Analysis of Factors Associated With Outcome in Patients With
Malignant Peritoneal Mesothelioma Undergoing Surgical
Debulking and Intraperitoneal Chemotherapy
By Andrew L. Feldman, Steven K. Libutti, James F. Pingpank, David L. Bartlett, Tatiana H. Beresnev, Sharon M. Mavroukakis,
Seth M. Steinberg, David J. Liewehr, David E. Kleiner, and H. Richard Alexander
Purpose: Malignant mesothelioma (MM) arising in the
peritoneal cavity is a rare neoplasm characterized by peritoneal progression and for which there are limited therapeutic options. We evaluated the peritoneal progressionfree and overall survival (PFS and OS, respectively) for
patients with peritoneal MM after surgical resection and
regional chemotherapy.
Patients and Methods: Forty-nine patients (28 males, 21
females; median age, 47 years; range, 16 to 76 years) with
MM underwent laparotomy, tumor resection, continuous
hyperthermic peritoneal perfusion with cisplatin (median
dose 250 mg/m2), and a single postoperative intraperitoneal dwell of fluorouracil and paclitaxel (n ⴝ 35) on protocols approved by the Institutional Review Board. Standard
techniques for actuarial analyses of potential prognostic
variables (Kaplan-Meier method with two-tailed log-rank
test and Cox proportional hazards model) were performed.
Results: At a median potential follow-up of 28.3 months,
median actuarial PFS is 17 months and actuarial OS is 92
months. Factors associated with improved PFS and OS by
the Cox proportional hazards model were a history of
previous debulking surgery, absence of deep tissue invasion, minimal residual disease after surgical resection (OS
only), and age younger than 60 years (OS only).
Conclusion: Surgical resection and regional chemotherapy for MM results in durable PFS and OS. Favorable
outcome is associated with age, tumor biology (selection of
patients with a history of previous debulking), lack of
invasive tumor growth, and minimal residual disease after
tumor resection.
J Clin Oncol 21:4560-4567. © 2003 by American
Society of Clinical Oncology.
ESOTHELIOMA IS a rare primary tumor of the serosal
membranes with a generally poor prognosis and an
annual incidence in the United States of about 2.2 per million per
year.1 Patients with primary peritoneal mesothelioma most commonly present with abdominal pain, increasing abdominal girth,
weight loss, abdominal mass, and/or ascites.2-4 Disease is usually
confined to the abdominal cavity until late stages of tumor progression, and death is almost always related to tumor progression in the
peritoneum.5 Pathologically, the tumor arises from mesothelial cells
lining the peritoneal cavity and can show a spectrum of histologic
appearances, ranging from well-differentiated adenomatoid forms
to poorly differentiated sarcomatoid variants.6
There have been no uniformly accepted treatment approaches
for patients with malignant peritoneal mesothelioma. Systemic
chemotherapy has historically had limited efficacy,7 although
recent data using an outpatient regimen of combination raltitrexed and oxaliplatin have shown a 20% partial response rate
and reasonable palliative benefit in patients with pleural or
peritoneal mesothelioma.8 On the basis of the natural history of
the disease, however, regional therapies designed to control
disease progression in the peritoneal cavity seem justified and
have the theoretical advantage of intensifying treatment to the
site of active disease while limiting unnecessary systemic toxicity.9 A pharmacokinetic advantage of intraperitoneal chemotherapy or cytokine therapy for patients with malignant peritoneal mesothelioma has been reported by us and others.10-12 A
variety of regional modalities alone or in combination, including
cytoreductive surgery, whole abdominal radiation, and intraperitoneal chemotherapy administered as a dwell or a continuous
intraoperative hyperthermic perfusion, has been reported in
patients with peritoneal mesothelioma.4,13-19 Median survival
time ranging from 5 to 34 months have been observed and seem
to be influenced by the extent of disease at presentation, ability
to surgically resect gross disease, sex, or intensity of treatment.4,13-15 We previously reported an 80% 2-year survival rate
in 18 patients undergoing operative tumor resection and continuous hyperthermic peritoneal perfusion (CHPP) for primary
peritoneal mesothelioma who were treated while enrolled onto
initial phase I or II studies.2 The purpose of this report is to
provide a detailed analysis of a larger cohort of 48 patients
treated with surgical resection and CHPP using the maximumtolerated dose of cisplatin on the basis of earlier investigation
combined with a single postoperative intraperitoneal dwell of
fluorouracil (FU) and paclitaxel. We evaluated various clinicopathologic parameters that might aid in patient selection for this
type of therapy and predict outcome in this patient population.
M
From the Surgical Metabolism Section, Surgery Branch, the Laboratory of
Pathology, and the Biostatistics & Data Management Section, Center for
Cancer Research, National Cancer Institute, National Institutes of Health,
Bethesda, MD.
Submitted April 22, 2003; accepted September 12, 2003.
Authors’ disclosures of potential conflicts of interest are found at the end
of this article.
Address reprint requests to H. Richard Alexander, MD, Surgical Metabolism Section, 10 Center Dr, 10/2B07, Bethesda, MD 20892-1502; e-mail:
[email protected].
© 2003 by American Society of Clinical Oncology.
0732-183X/03/2124-4560/$20.00
4560
Journal of Clinical Oncology, Vol 21, No 24 (December 15), 2003: pp 4560-4567
DOI: 10.1200/JCO.2003.04.150
4561
CHPP FOR PERITONEAL MESOTHELIOMA
PATIENTS AND METHODS
Patients
This study reviews data from 49 patients (18 of whom were the subjects
of an earlier report2) with histologically proven peritoneal mesothelioma who
underwent tumor debulking and CHPP on clinical protocols approved by the
Institutional Review Board at the National Cancer Institute (Bethesda, MD)
from September 1993 through June 2002. The nature of the treatment for the
49 patients included in this report was based on the design of the protocol in
which they were enrolled and included laparotomy and tumor resection or
debulking in all patients, CHPP with cisplatin in 14 patients, and CHPP with
cisplatin followed by intraperitoneal chemotherapy in 35 patients. Informed
consent was obtained from all patients. Additional eligibility criteria were
Eastern Cooperative Oncology Group performance status ⱕ 2; no comorbid
diseases; a life expectancy ⱖ 8 weeks; adequate renal function (serum
creatinine ⬍ 2.0 or 24-hour creatinine clearance ⱖ 75 mL/min); normal
hepatic function (normal bilirubin level, prothrombin time, and partial
thromboplastin time, and liver enzymes ⬍ 1.5 ⫻ normal); adequate hematopoietic parameters (WBC ⬎ 3,000/mL and platelet count ⬎ 75,000/mL);
no chemotherapy, radiotherapy, or immunotherapy in the 30 days before
treatment; and no evidence of extra-abdominal metastases.
CHPP Technique
Patients underwent exploratory laparotomy, lysis of adhesions, tumor
debulking, and CHPP as previously described.20 The goal of surgery was to
render each patient grossly free of disease. After the tumor debulking portion
of the procedure, two large-bore catheters were inserted through the
abdominal wall; the inflow was placed over the right lobe of the liver and the
outflow lay in the pelvis. Temperature probes were placed immediately
beneath the peritoneal lining on each side of the abdomen and in the pelvis,
and the abdominal fascia was closed. The catheters were connected to a
circuit consisting of a roller pump, a heat exchanger, and a reservoir. The
perfusion flow rate was maintained at 1.5 L/min primarily to warm the
peritoneal tissues using a perfusate volume that varied from 4 to 6 L
depending on the size of the potential space of the peritoneal cavity (enough
to distend the abdomen moderately). The peritoneal cavity was warmed to a
median temperature of 41°C, and cisplatin (Bristol-Meyers Squibb, Princeton, NJ) mixed in 1 L of 0.9% sodium chloride solution (United States
Pharmacopeia) was added to the perfusate at a median dose of 250 mg/m2.
Perfusion was continued for 90 minutes, during which there was constant,
manual agitation of the abdomen to minimize streaming and ensure even
distribution of the perfusate. Sodium thiosulfate was given as a loading
dose of 7.5 g/m2 intravenously over 20 minutes before addition of
cisplatin, followed by a continuous infusion at 2.13 g/m2/h for 12 hours
as described.21,22 Urine output was maximized via hydration (central
venous pressure ⬎ 12 mmHg, 30 minutes before CHPP) and diuretics to
maintain urine output at greater than 200 mL/h during the perfusion and
12 hours postoperatively.
Thirty-five patients were treated on a protocol that included chemotherapy
given as a single intraperitoneal dose between 7 and 10 days after the
operation of FU 800 mg/m2 and paclitaxel 125 mg/m2, each diluted in 1 L
normal saline and administered sequentially over 2 to 4 hours. All patients
received 100 mg hydrocortisone, 50 mg diphenhydramine, and 50 mg
ranitidine intravenously 30 minutes prior to treatment.
On-Study and Follow-Up Evaluation
Before treatment, each patient underwent a full medical history, physical
examination, routine laboratory studies, and a computed tomographic (CT)
scan of the chest, abdomen, and pelvis. Intraoperatively, the extent of
residual disease (RD) after debulking was assessed as follows: RD 0, no
gross RD; RD 1, fewer than 100 total lesions all smaller than 5 mm; RD 2,
more than 100 total lesions all less than 5 mm or any one greater than 5 mm;
and RD 3, residual tumor larger than 1 cm. Toxicity was assessed using the
National Cancer Institute common toxicity criteria (version 2.0). Patients
were evaluated 6 weeks postoperatively and then every 3 months for 1 year,
every 4 months for 1 year, and then every 6 months with blood work,
physical examination, and CT scan of the chest, abdomen, and pelvis to
assess for ascites or soft tissue masses indicative of tumor recurrence. No
second-look operation was performed for assessment of response. Patients
were considered to have stable disease until they had radiographic evidence
of recurrence.
Histologic Categorization of Tumors
Tumors obtained during the CHPP procedure from 47 patients were
evaluated histologically by two pathologists (A.L.F. and D.E.K.) and scored
by consensus. Diagnosis of mesothelioma was confirmed in each patient,
including review of pertinent immunohistochemical studies. Tumors were
categorized histologically as adenomatoid, tubulopapillary, solid-epithelioid,
or sarcomatoid. Adenomatoid and tubulopapillary tumors were grouped
together as low grade, whereas solid-epithelioid and sarcomatoid tumors
were grouped as high grade. When more than one histologic type was present
the tumor was classified according to the highest grade type present.
Independent of histologic type, tumors were classified according to the
presence or absence of deep tissue invasion and desmoplasia. Deep tissue
invasion was defined as invasion of tumor more than 0.5 mm from a defined
mesothelial surface. As described previously,23 desmoplasia was defined as
the presence of dense fibrous stroma within the tumor; these fibrous areas
could be nondescript in appearance, or have more distinctive patterns, such
as branching collagenous bands, whorls or complex meshworks, or a dense,
basket-weave pattern.
Immunohistochemical stains for p53, p27, and Ki-67 were performed on
5-␮m sections from representative paraffin blocks of the tumor specimens.
Adequate material for the performance of immunostaining was available for
38 (81%) of the 47 patients. Staining was carried out with adequate positive
and negative controls as previously described24 with minor modifications,
using the p27 monoclonal antibody Kip-1 (dilution 1:250; Transduction
Laboratories, Lexington, KY), the p53 monoclonal antibody DO7 (dilution
1:50; DAKO, Carpinteria, CA), and the Ki-67 antibody MIB-1 (dilution
1:100; Immunotech, Westbrook, ME) on an automated immunostainer
(Ventana Medical Systems Inc, Tucson, AZ). Antigen retrieval was carried
out using 10 mmol citrate at pH 6.0 with 0.1% Tween 20. Stains were scored
by a single investigator (A.L.F.) for each antibody. The percentage of
positive tumor cells was determined using a counting grid and based on a
minimum of 500 cells.
Statistical Analysis
The primary objective of the analysis was to identify prognostic factors
associated with progression-free survival (PFS) and overall survival (OS).
For each end point, an actuarial analysis was initially performed, using the
Kaplan-Meier method with two-tailed log-rank P values to evaluate potential
prognostic variables.25,26 After initial evaluation, some categories then were
pooled and the P values adjusted for the implicit multiple comparisons using
a conservative Bonferroni approach. On the basis of the univariate analyses,
a subset of variables was chosen (generally, if P ⬍ .15) to include in a Cox
proportional hazards analysis27 to determine which, if any, variables were
jointly important in prognosis. All P values are two-tailed.
RESULTS
Patient demographic and clinical data are shown in Table 1.
The median age was 47 years, with a slight male preponderance.
Only 16% of patients had received previous systemic chemotherapy, whereas almost half had undergone previous debulking
surgery. Almost two-thirds of patients had histologically highgrade tumors (epithelioid or sarcomatoid). The operative and
perfusion data are shown in Table 2. The extent of surgery was
dependent on the nature of the operative findings; the overall
goal was to render an individual free of gross disease. At a
minimum, individuals underwent complete lysis of adhesions to
4562
FELDMAN ET AL
Table 1.
Clinical and Pathology Characteristics in Patients
With Malignant Peritoneal Mesothelioma
Characteristic
No. of Patients
Total number
Sex
Women
Men
Age, years
Range
Mean
Median
Prior chemotherapy
None
Paclitaxel and cisplatin
Prior surgery
Exp lap and LOA
Tumor debulking and/or organ resection
None
Histologic type*
High grade
Epithelioid
Sarcomatoid
Low grade
Tubulopapillary
Adenomatoid
49
%
21
28
16-76
49
47
41
8
84
16
18
7
24
37
14
49
30
26
4
17
16
1
64
36
Abbreviations: Exp lap, exploratory laparotomy; LOA, lysis of
adhesions.
*Sufficient tissue for detailed histologic analysis was available in
47 patients.
promote complete and even distribution of the perfusate to the
peritoneal surfaces during CHPP. Most individuals had additional procedures including omentectomy in half of the patients
(25 of 49 patients) and additional organ resection in approximately one third of the patients (14 of 49 patients). Peritonectomy was performed for grossly involved areas of peritoneum as
described.28,29 The operating surgeon quantitated RD status after
surgery; 10% of patients had complete resection of gross disease
(RD 0) and one third of the patients had fewer than 100 tumor
implants all less than 5 mm in diameter (RD 1). Almost half of
the patients had small volume diffuse disease in situ at the end of
the procedure ( ⬎ 100 small tumor implants or any one greater
than 5 mm in diameter, RD 2) and just more than 10% had at
least a solitary residual tumor implant greater than 1 cm in
diameter (RD 3).
The mean total cisplatin dose was 450 mg (250 mg/m2 of ideal
body weight). The cisplatin was added to the circuit once stable
circulation of the perfusate had been achieved and the average
intraperitoneal temperature had generally reached 41°C. The
total volume of perfusate was generally kept to about 4 L, but
in some circumstances up to 6 L was used. Thirty-five patients
(72%) were also treated with a single postoperative intraperitoneal dwell of FU and paclitaxel. The mean total doses were
based on doses of 800 and 125 mg/m2, respectively.
Pathologic material was available from 47 of 49 patients
(96%). Of the 47 tumors, one (2%) was adenomatoid, 16 (34%)
were tubulopapillary, 26 (55%) were solid-epithelioid, and four
(9%) were sarcomatoid. Morphology of these subtypes was
similar to that described previously.30-32 The adenomatoid tumor
Table 2.
Operative and Perfusion Data
Operative procedure
Exp lap and LOA
Cytoreduction and omentectomy
Cytoreduction and organ resection
Cisplatin dose, mg
Mean
Range
Operative time, hours
Mean
Range
Peritoneal temperature, °C
Mean
Range
Perfusion flow rate, mL/min
Mean
Range
Residual disease status
RD 0: complete debulking
RD 1: ⬍ 100 lesions, all ⬍ 5 mm
RD 2: ⬎ 100 lesions or any ⬎ 5 mm
RD 3: any lesion size ⬎ 1 cm
Postoperative intraperitoneal dwell
No dwell
Dwell regimen, mg
Fluorouracil
Mean dose
Range
Paclitaxel
Mean dose
Range
Follow-up time, months
Mean
Range
Potential follow-up time, months
Mean
Range
No. of Patients
%
10
25
14
17
51
29
450
330-816
6.5
4-11.3
41
38.3-43
1,500
1,000-2,000
7
16
20
6
35
14
14
33
41
12
72
28
1,425
1,038-2,100
208
98-300
36
2-93⫹
28.3
1-106
Abbreviations: Exp lap, exploratory laparotomy; LOA, lysis of adhesions.
consisted of glandular formations of flattened epithelial cells in
a lacy, vacuolated configuration (features shared with microcystic mesothelioma). Tubulopapillary tumors (Fig 1A and 1B)
combined tubular configurations and papillary formations with
fibrovascular cores, generally composed of a single layer of
cuboidal epithelial cells. Solid-epithelioid tumors (Fig 1D and
1E) consisted predominantly of solid sheets of uniform polygonal cells, often with eosinophilic cytoplasm. Sarcomatoid tumors
(Fig 1F) demonstrated highly cellular tumors composed of
spindle cells with a fibroblastic appearance and arrangement in
bands or whorls.
On the basis of the small numbers of adenomatoid and
sarcomatoid tumors, two groups were distinguished for the
purpose of statistical analyses: low grade (adenomatoid and
tubulopapillary, 42%) and high grade (solid-epithelioid and
sarcomatoid, 58%). Deep invasion was present in 22 of 38
evaluated tumors (58%) and desmoplasia was present in 16 of 38
tumors (42%). Although most low-grade tumors in this series
were tubulopapillary without evidence of deep tissue invasion or
desmoplasia (Fig 1A and 1B), some low-grade lesions did show
4563
CHPP FOR PERITONEAL MESOTHELIOMA
Table 4.
Chemotherapy-Related Hematologic or
Metabolic Toxicities
Parameters
1-2
3-4
% of Patients With
Grade 3-4
Toxicity
WBC
Platelets
AST and ALT
Alkaline phosphatase
Amylase
Bilirubin
Creatinine
Hemoglobin
Nausea
2
13
24
17
12
6
4
10
—
6
2
9
1
4
10
7
2
2
13
4
19
2
9
21
15
4
4
Grade
Fig 1. Histopathology of peritoneal mesothelioma. (A, B) Low-grade, tubulopapillary type, without deep tissue invasion or desmoplasia; (C) low-grade,
tubulopapillary type, with deep invasion and desmoplasia; (D, E) high-grade,
epithelioid type, with deep invasion and desmoplasia; (F) high-grade, sarcomatoid
type. (A, C, and D, 100ⴛ; B and E, 600ⴛ; F, 400ⴛ).
features of invasion and/or desmoplasia (Fig 1C). Most highgrade tumors were epithelioid, showing invasion and/or desmoplasia (Fig 1D and 1E). Sarcomatoid tumors were rare (Fig 1F).
Forty tumors were analyzed immunohistochemically. Mean
scores (percentage of positive tumor cells) were 9.8% (range, 1%
to 73%) for MIB-1, 90.2% (range, 41% to 99%) for p27, and
8.0% (range, 0% to 60%) for p53 (including five tumors that
were completely negative).
There were 18 complications in 12 patients (25%) related to
the operative procedure (Table 3). Two patients required reoperation for fascial dehiscence or gastric perforation. The mean
Table 3.
Operative Morbidity
Morbidity
No. of Patients
Wound infection
Fascial dehiscence
Colonic enterocutaneous fistula
Pleural effusion
Pneumothorax
Prolonged ileus
Catheter sepsis
Urinary tract infection
Renal failure
Gastric perforation
Postoperative myocardial infarction
Postoperative atrial fibrillation
3
2
1
2
1
2
2
1
1
1
1
1
time between surgery and resumption of a regular diet was 8.5
days (range, 3 to 38 days). Chemotherapy-related complications
are shown in Table 4. Thirteen percent of patients had grade 3 or
greater neutropenia in a time course consistent with an effect of
paclitaxel and FU. Hyperamylasemia was observed in four
patients (8%) but was not associated with symptoms of pancreatitis. Similarly, the elevations in hepatic alanine aminotransferase, aspartate aminotransferase, and bilirubin were transient and
not of clinical consequence.
At a median potential follow-up of 28.3 months (range, 1 to
106 months), the median actuarial PFS and OS were 17 and 92
months, respectively; the 1- through 5-year estimates of PFS and
OS are shown in Table 5. Twenty-six of 49 patients (53%) had
symptomatic ascites preoperatively. After tumor resection and
intraperitoneal therapy, ascites was completely resolved in 15 of
26 patients (58%) and those 15 patients had complete resolution
for a median duration, determined actuarially, of 25.3 months
(range, 4 to 53⫹ months; Fig 2). Notably, RD status in 11 of 15
patients who experienced resolution of ascites was ⱖ RD 2,
suggesting that complete tumor resection in this subset was not
the explanation, and that CHPP with or without postoperative
intraperitoneal therapy may provide palliative benefit even in
those with gross RD.
An analysis was performed to identify prognostic factors
associated with PFS and OS. The results of the initial univariate
analysis of factors associated with either PFS or OS are shown in
Table 6. For continuously measured variables the nature of the
pooling for the univariate analyses is shown. In view of the large
number of factors evaluated, as shown in Table 6, without formal
adjustments for the number of factors evaluated and the exploratory nature of the evaluation, only small P values (⬍ .01)
Table 5.
Progression-Free
Survival
Parameter
Median
1-year estimate,
2-year estimate,
3-year estimate,
4-year estimate,
5-year estimate,
Outcome After Treatment in Patients With Malignant
Peritoneal Mesothelioma
95% CI
Overall
Survival
17 months
%
%
%
%
%
55
41
27
23
14
40 to 70
26 to 57
12 to 42
7.9 to 38
4.3 to 27
86
77
59
59
59
95% CI
92 months
76 to 97
63 to 90
41 to 78
41 to 78
41 to 78
4564
FELDMAN ET AL
Fig 2. Axial abdominal computed tomography scans showing complete resolution of ascites in a patient with malignant mesothelioma after tumor resection and
continuous hyperthermic peritoneal perfusion (CHPP). (A) Pre-CHPP; (B) 54 months status post CHPP.
should be interpreted as indicating statistically significant factors
from the univariate analysis, whereas P values between .01 and
.05 would suggest strong trends. RD was coded as defined in
Table 2. On the basis of the results presented in Table 6, the
following variables were initially evaluated in the Cox regression analysis of PFS: race, age, tumor grade, p27% (percentage
of tumor cells with positive staining), deep invasion, previous
debulking, and RD status. A backward selection process indicated that no history of previous debulking surgery and the
presence of deep invasion were simultaneously important independent adverse prognostic variables with respect to PFS (Table
7). For OS, the following variables were initially evaluated in the
Table 6.
Prognostic Significance of Clinicopathologic Variables Based on
Univariate Actuarial Analysis
Variable
Sex, male v female
Ethnicity or race, white v nonwhite
Age, ⱕ 60 v ⬎ 60 years
High grade, yes v no
p53%, quartiles
p27%, ⬍ 95% v ⱖ 95%
MIB-1, quartiles 3.6, 5.7, 9.4
Deep invasion, yes v no
Desmoplasia, yes v no
Residual disease†
Residual disease‡
Total cisplatin, ⬍ 450 v ⬎ 450 mg
Dwell, yes v no
Previous debulking, yes v no
Duration of illness, cutoff points: ⱕ 2 v 2 v ⱖ 8 months
Duration of illness, ⱕ 2 v ⬎ 2 months
*Adjusted for multiple comparisons.
†RD 0 v RD 1 v RD 2 v RD 3 as defined in Table 2.
‡RD 3 v all other categories.
Progression-Free
Overall
Survival, P
Survival, P
.37
.031
.49
.039
.95
.11
.53
.047
.75
.011
.009*
.72
.46
.004
.77
.62
.13
.51
.006*
.041
.56
.37
.22
.15
.78
.004
.001*
.56
.30
.005
.15
.15*
Cox regression analysis: sex, age, grade, deep invasion, previous
debulking surgery, RD, and duration of illness. The final model
included age older than 60 years, no history of previous
debulking surgery, the presence of deep invasion, and the
presence of RD nodules larger than 1 cm as important independent adverse prognostic variables associated with a greater risk
of death. Table 7 shows the parameter estimates, P values, and
hazard ratios for these variables. Kaplan-Meier actuarial OS
curves based on the presence or absence of the independent
adverse prognostic parameters are shown in Fig 3.
DISCUSSION
Malignant mesothelioma is a rare but lethal neoplasm; only
approximately 10% to 15% of patients with mesothelioma have
a primary peritoneal condition.33 Usually it is considered fatal,
with median survival durations in some series of untreated
patients ranging from 6 to 10 months.34 However, it does have a
variable biology, with some patients surviving for many years
after treatment.15,35 Others4,18-20 and our group2,12,20 have reported results using intraoperative and early postoperative chemotherapy via CHPP after tumor resection for patients with this
condition.20 In general, treatment strategies using surgical debulking and intraperitoneal chemotherapy have been associated
with median OS between 5 and 34 months.4,13-15 The median
PFS and OS of 17 and 92 months in this study, respectively,
suggest efficacy associated with this type of combined therapy
for selected patients with malignant peritoneal mesothelioma,
although the relative contribution of the different components of
treatment is not known.
A number of parameters have been associated with favorable
outcome in malignant pleural or peritoneal mesothelioma, including performance status, female sex, early stage at presentation, and younger age.15,33,35 Histology has been associated with
4565
CHPP FOR PERITONEAL MESOTHELIOMA
Table 7.
Adverse Prognostic Significance of Clinicopathologic Variables Based on Cox Proportional Hazards Model Analysis
End Point
Variable (in terms of poor prognosis)
Parameter Estimate
SE
P
Hazard Ratio
95% CI
PFS
No previous debulking v debulking
Deep invasion v no deep invasion
Age ⬎ 60 v ⱕ 60 years
No previous debulking v debulking
Deep invasion v no deep invasion
Residual disease ⬎ 1 cm v none ⬍ 1 cm
1.55
1.28
1.29
1.67
1.44
1.75
0.43
0.44
0.61
0.80
0.71
0.82
.0003
.003
.034
.036
.041
.032
4.70
3.60
3.65
5.33
4.24
5.76
2.02 to 10.9
1.53 to 8.48
1.10 to 12.1
1.12 to 25.4
1.06 to 16.9
1.16 to 28.5
OS
Abbreviations: PFS, progression-free survival; OS, overall survival.
outcome of peritoneal mesothelioma in some series.6,33 Attempts at
developing a histologic grading system have been hampered by
small sample size and inclusion of patients with peritoneal mesothelioma into series of patients with pleural mesothelioma.1,7,33,36,37
Fig 3. Effects of (A) age, (B) history (Hx) of previous debulking, and (C) status
of residual disease (resid. dis.) after debulking on overall survival after treatment.
In this study, we evaluated various clinical, treatment, and
pathologic characteristics with respect to their association with
PFS and OS for patients undergoing a combined treatment
program consisting of tumor resection, CHPP, and intraperitoneal chemotherapy. We used histologic morphology to categorize tumors into a two-tiered grading system (high or low grade).
The majority (94%) of low-grade tumors demonstrated tubulopapillary histology, whereas the majority of high-grade tumors
(87%) demonstrated epithelioid histology. Stromal invasion is a
well-characterized marker of malignancy in mesothelial proliferation,30 and in the setting of CHPP may relate to the ability to
perform adequate surgical debulking. The presence of desmoplasia also has been considered an indicator of malignancy in
mesothelial proliferation,30 and desmoplastic pleural mesotheliomas have been reported to behave more aggressively than
nondesmoplastic tumors.23 The immunohistochemical detection
of proliferation markers (such as MIB-1) and tumor suppressor
gene products such as p5338 have had important clinical and
prognostic significance in a variety of human cancers. p53 is a
human nuclear protein with tumor suppressor function that may
be lost when mutations occur. Several studies have suggested an
association between p53 mutations or overexpression and pleural
malignant mesothelioma.39-41 p27 (also known as p27kip1) is a
kinase inhibitor protein with cell cycle regulatory and putative tumor suppressor functions.42 Recent studies have demonstrated a survival advantage for patients with pleural
malignant mesothelioma who demonstrated high p27 immunoreactivity, as well as for those with a low proliferative
index on the basis of MIB-1 staining.43,44 These data
prompted us to evaluate the potential prognostic significance
of these markers in peritoneal mesothelioma.
Among the histologic features evaluated, histologic grade and
extent of invasion were associated with statistically significant
survival differences in the univariate analysis. In the Cox model
analysis, only the presence of deep invasion was identified as an
independent predictor of both PFS and OS. Thus, the presence of
deep invasion has prognostic implications beyond limiting the
extent of resection, suggesting possible biologic differences in
those tumors with the ability to invade deeply. Invasion was a
stronger independent prognostic variable than morphologic subtype, and no additional prognostic information was gained by
evaluating the presence of desmoplasia or immunohistochemical
staining with the markers employed.
Minimal RD after surgical resection was an independent
predictor of improved OS and may have related to some degree
4566
FELDMAN ET AL
to pretreatment tumor burden, which was not quantitated in this
study. Patients were selected for treatment on the basis of CT
scans showing disease that was estimated to be debulkable to at
least minimal RD. Some bias toward better outcome may have
been introduced by not treating those patients who had advanced
tumor burden. To that end, Sebbag and Sugarbaker45 showed
that pretreatment advanced tumor burden, expressed as the
Peritoneal Cancer Index, was found to be predictive of shortened
survival in patients undergoing subsequent surgical debulking
and intraoperative hyperthermic chemotherapy. The median
survival of six patients in this study with RD 3 (tumors ⬎ 1 cm)
was only 12 months, suggesting that alternative treatment
strategies must be considered in this high-risk group.
The association between advancing age and shortened survival
has been observed previously for patients with peritoneal mesothelioma15 and the exact reasons for this are not clear. Patients who had
a history of previous debulking surgery had an improved PFS and
OS and this may have been related to a more indolent biologic
behavior of the tumor. There might have been a tendency to offer
patients a second procedure if they had a durable PFS after an initial
operation. Selection bias, treatment effect, or a combination of the
two may have influenced outcome in this group.
On a broader plane the most pressing issue related to surgical
debulking and intraoperative or early postoperative intraperitoneal chemotherapy for patients with peritoneal surface malignancies relates to the lack of standardized criteria for patient
selection, staging, operative, and treatment procedures among
centers offering this type of treatment. Efficacy and outcome
may be related to any one or more of these parameters and yet
the extent of peritonectomy; the optimal type, doses, and
duration of chemotherapy; the amount of tissue hyperthermia;
and even technique of peritoneal perfusion are not consistent
among centers. Some consensus on these issues and the
conduct of multicenter trials will serve to advance meaningfully the use of this form of combined therapy for patients
with this condition. Factors such as age, history of previous
debulking surgery, presence of deep tissue invasion, and RD
status will be potentially important stratification parameters
for patients with peritoneal mesothelioma.
AUTHORS’ DISCLOSURES OF POTENTIAL
CONFLICTS OF INTEREST
The authors indicated no potential conflicts of interest.
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