuvant CRT. The interaction between Ki-67 and PCNA immunoexpression levels and the benefit of CRT was significant for Ki-67 (p = 0.03), but not for PCNA (p = 0.08) and p53 levels (p = 0.4). In a conclusion, high percentage of Ki-67-positive tumor cells in the preoperative biopsy predicts an decreased treatment response after preoperative CRT of rectal cancer. However, long-term follow-up and large studies are necessary to establish the value of regression grade and the need for its prediction by reliable biological markers.     

Pathological assessment of rectal carcinoma after preoperative therapy

Increasingly neoadjuvant therapy is being used to improve outcomes in patients with rectal carcinoma in which the circumferential resection margins are considered to be at risk for involvement if primary surgery were to be undertaken. Assessment of the response to this approach relies on radiological examination, particularly magnetic resonance imaging (MRI) studies. Following definitive surgery, careful histological examination allows full assessment of the tumour response to these preoperative approaches. Histological examination requires careful fixation, examination of the entire area occupied by the tumour prior to down‐staging and careful lymph node harvesting. Adequate fixation helps in these endeavours and the lymph node harvest appears to be unaffected by neoadjuvant chemo‐ or radiotherapy. Correlation between preoperative assessment of response by MRI and the subsequent histological assessment is close, but the presence of isolated residual neoplastic glands in a post‐treatment fibrotic stroma is impossible to detect prior to resection. The clinical significance of these microscopic foci remains uncertain, particularly in view of the prolonged tumour doubling time associated with colorectal adenocarcinoma. The preoperative discussion with the patient requires a synthesis of their own scan results and the experience of detailed clinico‐pathological studies. While MRI frequently predicts the presence or absence of residual tumour the possibility of under‐staging remains and this is of crucial importance if a ‘watch and wait’ policy is to be adopted following apparent complete clinical and radiological remission. The significance of potential residual microscopic disease in patients with apparent radiological complete remission needs further investigation but may need to be interpreted in individual patients in the context of overall life‐expectancy.     

A case of rectal carcinoma disappeared by the preoperative radiation

A 64-year-old man was admitted to our department with a diagnosis of rectal carcinoma. Preoperative histological diagnosis was highly differentiated adenocarcinoma of Dukes' A classification (Rb', Is', 20-25 mm in diameter, PM'). Preoperative radiation (2.5 Gray/time, total 30 Gray) and chemotherapy (PSK 3g/day x 3 weeks, ACNU 30 mg/m2/week x 3 weeks) were performed on this lesion. After these therapies, form of the tumor changed to IIa', SM', which was recognized by endo-scopic examination with rectal echography. A reduction of the size was 25%. Low anterior resection, curative operation, was performed 2 weeks after the therapy. The resected rectum was examined in detail, resulting in complete disappearance of the carcinoma cell and the tumor was replaced by the inflammatory cells, fibroblasts and granular cells. These findings were compatible with grade IVB of Ohboshi-Simosatos' classification.     

Tumour location and the effects of preoperative radiotherapy in the treatment of rectal cancer.

BACKGROUND: Preoperative radiotherapy improves local control and survival in rectal cancer, but may also increase postoperative morbidity and mortality rates. Establishing selection criteria for preoperative radiotherapy is crucial. The tumour level above the anus may be one such criterion. The effect of preoperative radiotherapy in relation to the distance between the tumour and the anus was therefore assessed. METHODS: In 457 patients operated for cure included in the Stockholm II Trial the local recurrence rate in irradiated and non-irradiated patients was analysed in relation to the tumour location (low, mid or upper rectum). RESULTS: Radiotherapy reduced the local recurrence rate from 30 to 20 per cent in low rectal cancer, from 25 to 11 per cent in mid rectal cancer and from 21 to 5 per cent for tumours in the upper rectum. CONCLUSION: With conventional surgical techniques preoperative radiotherapy plays an important role in rectal cancer irrespective of the location of the tumour. To irradiate only patients with tumours in the lower rectum and to omit this treatment for patients with tumours in the mid and upper rectum cannot be recommended. Whether this statement is valid with standardized total mesorectal excision (TME) surgery is not known. Until this knowledge is available the current indications for preoperative radiotherapy should probably also be used with TME surgery.     

Impaired anastomotic healing after preoperative radiotherapy followed by anterior resection for treatment of rectal carcinoma

BACKGROUND: Patients with rectal carcinoma undergoing total mesorectal excision (TME) have a lower recurrence rate with preoperative radiotherapy (RT). The aim of this study was to assess the side-effects in patients who had preoperative RT compared with those who did not receive it (because of palliative resections, advanced age or refusal). METHODS: From January 2001 to March 2003, 40 patients underwent resection and double-stapled anastomosis for rectal carcinoma. We compared 17 patients who received RT followed by resection and low rectal anastomosis, with 23 patients who did not have RT. RESULTS: After surgery 7/17 of the patients who had received RT developed anastomotic leaks. Anastomotic leakage was seen only once in the patients who did not have RT (41% v. 4%, p = 0.006). A protective stoma, which was performed in 11 patients in the RT group, did not prevent anastomotic leakage (4/11 leakage with stoma v. 3/6 leakage without stoma, p = 0.64). Median hospital stay was longer in the RT group (17.4 v. 13.7 days, p = 0.017). There was no difference in the number of minor postoperative complications between the two groups (24% v. 22%). CONCLUSION: Compared with surgery alone, preoperative short-term RT increased the number of anastomotic leaks and hospital stay, whether or not a protective stoma was performed.     

Lateral lymphadenectomy in the treatment of rectal carcinoma

The aim of this work is to present existence of the lateral lymphatic spread of metastases in patients with Dukes C low rectal carcinoma (60% of all patients), located at or bellow peritoneal reflexion. Prospective clinical investigation analyzed the group of 64 patients (32 underwent lateral lymphadenectomy and 32 didn't), all treated at Ist Surgical Clinic, Clinical Center of Serbia. Lateral lymphatic spread of metastases was proven by frozen section in 8 cases, so extensive lateral lymphadenectomy was performed. In the group of patients who underwent lateral lymphadenectomy, positive lymph nodes were registered in 18 patients (56.2%); in group of patients operated without lateral lymphadenectomy, metastatic lymph nodes were registered in 12 patients (37.5%). According to results of this investigation, method of lateral lymphadenectomy, as well as extensive lateral lymphadenectomy, is significant for exact determination of postoperative stage of the disease. Also, there is a significant increase in number of patients with Dukes C stage of the disease. In those patients, mesorectectomy alone is not sufficient.     

Current trends in the treatment of rectal carcinoma

Authors report their personal experience about 336 cases of curative surgery for rectal cancer. They describe technical surgical details universally accepted in Literature such as sharp total mesorectal excision, the extension of lymphadenectomy with high ligature of inferior mesenteritis artery while pelvic lymphadenectomy seems to be unuseful and burdened by high morbidity; finally they underline advantages offered by a colic pouch above all for lower incidence of anastomotic leakages. As adjuvant therapy is concerned, our actual tendency is a preoperative radiochemiotherapy of which we are still evaluating long-term results. Finally we analyzed correlations between cellular genetics and colo-rectal cancer.     

直肠癌术前淋巴化疗安全性分析

目的 研究直肠癌患者术前淋巴化疗应用的安全性.方法 观察淋巴化疗后局部和全身症状、心肝肾及造血功能变化、术后吻合口愈合情况以及检测淋巴化疗前30 min和淋巴化疗后48 h血CD3+、CD4+、CD8+、CD4+/CD8+、CD(16+56)+.结果 淋巴化疗对局部和全身症状、心肝肾及造血功能、术后吻合口愈合无明显影响;比较淋巴化疗前30 min与淋巴化疗后48 h,CD4+/CD8+升高(t=7.145,P＜0.05),CD3+、CD4+、CD8+、CD(16+56)+无明显变化(t=1.782,1.151,1.184,0.955,P＞0.05).结论 淋巴化疗具有安全性,短期内对机体免疫有一定促进作用.     

分子标记物预测直肠癌新辅助放化疗效果初步评价

目的：寻找预测直肠癌新辅助治疗效果的分子标志物。方法：对26例行新辅助治疗的进展期中低位直肠癌的治疗前活检标本的K-ras基因进行测序,同时通过免疫组织化学方法对分子标志物增殖细胞核抗体（Ki-67）、核转录因子（NF-KB）、细胞周期蛋白依赖性激酶1（CDK1）进行检测。对手术标本行病理分析和肿瘤消退分级评估。结果：本组病例新辅助治疗后获得病理完全缓解（pCR）的患者7例（26．9％）均为K-ras基因野生型,治疗后降期患者17例（65．4％）。K-ras基因是否突变同新辅助放化疗（CRT）能否达到pCR密切相关（P=0．048）。K-ras基因野生型患者的降期率和肿瘤消退率均为77．8％（14／18）,同突变型的降期率和肿瘤消退率比较P=0．063。结论：中低位直肠癌患者新辅助治疗前K-ras基因野生型可能预示着较好的新辅助治疗效果。     

On the clinical treatment of rectal carcinoma

From 1975 to 1986, 478 operations were performed on the patients with rectal carcinomas. Radical resection rate is 63.4%. We have studied the metastatic law of rectal tumors through lymph-duct, reverse invasion in wall, radiation and the hot-therapy before the operation. Extended lymph nodes resection were performed. The Dukes C 5 years survival rate was increased from 32.6 to 79.2 percent. Our results suggested that (1) local colorectal and rectal tract should be resected sufficiently. The operation of remaining anus should be based on sufficient radical resection. (2) Extended radical resection include the third stationary lymph nodes. The lateral lymph nodes should also be removed in association with tumor under the peritoneal reflection. (3) If hepatic metastasis was accompanied, the metastatic site should be removed as well as primary site. (4) In the case of late stage, palliative operation was performed. (5) As soon as the rectal tumor recur, the second operation will be administered. In the meanwhile, we suggested, in order to maximum increase 5 years survival rate, that multi-measures were adopted.     

Predicting the node-negative mesorectum after preoperative chemoradiation for locally advanced rectal carcinoma

Preoperative chemoradiation therapy (CRT) in patients with locally advanced rectal cancer allows for radical surgery with sphincter preservation in many patients. To determine whether patients downsized with preoperative CRT may be potential candidates for local excision, we investigated residual disease patterns after neoadjuvant treatment. A retrospective analysis was carried out of patients with T3 or T4 rectal adenocarcinoma who were treated with neoadjuvant CRT. Clinical and pathologic data were analyzed to (1) determine the response rates to preoperative CRT in the tumor bed and regional nodal basin and (2) identify the incidence of residual disease in the mesorectum in patients downsized to ≤T2. A total of 219 patients met the inclusion criteria. Preoperatively 193 patients (88%) were staged as T3, and 99 patients (47%) had clinical N1 disease. The pathologic complete response rate was 20% (43 of 219 patients). T stage was downsized in 64% of the patients (140 of 219), and 69% (67 of 97) of the patients with clinical N1 disease were rendered node negative. Seventeen percent (21 of 122) of patients downsized to ≤T2 had residual disease in the mesentery. With a median follow-up of 40 months, 182 patients (83%) remain alive and free of disease. Nine patients (4.1%) have had a local recurrence. Although tumor response rates to preoperative CRT within the bowel wall and lymph node basin are similar, one in six patients with pT0-2 tumors will have residual disease in the rectal mesentery and nodes. Despite a substantial reduction in tumor volume with neoadjuvant CRT, local excision should be recommended with caution in patients with locally advanced rectal cancer. Presented at Forty-Fourth Annual Meeting of The Society for Surgery of the Alimentary Tract, Orlando, Florida, May 18–21, 2003 (oral presentation).     

Long-term results and complications of preoperative radiation in the treatment of rectal cancer

A retrospective study of 149 patients with rectal cancer diagnosed between 1972 and 1979 was undertaken to compare survival, disease-free survival, recurrence sites, and long-term complications of 40 patients who received 4000 to 4500 rads of preoperative adjuvant radiotherapy (radiation group) with those of 109 patients treated by resection alone (control group). After a mean follow-up of 84 months and 99 months, respectively, survival of the irradiated patients was significantly better than that of controls (68% versus 52%, p less than 0.05). Disease-free survival of those patients rendered free of disease by treatment was also superior for the irradiated group (84% versus 57%, p less than 0.005). Local recurrence without signs of distant metastases developed only one-third as often in irradiated patients (6% versus 18%). Distant metastases, alone or in combination with local recurrence, were also less common after radiation (12% versus 27%). Second primary tumors developed in 15% and 10% of the respective groups, a difference that was not statistically significant. When we consider the survival benefit of preoperative radiation therapy, long-term complications were relatively mild. Delayed healing of the perineum was noted in two irradiated patients. Persistent diarrhea was severe enough to warrant treatment in only one case, and one patient required a colostomy for intestinal obstruction from pelvic fibrosis.     

局部复发性直肠癌的再手术治疗

目的 探讨局部复发性直肠癌（直肠癌根治术后）再次手术的价值。方法 回顾性分析再手术治疗的局部复发性直肠癌４８例。结果 ３３例行根治术,１５例行姑性手术。根治术组和姑息性手术组中位生存期分别为３５．２个月（８－８２个月）、１３个月（２－２３个月）,再手术５年生存率为３４．８％。结论 对于局部复发性直肠癌仍应积极手术,有助于延长生存期,提高生存质量。     

Patterns of residual disease after preoperative chemoradiation in ultrasound T3 rectal carcinoma

Background: Rectal carcinoma tends to recur locally, with invasion of adjacent organs and significant pelvic pain. Both radiation therapy alone and combined chemoradiation have been used in an attempt to decrease the local recurrence rate and thereby improve survival. Although preoperative chemoradiation can clinically downstage rectal tumors, the pathologic extent of the residual disease has not been studied. Methods: Thirty-seven patients with T3 rectal cancer diagnosed by transrectal ultrasonography (uT3) received 45 Gy with continuous infusion 5-fluorouracil (300 mg/m²/day). Proctoscopy with mucosal/submucosal biopsy was performed in patients (16 of 37) posttreatment and before definitive surgery. Results: Microscopic evaluation of the 37 resected specimens showed a 30% (11 patients) pathologic complete remission rate. The pattern of residual disease in the remaining 26 patients showed that nine (25%) had microscopic residual tumor without evidence of mucosal involvement. Of the 14 patients with a negative proctoscopic evaluation and biopsy only, five (36%) had no residual tumor on final pathology. Conclusions: After chemoradiation, the pathologic presentation of rectal cancer may be altered, making endoscopic procedures and mucosal/submucosal biopsies unreliable in detection of residual disease. Despite the relatively good pathologic complete remission rate noted in this study, all patients undergoing chemoradiation for uT3 rectal carcinomas need definitive surgical resection to confirm a complete clinical remission. Presented at the 46th Annual Cancer Symposium of the Society of Surgical Oncology, Los Angeles, California, March 18–21, 1993.