CD133 expression in rectal cancer after preoperative chemoradiotherapy

CD133‐positive cells have been reported to possess a cancer‐initiating‐cell phenotype and the property of resistance to chemoradiation therapy in colorectal cancer. The aim of the present study was to evaluate quantitative and locational changes in CD133‐positive cells in rectal cancer patients who received preoperative chemoradiation therapy. The prognostic significance of CD133 expression in patients with preoperative chemoradiation therapy was also analyzed. Immunohistochemical staining for CD133 and cancer‐initiating‐cell marker CD44 were performed in 92 surgically resected rectal cancers. Of the 92 cases, 43 patients received preoperative chemoradiation therapy and 49 patients underwent surgery alone. Forty pretherapic biopsy specimens from 43 patients in preoperative chemoradiation therapy group were also analyzed. CD133‐positive cases were more common in the preoperative chemoradiation therapy group than in the surgery‐alone group (P = 0.03). Further, CD133‐positive cases were more common in the preoperative chemoradiation therapy group than in pretherapic biopsy specimens (P = 0.02). In the preoperative chemoradiation therapy group, the CD133‐positive cases showed poorer prognosis than the CD133‐negative cases. On the other hand, the frequency of CD44‐positive case within cancer tissue was similar between the preoperative chemoradiation therapy group and the surgery‐alone group. CD44 expression in the preoperative chemoradiation therapy group was not associated with prognosis. CD44‐ and CD133‐positive cells were distributed evenly within the tumor both in the preoperative chemoradiation therapy group and surgery‐alone group, and locational alteration was not observed. The therapy‐resistant ability of CD133‐positive cells can be associated with poor outcome in the patients with preoperative chemoradiation therapy. (Cancer Sci 2010; 101: 906–912)     

The reliability of lymph-node staging in rectal cancer after preoperative chemoradiotherapy

AimsTo determine the prognostic significance of the nodal stage and number of nodes recovered in the surgical specimen after preoperative synchronous chemoradiation (SCRT) and surgery for locally advanced or unresectable rectal cancer.Materials and MethodsOne hundred and eighty-two consecutive patients with locally advanced or unresectable (T3/T4) rectal carcinomas were entered on a prospective database and treated in this department with preoperative chemoradiation, followed 6–12 weeks later by surgical resection. Most patients received chemotherapy in the form of low-dose folinic acid and 5-fluorouracil (5-FU) 350 mg/m² via a 60-min infusion on days 1–5 and 29–33 of a course of pelvic radiotherapy delivered at a dose of 45 Gy in 25 fractions over 33 days to a planned volume. After resection, patients with a positive circumferential margin (≤1 mm), extranodal deposits or Dukes' C histology received adjuvant 5-FU-based-chemotherapy (n = 40).ResultsAfter SCRT, 161 patients underwent resection. Twenty-one patients remained unresectable or refused an exenterative operation. Median follow-up is 36 months. Down-staging was achieved in most patients, with 19 having a complete pathological response (pT0). The median number of lymph nodes recovered for all patients was five (range 0–21). The 3-year survival rate for node-positive patients is 47%, for node-negative patients with less than three lymph nodes recovered is 62% and for node-negative patients with three or more lymph nodes recovered is 70%. Compared with node-positive patients, simple regression models revealed a reduced hazard ratio (HR) of 0.72 (0.36–1.43) for node-negative patients with less than three nodes recovered and 0.48 (0.26–0.89) for node-negative patients with three or more lymph nodes recovered. In a multivariate model, including nodal status, excision status, age and sex only positive excision margins significantly predicted a poor outcome: HR = 3.05 (1.55–5.97).ConclusionsThe number of nodes found after preoperative chemoradiation is a significant prognostic factor by univariate analysis. In this study, patients with node-negative histology, and at least three nodes recovered, had better long-term survival than patients in whom two or less nodes were recovered or with positive nodes. This effect was attenuated by the inclusion of excision status in multivariate models.     

Oxaliplatin and preoperative chemoradiotherapy in rectal cancer

Up to date, standard treatment of locally advanced rectal cancer is preoperative radiotherapy with concurrent chemotherapy. Results of FFCD and EORTC French randomised trials showed that preoperative radiochemotherapy with 5-fluorouracil (5FU) compared with radiotherapy increases operative specimen sterilisation and local control, without any benefit on overall survival. One of the greatest challenges in rectal cancer is to improve schedules of pre operative chemoradiotherapy. Oxaliplatin is proved to be a radiosentitizer and to be effective on advanced colorectal cancer. Consequently it is an adequate drug to associate with 5FU and radiation. Several phases I and II studied the association between 5FU infusion-oxaliplatin-radiation therapy or capecitabine-oxaliplatin-radiation therapy with a moderate toxicity (essentially diarrhoea) and a promising tumoral activity. All the studied schedules seem to have a similar efficiency with a questionable increased toxicity with continuous administration of 5FU or capecitabine. Only randomized trials comparing 5FU to 5FU or capecitabine plus oxaliplatin will attest the benefit of oxaliplatin on local control, sphincter preservation and overall survival, and will estimate its toxicity compared with monochemotherapy.     

Effectiveness of preoperative chemoradiotherapy for advanced rectal cancer

To determine the pathologic effectiveness of preoperative chemoradiotherapy (CRT) in patients with advanced rectal carcinoma, we reviewed clinical records of 76 patients who received preoperative pelvic radiation +/- chemotherapy. Since 2 patients refused operation and 2 died before surgery, 72 patients underwent operation with a mean delay of 19.9 days after completion of irradiation. Pathologic tumor regression grade (Grade 0-3) was determined by the amount of viable tumor versus necrosis and fibrosis. Grade 0, 1 a, 1 b, 2, and 3 (pCR) were observed in 0%, 25.0%, 38.9%, 27.8% and 2.8% of patients, respectively. The pathologic response (PR) rate was 75.0% when PR was defined as greater than grade 1 b (tumor regression more than 1/3). Downstaging was observed in 35.8% of patients, in which 5-year overall survival was significantly better than in patients without downstaging (90.0% vs. 50.1%, p<0.05). No correlation could be observed between PR and downstaging. CRT is a useful tool with a high PR rate in patients with advanced rectal cancer. More accurate and careful clinical staging is important to select adequate candidates for CRT. Multi-institutional clinical trials as well as standardizing the surgical procedure including LN dissection are required to validate the advantages of CRT for Japanese patients.     

Prognostic significance of tumor regression after preoperative chemoradiotherapy for rectal cancer.

PURPOSE: We assessed the impact of tumor regression grading (TRG) and its value in correlation to established prognostic factors in a cohort of rectal carcinoma patients treated by preoperative chemoradiotherapy (CRT). PATIENTS AND METHODS: TRG was evaluated on surgical specimens of 385 patients treated within the preoperative CRT arm of the CAO/ARO/AIO-94 trial: 50.4 Gy was delivered, fluorouracil was given in the first and fifth week, and surgery was performed 6 weeks thereafter. TRG was determined by the amount of viable tumor versus fibrosis, ranging from TRG 4 when no viable tumor cells were detected, to TRG 0 when fibrosis was completely absent. TRG 3 was defined as regression more than 50% with fibrosis outgrowing the tumor mass, TRG 2 was defined as regression less than 50%, and TRG 1 was defined basically as a morphologically unaltered tumor mass. We performed an initially unplanned, hypothesis-generating analysis with respect to the prognostic value of this TRG system. RESULTS: TRG 4, 3, 2, 1, 0 was found in 10.4%, 52.2%, 13.8%, 15.3%, and 8.3% of the resected specimens, respectively. Five-year disease-free survival (DFS) after CRT and curative resection was 86% for TRG 4, 75% for grouped TRG 2 + 3, and 63% for grouped TRG 0 + 1 (P = .006). On multivariate analysis, the pathologic T category and the nodal status after CRT were the most important independent prognostic factors for DFS. CONCLUSION: In this exploratory analysis, complete (TRG 4) and intermediate pathologic response (TRG 2 + 3) suggested improved DFS after preoperative CRT. TRG assessment should be implemented in pathologic evaluation and prospectively validated in further studies.     

Clinical parameters predicting pathologic tumor response after preoperative chemoradiotherapy for rectal cancer

PURPOSE: To identify pretreatment clinical parameters that could predict pathologic tumor response to preoperative chemoradiotherapy (CRT) for rectal cancer. METHODS AND MATERIALS: The study involved 351 patients who underwent preoperative CRT followed by surgery between October 2001 and July 2006. Tumor responses to preoperative CRT were assessed in terms of tumor downstaging and tumor regression. Statistical analyses were performed to identify clinical factors associated with pathologic tumor response. RESULTS: Tumor downstaging (defined as ypT2 or less) was observed in 167 patients (47.6%), whereas tumor regression (defined as Dworak's Regression Grades 3 or 4) was observed in 103 patients (29.3%) and complete regression in 51 patients (14.5%). Multivariate analysis found that predictors of downstaging were pretreatment hemoglobin level (p = 0.045), cN0 classification (p < 0.001), and serum carcinoembryonic antigen (CEA) level (p < 0.001), that predictors of tumor regression were cN0 classification (p = 0.044) and CEA level (p < 0.001), and that the predictor of complete regression was CEA level (p = 0.004). CONCLUSIONS: The data suggest that pretreatment CEA level is the most important clinical predictor of pathologic tumor response. It may be of benefit in the selection of treatment options as well as the assessment of individual prognosis.     

Predictive factors for early distant metastasis after neoadjuvant chemoradiotherapy in locally advanced rectal cancer

BACKGROUNDDistant relapse is the leading cause of cancer-related death in locally advanced rectal cancer. Neoadjuvant chemoradiation (NACRT) followed by surgery inevitably delays delivery of systemic treatment. Some patients show early distant metastasis before systemic treatment.AIMTo identify the most effective treatments. We investigated prognostic factors for distant metastasis, especially early distant metastasis, using the standard treatment paradigm to identify the most effective treatments according to recurrence risk.METHODSFrom January 2015 through December 2019, rectal cancer patients who underwent NACRT for having clinical T 3-4 or clinical N 1-2 disease according to the 8^th American Joint Committee on Cancer staging system were included. Radiotherapy was delivered to the whole pelvis with concomitant chemotherapy. Patients received surgery 6-8 wk after completion of NACRT. Adjuvant chemotherapy was administered at the physician’s discretion. RESULTSA total of 127 patients received NACRT. Ninety-three patients (73.2%) underwent surgery. The R0 resection rate was 89.2% in all patients. Pathologic tumor and node downstaging rates were 41.9% and 76.3%. Half the patients (n = 69) received adjuvant chemotherapy after surgery. The 3-year distant metastasis-free survival (DMFS) and overall survival (OS) rates were 81.7% and 83.5%. On univariate analyses, poorly differentiated tumors, > 5 cm, involvement of mesorectal fascia (MRF), or presence of extramural involvement (EMVI) were associated with worse DMFS and OS. Five patients showed distant metastasis at their first evaluation after NACRT. Patients with early distant metastasis were more likely to have poorly differentiated tumor (P = 0.025), tumors with involved MRF (P = 0.002), and EMVI (P = 0.012) than those who did not. CONCLUSIONEMVI, the involvement of MRF, and poor histologic grade were associated with early distant metastasis. In order to control distant metastasis and improve treatment outcome, selective use of neoadjuvant treatment according to individualized risk factors is necessary. Future studies are required to determine effective treatment strategies for patients at high risk for distant metastasis.     

Results of preoperative chemoradiotherapy for T4 rectal cancer

We reviewed clinical records of 11 cases with preoperative chemoradiotherapy to evaluate the clinical effectiveness of chemoradiotherapy for T4 rectal cancer. The preoperative radiotherapy consisted of 40-50 Gy delivered in fractions of 1 .8- 2.0 Gy per day, five days per week. A treatment of 5-fluorouracil, 500 mg/body per day intravenously, or oral UFT-E (300 mg/m2) with l-leucovorin (75 mg) per day, or oral S-1 (80 mg/m2) per day five days per week, was given during radiotherapy. One patient died due to pelvic abscess in 63 days after chemoradiotherapy. Invasive findings to the adjacent organs identified by CT and MRI disappeared in 6 cases with complete or partial response 1 month after chemoradiotherapy. Curative surgery was performed in 7 patients. Although the adjacent organs were also removed during surgery in 7 patients, there was no histological invasion to the adjacent organs in 4 patients, and one patient had histological complete disappearance of tumor. Although complications after surgery were found in all of the patients, they were improved by conservative treatment. Two of 7 patients with curative surgery had recurrence, but the rest of them survived without recurrence. Preoperative chemoradiotherapy was expected to be an effective treatment to improve the resection rate and prognosis for T4 rectal cancer. However, it was thought that it was necessary to be careful about severe toxicity, such as pelvic abscess.     

Local recurrence of rectal cancer after total mesorectal excision without preoperative radiotherapy

Background: At this moment, it is still debatable whether all patients with mobile rectal cancer who undergo surgical removal of the tumor should be treated with preoperative radiotherapy, since it is likely that only certain patients will benefit from this strategy. In this study, patients with mobile rectal cancer were immediately operated upon and only those with positive nodes or with incomplete resection received adjuvant radiotherapy. Aims of the Study: To investigate the local recurrence rate after the use of a selective policy of adjuvant radiotherapy and to determine risk factors for local recurrence. Methods: In a 5-yr-period, 178 patients with rectal cancer were referred to our institute. A total of 131 patients with mobile rectal cancer were treated with curative intent, which implied a microscopically radical resection and no signs of distant metastasis at operation. A retrospective analysis was undertaken to investigate the incidence of local recurrence in this curative group and to determine risk factors for local recurrence. Results: The postoperative mortality in the curative group was 5.3%. Local recurrences were observed in 6 patients (4.6%) after a median period of 25 mo (range 11–37); two of them also had distant metastases detected at the same time. The highest local recurrence rates were seen in men (5.3%), in distal rectal cancers (6.9%), and in the node-positive group (8.7%). Conclusion: A low local recurrence rate can be achieved after total mesorectal excision (TME) without preoperative radiotherapy. Our results suggest using preoperative radiotherapy only for those patients who are at a higher risk for local recurrence. Staging techniques for selection of these patients are at this moment still inappropriate.     

Role of preoperative local and distant staging in rectal cancer

Preoperative imaging in rectal cancer is very important, as accurate staging determines optimal treatment strategy. In this review, imaging modalities for locoregional and distant staging in rectal cancer are discussed. For local staging, superficial tumors are best staged using endorectal US (EUS), as EUS is the most accurate modality for assessment of tumor ingrowth into the rectal wall layers. The more advanced tumors are best imaged using MRI, because MRI accurately predicts the distance from tumor to mesorectal fascia, and thus the circumferential resection margin (CRM), as well as possible invasion into surrounding organs. For the prediction of the nodal status none of the three imaging modalities - EUS, MRI and CT - can be reliably used for clinical decision-making. Only MRI using lymph node specific contrast (such as ultrasmall paramagnetic iron oxide-enhanced MRI) seems promising for the detection of nodal disease. For the detection of distant metastases transabdominal ultrasound and chest X-ray are used as a primary screening tool. However, for the high prevalence group (stage III) both methods are insufficiently sensitive, and CT of the chest plus abdomen is preferred.     

Molecular prognostic factors in rectal cancer treated by preoperative chemoradiotherapy

The present study evaluated the expression of p53, pRb, hMLH1 and MDM2 prior to preoperative chemoradiotherapy (CRT) in patients with rectal cancer, and attempted to determine any correlation with treatment outcome. Forty-five patients with available pretreatment biopsy tissues and who received preoperative CRT were enrolled in this study. Preoperative CRT consisted of a median 50.4 Gy and 2 cycles of concurrent administration of 5-fluorouracil + leucovorin. Surgery was performed approximately seven weeks after CRT. Protein expression in formalin-fixed paraffin-embedded biopsy specimens was assessed by immunohistochemistry. A positive expression of p53, pRb, hMLH1 and MDM2 was found in 40, 46.7, 40 and 66.7% of the tissue specimens, respectively. The 5-year overall (OS), disease-free (DFS) and locoregional recurrence-free survival (LRFS) rates for patients included in the study were 71.3, 66.1 and 60.9%, respectively. p53 expression presented a significantly different OS (positive vs. negative, 45.8 vs. 86.2%; p=0.02). However, the expression of pRb, hMLH1 and MDM2 was not significant for OS. The expression of p53 was a borderline significant prognostic factor for DFS and for LRFS. Age, p53 and MDM2 expression were significant factors in the multivariate analysis performed for OS with 12 covariates, including 8 clinicopathological parameters and 4 proteins. No significant factor affected DFS or LRFS in the multivariate analysis. We suggest that the expression of p53 is a potential marker of survival. Determinations of this protein expression may be useful for selecting candidates from rectal cancer patients for more tailored treatment.     

直肠癌新辅助治疗后病理降期相关研究进展

术前同步放化疗已成为局部晚期直肠癌的标准治疗模式.新辅助治疗后病理降期与直肠癌预后关系密切,找到能预测直肠癌新辅助治疗病理降期标记,有着重要的临床意义.不同放化疗方案、靶向药物在新辅助治疗中的应用、新辅助治疗后至手术间隔时间与病理降期相关.     

局部进展期直肠癌术前放化疗的疗效评价

目的 分析临床病理变化特征,对局部进展期直肠癌手术前放化疗的进行评价。方法 36例局部进展期直肠癌患者行手术前放化疗。放疗总剂量为45Gy,每周5次,每次1.8Gy。全身化疗共2个疗程,四氢叶酸（folinic acid,FA)50mg,静脉滴入,随后静脉给予5－Fu 300mg/m^2。手术后2－4周开始追加2－4个疗程化疗。辅助治疗完成后4－6周采取手术治疗。结果 仅有2例（5．6％）患者出现Ⅲ度造血系统毒性反应,全组未出现Ⅲ-Ⅳ度胃肠反应、皮肤或泌尿系急性毒性反应。全部患者均采取手术治疗,全组无围手术期死亡,手术并发症为13．8％,未发生远期并发症。经过术前辅助治疗,肿瘤的平均直径平均缩小28．0％。4例（11．1％）达到病理完全缓解,病理总有效率（CR＋PR）为77．8％,肿瘤分期下降率达到52．8％。辅助治疗后,淋巴结的阴转率达到60．0％,淋巴结总阳性率由83．0％降至37．0％。结论 术前放疗＋全身化疗安全可靠,能使部分肿瘤病理完全缓解,缩小原发瘤,减少了局部淋巴结转移率,从而达到降低肿瘤分期,提高了手术的疗效。     

Concomitant occurrence of facial cutaneous and parotid gland metastases from rectal cancer after preoperative chemoradiotherapy

BACKGROUND: Unusual sites of metastasis to the parotid gland and face are reported in patients with colorectal cancer, but the localization to both sites at the same time has never been described so far. CASE REPORT: Here, we describe the case of a 76-year-old woman with a T3N1M0 G2 rectal adenocarcinoma, treated with preoperative chemoradiotherapy performed at suboptimal dosages due to unacceptable toxicity. At the end of the program, the re-staging demonstrated the presence of metastasis in both the left parotid gland and subcutaneously on the frontal region of her face while the primary locoregional tumour manifestation was radiologically down-staged (reduction in N staging from N1 to N0). The patient did not respond to any other treatment and died due to disease progression 15 months after the diagnosis. CONCLUSIONS: Metastatic tumours in the parotid gland are uncommon with a higher incidence of primary sites of the head and neck. Parotid involvement of rectal adenocarcinoma is also extremely rare, and concomitant involvement of both the parotid gland and the face was not previously described. In this case, we cannot rule out the hypothesis that the delay of surgical removal of the primary tumour and/or a specific action of concomitant chemoradiotherapy on the tumour cell phenotype could promote cancer cell spreading to unusual sites.