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Randomized clinical trial of short or long interval between neoadjuvant chemoradiotherapy and surgery for rectal cancer. BJS 2018; 105: 1417-1425.

Published: 29th August 2018

Authors: E. Akgun, C. Caliskan, O. Bozbiyik, T. Yoldas, M. Sezak, S. Ozkok et al.

Background

The optimal timing of surgery following preoperative chemoradiotherapy (CRT) is controversial. This trial aimed to compare pathological complete response (pCR) rates obtained after an interval of 8 weeks or less versus more than 8 weeks.

Method

Patients with locally advanced rectal adenocarcinoma situated within 12 cm of the anal verge (T3–4 or N+ disease) were randomized to undergo total mesorectal excision (TME) within 8 weeks (classical interval, CI group) or after 8 weeks (long interval, LI group) following CRT.

Results

Among the 327 included patients (CI 160, LI 167), the pCR rate was significantly higher in the LI group than in the CI group (10·0 versus 18·6 per cent; P = 0·027). The highest pCR rate (29 per cent) was observed between 10 and 11 weeks. There was statistically significant disease regression in the LI group, with better stage (P = 0·004) and T category (P = 0·001) than in the CI group. There was no significant difference in surgical quality (rates of tumour‐positive margins, TME quality, anastomotic leakage and intraoperative perforation) between the groups. The overall morbidity rate was 22·5 per cent in the CI group and 19·8 per cent in the LI group (P = 0·307). Regression analysis including sex, age, clinical stage, tumour location, tumour differentiation, TME quality, concomitant chemotherapy and interval to surgery revealed no statistically significant predictors of pCR.

Conclusion

Disease regression and pCR rate are increased with an interval between CRT and surgery exceeding 8 weeks. Registration number: NCT03287843 (http://www.clinicaltrials.gov).

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4 Comments

Jeremie H. Lefevre

1 year ago

We read with interest the article by Agkun et al. (1). The authors have to be congratulated for this important trial. In the current literature, there is a majority of retrospective studies with numerous bias evaluating the real impact of a longer waiting period (2).

We have several comments and questions on this study and the conclusion proposed by the authors.

It is stated that is a randomised clinical trial. However, no sample size calculation is given in the paper and the clinical trial registration was done in September 2017.

Why did the authors choose such a large interval of 4 weeks in each group? This will be difficult to translate in the clinical practice.

We were also surprised by the 2.5% anastomotic leakage rate described. The two recent GRECCAR trials (5 and 6) have shown a 15-17% of anastomotic complications (3,4).In addition the rate of 2.1% of N+ in the ypT0 group is very low compared to the 7-8% already published (3,5).

Can the authors precise how the perirectal fibrosis was evaluated?

We don’t agree with the conclusion as the short group includes patients operated at W4 or W5. Therefore the 10% of pCR is automatically significantly lower than the rate observed in the long duration group. The majority of the radiotherapy effect is gained after a waiting period longer than 7-8 weeks . Moreover, the multivariate analysis didn’t show any significant result.

Jeremie H. Lefevre
Department of Surgery
Saint-Antoine Hospital, AP-HP
184 rue du Faubourg Saint-Antoine
75012 Paris
France
jeremie.lefevre@aphp.fr

References:
1. Akgun E, Caliskan C, Bozbiyik O, Yoldas T, Sezak M, Ozkok S, Kose T, Karabulut B, Harman M, Ozutemiz O. Randomized clinical trial of short or long interval between neoadjuvant chemoradiotherapy and surgery for rectal cancer. Br J Surg 2018.
2. Petrelli F, Coinu A, Lonati V, Barni S. A systematic review and meta-analysis of adjuvant chemotherapy after neoadjuvant treatment and surgery for rectal cancer. Int J Colorectal Dis 2015;30(4): 447-457.
3. Lefevre JH, Mineur L, Kotti S, Rullier E, Rouanet P, de Chaisemartin C, Meunier B, Mehrdad J, Cotte E, Desrame J, Karoui M, Benoist S, Kirzin S, Berger A, Panis Y, Piessen G, Saudemont A, Prudhomme M, Peschaud F, Dubois A, Loriau J, Tuech JJ, Meurette G, Lupinacci R, Goasgen N, Parc Y, Simon T, Tiret E. Effect of Interval (7 or 11 weeks) Between Neoadjuvant Radiochemotherapy and Surgery on Complete Pathologic Response in Rectal Cancer: A Multicenter, Randomized, Controlled Trial (GRECCAR-6). J Clin Oncol 2016;34(31): 3773-3780.
4. Denost Q, Rouanet P, Faucheron JL, Panis Y, Meunier B, Cotte E, Meurette G, Kirzin S, Sabbagh C, Loriau J, Benoist S, Mariette C, Sielezneff I, Lelong B, Mauvais F, Romain B, Barussaud ML, Germain C, Picat MQ, Rullier E, Laurent C, French Research Group of Rectal Cancer S. To Drain or Not to Drain Infraperitoneal Anastomosis After Rectal Excision for Cancer: The GRECCAR 5 Randomized Trial. Ann Surg 2017;265(3): 474-480.
5. Rullier E, Vendrely V. Can mesorectal lymph node excision be avoided in rectal cancer surgery? Colorectal Dis 2011;13 Suppl 7: 37-42.

    Erhan Akgun

    1 year ago

    We are pleased that our recently published article drew the attention of one of the pioneers of rectal cancer treatment (1).

    As stated in the article, sample size calculation was given at the beginning of the statistical analysis section. The current study was planned at the beginning of 2005. Registration of a clinical trial was not mandatory at that time. The requirement of registration was understood when trial reached the publication stage.

    A four week interval was chosen since the 4-8 week waiting period following the preoperative chemoradiotherapy was generally accepted as the appropriate period at that time. In the majority of the randomized studies comparing short and long course chemoradiotherapy, surgery was carried out 4-6 weeks following the completion of radiotherapy (2,3). This period was 4-8 weeks in Stockholm III study (4).

    The total number of patients who had an anastomosis was 198. Correspondingly, our rate of clinical anastomotic leakage was 4%. This ratio is compatible with the literature (5). In addition, this rate includes only clinically detected leakages and no radiological leakage assessment was performed.

    Perirectal fibrosis was evaluated according to the surgeon’s observation.

    As previously mentioned, 4- and 5-week waiting periods were acceptable intervals at the time when the study was planned (2-4). Additionally, in the current study, pCR rate of the 4- and 5-week interval subgroup (28-42 days) was 14.3% (Figure 2). This finding is interpreted as the 4- and 5-week subgroup has not reduced the pCR ratio of the classic interval group.

    Erhan Akgun
    Department of Surgery
    Ege University, School of Medicine
    Bornova -İzmir
    Turkey
    bozbiyiko@gmail.com

    References:
    1. Lefevre JH , Mineur L , Kotti S , Rullier E, Rouanet P, de Chaisemartin C , et al. Effect of interval (7 or 11weeks) between neoadjuvant radiochemotherapy and surgery on complete pathologic response in rectal cancer: A multicenter, randomized, controlled trial (GRECCAR-6). JCO 2016; 34: 3773- 3780 .
    2. Bujko K , Nowacki MP , Nasierowska-Guttmejer A , Michalski W , Bebenek M , Kryj M. Long-term results of a randomized trial comparing preoperative short-course radiotherapy with preoperative conventionally fractionated chemoradiation for rectal cancer. Br J Surg 2006; 93:1215-1223
    3. Ngan SY , Burmeister B , Fisher RJ , Solomon M , Goldstain D , Joseph D , et al. Randomized trial of short-course radiotherapy versus long-course chemoradiation comparing rates of local recurrence in patients with T3 rectal cancer. J Clin Oncol 2012; 30:3827-3833
    4. Erlandsson J , Holm T , Pettersson D , Berglund A , Cedermark B , Radu C , et al. Optimal fractionation of preoperative radiotherapy and timing to surgery for rectal cancer (Stockholm III): a multicentre, randomized, non-blinded, phase 3, non-inferiority trial. Lancet Oncol 2017; 18:336-346.
    5. Jamnagerwalla M , Tay R , Steel M , Keck J , Jane I , Faraghan I ,et al. Impact of Surgical Complications Following Resection of Locally Advanced Rectal Adenocarcinoma on Adjuvant Chemotherapy Delivery and Survival Outcomes. Dis colon rectum 2016 ; 59: 916-924.

Wafi Attaallah

1 year ago

I read the article ‘Randomized clinical trial of short or long interval between neoadjuvant chemoradiotherapy and surgery for rectal cancer’ by E. Akgun et al. (1) with great interest. I wanted to draw attention to certain details in order to avoid misunderstanding by future readers.

The authors compared pathological complete response (pCR) rates obtained after an interval of 8 weeks or less (classical interval, CI group) versus more than 8 weeks (long interval, LI group) following preoperative chemoradiotherapy (CRT).

They found that the rates of pCR and stage regression were significantly higher in the LI group than in the CI group. According to these results they concluded that a pCR and regression of disease stage were significantly increased in patients who waited for more than 8 weeks after neoadjuvant therapy to undergo TME, which supports using this interval as the standard of care. However their results of Multiple Poisson regression analysis to identify variables that affected the pCR rate revealed no statistically significant prognostic factors. Furthermore, the difference between the two groups regarding interval to surgery also was found to be non-significant (Table 3). What I wanted to draw attention to here is that the significant difference between the two groups in univariate analysis has been become non-significant in the multivariate analysis which means that no significant difference is present.

Since researchers erroneously reject the null hypothesis, that is, infer that there is a difference in outcomes when there is really no difference, type 1 error is present and the conclusion is not justified according to the data presented.

Wafi Attaallah
Marmara University School of Medicine
Department of General Surgery
Istanbul
Turkey
drwafi2003@yahoo.com

Reference:
1. Randomized clinical trial of short or long interval between neoadjuvant chemoradiotherapy and surgery for rectal cancer E. Akgun, C. Caliskan, O. Bozbiyik , T. Yoldas , M. Sezak, et al. Br J Surg. 2018 Oct;105(11):1417-1425. doi: 10.1002/bjs.10984. Epub 2018 Aug 29.

    Timur Köse

    12 months ago

    We would like to thank to author for their interest in our paper and for taking the time to express their concerns. As indicated in Table 2, the relationship between interval and pCR was investigated by using Chi-Square square analysis, which is one of the appropriate methods for this type of variables. The relationship was found statistically significant and Type-I error level is presented in the table as p value. The accuracy of the result could be verified by the frequencies given in the table.

    Although the multiple regression analysis is a very powerful analytical method, the results from the univariate and multiple regressions tend to be conflicting. A variable may show very significant effect in the univariate analysis but has no role in the multiple regression model. In this study (1) all variables were included in the model without using a selection method because subtracting some of the variables that affect the response variable may ignore the possible effects of these variables (2). In this study (1), regression analysis including sex, age, clinical stage, tumour location, tumour differentiation, TME quality, concomitant chemotherapy and interval to surgery revealed no statistically significant predictors of pCR. These results were clearly stated in the article.

    Timur Köse
    Department of Biostatistics
    Ege University School of Medicine
    Bornova–Izmir
    Turkey
    bozbiyiko@gmail.com

    References:
    1. Akgun E, Caliskan C, Bozbiyik O, Yoldas T, Sezak M, Ozkok S, et al Randomized clinical trial of short or long interval between neoadjuvant chemoradiotherapy and surgery for rectal cancer. Br J Surg 2018; 105: 1417-1425.
    2. Ranstam J, Cook JA. Causal relationship and confounding in statistical models. Br J Surg. 2016; 103:1445-1446.