Coverage Policy Manual
Policy #: 1998034
Category: Medicine
Initiated: February 1998
Last Review: November 2018
  Cytoreduction Surgery with Hyperthermic Intraperitoneal Chemotherapy

Description:
Pseudomyxoma Peritonei
 
Pseudomyxoma peritonei is a clinicopathologic disease characterized by the production of mucinous ascites and mostly originates from epithelial neoplasms of the appendix. Appendix cancer is diagnosed in fewer than 1000 Americans each year; less than half are epithelial neoplasms (Maggiori, 2010). As mucin-producing cells of the tumor proliferate, the narrow lumen of the appendix becomes obstructed and subsequently leads to appendiceal perforation. Neoplastic cells progressively colonize the peritoneal cavity and produce copious mucin, which collects in the peritoneal cavity. Pseudomyxoma peritonei ranges from benign (disseminated peritoneal adenomucinosis) to malignant (peritoneal mucinous carcinomatosis), with some intermediate pathologic grades. Clinically, this syndrome ranges from early pseudomyxoma peritonei, usually discovered during imaging or a laparotomy performed for another reason, to advanced cases with a distended abdomen, bowel obstruction, and starvation.
 
The conventional treatment of pseudomyxoma peritonei is surgical debulking, repeated as necessary to alleviate pressure effects. However, repeated debulking surgeries become more difficult due to progressively thickened intra-abdominal adhesions, and this treatment is palliative, leaving visible or occult disease in the peritoneal cavity (Elias, 2008).
 
Peritoneal Carcinomatosis of Colorectal Origin
 
Peritoneal dissemination develops in 10% to 15% of patients with colon cancer. Treatment Despite the use of increasingly effective regimens of chemotherapy and biologic agents to treat advanced disease, peritoneal metastases are associated with a median survival of 6 to 7 months.
 
Peritoneal Carcinomatosis of Gastric Origin
 
Peritoneal carcinomatosis is detected in more than 30% of patients with advanced gastric cancer and is a poor prognostic indicator. The median survival is 3 months, and 5-year survival is less than 1% (Yonemura, 2007).Sixty percent of deaths from gastric cancer are attributed to peritoneal carcinomatosis (Yonemura, 2009).
 
Current chemotherapy regimens are nonstandard, and peritoneal seeding is considered unresectable for cure (Delotte, 2014).
 
Peritoneal Mesothelioma
 
Malignant mesothelioma is a relatively uncommon malignancy that may arise from the mesothelial cells lining the pleura, peritoneum, pericardium, and tunica vaginalis testis. In the United States, 200 to 400 new cases of diffuse malignant peritoneal mesothelioma are registered every year, accounting for 10% to 30% of all-type mesothelioma.6 Diffuse malignant peritoneal mesothelioma has traditionally been considered a rapidly lethal malignancy with limited and ineffective therapeutic options (Baratti, 2011). The disease is usually diagnosed at an advanced stage and is characterized by multiple variably sized nodules throughout the abdominal cavity. As the disease progresses, the nodules become confluent to form plaques, masses, or uniformly cover peritoneal surfaces. In most patients, death eventually results from locoregional progression within the abdominal cavity. In historical case series, treatment by palliative surgery, systemic or intraperitoneal chemotherapy, and abdominal irradiation has resulted in a median survival of 12 months (Baratti, 2011).
 
Surgical cytoreduction (resection of visible disease) in conjunction with hyperthermic intraperitoneal chemotherapy (HIPEC) is designed to remove visible tumor deposits and residual microscopic disease. By delivering chemotherapy intraperitoneally, drug exposure to the peritoneal surface is increased some 20-fold compared with systemic exposure. In addition, previous animal and in vitro studies have suggested that the cytotoxicity of mitomycin C is enhanced at temperatures greater than 39°C (102.2°F).
 
Ovarian Cancer
 
Several different types of malignancies can arise in the ovaries; epithelial carcinoma is the most common, accounting for 90% of malignant ovarian tumors. Epithelial ovarian cancer is the fifth most common cause of cancer death in women in the United States. Most ovarian cancer patients (>70%) present with widespread disease, and annual mortality is 65% of the incidence rate.
 
Current management of advanced epithelial ovarian cancer is cytoreductive surgery (CRS) followed by combination chemotherapy. Tumor recurrences are common, and the prognosis for recurrent disease is poor. CRS plus HIPEC in combination with systemic chemotherapy is being studied for primary and recurrent disease. Because HIPEC is administered at the time of surgery, treatment-related morbidity may be reduced compared with intraperitoneal chemotherapy administered postoperatively.
 
CRS plus HIPEC
 
CRS includes peritonectomy (ie, peritoneal stripping) procedures and multivisceral resections, depending on the extent of intra-abdominal tumor dissemination (Glockzin, 2009). CRS may be followed intraoperatively by the infusion of intraperitoneal chemotherapy, most commonly mitomycin C. The intraperitoneal chemotherapy may be heated, which is intended to improve the tissue penetration, and this is referred to as HIPEC. Inflow and outflow catheters are placed in the abdominal cavity, along with probes to monitor temperature. The skin is then temporarily closed during the chemotherapy perfusion, which typically runs for 1 to 2 hours.
 
CRS plus HIPEC is being evaluated for the following conditions:
 
· Pseudomyxoma peritonei;
· Peritoneal carcinomatosis of colorectal, gastric, or endometrial origin;
· Peritoneal mesothelioma;
· Ovarian cancer; and
· Appendiceal goblet cell tumors.
 
Regulatory Status
 
Mitomycin, carboplatin, and other drugs used for HIPEC have not been approved by the U.S. Food and Drug Administration (FDA) for this indication. Cyclophosphamide and nitrogen mustard are FDA-approved for intraperitoneal administration, but neither is used regularly for this purpose (Yan, 2010).
 
Several peritoneal lavage systems (FDA product code: LGZ) have been cleared for marketing by FDA through the 510(k) process to provide “warmed, physiologically compatible sterile solution” (eg, Performer® HT perfusion system; RanD Srl). None has received marketing approval or clearance to administer chemotherapy. FDA has issued warnings to manufacturers of devices that are FDA-cleared for peritoneal lavage using sterile saline solutions when these devices are marketed for off-label use in HIPEC (eg, ThermaSolutions; Belmont Instrument) (FDA, 2018).

Policy/
Coverage:
Effective November 2018
 
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
 
Cytoreductive surgery with intraoperative chemotherapy meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes for the treatment of:
 
    • pseudomyxoma peritonei;
    • diffuse malignant peritoneal mesothelioma; and
    • in newly diagnosed epithelial ovarian or fallopian tube cancer at the time of interval cytoreductive surgery when ALL of the following criteria are met:
 
        • the patient has stage III disease
        • The patient is not eligible for primary cytoreductive surgery or surgery had been performed but was incomplete and will receive neoadjuvant chemotherapy and subsequent interval debulking surgery; and
        • It is expected that complete or optimal cytoreduction can be achieved at time of the interval debulking surgery.
 
 
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
 
Cytoreductive surgery with intraoperative chemotherapy does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes for the treatment of peritoneal carcinomatosis from colorectal cancer, gastric cancer, endometrial cancer; and all other indications, including goblet cell tumors of the appendix.
 
For contracts without primary coverage criteria, cytoreductive surgery with intraoperative chemotherapy is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
 
Cytoreductive surgery with intraoperative chemotherapy in all other settings to treat ovarian cancer, including but not limited to stage IIIC or IV ovarian cancer, does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.
 
For contracts without primary coverage criteria cytoreductive surgery with intraoperative chemotherapy in all other settings to treat ovarian cancer, including but not limited to stage IIIC or IV ovarian cancer is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
 
Effective Prior to November 2018
 
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
 
Cytoreductive surgery with intraoperative chemotherapy meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes for the treatment of:
 
    • pseudomyxoma peritonei; and
    • diffuse malignant peritoneal mesothelioma.
 
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
 
Cytoreductive surgery with intraoperative chemotherapy does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes for the treatment of peritoneal carcinomatosis from colorectal cancer, gastric cancer, endometrial cancer; ovarian cancer; and all other indications, including goblet cell tumors of the appendix. This procedure is the subject of ongoing clinical trials in this indication.
 
For contracts without primary coverage criteria, cytoreductive surgery with intraoperative chemotherapy is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
 
Effective, Prior to January 2015
 
Cytoreductive surgery with intraoperative chemotherapy meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes for the treatment of:
    • pseudomyxoma peritonei; and
    • diffuse malignant peritoneal mesothelioma.
 
Cytoreductive surgery with intraoperative chemotherapy does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes for the treatment of peritoneal carcinomatosis from colorectal cancer.  This procedure is the subject of ongoing clinical trials in this indication.
 
For contracts without primary coverage criteria, cytoreductive surgery with intraoperative chemotherapy is considered investigational.  Investigational services are specific contract exclusions in most member benefit certificates of coverage.
 
Effective, prior to November 2011
Cytoreduction with intraoperative chemotherapy, with or without hyperthermia, or cytoreduction and early postoperative intraperitoneal chemotherapy, for the treatment of peritoneal carcinomatosis of any origin does not meet primary coverage criteria.  This technique continues to the be subject of ongoing trials to determine optimal patient selection and long term safety and effectiveness.  There is no consensus about drugs, doses, times, or technique.  
 
For contracts without primary coverage criteria cytoreduction with intraoperative chemotherapy, with or without hyperthermia, or cytoreduction and early postoperative intraperitoneal chemotherapy, for the treatment of peritoneal carcinomatosis of any origin is considered investigational.  Investigational services are an exclusion in the member benefit certificate.  
 
Effective prior to 9/9/10
 
Numerous phase II and III trials evaluating Hyperthermic Intraperitoneal Chemotherapy following Cytoreduction Surgery (HIPEC) following cytoreduction surgery in ovarian, peritoneal, colorectal, and appendiceal cancers are presently ongoing.  Procedures being studied in ongoing clinical trials do not meet  Primary Coverage Criteria for effectiveness.
 
For contracts without primary coverage criteria, HIPEC is considered investigational.  Investigational services are an exclusion in the member certificate of coverage.

Rationale:
Due to the detail of the rationale, the complete rationale is not available online. If you would like a hardcopy print, please email : codespecificinquiry@arkbluecross.com
2002-2005 Update
Cytoreduction and intraperitoneal hyperthermic chemotherapy has been investigated for the past 15 years, with many single institution case series and phase II trials reported. However, the two key pieces of data are a retrospective multi-institutional case series involving 28 institutions and 506 patients (Glehen, 2004) and the results of a randomized study (Verwaal, 2003). These 2 studies are reviewed in depth.
Multi-institutional Case Series
The study population consisted of patients with peritoneal carcinomatosis related to colorectal cancer who underwent the procedure between 1987 and 2002. Patients with extra-abdominal metastases were excluded. A variety of protocols for intraperitoneal operative chemotherapy were used; mitomycin C was the most common. Some patients also received intraperitoneal chemotherapy in the early postoperative procedure, sometimes after a prior operative infusion. In the early postoperative setting, fluorouracil was most common. A total of 20 patients (4%) died postoperatively. Major complications occurred in 116 patients (22.9%); digestive fistula was the most common major complication, occurring in 8.3% of patients, and was the cause of death in the 7 of the 20 patients who died. At a mean follow-up of 53 months, the morbidity and mortality rates were 22.9% and 4%, respectively, with a median survival of 19.2 months. Subgroup analysis of outcomes based on the completeness of resection reported that patients with complete resection of macroscopic disease had a median survival of 32.4 months compared to only 8 months in those cases for which complete resection was not possible. The completeness of resection was the most significant prognostic indicator. The overall recurrence rate was 73.3%, with peritoneal recurrences noted in 41.9% of patients. The authors concluded that these results echoed those reported in small case series.
Randomized Study
While studies were considered promising, patient bias could not be excluded, particularly because patients with better prognoses might be preferentially recruited for an aggressive surgical approach. To address these issues, a single institution study was undertaken that randomized 105 patients with peritoneal carcinomatosis to receive standard treatment with systemic chemotherapy (fluorouracil and leucovorin) and palliative surgery, if necessary (i.e., treatment of bowel obstruction) or to a second arm consisting of aggressive cytoreduction and intraperitoneal chemotherapy followed by standard systemic chemotherapy (Verwaal, 2003). Patients with other sites of metastases, i.e., lung or liver, were excluded. The cytoreductive procedure consisted of stripping the parietal peritoneum and resection of infiltrated viscera, if possible. Most often resection of the gall bladder, parts of the stomach, and spleen were performed. The greater omentum was also routinely removed. At the completion of resection, the presence of residual tumor was assessed. Hyperthermic mitomycin C was then administered intraperitoneally for 90 minutes. The most important complications were small bowel leakage and abdominal sepsis, but a total of 24% of patients suffered from severe or life-threatening complications, such as heart failure, arrhythmias, or renal failure. A total of 8 patients (16%) died as the result of treatment at 30 days. The main endpoint was survival, measured from the time of randomization to death from any cause. After a median follow-up of 21.6 months, 20 of 51 patients in the standard therapy group were still alive compared to 30 of 54 patients in the cytoreduction group. Median survival in the control and cytoreduction group was 12.6 months compared to 22.4 months, respectively. Subgroup analysis revealed that survival was particularly poor among patients with either residual tumor measuring greater than 2.5 mm or in patients with tumor involvement in 6 or more regions in the abdomen. In these groups, median survival was only around 5 months, compared to 29 months in patients with no residual tumor.
 
While these results were statistically significant, several issues still remain. In a letter to the editor, Markman )2004) points out that the reported survival benefit may be related primarily to the cytoreduction, with added chemotherapy only contributing to increased morbidity. In another letter, Hildebrandt (2004) raises the same issue, focusing on whether the hyperthermia adds any benefit to the intraperitoneal chemotherapy.  Finally, new targeted systemic treatment options have emerged for colon cancer, specifically cetuximab and bevacizumab, which offer additional palliative options for colon cancer.
 
Aside from the issues of the trial methodology, the results of the trial present complicated risk benefit questions that are not adequately addressed. If the main rationale for cytoreductive surgery is to provide a curative option, data regarding disease recurrence would be important. It is not known whether the survivors in either group are alive with or without disease. If the main rationale for the therapy is palliation in terms of prolonging life or relieving specific symptoms (e.g., related to ascites or bowel obstruction), it is important to determine the quality of life associated with the 10-month improvement in median survival. Quality of life data were not reported in this randomized trial; however, the high incidence of major complications, and the reported mean length of hospitalization of 29 days suggest that this aggressive surgical approach has a significant impact on quality of life. Quality of life was addressed in a separate case series of 64 patients undergoing cytoreductive surgery and intraperitoneal chemotherapy (McQuellon, 2001).  The Functional Assessment of Cancer Therapy focusing on colon cancer (FACT-C), activities of daily living, the brief pain inventory, and depression scales composed the quality of life instruments used. A total of 48 patients completed the assessment prior to and at a mean of 12 days after surgery; 16 of the original 64 patients did not complete the survey either due to death (n=11) or missed appointments. By 6 months’ follow-up, only 39 patients were available, either due to death or continuing dropout. Among the respondents, the overall quality of life decreased significantly from baseline to postsurgery, but improved to greater than baseline at 3 months. However, these data are difficult to interpret without a control group, and owing to the large number of dropouts due to death.
 
2006-2007 Update
A literature search was conducted through 2007. None of the studies identified results supporting changes in  the policy statement. The published studies report on case series treated with this technique but without results from comparable control groups. European investigators reported on results of treating 120 patients with peritoneal carcinomatosis from colorectal cancer with this technique (Cavaliere, 2006). Most received cisplatin and mitomycin-C. Three-year survival was 25.8%, but was 33.5% in those who could be “cytoreduced.”
 
Some studies have evaluated factors that may help to predict better prognosis for patients who have this procedure. da Silva and colleagues (2006) reported that a limited volume of carcinomatosis observed at cytoreduction and negative lymph nodes at the time of primary operation were associated with a favorable long-term result.  However, none of the studies address the concerns discussed previously.
 
In a study somewhat similar to this approach, European investigators (Nordinger, 2005) concluded that adjuvant fluorouracil-based regional chemotherapy (intraperitoneal or intraportal) did not add further benefit to that obtained with systemic chemotherapy alone in patients with stage II-III colorectal cancer.  In this study, overall 5-year survival was 72.3% for those who received regional and systemic chemotherapy compared with 72.0% for those who received only systemic chemotherapy.
 
2008 Update
The policy was updated with a literature review through May 2008 using MEDLINE®. The published literature continues to report on uncontrolled series, many from specialized centers. For example, van Leeuwen (2008) reported on the experience in a Swedish series of 103 patients treated from between 2003 and 2006.  This study was to explore factors associated with postoperative morbidity and survival. While postoperative mortality in this center was less than 1%, postoperative morbidity was 56%. Tumor type and optimal cytoreduction influenced survival. In this uncontrolled series, at 2 years overall survival was estimated at 72% and disease-free survival was 34%. Gusani (2008) reported results for a series of 122 patients who underwent this treatment for peritoneal carcinomatosis between 2002 and 2005.  Patients had a number of malignancies, including ovarian cancer (13%) and peritoneal mesothelioma (12%). Overall morbidity was 56%, major morbidity was 30%, and 30-day mortality was 1.6%. Abdominal complications were the most common major morbidity; this included abscess, fistula, and anastomotic leak. The most favorable diagnosis was appendiceal cancer with a reported 2-year survival of 67%. The authors note that controlled studies are needed to help define the role of this procedure in patients with peritoneal carcinomatosis.
 
2010 Update
The randomized study by Verwaal (2008) reported an 8-year follow-up of all patients still alive until 2007.  This update was with a minimum follow-up of 6 years for all patients (median 94 months; range 72–115 months). During the follow-up, 1 patient crossed over from the standard arm to the hyperthermic intraperitoneal chemotherapy (referred to in this study as “HIPEC”) arm after recurrent disease at 30 months after randomization (the standard arm being systemic chemotherapy only and the HIPEC arm systemic chemotherapy, cytoreductive surgery and hyperthermic intraperitoneal chemotherapy). At the time of this long-term follow-up, in the standard arm, 4 patients were still alive, 2 with disease and 2 without, and in the HIPEC arm, 5 patients were still alive, 2 with disease and 3 without. Disease-specific survival was reported as 12.6 months in the standard arm and 22.2 months in the HIPEC arm (p=0.028), and progression-free survival was 7.7 months in the standard arm and 12.6 months in the HIPEC arm (p=0.02).
 
An editorial addressing this randomized trial commented that while this study shows that cytoreductive surgery and HIPEC with systemic chemotherapy nearly doubles survival compared to systemic chemotherapy alone, it does not show how much of this benefit is derived from the surgery and how much from the HIPEC (Levine, 2008).
 
Cao and colleagues (2009) published a systematic review and meta-analysis of cytoreductive surgery (CRS) with perioperative intraperitoneal chemotherapy (PIC) for peritoneal carcinomatosis of colorectal origin.  They identified only 2 RCTs, 2 controlled observational studies, 3 multi-institutional studies and 40 case-series studies.  Primary sites other that colorectal were included in the patient population.  PIC might include hyperthermic intraperitoneal chemotherapy (HIPEC) and/or early postoperative intraperitoneal chemotherapy (EPIC) which might consist of normothermic intraperitoneal chemotherapy of various regimens.   They concluded that there was a significant improvement in survival associated with CRS and HIPEC compared with a palliative approach.  They expressed a need for further evaluation of the prognostic significance of lymph node and liver involvement.  Despite the encouraging data for CRS and PIC, caution for widespread use is advised:  characteristics of patients differed across treatment centers and individual trials; exclusion criteria differed in age limitations, liver involvement and node metastasis; mortality rates ranged from 0% to 12%; perioperative morbidity ranged from 14.8% to 57% but grading of morbidities varied in detail between studies.  
 
Glehen et al, 2010, published results of a retrospective, 25 French-speaking centers, review of 1290 patients with nongynecologic peritoneal carcinomatosis.  Fifty-two percent had received previous neoadjuvant or palliative systemic chemotherapy.  Eighty-six percent of patients received HIPEC and 17% received EPIC (3% received EPIC and HIPEC).  HIPEC procedures had variations in exposure techniques, drugs, duration, intraperitoneal temperatures, type of perfusate and flow rates.  In the postoperative period (30 days) there was a 4.1% mortality and major complications in 33.6% with 14% requiring reoperation.  Factors significantly increasing morbidity/mortality risk included increasing age, extent of the carcinomatosis assessed by the Peritoneal Cancer Index, and the experience of the institution where the procedure was performed.  Median follow-up was 45.3 months with 1-year, 3-year, and 5-year overall survival rates of 77%, 49% and 37% respectively, with corresponding disease-free survival rates of 55%, 28% and 22% respectively.  Overall median survival was 34 months but  much higher for those with pseudomyxoma peritonei (not reached) and appendiceal adenocarcinoma (77 months), and slightly higher for peritoneal mesothelioma (44 months).  
 
Elias, 2010, reported on a subset of patients from the report by Glehen 2010.  This subset consisted of 523 patients abdominal carcinomatosis arising from colorectal cancer.  All had best surgical effort at cytoreduction surgery:  443 had HIPEC, 84 and EPIC and 9 had both.  Seventy per cent of all patients had previously been treated with systemic chemotherapy that did not include new, targeted molecules.  Median survival for this group was 30.1 months.  For this group the overall 1-year, 3-year and 5-year survival rates were 81%, 41% and 27% respectively, while disease free survival rates were 47%, 15% and 10% respectively.  While the authors of this report suggested this technique should be considered "the current gold standard therapy, when feasible" and editorial (Khatri, 2010) proposed reservations about an article reporting results in a large group of patients treated with a collection of miscellaneous and nonstandardized techniques.  He emphasized this report, as well as previous reports, are unclear about the extent to which each of the components, surgery, HIPEC, EPIC, contributes to the outcome.
 
A trial of patients with peritoneal carcinomatosis randomized to aggressive surgical cytoreduction with or without HIPEC would provide more definitive evidence as to whether the survival advantage seen in the Verwaal trial was due to the extensive surgery rather than the regional chemotherapy. Such a trial is currently underway, NCT00769405.  This trial is still recruiting patients as of Sep 2010.
 
There are other ongoing clinical trials of cytoreduction surgery with hyperthermic intraperitoneal/intrathoracic chemotherapy for gynecologic cancers and mesothelioma in addition to other abdominal malignancies.  
 
2011 Update
 
Pseudomyxoma peritonei
A retrospective, multicenter cohort study evaluated the toxicity and prognostic factors after cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) and/or early postoperative intraperitoneal chemotherapy (EPIC), for diffuse peritoneal disease from malignancies of multiple different histologic origins (Glehen, 2010). The study included 1,290 patients from 25 institutions who underwent 1,344 procedures between 1989 and 2007. HIPEC was performed in 1,154 procedures. Postoperative mortality was 4.1%. The principal origin of peritoneal carcinomatosis was pseudomyxoma peritonei in 301 patients. Exclusion criteria were perioperative chemotherapy performed greater than 7 days after surgery and the presence of extra-abdominal metastases. Median overall survival (OS) for patients with pseudomyxoma peritonei was not reached (median OS for all patients was 34 months).
 
Peritoneal carcinomatosis from colorectal cancer
A retrospective, multicenter cohort study evaluated the toxicity and prognostic factors after CRS and HIPEC and/or EPIC, for diffuse peritoneal disease from malignancies of multiple different histologic origins (Glehen, 2010). The study included 1,290 patients from 25 institutions who underwent 1,344 procedures between 1989 and 2007. HIPEC was performed in 1,154 procedures. Postoperative mortality was 4.1%. The principal origin of peritoneal carcinomatosis was colorectal adenocarcinoma in 523 patients.. Exclusion criteria were perioperative chemotherapy performed greater than 7 days after surgery and the presence of extra-abdominal metastases. The overall median survival for patients with a colorectal primary was 30 months. Independent prognostic indicators in multivariate analysis were institution, histologic origin of the tumor, completeness of CRS, extent of carcinomatosis, and lymph node involvement.
 
Peritoneal mesothelioma
A 2011 systematic review by Baratti and colleagues searched the PubMed literature from 1979-2010 for studies on the clinical management of diffuse malignant peritoneal mesothelioma (DMPM) (Baratti, 2011). The review included 14 studies with a total of 427 patients; of them, 289 patients underwent CRS with HIPEC, EPIC in 2, or both in 106. Series that included patients with well-differentiated or low-grade types of mesothelioma were excluded. All of the included series were prospective non-randomized observational case-series studies without control groups. Mean patient age ranged from 49 to 55.7 years. All of the centers used peritonectomy procedures and multivisceral resections to remove all visible disease. HIPEC protocols varied widely among institutions in terms of technique, drugs, carriers, timing and temperature. Operative mortality and morbidity were reported in 11 mono-institutional series. Operative death rates ranged from 0% to 10.5%. Overall, it occurred in 11 of 373 assessable patients (3.1%). In a multi- institutional series, mortality was 2.2%. Severe and life-threatening complications were analyzed. Morbidity varied from 20 to 41%. For the patients who underwent CRS and HIPEC, median overall survival ranged from 29.5 to 92 months. It was not reached in 3 series, being longer than 100 months in one. The 1-, 2-, 3-, and 5-year overall survival rates varied from 43% to 88%, 43% to 77%, 43% to 70%, and 33% to 68%, respectively. In 4 series, median PFS ranged from 7.2 to 40 months.
 
The largest series in the systematic review was from an international registry study, for which 401 patients (99%) had complete follow-up (Yan, 2009). Of the 401 patients, 92% received HIPEC. Reasons for not receiving HIPEC included EPIC being given instead, intraoperative hemodynamic instability, and reason unclear. The median and 1-, 3-, and 5-year survival were 53 months, 81%, 60%, and 47%, respectively.
 
The review acknowledges the possibility of patient selection bias as an explanation for the superior survival noted with aggressive treatment over more conventional treatment modalities, since patients with poor performance status are generally excluded from CRS and HIPEC. The authors conclude that, even in the absence of controlled data, the evidence suggests that the use of CRS and HIPEC in the treatment of DMPM should be the benchmark against which other treatments should be evaluated.
 
A retrospective, multicenter cohort study evaluated the toxicity and prognostic factors after CRS and HIPEC and/or EPIC, for diffuse peritoneal disease from malignancies of multiple different histologic origins (Glehen, 2010). The study included 1,290 patients from 25 institutions who underwent 1,344 procedures between 1989 and 2007. HIPEC was performed in 1,154 procedures. Postoperative mortality was 4.1%. Principal origin of tumor was peritoneal mesothelioma in 88 patients. Exclusion criteria were perioperative chemotherapy performed greater than 7 days after surgery and the presence of extra-abdominal metastases. Median survival for the patients with mesothelioma was 41 months. Independent prognostic indicators in multivariate analysis were institution, origin of peritoneal carcinomatosis, completeness of CRS, extent of carcinomatosis, and lymph node involvement.
 
National Comprehensive Cancer Network (NCCN) Guidelines and National Cancer Institute (NCI) Physician Query Database (PDQ)
NCCN clinical practice guidelines in oncology for colon cancer (v.1.2012) consider the treatment of disseminated carcinomatosis with cytoreductive surgery and perioperative hyperthermic intraperitoneal chemotherapy to be investigational and do not endorse such therapy outside of a clinical trial.  
NCCN guidelines that specifically address the treatment of appendiceal tumors, pseudomyxoma peritonei and peritoneal mesothelioma are not identified.
 
Two randomized Phase III trials were identified and are outlined in the following paragraphs. A Phase III randomized study of systemic chemotherapy with versus without intraperitoneal chemohyperthermia in patients undergoing surgery for peritoneal carcinomatosis originating from colorectal cancer is ongoing (NCT00769405). Primary outcome is OS. Secondary outcome measures include recurrence-free survival (RFS), treatment toxicity, morbidity from surgical complications and prognostic factors of survival. Expected enrollment is 264, with a trial start date of February 2008.
 
A Phase III randomized pilot study of standard systemic therapy with versus without cytoreduction surgery and hyperthermic intraperitoneal mitomycin C in patients with advanced limited peritoneal dissemination of colon adenocarcinoma is recruiting patients. (NCT01167725) Primary outcome is OS. Secondary outcomes include PFS, quality of life, toxicity burden of these regimens, survival according to patient's peritoneal surface tumor genotype, and comparisons of circulating tumor cells in patients treated with these regimens. Expected enrollment is 340, and trial completion date is June 2011 (estimated).
 
Summary
Pseudomyxoma peritonei
Several case studies and a systematic review on the use of cytoreductive surgery and hyperthermic intraperitoneal chemotherapy have been published. Although no randomized trials or comparative studies have been published, the data have shown consistent, long-term DFS and OS with the use of this technique as compared to historic controls. The coverage statement was changed to include coverage of this indication.
 
Peritoneal mesothelioma
The conventional treatment of peritoneal mesothelioma (diffuse malignant type) has resulted in a median survival of approximately 12 months. Although the data on the use of cytoreductive surgery and perioperative intraperitoneal chemotherapy consists of non-randomized case series without control groups, they have shown a significant prolongation of survival ranging from 29.5 to 92 months. The coverage statement was changed to include coverage of this indication.
 
Peritoneal carcinomatosis from colorectal cancer
Numerous studies with different levels of evidence support the safety and feasibility of cytoreductive surgery and hyperthermic intraperitoneal chemotherapy, and existing data suggest a possible improvement in long-term survival of select patients. However, prospective randomized trials are needed to compare best available systemic therapy with and without cytoreductive surgery and hyperthermic intraperitoneal chemotherapy to determine the exact effects of each step, which are currently unknown. An ongoing Phase III trial (NCT00769405) addresses this question of how much of the survival benefit is derived from the cytoreduction and how much from hyperthermic intraperitoneal chemotherapy, as patients will be randomly assigned to hyperthermic intraperitoneal chemotherapy or no hyperthermic intraperitoneal chemotherapy after complete cytoreductive surgery.
 
2012 Update
A literature search conducted through September 2012 did not identify any new information that would prompt a change in the coverage statement. The status of the phase III clinical trial (NCT00769405) mentioned in the previous policy update is listed as unknown on the clinicaltrials.gov website. The policy statement is unchanged.
 
2013 Update
A literature search was conducted using the MEDLINE database through September 2013.  No new information was identified that would prompt a change in the coverage statement.
 
Peritoneal carcinomatosis from colorectal cancer
De Cuba and colleagues reported a 2013 systematic review and meta-analysis of studies of colorectal cancer patients with both peritoneal and liver metastases who received CRS and HIPEC plus curative resection de Cuba, 2013). In their review, the authors compared the results of studies in this population to those of patients without liver metastases who received modern systemic chemotherapy only (irinotecan, oxaliplatin, and a biologic) or CRS plus HIPEC or EPIC. Median overall survival ranged from 6 to 36 months in patients with liver metastases, from 10 to 24 months in patients (without liver metastases) who received systemic chemotherapy only, and from 19 to 63 months in patients (without liver metastases) who received CRS plus HIPEC or EPIC. Patients with liver metastases had a 24% greater risk of death than those without liver metastases who received CRS plus HIPEC or EPIC (pooled HR: 1.24 [95% CI: 0.96-1.60]; p=NS). The authors observed that comparisons across studies are impaired by lack of standardization of the HIPEC or EPIC procedure (exposure technique, drugs and doses used, duration of exposure, temperature and flow rates). In 2013, the American Society of Peritoneal Surface Malignancies, a consortium of cancer centers performing CRS with HIPEC, published recommendations for standardizing the delivery of HIPEC in colorectal cancer patients with peritoneal dissemination treated in the U.S. to further research in this area (Turaga, 2013).
 
In 2013, Tsilimparis and colleagues reported on quality of life in 90 consecutive patients at their institution who underwent CRS and HIPEC (Tsilimparis,2013). Primary tumors were colorectal (21%), ovarian (19%), pseudomyxoma peritonei (16%), appendiceal (16%), gastric (10%), and peritoneal mesothelioma (13%). Health-related quality of life was assessed using the German version of the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire, which assesses function and symptoms. Each scale/item is scored from 0 to 100, with higher scores indicating higher response (either greater function or greater symptom severity). The proportion of patients who returned questionnaires was 59% at 1 month, 47% at 6 months, 36% at 1 year, 19% at 2 years, and 7% at 3 years. After initial decline in the postoperative period, only constipation improved significantly at 6 months (42 patients). Pain, nausea/vomiting, and dyspnea improved significantly in the 6 patients reporting at 3 years. Mean global health status (patient self-assessment) and emotional function scores returned to baseline in the 17 patients reporting at 2 years, and physical and social function returned to baseline at 3 years. Other symptoms (fatigue, pain, insomnia, anorexia, and diarrhea), functions (role and cognitive), and financial problems worsened from baseline during the follow-up period. The authors acknowledge that quality of life studies in this patient population are complicated by survivor bias, varied primary diagnoses and natural history of disease.
 
In 2013, Klaver and colleagues reported a case series of 18 patients in 3 centers who had peritoneal recurrence of colorectal (13 patients) or appendiceal (5 patients) carcinomatosis and received a second CRS with HIPEC (mitomycin; 14 patients) or EPIC (5-fluorouracil; 3 patients) or both (1 patient) (Klaver, 2013). Median time to recurrence after the primary procedure was 14 months (range: 1–33). Mean peritoneal cancer index (PCI, a summary of both lesion size and distribution of peritoneal surface malignancy used to estimate the likelihood of complete cytoreduction; lower scores are better (Sugarbaker, 2005) was 6.3 on a scale of 39. No patients died within 30 days after the second procedure. During median follow-up of 10 months, 14 patients (78%) experienced a subsequent recurrence, with a median time to recurrence of 4.5 months. One- and 2-year OS were 74% and 50%, respectively.
 
Practice Guidelines and Position Statements
National Comprehensive Cancer Network (NCCN) clinical practice guidelines in oncology for colon cancer (v.3.2013) and for rectal cancer (v. 4.2013) consider the treatment of disseminated carcinomatosis with CRS and HIPEC to be investigational and do not endorse such therapy outside of a clinical trial (NCCN, 2013). NCCN guidelines that specifically address the treatment of appendiceal tumors, pseudomyxoma peritonei and peritoneal mesothelioma were not identified.
 
A 2012 practice parameter from the American Society of Colon and Rectal Surgeons states that the treatment of patients with peritoneal carcinomatosis may include surgical cytoreduction. The role of HIPEC remains “insufficiently defined” (Esquivel, 2007).
 
2014 Update
A literature search conducted through September 2014 did not reveal any new information that would prompt a change in the coverage statement. The key identified literature is summarized below.
 
Tabrizian and colleagues reported review outcomes, at a single tertiary institution, on cytoreductive surgery (CRS) with heated intraperitoneal chemotherapy (HIPEC). Tabrizian and colleagues reported this is an effective but morbid procedure in the treatment of peritoneal carcinomatosis (Tabrizian, 2014).  A total of 170 consecutive patients underwent CRS-HIPEC for peritoneal carcinomatosis between July 2007 and August 2012. The peritoneal cancer index (1-39) was used for peritoneal carcinomatosis (PC) staging. Mitomycin C (88.8%) was administered intraperitoneally at 42 °C for 90 mins. Risk factors associated with major morbidities were analyzed. The Kaplan-Meier method was used for survival analyses. The mean age was 55.1 (±11.3) years, and the majority (77.1%) of patients had complete cytoreduction (CC0-1). Tumor types included colorectal (n = 51, 30.0%), appendiceal (n = 50, 29.4 %), pseudomyxoma peritonei (n = 16, 9.4%), and other (n = 53, 31.2%). Factors associated with major complications were estimated blood loss (>400 ml), length of stay (>1 week), intraoperative blood transfusion, operative time (>6 h), and bowel anastomosis. Intraoperative blood transfusion was the only independent prognostic factor on multivariate analysis (p = 0.031). Median follow-up was 15.7 months (±1.2). The recurrence rates for colorectal and appendiceal carcinoma at 1 and 3 years were 40%, 53.5% and 68%, 79.1%, respectively. The 1- and 3-year overall survival for colorectal and appendiceal carcinomatosis was 74.0%, 32.5% and 89.4%, 29.3%, respectively. Intraoperative peritoneal cancer index (PCI) score (>16) and need for blood transfusion were factors independently associated with poor survival (p < 0.05).
 
The single institution experience of CRS/HIPEC procedures for peritoneal carcinomatosis demonstrates acceptable perioperative outcome and long-term survival. Optimal cytoreduction was achieved in the majority of cases. Intraoperative PCI > 16 was associated with poor survival. This series supports the safety of CRS-HIPEC in selected patients
 
An article written by Beckert and colleagues on the surgical management of peritoneal surface malignancy with respect to tumor type was identified (Beckert, 2013). Peritoneal tumor dissemination is still considered as a terminal disease. For the last two decades, cytoreductive surgery (CRS) combined with intraoperative hyperthermic chemotherapy (HIPEC) has been popularized by Paul Sugarbaker almost doubling survival in selected patients compared with systemic chemotherapy alone. Nowadays, this particular treatment protocol is available in comprehensive cancer centers with reasonable mortality and morbidity. However, patient selection is still challenging. In general, CRS and HIPEC is indicated in primary peritoneal tumours such as mesothelioma and pseudomyxoma peritonei as well as in peritoneal metastases derived from gastrointestinal malignancies and ovarian cancers. Since systemic tumour spread is uncommon in patients with peritoneal metastases, peritoneal tumor dissemination was defined as localised disease within the "compartment abdomen". However, CRS and HIPEC are only beneficial as long as complete cytoreduction is achieved (CC-0 or CC-1). Histopathological parameters, the Sugarbaker peritoneal carcinomatosis index (PCI) and general condition of the patient have been established as patient selection criteria. In primary peritoneal cancers, individual tumor biology is the predominant criterion for patient selection as opposed to intraabdominal tumor load in peritoneal metastases derived from gastrointestinal cancers. In gastric cancer, CRS and HIPEC should be restricted to synchronous limited disease because of its biological aggressiveness. In patients with free floating cancer cells without macroscopic signs of peritoneal spread, however, CRS and HIPEC following preoperative "neoadjuvant" chemotherapy preserves chances for cure. So far, there is no general recommendation for CRS and HIPEC by clinical practice guidelines. In the recent S3 guideline for treatment of colorectal cancer, however, CRS and HIPEC have been included as possible treatment options.
 
2015 Update
A literature search conducted through December 2014 did not reveal any new information that would prompt a change in the coverage statement. The key identified literature is summarized below.
 
Pseudomyxoma Peritonei
Jimenez et al (2014) conducted a retrospective review of a prospective database of patients with peritoneal carcinomatosis maintained by Mercy Medical Center in Baltimore (Jimenez, 2014). Two hundred two patients with peritoneal carcinomatosis from appendiceal cancer who underwent cytoreductive surgery (CRS)/HIPEC (hyperthermic intraperitoneal chemotherapy) were included; 125 patients (62%) had high-grade (HG) tumors (peritoneal mucinous carcinomatosis [PMCA]), and 77 patients (38%) had low-grade (LG) tumors (disseminated peritoneal adenomucinosis [DPAM]). Results for the entire cohort and for subgroups defined by tumor histology are shown in Table 1. In the HG (PMCA) group, Peritoneal Cancer Index (PCI), completeness of cytoreduction, and lymph node status were significantly associated with survival; in the LG (DPAM) group, completeness of cytoreduction was significantly associated with survival.
 
Recurrence
From the same Mercy Medical Center database studied by Jimenez et al (previously described), Sardi et al (2013) identified 26 patients who underwent repeat CRS/HIPEC for peritoneal carcinomatosis recurrence (Sardi, 2013). Sixteen patients (62%) had high-grade PMCA, and 10 patients (38%) had low-grade DPAM. Patients eligible for repeat CRS/HIPEC had Eastern Cooperative Oncology Group performance status 0 to 1. The proportion of patients who had a preoperative PCI score less than 20 (on a scale of 0-39) was 35% before second procedure and 75% before third procedure (1 of 4 patients). There were no 30-day postoperative deaths; postoperative morbidity was 42% after second procedure and 50% after third procedure. After second procedure, 1-, 3-, and 5-year OS was 91%, 53%, and 34%, respectively. After third procedure, 1-year OS was 75%.
 
Lord et al (2014) reported a retrospective cohort study of 512 patients with perforated appendiceal tumors and pseudomyxoma peritonei who received CRS/HIPEC at a single center in the UK and achieved complete cytoreduction (Lord, 2014). Thirty-five (26%) of 137 patients who recurred underwent repeat CRS/HIPEC; median time to recurrence was 26 months. Complete cytoreduction was achieved (again) in 20 patients (57%). Mean OS in patients without recurrence (n=375), patients who recurred and had repeat CRS/HIPEC (n=35), and patients who recurred but did not have repeat CRS/HIPEC (n=102) was 171 months (95% CI, 164 to 178), 130 months (95% CI, 105 to 153) and 101 months (84 to 119), respectively (log-rank test, p=0.001). Five-year survival was 91%, 79%, and 65%, respectively. The incidence of complications was similar between primary and repeat procedures.
 
Large, retrospective cohort studies have consistently shown median and 5-year OS as 47 to 156 months and 41% to 96%, respectively, for patients with pseudomyxoma peritonei who are treated with CRS/HIPEC. One retrospective study of 26 patients who underwent CRS/HIPEC for recurrence indicated 5-year OS of 34%. Procedure-related morbidity and mortality have generally decreased over time to acceptable levels (16% to 49% and 0% to 4%, respectively, in recent studies).
 
Peritoneal Carcinomatosis Gastrointestinal Origin
In 2014, Jafari et al published a retrospective review of surgical outcomes of 694 CRS/HIPEC cases performed for primary and metastatic peritoneal cancer using the National Surgical Quality Improvement Program database maintained by the American College of Surgeons (Jafari, 2014). Cancer diagnosis was unknown in 468 patients (67%). Of the remaining 226 patients, cancer diagnosis was appendiceal in 97 (14%), primary peritoneal in 73 (11%), and colorectal in 56 (8%). Fifteen percent of patients required intraoperative transfusions. Thirty-day mortality and morbidity were 2% and 33%, respectively. Thirty-day readmission and reoperation rates were 11% and 10%, respectively. Incidences of the most common postoperative complications (bleeding requiring transfusion, septic shock, pulmonary complications [on ventilator ≥48 hours, pneumonia, unplanned intubation], and organ or space infections) were 17%, 16%, 15%, and 9%, respectively.
 
Several authors have evaluated prognostic factors for patients undergoing CRS/HIPEC for peritoneal carcinomatosis of gastrointestinal origin. PCI (Elias, 2010)  (a summary of both lesion size and distribution of peritoneal surface malignancy used to estimate the likelihood of complete cytoreduction; lower scores are better (Jimenez, 2014; Elias, 2014; Nikolic, 2014; abrizian, 2014; Vallicelli, 2014), and completeness of cytoreduction (Jimenez, 2014; Vallicelli, 2014; Levine, 2014; Teo, 2013), were consistently associated with survival.
 
 
CRS and HIPEC in Peritoneal Carcinomatosis From Colorectal Cancer
The 1 RCT identified was a 2003 single institution study. Verwaal et al randomly assigned 105 patients with peritoneal carcinomatosis to standard treatment with systemic chemotherapy (fluorouracil and leucovorin) and palliative surgery, if necessary (ie, treatment of bowel obstruction), or to aggressive CRS and HIPEC followed by standard systemic chemotherapy (Verwaal, 2003). Patients with other sites of metastases, ie, lung or liver, were excluded. The cytoreductive procedure comprised stripping the parietal peritoneum and resecting infiltrated viscera, if possible. Most often, the gall bladder, parts of the stomach, and spleen were resected. The greater omentum also was routinely removed. At the completion of resection, the presence of residual tumor was assessed. Hyperthermic mitomycin C was then administered intraperitoneally for 90 minutes. In the cytoreduction group, 4 patients (8%) died as a result of treatment. The most important complications were small bowel leakage and abdominal sepsis, the most common grade 3 and grade 4 adverse events were leukopenia (7 patients [15%]) and gastrointestinal fistula (7 patients [15%]), respectively. The primary end point was OS, measured from the time of randomization to death from any cause. After a median follow-up of 21.6 months, 20 (39%) of 51 patients in the standard therapy group were still alive compared with 30 (55%) of 54 patients in the cytoreduction group (HR for death, 0.55; 95% CI, 0.32 to 0.95; p=0.032). Median OS in the control group was 12.6 months compared with 22.4 months in the cytoreduction group. Subgroup analysis revealed that OS was particularly poor among patients with either residual tumor measuring greater than 2.5 mm or in patients with tumor involvement in 6 or more regions in the abdomen. In these groups, median survival was approximately 5 months, compared with 29 months in patients with no residual tumor.
 
In 2014, the American Society of Peritoneal Surface Malignancies evaluated a clinical tool for selecting appropriate patients for CRS/HIPEC in a retrospective review of 1013 patients (Esquivel, 2014). Patients had peritoneal carcinomatosis from CRC and underwent CRS with (n=705) or without (n=308) HIPEC. The Peritoneal Surface Disease Severity Score (PSDSS) assesses preoperative symptoms, extent of peritoneal dissemination, and primary tumor histology and defines 4 stages by increasing disease severity (stage 1, least severe). For the CRS/HIPEC group, median OS was 41 months; 3-year and 5-year OS was 66% and 58%, respectively; median survival stratified by PSDSS prognostic group was 86, 43, 29, and 28 months for PSDSS stage 1, 2, 3, and 4, respectively; and PSDSS and Cytoreduction Score (a 4-point assessment of cytoreduction after CRS) were statistically associated with survival in multivariate logistic regression.
 
Quality of Life (QoL). Two studies described below were included in 2 systematic reviews published in 2014 that examined QoL outcomes in patients with peritoneal carcinomatosis who underwent CRS/HIPEC.50,51 Both reviews included studies that used structured QoL scales; Shan et al included 15 studies (total N=1583 enrolled patients) (Shan, 2014) 14 of which appeared in the review of 20 studies (total N=1181 respondents) by Seretis et al (Seretis, 2014). No RCTs were identified. Studies were heterogeneous in sample size (median: ~60; range: 5-216), response rate (most <85%), primary cancers (eg, gastrointestinal, ovarian, endometrial, and mesothelioma), QoL scales, and timing of QoL evaluations. Nonetheless, both reviews reported a decline in health-related QoL compared with baseline values up to 4 months after treatment. At 1 year, QoL scores improved to baseline values or above. In random effects meta-analysis of 8 studies (total N=499 enrolled patients), overall health (I2=38%) and emotional health (I2=41%) showed statistically significant improvements compared with baseline, but physical (I2=60%), social (I2=0%), and functional (I2=74%) health did not.50 Improvements were small to medium (standardized mean difference <0.4 for all outcomes). Although this evidence is suggests improvement from baseline in some QoL domains, the absence of parallel control groups limits interpretation of the results.
 
In 2014, Passot et al reported on QoL in 216 patients who underwent CRS/HIPEC for peritoneal carcinomatosis at a single center in France (Passot, 2014). Primary tumors were ovarian (35%), colorectal (26%), pseudomyxoma peritonei (19%), primary serous peritoneal carcinoma (4%), peritoneal mesothelioma (8%), gastric (6%), and other cancers in 1 patient each. QoL was assessed using the validated Gastro-Intestinal QoL Index questionnaire (GIQLI), which assesses symptoms, physical function, feelings, social integration, and effect of any medical intervention or treatment. The proportion of patients who returned questionnaires was 81% at baseline (preoperatively), 90% at 1 month postoperatively, 89% at 3 months and at 6 months, and 74% at 1 year. Mean GIQLI score decreased (worsened) substantially (>10%) from baseline for up to 6 months and, for 3 of 5 QoL domains assessed, returned to baseline at 12 months; mean symptoms and feelings did not return to baseline within 12 months. In multivariate analysis, factors associated with decreased QoL were cancer diagnosis at 3 months; presence of stoma at 6 months; and surgical time greater than 270 min and disease recurrence at 12 months.
 
Recurrence
In 2014, Williams et al reported a case series of 18 patients at a single center in Australia who underwent second CRS with HIPEC with (n=2) or without (n=11) EPIC or EPIC alone (n=4) following recurrence after initial CRS at the same center (Williams, 2014). One patient received no intraperitoneal chemotherapy. HIPEC followed by EPIC used mitomycin, HIPEC without EPIC used oxaliplatin, and EPIC (with or without HIPEC) used 5-fluorouracil.
 
One RCT demonstrated improved survival in patients with peritoneal carcinomatosis due to CRC who received CRS/HIPEC plus systemic chemotherapy compared with patients who received systemic chemotherapy alone. However, procedure-related morbidity and mortality were 98% and 16%, respectively, and systemic chemotherapy regimens did not use currently available biologic agents. Retrospective cohort studies have shown median and 2-year OS of 13 to 63 months and 12% to 83%, respectively. Procedure-related morbidity and mortality were 13% to 56% and 0% to 6%, respectively, similar to that observed in the American College of Surgeons National Surgical Quality Improvement Program. QoL data from uncontrolled studies are insufficient to form conclusions. Several studies indicated that PCI and completeness of cytoreduction are prognostic factors for survival. In 2 retrospective cohort studies of patients who underwent CRS/HIPEC for recurrence (total N=36), 2-year OS was approximately 50%. Procedure-related morbidity was 17% to 67%; there were no procedure-related deaths.
 
Gastric Cancer
Coccolini et al (2014) conducted a systematic review with meta-analysis of intraperitoneal chemotherapy for advanced gastric cancer in patients with or without peritoneal carcinomatosis.57 Literature was searched through 2012, and 20 RCTs that compared surgical treatment (primarily resection) plus intraperitoneal chemotherapy with surgical treatment alone were identified; of these, only 1 open-label RCT from Japan enrolled patients with peritoneal carcinomatosis treated with CRS/HIPEC. Yang et al (2011) randomized 68 patients (1:1) to CRS/cisplatin HIPEC or CRS alone.56 Median OS was 11.0 months (95% CI, 10.0 to 11.9) in the CRS/HIPEC group and 6.5 months (95% CI, 4.8 to 8.2) in the CRS only group (log-rank test, p=0.046). One-, 2-, and 3-year OS in the CRS/HIPEC and CRS only groups were 41.2% and 29.4%, 14.7% and 5.9%, and 5.9% and 0%, respectively. Incidence of serious adverse events was similar between groups (15% in the CRS/HIPEC group vs 12% in the CRS only group).
 
In 2014, Rudloff et al reported results of a preliminary, open-label, Phase 3 RCT in 17 patients from several U.S. centers who had gastric cancer metastatic to liver and lung and peritoneal carcinomatosis (Rudloff, 2014). Eligible patients could, in the opinion of the Principal Investigator, be resected to “no evidence of disease” based on imaging studies or staging laparoscopy. Patients were randomized using a computerized randomization algorithm to receive systemic chemotherapy with FOLFOXIRI (5fluorouracil, leucovorin, oxaliplatin, irinotecan) (n=8) or systemic chemotherapy plus gastrectomy and CRS/oxaliplatin HIPEC (n=9). Median and 1-year OS were 4.3 months and 0%, respectively, in the control group, and 11.3 months and 78%, respectively, in the CRS/HIPEC group (statistical testing not reported). Factors associated with survival more than 1 year in the CRS/HIPEC group were complete cytoreduction and initial PCI of 15 or less. Enrollment to complete a larger planned trial was discontinued due to slow accrual.
 
Yarema et al (2014) conducted a retrospective review of patients who had gastric cancer with peritoneal involvement and underwent HIPEC with (n=20 patients with limited peritoneal metastases) or without (n=10 patients with diffuse peritoneal carcinomatosis and symptomatic ascites) CRS at a single center in the Ukraine (Yarema, 2014). HIPEC used mitomycin-C plus cisplatin. Results were compared with contemporaneous control patients with gastric cancer who received palliative chemotherapy only (n=20 patients with limited peritoneal metastases) or best supportive care (n=10 patients with diffuse peritoneal carcinomatosis and symptomatic ascites). In 20 patients with limited disease who received CRS/HIPEC, median and 1-year OS was 12 months and 69%, respectively, compared with 8 months (log-rank test, p=0.004) and 25%, respectively, in controls. In multivariate analysis, factors statistically associated with survival were extent of peritoneal dissemination and completeness of cytoreduction. In patients with advanced disease who received HIPEC only, median OS was 3.5 months, compared with 2.4 months in controls (log-rank test, p=0.49).
 
In a small retrospective study at a single U.S. center, Kim et al (2014) reported no improvement in median OS (16 months) for patients with gastric cancer and peritoneal carcinomatosis who underwent surgical resection (n=17) or CRS/HIPEC (n=9) (Kim, 2014). One-, 2-, and 3-year OS in the control and CRS/HIPEC groups were 80% and 73%, 49% and 39%, and 49% and 39%, respectively (statistical testing not reported).
 
One small (N=17) RCT showed improved survival in patients with peritoneal carcinomatosis due to gastric cancer who received CRS/HIPEC compared with patients who received chemotherapy alone. Another small (N=68) RCT showed improved survival in patients who received CRS/HIPEC compared with CRS alone. These results were consistent with a retrospective review of 40 patients that showed improved survival with CRS/HIPEC compared with systemic chemotherapy alone, but not with a retrospective review of 26 patients that showed similar survival between CRS/HIPEC and gastric resection.
 
Peritoneal Carcinomatosis From Endometrial Cancer
Three small, non-U.S. cohort studies reported outcomes with CRS/HIPEC for primary (total N=6) or recurrent (confined to the peritoneum; total N=18) endometrial cancer with peritoneal carcinomatosis (Delotte, 2014; Abu-Zaid, 2014; Bakrin, 2010). Patients varied in histopathological subtype of cancer, prior treatment, interval from initial treatment to CRS/HIPEC (range: 0-120 months), preoperative PCI (range: 3-24), and postoperative treatment. All patients underwent CRS and intraoperative HIPEC with cisplatin plus doxorubicin (total N=19) or mitomycin (total N=5). Cytoreduction was complete in 18 patients (75%) and almost complete (minimal residual disease) in 3 patients (12.5%). Of 24 total patients, 5 (21%) died within 1 year (comparable to published survival estimates with systemic chemotherapy (Bakrin, 2010); 3 (12.5%) died at 12-19 months; 11 (46%) were alive and disease-free at the time of publication (median: 34 months; range: 2-125); and 4 (17%) were alive with recurrent disease (median: 21 months; range: 6-28). (One patient was lost to follow-up.) The largest study of 13 patients with primary or recurrent disease reported a median OS of 19 months and median DFS of 11 months.7 In all patients, grade 1 adverse events included anastomotic leak and cisplatin neurotoxicity. More severe complications occurred in 5 patients (21%) and included grade 4 septicemia and pulmonary embolism; pancytopenia and critical illness myopathy; and chronic renal failure. PCI score and completeness of cytoreduction were associated with survival.
 
Peritoneal Mesothelioma
Alexander et al (2013) reported on 211 patients from 3 tertiary care centers in the United States who had malignant peritoneal mesothelioma and had undergone CRS/HIPEC (Alexander, 2013). Results are shown in Table 4. On multivariate analysis, factors statistically associated with favorable outcome were age younger than 60 years, complete or almost complete cytoreduction, low histologic grade, and HIPEC with cisplatin (rather than mitomycin-C). Shetty et al (2014) similarly reported improved OS and reduced hospital stay with carboplatin HIPEC compared with mitomycin-C HIPEC in 44 patients with DMPM (Shetty. 2014).
 
Results of a 2014 systematic review that included 7 studies published after the Baratti et al review were aligned with these findings: Pooled 1-, 3- and 5-year survival estimates were 84%, 59%, and 42 %, respectively (Helm, 2014).
 
Retrospective cohort studies have shown median and 5-year OS of 30 to 92 months and 33% to 68%, respectively, for patients with peritoneal mesothelioma who are treated with CRS/HIPEC. Two studies indicated improved outcomes with platinum-containing HIPEC (cisplatin or carboplatin) compared with mitomycin-C. Procedure-related morbidity and mortality has remained relatively steady over time at approximately 35% and 5%, respectively.
 
Ovarian Cancer
In 2014, Spiliotis et al in Greece reported a single-center RCT of 120 women who had advanced (stage IIIc-IV), recurrent epithelial ovarian cancer after initial treatment with CRS or debulking surgery and systemic chemotherapy (Spiliotis, 2014). Between 2006-2013, eligible women were randomized preoperatively by computer assignment to CRS/HIPEC (using cisplatin plus paclitaxel for platinum-sensitive disease or doxorubicin plus paclitaxel or mitomycin for platinum-resistant disease) or to CRS followed by systemic chemotherapy. More patients in the CRS/HIPEC group had complete cytoreduction compared with the non-HIPEC group (65% vs 55%), and the CRS/HIPEC group had more patients with stage IIIc disease (68%) compared with the non-HIPEC group (60%). In Kaplan-Meier survival analysis, mean OS was 26.7 months in the CRS/HIPEC group versus 13.4 months in the non-HIPEC group (statistical tests not reported, p=0.006). In platinum-sensitive disease, survival was 26.8 months in the HIPEC group versus 15.2 months in the non-HIPEC group (p=0.035), but in platinum-resistant disease, survival did not differ statistically between groups (26.6 months in the HIPEC group vs 10.2 months in the non-HIPEC group; p-value not reported). A statistical test for interaction (treatment x platinum sensitivity) was not reported. Completeness of cytoreduction and PCI score were associated with survival. Treatment-related morbidity and mortality were not reported. Baseline between-group differences in completeness of cytoreduction, which is prognostic for survival, limit interpretation of the trial results.
 
Chiva et al (2015) reviewed CRS/HIPEC for treatment of ovarian cancer in the first- and second-line settings (Chiva, 2014). Eleven cohort studies in the first-line setting (total N=248) and 8 studies in the second-line setting (total N=499) that reported survival outcomes were included. Completeness of cytoreduction was 0 or 1 (minimal residual disease) in 88% and 93% of patients in the first- and second-line cohorts, respectively. In the first-line setting, weighted (for study sample size) median OS was 37 months (range: 27-78), median DFS was 14 months (range: 12-30), and 5-yr OS was 40% (range: 28-72). These results were considered comparable to outcomes observed without HIPEC in the first-line setting. In the second-line setting, which included only patients with chemotherapy-sensitive disease (DFS >6 months after completion of first-line treatment), weighted median OS was 36 months (range: 23-62), and median DFS was 20 months (range: 11-24). These results were inferior to those observed in studies of second-line CRS without HIPEC (median OS: 50-60 months). Severe (grade 3-4) morbidity was 25% and 19% in the first- and second-line cohorts, respectively. Mortality estimates (0%-7% in both cohorts) were similar to those observed in studies of CRS without HIPEC.
 
Bakrin et al reported a literature review in 2014 (Bakrin. 2014). In the first-line setting, 5 cohort studies (total N=184) reported median survival of 42 to 58 months with CRS/HIPEC; in 4 studies of CRS without HIPEC with or without intraperitoneal chemotherapy (total N=287), median survival was 29 to 66 months. For recurrent disease (second-line setting), 3 studies of CRS/HIPEC (total N=586) reported median survival of 38 to 52 months in patients with complete cytoreduction and 11 to 33 months in patients without complete cytoreduction; 3 studies of CRS without HIPEC (total N=460) reported median survival of 45 to 61 months in patients with complete cytoreduction and 8 to 20 months in patients without complete cytoreduction. In both first- and second-line settings, completeness of cytoreduction, extent of peritoneal carcinomatosis, and chemosensitivity to platinum were associated with survival. Overall procedure-related grade 3/4 morbidity and mortality were 2% to 29% and 2% to 5%, respectively. Other retrospective studies in patients with recurrent ovarian cancer have reported similar survival estimates (Le Brun, 2014; Cascales-Campos, 2014).
 
The Bakrin et al (2014) review included 3 non-U.S. case-control studies that compared CRS/HIPEC with CRS alone for recurrent ovarian cancer (total N=104) (Fagotti, 2012; Spiliotis, 2011; Munoz-Casares, 2009). Three- to 5-year survival ranged from 50% to 68% in the CRS/HIPEC groups versus 17% to 42% in the CRS only groups.
 
Cohort studies from Europe (total N=157) reported procedure-related morbidity and mortality of 16% to 42% and 6% to 8%, respectively, in first- and second-line settings (Massari, 2014; Robella, 2014; Konigsrainer, 2014; Coccolini, 2014). Median OS was 35 to 48 months in the first-line setting and 27 to 33 months in the second-line setting and varied by completeness of cytoreduction.
 
Cascales-Campos et al (2014) reported significantly reduced DFS in 9 patients who were age 75 or older at the time of CRS/HIPEC compared with 57 patients who were younger than 75 years (median DFS: 6 months vs 24 months), and significantly increased morbidity (grade 3/4 adverse events: 56% vs 16%) (Cascales-Campos, 2014). The authors suggested that patients 75 years of age or older should not receive CRS/HIPEC for treatment of ovarian cancer.
 
In 2005, Therma Solutions, Inc. sponsored an internet registry of patients with epithelial ovarian cancer who were treated with HIPEC at several participating U.S. institutions. 73 Initial results from 141 (85%) of 166 registered patients were published in 2010. The majority of patients (59%) received second-line HIPEC; others received HIPEC as first-line treatment (18%), for interval debulking (13%), or for consolidation (9%). Median follow-up was 18 months (range: <1-141). Median OS was 30.3 months (95% CI: 23.0 to 37.6), and 2-, 5-, and 10-year OS estimates were 49%, 25%, and 14%, respectively. Survival estimates adjusted for prognostic factors identified in univariate and multivariate analyses (platinum-sensitivity, completeness of cytoreduction, chemotherapy agent[s]used, duration of HIPEC perfusion, and duration of hospital stay) were not reported. Analysis of toxicity was not reported. The published web link to the registry (www.hyperoregistry.com) is currently not functional.
 
CRS/HIPEC has been studied for both primary advanced ovarian cancer and recurrent disease. For recurrent disease (second-line setting), evidence from 1 RCT from Greece and 3 non-U.S. case control studies showed improved survival with CRS/HIPEC compared with CRS without HIPEC. However, treatment groups in the RCT were unbalanced at baseline in completeness of cytroreduction, which has consistently been shown to be associated with survival. Several retrospective cohort studies and systematic reviews of cohort studies did not clearly indicate that HIPEC added to CRS improved upon published survival estimates in patients with ovarian cancer in the first- or second-line setting. Procedure-related morbidity and mortality estimates in the cohort studies were as high as 42% and 8%, respectively; however, these estimates are difficult to interpret in the absence of control arms (eg, CRS without HIPEC). In both first- and second-line settings, completeness of cytoreduction, extent of peritoneal carcinomatosis, and chemosensitivity to platinum have been shown to be prognostic factors.
 
Miscellaneous Tumors
Appendiceal Goblet Cell Tumors
Goblet cell tumors comprise a small proportion of appendiceal tumors (14%-19%).70 Goblet cell are aggressive, often presenting with peritoneal and ovarian metastases. Treatment commonly comprises appendectomy, right-sided hemicolectomy, and lymphadenectomy followed by chemotherapy. Five- and 10-year OS with this approach is 76% and 60%, respectively (Roy. 2014).
 
In a multicenter, retrospective cohort study, McConnell et al (2014) studied appendiceal goblet cell tumors (n=45) and compared outcomes with CRS/HIPEC with those in nonmucinous (n=52) and LG (n=567) and HG (n=89) mucinous appendiceal tumors (McConnell, 2014). All patients had peritoneal malignancy due to advanced disease, but none were identified as having pseudomyxoma peritonei. With a median follow-up of 49 months, patients with goblet cell tumors were found to have survival outcomes better than those in patients with LG mucinous tumors and similar to those in patients with HG mucinous tumors: Three-year OS in patients with goblet cell, LG mucinous, HG mucinous, and nonmucinous tumor was 63%, 81% (log-rank test vs goblet cell tumors, p=0.003), 40% (log-rank test vs goblet cell tumors, p=0.07), and 52% (log-rank test vs goblet cell tumors, p=0.48), respectively. In 489 patients (65%) who achieved complete cytoreduction, the pattern of 3-year DFS outcomes was similar: 43%, 73% (log-rank test vs goblet cell tumors, p<0.001), 44% (log-rank test vs goblet cell tumors, p=0.85), and 44% (log-rank test vs goblet cell tumors, p=0.82), respectively. Adverse events/complications of treatment were not reported. Grade 3/4 surgical complications occurred in approximately 20% of patients in each group.
 
A retrospective cohort study of patients with goblet cell tumors of the appendix reported survival outcomes with CRS/HIPEC that were reduced compared with published 5- and 10-year survival estimates.
 
Ongoing and Unpublished Clinical Trials
A search of online site ClinicalTrials.gov identified 18 active, randomized trials of CRS/HIPEC in patients with appendiceal or CRC (n=7), gastric cancer (n=4), ovarian cancer (n=6), and primary peritoneal cancer (n=1). One trial in patients with CRC (NCT02179489) and 3 of 4 trials in patients with gastric cancer (NCT02240524, NCT01683864, NCT01882933) are investigating prophylactic CRS/HIPEC for the prevention of peritoneal carcinomatosis. Most (4 of 6) trials in patients with ovarian cancer are for recurrent disease; NCT02124421 and NCT01628380 are in the first-line setting.
 
  • NCT01545141; Chemokine-Modulatory Regimen for Recurrent Resectable Colorectal Cancer; estimated enrollment 50; expected completion date Aug 2015.
 
  • NCT01580410; Surgery and Oxaliplatin or Mitomycin C in Treating Patients with Tumors of the Appendix; estimated enrollment 116; expected completion date May 2015.
 
  • NCT01628211; Second Look Laparoscopy in Colorectal Cancer; estimated enrollment 140; expected completion date Dec 2015.
 
  • NCT01815359; ICARuS Post-operative Intraperitoneal Chemotherapy (EPIC) and Hyperthermic Intraperitoneal Chemotherapy (HIPEC) after Optimal Cytoreductinve Surgery (CRS) for Neoplasms of the Appendix, Colon or Rectum with Isolated Peritoneal Metastasis; estimated enrollment 220; expected completion date Mar 2018.
 
  • NCT02231086; Adjuvant HIPEC in High Risk Colon Cancer (COLOPEC); estimated enrollment 176, expected completion date Jan 2022.
 
  • NCT01226394; Trial Comparing Simple Follow-up to Exploratory Laparotomy Plus “in Principle” (Hyperthermic Intraperitoneal Chemotherapy) HIPEC in Colorectal Patients (ProphyloCHIP); estimated enrollment 130; expected completion date Jun 2019.
 
  • NCT01279489; Trial Evaluating Surgery with Hyperthermic Intraperitoneal Chemotherapy (HIPEC) in Treating Patients With a High Risk of Developing Colorectal Peritoneal Carcinomatosis; estimated enrollment 300; expected completion date Oct 2023.
 
  • NCT02158988; Cytoreductive Surgery (CRS) with/without HIPEC in Gastric Cancer with Peritoneal Carcinomatosis (GASTRICPEC); estimated enrollment 180; expected completion date Sep 2017.
 
  • NCT02240524; Efficacy of HIPEXC in the Treatment of Patients with Locally Advanced Gastric Cancer; estimated enrollment 582; expected completion Sep 2017
 
  • NCT01683864; Randomized controlled Trial to Prevent Peritoneal Seeding in Gastric Cancer (HIPEC_Stomach); estimated enrollment 60; expected completion date Sep 2020.
 
  • NCT01882933; D2 Resection and HIPEC (Hyperthermic Intraperitoneal Chemo perfusion) in Locally Advanced Gastric Carcinoma (GASTRICHIP); estimated enrollment 322; expected completion date May 2021.
 
  • NCT02124421; Outcomes in CRS/HIPEC as Initial Treatment of Ovarian, Fallopian Tube and Primary Peritoneal Cancer; estimated enrollment 48; expected completion date Apr 2020.
 
  • NCT02328716; Cytoreduction with our without Intraoperative Intraperitoneal Hyperthermic Chemotherapy (HIPEC) in Patients with Peritoneal Carcinomatosis from Ovarian Cancer, Fallopian Tube or Primary Peritoneal Carconoma (CARCINOHIPEC); estimated enrollment 32; expected completion date Jan 2015.
 
  • NCT01539785; Hyperthermic Intra-peritoneal Chemotherapy (HIPEC) in Ovarian Cancer Recurrence (HORSE); estimated enrollment 158; expected completion date Sep 2018
 
 
 

CPT/HCPCS:
77605Hyperthermia, externally generated; deep (ie, heating to depths greater than 4 cm)
96446Chemotherapy administration into the peritoneal cavity via indwelling port or catheter

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