Int J Colorectal Dis DOI 10.1007/s00384-016-2546-1
ORIGINAL ARTICLE
Local excision of low rectal cancer treated by chemoradiotherapy: is it safe for all patients with suspicion of complete tumor response? Clotilde Debove 1 & Nathalie Guedj 2 & Ecoline Tribillon 1 & Léon Maggiori 1 & Magaly Zappa 3 & Yves Panis 1,4
Accepted: 25 February 2016 # Springer-Verlag Berlin Heidelberg 2016
Abstract Purpose The purpose of this study is to assess if local excision (LE) could be proposed if suspicion of complete tumor response (CR) after neoadjuvant chemoradiotherapy (CRT) for low rectal cancer (LRC) and this despite a potential risk of nodes (N+) or other tumor deposits (OTD) left in place. The aim was to assess in patients with LRC treated by CRT: (a) pathologic results of LE and total mesorectal excision (TME) in case of preoperative suspicion of CR and (b) the risk of N+ or OTD on TME if ypT0-Tis-T1 tumor. Patients Among 202 patients with LRC after CRT, 33 (16 %) with suspicion of CR underwent LE (n = 20) because of comorbidities and/or indication of definitive stoma or TME (n = 13). Pathologic examination of LE and TME specimens and oncological outcomes were assessed. Furthermore, 40/ 202 patients with pathologic CR on TME specimen (ypT0Tis-T1) were assessed for possible N+ or OTD. Results In the 33 patients with suspicion of CR: (a) after LE, tumor was ypT0-Tis-T1 in only 15/20 cases (75 %); (b) after TME, tumor was ypT0-Tis-T1 in only 7/13 cases (54 %).
* Yves Panis
[email protected]
1
Department of Colorectal Surgery, Beaujon Hospital (AP-HP), Paris VII University, Clichy, France
2
Department of Pathology, Beaujon Hospital (AP-HP), Paris VII University, Clichy, France
3
Department of Radiology, Beaujon Hospital (AP-HP), Paris VII University, Clichy, France
4
Service de Chirurgie Colorectale, Pôle des Maladies de l’Appareil Digestif, Hôpital Beaujon—Assistance Publique des Hôpitaux de Paris (APHP), Université Paris VII (Denis Diderot), 100 boulevard du Général Leclerc, 92110 Clichy, France
Among 40 patients with ypT0-Tis-T1 tumor on TME specimen, 4 (10 %) presented N+ and/or OTD. Conclusion In LRC with suspicion of CR after CRT, LE deserves a word of caution: 25 % of patients have in fact ypT2T3 tumors. Furthermore, in patients with ypT0-Tis or T1 on TME specimen, a 10 % risk of N+ and/or ODT is observed. Thus, patient with suspicion of CR after CRT and treated by LE is exposed to a possible incomplete oncologic treatment. Keywords Low rectal cancer . Complete tumor response . Local excision . Chemoradiotherapy
Introduction Treatment of locally advanced low rectal cancer (i.e., T3-T4 and/or N+) is based on neoadjuvant chemoradiotherapy (CRT) followed by surgery with total mesorectal excision (TME), leading to an improved local control with an expected rate of locoregional recurrence under 10 % [1–4]. Neoadjuvant CRT may lead to tumoral downstaging, reflected by decreased tumor size (downsizing), lower depth of tumor invasion, and lower risk of lymph node metastases [5]. In case of clinical and radiological suspicion of complete (ypT0) or near complete (ypTis or ypT1) tumor response (CR), patients could be potentially candidates to local excision (LE) as a definitive surgical alternative or even to a Bwatch and wait^ strategy, with surveillance only. This new paradigm of Borgan preservation^ after CRT is more and more proposed in expert centers [6]. Data supporting this strategy are however scarce. One randomized study (the GRECCAR 2 French study [7]) has been performed in order to assess if it can safely be proposed in all patients with infiltrant rectal cancer with suspicion of CR after neoadjuvant CRT but long-term oncologic results are not still
Int J Colorectal Dis
published. This concept is highly seductive, as it might not only avoid the risk of postoperative morbi-mortality and impaired function associated with TME [8] but also the risk of definitive stoma [5, 9]. However, the widespread of this Borgan preservation^ strategy might be impaired by several drawbacks: (a) preoperative clinical and radiological prediction of CR is still difficult [10, 11], and (b) patients treated by LE remain exposed to a potential risk of residual lymph nodes or other tumor deposit (OTD) left in place in the mesorectum, for which rates differ considerably in the reported series, from less than 5 [12–15] to 87 % [16]. In order to carefully evaluate the risks of LE after CRT, this study aimed to assess: (a) pathologic results of patients with low rectal tumor after CRT with suspicion of complete or near complete tumor response (T0-Tis-T1) treated by either local excision (LE) or total mesorectal excision (TME) and (b) the risk of lymph node involvement in patients treated by TME with ypT0-Tis or T1 tumor on the TME specimen.
Patients and methods Study population From January 2005 to May 2015, all consecutive patients who underwent a surgical resection for primary rectal adenocarcinoma in Beaujon Hospital were included in a prospective database. Among them, only patients with low rectal cancer (i.e., tumor located within 5 cm from the dentate line) and treated by neoadjuvant chemoradiotherapy (CRT) were included in this study. Demographic features (age, gender, body mass index), preoperative clinical features (American Society of Anesthesiology score, neoadjuvant treatment, tumor location), surgical features (procedure performed), pathological features (pTNM classification, margin involvement), and long-term oncologic results (death, overall and disease free survival, locoregional and distant metastases recurrences) were collected retrospectively into a dedicated database. Preoperative findings Neoadjuvant CRT was indicated because they presented low rectal cancer and advanced local disease (T3-T4 and/or N+ tumor) on endorectal ultrasound and/or pelvic magnetic resonance imaging (MRI) preoperative assessment. They received 50 Grays in 5 weeks associated with chemotherapy. All the patients were restaged at least 6 weeks after the completion of CRT. Besides clinical examination, an additional CT scan and an additional MRI or endorectal ultrasound were obtained in all cases. This restaging was performed for 2 main reasons. First, it helped the surgeon for the laparoscopic TME by carefully assessing the circumferential mesorectal
margin just before operation to reduce the risk of R1 resection. Second, it allowed the selection of patients with low rectal cancer for possible LE in case of suspicion of complete or near complete tumor response. As we previously described [6], a suspicion of CR in the present study was based on the following criteria: (a) clinical and proctoscopic assessment: no mucosal abnormality or only a small residual scar or ulcer (<2 cm in diameter), but without any macroscopic residual tumor; (b) new MRI: no residual tumor and no suspicion of mesorectal nodes involvement. In our strategy, we do not perform biopsy after CRT in case of a clinical suspicion of CR. Surgery Surgical strategy was systematically discussed in multidisciplinary team meeting. In our institution, laparoscopic TME remains the standard approach and was performed in almost all the patients, even in case of complete response. Local excision was therefore restricted to few highly selected patients with suspicion of CR or near CR, in whom TME procedure was supposed to be at risk for comorbidities and age or because patients refused abdominoperineal excision (APE) or because a total intersphincteric resection (ISR) was indicated but with very poor expected function. In all other patients with CR but without these criteria, TME remained the rule. TME was performed by laparoscopic approach as previously described [17]. Briefly, rectal dissection was carried out to the pelvic floor with TME and nerve preservation. For very low rectal tumors (i.e., located less than 10 mm from the dentate line), ISR was performed with either partial or total resection of the internal anal sphincter [18]. Reconstruction was either a conventional, stapled colorectal anastomosis, or a hand-sewn coloanal anastomosis. In both cases, a side-toend or an end-to-end anastomosis and a systematic temporary ileostomy were fashioned. After stapled anastomosis, the doughnuts were always inspected for completeness. A pelvic suction drain was always left in place behind the anastomosis. APE with definitive colostomy was performed in some patients with involvement of external sphincter or in case of tumor located more than 1 cm below the dentate line or for some aged patients for whom functional results of a very low anastomosis were supposed to be very bad (especially in case of a poor preoperative anal function). Local excision (LE) was realized in selected patients because of: (a) a high suspicion of CR on clinical, endoscopic, and/or new MRI assessment; (b) theoretical indication of APE or coloanal anastomosis with total ISR; (c) patients older than 75 years with poor anal sphincter function and/or severe comorbidities (i.e., obesity, cardiovascular or pulmonary disease, neurologic comorbidity, etc.). LE was performed either through transanal approach for very low rectal tumor or through transanal endoscopic microsurgery (TEM) for higher lesion in the low rectum.
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Pathologic examination Pathologic examination of the rectal specimen was performed according a standardized protocol [19]. The resection margin was defined as positive (R1) if 1 mm or less (either primary tumor, nodes or tumor deposit within the mesorectum). After RCT, a complete response (CR) was defined as the absence of residual tumor (ypT0). A near complete response was defined as the persistence of a tumor in the rectal wall, staged ypTis or ypT1. Pathological assessment of tumor regression after preoperative CRT was the tumor regression grade (TRG) [20]. LE was considered adequate if the following pathological features were present: ypT0, ypTis or ypT1, TRG ≤2, and negative margins. On the contrary, LE was considered as inadequate if yp ≥ T2 and/or positive margins and/or TRG ≥3 and/or lymphovascular invasion were present on the specimen. In these cases, an immediate secondary TME was proposed. Follow-up program All patients were followed every 3 months during the first 2 years after surgery then every 6 months during 3 years and annually thereafter. During follow-up, they underwent clinical examination, thoraco-abdomino-pelvic CT-scan, and blood sample for tumor markers (i.e., carcinoembryonic antigen and carbohydrate antigen 19.9 serum level). Colonoscopy was performed one year after surgery, then every 3 years. Statistical analysis Statistical analyses are presented as median ± standard deviation (range) for quantitative data and as number of cases (percentage of cases) for categorical variables. All analyses were performed using the Statistical Package for the Social Sciences (SPSS) software (SPSS Inc., version 22.0, Chicago, IL, USA). This study was conducted according to the ethical standards of the Committee on Human Experimentation of our institution and reported according to the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guidelines [21].
Among them, 33 patients with suspicion of CR were divided into in two groups: 20 patients underwent LE and 13 patients underwent TME. The baseline characteristics of these two groups are listed in Tables 1 and 2. Reason for choosing LE instead of standard TME was due in 20 patients to suspicion of CR associated with theoretical indication of either ISR (n = 15) or APE (n = 5) and presence of at least one of the following Bbad^ criteria for TME: (a) age more than 75 years (n = 5), (b) associated severe comorbidities (n = 8), and (c) refusal of APE by the patient (n = 7). Furthermore, among the 202 patients with low rectal cancer treated by neoadjuvant CRT, 40 patients treated by TME, presenting complete or near complete response on pathological examination (i.e., ypT0-Tis-T1), were assessed for exact location of possible invaded nodes (N+) or other mesorectal tumoral deposits (OTD). Characteristics of these patients are presented in Table 3. Surgery, either laparoscopic TME or LE, was performed after a mean of 10 ± 3 weeks (range, 5–21 weeks) after the end of CRT. Only 2 patients (3 %) underwent surgery before 6 weeks. Pathological results Among the 33 patients with suspicion of CR on the posttherapeutic assessment, 22 patients (67 %) were ypT0-TisT1 on pathological examination: 15 among the 20 patients treated by LE (75 %) and 7 among the 13 patients treated by TME (54 %). Thus, 11 patients suspected to have a CR (33 %) had, in fact, ypT2 or ypT3 tumors after either LE (5/20, 25 %) or TME (6/13, 46 %). Pathological examination showed a R1 resection rate of 15 % (n = 3/20) for local excision (3 ypT2-Nx tumors) and 15 % (n = 2/13) for TME (1 ypT2-N+ and 1 ypT3-N0 tumors). For the 40 patients with confirmed CR (ypT0-Tis-T1) on TME specimen, 4 patients (10 %) presented lymph node involvement and/or other mesorectal tumoral deposits: one presented OTD more than 1 cm above the scar of the tumor, one presented a mesorectal positive nodes more than 3 cm above the scar, one presented 2 positive nodes on the vascular pedicle associated with one mesorectal OTD more than 3 cm form the scar, the last patient presented 5 positive nodes in the mesorectum, more than 3 cm above the scar. Pathological examination showed a R1 resection rate of 2.5 % (n = 1/40) (1 ypT1-N+ tumor).
Results Immediate secondary TME Study population From January 2005 to May 2015, 202 patients with low rectal cancer treated by neoadjuvant CRT were operated on: 180 patients (89 %) underwent laparoscopic TME and 22 patients (11 %) local excision (LE).
After LE, 5 of 20 patients (25 %) have poor pathological criteria (T2-Nx-R0 (n = 1), T2-Nx-R1 (n = 3), and T3-Nx-R0 (n = 1)). Three of them (n = 3/20, 15 %) underwent immediate secondary TME after LE. Secondary TME was coloanal
Int J Colorectal Dis Table 1 Characteristics of 20 patients with low rectal cancer undergoing local excision after neoadjuvant chemoradiotherapy Local excision n = 20
Table 2 Characteristics of 13 patients with low rectal cancer undergoing laparoscopic total mesorectal excision (TME) after neoadjuvant chemoradiotherapy with suspicion of complete or near complete tumor response Laparoscopic TME n = 13
Gender Male
9 (45)a
Female
11 (55)
Gender Male Female
b
Age
68 (47–82)
BMIc
25 (19–42)
ASAd grade I
2 (10)
II
13 (65)
III
2 (10)
Unknown
3 (15)
Age BMIc
56 (42–63)b 24 (18–31)
ASAd grade I II
7 (54) 5 (38)
Pre-radiochemotherapy assessment
III IV
Modalities e
Only MRI
7 (35)
Only endorectal ultrasound
2 (10)
Both MRI and ultrasound
11 (55)
Staging T2-N0
4 (20)
T2-N+
9 (45)
T3-N0
1 (5)
T3-N+
6 (30)
Pre-radiochemotherapy assessment Modalities Only MRIe Only endorectal ultrasound Both MRI and ultrasound Stadification T2-N+ T3-N0 T3-N+
Post-radiochemotherapy assessment MRIe
18 (90)
T0-N0
7 (35)
T1-N0
11 (55)
Endorectal ultrasound
2 (10)
T0-N0
1 (5)
T1-N0
1 (5)
Surgery performed for local excision Transanal excision
16 (80)
Transanal endoscopic microsurgery
4 (20)
Pathological examination CRg or near CR
15 (75)
ypT0-Nx-R0
10 (50)
ypTis-Nx-R0
1 (5)
ypT1-Nx-R0
4 (20)
No CR
5 (25)
ypT2-Nx-R0
1 (5)
ypT2-Nx-R1
3 (15)
ypT3-Nx-R0
1 (5)
TMEh after local excision
3 (15)
Coloanal anastomosis
2 (10)
Abdominoperineal excision
1 (5)
a b
Median (range)
c
Body mass index
d
American Society of Anesthesiology Score
e
Magnetic resonance imaging
f
Intersphincteric resection
g
Complete response
h
Total mesorectal excision
1 (8) 0 (0)
5 (39) 2 (15) 6 (46) 5 (39) 2 (15) 6 (46)
Post-radiochemotherapy assessment by MRI
13 (100)
T0-N0 T1-N0 Surgery performed Coloanal anastomosis with total ISRf Coloanal anastomosis with partial ISR Pathological examination CRg or near CR ypT0-Tis-N0-R0 ypT1-N0-R0
9 (69) 4 (31)
No CR ypT2-N0-R0 ypT2-N + −R0 ypT2-N + −R1 ypT3-N0-R1 Adjuvant chemotherapy Yes No a
Number of patients (percentage)
9 (69)a 4 (31)
Number of patients (percentage)
b
Median (range)
c
Body mass index
d
American Society of Anesthesiology Score
e
Magnetic resonance imaging
f
Intersphincteric resection
g
Complete response
3 (23) 10 (77) 7 (54) 5 (38) 2 (15) 6 (46) 3 (23) 1 (8) 1 (8) 1 (8) 3 (23) 10 (77)
Int J Colorectal Dis Table 3 Characteristics of 40 patients treated by TME after chemoradiotherapy with complete tumoral response (CR) or near CR on pathological examination Laparoscopic TME n = 40
anastomosis in 2 cases and APE in 1 case. Pathological examination on the specimen had found no residual tumor in 2 patients and 1 ypT3-N2 tumor. The 2 others patients did not underwent a secondary TME because of age more than 75 years and/or severe comorbidities (n = 2).
Gender Male
24 (60)a
Female
16 (40) 61 (33–77)b
Age c
BMI
25 (18–34)
ASAd grade I
13 (32)
II
23 (58)
III
2 (5)
Unknown
2 (5)
Pre-radiochemotherapy assessment Modalities Only MRIe
10 (25)
Only endorectal ultrasound
7 (18)
Both MRI and ultrasound
23 (58)
Stadification T2-N0
2 (5)
T2-N+
6 (15)
T3-N0
3 (8)
T3-N+
26 (65)
T4-N+
3 (8)
Post-radiochemotherapy assessment by MRI
38 (95)
T0-N0
6 (15)
T1-N0
0 (0)
T2-N0
5 (13)
T3-N0
6 (15)
T1-N+
2 (5)
T2-N+
7 (17)
T3 or T4 N+
12 (30)
Surgical procedure Stapled colorectal anastomosis
6 (15)
Coloanal anastomosis with partial ISRf
23 (57)
Coloanal anastomosis with total ISR
10 (25)
Abdominoperineal excision
1 (3)
Pathological examination Without lymph node involvement ypT0-N0
23 (58)
ypTis-N0-R0
2 (5)
ypT1-N0-R0
11 (28)
With lymph node involvement or OTD
1
ypT0-OTD + −R0
1
ypTis-N + −R0
1
ypT1-N + −R1
1
OTD other tumor deposit a
4 (10)
ypT0-N + −R0
Number of patients (percentage)
b
Median (range)
c
Body mass index
d
American Society of Anesthesiology Score
e
Magnetic resonance imaging
Oncological results Mean follow-up was 28 ± 24 (range, 0–99) months. After this follow-up, among the 20 patients of the LE group, no patient was dead. Overall recurrence rate was 25 % (n = 5). Two patients (10 %) had local recurrence, respectively at 11 and 23 months after LE, and 3 patients (15 %) had distant recurrence. All the recurrences occurred in T0-NxR0 or Tis-Nx-R0 patients. The 5 patients with poor pathological criteria had no local recurrence after a mean follow-up of 31 (range, 4–86) months. Among the 13 patients of the TME group, no patient was dead. Only one patient had a metastatic recurrence (9 %). No patient had local recurrence. Among the 40 patients with confirmed CR on the pathological specimen, no patient was dead. Overall recurrence rate was 5 % (n = 2). One patient had T1-N2-R1 tumor at pathological examination, had both local and pulmonary recurrence 12 months after TME, and underwent secondary APE and thoracic surgery. The other patient had T0-N0-R0 tumor at pathological examination and had metastatic recurrence at 2 months after TME.
Discussion Our study showed that in patients with infiltrant low rectal cancer treated by neoadjuvant CRT, suspicion of CR or near CR is not always synonym of pathologic CR or near CR. Despite choosing strict criteria for CR or near CR (i.e., T0Tis-T1 N0 with no mucosal abnormality or only a small residual scar or ulcer but without any macroscopic residual tumor and on MRI, no residual tumor and no suspicion of mesorectal nodes involvement), tumor was still present in 25 % of the cases after LE and 46 % after TME. Furthermore, in patients with the Bbest^ TME specimen (i.e., ypT0-Tis-T1), 10 % of them still presented positives nodes or OTD, suggesting that if they were selected for LE, it will probably be an incomplete oncologic treatment. Thus, organ preservation must be probably today proposed only in highly selected patients not only with high suspicion of CR but also with at least 1 of the following criteria: theoretical indication of APE or coloanal anastomosis with total ISR, patients > 75 years and/or severe comorbidities. Improvements in neoadjuvant CRT techniques for rectal cancer have led to a high rate of downstaging and up to 24 % of CR is noted on pathologic specimen after TME
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[22]. With extended regimen of CRT, a 68 % rate of clinical tumor response was even recently reported by Habr-Gama [23]. For this reason, she developed the concept of Bwait and see^ after CRT, which allowed to avoid TME in approximately half of the patients [23, 24]. However, a recent review [25] have suggested that, among 8 series, the mean local failure rate after Bwait and see^ was 34 %, probably explained, at least in part, by the difficulty of preoperative correct assessment of CR by imaging [10]. For this reason, we, as well as others [7], preferred LE in case of suspicion of CR, instead of Bwait and see,^ as the pathologic examination will allow to select only Bgood^ patients for LE with ypT0 or ypT1 and R0 on the specimen. In the setting of LE after CRT in case of suspicion of CR or near CR, reported studies are confusing because some authors proposed this strategy only in selected tumors and not for all tumors for which neoadjuvant CRT is the rule (i.e., T3-T4 and/ or nodes positives): for example, Lezoche et al. [26] or the ACOSOG study [27] proposed LE only for T2 tumors, and Rullier et al. in the GRECCAR 2 study only for T2-T3 less than 4 cm in size [7]. Thus, the first possible misunderstanding can be that conclusions of such studies, if optimistic regarding Borgan preservation,^ can be safely extended to all patients with suspicion of CR undergoing neoadjuvant CRT. The truth for T2 tumor is probably not the truth for T3 or T4 tumors. This fact can be illustrated in the GRECCAR 2 study where 100 % of the ypT0 patients randomized in the TME arm presented no positive nodes [28]. This result is in opposition with previous studies reporting rates of nodes positives tumors around 5 to 10 % [29, 30] and 11 % in the present study. Furthermore, there is no standardized definition of CR: is it with biopsy, as in Habr-Gama protocol? Or with only a scar less than 2 cm in the GRECCAR 2 study? Other possible misunderstanding could be to select a Bbad^ patient for possible LE because of a dramatic tumor regression but with a Bsmall^ tumor remaining both clinically and on MRI. For us, this latter case is a contraindication to LE. Our criteria selection for LE includes no residual tumor on clinical examination and no tumor on MRI. But even with this policy, we observed that 25 % of our patients presented in fact on the LE specimen ypT2 or even ypT3 tumors, emphasizing another problems associated with LE after CRT: a good imaging technique allowing us to diagnose safely CR is still missing [10, 11]. The failure of clinical criteria to detect CR has been recently suggested in 61 TME specimens with ypT0 tumors: 40 had residual ulcers and 5 exophytic lesions, and only 16 (26 %) fulfilled criteria for CR [31]. A Bbad^ selection for LE with discovery of ypT2 or ypT3 tumors on the LE specimen must indicate immediate secondary TME. However, secondary TME was refused by 45 % of the patients from an Italian study [14] and by a third of the GRECCAR 2 study patients [28]. Very recently was published a large prospective study [32] including 51 patients treated by neoadjuvant RCT for T1-T2-
T3-N0 low rectal cancer. Among those patients, 47 were selected for LE by TEM because of good response. However, among them, 17 (36 %) presented in fact ypT2 or T3 tumor and/or N+ tumors. Furthermore, among these 17 patients scheduled for immediate secondary TME, 9 (53 %) refused completion surgery. This new problem can also be crucial because patients who refused a secondary TME are exposed to a very high risk of positives nodes and tumor recurrence [33]. A recent study from Lee et al. reporting 27 patients undergoing LE for T3 or T4 tumors after CRT showed 34 % of ypT2 and T3 tumors on the specimen, with significantly poorer survival rates than in patients with ypT0 or ypT1 tumors [34]. Finally, when secondary TME is performed, morbidity rate has been reported to be higher than after primary TME [35]. We believed that the choice for organ preservation with LE only must keep in mind all these problems and the oncologic risks associated with this choice. For all these reasons, today, we only propose LE in highly selected patients (i.e., aged patients with comorbidities and/or indication of APR or CAA with total ISR), representing only 10 % of all our patients undergoing neoadjuvant CRT for low rectal cancer [6]. Our study has some limitations. First, despite including 202 consecutive patients, there is few CR or near CR, leading to a small number of patients for subsequent analyses. However, this relatively small number of patients undergoing LE after neoadjuvant RCT reflected our actual policy to highly select patients for LE because of the risk of incomplete oncologic treatement despite the benefit of organ preservation. The results of the present study are also limited by its retrospective nature and by the relatively short follow-up of the patients included. In the future, with better assessment of tumor response, probably delayed after 10 or even 12 weeks [36, 37], the number of selected patients will increase. But because to date the main problem is to correctly diagnose CR or near CR before surgery, we continue to contraindicate this attitude of organ preservation even in case of suspicion of CR in patients without major comorbidity and with possible sphincter-saving surgery. In conclusion, possible extension of the new paradigm of organ preservation to all rectal cancer patients presenting suspicion of CR must wait not only improvement of imaging technique for the diagnosis of CR but also new randomized studies with long term oncologic results.
Conflict of interest The authors declare that they have no conflict of interest.
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