Preoperative chemoradiation versus radiation alone for stage II and III resectable rectal cancer

  • Review
  • Intervention

Authors


Abstract

Background

Preoperative radiotherapy (RT) decreases local recurrence rate and improves survival in stage II and III rectal cancer patients. The combination of chemotherapy with RT has a sound radiobiological rationale, and phase II trials of combined chemoradiation (CRT) have shown promising activity in rectal cancer.

Objectives

To compare preoperative RT with preoperative CRT in patients with resectable stage II and III rectal cancer.

Search methods

We searched the Cochrane Register of Controlled Trials, Web of Science, Embase.com, and Pubmed from 1975 until June 2012. A manual search was performed of Ann Surg, Arch Surg, Cancer, J Clin Oncol, Int J Radiat Oncol Biol Phys and the proceedings of ASTRO, ECCO and ASCO from 1990 until June 2012.

Selection criteria

Relevant studies randomized resectable stage II or III rectal cancer patients to at least one arm of preoperative RT alone or at least one arm of preoperative CRT.

Data collection and analysis

Primary outcome parameters included overall survival (OS) at 5 years and local recurrence (LR) rate at 5 years. Secondary outcome parameters included disease free survival (DFS) at 5 years, metastasis rate, pathological complete response rate, clinical response rate, sphincter preservation rate, acute toxicity, postoperative mortality and morbidity, and anastomotic leak rate. Outcome parameters were summarized using the Odds Ratio (OR) and associated 95% confidence interval (CI) using the fixed effects model.

Main results

Five trials were identified and included in the meta-analysis. From one of the included trials only preliminary data are reported. The addition of chemotherapy to preoperative RT significantly increased grade III and IV acute toxicity (OR 1.68-10, P = 0.002) and marginally affected postoperative overall morbidity (OR 0.67-1.00, P = 0.05) while no differences were observed in postoperative mortality or anastomotic leak rate. Compared to preoperative RT alone, preoperative CRT significantly increased the rate of complete pathological response (OR 2.12-5.84, P < 0.00001) although this did not translate into a higher sphincter preservation rate (OR 0.92-1.30, P = 0.32). The incidence of local recurrence at five years was significantly lower in the CRT group compared to RT alone (OR 0.39-0.72, P < 0.001). No statistically significant differences were observed in DFS (OR 0.92-1.34, P = 0.27) or OS (OR 0.79-1.14, P = 0.58) at five years.

Authors' conclusions

Compared to preoperative RT alone, preoperative CRT enhances pathological response and improves local control in resectable stage II and III rectal cancer, but does not benefit disease free or overall survival. The effects of preoperative CRT on functional outcome and quality of life are incompletely understood and should be addressed in future trials.

Résumé scientifique

Chimiothérapie préopératoire versus radiothérapie seule pour le cancer rectal résécable de stade II et III

Contexte

La radiothérapie (RT) préopératoire diminue le taux de récidive local et améliore la survie des patients atteints d'un cancer rectal de stade II et III. L'association de chimiothérapie et de RT a une justification radiobiologique solide, et les essais de phase II de la chimiothérapie combinée (CRT) ont montré une activité prometteuse sur le cancer rectal.

Objectifs

Comparer la RT préopératoire à la CRT préopératoire chez les patients avec un cancer rectal résécable de stade II et III.

Stratégie de recherche documentaire

Nous avons effectué des recherches dans le registre Cochrane des essais contrôlés, Web of Science, EMbase.com et Pubmed de 1975 à juin 2012. Une recherche manuelle a été effectuée dans Ann Surg, Arch Surg, J Clin Oncol, Int J Radiat Oncol Biol Phys et les actes de conférences d'ASTRO, ECCO et ASCO de 1990 à juin 2012.

Critères de sélection

Les études pertinentes randomisaient les patients atteints d'un cancer rectal résécable de stade II ou III dans au minimum un bras de RT préopératoire seule ou au minimum un bras de CRT préopératoire.

Recueil et analyse des données

Les paramètres des principaux critères de jugement comprenaient la survie globale (SG) à 5 ans et le taux de récidive locale (RL) à 5 ans. Les paramètres des critères de jugement secondaires incluaient la survie sans maladie (SSM) à 5 ans, la taux de métastase, la taux de réponse complète pathologique, le taux de réponse clinique, le taux de préservation des sphincters, la toxicité aigüe, la mortalité et la morbidité post-opératoire et le taux de fuite anastomotique. Les paramètres des critères de jugement ont été résumés à l'aide des rapports de cotes (ou Odds Ratio (OR)) et des intervalles de confiance (IC) à 95 % associés au modèle à effets fixes.

Résultats principaux

Cinq essais ont été identifiés et inclus dans la méta-analyse. A partir d'un des essais inclus, seules des données préliminaires ont été signalées. L'ajout de la chimiothérapie à la RT préopératoire a augmenté de manière significative la toxicité aigüe de stade III et IV (OR 1,68-10, P = 0,002) et affecté de manière marginale la morbidité globale post-opératoire (OR 0,67-1,00, P = 0,05) alors qu'aucune différence n'a été observée dans la mortalité postopératoire ou le taux de fuite anastomotique. Par rapport à la RT préopératoire seule, la CRT préopératoire a augmenté de manière significative le taux de réponse pathologique complète (OR 2,12-5,84, P < 0,00001) bien que cette donnée ne traduise pas un taux de préservation des sphincters plus élevé (OR 0,92-1,30, P = 0,32). L'incidence de la récidive locale à cinq ans était significativement plus basse dans le groupe avec CRT par rapport à la RT seule (OR 0,39-0,72), P < 0,001). Aucune différence statistiquement significative n'a été observée dans la SSM (OR 0,92-1,34, P = 0,27) ou la SG (OR 0,79-1,14, P = 0,58) à cinq ans.

Conclusions des auteurs

Par rapport à la RT préopératoire seule, la CRT préopératoire renforce la réponse pathologique et améliore le contrôle local dans le cancer rectal résécable de stade II et III, mais elle n'apporte rien dans la survie sans maladie ou la survie globale. Les effets de la CRT préopératoire sur le résultat fonctionnel ou la qualité de vie ne sont pas complètement compris et devraient être abordés dans des essais ultérieurs.

摘要

第二期與第三期可切除的大腸直腸癌之術前化學放射治療與單做放射治療比較

背景

術前放射治療(RT)降低第二期與第三期大腸直腸癌患者的局部復發率並且改善存活率。化學治療與RT的合併治療有健全的放射生物學基礎,且化學放射(CRT)合併治療的第二期試驗顯示,對於大腸直腸癌的作用是值得期待且有希望的。

目的

比較在可切除的第二期與第三期大腸直腸癌患者身上的術前RT與術前CRT。

搜尋策略

我們搜尋了Cochrane Register of Controlled Trials、Web of Science、Embase.com以及Pubmed等資料庫中從1975年至2012年6月止的資料。針對Ann Surg、Arch Surg、Cancer、J Clin Oncol、Int J Radiat Oncol Biol Phys以及 ASTRO、ECCO與 ASCO會議論文的人工搜尋,由1990年開始進行至2012年6月。

選擇標準

相關研究將可切除的第二期與第三期大腸直腸癌患者隨機分派為至少1個術前RT組或至少1個術前CRT組。

資料收集與分析

主要結果參數包括5年整體存活期(OS)與5年局部復發率(LR)。次要結果參數包括5年無病存活期(DFS)、轉移率、病理完全反應率、臨床反應率、括約肌保存率、急性毒性、術後死亡率與發病率,以及吻合口漏率。結果參數以勝算比(OR)來做總結,並結合95%信賴區間(CI)的固定效應模式。

主要結果

找出了5個試驗並且收錄在統合分析中,其中1個收錄的研究只記錄初步資料。術前RT之外的化學治療顯著地增加第三與第四級急性毒性(OR 1.68-10, P = 0.002)且稍微影響術後整體發病率(OR 0.67-1.00, P = 0.05),然而對於術後死亡率或吻合口漏率則沒有觀察到差異。雖然無法轉化為較高的括約肌保存率(OR 0.92-1.30, P = 0.32),但與單獨做術前RT比較,術前CRT顯著增加病理完全反應率(OR 2.12-5.84, P < 0.00001)。5年局部復發率在CRT組中顯著低於單獨做RT的組(OR 0.39-0.72, P < 0.001)。在5年DFS(OR 0.92-1.34, P = 0.27)或5年OS(OR 0.79-1.14, P = 0.58)中則沒有觀察到統計上的顯著差異。

作者結論

相較於單做術前RT,術前CRT加強了病理反應並改善對可切除的第二期與第三期大腸直腸癌的局部控制,但是對無病存活期與整體存活率則沒有效益。並沒有完全瞭解術前CRT對於功能性結果以及生活品質的效應,未來的試驗應該要處理這個部分。

譯註

翻譯者:臺北醫學大學考科藍臺灣研究中心(Cochrane Taiwan)

本翻譯計畫由臺北醫學大學考科藍臺灣研究中心(Cochrane Taiwan)、台灣實證醫學學會及東亞考科藍聯盟(EACA)統籌執行
聯絡E-mail:cochranetaiwan@tmu.edu.tw

Resumo

Quimiorradiação versus radioterapia isolada no pré-operatório de pacientes com câncer retal ressecável estádios II e III

Introdução

Nos pacientes com câncer retal estádios II e III, a radioterapia pré-operatória (RT) reduz a taxa de recorrência local e melhora a sobrevida. A combinação da quimioterapia com a RT (quimiorradiação, QRT) tem fundamento lógico radiobiológico. Os resultados dos estudos de fase II com QRT são animadores para pacientes com câncer retal.

Objetivos

Comparar a RT pré-operatória com o QRT pré-operatória em pacientes com câncer retal ressecável estádios II e III.

Métodos de busca

Nós procuramos no Cochrane Register of Controlled Trials, Web of Science, Embase.com e Pubmed de 1975 até junho de 2012. Fizemos busca manual nos periódicos Ann Surg, Arch Surg, Cancer, J Clin Oncol, Int J Radiat Oncol Biol Phys e nos anais de congressos da ASTRO, ECCO e ASCO de 1990 até junho de 2012.

Critério de seleção

Incluímos estudos randomizados relevantes envolvendo pacientes com câncer retal ressecável estádios II ou III com pelo menos um braço do estudo submetido a RT pré-operatória isolada ou pelo menos um braço do estudo submetido a QRT pré-operatória.

Coleta dos dados e análises

Os desfechos primários foram a sobrevida global em cinco anos e a taxa local de recidiva (RL) em cinco anos. Os desfechos secundários foram a sobrevida livre da doença (SLD) em cinco anos, taxa de metástases, taxa de resposta patológica completa, taxa de resposta clínica, taxa da preservação do esfíncter, toxicidade aguda, mortalidade e morbidade pós-operatória, e taxa de vazamento (deiscência) da anastomose. Os desfechos foram sintetizados usando a razão de chances (OR) e o intervalo de confiança de 95% (95% CI) usando o modelo de efeito fixo.

Principais resultados

Cinco estudos foram identificados e incluídos na metanálise. Um dos estudos incluídos relatou apenas dados preliminares. A adição da quimioterapia à RT pré-operatória aumentou significativamente a proporção de pacientes com toxicidade aguda classes III e IV (OR 1,68-100; P = 0,002), teve um efeito limítrofe sobre a morbidade total pós-operatória (OR 0,67-1.00; P = 0,05) e não modificou a mortalidade pós-operatória ou a taxa de vazamento da anastomose. Comparada à RT pré-operatória sozinha, a QRT pré-operatória aumentou significativamente a taxa da resposta patológica completa (OR 2,12-5,84; P < 0,00001), embora isso não tenha sido acompanhado por uma taxa mais alta da preservação do esfíncter (OR 0,92-1,30; P = 0,32). A incidência de recidiva local em cinco anos foi significativamente menor no grupo de QRT comparado ao de RT isolada (OR 0,39-0,72; P < 0,001). Nenhuma diferença estatística significativa foi observada na sobrevida livre de doença (OR 0,92-1,34; P = 0,27) ou sobrevida global (OR 0,79-1,14; P = 0,58) em cinco anos.

Conclusão dos autores

Comparada à RT pré-operatória isolada, a QRT pré-operatória aumenta a resposta patológica e melhora o controle local nos pacientes com câncer retal ressecável estádios II e III, mas não está associado a benefícios para sobrevida livre de doença ou global. Os efeitos da QRT pré-operatória sobre os desfechos de funcionalidade e qualidade de vida ainda não estão claros e devem ser avaliados em estudos futuros.

Notas de tradução

Tradução do Centro Cochrane do Brasil (Flávia Maria Ribeiro Vital)

摘要

术前放化疗与单纯术前放疗对可切除直肠癌II 期III 期患者的治疗比较

研究背景

术前放射性疗法(Preoperatiev Radiotherapy RT)能降低直肠癌II期III期患者的局部复发率和提高患者生存率。在可靠的放射生物学原理基础上,对术前化学疗法(化疗)与放射性疗法(放疗)进行结合,并发现其在放化疗的第二阶段试验中对直肠癌治疗潜力巨大。

研究目的

比较术前放疗与术前放化疗在可切除直肠癌II期III期患者中的治疗效果。

检索策略

我们对Cochrane对照试验注册库(Cochrane Register of Controlled trials),科学引文索引数据库(Web of Science),Embase数据库 和Pubmed数据库的文献进行了检索。检索自1975年至2012年6月发表的文献。此外,我们还手动检索了《外科学年鉴》(Ann Surg),《外科学文献》(Arch Surg),《癌症》(Cancer),《临床肿瘤学杂志》(J Clin Oncol),《国际放射肿瘤学杂志》(Int J Radiat Oncol Biol Phys)和一些国外学会的会议论文,包括了美国放射肿瘤学会(ASTRO),欧洲癌症组织(ECCO)和美国临床肿瘤学会(ASCO)。检索自1990年至2012年6月发表的文献。

标准/纳入排除标准

纳入将可切除直肠癌II期III期患者随机分成单独接受术前放疗组(至少一组)或术前放化疗组(至少一组)的相关研究。

数据收集与分析

主要的结局参数包括了五年内整体存活数(OS)和五年内的局部复发率(LR)。次要的结局参数包括了五年内的无病生存率(DFS),转移率,病理完全反应率,临床反应率,保肛率,急性毒性,术后死亡率和发病率和吻合口漏发生率。结局指标通过比值比(Odds Ratio, OR)和相关的95%可信区间(CI)进行总结,meta分析使用固定效应模型。

主要结果

本系统综述的meta分析纳入了五项临床试验。有一项研究只报道了初步研究数据。在术前放疗增加化疗明显增加了三级和四级急性中毒率(OR 1.68-10, P=0.002),且最低限度地影响术后发病率(OR 0.67-1.00, P=0.05),但经观察术后发病率与吻合泄漏率没有显著差异。术前放化疗比单独使用术前放疗更有效地提高了病理完全反应率(OR 2.12-5.84, P<0.00001),但是保肛率却没有相应地提高(OR 0.92-1.30, P=0.32)。相比单独使用术前放疗,术前放化疗能有效地降低患者在术后五年内的局部复发率(OR 0.39-0.72,P<0.001)。两组患者五年内的无病生存率(OR 0.92-1.34, P=0.27)和总存活率(OR 0.79-1.14, P=0.58)的差异不具有数据学统计意义。

作者结论

相比单独使用术前放疗,术前放化疗能增强病理反应及提高在可切除直肠癌II期III期患者的局部控制力,但不能提高无病生存率或总存活数。术前放化疗在其功能结局和生活质量上的效果尚未得到充分的解释和报告,因此还需要在今后的临床试验中强调。

翻译注解

译者:狄晓雪、梁若岚(北京中医药大学中医英语专业本科生);审校:狄晓雪、梁若岚、李迅 北京中医药大学循证医学中心

Plain language summary

Radiotherapy alone versus radiotherapy combined with chemotherapy before operation of rectal cancer

Patients with cancer of the rectum, the end part of the large bowel immediately above the anus, are treated with surgery. When the tumour is deemed to present a high risk of recurrence after surgery, a course of radiotherapy (RT) is administered before the operation. It has been proven in clinical studies that this 'preoperative' radiotherapy improves the outcome in rectal cancer patients. Recently, several studies have investigated the combination of radiotherapy with chemotherapy (CRT) before surgery. In theory, adding chemotherapy enhances the antitumour activity of radiotherapy. This meta-analysis has summarized the results of five studies that compared preoperative RT alone with preoperative CRT in rectal cancer patients. All of these studies were randomized, which means that the decision to administer either RT or CRT was determined by chance (ballot draw). The results of the meta-analysis may be summarized as follows. Compared to RT alone, preoperative CRT leads to increased side effects during treatment. Also, postoperative complications are somewhat increased, although the risk of dying from postoperative complications is similar. Preoperative CRT is more effective in causing tumour shrinkage (downstaging), and in preventing local recurrence of the disease. However, addition of chemotherapy did not result in more sphincter preserving surgeries, and did not affect the overall survival in rectal cancer patients.

Résumé simplifié

Radiothérapie seule versus radiothérapie associée à une chimiothérapie avant l'opération d'un cancer rectal

Les patients souffrant d'un cancer du rectum, l'extrémité du gros intestin située juste au dessus de l'anus, sont traités par la chirurgie. Lorsque la tumeur est jugée comme présentant un risque élevé de récidive après la chirurgie, une série de radiothérapie (RT) est administrée avant l'opération. Il a été prouvé dans les études cliniques que cette radiothérapie 'préopératoire' améliore le résultat des patients atteints d'un cancer rectal. Dernièrement, plusieurs études ont examiné l'association de la radiothérapie et de la chimiothérapie (CRT) avant la chirurgie. En théorie, le fait d'ajouter la chimiothérapie augmente l'activité anti-tumeur de la radiothérapie. Cette méta-analyse a résumé les résultats de cinq études qui comparaient la RT préopératoire seule à la CRT préopératoire sur les patients atteints d'un cancer rectal. Toutes ces études étaient randomisées, ce qui signifie que la décision d'administrer soit la RT, soit la CRT a été déterminée de manière aléatoire (tirage au sort). Les résultats de la méta-analyse peuvent être résumés comme suit. Par rapport à la RT seule, la CRT préopératoire entraîne plus d'effets secondaires pendant le traitement. De même, les complications post-opératoires sont parfois plus nombreuses, bien que le risque de décès lié aux complications post-opératoires soit similaire. La CRT préopératoire est plus efficace pour réduire la taille de la tumeur (réduction tumorale) et prévenir la récidive locale de la maladie. Pour autant, l'ajout de la chimiothérapie n'a pas entraîné plus de chirurgies pour préserver les sphincters; et n'a pas affecté la survie globale chez les patients atteints d'un cancer rectal.

Notes de traduction

Traduit par: French Cochrane Centre 1st March, 2013
Traduction financée par: Pour la France : Ministère de la Santé. Pour le Canada : Instituts de recherche en santé du Canada, ministère de la Santé du Québec, Fonds de recherche de Québec-Santé et Institut national d'excellence en santé et en services sociaux.

Laički sažetak

Sama radioterapija naspram radioterapije u kombinaciji s kemoterapijom prije operacije raka rektuma

Bolesnici s rakom rektuma, odnosno završnog dijela debelog crijeva neposredno iznad anusa, liječe se operacijom. Kad se smatra da tumor posjeduje visoki rizik od recidiva nakon operacije, prije operacije se primjenjuje slijed radioterapije (RT). Dokazano je u kliničkim studijama da ova 'preoperativna' radioterapija poboljšava ishod u bolesnika s rakom rektuma. Nedavno je nekoliko ispitivanja istraživalo primjenu kombinacije radioterapije s kemoterapijom (KRT) prije kirurškog zahvata. Teoretski, dodavanje kemoterapije poboljšava antitumorsko djelovanje radioterapije. Ovaj Cochrane sustavni pregled sažeo je rezultate pet studija koje su uspoređivale preoperativnu samu RT sa preoperativnom KRT u bolesnika s rakom rektuma. Sve su ove studije bile randomizirane, što znači da je odluka za davanje bilo RT ili KRT određena slučajnim odabirom (izvlačenjem listića). Rezultati metaanalize mogu se sažeti kako slijedi. U usporedbi sa samom RT, preoperativna KRT dovodi do povećanja nuspojava tijekom liječenja. Također, donekle su povećane poslijeoperacijske komplikacije, iako je rizik od smrti od poslijeoperacijskih komplikacija sličan. Preoperativna KRT je učinkovitija u uzrokovanju smanjenja tumora (smanjenje stadija), te u sprječavanju lokalnog recidiva bolesti. Međutim, dodavanje kemoterapije nije rezultiralo s više operacija za očuvanje sfinktera, te nije utjecalo na ukupno preživljenje u bolesnika s rakom rektuma.

Bilješke prijevoda

Hrvatski Cochrane
Prevela: Katarina Vučić
Ovaj sažetak preveden je u okviru volonterskog projekta prevođenja Cochrane sažetaka. Uključite se u projekt i pomozite nam u prevođenju brojnih preostalih Cochrane sažetaka koji su još uvijek dostupni samo na engleskom jeziku. Kontakt: cochrane_croatia@mefst.hr

淺顯易懂的口語結論

大腸直腸癌手術前單做放射治療與放射治療合併化學治療之比較

直腸罹癌的患者,是以手術來治療在肛門正上方的大腸末端。當腫瘤的術後復發風險被視為高的話,會在術前給予放射治療(RT)。臨床研究已經證實這種術前放射治療改善大腸直腸癌患者的結果。近來有不少研究調查在手術前進行放射治療合併化學治療(CRT)。理論上,增加化學治療能加強放射治療對抗腫瘤的活動力。本統合分析概括了5個比較術前RT與術前CRT對於大腸直腸癌患者的研究結果。所有的研究都是隨機的,意思是指不論給予RT或CRT的決定都是偶然(抽籤)。統合分析的結果可以概括如下:相較於只做RT,術前CRT導致治療中的副作用增加;再者,雖然死於術後併發症的風險相似,但術後併發症也有些微的增加。術前CRT對於造成腫瘤萎縮(縮小)與預防此疾病的局部復發較為有效。然而,額外的化學治療沒有導致更多的括約肌保存手術,也沒有影響大腸直腸癌患者的整體存活率。

譯註

翻譯者:臺北醫學大學考科藍臺灣研究中心(Cochrane Taiwan)

本翻譯計畫由臺北醫學大學考科藍臺灣研究中心(Cochrane Taiwan)、台灣實證醫學學會及東亞考科藍聯盟(EACA)統籌執行
聯絡E-mail:cochranetaiwan@tmu.edu.tw

Resumo para leigos

Radioterapia isolada comparada com radioterapia combinada com quimioterapia antes da cirurgia de câncer retal

As pessoas com câncer do reto (a parte final do intestino grosso, que fica acima do ânus) são tratadas com cirurgia. Quando o tumor apresenta alto risco de recidiva após a cirurgia, esses pacientes também fazem sessões de radioterapia (RT) antes da operação. Estudos clínicos concluíram que essa RT pré-operatória melhora o resultado em pacientes com câncer retal. Recentemente, diversos estudos investigaram a combinação da RT com quimioterapia (QRT) antes da cirurgia. Em teoria, adicionar quimioterapia aumentaria o efeito antitumoral da RT. Esta revisão sintetizou os resultados de cinco estudos que compararam a RT pré-operatória sozinha contra a QRT pré-operatória em pacientes com câncer retal. Todos esses estudos eram randomizados, o que significa que a decisão de ser tratado com RT ou QRT foi determinada por acaso (sorteio). Os resultados da metanálise podem ser resumidos como se segue. Comparada à RT sozinha, a QRT pré-operatória aumenta os efeitos colaterais durante o tratamento e também aumenta as complicações pós-operatórias embora o risco de morrer dessas complicações seja similar. A QRT pré-operatória é mais eficaz para diminuir o tumor (reduzir o estadio), e em impedir a recidiva local da doença. Entretanto, a adição de quimioterapia não aumentou a chance de os pacientes com câncer retal terem cirurgias que preservem, o esfíncter anal, e não afetou sua sobrevida global.

Notas de tradução

Tradução do Centro Cochrane do Brasil (Flávia Maria Ribeiro Vital)

概要

术前放化疗与术前放疗对可切除直肠癌II 期III 期患者的治疗比较

比较直肠癌术前单独使用放射性疗法和术前放射性疗法,化学疗法的放化疗结合治疗疗效 直肠癌(即在肛门上大肠末端发生癌变)的患者,应予手术进行治疗。因为直肠癌术后复发率高具有复发的高风险,所以需在其手术前进行增加放射性疗法(放疗)。临床研究表明,术前放疗可提高改善直肠癌的预后。近期一些研究对放疗与化疗在直肠癌术前的结合治疗进行了研究探讨。理论上,在放疗基础上结合化疗能增强放疗抗癌的效果。这篇meta分析总结了五项研究中的直肠癌术前放疗及放化疗的治疗效果比较。所有的这些研究都具有随机性,这意味着随机(抽签)决定直肠癌患者是接受术前放疗还是放化疗。以下是这篇meta分析总结的结果:比较术前放疗和术前放化疗,它们在术后因并发症导致的死亡风险是相似的,但术前放化疗会增加治疗中的副作用,且其术后的并发症也会相应增加。虽然术前放化疗更能有效缩小癌症范围肿瘤面积,防止癌症疾病局部复发。但是,术前放化疗的结合不能增加括约肌保留保肛率和提高直肠癌患者的总存活率。

翻译注解

译者:狄晓雪、梁若岚(北京中医药大学中医英语专业本科生);审校:狄晓雪、梁若岚、李迅 北京中医药大学循证医学中心

Background

The incidence of fatal cases of colorectal cancer in Europe exceeds 200000 per year. Due to the specific anatomy and biology of rectal cancer, surgery alone historically has been associated with local recurrence in up to one in four patients. Locally recurrent disease is usually incurable, causes important morbidity and suffering and gives rise to systemic metastases. In the last few decades, improvements in surgical technique have dramatically lowered the incidence of locally recurrent disease. Careful pathological studies have clearly demonstrated that the major cause of local recurrence is the persistence of tumour foci within the mesorectum (Quirke 1986; Quirke 2003). Intact removal of the entire mesorectum (total mesorectal excision or TME) in cancers of the mid or lower third of the rectum was pioneered by Heald and has resulted in local recurrence rates lower than 5-10% (Heald 1982; Heald 1998; Enker 1999). The importance of complete removal of the surrounding mesorectum necessitates precise preoperative evaluation of the circumferential resection margin using imaging. Recently, magnetic resonance imaging (MRI) using a phased array coil has emerged as the imaging modality of choice in the preoperative evaluation of locally advanced rectal cancer (Beets-Tan 2003; Beets-Tan 2005; Brown 2004; Daniels 2005; Brown 2006).
Parallel to improvements in surgical technique, adjuvant therapy regimens have been tested in clinical trials in an effort to reduce local recurrence rates. Neoadjuvant radiotherapy (RT) has been shown to significantly decrease local recurrence rate and improve survival provided a biologically equivalent dose (BED) of at least 30 Gy is administered (Gray 2001). The advantages of preoperative over postoperative RT include enhanced effectiveness in well oxygenated tissue, downstaging of advanced tumors and better treatment compliance (Glimelius 2002). The theoretical superiority of the preoperative approach over postoperative adjuvant therapy has been confirmed in the recent German rectal cancer trial (Sauer 2004). The effect of preoperative RT on local recurrence rate is consistent even when optimal surgical technique (TME) is implemented. This was demonstrated by the results of the Dutch rectal cancer trial which randomized rectal cancer patients to undergo either RT followed by TME or TME alone in the setting of a national surgical training programme (Kapiteijn 2001, Peeters 2007). Compared to TME alone, 5x5 Gray (Gy) of RT followed by TME resulted in a significantly lower local recurrence rate, although no improvement in overall survival (OS) was noted.
Although preoperative RT results in a complete pathological response in a minority of patients, significant downsizing is rarely achieved using short schedule RT regimens. In order to improve tumour response, preoperative RT has been combined with chemotherapeutic regimens. There is a strong radiobiological rationale to combine RT with chemotherapy. Combined chemoradiation (CRT) for rectal cancer was introduced in the adjuvant setting and subsequently in irresectable disease, where significant downsizing and downstaging was observed in many patients resulting in achievement of a resectable status in some cases (Minsky 1993; Minsky 1997). The argument for preoperative CRT in resectable disease is based primarily on possible downsizing and downstaging of tumors close to the circumferential resection margin or the sphincter apparatus, thereby enhancing both R0 resection and the sphincter preservation rate. The paramount importance of performing the resection with a negative CRM was shown in several clinical studies (Nagtegaal 2002). Secondly, the addition of chemotherapy could eliminate microscopic systemic disease present at the time of surgery. Possible concerns of preoperative CRT include an increase of both local and systemic toxicity and over treatment of inaccurately staged patients (Ammann 2003). Several phase I and II studies using preoperative CRT have shown a promising tumour response with acceptable toxicity (Rodel 2003; Osti 2004). A limited number of prospective randomized trials comparing preoperative RT alone with preoperative CRT in resectable rectal cancer are published or ongoing.

Objectives

To compare preoperative RT with preoperative CRT in patients with resectable stage II or III rectal cancer.

Methods

Criteria for considering studies for this review

Types of studies

Randomized controlled trials (RCT's) which randomized patients before surgery with curative intent to one of at least two schedules of preoperative therapy including RT and CRT.

Types of participants

Patients with clinical stage II or III resectable rectal cancer undergoing preoperative RT or CRT followed by surgery.

Types of interventions

Preoperative RT or CRT using fractionated external radiotherapy followed by surgery with curative intent (resectable rectal cancer). The surgical procedure must consist of rectal amputation or sphincter preserving anterior resection using an open or laparoscopic approach; local excisions are excluded.

Types of outcome measures

Primary
- local recurrence rate at 5 years
Secondary
- overall survival at 5 years
- disease free survival at 5 years
- systemic metastasis rate
- pathological complete response rate
- clinical response rate
- sphincter preservation rate
- postoperative mortality within 30 days
- postoperative morbidity
- anastomotic leak rate

Search methods for identification of studies

See: Colorectal Cancer Group methods used in reviews.

We searched the following electronic databases
- Cochrane Central Register of Controlled Trials
- ISI Web of Science (Science Citation Index, Current Contents) from 1975 until June 2012
- Embase.com
- Pubmed

Electronic database searches were performed with MeSH terms and free text terms:

-MeSH: \Rectal Neoplasms"[MeSH] AND\
Radiotherapy"[MeSH] AND \Drug Therapy"[MeSH]
-Free text terms:
rectal, rectum, cancer, adenocarcinoma, neoplasm, radiotherapy, irradiation, chemotherapy, chemoradiation, radiochemotherapy, combined modality, multimodal, preoperative, neoadjuvant

Manual search/abstract search

- Journals from 1990: Ann Surg, Arch Surg, Cancer, J Clin Oncol, Int J Radiat Oncol Biol Phys
- Proceedings from ASTRO, ECCO and ASCO

No language constraints were applied.

Data collection and analysis

All three reviewers obtained the full text of all relevant studies and these were assessed for methodological quality according to the Cochrane Collaboration's tool for assessing the risk of bias (Higgins 2011). Methodological details relevant for potential bias included sequence generation, allocation concealment, blinding, incomplete outcome data, and selective outcome reporting. Disagreement was resolved by consensus.
Data were extracted by one reviewer (KF) on custom designed forms and entered in a computer database for transfer and statistical analysis in the Review Manager software. The data extracted included first author, year of publication, source, method of preoperative therapy and surgery, method of randomization, number of patients included, randomized, and analysed, and outcome parameters as listed above. Data accuracy was verified by the senior author (WPC).
RT dose was converted to the biologically equivalent dose (BED) using the linear quadratic equivalent formula (Dale 2005): BED = nd(1+1/(α/β)-(γ/α)(T-Tk), with n = number of fractions, d = dose per fraction, α/β = the linear quadratic quotient (set at 10 Gy), γ/α= repair rate (set at 0.6 Gy/d), and Tk = the initial time delay in days (set at 7). Differences between categorical outcome parameters were quantified using the odds ratio (OR) and corresponding 95% confidence interval (95CI). Summary statistics were calculated using the Mantel-Haenszel methods. Heterogeneity analysis was performed using the Q test, with significance accepted when P<0.1. When present, heterogeneity was addressed as recommended by the Cochrane Collaboration Handbook (Higgins 2011).

Results

Description of studies

See: Characteristics of included studies; Characteristics of ongoing studies.

The initial search was performed in June 2007. Of a total of 17925 studies resulting from the primary search, 324 papers were selected for full review. In all, 320 papers were discarded (Table 1). Four randomized trials were identified comparing preoperative RT with preoperative CRT in resectable stage II or III rectal cancer (Bosset 2006; Boulis-Wassif 1984; Bujko 2006; Gerard 2006). The search was repeated, using similar criteria, in June 2012. A total of 1041 abstracts was selected and scrutinized, resulting in addition of one randomized trial (Latkauskas 2011) to the search results.

Table 1. excluded studies
TypeN
Non randomized trials144
Adjuvant therapy trials28
Trials not including at least one chemotherapy arm combined with radiotherapy71
Trials not including radiotherapy27
Trials using local or no resection18
Trials including other tumour types25
Trials not including stage II/III cancer7
Total320

Boulis-Wassif 1984: From November 1972 through April 1976, Boulis-Wassif et al. recruited 247 patients with histologically proven localized adenocarcinoma of the rectum and no clinical of surgical evidence of distant metastases. All patients in both groups received preoperative RT by two parallel opposing diamond and chimney fields. All patients received a total dose of 34.5 Gy in 15 fractions of 2.3 Gy each over a total treatment time of 18 days (BED = 35.8 Gy). In the preoperative CRT group, intravenous 5-FU injection (375 mg/m2) was administered during the first 4 days of irradiation. Surgery usually followed within 2 weeks after the last irradiation. Two patients died before surgery. Assessed outcomes included ease of surgery, type of operation, radical resectability rate, histopathological response, postoperative mortality, postoperative period of hospitalizations, local control of the disease, distant metastases, disease free survival, and median survival. Follow-up was available up to 7 years.

Bujko 2006: From April 1999 until February 2002, Bujko et al. included 316 patients with resectable T3-T4 rectal carcinoma without sphincter infiltration and with a lesion accessible to digital rectal examination. Patients were randomised to either preoperative 5 x 5 Gy short-term RT (BED = 37.5 Gy) with subsequent total mesorectal excision (TME) performed within 7 days or to CRT to a total dose of 50.4 Gy (1.8 Gy per fraction during 25 days; BED = 42.2 Gy) concomitantly with two courses of bolus 5-fluorouracil (325 mg/m2) and leucovorin during weeks 1 and 5 of RT. Chemoradiation was followed by TME after 4-6 weeks. Three patients did not undergo surgery. Assessed outcomes were acute postirradiation toxicity, sphincter preservation rate, postoperative mortality, pathology, overall survival, disease free survival, local recurrence rate, distant metastases, late toxicity and incidence of permanent stoma. Median follow up was 48 months.

Gerard 2006: Between April 1993 and November 2003, Gerard et al. recruited 762 patients with a histologically confirmed, previously untreated rectal adenocarcinoma accessible to digital rectal examination (T3 or resectable T4 tumour with no evidence of distant metastases). Patients were allocated to two treatment arms: preoperative RT vs. preoperative CRT, both followed by surgery. RT was delivered with photons from a linear accelerator in a three- or four-field box technique. The dose per fraction was 1.8 Gy and all fields were treated each day with five fractions per week. The total dose was 45 Gy in 25 fractions during 5 weeks (BED = 42.2 Gy). Concurrent chemotherapy (CT) consisted of bolus 5-fluorouracil (350 mg/m2) and leucovorin administered during week 1 and 5 of RT. Surgery was planned between 3 and 10 weeks after the end of the preoperative RT (+/- CT). TME was recommended. Assessed outcomes were surgical procedures and postoperative complications, pathology, overall survival, progression free survival, and local recurrence. Median follow-up was 81 months.

Bosset 2006: Between April 1993 and March 2003, Bosset et al. recruited 1011 patients with a T3 or resectable T4 M0 adenocarcinoma of the rectum within 15 cm from the anal margin and without previous treatment for this disease (EORTC 22921 trial). Patients were allocated to four treatment arms: preoperative RT, preoperative CRT, preoperative RT plus postoperative CT and preoperative CRT plus postoperative CT. Radiotherapy consisted of 45 Gy delivered to the posterior pelvis in 25 fractions of 1.8 Gy over a period of 5 weeks (BED = 42.2 Gy). The target volume of RT was not a classical pelvic volume but was limited to the main field of tumour spread and to the perirectal nodes. Preoperative chemotherapy was delivered in two 5-day courses of 5-fluorouracil (350 mg/m2) with leucovorin during the first and fifth weeks of RT. Surgery was scheduled to take place 3 to 10 weeks after treatment. TME was recommended beginning in 1999. Assessed outcomes were toxicity of the preoperative treatment, surgical procedures performed, rate of postoperative complications, pathology, late side effects, overall survival, disease free survival, and local and distant recurrence rate. Median follow-up of 5.4 years.

Latkauskas 2011: Latkauskas et al. evaluated 145 patients with histologically proven rectal cancer between 2007 and 2010. Eighty-three patients were e legible and randomized to receive either short term radiotherapy (5x5 Gy, N=37) or CRT (50 Gy in 25 fractions with 5-fluorouracil, N=46). In both groups, surgery was performed after a 6 weeks waiting period. Sample size was based on downstaging rate as primary endpoint; other endpoints were not defined. The included paper reports on preliminary data (surgical and pathological outcome).

Risk of bias in included studies

Randomisation was adequately performed in four studies using communication with a central office; the study by Latkauskas et al. does not specify the randomization method used. Three studies based randomisation on the minimization method (Bujko 2006; Gerard 2006; Bosset 2006). In the fourth study, the randomisation method is not specified (Boulis-Wassif 1984). None of the studies were described as double blind or used blinded outcome assessment. Description of withdrawals and dropouts was given in four out of five studies. There were no imbalances between treatment arms in the number of patients that did not undergo the complete trial procedure. Three studies were performed on an intention-to-treat basis (Bujko 2006; Gerard 2006; Bosset 2006); no imbalances were identified between treatment arms.

Effects of interventions

The main primary outcome parameter was the local recurrence rate at five years, which was reported in three studies (Bosset 2006; Boulis-Wassif 1984; Gerard 2006). In the RT group, 122 of 740 patients (16.5%) developed a local recurrence while in the CRT group this event was observed in 71 out of 754 patients (9.4%). (Figure 1, Figure 2) This difference was statistically significant (OR 0.53, 95%CI 0.39-0.72, P < 0.001). No statistically significant heterogeneity among studies was present (P = 0.12). Survival data at 5 years were available in three studies (Bosset 2006; Boulis-Wassif 1984; Gerard 2006). In the CRT group, 644 of 1007 patients (63.9%) were alive at 5 years while in the RT group 647 of 993 patients (65.2%) survived 5 years. (Figure 3, Figure 4) This difference did not reach statistical significance (OR 0.95, 95%CI 0.79-1.14, P = 0.58). No heterogeneity was present (P = 0.15).
The results of the analysis of the secondary outcome parameters were as follows. Disease free survival at 5 years, available in the studies of Bosset 2006 and Gerard 2006, was 507/881 (57.5%) in the CRT group and 479/872 (54.9%) in the RT group. This difference was not statistically significant (OR 1.11, 95%CI 0.92-1.34, P = 0.27). (Figure 5, Figure 6) Significant heterogeneity did not occur (P = 0.64). Grade III or IV treatment related toxicity developed in 151 of 1015 patients (14.9%) treated with CRT while in patients treated with RT alone, this occurred in 52 of 1017 patients (5.1%). (Figure 7) This difference was statistically significant (OR 4.1, 95%CI 1.68-10, P = 0.002). There was, however, significant heterogeneity (P = 0.005) which remained when the data were reanalysed using the random effects assumption. Among patients who underwent surgery, sphincter preservation was possible in 583 of 1157 patients (50.4%) in the CRT group and in 553 of 1145 patients (48.3%) in the RT group; this difference failed to reach statistical significance (OR 1.09, 95%CI 0.92-1.30, P = 0.32). (Figure 8) No heterogeneity was observed (P = 0.48). Postoperative 30 day mortality was observed in 31 of 1122 (2.8%) patients in th CRT group and in 21 of 1117 (1.9%) patients in the RT group. This difference did not reach statistical significance (OR 1.48, 95%CI 0.84-2.6, P = 0.17); no heterogeneity was detected (P = 0.6).Figure 9 Postoperative morbidity was marginally higher in the CRT group (OR 0.67-1.00, P = 0.05) (Figure 10) while no differences in anastomotic leak rate were detected (OR 0.62-1.84, P = 0.81). (Figure 11) Pathological complete response (i.e., ypT0N0) of the resected specimen was observed in 135 of 1142 patients (11.8%) in the CRT group and in 40 of 1142 patients (3.5%) in the RT group. (Figure 12) This difference was statistically significant (OR 3.52, 95%CI 2.12-5.84, P < 0.00001) while significant heterogeneity for this parameter was not observed (P = 0.25).

Figure 1.

Forest plot of comparison: 1 radiotherapy vs radiochemotherapy, outcome: 1.10 Local Recurrence at 5y.

Figure 2.

Forest plot of comparison: 1 radiotherapy vs radiochemotherapy, outcome: 1.12 HR_LR.

Figure 3.

Forest plot of comparison: 1 radiotherapy vs radiochemotherapy, outcome: 1.1 Overall Survival at 5y.

Figure 4.

Forest plot of comparison: 1 radiotherapy vs radiochemotherapy, outcome: 1.2 HR_OS.

Figure 5.

Forest plot of comparison: 1 radiotherapy vs radiochemotherapy, outcome: 1.3 Disease free survival at 5 y.

Figure 6.

Forest plot of comparison: 1 radiotherapy vs radiochemotherapy, outcome: 1.11 HR_DFS.

Figure 7.

Forest plot of comparison: 1 radiotherapy vs radiochemotherapy, outcome: 1.6 Grade III - IV toxicity.

Figure 8.

Forest plot of comparison: 1 radiotherapy vs radiochemotherapy, outcome: 1.7 Sphincter preservation.

Figure 9.

Forest plot of comparison: 1 radiotherapy vs radiochemotherapy, outcome: 1.4 Mortality 30 d.

Figure 10.

Forest plot of comparison: 1 radiotherapy vs radiochemotherapy, outcome: 1.5 Postop morbidity.

Figure 11.

Forest plot of comparison: 1 radiotherapy vs radiochemotherapy, outcome: 1.9 Anastomotic leak.

Figure 12.

Forest plot of comparison: 1 radiotherapy vs radiochemotherapy, outcome: 1.8 pCR.

Because of the limited number of included studies, no sensitivity analysis was performed.

Discussion

Preoperative RT has been shown to reduce local recurrence rates and marginally improve survival over surgery alone provided a BED > 30 Gy is delivered to the target region (Gray 2001). The current review addresses the question whether the addition of chemotherapy to preoperative RT further improves pathological and clinical outcome parameters. Five randomized trials were identified comparing preoperative CRT with preoperative RT alone in resectable, locally advanced rectal cancer. Although there was considerable variation in radiotherapy dose and fractionation, all five studies have used a BED > 30 Gy. In three trials (Gerard 2006; Boulis-Wassif 1984; Bosset 2006), RT regimens were identical in both groups. The study by Latkauskas et al. compared two different regimens, but with a similar interval to surgery (Latkauskas 2011). In the Polish study (Bujko 2005, Bujko 2006), RT dose and fractionation as well as time interval until surgery were different in both groups (5x5 Gy followed by immediate surgery versus 50.4 Gy with chemotherapy followed by surgery after a waiting period of 4-6 weeks). In this study, therefore, it remains unclear whether the observed differences in tumour response between both arms are attributable to the addition of chemotherapy or to a different RT schedule and a different waiting period until surgery. Since, moreover, actuarial local recurrence data at five years are not available in this study, it was left out from the meta-analysis of local recurrence at five years. This analysis demonstrates a significant reduction in local recurrence rate with the addition of chemotherapy (OR 0.39-0.72, P < 0.001). Importantly, the cumulative incidence rates of local recurrence in the RT group of the studies of Bosset 2006 and Gerard 2006 (17%) and in both groups of the study of Boulis-Wassif 1984 (15%) seem high compared to the 5.5% local recurrence rate at five years achieved by the Dutch rectal cancer trial using 5x5 Gy preoperative RT followed by surgery (van den Brink 2004). Differences in stage distribution and variation in surgical technique might explain this observation. Indeed, during the Dutch rectal cancer trial a formal surgical training and quality control program was implemented in order to guarantee optimal surgery (TME). The study of Boulis-Wassif 1984 predated the introduction of TME surgery (inclusion period 1972-1976), whereas in the studies of Bosset 2006 and Gerard 2006, TME surgery was 'recommended' without any formal surgical training or quality control.
Although in the study of Boulis-Wassif 1984 a marginally significant five year survival benefit was associated with CRT, the combined analysis failed to demonstrate a significant difference in either overall or disease free survival at five years (OR 0.79-1.14, P = 0.58 and OR 0.92-1.34, P = 0.27, respectively). One of the hypotheses formulated to explain the observed lack of survival benefit found in many pre- or postoperative adjuvant therapy trials in rectal cancer is the existence of early, subclinical systemic disease present at diagnosis. This hypothesis is supported by the finding that the rate of distant metastatic disease in all four trials is consistently around 30%, without any difference between CRT and RT groups, indicating a future role of more effective systemic therapy to eradicate micrometastatic disease from the onset of therapy. Others have argued that the follow up time of the included trials is too short to observe a survival benefit, or that the incidence of local recurrence is too low to influence survival (Gerard 2006).
Grade III and IV acute treatment related toxicity was more pronounced in the CRT group in the three studies reporting this parameter (Bosset 2006; Bujko 2006; Gerard 2006), with an overall OR of 1.68-10 and a P value of 0.002. However, chemotherapy related toxicity was generally acceptable as evidenced by the high compliance rates in the studies mentioned (82%, 78.1%, and 69% respectively). In resected patients, no differences were observed in 30 day mortality or anastomotic leak rate, but a marginally significant difference in overall postoperative morbidity was found. The results concerning anastomotic leakage should be interpreted with caution, since the exceedingly low leakage rate in the study of Bosset compared to currently accepted and published leakage rates following anterior resection suggests underreporting of this specific complication.
Postoperative quality of life (QoL) is an important, though often underreported aspect of cancer trials. From the Swedish and Dutch rectal cancer trials, it is known that preoperative 5x5 Gy followed by surgery significantly worsens functional outcome in terms of bowel, sexual, and bladder function compared to surgery alone (Holm 1996; Dahlberg 1998; Peeters 2005). A number of phase II trials have suggested that preoperative CRT followed by surgery does not adversely affect functional outcome (Feliu 2002; Bosset 2000). The scarce available data in the four included studies did not allow to perform a meta-analysis of QoL related parameters. However, preliminary functional outcome data of the EORTC 22921 study (published as abstract only) demonstrated a significantly worse anorectal function in CRT patients compared to RT alone (Mercier 2005). Interestingly, in the final results paper of this study the incidence of 'late side effects' including fecal incontinence did not seem to differ between the four treatment arms (Bosset 2006).
The results of the meta-analysis confirm the enhanced cytotoxic efficacy of combined RT with 5-fluorouracil based chemotherapy. The incidence of a complete pathological response (pCR, ypT0N0) was 135 of 1142 patients (11.8%) in the CRT group and 40 of 1142 patients (3.5%) in the RT group; this difference was statistically highly significant (OR 3.52, 95%CI 2.12-5.84, P < 0.00001) while no heterogeneity was observed between the four studies. The results of the EORTC study moreover confirmed the difference in radioresponsiveness of the tumour in the bowel wall compared to that of mesorectal lymph nodes, as evidenced by nodal involvement in up to 12% of ypT0 patients (Bosset 2004). Although in two studies (Bosset 2006; Boulis-Wassif 1984) a trend towards increased sphincter preservation was observed in the CRT group, the overall results failed to demonstrate an increase in sphincter preserving surgery following CRT notwithstanding the downsizing and downstaging effect often noted with the combined therapy. This finding may be related to reluctance of the colorectal surgeon to alter a preoperative assessment of the need to perform a rectal amputation, since reversal of this decision would possibly imply performing an anastomosis in previously macroscopically invaded tissue. Moreover, in at least two studies it was specifically advised not to change a preoperative decision to perform a rectal amputation even after a significant downsizing. Data from the German rectal cancer trial, however, suggested that a change in operative strategy (i.e., perform sphincter preserving surgery when a significant clinical response is observed) may be safely performed. Longer follow up will be needed to confirm the safety of this approach. Mature results (including recurrence and survival data) from the study by Latkauskas et al. are awaited. An ongoing study by the Berlin Cancer Society, randomises patients with histologically proven rectal cancer staged T2N+ or T3 to receive either SCRT (25 Gy in five fractions of 5 Gy) plus TME-surgery within 5 days or CRT (50.4 Gy in 28 fractions of 1.8 Gy, continuous infusion 5-fluorouracil) plus TME-surgery 4-6 weeks later (Siegel 2009). All patients receive adjuvant chemotherapy (12 weeks continuous infusional 5-FU) and are followed up for 5 years. TME-quality is independently documented by the surgeon and the pathologist; the primary endpoint is local recurrence at five years.

Authors' conclusions

Implications for practice

Compared to preoperative RT alone, preoperative CRT enhances tumour response and improves local recurrence rates. The addition of chemotherapy causes a moderate increase in acute toxicity and overall postoperative morbidity, although anastomotic leakage rate or 30 day mortality are not enhanced. At this moment, it is unclear from the available data whether the addition of chemotherapy to preoperative RT influences sphincter preservation. Patients should be informed about the possible functional and QoL related aspects of preoperative therapy.

Implications for research

1. Since the improvement of local control obtained with CRT did not translate into a better overall or disease free survival and up to one third of all patients develop distant spread, priority should be given to trials addressing early subclinical systemic spread;
2. Trials are needed that specifically address the oncological safety of performing sphincter preserving surgery (including intersphincteric resection and colo-anal anastomosis) in patients deemed to require amputation before the start of CRT and in whom a significant clinical response is observed;
3. Preoperative therapy trials in rectal cancer should include formal evaluation of functional and QoL related aspects of therapy.

Acknowledgements

Wim P Ceelen is a senior clinical researcher of the Fund for Scientific Research - Flanders (FWO).

Data and analyses

Download statistical data

Comparison 1. radiotherapy vs radiochemotherapy
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Overall Survival at 5y32000Odds Ratio (M-H, Fixed, 95% CI)1.05 [0.88, 1.27]
2 HR_OS40Hazard Ratio (95% CI)1.02 [0.89, 1.17]
3 Disease free survival at 5 y21753Odds Ratio (M-H, Fixed, 95% CI)0.90 [0.74, 1.09]
4 Mortality 30 d52322Odds Ratio (M-H, Random, 95% CI)1.48 [0.83, 2.63]
5 Postop morbidity42077Odds Ratio (M-H, Random, 95% CI)0.82 [0.67, 1.00]
6 Grade III - IV toxicity32032Odds Ratio (M-H, Random, 95% CI)4.10 [1.68, 10.00]
7 Sphincter preservation52302Odds Ratio (M-H, Random, 95% CI)1.09 [0.92, 1.30]
8 pCR52284Odds Ratio (M-H, Random, 95% CI)3.52 [2.12, 5.84]
9 Anastomotic leak41151Odds Ratio (M-H, Random, 95% CI)1.07 [0.62, 1.84]
10 Local Recurrence at 5y31494Odds Ratio (M-H, Fixed, 95% CI)0.53 [0.39, 0.72]
11 HR_DFS40Hazard Ratio (95% CI)0.99 [0.84, 1.17]
12 HR_LR30Hazard Ratio (95% CI)0.71 [0.52, 0.95]
Analysis 1.1.

Comparison 1 radiotherapy vs radiochemotherapy, Outcome 1 Overall Survival at 5y.

Analysis 1.2.

Comparison 1 radiotherapy vs radiochemotherapy, Outcome 2 HR_OS.

Analysis 1.3.

Comparison 1 radiotherapy vs radiochemotherapy, Outcome 3 Disease free survival at 5 y.

Analysis 1.4.

Comparison 1 radiotherapy vs radiochemotherapy, Outcome 4 Mortality 30 d.

Analysis 1.5.

Comparison 1 radiotherapy vs radiochemotherapy, Outcome 5 Postop morbidity.

Analysis 1.6.

Comparison 1 radiotherapy vs radiochemotherapy, Outcome 6 Grade III - IV toxicity.

Analysis 1.7.

Comparison 1 radiotherapy vs radiochemotherapy, Outcome 7 Sphincter preservation.

Analysis 1.8.

Comparison 1 radiotherapy vs radiochemotherapy, Outcome 8 pCR.

Analysis 1.9.

Comparison 1 radiotherapy vs radiochemotherapy, Outcome 9 Anastomotic leak.

Analysis 1.10.

Comparison 1 radiotherapy vs radiochemotherapy, Outcome 10 Local Recurrence at 5y.

Analysis 1.11.

Comparison 1 radiotherapy vs radiochemotherapy, Outcome 11 HR_DFS.

Analysis 1.12.

Comparison 1 radiotherapy vs radiochemotherapy, Outcome 12 HR_LR.

What's new

DateEventDescription
25 January 2013New search has been performedReview update with one new trial included
25 January 2013New citation required but conclusions have not changedReview update with one new trial included

History

Protocol first published: Issue 2, 2006
Review first published: Issue 1, 2009

DateEventDescription
26 February 2007New citation required and conclusions have changedSubstantive amendment

Contributions of authors

General coordination and writing: Wim Ceelen, Yves Van Nieuwenhove

Literature search, data extraction, data verification: Laura De Caluwé, Wim Ceelen, Yves Van Niewenhove

Declarations of interest

None.

Characteristics of studies

Characteristics of included studies [ordered by study ID]

Bosset 2006

Methods1.Randomization method: telephone to central office (assumed)
2. Abdominal imaging: CT
3. Chest imaging: CXR
4. 4 arm study: Arm 1 preop RT + S; Arm 2 preop XRT + concurrent 5FU LV + S;Arm 3 preop RT + S + post op 5FU LV ; Arm 4 preop RTCT+ S + postop 5FU LV
5. Total randomized 1011
Participants1. Rectal Cancer
2. Location: within 15 cm from anal verge
3. Resectability: locally resectable
4. T3 or resectable T4 (defined by clinical criteria or endoscopic ultrasound)
5. WHO PS 0-1
6. </=80yr
Interventions1.Surgery: AP/anterior resection or Hartman with TME
2. RT : 45 Gy in 25fr.
3. RT volume: 5cm above and below tumour and perirectal nodes below S2-3. If tumour above 10cm, include
only 3 cm above tumour. If tumour in low rectum, S2-3 to perineum. Posteriorly to include entire sacrum with 3cm beyond macroscopic extension
4. RT-S: within 3-10 weeks of completing neoadjuvant therapy
5. 3 or 4 field
6. Chemotherapy: 5FU 325mg/m2/d; Leucovorin 20mg/m2/day Dy1-5 & 28-32 for arms 2 and 4, and
postoperative for arms 3 and 4
Outcomes1. Duration of FU: 5.4 yrs
2. Perioperative mortality: CRTS 2.4 % (12/506) RTS 1.2% (6/505)
3. Mets (liver) @ lap: Y
4. Curative resection: not stated
5. Overall resection: 94.5 %
6. Compliance to radiotherapy: CRTS 483/506 (95.5%) RTS 495/505 (98.0%)
7. OAS: Y
8. CSS?
9. Tox post RT: Y
10. Acute tox post S: Y
11. Late tox post S: Y
12. LR: Y
13. QOL: N
14. Proportion sfincter sparing: CRTS 267/506 (52.8%) RTS 255/505 (50.5%)
15. Proportion downstaging: Y
Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Allocation concealment (selection bias)Low riskA - Adequate

Boulis-Wassif 1984

Methods1.Randomization method: not stated. conducted by cooperative group. Likely via central office
2. Abdominal imaging: Not stated
3. Chest imaging: Not stated
4. Study arm (Preop chemoradiotherapy arm) : 171randomized, 45 excluded.
5. Control arm (Preop radiotherapy arm): 168 randomized , 47 excluded
Participants1. Rectal Cancer
2. Location: below within 15cm anal verge
3. Resectability: fit for surgery
Interventions1.Surgery: AP/anterior resection
2. RT : 3450 cGy in 15fr. (for both arms)
3. BED: 35.2Gy1
4. RT volume: ''chimney and diamond fields" paraaortic and pelvis.
5. RT-S: within 2 wk
6. 2 field
7. Cointervention: none
8. 2 arms, control (Radiotherapy followed by surgery), Study (Chemoradiotherapy followed by surgery)
9.Chemotherapy: 5FU 10mg/kg/d day 1-4
Outcomes1.Duration of FU: mean 5.2yrs
2. Perioperative mortality: CRTS 19/126 RTS 11/121
3. Mets @ lap: CRTS 13/126 RTS 15/121
4. Curative resection: Not stated
5. Overall resection: CRTS 121, RTS 124
6. Compliance to radiotherapy: not given
7. OAS: Y
8. CSS: N
9. Tox post RT: not given
10: Acute tox post S: not given
No complication not given
11. Late tox post S: not given
12: LR: N
13. QoL:N
Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Allocation concealment (selection bias)Low riskA - Adequate

Bujko 2006

Methods1.Randomization method: telephone to central office
2. Abdominal imaging: ultrasound or CT
3. Chest imaging: CXR
4. XRT + S arm : (short XRT)155 randomized, 0 excluded.
5. Arm B: (Long XRT+CT): 157 randomized , 0 excluded
Participants1. Rectal Cancer
2. Location: inferior edge palpable of digital exam
3. Resectability: locally resectable
4. T3 or resectable T4
5. not involving sphincter
Interventions1.Surgery: AP/anterior resection or Hartman with TME
2. RT : XRT +S arm: 2500cGy cGy in 5fr. ; Arm B: 50.4Gy in 28 fr with concomitant CT weeks 1 & 5
3. BED: Arm A 38.7Gy10, Arm B 40.9Gy10
4. RT volume: Not stated
5. RT-S: XRT+S within 7 days; Arm B: within 4-6 weeks
6. 3 or 4 field
7. Arm B chemotherapy: 5FU 325mg/m2/d; Leucovorin 20mg/m2/day Dy1-5 & 28-32
Outcomes1.Duration of FU: not stated
2. Perioperative mortality: XRT+S 0/155 Arm B 0/157
3. Mets @ lap: not stated
4. Curative resection: not stated
5. Overall resection: XRT+S 145/155 Arm B 147/157
6. Compliance to radiotherapy: XRT+S 152/155 Arm B 141/157
7. OAS: N
8. CSS: N
9. Tox post RT: no complications XRT+S 118/155 Arm B 24/157 Any complications XRT+S 37/155 Arm
B 133/157 Gd 3-4 XRT + S 5/155 Arm B 26/157 Gd 5 (Death) XRT +S 0/155 Arm B 2/157
10: Acute tox post S: Not stated
11. Late tox post S: not given
12: LR: N
13. QoL:N
14. Proportion sphincter sparing
15. Proportion downstaged (by T stage, N stage, Tumor size)
Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Allocation concealment (selection bias)Low riskA - Adequate

Gerard 2006

Methods1.Randomization method: not stated
2. Abdominal imaging: liver sonography - CT scan
3. Chest imaging: CXR
4. Study arm: CRT 375
5. Control arm: RT 367
Participants1. Rectal Cancer
2. Location: accessible by digital examination
3. Resectability: locally resectable
Interventions2 arms: preop XRT vs preop CRT
1.Surgery: TME recommended
2. RT 45Gy in 25 fr for both arms
3. BED: 32.5Gy10
4. RT volume: NA
5. RT-S: NA
6. NA
7. Cointervention: postoperative CT (5FU FA) x 4 cycles
Outcomes1.Duration of FU: 81m
2. Perioperative mortality (60 days): 2% for both arms
3. Mets @ lap: not stated
4. Curative resection: not stated
5. Overall resection: not stated
6. Compliance to radiotherapy: not stated
7. OAS: Y
8. CSS: Y
9. Tox (gr 3-4) post RT: Preop RT arm: 10/367 CRT arm: 55/375
10: Acute tox post S: not stated
11. Late tox post S: Y
Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Allocation concealment (selection bias)Low riskA - Adequate

Latkauskas 2011

Methods

1. Randomization method: not stated

2. Abdominal imaging: abdominal US, EUS, CT scan and MRI pelvis

3. Chest imaging: CXR

4. Study arm: CRT 46
5. Control arm: RT 37

Participants

1. Rectal cancer stage II and III

2. less than 15 cm from anal verge

3. <80 years old, no other cancer during last 5 years

Interventions

1. CRT: 50 Gy in 25 fractions, 1.8-2 Gy/fraction over 5 weeks with 5-FU/LV during week 1 and 5

2. RT: 25 Gy in 5 fractions

3. Surgery: after 6 weeks in both groups

Outcomes1. Duration of FU: not stated
2. Perioperative mortality: not stated
3. Mets @ lap: not stated
4. Curative resection: 91.3% (CRT), 86.5% (RT)
5. Overall resection: 37/37 (RT), 46/46 (CRT)
6. Compliance to radiotherapy: not stated
7. OAS: not stated
8. CSS: not stated
9. Tox (gr 3-4) post RT: not stated
10: Acute tox post S: not stated
11. Late tox post S: not stated
Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Allocation concealment (selection bias)Low risk 

Characteristics of ongoing studies [ordered by study ID]

Siegel 2009

Trial name or titlePreoperative short-course radiotherapy versus combined radiochemotherapy in locally advanced rectal cancer: a multi-centre prospectively randomised study of the Berlin Cancer Society
MethodsProspective Randomized trial
ParticipantsPrimary rectal cancer within 12 cm from anal verge, cT3N+, cT3N0, or cT2N+
InterventionsShort course RT consists of single doses of 5.0 Gy in five fractions within one week up to a total dose of 25 Gy. For CRT, standard fractions of 1.8 Gy/d are given 5 times a week up to a total dose of 50.4 Gy; concomitant chemotherapy consists of continuous 5-FU-infusion 225 mg per square meter per day.
OutcomesLocal recurrence after five years follow up has been chosen as primary endpoint.
Starting date2008
Contact information

Peter M Schlag email: pmschlag@charite.de

Department of Surgery and Surgical Oncology, Charité – Universitätsmedizin Berlin, Berlin, Germany

Notes 

Ancillary