# A multicentric randomized controlled trial on the impact of lengthening the interval between neoadjuvant radiochemotherapy and surgery on complete pathological response in rectal cancer (GRECCAR-6 trial): rationale and design

Jérémie H. Lefevre, Alexandra Rousseau, Magali Svrcek, Yann Parc, Tabassome Simon, Emmanuel Tiret

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Jérémie H. Lefevre, Alexandra Rousseau, Magali Svrcek, Yann Parc, Tabassome Simon, et al.. A multicentric randomized controlled trial on the impact of lengthening the interval between neoadjuvant radiochemotherapy and surgery on complete pathological response in rectal cancer (GRECCAR-6 trial): rationale and design. BMC Cancer, 2013, 13, pp.417. 10.1186/1471-2407-13-417. hal-01548289

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# A multicentric randomized controlled trial on the impact of lengthening the interval between neoadjuvant radiochemotherapy and surgery on complete pathological response in rectal cancer (GRECCAR-6 trial): rationale and design

Jérémie H Lefevre<sup>1,2*</sup>, Alexandra Rousseau<sup>3</sup>, Magali Svrcek<sup>2,4</sup>, Yann Parc<sup>1,2</sup>, Tabassome Simon<sup>2,3</sup>, Emmanuel Tiret<sup>1,2</sup> and The French Research Group of Rectal Cancer Surgery (GRECCAR)

**Abstract**

**Background:** Neoadjuvant radiochemotherapy (RCT) is now part of the armamentarium of cancer of the lower and middle rectum. It is recommended in current clinical practice prior to surgical excision if the lesion is classified T3/T4 or N+. Histological complete response, defined by the absence of persistent tumor cell invasion and lymph node (ypT0N0) after pathological examination of surgical specimen has been shown to be an independent prognostic factor of overall survival and disease-free survival. Surgical excision is usually performed between 6 and 8 weeks after completion of CRT and pathological complete response rate ranges around 12%. In retrospective studies, a lengthening of the interval after RCT beyond 10 weeks was found as an independent factor increasing the rate of pathological complete response (between 26% and 31%), with a longer disease-free survival and without increasing the operative morbidity. The aim of the present study is to evaluate in 264 patients the rate of pathological complete response rate of rectal cancer after RCT by lengthening the time between RCT and surgery.

**Methods/design:** The current study is a multicenter randomized trial in two parallel groups comparing 7 and 11 weeks of delay between the end of RCT and cancer surgery of rectal tumors. At the end of the RCT, surgery is planified and randomization is performed after patient's written consent for participation. The histological complete response (ypT0N0) will be determined with analysis of the complete residual tumor and double reading by two pathologists blinded of the group of inclusion. Patients will be followed in clinics for 5 years after surgery. Participation in this trial does not change patient's management in terms of treatment, investigations or visits. Secondary endpoints will include overall and disease free survival, rate of sphincter conservation and quality of mesorectal excision. The number of patients needed is 264.

**Trial registration:** ClinicalTrial.gov: NCT01648894

**Keywords:** Rectal cancer, Radiochemotherapy, Complete histological response, Procedure

<footnote>* Correspondence: jeremie.lefevre@sat.aphp.fr</footnote>

<footnote n="1"><sup>1</sup>Assistance Publique-Hôpitaux de Paris (AP-HP), Department of Digestive Surgery, Hôpital Saint-Antoine, 184, rue du Fbg Saint-Antoine, 75012 Paris, France</footnote>

<footnote n="2"><sup>2</sup>University Pierre & Marie Curie (UPMC-Paris 06), Paris, France
Full list of author information is available at the end of the article</footnote>
## Background

Rectal cancer represents 12 000 new cases each year in France [1]. Its management is based on a multidisciplinary management with radiotherapy, chemotherapy and surgery.

## Surgery

Surgery consisting of total excision of the mesorectum has improved over time. The studies of Heald [2,3] have showed that local recurrence rate was directly related to the preservation of the fascia recti during the dissection of the rectum. In countries where this surgical procedure was emphasized, the local recurrence rate and life expectancy after treatment of rectal cancer were improved [4,5]. In Sweden, after learning of the mesorectal excision technique, 447 patients were compared to older cohorts, the local recurrence rate at 5 years was increased from 20.5% to 8.2% and 5-year survival of 65.8% to 77.3% (p < 0.001 for both comparisons).

## Radiotherapy

Before the widespread diffusion of the technique of mesorectal excision, many studies, including 4 randomized studies, had compared pre-operative radiotherapy (RT) versus surgery alone [6-9]. Results showed only a benefit in terms of local control with a reduction of 10% to 5% of the recurrence rate local for patients with optimal dissection of the mesorectum, but no survival benefit. In 1997, a randomized study in 1168 subjects showed an improved survival with neoadjuvant RT: survival at 9 years was 65% for patients with no radiotherapy compared to 74% for patients with neoadjuvant RT (p = 0.002) [9]. Local recurrence for patients treated by surgery alone was also more frequent (27% (150/557) compared to 11% (63/553), p < 0.001) [9]. This finding was explained by a suboptimal surgical resection without complete mesorectum excision. As a consequence, an international randomized trial study comparing RT + surgery versus surgery alone with quality control of excision mesorectum [10] was conducted in 1805 patients. The results confirmed a higher rate of local control at 2 years in patients with preoperative radiotherapy (2.4% vs. 8.3%, p < 0.001), with no difference in terms of survival (82% vs. 81.8%, p = 0.84). Early postoperative complications were higher in the RT + surgery group (48% vs. 41%, p < 0.01) [11]. After a minimum of 5 years of follow-up, long-term complications; were more frequent in the preoperative radiotherapy group with (62% and 56% versus 38% and 33% of episodes of incontinence and pad wearing respectively; p < 0.001) [12]. As postoperative morbidity and results functional obtained after preoperative RT were very significantly altered, the authors recommended such treatment only in patients at high risk of local recurrence. These recommendations were proposed by the French

experts for the treatment of rectal cancer and were approved by the Haute Autorité de Santé in 2007 [13].

## Chemoradiotherapy

Other studies have evaluated the impact of adding chemotherapy to RT [14,15]. The randomized trial of Bosset et al. included between 1993 and 2003, 1011 patients with rectal cancer T3 or T4 and analysed the impact of addition of chemotherapy based on 5-fluorouracil to RT 45Gy [14] compared with preoperative RT alone. The complete response rate (pT0) on resected specimen was 5.3% in the RT alone group and 13.7% in the chemoradiotherapy (CRT) group (odds ratio = 2.84, 95%CI: 1.75 to 4.59, p < 0.0001) [15]. No benefit in overall survival or disease-free survival was observed in CRT group despite a significant improvement rate of local recurrence at 5 years (8.7% in the CRT compared to 17.1% after RT alone vs., p = 0.002). However, the results cannot be generalized because of the lack of uniform total mesorectal excision for all patients included in this study.

However, CRT has allowed the team of Pr. Habr-Gama to obtain a complete clinical regression of tumor rectal in 26.8% of cases (71/265 patients) [16]. The protocol consisted of 50 Gy radiation therapy combined with chemotherapy based on 5-fluorouracil and leucovorin. This group of patients had not been operated and simple surveillance without resection was performed. After a mean follow-up of 57 months, only 2 patients (2.8%) had local recurrence and 3 had distant metastases. The 5-year recurrence rate was 7%. The complete clinical response was associated with better overall survival at 5 years: 100% versus 88% (p = 0.01).

In a retrospective series of the Cleveland Clinic, among 238 patients treated with neoadjuvant CRT, 58 (24.4%) had a ypT0N0 tumor on pathological exam. Postoperative morbidity was similar in the neoadjuvant CRT group and in the no-pCR group, but there was a better local control (5 years local recurrence rate: 0% vs. 10.6%, p < 0.001) [17].

## Complete response: the importance of the period between the end of radiotherapy and surgery

The median complete response rate is about 12% [7-27%] in the main series of rectal cancer treated with RT or RCT [18-31]. A randomized study in 1999 had already found an effect in tumor reduction after RT between two intervals (2 weeks or 7 weeks) clinical response increased from 53.1% to 71.7% (p = 0.007) and pCR or near complete (persistence of some tumor cells) increased from 10.3% to 26% (p = 0.0054) [21]. The results of this study cannot be generalized, considering the use of a technique of mesorectal excision other than the widely distributed and administered neoadjuvant therapy (RT alone of 40 Gy). However the interest of extending the period after RT was
obvious. In 2003, Moore's team showed that among 155
rectal cancers treated with neo-adjuvant RCT (50 Gy +
5-fluorouracil), the rate of complete response increased
from 9% to 23% between patients operated on before
the 40th day (between 6th and 7th week) and those oper-
ated on after waiting more than 7 weeks (p = 0.09) [27].

Following the work of Prof. Habr-Gama, other au-
thors have attempted to identify factors associated with
a pCR after surgical resection. The first study published
by Tulchinsky et al. [29] in 2008 reported the retro-
spective findings on the time between preoperative CRT
(45–50 Gy + 5-fluorouracil) and surgery (less or more
than 7 weeks) in 132 patients operated on by anterior re-
section or abdomino-perineal resection between 2000 et
2006. The rate of pCR or near complete (persistence of
microscopic foci of adenocarcinoma in the rectal wall
without lymph node) was 28% in the resected specimen.
The single independent factor associated with a good re-
sponse was the period between the end of RT and surgery:
17% in the group operated <7 weeks against 35% in the
other group operated after 7 weeks (p = 0.03). There was
no association between the duration of interval before sur-
gery and postoperative morbidity (complications, transfu-
sion, duration of hospitalization). Kalady et al. studied
retrospectively (1997–2007) records of 306 patients oper-
ated for a rectal cancer after CRT (50 Gy and 5-
fluorouracil) [30]. The dose of radiation received in each
group was similar. The rate of pCR (ypT0N0) was 24% in
this study. Time between the end of RCT and surgery, with
a cut-off estimated at 8 weeks was the single prognostic
factor for pCR in uni- and multivariate analysis (OR =
2.63–95%CI [1.13 to 6.12], p = 0.02). A. The pathological
complete response rate increased from 16.3% (14/86) in
the group operated <8 weeks against 30.8% (28/91) for
other (p = 0.03). The authors observed that the period be-
tween 8 and 10 weeks showed the greatest number of
complete responses and that there was no more gain over
14 weeks. This retrospective study did not give any explan-
ation on the reasons for variations in the time between the
end of radiotherapy and surgery [32]. The group of patients
with pCR had a better overall survival with a follow-up of
60 months (91% versus 80%, p = 0.046) and less local re-
currence at 5 years (0% versus 11%, p = 0.023). A Korean
study analyzed retrospectively the data from 12 centers of
306 patients with a tumor classified ypT0 following CRT.
This study confirmed the favourable impact of pCR after
neoadjuvant CRT on survival: the 5-year overall survival
of these patients having 93.4% of tumors initially classified
T3 or T4 was 92.8%. Disease-free survival at 5 years was
84.6%. Finally, Kalady et al. compared the outcomes in a
retrospective series of 177 patients operated for a rectal
cancer after neoadjuvant treatment between patients oper-
ated before 8 weeks or after 8 weeks following the end of
CRT between 1997 and 2007. Postoperative morbidity or

mortality were similar between the two period group. The
rate of pCR was lower in the <8 weeks group compared
with the > 8 weeks group (16.2% vs. 31.1%, p = 0.027).
Moreover, the 3 years local recurrence rate was significant
lower in the >8 weeks (1.2% vs. 3.9%, p = 0.04) [33].

All these publications are retrospective and the real
impact of the delay between the end of CRT and surgery
is still a matter of debate [34].

Aims

The main objective of our study is to evaluate in a ran-
domized trial the impact of a longer interval between the
end of CRT and rectal cancer surgery (7 weeks versus
11 weeks) on the rate of pathological complete response.
Secondary outcomes include overall and disease free sur-
vival, quality of mesorectal excision, rate of sphincter
preservation.

Methods and design

This study is a multicenter randomized open-label con-
trolled trial in parallel groups, comparing two periods be-
tween the end of CRT and cancer surgery of rectal
tumors: 7 weeks versus 11 weeks. This study has been ap-
proved by a national Institutional Review Board: the Re-
gional Comity of Patients Protection of South-West I,
N°1-12-19:30/08/12 and by the National Agency of Medi-
cine and Medical Products (ANSM: B111580-10). This
study is supported by a grant from the French Ministry of
Health (PHRCN 2011, AOM 11314). The research carried
out will be on accordance with Helsinki declaration.

Participants

The institutional promoter is the AP-HP (Assistance
Publique-Hôpitaux de Paris – DRCD: Département de la
Recherche Clinique). Patients are included from several
departments of surgery or oncology (n=26) in France
(see list of participating centers in the Acknowledgments
section). All participating sites signed a convention with
the DRCD for ethical approval before beginning of inclu-
sion. All patients must fulfil the following criteria: T3/T4
and/or TxN + mid or low third rectal cancer and com-
pleted RCT. The complete inclusion and exclusion criteria
are given in Table 1. After oral and written explanation
about the purpose of this study, the patient gives his
written consent agreeing to participate to the protocol
(Figure 1).

Randomization

After completion of the pre-intervention assessments,
the patients are randomly assigned to the period group
(ratio 1:1) by Internet. Blocked centralized randomisa-
tion with stratification by centre will be prepared by
URC-Est.
<table><caption>Table 1 Inclusion and exclusion criteria</caption><thead><tr><td>Inclusion criteria</td><td>Exclusion criteria</td></tr></thead><tbody><tr><td><ul><li>age over 18 years, no age limit higher</li><li>Performance status evaluated by the Eastern Cooperative Oncology Group (ECOG) score: 0-1</li><li>Patients with cancer of the middle or lower rectum (lesion located within 10 cm from the dentate line or 12 cm from the anal margin) proved by pathology,</li><li>T3-T4N0, TxN+ on ultrasound-endoscopy and MRI, without secondary localization (M0) on the thoraco-abdominal (or chest radiography and abdominal ultrasound)</li><li>Patient who received a protocol between 45-50 Gy of radiotherapy and chemotherapy based on 5-fluorouracil for an average duration of 5 weeks for the management of rectal cancer,</li><li>Curative surgical treatment planned following radiochemotherapy with total mesorectal excision,</li><li>Free and informed consent signed by the patient,</li><li>Patient affiliated to a social security scheme or beneficiary of such plan (except AME)</li><li>Patient able, according to the investigator, to comply with the requirements of the study.</li></ul></td><td><ul><li>Patient with metastasis,</li><li>T1 or T2N0 tumor classified by echo -endoscopy and MRI,</li><li>rectal tumor with lower pole is more than 12 cm from the anal margin or 10 cm from the dentate line,</li><li>Patient did not complete the full protocol of radiotherapy,</li><li>History of tumors (other than basal cell carcinoma and / or carcinoma in situ of the cervix)</li><li>A patient with impaired or incompetent</li><li>investigator by not allowing him a good understanding of the requirements of the study, person under guardianship, persons under guardianship, persons deprived of their liberty by judicial or administrative body, adult subject to legal protection or unable to consent.</li></ul></td></tr></tbody></table>

## Intervention

### Surgical resection with total mesorectal excision (TME)

The anaesthesia consultation is planned before the surgery according to the habits of each department. Participation in the study does not alter the anaesthetic procedures. The patient is admitted the day before surgery in the surgical ward.

The type of resection (coloanal anastomosis, abdominoperineal resection, delayed anastomosis, drainage, laparoscopic approach...) is not influenced by the participation to this protocol. As the rectal tumor is located in the mid- or low rectum a TME is required.

### Pathological exam

The pathological exam required has been already published in the National French Guidelines [35]. A standardized routine pathology examination was performed using the protocol of Quirke et al. [36]. After fixation in 10% formalin and inking to assess the circumferential margin, the whole tumor was cut transversely. According to the macroscopical features, different techniques for sampling of tumor tissues were applied in order to avoid any under staging of the specimen:

- If there was only ulceration and fibrotic changes without any visible tumoral lesion or if the tumor residual measured less than 3 cm in diameter, the lesion was examined entirely;

- If the residual tumor measured more than 3 cm in diameter, one selected block per cm of tumor was processed.

If the first selected blocks were free of tumor, complementary blocks were taken and the macroscopically residual lesion was examined in toto. A diagnosis of pCR will only be made after examination of the whole macroscopically residual lesion [37]. The tumor response is evaluated by inclusion of all residual tumor and the response to CRT is graded with the scales of Rodel and Dvorak [22,38]. A double reading of slides will be made for each patient by two independent pathologists blinded to the randomization group of the patient to confirm the ypT stade as the two regression scores. In case of disagreement between the two pathologists, they should jointly give a mutual result.

## Outcomes and assessments

### Primary outcome

Rate of histological complete response after double reading by two different pathologist.

### Secondary outcomes

Mobidity, sphincter preservation rate, overall and disease-free survival.

### Surgical data

During surgery, the operating data are provided on the e-CRF (digital rectal examination under general anaesthesia, type of surgery (anterior resection or abdominoperineal resection), operative time, intraoperative bleeding, macroscopic
<figure><img src="image_2.png" /><figcaption>Figure 1 Flow chart.</figcaption></figure>

appearance of the mesorectum, distance from the distal limit of resection.

## Morbidity and mortality

The postoperative complications are noted by the surgeon in the e-CRF during hospitalization (about 10–15 days) and during the first 3 months. Postoperative death is defined as death occurring within 30 postoperative days or during the first hospitalization. Postoperative complications are defined by the occurrence of medical or surgical complications within 90 postoperative days

or during the first hospitalization. Morbidity will be evaluated with the new classification of surgical complications by Dindo et al. which includes 5 grades [39,40].

## Pathological exam

Usual data are recorded: distal and circumferential margins, number of resected and invaded nodes, tumoral differenciation, presence of vascular embols (veinous or lymphatic, intra or extra-mural), perineural engainement, quality of mesorectal excision. The resected specimen will
be staged according to American Joint Committee on
Cancer (AJCC) criteria (7th version).

Rate of sphincter preservation

Comparison between the planned intervention at the
time of the randomisation and the resection performed
after peroperative digital exam will be performed.

Oncological follow-up

Patients will be followed in clinics for 5 years according to
the habits of each department. Usual follow-up is com-
posed of clinical exam, CEA analysis, CT-scan or Chest
Radiography with abdominal ultra-sound every 3–4 months
during the first three years and every 6 months for the last
two years.

Samples size and statistical considerations

With a sample of 264 patients, GRECCAR6 trial has
80% of power to detect at least a two fold increase in the
complete response rate in the 11 weeks group compared
to the 7 weeks group. This hypothesis assumes that the
complete response rate in the 7 weeks group is similar
to the usual rate of complete response after 6–8 weeks
(12% (Kalady et al. Bosset et al. Hiotis et al.)), with an
expected complete response rate in the 11 weeks group
of 26% and 10% of drop-outs, using a two-sided test at
the 0.05 significance level.

Intention to treat analysis of the primary endpoint will
be performed once all randomized patients have
6 months of follow-up. Analysis of survival will be
performed after at least 5 years of follow-up. A futility
analysis [41] is planned after randomization after 132 pa-
tients, using a Bayesian statistical interference, with no
impact on Type 1 error [42].

Discussion

While several retrospective studies has emphasised the
role of longer interval on efficiency of radiochemother-
apy on histological tumoral response, this multicentric
randomized trial is the first to evaluate this factor. The
major drawback of previous studies is that no explana-
tions are given on the reasons for variations in the time
between the end of radiotherapy and surgery [29,32,43].
Indeed, the time interval was decided by the surgeon or
maybe in case of favourable clinical response, mainly au-
thors advocate other factors such as patient morbidity or
logistical scheduling issues [33].

This trial could then identify a simple and cheap factor
influencing the rate of pCR. While it is still not obvious
that pCR is a good suggorate marker of the overall sur-
vival [44] based on previous randomized control trial on
CRT, it is probable that it could be a prognosis marker
of rectal conservation. One publication showed that

patients operated after 8 weeks may have significantly
less local recurrences.

Indeed, if waiting 4 more weeks increase the rate of
pCR, more patients could avoid a morbid surgical pro-
cedure such as an abdomino-perineal resection. This
new management is still limited due to the actual diffi-
culties to identify patients with pCR before surgery.
Advances in radiological imaging may facilitate this im-
portant point.

Finally, this long delay would allow the use of chemo-
therapy during this 3 months waiting period. This could
reduce the risk of synchronous metastasis that may
occur during the waiting period.

Competing interests

The authors declare that they have no competing interests.

Authors' contributions

JHL: conception of the study, writing of the manuscript. AR: statistical analysis and help to draft the manuscript. MS: pathological exam and help to draft the manuscript. YP: writing of the manuscript. TS: coordination of the study. ET: conception and coordination of the study. All authors read and approved the manuscript.

Acknowledgments

• Sponsor was « Assistance Publique – Hôpitaux de Paris ».

• The URC-est from University Hospital of Paris Est for its logistic help.

• The study was funding by a grant from PHRCN 2011 (Ministère de la Santé).
Thank you for adding this list of participating centers:

Participating centers:

1. Pr. Yann Parc, Hôpital Saint-Antoine, Paris, yann.parc@sat.aphp.fr

2. Pr. Yves Panis, Hôpital Beaujon, Clichy, yves.panis@bjn.aphp.fr

3. Pr. Karoui Médhi, Hôpital Pitié Salpetrière, Paris, medhi.karoui@psl.aphp.fr

4. Pr. Benoist Stéphane, Hôpital Bicêtre, Le Kremlin Bicêtre,
stephane.benoist@bct.aphp.fr

5. Dr. Loriau Jérôme, GH Saint Joseph, Paris, jloriau@gmail.com

6. Dr. Pezet Denis, CHU Estaing, Clermont Ferrand, dpezet@chu.clermontferrand.fr

7. Pr. Portier Guillaume, Hôpital Purpan, Toulouse, portier.g@chu-toulouse.fr

8. Dr. De Chaisemartin Cécile, Institut Paoli-Calmette, Marseille,
dchaisemartin@marseille.fnlcc.fr

9. Dr. Jafari Mehrdad, Centre Oscar Lambret, Lille, m-jafari@o-lambret.fr

10. Pr. Mariette Christophe, CHRU de Lille, christophe.mariette@chru-lille.fr

11. Pr. Prudhomme Michel, GHU Carémeau, Nimes, michel.prudhomme@chu-
nimes.fr

12. Dr. Meunier Bernard, CHU Rennes, Rennes, bernard.meunier@chu-rennes.fr

13. Pr. Tuech Jean Jacques, CHU Rouen, Rouen, jean-jacques.tuech@chu-rouen.fr

14. Dr. Meurette Guillaume, Hôtel Dieu, CHU Nantes, guillaume.meurette@wanadoo.fr

15. Pr. Rullier Eric, CHU Saint-André, Bordeaux, eric.rullier@chu-bordeaux.fr

16. Pr. Dousset Bertrand, CHU Cochin, Paris, bertrand.dousset@cch.aphp.fr

17. Pr. Berger Anne, Hôpital Georges Pompidou, Paris, anne.berger@egp.aphp.fr

18. Pr. Pruvot François-René, CHRU de Lille, frpruvot@chru-lille.fr

19. Dr. Eddy COTTE, CH Lyon Sud, eddy.cotte@chu-lyon.fr

20. Dr. George MANTION, CHU Jean Minjoz, Besançon,
georges.mantion@univ-fcomte.fr

21. Dr. Laurent MINEUR, Institut Sainte Catherine, Avignon, I.mineur@isc84.org

22. Dr. Jérôme DESRAME, Hôpital Privé Jean Mermoz, Lyon,
jerome.desrame@orange.fr

23. Pr. Christophe TRESALLET, Hôpital Pitie Salpêtrière, Paris,
christophe.tresallet@psl.aphp.fr

24. Dr. Nicolas GOASGUEN, Hôpital de la Croix Saint Simon, Paris,
NGoasguen@hopital-dcss.org

25. Dr. Laura BEYER, Hôpital Nord, Marseille, laura.beyer@ap-hm.fr

26. Dr. Frédérique- Sophie PESCHAUD, Hôpital Ambroise Paré,
Boulogne-Billancourt, frederique.peschaud@apr.aphp.fr
**Author details**

¹Assistance Publique-Hôpitaux de Paris (AP-HP), Department of Digestive Surgery, Hôpital Saint-Antoine, 184, rue du Fbg Saint-Antoine, 75012 Paris, France. ²University Pierre & Marie Curie (UPMC-Paris 06), Paris, France. ³AP-HP, Clinical Research Unit (URC-Est), Department of Clinical Pharmacology, Hôpital Saint-Antoine, Paris, France. ⁴AP-HP, Department of pathology, Hôpital Saint-Antoine, Paris, France.

Received: 2 March 2013 Accepted: 9 September 2013

Published: 12 September 2013

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doi:10.1186/1471-2407-13-417

**Cite this article as:** Lefevre *et al*. A multicentric randomized controlled trial on the impact of lengthening the interval between neoadjuvant radiochemotherapy and surgery on complete pathological response in rectal cancer (GRECCAR-6 trial): rationale and design. *BMC Cancer* 2013 **13**:417.

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