Intraperitoneal Chemotherapy for Peritoneal SurfaceMalignancy: Experience with 1,000 Patients

Edward A Levine, MD, FACS, John H Stewart IV, MD, FACS, Perry Shen, MD, FACS, Gregory B Russell, MS,Brian L Loggie, MD, FACS, Konstantinos I Votanopoulos, MD, PhD, FACS

BACKGROUND: Peritoneal dissemination of abdominal malignancy (carcinomatosis) has a clinical coursemarked by bowel obstruction and death; it traditionally does not respond well to systemictherapy and has been approached with nihilism. To treat carcinomatosis, we use cytoreductivesurgery (CS) with hyperthermic intraperitoneal chemotherapy (HIPEC).

METHODS: A prospective database of patients has been maintained since 1992. Patients with biopsy-provenperitoneal surface disease were uniformly evaluated for, and treated with, CS andHIPEC. Patientdemographics, performance status (Eastern Cooperative Oncology Group), resection status, andperitoneal surface disease were classified according to primary site. Univariate and multivariateanalyses were performed. The experience was divided into quintiles and outcomes compared.

RESULTS: Between 1991 and 2013, a total of 1,000 patients underwent 1,097 HIPEC procedures. Meanage was 52.9 years and 53.1% were female. Primary tumor site was appendix in 472 (47.2%),colorectal in 248 (24.8%),mesothelioma in 72 (7.2%), ovary in 69 (6.9%), gastric in 46 (4.6%),and other in 97 (9.7%). Thirty-daymortality rate was 3.8% andmedian hospital stay was 8 days.Median overall survival was 29.4 months, with a 5-year survival rate of 32.5%. Factors corre-lating with improved survival on univariate andmultivariate analysis (p� 0.0001 for each) werepreoperative performance status, primary tumor type, resection status, and experience quintile(p ¼ 0.04). For the 5 quintiles, the 1- and 5-year survival rates, as well as the complete cytor-eduction score (R0, R1, R2a) have increased, and transfusions, stoma creations, and compli-cations have all decreased significantly (p < .001 for all).

CONCLUSIONS: This largest reported single-center experience with CS and HIPEC demonstrates that prog-nostic factors include primary site, performance status, completeness of resection, andinstitutional experience. The data show that outcomes have improved over time, with morecomplete cytoreduction and fewer serious complications, transfusions, and stomas. This wasdue to better patient selection and increased operative experience. Cytoreductive surgery withHIPEC represents a substantial improvement in outcomes compared with historical series,and shows that meaningful long-term survival is possible for selected carcinomatosis patients.Multi-institutional cooperative trials are needed to refine the use of CS and HIPEC. (J AmColl Surg 2014;218:573e587. � 2014 by the American College of Surgeons)

Disseminated peritoneal surface malignant disease (PSD)or carcinomatosis has traditionally been approached withtherapeutic nihilism because patients typically progressed

to death due to bowel obstruction in less than a year.1

Peritoneal surface malignant disease results from intraca-vitary dissemination of tumor from a variety of primary

CME questions for this article available athttp://jacscme.facs.org

Disclosure Information: Authors have nothing to disclose. Timothy J Eberlein,Editor-in-Chief, has nothing to disclose.

Supported, in part, by the Smith family fund and the ComprehensiveCancer Center of Wake Forest University. Biostatistics shared resourcesupported by NCI CCSG P30CA012197.

Presented at the Southern Surgical Association 125th Annual Meeting, HotSprings, VA, December 2013.

Received December 9, 2013; Accepted December 10, 2013.From the Surgical Oncology Service, Department of General Surgery (Levine,Stewart, Shen, Votanopoulos), Section on Biostatistics, Department of PublicHealth Sciences (Russell), Wake Forest University School of Medicine,Winston-Salem, NC and Surgical Oncology Section, Department of GeneralSurgery, Creighton University School of Medicine, Omaha, NE (Loggie).Correspondence address: Edward A Levine, MD, FACS, Surgical OncologyService, Department of General Surgery, Wake Forest University School ofMedicine, Medical Center Blvd, Winston-Salem, NC 27157. email:elevine@wakehealth.edu

573ª 2014 by the American College of Surgeons ISSN 1072-7515/13/$36.00

Published by Elsevier Inc. http://dx.doi.org/10.1016/j.jamcollsurg.2013.12.013

pathologic lesions. Such findings are all too common forgastrointestinal and ovarian carcinomas, and are also seenwith unusual malignancies, such as sarcoma, mesotheli-oma, and urachal carcinoma.Frequently, PSD is confined to the peritoneal cavity

without extra-abdominal disease. Therefore, a regionalapproach to selected patients with PSD is reasonable. Inthe 1980s, aggressive multimodality treatment of peritonealsurface malignancies was attempted to improve outcomes.Centers explored treatment options such as peritonectomyprocedures,2 intraperitoneal injection of 32P, immuno-therapy,3 photodynamic therapy,4,5 hyperthermic intraperi-toneal chemotherapy (HIPEC), and early postoperativeintraperitoneal chemotherapy.6-8 During the past 2 decades,there has been ever-increasing interest in such regional ther-apy for PSD. This has been stimulated by publication of aprospective randomized trial for PSD from colorectal sour-ces,9 as well as successes with ovarian cancer.10,11

The optimal management of patients with PSDremains a matter of debate. Systemic chemotherapy forPSD is limited, in part, by its restricted ability to enterthe peritoneal cavity. The localization of tumor withinthe peritoneum without distant metastasis makes anaggressive regional approach attractive. Several groupshave treated peritoneal surface dissemination of appendi-ceal tumors with debulking procedures.12-14 However,these procedures are frequently unable to remove all ofthe microscopic tumor.Our approach to selected patients with PSD has been to

combine aggressive CS (with the goal or resection of allgross disease) with chemoperfusion to address microscopicresidual. Because surgery alone cannot address such micro-scopic residual, we have used intraoperative intraperitonealchemotherapy as an adjuvant. An intraperitoneal chemo-therapy perfusion done at the same time as CS has severaladvantages: first, intracavitary chemotherapy achievesdrug levels far higher than can be obtained with even themost aggressive systemic administration, which can over-come relative drug resistance; next, after CS, all peritonealsurfaces are exposed (all adhesions lysed), which allows forbetter drug distribution (vs postoperative). Additionally,the single intraoperative dose eliminates the considerable

compliance/tolerance issues encountered with postopera-tive administration of several cycles of treatment.10,11,15

The rationale for hyperthermia is based on laboratorystudies showing synergy with certain drugs, and it has theadvantage of avoiding hypothermia, which is frequentlyencountered with prolonged open procedures.We have previously reported our experience8 as well as

subsets of patients treated with CS and HIPEC for PSDfrom appendiceal,16,17 colorectal,18,19 gastric,20 smallbowel,21 and urachal22 carcinomas, as well as sarcoma-tosis23 and mesothelioma.24 Here we examine our experi-ence with patients undergoing CS and HIPEC for PSDto evaluate our outcomes with the first 1,000 patients.

METHODSPatients who underwent CS and HIPEC for PSD atWake Forest University School of Medicine Baptist Hos-pital between 1991 and 2013 were identified from a pro-spective database. This database has been continuouslyapproved by the Institutional Review Board at Wake For-est University. Clinical data on all patients were recordedin the database and maintained by a dedicated data man-agement unit. All patients were evaluated in the SurgicalOncology Clinics preoperatively. Evaluations included, ata minimum, a complete history, examination, pathologicreview, CT or MRI imaging, blood counts, and renal andliver functions. To be considered for CS and HIPEC,patients needed to have normal organ function (serumcreatinine <3 mg/dL, alkaline phosphatase and serumaspartate transaminase or alanine transaminase <3 timesthe upper limit of normal, white blood cell count�4,000/mm3, and platelet count �100,000 mm3). Eval-uation of preoperative CT or MRI imaging focused onthe absence of extra-abdominal metastasis, parenchymalhepatic metastasis (limited, completely resectable andhepatic and liver surface lesions allowed), bulky small boweldisease, multi-station bowel obstruction, ureteral, orbiliary obstruction. Tumors were categorized accordingto the primary site of origin. Before CS and HIPEC,patients had their pathology reviewed by the Wake ForestUniversity Department of Pathology. This was comparedwith final pathology from specimens garnered at the timeof CS to reach a final diagnosis for the database. Patientswith bulky pelvic disease or multiple previous pelvic pro-cedures were routinely considered for urologic consulta-tion for cystoscopy, with temporary externalized ureteralstent placement at the start of the procedure to facilitateretroperitoneal and pelvic dissection. Morbidity wasdefined according to the Clavien-Dindo25 classificationsystem. Postoperative mortality was assessed at 30 daysafter the procedure. The clinical experience was divided

Abbreviations and Acronyms

CS ¼ cytoreductive surgeryHIPEC ¼ hyperthermic intraperitoneal chemotherapyMMC ¼ mitomycin COS ¼ overall survivalPMP ¼ pseudomyxoma peritoneiPSD ¼ peritoneal surface (malignant) disease

574 Levine et al Peritoneal Surface Malignancy J Am Coll Surg

into 5 quintiles of 200 patients each. These correspondedto cases done between December 30, 1991 and May 23,2000 for the first quintile, May 25, 2000 and March 28,2005 for the second quintile, April 4, 2005 and June 9,2008 for the third quintile, June 10, 2008 and August30, 2010 for the fourth quintile, and September 2,2010 and June 10, 2013 for the fifth quintile.

Cytoreductive surgery

The goal of CS was removal of all gross disease in allcases. Cytoreductive surgery consisted of the removal ofgross tumor and involved organs, peritoneum, or tissuedeemed technically feasible and safe for the patient. Onopening the abdomen, the quantity and distribution ofdisease and/or ascites present was noted and quantitated(since 2005) by the peritoneal carcinomatosis index.26

This included routine supracolic omentectomy in all caseswhere it was not performed previously. Peritoniectomyprocedures were performed only as indicated by the pres-ence of visible disease.2,8 Any tumors adherent or invasiveto vital structures that could not be removed were cytore-duced using standard techniques or the cavitational ultra-sonic surgical aspirator. The resection status of patientswas judged after CS using the following classification:R0, complete removal of all visible tumor and negativecytological findings or microscopic margins; R1, com-plete removal of all visible tumor and positive post-perfusion cytological findings or microscopic margins;R2a, minimal residual tumor, nodule(s) measuring�0.5 cm; R2b, gross residual tumor, nodule >0.5 cmbut �2 cm; and R2c, extensive disease remaining, nod-ules >2 cm.27

Intraperitoneal hyperthermic chemotherapy

Near the completion of CS, patients were cooled to a coretemperature of approximately 34�C to 35�C by passivemeasure (ie, not warming airway gases or intravenoussolutions and cooling the room). Constant patient andperfusate temperature monitoring was performed in allcases. After CS was completed, peritoneal perfusion wasfacilitated via two 22F inflow and two 32F outflow cath-eters placed percutaneously into the abdominal cavity.Temperature probes were placed on the inflow andoutflow tubing and were continuously monitored. Theabdominal skin incision was closed temporarily with arunning cutaneous suture to prevent leakage of peritonealperfusate. A perfusion circuit was established withapproximately 3 L crystalloid (typically Ringer’s lactateor plasmalyte). Flow rates of approximately 1 L/minwere maintained using a roller pump managed by a perfu-sionist. The circuit continued through a single rollerpump, through a heat exchanger, and then to the patient.

Once a stable perfusion circuit was established andoutflow temperature was >38.5�C, the chemotherapywas introduced into the perfusion circuit. A maximuminflow temperature of 43�C was tolerated during perfu-sion, with a target outflow temperature at the pelvis of40�C. The abdomen was gently massaged throughoutperfusion to improve drug distribution to all peritonealsurfaces. Total planned perfusion time after the initialaddition of chemotherapy was typically 120 minutes.Although several chemotherapeutic agents were used,most patients received mitomycin c (MMC). TheMMC was dosed based on volume of perfusate necessaryto establish a stable circuit (typically 3 L). When MMCwas used, 30 mg was added to the perfusate at the initi-ation of the HIPEC, and at 60 minutes an additional 10mg MMC was added to keep MMC perfusate concentra-tions >5 mg/mL. In certain patients (eg, elderly individ-uals, those with extensive previous chemotherapy, poorperformance status), reductions in the dose of MMC(to 30 mg total) or perfusion time (to 60 to 90 minutes)were made to minimize hematotoxicity. Other chemo-therapeutic agents were also used based on primary tumorsite and previous systemic therapy. Since 2004, we haveused cisplatin 250 mg/M2 with sodium thiosulfate formesothelioma cases.24 Ovarian cases used cisplatin or car-boplatinum (1,000 mg/M2).28 Sarcoma cases (and gastro-intestinal stromal tumor before the introduction ofimatinib) were perfused with MMC with or withoutmitoxantrone. We also used oxaliplatin (200 mg/M2)29

for select appendiceal and colonic cases.

Clinical follow-up

Clinical follow-up occurred at 1 month and then at leastevery 6 months thereafter for up to 5 years. After 5 yearsfrom the last HIPEC, follow-up was suggested on anannual basis. Blood counts, liver functions, and tumormarkers (as appropriate), as well as abdominal and pelvicCT or MRI scans with intravenous contrast, wereobtained with each follow-up visit and when clinicallyindicated. Patients were typically followed jointly withmedical oncologists. Some patients received systemicchemotherapy at the discretion of their medical oncolo-gists. Of the first 1,000 patients on the HIPEC database,78 were lost to follow-up (7.8%). The longest survivorafter HIPEC underwent the procedure 225 months ago.

Statistical analysis

All data were collected prospectively; descriptive statisticswere generated for all measures, including means, ranges,and standard deviations for continuous measures and fre-quencies and proportions for categorical data. Overallsurvival (OS) was calculated from the date of CS and

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HIPEC to the last known date of follow-up or date ofdeath. Estimates of survival were calculated using theKaplan-Meier (product-limit) method; analysis usingCox proportional hazards was performed on all pertinentclinicopathologic variables to determine each one’s associ-ation with survival. Group comparisons of OS were per-formed using the approximate chi-square statistic for thelog-rank test. Additionally, the Cox proportional hazardsregression model was used in a stepwise fashion toperform a multivariate analysis of clinicopathologicfactors to determine an overall model of independentpredictors of OS. Statistical significance was defined asp � 0.05.

RESULTS

Patients and clinicopathologic features

A total of 1,000 patients underwent 1,097 HIPEC proce-dures between December 30, 1991 and June 10, 2013.This study was approved by our Institutional ReviewBoard. Patient outcomes data stratified by experiencequintiles are listed in Table 1. Mean age was 52.9 �12.4 years (range 11 to 87 years of age); 53.1% were fe-male. Median ICU and hospital stays are currently 1 and8 days, which has decreased significantly from 2 and 9days in the first quintile p ¼ 0.03 and p < 0.0001,respectively (Table 1). As part of the CS, 19.0% ofpatients had an ileostomy (12%) or colostomy (7%)created. However, the frequency of stoma placementhas decreased considerably over time. The organs resectedas part of the CS are listed in Table 2. Most (68%) of thepatients had received systemic chemotherapy beforeHIPEC. Median hospital stay was 9 days, with a meanof 14.1 days (�16.3 days). Most (73%) patients wereadmitted to the ICU with a mean stay of 1 to 2 days,with a decrease in ICU stay found over time.Primary sites of origin for the patients were as follows:

adrenal, n ¼ 2 (0.2%); appendix, n ¼ 472 (47.2%); colo-rectal, n ¼ 248 (24.8%); gallbladder, n ¼ 5 (0.5%);gastric, n ¼ 46 (4.6%); gastrointestinal stromal tumor,n ¼ 9 (2%); liver, n ¼ 2 (0.2%); mesothelioma, n ¼72 (7.2%); ovary, n ¼ 66 (6.9%); pancreas (cysticneoplasm and IPMT), n ¼ 6 (0.6%); sarcoma, n ¼ 14(1.4%); small bowel, n ¼ 17 (1.7%); urachal, n ¼ 5(1.1%); and unknown, n ¼ 19 (1.9%). Median survivalwas significantly different by site of origin as follows:appendix, 63.5 months; colorectal, 16.4 months; gastric,6.1 months; mesothelioma, 27.1 months; ovary, 28.5months; and sarcoma, 28.1 months (p ¼ 0.0001). Forother histologic sites of origin, the series has too few casesfor meaningful analysis. The distribution of the primarysources of PSD has changed over time, with increases

in appendiceal primary cases and decreases in gastricand sarcoma cases.Operative and perfusion data are summarized in

Table 1. Mean peritoneal carcinomatosis index was 12.Length of the operation (range 183 to 1,531 minutes)was dependent on the extent and location of disease atexploration, but averaged just <10 hours. The quantityof residual disease was recorded by the primary surgeonand was scored according to the R status for residual dis-ease.30 The R status of all patients undergoing HIPEC islisted in Table 1. The resection status was a significantpredictor of survival (p < 0.0001). For the purposes ofsurvival calculations, R0 and R1 were combined becauseof difficulties in clearly separating them (as radial marginsare typically positive) in the setting of PSD.

Morbidity and mortality

The 30-day postoperative morbidity and mortality were42% and 3.8%, respectively. Thirty-eight patients inthis study died within 30 days of HIPEC. Wound infec-tion, hematologic toxicity, sepsis, respiratory failure, anas-tomotic leak, pneumonia, and enterocutaneous fistulaaccount for the majority of the postoperative complica-tions in this cohort of patients. The mortality rates didnot change significantly by quintile and range from2.5% (fifth quintile) to 6% (second quintile). Patientswho experienced a complication had poorer survivalthan those who did not (p < 0.001). This differenceremained significant on multivariate analysis. Complica-tions were less common in patients undergoing R0/1resections when compared with cases with more residual(p ¼ 0.04).

Experience over time

To evaluate our experience over time, we divided ourpatient experience into 5 time periods (quintiles) of 200patients each. Median survival times for the 5 quintilesare 16.4, 28.5, 40.7, 34.3þ, and 22.9þ months, respec-tively (p ¼ 0.006) (Fig. 1). However, median length ofstay was evenly distributed over the quintiles at 9, 9,10, 8, and 9 days, respectively. Mean (�SD) length ofstay was 14.7 (�17.7), 15.3 (�17.9), 17.0 (�20.3),12.1 (�13.1), and 13.2 (�13.7) days, respectively(p ¼ 0.048). The middle quintile is significantly higherthan the fourth (p ¼ 0.005) and the last (p ¼ 0.028).Selection of patients changed significantly during the

experience, with increased rates of appendiceal (p <0.0001) and ovarian (p ¼ 0.0005) primary cases, and de-creases in gastric (p < 0.0001) and sarcoma (p ¼ 0.02)cases. Rates over time for mesothelioma and colonic can-cer primary have not changed significantly. The rate ofcolostomy and ileostomy varied significantly over the

576 Levine et al Peritoneal Surface Malignancy J Am Coll Surg

time quintiles (p ¼ 0.0003 and p ¼ 0.0009, respectively).The rate of complications varied significantly over theexperience quintiles, with the highest rate during thethird quintile (p < 0.0001). Median hospital and ICUstays decreased over time (p ¼ 0.03 and p < 0.0001,respectively).

The mortality rate ranged from 2.6% to 7.0% duringthe 5 quintiles without significant differences. The rateof complete resection (as defined by R0, R1, or R2a)increased with each quintile (55.0%, 74.0%, 76.4%,83%, and 88.3%, respectively; p < 0.001). Class IVand V complications decreased over time (45.0%,

Table 1. Clinicopathologic Data for 1,000 Patients Undergoing Cytoreductive Surgery and Hyperthermic IntraperitonealChemotherapy for Peritoneal Surface Disease

Clinicopathologic data

Quintile

p Value1 2 3 4 5

Primary, n (%)

Appendix (n ¼ 472) 56 (28) 80 (40) 116 (58) 121 (60.5) 99 (49.5)

Colon (n ¼ 232) 58 (29) 50 (25) 40 (20) 40 (20) 44 (22)

Gastric (n ¼ 46) 27 (13.5) 12 (6) 3 (1.5) 2 (1) 2 (1)

Mesothelioma (n ¼ 72) 12 (6) 13 (6.5) 12 (6) 12 (6) 23 (11.5)

Ovary (n ¼ 69) 18 (9) 25 (12.5) 5 (2.5) 8 (4) 13 (6.5)

Others (n ¼ 109) 29 (14.5) 20 (10) 24 (12) 17 (8.5) 19 (9.5)

Complications, n (%) <0.0001

No (n ¼ 422) 92 (46) 76 (38) 49 (24) 90 (45) 115 (58)

Yes (n ¼ 578) 108 (54) 124 (62) 151 (76) 110 (55) 85 (42)

Transfusion, n (%)

No 80 (45.2) 104 (68.9) 129 (68.3) 129 (65.2) 149 (76.8)

Yes 97 (54.8) 47 (31.1) 60 (31.7) 69 (34.8) 45 (23.2)

Stoma, n (%) 0.001

No 160 (88.4) 141 (70.5) 160 (80.0) 159 (79.5) 193 (86.5)

Colostomy 15 (8.3) 28 (14.0) 8 (4.0) 14 (7.0) 7 (3.5)

Ileostomy 6 (3.3) 31 (15.5) 32 (16.0) 27 (13.5) 22 (11.0)

ECOG, n (%) <0.0001

0 53 (26.8) 84 (42.0) 85 (42.5) 115 (59.0) 105 (54.7)

1 99 (50.0) 86 (43.0) 82 (41.0) 57 (29.2) 64 (33.3)

2 36 (18.2) 22 (11.0) 28 (14.0) 19 (9.7) 16 (8.3)

3 or 4 10 (5.1) 8 (4.0) 5 (2.5) 4 (2.1) 7 (3.7)

Resection, n (%) <0.0001

R0/R1 71 (35.5) 93 (46.5) 103 (51.8) 93 (46.5) 104 (52.8)

R2a 39 (19.5) 55 (27.5) 49 (24.6) 73 (36.5) 69 (35.0)

R2b 31 (15.5) 32 (16.0) 34 (17.1) 28 (14.0) 15 (7.6)

R2c 59 (29.5) 20 (10.0) 13 (6.5) 6 (3.0) 9 (4.6)

Clavien-Dindo, n (%) <0.003

0 59 (30.6) 72 (36.0) 59 (29.5) 65 (32.5) 39 (29.8)

I 11 (5.2) 11 (5.5) 13 (6.5) 31 (15.5) 16 (12.2)

II 75 (38.9) 54 (27.0) 53 (26.5) 51 (25.5) 35 (26.7)

III 27 (14.0) 34 (17.0) 49 (24.5) 33 (16.5) 23 (17.6)

IV 14 (7.2) 17 (8.5) 21 (10.5) 12 (6.0) 13 (9.9)

V 8 (3.1) 12 (6.0) 5 (2.5) 8 (4.0) 5 (3.8)

Median hospital LOS, d 9 9 10 9 8 0.03

Median ICU LOS, d 2 2 1 1 1 <0.0001

Pre-HIPEC systemic chemotherapy, n (%)

No 59 (36) 122 (61) 107 (54) 85 (42) 48 (32)

Yes 105 (64) 77 (39) 93 (46) 115 (58) 100 (68)

ECOG, Eastern Cooperative Oncology Group; HIPEC, hyperthermic intraperitoneal chemotherapy; LOS, length of stay.

Vol. 218, No. 4, April 2014 Levine et al Peritoneal Surface Malignancy 577

26.0%, 23.6%, 17.0%, and 11.7%, respectively;p < 0.001). Rates of stoma creation (ileostomy or colos-tomy) decreased over time (11.8%, 29.5%, 20.0%, 20.6%,and 15.1% respectively; p < 0.001). In addition, the1- and 5-year OS rates have increased over time (with the5-year median OS not yet reached for the latest 2 quintiles).

Survival and follow-up

For the cohort of 1,000 patients with a median follow-upof 54.1 months, median OS was 29.4 months. One, 3-,5-, 10-, and 15-year OS rates (�SE) were 72.3%(�1.5%), 44.6% (�1.7%), 31.5% (�1.8%), 18.1%(�1.9%), and 10.7% (�2.7%), respectively (see Figs. 1to 5). Second HIPEC was performed on 89 selected pa-tients for recurrent/persistent disease,30 with 8 subjectsundergoing 3 procedures. When plotting the overall sur-vival time after repeat vs initial HIPEC, the results arestrikingly similar (Fig. 6). Survival rates include operativemortality. A univariate analysis of clinicopathologic fac-tors was performed to identify singularly significant prog-nostic factors associated with OS after CS and HIPEC forPSD. Multivariate analysis of factors effecting survivalwas performed via a stepwise regression technique. Thisanalysis allowed for all variables regardless of level of sig-nificance in the univariate analysis. The Cox proportionalhazards regression model found that 5 clinicopathologicfactors were independent predictors of OS: tumor histol-ogy, resection status, complications, and performance sta-tus (Table 3). Figures 1 to 6 depict the Kaplan-Meieractuarial survival curves for these factors.

DISCUSSIONCytoreductive surgery and HIPEC represent a substantialoperative undertaking for both patient and surgeon.Mean operative times are approximately 10 hours, withICU and hospital stays that consume substantial re-sources. Morbidity and mortality have improved overtime but remain significant; straightforward preoperativediscussions with the patient and family are, therefore,

Figure 1. Overall survival by quintile of experience, difference sig-nificant (p ¼ 0.0006).

Figure 2. Overall survival for 1,000 patients treated with cytore-ductive surgery and hyperthermic intraperitoneal chemotherapy.

Table 2. Listing of Organs Resected as Part of theCytoreductive Surgery in Addition to Peritoneal Resections*

Organ resected n %

Diaphragm 98 9.8

Colon 500 50.0

Rectum 78 7.8

Small bowel 322 32.2

Stomach 111 11.1

Spleen 416 41.6

Uterus 91 17.1y

Ovaries 170 32.0y

Gallbladder 291 29.1

Pancreas 62 6.2

Appendix 102 10.2

Omentum 717 71.7

Kidney 12 1.2

Lung 4 0.4

Liver 102 10.2

Bladder 25 2.5

Adrenal 3 .3

Umbilicus 27 2.7

*Omentectomy (supracolic) was performed routinely if not previouslyresected.yPercentage of female patients.

578 Levine et al Peritoneal Surface Malignancy J Am Coll Surg

necessary. However, properly selected patients have a realchance at long-term survival that is rarely, if ever, realizedwithout such aggressive efforts. Clearly, long-term sur-vival is possible for patients with PSD. In our experience,we have modified our approach to PSD in terms of pa-tient selection and, to a lesser extent, operative techniques.Systemic chemotherapy for PSD has been the tradi-

tional approach, but is hampered by limited entry intothe peritoneum. Any systemic chemotherapy for intraper-itoneal disease must overcome the plasma-peritonealpartition to reach molecular targets. Pharmacokineticstudies have confirmed the presence of this peritoneal-plasma partition by demonstrating that drugs deliveredinto the peritoneal cavity have a clearance that is inverselyproportional to the square root of its molecularweight.31-33 Delivery of intraperitoneal chemotherapycan be viewed as a tool to overcome this drug resistance,as well the toxicity attendant to systemic administration.Because of this partition, drugs without lipophilic proper-ties and high molecular weights have optimal characteris-tics for intraperitoneal application. The pharmacokineticadvantage of intraperitoneal perfusion is substantial andcan be quantified by the area under the curve ratios ofperitoneal fluid to plasma that favor retention of drugin the peritoneum.34-40

In addition to the pharmacokinetic advantage thatintraperitoneal chemotherapy infusion (after maximaltumor debulking) offers, the addition of hyperthermiaeffects cell membranes, cytoskeletons, synthesis ofmacromolecules, and DNA repair mechanisms.41,42

Our institution and others have primarily used MMC.The synergy between MMC and hyperthermia occursindependent of the cell cycle, allowing for considerable

tumoricidal activity with relatively brief exposures.43-45

Additionally, the hyperthermia ameliorates the hypo-thermia frequently encountered during long open oper-ative procedures.There is a paucity of data on the use of systemic ther-

apy for PSD in general, and for appendiceal tumors,46

specifically the more common low-grade tumors. There-fore, the foundation of treatment for PSD of appendicealmalignancies remains aggressive CS followed by hyper-thermic peritoneal perfusion. Removal of bulk disease isimperative, however, as even the most ambitious perfu-sion strategies penetrate a maximum 5 mm into perito-neal surfaces. Aggressive CS allows hyperthermicchemoperfusion to address the microscopic or small-volume residual. Consequently, the foundation of treat-ment of PSD for appendiceal disease remains aggressiveCS followed by HIPEC.Pathologic characteristics clearly impact the clinical

outcomes of patients with PSD. For appendiceal tumors,patients with low-grade mucinous carcinoma peritonei(which is also described as disseminated peritoneal adeno-mucinosis or pseudomyxoma peritonei [PMP]) experi-ence better clinical outcomes than those with highergrade nonmucinous appendiceal malignancies.47-54 We,and others, have previously shown that the survival ratein patients with high-grade lesions was significantly lowerthan for the low-grade PSD.8,16,17 This is not an unex-pected finding based on the biological and molecular dif-ferences between low- and high-grade nonmucinousappendiceal tumors.16,17,49 We have recently describedthe genomics of appendiceal tumors and found them tobe dramatically different from colorectal epithelial neo-plasms.49 Such studies are important to determining the

Figure 4. Overall survival by preoperative performance status,differences significant (p < 0.0001).

Figure 3. Overall survival by primary tumor site, differences signif-icant (p < 0.0001).

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biologic underpinnings of PMP and seeking actionabletargets for personalized therapies.Appendiceal cancer with PMP has been considered the

classic indication for HIPEC, as PMP rarely metastasizesbeyond the peritoneal space and pelvis. Five-year survivalrates after HIPEC for PMP range between 66% and 97%,and our experience is consistent with those results.50-53 Tu-mor histology is a major driver of prognosis for patientswith PMP. The outcomes with the low-grade diseasewith PSD are considerably better than those ofintermediate- or high-grade disease in the originaldescription of the histologic subtypes of PMP.55 Webelieve that the behavior of PMP/appendiceal carcinomais best described simply as low and high grade rather thana more cumbersome 3-tier classification.16,17 This clearlydemonstrates the differences in tumor biology amongthese histologic subgroups of PMP, and is readily repro-ducible when reviewed by pathologists.This study confirms our previous reports that patients

with Eastern Cooperative Oncology Group performancescores of 2 to 3 had significantly poorer overall survivalthan those with scores of 0 or 1.8,18 This also highlightsthe importance of evaluating candidates for the procedurewhen they are medically fit to undergo such a large-scaleintervention. Preoperative performance scores and qualityof life indices clearly predict outcomes56 Therefore, weselect patients for HIPEC with Eastern CooperativeOncology Group scores of 2 or better. Despite recent im-provements in systemic therapy for colorectal cancer,treating patients with second-line therapy when their per-formance status declines can deprive candidates of the op-portunity to be salvaged with CS and HIPEC. We suggestthat if systemic chemotherapy will be used preoperatively,that it be limited to 3 to 6 cycles to avoid substantial

decrements in performance status attendant to prolongedsystemic chemotherapy.56

Patients undergoing complete CS before HIPEC hadsuperior outcomes compared with those who underwentincomplete CS regardless of site of the primary lesion(Fig. 5). This finding confirms data from our institutionand others that demonstrate a considerable survival advan-tage for patients undergoing R0/R1 resection comparedwith those with R2 resections.8,18,57,58 In a review of 506patients, Glehen and colleagues analyzed the survival ofpatients with peritoneal surface malignancies from colo-rectal primary tumors undergoing incomplete CS followedby HIPEC, and found that this treatment paradigmresulted in limited long-term survival.48 Patients who areunable to undergo significant CS (R2a or better) at lapa-rotomy can be spared the potential toxicity of HIPEC.Our rate of complete cytoreduction increased substantiallyover time, which likely results more from better patientselection than from improvements in surgical techniques.Surgical resection remains the primary mode of therapy

for colon and rectal cancer. Treatment options for pa-tients with unresectable metastatic disease have improvedsubstantially in the past few years. Patients with stage IVcolorectal cancer treated with newer combinations ofcytotoxic chemotherapy,59 and/or biological agents,60

have resulted in an unprecedented median survival ofapproximately 20 months, although at considerablecost. However, such therapeutic combinations are notan optimal treatment strategy for all categories of stageIV disease. Patients with PSD from colorectal cancertreated with modern systemic therapy have poorer sur-vival rates than those with metastases to other sites,with 5-year survival rates of 6.0% vs 4.1% with modern

Figure 6. Overall survival by postoperative major complication(p < 0.0001).

Figure 5. Overall survival by resection status (p < 0.0001).

580 Levine et al Peritoneal Surface Malignancy J Am Coll Surg

chemotherapy.61 Patients undergoing CS and HIPEChad a 5-year survival rate of 17%, with those undergoingR0/1 resections being more than 4 times that.19 Thisfinding is consistent with other high-volume centers.62-64

In addition, it must be kept in mind that most of the pa-tients undergoing HIPEC for colorectal cancer have beentreated with systemic chemotherapy before HIPEC.Therefore, they are well into the 12.7-month median sur-vival found with systemic chemotherapy alone, and pre-sent a treatment lead time against any benefit ofHIPEC vs systemic therapy.61

This experience is supported by the randomized trialfrom the Netherlands that compared palliative surgerywith chemotherapy with CS and HIPEC with the samesystemic chemotherapy.9 That randomized trial found adoubling of survival for patients treated with CS andHIPEC.9 Therefore, we concur with the consensus state-ment from the American Society of Peritoneal SurfaceMalignancies that systemic therapy alone is no longerappropriate for patients with limited peritoneal dissemi-nation from a primary or recurrent colon cancer.65 Thesurgical management of PSD of colorectal origin withCS and HIPEC has been clearly defined and continuesto improve. This aggressive strategy has resulted inlong-term survival rates that are unprecedented in theliterature. Despite the cost of considerable morbidity,properly selected patients have a real opportunity for

survival in a situation that was previously approachedwith purely palliative intent.We have avoided addressing PSD from hepatic, biliary,

and pancreatic sources principally because of difficultyobtaining control of the primary lesion, and a paucity ofagents with considerable activity. Similarly, we currentlyconsider patients with gastric cancer after a response tosystemic chemotherapy and only if R0/1 resection canbe anticipated. Peritoneal surface (malignant) diseasefrom sarcoma (sarcomatosis) is now a rare indication forHIPEC. Although we had some success with the proce-dure and have long-term survivors, we have no confidencein the activity of the chemotherapy in this setting, and nolonger offer the procedure to patients with disseminatedgastrointestinal stromal tumors or liposarcoma.23

Primary peritoneal mesothelioma is a much less com-mon entity than the pleural malignancy.57 Although themolecular characteristics of peritoneal disease differ onlyslightly from the pleural disease, the clinical courses aredisparate.66,67 Peritoneal disease typically presents with as-cites, abdominal pain, and eventually bowel obstruction.The disease tends to remain within the abdominal cavityuntil late in the course and distant metastasis is distinctlyuncommon, making this an excellent opportunity for CSand HIPEC. We and others have previously reportedour experience with this modality,24,68-74 which representsa great improvement over even the best systemic

Table 3. Univariate and Multivariate Analysis of Prognostic Significance of Clinicopathologic Variables Based on StepwiseRegression Analysis

Variables p Value Hazard ratio

Univariate

Race 0.31

Peritoneal carcinomatosis index <0.0001 1.28 for each 5-unit increase

Resection status <0.0001 1.6�5.7

Sex 0.039 0.85

Complications <0.0001 1.5

Length of operation 0.041 1.03 (each additional hour)

Previous CS and HIPEC <0.0001 0.45

Age 0.028 1.04 (each 5-year increase)

Temperature of perfusate 0.73

Length of perfusion with chemotherapy 0.21

Primary tumor histology (site) <0.0001 0.24�2.7 (depending on primary)

Performance status (ECOG) <0.0001 2.8 for 2, 4.3 for 3 or 4

Experience quintile 0.006 1.5 (quintile 1 vs 5)

Multivariate

Resection status <0.0001

Performance status (ECOG) <0.0001

Primary tumor histology (site) <0.0001

Complications <0.0001

Experience quintile 0.043

CS, cytoreductive surgery; ECOG, Eastern Cooperative Oncology Group; HIPEC, hyperthermic intraperitoneal chemotherapy.

Vol. 218, No. 4, April 2014 Levine et al Peritoneal Surface Malignancy 581

therapy.24,66,68-70 In our initial study, we used MMC as theagent24 but have changed to cisplatin after reports fromthe surgery branch of the National Cancer Institute.24,68,69

The experience with CS and HIPEC for peritonealmesothelioma has led to a proposed staging system, whichwe support.74 We believe that mesothelioma representsone of the strongest cases for combining HIPEC with CS.It is estimated that only a handful of patients who are

potential candidates for CS and HIPEC actually receiveit, which is underscored by the relatively small number ofpatients accrued to the trials and studies for PSD at largeperfusion centers. It is clear that expanding the numberof centers should be done by surgical oncologists whohave more than a passing knowledge of systemic chemo-therapy and are comfortable with the rigors of aggressiveoperative procedures in the abdomen.30 This has led toconsensus statements by a group of surgeons with an inter-est inCS andHIPEC,which outlines an evaluation strategyfor PSD from colorectal carcinoma.62,65

Although results reported from perfusion centers repre-sent a substantial improvement in duration and likelyquality of life,75-78 the majority of patients undergoingthese procedures will experience tumor recurrence. Evalu-ating patients for a second CS and HIPEC will becomean ever more common problem as patients with PMPsurvive long enough to require multiple procedures.30,79,80

We and others believe that, in selected patients, a secondCS and chemoperfusion can be of value (Fig. 7). In eval-uating patients for second cytoreduction, the same criteriathat are used to select patients for the first remain impor-tant. Specifically, the patients must remain medically fitenough to tolerate a major operative procedure, be freeof extra-abdominal metastasis, and have disease thatseems amenable to complete cytoreduction. Additionally,the time to recurrence after initial cytoreduction and thecompleteness of the initial cytoreduction should beconsidered in deciding to proceed with another proce-dure. Patients with bulk residual disease after an initialcytoreduction for PSD should not be considered candi-dates for second cytoreductive procedures.30,79,80 In thisstudy, 89 patients underwent a second (or third) HIPEC.Although such cases had good outcomes, with survivalsimilar to the experience with an initial procedure,when chosen appropriately iterative procedures can “resetthe clock” to the time of the initial HIPEC. We do recog-nize that this survival advantage clearly represents a selec-tion bias in choosing patients for repeat procedures.Several issues surround the future of CS and HIPEC

for PSD. Chief among them is how to make such therapystandardized and available to large numbers of patients.There are currently approximately 100 active centers inthe United States, but only approximately a dozen with

experience of >100 cases. These operative proceduresrequire aggressive cytoreduction and are lengthy, chal-lenging, potentially morbid, and use a great deal of hos-pital, blood bank, and surgical house officer resources.Resource use and safety of chemotherapy in the operatingroom remain daunting for many centers. Additionally,great care needs to be taken in selecting patients toundergo this procedure. The financial cost of theseprocedures can be considerable; even considering thepotential feasibility of laparoscopic approaches to selectedpatients with PSD, the cost of these procedures will remainsubstantial. However, when viewed in the context of theskyrocketing costs for multi-agent chemotherapy,59,60

with increasing use of biologic agents costing in excess of$100,000,81,82 we maintain that HIPEC should be costeffective for appropriately selected patients.Our experience has evolved and improved during the 2

decades of this study. This implies a learning curve, whichwe estimate to be in the range of 50 to 200 cases.Although we would like to think our surgical techniqueshave improved considerably over time, we believe that itis primarily better patient selection that accounts for theimproved outcomes. In addition, even with our experi-ence, for most primary site tumors the optimal time,dose, temperature, and chemotherapeutic agent for perfu-sion are not based on class I data. Therefore, additionalinvestigation into these variables remains important.Fundamental questions about HIPEC for PSD need to be

addressed. Foremost among these is whether the addition ofHIPEC after CS is of value. It seems obvious that the value ofHIPEC should depend on the tumor being treated. The onlycompleted randomized trial forCS andHIPECevaluated pa-tients with PSD from colorectal primary and appendiceal

Figure 7. Overall survival for second vs initial hyperthermic intra-peritoneal chemotherapy procedures.

582 Levine et al Peritoneal Surface Malignancy J Am Coll Surg

lesions.9 That trial compared CS and HIPEC with standardsystemic chemotherapywith standard systemic therapy (fluo-rouracil and leucovorin) and found the CS and HIPECdoubled the survival.9 However, to date, no study hascompared CS with or without HIPEC.9,62 Clearly, it wouldbe desirable to evaluate the value of HIPEC vs CS alone ina multicenter prospective randomized trial, and such a trialin France is now accruing patients.However, such a random-ized controlled trial has proven difficult to complete andefforts have previously failed, as many patients presentingthemselves for evaluation refuse to consider such a randomi-zation.62,83 Efforts to bring CS and HIPEC to multicentertrials have not been embraced by the cooperative oncologygroups to date. A recent study offered via the AmericanCollege of Surgeons Oncology Group accrued a singlepatient (coincidentally from our site), before closure due tolack of accrual. However, such difficulties in performing ran-domized trials do not mean they should not be pursued.

CONCLUSIONSThe advancement of Centers of Excellence as well as theinitiation of cooperative group trials will help to define theimproved approaches for peritoneal spread for PSD. Thefuture of CS and HIPEC for PSD lies in multicenter andrandomized trials that not only investigate response and sur-vival, but also standardization of techniques, quality of life,and integration with ever-improving systemic therapy. Ourexperience clearly shows that long-term survival is possibleafter a diagnosis of PSD, and that approaching such patientswith therapeutic nihilism is no longer appropriate.

Author Contributions

Study conception and design: Levine, LoggieAcquisition of data: Levine, Stewart, Shen, Loggie,Votanopoulos

Analysis and interpretation of data: RussellDrafting of manuscript: LevineCritical revision: Levine, Stewart, Shen, Loggie,Votanopoulos

Acknowledgment: The authors wish to acknowledge thesubstantial contributions of fellows, house officers, perfu-sionists, nurses, enterostomal therapists, psychosocial oncol-ogists, pathologists, urologists, and radiologists whocontributed to the care of these patients. We would alsolike to thank Joan L Feder for her editorial support andKathleen Cummins for her ongoing support of the database.

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Discussion

DR CHARLES STALEY (Atlanta, GA): Historically, carcinomatosis

from disseminated cancer has been associated with a short survival,poor quality of life, and unsatisfactory response rates to systemicchemotherapy. The Wake Forest group has been at the forefront ofcytoreductive surgery and hyperthermic intraperitoneal chemotherapy

(HIPEC) for the last 20 years. This presentation highlighted theirexperience with 1,000 patients, which demonstrated that the primarysite histology, performance status, and completeness of resection are

the most important prognostic factors for long-term survival.Similar to other complex surgical oncology operations, cytore-

ductive surgery and HIPEC can be done with low mortality and

acceptable morbidity in experienced centers. What percentage ofthose patients who looked to be resectable at preoperative imagingare explored and found to be unresectable? And is there any role of

laparoscopy in sorting out these patients? Because performance sta-tus is important, are there any minimal nutritional parameters youused to make patient selection? Are there certain pathologic sub-types, like signet ring histology, that you’d not consider for cytore-

ductive surgery and HIPEC based on their poor tumor biology?As a relative newcomer in this field, I am discouraged by the lack

of standardization of these procedures, chemotherapy, drug selec-

tion, and lack of clinical trials, which certainly adds to the skepti-cism of some about this treatment approach. What simple steps canwe take to start to turn this around? We certainly need to continue

to educate our medical oncology colleagues about this procedureand to facilitate early referral of more treatable patients with low-volume disease instead of the usual chemorefractory bulky disease

with reduced performance status.

DR FREDERICK GREENE (Charlotte, NC): Today we have hearda landmark paper presented by Dr Levine and his colleagues, who

are indeed experts in the technique of cytoreductive surgery andHIPEC for peritoneal-based malignancy. They have used a pro-spective database to carefully evaluate these 1,000 patients, andhave shown that at least in the hands of experts, increasing experi-

ence is directly related to overall survival and inversely related tosignificant complications. You have not mentioned the use of lap-aroscopy either as a preoperative staging tool or as a method of

attaining cytoreduction. Could you please discuss the use of a lapa-roscope in your patient population?

You state that the average time for these procedures is just under

10 hours. In this economic era, how can we effectively plan foroperating room time and justify the use of personnel in initiatinga program of cytoreductive surgery and HIPEC?

Finally, we continue to report 30-day morbidity and mortalityin our discussions of operative outcomes. Because many patientscontinue to remain hospitalized or sustain complications beyond30 days, have you looked at 60-day outcomes and beyond to assess

morbidity and mortality directly related to cytoreductive surgeryand HIPEC?

DR LD BRITT (Norfolk, VA): Not to sound like one of the officialsin the Hunger Games at Capital City, but how would you respond

to the insurance company pundit who would say this sort ofapproach is not cost effective?

DR WILLIAM CHAPMAN (St Louis, MO): This is a great paperand, really opens a lot of eyes to considering this option in patients

with peritoneal disease. What about when there is resectable meta-static disease in the liver, but also peritoneal disease; should we beconsidering the combination of major hepatectomy with peritonec-

tomy? More recently, we have taken the view for colorectal livermetastases that if all gross disease can be resected, proceed withhepatectomy. However, I think most liver surgeons at most livercenters with any component of significant peritoneal disease do

not proceed and instead declare the patient unresectable. So Iwould be curious about any data you have in that regard to clarifyif we should be considering resection in this setting also?

DR EMMANUEL ZERVOS (Greenville, NC): You commented onchemotherapy before, but I wonder if you might comment on what

impact adjuvant chemotherapy had on your observation ofimproved outcomes in the latter quintiles.

DR EDWARD A LEVINE: First, in terms of laparoscopy, does it

have a role? Yes, of course it does. For patients particularly withlow volumes of peritoneal surface disease, it is possible to stagethem to see if you are likely to be able to achieve satisfactory cytore-

duction. Further, select low volume cases can be done laparoscopi-cally. However, the problem is that many of these patients havehad several operations previously, which can make mobilization

exceedingly difficult or frankly, not possible. So there is a role for lap-aroscopy, but unfortunately, its role is limited because many of thesepatients, particularly once they have significant peritoneal volume of

disease, are not going to be candidates for a laparoscopic approach.In terms of nutritional status, yes, absolutely we look closely at

nutritional parameters. We want to see an albumin close to thenormal range, certainly above 3 g/dL. I usually tell my residents

who are coming through for the first time to ask themselves ifthey would perform a Whipple procedure on these patients? Ifthe answer is no, then the answer is no. Although some patients

can become candidates with preoperative nutritional support, thosewho cannot should not be offered the procedure.

Histology of the primary lesion is a key prognostic variable.

Further, patients who have signet ring cells, though not a part ofthis manuscript and analysis, have a poorer prognosis than thosewho did not have the signet ring histology, particularly for colonand appendiceal tumors. Those patients can be long-term survi-

vors. However, they are going to need a more complete cytoreduc-tion than others. Leaving gross disease behind in those patients willnot likely be associated with long-term survival.

For morbidity and mortality, I presented a 30-day mortality rate. Iwould agree that frequently, and this procedure is no exception, mor-tality does not end at 30 days for processes that are directly related to

the procedure. Probably a more reasonable number is 120 days, whichis a number we don’t usually use. At 6 months, the overall mortalitymight be closer to 6%. Mortality continues to increase slightly over

the course of the first 2 to 3 months before it levels off. And their per-formance status, and we’ve looked at quality of life for these patients,

586 Levine et al Discussion J Am Coll Surg

really does not level out for about 2 months. However, by 6 months,quality of life measures are back to or above baseline in most cases.

Parenchymal hepatic metastases, but not hepatic surface orcapsular disease, were considered a contraindication to the procedurefor the first decade of our experience. However, we have found that if

you can get a complete cytoreduction in the liver and the perito-neumdthe “and” here is crucial because you have to clear all the dis-ease from both sitesdthe overall survival actually looks quite similar.

Although 5-year survival is not quite as good as you would expect forliver disease alone, it remains impressive to us. We have taken theapproach that if liver disease can be completely cleared with lessthan a lobectomy or a combination of resections and radiofrequency

ablations, and a complete peritoneal cytoreduction, leaving no grossdisease behind, it’s probably worth pursuing in some selected patients.

Dr Britt cuts to the heart of the matterdhow do you defend thecost? This is an expensive operation, make no mistake about it. The

average hospital stays are lengthy, the operating room time expen-sive, and the procedures associated with it are expensive. The thingyou have to keep in mind is what will happen to these patients if

they do not undergo this procedure. A very, very few of themwill be long-term survivors. Additionally, you have to comparethat with the cost of systemic chemotherapy, which, if you have

colon cancer, you use an oxaliplatin-based regimen, a iriniotecan-based regimen, bevacizumab followed up with biologic agents.You are looking at perhaps $200,000 over the course of 2 years.If you view it in that light in terms of the entire history of cost

to the patient, this procedure becomes cost effective, if not abargain.

Vol. 218, No. 4, April 2014 Levine et al Discussion 587