Cytoreductive Surgery and Intraperitoneal Hyperthermic

8/12/2019 Cytoreductive Surgery and Intraperitoneal Hyperthermic

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Cytoreductive Surgery and Intraperitoneal Hyperthermic

Chemotherapy With Mitomycin C for Peritoneal Carcinomatosis

from Nonappendiceal Colorectal Carcinoma

Perry Shen, MD, Jason Hawksworth, MD, James Lovato, PhD, Brian W. Loggie, MD,

Kim R. Geisinger, MD, Ronald A. Fleming, PharmD, and Edward A. Levine, MD

Background: Cytoreductive surgery (CS) and intraperitoneal hyperthermic chemotherapy(IPHC) are efficacious in patients with disseminated mucinous tumors of the appendix. We reviewed

our experience using this approach for nonappendiceal colorectal cancer (NACC).Methods: We performed a retrospective chart review of a prospective database for patients

undergoing CS and IPHC with mitomycin C for peritoneal carcinomatosis from colorectal primarylesions between December 1991 and April 2002.

Results:There were 77 patients, with a median age of 54 years. Peritoneal carcinomatosis wassynchronous and metachronous in 27% and 73% patients, respectively. Seventy-five percent ofpatients (n 58) had received chemotherapy prior to IPHC. Complete resection of all gross diseasewas accomplished in 37 patients (48%). The mean carcinoembryonic antigen level decreased froma preoperative value of 31.2 to a postoperative value of 6.9 (P .0001). Overall survival (OS) at1, 3, and 5 years was 56%, 25%, and 17%, respectively. With a median follow-up of 15 months, themedian OS was 16 months. Perioperative morbidity and mortality were 30% and 12%, respectively.Hematologic toxicity occurred in 15 patients (19%). Cox regression analysis identified poorperformance status (P .018), bowel obstruction (P .001), malignant ascites (P .001), andincomplete resection of gross disease (P .011) as independent predictors of decreased survival.Patients with complete resection of all gross disease had a 5-year OS of 34%, with a median OS of

28 months.Conclusions: CS and IPHC with mitomycin C can improve outcomes for select patients with

peritoneal spread from NACC. One third of patients who undergo complete resection of grossdisease have long-term survival.

Key Words: ChemotherapyColorectal cancerHyperthermiaPeritoneal carcinomatosisSurgery.

The treatment of patients with peritoneal carcinomatosis

(PC) from gastrointestinal malignancies is in evolution. PC

is the most common cause of death in patients resected for

intra-abdominal carcinomas.1 A multicenter study prospec-

tively following 370 patients with PC of nongynecologic

origin revealed a mean and median overall survival (OS) of

6.0 and 3.1 months, respectively.2

Surgical resection alone has been demonstrated to be

ineffective for the treatment of PC, with median surviv-

als of 1, 1, .7, and 6 months for PC from gastric, small

bowel, pancreas, and colorectal cancer treated in this

fashion.3 Attempts at controlling PC with either external

beam radiation therapy or brachytherapy have failed to

demonstrate efficacy.4 The use of systemic chemother-

apy for PC has not been shown to be efficacious, as many

patients present with PC after systemic chemotherapy

fails.5

Received May 8, 2003; accepted October 8, 2003.From Wake Forest University Baptist Medical Center (PS, JH, JL,

KRG, EAL) and Kucera Pharmaceutical Company (RAF), Winston-

Salem, NC; and Creighton University Cancer Center (BWL), Omaha,Nebraska.

Address correspondence and reprint requests to: Perry Shen, MD,

Surgical Oncology Service, Wake Forest University Medical Center,Medical Center Blvd., Winston-Salem, NC 27157; Fax: 336-716-9758;

E-mail: [email protected].

Published by Lippincott Williams & Wilkins 2004 The Society of SurgicalOncology, Inc.

Annals of Surgical Oncology,11(2):178186

DOI: 10.1245/ASO.2004.05.009

178


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Intraperitoneal administration of chemotherapy has

the benefit of delivering higher concentrations of cyto-

toxic drug locally to the site of the tumor while mini-

mizing systemic toxicity, in comparison with intravenous

administration. Pharmacokinetic studies have demon-

strated a 107-fold increase in the concentration of mito-mycin C (MMC) in the intraperitoneal perfusate versus

plasma concentrations when administered systemically.5

Recent studies have reported on the combination of cy-

toreductive surgery and intraoperative intraperitoneal

chemotherapy612 administered under hyperthermic con-

ditions (40C to 43C). The administration of intraperi-

toneal chemotherapy at the time of surgery allows a

potentially more even distribution of drug, without the

potential of catheter-related complications and postoper-

ative adhesions. Hyperthermia has been shown to poten-

tiate the cytotoxicity of drugs such as MMC and cispla-

tin.13,14 These interactions are enhanced under hypoxicconditions, which is not true for most agents given after

surgical resection.

A report from Sugarbaker and colleagues15 at the

Washington Cancer Institute described the use of cytore-

ductive surgery (CS) and intraoperative and periopera-

tive intraperitoneal chemotherapy with 5-fluorouracil

and MMC for 385 patients with PC from appendiceal

malignancy. Patients with complete cytoreduction and

pathology demonstrating adenomucinosis and adenocar-

cinoma had 5-year OS rates of 86% and 50%, respec-

tively. Piso et al.16 also reported their experience with

intraoperative hyperthermic intraperitoneal cisplatin af-ter peritonectomy procedures for PC from appendiceal

carcinoma. They reported a mean OS time of 39 months,

with a 4-year OS rate of 75%. Patients with complete

versus incomplete cytoreduction had a 4-year OS rate of

92% and 40%, respectively (P .02). Another study

report, by Zoetmulder and associates,17 described their

experience with IPHC with MMC for pseudomyxoma

peritonei in 46 patients. The actuarial survival rate at 3

years was 81%. These published results for over 400

patients provide strong evidence for the use of an ag-

gressive multimodality approach to this rare disease pro-

cess, especially when standard surgical therapy results inonly a 10-year OS of 10% to 30%.18 In addition, we

recently reviewed our experience with 109 patients

treated with PC from various histologies and found that

an appendiceal primary was an independent predictor of

improved survival.19

Data regarding the use of CS and IPHC for other types

of histologies have not been as extensively studied. Spe-

cifically, the treatment of PC from nonappendiceal colo-

rectal carcinoma (NACC) with CS and IPHC with ad-

ministration of MMC has been examined in only a

limited fashion. Both Loggie et al.20 and Sugarbaker et

al.21 have reported a significant difference in outcome for

patients with appendiceal versus colorectal primaries.

Other trials have suggested a benefit of CS and IPHC

for PC from colorectal cancer, including one prospective

randomized trial.22,23 However, these trials included ap-pendiceal cancers in their study populations, making it

difficult to determine the true effect of this approach. We

reviewed our experience with CS and IPHC using MMC

for PC from NACC to examine their demographics,

clinical outcome, predictors of survival, factors contrib-

uting to postoperative morbidity/mortality, and methods

to improve patient selection.

METHODS

The study protocol was reviewed and approved by the

Institutional Review Board of the Wake Forest Univer-sity School of Medicine. Eligible patients were enrolled

in the protocol from December 1991 through April 2002.

All patients with PC from NACC primaries were en-

rolled in the study cohort. The Eastern Cooperative On-

cology Group (ECOG) performance status was recorded

for all patients enrolled in the protocol.24

Cytoreductive Surgery

All patients enrolled in the study protocol were oper-

ated on by one of three surgeons (BWL, EAL, PS), each

with significant experience with CS. CS consisted of the

removal of all gross tumors with involved organs, peri-toneum, or tissue that was deemed technically feasible

and safe for the patient. Any tumor adherent or invasive

to vital structures that could not be removed was cytore-

duced with the Cavitron Ultrasonic Surgical Aspirator

device. Peritonectomy was performed as indicated. The

resection status of patients was estimated following CS

with use of the following classification: R0, complete

removal of all visible tumor and negative cytology or

negative microscopic margins; R1, complete removal of

all visible tumor and positive cytology or microscopic

margins; R2a, minimal residual tumor, nodule(s) .5 cm;

R2b, gross residual tumor, nodule

.5 cm but

2 cm;and R2c, extensive disease remaining, nodules 2 cm.

Intraperitoneal Hyperthermic Chemotherapy

Patients were cooled to a core temperature of about

34C to 35C by passive measures (i.e., not warming

airway gases or intravenous solutions and cooling the

room). After CS was completed, peritoneal perfusion

inflow and outflow catheters were placed percutaneously

into the abdominal cavity. Temperature probes were

placed on the inflow and outflow catheters. The abdom-

179IPHC FOR COLORECTAL PERITONEAL CARCINOMATOSIS

Ann Surg Oncol, Vol. 11, No. 2, 2004


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inal skin incision was closed temporarily with a running

suture to prevent leakage of peritoneal perfusate. A per-

fusion circuit was established with approximately 3 L of

Ringers lactate. Flow rates of approximately 600 to 900

mL/min were maintained with a roller pump managed by

the pump technician. The circuit continued through asingle roller pump, through a heat exchanger (SCI-MED,

No. A-714; Gish Biomedical, Irvine, Ca), and then to the

patient.

Constant temperature monitoring was performed with

temperature probes placed on both the inflow and out-

flow catheters. Once inflow temperatures exceeded a

temperature of 38.5C, 30 mg of MMC was added to the

perfusate, and at 60 minutes an additional 10 mg of

MMC was added to the perfusate to keep MMC perfus-

ate concentrations 5 g/mL. A maximum inflow tem-

perature of 40.5C was achieved during the perfusion,

with outflow at the pelvis of 39.5C. The abdomen wasgently massaged throughout the perfusion to improve

drug distribution to all peritoneal surfaces. The total

perfusion time after the initial addition of MMC was 120

minutes. In certain patients (elderly, those with extensive

prior chemotherapy, those with inanition or poor perfor-

mance status, and those having extensive peritoneal

stripping during surgery), reductions in the dose of MMC

(to 30 mg total) and/or the perfusion time (6090 min-

utes) were made because of concerns about potential

toxicity. The peritoneum was washed out with 3 L of

lactated Ringer solution, and the abdomen was reopened

for removal of perfusion catheters.In 2000, a new perfusion device (ViaCirq, Pittsburgh,

PA) was introduced that allowed the perfusate to be

heated to higher temperatures. Subsequent sessions of

IPHC were conducted with a maximum inflow temper-

ature of 43C and a minimum outflow temperature of

40.5C.

Perioperative Evaluation

Perioperative morbidity in the database was classified

into four main groups: bowel leak, respiratory failure,

infection, and sepsis. Bowel leak was defined by any

occurrence of an anastomotic leak or bowel perforation,respiratory failure was defined by any extended period of

mechanical respiration beyond the first 24 hours after

surgery or any incidence of reintubation (regardless of

cause), and infection was defined as any infection of the

wound, abdomen, catheter, blood, or lung. Sepsis was

defined as a worsening clinical condition requiring man-

agement in the intensive care unit. Other complications

not covered by these four categories were also included

in the database. These included deep venous thrombosis,

ileus, pneumonia, renal failure, and pleural effusion.

Clinical Follow-Up

Clinical follow-up occurred at 1 month, 3 months, and

then every 3 months thereafter for up to 1 year. After 1

year, follow-up was at 3-month intervals or less fre-

quently if the patient continued to remain without evi-

dence of disease. Abdominal and pelvic CT scans wereobtained at 3, 6, and 12 months postoperatively or when

clinically indicated. Some patients received systemic

chemotherapy after referral back to their medical

oncologists.

Statistical Analysis

OS was calculated from the date of CS and IPHC to

the last recorded date of follow-up or recorded date of

death. All data were collected prospectively. Kaplan-

Meier analysis was performed on all pertinent clinico-

pathologic variables to determine estimates of survival

over time. Group comparisons of OS were done with thelog-rank test. Coxs proportional hazards regression

model was used to perform multivariate analysis of clin-

icopathologic factors to determine independent predic-

tors of OS. Fishers exact test was used to correlate type

of surgical procedure with postoperative morbidity. A P

value .05 was considered significant for the purposes

of this manuscript.

RESULTS

Patients

A total of 77 patients with PC from NACC wereenrolled in the protocol. Table 1 lists demographic char-

acteristics and baseline data. The median age was 54

years. The primary sites were 74 in the colon and 3 in the

rectum. All patients had a histologic diagnosis of adeno-

carcinoma. PC was synchronous and metachronous in

27% and 73% of patients, respectively. In those with

metachronous presentation, median disease-free interval

between primary diagnosis and peritoneal disease was 14

months (range, 3 to 85 months). More than three quarters

of patients had undergone prior surgery or chemother-

apy. About one third of patients presented with either

bowel obstruction or malignant ascites. Complete resec-tion of all gross disease was accomplished in 37 patients

(48%). Table 2 correlates resection status with type of

surgical procedure performed. Pre-IPHC cytology was

not performed or the results were not available in ap-

proximately one quarter of patients.

Survival and Follow-Up

For the cohort of 77 patients, 3-year and 5-year OS

was 25% and 17%, respectively. The median OS was 16

months (95% confidence interval [CI], 1026) with a

180 P. SHEN ET AL.



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median follow-up of 15 months. Table 3 displays the

results of a log-rank analysis of multiple clinical and

pathologic variables. Fifty-two patients (68%) have had a

recurrence, with a median time to progression of 7

months (range, 331). The mean carcinoembryonic an-

tigen decreased from a preoperative value of 31.2 to

postoperative value of 6.9 (P

.0001).Multivariate analysis demonstrated four clinicopatho-

logic factors that were independent predictors of OS

(Table 4): performance status (ECOG) of 0/1, R0/1 re-

section, no bowel obstruction, and no malignant ascites.

Figs. 14 depict the log-rank survival curves for these

factors.

Morbidity and Mortality

Perioperative morbidity and mortality were 30% and

12%, respectively. Mortality was calculated as postoper-

ative deaths directly attributable to the procedure, regard-

less of the time interval since the operation. Causes of

death included bowel perforation (n 2), bone marrow

suppression (n 2), respiratory failure (n 4), and

anastomotic leak (n 1). In the patient group with all the

independent predictors of OS (ECOG performance statusof 0/1, R0/1 resection, no bowel obstruction, no malig-

nant ascites), the perioperative mortality was 4% (1/25).

Fifteen subjects (19%) developed hematologic toxicity

requiring growth factor support or platelet transfusion.

Thirty-three patients (43%) required a blood transfusion,

with a median of 2 units (range, 117) transfused. The

median operative time and length of hospital stay for CS

and IPHC were 9 hours (range, 516) and 10 days (range,

5150), respectively.

Chi-square analysis and Fishers exact test were used

to correlate the occurrence of a perioperative complica-

tion (bowel leak, infection, respiratory failure, sepsis)with the performance of either a bowel resection (n

49) or bowel anastomosis (n 42). Patients with resec-

tion but no anastomosis had ostomies created. There was

no correlation of either bowel resection or anastomosis

with perioperative complications as a group. However,

when complications were individually analyzed against

bowel resection and anastomosis, there was a significant

correlation of sepsis with bowel anastomosis (P .0032)

(see Table 5).

Delivery of Intraperitoneal and Adjuvant

ChemotherapySixty-one patients (79%) received the standard intra-

peritoneal 2-hour perfusion of 40 mg MMC. Another

three patients (4%) underwent a 2-hour perfusion, but

two of them received 30 mg MMC and one especially

large patient received 50 mg MMC. Twelve patients

underwent a 1-hour perfusion with the following

amounts of MMC administered: for three patients (4%),

40 mg, and for nine (12%), 30 mg. One patient received

40 mg MMC in a 1.5-hour perfusion.

DISCUSSION

In 1995 Sugarbaker et al.21 published their experience

using perioperative intraperitoneal 5-fluorouracil and

MMC without hyperthermia for patients with PC sec-

ondary to appendiceal and colorectal cancer. The 3-year

OS rates for the appendiceal and colorectal PC patients

were 70% and 30%, respectively (P .0001). In 2000,

Loggie et al.20 published a report from our institution

examining the outcomes for patients with disseminated

peritoneal cancer of gastrointestinal origin. The median

OS of patients with colorectal primaries was 15 months.

TABLE 1. Patient demographics and baseline data

Baseline clinicopathologic variables

No.

(%)

Total 77 (100)

Age

55 y 41 (53)55 y 36 (47)

SexMale 45 (58)

Female 32 (42)Race

White 73 (95)

Black 4 (5)Previous treatment

Surgery 67 (87)Chemotherapy 58 (75)Radiation 6 (8)

Performance status (ECOG)0 18 (23)1 46 (60)

2 7 (9)

3 2 (3)4 4 (5)

Bowel obstructionYes 22 (29)

No 55 (71)Malignant ascites

Yes 26 (34)No 51 (66)

Liver metastases

Yes 10 (13)No 65 (84)Unknown 2 (3)

HistologyMucinous 43 (56)

Signet ring cell 7 (9)Not otherwise specified 27 (35)

Pre-IPHC cytologyPositive 31 (40)Negative 28 (36)

Unknown 18 (24)

ECOG, Eastern Cooperative Oncology Group; IPHC, intraperitonealhyperthermic chemotherapy.




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The median OS for appendiceal primaries had not been

reached. A study in France by Elias and associates22 used

both early intraperitoneal and hyperthermic intraopera-

tive intraperitoneal chemotherapy with a combination ofagents: 5-fluorouracil, MMC, and cisplatin. The results

of two separate trials were combined in one report.22 The

study cohort was patients with PC arising from colorectal

adenocarcinomas, of which 14% were mucinous cancers

of the appendix. All patients in this study had an R0/1

resection with all gross disease removed. The 5-year OS

was 27%, with a median OS of 36 months. These results

are comparable to those for our subset of patients with a

similar type of resection status.

A prospective study on the natural history of PC from

colorectal cancer demonstrated a median OS of 5

months.2

This subset of patients did not includepseudomyxoma peritonei. The median OS of patients in

our study was 16 months, with a 5-year OS of 17%.

Three quarters of the patients had already undergone

systemic chemotherapy for metastatic disease that failed.

Univariate predictors of survival were performance sta-

tus, resection status, bowel obstruction status, malignant

ascites status, liver metastases status, and pre-IPHC cy-

tology status. The best outcomes were for patients un-

dergoing an R0 resection, which yielded a 5-year OS of

55%, with a median OS that has not yet been reached.

On multivariate Cox regression analysis, only four

factors remained independent predictors of OS: ECOG

performance status of 0/1, R0/1 resection status, absence

of bowel obstruction, and absence of malignant ascites.Two of these factorsperformance status and bowel

obstructionappear to favor patients who will best tol-

erate the significant physiological stress induced by the

multimodality application of not only extensive CS but

also IPHC. The other two factorsresection status and

ascitesappear to identify patients with more limited

disease that best responds to CS and IPHC from an

oncologic perspective. Three of these four factors can be

determined preoperatively and help to optimize patient

selection. The fourth factor, resection status, is a variable

that is most accurately determined intraoperatively. The

use of a peritoneal carcinomatosis index has been re-ported to be predictive of resectability in patients with

PC.15 However, because this index can be determined

only at the time of laparotomy, it does not help prevent

unnecessary surgery.

Complications after CS and IPHC can be due to the

extensive surgery or the intraperitoneal chemotherapy or

the combination of both. Major peritonectomy proce-

dures were not performed when cytoreduction with the

Cavitron Ultrasonic Surgical Aspirator was possible. The

most significant detrimental effect is on the hematologic,

TABLE 2. Surgical procedures correlated with resection status

Procedure R0 R1 R2a R2b R2c Total

Tumor debulking 7 15 3 4 10 39Retroperitoneal LND 2 3 5

Small bowel resection 3 9 7 5 6 30

Splenectomy 3 4 4 1 1 13Colon resection 7 5 8 4 4 28

Rectum resection 2 6 3 1 12Omentectomy 6 13 10 4 10 43

Bladder 1 1Umbilicus resection 2 1 3 6Pancreas resection 2 2 1 3 8

Colostomy 3 3 1 3 10Gastrostomy 4 4

Tube thoracostomy 1 1 2Salpingo-oopherectomy 1 7 3 4 15Hysterectomy 4 1 5

Peritonectomy 1 1 2Liver resection 1 2 2 2 7Cholecystectomy 2 3 1 1 7

Hepatic cryoablation 2 1 3

Appendectomy 1 1 3 5Diaphragm excision 1 1 2Gastrectomy 1 1 2Nephrouterectomy 1 1

Abdominal wallexcision

1 1

Total 34 85 58 22 52

LND, lymph node dissection.

182 P. SHEN ET AL.



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pulmonary, and gastrointestinal organ systems.25 The

perioperative morbidity and mortality in our study cohort

were 30% and 12%, respectively. Although the morbid-

ity compares favorably with that in other published se-

ries, the mortality is substantial for any surgical proce-dure, especially one that is performed with palliative

intent. However, we counted all deaths related to CS and

IPHC, not limiting the number to deaths occurring only

within 30 days of the procedure.

Respiratory failure accounted for 44% of the peri-

operative deaths. MMC has been reported to cause

adult respiratory distress syndrome in patients exposed

to FIO2 concentrations greater than 50% periopera-

tively.26 This complication usually manifests after

multiple doses in patients given the drug systemically

with other chemotherapy combinations. The marrow

toxicity that can occur with MMC usually occurs 4 8

weeks after systemic administration,26 but the two

patients who developed fatal myelosuppression had

evidence of hematologic toxicity within 72 hours ofIPHC. Previous studies have shown that platelet

counts begin to decline after the procedure and typi-

cally return to normal values within 12 weeks.27,28

The differences in timing of nadir counts between

IPHC and intravenous bolus MMC may be due to

kinetic differences from the two administration

schedules.

We have previously reported that there is a direct

relationship between hematologic toxicity and MMC

concentrations in plasma.29 The AUCs of MMC in

TABLE 3. Univariate analysis of clinical and pathologic variables for overall survival

Factor n Expired

Percent Surviving (SE) Survival (mo)

P value3 y 5 y Median 95% CI

Overall 77 45 25.0 (2.5) 17.3 (3.3) 15.9 10.225.5

Age .98855 41 24 22.0 (3.8) 17.6 (4.4) 17.8 6.432.8

55 36 21 28.1 (3.3) 28.1 (4.8) 14.6 10.036.2

Race .716White 73 42 26.2 (2.5) 18.2 (3.3) 15.9 10.225.5

Nonwhite 4 3 .0 (NA) .0 (NA) 18.6 3.85NA

Gender .619

Male 45 25 25.9 (3.3) 17.3 (4.4) 12.7 5.432.8Female 32 20 24.1 (3.8) 16.0 (5.6) 15.9 11.747.7

Prior surgery .284

No 10 6 40.5 (4.3) 27.0 (5.9) 25.5 10.0NAYes 67 39 22.2 (3.0) 15.5 (3.9) 12.7 10.223.0

Prior chemotherapy .439

No 19 10 19.6 (6.2) 9.8 (9.5) 16.4 14.6NAYes 58 35 26.1 (2.7) 19.3 (3.4) 10.4 5.432.3

Prior radiation .314

No 71 40 28.1 (2.4) 19.5 (3.3) 14.6 10.232.3Yes 6 5 .0 (NA) .0 (NA) 16.4 3.5NA

Performance status .000401 64 33 32.0 (2.4) 22.1 (3.2) 17.8 12.536.2

24 13 12 .0 (NA) .0 (NA) 3.8 2.0NA

Resection status .0005R0 13 4 69.2 (2.2) 55.3 (3.1) NR 16.4NA

R1 24 11 19.1 (6.2) 19.1 (6.2) 17.8 10.2NAR2a 11 7 28.0 (5.9) 14.0 (9.2) 12.7 4.2NAR2b 9 6 .0 (NA) .0 (NA) 4.1 3.5NA

R2c 20 17 6.0 (9.7) .0 (NA) 5.0 2.418.2

Bowel obstruction .0001

No 55 30 32.4 (2.4) 22.4 (3.2) 20.9 12.736.2Yes 22 15 .0 (NA) .0 (NA) 4.1 2.0NA

Malignant ascites .0001

No 51 27 32.7 (2.5) 22.1 (3.4) 20.9 15.938.9Yes 26 18 6.9 (9.5) 6.9 (9.5) 4.2 2.410.4

Liver metastases .031No 65 35 26.6 (2.7) 19.4 (3.5) 15.9 10.232.3Yes 10 9 12.0 (9.3) .0 (NA) 12.7 1.5NA

Pre-IPHC cytology .004Negative 28 15 44.9 (2.4) 33.2 (3.2) 27.8 11.7NAPositive 31 23 9.4 (6.7) 4.7 (9.7) 9.9 4.219.6

SE, standard error; CI, confidence interval; NA, not applicable; NR, not reached; IPHC, intraperitoneal hyperthermic chemotherapy.




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plasma after a 2-hour IPHC perfusion are similar to thatobserved after an intravenous bolus of MMC. The dosing

rationale for MMC during IPHC was to achieve a peri-

toneal concentration of 510 g/mL in a fixed volume of

perfusate, versus the standard practice of dosing by body

surface area. Several recent reviews in the oncology

literature question whether dosing by body surface area

is any better than fixed dosing.3032 Given the tremen-

dous pharmacokinetic variations between patients, dos-

ing differences by body surface area may not be signif-

icant when the real sources of variability are the organs

(or enzymes, etc.) responsible for drug elimination (renal

function for renally eliminated drugs and hepatic func-

tion for hepatically cleared drugs).

Three of the patients died of either bowel leak or

perforation, which appears more plausible given the of-

ten extensive nature of the surgery and evidence from

animal models that intraperitoneal chemotherapy with

MMC has an adverse effect on anastomotic bowel heal-

ing.33 It is interesting that only one of these deaths was

due to an anastomotic leak, whereas the other two pa-

tients who died developed bowel perforations at a site

other than the anastomosis. The two patients with perfo-

rations presented with bowel obstruction, whereas the

patient with an anastomotic leak had obstructive jaun-

dice. Cox regression analysis has clearly identified bowel

obstruction as an independent predictor of decreased OS,

and we no longer perform IPHC in such patients. When

we conducted a Fishers exact test to correlate the pres-

ence of a bowel resection or anastomosis with compli-

cations, we found that the presence of a bowel anasto-

mosis was significantly correlated with sepsis. However,

on Cox regression analysis (Table 4), the hazard ratio for

bowel anastomosis was .9. It appears the creation of a

FIG. 1. Overall survival as related to performance status (EasternCooperative Oncology Group). FIG. 3. Overall survival as related to bowel obstruction.

TABLE 4. Cox regression analysis of overall survival

Factor Hazard ratio 95% CI P value

Age

55 vs. 55 .97 .501.85 .92

Race

Nonwhite vs. white .84 .252.89 .79Sex

Female vs. male 1.69 .863.32 .13Performance status

2 vs. 0/1 2.36 1.164.82 .018Resection status

R2 vs. R0/1 2.35 1.224.55 .011

Bowel obstruction present 3.47 1.627.44 .001Ascites present 3.23 1.636.38 .001

Liver metastases present 2.13 .905.07 .087Lymph node involvement 1.35 .712.58 .370Anastamosis present .90 .431.89 .790

CI, confidence interval.

FIG. 2. Overall survival as related to resection status.

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bowel anastomosis may increase the risk of perioperative

complications but not perioperative mortality. Although

we do not believe bowel anastomosis during IPHC is

contraindicated, we believe its association with periop-

erative complications should be considered in light of the

patients overall status, especially when the creation of a

stoma is another option.

When perioperative mortality among patients with the

independent predictors of OS was assessed, the death

rate was 4%. This conclusion should not be surprising,

because these are the patients who presented in the best

physiological condition with grossly resectable disease.Our experience with these 77 patients reflects an aggres-

sive approach for patients with advanced cancer who

have few meaningful therapeutic options. Some of these

patients presented in poor health due to their malignant

disease, and the perioperative mortality reflects the tre-

mendous stress this multimodality approach places on

the patient. However, our data clearly demonstrate that

for select patients with PC from NACC, the application

of CS and IPHC with MMC can extend survival. Other

reports from our institution have shown that quality of

life, a vital parameter for the evaluation of palliative

interventions, is also preserved for the majority of pa-tients, both in the short term and in the long term.34,35

One criticism of the use of CS and IPHC is the lack of

randomized, controlled trials confirming its efficacy in

comparison with supportive care, surgery alone, or sys-

temic chemotherapy. A recent prospective trial in Europe

randomized 104 patients with PC from colorectal adeno-

carcinoma to CS and IPHC with MMC, followed by

systemic therapy with 5-fluorouracil/leucovorin, in com-

parison with CS and systemic 5-fluorouracil/leucovorin

alone. With a mean follow-up of 24 months, the 2-year

OS was 43% in the IPHC arm (median OS, 21 months)

and 16% in the standard therapy arm (median OS, 10

months) (P .0145).23 Previous studies of untreated

patients with metastatic colorectal cancer have revealed

median OS of 1419 months with the use of new sys-

temic chemotherapeutic agents such as irinotecan and

oxaliplatin.3638 Our study revealed that patients under-

going R0/1 resection had a median OS of 28 months. Inaddition, our study provides information on which clin-

icopathologic factors predict improved outcome from

this procedure.

Future research directions may include the use of

molecular markers to determine which patients will de-

rive the most benefit. Just as the preoperative carcino-

embryonic antigen level was seen to significantly de-

crease after CS and IPHC, investigations with other

surrogate markers may yield more prognostic informa-

tion. We previously reported that the presence of a poly-

morphism that causes reduced activity of quinone oxi-

doreductase 1 (NQO1) is associated with a decrease insurvival for patients undergoing CS and IPHC for PC.39

NQO1 is important in the activation of MMC. Such a

mutation found in tumor tissue of patients with PC may

identify those who should be treated with agents other

than MMC or undergo alternative treatments. Multi-

center trials are needed to confirm these findings and

improve perioperative and long-term outcome.

REFERENCES

1. Pilati P, Rossi CR, Mocellin S, et al. Multimodal treatment of

peritoneal carcinomatosis and sarcomatosis. Eur J Surg Oncol

2001;27:12534.2. Sadeghi B, Arvieux C, Glehen O, et al. Peritoneal carcinomatosis

from non-gynecologic malignancies: results of the EVOCAPE 1multicentric prospective study. Cancer2000;88:35863.

3. Chu DZ, Lang NP, Thompson C, Osteen PK, Westbrook KC.Peritoneal carcinomatosis in nongynecologic malignancy: a pro-spective study of prognostic factors. Cancer 1989;63:3647.

4. Wong CS, Harwood AR, Cummings BJ, Keane TJ, Thomas GM,Rider WD. Total abdominal irradiation for cancer of the colon.

Radiother Oncol 1984;2:20914.5. Dedrick RL. Theoretical and experimental bases of intraperitoneal

chemotherapy. Semin Oncol 1985;12:16.

6. Schneebaum S, Arnold MW, Staubus A, Young DC, Dumond D,Martin EW Jr. Intraperitoneal hyperthermic perfusion with mito-

TABLE 5. Fishers exact test correlating bowelanastomosis with sepsisa

Sepsis

Anastomosis

TotalNo Yes

No 35 33 68Yes 0 9 9Total 35 42

a P .0032

FIG. 4. Overall survival as related to malignant ascites.




9/9

mycin C for colorectal cancer with peritoneal metastases. Ann Surg

Oncol1996;3:4450.7. Yonemura Y, Fujimura T, Fushida S, et al. Hyperthermo-chemo-

therapy combined with cytoreductive surgery for the treatment of

gastric cancer with peritoneal dissemination. World J Surg 1991;15:5305.

8. Bartlett DL, Buell JF, Libutti SK, et al. A phase I trial of contin-uous hyperthermic peritoneal perfusion with tumor necrosis factorand cisplatin in the treatment of peritoneal carcinomatosis. Cancer1998;83:1251 61.

9. Park BJ, Alexander HR, Libutti SK, et al. Treatment of primaryperitoneal mesothelioma by continuous hyperthermic peritoneal

perfusion (CHPP). Ann Surg Oncol 1999;6:58290.10. Stephens AD, Alderman R, Chang D, et al. Morbidity and mor-

tality analysis of 200 treatments with cytoreductive surgery andhyperthermic intraoperative intraperitoneal chemotherapy usingthe coliseum technique. Ann Surg Oncol 1999;6:7906.

11. Cavaliere F, Di Filippo F, Botti C, et al. Peritonectomy andhyperthermic antiblastic perfusion in the treatment of peritoneal

carcinomatosis. Eur J Surg Oncol 2000;26:48691.12. Beaujard AC, Glehen O, Caillot JL, et al. Intraperitoneal chemo-

hyperthermia with mitomycin C for digestive tract cancer patients

with peritoneal carcinomatosis. Cancer2000;88:25129.13. Watanabe M, Tanaka R, Hondo H, Kuroki M. Effects of antineo-

plastic agents and hyperthermia on cytotoxicity toward chronically

hypoxic glioma cells. Int J Hyperthermia 1992;8:1318.14. Teicher BA, Kowal CD, Kennedy KA, Sartorelli AC. Enhance-

ment by hyperthermia of the in vitro cytotoxicity of mitomycin Ctoward hypoxic tumor cells. Cancer Res 1981;41:10969.

15. Sugarbaker PH, Chang D. Results of treatment of 385 patients with

peritoneal surface spread of appendiceal malignancy. Ann SurgOncol1999;6:72731.

16. Piso P, Bektas H, Werner U, et al. Improved prognosis followingperitonectomy procedures and hyperthermic intraperitoneal che-motherapy for peritoneal carcinomatosis from appendiceal carci-

noma. Eur J Surg Oncol 2001;27:28690.17. Witkamp AJ, de Bree E, Kaag MM, van Slooten GW, van Co-

evorden F, Zoetmulder FA. Extensive surgical cytoreduction and

intraoperative hyperthermic intraperitoneal chemotherapy in pa-

tients with pseudomyxoma peritonei. Br J Surg 2001;88:45863.18. Wirtzfeld DA, Rodriguez-Bigas M, Weber T, Petrelli NJ. Dissem-

inated peritoneal adenomucinosis: a critical review. Ann SurgOncol 1999;6:797801.

19. Shen P, Levine EA, Hall J, et al. Factors predicting survival afterintraperitoneal hyperthermic chemotherapy with mitomycin C af-

ter cytoreductive surgery for patients with peritoneal carcinoma-tosis. Arch Surg 2003;138:2633.

20. Loggie BW, Fleming RA, McQuellon RP, Russell GB, Geisinger

KR. Cytoreductive surgery with intraperitoneal hyperthermic che-motherapy for disseminated peritoneal cancer of gastrointestinalorigin. Am Surg 2000;66:5618.

21. Sugarbaker PH, Jablonski KA. Prognostic features of 51 colorectaland 130 appendiceal cancer patients with peritoneal carcinomatosis

treated by cytoreductive surgery and intraperitoneal chemotherapy.

Ann Surg 1995;221:124 32.

22. Elias D, Blot F, El Otmany A, et al. Curative treatment ofperitoneal carcinomatosis arising from colorectal cancer bycomplete resection and intraperitoneal chemotherapy. Cancer2001;92:716.

23. Zoetmulder FAN, Verwaal V, Ruth S. Hyperthermic intraperito-

neal chemotherapy (HIPEC) with mitomycin C significantly im-

proves survival in patients with peritoneal carcinomatosis of colo-

rectal origin. ASCO Prog Proc 2002;21:147a.

24. Schag CC, Heinrich RL, Ganz PA. Karnofsky performance status

revisited: reliability, validity, and guidelines.J Clin Oncol 1984;

2:18793.25. Loggie BW, Fleming R. Complications of heated intraperitoneal

chemotherapy and strategies for prevention. In:Peritoneal Carci-

nomatosis: Principles Of Management. Boston: Kluwer Academic

Publishers, 1996:22233.

26. Berkery R, Cleri L, Skarin A. Chemotherapeutic agents. In: On-

cology Pocket Guide To Chemotherapy. Philadelphia: SmithKline

Beecham, 1997:17780.

27. Sayage AC, Gilly FN, Carry PY, et al. Intraoperative chemohy-

perthermia in the management of digestive cancers. A general

review of literature.Oncology 1993;50:3337.

28. Fujimoto S, Shrestha RD, Kokubun M, et al. Clinical trial with

surgery and intraperitoneal hyperthermic perfusion for peritoneal

recurrence of gastrointestinal cancer. Cancer1989;64:154 60.

29. Fleming R, Loggie BW, Russell GB, Rice MA. Systemic exposure

of MMC during intraperitoneal administration is correlated with

hematologic toxicity and survival in patients with peritoneal car-cinomatosis. Proc Am Assoc Cancer Res 1998;39:599.

30. Gurney H. Dose calculation of anticancer drugs: a review of the

current practice and introduction of an alternative. J Clin Oncol1996;14:2590 611.

31. Ratain MJ. Body-surface area as a basis for dosing of anticancer

agents: science, myth, or habit? J Clin Oncol 1998;16:22978.

32. Baker SD, Verweij J, Rowinsky EK, et al. Role of body-surface

area in dosing of investigational anticancer agents in adults: 1991

2001. J Natl Cancer Inst 2002;94:18838.

33. Fumagalli U, Trabucchi E, Soligo M, et al. Effects of intraperito-

neal chemotherapy on anastomotic healing in the rat. J Surg Res1991;50:827.

34. McQuellon RP, Loggie BW, Fleming RA, Russell GB, Lehman

AB, Rambo TD. Quality of life after intraperitoneal hyperthermic

chemotherapy (IPHC) for peritoneal carcinomatosis. Eur J Surg

Oncol 2001;27:6573.35. McQuellon RP, Loggie BW, Lehman AB, et al. Long-term survi-

vorship and quality of life after cytoreductive surgery plus intra-

peritoneal hyperthermic chemotherapy for peritoneal carcinomato-

sis. Ann Surg Oncol 2003;10:155 62.

36. Saltz LB, Cox JV, Blanke C, et al. Irinotecan plus fluorouracil and

leucovorin for metastatic colorectal cancer. Irinotecan Study

Group. N Engl J Med2000;343:90514.

37. de Gramont A, Figer A, Seymour M, et al. Leucovorin and flu-

orouracil with or without oxaliplatin as first-line treatment in

advanced colorectal cancer. J Clin Oncol 2000;18:2938 47.

38. Giacchetti S, Perpoint B, Zidani R, et al. Phase III multicenter

randomized trial of oxaliplatin added to chronomodulated fluorou-

racil-leucovorin as first-line treatment of metastatic colorectal can-

cer. J Clin Oncol 2000;18:13647.

39. Fleming RA, Drees J, Loggie BW, et al. Clinical significance of a

NAD(P)H: quinone oxidoreductase 1 polymorphism in patientswith disseminated peritoneal cancer receiving intraperitoneal hy-

perthermic chemotherapy with mitomycin C. Pharmacogenetics2002;12:317.

186 P. SHEN ET AL.


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