后程加速超分割放射加顺铂治疗食管癌的临床研究

目的观察后程加速超分割放疗同期单药顺铂化疗对食管癌的放射增效作用。方法将符合入选条件的104例食管鳞状细胞癌患者随机分为后程加速超分割放疗组（简称单放组，53例）和后程加速超分割放射加顺铂组（简称放化组，51例）。放疗方法2个组相同．前3周为常规放疗（2Gy／次，1次／d，5d／周），后2周改为加速超分割放疗（1．5Gy／次，2次／d，间隔6h或以上，5d／周）。顺铂于放疗第1、5周分别给予20mg／d，连续5d。结果单放组和放化组的中位生存期分别为12，2、17，0个月。单放组1、3年生存率分别为52.8％、20．8％，放化组的分别为58．0％、24.0％（P〉0．05）。放化组的胃肠道及血液方面的急性反应较明显，而急性食管炎及晚期副反应无明显增加。结论后程加速超分割放射加顺铂治疗食管癌较单纯后程加速超分割放疗有提高总生存率的趋势。     

后程加速超分割放疗和辅助化疗治疗鼻咽癌的临床研究

观察鼻咽癌（NPC）后程加速超分割放疗和辅助化疗的急性反应及近期疗效。方法　按随机方法将26例早期（Ⅰ～Ⅱ期）NPC分为常规分割放疗组及后程加速超分割放疗组，54例晚期（Ⅲ～Ⅳ期）NPC分为常规分割放疗组，后程加速超分割放疗组及后程加速超分割放疗辅助化疗组。结果后程加速超分割放疗辅助化疗组原发肿瘤肉眼消失剂量明显低于未加化疗的其它二组（P＜0．05），各组急性反应程度无明显差异（P＞0．05），而后程加速超分割放疗（包括辅助化疗组）组治疗结束时肿物残存率与常规放疗组相比有下降趋势。结论后程加速超分割放疗和辅助化疗可能为NPC治疗的一种较好的方法，值得进一步研究。     

加速超分割放射治疗的理论与实践

８０年代以来，在放射生物学的迅速发展及有力推动下，临床放射治疗学出现了新的突破，延续多年的常规放疗方法（即每天１次，每周５天，每次１．８～２Ｇｙ）开始趋于动摇，超分割特别是加速超分割在头颈部肿瘤、肺癌、食管癌等一些恶性肿瘤的治疗上取得了令人鼓舞的疗效...     

11例食管癌后程加速放疗临床观察

目的：观察食管癌后程加速超分割放疗的疗效。放射反应及并发症，方法：自1994年－1999年共观察了11例食管癌后程加速放射治疗患，前2／3疗程为常规放疗（40Gy/20次／4周），后1／3疗程行加速分割放疗，每日2次，每次1．3－1．4Gy，间隔时间≥6小时，总剂量60Gy／34－35次／5周。结果：生存情况：1年72．7％（8／11）、2年45．4％（5／11），3年27．3（3／11）、4年18．2（2／11）5年18．2（2／11）。放射反应与常规照射无明显差异。结论：食管癌后程加速超分割放疗生存时间较长，但由于本组病例较少，尚需进一步观察，放疗反应尚可耐受，但对年龄大、有慢性支气管炎应慎用此疗法。     

临床Ⅱ期肺鳞癌的后程加速超分割三维适形放疗

笔者对56例因种种原因未手术的Ⅱ期肺鳞癌患者常规分割放疗后，用信封法随机均分为超分割组（经CT定位进行后程加速超分割三维适形放疗）和对照组（常规分割放疗），现将Ⅱ期临床试验结果报道如下。     

盆腔放疗中放射性直肠损伤的预防

放疗在盆腔肿瘤中的治疗作用日益受到重视，治疗的同时会发生不同程度的放射性直肠损伤，通过改进放射技术、照射剂量和优化分割剂量、使用辐射防护剂等可以减少和预防放射性直肠损伤。放疗技术的改进包括三维适形放疗（3D-CRT）和调强放疗（IMRT）等精确放疗技术，提高肿瘤靶区的剂量，并使肿瘤靶区剂量分布更均匀，能够较好地避开周围的重要器官和组织，减轻正常器官和组织的放射损伤。照射剂量和分割剂量的优化，其机制是根据不同组织的细胞增殖快慢不同，分别给予大剂量分割、超分割和加速超分割，提高肿瘤控制率。使用辐射防护剂保护正常组织的机制是通过阻止自由基的间接损伤和修复直接、间接损伤的DNA，促进损伤细胞的恢复，同时不保护肿瘤组织。     

100例逐级加量全程加速超分割治疗食管癌的研究

目的：探讨逐级加量全程加速超分割和后程加速超分割治疗食管癌的疗效和毒性。方法：100例符合入组条件的食管鳞癌病例随机分为逐级加量全程加速超分割放疗组（全程组）和后程加速超分割放疗组（后程组）各50例。后程组前4周常规放疗，每天照射1次，DT40Gy，20次，后2周超分割放疗，每天照射2次，每次DT1．5Gy，间隔6～8小时，DT30Gy，总剂量DT70Gy，40次，40～45天；全程组采用全程超分割放疗，每天照射2次，间隔6～8小时，第1、2周每次照射DT1．2Gy，第3、4周每次照射DT1．4Gy，第5周每次照射DT1．6Gy，总剂量DT68Cy，50次，34～38天。结果：全部病例随访率100％。全程组和后程组的1、2、3年局部控制率分别为78．5％、72．8％、70．8％和77．7％、69．1％、55．3％（P=0．054）；1、2、3年生存率分别为94％、64％、50％和84％、60％、37％（P=0．049）。急性反应和后期损伤无明显差异（P〉0．05）。结论：逐级加量全程加速超分割提高了食管癌放疗的局控率，有可能提高长期生存率。正常组织急性反应和晚期放射损伤并没有增加。     

后程加速超分割放疗中胸段食管癌临床Ⅲ期试验

目的采用前瞻随机性研究，探讨后程加速超分割放疗（ｌａｔｅｃｏｕｒｓｅａｃｃｅｌｅｒａｔｅｄｈｙｐｅｒｆｒａｃｔｉｏｎａｔｉｏｎｒａｄｉｏｔｈｅｒａｐｙ，ＬＣＡＨＲ）能否提高中胸段食管癌疗效。材料与方法１９９２年４月到１９９４年６月，１０４例中胸段食管癌经分层随机分加速超分割治疗组（Ｅ组）５１例，常规治疗组（Ｃ组）５３例，两组患者一般临床资料差异无统计学意义。放射总剂量Ｅ组：６５．６±１．９Ｇｙ，照射３６（３４～３８）次／３８（３６～４７）天；Ｃ组：总剂量６６．０±１．３Ｇｙ，照射３３（３２～３４）次／４５（４３～５０）天。结果急性放射性食管炎Ｅ组８８％，Ｃ组７２％（Ｐ＝０．０１５）。Ｅ组在不同随访期有２例死于食管大出血，１例出现放射性肺炎。１，２，３年局控率Ｅ组为７８％、５７％、４３％而Ｃ组为５８％、３６％、２６％（Ｐ＝０．０４７）；１，２，３年生存率Ｅ组为７５％、５１％、４１％而Ｃ组为５６％、３６％、２３％（Ｐ＝０．０４２）。结论（１）后程加速超分割放疗能为患者耐受。（２）后程加速超分割放疗提高了局控及生存率。     

食管癌后程加速超分割调强适形放疗及联用尼妥珠单抗的研究

目的 比较食管癌后程加速超分割调强适形放疗和后程加速超分割调强适形放疗联用尼妥珠单抗的疗效与毒性.方法 64例无远处转移的初治、评估认为无法耐受同步放化疗的食管鳞状细胞癌患者随机分组,32例行后程加速超分割调强适形放疗（后超调强组）：先行放疗41.4 Gy/23次,共5周,后行放疗27 Gy/18次,共2周;32例行后程加速超分割调强适形联合尼妥珠单抗治疗（联合组）：放射治疗方法同后超调强组,在放射治疗的开始时同期均加用6～8周的尼妥珠单抗（200 mg,静脉滴注,1次/周,共6～8周）,从放疗第1天起执行.观察指标主要包括食管和肺的近期急性反应和后期放射损伤、过敏等不良反应以及临床受益率、1～3年局控率、无瘤生存率、总体生存率等.结果 后超调强组和联合组患者在放射性食管炎、放射性肺炎、骨髓抑制、消化道反应、皮疹、过敏等不良反应的发生方面差异无统计学意义（P＞0.05）.晚期并发症主要表现为食管狭窄和肺纤维化,两组比较差异无统计学意义（P＞0.05）.联合组有1例患者出现过敏性休克后放弃治疗.后超调强组和联合组患者临床受益率分别为75.0％（24/32）、93.7％（30/32）,两组差异有统计学意义（P＜0.05）.联合组总生存率和无瘤生存率均高于后超调强组,但差异无统计学意义（P＞0.05）.结论 后程加速超分割调强适形放疗联合尼妥珠单抗治疗食管癌临床受益率明显高于后超调强组,但无瘤生存率和总体生存率的差别无统计学意义;后程加速超分割调强适形放疗联合尼妥珠单抗治疗食管癌未明显增加不良反应,部分可能出现过敏反应,应注意预防和加强处理.     

鼻咽癌三种分割放疗的前瞻性随机研究

目的：探讨和比较三种不同放疗方法对鼻咽癌的疗效。方法：将120例鼻咽癌随机分为3组，每组40例，A组连续放疗，B组超分割放疗，C组分段放疗。结果：5年生存率3组相仿，但超分割组和分段组在减少放射后遗症和劳动能力恢复方面优于连续放疗组。结论：超分割和分段放疗对于鼻咽癌生存者的生存质量的提高是有益的。     

Altered Fractionation in Radiation Therapy for Squamous-Cell Carcinoma of the Head and Neck

Following is a review of altered fractionation in radiation therapy for head and neck cancer. The goals of altered fractionation are to increase local-regional control and/or reduce the risk of late complications. Altered fractionation schedules can be broadly classified as accelerated fractionation and hyperfractionation. Data indicate that some of these schedules, particularly hyperfractionated radiation therapy, offer improved results compared to conventionally fractionated radiation therapy. Most investigators have observed no significant increased risk of late complications with the dose-fractionation schedules described.     

Radiotherapy for cancer of the head and neck: altered fractionation regimens

A greater understanding of radiobiology led to the development of two classes of radiation fractionation schedules for the treatment of head and neck cancers. The aim of accelerated fractionation is to reduce tumour proliferation, which is a major cause of relapse, by shortening the total duration of radiotherapy. By contrast, hyperfractionation exploits the differential sensitivity of tumour cells and normal tissues to radiation, to increase the therapeutic gain. The results of clinical trials of various types of altered fractionation schedules in head and neck carcinomas are examined in this review. Acceleration of radiation by 1 week without dose reduction and hyperfractionation are consistently better than standard fractionation for locoregional control of intermediate to advanced carcinomas without an increase in late toxic effects. However, improvement in survival of patients has not been consistent. Clinical investigations show that improvement in locoregional disease control and consistent gain in survival have been achieved with combinations of radiotherapy and concurrent chemotherapy in patients with mostly stage IV carcinomas. However, these benefits have been at the expense of increased late morbidity. Consequently, concurrent radiochemotherapy is now preferred for non-surgical treatment of patients with locally advanced carcinomas, whereas altered fractionation is generally selected for patients with intermediate-stage tumours or who are medically unfit to receive chemotherapy. Further data is needed before the combination of altered fractionation with chemotherapy can be recommended outside of a study setting.     

Altered fractionation: limited by mucosal reactions?

The effectiveness of accelerated fractionation and hyperfractionation in cancer of the head and neck has been confirmed by randomized studies. These new fractionation strategies are almost invariably accompanied by an increase of early normal tissue reactions, in particular mucosal reactions. This paper presents a survey of the available experimental and clinical mucositis data and aims to assess to what extent the upper aerodigestive tract mucosa is limiting to treatment intensification by altered fractionation.

The rate of dose delivery is the most important determinant for early radiation reactions. With accelerated radiotherapy, relative to a conventional treatment of 7 weeks, the achievable gain in treatment time is 2 weeks at most with the mucosa being the limiting tissue. Any further acceleration requires a reduction of dose. Manipulations with the temporal distribution of dose, fraction dose, and optimization of interfraction intervals can improve tolerance but probably do not allow significant further intensification of the existing accelerated schedules. Dose escalation by hyperfractionation does not seem to be directly limited by early mucosal reactions. Late reacting tissues are more likely to limit intensification of these schedules.

Suggestions for further improvement of treatment outcome include: the generation of a potent agent which can ameliorate radiation mucositis and so permit further intensification of radiotherapy schedules; combination of altered fractionation schedules with hypoxic modifiers; and tailoring of the treatment strategy based on patient and tumour characteristics.     

Comparison of accelerated hyperfractionated radiotherapy and conventional radiotherapy for supratentorial malignant glioma

Between 1988 and 1993, 71 patients with glioblastoma or anaplastic astrocytoma were treated either with accelerated hyperfractionation radiotherapy (1.5 Gy twice daily to a total dose of 69 Gy, n = 35) or with conventional fractionation radiotherapy (1.8 Gy daily to 64.8 Gy, n = 36). Two patients in each group did not complete radiotherapy, leaving 67 evaluable. All patients received the chemotherapeutic regime ACNU intraarterially (50 mg/m2) or intravenously (100 mg/m2) prior to and after radiotherapy. Between 1990 and 1992, 19 patients also received intravenous interferon-beta (3 x 10(6) U, three times weekly) during radiotherapy. The median survival time was 14.5 months for the accelerated hyperfractionation group and 14 months for the conventional fractionation group. The median time to progression was 12 months for the accelerated hyperfractionation group and 9.5 months for the conventional fractionation group. There was no significant difference in either survival (P = 0.89) or progression-free survival (P = 0.25) between the accelerated hyperfractionation and conventional fractionation groups. Interferon therapy was associated with poorer survival. Brain necrosis developed in four out of 10 patients receiving accelerated hyperfractionation radiotherapy plus interferon-beta, but in none of nine patients receiving conventional fractionation radiotherapy plus interferon (P = 0.033). In conclusion, our study failed to demonstrate any possible benefit of accelerated hyperfractionation radiotherapy for malignant glioma. The incidence of brain necrosis may be increased by combining accelerated hyperfractionation radiotherapy and interferon-beta.      

后程缩野加速超分割放疗联合化疗治疗Ⅲ和Ⅳa期鼻咽癌的临床研究

 目的　研究后程缩野加速超分割放疗联合化疗治疗Ⅲ和Ⅳa期鼻咽癌的疗效和毒副作用。方法　 178例Ⅲ和Ⅳa期鼻咽癌患者随机分为研究组和对照组 ,均先诱导化疗两疗程 ,而后研究组行常规分割放疗 4 0Gy加缩野加速超分割放疗至 70～ 76Gy ,对照组常规分割放疗 70Gy ,放疗后两组均再化疗两疗程。结果　肿瘤原发灶CR、PR率 ,1、3年局部控制率和 3年无瘤生存率两组间有显著性差异 ;1、3年生存率和 3年累计远处转移率两组间无显著性差异 ;研究组Ⅱ～Ⅲ度急性放射性口咽黏膜反应发生率高于对照组。结论　后程缩野加速超分割放疗联合化疗提高了Ⅲ和Ⅳa期鼻咽癌的肿瘤消退率、局部控制率及无瘤生存率 ,急性放射反应加重但可以耐受 ,能否提高总生存率有待进一步观察     

Early Reactions as Dose-Limiting Factors in Radiotherapy

Early side effects of radiation therapy are generally the result of mitotic-linked cell death in rapidly renewing tissues and secondary impaired tissue function. Various types of acute normal tissue reactions are briefly summarized in this article. In general, with conventionally fractionated radiation treatment, the acute normal tissue reactions are within acceptable limits. However, new radiotherapy strategies, such as hyperfractionation and accelerated fractionation, induce more severe acute toxicity. Particularly, with most altered fractionation schedules, the mucosal reaction of the upper aerodigestive tract is elevated to the upper limit of tolerance. Early mucosal reactions may also become dose limiting when radiation is combined with chemotherapy as, for instance, for the treatment of head and neck cancer or pelvic neoplasms. Bone marrow is the critical organ for combination of chemotherapy and wide field irradiation. There is an increasing body of evidence that iatrogenic acute normal tissue toxicity has become a major obstacle for treatment intensification for a variety of cancers. Therefore, effective measures to ameliorate these side effects are essential for further development of cancer therapy. Methods to reduce the severity of acute toxicity are being investigated.     

后程加速超分割放疗和常规分割加腔内放疗食管癌的回顾性分析

目的 回顾分析和比较后程加速超分割放疗（后超组）与常规分割＋腔内放疗（腔内组）食管癌的疗效.方法 对1994年5月至1999年11月间4个小样本前瞻性研究的后超组（135例）和腔内组（130例）治疗食管癌的病例进行分析比较.后超组前3周常规分割照射3000cGy（分15次3周完成）,后2周采用加速超分割照射3000 cGy（分20次2周完成;150 cGy/次,2次/d,2次相隔6 h,5d/周）.腔内组常规分割照射5000 cGy（分25次5周完成）＋腔内照射1000 cGy（分2次）.结果 后超组和腔内组1、3、5年总生存率分别为61.8%、27.9%、19.9%和53.5%、25.2%、18.4%（P＞0.05）.后超组和腔内组急性放射性食管炎的发生率分别为61.5%和57.0%（P=0.235）,且RTOG分级3级食管炎比较两组差异也无统计学意义.结论 两种放疗方式食管癌的生存率无明显差别,但后程加速超分割技术操作方便,易于在临床中实施.     

Accelerated hyperfractionation (AHF) compared to conventional fractionation (CF) in the postoperative radiotherapy of locally advanced head and neck cancer: influence of proliferation

Based on the assumption that an accelerated proliferation process prevails in tumour cell residues after surgery, the possibility that treatment acceleration would offer a therapeutic advantage in postoperative radiotherapy of locally advanced head and neck cancer was investigated. The value of T(pot) in predicting the treatment outcome and in selecting patients for accelerated fractionation was tested. Seventy patients with (T2/N1-N2) or (T3-4/any N) squamous cell carcinoma of the oral cavity, larynx and hypopharynx who underwent radical surgery, were randomized to either (a) accelerated hyperfractionation: 46.2 Gy per 12 days, 1.4 Gy per fraction, three fractions per day with 6 h interfraction interval, treating 6 days per week or (b) Conventional fractionation: 60 Gy per 6 weeks, 2 Gy per fraction, treating 5 days per week. The 3-year locoregional control rate was significantly better in the accelerated hyperfractionation (88 +/- 4%) than in the CF (57+/- 9%) group, P=0.01 (and this was confirmed by multivariate analysis), but the difference in survival (60 +/- 10% vs 46 +/- 9%) was not significant (P=0.29). The favourable influence of a short treatment time was further substantiated by demonstrating the importance of the gap between surgery and radiotherapy and the overall treatment time between surgery and end of radiotherapy. Early mucositis progressed more rapidly and was more severe in the accelerated hyperfractionation group; reflecting a faster rate of dose accumulation. Xerostomia was experienced by all patients with a tendency to be more severe after accelerated hyperfractionation. Fibrosis and oedema also tended to be more frequent after accelerated hyperfractionation and probably represent consequential reactions. T(pot) showed a correlation with disease-free survival in a univariate analysis but did not prove to be an independent factor. Moreover, the use of the minimum and corrected P-values did not identify a significant cut-off. Compared to conventional fractionation, accelerated hyperfractionation did not seem to offer a survival advantage in fast tumours though a better local control rate was noted. This limits the use of T(pot) as a guide for selecting patients for accelerated hyperfractionation. For slowly growing tumours, tumour control and survival probabilities were not significantly different in the conventional fractionation and accelerated hyperfractionation groups. A rapid tumour growth was associated with a higher risk of distant metastases (P=0.01). In conclusion, tumour cell repopulation seems to be an important determinant of postoperative radiotherapy of locally advanced head and neck cancer despite lack of a definite association between T(pot) and treatment outcome. In fast growing tumours accelerated hyperfractionation provided an improved local control but without a survival advantage. To gain a full benefit from treatment acceleration, the surgery-radiotherapy gap and the overall treatment time should not exceed 6 and 10 weeks respectively.     

Altered fractionation in definitive irradiation of squamous cell carcinoma of the head and neck

The likelihood of local control after radiation therapy may be improved by increasing total dose or decreasing overall time. The probability of late complications increases with dose per fraction. Altered fractionation techniques usually employ two or more fractions per day using a dose per fraction that is similar or less than that employed in conventional fractionation. Altered fractionation may be broadly classified as hyperfractionation or accelerated fractionation. Data suggest that altered fractionation schedules may improve local control (and to a lesser extent, survival) compared with conventional irradiation.     

Altered fractionation and combined radio-chemotherapy approaches: pioneering new opportunities in head and neck oncology

Squamous cell carcinoma of the head and neck (HNSCC) are increasingly treated by multimodality approaches combining surgery, radiotherapy and chemotherapy. Randomised controlled trials have demonstrated major improvements in loco-regional tumour control from altered fractionation radiotherapy, accelerated fractionation and hyperfractionation, as compared with conventional fractionation. This experience is summarised, and the limit as to how far these modifications can be taken is discussed. It is emphasised that radiation fractionation will need to be optimised separately in multimodality strategies. Combined chemotherapy and radiotherapy has also been shown in phase III trials to produce an improved survival and an improved disease control. Chemotherapy may be given as neoadjuvant, concurrent or adjuvant treatment and the biological rationales for each of these, and the data supporting them, are reviewed. Although, large meta-analyses have shown concurrent chemoradiation to be the most effective, there is still a strong rationale for trying to develop neoadjuvant and adjuvant schedules. New, more active drugs may be important in this context. As therapy is becoming more intense, a careful recording and reporting of treatment-related morbidity is a crucial element in estimating the therapeutic gain from competing therapeutic management strategies. Development of non-cytostatic drugs and individualization of therapy using molecular prognostic markers are exciting areas of research with a great potential for improving therapy in the next decade and these are briefly discussed. Finally, a number of avenues for further research are identified.