- Email: [email protected]
Mentored experience of establishing a national peritoneal malignancy programme – Experience of first 50 operative cases
Accepted Manuscript Mentored experience of establishing a national peritoneal malignancy programme – experience of first 50 operative cases K.H. Chang, M. Kazanowski, O. Staunton, R.A. Cahil, B.J. Moran, C. Shields, J. Mulsow, MD FRCSI PII:
S0748-7983(16)30945-3
DOI:
10.1016/j.ejso.2016.10.007
Reference:
YEJSO 4497
To appear in:
European Journal of Surgical Oncology
Received Date: 6 May 2016 Revised Date:
13 August 2016
Accepted Date: 7 October 2016
Please cite this article as: Chang K, Kazanowski M, Staunton O, Cahil R, Moran B, Shields C, Mulsow J, Mentored experience of establishing a national peritoneal malignancy programme – experience of first 50 operative cases, European Journal of Surgical Oncology (2016), doi: 10.1016/j.ejso.2016.10.007. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT Title:
Mentored experience of establishing a national peritoneal malignancy programme – experience of first 50 operative cases
Authors:
KH Chang1, M Kazanowski1, Staunton O1, RA Cahil1, BJ Moran2, C Shields1,
Affiliations:
1
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J Mulsow1
National Centre for Peritoneal Malignancy, Mater Misericordiae University
Hospital, Dublin, Ireland 2
Peritoneal Malignancy Institute, Basingstoke and North Hampshire Hospital,
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Basingstoke, United Kingdom
Email addresses:
[email protected]
MK:
[email protected]
OS:
[email protected]
RAC:
[email protected]
BJM:
[email protected]
CS:
[email protected]
§
Corresponding author:
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JMM:
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KHC:
[email protected]
Mr. Jurgen Mulsow MD FRCSI
Address:
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Consultant General & Colorectal Surgeon
Department of Surgery,
Tel:
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National Centre for Peritoneal Malignancy, Mater Misericordiae University Hospital, Dublin 7, Ireland.
+353 1 854 5091
Fax:
+353 1 854 5242
Word count:
232 (abstract) 2987 (main text)
ACCEPTED MANUSCRIPT Abstract
Background: Cytoreductive Surgery (CRS) and Hyperthermic Intraperitoneal Chemotherapy (HIPEC) are considered standard of care for pseudomyxoma peritonei (PMP) and selected patients with
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colorectal peritoneal metastases (CPM) or peritoneal mesothelioma. A National Peritoneal Malignancy programme was established in Ireland (population of 4.5 million) in May 2013 with mentoring and support from the Peritoneal Malignancy Institute, Basingstoke UK. This study reviews the operative and oncological outcomes for the first 50 patients who underwent
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CRS and HIPEC in Ireland. Methods:
This is a retrospective review of all patients referred, and of the subset who underwent CRS
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and HIPEC, for peritoneal malignancy in Ireland between May 2013 and November 2015. Results:
During the study period, 130 patients were referred and 50 patients were selected for CRS and HIPEC. Three patients were found to have unresectable disease at laparotomy. Of the remaining 47 patients, eight had major tumour debulking. In total, 39 underwent complete
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cytoreduction and 45 received HIPEC. After a median follow up of 12.7 months, 12 patients had developed further metastatic disease. The rates of complete cytoreduction, complication and operative mortality were 83%, 0% and 0% respectively. There were no major ClavienDindo grade III/IV morbidity.
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Conclusions:
We report the successful establishment of a national peritoneal malignancy programme. Mentoring from an experienced centre may have shortened the known learning curve evident
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by our encouraging outcomes. The follow-up period is short, however our early results are comparable with internationally reported figures.
ACCEPTED MANUSCRIPT Keywords
peritoneal malignancy, pseudomyxoma peritonei, peritoneal metastasis, cytoreductive
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surgery, hyperthermic intraperitoneal chemotherapy, outcomes
ACCEPTED MANUSCRIPT Introduction
The concept of heated intraperitoneal chemotherapy was first described in a patient with peritoneal dissemination from a mucinous neoplasm of the appendix by Spratt et al in 1980
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[1]. The treatment strategy for peritoneal malignancy has evolved to a combination of macroscopic tumour removal, entitled cytoreductive surgery (CRS), and hyperthermic intraperitoneal chemotherapy (HIPEC) [2-7]. The aim is to achieve a complete macroscopic tumour removal (complete cytoreduction) and to augment the surgical cytoreduction with
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HIPEC. CRS and HIPEC is now regarded as the standard of care in the management of patients with pseudomyxoma peritonei (PMP) and selected patients with peritoneal mesothelioma [8-9]. In patients with PMP, for whom a complete cytoreduction is not
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possible, major tumour debulking may achieve symptom control and even long term survival [10]. There is also now accumulating evidence to support this combined approach in selected patients with resectable colorectal peritoneal metastases (CPM) and metastatic ovarian cancer [11-13].
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The expanding indications for CRS/HIPEC have resulted in a rapid increase in the number of centres internationally offering treatment to patients with peritoneal malignancy. The learning curve to providing optimal peri-operative and long-term oncological outcomes can however be steep. Even in high volume centres, the morbidity (0-50%) and mortality (0-6%) following
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CRS/HIPEC can be significant [14]. Ensuring low post-operative morbidity and optimal longterm oncological outcomes is a key marker of performance in the successful delivery of a peritoneal malignancy treatment programme. Mentoring by experienced centres may help
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fledgling units to optimise outcomes early in their experience [15-17].
Historically, patients diagnosed with peritoneal malignancy in Ireland have been referred to the Peritoneal Malignancy Institute in Basingstoke (UK) where, in total, more than 1200 patients have been treated since 1994 [18, 19]. Subsequent follow-up was conducted locally through an outreach programme [20]. In May 2013, due to the expanding indications for CRS/HIPEC and increasing demand for this service in Ireland, it was decided to establish a single centre national peritoneal malignancy programme, catering for the population of 4.5 million. The programme was to be delivered locally by a multidisciplinary team led by two colorectal surgeons who had experience in the field of CRS/HIPEC and involved supervision
ACCEPTED MANUSCRIPT and mentoring from the senior surgeon at the Basingstoke Peritoneal Malignancy Institute, as well as a multidisciplinary exchange of expertise involving surgeons, nurses, anaesthetists and other support staff. In November 2015, the 50th operative case for peritoneal malignancy in Ireland was
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performed. Herein we report our experience of establishing a national peritoneal malignancy programme and in doing so explore the role of mentorship by an experienced centre in
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optimising early surgical and oncological outcomes.
ACCEPTED MANUSCRIPT Patients & Methods
Study Overview This is a retrospective analysis of consecutive patients treated for peritoneal malignancy at the
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single national peritoneal malignancy centre between May 2013 and November 2015. Data on patient demographics, clinicopathological variables, operative outcomes, and oncological outcomes was extracted from a prospectively maintained database.
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Mentoring process
The decision to establish a peritoneal malignancy programme within Ireland was made approximately eight months prior to the first case being performed. A number of visits (four
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weeks in total) were made by the lead surgeons to the Peritoneal Malignancy Institute Basingstoke to observe practice including out-patient assessment, pre-operative staging, multidisciplinary decision making, peri- and intra-operative care, and post-operative followup and surveillance. Further multidisciplinary (nursing, surgery, anaesthesia) visits to Basingstoke followed. The surgical team from Dublin also joined and participated in meetings
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of the Peritoneal subcommittee of the Association of Coloproctology of the Great Britain and Ireland. Standardised operating procedures, mirroring those in Basingstoke, were subsequently established for patient evaluation and selection, operative management, postoperative care, and follow-up. Reciprocal visits to Dublin were made by the lead surgeon
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from Basingstoke and a number of multidisciplinary meetings followed, including surgeons, anaesthetists, intensivists, radiologists, oncologists, pathologists, pharmacy, dietetics, physiotherapy, theatre and ward nursing, both for staff education and to agree treatment
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protocols and ensure appropriate resourcing. A dedicated peritoneal malignancy nurse was appointed and a clinical database established. Data was also prospectively entered into the UK and Ireland registry. A business case outlining expected clinical activity, resource needs, and associated costs was submitted to the governing health authority. All prospective cases were discussed at the in-house multidisciplinary meeting and initially also by teleconference between Dublin and Basingstoke. As experience grew, teleconferencing was used selectively when decision making was not straightforward. The first case (a female with synchronous CPM) for CRS/HIPEC was identified and scheduled for May 2013 with direct supervision and participation by the mentoring surgeon. Throughout the subsequent development of the programme reciprocal surgeon visits (approximately four per year) between Dublin and
ACCEPTED MANUSCRIPT Basingstoke have continued, nursing staff have attended annual training meetings delivered in Basingstoke, and regular contact between the departments has been maintained.
Patients All patients with a diagnosis of peritoneal malignancy (primary or metastatic) referred during
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the study period were included in the analysis. The indication for referral in the vast majority of patients was CPM, metastatic appendix adenocarcinoma or evidence of pseudomyxoma peritonei.
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Standard staging investigations included lower gastrointestinal endoscopy and computed tomography (CT). Positron emission tomography–CT (PET-CT) was used selectively to exclude non-peritoneal distant metastatic disease. Magnetic resonance imaging (MRI) was
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employed selectively to locally stage pelvic primary or metastatic disease or to determine small bowel involvement. Serum tumour markers including carcinoembryonic antigen (CEA), CA19-9 and CA-125 were measured. Staging laparoscopy was used to assess tumour extent and resectability in patients with CPM who had inconclusive imaging.
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All patients were discussed in a multidisciplinary team meeting. Exclusion criteria for surgery included poor performance status or significant medical comorbidity, extensive peritoneal disease in the case of CPM, disease that was unresectable due to its anatomical location, and unresectable large volume non-peritoneal distant metastatic disease. Relative exclusion
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criteria included adverse tumour biology (signet ring, lymph node involvement) and progression of disease during systemic chemotherapy. The Peritoneal Cancer Index (PCI) was used to calculate the tumour volume and distribution [21]. Post-operative morbidity and
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mortality were recorded using the Clavien-Dindo classification [22]. Survival and disease recurrence were documented and analysed.
Perioperative Management All patients underwent pre-operative anaesthetic assessment for medical optimisation. Vaccinations were given two weeks prior to surgery if splenectomy was anticipated. Full mechanical bowel preparation was used when colonic resection was anticipated. Nutritional drinks were given the evening before and the morning of surgery. All patients received 24 hours of prophylactic antibiotics. Epidural analgesia was the pain management modality of choice for up to six days postoperatively. All patients received parenteral nutrition
ACCEPTED MANUSCRIPT immediately post-operatively and enteral nutrition was initiated slowly at the fourth postoperative day, or when tolerated. All patients received prophylactic low molecular weight heparin (LMWH) the evening before surgery and daily post-operatively. Pneumatic intermittent compression boots were used until fully mobile. Thromboembolic deterrent stockings were used until hospital discharge. Selected high risk patients received further
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LMWH after discharge for up to four week post-operatively.
Surgical Technique
All procedures were performed by two colorectal surgeons (JM and CS). Surgical technique
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was as previously described [18]. All patients underwent a long midline laparotomy excising the umbilicus and any laparoscopic port sites. The greater and lesser omentum and the falciform ligament were routinely resected. In females, bilateral salpingo-oophorectomy was
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routinely performed. Further visceral resections depended on disease extent, and included splenectomy, liver resection and/or Glisson capsulectomy, segmental or total colectomy, anterior resection or abdominoperineal excision, small bowel resection, hysterectomy, partial cystectomy, partial or total gastrectomy. The liver was mobilised to facilitate right diaphragmatic peritoneal stripping or to allow liver wedge resection or Glisson capsulectomy.
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Partial or complete peritonectomy was performed depending on the underlying pathology and the extent of disease. The number of peritonectomies (up to five) was recorded in each case (right and left hemi-diaphragmatic, right and left parietal, pelvic).
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HIPEC was administered using the open colosseum technique. For patients with CPM or PMP mitomycin C was the agent of choice at a dose of 10mg/m2, heated to 41oC for 60 minutes. Cisplatin (50mg/m2) and doxorubicin (15mg/m2) were the chemotherapeutic agents of choice
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in treating patients with peritoneal mesothelioma. HIPEC was administered using the Sun Chip delivery system (Gamidatech, Eaubonne, France).
The presence of residual disease was recorded by the Completeness of Cytoreduction score (CC): CC-0, no residual tumour; CC-1, no residual tumour nodule greater than 2.5mm; CC-2, no residual tumour greater than 25mm; CC-3, residual nodules greater than 25mm.
ACCEPTED MANUSCRIPT Statistical Analysis Statistical analysis was performed using SPSS 18.0 software (Chicago, IL). KilmogorovSmirnoff test was used to determine normality of distribution. Parametric data were expressed
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as mean ± standard deviation. Non-parametric data were expressed as median (range).
ACCEPTED MANUSCRIPT Results
Patients During the study period, 130 patients were referred for assessment and management of peritoneal malignancy, 41 patients were deemed not suitable for CRS/HIPEC. Of these, 29
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who were considered inoperable due to disease burden or comorbidity; 10 received systematic chemotherapy due to heavy or extra-peritoneal disease burden with a view to CRS/HIPEC if a satisfactory response was demonstrated; and two underwent pelvic exenteration for locally recurrent tumour without the need for HIPEC. A further 23 patients were undergoing
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investigation and multidisciplinary meeting discussion at the time of reporting and 12 patients at risk of developing PMP (following resection of a mucinous appendiceal neoplasm without current evidence of PMP) had been entered into a surveillance programme. Four patients had
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benign peritoneal disease and were treated non-operatively. Fifty patients were considered suitable for CRS and HIPEC. Of these, 24 had PMP of appendiceal origin and 26 patients had peritoneal metastases. Clinical and demographic data for the patients who underwent surgery are summarised in Table 1. The classification of PMP was adopted from a recent study [23].
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At the time of surgery, three patients (two with PMP, and one with metachronous metastatic disease from a previously resected caecal mucinous adenocarcinoma) were found to have extensive inoperable disease and surgery was abandoned. Eight patients underwent major tumour debulking (CC-2 or CC-3) as a complete cytoreduction was not possible due to
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extensive infiltration of the retroperitoneum or pelvic side wall, involvement of the porta hepatis, or widespread small bowel involvement. Of these, two patients with PMP were determined pre-operatively to have inoperable disease and underwent planned major tumour
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debulking for symptom control. The remaining six patients were found to have disease intraoperatively that was not amenable to complete cytoreduction and therefore underwent major tumour debulking and HIPEC. One patient with peritoneal metastases of unknown origin was found at laparotomy to have widely metastatic cholangiocarcinoma.
The remaining 39 patients underwent complete (CC-0 or CC-1) cytoreduction and HIPEC. Excluding the three patients who had open and close laparotomy with unresectable disease, the rate of complete cytoreduction was 83% (84% in the CPM group and 81.8% in the PMP group).
ACCEPTED MANUSCRIPT Surgical Procedures Of the 50 patients who underwent surgery, 24 had previously undergone staging laparoscopy, 12 in the CPM group and 12 in the PMP group.
Of the 47 patients who underwent CRS/HIPEC, the visceral resections performed are
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summarised in Table 2. In this group, 24 patients required a stoma (11 defunctioning; 13 end) due to multiple anastomoses, low rectal anastomosis or subtotal or total colectomy.
Operative Outcomes
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The median critical care unit stay (intensive care/high dependency unit) was 5 days (range 0 – 16 days). The median length of hospital stay was 14 days (range 6 – 66 days).
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Sixteen patients (32.0%) developed 21 grade I/II postoperative morbidities (surgical site infection 3; urinary sepsis 5; pleural effusion 2; line sepsis 5; pancreatitis 1; respiratory tract infection 5). No patient required reoperation. There was no grade III/IV morbidity. There was no 30-day post-operative mortality.
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A total of 29 patients received blood transfusion post-operatively. The median number of units of blood transfused was one (range 0 – 8) and was higher in the PMP group (median 2, range 0 – 8) than in the CPM group (median 0, range 0 – 8).
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Oncological Outcomes
At the time of writing, the median follow up was 12.7 months. Of the 11 patients who
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underwent non-curative surgery, two had died from disease progression.
Of the 39 patients who underwent potentially curative CRS/HIPEC, 12 had developed disease recurrence, at a median of 8.5 months after surgery. All but one of the twelve patients who developed disease recurrence had a primary diagnosis of colorectal cancer. Two patients developed pleural recurrence following resection of aggressive tumour infiltrating the diaphragm; one patient developed recurrence following resection of disseminated high grade mucinous tumour of signet ring morphology; two patients had aggressive high grade mucinous tumour with lymph node involvement; two had extensive tumour which responded poorly to neo-adjuvant chemotherapy; two patients recurred following surgery for tumour mass with localised perforation and secondary intestinal obstruction; and a final patient
ACCEPTED MANUSCRIPT developed mesenteric nodal recurrence following resection for metachronous CPM from a
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poorly differentiated mucinous colonic adenocarcinoma.
ACCEPTED MANUSCRIPT Discussion We report the establishment of a single centre national peritoneal malignancy programme, catering for a population of 4.5 million, with acceptable early surgical and oncological outcomes. The 50th case of CRS/HIPEC was performed approximately 30 months after the establishment of the programme (six cases in 2013, 21 cases in 2014 and 23 cases to the time
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of analysis in 2015). We have since seen a rapid and sustained increase in the number of patients referred nationally and estimate that 40 cases of CRS/HIPEC will be performed in our third full year of activity. The operative mortality (0%), grade I/II morbidity (32%) and severe morbidity (0%) rates in this initial experience of 50 cases are comparable to, and
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indeed superior, to internationally reported results [14]. Severe morbidity following major complex surgery is however unavoidable. A systematic review of multiple series reported mortality rate of up to 6% and morbidity rate of up to 50% [14] following CRS. In our further
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experience two patients (patients 76 and 79) have required re-operation for bleeding related complications following surgery for PMP.
Local factors have contributed to our programme’s initial success. In particular, existing surgical expertise in the management of patients with advanced intra-abdominal cancer,
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supported by experienced diagnostic and interventional radiologists and the largest intensive care unit in Ireland, has provided a suitable basis for the addition of a new complex multidisciplinary programme. We have also benefited from collaboration with the wider peritoneal malignancy community. Mentorship from an established peritoneal malignancy
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centre has however been the crucial step in the development of our programme. Surgical and institutional mentoring from high volume centres have previously been shown to improve outcomes in centres performing complex surgery [15-17, 24-26]. CRS/HIPEC is a complex
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procedure with potential for significant morbidity and mortality and involves a steep learning curve to achieve surgical proficiency and optimise operative and oncological outcomes [2729]. Mohamed et al. emphasised the importance of the ‘global learning curve’ whereby the effective dissemination of learned experience in established high volume centres may help to minimise morbidity and mortality in newer centres [17]. It has been estimated that an experience of between 90 and 180 procedures is required to attain proficiency in CRS/HIPEC and optimise operative and oncological outcomes [27-29]. Our programme is still in its infancy and continues to evolve however with the benefit of mentorship we may have been able to somewhat shorten this learning curve.
ACCEPTED MANUSCRIPT Our initial experience has however not been without negatives. Six patients were first found to have inoperable disease at surgery, three of whom underwent open and close laparotomy. The remaining three patients underwent focused resection with the aim of palliation. Three of these patients had undergone staging laparoscopy at which time unresectable pelvic side wall or retroperitoneal disease was not appreciated fully due to compromised views attributable to
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adhesions. In retrospect, unresectable disease was evident on pre-operative imaging in one patient due to encasement of the superior mesenteric vessels and in a second patient with PMP who had developed a tumour bloc encasing the stomach and small bowel. Four of the six
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patients with inoperable disease were treated early in our evolving experience.
Laparoscopy has been shown to reduce the rate of open and close laparotomy and may overcome some of the limitations of conventional staging modalities in patients with
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peritoneal malignancy. We performed staging laparoscopy in almost 50% of our cohort. While the PCI was frequently underestimated at laparoscopy, all but three of the twenty four patients went on to have a complete cytoreduction. As was our experience, the benefit of laparoscopy may be reduced in patients who have undergone prior open surgery. Port site metastases are also not an infrequent consequence of laparoscopy and may be difficult to
[30]
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eradicate. For this reason we have now evolved to the use of a single port staging technique
Eleven patients in our series developed disease recurrence following complete cytoreduction
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for colorectal peritoneal metastases. The existing published literature has suggested that patients with aggressive tumour biology as indicated by poor differentiation, high tumour grade, mucinous phenotype, signet ring morphology and advanced nodal disease may be more
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likely to develop early disease recurrence even after complete cytoreduction [9, 18, 19]. Lack of response to neo-adjuvant treatment may also be an adverse feature. Our initial experience is consistent with these findings with all but one of the eleven patients who developed tumour recurrence showing at least one adverse feature.
In our short follow-up period, one patient who had undergone extensive resection, including gastrectomy, for PMP had developed disease recurrence. Patients with PMP in our series had more extensive peritoneal disease as evidenced by higher PCI scores, and underwent more extensive multi-visceral resections. However, once a complete cytoreduction can be achieved,
ACCEPTED MANUSCRIPT patients with PMP have a longer-lasting disease-free interval [19] than those undergoing
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surgery for CPM.
ACCEPTED MANUSCRIPT Conclusions We report our initial experience of establishing a national peritoneal malignancy treatment programme. With the benefit of mentorship from an experience centre we may have shortened the learning curve for this complex procedure and report satisfactory early outcomes. Our experience continues to evolve and will likely benefit from ongoing collaboration as we seek
CRS/HIPEC for peritoneal malignancy.
Conflict of Interest
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All authors declare no conflict of interest.
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to optimise patient selection and improve early and long-term outcomes following
ACCEPTED MANUSCRIPT References
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Tech Coloproctol 2009;13:373-4. 3. Lo CH, Bohmer RD, Blomfield PI. An evidence-based approach: Sugarbaker protocol and pseudomyxoma peritonei of appendiceal origin. ANZ J Surg 2008;78:327-8.
4. Bryant J, Clegg AJ, Sidhu MK, Brodin H, Royle P, Davidson P. Systematic review of
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the Sugarbaker procedure for pseudomyxoma peritonei. Br J Surg 2005;92:153-8.
5. Moran BJ. Establishment of a peritoneal malignancy treatment centre in the United Kingdom. Eur J Surg Oncol 2006;32(6):614-8.
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6. Murphy EM, Sexton R, Moran BJ. Early results of surgery in 123 patients with pseudomyxoma peritonei from a perforated appendiceal neoplasm.Dis Colon Rectum 2007;50(1):37-42.
7. Yan TD, Deraco M, Baratti D, et al. Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy for malignant peritoneal mesothelioma: multi-institutional
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experience. J Clin Oncol 2009;27(36):6237-42.
8. Gonzalez-Moreno S. Peritoneal surface oncology: a progress report. Eur J SurgOncol 2006;32:593-6.
9. Helm JH, Miura JT, Glenn JA, et al. Cytoreductive surgery and Hyperthermic
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intraperitoneal chemotherapy for malignant peritoneal mesothelioma: a systematic review and meta-analysis. Ann Surg Oncol 2015;22:1686-93. 10. Gough DB, Donohue JH, Schutt AJ, et al. Pseudomyxoma peritonei: long-term patient
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survival with an aggressive regional approach. Ann Surg 1994;219:112-9. 11. Esquivel J, Elias D, BarattiD, Kusamura S, Deraco M. Consensus statement on the loco regional treatment of colorectal cancerwith peritoneal dissemination. J Surg Oncol 2008;98:263-7.
12. Elias D, Lefevre JH, Chevalier J, et al. Complete cytoreductive surgery plus intraperitoneal chemohyperthermia with oxaliplatin for peritoneal carcinomatosis of colorectal origin. J Clin Oncol 2009;27:681-5. 13. Verwaal VJ, van Ruth S, de Bree E,et al. Randomized trial of cytoreductionand hyperthermic intraperitoneal chemotherapy versus systemic chemotherapyand palliative surgery inpatients with peritoneal carcinomatosisof colorectal cancer. J Clin Oncol
ACCEPTED MANUSCRIPT 2003;21:3737-43. 14. Chua TC, Yan TD, Saxena A, Morris DL.Should the treatment of peritonealcarcinomatosisby cytoreductive surgery andhyperthermic intraperitoneal chemotherapystill be regarded as a highly morbid procedure?: a systematic review of morbidity and mortality. Ann Surg 2009;249:900-7.
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15. García-Matus R, Hernández-Hernández CA, Leyva-García O, et al. Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy in the treatment of peritoneal carcinomatosis: initial experience in Oaxaca, Mexico. Am Surg 2012;78(9):942-6.
16. Kusamura S, Baratti D, Virzì S, et al. Learning curve for cytoreductive surgery and
two centres. J Surg Oncol 2013;107(4):312-9.
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hyperthermic intraperitoneal chemotherapy in peritoneal surface malignancies: analysis of
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intraperitoneal chemotherapy: the importance of a learning curve. Cancer J 2009;15(3):196-9. 18. Youssef H, Newman C, Chandrakumaran K, Mohamed F, Cecil TD, Moran BJ. Operative findings, early complications, and long-term survival in 456 patients with pseudomyxoma peritonei syndrome of appendiceal origin. Dis Colon Rectum 2011;54:293-9. 19. Moran B, Cecil T, Chandrakumaran K, Arnold S, Mohamed F, Venkatasubramaniam A.
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The results of cytoreductive surgery and hyperthermic intraperitoneal chemotherapy in 1200 patients with peritoneal malignancy. Colorectal Dis 2015;17(9):772-8. 20. Crawford C, Janjua AZ, Chandrakumaran K, Moran B. Operability and early outcome in 48 Irish patients with peritoneal malignancy treated by surgery and intraperitoneal
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chemotherapy in a specialized centre. Surgeon 2013;11(1):30-4. 21. Jacquet P, Sugarbaker PH. Clinical research methodologiesin diagnosis and staging of patients with peritoneal carcinomatosis.In: Sugarbaker PH, ed. PeritonealCarcinomatosis:
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Principles of Management.Boston, MA: Kluwer Academic Publishers;1996:359-74. 22. Dindo D, Demartines N, Clavien PA. Classification of surgical complications: a new proposal with evaluation in a cohort of 6336 patients and results of a survey. Ann Surg 2004;240(2):205-13.
23. Carr NJ, Cecil TD, Mohamed F, et al. A Consensus for Classification and Pathologic Reporting of Pseudomyxoma Peritonei and Associated Appendiceal Neoplasia: The Results of the Peritoneal Surface Oncology Group International (PSOGI) Modified Delphi Process. Am J Surg Pathol 2016;40(1):14-26. 24. Martling AL, Holm T, Rutqvist LE, Moran BJ, Heald RJ, Cedemark B. Effect of a surgical training programme on outcome of rectal cancer in the County of Stockholm.
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peritoneal malignancy. Colorectal Dis 2015 Nov; video vignette.
ACCEPTED MANUSCRIPT Table 1. Demographic and clinical data for patients who underwent planned CRS/HIPEC (n=50) PMP
(n = 26)
(n = 24)
Age (years)a
59.4 ± 8.1
57.8 ± 14.1
Sex (male)
14 (53.8%)
9 (37.5%)
Body Mass Index (m2/kg)a
27.9 ± 4.3
ASA classification 11 (42.3%)
III
15 (57.7%)
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II
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Peritoneal Metastases
Clinical presentation
24.9 ± 3.0
14 (58.3%) 10 (41.7%)
11 (42.3%)
16 (66.7%)
Metachronous
15 (57.7%)
8 (33.3%)
10 (38.5%)
3 (12.5%)
8.7 ± 5.8
20.3 ± 8.8
(range 2 – 21)
(range 6 – 39)
Colonic adenocarcinoma
23 (88.5%)
0
CRC of unknown origin
1 (3.8%)
0
Rectal adenocarcinoma
1 (3.8%)
0
1 (3.8%)
0
0
17 (70.8%)
0
4 (16.7%)
Ovarian serous carcinoma
0
1 (4.2%)
Adenomucinosis, non-specified
0
2 (8.3%)
CC-0 or 1
21 (80.8%)
18 (75.0%)
CC-2 or 3
5 (19.2%)
6 (25.0%)
12 (46.2%)
12 (50.0%)
Neoadjuvant chemotherapy Operative PCIa
Primary tumour
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Colorectal
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Gallbladder cholangiocarcinoma Appendix
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Synchronous
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Low grade neoplasm
High grade or invasive neoplasm
CC score
Staging laparoscopy
CRS, Cytoreductive surgery; HIPEC, hyperthermic intraperitoneal chemotherapy; PMP, pseudomyxoma peritonei; ASA, American Society of Anaesthesiologist; PCI, peritoneal
ACCEPTED MANUSCRIPT cancer index; CRC, colorectal cancer; N/A, not available or applicable; CCR, completeness of cytoreduction
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mean ± standard deviation
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a
ACCEPTED MANUSCRIPT Table 2. Operative procedures in patients undergoing CRS/HIPEC
Peritoneal Metastases
PMP
(n = 26)
(n = 24)
11
13
Organs Resected
Subtotal/total colectomy
3 9
Small bowel
10
Ovary/ovaries
8
Liver wedge resection
7
Liver capsule
0
Gallbladder
3
Uterus Diaphragm Spleen Urinary bladder
End ileostomy End colostomy
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Stomas Fashioned
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Stomach
Loop ileostomy
Number of Peritonectomiesa
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PMP, pseudomyxoma peritonei a
median (range)
7
4
9
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Rectum
8
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Segmental colectomy
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Colon
1 11 12
4
8
4
0
1
9
0
1
0
1
5
6
1
8
4
0
1 (0 – 4)
4 (0 – 5)
S0748-7983(16)30945-3
DOI:
10.1016/j.ejso.2016.10.007
Reference:
YEJSO 4497
To appear in:
European Journal of Surgical Oncology
Received Date: 6 May 2016 Revised Date:
13 August 2016
Accepted Date: 7 October 2016
Please cite this article as: Chang K, Kazanowski M, Staunton O, Cahil R, Moran B, Shields C, Mulsow J, Mentored experience of establishing a national peritoneal malignancy programme – experience of first 50 operative cases, European Journal of Surgical Oncology (2016), doi: 10.1016/j.ejso.2016.10.007. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT Title:
Mentored experience of establishing a national peritoneal malignancy programme – experience of first 50 operative cases
Authors:
KH Chang1, M Kazanowski1, Staunton O1, RA Cahil1, BJ Moran2, C Shields1,
Affiliations:
1
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J Mulsow1
National Centre for Peritoneal Malignancy, Mater Misericordiae University
Hospital, Dublin, Ireland 2
Peritoneal Malignancy Institute, Basingstoke and North Hampshire Hospital,
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Basingstoke, United Kingdom
Email addresses:
[email protected]
MK:
[email protected]
OS:
[email protected]
RAC:
[email protected]
BJM:
[email protected]
CS:
[email protected]
§
Corresponding author:
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JMM:
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KHC:
[email protected]
Mr. Jurgen Mulsow MD FRCSI
Address:
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Consultant General & Colorectal Surgeon
Department of Surgery,
Tel:
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National Centre for Peritoneal Malignancy, Mater Misericordiae University Hospital, Dublin 7, Ireland.
+353 1 854 5091
Fax:
+353 1 854 5242
Word count:
232 (abstract) 2987 (main text)
ACCEPTED MANUSCRIPT Abstract
Background: Cytoreductive Surgery (CRS) and Hyperthermic Intraperitoneal Chemotherapy (HIPEC) are considered standard of care for pseudomyxoma peritonei (PMP) and selected patients with
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colorectal peritoneal metastases (CPM) or peritoneal mesothelioma. A National Peritoneal Malignancy programme was established in Ireland (population of 4.5 million) in May 2013 with mentoring and support from the Peritoneal Malignancy Institute, Basingstoke UK. This study reviews the operative and oncological outcomes for the first 50 patients who underwent
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CRS and HIPEC in Ireland. Methods:
This is a retrospective review of all patients referred, and of the subset who underwent CRS
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and HIPEC, for peritoneal malignancy in Ireland between May 2013 and November 2015. Results:
During the study period, 130 patients were referred and 50 patients were selected for CRS and HIPEC. Three patients were found to have unresectable disease at laparotomy. Of the remaining 47 patients, eight had major tumour debulking. In total, 39 underwent complete
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cytoreduction and 45 received HIPEC. After a median follow up of 12.7 months, 12 patients had developed further metastatic disease. The rates of complete cytoreduction, complication and operative mortality were 83%, 0% and 0% respectively. There were no major ClavienDindo grade III/IV morbidity.
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Conclusions:
We report the successful establishment of a national peritoneal malignancy programme. Mentoring from an experienced centre may have shortened the known learning curve evident
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by our encouraging outcomes. The follow-up period is short, however our early results are comparable with internationally reported figures.
ACCEPTED MANUSCRIPT Keywords
peritoneal malignancy, pseudomyxoma peritonei, peritoneal metastasis, cytoreductive
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surgery, hyperthermic intraperitoneal chemotherapy, outcomes
ACCEPTED MANUSCRIPT Introduction
The concept of heated intraperitoneal chemotherapy was first described in a patient with peritoneal dissemination from a mucinous neoplasm of the appendix by Spratt et al in 1980
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[1]. The treatment strategy for peritoneal malignancy has evolved to a combination of macroscopic tumour removal, entitled cytoreductive surgery (CRS), and hyperthermic intraperitoneal chemotherapy (HIPEC) [2-7]. The aim is to achieve a complete macroscopic tumour removal (complete cytoreduction) and to augment the surgical cytoreduction with
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HIPEC. CRS and HIPEC is now regarded as the standard of care in the management of patients with pseudomyxoma peritonei (PMP) and selected patients with peritoneal mesothelioma [8-9]. In patients with PMP, for whom a complete cytoreduction is not
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possible, major tumour debulking may achieve symptom control and even long term survival [10]. There is also now accumulating evidence to support this combined approach in selected patients with resectable colorectal peritoneal metastases (CPM) and metastatic ovarian cancer [11-13].
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The expanding indications for CRS/HIPEC have resulted in a rapid increase in the number of centres internationally offering treatment to patients with peritoneal malignancy. The learning curve to providing optimal peri-operative and long-term oncological outcomes can however be steep. Even in high volume centres, the morbidity (0-50%) and mortality (0-6%) following
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CRS/HIPEC can be significant [14]. Ensuring low post-operative morbidity and optimal longterm oncological outcomes is a key marker of performance in the successful delivery of a peritoneal malignancy treatment programme. Mentoring by experienced centres may help
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fledgling units to optimise outcomes early in their experience [15-17].
Historically, patients diagnosed with peritoneal malignancy in Ireland have been referred to the Peritoneal Malignancy Institute in Basingstoke (UK) where, in total, more than 1200 patients have been treated since 1994 [18, 19]. Subsequent follow-up was conducted locally through an outreach programme [20]. In May 2013, due to the expanding indications for CRS/HIPEC and increasing demand for this service in Ireland, it was decided to establish a single centre national peritoneal malignancy programme, catering for the population of 4.5 million. The programme was to be delivered locally by a multidisciplinary team led by two colorectal surgeons who had experience in the field of CRS/HIPEC and involved supervision
ACCEPTED MANUSCRIPT and mentoring from the senior surgeon at the Basingstoke Peritoneal Malignancy Institute, as well as a multidisciplinary exchange of expertise involving surgeons, nurses, anaesthetists and other support staff. In November 2015, the 50th operative case for peritoneal malignancy in Ireland was
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performed. Herein we report our experience of establishing a national peritoneal malignancy programme and in doing so explore the role of mentorship by an experienced centre in
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optimising early surgical and oncological outcomes.
ACCEPTED MANUSCRIPT Patients & Methods
Study Overview This is a retrospective analysis of consecutive patients treated for peritoneal malignancy at the
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single national peritoneal malignancy centre between May 2013 and November 2015. Data on patient demographics, clinicopathological variables, operative outcomes, and oncological outcomes was extracted from a prospectively maintained database.
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Mentoring process
The decision to establish a peritoneal malignancy programme within Ireland was made approximately eight months prior to the first case being performed. A number of visits (four
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weeks in total) were made by the lead surgeons to the Peritoneal Malignancy Institute Basingstoke to observe practice including out-patient assessment, pre-operative staging, multidisciplinary decision making, peri- and intra-operative care, and post-operative followup and surveillance. Further multidisciplinary (nursing, surgery, anaesthesia) visits to Basingstoke followed. The surgical team from Dublin also joined and participated in meetings
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of the Peritoneal subcommittee of the Association of Coloproctology of the Great Britain and Ireland. Standardised operating procedures, mirroring those in Basingstoke, were subsequently established for patient evaluation and selection, operative management, postoperative care, and follow-up. Reciprocal visits to Dublin were made by the lead surgeon
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from Basingstoke and a number of multidisciplinary meetings followed, including surgeons, anaesthetists, intensivists, radiologists, oncologists, pathologists, pharmacy, dietetics, physiotherapy, theatre and ward nursing, both for staff education and to agree treatment
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protocols and ensure appropriate resourcing. A dedicated peritoneal malignancy nurse was appointed and a clinical database established. Data was also prospectively entered into the UK and Ireland registry. A business case outlining expected clinical activity, resource needs, and associated costs was submitted to the governing health authority. All prospective cases were discussed at the in-house multidisciplinary meeting and initially also by teleconference between Dublin and Basingstoke. As experience grew, teleconferencing was used selectively when decision making was not straightforward. The first case (a female with synchronous CPM) for CRS/HIPEC was identified and scheduled for May 2013 with direct supervision and participation by the mentoring surgeon. Throughout the subsequent development of the programme reciprocal surgeon visits (approximately four per year) between Dublin and
ACCEPTED MANUSCRIPT Basingstoke have continued, nursing staff have attended annual training meetings delivered in Basingstoke, and regular contact between the departments has been maintained.
Patients All patients with a diagnosis of peritoneal malignancy (primary or metastatic) referred during
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the study period were included in the analysis. The indication for referral in the vast majority of patients was CPM, metastatic appendix adenocarcinoma or evidence of pseudomyxoma peritonei.
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Standard staging investigations included lower gastrointestinal endoscopy and computed tomography (CT). Positron emission tomography–CT (PET-CT) was used selectively to exclude non-peritoneal distant metastatic disease. Magnetic resonance imaging (MRI) was
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employed selectively to locally stage pelvic primary or metastatic disease or to determine small bowel involvement. Serum tumour markers including carcinoembryonic antigen (CEA), CA19-9 and CA-125 were measured. Staging laparoscopy was used to assess tumour extent and resectability in patients with CPM who had inconclusive imaging.
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All patients were discussed in a multidisciplinary team meeting. Exclusion criteria for surgery included poor performance status or significant medical comorbidity, extensive peritoneal disease in the case of CPM, disease that was unresectable due to its anatomical location, and unresectable large volume non-peritoneal distant metastatic disease. Relative exclusion
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criteria included adverse tumour biology (signet ring, lymph node involvement) and progression of disease during systemic chemotherapy. The Peritoneal Cancer Index (PCI) was used to calculate the tumour volume and distribution [21]. Post-operative morbidity and
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mortality were recorded using the Clavien-Dindo classification [22]. Survival and disease recurrence were documented and analysed.
Perioperative Management All patients underwent pre-operative anaesthetic assessment for medical optimisation. Vaccinations were given two weeks prior to surgery if splenectomy was anticipated. Full mechanical bowel preparation was used when colonic resection was anticipated. Nutritional drinks were given the evening before and the morning of surgery. All patients received 24 hours of prophylactic antibiotics. Epidural analgesia was the pain management modality of choice for up to six days postoperatively. All patients received parenteral nutrition
ACCEPTED MANUSCRIPT immediately post-operatively and enteral nutrition was initiated slowly at the fourth postoperative day, or when tolerated. All patients received prophylactic low molecular weight heparin (LMWH) the evening before surgery and daily post-operatively. Pneumatic intermittent compression boots were used until fully mobile. Thromboembolic deterrent stockings were used until hospital discharge. Selected high risk patients received further
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LMWH after discharge for up to four week post-operatively.
Surgical Technique
All procedures were performed by two colorectal surgeons (JM and CS). Surgical technique
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was as previously described [18]. All patients underwent a long midline laparotomy excising the umbilicus and any laparoscopic port sites. The greater and lesser omentum and the falciform ligament were routinely resected. In females, bilateral salpingo-oophorectomy was
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routinely performed. Further visceral resections depended on disease extent, and included splenectomy, liver resection and/or Glisson capsulectomy, segmental or total colectomy, anterior resection or abdominoperineal excision, small bowel resection, hysterectomy, partial cystectomy, partial or total gastrectomy. The liver was mobilised to facilitate right diaphragmatic peritoneal stripping or to allow liver wedge resection or Glisson capsulectomy.
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Partial or complete peritonectomy was performed depending on the underlying pathology and the extent of disease. The number of peritonectomies (up to five) was recorded in each case (right and left hemi-diaphragmatic, right and left parietal, pelvic).
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HIPEC was administered using the open colosseum technique. For patients with CPM or PMP mitomycin C was the agent of choice at a dose of 10mg/m2, heated to 41oC for 60 minutes. Cisplatin (50mg/m2) and doxorubicin (15mg/m2) were the chemotherapeutic agents of choice
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in treating patients with peritoneal mesothelioma. HIPEC was administered using the Sun Chip delivery system (Gamidatech, Eaubonne, France).
The presence of residual disease was recorded by the Completeness of Cytoreduction score (CC): CC-0, no residual tumour; CC-1, no residual tumour nodule greater than 2.5mm; CC-2, no residual tumour greater than 25mm; CC-3, residual nodules greater than 25mm.
ACCEPTED MANUSCRIPT Statistical Analysis Statistical analysis was performed using SPSS 18.0 software (Chicago, IL). KilmogorovSmirnoff test was used to determine normality of distribution. Parametric data were expressed
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as mean ± standard deviation. Non-parametric data were expressed as median (range).
ACCEPTED MANUSCRIPT Results
Patients During the study period, 130 patients were referred for assessment and management of peritoneal malignancy, 41 patients were deemed not suitable for CRS/HIPEC. Of these, 29
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who were considered inoperable due to disease burden or comorbidity; 10 received systematic chemotherapy due to heavy or extra-peritoneal disease burden with a view to CRS/HIPEC if a satisfactory response was demonstrated; and two underwent pelvic exenteration for locally recurrent tumour without the need for HIPEC. A further 23 patients were undergoing
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investigation and multidisciplinary meeting discussion at the time of reporting and 12 patients at risk of developing PMP (following resection of a mucinous appendiceal neoplasm without current evidence of PMP) had been entered into a surveillance programme. Four patients had
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benign peritoneal disease and were treated non-operatively. Fifty patients were considered suitable for CRS and HIPEC. Of these, 24 had PMP of appendiceal origin and 26 patients had peritoneal metastases. Clinical and demographic data for the patients who underwent surgery are summarised in Table 1. The classification of PMP was adopted from a recent study [23].
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At the time of surgery, three patients (two with PMP, and one with metachronous metastatic disease from a previously resected caecal mucinous adenocarcinoma) were found to have extensive inoperable disease and surgery was abandoned. Eight patients underwent major tumour debulking (CC-2 or CC-3) as a complete cytoreduction was not possible due to
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extensive infiltration of the retroperitoneum or pelvic side wall, involvement of the porta hepatis, or widespread small bowel involvement. Of these, two patients with PMP were determined pre-operatively to have inoperable disease and underwent planned major tumour
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debulking for symptom control. The remaining six patients were found to have disease intraoperatively that was not amenable to complete cytoreduction and therefore underwent major tumour debulking and HIPEC. One patient with peritoneal metastases of unknown origin was found at laparotomy to have widely metastatic cholangiocarcinoma.
The remaining 39 patients underwent complete (CC-0 or CC-1) cytoreduction and HIPEC. Excluding the three patients who had open and close laparotomy with unresectable disease, the rate of complete cytoreduction was 83% (84% in the CPM group and 81.8% in the PMP group).
ACCEPTED MANUSCRIPT Surgical Procedures Of the 50 patients who underwent surgery, 24 had previously undergone staging laparoscopy, 12 in the CPM group and 12 in the PMP group.
Of the 47 patients who underwent CRS/HIPEC, the visceral resections performed are
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summarised in Table 2. In this group, 24 patients required a stoma (11 defunctioning; 13 end) due to multiple anastomoses, low rectal anastomosis or subtotal or total colectomy.
Operative Outcomes
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The median critical care unit stay (intensive care/high dependency unit) was 5 days (range 0 – 16 days). The median length of hospital stay was 14 days (range 6 – 66 days).
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Sixteen patients (32.0%) developed 21 grade I/II postoperative morbidities (surgical site infection 3; urinary sepsis 5; pleural effusion 2; line sepsis 5; pancreatitis 1; respiratory tract infection 5). No patient required reoperation. There was no grade III/IV morbidity. There was no 30-day post-operative mortality.
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A total of 29 patients received blood transfusion post-operatively. The median number of units of blood transfused was one (range 0 – 8) and was higher in the PMP group (median 2, range 0 – 8) than in the CPM group (median 0, range 0 – 8).
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Oncological Outcomes
At the time of writing, the median follow up was 12.7 months. Of the 11 patients who
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underwent non-curative surgery, two had died from disease progression.
Of the 39 patients who underwent potentially curative CRS/HIPEC, 12 had developed disease recurrence, at a median of 8.5 months after surgery. All but one of the twelve patients who developed disease recurrence had a primary diagnosis of colorectal cancer. Two patients developed pleural recurrence following resection of aggressive tumour infiltrating the diaphragm; one patient developed recurrence following resection of disseminated high grade mucinous tumour of signet ring morphology; two patients had aggressive high grade mucinous tumour with lymph node involvement; two had extensive tumour which responded poorly to neo-adjuvant chemotherapy; two patients recurred following surgery for tumour mass with localised perforation and secondary intestinal obstruction; and a final patient
ACCEPTED MANUSCRIPT developed mesenteric nodal recurrence following resection for metachronous CPM from a
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poorly differentiated mucinous colonic adenocarcinoma.
ACCEPTED MANUSCRIPT Discussion We report the establishment of a single centre national peritoneal malignancy programme, catering for a population of 4.5 million, with acceptable early surgical and oncological outcomes. The 50th case of CRS/HIPEC was performed approximately 30 months after the establishment of the programme (six cases in 2013, 21 cases in 2014 and 23 cases to the time
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of analysis in 2015). We have since seen a rapid and sustained increase in the number of patients referred nationally and estimate that 40 cases of CRS/HIPEC will be performed in our third full year of activity. The operative mortality (0%), grade I/II morbidity (32%) and severe morbidity (0%) rates in this initial experience of 50 cases are comparable to, and
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indeed superior, to internationally reported results [14]. Severe morbidity following major complex surgery is however unavoidable. A systematic review of multiple series reported mortality rate of up to 6% and morbidity rate of up to 50% [14] following CRS. In our further
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experience two patients (patients 76 and 79) have required re-operation for bleeding related complications following surgery for PMP.
Local factors have contributed to our programme’s initial success. In particular, existing surgical expertise in the management of patients with advanced intra-abdominal cancer,
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supported by experienced diagnostic and interventional radiologists and the largest intensive care unit in Ireland, has provided a suitable basis for the addition of a new complex multidisciplinary programme. We have also benefited from collaboration with the wider peritoneal malignancy community. Mentorship from an established peritoneal malignancy
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centre has however been the crucial step in the development of our programme. Surgical and institutional mentoring from high volume centres have previously been shown to improve outcomes in centres performing complex surgery [15-17, 24-26]. CRS/HIPEC is a complex
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procedure with potential for significant morbidity and mortality and involves a steep learning curve to achieve surgical proficiency and optimise operative and oncological outcomes [2729]. Mohamed et al. emphasised the importance of the ‘global learning curve’ whereby the effective dissemination of learned experience in established high volume centres may help to minimise morbidity and mortality in newer centres [17]. It has been estimated that an experience of between 90 and 180 procedures is required to attain proficiency in CRS/HIPEC and optimise operative and oncological outcomes [27-29]. Our programme is still in its infancy and continues to evolve however with the benefit of mentorship we may have been able to somewhat shorten this learning curve.
ACCEPTED MANUSCRIPT Our initial experience has however not been without negatives. Six patients were first found to have inoperable disease at surgery, three of whom underwent open and close laparotomy. The remaining three patients underwent focused resection with the aim of palliation. Three of these patients had undergone staging laparoscopy at which time unresectable pelvic side wall or retroperitoneal disease was not appreciated fully due to compromised views attributable to
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adhesions. In retrospect, unresectable disease was evident on pre-operative imaging in one patient due to encasement of the superior mesenteric vessels and in a second patient with PMP who had developed a tumour bloc encasing the stomach and small bowel. Four of the six
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patients with inoperable disease were treated early in our evolving experience.
Laparoscopy has been shown to reduce the rate of open and close laparotomy and may overcome some of the limitations of conventional staging modalities in patients with
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peritoneal malignancy. We performed staging laparoscopy in almost 50% of our cohort. While the PCI was frequently underestimated at laparoscopy, all but three of the twenty four patients went on to have a complete cytoreduction. As was our experience, the benefit of laparoscopy may be reduced in patients who have undergone prior open surgery. Port site metastases are also not an infrequent consequence of laparoscopy and may be difficult to
[30]
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eradicate. For this reason we have now evolved to the use of a single port staging technique
Eleven patients in our series developed disease recurrence following complete cytoreduction
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for colorectal peritoneal metastases. The existing published literature has suggested that patients with aggressive tumour biology as indicated by poor differentiation, high tumour grade, mucinous phenotype, signet ring morphology and advanced nodal disease may be more
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likely to develop early disease recurrence even after complete cytoreduction [9, 18, 19]. Lack of response to neo-adjuvant treatment may also be an adverse feature. Our initial experience is consistent with these findings with all but one of the eleven patients who developed tumour recurrence showing at least one adverse feature.
In our short follow-up period, one patient who had undergone extensive resection, including gastrectomy, for PMP had developed disease recurrence. Patients with PMP in our series had more extensive peritoneal disease as evidenced by higher PCI scores, and underwent more extensive multi-visceral resections. However, once a complete cytoreduction can be achieved,
ACCEPTED MANUSCRIPT patients with PMP have a longer-lasting disease-free interval [19] than those undergoing
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surgery for CPM.
ACCEPTED MANUSCRIPT Conclusions We report our initial experience of establishing a national peritoneal malignancy treatment programme. With the benefit of mentorship from an experience centre we may have shortened the learning curve for this complex procedure and report satisfactory early outcomes. Our experience continues to evolve and will likely benefit from ongoing collaboration as we seek
CRS/HIPEC for peritoneal malignancy.
Conflict of Interest
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All authors declare no conflict of interest.
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to optimise patient selection and improve early and long-term outcomes following
ACCEPTED MANUSCRIPT References
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4. Bryant J, Clegg AJ, Sidhu MK, Brodin H, Royle P, Davidson P. Systematic review of
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the Sugarbaker procedure for pseudomyxoma peritonei. Br J Surg 2005;92:153-8.
5. Moran BJ. Establishment of a peritoneal malignancy treatment centre in the United Kingdom. Eur J Surg Oncol 2006;32(6):614-8.
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6. Murphy EM, Sexton R, Moran BJ. Early results of surgery in 123 patients with pseudomyxoma peritonei from a perforated appendiceal neoplasm.Dis Colon Rectum 2007;50(1):37-42.
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experience. J Clin Oncol 2009;27(36):6237-42.
8. Gonzalez-Moreno S. Peritoneal surface oncology: a progress report. Eur J SurgOncol 2006;32:593-6.
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intraperitoneal chemotherapy for malignant peritoneal mesothelioma: a systematic review and meta-analysis. Ann Surg Oncol 2015;22:1686-93. 10. Gough DB, Donohue JH, Schutt AJ, et al. Pseudomyxoma peritonei: long-term patient
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survival with an aggressive regional approach. Ann Surg 1994;219:112-9. 11. Esquivel J, Elias D, BarattiD, Kusamura S, Deraco M. Consensus statement on the loco regional treatment of colorectal cancerwith peritoneal dissemination. J Surg Oncol 2008;98:263-7.
12. Elias D, Lefevre JH, Chevalier J, et al. Complete cytoreductive surgery plus intraperitoneal chemohyperthermia with oxaliplatin for peritoneal carcinomatosis of colorectal origin. J Clin Oncol 2009;27:681-5. 13. Verwaal VJ, van Ruth S, de Bree E,et al. Randomized trial of cytoreductionand hyperthermic intraperitoneal chemotherapy versus systemic chemotherapyand palliative surgery inpatients with peritoneal carcinomatosisof colorectal cancer. J Clin Oncol
ACCEPTED MANUSCRIPT 2003;21:3737-43. 14. Chua TC, Yan TD, Saxena A, Morris DL.Should the treatment of peritonealcarcinomatosisby cytoreductive surgery andhyperthermic intraperitoneal chemotherapystill be regarded as a highly morbid procedure?: a systematic review of morbidity and mortality. Ann Surg 2009;249:900-7.
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15. García-Matus R, Hernández-Hernández CA, Leyva-García O, et al. Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy in the treatment of peritoneal carcinomatosis: initial experience in Oaxaca, Mexico. Am Surg 2012;78(9):942-6.
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intraperitoneal chemotherapy: the importance of a learning curve. Cancer J 2009;15(3):196-9. 18. Youssef H, Newman C, Chandrakumaran K, Mohamed F, Cecil TD, Moran BJ. Operative findings, early complications, and long-term survival in 456 patients with pseudomyxoma peritonei syndrome of appendiceal origin. Dis Colon Rectum 2011;54:293-9. 19. Moran B, Cecil T, Chandrakumaran K, Arnold S, Mohamed F, Venkatasubramaniam A.
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The results of cytoreductive surgery and hyperthermic intraperitoneal chemotherapy in 1200 patients with peritoneal malignancy. Colorectal Dis 2015;17(9):772-8. 20. Crawford C, Janjua AZ, Chandrakumaran K, Moran B. Operability and early outcome in 48 Irish patients with peritoneal malignancy treated by surgery and intraperitoneal
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chemotherapy in a specialized centre. Surgeon 2013;11(1):30-4. 21. Jacquet P, Sugarbaker PH. Clinical research methodologiesin diagnosis and staging of patients with peritoneal carcinomatosis.In: Sugarbaker PH, ed. PeritonealCarcinomatosis:
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malignancies. Ann Surg 2012;255(2):348-56.
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30. Kazanowski M, Al Furajii H, Shields C, Mulsow J. Single port laparoscopic staging for
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peritoneal malignancy. Colorectal Dis 2015 Nov; video vignette.
ACCEPTED MANUSCRIPT Table 1. Demographic and clinical data for patients who underwent planned CRS/HIPEC (n=50) PMP
(n = 26)
(n = 24)
Age (years)a
59.4 ± 8.1
57.8 ± 14.1
Sex (male)
14 (53.8%)
9 (37.5%)
Body Mass Index (m2/kg)a
27.9 ± 4.3
ASA classification 11 (42.3%)
III
15 (57.7%)
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II
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Peritoneal Metastases
Clinical presentation
24.9 ± 3.0
14 (58.3%) 10 (41.7%)
11 (42.3%)
16 (66.7%)
Metachronous
15 (57.7%)
8 (33.3%)
10 (38.5%)
3 (12.5%)
8.7 ± 5.8
20.3 ± 8.8
(range 2 – 21)
(range 6 – 39)
Colonic adenocarcinoma
23 (88.5%)
0
CRC of unknown origin
1 (3.8%)
0
Rectal adenocarcinoma
1 (3.8%)
0
1 (3.8%)
0
0
17 (70.8%)
0
4 (16.7%)
Ovarian serous carcinoma
0
1 (4.2%)
Adenomucinosis, non-specified
0
2 (8.3%)
CC-0 or 1
21 (80.8%)
18 (75.0%)
CC-2 or 3
5 (19.2%)
6 (25.0%)
12 (46.2%)
12 (50.0%)
Neoadjuvant chemotherapy Operative PCIa
Primary tumour
TE D
Colorectal
EP
Gallbladder cholangiocarcinoma Appendix
M AN U
Synchronous
AC C
Low grade neoplasm
High grade or invasive neoplasm
CC score
Staging laparoscopy
CRS, Cytoreductive surgery; HIPEC, hyperthermic intraperitoneal chemotherapy; PMP, pseudomyxoma peritonei; ASA, American Society of Anaesthesiologist; PCI, peritoneal
ACCEPTED MANUSCRIPT cancer index; CRC, colorectal cancer; N/A, not available or applicable; CCR, completeness of cytoreduction
EP
TE D
M AN U
SC
RI PT
mean ± standard deviation
AC C
a
ACCEPTED MANUSCRIPT Table 2. Operative procedures in patients undergoing CRS/HIPEC
Peritoneal Metastases
PMP
(n = 26)
(n = 24)
11
13
Organs Resected
Subtotal/total colectomy
3 9
Small bowel
10
Ovary/ovaries
8
Liver wedge resection
7
Liver capsule
0
Gallbladder
3
Uterus Diaphragm Spleen Urinary bladder
End ileostomy End colostomy
EP
Stomas Fashioned
TE D
Stomach
Loop ileostomy
Number of Peritonectomiesa
AC C
PMP, pseudomyxoma peritonei a
median (range)
7
4
9
M AN U
Rectum
8
SC
Segmental colectomy
RI PT
Colon
1 11 12
4
8
4
0
1
9
0
1
0
1
5
6
1
8
4
0
1 (0 – 4)
4 (0 – 5)