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									                            National Medical Policy
Subject:                Intraperitoneal Hyperthermic Chemotherapy
                        for Abdominopelvic Cancers

Policy Number:          NMP346

Effective Date*: June 2007

Updated:                June 2008, July 2009, July 2010, February
                        2011, November 2011,


           This National Medical Policy is subject to the terms in the
                              IMPORTANT NOTICE
                          at the end of this document

              The Centers for Medicare & Medicaid Services (CMS)
      For Medicare Advantage members please refer to the following for coverage
                                guidelines first:

Use                                         Reference/Website Link
       Source
       National Coverage Determination
       (NCD)
       National Coverage Manual Citation
       Local Coverage Determination (LCD)
       Article (Local)
       Other
X      None                                 Use Health Net Policy

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    in ALL regions.
 Medicare LCDs and Articles apply to members in specific regions. To access your
    specific region, select the link provided under “Reference/Website” and follow the
    search instructions. Enter the topic and your specific state to find the coverage
    determinations for your region
 If more than one source is checked, you need to access all sources as, on
    occasion, an LCD or article contains additional coverage information than
    contained in the NCD or National Coverage Manual.
 If there is no NCD, National Coverage Manual or region specific LCD/Article,
    follow the Health Net Hierarchy of Medical Resources for guidance.




Interperitoneal Hyperthermic Chemotherapy for Abdominopelvic Cancers Nov 11          1
Current Policy Statement (Update November 2011 – A Medline search failed to
reveal any studies that would cause Health Net, Inc. to change its current position)

Health Net, Inc. considers Intraperitoneal Hyperthermic Chemotherapy (IPHC) as an
adjunct to aggressive cytoreductive surgery medically necessary for either of the
following indications:

1.   Treatment of appendiceal carcinoma

2.   Prophylactic use for locally advanced gastric cancer without macroscopic
     peritoneal metastasis or distant metastasis

Health Net, Inc considers the therapeutic use of IPHC as an adjunct to aggressive
cytoreductive surgery (i.e. peritonectomy) in patients with peritoneal carcinomatosis
from all other abdominopelvic malignancies investigational as the benefit of this
treatment has not been validated in randomized controlled trials.

Definitions
 PC           Peritoneal carcinomatosis
 CRS          Cytoreductive surgery
 IPHC         Intraperitoneal Hyperthermic Chemotherapy
 CNNP         Chemonormothermic peritoneal perfusion
 DFS          Disease free survival
 OS           Overall survival
 PM           Peritoneal mesothelioma
 DMPM         Diffuse malignant peritoneal mesothelioma
 EPIC         Intraperitoneal chemotherapy
 EOC          Epithelial ovarian cancer

Codes Related To This Policy
ICD-9 Codes (may not be an all inclusive list)
151                  Malignant neoplasm of stomach
153.0 – 153.9        Malignant neoplasm of the colon
154.0                Malignant neoplasm of rectosigmoid junction
158.0                Malignant neoplasm of retroperitoneum and peritoneum
158.8                Malignant neoplasm of specified parts of peritoneum
158.9                Malignant neoplasm of peritoneum, unspecified
183.0                Malignant neoplasm of ovary
197.6                Secondary malignant neoplasm of retroperitoneum and
                     peritoneum
199.0                Malignant neoplasm without specification of site, disseminated
230.2                Carcinoma in situ of stomach
235.2                Neoplasm of uncertain behavior, stomach, intestines, and
                     rectum
235.4                Neoplasm of uncertain behavior, retroperitoneum and
                     peritoneum
789.5                Ascites

CPT Codes
77605                Hyperthermia, externally generated; deep (i.e., heating to
                     depths
96445                Chemotherapy administration into peritoneal cavity, requiring
                     and including peritoneocentesis (code deleted 12/2010)


Interperitoneal Hyperthermic Chemotherapy for Abdominopelvic Cancers Nov 11            2
96446                Chemotherapy administration into the peritoneal cavity via
                     indwelling port or catheter
HCPCS Codes
N/A

Scientific Rationale – Update November 2011
The National Cancer Comprehensive Network (NCCN, 2012) on Colon and Rectal
Cancer notes that cytoreductive debulking and / or intraperitoneal chemotherapy are
not recommended outside the setting of a clinical trial. The panel currently considers
the treatment of disseminated carcinomatosis with cytoreductive surgery (i.e.
peritoneal stripping surgery) and perioperative hyperthermic intraperitoneal
chemotherapy to be investigational and does not endorse such surgery outside a
clinical trial. However, the panel recognizes the need for randomized clinical trials
that will address the risks and benefits associated with each of these modalities.

Scientific Rationale – Update February 2011
Van der Speeten et al (2010) investigated 145 individuals with colorectal or
appendiceal carcinomatosis resected using cytoreductive surgery prior to treatment
with hyperthermic intraperitoneal chemotherapy with mitomycin C as part of a
multidrug regimen. The effect of clinical and surgical factors on drug distribution
after single intraperitoneal bolus administration with mitomycin C was determined.
The pharmacokinetics of 145 patients treated with intraperitoneal mitomycin C
showed a 27 times greater exposure to peritoneal surfaces when compared to
plasma. At 90 min, 29% of the drug remained in the chemotherapy solution, 62%
was retained in the body, and 9% was excreted in the urine. The extent of
peritonectomy increased the clearance of mitomycin C from the peritoneal space (p
= 0.051). A major resection of visceral peritoneal surface and a contracted
peritoneal space reduced drug clearance. A contracted peritoneal space significantly
reduced (p = 0.0001) drug concentrations in the plasma. The investigators
concluded surgical and clinical factors may require modifications of drug dose or
timing of chemotherapy administration. A large visceral resection and a contracted
peritoneal space caused a reduced mitomycin C clearance. Total diffusion surface is
an important determinant of mitomycin C pharmacokinetics.

Lim et al (2010) assess quality of life (QoL) in patients at least 12 months after
HIPEC using Oxaliplatin. Patients completed a questionnaire before and after
surgery at 1, 3, 6 and 12 months. QoL was assessed with the EORTC QLQ-C30
questionnaire. 32 of 35 patients who had undergone HIPEC were interviewed. PC
originated in primary lesions of the colon/rectum (N = 17), ovary (N = 3), stomach
(N = 3), appendix (N = 2), mesothelium (N = 2), pseudomyxoma peritonei (N = 3)
and primary carcinoma of peritoneum (N = 2). The percentage of patients
completing the questionnaire at each time point was: baseline = 87% (N = 28); 1
and 3 months = 46% (N = 15); 6 months = 62% (N = 20); and 12 months = 59%
(N = 19). Morbidity and mortality were respectively 35 and 5%. Median hospital stay
was 19 days. QoL score had decreased considerably in 60% of patients in the early
postoperative assessment period after HIPEC (1 month), as compared with baseline
score. Forty five per cent had reported significant pain and limitations on physical
functioning. QoL score had returned to baseline at 3 months in 53,3% of patients:
20% reported lack of energy and fatigue. Fifty-five and 73% of patients had
recovered their overall QoL at 6 and 12 months, respectively. Also, psychosocial
problems, diarrhea and constipation, and peripheral neuropathy of oxaliplatin were
reported in 20% of survivors over the course of the first year after HIPEC.




Interperitoneal Hyperthermic Chemotherapy for Abdominopelvic Cancers Nov 11            3
The investigators concluded short-term QoL with physical and functional well-being
are impaired in the first few months after surgery plus HIPEC using oxaliplatin. Long-
term QoL returns to baseline at 3 months; however 20% of patients still report
psychosocial problems, gastrointestinal symptoms and oxaliplatin-induced
neuropathy. It is useful and important for patients to see this HIPEC QoL data at the
time of consultation before treatment.

Glehen et al (2010) performed a retrospective multicenter cohort study in French-
speaking institutions to evaluate toxicity and principal prognostic factors after
cytoreductive surgery and HPIC (hyperthermic intraperitoneal chemotherapy) and/or
early postoperative intraperitoneal chemotherapy [EPIC]) for PC from
nongynecologic malignancies. The study included 1290 patients from 25 institutions
who underwent 1344 procedures. HIPEC was performed in 1154 procedures. The
principal origins of PC were colorectal adenocarcinoma (N = 523), pseudomyxoma
peritonei (N = 301), gastric adenocarcinoma (N = 159), peritoneal mesothelioma (N
= 88), and appendiceal adenocarcinoma (N = 50). The overall morbidity and
mortality rates were 33.6% and 4.1%, respectively. In multivariate analysis, patient
age, the extent of PC, and institutional experience had a significant influence on
toxicity. The overall median survival was 34 months; and the median survival was 30
months for patients with colorectal PC, not reached for patients with pseudomyxoma
peritonei, 9 months for patients with gastric PC, 41 months for patients with
peritoneal mesothelioma, and 77 months for patients with PC from appendiceal
adenocarcinoma. Independent prognostic indicators in multivariate analysis were
institution, origin of PC, completeness of cytoreductive surgery, extent of
carcinomatosis, and lymph node involvement. The investigators concluded a
therapeutic approach that combined cytoreductive surgery with HPIC was able to
achieve long-term survival in a selected group of patients who had PC of nonovarian
origin and had acceptable morbidity and mortality. They noted the current results
indicated that this treatment should be centralized to institutions with expertise in
the management of PC.

Frenel et al (2011) investigated the feasibility and safety of oxaliplatin-based
hyperthermic intraperitoneal chemotherapy (HIPEC) associated with cytoreductive
surgery (CRS) in 31 patients with peritoneal carcinomatosis resulting from primary
advanced or relapsing epithelial ovarian cancer (EOC). Patients received
neoadjuvant platin-based chemotherapy followed by oxaliplatin-based HIPEC
associated with CRS as consolidation of primary therapy (n=19) or for relapsing
disease (n=12). Grade 3/4 complications were recorded according to National Cancer
Institute definitions. Median peritoneal carcinomatosis index (PCI) was 2.7 after
neoadjuvant chemotherapy. Mean duration of surgery was 352min (range 105-614)
and median hospital stay was 11 days (range 6-87). Grade 3 toxicity was observed
in nine patients: five required repeat surgery, two an invasive procedure, four
rehospitalization, and three a return to the ICU. No grade 4 toxicity occurred,
excepted one hypokalemia. Median progression-free survival (PFS) for primary
advanced EOC was 13.2 months and 1-year PFS was 59.3%. Median PFS for
relapsing patients was 14.3 months and 1-year PFS was 54.4%. The investigators
concluded CRS with oxaliplatin-based HIPEC is feasible and relatively safe in
recurrent and primary EOC. HIPEC after neoadjuvant chemotherapy reduces the PCI
and decreases the number of surgical procedures and morbidity. They noted further
evaluations of this procedure are required to assess the survival benefits.

Dovern et al (2010) performed a m multi-database search was conducted focusing
on mortality, morbidity and overall and disease-free (DF) survival rates of HIPEC



Interperitoneal Hyperthermic Chemotherapy for Abdominopelvic Cancers Nov 11          4
added to CRS in ovarian cancer. 16 studies were identified reporting the results of
CRS followed by HIPEC of 546 patients with advanced ovarian cancer. Postoperative
mortality was reported for 14 out of 481 patients in total (2.9%). The major
morbidity rate varied between 3.4 and 50.0%. In all but one study (533 patients),
185 events were reported (34.5%) and 21 re-interventions after 476 operations
(4.4%). Survival data ranged from 10.0 to 57.1 months for the DF survival and from
19.0 to 76.1 months for the overall survival. Optimal cytoreduction and recurrent
disease were associated with a better outcome in selected cases. The reviews
concluded adding HIPEC to the current treatment modalities for ovarian cancer
seems to be feasible. Improved survival rates have been reported at the cost of
acceptable mortality rates. Nevertheless, there was a selection bias, the morbidity
should not be underestimated and it is unclear yet which patient will benefit most
from this treatment. Randomized controlled trials will provide an answer to this
question.

Roviello et al (2010) analyzed the outcomes of cytoreductive surgery and HIPEC in
patients with peritoneal carcinomatosis from ovarian cancer. Fifty-three patients
with peritoneal carcinomatosis from primary (45 cases) and recurrent (8 cases)
ovarian cancer were previously treated by systemic chemotherapy with platinum and
taxanes and then submitted to surgical cytoreduction and HIPEC (cisplatin and
mitomycin-C) with a closed abdomen technique. The median follow-up period was 27
months (range: 3-107). At the end of operation a complete cytoreduction (CCR-0)
was obtained in 37 patients (70%). Major morbidity occurred in 12 patients (23%);
reoperation was necessary in 2 patients (4%), and no postoperative mortality was
observed. Overall 5-year survival probability was 55%; it was 71% in CCR-0, 44% in
CCR-1, and none in patients with CCR-2 or CCR-3 residual tumor (log-rank test: P =
0.017). The cumulative risk of recurrence in 37 CCR-0 cases was 54% at 5 years
from operation. The investigators concluded the results of the study indicate the
feasibility and the potential benefit of a protocol including systemic chemotherapy,
surgical cytoreduction and HIPEC in patients with peritoneal carcinomatosis from
ovarian cancer. A phase III trial to compare this approach with conventional
treatment is needed.

Lim et al (2009) evaluated the toxicities and treatment response of intraoperative
hyperthermic intraperitoneal chemotherapy (HIPEC) in patients with advanced
epithelial ovarian cancer. Intraoperative HIPEC (cisplatin 75 mg/m(2), 41.5 degrees
C, 90 min) was performed in 30 patients with residual tumor of <1 cm after
cytoreductive surgery between January 2007 and February 2008. All the patients
received adjuvant chemotherapy with combination platinum and taxane. Adverse
events and responses to primary treatment were evaluated and scored as follows:
grade I, observation; grade II, medical treatment; grade III, intervention; and grade
IV, reoperation or admission to the intensive care unit. No deaths or grade IV
morbidities were observed. One hundred seven adverse events were identified in 30
patients (grade I, 40; grade II, 46; grade III, 21). The most common adverse events
affected the hematologic system (n = 26), followed by the gastrointestinal system (n
= 23). Most adverse events were anemias requiring transfusion and nausea/vomiting
requiring medication. Twenty-eight patients (93%) experienced complete remission,
and two patients (7%) had progressive disease. The authors concluded HIPEC after
extensive cytoreductive surgery for ovarian cancer is a procedure with acceptable
morbidity that patients can tolerate. More follow-up is needed to determine the effect
of HIPEC on survival.




Interperitoneal Hyperthermic Chemotherapy for Abdominopelvic Cancers Nov 11         5
According to the 2011 NCCN recommendations on colorectal cancer, aggressive
cytoreduction debulking and/or intraperitoneal chemotherapy are not recommended
outside the setting of a clinical trial. The panel currently considers the treatment of
disseminated carcinomatosis with cytoreductive surgery (i.e peritoneal stripping
surgery) and perioperative hyperthermic intraperitoneal chemotherapy to be
investigational and does not endorse such therapy outside of a clinical trial. The
2011 NCCN guidelines on ovarian cancer recommends intraperitoneal (IP) therapy
for stage III patients with optimally debulked (< 1 cm residual) disease based on
RCT's (category 1), however, they make no recommendations regarding
hyperthermic intraperitoneal chemotherapy.

Prospective randomized control trials are needed to compare long-term and
progression-free survival under the best available systemic therapy with or without
cytoreductive surgery and hyperthermic intraperitoneal chemother. Hyperthermic
intraperitoneal chemotherapy continues to investigated in clinical trials.

Scientific Rationale – Update July 2010
There remains many unanswered questions regarding intraperitoneal hyperthermic
chemotherapy (IPHC) as an adjunct to aggressive cytoreductive surgery in the
treatment of peritoneal carcinomatosis from abdominopelvic malignancies.
Prospective randomized trials are necessary to validate the efficacy of IPHC in both
the treatment and prevention of peritoneal surface malignancy.

Franko et al (2010) evaluated consecutive patients with colorectal carcinomatosis
treated by CRS combined with IPHC. The control group patients with carcinomatosis
received contemporary chemotherapy alone. Overall survival was the primary
endpoint. All patients underwent systemic chemotherapy. The CRS/IPHC group (n =
67) was similar to the control group (n = 38) in sex, tumor grade, site of tumor
origin, T status, and N status. The control group was, however, older (59 vs 51
years; P<.001). Median survival measured from the diagnosis of peritoneal disease
was longer with CRS combined with IPHC (34.7 months vs 16.8 months; P<.001).
Presence of liver metastasis was a significant negative predictor of survival (hazard
ratio, 2.13). The authors concluded that contemporary chemotherapy is associated
with prolonged survival among patients with carcinomatosis as compared with
historical controls, and the addition of CRS combined with IPHC to modern
chemotherapy regimens may significantly prolong survival. CRS combined with IPHC
and systemic chemotherapy are not competitive therapies, and they both have a role
in a multidisciplinary approach to patients with carcinomatosis.

Bretcha-Boix et al (2010) assessed the outcomes after treating patients with
peritoneal carcinomatosis of colonic origin by means of CRS and IPHC followed by
early postoperative intraperitoneal chemotherapy (EPIC). Tumor resection was
performed in accordance with the guidelines for oncologic surgery. Selective
peritonectomies and remnant nodule electroevaporation were performed with the
aim of achieving a complete cytoreduction. Peritoneal perfusion was carried out
according to the Coliseum technique at 0.5-1 L/min, and chemotherapy was
administered at 42oC for 40-90 min. Mitomycin C 10-12.5 mg/m(2) or oxaliplatin
360 mg/m(2) was used. Postoperative intraperitoneally administered 5-fluorouracil
(5-FU) (650 mg/m(2) per day) was given for 5 consecutive days. Twenty patients
were treated. The mean peritoneal cancer index was 11 (range 2-39). Fifteen
patients had undergone complete CRS. The morbidity was 40%. There was one case
of death due to bone marrow aplasia. Ten patients had recurrence; five of them
underwent salvage surgery. Two patients were treated with a second IPHC. Actuarial



Interperitoneal Hyperthermic Chemotherapy for Abdominopelvic Cancers Nov 11               6
overall survival and progression-free survival were 36% and 30% at 5 years,
respectively, with a median follow-up of 18 (range 8-28) months. The authors
concluded CRS combined with IPHC is a feasible technique that might increase
patient survival, representing a potential cure for selected patients who have no
other alternatives.

Carrabin et al (2010) assessed the feasibility and efficacy of CRS followed by IPHC
without adjuvant chemotherapy for relapsed or persistent advanced ovarian cancer.
This observational study included stage IIIC ovarian cancer patients due to undergo
CRS (interval debulking or recurrent surgery) followed by IPHC with oxaliplatin (460
mg/m2) for 30 min. Twenty-two patients (12 interval debulking procedures and 10
recurrence procedures) were enrolled. IPHC was not performed in four patients
because of operative findings. No patient received adjuvant chemotherapy after
IPHC. Patients were followed up routinely until recurrence or death. Median
peritoneal cancer index at surgery was 6 (range: 1-18). Before IPHC, all patients had
completeness of cytoreduction scores of 0 or 1. Median length of hospital stay was
21 days (range 13-65). Ten patients (55.6%) had CTCAE grade 3-4 toxicity,
including three patients (16.7%) requiring reoperation. No postoperative mortality
was observed. With a median follow-up of 38 months (CI 95% 23.8-39.2), median
overall survival was not reached. The 3-year overall survival rate was 83% (CI 95%
54-95). Median disease-free survival was, respectively, 16.9 months (CI 95% 10.2-
23.2) and 10 months (CI 95% 4.5-11.3) for patients undergoing interval debulking
or recurrence surgery. The authors concluded IPHC without adjuvant chemotherapy
is both feasible and safe, but with a high rate of grade 3-5 toxicity. Survival results
are encouraging but should be confirmed in a randomized trial.

Helm et al (2010) reported on the (HYPER-O), an internet-based registry of
collected data from collaborating institutions in the U.S. Eligibility included women
with invasive epithelial ovarian cancer (EOC) treated with IPHC. Borderline and
nonepithelial cancers were excluded. As of July 1, 2008, 141 women were eligible
for analysis treated at the following time points: frontline (n = 26), interval
debulking (n = 19), consolidation (n = 12), and recurrence (n = 83). The mean
perfusion temperatures were 38.5 to 43.6 degrees C (median, 41.9 degrees C) for
inflow and 36.9 to 42.9 degrees C (median, 41 degrees C) for outflow for 30 to 120
minutes. Treatment was with a platinum agent (n = 72), mitomycin (n = 53), or a
combination (n = 14). Median follow-up was 18 months (range, 0.3-140.5 months)
and median overall survival 30.3 months (95% confidence interval, 23.0-37.6) with
2-, 5-, and 10-year overall survival probabilities of 49.1%, 25.4%, and 14.3%,
respectively. Of the 141 patients, 110 (78%) experienced recurrence of ovarian
cancer and 87 died, 3 (0.5%) dying within 30 days of surgery. In the multivariable
analysis, the factors significant for increased survival were sensitivity to platinum
response (P = 0.048), completeness of cytoreduction scores of 1 or 0 (P = 0.025),
carboplatin alone or a combination of 2 or more chemotherapy agents used (P =
0.011), and duration of hospital stays of 10 days or less (P = 0.021). The authors
concluded that IPHC is a viable additional treatment option for patients with invasive
EOC and may extend life in selected groups, noting that further study in randomized
controlled trials is warranted.

Chua et al (2009) performed a systematic review of studies that that report the
efficacy of CRS and IPHC for ovarian cancer peritoneal carcinomatosis. Nineteen
studies each of more than ten patients reporting treatment results of IPHC of
patients with both advanced and recurrent ovarian cancer were included and data
were extracted. All studies were observational case series. The overall rate of severe



Interperitoneal Hyperthermic Chemotherapy for Abdominopelvic Cancers Nov 11          7
perioperative morbidity ranged from 0 to 40% and mortality rate varied from 0 to
10%. The overall median survival following treatment with IPHC ranged from 22 to
64 months with a median disease-free survival ranging from 10 to 57 months. In
patients with optimal cytoreduction, a 5-year survival rate ranging from 12 to 66%
could be achieved. The reviewers concluded that despite the heterogeneity of the
studies reviewed, current evidence suggest that complete CRS and IPHC may be a
feasible option with potential benefits that are comparable with the current standard
of care. They noted further a randomized trial is required to establish the role of
IPHC in ovarian cancer.

Vaira et al (2009) reported the results of a twelve year single-institution experience
on 60 consecutive patients affected by PMP, treated by cytoreductive surgery and
the original semi-closed IPHC technique, with special reference to overall survival
(OS) and progression-free survival (PFS). The postoperative morbidity rate was
45% (27 patients); surgical morbidity was observed in 19 patients and medical
complications in 9 cases. No postoperative deaths were observed. The survival data,
53 patients were analyzed (the last 7 were considered only for the complications
rate, postoperative mortality and cancer features, not for OS or PFS because they
were too recent for evaluation). At the final follow-up of the 53 patients, five and ten
years OS were respectively 94% and 84.6%, DFS was 80% and 70% at five and ten
years respectively. The follow-up data indicated that the survival probability may be
good in patients with histological type appendicular adenoma optimally cytoreduced
(CCR-0). If preoperative chemotherapy was performed, it represented a negative
prognostic factor with statistically significant impact both on OS and DFS. The
authors concluded that CRS plus IPHC, even when combined with an aggressive
surgical procedure, is associated with an acceptable risk of postoperative
complications and mortality. The combined treatment results in DFS and OS rates
that are not described in the literature for surgery associated with systemic
chemotherapy and, in the authors’ opinion, may be considered the gold standard
treatment for this rare tumor.

According to NCCN recommendations on colorectal cancer, aggressive cytoreduction
debulking and/or intraperitoneal chemotherapy are not recommended outside the
setting of a clinical trial. The panel currently considers the treatment of
disseminated carcinomatosis with cytoreductive surgery (ie peritoneal stripping
surgery) and perioperative hyperthermic intraperitoneal chemotherapy to be
investigational and does not endorse such therapy outside of a clinical trial. The
NCCN does not address IPHC in any other of the other clinical practice guidelines in
Oncology.

Scientific Rationale – Update July 2009
Approximately half of gastric cancers with serosal erosion progress to peritoneal
carcinomatosis (PC). PC is generally treated with cytoreductive surgery (CRS), in an
effort to remove all or nearly all macroscopic tumor from peritoneal tissues,
however, micrometastases often remains in the peritoneal space. Both randomized
and non-randomized trials have investigated IPHC immediately following surgery in
patients with gastric cancer. The studies have investigated intraperitoneal
hyperthermic chemotherapy (IPHC) in addition to surgery, as a prophylactic
treatment in patients with locally advanced gastric cancer, (i.e., invaded the serosal
wall, but no macroscopic tumor even in nearby peritoneum, and thus no PC) as well
as a therapeutic treatment in patients with evidence of PC. The studies provide
conflicting evidence regarding the effectiveness of therapeutic IPHC as an adjunct to
aggressive CRS in patients with evidence of peritoneal metastasis of gastric origin,



Interperitoneal Hyperthermic Chemotherapy for Abdominopelvic Cancers Nov 11            8
however, several small to moderately sized trials, including 4 that were randomized,
provide evidence that the prophylactic use of IPHC in patients with locally advanced
gastric cancer does improve survival and reduction in recurrence.

In a randomized controlled trial reported by Yonemura (2001), one-hundred and
thirty-nine patients with T2-4 gastric cancer underwent curative gastrectomy with
extended lymphadenectomy. In an effort to evaluate if IPHC could eliminate
microscopic residual disease and improve survival, patients were randomly allocated
surgery + IPHC, surgery and chemonormothermic peritoneal perfusion (CNNP) and
surgery alone. In the IPHC and CNPP groups, the peritoneal cavity was perfused
with 6-8 liters of heated saline at, respectively, 42-43 degrees C and 37 degrees C
with 30 mg of mitomycin C and 300 mg of cisplatin by an extracorporeal circulation
machine. Major operative complication occurred in 19% (9/48) of IPHC group, 14%
(6/44) in the CNPP and 19% (9/47) in the surgery alone group. Complication which
uniquely developed after IPHC was bowel perforation. Mortality rates of each group
were 4% (2/48), 0% (0/44) and 4% (2/47) in the IPHC, CNPP and surgery alone
group, respectively. Overall 5-year survival rates of IPHC, CNPP and surgery alone
groups were 61%, 43% and 42%, respectively. In a subset analysis, patients with
gastric cancer having serosal invasion or lymph node metastasis have shown a
statistically significant improvement in survival when treated with IPHC. However,
CNNP had no survival benefit. By analyzing with Cox proportional hazard model,
IPHC emerged as an independent prognostic factor for good survival. Surgery alone
had three-fold higher risk of death than IPHC.

In another RCT, Fujimura et al (1994), sought to evaluate the effects of IPHC for the
prevention of peritoneal recurrence of gastric cancer. Following surgery for gastric
cancer, twenty-two patients were treated with perfusion using about 10 liters of
saline heated to 41 degrees to 42 degrees C (CNPP group); 18 patients were treated
with saline heated to 37 degrees to 38 degrees C (IPHC group); and 18 patients
underwent only gastric surgery without perfusion (control group). There were two
deaths (9%) due to peritoneal recurrence in the IPHC group, four (22%) in the CNPP
group, and four (22%) in the control group. The 1-, 2-, and 3-year survival rates
were 95%, 89%, and 68%, in the IPHC group; 81%, 75%, and 51%, in the CNPP
group; and 43%, 23%, and 23%, in the control group, respectively.

In a RCT, Hamazoe et al (1994) evaluated the efficacy of IPHC as a prophylactic
treatment for prevention of peritoneal recurrence of gastric cancer with serosal
invasion. 82 patients with gross serosal invasion but no gross peritoneal metastasis
were divided by random sampling into two groups before undergoing potentially
curative surgery for gastric cancer: 42 patients were scheduled to receive IPHC,
whereas 40 were not scheduled to receive this treatment. IPHC was administered
immediately after closing the abdomen after gastric resections while the patients
were still on the operating table under general anesthesia. The 5-year survival rate
(64.2%) of patients in the IPHC group was higher than that (52.5%) of patients in
the control group although the difference was not significant. Of several patterns of
cancer recurrence, peritoneal recurrence was more frequent in the control group
than in the IPHC group. The mortality rate from peritoneal recurrence in the case of
patients in the IPHC group was much lower than that of patients in the control group.
IPHC did not induce anastomotic breakdown or chemical peritonitis after surgery.

Fujimoto et al (1999) randomized 141 gastric carcinoma patients with macroscopic
serosal invasion to surgery and IPHC (n=71) or surgery alone (n=70). IPHC was
performed just after gastric resection and alimentary tract reconstruction under



Interperitoneal Hyperthermic Chemotherapy for Abdominopelvic Cancers Nov 11         9
general anesthesia along with systemic hyperthermia. Postoperative complications
were reported in 2 of the 71 patients in the IPHC group and in 2 of the 70 patients in
the control group. The peritoneal recurrence rate in the IPHC group was significantly
decreased compared with that in the control group. The 2-year, 4-year, and 8-year
survival rates for the IPHC group were 88%, 76%, and 62%, respectively, whereas
those for the control group were 77%, 58%, and 49%, respectively. The IPHC group
thus reaped a significant survival benefit (P = 0.0362) compared with the control
group.

Zhu et al (2006) investigated the clinical effects and safety of IPHC for 118 advanced
gastric cancer patients with serosal invasion. 52 underwent IPHC after gastrectomy
and 66 were treated with gastrectomy only. Among these cases, 96 patients without
macroscopic peritoneal metastases were selected for the prophylactic study, 22 with
peritoneal metastases were selected for the therapeutic study. For the prophylactic
study, the IPHC procedure improves postoperative survival rate and decrease the
incidence of peritoneal recurrence, and is an independent prognostic factor for these
patients. For the therapeutic study, postoperative survival times were longer if IPHC
was undertaken. No surgery-related death occurred. The incidence of renal
dysfunction was higher in the IPHC group, but all patients recovered without
hemodialysis. The investigators authors concluded IPHC is a safe procedure that
improves the survival prognosis for AGC patients with serosal invasion, especially for
patients without peritoneal metastasis due to the reduction of postoperative
peritoneal recurrence.

In a non-randomized trial of patients with advanced gastric carcinoma patients with
PC, Fujimoto et al (1997) compared the efficacy of IPHC and aggressive surgery in
48 patients to 18 patients treated with surgery alone. The survival period was
extended for the 48 patients who underwent surgery plus IPHC compared with the
control patients. Of the 29 patients with peritoneal carcinomatosis in the upper
abdominal cavity, the 21 patients treated with IPHC and surgery had survival periods
superior to those of the 8 patients treated by surgery alone. The 5-year survival rate
of the 18 IPHC patients with countable metastases in the entire cavity was 41.6%,
whereas the 50% survival duration of the control group was 110 days. Nineteen
patients with numerous metastases in the entire cavity died within 673 days,
regardless of whether or not IPHC was used.

Hirose et al (1999) evaluated IPHC combined with surgery in thirty-two patients with
advanced gastric cancer. 15 patients without peritoneal metastasis were treated to
prevent peritoneal recurrence whereas 17 patients were treated therapeutically for
peritoneal metastases. The postoperative outcome of both groups was compared
with that of control patients treated with surgery alone. Peritoneal recurrence was
less frequent (26%) and the 5-year survival rate was significantly higher (39%) in
the patients with prophylactic IPHC than in 40 control patients (42 and 17%,
respectively). The patients with therapeutic IPHC showed significantly better median
survival than did 20 control patients (11 vs. 6 months). Cox multivariate regression
analysis revealed that IPHC was an independent prognostic factor in the prophylactic
study (hazard ratio = 0.3965), and that the independent prognostic factor in the
therapeutic study was not IPHC but complete resection of the peritoneal metastasis.
The investigator concluded that IPHC had no marked benefit for established
peritoneal metastasis.




Interperitoneal Hyperthermic Chemotherapy for Abdominopelvic Cancers Nov 11         10
IPHC continues to be investigated as an adjunct to surgery for the treatment of
other abdominopelvic cancers that have metastasized or may metastasize into the
peritoneal cavity (i.e., peritoneal carcinomatosis).

Verwaal et al (2003) randomized 105 patients with PC of colorectal origin to receive
either standard treatment consisting of systemic chemotherapy (fluorouracil-
leucovorin) with or without palliative surgery, or experimental therapy consisting of
aggressive cytoreduction with IPHC, followed by the same systemic chemotherapy
regime. The primary end point was survival. After a median follow-up period of 21.6
months, the median survival was 12.6 months in the standard therapy arm and 22.3
months in the experimental therapy arm. The treatment-related mortality in the
aggressive therapy group was 8%. Most complications from IPHC were related to
bowel leakage. Subgroup analysis of the IPHC group showed that patients with 0 to 5
of the 7 regions of the abdominal cavity involved by tumor at the time of the
cytoreduction had a significantly better survival than patients with 6 or 7 affected
regions. If the cytoreduction was macroscopically complete (R-1), the median
survival was also significantly better than in patients with limited (R-2a), or
extensive residual disease, (R-2b). The investigators concluded that cytoreduction
followed by IPHC improves survival in patients. However, patients with involvement
of six or more regions of the abdominal cavity, or grossly incomplete cytoreduction,
had still a grave prognosis.

In 2008, Verwaal et al updated the trial to a minimal follow-up of 6 years to show
long-term results. For all patients still alive, the follow-up was updated until 2007. In
the original study, four patients were excluded-two because of no eligible
histology/pathology and two because of major protocol violations. After
randomization, four patients in the IPHC arm and six in the control arm were not
treated using the intended therapy, one patient because of withdrawal, one because
of a life-threatening other malignant disease and the others because of progressive
disease before initiation of the treatment. During the follow-up, one patient was
crossed over from the control arm and underwent cytoreduction and IPHC for
recurrent disease, after the assigned treatment was completed. The data from these
patients were censored at the moment of the cross-over. Progression-free and
disease-specific survival were analyzed using the Kaplan Meyer test and compared
using the log rank method. At the time of this update, the median follow-up was
almost 8 years. In the standard arm, 4 patients were still alive, 2 with and 2 without
disease; in the IPHC arm, 5 patients were still alive, 2 with and 3 without disease.
The median progression-free survival was 7.7 months in the control arm and 12.6
months in the IPHC arm. The median disease-specific survival was 12.6 months in
the control arm and 22.2 months in the IPHC arm. The 5-year survival was 45% for
those patients in whom a R1 resection was achieved.

In a phase II non-randomized prospective trial reported by Lanuke et al (2009), 101
consecutive patients with PC were treated with CRS and IPHC and early
postoperative intraperitoneal chemotherapy. The majority (82%) of patients, median
age 49 years had complete macroscopic cytoreduction (completeness of
cytoreduction score, 0) despite a generally extensive tumor burden. Perioperative
mortality and grade III/IV morbidity rates were 4% and 39%, respectively.
Preliminary median disease free survival (DFS) and overall survival (OS) had not yet
been defined for appendix tumors at a median follow-up period of 16 months (range,
1-86 mo). Median DFS and OS for colonic tumors are 8 months and 26 months,
respectively, with a median follow-up period of 12 months (range, 1-48 mo).




Interperitoneal Hyperthermic Chemotherapy for Abdominopelvic Cancers Nov 11           11
Elias et al (2009) compared the long-term survival of 48 patients with gross PC from
colorectal adenocarcinoma who had undergone cytoreductive surgery plus IPHC to a
standard comparable group of 48 patients with colorectal PC treated with palliative
chemotherapy (oxaliplatin or irinotecan) during the same period. All characteristics
were comparable except age and tumor differentiation. There was no difference in
systemic chemotherapy, with a mean of 2.3 lines per patient. Median follow-up was
95.7 months in the standard group versus 63 months in the IPHC group. Two-year
and 5-year overall survival rates were 81% and 51% for the IPHC group,
respectively, and 65% and 13% for the standard group, respectively. Median
survival was 23.9 months in the standard group versus 62.7 months in the IPHC
group. The investigators concluded that patients with isolated, resectable PC achieve
a median survival of 24 months with modern chemotherapies, but only surgical
cytoreduction plus IPHC is able to prolong median survival to roughly 63 months,
with a 5-year survival rate of 51%.

Cao et al (2009) performed a meta-analysis of the survival outcomes of patients with
colorectal PC of colorectal origin with particular focus on CRS and IPHC. Four
comparative studies and 43 observational studies of CRS with IPHC were identified.
The author noted that a significant improvement in survival was associated with
treatment by CRS and IPHC compared with palliative approach. The pooled data did
not show a significant improvement in overall survival for patients treated by CRS
and IPHC versus surgery and systemic chemotherapy, however, the overall effect of
IPHC is significantly better than the control group. The author noted there is a need
for further evaluation of the prognostic significance of lymph node and liver
involvement, ideally in large prospective trials.

Lim et al (2009) evaluated IPHC (cisplatin 75 mg/m(2), 41.5 degrees C, 90 min) in
30 patients with advanced epithelial ovarian cancer and residual tumor of <1 cm
after cytoreductive surgery in an uncontrolled clinical trial. All patients received
adjuvant chemotherapy with combination platinum and taxane. Adverse events and
responses to primary treatment were evaluated and scored as follows: grade I,
observation; grade II, medical treatment; grade III, intervention; and grade IV,
reoperation or admission to the intensive care unit. No deaths or grade IV
morbidities were observed. One hundred seven adverse events were identified in 30
patients (grade I, 40; grade II, 46; grade III, 21). The most common adverse events
affected the hematologic system (n = 26), followed by the gastrointestinal system (n
= 23). Most adverse events were anemias requiring transfusion and nausea/vomiting
requiring medication. Twenty-eight patients (93%) experienced complete remission,
and two patients (7%) had progressive disease. The investigator concluded that
although IPHC after extensive cytoreductive surgery for ovarian cancer is a
procedure with acceptable morbidity, more follow-up is needed to determine its
effect on survival.

In a prospective, single-center nonrandomized phase II study, Di Giorgio et al (2008)
enrolled 47 patients with primary advanced or recurrent ovarian cancer and diffuse
PC. 22 underwent primary and 25 secondary cytoreduction plus immediate IPHC
followed by systemic chemotherapy. The overall mean Sugarbaker peritoneal cancer
index was 14.9. A mean of 6 surgical procedures were required per patient. In
87.3% of the patients debulking achieved optimal cytoreduction (Sugarbaker
completeness of cytoreduction [CC] score 0-1), whereas in 12.7% it left macroscopic
residual disease (CC-2 or CC-3). Major complications developed in 21.3% of the
patients and the in-hospital mortality rate was 4.2%. The mean overall survival was
30.4 months, median survival was 24 months, and mean disease-free survival was



Interperitoneal Hyperthermic Chemotherapy for Abdominopelvic Cancers Nov 11       12
27.4 months. Five-year survival was 16.7%. Univariate (log-rank test and analysis of
variance) and multivariate analyses (Cox proportional-hazard model) identified the
CC score as the main factor capable of independently influencing survival.

Passot et al (2008) performed a retrospective analysis of nineteen patients with
diffuse malignant peritoneal mesothelioma (DMPM) treated with CRS and IPHC.
Sixteen patients presented stage 3 or 4 PM according to the Gilly classification.
Optimal cytoreductive surgery was performed for 11 patients (complete macroscopic
resection or residual tumor nodules less than 2.5mm). No post-operative deaths
occurred but 9 patients (47%) presented grade III or IV post-operative
complications. The overall median survival was 36.9 months; completeness of
cytoreduction was the only significant prognostic factor.

Barrati et al (2009) reported clinical data on 70 patients with diffuse malignant
peritoneal mesothelioma (DMPM) undergoing cytoreduction and IPHC prospectively
collected. After a median follow-up of 43 months, disease progression occurred in
38 patients. Progressive disease distribution in 13 abdominopelvic regions was
analyzed. In 28 patients undergoing adequate cytoreduction (residual tumor < or
=2.5 mm), clinicopathological factors correlating to disease progression in each
region were investigated. Median time to progression was 9 months. Median survival
from progression was 8 months. The failure pattern was categorized as peritoneal
progression (n = 31), liver metastases (n = 1), abdominal lymph-node involvement
(n = 2), pleural seeding (n = 4). Small bowel was the single site most commonly
involved (n = 27). Residual tumor < or =2.5 mm (versus no visible) was the only
independent risk factor for disease progression in epigastric region, upper ileum,
upper jejunum, and lower jejunum. Progressive disease was treated with second
IPHC in 3 patients, debulking in 4, systemic chemotherapy in 16, and supportive care
in 15. At multivariate analysis, time to progression <9 months, poor performance
status, and supportive care correlated to reduced survival from progression. The
authors concluded that minimal residual disease, compared with macroscopically
complete cytoreduction, correlated to failure in critical anatomical areas, suggesting
the need for maximal cytoreductive surgical efforts, notong that in selected patients,
aggressive management of progressive disease seems worthwhile.

At this time, the available evidence regarding IPHC for the treatment of PC from
various abdominopelvic malignancies is limited to uncontrolled studies and non-
randomized studies. The current evidence is also weak regarding gains in quality of
life. The extent of intraperitoneal tumor dissemination and the completeness of
cytoreduction are the leading predictors of postoperative patient outcome, thus
patient selection is crucial. Although some studies have demonstrated a benefit in
terms of patient survival, it remains unclear if the improved outcomes were related
to the cytoreductive surgery itself, and/or postoperative systemic chemotherapy.
Prospective randomized trials are necessary to validate the efficacy of perioperative
intraperitoneal hyperthermic chemotherapy in both the treatment and prevention of
peritoneal surface malignancy.

Scientific Rationale – Update June 2008
Clinical trials are ongoing investigating the efficacy of intraperitoneal hyperthermic
chemotherapy as an adjunct to cytoreductive surgery for both the prevention of
peritoneal carcinomatosis as well as for the treatment of abdominopelvic cancers
(i.e., nonappendiceal) that have penetrated or metastasized into the peritoneal
cavity. Varying degrees of success have been reported, and although some studies
have demonstrated a benefit in terms of patient survival from intraperitoneal



Interperitoneal Hyperthermic Chemotherapy for Abdominopelvic Cancers Nov 11          13
hyperthermic chemotherapy, treatment-related morbidity rates are high. At this
time, there are many unanswered questions including definitive patient selection, the
most effective drug combination and optimal treatment protocol. Technical aspects
of the procedure such as the optimal temperature of the chemotherapeutic agents,
the length of time for the intraperitoneal hyperthermic chemotherapy (IPHC)
perfusion, and the efficacy and safety of open and closed chemoperfusion need to be
determined and standardized. Randomized, controlled trials confirming the efficacy
of IPHC in comparison with supportive care, surgery alone, or systemic
chemotherapy is necessary.

According to National Comprehensive Cancer Network (NCCN), the goal of treatment
of most abdominal/peritoneal masses is palliative, rather than curative. In their
published practice guidelines on colon cancer and rectal cancer, the NCCN states:
“The panel does not recommended cytoreductive resection of disseminated
carcinomatosis with hyperthermia and intraperitoneal chemotherapy outside the
setting of the clinical trial.”

Scientific Rationale
The peritoneum is a thin membrane that lines the abdominal and pelvic cavities and
covers most of the abdominal viscera. It is composed of a layer of mesothelium
supported by a thin layer of connective tissue. Patients with gastrointestinal,
ovarian, or mesothelial cancers are considered at risk of seeding to the peritoneal
cavity and for peritoneal carcinomatosis (PC). Intraperitoneal free cancer cells that
can migrate and adhere to the peritoneum are responsible for peritoneal seeding.
Some seeding or spillage of free tumor cells may also occur during surgical removal
of abdominopelvic cancers. Peritoneal carcinomatosis (PC) represents the terminal
stage of the disease and is associated with a poor prognosis. Patients with
documented peritoneal carcinomatosis have a particularly short survival (median 3 to
6 months, less in the setting of ascites or peritoneal masses larger than 2 cm).

Cytoreductive surgery may be considered in patients whose cancer has spread to the
peritoneal surfaces in the absence of bloodborn or lymphatic metastases.
Cytoreductive surgery is a combination of peritoneal stripping procedures and
resections that remove all macroscopic tumor tissue from the abdominal cavities of
patients with PC. The use of systemic chemotherapy has not been shown to be
effective in the management of PC, due to poor penetration of the cytotoxic agents
into the peritoneal cavity.

Intraperitoneal hyperthermic chemotherapy (IPHC or HIPEC) has been proposed as
an adjunct to cytoreductive surgery for both the prevention of peritoneal
carcinomatosis as well as for the treatment of such cancers that have penetrated or
metastasized into the peritoneal cavity. Experimental studies found that elevated
temperatures of 41ºC to 44ºC were toxic to tumor cells and that the cytopenetration
and cytotoxicity of selected chemotherapeutic agents (e.g., mitomycin C, cisplatin,
doxorubicin) increased dramatically under hyperthermic conditions. IPHC is applied
during surgery via an open or closed abdominal approach. The closed technique is
performed to eliminate the risk of aerosolization and direct contact of the toxic
chemotherapeutic agent with staff members. After completion of the cytoreductive
procedure, peritoneal perfusion inflow and outflow catheters are placed
percutaneously into the abdominal cavity. Temperature probes are placed on the
inflow and outflow catheters just outside the exit sites from the abdomen. The
abdominal skin incision is closed temporarily with a running cutaneous suture to
prevent leakage of peritoneal perfusate. The chemolytic agent is heated and then



Interperitoneal Hyperthermic Chemotherapy for Abdominopelvic Cancers Nov 11       14
allowed to flow into the peritoneal cavity raising the temperature of the tissues
within the cavity to 106-108° Fahrenheit (F). The goal of IPHC is to enhance the
cytotoxic effect of chemotherapeutic drugs, thereby killing disseminated tumor cells
and reducing the risk of tumor recurrence. Temperatures are monitored throughout
the procedure. The abdomen is gently massaged throughout the perfusion to
improve drug distribution to all peritoneal surfaces. The increase in the patient’s core
body temperature during IPHC helps to offset the hypothermia associated with
lengthy cytoreductive surgical procedures. The difference between traditional
intraperitoneal chemotherapy (IPC), and intraperitoneal hyperthermic chemotherapy
(IPHC) is that in IPC, the chemolytic agents may be infused at the time of surgery or
over a course of several days, however, these agents are not heated before being
infused. Studies suggest that outcomes are most favorable among patients who are
able to undergo complete or nearly complete surgical cytoreduction prior to IPHC.
The procedure is technically challenging and treatment-related morbidity rates are
high.

In March 2005, a guidance from the National Institute for Clinical Excellence (NICE)
concluded that the evidence on the safety and efficacy of complete cytoreduction and
heated intraoperative intraperitoneal chemotherapy (the Sugarbaker technique) for
peritoneal carcinomatosis was not adequate to recommend its use outside of a
clinical trial.

According to the American Cancer Society, while hyperthermia is a promising way to
improve cancer treatment, it is largely an experimental technique at this time.
According to the National Cancer Institute, “ Hyperthermia has been investigated in
combination with radiation therapy and/or chemotherapy. Many of these studies,
but not all, have shown a significant reduction in tumor size when hyperthermia is
combined with other treatments. However, not all of these studies have shown
increased survival in patients receiving the combined treatments. A number of
challenges must be overcome before hyperthermia can be considered a standard
treatment for cancer. Many clinical trials are being conducted to evaluate the
effectiveness of hyperthermia in combination with other therapies for the treatment
of different cancers while other studies focus on improving hyperthermia
techniques.”

Kianmanesh et al. (2007) evaluated outcomes in 43 patients presenting with
peritoneal carcinomatosis (PC) from colorectal cancer, with or without liver
metastases (LMs) who were treated with cytoreductive surgery (CS) and
hyperthermic intraperitoneal chemotherapy (HIPEC). Sixteen patients had LM’s,
ascites was present in 12 patients, and 11 presented with occlusion at the time of PC
diagnosis. Seventy-seven percent of the patients were Gilly 3 (diffuse nodules, 5-20
mm) and Gilly 4 (diffuse nodules>20 mm). The main endpoints were morbidity,
mortality, completeness of cancer resection (CCR), and actuarial survival rates. The
CS was considered as CCR-0 (no residual nodules) or CCR-1 (residual nodules <5
mm) in 30 patients (70%). Iterative procedures were performed in 26% of patients.
Three patients had prior to CS + HIPEC, 10 had concomitant minor liver resection,
and 3 had differed liver resections (2 right hepatectomies) 2 months after CS +
HIPEC. The mortality rate was 2.3% (1 patient). Seventeen patients (39%)
presented one or multiple complications. Complications included deep abscess (n =
6), wound infection (n = 5), pleural effusion (n = 5), digestive fistula (n = 4),
delayed gastric emptying syndrome (n = 4), and renal failure (n = 3). Two patients
(3.6%) were reoperated. The median survival was 38.4 months. Actuarial 2- and 4-
year survival rates were 72% and 44%, respectively. The survival rates were not



Interperitoneal Hyperthermic Chemotherapy for Abdominopelvic Cancers Nov 11          15
significantly different between patients who had CS + HIPEC for PC alone (including
the primary resection) versus those who had associated LMs resection (median
survival, 35.3 versus 36.0 months, P = 0.73).

Piso et al. (2007) analyzed morbidity, mortality, and survival after major
cytoreductive surgery and intraperitoneal chemotherapy. Thirty-two patients with
peritoneal carcinomatosis from primary colorectal carcinoma had cytoreduction
followed by HIPEC consisting of mitomycin C and doxorubicin. Data was analyzed
retrospectively. Of all patients, 16 had appendix and 16 non-appendiceal colorectal
carcinoma. A macroscopically complete cytoreduction was achieved in 24 patients by
parietal and visceral peritonectomy procedures. All resections were combined with
HIPEC. Overall morbidity was 34%. Most frequent surgical complications were
intestinal obstruction (4/32), enteric fistula (2/32), pancreatitis (2/32), and bile
leakage (2/32). One patient presented grade 4 renal toxicity. There was no hospital
mortality. The median follow-up was 12 months. The 1-year overall survival rate was
96%. The investigator concluded that cytoreductive surgery combined with HIPEC is
associated with an acceptable morbidity and low mortality. Complete cytoreduction
may improve survival, particularly in well-selected patients having a low tumor
volume and no extra-abdominal metastases.

In a prospective phase II study reported by Elias et al. (2007), the morbidity and
mortality of optimal cytoreduction, optimal IPHC combining oxaliplatin and
irinotecan, and an optimal homogeneous intraperitoneal temperature of 43 degrees
C were analyzed in 106 patients with peritoneal carcinomatosis (PC). After complete
resection of the PC, HIPEC was performed by the Coliseum technique with oxaliplatin
combined with irinotecan in 2 L/m of 5% dextrose, over 30 minutes at a real
intraperitoneal temperature of 43 degrees C. During the hour preceding HIPEC,
patients received 5-fluorouracil and leucovorin intravenously, resulting in tritherapy.
Postoperative mortality and morbidity rates were 4% and 66%, respectively. The
most frequent complications were digestive fistula (24%), lung infection (16%), and
severe hematological toxicity (11%). Statistical correlation was evidenced between
morbidity and the carcinomatosis score, the number of resected organs, the duration
of surgery and blood loss. The author concluded this new approach, optimized in
three respects (complete cytoreduction, combination oxaliplatin with irinotecan, and
high temperature) has resulted in a relatively high but acceptable incidence of
adverse events considering the expected advantage for survival.

A multicenter study reported by Cavaliere et al. (2006) investigated 120 patients
with PC from colorectal cancer. Patients were treated by cytoreductive surgery and
intra-operative hyperthermic chemoperfusion (HIPEC) with cisplatin (CDDP) and
mitomycin-c (MMC). A small group of patients were treated with oxaliplatin (LOHP)
following the Elias et al. scheme (intravenous 5-fluorouracil and leucovorin ) followed
by intraperitoneal perfusion with LOHP in 2 l/m2, during 30 min at 43 degrees C. CC-
0 cytoreduction was achieved in 85.2% of the patients. Major morbidity and
mortality was 22.5% and 3.3%, respectively. No G4 toxicity was registered. The
three-year survival was 25.8%. The difference in survival evaluating complete
cytoreduction (CC-0) vs. incomplete (CC1-2; residual tumor nodules greater than 2.5
mm) was statistically significant (p < 0.0001). Evaluating only the patients that
could be cytoreduced to CC-0, the 3-year survival was raised to 33.5%. The patients
treated with oxaliplatin were alive and free-of-disease after a 16-month median
follow-up.




Interperitoneal Hyperthermic Chemotherapy for Abdominopelvic Cancers Nov 11         16
Helm et al. (2007) investigated eighteen patients with ovarian cancer (disease </=5
mm) who had surgical cytoreduction (SSC) with hyperthermic intraperitoneal
chemotherapy (IPHC). Characteristics were median age 64 years, mean prior
laparotomies 1.4, mean chemotherapy regimens 3.2, mean time from initial therapy
to IPHC 30.6 months. Original histology: papillary serous 12, poorly differentiated
adenocarcinoma 1, serous low malignant potential 2, mucinous 1 and mixed
subtypes 2. 13 had recurrent disease and 5 had persistent disease following front-
line therapy. 15 received cisplatin and 3 mitomycin C. The maximum dimension of
residual lesions at the end of surgery prior to IPHC was nil (n=11), </=2 mm (n=4),
</=5 mm (n=2) and </=10 mm (n=1). Mean time to return of bowel function was 7
days and mean time to hospital discharge 11.5 days. All patients developed CTEP
grade 1 or 2 metabolic or hematologic toxicities. CTEP grade 3 or 4 metabolic toxicity
occurred in 72% and a hematologic toxicity in 28%. There was one peri-operative
death due to pulmonary embolus. Median progression-free interval was 10 months
and median overall survival was 31 months. Improved outcome was significantly
related to the size of residual disease prior to IPHC and postoperative chemotherapy.
The investigator concluded that IPHC is a relatively well-tolerated procedure with the
majority of the morbidity being related to the associated surgery. When combined
with SSC it has the potential to extend quality life in some patients with recurrent
ovarian cancer and warrants continued research. Randomized studies are needed
earlier in the course of the disease.

Smeenk et al. (2007) studied the progression of pseudomyxoma peritonei (PMP) in
96 patients treated primarily by cytoreductive surgery (CRS) with hyperthermic
intraperitoneal chemotherapy (HIPEC). Median follow-up was 51.5 months. Median
progression free survival (PFS) was 28.2 months. Progressive disease was mainly
located sub hepatic (38%) or in multiple regions (36%). Pathological
dedifferentiation was observed in 8 patients (20%). The choice of treatment
depended on pathology, extent of disease and PFS. Seventeen patients were treated
for progression by second CRS with (n=8) or without HIPEC (n=10). The 3-years
overall survival (OS) probability after this treatment was 100% and 53.3%,
respectively. Fifteen patients with (slow) progression were observed. Three-years OS
probability of these patients was 66.0%. All patients treated for progression by
systemic chemotherapy only (n=6) had died of disease after a median follow up of
14.8 months. A longer PFS after primary treatment was associated with longer OS
after progression. The investigator concluded progressive PMP after primary CRS
with HIPEC is probably the result of technical failure and/or tumor biology.
Management of progressive PMP can be valuable for selected patients and should
depend primarily on the PFS.

Tarasov et al. (2006) reported that the use of cytoreductive surgery and
intraoperative intraperitoneal chemohyperthermic perfusion (IPHC) improves the end
results significantly in patients with peritoneal carcinomatosis. In a study of 45
patients with gastric cancer (15), ovarian and cervical carcinoma ('17), colorectal
cancer (8) and miscellaneous cancers involving advanced peritoneal carcinomatosis,
IPHC was carried out immediately after cytoreductive surgery including
peritonectomy (Sugarbaker.) Postoperative complication and lethality frequency was
37.7 and 22.2%, respectively; mean survival--17 months. Eight patients have
survived without signs of relapse; three of them--for more than 2 years. The author
concluded that cytoreductive surgery plus IPHC protocol for peritoneal
carcinomatosis increases survival time 3-fold and improves quality of life.




Interperitoneal Hyperthermic Chemotherapy for Abdominopelvic Cancers Nov 11        17
Tuttle et al. (2006) evaluated the toxicity and quality of life for patients with
peritoneal metastases after cytoreductive surgery (CS) plus hyperthermic
intraperitoneal chemotherapy (HIPC). 35 patients with peritoneal metastases from
primary cancer sites that included the appendix (19 patients), colon (7),
mesothelioma (3), stomach (2), small bowel (2), gallbladder (1), and unknown (1).
The patients underwent CS in an effort to remove all or nearly all peritoneal tumor
nodules. Using a closed technique, hyperthermic mitomycin C was delivered into the
peritoneal cavity for 90 min. Before treatment and then at 4-month postoperative
intervals, the patients quality of life was assessed using the cancer therapy-colon
subscale (FACT-C) instrument. The reviewer found that the postoperative mortality
rate was 0%; adverse events occurred in 18 (51%) patients. The median survival
time was 21.4 months. Quality of life measurements, including trial outcome index
(TOI), FACT-colon, and FACT-general, returned to baseline 4 months after treatment
and were significantly improved at 8 and 12 months. 14 had died of progressive
disease and 1 of an unrelated cause. The reviewer concluded that despite early
toxicity, CS plus HIPC might prolong the overall survival rate of patients with
peritoneal metastases and improve quality of life measurements.

Roviello et al. (2006) reported that IPHC combined with cytoreductive surgery
involves a high risk of morbidity, but postoperative complications could be resolved
in most cases with correct patient selection and adequate postoperative care. Tumor
residual and advanced age significantly increase the risk of morbidity after this
procedure. Fifty-nine patients with peritoneal carcinomatosis (PC) from abdominal
neoplasms underwent 61 treatments using this technique. Surgical debulking,
completed by partial or total peritonectomy, was performed in most cases. In 16
patients with positive peritoneal cytology without macroscopic peritoneal disease,
IPHC was performed in order to prevent peritoneal recurrence. IHCP was carried out
throughout the abdominopelvic cavity for 60 minutes using a closed abdomen
technique. Mitomycin C and cisplatin were the anticancer drugs generally used.
Mean hospital stay was 13 +/- 7 days. Postoperative complications occurred in 27
patients (44.3%); of these, major morbidity was observed in 17 (27.9%). The most
frequent complications were wound infection (9 cases), grade 2 or greater
hematological toxicity (5 cases), intestinal fistula (5 cases), and pleural effusion
requiring drainage (5 cases). Reoperation was necessary in 5 patients (8.2%). One
patient with multiorgan failure died in the postoperative period. Multivariate analysis
of several variables identified completeness of cancer resection, and age as
independent predictors of postoperative morbidity. Preliminary follow-up data
indicated that survival probability may be high in patients with ovarian or colorectal
cancer and low in patients with gastric cancer.

A phase II study reported by Kasamura et al. (2006) analyzed the morbidity and
mortality of cytoreductive surgery (CRS) + intraperitoneal hyperthermic perfusion
(IPHP) in the treatment of peritoneal surface malignancies. A total of 205 patients
(50 with peritoneal mesothelioma, 49 with pseudomyxoma peritonei, 41 with ovarian
cancer, 32 with abdominal sarcomatosis, 13 with colon cancer, 12 with gastric
cancer, and 8 with carcinomatosis from other origins) underwent 209 consecutive
procedures. Four patients underwent the intervention twice because of disease
relapse. IPHP through the closed abdomen technique was conducted with a
preheated (42.5 degrees C) perfusate containing cisplatin + mitomycin C or cisplatin
+ doxorubicin. The investigator reported that the major morbidity rate was 12%.
The most significant complications were 23 anastomotic leaks or bowel perforations,
4 abdominal bleeds, and 4 sepses. Operative mortality rate was 0.9%. On logistic
regression model multivariate analysis, extent of cytoreduction and dose of cisplatin



Interperitoneal Hyperthermic Chemotherapy for Abdominopelvic Cancers Nov 11          18
for IPHP > or = 240 mg were independent risk factors for major morbidity. Ten
patients presented with Grade 3 to 4 toxicity. The author concluded CRS + IPHP
presented acceptable morbidity, toxicity, and mortality rates, all of which support
prospective Phase III clinical trials.

Stewart et al. (2006) reported on cytoreductive surgery and IPHC for peritoneal
dissemination (PD) from the appendix. 110 cases of PD from proven appendiceal
neoplasms treated with IPHC were identified from a prospectively managed
database. Tumor samples were classified on pathologic review as disseminated
peritoneal adenomucinosis (n = 55), peritoneal mucinous carcinomatosis (PMCA)
with intermediate features (n = 18), PMCA (n = 29), or high-grade nonmucinous
lesions (n = 8). A retrospective review was performed with long-term survival as the
primary outcome measure. A total of 116 IPHCs were performed. The 1-, 3-, and 5-
year survival rates for all cases were 79.9% +/- 4.1%, 59.0% +/- 5.7%, and 53.4%
+/- 6.5%, respectively. When stratified by histology, disseminated peritoneal
adenomucinosis and intermediate tumors had better 3-year survival rates (77% +/-
7% and 81% +/- 10%) than PMCA and high-grade nonmucinous lesions (35% +/-
10% and 15% +/- 14%). Age at presentation, performance status, time between
diagnosis and IPHC, resection status and length of hyperthermic chemoperfusion
were independently associated with survival. The reviewer concluded that the data
show that long-term survival is anticipated in most patients who are treated with
cytoreduction and IPHC for appendiceal PD. The findings presented underscore the
important prognostic characteristics that predict outcome after IPHC in patients with
PD and established a framework for the consideration of IPHC in future trials for
appendiceal PD.

Schmidt et al. (2005) reported that cytoreductive surgery combined with HIPEC is
associated with an increased morbidity and mortality, however, complications were
predominantly related to the surgery. Following this aggressive treatment, survivors
may achieve a satisfactory quality of life. Sixty-seven patients with PC were treated
with complete macroscopical cytoreduction followed by HIPEC (using cisplatin,
mitomycin or mitoxantrone). Quality of life was assessed with the EORTC QLQ-C30
questionnaire. Patients had a variety of primary tumors, including appendix
carcinomas (22/67). Complete cytoreduction was achieved in 58% of the patients.
Overall morbidity was 34%. Post-operative mortality was 4.5%. The mean score for
global health status of long-term survivors (20 questionnaires/25 patients) was 62.6
(73.3 for the control population, p=0.07). Functional status, particularly the role
(56.4) and the social functioning (53.9) were impaired.

According to Glehen et al. (2004), three principal studies dedicated to the natural
history of peritoneal carcinomatosis (PC) from colorectal cancer consistently showed
median survival ranging between 6 and 8 months. New approaches combining
cytoreductive surgery and perioperative intraperitoneal chemotherapy suggest
improved survival. A retrospective multicenter study was performed to evaluate this
combined treatment and to identify the principal prognostic indicators. 506 patients
had cytoreductive surgery and perioperative intraperitoneal chemotherapy
(intraperitoneal chemohyperthermia and/or immediate postoperative intraperitoneal
chemotherapy). PC from appendiceal origin was excluded. Median follow-up was 53
months. The morbidity and mortality rates were 22.9% and 4%, respectively. The
overall median survival was 19.2 months. Patients in whom cytoreductive surgery
was complete had a median survival of 32.4 months, compared with 8.4 months for
patients in whom complete cytoreductive surgery was not possible. Positive
independent prognostic indicators by multivariate analysis were complete



Interperitoneal Hyperthermic Chemotherapy for Abdominopelvic Cancers Nov 11           19
cytoreduction, treatment by a second procedure, limited extent of PC, age less than
65 years, and use of adjuvant chemotherapy. The use of neoadjuvant chemotherapy,
lymph node involvement, presence of liver metastasis, and poor histologic
differentiation were negative independent prognostic indicators. The investigator
concluded that cytoreductive surgery with perioperative intraperitoneal
chemotherapy achieved long-term survival in a selected group of patients with PC
from colorectal origin with acceptable morbidity and mortality. The complete
cytoreductive surgery was the most important prognostic indicator.

Hall et al. (2004) reported that treatment of peritoneal carcinomatosis from
appendiceal and colorectal sources with intraperitoneal hyperthermic chemotherapy
(IPHC) combined with aggressive cytoreductive surgery has been shown to be
effective, however, for the treatment of peritoneal carcinomatosis from gastric
carcinoma, this modality has limited potential and careful patient selection is
imperative. The authors report that patients in whom an R0/R1 resection appear to
be the best candidates. In this study, thirty-four patients with peritoneal
carcinomatosis due to gastric carcinoma underwent gastric resection with
cytoreductive surgery followed by IPHC with mitomycin C. A control group consisting
of 40 contemporaneous patients, who underwent radical gastrectomy without
extended nodal resection, was identified through the tumor registry. Despite more
advanced disease in the IPHC group compared to the control group, overall survival
in the two groups was similar. Proportional-hazards regression analysis showed that
only resection status was significantly correlated with improved survival. Within the
IPHC group, patients who underwent an R0/R1 resection had increased survival
times (11.2 vs. 3.3 months) vs. those who underwent R2 resection. The group who
had an R0/R1 resection had 1- and 2-year survival rates of 45% and 45% compared
to 16% and 8%, respectively, in the R2 group.

In summary, the published studies to date have included a small number of
individuals with various locations of primary cancer, different stages of peritoneal
carcinomatosis, and varying degrees of success with cytoreductive surgery. Although
some studies have demonstrated a benefit in terms of patient survival from
IPHC/HIPEC treatment, treatment-related morbidity rates are high. Definitive patient
selection remains undefined. In addition, the most effective drug combination and
optimal treatment protocol remains unclear. Technical aspects of the procedure such
as the optimal temperature of the chemotherapeutic agents, the length of
time for the IPHC perfusion, and the efficacy and safety of open and closed
chemoperfusion need to be determined and standardized. It remains unclear as to
whether the survival benefit from IPHC/HIPEC can be attributed to the cytoreductive
surgery, patient selection, or both. Although, cytoreductive surgery plus
hyperthermic intraperitoneal chemotherapy (IPHC/HIPEC) appears to be a promising
treatment for patients with peritoneal malignancies, further randomized prospective
trials are necessary to validate the efficacy of perioperative intraperitoneal
hyperthermic chemotherapy in both the treatment and prevention of peritoneal
surface malignancy. Several clinical trials are currently underway to determine the
effectiveness of using IPHC/HIPEC.

Review History
June 2007            Medical Advisory Council, initial approval
June 2008            Update – no revisions
July 2009            Added the prophylactic use of IPHC for locally advanced gastric
                     cancer without macroscopic peritoneal metastasis or distant
                     metastasis as medically necessary



Interperitoneal Hyperthermic Chemotherapy for Abdominopelvic Cancers Nov 11        20
July 2010           Update – no revisions
February 2011       Update – no revisions. Code updates
November 2011       Update. Added revised Medicare Table. No Revisions.

Patient Education Websites
English
1. National Cancer Institute. Hyperthermia in Cancer Treatment: Questions and
   Answers. Available at:
   http://www.cancer.gov/templates/doc.aspx?viewid=C5006D69-7257-47B4-
   A416-519AD402A243

Spanish
2. American Academy of Family Physicians. Cáncer: escogiendo un programa de
   tratamiento. Acesso en:
   http://familydoctor.org/online/famdoces/home/common/cancer/treatment/721.ht
   ml

This policy is based on the following evidence-based guidelines:
1.  National Institute for Clinical Excellence. Complete cytoreduction and heated
    intraperitoneal intraoperative chemotherapy (Sugarbaker technique) for
    peritoneal carcinomatosis – guidance. March 2005. Available at:
    http://guidance.nice.org.uk/IPG116/guidance/pdf/English
2. National Cancer Institute. Hyperthermia in cancer treatments: questions and
    answers. Cancer Facts. Revised Aug 2004.
3. American Cancer Society. Hyperthermia. Available at:
    http://www.cancer.org/docroot/ETO/content/ETO_1_2x_Hyperthermia.asp?sitea
    rea=&level=
4. Hayes Medical Technology Directory. Intraperitoneal Hyperthermic
    Chemotherapy for Abdominopelvic Cancers. June 2006.
5. National Comprehensive Cancer Network. Practice guidelines in Oncology –
    v.1.2007. Gastric Cancer. Available at:
    http://www.nccn.org/professionals/physician_gls/PDF/gastric.pdf
6. National Comprehensive Cancer Network. Practice guidelines in Oncology –
    v.2.2007. Colon Cancer. Available at:
    http://www.nccn.org/professionals/physician_gls/PDF/colon.pdf
7. National Cancer Institute. Hyperthermia in Cancer Treatment: Questions and
    Answers. Available at:
    http://www.cancer.gov/cancertopics/factsheet/Therapy/hyperthermia
8. American Cancer Society. Hyperthermia. Available at:
    http://www.cancer.org/docroot/ETO/content/ETO_1_2x_Hyperthermia.asp
9. National Comprehensive Cancer Network. Practice guidelines in Oncology –
    v.1.2008. Rectal Cancer. Available at:
    http://www.nccn.org/professionals/physician_gls/PDF/rectal.pdf
10. National Comprehensive Cancer Network. NCCN clinical practice guidelines in
    Oncology. Colon Cancer. V.3. 2010. Available at:
    http://www.nccn.org/professionals/physician_gls/PDF/colon.pdf
11. National Comprehensive Cancer Network. NCCN clinical practice guidelines in
    Oncology. Gastric Cancer. Version 2.2011. Available at:
    http://www.nccn.org/professionals/physician_gls/pdf/gastric.pdf
12. National Comprehensive Cancer Network. NCCN clinical practice guidelines in
    Oncology. Colon Cancer. Version 1.2012. Available at:
    http://www.nccn.org/professionals/physician_gls/pdf/colon.pdf



Interperitoneal Hyperthermic Chemotherapy for Abdominopelvic Cancers Nov 11     21
13. National Comprehensive Cancer Network. NCCN clinical practice guidelines in
    Oncology. Rectal Cancer. Version 2.2012. Available at:
    http://www.nccn.org/professionals/physician_gls/pdf/rectal.pdf
14.

References – Update November 2011
1.   Elias D, Gilley F, Boutite F, et al. Peritoneal colorectal carcinomatosis treated
     with surgery and perioperative intraperitoneal chemotherapy retrospective
     analysis of 523 patients from a multicentre French study. J Clinical Oncology
     2010; 28. 63-68.
2.

References – Update February 2011
1.  Cavaliere F, De Simone M, Virzì S, et al. Prognostic factors and oncologic
    outcome in 146 patients with colorectal peritoneal carcinomatosis treated with
    cytoreductive surgery combined with hyperthermic intraperitoneal
    chemotherapy: Italian multicenter study S.I.T.I.L.O. Eur J Surg Oncol. 2010
    Nov 17.
2. Dovern E, de Hingh IH, Verwaal VJ, et al. Hyperthermic intraperitoneal
    chemotherapy added to the treatment of ovarian cancer. A review of achieved
    results and complications. Eur J Gynaecol Oncol. 2010;31(3):256-61
3. Esquivel J, Averbach A, Chua TC. Laparoscopic Cytoreductive Surgery and
    Hyperthermic Intraperitoneal Chemotherapy in Patients with Limited Peritoneal
    Surface Malignancies: Feasibility, Morbidity and Outcome in an Early Experience.
    Ann Surg. 2011 Jan 6.
4. Frenel JS, Leux C, Pouplin L, et al. Oxaliplatin-based hyperthermic
    intraperitoneal chemotherapy in primary or recurrent epithelial ovarian cancer: A
    pilot study of 31 patients. Surg Oncol. 2011 Jan 1;103(1):10-6.
5. Glehen O, Gilly FN, Boutitie F, et al. Toward curative treatment of peritoneal
    carcinomatosis from nonovarian origin by cytoreductive surgery combined with
    perioperative intraperitoneal chemotherapy: A multi-institutional study of 1290
    patients. Cancer. 2010 Dec 15;116(24):5608-18
6. González-Moreno S, González-Bayón LA, Ortega-Pérez G. Hyperthermic
    intraperitoneal chemotherapy: Rationale and technique. World J Gastrointest
    Oncol. 2010 Feb 15;2(2):68-75.
7. Kim JH, Lee JM, Ryu KS, et al. Consolidation hyperthermic intraperitoneal
    chemotherapy using paclitaxel in patients with epithelial ovarian cancer. g Oncol.
    2010 Feb 1;101(2):149-55.
8. Li C, Yan M, Chen J, Xiang M, et al. Surgical resection with hyperthermic
    intraperitoneal chemotherapy for gastric cancer patients with peritoneal
    dissemination. J Surg Oncol. 2010 Oct 1;102(5):361-5.
9. Lim MC, Kang S, Choi J, et al. Hyperthermic intraperitoneal chemotherapy after
    extensive cytoreductive surgery in patients with primary advanced epithelial
    ovarian cancer: interim analysis of a phase II study. Ann Surg Oncol. 2009
    Apr;16(4):993-1000
10. Lim C, Tordjmann D, Gornet JM, et al. Prospective study of quality of life after
    cytoreductive surgery and hyperthermic intraperitoneal chemotherapy using
    oxaliplatin for peritoneal carcinomatosis. Bull Cancer. 2010 Sep 1;97(9):1053-
    60
11. Ross A, Sardi A, Nieroda C, et al. Clinical utility of elevated tumor markers in
    patients with disseminated appendiceal malignancies treated by cytoreductive
    surgery and HIPEC. Eur J Surg Oncol. 2010 Aug;36(8):772-6




Interperitoneal Hyperthermic Chemotherapy for Abdominopelvic Cancers Nov 11              22
12. Roviello F, Pinto E, Corso G, et al. Safety and potential benefit of hyperthermic
    intraperitoneal chemotherapy (HIPEC) in peritoneal carcinomatosis from primary
    or recurrent ovarian cancer. J Surg Oncol. 2010 Nov 1;102(6):663-70
13. Van der Speeten K, Stuart OA, Chang D, et al. Changes induced by surgical and
    clinical factors in the pharmacology of intraperitoneal mitomycin C in 145
    patients with peritoneal carcinomatosis. Cancer Chemother Pharmacol. 2010
    Sep 21

References – Update July 2010
1.  Bretcha-Boix P, Farré-Alegre J, Sureda M, et al. Cytoreductive surgery and
    perioperative intraperitoneal chemotherapy in patients with peritoneal
    carcinomatosis of colonic origin: outcomes after 7 years' experience of a new
    centre for peritoneal surface malignancies. Clin Transl Oncol. 2010
    Jun;12(6):437-42.
2. Cao C, Yan TD, Black D, Morris DL. A systematic review and meta-analysis of
    cytoreductive surgery with perioperative intraperitoneal chemotherapy for
    peritoneal carcinomatosis of colorectal origin. Ann Surg Oncol. 2009
    Aug;16(8):2152-65. Epub 2009 May 12.
3. Carrabin N, Mithieux F, Meeus P, et al. Hyperthermic intraperitoneal
    chemotherapy with oxaliplatin and without adjuvant chemotherapy in stage IIIC
    ovarian cancer. Bull Cancer. 2010 Apr;97(4):E23-32.
4. Chua TC, Koh JL, Yan TD, et al. Cytoreductive surgery and perioperative
    intraperitoneal chemotherapy for peritoneal carcinomatosis from small bowel
    adenocarcinoma. J Surg Oncol. 2009 Aug 1;100(2):139-43.
5. Chua TC, Morris DL, Esquivel J. Impact of the peritoneal surface disease
    severity score on survival in patients with colorectal cancer peritoneal
    carcinomatosis undergoing complete cytoreduction and hyperthermic
    intraperitoneal chemotherapy. Ann Surg Oncol. 2010 May;17(5):1330-6.
6. Chua TC, Pelz JO, Kerscher A, et al. Critical analysis of 33 patients with
    peritoneal carcinomatosis secondary to colorectal and appendiceal signet ring
    cell carcinoma. Ann Surg Oncol. 2009 Oct;16(10):2765-70.
7. Chua TC, Robertson G, Liauw W, et al. Intraoperative hyperthermic
    intraperitoneal chemotherapy after cytoreductive surgery in ovarian cancer
    peritoneal carcinomatosis: systematic review of current results. J Cancer Res
    Clin Oncol. 2009 Dec;135(12):1637-45.
8. Chua TC, Yan TD, Smigielski ME, et al. Long-term survival in patients with
    pseudomyxoma peritonei treated with cytoreductive surgery and perioperative
    intraperitoneal chemotherapy: 10 years of experience from a single institution.
    Ann Surg Oncol. 2009 Jul;16(7):1903-11.
9. Elias D, Gilly F, Quenet F, et al. Pseudomyxoma peritonei: a French multicentric
    study of 301 patients treated with cytoreductive surgery and intraperitoneal
    chemotherapy. Eur J Surg Oncol. 2010 May;36(5):456-62
10. Franko J, Ibrahim Z, Gusani NJ, et al. Cytoreductive surgery and hyperthermic
    intraperitoneal chemoperfusion versus systemic chemotherapy alone for
    colorectal peritoneal carcinomatosis. Cancer. 2010 May 13.
11. Gammon DC, Dutton T, Piperdi B, et al. Cytoreductive surgery and
    intraperitoneal hyperthermic chemotherapy in the treatment of peritoneal
    carcinomatosis. Am J Health Syst Pharm. 2009 Jul 1;66(13):1186-90.
12. Glehen O, Gilly FN, Arvieux C, et al. Peritoneal Carcinomatosis from Gastric
    Cancer: A Multi-Institutional Study of 159 Patients Treated by Cytoreductive
    Surgery Combined with Perioperative Intraperitoneal Chemotherapy. Ann Surg
    Oncol. 2010 Mar 25.




Interperitoneal Hyperthermic Chemotherapy for Abdominopelvic Cancers Nov 11        23
13. Helm CW, Richard SD, Pan J, et al. Hyperthermic intraperitoneal chemotherapy
    in ovarian cancer: first report of the HYPER-O registry. Int J Gynecol Cancer.
    2010 Jan;20(1):61-9.
14. Katayama K, Yamaguchi A, Murakami M, et al. Chemo-hyperthermic peritoneal
    perfusion (CHPP) for appendiceal pseudomyxoma peritonei. Int J Clin Oncol.
    2009 Apr;14(2):120-4.
15. Kerscher AG, Mallalieu J, Pitroff A, et al. Morbidity and mortality of 109
    consecutive cytoreductive procedures with hyperthermic intraperitoneal
    chemotherapy (HIPEC) performed at a community hospital. World J Surg. 2010
    Jan;34(1):62-9.
16. Lygidakis NJ, Patil A, Giannoulis K, et al. Laparoscopic hyperthermic
    intraperitoneal chemotherapy as adjuvant modality following radical surgery for
    advanced rectal cancer a new look to an old problem. Hepatogastroenterology.
    2010 Jan-Feb;57(97):73-5.
17. Muñoz-Casares FC, Rufián S, Rubio MJ, et al. The role of hyperthermic
    intraoperative intraperitoneal chemotherapy (HIPEC) in the treatment of
    peritoneal carcinomatosis in recurrent ovarian cancer. Clin Transl Oncol. 2009
    Nov;11(11):753-9.
18. Omohwo C, Nieroda CA, Studeman KD, et al. Complete cytoreduction offers
    longterm survival in patients with peritoneal carcinomatosis from appendiceal
    tumors of unfavorable histology. J Am Coll Surg. 2009 Sep;209(3):308-12
19. Sideris L, Mitchell A, Drolet P, et al. Surgical cytoreduction and intraperitoneal
    chemotherapy for peritoneal carcinomatosis arising from the appendix. Can J
    Surg. 2009 Apr;52(2):135-41
20. Spiliotis J, Rogdakis A, Vaxevanidou A, et al. Morbidity and mortality of
    cytoreductive surgery and hyperthermic intraperitoneal chemotherapy in the
    management of peritoneal carcinomatosis. J BUON. 2009 Apr-Jun;14(2):259-
    64.
21. Vaira M, Cioppa T, D'Amico S, et al. Treatment of peritoneal carcinomatosis
    from colonic cancer by cytoreduction, peritonectomy and hyperthermic
    intraperitoneal chemotherapy (HIPEC). Experience of ten years. In Vivo. 2010
    Jan-Feb;24(1):79-84
22. Vaira M, Cioppa T, DE Marco G, , et al. Management of pseudomyxoma
    peritonei by cytoreduction+HIPEC (hyperthermic intraperitoneal chemotherapy):
    results analysis of a twelve-year experience. In Vivo. 2009 Jul-Aug;23(4):639-
    44.
25. Varban O, Levine EA, Stewart JH, et al. Outcomes associated with cytoreductive
    surgery and intraperitoneal hyperthermic chemotherapy in colorectal cancer
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    Aug 1;115(15):3427-36.
26. Yan TD, Deraco M, Baratti D, et al. Cytoreductive surgery and hyperthermic
    intraperitoneal chemotherapy for malignant peritoneal mesothelioma: multi-
    institutional experience. J Clin Oncol. 2009 Dec 20;27(36):6237-42
27. Yang XJ, Li Y, Yonemura Y. Cytoreductive surgery plus hyperthermic
    intraperitoneal chemotherapy to treat gastric cancer with ascites and/or
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    May 1;101(6):457-64

References – Update July 2009
1.   Baratti D, Kusamura S, Cabras AD et al. Diffuse malignant peritoneal
     mesothelioma: Failure analysis following cytoreduction and hyperthermic
     intraperitoneal chemotherapy (HIPEC). Ann Surg Oncol. 2009 Feb; 16(2): 463-
     72.



Interperitoneal Hyperthermic Chemotherapy for Abdominopelvic Cancers Nov 11         24
2.    Baratti D, Kusamura S, Sironi A, et al. Multicystic peritoneal mesothelioma
      treated by surgical cytoreduction and hyperthermic intra-peritoneal
      chemotherapy (HIPEC). In Vivo. 2008 Jan-Feb; 22(1): 153-7.
3.    Cao C, Yan TD, Black D, Morris DL. A Systematic Review and Meta-Analysis of
      Cytoreductive Surgery with Perioperative Intraperitoneal Chemotherapy for
      Peritoneal Carcinomatosis of Colorectal Origin. Ann Surg Oncol. 2009 May 12
4.    Chua TC, Yan TD, Morris DL. Outcomes of cytoreductive surgery and
      hyperthermic intraperitoneal chemotherapy for peritoneal mesothelioma: the
      Australian experience. J Surg Oncol. 2009 Feb 1; 99(2): 109-13.
5.    Cioppa T, Vaira M, Bing C et al. Cytoreduction and hyperthermic intraperitoneal
      chemotherapy in the treatment of peritoneal carcinomatosis from
      pseudomyxoma peritonei. World J Gastroenterol. 2008 Nov 28; 14(44): 6817-
      23.
6.    Confuorto G, Giuliano ME, Grimaldi A, Viviano C. Peritoneal carcinomatosis from
      colorectal cancer: HIPEC? Surg Oncol. 2007 Dec; 16 Suppl 1:S149-52
7.    Deng HJ, Wei ZG, Zhen L et al. Clinical application of perioperative continuous
      hyperthermic peritoneal perfusion chemotherapy for gastric cancer. Nan Fang Yi
      Ke Da Xue Xue Bao. 2009 Feb; 29(2): 295-7.
8.    Di Giorgio A, Naticchioni E, Biacchi D, et al. Cytoreductive surgery
      (peritonectomy procedures) combined with hyperthermic intraperitoneal
      chemotherapy (HIPEC) in the treatment of diffuse peritoneal carcinomatosis
      from ovarian cancer. Cancer. 2008 Jul 15; 113(2): 315-25.
9.    Elias D, Lefevre JH, Chevalier J, et al. Complete cytoreductive surgery plus
      intraperitoneal chemohyperthermia with oxaliplatin for peritoneal carcinomatosis
      of colorectal origin. J Clin Oncol. 2009 Feb 10; 27(5): 681-5.
10.   Elias D, Benizri E, Di Pietrantonio D et al. Comparison of two kinds of
      intraperitoneal chemotherapy following complete cytoreductive surgery of
      colorectal peritoneal carcinomatosis. Ann Surg Oncol. 2007 Feb; 14(2): 509-14
11.   Esquivel J, Elias D, Baratti D, et al. Consensus statement on the loco regional
      treatment of colorectal cancer with peritoneal dissemination. J Surg Oncol. 2008
      Sep 15; 98(4): 263-7.
12.   Fagotti A, Paris I, Grimolizzi F et al. Secondary cytoreduction plus oxaliplatin-
      based HIPEC in platinum-sensitive recurrent ovarian cancer patients: a pilot
      study. Gynecol Oncol. 2009 Jun; 113(3): 335-40.
13.   Franko J, Gusani NJ, Holtzman MP et al. Multivisceral resection does not affect
      morbidity and survival after cytoreductive surgery and chemoperfusion for
      carcinomatosis from colorectal cancer. Ann Surg Oncol. 2008 Nov; 15(11):
      3065-72.
14.   Fujimoto S, Takahashi M, Mutou T et al. Successful intraperitoneal hyperthermic
      chemoperfusion for the prevention of postoperative peritoneal recurrence in
      patients with advanced gastric carcinoma. Cancer. 1999 Feb 1; 85(3): 529-34
15.   Fujimoto S, Takahashi M, Mutou T et al. Improved mortality rate of gastric
      carcinoma patients with peritoneal carcinomatosis treated with intraperitoneal
      hyperthermic chemoperfusion combined with surgery. Cancer. 1997 Mar 1;
      79(5): 884-91.
16.   Fujimura T, Yonemura Y, Muraoka K, et al. Continuous hyperthermic peritoneal
      perfusion for the prevention of peritoneal recurrence of gastric cancer:
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17.   Glehen O, Schreiber V, Cotte E, et al. Cytoreductive surgery and intraperitoneal
      chemohyperthermia for peritoneal carcinomatosis arising from gastric cancer.
      Arch Surg. 2004 Jan; 139(1): 20-6.




Interperitoneal Hyperthermic Chemotherapy for Abdominopelvic Cancers Nov 11         25
18. Hamazoe R, Maeta M, Kaibara N. Intraperitoneal thermochemotherapy for
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    randomized controlled study. Cancer. 1994 Apr 15; 73(8): 2048-52.
19. Hayes Medical Technology Directory. Intraperitoneal Hyperthermic
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20. Hayes Medical Technology Directory. Intraperitoneal Hyperthermic
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21. Hayes Medical Technology Directory. Intraperitoneal Hyperthermic
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22. Hesdorffer ME, Chabot J, DeRosa C, Taub R. Peritoneal mesothelioma. Curr
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23. Hirose K, Katayama K, Iida A, et al. Efficacy of continuous hyperthermic
    peritoneal perfusion for the prophylaxis and treatment of peritoneal metastasis
    of advanced gastric cancer: evaluation by multivariate regression analysis.
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24. Katayama K, Yamaguchi A, Murakami M et al. Chemo-hyperthermic peritoneal
    perfusion (CHPP) for appendiceal pseudomyxoma peritonei. Int J Clin Oncol.
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25. Kunisaki C, Shimada H, Akiyama H, et al. Therapeutic outcomes of continuous
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26. Lanuke K, Mack LA, Temple WJ. Phase II study of regional treatment for
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27. Laterza B, Kusamura S, Baratti D, et al. Role of explorative laparoscopy to
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28. Lim MC, Kang S, Choi J, et al. Hyperthermic intraperitoneal chemotherapy after
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    ovarian cancer: interim analysis of a phase II study. Ann Surg Oncol. 2009 Apr;
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29. Macrì A, Maugeri I, Trimarchi G, et al. Evaluation of quality of life of patients
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30. Minicozzi A, Borzellino G, Momo EN et al. Treatment of the peritoneal
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31. Müller H, Hahn M, Weller L, Simsa J. Strategies to reduce perioperative
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32. Nesher E, Greenberg R, Avital S et al. Cytoreductive surgery and intraperitoneal
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    mesothelioma: treatment with cytoreductive surgery combined with




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      hyperthermic intraperitoneal chemotherapy. J Chir (Paris). 2008 Sep-Oct;
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33.   Passot G, Cotte E, Brigand C, et al. Peritoneal mesothelioma: treatment with
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34.   Sideris L, Mitchell A, Drolet P et al. Surgical cytoreduction and intraperitoneal
      chemotherapy for peritoneal carcinomatosis arising from the appendix. 1: Can J
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35.   Spiliotis J, Tentes AA, Vaxevanidou A, et al. Cytoreductive surgery and
      hyperthermic intraperitoneal chemotherapy in the management of peritoneal
      carcinomatosis. Preliminary results and cost from two centers in Greece. J
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36.   Varban O, Levine EA, Stewart JH et al. 1: Outcomes associated with
      cytoreductive surgery and intraperitoneal hyperthermic chemotherapy in
      colorectal cancer patients with peritoneal surface disease and hepatic
      metastases. Cancer. 2009 Jun 4.
37.   Verwaal VJ, Bruin S, Boot H, et al. 8-year follow-up of randomized trial:
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      chemotherapy in patients with peritoneal carcinomatosis of colorectal cancer.
      Ann Surg Oncol. 2008 Sep; 15(9): 2426-32.
38.   Verwaal VJ, van Ruth S, Witkamp A, et al. Long-term survival of peritoneal
      carcinomatosis of colorectal origin. Ann Surg Oncol. 2005 Jan; 12(1): 65-71.
39.   Verwaal VJ, van Ruth S, de Bree E et al. Randomized trial of cytoreduction and
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40.   Virzi S, Iusco D, Grassi A, et al. Adjuvant hyperthermic intraperitoneal
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      30
41.   Yang XJ, Li Y, al-shammaa Hassan AH et al. Cytoreductive surgery plus
      hyperthermic intraperitoneal chemotherapy improves survival in selected
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42.   Yonemura Y, de Aretxabala X, Fujimura T et al. Intraoperative
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Interperitoneal Hyperthermic Chemotherapy for Abdominopelvic Cancers Nov 11                               34
The Policies do not constitute authorization or guarantee of coverage of particular procedure, drug, service
or supply. Members and providers should refer to the Member contract to determine if exclusions,
limitations, and dollar caps apply to a particular procedure, drug, service or supply.

Policy Limitation: Member’s Contract Controls Coverage Determinations.
The determination of coverage for a particular procedure, drug, service or supply is not based upon the
Policies, but rather is subject to the facts of the individual clinical case, terms and conditions of the
member’s contract, and requirements of applicable laws and regulations. The contract language contains
specific terms and conditions, including pre-existing conditions, limitations, exclusions, benefit maximums,
eligibility, and other relevant terms and conditions of coverage. In the event the Member’s contract (also
known as the benefit contract, coverage document, or evidence of coverage) conflicts with the Policies,
the Member’s contract shall govern. Coverage decisions are the result of the terms and conditions of the
Member’s benefit contract. The Policies do not replace or amend the Member’s contract. If there is a
discrepancy between the Policies and the Member’s contract, the Member’s contract shall govern.

Policy Limitation: Legal and Regulatory Mandates and Requirements.
The determinations of coverage for a particular procedure, drug, service or supply is subject to applicable
legal and regulatory mandates and requirements. If there is a discrepancy between the Policies and legal
mandates and regulatory requirements, the requirements of law and regulation shall govern.

Policy Limitations: Medicare and Medicaid.
Policies specifically developed to assist Health Net in administering Medicare or Medicaid plan benefits and
determining coverage for a particular procedure, drug, service or supply for Medicare or Medicaid
members shall not be construed to apply to any other Health Net plans and members. The Policies shall
not be interpreted to limit the benefits afforded Medicare and Medicaid members by law and regulation.




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