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 primary
lesions between December 1991 and April 2002.
Results: There were 77 patients, with a median age of 54 years. Peritoneal carcinomatosis was
synchronous and metachronous in 27% and 73% patients, respectively. Seventy-five percent of
patients (n 58) had received chemotherapy prior to IPHC. Complete resection of all gross disease
was accomplished in 37 patients (48%). The mean carcinoembryonic antigen level decreased from
a preoperative value of 31.2 to a postoperative value of 6.9 (P .0001). Overall survival (OS) at
1, 3, and 5 years was 56%, 25%, and 17%, respectively. With a median follow-up of 15 months, the
median OS was 16 months. Perioperative morbidity and mortality were 30% and 12%, respectively.
Hematologic toxicity occurred in 15 patients (19%). Cox regression analysis identified poor
performance status (P .018), bowel obstruction (P .001), malignant ascites (P .001), and
incomplete 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 gross
disease have long-term survival.
Key Words: ChemotherapyColorectal cancerHyperthermiaPeritoneal carcinomatosis
Surgery.
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: pshen@wfubmc.edu.
Published by Lippincott Williams & Wilkins 2004 The Society of Surgical
Oncology, Inc.
Annals of Surgical Oncology, 11(2):178186
DOI: 10.1245/ASO.2004.05.009
178
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
chemotherapy
612
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 hypoxic
conditions, which is not true for most agents given after
surgical resection.
A report from Sugarbaker and colleagues
15
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 in
only 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: R
0
, complete
removal of all visible tumor and negative cytology or
negative microscopic margins; R
1
, complete removal of
all visible tumor and positive cytology or microscopic
margins; R
2a
, minimal residual tumor, nodule(s) .5 cm;
R
2b
, gross residual tumor, nodule .5 cm but 2 cm;
and R
2c
, 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-
179 IPHC FOR COLORECTAL PERITONEAL CARCINOMATOSIS
Ann Surg Oncol, Vol. 11, No. 2, 2004
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 a
single 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 was
gently 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 were
obtained 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 the
log-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 were
enrolled 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.
Ann Surg Oncol, Vol. 11, No. 2, 2004
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 status
of 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
Chemotherapy
Sixty-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)
Sex
Male 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 obstruction
Yes 22 (29)
No 55 (71)
Malignant ascites
Yes 26 (34)
No 51 (66)
Liver metastases
Yes 10 (13)
No 65 (84)
Unknown 2 (3)
Histology
Mucinous 43 (56)
Signet ring cell 7 (9)
Not otherwise specified 27 (35)
Pre-IPHC cytology
Positive 31 (40)
Negative 28 (36)
Unknown 18 (24)
ECOG, Eastern Cooperative Oncology Group; IPHC, intraperitoneal
hyperthermic chemotherapy.
181 IPHC FOR COLORECTAL PERITONEAL CARCINOMATOSIS
Ann Surg Oncol, Vol. 11, No. 2, 2004
The median OS for appendiceal primaries had not been
reached. A study in France by Elias and associates
22
used
both early intraperitoneal and hyperthermic intraopera-
tive intraperitoneal chemotherapy with a combination of
agents: 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 include
pseudomyxoma 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 39
Retroperitoneal LND 2 3 5
Small bowel resection 3 9 7 5 6 30
Splenectomy 3 4 4 1 1 13
Colon resection 7 5 8 4 4 28
Rectum resection 2 6 3 1 12
Omentectomy 6 13 10 4 10 43
Bladder 1 1
Umbilicus resection 2 1 3 6
Pancreas resection 2 2 1 3 8
Colostomy 3 3 1 3 10
Gastrostomy 4 4
Tube thoracostomy 1 1 2
Salpingo-oopherectomy 1 7 3 4 15
Hysterectomy 4 1 5
Peritonectomy 1 1 2
Liver resection 1 2 2 2 7
Cholecystectomy 2 3 1 1 7
Hepatic cryoablation 2 1 3
Appendectomy 1 1 3 5
Diaphragm excision 1 1 2
Gastrectomy 1 1 2
Nephrouterectomy 1 1
Abdominal wall
excision
1 1
Total 34 85 58 22 52
LND, lymph node dissection.
182 P. SHEN ET AL.
Ann Surg Oncol, Vol. 11, No. 2, 2004
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 FIO
2
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 48
weeks after systemic administration,
26
but the two
patients who developed fatal myelosuppression had
evidence of hematologic toxicity within 72 hours of
IPHC. 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 value 3 y 5 y Median 95% CI
Overall 77 45 25.0 (2.5) 17.3 (3.3) 15.9 10.225.5
Age .988
55 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 .716
White 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 5.432.8
Female 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 10.0NA
Yes 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 14.6NA
Yes 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 10.232.3
Yes 6 5 .0 (NA) .0 (NA) 16.4 3.5NA
Performance status .0004
01 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 .0005
R0 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 10.2NA
R2a 11 7 28.0 (5.9) 14.0 (9.2) 12.7 4.2NA
R2b 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 12.736.2
Yes 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 15.938.9
Yes 26 18 6.9 (9.5) 6.9 (9.5) 4.2 2.410.4
Liver metastases .031
No 65 35 26.6 (2.7) 19.4 (3.5) 15.9 10.232.3
Yes 10 9 12.0 (9.3) .0 (NA) 12.7 1.5NA
Pre-IPHC cytology .004
Negative 28 15 44.9 (2.4) 33.2 (3.2) 27.8 11.7NA
Positive 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.
183 IPHC FOR COLORECTAL PERITONEAL CARCINOMATOSIS
Ann Surg Oncol, Vol. 11, No. 2, 2004
plasma after a 2-hour IPHC perfusion are similar to that
observed 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 (Eastern
Cooperative 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 .79
Sex
Female vs. male 1.69 .863.32 .13
Performance status
2 vs. 0/1 2.36 1.164.82 .018
Resection status
R2 vs. R0/1 2.35 1.224.55 .011
Bowel obstruction present 3.47 1.627.44 .001
Ascites present 3.23 1.636.38 .001
Liver metastases present 2.13 .905.07 .087
Lymph node involvement 1.35 .712.58 .370
Anastamosis present .90 .431.89 .790
CI, confidence interval.
FIG. 2. Overall survival as related to resection status.
184 P. SHEN ET AL.
Ann Surg Oncol, Vol. 11, No. 2, 2004
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. In
addition, 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 in
survival 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.
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