Hyperthermic Intraperitoneal Chemotherapy for Select Intra-Abdominal and Pelvic Malignancies - CAM 20307

Description
Cytoreductive surgery (CRS) includes peritonectomy (i.e., peritoneal stripping) procedures and multivisceral resections, depending on the extent of intra-abdominal tumor dissemination. CRS may be followed intraoperatively by infusion of intraperitoneal chemotherapy with or without heating, which is intended to improve the tissue penetration of the chemotherapy. When heated, this is referred to as hyperthermic intraperitoneal chemotherapy (HIPEC). CRS and HIPEC have been proposed for a number of intra-abdominal and pelvic malignancies such as pseudomyxoma peritonei and peritoneal carcinomatosis from colorectal, gastric, or endometrial cancer.

For individuals who have pseudomyxoma peritonei who receive CRS plus HIPEC, the evidence includes cohort studies and a systematic review. Relevant outcomes are overall survival, disease-specific survival, quality of life, and treatment-related mortality and morbidity. Uncontrolled studies of primary treatment of pseudomyxoma peritonei with CRS plus HIPEC have reported a median and a 5-year overall survival ranging from 47 to 156 months and 41% to 96%, respectively. Two small retrospective studies, who underwent CRS plus HIPEC for recurrence, indicated 5-year overall survival rates ranging from 34% to 79%. Procedure-related morbidity and mortality have decreased over time. Controlled studies are needed to draw conclusions about the efficacy and safety of CRS plus HIPEC compared with standard treatment (CRS alone). The evidence is insufficient to determine the effects of the technology on health outcomes.

Although no randomized trials or comparative studies have been published, uncontrolled study data have shown consistent, long-term overall survival with use of this technique. Procedure-related morbidity and mortality have decreased over time. Because the prevalence of pseudomyxoma peritonei is very low, conducting high-quality trials is difficult. For these reasons, CRS plus HIPEC may be considered medically necessary for this indication.

For individuals who have peritoneal carcinomatosis of colorectal origin who receive CRS plus HIPEC, the evidence includes a randomized controlled trial (RCT), systematic reviews, and a large number of observational studies. Relevant outcomes are overall survival, disease-specific survival, quality of life, and treatment-related mortality and morbidity. A meta-analysis of controlled studies found that CRS plus HIPEC, compared with traditional therapy without HIPEC, was associated with significantly higher survival rates and was not associated with significantly higher treatment-related morbidity rates. The RCT, in which patients with peritoneal carcinomatosis due to colorectal cancer were followed for at least 6 years, demonstrated improved survival in patients who received CRS plus HIPEC and systemic chemotherapy compared with patients who received systemic chemotherapy alone. However, procedure-related morbidity and mortality rates were relatively high, and systemic chemotherapy regimens did not use currently available biologic agents. The evidence is insufficient to determine the effects of the technology on health outcomes.

For individuals who have peritoneal carcinomatosis of gastric origin who receive CRS plus HIPEC, the evidence includes 2 small RCTs, observational studies, and a systematic review. Relevant outcomes are overall survival, disease-specific survival, quality of life, and treatment-related mortality and morbidity. A 2017 meta-analysis identified 2 RCTs and 12 controlled nonrandomized studies comparing surgery plus HIPEC with standard surgical management in patients who had peritoneal carcinomatosis due to gastric cancer. The meta-analysis found significantly better survival in the surgery plus HIPEC group at 1 year but not at 2 or 3 years. An RCT found better survival in patients who received CRS plus HIPEC compared with an alternative treatment. The evidence is insufficient to determine the effects of the technology on health outcomes.

For individuals who have peritoneal carcinomatosis of endometrial origin who receive CRS plus HIPEC, the evidence includes cohort studies. Relevant outcomes are overall survival, disease-specific survival, quality of life, and treatment-related mortality and morbidity. Only uncontrolled studies with small sample sizes were available (< 25 patients). Randomized trials that compare CRS plus HIPEC with standard treatment (e.g., CRS alone or systemic chemotherapy alone) are needed. The evidence is insufficient to determine the effects of the technology on health outcomes.

For individuals who have peritoneal mesothelioma who receive CRS plus HIPEC, the evidence includes retrospective cohort studies and systematic reviews. Relevant outcomes are overall survival, disease-specific survival, quality of life, and treatment-related mortality and morbidity. Uncontrolled studies have shown median and 5-year overall survival ranging from 30 to 92 months and 33% to 68%, respectively, for patients who had peritoneal mesothelioma treated with CRS plus HIPEC. Reported procedure-related morbidity and mortality were approximately 35% and 5%, respectively. Although no RCTs or comparative studies have been published, uncontrolled study data have shown reasonable rates of overall survival with the use of this technique. Procedure-related morbidity and mortality have remained steady over time. Because the prevalence of peritoneal mesothelioma is very low, conducting high-quality trials is difficult. Thus, although the evidence is insufficient to determine the effects of the technology on health outcomes, for the reasons discussed above, CRS plus HIPEC may be considered medically necessary for this indication.

For individuals who have newly diagnosed stage III ovarian cancer who receive CRS plus HIPEC, the evidence includes an RCT. Relevant outcomes are overall survival, disease-specific survival, quality of life, and treatment-related mortality and morbidity. For patients with newly diagnosed stage III ovarian cancer who had received neoadjuvant chemotherapy, HIPEC increased the time to disease recurrence and reduced mortality. HIPEC did not increase serious adverse events compared with surgery alone. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.

For individuals who have recurrent stage IIIC or IV ovarian cancer who receive CRS plus HIPEC, the evidence includes an RCT and systematic review. Relevant outcomes are overall survival, disease-specific survival, quality of life, and treatment-related mortality and morbidity. For recurrent stage IIIC or IV disease (second-line setting), evidence from an RCT indicated that CRS plus HIPEC improved survival compared with CRS without HIPEC. However, interpretation of this study is limited because treatment groups in this RCT were unbalanced at baseline (variation in the completeness of cytoreduction), which has been shown to be associated with survival. The evidence is insufficient to determine the effects of the technology on health outcomes.

For individuals who have appendiceal goblet cell tumors who receive CRS plus HIPEC, the evidence includes a case series. Relevant outcomes are overall survival, disease-specific survival, quality of life, and treatment-related mortality and morbidity. One retrospective series was identified. Additional studies—preferably controlled and ideally RCTs—are needed. The evidence is insufficient to determine the effects of the technology on health outcomes.

Background 
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 1,000 Americans each year; less than half are epithelial neoplasms.1 The incidence of pseudomyxoma peritonei is estimated at 2 cases per 1 million individuals.2 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 laparotomy performed for another reason, to advanced cases with a distended abdomen, bowel obstruction, and starvation.

Treatment
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.3

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%.4 Sixty percent of deaths from gastric cancer are attributed to peritoneal carcinomatosis.5

Treatment
Current chemotherapy regimens are nonstandard, and peritoneal seeding is considered unresectable for a cure.6

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 U.S., 200 to 400 new cases of diffuse malignant peritoneal mesothelioma are registered every year, accounting for 10% to 30% of all-type mesothelioma.7 Diffuse malignant peritoneal mesothelioma has traditionally been considered a rapidly lethal malignancy with limited and ineffective therapeutic options.7 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 median survival of 12 months.7

Treatment
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 U.S. Most ovarian cancer patients (>70%) present with widespread disease, and annual mortality is 65% of the incidence rate.

Treatment
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.

Regulatory Status
Mitomycin, oxaliplatin, carboplatin, and other drugs used for HIPEC have not been approved by the U.S. Food and Drug Administration (FDA) for this indication.

Several peritoneal lavage systems (FDA product code: LGZ) have been cleared for marketing by the FDA through the 510(k) process to provide "warmed, physiologically compatible sterile solution" (e.g., Performer® HT perfusion system; RanD Srl). None has received marketing approval or clearance to administer chemotherapy. The 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 (e.g., ThermaSolutions8; Belmont Instrument9).

Table 1. Hyperthermic Intraperitoneal Lavage Devices Cleared by the U.S. Food and Drug Administration  

Device Manufacturer Date Cleared 510(k) No. Indication
FluidSmart THERMEDX LLC 9/5/2017 K172048 For irrigation, distention, fluid warming, and fluid volume/deficit measurements in endoscopic procedures within gynecology, urology, and orthopedic disciplines.
Hang&Go PAC RanD S.r.l. 12/28/2016 K161613 To recirculate, filtrate and perfuse physiologically compatible sterile solution (i.e., saline solution) in the thoracic or abdominal cavity
The Belmont Hyperthermia Pump BELMONT INSTRUMENT CORPORATION 9/2/2015 K152208 To raise the temperature of the thoracic or peritoneal cavity to the desired target temperature by continuously lavaging the cavity with circulating warmed sterile solution

Policy
Cytoreductive surgery plus hyperthermic intraperitoneal chemotherapy (HIPEC) at the time of surgery may be considered MEDICALLY NECESSARY for the treatment of:

  • pseudomyxoma peritonei; and
  • diffuse malignant peritoneal mesothelioma.

The use of HIPEC may be considered MEDICALLY NECESSARY 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 (see Policy Guidelines);
  • 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 (see Policy Guidelines); and
  • It is expected that complete or optimal cytoreduction can be achieved at time of the interval debulking surgery (see Policy Guidelines).

The use of HIPEC in all other settings to treat ovarian cancer, including but not limited to stage IIIC or IV ovarian cancer, is considered NOT MEDICALLY NECESSARY

Cytoreductive surgery plus HIPEC are considered NOT MEDICALLY NECESSARY for:

  • peritoneal carcinomatosis from colorectal cancer, gastric cancer, or endometrial cancer; and
  • all other indications, including goblet cell tumors of the appendix.

Policy Guidelines
Ovarian cancer staging is as follows:

  • Stage I: The cancer is confined to the ovary or fallopian tube.
  • Stage II: The cancer involves one or both ovaries with pelvic extension.
  • Stage III: The cancer has spread within the abdomen.
  • Stage IV: The cancer is widely spread throughout the body.

Eligibility for neoadjuvant chemotherapy and interval debulking surgery is based on a high perioperative risk profile (i.e., the patient is a poor candidate to withstand an aggressive initial cytoreductive procedure) or a low likelihood of achieving cytoreduction to less than 1 cm (i.e., the patient has extensive disease that precludes upfront optimal cytoreduction) or surgery has been performed but was incomplete (i.e., after surgery, 1 or more residual tumors measuring >1 cm in diameter were present).

Complete cytoreduction is defined as no visible disease and optimal cytoreduction as 1 or more residual tumors measuring 10 mm or less in diameter remaining.

Coding
Please see the Codes table for details.

Cytoreduction
There is no specific CPT code for the surgical component of this complex procedure. It is likely that a series of CPT codes would be used describing exploratory laparotomies of various components of the abdominal cavity, in addition to specific codes for resection of visceral organs, depending on the extent of the carcinomatosis.

Intraperitoneal Chemotherapy
CPT code 96446 identifies "chemotherapy administration into the peritoneal cavity via indwelling port or catheter." When performed using a temporary catheter or performed intraoperatively, the unlisted code 96549 (unlisted chemotherapy procedure) would be reported.

Hyperthermia
This procedure does not refer to the external application of heat as described by CPT code 77605. There are no codes for the heating of the chemotherapy.

Benefit Application
BlueCard/National Account Issues
Cytoreduction and intraperitoneal hyperthermic chemotherapy is a specialized procedure and may be offered at limited centers. Therefore, out-of-network referral may be requested.

Rationale 
This evidence review was created in June 2005 and has been updated regularly with searches of the PubMed database. The most recent literature update was performed through June 3, 2021.

Evidence reviews assess the clinical evidence to determine whether the use of a technology improves the net health outcome. Broadly defined, health outcomes are length of life, quality of life (QOL), and ability to function-including benefits and harms. Every clinical condition has specific outcomes that are important to patients and to managing the course of that condition. Validated outcome measures are necessary to ascertain whether a condition improves or worsens; and whether the magnitude of that change is clinically significant. The net health outcome is a balance of benefits and harms.

To assess whether the evidence is sufficient to draw conclusions about the net health outcome of a technology, 2 domains are examined: the relevance and the quality and credibility. To be relevant, studies must represent 1 or more intended clinical use of the technology in the intended population and compare an effective and appropriate alternative at a comparable intensity. For some conditions, the alternative will be supportive care or surveillance. The quality and credibility of the evidence depend on study design and conduct, minimizing bias and confounding that can generate incorrect findings. The randomized controlled trial (RCT) is preferred to assess efficacy; however, in some circumstances, nonrandomized studies may be adequate. Randomized controlled trials are rarely large enough or long enough to capture less common adverse events and long-term effects. Other types of studies can be used for these purposes and to assess generalizability to broader clinical populations and settings of clinical practice.

Pseudomyxoma Peritonei
Clinical Context and Therapy Purpose
The purpose of cytoreductive surgery (CRS) plus hyperthermic intraperitoneal chemotherapy (HIPEC) in patients with pseudomyxoma peritonei is to provide a treatment option that is an alternative to or an improvement on existing therapies.

The question addressed in this evidence review is: Does the use of CRS plus HIPEC improve the net health outcome in patients with pseudomyxoma peritonei?

The following PICO was used to select literature to inform this review.

Populations
The relevant population(s) of interest are individuals with pseudomyxoma peritonei.

Interventions
The combination therapy being considered is CRS plus HIPEC.

Cytoreductive surgery includes peritonectomy (i.e., peritoneal stripping) procedures and multivisceral resections, depending on the extent of intra-abdominal tumor dissemination.10 It may be followed 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 the temperature. The skin is then temporarily closed during the chemotherapy perfusion, which typically runs for 1 to 2 hours.

Comparators
The following therapies are currently being used to treat pseudomyxoma peritonei: CRS alone and systemic chemotherapy.

Outcomes
The general outcomes of interest are overall survival (OS), disease-specific survival (eg, progression-free survival [PFS]), QOL, treatment-related mortality, and treatment-related morbidity.

Morbidity and mortality from the procedure are measured in the early postoperative period. Survival outcomes (PFS and OS) should be measured out to 5 years.

Study Selection Criteria
Methodologically credible studies were selected using the following principles:

  • To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs;
  • In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.
  • To assess long-term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.
  • Studies with duplicative or overlapping populations were excluded.

Review of Evidence
Discussion for this indication is divided into primary treatment and treatment for recurrence. Table 2 summarizes relevant studies on CRS plus HIPEC in pseudomyxoma peritonei.

Primary Treatment
Studies describing CRS plus HIPEC as primary treatment in pseudomyxoma peritonei are summarized in Table 2; studies that included at least 60 patients are discussed further in the text below.

Jimenez et al. (2014) retrospectively reviewed a prospective database of patients with peritoneal carcinomatosis maintained by a U.S. medical center.11 Two hundred two patients with peritoneal carcinomatosis from appendiceal cancer who underwent CRS plus HIPEC were included; 125 (62%) patients had high-grade tumors (peritoneal mucinous carcinomatosis), and 77 (38%) patients had low-grade tumors (disseminated peritoneal adenomucinosis). Results for the entire cohort and for subgroups defined by tumor histology are shown in Table 2. In the high-grade peritoneal mucinous carcinomatosis group, Peritoneal Cancer Index (PCI) score (scale range, 0 to 39), completeness of cytoreduction, and lymph node status were significantly associated with survival; in the low-grade disseminated peritoneal adenomucinosis group, completeness of cytoreduction was significantly associated with survival.

Glehen et al. (2010) published a retrospective, multicenter cohort study that evaluated toxicity and prognostic factors after CRS plus HIPEC and/or unheated intraperitoneal chemotherapy for 5 days postoperatively.12 Patients had diffuse peritoneal disease from malignancies of multiple different histologic origins. Exclusion criteria were perioperative chemotherapy performed more than 7 days after surgery and the presence of extra-abdominal metastases. The study included 1290 patients from 25 institutions who underwent 1344 procedures between 1989 and 2007. In 1154 procedures, HIPEC was performed. Postoperative mortality was 4.1%. The principal origin of peritoneal carcinomatosis was pseudomyxoma peritonei in 301 patients. Median OS for patients with pseudomyxoma peritonei was not reached (the median OS for all patients was 34 months ).

Additional information about the subgroup of patients with pseudomyxoma peritonei was provided by Elias et al. (2010).13 Cytoreductive surgery was conducted in 219 (73%) patients, and HIPEC was performed in 255 (85%). The primary tumor site was the appendix in 91% of patients, the ovary in 7%, and unknown in 2%. Tumor histology was disseminated peritoneal adenomucinosis in 51%, peritoneal carcinomatosis with intermediate features in 27%, and peritoneal mucinous carcinomatosis in 22%. The postoperative mortality was 4% and the morbidity rate, 40%. Mean follow-up was 88 months. One-, 3-, and 5-year OS rates were 89.4%, 84.8%, and 72.6%, respectively. The 10-year OS rate was 54.8%. Median OS had not yet been reached but would exceed 100 months. Disease-free survival (DFS) was 56% at 5 years (the median duration of DFS was 78 months). A multivariate analysis identified 5 prognostic factors: extent of peritoneal seeding (p =.004), institution (p <.001), pathologic grade (p =.03), sex (p =.02), and use of HIPEC (p =.04). When only the 206 patients with complete CRS were considered, the extent of peritoneal seeding was the only significant prognostic factor (p =.004).

Chua et al. (2009) reported on the long-term survival of 106 patients with pseudomyxoma peritonei treated between 1997 and 2008 with CRS plus HIPEC and/or unheated intraperitoneal chemotherapy for 5 days postoperatively.14 Sixty-nine percent of patients had complete cytoreduction. Eighty-three (78%) patients had HIPEC intraoperatively, 81 (76%) patients had unheated postoperative intraperitoneal chemotherapy, and 67 (63%) patients had both. Seventy-three patients had disseminated peritoneal adenomucinosis, 11 had peritoneal mucinous carcinomatosis, and 22 had mixed tumors. The mortality rate was 3%, and the severe morbidity rate was 49%. The median follow-up was 23 months (range, 0 to 140 months). The median OS was 104 months with a 5-year OS rate of 75%. Median PFS was 40 months with 1-, 3-, and 5-year PFS rates of 71%, 51%, and 38%, respectively. Factors influencing OS included the histopathologic type of tumor (p =.002), with the best survival in patients with disseminated peritoneal adenomucinosis and worst survival in patients with peritoneal mucinous carcinomatosis. Other factors influencing survival were the use of both HIPEC and unheated postoperative intraperitoneal chemotherapy, completeness of cytoreduction, and severe morbidity.

Vaira et al. (2009) reported on a single institution's experience managing pseudomyxoma peritonei with CRS and HIPEC in 60 patients, 53 of whom had final follow-up data.15 The postoperative morbidity rate was 45%; no postoperative deaths were observed. The primary tumor was appendiceal adenocarcinoma in 72% of patients and appendiceal adenoma in 28%. Approximately half of the patients with adenocarcinoma had received previous systemic chemotherapy. Five- and 10-year OS rates were 94% and 85%, respectively; 5- and 10-year DFS rates were 80% and 70%, respectively. Significant differences in improved OS were observed in patients who had complete CRS (p <.003) and in those with histologic type disseminated peritoneal adenomucinosis compared with those with peritoneal mucinous carcinomatosis (p <.014).

Elias et al. (2008) reported on the results of 105 consecutive patients with pseudomyxoma peritonei treated between 1994 and 2006 with CRS plus HIPEC.3 The primary tumor was the appendix in 93 patients, ovary in 3, urachus in 1, pancreas in 1, and indeterminate in 7. Tumor histology was disseminated peritoneal adenomucinosis in 48% of patients, intermediate in 35%, and peritoneal mucinous carcinomatosis in 17%. At the end of the surgery, 72% of patients had no visible residual peritoneal lesions. The postoperative mortality rate was 7.6% and the morbidity rate was 67.6%. The median follow-up was 48 months, and 5-year OS and PFS rates were 80% (95% confidence interval [CI], 68% to 88%) and 68% (95% CI, 55% to 79%), respectively. On multivariate analysis, 2 factors had a negative influence on DFS: serum carbohydrate antigen 19-9 level (a marker of biliopancreatic malignancy) greater than 300 units/mL and nondisseminated peritoneal adenomucinosis tumor histology.

Table 2. Primary and Recurrence Study Results for CRS Plus HIPEC in Pseudomyxoma Peritonei

Study N Postoperative Mortality/Morbidity, % Median OS, mo 5-Year OS, % Median PFS, mo 5-Year PFS, %
Primary treatment            
Jimenez et al. (2014)11 202 0/16 90 56 40 44
H igh-grade tumor (peritoneal mucinous carcinomatosis) 125 NR 47 41 26 34
L ow-grade tumor (disseminated peritoneal adenomucinosis) 77 NR Not reacheda 83 NR 58
Marcotte et al. (2014)16 58 2/40 NR 77 NR 50b
Glehen et al. (2010)12 301 4/40 34 73 78 56
Chua et al. (2009)14 106 3/49 104 75 40 38
Vaira et al. (2009) 15 60 0/45 NR 94 NR 80
Elias et al. (2008)3 105 8/68 >100 80 NR 68
Yan et al. (2007)17 (SR) NR NR 51 to 156 52 to 96 NR NR
Recurrence            
Lord et al. (2015)18,c 35 NR 129.5e 79 NR NR
Sardi et al. (2013)19,d 26 0/42 NR 34 NR NR

CRS: cytoreductive surgery; HIPEC: hyperthermic intraperitoneal chemotherapy; NR: not reported; OS: overall survival; PFS: progression-free survival; SR: systematic review.
a  Median OS not reached with mean follow-up of 36 months.
b  Five-year disease-free survival.
c  Data from Lord et al. (2015) represents 35 patients who had recurrence and redo CRS plus HIPEC out of 512 patients in the total study cohort.
d  Results after second procedure shown.
e  Mean OS.

Recurrence
From the same U.S. medical center database studied by Jimenez et al. (2014; previously described), Sardi et al. (2013) identified 26 patients who underwent repeat CRS plus HIPEC for peritoneal carcinomatosis recurrence.19 Sixteen (62%) patients had high-grade peritoneal mucinous carcinomatosis and 10 (38%) patients had low-grade disseminated peritoneal adenomucinosis. Patients eligible for repeat CRS plus HIPEC had Eastern Cooperative Oncology Group Performance Status scores of 0 or 1. The proportion of patients who had a preoperative PCI score of less than 20 was 35% before the second procedure and 75% before the third procedure (1/4 patients). There were no 30-day postoperative deaths; postoperative morbidity was 42% after the second procedure and 50% after the third procedure. After the second procedure, 1-, 3-, and 5-year OS rates were 91%, 53%, and 34%, respectively. After the third procedure, the 1-year OS rate was 75%.

Lord et al. (2015) reported on a retrospective cohort study of 512 patients with perforated appendiceal tumors and pseudomyxoma peritonei who received CRS plus HIPEC at a single center in the U.K. and achieved complete cytoreduction.18 Thirty-five (26%) of 137 patients who experienced recurrence underwent repeat CRS plus HIPEC; median time to recurrence was 26 months. Complete cytoreduction was achieved (again) in 20 (57%) patients. The mean OS in patients without recurrence (n=375), patients who recurred and had repeat CRS plus HIPEC (n=35), and patients who recurred but did not have repeat CRS plus HIPEC (n=102) was 171 months (95% CI, 164 to 178 months), 130 months (95% CI, 105 to 153 months), and 101 months (95% CI, 84 to 119 months) across the 3 groups, respectively (p =.001). Five-year survival rates were 91%, 79%, and 65%, respectively. The incidence of complications was similar between primary and repeat procedures.

Section Summary: Pseudomyxoma Peritonei
Retrospective cohort studies and systematic reviews have reported median survival ranging from 47 to 156 months and 5-year OS ranging from 41% to 96% for patients with primary treatment for pseudomyxoma peritonei treated with CRS plus HIPEC. Two retrospective studies reported results of CRS plus HIPEC for recurrence with 5-year OS rates of 34% and 79%. Although no direct comparisons between CRS plus HIPEC and other interventions have been published, traditional surgical debulking is not curative, and complete CRS alone (without HIPEC) has been associated with a 5-year OS of approximately 50%, along with high recurrence rates (91%, with a median DFS of 24 months).3, Median PFS with CRS plus HIPEC as primary treatment has been reported as 40 to 78 months, with 5-year PFS rates of 38% to 80%. Procedure-related morbidity and mortality have generally decreased over time. Because the prevalence of pseudomyxoma peritonei is very low, conducting comparative trials is difficult.

Peritoneal Carcinomatosis of Colorectal Origin
Clinical Context and Therapy Purpose
The purpose of CRS plus HIPEC in patients with peritoneal carcinomatosis of colorectal origin is to provide a treatment option that is an alternative to or an improvement on existing therapies.

The question addressed in this evidence review is: Does the use of CRS plus HIPEC improve the net health outcome in patients with peritoneal carcinomatosis of colorectal origin?

The following PICO was used to select literature to inform this review.

Populations
The relevant population(s) of interest are individuals with peritoneal carcinomatosis of colorectal origin.

Interventions
The combination therapy being considered is CRS plus HIPEC.

Cytoreductive surgery includes peritonectomy (i.e., peritoneal stripping) procedures and multivisceral resections, depending on the extent of intra-abdominal tumor dissemination.10 It may be followed 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 the temperature. The skin is then temporarily closed during the chemotherapy perfusion, which typically runs for 1 to 2 hours.

Comparators
The following therapies are currently being used to treat peritoneal carcinomatosis of colorectal origin: CRS alone and systemic chemotherapy.

Outcomes
The general outcomes of interest are OS, disease-specific survival (eg, PFS), QOL, treatment-related mortality, and treatment-related morbidity.

Morbidity and mortality from the procedure are measured in the early postoperative period. Survival outcomes (PFS and OS) should be measured out to 5 years.

Study Selection Criteria
Methodologically credible studies were selected using the following principles:

  • To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs;
  • In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.
  • To assess long-term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.
  • Studies with duplicative or overlapping populations were excluded.

Review of Evidence
Systematic Reviews
Huang et al. (2017) published a systematic review and meta-analysis of studies assessing CRS plus HIPEC in patients with peritoneal carcinomatosis from colorectal cancer.20 Reviewers included 76 studies published between 1993 and 2016. Fifteen studies were controlled, 1 of which was an RCT, and 61 were uncontrolled studies. In a meta-analysis of the controlled studies, there was a significantly higher survival rate in patients who received CRS plus HIPEC compared with standard therapy (eg, palliative surgery alone or with systemic chemotherapy) (pooled hazard ratio [HR], 2.67; 95% CI, 2.21 to 3.23; I= 0%, p <.001). In sensitivity analyses, date of publication, geographic location of study conduct, and chemotherapy regimen used in the HIPEC procedure did not have a significant impact. In the controlled studies, the mean mortality rate was 4.3% in the CRS plus HIPEC group compared with 6.2% in the traditional treatment group (p =.423). The mean morbidity rate was 19.8% in the CRS plus HIPEC group and 20.5% in the traditional treatment group (p =.815). In all 76 studies, the mean mortality rate was 2.8% and mean morbidity rate was 33%.

Two systematic reviews published in 2014 examined QOL outcomes in patients with peritoneal carcinomatosis who underwent CRS plus HIPEC.21,22 Both reviews included studies that used structured QOL scales; Shan et al. (2014) included 15 studies (N = 1583 patients),21 14 of which appeared in the review of 20 studies (N = 1181 patients) by Seretis et al. (2014).22 No RCTs were identified. Studies were heterogeneous in terms of sample sizes (median, »60 patients; range, 5 to 216 patients), response rates (most <85%), primary cancers (eg, gastrointestinal, ovarian, endometrial, 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 posttreatment. At 1 year, QOL scores improved to baseline values or above. In a random-effects meta-analysis of 8 studies (n = 499 patients), overall health (I= 38%) and emotional health (I= 41%) showed statistically significant improvements compared with baseline, but physical (I= 60%), social (I= 0%), and functional (I= 74%) health did not.21, Improvements were small to medium (standardized mean difference, < 0.4 for all outcomes). Although this evidence would suggest improvements from baseline in some QOL domains, the absence of parallel control groups limits interpretation of the results.

Randomized Controlled Trials
Two RCTs have compared CRS plus HIPEC to CRS alone in patients with peritoneal colorectal metastases. Trials not previously included in the meta-analyses above are summarized in Tables 3 through 6 below.

Quenet et al. (2021) reported results from a randomized, open label RCT comparing CRS plus oxaliplatin-based HIPEC to CRS alone in patients with colorectal cancer and peritoneal metastases (Tables 3 through 6).23 Most patients in the trial achieved complete cytoreduction, and all patients had < 1 mm of residual disease after cytoreduction. After a median follow-up of 63.8 months, the primary endpoint of median OS was not significantly different between groups. Other survival outcomes were also similar between groups. Subgroup analyses did not identify any differences in OS between treatments in any subgroup. Grade 3 or 4 adverse events were similar between groups in the first 30 days post-treatment, but CRS plus HIPEC was associated with higher adverse event rates 31 to 60 days posttreatment. Limitations of this trial include a short duration of HIPEC administration (30 minutes vs. 90 to 120 minutes) and the extensive use of systemic oxaliplatin-based chemotherapy prior to surgery.

Table 3. Summary of Key RCT Characteristics

Study; Trial Countries Sites Dates Participants Interventions
          Active Comparator
Quenet et al. (2021)23 France 17 2008-2014 265 patients aged 18 to 70 years with colorectal cancer with peritoneal metastases, WHO performance status of 0 or 1, and PCI ≤ 25; all patients had complete macroscopic resection or surgical resection with less than 1 mm residual tumor tissue 133 patients received CRS plus HIPEC 132 patients received CRS alone

CRS: cytoreductive surgery; HIPEC; hyperthermic intraperitoneal chemotherapy; PCI: Peritoneal Cancer Index; RCT: randomized controlled trial; WHO: World Health Organization.

Table 4. Summary of Key RCT Results

Study Median OS, mo Median RFS, mo 5-year OS, % 5-year RFS, % Grade 3 or 4 AEs, %
Quenet et al. (2021)23         Days 1 through 30; Days 31 through 60
N     265 265  
CRS alone 41.2 11.1 36.7 13.1 32; 15
CRS plus HIPEC 41.7 13.1 39.4 14.8 42; 26
HR (95% CI) 1.00 (0.63 to 1.58) 0.91 (0.71 to 1.15)      
p .99 .43 NR NR .083;.035

AE: adverse event; CI: confidence interval; CRS: cytoreductive surgery; HIPEC: hyperthermic intraperitoneal chemotherapy; HR: hazard ratio; NR: not reported; OS: overall survival; RCT: randomized controlled trial; RFS: relapse-free survival.

Table 5. Study Relevance Limitations

Study Populationa Interventionb Comparatorc Outcomesd Follow-Upe
Quenet et al. (2021)23 4. Approximately 90% of patients achieved complete cytoreduction, which may have limited the benefit achieved with the addition of HIPEC; patients deemed not amenable to complete resection were excluded from the trial     6. No clinical significant difference found between treatment groups  

The study limitations stated in this table are those notable in the current review; this is not a comprehensive gaps assessment.
HIPEC: hyperthermic intraperitoneal chemotherapy.
Population key: 1. Intended use population unclear; 2. Clinical context is unclear; 3. Study population is unclear; 4. Study population not representative of intended use.
Intervention key: 1. Not clearly defined; 2. Version used unclear; 3. Delivery not similar intensity as comparator; 4. Not the intervention of interest.
c  Comparator key: 1. Not clearly defined; 2. Not standard or optimal; 3. Delivery not similar intensity as intervention; 4. Not delivered effectively.
d  Outcomes key: 1. Key health outcomes not addressed; 2. Physiologic measures, not validated surrogates; 3. No CONSORT reporting of harms; 4. Not establish and validated measurements; 5. Clinical significant difference not prespecified; 6. Clinical significant difference not supported.
e  Follow-Up key: 1. Not sufficient duration for benefit; 2. Not sufficient duration for harms.

Table 6. Study Design and Conduct Limitations

Study Allocationa Blindingb Selective Reportingc Data Completenessd Powere Statisticalf
Quenet et al. (2021)23, 2. Open-label 1 – 3. Not blinded        

The study limitations stated in this table are those notable in the current review; this is not a comprehensive gaps assessment.
Allocation key: 1. Participants not randomly allocated; 2. Allocation not concealed; 3. Allocation concealment unclear; 4. Inadequate control for selection bias.
Blinding key: 1. Not blinded to treatment assignment; 2. Not blinded outcome assessment; 3. Outcome assessed by treating physician.
c  Selective Reporting key: 1. Not registered; 2. Evidence of selective reporting; 3. Evidence of selective publication.
d  Data Completeness key: 1. High loss to follow-up or missing data; 2. Inadequate handling of missing data; 3. High number of crossovers; 4. Inadequate handling of crossovers; 5. Inappropriate exclusions; 6. Not intent to treat analysis (per protocol for noninferiority trials).
e  Power key: 1. Power calculations not reported; 2. Power not calculated for primary outcome; 3. Power not based on clinically important difference.
f  Statistical key: 1. Analysis is not appropriate for outcome type: (a) continuous; (b) binary; (c) time to event; 2. Analysis is not appropriate for multiple observations per patient; 3. Confidence intervals and/or p values not reported; 4. Comparative treatment effects not calculated.

A trial by Verwaal et al. (2003), included in Huang et al. (2017), randomized 105 patients with peritoneal carcinomatosis to standard treatment with systemic chemotherapy (fluorouracil and leucovorin) and palliative surgery, if necessary (i.e., treatment of bowel obstruction), or to CRS plus HIPEC followed by standard systemic chemotherapy.24 Patients with other sites of metastases (i.e., lung or liver) were excluded. The primary endpoint 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 (hazard ratio [HR] for death, 0.55; 95% CI, 0.32 to 0.95; p =.032). The 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 a residual tumor measuring greater than 2.5 mm and 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 the cytoreduction group, 4 (8%) patients died from treatment. The most important complications were small bowel leakage and abdominal sepsis; the most common grade 3 and 4 adverse events were leukopenia (7 [15%] patients) and gastrointestinal fistula (7 [15%] patients), respectively.

Verwaal et al. (2008) reported on the 8-year follow-up to the RCT and evaluated all patients alive until 2007.25 Minimum follow-up was 6 years (median, 7.8 years; range, 6 to 9.6 years). During follow-up, 1 patient crossed over from the standard arm to the CRS plus HIPEC arm after recurrent disease 30 months postrandomization. The median disease-specific survival was 12.6 months in the standard arm and 22.2 months in the CRS plus HIPEC arm (p =.028). Median PFS was 7.7 months in the standard arm and 12.6 months in the CRS plus HIPEC arm (p =.02).

Section Summary: Peritoneal Carcinomatosis of Colorectal Origin
Two RCTs, a number of observational studies, and systematic reviews of these studies have been published. A 2017 systematic review included 76 studies, of which 15 were controlled and 1 was an RCT. In a meta-analysis of the controlled studies, there was a significantly higher survival rate in patients who received CRS plus HIPEC compared with standard therapy (eg, palliative surgery alone or with systemic chemotherapy). Also, in the controlled studies, CRS plus HIPEC was not associated with a significantly higher rate of treatment-related morbidity. One RCT, in which patients were followed for at least 6 years, demonstrated improved survival in patients with peritoneal carcinomatosis due to colorectal cancer who received CRS plus HIPEC and systemic chemotherapy compared with patients who received systemic chemotherapy alone. At the 8-year follow-up, disease-specific survival was 22.2 months in the CRS plus HIPEC arm and 12.6 months in the control arm. However, procedure-related morbidity and mortality were relatively high; 4 (8%) patients in the CRS plus HIPEC group died from treatment. A more recent RCT found no survival benefit with CRS plus HIPEC over CRS alone, and a higher rate of adverse events 31 to 60 days post-procedure in the CRS plus HIPEC group. The lack of benefit seen with HIPEC in this trial may have been due to several factors, including the short duration of HIPEC treatment, the extensive use of preprocedural systemic chemotherapy, and the high rates of complete cytoreduction achieved in both groups.

Peritoneal Carcinomatosis of Gastric Origin
Clinical Context and Therapy Purpose
The purpose of CRS plus HIPEC in patients with peritoneal carcinomatosis of gastric origin is to provide a treatment option that is an alternative to or an improvement on existing therapies.

The question addressed in this evidence review is: Does the use of CRS plus HIPEC improve the net health outcome in patients with peritoneal carcinomatosis of gastric origin?

The following PICO was used to select literature to inform this review.

Populations
The relevant population(s) of interest are individuals with peritoneal carcinomatosis of gastric origin.

Interventions
The combination therapy being considered is CRS plus HIPEC.

Cytoreductive surgery includes peritonectomy (i.e., peritoneal stripping) procedures and multivisceral resections, depending on the extent of intra-abdominal tumor dissemination.10 It may be followed 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 the temperature. The skin is then temporarily closed during the chemotherapy perfusion, which typically runs for 1 to 2 hours.

Comparators
The following therapies are currently being used to treat peritoneal carcinomatosis of gastric origin: CRS alone and systemic chemotherapy.

Outcomes
The general outcomes of interest are OS, disease-specific survival (eg, PFS), QOL, treatment-related mortality, and treatment-related morbidity.

Morbidity and mortality from the procedure are measured in the early postoperative period. Survival outcomes (PFS and OS) should be measured out to 5 years.

Study Selection Criteria
Methodologically credible studies were selected using the following principles:

  • To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs;
  • In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.
  • To assess long-term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.
  • Studies with duplicative or overlapping populations were excluded.

Review of Evidence
Systematic Reviews
Desiderio et al. (2017) published a meta-analysis of controlled studies comparing CRS plus HIPEC with standard surgical management in the treatment of advanced gastric cancer.26 A separate analysis was conducted of studies focused on patients with and without peritoneal carcinomatosis. For the treatment of patients with peritoneal carcinomatosis of gastric origin, reviewers identified 2 small RCTs (discussed below) and 12 controlled nonrandomized studies. In a meta-analysis of survival at 1 year, there was a significantly higher survival rate in the group receiving HIPEC than the group receiving control treatment (relative risk, 0.67; 95% CI, 0.52 to 0.86; p =.002). However, there was no significant difference between HIPEC and control groups in 2-year survival (relative risk, 0.87; 95% CI, 0.73 to 1.04; p =.12) or 3-year survival (relative risk, 0.99; 95% CI, 0.93 to 1.06; p =.85).

Randomized Controlled Trials
Rudloff et al. (2014) reported on results of a preliminary, open-label RCT in 17 patients from several U.S. centers who had gastric cancer metastatic to the liver and lung and peritoneal carcinomatosis.27 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 assigned using a computerized randomization algorithm to systemic chemotherapy (n = 8) or to systemic chemotherapy plus gastrectomy and CRS plus 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 plus HIPEC group (statistical testing not reported). Factors associated with survival more than 1 year in the CRS plus HIPEC group were complete cytoreduction and initial PCI score of 15 or less. Enrollment to complete a larger planned trial was discontinued due to slow accrual.

Yang et al. (2011) randomized 68 patients (1:1) to CRS plus HIPEC or to CRS alone.28, Median OS was 11.0 months (95% CI, 10.0 to 11.9 months) in the CRS plus HIPEC group and 6.5 months (95% CI, 4.8 to 8.2 months) in the CRS-only group (p =.046). One-, 2-, and 3-year OS rates in the CRS plus HIPEC and CRS-only groups were 41.2% and 29.4%, 14.7% and 5.9%, and 5.9% and 0%, respectively. The incidence of serious adverse events was similar between groups (15% in the CRS plus HIPEC group vs. 12% in the CRS-only group).

Section Summary: Peritoneal Carcinomatosis of Gastric Origin
A 2017 meta-analysis identified 2 RCTs and 12 controlled nonrandomized studies comparing CRS plus HIPEC with standard surgical management in patients with peritoneal carcinomatosis due to gastric cancer. The meta-analysis found significantly increased rates of survival in the CRS plus HIPEC group at 1 year but there was no difference in survival rates at 2 or 3 years. One small (N = 17) preliminary RCT showed improved survival in patients with peritoneal carcinomatosis due to gastric cancer who received CRS plus HIPEC compared with patients who received chemotherapy alone. Another (N = 68) RCT showed improved survival in patients who received CRS plus HIPEC compared with CRS alone. Additional study in a larger sample is needed.

Peritoneal Carcinomatosis of Endometrial Origin
Clinical Context and Therapy Purpose
The purpose of CRS plus HIPEC in patients with peritoneal carcinomatosis of endometrial origin is to provide a treatment option that is an alternative to or an improvement on existing therapies.

The question addressed in this evidence review is: Does the use of CRS plus HIPEC improve the net health outcome in patients with peritoneal carcinomatosis of endometrial origin?

The following PICO was used to select literature to inform this review.

Populations
The relevant population(s) of interest are individuals with peritoneal carcinomatosis of endometrial origin.

Interventions
The combination therapy being considered is CRS plus HIPEC.

Cytoreductive surgery includes peritonectomy (i.e., peritoneal stripping) procedures and multivisceral resections, depending on the extent of intra-abdominal tumor dissemination.10, It may be followed 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 the temperature. The skin is then temporarily closed during the chemotherapy perfusion, which typically runs for 1 to 2 hours.

Comparators
The following therapies are currently being used to treat peritoneal carcinomatosis of endometrial origin: CRS alone and systemic chemotherapy.

Outcomes
The general outcomes of interest are OS, disease-specific survival (eg, PFS), QOL, treatment-related mortality, and treatment-related morbidity.

Morbidity and mortality from the procedure are measured in the early postoperative period. Survival outcomes (PFS and OS) should be measured out to 5 years.

Study Selection Criteria
Methodologically credible studies were selected using the following principles:

  • To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs; 
  • In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies. 
  • To assess long-term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought. 
  • Studies with duplicative or overlapping populations were excluded.

Review of Evidence
Cohort Studies
No RCTs or nonrandomized comparative studies were identified. Two noncomparative, non-U.S. retrospective cohort studies have reported outcomes for CRS plus HIPEC in primary or recurrent endometrial cancer with peritoneal metastasis; these studies are summarized in Tables 7 and 8.29,30 These studies are limited by their retrospective observational designs and lack of control groups.

Navarro-Barrios et al. (2020) reported on a cohort of 43 patients with primary (n = 15) or recurrent (n = 28) peritoneal dissemination of endometrial cancer undergoing CRS plus HIPEC.29 Histopathologic subtype of cancer was endometroid carcinoma in 35% of patients and non-endometroid carcinoma in 65%. Median PCI at the time of surgery was 12 (interquartile range, 7 to 19). Complete cytoreduction was achieved in 41 (95%) patients. Postoperative complications were observed in 14 patients (33%). Five-year relapse-free survival (RFS) and OS were 23% and 34%, respectively. Factors associated with decreased RFS were preoperative chemotherapy (p =.027), resection of more than 3 peritoneal areas (p =.010), cytoreduction of the supramesocolic compartment (p =.023), HIPEC treatment with paclitaxel (p =.013), and the presence of metastatic lymph nodes in histological analysis (p =.029). Of note, 21 patients (61%) underwent adjuvant therapies after CRS plus HIPEC, further limiting the study's ability to specifically demonstrate benefit for CRS plus HIPEC.

Cornali et al. (2018) reported on a cohort of 33 patients undergoing primary (n = 5) or secondary (n = 28) CRS plus HIPEC for peritoneal metastatic spread from advanced or recurrent endometrial cancer.30 Median PCI was 15 (range, 3 to 35). Complete cytoreduction was achieved in 22 patients (66.6%). Major postoperative morbidity (Clavien-Dindo grade 3 or 4) occurred in 21%, and the postoperative mortality rate was 3% (1 patient experienced intraoperative massive pulmonary embolism). Adjuvant chemotherapy was given to 30 patients post-surgery. Rates of 5-year OS and PFS were 30% and 15.5%, respectively. Median OS and PFS were 33.1 months and 18 months, respectively. Complete cytoreduction was associated with increased OS (p <.016).

Table 7. Summary of Key Cohort Study Characteristics for CRS Plus HIPEC in Peritoneal Carcinomatosis of Endometrial Origin

Study Country Dates Participants Follow-Up
Navarro-Barrios et al. (2020)29 Spain (8 centers) 2012-2018 Patients with endometrial cancer and primary or recurrent peritoneal dissemination undergoing CRS plus HIPEC; ECOG performance status 0 to 2 Median, 25 months (IQR, 10 to 37 months)
Cornali et al. (2018)30 Italy and Greece (2 centers) 2002-2016 Patients with peritoneal metastatic spread from advanced or recurrent endometrial cancer; age < 75 years; ECOG performance status 0 to 2 Median, 73 months (range, 8 to 141 months)

CRS: cytoreductive surgery; ECOG: Eastern Cooperative Oncology Group; HIPEC: hyperthermic intraperitoneal chemotherapy; IQR: interquartile range.

Table 8. Summary of Key Cohort Study Results for CRS Plus HIPEC in Peritoneal Carcinomatosis of Endometrial Origin

Study N Postoperative complications, % Postoperative morbidity/mortality, % 5-year OS, % Median OS, mo 5-year RFS, % 5-year PFS, % Median PFS, mo
Navarro-Barrios et al. (2020)29 43 33 NR 34 NR 23 NR NR
Cornali et al. (2018)30 33 NR 21/3 30 33.1 NR 15.5 18

CRS: cytoreductive surgery; HIPEC: hyperthermic intraperitoneal chemotherapy; NR: not reported; OS: overall survival; PFS: progression-free survival; RFS: relapse-free survival.

Section Summary: Peritoneal Carcinomatosis From Endometrial Cancer
Two uncontrolled retrospective cohort studies in patients with primary or recurrent endometrial cancer and peritoneal carcinomatosis have suggested that survival with CRS plus HIPEC may be better than systemic chemotherapy (median OS, 33.1 months vs. < 12 months in published reports). However, 1 study reported a complication rate of 33%, and major postoperative morbidity was reported in 21% of patients in another study. Further, absent parallel control groups, potential bias was introduced by confounding factors, such as disease history, cancer subtype, preoperative PCI score, and treatment. Randomized trials comparing CRS plus HIPEC with standard treatment (surgery [including CRS], systemic chemotherapy, brachytherapy, radiotherapy, and/or hormone therapy) in larger numbers of patients are needed.

Peritoneal Mesothelioma
Clinical Context and Therapy Purpose
The purpose of CRS plus HIPEC in patients with peritoneal mesothelioma is to provide a treatment option that is an alternative to or an improvement on existing therapies.

The question addressed in this evidence review is: Does the use of CRS plus HIPEC improve the net health outcome in patients with peritoneal mesothelioma?

The following PICO was used to select literature to inform this review.

Populations
The relevant population(s) of interest are individuals with peritoneal mesothelioma.

Interventions
The combination therapy being considered is CRS plus HIPEC.

Cytoreductive surgery includes peritonectomy (i.e., peritoneal stripping) procedures and multivisceral resections, depending on the extent of intra-abdominal tumor dissemination.10, It may be followed 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 the temperature. The skin is then temporarily closed during the chemotherapy perfusion, which typically runs for 1 to 2 hours.

Comparators
The following therapies are currently being used to treat peritoneal mesothelioma: CRS alone, systemic chemotherapy, and radiotherapy.

Outcomes
The general outcomes of interest are OS, disease-specific survival (eg, PFS), QOL, treatment-related mortality, and treatment-related morbidity.

Morbidity and mortality from the procedure are measured in the early postoperative period. Survival outcomes (PFS and OS) should be measured out to 5 years.

Study Selection Criteria
Methodologically credible studies were selected using the following principles:

  • To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs; 
  • In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies. 
  • To assess long-term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought. 
  • Studies with duplicative or overlapping populations were excluded.

Review of Evidence
Systematic Reviews
For a systematic review, Baratti et al. (2011) searched the PubMed database for studies on the clinical management of diffuse malignant peritoneal mesothelioma.7 They included 14 studies with a total of 427 patients, 289 of whom underwent CRS plus HIPEC with 106 receiving both HIPEC and early postoperative intraperitoneal chemotherapy. Studies that included patients with well-differentiated or low-grade types of mesothelioma were excluded. All selected studies were prospective, uncontrolled case series. The mean patient age ranged from 49 to 56 years. All institutions used peritonectomy and multivisceral resection to remove the visible disease. Protocols for HIPEC varied widely across institutions in terms of techniques, drugs, carriers, timing, and temperatures. Operative mortality and morbidity were reported in 11 single-institution case series. Operative mortality rates ranged from 0% to 10.5%. Overall, death occurred in 11 (3.1%) of 373 assessable patients. In a multi-institutional series, mortality was 2.2%. Morbidity (severe and life-threatening complications) varied from 20% to 41%. For patients who underwent CRS plus HIPEC, median OS ranged from 29.5 to 92 months. The median OS was not reached in 3 series but exceeded 100 months in 1 of them. One-, 2-, 3-, and 5-year OS rates varied from 43% to 88%, 43% to 77%, 43% to 70%, and 33% to 68%, respectively. In 4 studies, median PFS ranged from 7.2 to 40 months.

Results of a systematic review by Helm et al. (2015), which included 7 studies published after the Baratti et al. (2011) review, aligned with Baratti's findings: pooled 1-, 3-, and 5-year survival estimates were 84%, 59%, and 42%, respectively.31

Observational Studies
Table 9 summarizes relevant observational studies on peritoneal mesothelioma; the largest studies (N > 50 patients) are discussed further below.

Table 9. Study Results for CRS Plus HIPEC in Peritoneal Mesothelioma

Study N Postoperative, % Median OS, mo 5-Year OS, % Median PFS, mo
    Mortality Morbidity      
Robella et al. (2014)32 42 7 36 65 44 NR
Alexander et al. (2013)33 211 2 30 38 41 NR
Glehen et al. (2010)12 88 NR NR 41 NR NR
Yan et al. (2009)34 401 NR NR 53 47 NR

CRS: cytoreductive surgery; HIPEC: hyperthermic intraperitoneal chemotherapy; NR: not reported; OS: overall survival; PFS: progression-free survival.

The largest observational study (which was included in both systematic reviews) was an international registry study by Yan et al. (2009), for which 401 (99%) patients had a complete follow-up.34 Of these patients, 92% received HIPEC. Median and 1-, 3-, and 5-year survival rates were 53 months, 81%, 60%, and 47%, respectively.

Alexander et al. (2013) reported on 211 patients from 3 U.S. tertiary care centers who had malignant peritoneal mesothelioma and had undergone CRS plus HIPEC.33 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).

In the retrospective, multicenter cohort study by Glehen et al. (2010), discussed in the Pseudomyxoma Peritonei section, the principal origin of the tumor was peritoneal mesothelioma in 88 patients.12 The median survival for this group of patients was 41 months. Independent prognostic indicators in multivariate analysis were: institution, the origin of peritoneal carcinomatosis, completeness of CRS, the extent of carcinomatosis, and lymph node involvement.

Section Summary: Peritoneal Mesothelioma
Retrospective cohort studies have shown median and 5-year OS ranging from 30 to 92 months and from 33% to 68%, respectively, for patients with peritoneal mesothelioma treated with CRS plus HIPEC. Although no RCTs or comparative studies have been published, historical case series have reported a median survival of 12 months with treatment by palliative surgery, systemic or intraperitoneal chemotherapy, and abdominal irradiation. Procedure-related morbidity and mortality rates with CRS plus HIPEC have remained relatively steady over time, at approximately 35% and 5%, respectively. Because the prevalence of peritoneal mesothelioma is very low, conducting comparative trials is difficult.

Newly Diagnosed Stage III Ovarian Cancer
Clinical Context and Therapy Purpose
The purpose of CRS plus HIPEC in patients with newly diagnosed stage III ovarian cancer is to provide a treatment option that is an alternative to or an improvement on existing therapies.

The question addressed in this evidence review is: Does the use of CRS plus HIPEC improve the net health outcome in patients with newly diagnosed stage III ovarian cancer?

The following PICO was used to select literature to inform this review.

Populations
The relevant population(s) of interest are individuals with newly diagnosed stage III ovarian cancer.

Interventions
The combination therapy being considered is CRS plus HIPEC.

Cytoreductive surgery includes peritonectomy (i.e., peritoneal stripping) procedures and multivisceral resections, depending on the extent of intra-abdominal tumor dissemination.10 It may be followed 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 the temperature. The skin is then temporarily closed during the chemotherapy perfusion, which typically runs for 1 to 2 hours.

Comparators
The following therapies are currently being used to treat newly diagnosed stage III ovarian cancer: CRS alone and systemic chemotherapy.

Outcomes
The general outcomes of interest are OS, disease-specific survival (eg, PFS), QOL, treatment-related mortality, and treatment-related morbidity.

Morbidity and mortality from the procedure are measured in the early postoperative period. Survival outcomes (PFS and OS) should be measured out to 5 years.

Study Selection Criteria
Methodologically credible studies were selected using the following principles:

  • To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs; 
  • In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies. 
  • To assess long-term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought. 
  • Studies with duplicative or overlapping populations were excluded.

Review of Evidence
Systematic Reviews
Zhang et al. (2019) published a systematic review and meta-analysis assessing the impact of HIPEC on patients with ovarian cancer.35 Thirteen studies (N ranging from 12 to 122) with patients with advanced (stage IC to IV) primary ovarian cancer were included. Groups treated with HIPEC had a better OS (HR, 0.59; 95% CI, 0.46 to 0.72) and PFS (HR, 0.41; 95% CI, 0.32 to 0.54) than those who did not receive HIPEC. The review was limited by the inclusion of only English language studies, the small number of RCTs (n = 2) identified for inclusion, and only 1 of the included studies reporting information about adverse events.

Wang et al. (2019) published a systematic review analyzing the effects of HIPEC and CRS for ovarian cancer patients.36 Thirteen studies, all but 3 of which were also used in Zhang et al. (2019), were included in the review. In a subgroup analysis of patients with primary ovarian cancer, OS (HR, 0.57; 95% CI, 0.40 to 0.83; p =.04) and DFS (HR, 0.61; 95% CI, 0.47 to 0.80; p <.01) were significantly improved for the HIPEC group. The study was limited by the level of heterogeneity among the study populations and by some of the included studies not reporting morbidity for the control group.

Randomized Controlled Trials
One RCT has been published on CRS plus HIPEC for ovarian cancer (see Table 10). Van Driel et al. (2018) reported that CRS plus HIPEC reduced mortality for patients with newly diagnosed stage III epithelial ovarian cancer (see Table 11).37 Disease recurrence or death occurred in 81% of patients treated with CRS plus HIPEC compared with 89% treated with CRS alone. At 5-year follow-up, 50% of patients treated with CRS plus HIPEC had died compared with 62% treated with CRS alone (p =.02). Median OS was 45.7 months in the HIPEC group and 33.9 months in the control group. The incidence of grade 3 or 4 adverse events was similar in both groups (25% for surgery alone vs. 27% for CRS plus HIPEC; p =.76).

Table 10. Summary of Key RCT Characteristics

Study; Trial Countries Sites Dates Participants Interventions
          Active Comparator
Van Driel et al. (2018)37 EU 8 2007-2017 245 women with newly diagnosed stage III epithelial ovarian cancer after 3 cycles of carboplatin and paclitaxel and complete or optimal cytoreduction 122 patients received CRS plus HIPEC 123 patients received CRS alone

CRS: cytoreductive surgery; EU: European Union; HIPEC; hyperthermic intraperitoneal chemotherapy; RCT: randomized controlled trial.

Table 11. Summary of Key RCT Results

Study Disease Recurrence or Death, n (%) Median RFS, mo Mortality at Median of 4.7 Years, n (%) Median OS, mo Grade 3 or 4 AEs, %
Van Driel et al. (2018)37          
N 245        
CRS alone 110 (89) 10.7 76 (62) 33.9 25
CRS plus HIPEC 99 (81) 14.2 61 (50) 45.7 27
HR (95% CI) 0.66 (0.50 to 0.87)   0.67 (0.48 to 0.94)    
p .003   .02   .76

AE: adverse event; CI: confidence interval; CRS: cytoreductive surgery; HIPEC: hyperthermic intraperitoneal chemotherapy; HR: hazard ratio; OS: overall survival; RCT: randomized controlled trial; RFS: relapse-free survival (disease recurrence or progression or death).

The limitations tables (see Tables 12 and 13) below display notable limitations identified in each study. This information is synthesized as a summary of the body of evidence following each table and provides the conclusions on the sufficiency of the evidence supporting the position statement. The major limitation of the van Driel et al. (2018) trial was the lack of blinding, which might be expected to have a minor effect on the objective measure of mortality.

Table 12. Study Relevance Limitations

Study Populationa Interventionb Comparatorc Outcomesd Follow-Upe
Van Driel et al. (2018)37 4. There were very selective inclusion criteria, so the effect of the intervention on a broader patient population (e.g., recurrent disease) is unknown        

The study limitations stated in this table are those notable in the current review; this is not a comprehensive gaps assessment.
Population key: 1. Intended use population unclear; 2. Clinical context is unclear; 3. Study population is unclear; 4. Study population not representative of intended use.
Intervention key: 1. Not clearly defined; 2. Version used unclear; 3. Delivery not similar intensity as comparator; 4. Not the intervention of interest.
c  Comparator key: 1. Not clearly defined; 2. Not standard or optimal; 3. Delivery not similar intensity as intervention; 4. Not delivered effectively.
d  Outcomes key: 1. Key health outcomes not addressed; 2. Physiologic measures, not validated surrogates; 3. No CONSORT reporting of harms; 4. Not establish and validated measurements; 5. Clinical significant difference not prespecified; 6. Clinical significant difference not supported.
e  Follow-Up key: 1. Not sufficient duration for benefit; 2. Not sufficient duration for harms.

Table 13. Study Design and Conduct Limitations

Study Allocationa Blindingb Selective Reportingc Data Completenessd Powere Statisticalf
Van Driel et al. (2018)37   1-3. Not blinded        

The study limitations stated in this table are those notable in the current review; this is not a comprehensive gaps assessment.
Allocation key: 1. Participants not randomly allocated; 2. Allocation not concealed; 3. Allocation concealment unclear; 4. Inadequate control for selection bias.
Blinding key: 1. Not blinded to treatment assignment; 2. Not blinded outcome assessment; 3. Outcome assessed by treating physician.
c  Selective Reporting key: 1. Not registered; 2. Evidence of selective reporting; 3. Evidence of selective publication.
d  Data Completeness key: 1. High loss to follow-up or missing data; 2. Inadequate handling of missing data; 3. High number of crossovers; 4. Inadequate handling of crossovers; 5. Inappropriate exclusions; 6. Not intent to treat analysis (per protocol for noninferiority trials).
e  Power key: 1. Power calculations not reported; 2. Power not calculated for primary outcome; 3. Power not based on clinically important difference.
f  Statistical key: 1. Analysis is not appropriate for outcome type: (a) continuous; (b) binary; (c) time to event; 2. Analysis is not appropriate for multiple observations per patient; 3. Confidence intervals and/or p values not reported; 4. Comparative treatment effects not calculated.

Section Summary: Newly Diagnosed Stage III Ovarian Cancer
Evidence for HIPEC includes systematic reviews and an RCT in patients with newly diagnosed stage III epithelial ovarian cancer who were treated with neoadjuvant chemotherapy and had complete or optimal cytoreduction. In this study, HIPEC increased the time to disease recurrence and reduced mortality. It did not increase serious adverse events compared with surgery alone. The major limitation in the trial was the lack of blinding, which might be expected to have a minor effect on the objective measure of mortality. An additional RCT in patients with stage IIIC disease undergoing primary treatment was scheduled to be completed in 2018, but the results of this study appear to remain unpublished, indicating possible publication bias.

Recurrent Stage IIIC or IV Ovarian Cancer
Clinical Context and Therapy Purpose
The purpose of CRS plus HIPEC in patients with recurrent stage IIIC or IV ovarian cancer is to provide a treatment option that is an alternative to or an improvement on existing therapies.

The question addressed in this evidence review is: Does the use of CRS plus HIPEC improve the net health outcome in patients with recurrent stage IIIC or IV ovarian cancer?

The following PICO was used to select literature to inform this review.

Populations
The relevant population(s) of interest are individuals with recurrent stage IIIC or IV ovarian cancer.

Interventions
The combination therapy being considered is CRS plus HIPEC.

Cytoreductive surgery includes peritonectomy (i.e., peritoneal stripping) procedures and multivisceral resections, depending on the extent of intra-abdominal tumor dissemination.10 It may be followed 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 the temperature. The skin is then temporarily closed during the chemotherapy perfusion, which typically runs for 1 to 2 hours.

Comparators
The following therapies are currently being used to treat recurrent stage IIIC or IV ovarian cancer: CRS alone and systemic chemotherapy.

Outcomes
The general outcomes of interest are OS, disease-specific survival (eg, PFS), QOL, treatment-related mortality, and treatment-related morbidity.

Morbidity and mortality from the procedure are measured in the early postoperative period. Survival outcomes (PFS and OS) should be measured out to 5 years.

Study Selection Criteria
Methodologically credible studies were selected using the following principles:

  • To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs; 
  • In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies. 
  • To assess long-term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought. 
  • Studies with duplicative or overlapping populations were excluded.

Review of Evidence
Systematic Reviews
A systematic review and meta-analysis of studies assessing CRS plus HIPEC for treating ovarian cancer was published by Huo et al. (2015).38 Reviewers selected studies that included more than 10 patients with primary or recurrent ovarian cancer who were treated with CRS plus HIPEC. Thirty-seven studies were identified, 9 comparative studies and 28 uncontrolled studies. Only 1 RCT (Spiliotis et al. [2015]39), described below, was identified in the literature search. A pooled analysis of 8 studies comparing CRS plus HIPEC with CRS plus non-HIPEC chemotherapy found significantly higher 1-year survival in the CRS plus HIPEC group (odds ratio, 4.24; 95% CI, 2.17 to 8.30). There were similar findings on 3-year survival (pooled odds ratio, 4.31; 95% CI, 2.11 to 8.11). Most of the comparative studies were not randomized and thus subject to potential selection and observational biases.

Zhang et al. (2019; see previous indication) also included results for patients with recurrent ovarian cancer.35 In this subgroup, HIPEC had significantly improved OS (HR, 0.45; 95% CI, 0.24 to 0.83) compared with groups that did not receive HIPEC; however, PFS (HR, 0.55; 95% CI, 0.27 to 1.11) was not significantly improved.

Wang et al. (2019; see previous indication) also provided a subgroup analysis of patients with recurrent ovarian cancer.36 In this population, the HIPEC group had significantly improved OS (HR, 0.48; 95% CI, 0.24 to 0.96; p <.01) but not DFS (HR, 0.59; 95% CI, 0.33 to 1.08; p =.09).

Randomized Controlled Trials
Spiliotis et al. (2015) reported on a single-center RCT of 120 women who had recurrent stage IIIC or IV ovarian cancer after surgery and systemic chemotherapy (see Table 14).39 In Kaplan-Meier survival analysis, mean OS was 26.7 months in the CRS plus HIPEC group and 13.4 months in the non-HIPEC group (p =.006) (see Table 15). However, completeness of cytoreduction and PCI score were associated with survival, and these measures were not comparable between groups. Treatment-related morbidity and mortality were not reported.

Table 14. Summary of Key RCT Characteristics

Study; Trial Countries Sites Dates Participants Interventions
          Active Comparator
Spiliotis et al. (2015)39 EU 1 2006-2013 120 women with advanced (stage IIIC or IV) recurrent epithelial ovarian cancer CRS plus HIPEC CRS plus systemic chemotherapy

CRS: cytoreductive surgery; EU: European Union; HIPEC; hyperthermic intraperitoneal chemotherapy; RCT: randomized controlled trial.

Table 15. Summary of Key RCT Results

Study Disease Recurrence or Death, n (%) Median RFS, mo Mortality , n (%) Median OS, mo Grade 3 or 4 AEs, %
Spiliotis et al. (2015)39          
CRS plus systemic chemotherapy       13.4  
CRS plus HIPEC       26.7  
p       .006  

AE: adverse event; CRS: cytoreductive surgery; HIPEC: hyperthermic intraperitoneal chemotherapy; OS: overall survival; RCT: randomized controlled trial; RFS: relapse-free survival (disease recurrence or progression or death).

Limitations in relevance and design and conduct are noted in Tables 16 and 17. For the Spiliotis et al. (2015) study, baseline between-group differences in the stage of disease and completeness of cytoreduction, which is a prognostic indicator for survival, limit interpretation of the trial results.

Table 16. Study Relevance Limitations

Study Populationa Interventionb Comparatorc Outcomesd Follow-Upe
Spiliotis et al. (2015)39 3. The HIPEC group had more patients with stage IIIC disease (68% vs. 60%)   3. More patients in the HIPEC group had complete cytoreduction (65% vs. 55%).    

The study limitations stated in this table are those notable in the current review; this is not a comprehensive gaps assessment.
HIPEC: hyperthermic intraperitoneal chemotherapy.
Population key: 1. Intended use population unclear; 2. Clinical context is unclear; 3. Study population is unclear; 4. Study population not representative of intended use.
Intervention key: 1. Not clearly defined; 2. Version used unclear; 3. Delivery not similar intensity as comparator; 4. Not the intervention of interest.
c  Comparator key: 1. Not clearly defined; 2. Not standard or optimal; 3. Delivery not similar intensity as intervention; 4. Not delivered effectively.
d  Outcomes key: 1. Key health outcomes not addressed; 2. Physiologic measures, not validated surrogates; 3. No CONSORT reporting of harms; 4. Not establish and validated measurements; 5. Clinical significant difference not prespecified; 6. Clinical significant difference not supported.
e  Follow-Up key: 1. Not sufficient duration for benefit; 2. Not sufficient duration for harms.

Table 17. Study Design and Conduct Limitations

Study Allocationa Blindingb Selective Reportingc Data Completenessd Powere Statisticalf
Spiliotis et al. (2015)39   1 – 3. Not blinded        

The study limitations stated in this table are those notable in the current review; this is not a comprehensive gaps assessment.
Allocation key: 1. Participants not randomly allocated; 2. Allocation not concealed; 3. Allocation concealment unclear; 4. Inadequate control for selection bias.
Blinding key: 1. Not blinded to treatment assignment; 2. Not blinded outcome assessment; 3. Outcome assessed by treating physician.
c  Selective Reporting key: 1. Not registered; 2. Evidence of selective reporting; 3. Evidence of selective publication.
d  Data Completeness key: 1. High loss to follow-up or missing data; 2. Inadequate handling of missing data; 3. High number of crossovers; 4. Inadequate handling of crossovers; 5. Inappropriate exclusions; 6. Not intent to treat analysis (per protocol for noninferiority trials).
e  Power key: 1. Power calculations not reported; 2. Power not calculated for primary outcome; 3. Power not based on clinically important difference.
f  Statistical key: 1. Analysis is not appropriate for outcome type: (a) continuous; (b) binary; (c) time to event; 2. Analysis is not appropriate for multiple observations per patient; 3. Confidence intervals and/or p values not reported; 4. Comparative treatment effects not calculated.

Section Summary: Recurrent Stage IIIC or IV Ovarian Cancer
Cytoreductive surgery plus HIPEC has been studied in an RCT of patients with recurrent stage IIIC or IV ovarian cancer. For recurrent disease (second-line setting), evidence from an RCT indicated that CRS plus HIPEC improved survival compared with CRS without HIPEC. Treatment groups in this RCT were unbalanced at baseline and in the completeness of cytoreduction, which has consistently been shown to be associated with survival. An additional RCT in patients with recurrent disease was scheduled to be completed in 2018, but the results of this study appear to remain unpublished, indicating possible publication bias.

Appendiceal Goblet Cell Tumors
Clinical Context and Therapy Purpose
The purpose of CRS plus HIPEC in patients with appendiceal goblet cell tumors is to provide a treatment option that is an alternative to or an improvement on existing therapies.

The question addressed in this evidence review is: Does the use of CRS plus HIPEC improve the net health outcome in patients with appendiceal goblet cell tumors?

The following PICO was used to select literature to inform this review.

Populations
The relevant population(s) of interest are individuals with appendiceal goblet cell tumors.

Interventions
The combination therapy being considered is CRS plus HIPEC.

Cytoreductive surgery includes peritonectomy (i.e., peritoneal stripping) procedures and multivisceral resections, depending on the extent of intra-abdominal tumor dissemination.10 It may be followed 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 the temperature. The skin is then temporarily closed during the chemotherapy perfusion, which typically runs for 1 to 2 hours.

Comparators
The following therapies are currently being used to treat appendiceal goblet cell tumors: CRS alone and systemic chemotherapy.

Outcomes
The general outcomes of interest are OS, disease-specific survival (eg, PFS), QOL, treatment-related mortality, and treatment-related morbidity.

Morbidity and mortality from the procedure are measured in the early postoperative period. Survival outcomes (PFS and OS) should be measured out to 5 years.

Study Selection Criteria
Methodologically credible studies were selected using the following principles:

  • To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs; 
  • In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies. 
  • To assess long-term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought. 
  • Studies with duplicative or overlapping populations were excluded.

Review of Evidence
Cohort Studies
Sluiter et al. (2020) analyzed a propensity score-matched cohort of 44 patients with peritoneally-metastasized goblet cell carcinoids, comparing survival outcomes in patients receiving CRS plus HIPEC versus surgery alone (see Tables 18 and 19).40 In this observational analysis, CRS plus HIPEC was associated with improved median OS compared to surgery alone (39 months vs. 12 months). Surgery without HIPEC was correlated with poor OS in a multivariate model (HR, 2.77; 95% CI, 1.06 to 7.26), as was high age and the presence of ovarian metastases. This analysis is limited by the sample size and observational design; although propensity score matching was used to reduce selection bias, differences between patient groups likely remained and confounding by treatment indication cannot be ruled out. It is unclear how many patients attained complete cytoreduction in each treatment group, and differences in the rate of complete cytoreduction may have influenced outcomes.

Table 18. Summary of Key Observational Comparative Study Characteristics

Study Study Type Country Dates Participants CRS plus HIPEC Surgery alone Follow-Up
Sluiter et al. (2020)40 Propensity score-matched cohort Netherlands and Belgium 2003-2016 Patients with confirmed peritoneal metastases of goblet cell carcinoids 22 22 Mean, 21.2 months

CRS: cytoreductive surgery; HIPEC: hyperthermic intraperitoneal chemotherapy.

Table 19. Summary of Key Observational Comparative Study Results

Study Median OS, mo
Sluiter et al. (2020)40  
CRS plus HIPEC 39
Surgery alone 12
p .017
HR (95% CI), p 2.77 (1.06 to 7.26), p =.038

CI: confidence interval; CRS: cytoreductive surgery; HIPEC: hyperthermic intraperitoneal chemotherapy; HR: hazard ratio; OS:overall survival.

Noncomparative retrospective cohort studies have reported on additional outcomes with CRS plus HIPEC in patients with appendiceal goblet cell tumors. In a multicenter, retrospective cohort study, McConnell et al. (2014) studied appendiceal goblet cell tumors (n = 45) and compared outcomes for CRS plus HIPEC with those in nonmucinous (n = 52) and low-grade (n = 567) and high-grade (n = 89) mucinous appendiceal tumors.41 All patients had peritoneal malignancy due to advanced disease but none was identified as having pseudomyxoma peritonei. With a median follow-up of 49 months, patients with goblet cell tumors had better survival outcomes than those in patients with low-grade mucinous tumors and similar outcomes to those in patients with high-grade mucinous tumors: 3-year OS rates in patients with goblet cell, low-grade mucinous, high-grade mucinous, and nonmucinous tumor were 63%, 81% (p =.003), 40% (p =.07), and 52% (p =.48), respectively. In 489 (65%) patients who achieved complete cytoreduction, the pattern of 3-year DFS outcomes was similar: 43%, 73% (p <.001), 44% (p =.85), and 44% (p =.82), respectively (p values for rates vs. goblet cell tumors). Treatment-related adverse events were not reported. Grade 3 or 4 surgical complications occurred in approximately 20% of patients in each group.

A noncomparative, single-center retrospective cohort study by Zambrano-Vera et al. (2020) reported outcomes in 20 patients with peritoneal carcinomatosis from appendiceal goblet cell carcinoma who successfully underwent CRS plus HIPEC.42, Complete cytoreduction was achieved in 75%. Grade 3 postoperative complications were reported in 15%. With a median follow-up time of 70 months, 1-, 3-, and 5-year OS rates were 100%, 75%, and 65%, respectively. Median OS was not reached at 5 years. Rates of 1-, 3-, and 5-year PFS were 94%, 67%, and 59%, respectively, with a median PFS of 97 months.

Section Summary: Appendiceal Goblet Cell Tumors
Evidence is limited to retrospective cohort studies of patients with goblet cell tumors of the appendix. A propensity score-matched analysis found that CRS plus HIPEC was associated with improved median survival compared to surgery alone. However, this analysis was limited by the retrospective nature of the data and small sample size (N= 44). Rates of complete cytoreduction were not reported or accounted for in this study, so between-group differences in this or other variables may have influenced the observed outcomes. Noncomparative retrospective studies have found 3-year survival rates of 63% to 75% with CRS plus HIPEC, and 1 study reported a 5-year survival rate of 65%.

Summary of Evidence
For individuals who have pseudomyxoma peritonei who receive CRS plus HIPEC, the evidence includes cohort studies and a systematic review. Relevant outcomes are OS, disease-specific survival, QOL, and treatment-related mortality and morbidity. Retrospective cohort studies and systematic reviews have reported median survival ranging from 47 to 156 months and 5-year OS ranging from 41% to 96% for patients with primary treatment for pseudomyxoma peritonei treated with CRS plus HIPEC. Two retrospective studies reported results of CRS plus HIPEC for recurrence with 5-year OS rates of 34% and 79%. Although no direct comparisons between CRS plus HIPEC and other interventions have been published, traditional surgical debulking is not curative, and complete CRS alone (without HIPEC) has been associated with a 5-year OS of approximately 50%, along with high recurrence rates (91%, with a median disease-free survival of 24 months). Median PFS with CRS plus HIPEC as primary treatment has been reported as 40 to 78 months, with 5-year PFS rates of 38% to 80%. Procedure-related morbidity and mortality have generally decreased over time. Because the prevalence of pseudomyxoma peritonei is very low, conducting comparative trials is difficult. The evidence is sufficient to determine that the technology results in an improvement in the net health outcome.

For individuals who have peritoneal carcinomatosis of colorectal origin who receive CRS plus HIPEC, the evidence includes RCTs, systematic reviews, and a large number of observational studies. Relevant outcomes are OS, disease-specific survival, QOL, and treatment-related mortality and morbidity. A meta-analysis of controlled studies found that CRS plus HIPEC, compared with traditional therapy without HIPEC, was associated with significantly higher survival rates and was not associated with significantly higher treatment-related morbidity rates. One RCT, in which patients with peritoneal carcinomatosis due to colorectal cancer were followed for at least 6 years, demonstrated improved survival in patients who received CRS plus HIPEC and systemic chemotherapy compared with patients who received systemic chemotherapy alone. However, procedure-related morbidity and mortality rates were relatively high, and systemic chemotherapy regimens did not use currently available biologic agents. A more recent RCT found no survival benefit with CRS plus HIPEC over CRS alone, and a higher rate of adverse events 31 to 60 days post-procedure in the CRS plus HIPEC group. The lack of benefit seen with HIPEC in this trial may have been due to several factors, including the short duration of HIPEC treatment, the extensive use of preprocedural systemic chemotherapy, and the high rates of complete cytoreduction achieved in both groups. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

For individuals who have peritoneal carcinomatosis of gastric origin who receive CRS plus HIPEC, the evidence includes 2 small RCTs, observational studies, and a systematic review. Relevant outcomes are OS, disease-specific survival, QOL, and treatment-related mortality and morbidity. A 2017 meta-analysis identified 2 RCTs and 12 controlled nonrandomized studies comparing surgery plus HIPEC with standard surgical management in patients who had peritoneal carcinomatosis due to gastric cancer. The meta-analysis found significantly better survival in the surgery plus HIPEC group at 1 year but not at 2 or 3 years. One small (N = 17) preliminary RCT showed improved survival in patients with peritoneal carcinomatosis due to gastric cancer who received CRS plus HIPEC compared with patients who received chemotherapy alone. Another (N = 68) RCT showed improved survival in patients who received CRS plus HIPEC compared with CRS alone. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

For individuals who have peritoneal carcinomatosis of endometrial origin who receive CRS plus HIPEC, the evidence includes cohort studies. Relevant outcomes are OS, disease-specific survival, QOL, and treatment-related mortality and morbidity. Only uncontrolled retrospective cohort studies were available, with the largest including only 43 patients. Randomized trials that compare CRS plus HIPEC with standard treatment (eg, CRS alone or systemic chemotherapy alone) are needed. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

For individuals who have peritoneal mesothelioma who receive CRS plus HIPEC, the evidence includes retrospective cohort studies and systematic reviews. Relevant outcomes are OS, disease-specific survival, QOL, and treatment-related mortality and morbidity. Retrospective cohort studies have shown median and 5-year OS ranging from 30 to 92 months and from 33% to 68%, respectively, for patients with peritoneal mesothelioma treated with CRS plus HIPEC. Although no RCTs or comparative studies have been published, historical case series have reported a median survival of 12 months with treatment by palliative surgery, systemic or intraperitoneal chemotherapy, and abdominal irradiation. Procedure-related morbidity and mortality rates with CRS plus HIPEC have remained relatively steady over time, at approximately 35% and 5%, respectively. Because the prevalence of peritoneal mesothelioma is very low, conducting comparative trials is difficult. The evidence is sufficient to determine that the technology results in an improvement in the net health outcome.

For individuals who have newly diagnosed stage III ovarian cancer who receive CRS plus HIPEC, the evidence includes systematic reviews and an RCT. Relevant outcomes are OS, disease-specific survival, QOL, and treatment-related mortality and morbidity. For patients with newly diagnosed stage III ovarian cancer who had received neoadjuvant chemotherapy, HIPEC increased the time to disease recurrence and reduced mortality. It did not increase serious adverse events compared with surgery alone. The evidence is sufficient to determine that the technology results in an improvement in the net health outcome.

For individuals who have recurrent stage IIIC or IV ovarian cancer who receive CRS plus HIPEC, the evidence includes an RCT and systematic reviews. Relevant outcomes are OS, disease-specific survival, QOL, and treatment-related mortality and morbidity. For recurrent stage IIIC or IV disease (second-line setting), evidence from an RCT indicated that CRS plus HIPEC improved survival compared with CRS without HIPEC. However, interpretation of this study is limited because treatment groups in this RCT were unbalanced at baseline (variation in the completeness of cytoreduction), which has been shown to be associated with survival. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

For individuals who have appendiceal goblet cell tumors who receive CRS plus HIPEC, the evidence includes retrospective cohort studies. Relevant outcomes are OS, disease-specific survival, QOL, and treatment-related mortality and morbidity. A propensity score-matched analysis found that CRS plus HIPEC was associated with improved median survival compared to surgery alone. However, this analysis was limited by the retrospective nature of the data and small sample size (N = 44). Rates of complete cytoreduction were not reported or accounted for in this study, so between-group differences in this or other variables may have influenced the observed outcomes. Additional studies-preferably controlled and ideally, RCTs-are needed. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

The purpose of the following information is to provide reference material. Inclusion does not imply endorsement or alignment with the evidence review conclusions.

Practice Guidelines and Position Statements
Guidelines or position statements will be considered for inclusion in ‘Supplemental Information’ if they were issued by, or jointly by, a US professional society, an international society with US representation, or National Institute for Health and Care Excellence (NICE). Priority will be given to guidelines that are informed by a systematic review, include strength of evidence ratings, and include a description of management of conflict of interest.

National Comprehensive Cancer Network
The NCCN guidelines include the following relevant recommendation for colon cancer (v. 2.2021): "The panel currently believes that complete cytoreductive surgery and/or intraperitoneal chemotherapy can be considered in experienced centers for selected patients with limited peritoneal metastases for whom R0 resection can be achieved. However, the significant morbidity and mortality associated with HIPEC, as well as the conflicting data on clinical efficacy, make this approach very controversial."43

The NCCN guidelines on gastric cancer (v. 2.2021) state that "HIPEC or laparoscopic HIPEC may be a therapeutic alternative for carefully selected stage IV patients in the setting of ongoing clinical trials and is under further clinical investigation."6 The NCCN guidelines on uterine neoplasms (v. 3.2021) and rectal cancer (v. 1.2021) do not discuss cytoreductive surgery (CRS) plus hyperthermic intraperitoneal chemotherapy (HIPEC). 44,45

The NCCN guidelines on ovarian cancer (v.1.202 1) state that "patients with low volume residual disease after surgical cytoreduction for invasive epithelial ovarian or peritoneal cancer are potential candidates for intraperitoneal chemotherapy" and "HIPEC with cisplatin (100 mg/m2) can be considered at the time of interval debulking surgery for stage III disease."46

In 2017, the practice guidelines on the treatment of colon cancer by the American Society of Colon and Rectal Surgeons stated that treatment of patients with isolated peritoneal carcinomatosis may include CRS in conjunction with perioperative intraperitoneal chemotherapy, with or without hyperthermia.47

In 2019, the American Society of Colon and Rectal Surgeons guidelines on the management of appendiceal neoplasms stated that "in selected patients with appendiceal epithelial neoplasms, intraperitoneal chemotherapy may offer additional benefit for reducing peritoneal disease recurrence compared with CRS alone." The guidelines mention that HIPEC performed concurrently with CRS is the most common method of delivering this intraperitoneal chemotherapy.48

Society of Surgical Oncology
In 2007, the Society of Surgical Oncology issued a consensus statement on cytoreductive surgery and HIPEC in the management of peritoneal surface malignancies of colonic origin.49 The Society recommended that patients with peritoneal carcinomatosis without distant disease, in whom complete cytoreduction is possible, undergo HIPEC before systemic therapy. As of June 2021, an updated statement has not been published.

Chicago Consensus Working Group
In 2020, the Chicago Consensus Working Group for the Management of Peritoneal Surface Malignancies published a consensus statement on the management of ovarian neoplasms.50 The consensus statement mentions HIPEC, and includes it in its management pathway for patients with peritoneal metastasis from epithelial ovarian cancer. However, the authors also state that "level I evidence is lacking for HIPEC at the time of primary CRS or for stage IV disease" and "similarly, no level I evidence exists for HIPEC use in patients with rare ovarian histologies." Other consensus statements from this group on appendiceal neoplasms, peritoneal mesothelioma, gastric metastases, and colorectal metastases include CRS plus intraperitoneal chemotherapy or CRS +/- intraperitoneal chemotherapy in their management pathways; however, they do not specify whether this intraperitoneal chemotherapy should be HIPEC or another form of intraperitoneal chemotherapy.51,52,53,54

U.S. Preventive Services Task Force Recommendations
Not applicable.

Ongoing and Unpublished Clinical Trials
Some currently ongoing or unpublished trials that might influence this review are listed in Table 20.

Table 20. Summary of Key Trials

NCT No. Title Enrollment Completion Date
Ongoing    
Colorectal and appendiceal cancer    
NCT01815359 ICARuS Post-operative Intraperitoneal Chemotherapy (EPIC) and Hyperthermic Intraperitoneal Chemotherapy (HIPEC) After Optimal Cytoreductive Surgery (CRS) for Neoplasms of the Appendix, Colon or Rectum With Isolated Peritoneal Metastasis 282 Sep 202 2
NCT02614534 Multicentre, Randomized Clinical Trial to Evaluate Safety and Efficacy of Hyperthermic Intra-peritoneal Chemotherapy (HIPEC) With Mitomycin C Used During Surgery for Treatment of Locally Advanced Colorectal Carcinoma 200 Oct 2023
Gastric cancer    
NCT02158988 Prospective Multicenter Phase III Trial Using CRS With / Without HIPEC After Preoperative Chemotherapy in Patients With Peritoneal Carcinomatosis of Gastric Cancer Incl. Adenocarcinoma of the Esophagogastric Junction 105 Sep 2021
NCT01882933 GASTRICHIP : D2 Resection and HIPEC (Hyperthermic Intraperitoneal Chemoperfusion) in Locally Advanced Gastric Carcinoma. A Randomized and Multicentric Phase III Study 367 May 202 6
Ovarian cancer    
NCT01767675 A Phase II Randomized Study: Outcomes After Secondary Cytoreductive Surgery With or Without Carboplatin Hyperthermic Intraperitoneal Chemotherapy (HIPEC) Followed by Systemic Combination Chemotherapy for Recurrent Platinum-Sensitive Ovarian, Fallopian Tube, or Primary Peritoneal Cancer 99 Jan 202 2
NCT02124421 Phase II Randomized Study: Cytoreductive Surgery (CRS) With/Without Carboplatin Hyperthermic Intraperitoneal Chemotherapy (HIPEC) Followed by Adjuvant Chemotherapy as Initial Treatment of Ovarian, Fallopian Tube, & Primary Peritoneal Cancer 48 Apr 2028
NCT01376752 A Phase III Randomized Study Evaluating Hyperthermic Intra-Peritoneal Chemotherapy (HIPEC) in the Treatment of Relapse Ovarian Cancer 4 15 Sep 2024
NCT04473339 A Randomized Prospective Trail of Hyperthermic Intraperitoneal Chemotherapy (HIPEC) in Recurrent Ovarian Cancer Patients With Mutations in Homologous Recombination Repair (HRR) Genes 280 Dec 2023
NCT03772028 Phase III Randomized Clinical Trial for Stage III Epithelial Ovarian Cancer Randomizing Between Primary Cytoreductive Surgery With or Without Hyperthermic Intraperitoneal Chemotherapy 538 Apr 2025
Unpublished
Gastric cancer
NCT02240524 A Phase III Study of Hyperthermic Intraperitoneal Chemotherapy in the Treatment of Locally Advanced Gastric Cancer After radical Gastrectomy With D2 Lymphadenectomy 582 July 2019 (unknown)
Ovarian cancer
NCT01628380 Stage IIIC Unresectable Epithelial Ovarian/Tubal Cancer With Partial or Complete Response After 1st Line Neoadjuvant Chemotherapy (3 Cycles CBDCA+Paclitaxel): a Phase 3 Prospective Randomized Study Comparing Cytoreductive Surgery + Hyperthermic Intraperitoneal Chemotherapy (CDDP+Paclitaxel) + 3 Cycles CBDCA+Paclitaxel vs Cytoreductive Surgery Alone + 3 Cycles CBDCA+Paclitaxel 94 Jul 2018
(unknown)
NCT01539785 Surgery Plus Hyperthermic Intra-peritoneal Chemotherapy (HIPEC) Versus Surgery Alone in Patients With Platinum-sensitive First Recurrence of Ovarian Cancer: a Prospective Randomized Multicenter Trial 158 Sep 2018 (unknown)

NCT: national clinical trial.

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Coding Section    

Codes Number Description
CPT 96446 Chemotherapy administration into the peritoneal cavity via indwelling port or catheter
  96459 Unlisted chemotherapy procedure (When performed using a temporary catheter or performed intraoperatively, this code would be reported)
ICD-10-CM C45.1 Mesothelioma of peritoneum
  C56.1- C56.9 Malignant neoplasm of ovary code range
  C78.6 Secondary malignant neoplasm of retroperitoneum and peritoneum (includes pseudomyxoma peritonei)
  C79.60- C79.63 Secondary malignant neoplasm of ovary code range
  D12.1 Benign neoplasm of appendix
ICD-10-PCS   No specific code for cytoreductive surgery; coding would be based on what is excised
  DWY38ZZ Radiation oncology, anatomic regions, other radiation, abdomen, hyperthermia
  DWY68ZZ Radiation oncology, anatomic regions, other radiation, pelvic region, hyperthermia
Type of service  Oncology   
Place of service  Inpatient/outpatient   

This medical policy was developed through consideration of peer-reviewed medical literature generally recognized by the relevant medical community, U.S. FDA approval status, nationally accepted standards of medical practice and accepted standards of medical practice in this community, Blue Cross Blue Shield Association technology assessment program (TEC) and other non-affiliated technology evaluation centers, reference to federal regulations, other plan medical policies and accredited national guidelines.

"Current Procedural Terminology © American Medical Association. All Rights Reserved." 

History From 2013 Forward     

01/10/2022 

Annual review, no change to policy intent. Updating rationale, references and coding. 

01/19/2021 

Annual review, no change to policy intent. Updating background, regulatory status, guidelines, coding, rationale and references. 

01/13/2020 

Annual review, no change to policy intent. Updating regulatory status, rationale and references. 

08/12/2019 

Interim review to indicate that cytoreductive surgery plus HIPEC is considered NOT MEDICALLY NECESSARY for peritoneal carcinomatosis from colorectal cancer, gastric cancer or endometrial cancer and for all other indications, including goblet cell tumors of the appendix. Also indicating the use of HIPEC in all other settings to treat ovarian cancer, including, but not limited to stageIIIC or IV ovarian cancer is considered NOT MEDICALLY NECESSARY. Both statements previously indicated that the services were INVESTIGATIONAL for those issues. No other changes made. 

02/07/2019 

Annual review, medical necessity verbiage updated to include newly diagnosed stage III ovarian cancer. Updating title, background, description, guidelines, rationale, references and coding.

02/07/2018 

Annual review, no change to policy intent. Updating rationale and references.

01/04/2017 

Annual review, no change to policy intent. Updating background, description, rationale and references. 

01/28/2016 

Annual review, no change to policy intent. Adding regulatory status. 

02/04/2015 

Interim review, updating title. Adding "Investigational policy statement for ovarian cancer, peritoneal carcinomatosis due to gastric cancer or endometrial cancer, and for all other indications.", Updated description, background, guidelines. Added regulatory status and coding. 

11/25/2014 

Annual review, no change to policy intent. Updated description, rationale and references. Added coding and policy guidelines.

11/07/2013

Updated title.  Added Benefit Application Section.

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