# Recurrence of pseudomyxoma peritonei after cytoreductive surgery and hyperthermic intraperitoneal chemotherapy

F. Mercier, F. Dagbert, M. Pocard, D. Goéré, F. Quenet, R. Wernert, F.

Dumont, Cecile Brigand, G. Passot, O. Glehen

► To cite this version:

F. Mercier, F. Dagbert, M. Pocard, D. Goéré, F. Quenet, et al.. Recurrence of pseudomyxoma peritonei after cytoreductive surgery and hyperthermic intraperitoneal chemotherapy. BJS Open, 2019, 3 (2), pp.195-202. 10.1002/bjs5.97 . hal-04837828

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# Recurrence of pseudomyxoma peritonei after cytoreductive surgery and hyperthermic intraperitoneal chemotherapy

F. Mercier<fnref n="1" /> ID, F. Dagbert⁹, M. Pocard<fnref n="3" />, D. Goéré⁴, F. Quenet<fnref n="5" />, R. Wernert⁶, F. Dumont⁷, C. Brigand<fnref n="8" />, G. Passot<fnref n="1" />,² ID and O. Glehen<fnref n="1" />,², on behalf of the RENAPE Network*

*Correspondence to:* Dr F. Mercier, Department of Surgical Oncology, Centre Hospitalier Lyon Sud, 165 Chemin du Grand Revoyet, 69495 Pierre Bénite, France (e-mail: fredmdmercier@gmail.com)

**Background:** Pseudomyxoma peritonei (PMP) is a rare clinical condition characterized by mucinous ascites, typically related to appendiceal or ovarian tumours. Current standard treatment involves cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC), but recurrences occur in 20-30 per cent of patients. The aim of this study was to define the timing and patterns of recurrence to provide a basis for modifying follow-up of these patients.

**Methods:** This observational study examined a prospectively developed multicentre national database (RENAPE working group) to identify patients with recurrence after optimal CRS and HIPEC for PMP. Postoperative complications, long-term outcomes and potential prognostic factors were evaluated.

**Results:** Of 1411 patients with proven PMP, 948 were identified who had undergone curative CRS and HIPEC. Among these patients, 229 first recurrences (24·2 per cent) were identified: 196 (20·7 per cent) occurred within the first 5 years (early recurrence) and 30 (3·2 per cent) occurred between 5 and 10 years. Three patients developed a first recurrence more than 10 years after the original treatment. The mean(s.d.) time to first recurrence was 2·36(2·21) years. Preoperative chemotherapy and high-grade pathology were significant factors for early recurrence. Overall survival for the entire group was 77·9 and 63·1 per cent at 5 and 10 years respectively. The principal site of recurrence was the peritoneum.

**Conclusion:** Recurrence of PMP was rare after 5 years and exceptional after 10 years.

Funding information

No funding

Paper accepted 5 July 2018

Published online 27 September 2018 in Wiley Online Library (www.bjsopen.com). DOI: 10.1002/bjs5.97

## Introduction

Pseudomyxoma peritonei (PMP) is a condition characterized by mucinous ascites, which leads to abdominal distension, pain, bowel obstruction and anorexia. It results from extensive mucin secretion by a primary tumour in the peritoneal cavity, most commonly originating in the appendix or ovary<fnref n="1" />, but occasionally from mucinous colorectal tumours<fnref n="1" />⁻<fnref n="3" />. Treatment for PMP has evolved over the past two decades, and now ideally involves complete cytoreductive surgery combined with hyperthermic intraperitoneal chemotherapy (CRS plus HIPEC). When

performed in a high-volume centre, this combination can achieve overall survival (OS) rates of over 60 per cent at 10 years⁴, although, PMP being a heterogeneous disease, survival varies according to disease aggressiveness, primary pathology and the extent of tumour removal during the initial surgery<fnref n="5" />,⁶. Surveillance is warranted as patients who develop a recurrence may be amenable to repeat surgery, leading to extended survival⁷,<fnref n="8" />.

Patterns of recurrence in these slow-growing tumours are currently not well defined, and optimal surveillance has not been standardized. The aim of the present study was

<footnote n="1">¹Department of Digestive Surgery, Centre Hospitalier Lyon Sud, and ²Equipe Mixte de Recherche 3738, Université Claude Bernard Lyon 1, Lyon,</footnote>

<footnote n="3">³Surgical Oncological and Digestive Unit, Lariboisière University Hospital, Paris, ⁴Department of Surgery, Gustave Roussy Institute, Villejuif,</footnote>

<footnote n="5">⁵Department of Surgical Oncology, Institut du Cancer de Montpellier, Montpellier, ⁶Department of Surgical Oncology, Institut de Cancérologie de l'Ouest (ICO) Paul Papin Cancer Centre, Angers, ⁷Department of Surgical Oncology, ICO René Gauducheau Cancer Centre, St Herblain, and</footnote>

<footnote n="8">⁸Department of Digestive Surgery, Hautepierre University Hospital, Strasbourg, France, and ⁹Department of Digestive Surgery, Centre Hospitalier Universitaire de Montreal, Montreal, Quebec, Canada</footnote>

<footnote>*Members of the RENAPE Network are co-authors of this study and can be found under the heading Collaborators.</footnote>
<figure><img src="image_2.png" /><figcaption>**Fig. 1** Flow chart of patient selection and study groups selected for analysis of pseudomyxoma peritonei (PMP). CRS, cytoreductive surgery; HIPEC, hyperthermic intraperitoneal chemotherapy</figcaption></figure>

to evaluate long-term recurrence patterns in PMP treated with optimal CRS + HIPEC, to provide a better definition of the follow-up required after apparent complete disease eradication.

## Methods

A prospective multicentre database (RENAPE working group) was used to identify all patients who had undergone surgery for PMP between 1993 and 2015⁹. The study was conducted in accordance with the tenets of the Declaration of Helsinki. The diagnosis of PMP was based on preoperative CT, operative findings and pathological confirmation. Preoperative data included patient demographics, origin of the primary tumour, number and type of previous interventions, and the use and type of systemic neoadjuvant therapy. Operative data included the Peritoneal Cancer Index (PCI), calculated during the operation¹⁰, size of residual lesions, duration of the surgery and the type of HIPEC used. Pathological analyses included histological grade (according to the WHO 2010 classification) and lymph node involvement⁶,¹¹. Tumours were graded as described by Carr¹¹. Postoperative systemic treatments, long-term survival and recurrence were recorded.

All patients analysed were treated with optimal CRS, and HIPEC was administered with either a closed or an open technique, as described previously¹². Patients were excluded from analysis when they underwent a palliative debulking procedure. The quality of CRS was defined according to the Sugarbaker completeness of cytoreduction (CC) score¹⁰: CC-0, no macroscopic residual tumour; CC-1, residual tumour smaller than 2·5 mm; CC-2, residual tumour between 2·5 and 25 mm; and CC-3, residual tumour greater than 25 mm. When the score was CC-0 or CC-1, the CRS was considered complete. To achieve optimal CRS, patients underwent multiple peritonectomies and visceral resection of involved organs. For patients who had multiple CRS + HIPEC treatments, only the first treatment was included in the analysis. Patients were excluded when the follow-up was insufficient for this analysis (less than 5 years).

Patients were followed up for recurrence according to the individual institutional guidelines. Follow-up for patients with low-grade tumours tended to include physical examination, estimation of cancer markers, and CT or MRI 6 months after surgery and every year up to 10 years. Follow-up for patients with high-grade tumours was generally followed in a manner similar
<table><caption>**Table 1** Sites and time to recurrence in patients with recurrent pseudomyxoma peritonei</caption><thead><tr><th></th><th>All recurrences<br>(n = 226)*</th><th>Early recurrence<br>(n = 196)</th><th>Late recurrence<br>(n = 30)*</th><th>P‡</th></tr></thead><tbody><tr><td>Type of recurrence</td><td></td><td></td><td></td><td>0.331</td></tr><tr><td>Peritoneal</td><td>148 of 225 (65.8)</td><td>129 (65.8)</td><td>19 of 29 (66)</td><td></td></tr><tr><td>Extraperitoneal†</td><td>45 of 225 (20.0)</td><td>37 (18.9)</td><td>8 of 29 (28)</td><td></td></tr><tr><td>Both</td><td>32 of 225 (14.2)</td><td>30 (15.3)</td><td>2 of 29 (7)</td><td></td></tr><tr><td>Time to recurrence (years)</td><td></td><td></td><td></td><td></td></tr><tr><td>Mean(s.d.)</td><td>2.36(2.21)</td><td>1.63(1.15)</td><td>7.15(1.30)</td><td></td></tr><tr><td>Median (range)</td><td>1.53 (0.11–9.91)</td><td>1.24 (0.11–4.93)</td><td>6.96 (5.14–9.91)</td><td></td></tr></tbody></table>

Values in parentheses are percentages unless indicated otherwise. *Data on type of recurrence were missing for one patient. †Extraperitoneal sites included liver, lung, lymph node, pleura and bone. ‡χ² test.

<table><caption>**Table 2** Clinicopathological and morbidity characteristics of patients with pseudomyxoma peritonei</caption><thead><tr><th></th><th>No. of patients*<br>(n = 259)</th><th>No recurrence<br>(n = 33)</th><th>Early recurrence<br>(n = 196)</th><th>Late recurrence<br>(n = 30)</th><th>P§</th></tr></thead><tbody><tr><td>Age at surgery (years)†</td><td>53.9(11.6)</td><td>51.6(9.7)</td><td>54.9(11.8)</td><td>50.1(11.2)</td><td>0.052¶</td></tr><tr><td>Sex ratio (F : M)</td><td>153 : 106</td><td>22 : 11</td><td>116 : 80</td><td>15 : 15</td><td>0.405</td></tr><tr><td>Site of primary lesion</td><td></td><td></td><td></td><td></td><td>1.000</td></tr><tr><td>Appendix</td><td>221 of 233 (94.8)</td><td>29 of 30 (97)</td><td>163 of 173 (94.2)</td><td>29 (97)</td><td></td></tr><tr><td>Ovary</td><td>9 of 233 (3.9)</td><td>1 of 30 (3)</td><td>7 of 173 (4.0)</td><td>1 (3)</td><td></td></tr><tr><td>Other</td><td>3 of 233 (1.3)</td><td>0 of 30 (0)</td><td>3 of 173 (1.7)</td><td>0 (0)</td><td></td></tr><tr><td>Previous surgery</td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Laparoscopy</td><td>87 (33.6)</td><td>10 (30)</td><td>68 (34.7)</td><td>9 (30)</td><td>0.802</td></tr><tr><td>Laparotomy</td><td>66 (25.5)</td><td>7 (21)</td><td>48 (24.5)</td><td>11 (37)</td><td>0.302</td></tr><tr><td>Cytoreduction</td><td>90 (34.7)</td><td>13 (39)</td><td>69 (35.2)</td><td>8 (27)</td><td>0.550</td></tr><tr><td>Preoperative chemotherapy</td><td>95 of 257 (37.0)</td><td>6 (18)</td><td>81 of 195 (41.5)</td><td>8 of 29 (28)</td><td>0.020</td></tr><tr><td>PCI‡</td><td>23 (2–36)</td><td>11 (3–36)</td><td>24 (2–36)</td><td>16 (3–33)</td><td>0.046¶</td></tr><tr><td>Duration of surgery (min)‡</td><td>480 (90–875)</td><td>420 (150–690)</td><td>480 (95–875)</td><td>420 (90–765)</td><td>0.285¶</td></tr><tr><td>CC score</td><td></td><td></td><td></td><td></td><td>0.502</td></tr><tr><td>CC-0</td><td>201 (77.6)</td><td>28 (85)</td><td>149 (76.0)</td><td>24 (80)</td><td></td></tr><tr><td>CC-1</td><td>58 (22.4)</td><td>5 (15)</td><td>47 (24.0)</td><td>6 (20)</td><td></td></tr><tr><td>WHO classification</td><td></td><td></td><td></td><td></td><td>&lt; 0.001</td></tr><tr><td>Low grade</td><td>62 of 199 (31.2)</td><td>15 of 25 (60)</td><td>33 of 147 (22.4)</td><td>14 of 27 (52)</td><td></td></tr><tr><td>High grade</td><td>137 of 199 (68.8)</td><td>10 of 25 (40)</td><td>114 of 147 (77.6)</td><td>13 of 27 (48)</td><td></td></tr><tr><td>Postoperative chemotherapy</td><td>36 of 258 (14.0)</td><td>2 (6)</td><td>32 (16.3)</td><td>2 of 29 (7)</td><td>0.178</td></tr><tr><td>Major complications</td><td>127 of 257 (49.4)</td><td>15 (45)</td><td>96 of 194 (49.5)</td><td>16 (53)</td><td>0.822</td></tr></tbody></table>

to protocols used for colorectal adenocarcinoma with physical examination, estimation of cancer markers and CT every 3 months in the first 2 years, every 6 months for the next 3 years, and then annually for life. Recurrences were confirmed with CT, abdominal MRI or PET, according to previously published criteria¹³. When the diagnosis could not be ascertained with radiology, exploratory laparoscopy with biopsy was performed to confirm recurrence.

Three patient groups were created for comparative purposes: patients with no recurrence after follow-up of at least 10 years, those with early recurrence within 5 years, and those with late recurrence between 5 and 10 years. Recurrences at more than 10 years of follow-up were excluded from the statistical analysis.

<table><caption>**Table 3** Site of recurrence according to pathological tumour grade</caption><thead><tr><th></th><th>All patients<br>with recurrence<br>(n = 173)*</th><th>Low grade<br>(n = 46)</th><th>High grade<br>(n = 127)</th><th>P†</th></tr></thead><tbody><tr><td>Type of recurrence</td><td></td><td></td><td></td><td>0.620</td></tr><tr><td>Peritoneal</td><td>109 (63.0)</td><td>28 (61)</td><td>81 (63.8)</td><td></td></tr><tr><td>Extraperitoneal</td><td>37 (21.4)</td><td>12 (26)</td><td>25 (19.7)</td><td></td></tr><tr><td>Both</td><td>27 (15.6)</td><td>6 (13)</td><td>21 (16.5)</td><td></td></tr></tbody></table>

## Statistical analysis

All statistical analyses were performed with SAS® 9.3 software (SAS Institute, Cary, North Carolina, USA).

<footnote>*With percentages in parentheses unless indicated otherwise values are †mean(s.d.) and ‡median (range). PCI, Peritoneal Cancer Index; CC, completeness of cytoreduction. §χ² or Fisher's exact test, except ¶ANOVA or Kruskal-Wallis test.</footnote>

<footnote>Values in parentheses are percentages. *Data on type of recurrence were missing for 53 patients. †χ² test.</footnote>
<figure><img src="image_3.png" /><figcaption>**Fig. 2** Kaplan-Meier curve for overall survival of patients with recurrent pseudomyxoma peritonei following cytoreductive surgery plus hyperthermic intraperitoneal chemotherapy</figcaption></figure>

Descriptive data are expressed as mean(s.d.), results for quantitative variables as median (range or 95 per cent c.i.) values, and qualitative data as the numbers with percentages. $\chi^2$ or Fisher's exact test was performed to evaluate unpaired data. For paired data, ANOVA was performed. The Kruskal-Wallis test was used when there was non-normality. *Post hoc* analyses were performed with the Tukey, Games-Howell or Dunn test to identify

paired groups with statistically significant differences. Estimates of survival were calculated using the Kaplan-Meier method and compared with the log rank test. Significance was set at $P < 0.050$.

## Results

Of a total of 1411 PMP treatments during the study period, 394 patients who either underwent incomplete cytoreduction or did not receive HIPEC were excluded. A further 69 patients with missing data for recurrence were also excluded. A total of 948 patients met the inclusion criteria, of whom 229 (24·2 per cent) developed a recurrence (Fig. 1). Among the recurrences, 196 (85·6 per cent) occurred before the 5-year follow-up, 30 (13·1 per cent) between the 5-year and 10-year follow-up, and three (1·3 per cent) after the 10-year follow-up (excluded from the statistical analysis). After optimal CRS + HIPEC, the mean time to first recurrence was 2·36(2·21) years (Table 1).

Of the three comparator groups created, there were 33 patients with no recurrence after follow-up of at least 10 years, 196 who developed early recurrence within 5 years and 30 who developed late recurrence between 5 and 10 years (Fig. 1).

Patient characteristics are presented in Table 2. In the vast majority of patients (94·8 per cent), PMP was of appendiceal origin. The three patient groups underwent similar numbers of previous surgical treatments. Those with no recurrence after 10 years had a lower rate of preoperative

<figure><img src="image_4.png" /><figcaption>**Fig. 3** Kaplan-Meier curve for overall survival of patients with recurrent pseudomyxoma peritonei following cytoreductive surgery plus hyperthermic intraperitoneal chemotherapy, according to site of recurrence. $P = 0.570$ (log rank test)</figcaption></figure>
<figure><img src="image_5.png" /><figcaption>Fig. 4 Recurrence of pseudomyxoma peritonei according to time of detection after surgery</figcaption></figure>

systemic chemotherapy (18 per cent) than the other two
groups (41.5 per cent for early and 28 per cent for late
recurrence; P = 0.019). Postoperative systemic chemother-
apy rates were similar between the groups. The WHO
pathological classification of PMP indicated significantly
more high-grade disease in the early recurrence group
(77.6 per cent) compared with late recurrence (48 per cent)
and no recurrence (40 per cent) groups (P < 0.001). Intra-
operative PCI values were significantly different between
no recurrence and early recurrence groups (11 *versus* 24
respectively; P = 0.046).

The mean time to recurrence was 1.63 years in the
early recurrence group and 7.15 years in the late recur-
rence group, but the type of recurrence (peritoneal or
extraperitoneal) was not significantly different between
groups (Table 1). The peritoneum was the most frequent
recurrence site (65.8 per cent for early and 66 per cent for
late recurrence). Extraperitoneal sites were implicated in
18.9 per cent of early recurrences and 28 per cent of late
recurrences. Both peritoneal and extraperitoneal sites were
involved in 15.3 per cent of early recurrences and 7 per
cent of late recurrences. Sites of recurrence were not sig-
nificantly different between the groups when defined by the
timing of the recurrence (P = 0.331) (Table 1). The organs
involved in extraperitoneal recurrence included liver, lung,
lymph node, pleura and bone, in descending order of fre-
quency. There was no difference in recurrence site between
tumour grades (Table 3).

The entire group had 5- and 10-year OS rates of 77.9
and 63.1 per cent respectively. After excluding patients with
no recurrence, to determine survival among patients with
recurrence, the 5- and 10-year OS rates were 73.8 and 53.6
per cent respectively (Fig. 2).

When OS rates were analysed according to site of recur-
rence there was no significant difference in survival among
patients with recurrence that occurred within the peri-
toneum, outside the peritoneum or at both sites (Fig. 3).

The precise timing of recurrences, indicated by the num-
ber of recurrences in each 2-month interval, is shown in
Fig. 4.

Discussion

The major finding of this study was the confirmation
that about 25 per cent of patients treated with optimal
CRS + HIPEC experienced a recurrence. PMP pathology
and the use of preoperative chemotherapy were significant
prognostic factors for recurrence. Although the mean time
to recurrence was nearly 2.5 years, 14.4 per cent of patients
(33 of 229) experienced a recurrence after 5 years. The OS
rate of patients with a recurrent PMP who underwent a
second optimal cytoreduction and HIPEC treatment was
similar to that reported previously for patients treated for a
first PMP¹⁴. The PCI score and site of recurrence did not
significantly impact on the timing of recurrence.

The present study focused on patients who under-
went optimal CRS+HIPEC. Of the 948 patients treated
with this regimen, 229 (24.2 per cent) had a recurrence
during follow-up, similar to the 26.8 per cent recur-
rence rate reported by the Basingstoke group⁸ for 712
patients who received optimal CRS+HIPEC. Among
recurrences in the present study, 85.6 per cent occurred
within 5 years. In contrast, in a large population of
patients with colorectal cancer, late recurrences (more
than 5 years) following a curative resection accounted for
only 4.3 per cent of all recurrences, and late recurrences
were more likely to occur with less aggressive primary
tumours¹⁵.

The largest international PMP registry¹⁴ has defined pre-
dictors of poor disease-free survival as: previous systemic
chemotherapy, high histopathological grade, major post-
operative complications, high PCI, and no HIPEC after
CRS. Those markers were consistent with the present
results, where patients with aggressive histology (high
grade) were more likely to experience early recurrence
(before 5 years), and patients with low-grade disease more
likely to experience late recurrence.

For most types of peritoneal metastasis, a high intraoper-
ative PCI has been associated with a poor prognosis¹⁵⁻¹⁷.
This is not always the case, however, according to a Peri-
toneal Surface Oncology Group International review¹⁴, in
which patients with mucinous disease of the peritoneum
were considered to represent a distinct group that exhib-
ited high survival rates, despite a very high PCI. The
present results did not show a statistically significant
association between the intraoperative PCI and timing
of recurrence, although the intraoperative PCI score was
greater in the early than in the late recurrence group (24
versus 16 respectively). This may reflect the small sizes of
the comparator groups.

Previous systemic chemotherapy is another factor asso-
ciated with poor prognosis. In the present study, the
vast majority (82 per cent, 27 of 33) of patients with
no recurrence after 10 years had not received preopera-
tive chemotherapy. The proportion of patients who had
received preoperative chemotherapy was significantly
higher in the early recurrence than in the late recurrence
group (41.5 versus 28 per cent). This might reflect a more
aggressive pathology or a higher tumour burden that
led the physician to determine a need for chemotherapy
before surgery. Alternatively, the association between early
recurrence and preoperative chemotherapy could be that
chemoresistant tumour cell clones were selectively spared
after systemic chemotherapy. This possibility suggests that
the timing and the route of administration of chemother-
apy may be important factors in preventing chemoresistant
cell selection.

The location of recurrence was not influenced by the tim-
ing of recurrence. Recurrences were exclusively peritoneal
in approximately two-thirds of each group. Only about
one-quarter of patients in the early and late recurrence
groups had an isolated extraperitoneal recurrence. A recent
study⁷ reported that, in patients treated with curative intent
for a first PMP recurrence after optimal CRS + HIPEC,
the 5-year OS rate was 83 per cent, compared with
only 27 per cent in patients with extensive disease not
amenable to optimal CRS + HIPEC. The present results

were consistent with those from that study: among all
patients who had a recurrence, 5- and 10-year OS rates
were 73.8 and 53.6 per cent respectively, compared with
their reported rates of 68 and 61 per cent⁷. These find-
ings emphasize the need for early detection of recurrence,
as a good outcome is achievable when recurrent disease is
resectable.

The ideal follow-up regimen after CRS + HIPEC for PMP has not been standardized. Exposure to radiation, as a result of multiple CT scans, has been shown to be associated with an increased risk of secondary malignancy, particularly in younger patients¹⁸. Abdominal MRI can provide adequate detection of peritoneal mucinous accumulations, and the results seemed better than those achieved with CT in some centres¹³. Abdominal MRI may be an alternative to CT for follow-up imaging, particularly in patients with low-grade PMP, in whom the risk of extraperitoneal recurrence is low¹⁴,¹⁹. Most recurrences in the present series occurred within the first 2 years after treatment, supporting the need for frequent surveillance during this interval.

This study has limitations. The inclusion period was
long (23 years, from 1993 to 2015) and survival has
improved over time as techniques have been modified<sup>20</sup>.
In 1992, few centres performed CRS. Follow-up methods
have also changed, such as the inclusion of MRI. The
greater sensitivity of MRI in detecting recurrence may
have affected the apparent distribution of recurrences
between the follow-up time intervals defined in this study.
HIPEC regimens and exposure times varied in different
centres. Lack of standardization may have been associ-
ated with variations in patterns of recurrence between
centres that could not be identified. As with all retro-
spective designs, sample size and missing data may have
introduced bias.

The outcomes of CRS + HIPEC for PMP are improv-
ing and encouraging, particularly after optimal resection of
the disease. As one in four patients experienced recurrence
and more than 10 per cent of recurrences occurred after
5 years of follow-up, it seems appropriate to follow these
patients for at least 10 years. The ideal surveillance regimen
remains to be defined, but the present results support com-
binations of CT and abdominal MRI for at least 10 years,
conducted more frequently in the first 2 years, and focusing
on abdominal recurrences that might be amenable to repeat
surgery.

Collaborators

Members of the RENAPE Network include: J. Abba (Department of
Digestive Surgery, Grenoble University Hospital, Grenoble, France);
K. Abboud (Department of General Surgery, Centre Hospitalier Universitaire, Jean Monnet University, Saint Étienne, France); M. Alyami (Department of Digestive Surgery, Lyon-Sud University Hospital, Lyon, France); C. Arvieux (Department of Digestive Surgery, Grenoble University Hospital, Grenoble, France); G. Averous (Department of Pathology, Hautepierre University Hospital, Strasbourg, France); N. Bakrin (Department of Digestive Surgery, Lyon-Sud University Hospital, Lyon, France); G. Balagué (Department of Radiology, Claudius Regaud Institute, Toulouse, France); V. Barrau (Department of Radiology, Centre Cardiologique du Nord, Saint Denis, France); H. Ben Rejeb (Department of Pathology, Bergonie Institute, Bordeaux, France); J.-M. Bereder (Department of Digestive Surgery, Archet 2 University Hospital, Nice, France); I. Berton-Rigaud (Department of Digestive Oncology, Institut de Cancérologie de l'Ouest (ICO) René Gauducheau Cancer Centre, Saint-Herblain, France); F. Bibeau (Department of Pathology, Côte de Nacre University Hospital, Caen, France); I. Bonnefoy (Department of Digestive Surgery, Lyon-Sud University Hospital, Lyon, France); D. Bouzard (Department of Surgery, Louis Mourier University Hospital, Colombes, France); I. Bricault (Department of Radiology, Grenoble University Hospital, Grenoble, France); C. Caramella (Department of Radiology, Gustave Roussy Institute, Villejuif, France); S. Carrère (Department of Surgical Oncology, Val d'Aurelle Montpellier Cancer Centre, Montpellier, France); C. de Chaisemartin (Department of Surgical Oncology, Paoli Calmettes Institute, France); M. Chassang (Department of Radiology, Archet 2 University Hospital, Nice, France); A. Chevallier (Department of Pathology, Archet 2 University Hospital, Nice, France); T. Courvoisier (Department of Digestive Surgery, Poitiers University Hospital, Poitiers, France); P. Dartigues (Department of Pathology, Gustave Roussy Institute, Villejuif, France); A. Dohan (Department of Radiology, Lariboisière University Hospital, Paris, France); C. Eveno (Surgical Oncological and Digestive Unit, Lariboisière University Hospital, Paris, France); M. Faruch-Bilfeld (Department of Radiology, University Hospital of Toulouse, Toulouse, France); G. Ferron (Department of Surgical Oncology, IUCT Oncopole, Toulouse, France); J. Fontaine (Department of Pathology, Lyon-Sud University Hospital, Lyon, France); L. Fournier (Department of Radiology, Georges Pompidou European Hospital, Paris, France); E. Gabiache (Department of Radiology, Claudius Regaud Institute – l'Institut Universitaire du Cancer de Toulouse (IUCT), Toulouse, France); J. Gagnire (Department of Digestive Surgery, Estaing University Hospital, Clermont-Ferrand, France); D. Geffroy (Department of Radiology, ICO René Gauducheau Cancer Centre, Saint-Herblain, France); L. Ghouti (Department of Digestive Surgery, Purpan University Hospital, Toulouse, France); F.-N. Gilly (Department of Digestive Surgery, Centre Hospitalier Lyon-Sud, Pierre-Bénite, Lyon, France); L. Gladieff (Department of Medical Oncology, Claudius Regaud Institute IUTC, Toulouse, France); A. Guibal (Department of Radiology, Hospital of Perpignan, Perpignan, France); J.-M. Guilloit (Department of Surgical Oncology, François Baclesse Comprehensive Cancer Centre, Caen, France); F. Guyon (Department of Surgical Oncology, Bergonie Institute, Bordeaux, France); B. Heyd (Department of Digestive Surgery, Minjoz University Hospital, Besançon, France); C. Hoeffel (Department of Radiology, Robert Debré University Hospital, Reims, France); C. Hordonneau (Department of Radiology, Montpied University Hospital, Clermont-Ferrand, France); S. Isaac (Department of Pathology, Centre Hospitalier Lyon-Sud, Pierre-Bénite, Lyon, France); P. Jourdan-Enfer (Department of Digestive Surgery, Lyon-Sud University Hospital, Lyon, France); R. Kaci (Department of Pathology, Lariboisière University Hospital, Paris, France); R. Kianmanesh (Department of Digestive Surgery, Robert Debré University Hospital, Reims, France); C. Labbé-Devilliers (Department of Radiology, ICO René Gauducheau Cancer Centre, Saint-Herblain, France); J. Lacroix (Department of Radiology, François

Baclesse Comprehensive Cancer Centre, Caen, France); B. Lelong (Department of Surgical Oncology, Paoli Calmettes Institute, Marseilles, France); A. Leroux-Broussier (Department of Pathology, Lorraine Institute of Oncology, Vandoeuvre-les-Nancy, France); Y. Lherm (Hospices Civils de Lyon, Pôle Information Médicale Evaluation Recherche, Unité de Recherche Clinique, Lyon, France); R. Lo Dico (Surgical Oncological and Digestive Unit, Lariboisière University Hospital, Paris, France); G. Lorimier (Department of Digestive Surgery, Angers University Hospital, Angers, France); C. Malhaire (Department of Radiology, Curie Institute, Paris, France); F. Marchal (Department of Surgical Oncology, Lorraine Institute of Oncology, Vandoeuvre-les-Nancy, France); P. Mariani (Department of Surgical Oncology, Curie Institute, Paris, France); E. Mathiotte (Hospices Civils de Lyon, Pôle Information Médicale Evaluation Recherche, Unité de Recherche Clinique, Lyon, France); P. Meeus (Department of Surgery, Léon Bérard Comprehensive Cancer Centre, Lyon, France); E. Mery (Department of Pathology, Claudius Regaud Institute IUTC, Toulouse, France); S. Msika (Department of Surgery, Louis Mourier University Hospital, Colombes, France); C. Nadeau (Gynaecology and Obstetrics Ward, Mother and Child Pole, Poitiers University Hospital, University of Poitiers, Poitiers, France); S. Nougaret (Department of Surgical Oncology, Val d'Aurelle Montpellier Cancer Centre, Montpellier, France); P. Ortega-Deballon (Department of Digestive Surgical Oncology, University Hospital of Dijon, Dijon, France); B. Paquette (Department of Digestive Surgery, Minjoz University Hospital, Besançon, France); O. Pellet (Imagerie Nucléaire de l'Ouest Lyonnais et de l'Ain (INOLA), Lyon, France); P. Peyrat (Department of Surgery, Léon Bérard Comprehensive Cancer Centre, Lyon, France); D. Pezet (Department of Digestive Surgery, Estaing University Hospital, Clermont-Ferrand, France); N. Pirro (Department of Digestive Surgery, Timône University Hospital, Marseilles, France); M. Pocard (Surgical Oncological and Digestive Unit, Lariboisière University Hospital, Paris, France); F. Poizat (Department of Pathology, Paoli Calmettes Institute, Marseilles, France); J. Porcheron (Department of Digestive Surgery, St Etienne University Hospital, St Etienne, France); P. Rat (Department of Digestive Surgical Oncology, University Hospital of Dijon, Dijon, France); P. Rousselot (Department of Pathology, François Baclesse Comprehensive Cancer Centre, Caen, France); P. Rousset (Department of Radiology, Centre Hospitalier Lyon-Sud, Pierre-Bénite, Lyon, France); H. Senellart (Department of Medical Oncology, ICO René Gauducheau Cancer Centre, Saint-Herblain, France); M. Serrano (Department of Digestive Surgery, Lyon-Sud University Hospital, Lyon, France); V. Servois (Department of Radiology, Curie Institute, Paris, France); O. Sgarbura (Department of Surgical Oncology, Val d'Aurelle Montpellier Cancer Centre, Montpellier, France); A. Skanjeti (Department of Radiology, Lyon-Sud University Hospital, Lyon, France); M. Svrcek (Department of Pathology, Hospital Saint-Antoine Assistance Publique – Hôpitaux de Paris (AP-HP), Paris, France); R. Tetreau (Department of Radiology, Val d'Aurelle Montpellier Cancer Centre, Montpellier, France); E. Thibaureau (Department of Surgical Oncology, ICO René Gauducheau Cancer Centre, Saint-Herblain, France); Y. Touchefeu (Department of Gastroenterology, Nantes University Hospital, Nantes, France); J.-J. Tuech (Department of Digestive Surgery, Charles Nicolle University Hospital, Rouen, France); S. Valmary-Degano (Department of Pathology, Minjoz University Hospital, Besançon, France); D. Vaudoyer (Department of Digestive Surgery, Lyon-Sud University Hospital, Lyon, France); S. Velasco (Department of Radiology, Poitiers University Hospital, Poitiers, France); V. Verriele-Beurrier (Department of Pathology, ICO Paul Papin Cancer Centre, Angers, France); L. Villeneuve (Hospices Civils de Lyon, Pôle Information Médicale Evaluation Recherche, Unité de Recherche Clinique, Lyon, France); F. Zinzindohoue (Department of Digestive and General Surgery, Georges Pompidou European Hospital, Paris, France).
## Acknowledgements

The authors thank C. Maurice for expert help with data analysis and L. Villeneuve for help with data collection. Disclosure: The authors declare no conflict of interest.

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