National Medical Policy

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1 National Medical Policy Subject: Policy Number: Intraperitoneal Hyperthermic Chemotherapy for Abdominopelvic Cancers NMP346 Effective Date*: June 2007 Updated: November 2014 This National Medical Policy is subject to the terms in the IMPORTANT NOTICE at the end of this document For Medicaid Plans: Please refer to the appropriate Medicaid Manuals for coverage guidelines prior to applying Health Net Medical Policies The Centers for Medicare & Medicaid Services (CMS) For Medicare Advantage members please refer to the following for coverage guidelines first: Use Source Reference/Website Link National Coverage Determination (NCD) National Coverage Manual Citation Local Coverage Determination (LCD)* Article (Local)* Other X None Use Health Net Policy Instructions Medicare NCDs and National Coverage Manuals apply to ALL Medicare members 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. *Note: Health Net must follow local coverage determinations (LCDs) of Medicare Administration Contractors (MACs) located outside their service area when those MACs have exclusive coverage of an item or service. (CMS Manual Chapter 4 Section 90.2) Interperitoneal Hyperthermic Chemotherapy for Abdominopelvic Cancers Nov 14 1

2 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. Current Policy Statement Health Net, Inc. considers Intraperitoneal Hyperthermic Chemotherapy (IPHC) as an adjunct to aggressive cytoreductive surgery medically necessary any of the following indications: 1. Treatment of appendiceal carcinoma 2. Prophylactic use for locally advanced gastric cancer without macroscopic peritoneal metastasis or distant metastasis 3. Pseudomyxoma Peritonei 4. Malignant Peritoneal Mesothelioma Health Net, Inc considers the therapeutic use of IPHC as an adjunct to aggressive cytoreductive surgery (i.e. peritonectomy, or peritoneal stripping surgery) 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 HIPEC Hyperthermic intraperitoneal chemotherapy Codes Related To This Policy NOTE: The codes listed in this policy are for reference purposes only. Listing of a code in this policy does not imply that the service described by this code is a covered or noncovered health service. Coverage is determined by the benefit documents and medical necessity criteria. This list of codes may not be all inclusive. On October 1, 2015, the ICD-9 code sets used to report medical diagnoses and inpatient procedures will be replaced by ICD-10 code sets. Health Net National Medical Policies will now include the preliminary ICD-10 codes in preparation for this transition. Please note that these may not be the final versions of the codes and that will not be accepted for billing or payment purposes until the October 1, 2015 implementation date. Interperitoneal Hyperthermic Chemotherapy for Abdominopelvic Cancers Nov 14 2

3 ICD-9 Codes (may not be an all inclusive list) Malignant neoplasm of stomach Malignant neoplasm of the colon Malignant neoplasm of rectosigmoid junction Malignant neoplasm of retroperitoneum and peritoneum Malignant neoplasm of ovary and other uterine adnexa Secondary malignant neoplasm of retroperitoneum and peritoneum Malignant neoplasm without specification of site, disseminated Carcinoma in situ of stomach Neoplasm of uncertain behavior, stomach, intestines, and rectum Neoplasm of uncertain behavior, retroperitoneum and peritoneum Malignant ascites ICD-10 Codes C16.0-C16.9 Malignant neoplasm of stomach C18.0-C18.9 Malignant neoplasm of the colon C19 Malignant neoplasm of rectosigmoid junction C48.0-C48.8 Malignant neoplasm of retroperitoneum and peritoneum C56.1-C56.9 Malignant neoplasm of ovary C78.6 Secondary malignant neoplasm of retroperitoneum and peritoneum C8Ø.Ø Disseminated malignant neoplasm, unspecified DØØ.2 Carcinoma in situ of stomach D37.1 Neoplasm of uncertain behavior of stomach D37.2 Neoplasm of uncertain behavior of small intestine D37.4 Neoplasm of uncertain behavior of colon D37.5 Neoplasm of uncertain behavior of rectum D48.3 Neoplasm of uncertain behavior of retroperitoneum D48.4 Neoplasm of uncertain behavior of peritoneum R18.Ø Malignant ascites CPT Codes Hyperthermia, externally generated; deep (i.e., heating to depths Chemotherapy administration into the peritoneal cavity via indwelling port or catheter HCPCS Codes N/A Scientific Rationale Update November 2014 Per the NCCN Guidelines on Colon Cancer (Version ) aggressive cytoreductive debulking and/or intraperitoneal chemotherapy are not recommended outside the setting a clinical trial. This guideline also notes that adenocarcinomas of he small bowel or appendix are rare cancers for which no NCCN Guidelines exist. However, although data on treatment of appendiceal adenocarcinoma are limited, most patients receive debulking surgery with systemic or intraperitoneal therapy. NCCN (2015) also notes that approximately 17% of patients with metastatic colorectal cancer have peritoneal carcinomatosis, with 2% having the peritoneum as Interperitoneal Hyperthermic Chemotherapy for Abdominopelvic Cancers Nov 14 3

4 the only site of metastasis. Patients with peritoneal metastasis generally have a shorter overall survival than those without peritoneal involvement. The goal of treatment for most abdominal/peritoneal metastases is palliative, rather than curative and consists of systemic therapy with palliative surgery or stenting if needed. Per Swanson, (UpToDate, 2013) aggressive cytoreductive surgery and IPHC are less likely to produce lasting benefit for mucinous peritoneal carcinomatosis, and patient selection is critical. Rapid recurrence of the peritoneal surface disease, combined with progression of nodal or extraperitoneal systemic disease, interferes with longterm benefit. This approach is best suited to asymptomatic patients with small volume peritoneal carcinomatosis who are likely to be successfully cytoreduced (leaving behind deposits <2.5 mm) with surgical debulking. Scientific Rationale Update November 2013 In the NCCN guidelines on Colon and Rectal Cancer (Version 1, 2014) notes the following: The NCCN panel currently considers the treatment of disseminated carcinomatosis with cytoreductive surgery (i.e., peritoneal stripping surgery) and perioperative hyperthermic intraperitoneal chemotherapy (HIPEC) investigational and does not endorse this therapy outside of a clinical trial. However, the panel recognizes the need for randomized clinical trials that will address the risks and benefits association with each of these modalities. The NCCN Guidelines on Gastric Cancer (Version ) has no mention of cytroreductive surgery nor hyperthermic intraperitoneal chemotherapy. Scientific Rationale Update November 2012 Pseudomyxoma Peritonei Pseudomyxoma peritonei (PMP) is characterized by the progressive accumulation of mucinous tumor cells within the abdomen and pelvis. The most common sites of origin of the tumor are the appendix and ovary. The degree of malignant potential is variable; about 50% of patients live 5 years. Seventy-five percent of patients with PMP are women between 45 and 75 years of age. A number of studies have examined the use of cytoreductive surgery plus hyperthermic intraperitoneal chemotherapy as a treatment for pseudomyxoma peritonei. Studies report this treatment is effective and has acceptable morbidity and mortality rates. The largest series of patients reports an operative mortality of 2%, morbidity of 40%, and a median survival of 13 years. Chua et al (2012) evaluated outcome and long-term survival after cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) consolidated through an international registry study. This was a retrospective multi-institutional registry established through collaborative efforts of participating units affiliated with the Peritoneal Surface Oncology Group International. Two thousand two hundred ninety-eight patients from 16 specialized units underwent CRS for PMP. Treatmentrelated mortality was 2% and major operative complications occurred in 24% of patients. The median survival rate was 196 months (16.3 years) and the median progression-free survival rate was 98 months (8.2 years), with 10- and 15-year survival rates of 63% and 59%, respectively. Multivariate analysis identified prior chemotherapy treatment (P <.001), peritoneal mucinous carcinomatosis (PMCA) Interperitoneal Hyperthermic Chemotherapy for Abdominopelvic Cancers Nov 14 4

5 histopathologic subtype (P <.001), major postoperative complications (P =.008), high peritoneal cancer index (P =.013), debulking surgery (completeness of cytoreduction [CCR], 2 or 3; P <.001), and not using HIPEC (P =.030) as independent predictors for a poorer progression-free survival. Older age (P =.006), major postoperative complications (P <.001), debulking surgery (CCR 2 or 3; P <.001), prior chemotherapy treatment (P =.001), and PMCA histopathologic subtype (P <.001) were independent predictors of a poorer overall survival. Reviewers concluded the combined modality strategy for PMP may be performed safely with acceptable morbidity and mortality in a specialized unit setting with 63% of patients surviving beyond 10 years. Minimizing nondefinitive operative and systemic chemotherapy treatments before definitive cytoreduction may facilitate the feasibility and improve the outcome of this therapy to achieve long-term survival. Optimal cytoreduction achieves the best outcomes. Arjona-Sánchez et al (2011) sought to analyze survival rates and prognostic factors in patients undergoing maximal cytoreduction and HIPEC. Thirty patients were selected from a prospective database of records for patients undergoing cytoreduction and HIPEC with mitomycin C or paclitaxel. Overall survival (OS), disease free survival (DFS), and the prognostic factors influencing them, were examined using multivariate analysis. Median follow-up was 44 months (range, 8-144). Histological classification of PMPs was disseminated peritoneal adenomucinosis (DPAM) in 6/30 of cases, PMCA-I in 10/30 and PMCA in 14/30. Complete cytoreduction (CC-0 and CC-1) was achieved in 28/30 of patients and CC-2 in 2/30. Median OS was 111 months (range 0-230) and five-year OS rate was 67%. Median DFS was 53.5 months (range 0-120) and 5-year DFS rate was 44%. Incomplete cytoreduction, lymph node involvement and PCI>20 were associated with poor prognosis for OS, while lymph node involvement, elevated CA-125 levels, unfavourable histology and previous chemotherapy were associated with poor outcomes for DFS. There was morbidity of Grade 3 or higher in 9/30. Post-operative mortality occurred in 1 case. Investigators concluded cytoreduction plus peritonectomy procedures combined with HIPEC is a safe treatment and could improve survival rates. Since the optimal cytoreduction is the primary prognostic factor, patients should be centralized under the care of experienced teams. Ba et al (2011) evaluated the safety and efficacy of HIPEC in the prevention and treatment of PMP recurrence after CRS. Studies published in English before 2010 on HIPEC after CRS for PMP were searched in PubMed database. Each study was carefully evaluated based on pre-determined criteria. Study results were comprehensively displayed in a form. A descriptive systematic review was performed. A total of 11 studies were included. The median survival time of patients in these studies ranged from 25.6 months to 156 months. The ranges of 1-year, 2- year, 3-year, 5-year, and 10-year survival rates were 72%-100%, 55%-96%, 59%- 96%, 52%-96%, and 55%-96%, respectively. The overall complication rate ranged from 2%-15%, and the total perioperative mortality were from 0 to 7%. Reviewers concluded HIPEC after CRS is effective and safe for patients with PMP. Per Youssef et al (2011), reported that PMP, usually originating from a perforated mucinous appendiceal tumor, is optimally treated with complete macroscopic tumor removal (complete cytoreduction) combined with heated intraperitoneal chemotherapy. When complete cytoreduction is not achievable, major tumor debulking is undertaken. The authors report the long-term follow-up of patients undergoing surgery for perforated appendiceal tumors in a national pseudomyxoma center. Between March 1994 and July 2009, 456 patients with pseudomyxoma Interperitoneal Hyperthermic Chemotherapy for Abdominopelvic Cancers Nov 14 5

6 peritonei syndrome from perforated appendiceal tumors underwent surgery. The treatment strategy involved a combination of cytoreductve surgery aiming for macroscopic tumor removal, combined with hyperthermic intraperitoneal chemotherapy with mitomycin C. Where complete tumor removal was not possible, maximal tumor debulking was performed. Perioperative outcomes and predicted 5- and 10-year survival were reported. Overall 15 of 456 (3%) tumors were not resectable at laparotomy. Of the 441 patients who had resection, 289 (66%) had complete cytoreduction and 152 (34%) had major tumor debulking. Postoperative in-hospital mortality was 1.6% and grade 3/4 morbidity was 7%. The Kaplan-Meier method predicted 5- and 10-year overall survival of 69% and 57%, respectively. Five- and 10-year predicted survival was 87% and 74% for the 289 patients who had complete cytoreduction compared with 34% and 23% for the 152 who had major tumor debulking. Authors concluded complete tumor removal was achieved in 289 of 441 (66%) patients with peritoneal dissemination from perforated appendiceal tumors with good long-term survival and probable cure in more than two-thirds. Malignant Peritoneal Mesothelioma Malignant mesothelioma is a rare, highly lethal malignancy of the serosal membranes of the pleura, peritoneum, pericardium, or tunica vaginalis testes. The peritoneum is the second most frequent site of origin of mesothelioma, following the pleura. The pathogenesis of all forms of mesothelioma is strongly associated with industrial pollutants, of which asbestos is the principal carcinogen associated with the disease. The majority of cases of malignant peritoneal mesothelioma (MPM) present with diffuse peritoneal involvement and are variably referred to as diffuse peritoneal mesothelioma, malignant peritoneal mesothelioma or just peritoneal mesothelioma. Diffuse malignant peritoneal mesothelioma (DMPM) is highly aggressive. The neoplasm tends to involve all peritoneal surfaces, producing masses and plaques of tumor that are hard and white. In contrast to pseudomyxoma peritonei, local invasion of intra-abdominal organs, such as the liver, intestine, bladder, and abdominal wall, can occur and encasement of bowel can create a malignant bowel obstruction. Complete surgical resection is usually not possible because of the extent of disease. Systemic chemotherapy and abdominal radiation have been tried, without significant improvement in survival. As with pseudomyxoma peritonei, combined-modality approaches using surgery and IPHC may offer substantial improvements compared to historical controls. There have been several retrospective series using this technique, with median survival rates of 30 to 60 months, and even 5-year survival rates of up to 50%. Based on results of retrospective studies along with the rarity of the disease, a multiinstitutional data registry from eight institutions was created. Yan et al (2009) reported results of this multi-institutional registry study that evaluated CRS combined with HIPEC for DMPM. Chemotherapeutic regimens varied (cisplatin, mitomycin, and doxorubicin were most commonly used), as did the timing and administration of the chemotherapy. The registry included 405 patients with DMPM treated by a uniform approach that used CRS and HIPEC. The primary end point was overall survival. The secondary end point was evaluation of prognostic variables for overall survival. Follow-up was complete in 401 patients (99%). The median followup period for the patients who were alive was 33 months (range, 1 to 235 months). The mean age was 50 years (standard deviation [SD], 14 years). Three hundred eighteen patients (79%) had epithelial tumors. Twenty-five patients (6%) had positive lymph nodes. The mean peritoneal cancer index was 20. One hundred eighty-seven patients (46%) had complete or near-complete cytoreduction. Three Interperitoneal Hyperthermic Chemotherapy for Abdominopelvic Cancers Nov 14 6

7 hundred seventy-two patients (92%) received HIPEC. One hundred twenty-seven patients (31%) had grades 3 to 4 complications. Nine patients (2%) died perioperatively. The mean length of hospital stay was 22 days (SD, 15 days). The overall median survival was 53 months (1 to 235 months), and 3- and 5-year survival rates were 60% and 47%, respectively. Four prognostic factors were independently associated with improved survival in the multivariate analysis: epithelial subtype (P <.001), absence of lymph node metastasis (P <.001), completeness of cytoreduction scores of CC-0 or CC-1 (P <.001), and HIPEC (P =.002). The authors concluded the data suggests that CRS combined with HIPEC achieved prolonged survival in selected patients with DMPM. Votanopoulos et al (2012) performed a retrospective analysis of 868 CRS/HIPEC procedures was performed. Type of primary, functional status, completion of resection, hospitalization, morbidity, mortality, and survival were reviewed. Sixtytwo patients (7.7%) underwent a second CRS/HIPEC, including 33 patients with appendiceal primaries, 8 ovarian, 7 mesotheliomas, 4 colon cancers, and 10 various malignancies. Median follow-up was 60.8 months. Median overall survival in months was 85.3 for appendiceal cancer, 52.9 for mesothelioma, 60.1 for ovarian, and for colon cancer. R1 resection was achieved in 43.5% after both procedures. Median survival after the second cytoreduction was 52.1 months for appendiceal cancer, 21.8 for mesothelioma, 53.9 for ovarian, and 55.7 for colon cancer. Median survival was 55.7 months for R1 resection, 20.3 months for R2a resection, and 15.5 months for R2b-R2c. Median ICU and hospital stay was 1 and 7.5 days, respectively. The 30- day morbidity after the second CRS/HIPEC was 48.4% and mortality was 3.2%. In multivariate analysis, the R status of the second CRS/HIPEC (p = 0.013) and the interval between the 2 procedures (p = 0.009) were significant in predicting improved survival. Investigators concluded in experienced tertiary centers and for selected patients, a repeat CRS/HIPEC procedure has morbidity and mortality similar to the initial cytoreduction. Survival depends primarily on the completion of the repeat cytoreduction and favorable biology of the tumor. Bijelic et al (2012) initiated a Phase II study of adjuvant intraperitoneal pemetrexed combined with intravenous cisplatin for patients undergoing CRS and HIPEC for diffuse malignant peritoneal mesothelioma (DMPM). The treatment consisted of pemetrexed 500mg/m(2) intraperitoneally and cisplatin 50mg/m(2) intravenously given simultaneously on day 1 of every 21 day cycle for 6 cycles. The primary endpoint of the study was treatment related toxicity. From July 2007 until July 2009 ten patients were enrolled. Nine of 10 completed all 6 cycles of adjuvant treatment per protocol. The most common toxicities were fatigue, nausea and abdominal pain grade 1 or 2. There was one grade 3 toxicity consisting of a catheter infection. The median survival for all 10 patients was 33.5 months. Pharmacokinetic analysis of intraperitoneal pemetrexed showed a peritoneal to plasma area under the curve ratio of 70. Investigators concluded their study shows that adjuvant intravenous cisplatin and intraperitoneal pemetrexed can be used following CRS and HIPEC for DMPM with low morbidity. Sugarbaker et al (2012) reported cytoreductive surgery combined with hyperthermic intraperitoneal chemotherapy (HIPEC) is a treatment option for selected patients with pseudomyxoma peritonei (PMP) and diffuse malignant peritoneal mesothelioma (DMPM). Tumor infiltration of the hemidiaphragm requiring partial resection occurs as a result of large volume and/or invasive disease at this anatomic site. Transmission of disease from abdomen to chest is a great danger in this group of patients. From a prospective database, patients who had diaphragm resection and then hyperthermic thoracoabdominal chemotherapy (HITAC) as a component of a Interperitoneal Hyperthermic Chemotherapy for Abdominopelvic Cancers Nov 14 7

8 cytoreductive surgical procedure were identified. Data from control patients receiving HIPEC or hyperthermic intrathoracic chemotherapy (HITOC) were analyzed for comparison. The morbidity, mortality, survival, and recurrence rate within the thoracic space were presented. Thirty patients had partial resection of a hemidiaphragm as part of a cytoreductive surgical procedure that utilized HITAC. The pharmacologic benefit of intracavitary chemotherapy administration was documented with an area under the curve ratio of intracavitary concentration times time to plasma concentration times time of 27 ± 10 for mitomycin C and 75 ± 26 for doxorubicin. Comparing percent chemotherapy absorbed for a ninety-minute treatment showed the largest for HIPEC, then for HITAC, and lowest for HITOC. The incidence of grade 3 and 4 adverse events was 43%. There was no mortality. Adjustments in the chemotherapy dose are not necessary with HITAC. The morbidity was high, the survival was acceptable, and intrathoracic recurrence was low Turner et al (2012) reported median overall survivals of up to 7 years have been observed in series of patients with malignant peritoneal mesothelioma (MPM) selected for operative cytoreduction and HIPEC. Factors associated with good outcome are female gender, age less or equal to 60 years, and the ability to achieve a complete extirpation of all gross peritoneal disease. In patients with symptomatic ascites, complete palliation is achieved in almost all cases. However, this treatment strategy is not without complications and carries a morbidity of 25% and mortality up to 7%. Despite these risks, the best overall survival data have been associated with this surgical approach. The authors noted at their institution, they advocate cytoreduction and HIPEC as the standard management for patients with MPM for whom operative cytoreduction appears possible and safe. The authors believe this treatment approach should be considered as the standard of care for patients with MPM. 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 = ) drug concentrations in the plasma. The investigators concluded surgical and clinical factors may require modifications of drug dose or Interperitoneal Hyperthermic Chemotherapy for Abdominopelvic Cancers Nov 14 8

9 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. 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. Longterm 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 Frenchspeaking 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. Interperitoneal Hyperthermic Chemotherapy for Abdominopelvic Cancers Nov 14 9

10 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 ) 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 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 Interperitoneal Hyperthermic Chemotherapy for Abdominopelvic Cancers Nov 14 10

11 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 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. 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). Interperitoneal Hyperthermic Chemotherapy for Abdominopelvic Cancers Nov 14 11

12 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 L/min, and chemotherapy was administered at 42oC for min. Mitomycin C 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 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% ), 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% ) and 10 months (CI 95% ) 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 Interperitoneal Hyperthermic Chemotherapy for Abdominopelvic Cancers Nov 14 12

13 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, months) and median overall survival 30.3 months (95% confidence interval, ) 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 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. Interperitoneal Hyperthermic Chemotherapy for Abdominopelvic Cancers Nov 14 13

14 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, 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, 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 Interperitoneal Hyperthermic Chemotherapy for Abdominopelvic Cancers Nov 14 14

15 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 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 = ) 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 Interperitoneal Hyperthermic Chemotherapy for Abdominopelvic Cancers Nov 14 15

16 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 = ), 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. 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 (fluorouracilleucovorin) 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 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 Interperitoneal Hyperthermic Chemotherapy for Abdominopelvic Cancers Nov 14 16

17 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). 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 Interperitoneal Hyperthermic Chemotherapy for Abdominopelvic Cancers Nov 14 17

18 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 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 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. Interperitoneal Hyperthermic Chemotherapy for Abdominopelvic Cancers Nov 14 18

19 At this time, the available evidence regarding IPHC for the treatment of PC from various abdominopelvic malignancies is limited to uncontrolled studies and nonrandomized 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 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 Interperitoneal Hyperthermic Chemotherapy for Abdominopelvic Cancers Nov 14 19

20 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 allowed to flow into the peritoneal cavity raising the temperature of the tissues within the cavity to 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 Interperitoneal Hyperthermic Chemotherapy for Abdominopelvic Cancers Nov 14 20