Adjuvant and neoadjuvant radiotherapy and concurrent radiochemotherapy for rectal cancer

Radical surgery with negative margins remains the most important prognostic factor in the treatment of rectal cancer. Combined modality treatment is the recommended standard adjuvant therapy for patients with locally advanced rectal cancer in the USA and in Germany. During the last decade substantial progress has been made in treatment modalities: surgical management currently includes a broad spectrum of operative procedures ranging from radical operations to innovative sphincter-preserving techniques. Specialized groups have reported excellent local control rates with total mesorectal excision (TME) alone. New and improved radiation techniques (conformai radiotherapy, intraoperative radiotherapy) and innovative schedules (protracted intravenous infusion, chronomodulated infusion) and combinations (oxaliplatin, irinotecan) of chemotherapy may have the potential to further increase the therapeutic benefit of adjuvant treatment. Moreover, the basic issue of timing of radio-(chemo-) therapy preoperative versus postoperative within a multimodality regimen is currently being addressed in prospective trials. Evidently, the current monolithic approaches, established by studies conducted more than a decade ago, to apply either the same schedule of postoperative radiochemotherapy to all patients with stage II/III rectal cancer or to give preoperative intensive short-course radiation according to the Swedish concept for all patients with resectable rectal cancer irrespective of tumor stage and treatment goal (e.g. sphincter preservation), need to be questioned. This review will discuss different irradiation settings in more recent and ongoing studies of perioperative radiotherapy for rectal cancer and will focus on the issue which patient should receive radiotherapy at all, and if so, how and when?     

Radiotherapy and concurrent radiochemotherapy for rectal cancer

Adjuvant radiotherapy with or without chemotherapy has been used widely in an attempt to improve outcome in rectal cancer. For locally advanced disease, postoperative radiochemotherapy significantly improved both local control and overall survival when compared with surgery alone or surgery plus irradiation. This prompted a National Cancer Institute Consensus Conference in the United States in 1990 to recommend postoperative radiochemotherapy for patients with TNM stage II and III rectal cancer as standard treatment. In Europe, several randomized studies tested preoperative radiotherapy in comparison to surgery alone and showed lower local failure rates. A recent meta-analysis concluded that the combination of preoperative radiotherapy and surgery, as compared with surgery alone, significantly improves local control and overall survival. These results are, however, challenged by more recent reports of extraordinarily low local failure rates following improved surgical techniques, including total mesorectal excision. Evidently, the current monolithic approaches to either apply the same schedule of postoperative radiochemotherapy to all patients with stage II/III rectal cancer or to give preoperative intensive short-course radiation according to the Swedish concept for all patients with resectable rectal cancer irrespective of tumor stage and treatment goal (e.g. sphincter preservation), need to be questioned.     

Perioperative radiotherapy in rectal cancer

Local failure of rectal cancer is one of the principal causes of morbidity and mortality. In order to lower unacceptably high local failure rates, pre- or postoperative radiotherapy has been extensively investigated. The collected information from all controlled trials reported so far shows that the proportion of local recurrences is reduced to less than half when radiotherapy up to moderately high doses is given preoperatively. This reduction is smaller after postoperative radiotherapy, even if higher doses are used. In addition, there is a positive influence on survival from preoperative radiotherapy. Improved survival has also been seen in trials using postoperative radiotherapy, but only when combined with chemotherapy. With proper radiation techniques, sufficiently high doses can be given preoperatively with little, if any, increase in postoperative mortality and morbidity. Furthermore, late toxicity can be anticipated to be low provided the technique is optimal. The beneficial effects noted so far have been achieved in trials where 'standard' surgery has been used, followed by a local recurrence rate of more than 20% (average 29%, range 23-46%) of the patients. It is, however, possible that the reduction in local failure rates is proportionally even greater added to 'optimal' surgery, although the absolute number of failures prevented is lower.     

可切除低位直肠癌术前同步放化疗临床观察

目的 观察可切除低位直肠癌术前同步放疗化疗临床疗效及安全性.方法 23例可切除低位直肠癌患者,术前予4野盆腔照射,放疗总剂量为46Gy.200cGy/f,5f/W,并于放疗第1、4周同步亚叶酸钙200 mg,静脉输注d1～d5,氟脲嘧啶500 mg/m<'2>/d,持续静脉输注d1～d5化疗,完成放化疗后,4周手术,术...     

预测直肠癌术前同步放化疗敏感性的指示剂

局部晚期直肠癌的术前同步放化疗可明显提高局控率,对于达到病理完全缓解的患者还可提高生存率,但临床疗效个体差异大.近年来研究发现,存活素、P53和P21、端粒酶、生长激素受体(GHR)、自身抗原ku70、凋亡蛋白Bax、抗凋亡蛋白Bcl-2、肿瘤增殖标记物Ki67、血管内皮生长因子(VEGF)等与直肠癌术前同步放化疗的敏感性相关,可预测术前放化疗的敏感性.     

Biological predictive factors in rectal cancer treated with preoperative radiotherapy or radiochemotherapy

We analysed the expression of microsatellite instability, p53, p21, vascular endothelial growth factor and thymidylate synthase (TS) in pretreatment biopsy specimens from 57 locally advanced rectal cancers. The aim of the study was to correlate the expression of these markers with pathological response. Nineteen patients were treated with preoperative concomitant radiotherapy (RT) and fluorouracil/oxaliplatin-based chemotherapy (RCT), while 38 had RT alone. Pathological complete remission (pCR) and microfoci residual tumour (micR) occurred more frequently in patients treated with RCT (P=0.002) and in N0 tumours (P=0.004). Among patients treated with RCT, high TS levels were associated with a higher response rate (pCR+micR; P=0.015). No such correlation was found in the RT group. The other molecular factors were of no predictive value. Multivariate analysis confirmed a significant interaction between nodal status and the probability of achieving a pathological response (P=0.023) and between TS expression and treatment, indicating that a high TS level is predictive of a higher pathological response in the RCT subset (P=0.007). This study shows that lymph node status is the most important predictive factor of tumour response to preoperative treatment. Thymidylate synthase expression assessed immunohistochemically from pretreatment tumour biopsies may be a useful predictive marker of rectal tumour response to preoperative RCT.     

奥沙利铂为主的联合化疗结合同期放射治疗晚期直肠癌

目的：评价奥沙利铂联合氟尿嘧啶、亚叶酸钙结合同期放疗的疗效。方法：奥沙利铂（L－OHP）130mg/m^2静脉滴注2小时，第1天；氟尿嘧（5－FU）300mg/m^2静脉滴注，第1－5天，亚叶酸钙（CF）200mg/m^2静脉滴注，第1－5天，21天为1周期，治疗3周期。放疗与化疗同期进行，体外照射全盆腔DT50－60GY／25－30次（5－6周）。结果：共治疗30例，近期疗效完全缓解（CR）1例；部分缓解（PR）15例；总有效率53．3％。一年生存率为70％（21／30）。主要毒副反应是消化道反应、神经毒性、放射性直肠炎，骨髓抑制轻微。结论：奥沙利铂为主的联合化疗结合同期放疗是治疗晚期直肠癌的有效方法。     

Long-term quality-of-life after neoadjuvant short-course radiotherapy and long-course radiochemotherapy for locally advanced rectal cancer

Purpose

To evaluate long-term quality-of-life (QoL) after neoadjuvant short-course radiotherapy (SC-RT) and long-course radiochemotherapy (LC-RCHT) for locally advanced rectal cancer.

Methods

Between 1999 and 2008, 225 patients were treated with curative intent for locally advanced rectal cancer using neoadjuvant SC-RT (n = 108) or LC-RCHT (n = 117). SC-RT delivered 10 × 2.9 Gy twice daily with immediate surgery. LC-RCHT delivered 28 × 1.8 Gy concomitant with 5-FU based chemotherapy and delayed surgery. A cross-sectional QoL analysis was performed in disease-free patients using the EORTC-QLQ-C30 and EORTC-QLQ-CR29 questionnaires.

Results

After a median follow-up of 67 months, 133 patients were disease-free of which 120 (90%) returned the QoL questionnaires. Patients in the LC-RCHT cohort had a higher rate of uT4, uN+ and low tumor location. No difference in QoL was observed between SC-RT and LC-RCHT except an improved physical functioning in the LC-RCHT group (p = 0.04). Comparing our total patient cohort with the general German population showed no difference in global health status but decreased QoL in several functional and bowel symptom scores.

Conclusions

The finding of comparable long-term QoL after SC-RT and LC-RCHT adds to our knowledge of equivalent oncological outcome and may be useful in the decision making process between the two neoadjuvant approaches.     

直肠癌新辅助放化疗

根治性手术结合术后放、化疗一度被作为国际公认的Ⅱ及Ⅲ期直肠癌的标准疗法。近年,新辅助放化疗逐渐得到广泛的关注。大量研究表明,与术后放化疗相比,新辅助放化疗结合根治性手术的多模式联合治疗在降低直肠癌的局部复发率、延长生存时间等方面均显示出更好的效果,特别是在提高保肛率方面具有突出的优势。目前认为,新辅助放化疗适用于局部进展期(T3~4)或有系膜内淋巴结转移的低位直肠癌患者(Ⅱ~Ⅲ期)。随着先进的诊断技术、更优化的放疗模式,以及更多有效的药物及新配伍方案的引入,对直肠癌患者采取个体化的术前新辅助治疗,将使直肠癌的治疗效果得到进一步提高。     

同步放化疗与序贯放化疗对晚期食管癌的临床疗效分析

目的探讨同步放化疗和序贯放化疗对晚期食管癌患者生存期和并发症等临床疗效的差异。方法选取2013年4月至2015年4月间江苏省泰州巿第二人民医院收治的82例晚期食管癌患者,采用随机数表法分为同步放化疗组和序贯放化疗组,每组41例。观察并比较两组患者的生存期、生活质量、病灶缓解情况和不良反应情况。结果同步组1~2年生存率低于序贯组,>2年生存率大于序贯组,差异均有统计学意义(均P<0.05)。两组患者<1年生存率比较,差异无统计学意义(P>0.05)。序贯组患者中位生存期和进展期分别为17.3个月和12.5个月,同步组患者的中位生存期和进展期分别为22.3个月和14.2个月。同步组患者的吞咽哽咽感、呕血和胸骨后疼痛方面评分均高于序贯组患者,差异均有统计学意义(均P<0.05)。同步组客观缓解率(ORR)和疾病控制率(DCR)均大于序贯组,差异均有统计学意义(均P<0.05)。两组患者在治疗期间均无IV度不良反应发生;序贯组0度和I度放射性食管炎、0度血液毒性及0度和I度胃肠道毒副作用发生例数多于同步组,差异有统计学意义(P<0.05)。结论采用同步和序贯放化疗治疗晚期食管癌安全性良好,但同步放化疗在提高晚期食管癌患者生存期,改善生活质量和疾病疗效方面优于序贯放化疗。     

复方中药同步放化疗治疗局部晚期直肠癌的临床研究

目的:探讨复方中药同步放化疗治疗局部晚期直肠癌的疗效。方法:将50例局部晚期直肠癌患者,随机分为治疗组和对照组各25例,所有患者均接受同步放化疗,治疗组在放化疗的同时同步服用复方中药,从放化疗开始连续用至治疗结束,对照组只行放化疗,治疗完成后评价疗效和毒副反应。结果:治疗组总有效率(CR+PR)为88.0%,完全缓解率(CR)为36.0%;对照组总有效率(CR+PR)为68.0%,完全缓解率(CR)为28.0%,两组间总有效率差异无统计学意义(P＞0.05) 。放疗相关毒副反应主要为肛门不适及消化道症状。对照组肛门不适、大便带血、恶心及呕吐、腹痛、腹泻发生率明显高于治疗组(P＜0.05)。治疗组大于Ⅱ级的放射性直肠炎、放射性膀胱炎及骨髓抑制等毒副反应总发生率为12.0%,远低于对照组的40.0%,两组间差异有统计学意义(P＜0.05)。与对照组比较,治疗组明显提高晚期结直肠癌患者的NK 细胞及CD4/CD8(P＜0.05)。结论:复方中药联合放化疗可提高局部晚期直肠癌近期疗效,明显减轻放化疗所致的毒副反应,改善免疫功能。     

局部晚期直肠癌的术前同步放射治疗和化疗

目的 观察１５例局部晚期直肠癌术前放射治疗和化疗（术前放化组）后外科手术的结果，以同期２７例直肠癌术前放射治疗加手术治疗作为对照组，分析其疗效及毒副反应。方法 １５例局部晚期直肠癌予术前放射治疗（ＤＴ４０～４６Ｇｙ，２０～２３次，４～５周完成）加同步化疗（氟尿嘧啶加甲酰甲氢叶酸钙静脉滴注和脱氧氟尿苷口服），对照组为同期２７例局部晚期直肠癌，予术前放射治疗，ＤＴ４０～５０Ｇｙ，２０～２５次，４～５周     

Preoperative irinotecan/5-FU/leucovorin plus concurrent radiotherapy in rectal cancer

PURPOSE: To evaluate results of preoperative irinotecan/5-FU/leucovorin plus radiotherapy for locally-advanced rectal cancer. METHODS: Thirty-five patients with locally-advanced rectal cancer were treated with preoperative irradiation 46 Gy plus concurrent chemotherapy(irinotecan 10 mg/m(2)/d d1-d5, d22-d26, 5-FU 350 mg/m(2)/d d1-d5, d22-d26, and leucovorin 20 mg/m(2) d1-d5, d22-d26), followed by radical surgery. RESULTS: There were no treatment-related deaths. Acute toxicity was mainly in neutropenia and diarrhea, with both grade 4 neutropenia and grade 3 diarrhea observed in 4 patients(11%). Radical resectability was performed in 29 patients(83%)with sphincter preservation surgery in 7 patients. Six patients did not undergo the planned surgery due to patient refusal and disease progression. A complete pathological response was observed in 14%(4/29). Pathological T-downstaging was observed in 55%(16/29). CONCLUSIONS: These results suggest that preoperative radiochemotherapy with irinotecan/5-FU/leucovorin is safe and effective in tumor downstaging and allows sphincter-saving resection to be performed in locally-advanced rectal cancer.     

阿米福汀对直肠癌同步放化疗患者的保护作用

目的：探讨阿米福汀（AMI）对直肠癌同步放化疗患者的保护作用。方法选取经病理组织学证实的直肠癌患者80例,随机分为治疗组和对照组,每组各40例。所有患者均予盆腔适形调强放射治疗及口服卡培他滨同步化疗。治疗组在同步放化疗基础上加用AMI治疗,观察两组患者的不良反应,并进行对比分析。结果治疗组Ⅱ~Ⅳ级急性直肠炎的发生率为12.5%,明显低于对照组的32.5%,差异具有统计学意义（P﹤0.05）;两组患者均无Ⅲ～Ⅳ级泌尿系统不良反应发生;治疗组中性粒细胞减少发生率为22.5%,明显低于对照组的45%,差异具有统计学意义（P﹤0.05）。AMI相关不良反应有：低血压2例,Ⅲ级呕吐2例,面部温热感1例;无因AMI相关不良反应而中断治疗者。结论 AMI可预防或减轻放化疗带来的不良反应,值得临床推广应用。     

国产奥沙利铂为主的联合化疗结合同期放射治疗晚期直肠癌

目的：了解和评价国产奥沙利铂联合氟尿嘧啶、亚叶酸钙联合同期放射治疗晚期直肠癌的有效性和安全性。方法：国产奥沙利铂(L-OHP)130mg/m^2静脉滴注2小时，第l天；氟尿嘧啶(5-Fu)300mg/m^2静脉滴注，第l～5天；亚叶酸钙(CF)200mg／m^2静脉滴注，第l～5天，2l天为l周期。治疗3周期。与化疗同步进行全盆腔放疗，体外照射DT50～60GY／25～30次(5～6周)。结果：共治疗52例，近期疗效完全缓解(CR)2例；部分缓解(PR)27例；总有效率55．7％。一年生存率为79．0％(4l／30)，2年生存率为48．0％(25／52)。主要毒副反应是消化道反应、神经毒性和放射性直肠炎，而骨髓抑制轻微。结论：国产奥沙利铂为主的联合化疗结合同期放疗治疗晚期直肠癌的效果好，其毒性患可以耐受.     

Phase I trial evaluating the concurrent combination of radiotherapy and capecitabine in rectal cancer.

PURPOSE: To establish the feasibility of concurrent radiotherapy and capecitabine and define the maximum-tolerated dose (MTD) in patients with rectal cancer. PATIENTS AND METHODS: Thirty-six patients with rectal cancer received treatment in the adjuvant, neoadjuvant, or palliative setting with a total irradiation dose of 50.4 Gy with 1.8 Gy/d in approximately 6 weeks. Capecitabine was administered at escalating doses from 250 to 1,250 mg/m(2) bid (including weekends) for the duration of radiotherapy. The MTD was defined when two or more patients in a cohort of three or six patients experienced dose-limiting toxicities. RESULTS: Dose-limiting grade 3 hand-foot syndrome was observed in two of six patients treated at a capecitabine dose of 1,000 mg/m(2) bid. Other toxicities were generally rare and/or mild, with only one case of non-dose-limiting grade 3 diarrhea and a single patient with grade 3 skin toxicity. Myelosuppression consisted mainly of leukocytopenia, with a maximum severity of grade 2. Thus, a dosage of 825 mg/m(2) bid is the recommended dose level for further evaluation. One pathologic complete remission of a T3N1 tumor and nine partial remissions were observed in 10 patients treated in the neoadjuvant setting. CONCLUSION: The recommended dose for phase II evaluation is capecitabine 825 mg/m(2) bid, administered without break during a conventional radiotherapy period of about 6 weeks. This combined-modality approach proved to be a feasible and well-tolerated treatment option with promising preliminary efficacy results in rectal cancer.     

Preoperative concurrent radiotherapy with capecitabine before total mesorectal excision in locally advanced rectal cancer

PURPOSE: Capecitabine is an attractive radiosensitizer which can be tumor specific. This study was undertaken to evaluate the toxicity and efficacy of oral capecitabine when used with preoperative radiation therapy. METHODS AND MATERIALS: We conducted a prospective Phase II trial to assess the pathologic response, sphincter preservation effect, and acute toxicity of preoperative chemoradiation (CRT) in locally advanced (uT3-4/N +) but resectable adenocarcinoma of the lower two-thirds of the rectum. The radiation dose was 50 Gy over 5 weeks (46 Gy to whole pelvis + 4 Gy boost), and capecitabine was administered daily at a dose of 1650 mg/m(2) during the entire course of radiation therapy. Surgery was performed with standardized total mesorectal excision 4 to 6 weeks after completion of CRT and followed by four cycles of capecitabine (2500 mg/m(2)/day for 14 days). RESULTS: Ninety-five patients were entered into this study; their median age was 55 (range, 31-75 years). Ninety (95%) patients completed preoperative CRT as planned, and complete resection was achieved in 92 of 94 resected cases (98%). Downstaging rate was 71% (56/79) on endorectal ultrasonography, and it was 76% (71/94) on pathology finding. No tumor cell was observed in the specimens of 11 patients (12%). Among the 54 whose tumor was located within 5 cm from the anal verge, 40 patients (74%) underwent sphincter-preserving procedures. Elevation of the distal tumor margin from the anal verge by preoperative CRT was 0.8 +/- 1.3 cm. Grade 3 toxicities were rare (diarrhea in 3% and neutropenia in 1%). CONCLUSION: Preoperative CRT using capecitabine achieved encouraging rates of tumor downstaging and sphincter preservation with a low toxicity profile.     

Long-term follow-up of concurrent radiotherapy and chemotherapy for locally advanced cervical cancer: 12-Year survival after radiochemotherapy

Recently randomized trials show an overall survival advantage of 30% for cisplatin-based chemotherapy given concurrently with radiation therapy. Current data do not allow to conclude which drugs could be best combined with cisplatin. Here we report the very long-term results of a prospective phase II trial of concurrent radiochemotherapy in advanced cancer of the cervix. Psychological impact has been evaluated with long-term survivors. Patient with squamous cell carcinoma of the cervix FIGO stage IIB, III or IVA received a concomitant chemotherapy with cisplatin, fluorouracil and mitomycin C and radiotherapy. From June 1988 to September 1990, 22 of 23 patients were eligible. The overall response rate was 82%. All 22 patients treated showed acute hematological toxicity and two patients developed severe late bowel toxicity. Ten patients (45%) were alive after a median observation time of 145.5 months. Intolerance to certain food and vaginal changes due to radiotherapy remain problematic. The lack of improvement compared to cisplatin alone and late bowel toxicity do not support the use of mitomycin C in the combination of the concurrent treatment of chemoradiation. The psychological impact of this treatment should not be minimized. Most problems tend to diminish with time with the exception of intestinal side effects and vaginal changes.     

直肠癌新辅助放化疗的临床疗效分析

目的探讨新辅助放化疗对中晚期直肠癌患者的近期疗效及预后的影响。方法回顾性分析2011年4月至2014年10月间经肿瘤多学科协作综合治疗组(MDT)讨论的152例直肠癌患者的资料,其中60例患者完成同步新辅助放化疗后行手术,化疗方案为卡培他滨825 mg·m-2·d-1,放射治疗采用三维适形放射治疗(3DCRT)或调强适形放射治疗(IMRT),同步放化疗结束后4~8周进行肿瘤切除手术,观察患者的临床疗效。结果 60例患者在采用新辅助放化疗后,50例患者实施了保肛手术,保肛率为83.3%。放化疗后,32例患者的磁共振成像-肿瘤-淋巴结-转移(MRI-TNM)分期降期显著,降期率为53.3%,临床症状完全缓解10例,完全缓解率为16.7%。实施手术的58例患者中,56例患者的术后肿瘤组织有不同程度的缩小、坏死或肿瘤血管闭塞,总有效率为68.9%。结论直肠癌新辅助放化疗可降低肿瘤分期,提高肿瘤切除率及保肛率,但远期疗效及不良反应需进一步观察。