Brief Article Open Access
Copyright ©2012 Baishideng. All rights reserved.
World J Gastrointest Surg. Jun 27, 2012; 4(6): 135-140
Published online Jun 27, 2012. doi: 10.4240/wjgs.v4.i6.135
Cytoreductive surgery and hyperthermic intraperitoneal chemoperfusion: The University of Arizona early experience
Ioannis T Konstantinidis, Christine Young, Vassiliki L Tsikitis, Tun Jie, Evan S Ong, Department of Surgery, The University of Arizona College of Medicine, 1501 N. Campbell Av. PO Box 245131, Tucson, AZ 85724-5131, United States
Ellyn Lee, Department of Medicine, The University of Arizona College of Medicine, 1501 N. Campbell Av. PO Box 245131, Tucson, AZ 85724-5131, United States
Author contributions: Konstantinidis IT wrote the manuscript; Young C provided the data; Tsikitis VL, Lee E and Jie T critically revised the manuscript; Ong ES conceived and designed the study and critically revised the manuscript
Correspondence to: Evan S Ong, MD, MS, Department of Surgery, The University of Arizona College of Medicine, 1501 N. Campbell Avenue, PO Box 245131, Tucson, AZ 85724-5058, United States. eong@surgery.arizona.edu
Telephone: +1-520-6264153 Fax: +1-520-6267138
Received: December 18, 2011
Revised: June 22, 2012
Accepted: June 24, 2012
Published online: June 27, 2012

Abstract

AIM: To evaluate the safety and effectiveness of our new cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemoperfusion (HIPEC) program.

METHODS: Retrospective review of patients with gastrointestinal malignancies who were suitable candidates for CRS and HIPEC between 12/1/2009 and 10/1/2010. All clinicopathologic data were reviewed with a special focus on the surgical outcome and the postoperative morbidity and mortality.

RESULTS: Fourteen patients were identified. Median age was 64 years; seven were female. The primary tumors were: colonic (29%), appendiceal (36%), peritoneal mesothelioma (14%), gastric (7%), adenocarcinoma of unknown primary (7%), and gastrointestinal stromal tumor (7%). Eleven patients (79%) received CRS/HIPEC, three for palliation. Three patients that did not undergo CRS/HIPEC had an average peritoneal cancer index (PCI) of 25. The eight patients that underwent curative CRS/HIPEC had an average PCI of 10 and a completeness of cytoreduction score of 0 (87.5%) or 1 (12.5%). Postoperative morbidity was 36%; the worst adverse event was Grade 3 ileus. Mortality rate was 0%.

CONCLUSION: CRS with HIPEC is safe and feasible at tertiary institutions with fledgling programs. PCI is an accurate predictor of surgical outcomes.

Key Words: Cytoreductive surgery, Hyperthermic intraperitoneal chemoperfusion, Peritoneal carcinomatosis, Early outcomes



INTRODUCTION

Peritoneal carcinomatosis (PC) arising from intra-peritoneal seeding of cancer cells is a relatively frequent phenomenon for a variety of gastrointestinal malignancies. The two main mechanisms that are believed to contribute to the intra-abdominal spread of cancer cells is either preoperatively as a result of full thickness invasion of an organ by the cancer or intraoperatively as a result of surgical manipulations[1].

The presence of peritoneal disease has been associated with a grave prognosis and a survival of less than 6 mo[2]. The traditional approach for many decades was palliative chemotherapy with surgery reserved only for complications such as intestinal obstruction. An aggressive surgical approach using cytoreduction for PC and, correlation of residual disease with survival was initially recognized in the treatment of ovarian cancer[3,4]. The combination of cytoreductive surgery (CRS) followed by hyperthermic intraperitoneal chemoperfusion (HIPEC) is a treatment that has gained increasing popularity amongst surgical oncologists in the last two decades[5-8]. It is now established that patient survival after CRS and HIPEC directly correlates with the extent of the achieved cytoreduction[9-15] and a randomized controlled trial has shown a survival benefit of CRS with HIPEC for colorectal cancer in comparison to palliative chemotherapy[12]. CRS with HIPEC is slowly growing to become the standard of care in the setting of PC for certain malignancies[7,16-23].

The recognition of the survival benefit after CRS and HIPEC has contributed in this technique gaining popularity. Many institutions have published their experience on series of more than 100 patients[10-13,15,24,25]. Therefore, the existing knowledge in the literature mainly reflects the long-standing experience of those tertiary centers. CRS and HIPEC is associated with a significant morbidity and mortality; even in high volume institutions, the mortality rate is reported between 0.9%-5.8% and the reported rate of major or grade III/IV morbidity is between 12%-52%[8,10-13,15,18,24-28]. Some authors have emphasized the importance of a learning curve in performing this technique safely and effectively[29]. While it is necessary to provide this treatment modality to larger numbers of patients in a safe way there is limited knowledge on the experience of newly-started programs. Our aim was to review our experience with CRS and HIPEC in our newly established peritoneal surface malignancy program with an emphasis on the safety and effectiveness of this technique.

MATERIALS AND METHODS

From 12/1/2009 to 10/1/2010 we reviewed the clinicopathologic data of fourteen patients with gastrointestinal malignancies who were considered suitable candidates for CRS and HIPEC. All patients had a histologic diagnosis of a peritoneal surface malignancy with no evidence of extra-abdominal metastasis at the time of surgery based on preoperative imaging. Clinicopathologic characteristics, operative data and 30-d morbidity and mortality were evaluated. All procedures were performed by a surgical oncologist trained in CRS and HIPEC (Ong ES) with the assistance of a colorectal surgeon (Tsikitis VL) and a hepatobiliary surgeon (Jie T) when needed.

The extent of peritoneal disease was recorded using the peritoneal cancer index (PCI) and the presence of residual disease was reported postoperatively using the completeness of cytoreduction score (CCR)[30]. The PCI combines assessment of the thickness of the lesion size (LS: 0 for no macroscopic tumor, 1 if tumor < 0.5 cm, 2 if tumor 0.5-5 cm and 3 if tumor > 5 cm) and tumor distribution (abdominopelvic region 0-12) and quantifies the disease as a numerical score 0-39. The CCR equals 1 if no nodule > 2.5 mm remained, 2 if nodules 2.5 mm-2.5 cm remained and 3 if nodules > 2.5 cm remained. Following surgical cytoreduction, HIPEC was performed with the instillation of mitomycin (40 mg) into the abdomen using the closed coliseum technique at approximately 42 degrees celcius for 90 min. Morbidity was evaluated using the common terminology criteria for adverse events version 3.0 of the National Institute of Health criteria[31].

RESULTS
Clinicopathologic characteristics

Fourteen patients with attempted CRS with HIPEC were identified. The median age was 64 years (range 43-77 years) and seven (50%) were females. Clinicopathologic factors are listed in Table 1. All patients underwent preoperative computed tomography (CT) scans and five of them underwent also positron emission tomography scans. Appendiceal adenocarcinoma and colonic adenocarcinoma comprised 65% of the primary tumors (Figure 1). The rest of the pathologies were peritoneal mesothelioma (14%), gastric adenocarcinoma (7%), gastrointestinal stromal tumor (7%) and adenocarcinoma of unknown primary (7%). Of these 14 patients, 11 (79%) eventually received CRS and HIPEC for curative intent. For the other three patients the procedure was abandoned secondary to the extent of the intra-abdominal disease which precluded a safe cytoreduction.

Table 1 Clinicopathologic characteristics of 14 patients with attempted cytoreductive surgery and hyperthermic intraperitoneal chemoperfusion n (%).
Age (yr), median (range)64 (43-77)
Female gender7 (50)
Preoperative imaging
Computerized tomography14 (100)
Positron emission tomography5 (36)
Type of cancer
Appendiceal5 (36)
Colonic4 (29)
Mesothelioma2 (14)
Gastric1 (7)
GIST1 (7)
Unknown1 (7)
Successful CRS and HIPEC11 (79)
Curative intent CRS and HIPEC8 (57)
PCI for curative CRS/HIPEC, median (range)5 (3-26)
CCR for curative CRS/HIPEC, median (range)0 (0-1)
Figure 1
Figure 1 Relevant frequency of primary cancers for 14 patients.
Procedures performed

CRS with HIPEC was performed in 11 patients. For eight patients the procedure had curative intent (mean PCI: 8) whereas for three of them the procedure had a palliative intent (mean PCI: 25). The indication for operation in the latter group was palliation of malignant ascites in two patients and the HIPEC was performed laparoscopically, whereas the third patient could not undergo curative operation due to the extend of the disease. The organs which were resected in addition to the peritonectomies are demonstrated in Table 2. Patients operated with curative intent (n = 8) underwent two gastrectomies, seven colectomies, three small bowel resections, two salpingoophorectomies, four splenectomies, one distal pancreatectomy, two liver resections and six cholecystectomies. Patients operated with curative intent underwent an optimal cytoreduction with CCR of 0 (87.5%) or 1 (12.5%).

Table 2 Cytoreductive surgery and hyperthermic intraperitoneal chemoperfusion organ resections according to tumor type.
CRS and HIPEC procedures (n = 11)Colon (n = 2)Appendix (n = 4)Mesothelioma (n = 2)Gastric (n = 1)Other1 (n = 2)
Gastrectomy01010
Total01
Wedge10
Colectomy24010
Total colectomy010
Right hemicolectomy120
Left hemicolectomy001
Sigmoidectomy/LAR11
Small bowel resection10020
Salpingo-oophorectomy11000
Pancreatectomy (distal)01000
Splenectomy11110
Cholecystectomy22110
Liver resection11000
Left lateral segmentectomy10
Wedge resection01
Palliative procedures (n = 3)
Laparoscopic HIPEC00002
Limited debulking and HIPEC01000

No patient was re-operated for a complication. One patient underwent a takedown of a loop ileostomy 2 mo after the initial CRS. Another one had repeat of CRS and HIPEC 10 mo after the first surgery for recurrence.

Postoperative course

There was no difference in the mean length of hospital stay between those patients who underwent CRS with HIPEC vs those who did not (9 d for both groups). The postoperative course for patients who underwent CRS and HIPEC is summarized in Table 3. Overall, the postoperative morbidity was 36% with the worst adverse event being grade 3 ileus in three patients and 30-d mortality rate being 0%.

Table 3 Postoperative course in 11 patients who underwent cytoreductive surgery and hyperthermic intraperitoneal chemoperfusion.
Complicationn (%)
30-d mortality0
30-d morbidity4 (36)
Ileus grade 33 (27)
Hypertension grade 31 (9)
In-hospital stay (d), median (range)9 (5-18)

Two of the three patients who underwent palliative CRS and HIPEC died of disease after 1 and 6 mo whereas the third is alive with disease 5 mo postoperatively.

DISCUSSION

Peritoneal dissemination of gynecological and gastrointestinal malignancies has been traditionally regarded as a terminal condition amenable only to palliative chemotherapy until the introduction of CRS followed by HIPEC two decades ago[5,6]. There is an increasing enthusiasm about CRS and HIPEC due to the survival benefits in selected patients[7-9] however, most of the available literature still consists of the experience from a selected small number of high volume tertiary centers[10-13,24]. In this report, we reviewed the results of the first year of our newly established peritoneal surface malignancy program focusing mainly on procedure safety and initial effectiveness at an early program.

CRS combined with intra-peritoneal chemotherapy can be used either with therapeutic or palliative intent. It is considered by many as the standard of care for peritoneal mesothelioma and appendiceal mucinous neoplasms[16-20,23,32] whereas its use for colon cancer with low volume peritoneal disease is supported by a consensus statement of experts[7]. Moreover, for rare peritoneal processes such as sarcomatosis it appears as the only promising treatment[21,22]. Data are conflicting for gastric cancer, however the greatest benefit appears to be derived for stage III serosa invading gastric cancer with limited, resectable peritoneal dissemination[33-35]. More studies are needed before conclusions can be drawn. The integration of CRS and HIPEC in the setting of systemic chemotherapy has not been well studied yet. The most common regimen used is neoadjuvant FOLFOX before CRS and HIPEC. One should keep in mind that delay in the use of CRS and HIPEC can waste the opportunity of benefit due to disease progression on systemic chemotherapy and can also be associated with increased postoperative morbidity. Interestingly, recent reports emphasize that even failure of the neoadjuvant chemotherapy is not a contra-indication to CRS in the setting of absence of extraperitoneal metastases[36,37]. More research and multi-institutinal efforts are needed in order to define the best multi-modality treatments.

In our cohort, the majority (65%) of patients were operated for peritoneal dissemination of cancers that originated from the appendix and colon. This is similar to large series reported by tertiary high volume centers around the world where these two malignancies represent the main bulk of the patient population[11,13,25-27,38]. Most of the patients underwent CRS and HIPEC with curative intent (87.5%) and had a median CCR of 0. Three patients could not undergo CRS and HIPEC due to the extent of intra-abdominal disease. All three patients underwent preoperative CT imaging. Unfortunately, CT imaging has been previously demonstrated to have limitations in detecting the location and extent of peritoneal disease[39]. Three other patients underwent palliative laparoscopic HIPEC for recurrent malignant ascites requiring frequent paracentesis, among which a patient with GIST and another with adenocarcinoma of unknown origin. Although there are only anecdotal reports about the use of CRS and HIPEC for tumors like GIST and there is no proven benefit compared to systemic chemotherapy however, HIPEC is an effective procedure for the prevention of recurrent malignant ascites[40].

CRS and HIPEC is associated with significant morbidity and mortality[26,28,31]. In centers with long-term experience with this technique the reported mortality rate appears to be around 3% and the reported incidence of grade III-IV complications between 31%-43%[8-13,15,18,24-28]. In our cohort of eleven patients we did not experience any mortality whereas the overall morbidity was 36%. The most serious morbidity was grade 3 ileus in three of our patients. We did not experience other surgical complications which are frequent after this procedure such as abdominal abscesses, perforations, fistulas or anastomotic leaks[28]. We believe that prior training on CRS and HIPEC technique, through fellowship training, is important for good surgical outcomes as well as the additional cooperation of experienced colorectal and hepatobiliary surgeons to make multi-organ resections safe. Although the small number of patients introduces selection bias in our study, we believe that CRS and HIPEC can be initiated safely in a new peritoneal surface malignancy program when the prior conditions are met.

The short follow-up period of our patients precludes meaningful survival analyses. However, in our study the PCI was a useful exclusionary measure for determining cases that could be operated for curative vs palliative intent. Procedures performed with palliative intent were associated with poor survival outcome. Many studies have previously shown that the PCI is a strong prognostic indicator after CRS and HIPEC[10-14,41]. Some authors believe that a PCI over 20 should be considered a relative contraindication for this technique[8]. Other studies have addressed issues like quality of life and cost-effectiveness. Although initially impaired as in any large operation, the quality of life is expected to closely return to the previous baseline as early as 4 mo postoperatively[42]. There is even evidence to show that a portion of long term survivors experience an improved quality of life[43]. CRS and HIPEC results in parallel increases in both health costs and survival and, it can be considered a cost-effective technique in the appropriate setting[44].

In conclusion, our early experience with CRS followed by HIPEC was performed with no mortality and acceptable morbidity during the first year of the establishment of a new peritoneal surface malignancy program. The PCI score predicts the surgical outcomes. Improvements in the preoperative imaging will allow for better patient selection which hopefully translates into better outcomes.

COMMENTS
Background

The use of cytoreductive surgery (CRS) combined with hyperthermic intraperitoneal chemoperfusion (HIPEC) for peritoneal carcinomatosis (PC) has been increasing and is now considered standard of care for certain malignancies. There is need of expanding the use of this technique in more institutions.

Research frontiers

The existing literature on CRS and HIPEC reflects mainly the experience of a relatively limited number of tertiary centers with long standing experience with this technique. More data on the expected outcomes of peritoneal surface malignancy programs in their birth are needed. In this study the authors demonstrate that CRS and HIPEC can be performed safely and effectively in newly established programs from appropriately trained surgeons and carefully selected patients.

Innovations and breakthroughs

In centers of excellence and significant experience with CRS and HIPEC, these extensive operations can be performed with low mortality and acceptable morbidity. In this study the authors report that in our cohort of fourteen patients we experienced no mortality whereas the morbidity parallels that reported in the literature. They emphasize on the factors of careful patient selection, appropriate training with the technique and multi-modality surgical teams when needed in order to perform those operations successfully from the establishment of a new peritoneal surface malignancy program.

Applications

The description of the experience of newly established peritoneal malignancy programs will aid in the safe spread of this continuously growing technique.

Terminology

PC is the intra-peritoneal seeding of cancer cells and is a frequent mode of cancer spread for a variety of neoplasms. CRS aims to eliminate the presence of macroscopic peritoneal disease and Hyperthermic Intraperitoneal Chemotherapy aims in the delivering of the chemotherapeutic agents directly to the cancer cells in the peritoneal surfaces.

Peer review

This is a well-written clinical experience of HIPEC procedure in a limited number of pts describing the learning curve of this innovative treatment. Authors should expand the Discussion by performing a more in-depth analysis of the current indication and strategic position of the procedure concerning its integration with systemic therapies.

Footnotes

Peer reviewer: Lberto Zaniboni, MD, UO di Oncologia, Fondazione Poliambulanza, Via Bissolati 57, Brescia 25124, Italy

S- Editor Wang JL L- Editor A E- Editor Zheng XM

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