Blue Cross of Idaho Logo

Express Sign-on

Thank you for registering with Blue Cross of Idaho

If you are an Individual or Family Member, please register here.

If you are a Medicare Advantage or Medicare Supplement member, please register here.

New Options for Affordable Health Insurance

 

MP 2.03.07 Cytoreductive Surgery and Perioperative Intraperitoneal Chemotherapy for Select Intra-Abdominal and Pelvic Malignancies

Medical Policy    
Section
Medicine 
Original Policy Date
6/27/05 
Last Review Status/Date
Reviewed with literature search/1:2015
Issue
1:2015
  Return to Medical Policy Index

Disclaimer

Our medical policies are designed for informational purposes only and are not an authorization, or an explanation of benefits, or a contract.  Receipt of benefits is subject to satisfaction of all terms and conditions of the coverage.  Medical technology is constantly changing, and we reserve the right to review and update our policies periodically.


Description

CRS and HIPEC

CRS comprises peritonectomy (ie, peritoneal stripping) procedures and multivisceral resections, depending on the extent of intra-abdominal tumor dissemination.(1) The surgical procedure may be followed intraoperatively by the infusion of hyperthermic chemotherapy, most commonly mitomycin C. Inflow and outflow catheters are placed in the abdominal cavity, along with temperature probes to monitor temperature. The skin is then temporarily closed during the chemotherapy perfusion, which typically runs for 1 to 2 hours. This procedure is referred to as HIPEC.

Pseudomyxoma Peritonei

Pseudomyxoma peritonei is a clinicopathologic entity characterized by the production of mucinous ascites and mostly originates from epithelial neoplasms of the appendix. Appendix cancer is diagnosed in fewer than 1000 Americans each year; less than half are epithelial neoplasms.(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, fortuitously discovered on imaging or during a laparotomy performed for another reason, to advanced cases with a distended abdomen, bowel obstruction, and starvation. The conventional treatment of pseudomyxoma peritonei is surgical debulking repeated as necessary to alleviate pressure effects. However, repeated debulking surgeries become ever more difficult due to progressively thickened intraabdominal adhesions, and this treatment is palliative, leaving visible or occult disease in the peritoneal cavity.(3) Five-year OS depends on tumor histology and ranges from 6% for high-grade (HG) tumors to 75% for low-grade (LG) tumors.(4,5)

Gastrointestinal Cancers (Colorectal, Gastric) and Peritoneal Carcinomatosis

Peritoneal dissemination develops in approximately 10% to 15% of patients with colon cancer and, despite the use of increasingly effective regimens of chemotherapy and biologic agents in the treatment of advanced disease, peritoneal metastases are associated with a median survival of 6 to 7 months.

Peritoneal carcinomatosis is detected in more than 30% of patients with advanced gastric cancer and is a poor prognostic indicator. Median survival is 3 months, and 5-year survival is less than 1%.(6) Sixty percent of deaths from gastric cancer are attributed to peritoneal carcinomatosis.(7) Current chemotherapy regimens are nonstandard, and peritoneal seeding is considered unresectable for cure.(8)

Mesothelioma

Malignant mesothelioma is a relatively uncommon malignancy that may arise from the mesothelial cells lining the pleura, peritoneum, pericardium, and tunica vaginalis testis. In the United States, 200 to 400 new cases of diffuse malignant peritoneal mesothelioma (DMPM) are registered every year, accounting for 10% to 30% of all-type mesothelioma.(9) DMPM has traditionally been considered as a rapidly lethal
malignancy with limited and ineffective therapeutic options.(9) 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 occurs as a result of locoregional progression within the abdominal cavity. In historical case series, treatment by palliative surgery, systemic/intraperitoneal chemotherapy, and abdominal irradiation resulted in a median survival of approximately 12 months.(9)

Surgical cytoreduction (resection of visible disease) in conjunction with 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 ovary; epithelial carcinoma is the most common type, accounting for 90% of malignant ovarian tumors. Epithelial ovarian cancer is the fifth most common cause of cancer death in women in the United States. New cases and deaths from ovarian cancer in 2014 are estimated at 21,980 and 14,270, respectively.(10) Most ovarian cancer patients (>70%) present with widespread disease, and annual mortality is approximately 65% of the incidence rate.

Current management of advanced epithelial ovarian cancer is CRS followed by combination chemotherapy. Treatment guidelines recommend intraperitoneal chemotherapy for patients with optimally debulked (<1 cm) stage 2 disease (pelvic extension of tumor) or stage 3 disease (peritoneal extension of tumor).(11) Estimated median OS is 66 months with and 37 to 49 months without intraperitoneal chemotherapy, respectively.(12,13) However, tumor recurrences are common, and prognosis for recurrent disease is poor.

CRS/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, carboplatin, and other drugs used for HIPEC have not been U.S. Food and Drug Administration (FDA)‒approved for this indication. Cyclophosphamide and nitrogen mustard are FDA-approved for intraperitoneal administration, but neither drug is used regularly for this purpose.(14)

Several peritoneal lavage systems (Product Code LGZ) have been FDA-cleared to provide “warmed, physiologically compatible sterile solution” (eg, Performer® HT perfusion system; RanD S.R.L., Medolla, Italy(15) ). None has received marketing approval or clearance to administer chemotherapy. FDA has issued warning letters to manufacturers of devices that are FDA-cleared for peritoneal lavage using sterile saline solutions when these devices are marketed for off-label use in HIPEC (eg, ThermaSolutions Inc., Minneapolis, MN(16) ; Belmont Instrument Corp., Billerica, MA(17))


Policy

 

Cytoreductive surgery and perioperative intraperitoneal chemotherapy may be considered medically necessary for the treatment of:

  • pseudomyxoma peritonei; and
  • diffuse malignant peritoneal mesothelioma.

Cytoreductive surgery and perioperative intraperitoneal chemotherapy is considered investigational for:

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

Policy Guidelines

Coding

The coding for this overall procedure would likely involve codes for the surgery, the intraperitoneal chemotherapy, and the hyperthermia.

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 external application of heat as described by CPT 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 policy was created in 2005, with the most recent MEDLINE literature review performed through January 2, 2015.

Pseudomyxoma Peritonei

Studies discussed next and other studies are summarized in Table 1.

Table 1. Summary of Studies of CRS and HIPEC in Pseudomyxoma Peritonei

Study

N

Postoperative
Mortality/Morbidity, %

Median OS, m

5-year OS %

Median PFS, m

5-year PFS, %

Primary Treatment

Jimenez (2014)18

202
125HG
77LG

0/16
NR
NR

90
47
Not reacheda

56
41
83

40
26
NR

44
34
58

Marcotte (2014)19

58

2/40

NR

77

NR

50b

Glehen (2010)20

255

4/40

>100

73

78

56

Chua (2009)21

106

3/49

104

75

40

38

Vaira (2009)22

60

0/45

NR

94

NR

80

Elias (2008)3

105

8/68

NR

80

NR

68

Yan (2007)23 (SR)

NR

NR

51-156

52-96

NR

NR

Recurrence

Sardi (20103)24,c

26

0/42

NR

34

NR

NR


CRS: cytoreductive surgery; HG: high-grade tumor (peritoneal mucinous carcinomatosis); HIPEC: hyperthermic intraperitoneal chemotherapy; LG: low-grade tumor (disseminated peritoneal adenomucinosis); m: months; N: number of patients; NR: not reported; OS: overall survival; PFS: progression-free survival; SR: systematic review.

aMedian OS not reached with mean follow-up of 36 months.
bFive-year disease-free survival.
cResults after second procedure shown.

Primary Treatment

Jimenez et al (2014) conducted a retrospective review of a prospective database of patients with peritoneal carcinomatosis maintained by Mercy Medical Center in Baltimore.(18) Two hundred two patients with peritoneal carcinomatosis from appendiceal cancer who underwent cytoreductive surgery hyperthermic intraperitoneal chemotherapy (CRS/HIPEC) were included; 125 patients (62%) had highgrade (HG) tumors (peritoneal mucinous carcinomatosis [PMCA]), and 77 patients (38%) had low-grade (LG) tumors (disseminated peritoneal adenomucinosis [DPAM]). Results for the entire cohort and for subgroups defined by tumor histology are shown in Table 1. In the HG (PMCA) group, Peritoneal Cancer Index (PCI), completeness of cytoreduction, and lymph node status were significantly associated with survival; in the LG (DPAM) group, completeness of cytoreduction was significantly associated with survival.

In 2010, Glehen et al published a retrospective, multicenter cohort study to evaluate toxicity and prognostic factors after CRS and HIPEC and/or unheated intraperitoneal chemotherapy for 5 days postoperatively.(20) 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. HIPEC was performed in 1154 procedures. Postoperative mortality was 4.1%. The principal origin of peritoneal carcinomatosis was pseudomyxoma peritonei in 301 patients. Median overall survival (OS) for patients with pseudomyxoma peritonei was not reached (median OS for all patients, 34 months.)

Additional information about the subgroup of patients with pseudomyxoma peritonei was provided by Elias et al.(25) CRS was achieved in 219 patients (73%), 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%. Postoperative mortality was 4% and morbidity, 40%. Mean follow-up was 88 months. The 1-, 3-, and 5-year OS rates were 89.4%, 84.8%, and 72.6%, respectively. The 10-year survival rate was 54.8%. Median survival had not
yet been reached but will exceed 100 months. Disease-free survival (DFS) was 56% at 5 years, and median duration of DFS was 78 months. A multivariate analysis identified 5 prognostic factors: extent of peritoneal seeding (p=0.004), institution (p<0.001), pathologic grade (p=0.03), sex (p=0.02), and use of HIPEC (p=0.04). When only the 206 patients with complete CRS were considered, the extent of peritoneal seeding was the only significant prognostic factor (p=0.004).

Chua et al (2009) reported the long-term survival of 106 patients with pseudomyxoma peritonei treated between 1997 and 2008 with CRS and HIPEC and/or unheated intraperitoneal chemotherapy for 5 days postoperatively.(21) Sixty-nine percent of patients had complete cytoreduction. Eighty-three patients (78%) had HIPEC intraoperatively, 81 patients (76%) had unheated postoperative intraperitoneal chemotherapy, and 67 patients (63%) had both. Seventy-three patients had disseminated peritoneal adenomucinosis, 11 had peritoneal mucinous carcinomatosis, and 22 had mixed tumors. Mortality rate was 3%, and severe morbidity rate was 49%. Median follow-up was 23 months (range, 0-140 months). Median OS was 104 months with a 5-year survival rate of 75%. Median progression-free survival (PFS) was 40 months with 1-, 3-, and 5-year PFS rates of 71%, 51%, and 38%, respectively. Factors influencing OS included histopathologic type of tumor (p=0.002), with best survival in patients with disseminated peritoneal adenomucinosis and worst survival in patients with peritoneal mucinous carcinomatosis. Factors influencing survival include histopathologic type of tumor, the use of both HIPEC and unheated postoperative intraperitoneal chemotherapy, completeness of cytoreduction, and severe morbidity.

Vaira et al (2009) reported their experience managing pseudomyxoma peritonei with CRS and HIPEC in a single institution in 60 patients, 53 of whom had final follow-up data.(22) 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, and 5- and 10-year DFS rates were 80% and 70%, respectively. Significant differences in improved OS were observed in patients who experienced complete surgical cytoreduction (p<0.003) and in those with histologic type disseminated peritoneal adenomucinosis versus those with peritoneal mucinous carcinomatosis (p<0.014).

In 2008, Elias et al reported the results of 105 consecutive patients with pseudomyxoma peritonei treated between 1994 and 2006 with CRS and 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 surgery, 72% of patients had no visible residual peritoneal lesions. Postoperative mortality was 7.6% and morbidity, 67.6%. Median follow-up was 48 months, and 5-year OS and DFS were 80% (95% confidence interval [CI], 68% to 88%) and 68% (95% CI, 55% to 79%), respectively. On multivariate analysis, 2 factors that had a negative influence on DFS were identified, serum carbohydrate antigen (CA) 19.9 level (a marker of biliopancreatic malignancy) greater than 300 units/mL and nondisseminated peritoneal adenomucinosis tumor histology.

In 2007, Yan et al conducted a systematic review of all relevant studies from 1996 to 2006 on the efficacy of CRS and intraperitoneal chemotherapy for pseudomyxoma peritonei.(23) There were no randomized controlled trials (RCTs) or comparative studies. Ten studies were included (863 patients); all were uncontrolled, observational studies. Two studies had relatively long-term follow-up of 48 and 52 months, and median follow-up in the remaining studies was less than 3 years (range, 19-35 months). Median survival across all studies ranged from 51 to 156 months. One-, 2-, 3-, and 5-year survival rates varied from 80% to 100%, 76% to 96%, 59% to 96%, and 52% to 96%, respectively. Overall mortality rates varied from 0% to 18% and morbidity from 33% to 56%.

Recurrence

From the same Mercy Medical Center database studied by Jimenez et al (previously described), Sardi et al (2013) identified 26 patients who underwent repeat CRS/HIPEC for peritoneal carcinomatosis recurrence.(24) Sixteen patients (62%) had HG PMCA, and 10 patients (38%) had LG DPAM. Patients eligible for repeat CRS/HIPEC had Eastern Cooperative Oncology Group Performance Status 0 to 1. The proportion of patients who had a preoperative PCI score less than 20 (scale, 0-39) was 35% before second procedure and 75% before third procedure (1/4 patients). There were no 30-day postoperative deaths; postoperative morbidity was 42% after second procedure and 50% after third procedure. After second procedure, 1-, 3-, and 5-year OS was 91%, 53%, and 34%, respectively. After third procedure, 1-year OS was 75%.

Lord et al (2014) reported a retrospective cohort study of 512 patients with perforated appendiceal tumors and pseudomyxoma peritonei who received CRS/HIPEC at a single center in the U.K. and achieved complete cytoreduction.(26) Thirty-five (26%) of 137 patients who recurred underwent repeat CRS/HIPEC; median time to recurrence was 26 months. Complete cytoreduction was achieved (again) in 20 patients
(57%). Mean OS in patients without recurrence (n=375), patients who recurred and had repeat CRS/HIPEC (n=35), and patients who recurred but did not have repeat CRS/HIPEC (n=102) was 171 months (95% CI, 164 to 178), 130 months (95% CI, 105 to 153) and 101 months (84 to 119), respectively (log-rank test, p=0.001). Five-year survival was 91%, 79%, and 65%, respectively. The incidence of complications was similar between primary and repeat procedures.

Section Summary

Large, retrospective cohort studies have consistently shown median and 5-year OS as 47 to 156 months and 41% to 96%, respectively, for patients with pseudomyxoma peritonei who are treated with CRS/HIPEC. One retrospective study of 26 patients who underwent CRS/HIPEC for recurrence indicated 5-year OS of 34%. Procedure-related morbidity and mortality have generally decreased over time to acceptable levels (16% to 49% and 0% to 4%, respectively, in recent studies).

Peritoneal Carcinomatosis of Gastrointestinal Origin (Colorectal, Gastric)

Several authors have evaluated prognostic factors for patients undergoing CRS/HIPEC for peritoneal carcinomatosis of gastrointestinal origin. PCI(25) (a summary of both lesion size and distribution of peritoneal surface malignancy used to estimate the likelihood of complete cytoreduction; lower scores are better)(18,27-30) and completeness of cytoreduction(18,30-32) were consistently associated with survival.

Colorectal Cancer

Studies discussed next and other studies are summarized in Table 2.

Table 2. Summary of Studies of CRS and HIPEC in Peritoneal Carcinomatosis From Colorectal Cancer

Study

N

Postoperative Mortality/Morbidity, %

Median OS, mo

2-Year OS, %

Primary Treatment

ASPSM (2014)33

705

NR

41

NR

Baratti (2014)34

101

3/24

32

NR

Elias (2014)27

139

6/22

39

39

Huang (2014)35,a

33

0/29

14

20

Nikolic (2014)28

61

NR/13

51

59

DeCuba (2013)36 (SR)

NR

NR

6-36 (with liver mets)
19-63 (no liver mets)
10-24 (c, no liver mets)

NR

Klaver (2013)37

604

NR

NR

83

Glehen (2010)20

523

NR

30

NR

2009-2010 reviews 1,2,38

NR

NR

13-63

NR

Elias (2008)39

48
48 ( c)

NR

63
24

NR

Van Leeuwen (2008)40

103

1/56

NR

72

Gleehen (2004)41

506

4/23

19
32 (cr)/8 (no cr)

NR

Verwaal (2003)42
(RCT)

54

51 ( c)

16/15

22
29 (cr)/5 (no cr)
13

55

39

Recurrence

Williams (2014)43

18

0/67

23

48

Klaver (2013)37

18

0/17

NR

50


ASPSM: American Society of Peritoneal Surface Malignancies; c, control; cr: complete resection of macroscopic disease; CRS: cytoreductive surgery; HIPEC: hyperthermic intraperitoneal chemotherapy; mets: metastases; NR: not reported; OS: overall survival; RCT: randomized controlled trial; SR: systematic review.
aNonrandomized comparative study.

Primary Treatment

De Cuba et al reported a 2013 systematic review and meta-analysis of studies of colorectal cancer (CRC) patients with both peritoneal and liver metastases who received CRS and HIPEC plus curative resection.(36) In their review, the authors compared the results of studies in this population with those of patients without liver metastases who received modern systemic chemotherapy only (irinotecan, oxaliplatin, and a biologic) or CRS plus HIPEC or unheated intraperitoneal chemotherapy for 5 days postoperatively. Median OS ranged from 6 to 36 months in patients with liver metastases, 10 to 24 months in patients (without liver metastases) who received systemic chemotherapy only, and from 19 to 63 months in patients (without liver metastases) who received CRS plus HIPEC or unheated postoperative intraperitoneal chemotherapy. Patients with liver metastases had a 24% greater risk of death than those without liver metastases who received CRS plus HIPEC or unheated postoperative intraperitoneal chemotherapy (pooled hazard ratio [HR], 1.24; 95% CI, 0.96 to 1.60; p=NS). The authors observed that comparisons across studies are impaired by lack of standardization of the HIPEC or unheated postoperative intraperitoneal chemotherapy procedure (exposure technique, drugs and doses used, duration of exposure, temperature, flow rates). In 2013, the American Society of Peritoneal Surface Malignancies, a consortium of cancer centers performing CRS with HIPEC, published recommendations for standardizing the delivery of HIPEC in CRC patients with peritoneal dissemination treated in the United States to further research in this area.(44) Closed HIPEC using 40 mg of mitomycin C at 42°C for 90 minutes was recommended.

Reviews from 2009 and 20101,2,38 summarized studies of colorectal peritoneal carcinomatosis treated with CRS and HIPEC, some of which are included in the next section. These included 1 RCT (discussed next) with a second publication after 8 years of follow-up,(42,45) 1 comparative study,(46) and numerous observational studies. Across studies, median OS after CRS and HIPEC in patients with peritoneal
dissemination from colon cancer ranged from 13 to 63 months (median, ±18 months). A 2008 study by Elias et al39 reported median OS of 63 months, which may be explained by the use of more contemporary chemotherapeutic regimens in the treatment of advanced-stage colon cancer compared with earlier studies in which previous standard therapy was used.(1) For comparison, published reports of outcomes after systemic treatment of metastatic colon cancer with polychemotherapy (with or without biologic agents) ranged from 14.8 months to 22.6 months (median, 19.2 months).(1)

The 1 RCT identified was a 2003 single institution study.(42) Verwaal et al randomly assigned 105 patients with peritoneal carcinomatosis to standard treatment with systemic chemotherapy (fluorouracil and leucovorin) and palliative surgery, if necessary (ie, treatment of bowel obstruction), or to aggressive CRS and HIPEC followed by standard systemic chemotherapy. Patients with other sites of metastases, ie, lung or liver, were excluded. The cytoreductive procedure comprised stripping the parietal peritoneum and resecting infiltrated viscera, if possible. Most often, the gall bladder, parts of the stomach, and spleen were resected. The greater omentum also was routinely removed. At the completion of resection, the presence of residual tumor was assessed. Hyperthermic mitomycin C was then administered intraperitoneally for 90 minutes. In the cytoreduction group, 4 patients (8%) died as a result of treatment. The most important complications were small bowel leakage and abdominal sepsis; the most common grade 3 and grade 4 adverse events were leukopenia (7 patients [15%]) and gastrointestinal fistula (7 patients [15%]), respectively. The primary end point was OS, measured from the time of randomization to death from any cause. After a median follow-up of 21.6 months, 20 (39%) of 51 patients in the standard therapy group were still alive compared with 30 (55%) of 54 patients in the cytoreduction group (HR for death, 0.55; 95% CI, 0.32 to 0.95; p=0.032). Median OS in the control group was 12.6 months compared with 22.4 months in the cytoreduction group. Subgroup analysis revealed that OS was particularly poor among patients with either residual tumor measuring greater than 2.5 mm or in patients with tumor involvement in 6 or more regions in the abdomen. In these groups, median survival was approximately 5 months, compared with 29 months in patients with no residual tumor.

An editorial on this randomized trial commented that although this study showed that CRS and HIPEC with systemic chemotherapy nearly doubled survival compared with systemic chemotherapy alone, it did not show how much of this benefit is derived from the surgery and how much from the HIPEC,(47) and in a letter to the editor, Markman pointed out that the reported survival benefit may be primarily related to the
cytoreduction, with added chemotherapy only contributing to increased morbidity.(48) Finally, new targeted systemic treatment options have emerged for colon cancer, specifically cetuximab and bevacizumab, which offer additional palliative options for colon cancer; the chemotherapy used in the randomized trial is no longer considered standard.

Aside from methodologic issues, results of the trial present complicated risk benefit questions that are not adequately addressed. If the main rationale for CRS with HIPEC is to provide a curative option, data regarding disease recurrence would be important. However, it is unknown whether survivors in either group lived with or without disease. If the main rationale for the therapy is palliation in terms of prolonging life or relieving specific symptoms (eg, related to ascites or bowel obstruction), it is important to determine the quality of life (QOL) associated with the 10-month improvement in median survival. QOL data were not reported in this randomized trial; however, the high incidence of major complications, and the reported mean length of hospitalization (29 days) suggested that this aggressive surgical approach has a significant impact on QOL.

In 2008, Verwaal et al reported 8-year follow-up of all patients who were alive until 2007.(45) Minimum follow-up was 6 years for all patients (median, 7.8 years; range, 6-9.6). During follow-up, 1 patient crossed over from the standard arm to the CRS/HIPEC arm after recurrent disease at 30 months after randomization. At the time of this long-term follow-up, in the standard arm, 4 patients were still alive, 2 with disease and 2 without disease, and in the HIPEC arm, 5 patients were still alive, 2 with disease and 3 without disease. Median disease-specific survival was 12.6 months in the standard arm and 22.2 months in the CRS/HIPEC arm (p=0.028). Median PFS was 7.7 months in the standard arm and 12.6 months in the CRS/HIPEC arm (p=0.02).

In 2014, the American Society of Peritoneal Surface Malignancies evaluated a clinical tool for selecting appropriate patients for CRS/HIPEC in a retrospective review of 1013 patients.(33) Patients had peritoneal carcinomatosis from CRC and underwent CRS with (n=705) or without (n=308) HIPEC. The Peritoneal Surface Disease Severity Score (PSDSS) assesses preoperative symptoms, extent of peritoneal dissemination, and primary tumor histology and defines 4 stages by increasing disease severity (stage 1, least severe). For the CRS/HIPEC group, median OS was 41 months; 3-year and 5-year OS was 66% and 58%, respectively; median survival stratified by PSDSS prognostic group was 86, 43, 29, and 28 months for PSDSS stage 1, 2, 3, and 4, respectively; and PSDSS and Cytoreduction Score (a 4-point assessment of cytoreduction after CRS) were statistically associated with survival in multivariate logistic regression.

In the 2010 retrospective, multicenter cohort study described earlier,(20) the principal origin of peritoneal carcinomatosis was colorectal adenocarcinoma in 523 patients. Median OS for this group was 30 months. Independent prognostic indicators in multivariate analysis were institution, histologic origin of the tumor, completeness of CRS, extent of carcinomatosis, and lymph node involvement.

Quality of Life

Two studies(49,50) described next were included in 2 systematic reviews published in 2014 that examined QOL outcomes in patients with peritoneal carcinomatosis who underwent CRS/HIPEC.(51,52) Both reviews included studies that used structured QOL scales; Shan et al included 15 studies (total N=1583 enrolled patients),(51) 14 of which appeared in the review of 20 studies (total N=1181 respondents) by Seretis et al.(52) No RCTs were identified. Studies were heterogeneous in sample size (median, ±60; range, 5-216), response rate (most <85%), primary cancers (eg, gastrointestinal, ovarian, endometrial, mesothelioma), QOL scales, and timing of QOL evaluations. Nonetheless, both reviews reported a decline in healthrelated QOL compared with baseline values up to 4 months after treatment. At 1 year, QOL scores
improved to baseline values or above. In random effects meta-analysis of 8 studies (total N=499 enrolled patients), overall health ( =38%) and emotional health ( =41%) showed statistically significant improvements compared with baseline, but physical ( =60%), social (=0%), and functional ( =74%) health did not.(51) Improvements were small to medium (standardized mean difference <0.4 for all outcomes). Although this evidence suggests improvement from baseline in some QOL domains, the absence of parallel control groups limits interpretation of the results.

In 2014, Passot et al reported on QOL in 216 patients who underwent CRS/HIPEC for peritoneal carcinomatosis at a single center in France.(53) Primary tumors were ovarian (35%), colorectal (26%), pseudomyxoma peritonei (19%), primary serous peritoneal carcinoma (4%), peritoneal mesothelioma (8%), gastric (6%), and other cancers in 1 patient each. QOL was assessed using the validated Gastro-Intestinal Quality of Life Index (GIQLI), which assesses symptoms, physical function, feelings, social integration, and effect of any medical intervention or treatment. The proportion of patients who returned questionnaires was 81% at baseline (preoperatively), 90% at 1 month postoperatively, 89% at 3 months and at 6 months, and 74% at 1 year. Mean GIQLI score decreased (worsened) substantially (>10%) from baseline for up to 6 months and, for 3 of 5 QOL domains assessed, returned to baseline at 12 months; mean symptoms and feelings did not return to baseline within 12 months. In multivariate analysis, factors associated with decreased QOL were cancer diagnosis at 3 months; presence of stoma at 6 months; and surgical time greater than 270 min and disease recurrence at 12 months.

In 2013, Tsilimparis et al reported on QoL in 90 consecutive patients at a single center in Germany who underwent CRS and HIPEC.(49) Primary tumors were colorectal (21%), ovarian (19%), pseudomyxoma peritonei (16%), appendiceal (16%), gastric (10%), and peritoneal mesothelioma (13%). Health-related QOL was assessed using the German version of the European Organization for Research and Treatment
of Cancer QoL Questionnaire, which assesses function and symptoms. Each scale/item is scored from 0 to 100, with higher scores indicating higher response (either greater function or greater symptom severity). The proportion of patients who returned questionnaires was 59% at 1 month, 47% at 6 months, 36% at 1 year, 19% at 2 years, and 7% at 3 years. After initial decline in the postoperative period, only constipation improved significantly at 6 months (42 patients). Pain, nausea/vomiting, and dyspnea improved significantly in the 6 patients reporting at 3 years. Mean global health status (patient selfassessment) and emotional function scores returned to baseline in the 17 patients reporting at 2 years, and physical and social function returned to baseline at 3 years. Other symptoms (fatigue, pain, insomnia, anorexia, diarrhea), functions (role and cognitive), and financial problems worsened from baseline during the follow-up period. The authors acknowledged that QOL results in this patient sample were complicated by survivor bias, varied primary diagnoses, and natural history of disease.

In 2001, McQuellon et al reported QOL outcomes for a case series of 64 patients undergoing CRS and intraperitoneal chemotherapy for peritoneal carcinomatosis.(50) QoL instruments used were the Functional Assessment of Cancer Therapy‒Colon, activities of daily living subscale of the 36-Item Short-Form Health Survey, Brief Pain Inventory, and Center for Epidemiologic Studies–Depression scales. Forty-eight of 64 enrolled patients (75%) completed the assessment before and at a mean of 12 days after surgery; 16 patients (25%) did not complete the survey either due to death (n=11) or missed appointments. By 6 months’ follow-up, only 39 patients (61%) were available, either due to death or continuing dropout. Among the respondents, overall QOL decreased significantly from baseline to postsurgery but improved to greater than baseline at 3 months. However, these data are difficult to interpret without a control group and owing to the large number of dropouts due to death.

Recurrence

In 2014, Williams et al reported a case series of 18 patients at a single center in Australia who underwent second CRS with HIPEC with (n=2) or without (n=11) unheated intraperitoneal chemotherapy for 5 days postoperatively or unheated postoperative intraperitoneal chemotherapy alone (n=4) following recurrence after initial CRS at the same center.(43) One patient received no intraperitoneal chemotherapy. HIPEC
followed by unheated postoperative intraperitoneal chemotherapy used mitomycin, HIPEC without unheated postoperative intraperitoneal chemotherapy used oxaliplatin, and unheated postoperative intraperitoneal chemotherapy (with or without HIPEC) used 5-fluorouracil. Results are shown in Table 2.

In 2013, Klaver et al reported a case series of 18 patients in 3 centers who had peritoneal recurrence of colorectal (13 patients) or appendiceal (5 patients) carcinomatosis and received a second CRS with HIPEC (mitomycin; 14 patients) or unheated intraperitoneal chemotherapy for 5 days postoperatively (5-fluorouracil; 3 patients) or both (1 patient).(37) Median time to recurrence after the primary procedure was 14 months (range, 1-33). Mean PCI was 6.3 (scale, 0-39). No patients died within 30 days after the second procedure. During median follow-up of 10 months, 14 patients (78%) experienced a subsequent recurrence, with a median time to recurrence of 4.5 months. One- and 2-year OS were 74% and 50%, respectively.

Section Summary

One RCT demonstrated improved survival in patients with peritoneal carcinomatosis due to CRC who received CRS/HIPEC plus systemic chemotherapy compared with patients who received systemic chemotherapy alone. However, procedure-related morbidity and mortality were 98% and 16%, respectively, and systemic chemotherapy regimens did not use currently available biologic agents. Retrospective cohort studies have shown median and 2-year OS of 13 to 63 months and 12% to 83%, respectively. Procedure-related morbidity and mortality were 13% to 56% and 0% to 6%, respectively, similar to that observed in the American College of Surgeons National Surgical Quality Improvement Program. QoL data from uncontrolled studies are insufficient to form conclusions. Several studies indicated that PCI and completeness of cytoreduction are prognostic factors for survival. In 2 retrospective cohort studies of patients who underwent CRS/HIPEC for recurrence (total N=36), 2-year OS was approximately 50%. Procedure-related morbidity was 17% to 67%; there were no procedurerelated deaths.

Gastric Cancer

Studies discussed next are summarized in Table 3.

Table 3. Summary of Studies of CRS and HIPEC in Peritoneal Carcinomatosis From Gastric Cancer

Study

N

Postoperative Mortality/Morbidity, %

Median OS, mo

1-Year OS, %

Rudloff (2014)54 (RCT)

9
8 ( c)c

11/100b
NA

11
4

78
0

Yarema (2014)55,a

20
20 ( c)c

NR

12d
8

69
25

Kim (2014)55,a

9
17 ( c)e

NR

16
16

73
80

Yang (2011)57 (RCT)

34
34 ( c)f

NR

11g
7

41
29


c: control; CRS: cytoreductive surgery; HIPEC: hyperthermic intraperitoneal chemotherapy; NA: not applicable; NR: not reported; OS: overall survival; RCT: randomized controlled trial; SR: systematic review.
aNonrandomized comparative study.
bNinety-day.
cSystemic chemotherapy only.
dLog-rank test vs control (p=0.004).
eSurgical resection.
fCytoreductive surgery only.
gLog-rank test vs control (p=0.049).

Coccolini et al (2014) conducted a systematic review with meta-analysis of intraperitoneal chemotherapy for advanced gastric cancer in patients with or without peritoneal carcinomatosis.(58) Literature was searched through 2012, and 20 RCTs that compared surgical treatment (primarily resection) plus intraperitoneal chemotherapy with surgical treatment alone were identified; of these, only 1 open-label RCT from Japan enrolled patients with peritoneal carcinomatosis treated with CRS/HIPEC. Yang et al (2011) randomized 68 patients (1:1) to CRS/cisplatin HIPEC or CRS alone.(57) Median OS was 11.0 months (95% CI, 10.0 to 11.9) in the CRS/HIPEC group and 6.5 months (95% CI, 4.8 to 8.2) in the CRS only group (log-rank test, p=0.046). One-, 2-, and 3-year OS in the CRS/HIPEC and CRS only groups were 41.2% and 29.4%, 14.7% and 5.9%, and 5.9% and 0%, respectively. Incidence of serious adverse events was similar between groups (15% in the CRS/HIPEC group vs 12% in the CRS only group).

In 2014, Rudloff et al reported results of a preliminary, open-label, phase 3 RCT in 17 patients from several U.S. centers who had gastric cancer metastatic to liver and lung and peritoneal carcinomatosis.(54) Eligible patients could, in the opinion of the Principal Investigator, be resected to “no evidence of disease” based on imaging studies or staging laparoscopy. Patients were randomized using a computerized randomization algorithm to receive systemic chemotherapy with FOLFOXIRI (5‐fluorouracil, leucovorin, oxaliplatin, irinotecan) (n=8) or systemic chemotherapy plus gastrectomy and CRS/oxaliplatin HIPEC (n=9). Median and 1-year OS were 4.3 months and 0%, respectively, in the control group, and 11.3 months and 78%, respectively, in the CRS/HIPEC group (statistical testing not reported). Factors associated with survival more than 1 year in the CRS/HIPEC group were complete cytoreduction and initial PCI of 15 or less. Enrollment to complete a larger planned trial was discontinued due to slow accrual.

Yarema et al (2014) conducted a retrospective review of patients who had gastric cancer with peritoneal involvement and underwent HIPEC with (n=20 patients with limited peritoneal metastases) or without (n=10 patients with diffuse peritoneal carcinomatosis and symptomatic ascites) CRS at a single center in the Ukraine.(55) HIPEC used mitomycin-C plus cisplatin. Results were compared with contemporaneous control patients with gastric cancer who received palliative chemotherapy only (n=20 patients with limited peritoneal metastases) or best supportive care (n=10 patients with diffuse peritoneal carcinomatosis and symptomatic ascites). In 20 patients with limited disease who received CRS/HIPEC, median and 1-year OS was 12 months and 69%, respectively, compared with 8 months (log-rank test, p=0.004) and 25%,
respectively, in controls. In multivariate analysis, factors statistically associated with survival were extent of peritoneal dissemination and completeness of cytoreduction. In patients with advanced disease who received HIPEC only, median OS was 3.5 months, compared with 2.4 months in controls (log-rank test, p=0.49).

In a small retrospective study at a single U.S. center, Kim et al (2014) reported no improvement in median OS (16 months) for patients with gastric cancer and peritoneal carcinomatosis who underwent surgical resection (n=17) or CRS/HIPEC (n=9).(56) One-, 2-, and 3-year OS in the control and CRS/HIPEC groups were 80% and 73%, 49% and 39%, and 49% and 39%, respectively (statistical testing not reported).

Section Summary

One small (N=17) RCT showed improved survival in patients with peritoneal carcinomatosis due to gastric cancer who received CRS/HIPEC compared with patients who received chemotherapy alone. Another small (N=68) RCT showed improved survival in patients who received CRS/HIPEC compared with CRS alone. These results were consistent with a retrospective review of 40 patients that showed improved survival with CRS/HIPEC compared with systemic chemotherapy alone, but not with a retrospective review of 26 patients that showed similar survival between CRS/HIPEC and gastric resection.

Peritoneal Carcinomatosis From Endometrial Cancer

Three small, non-U.S. cohort studies reported outcomes with CRS/HIPEC for primary (total N=6) or recurrent (confined to the peritoneum; total N=18) endometrial cancer with peritoneal carcinomatosis.(8,11,59) Patients varied in histopathologic subtype of cancer, prior treatment, interval from initial treatment to CRS/HIPEC (range, 0-120 months), preoperative PCI (range, 3-24), and postoperative treatment. All patients underwent CRS and intraoperative HIPEC with cisplatin plus doxorubicin (total N=19) or mitomycin (total N=5). Cytoreduction was complete in 18 patients (75%) and almost complete (minimal residual disease) in 3 patients (12.5%). Of 24 total patients, 5 (21%) died within 1 year
(comparable with published survival estimates with systemic chemotherapy59 ); 3 (12.5%) died at 12-19 months; 11 (46%) were alive and disease-free at the time of publication (median, 34 months; range, 2-125); and 4 (17%) were alive with recurrent disease (median, 21 months; range, 6-28). (One patient was lost to follow-up.) The largest study of 13 patients with primary or recurrent disease reported a median OS of 19 months and median DFS of 11 months.(8) In all patients, grade 1 adverse events included anastomotic leak and cisplatin neurotoxicity. More severe complications occurred in 5 patients (21%) and included grade 4 septicemia and pulmonary embolism; pancytopenia and critical illness myopathy; and chronic renal failure. PCI score and completeness of cytoreduction were associated with survival.

Section Summary

Cohort studies in 24 patients with primary or recurrent endometrial cancer and peritoneal carcinomatosis suggest that survival with CRS/HIPEC may be improved compared with systemic chemotherapy (median OS, 19 months vs <12 months in published reports). However, severe complications occurred in 21% of patients. Further, in the absence of parallel control groups, potential bias is introduced by confounding factors, such as disease history, cancer subtype, preoperative PCI, and treatment. Randomized trials that compare CRS/HIPEC with standard treatment (surgery [including CRS], systemic chemotherapy, brachytherapy, radiotherapy, and/or hormone therapy) in larger numbers of patients are needed.

Peritoneal Mesothelioma

Studies discussed next and studies published subsequently are summarized in Table 4.

Table 4. Summary of Studies of CRS and HIPEC in Peritoneal Mesothelioma

Study

N

Postoperative Mortality/Morbidity, %

Median OS, mo

5-Year OS, %

Median PFS, mo

Robella (2014)60

42

7/36

65

44

NR

Alexander (2013)61

211

2/30

38

41

NR

Baratti (2011)9 (SR)

427

0-11/20-41

30-92

33-68

7-40

Glehen (2010)20

88

NR

41

NR

NR

Yan (2009)62

401

NR

53

47

NR


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

Alexander et al (2013) reported on 211 patients from 3 tertiary care centers in the United States who had malignant peritoneal mesothelioma and had undergone CRS/HIPEC.(61) Results are shown in Table 4. On multivariate analysis, factors statistically associated with favorable outcome were age younger than 60 years, complete or almost complete cytoreduction, low histologic grade, and HIPEC with cisplatin (rather
than mitomycin-C). Shetty et al (2014) similarly reported improved OS and reduced hospital stay with carboplatin HIPEC compared with mitomycin-C HIPEC in 44 patients with DMPM.(63)

For a 2011 systematic review, Baratti et al searched the PubMed database from 1979 to 2010 for studies on the clinical management of diffuse malignant peritoneal mesothelioma (DMPM).(9) The review included 14 studies with a total of 427 patients, 289 of whom underwent CRS with HIPEC, 2 with unheated intraperitoneal chemotherapy for 3-5 days postoperatively, and 106 with both. Studies that included patients with well-differentiated or low-grade types of mesothelioma were excluded. All included studies were prospective, uncontrolled case series. Mean patient age ranged from 49 to 56 years. All institutions used peritonectomy and multivisceral resection to remove visible disease. HIPEC protocols varied widely among institutions in terms of technique, drugs, carriers, timing and temperature. Operative mortality and morbidity were reported in 11 monoinstitutional series. Operative mortality ranged from 0% to 10.5%. Overall, death occurred in 11 (3.1%) of 373 assessable patients. In one multi-institutional series, mortality was 2.2%. Morbidity (severe and life-threatening complications) varied from 20% to 41%. For patients who underwent CRS and HIPEC, median OS ranged from 29.5 to 92 months. Median OS was not reached in 3 series, but exceeded 100 months in one of these. 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 2014 systematic review that included 7 studies published after the Baratti et al review were aligned with these findings: Pooled 1-, 3-, and 5-year survival estimates were 84%, 59%, and 42 %, respectively.(64)

The largest study in both systematic reviews was a 2009 international registry study by Yan et al, for which 401 patients (99%) had complete follow-up.(62) Of these patients, 92% received HIPEC. Reasons for not receiving HIPEC included unheated intraperitoneal chemotherapy for 5 days postoperatively being given instead, intraoperative hemodynamic instability, and unclear reason. Median and 1-, 3-, and 5-year survival rates were 53 months, 81%, 60%, and 47%, respectively.

The review acknowledged the possibility of patient selection bias as an explanation for the superior survival noted with aggressive treatment over more conventional treatment modalities, because patients with poor performance status are generally excluded from CRS and HIPEC. The authors concluded that, even in the absence of controlled data, the evidence suggests that the use of CRS and HIPEC in the treatment of DMPM should be the benchmark against which other treatments should be evaluated.

In the 2010 retrospective, multicenter cohort study described,(20) the principal origin of tumor was peritoneal mesothelioma in 88 patients. Median survival for this group of patients was 41 months. Independent prognostic indicators in multivariate analysis were institution, origin of peritoneal carcinomatosis, completeness of CRS, extent of carcinomatosis, and lymph node involvement.

Section Summary

Retrospective cohort studies have shown median and 5-year OS of 30 to 92 months and 33% to 68%, respectively, for patients with peritoneal mesothelioma who are treated with CRS/HIPEC. Two studies indicated improved outcomes with platinum-containing HIPEC (cisplatin or carboplatin) compared with mitomycin-C. Procedure-related morbidity and mortality has remained relatively steady over time at approximately 35% and 5%, respectively.

Ovarian Cancer

Studies discussed next are summarized in Table 5.

Table 5. Summary of Studies of CRS and HIPEC in Ovarian Cancer

Study

N

Postoperative Mortality/Morbidity, %

Median OS, mo

5-Year OS, %

Primary Treatment

Cohort studies

European studies 65-67

157a

6-8/16-42a

35-48

NR

Chiva (2015) (SR)68

248

0-7/25

37

40

 

184
287(c)

2-5/2-29a

42-58
29-66 (c)b

NR

Bakrin (2014) (SR)69

 

 

 

 

Recurrence

Randomized controlled trials

Spiliotis (2014)70

60
60 (c)

NR
NR

26.7c
13.4 (c)c

NR

Case-control studies

Fagotti (2012)71

30
37 (c)

NR

NR

68
42 (c)

Spiliotis (2011)72

24
24 (c)

NR

19.4
11.2 (c)

NR

Munoz-Casares (2009)73

14
12 (c)

NR

NR

58
17 (c)

Cohort studies

European studies65-67

157a

6-8/16-42a

NR

NR

Chiva (2015)68

499

0-7/19

36

NR

Bakrin (2014) (R)69

586
460(c)

2-5/2-29a

38-52 (cr)/11-33 (no cr)
45-61(c;cr)/8-20(c;no cr)

NR

Multiple treatment settings

HYPER-O Registry (2010)74

141

NR

30.3

25

c: control; cr: complete resection of macroscopic disease; CRS: cytoreductive surgery; HIPEC: hyperthermic intraperitoneal chemotherapy; NR: not reported; OS: overall survival; R: review; RCT: randomized controlled trial; SR: systematic review.
aFor first- and second-line settings combined.
bCRS without HIPEC with or without intraperitoneal chemotherapy.
cMean OS.

In 2014, Spiliotis et al in Greece reported a single-center RCT of 120 women who had advanced (stage IIIc-IV), recurrent epithelial ovarian cancer after initial treatment with CRS or debulking surgery and systemic chemotherapy.(70) Between 2006 and 2013, eligible women were randomized preoperatively by computer assignment to CRS/HIPEC (using cisplatin plus paclitaxel for platinum-sensitive disease or doxorubicin plus paclitaxel or mitomycin for platinum-resistant disease) or to CRS followed by systemic chemotherapy. More patients in the CRS/HIPEC group had complete cytoreduction compared with the non-HIPEC group (65% vs 55%), and the CRS/HIPEC group had more patients with stage IIIc disease (68%) compared with the non-HIPEC group (60%). In Kaplan-Meier survival analysis, mean OS was 26.7months in the CRS/HIPEC group versus 13.4 months in the non-HIPEC group (statistical tests not reported, p=0.006). In platinum-sensitive disease, survival was 26.8 months in the HIPEC group versus 15.2 months in the non-HIPEC group (p=0.035), but in platinum-resistant disease, survival did not differ statistically between groups (26.6 months in the HIPEC group vs 10.2 months in the non-HIPEC group; p value not reported). A statistical test for interaction (treatment x platinum sensitivity) was not reported. Completeness of cytoreduction and PCI score were associated with survival. Treatment-related morbidity and mortality were not reported. Baseline between-group differences in completeness of cytoreduction, which is prognostic for survival, limit interpretation of the trial results.

Chiva et al (2015) reviewed CRS/HIPEC for treatment of ovarian cancer in the first- and second-line settings.(68) Eleven cohort studies in the first-line setting (total N=248) and 8 studies in the second-line setting (total N=499) that reported survival outcomes were included. Completeness of cytoreduction was 0 or 1 (minimal residual disease) in 88% and 93% of patients in the first- and second-line cohorts, respectively. In the first-line setting, weighted (for study sample size) median OS was 37 months (range, 27-78), median DFS was 14 months (range, 12-30), and 5-year OS was 40% (range, 28-72). These results were considered comparable with outcomes observed without HIPEC in the first-line setting. In the second-line setting, which included only patients with chemotherapy-sensitive disease (DFS >6 months after completion of first-line treatment), weighted median OS was 36 months (range, 23-62), and median DFS was 20 months (range, 11-24). These results were inferior to those observed in studies of secondline CRS without HIPEC (median OS, 50-60 months). Severe (grade 3-4) morbidity was 25% and 19% in the first- and second-line cohorts, respectively. Mortality estimates (0%-7% in both cohorts) were similar
to those observed in studies of CRS without HIPEC.

Bakrin et al reported a literature review in 2014.(69) In the first-line setting, 5 cohort studies (total N=184) reported median survival of 42 to 58 months with CRS/HIPEC; in 4 studies of CRS without HIPEC with or without intraperitoneal chemotherapy (total N=287), median survival was 29 to 66 months. For recurrent disease (second-line setting), 3 studies of CRS/HIPEC (total N=586) reported median survival of 38 to 52
months in patients with complete cytoreduction and 11 to 33 months in patients without complete cytoreduction; 3 studies of CRS without HIPEC (total N=460) reported median survival of 45 to 61 months in patients with complete cytoreduction and 8 to 20 months in patients without complete cytoreduction. In both first- and second-line settings, completeness of cytoreduction, extent of peritoneal carcinomatosis,
and chemosensitivity to platinum were associated with survival. Overall procedure-related grade 3/4 morbidity and mortality were 2% to 29% and 2% to 5%, respectively. Other retrospective studies in patients with recurrent ovarian cancer have reported similar survival estimates.(75,76)

The Bakrin et al (2014) review included 3 non-U.S. case-control studies that compared CRS/HIPEC with CRS alone for recurrent ovarian cancer (total N=104).(71-73) Three- to 5-year survival ranged from 50% to 68% in the CRS/HIPEC groups versus 17% to 42% in the CRS only groups.

Cohort studies from Europe (total N=157) reported procedure-related morbidity and mortality of 16% to 42% and 6% to 8%, respectively, in first- and second-line settings.(65-67,77) Median OS was 35 to 48 months in the first-line setting and 27 to 33 months in the second-line setting and varied by completeness of cytoreduction.

Cascales-Campos et al (2014) reported significantly reduced DFS in 9 patients who were age 75 or older at the time of CRS/HIPEC compared with 57 patients who were younger than 75 years (median DFS, 6 months vs 24 months), and significantly increased morbidity (grade 3/4 adverse events, 56% vs 16%).(78) The authors suggested that patients 75 years of age or older should not receive CRS/HIPEC for treatment of ovarian cancer.

In 2005, ThermaSolutions Inc. sponsored an internet registry of patients with epithelial ovarian cancer who were treated with HIPEC at several participating U.S. institutions.(74) Initial results from 141 (85%) of 166 registered patients were published in 2010. Most patients (59%) received second-line HIPEC; others received HIPEC as first-line treatment (18%), for interval debulking (13%), or for consolidation (9%).
Median follow-up was 18 months (range, <1-141). Median OS was 30.3 months (95% CI, 23.0 to 37.6), and 2-, 5-, and 10-year OS estimates were 49%, 25%, and 14%, respectively. Survival estimates adjusted for prognostic factors identified in univariate and multivariate analyses (platinum-sensitivity, completeness of cytoreduction, chemotherapy agent[s]used, duration of HIPEC perfusion, duration of hospital stay) were not reported. Analysis of toxicity was not reported. The published web link to the registry (www.hyperoregistry.com) is currently not functional.

Section Summary

CRS/HIPEC has been studied for both primary advanced ovarian cancer and recurrent disease. For recurrent disease (second-line setting), evidence from 1 RCT from Greece and 3 non-U.S. case-control studies showed improved survival with CRS/HIPEC compared with CRS without HIPEC. However, treatment groups in the RCT were unbalanced at baseline in completeness of cytoreduction, which has consistently been shown to be associated with survival. Several retrospective cohort studies and systematic reviews of cohort studies did not clearly indicate that HIPEC added to CRS improved on published survival estimates in patients with ovarian cancer in the first- or second-line setting. Procedurerelated morbidity and mortality estimates in the cohort studies were as high as 42% and 8%, respectively; however, these estimates are difficult to interpret in the absence of control arms (eg, CRS without HIPEC). In both first- and second-line settings, completeness of cytoreduction, extent of peritoneal carcinomatosis, and chemosensitivity to platinum have been shown to be prognostic factors.

Miscellaneous Tumors

Appendiceal Goblet Cell Tumors

Goblet cell carcinoid tumors of the appendix comprise a small proportion of appendiceal tumors (14%-19%).(71) Goblet cell tumors are aggressive, often presenting with peritoneal and ovarian metastases. Treatment commonly comprises appendectomy, right-sided hemicolectomy, and lymphadenectomy followed by chemotherapy. Five- and 10-year OS with this approach is 76% and 60%, respectively.(79)

In a multicenter, retrospective cohort study, McConnell et al (2014) studied appendiceal goblet cell tumors (n=45) and compared outcomes with CRS/HIPEC with those in nonmucinous (n=52) and LG (n=567) and HG (n=89) mucinous appendiceal tumors.(80) All patients had peritoneal malignancy due to advanced disease, but none were identified as having pseudomyxoma peritonei. With a median follow-up of 49
months, patients with goblet cell tumors were found to have survival outcomes better than those in patients with LG mucinous tumors and similar to those in patients with HG mucinous tumors: Three-year OS in patients with goblet cell, LG mucinous, HG mucinous, and nonmucinous tumor was 63%, 81% (logrank test vs goblet cell tumors, p=0.003), 40% (log-rank test vs goblet cell tumors, p=0.07), and 52% (logrank test vs goblet cell tumors, p=0.48), respectively. In 489 patients (65%) who achieved complete cytoreduction, the pattern of 3-year DFS outcomes was similar: 43%, 73% (log-rank test vs goblet cell tumors, p<0.001), 44% (log-rank test vs goblet cell tumors, p=0.85), and 44% (log-rank test vs goblet cell tumors, p=0.82), respectively. Adverse events/complications of treatment were not reported. Grade 3/4
surgical complications occurred in approximately 20% of patients in each group.

Section Summary

A retrospective cohort study of patients with goblet cell tumors of the appendix reported survival outcomes with CRS/HIPEC that were reduced compared with published 5- and 10-year survival estimates.

Ongoing and Unpublished Clinical Trials

A search of ClinicalTrials.gov identified 18 active, randomized trials of CRS/HIPEC in patients with appendiceal or CRC (n=7), gastric cancer (n=4), ovarian cancer (n=6), and primary peritoneal cancer (n=1). These trials are listed in Table 6. One trial in patients with CRC (NCT02179489) and 3 of 4 trials in patients with gastric cancer (NCT02240524, NCT01683864, NCT01882933) are investigating prophylactic CRS/HIPEC for the prevention of peritoneal carcinomatosis. Most (4/6) trials in patients with ovarian cancer are for recurrent disease; NCT02124421 and NCT01628380 are in the first-line setting.

The randomized, multicentric, phase 3 PRODIGE-7 trial compares CRS alone with CRS plus HIPEC in patients with peritoneal carcinomatosis. This trial has reportedly neared completion of accrual and preliminary results are awaited.(44) PRODIGE-7 is registered in the European Union Clinical Trials Register (EudraCT number: 2006-006175-20).

Table 6. Ongoing Randomized Trials of CRS/HIPEC Listed on ClinicalTrials.gov

NCT Number

Title

Enrollmenta

Completion Dateb

Appendiceal and colorectal cancer

NCT01545141

Chemokine-Modulatory Regimen for Recurrent Resectable Colorectal Cancer

50

Aug 2015

NCT01580410

Surgery and Oxaliplatin or Mitomycin C in Treating Patients With Tumors of the Appendix

116

May 2015

NCT01628211

Second Look Laparoscopy in Colorectal Cancer

140

Dec 2015

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

220

Mar 2018

NCT02231086

Adjuvant HIPEC in High Risk Colon Cancer (COLOPEC)

176

Jan 2022

NCT01226394

Trial Comparing Simple Follow-up to Exploratory Laparotomy Plus "in Principle" (Hyperthermic Intraperitoneal Chemotherapy) HIPEC in Colorectal Patients" (ProphyloCHIP)

130

Jun 2019

NCT02179489

Trial Evaluating Surgery With Hyperthermic Intraperitoneal Chemotherapy (HIPEC) in Treating Patients With a High Risk of Developing Colorectal Peritoneal Carcinomatosis

300

Oct 2023

Gastric cancer

NCT02158988

Cytoreductive Surgery (CRS) With/Without HIPEC in Gastric Cancer With Peritoneal Carcinomatosis (GASTRIPEC)

180

Sep 2017

NCT02240524

Efficacy of HIPEC in the Treatment of Patients With Locally Advanced Gastric Cancer

582

July 2019

NCT01683864

Randomized Controlled Trial to Prevent Peritoneal Seeding in Gastric Cancer (HIPEC_Stomach)

60

Sep 2020

NCT01882933

D2 Resection and HIPEC (Hyperthermic Intraperitoneal Chemoperfusion) in Locally Advanced Gastric Carcinoma

(GASTRICHIP)

322

May 2021

Ovarian cancer

NCT02124421

Outcomes in CRS/HIPEC as Initial Treatment of Ovarian, FallopianTube and Primary Peritoneal Cancer

48

Apr 2020

NCT02328716

Cytoreduction With or Without Intraoperative Intraperitoneal Hyperthermic Chemotherapy (HIPEC) in Patients With Peritoneal Carcinomatosis From Ovarian Cancer, Fallopian Tube or Primary Peritoneal Carcinoma (CARCINOHIPEC)

32

Jan 2015

NCT01539785

Hyperthermic Intra-peritoneal Chemotherapy (HIPEC) in Ovarian Cancer Recurrence (HORSE)

158

Sep 2018

NCT00426257

Secondary Debulking Surgery +/- Hyperthermic IntraperitonealChemotherapy in Stage III Ovarian Cancer

280

Dec 2016

NCT01376752

Hyperthermic Intra-Peritoneal Chemotherapy (HIPEC) in RelapseOvarian Cancer Treatment (CHIPOR)

444

Dec 2018

NCT01628380

Phase 3 Trial Evaluating Hyperthermic Intraperitoneal Chemotherapy in Upfront Treatment of Stage IIIC Epithelial Ovarian Cancer (CHORINE)

94

Jul 2018

NCT01767675

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

98

Jan 2018

NCT01882920

Goal Directed Therapy (GDT) in Cytoreductive Surgery (CRS) and Hyperthermic Intra Peritoneal Chemotherapy (HIPEC)

80

Sep 2014


aEstimated.
bExpected.

Summary of Evidence

Pseudomyxoma Peritonei

Several case studies and a systematic review on the use of cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) have been published. Although no randomized trials or comparative studies have been published, data have shown consistent, long-term disease-free survival and overall survival with the use of this technique. Procedure-related morbidity and mortality have decreased over time. Because the prevalence of pseudomyxoma peritonei is very low, the conduct of high-quality trials is difficult. Therefore, based on the available evidence, CRS and HIPEC may be considered medically necessary for this indication.

Peritoneal Carcinomatosis of Gastrointestinal Origin

In patients with peritoneal carcinomatosis from colorectal cancer (CRC), numerous studies with different levels of evidence support the safety and feasibility of CRS and HIPEC, and existing data suggest a possible improvement in long-term survival of select patients. However, peritoneal carcinomatosis from CRC is not uncommon (occurring in 10%-15% of patients with CRC), and systemic chemotherapy treatments are available. Therefore, prospective randomized trials are needed to compare best available systemic therapy with and without CRS and HIPEC to determine optimal regimens and the exact effects of each step, which are currently unknown; an ongoing phase 3 trial (PRODIGE-7) addresses the question of how much survival benefit is derived from cytoreduction and how much from HIPEC, as patients will be randomly assigned to HIPEC or no HIPEC after CRS. Additionally, quality-of-life data do not provide a clear picture of patient benefit. Therefore, CRS and HIPEC are considered investigational for this indication.

In patients with peritoneal carcinomatosis from gastric cancer, 2 small randomized controlled trials (RCTs) and 2 small retrospective comparative studies reported inconsistent results, due primarily to differing interventions in the comparator group. Given that patients eligible for CRS/HIPEC must be surgical candidates, the most appropriate comparator would be gastric resection with or without systemic chemotherapy administered to both treatment groups in a comparative study. The RCT that used this design reported reduced survival in the CRS/HIPEC group, although the trial was small (N=26) and statistical testing was not reported. Evidence is therefore insufficient to support the use of CRS/HIPEC in patients with peritoneal carcinomatosis due to gastric cancer.

Peritoneal Carcinomatosis From Endometrial Cancer

Three small cohort studies in patients with peritoneal carcinomatosis due to endometrial cancer provide insufficient evidence to assess net health outcome with CRS/HIPEC in comparison with standard treatment (surgery, systemic chemotherapy, radiotherapy, and/or hormone therapy). CRS/HIPEC is therefore investigational for this indication.

Peritoneal Mesothelioma

The conventional treatment of peritoneal mesothelioma (diffuse malignant type) has resulted in a median survival of approximately 12 months. Although data on the use of CRS and HIPEC comprises nonrandomized case series without control groups, these have shown a significant prolongation of median survival ranging from 29.5 to 92 months. Procedure-related morbidity and mortality has remained relatively steady over time at approximately 35% and 5%, respectively. Because the prevalence of peritoneal mesothelioma is low, the conduct of high-quality trials is difficult. Therefore, based on the available evidence, CRS and HIPEC may be considered medically necessary for this indication.

Ovarian Cancer

Evidence for CRS/HIPEC in primary advanced and recurrent ovarian cancer is accumulating. Currently, results from 1 RCT with methodologic flaws, case control studies, and cohort studies are inconsistent; the RCT and case-control studies show improved survival with CRS/HIPEC in the second-line setting compared with CRS without HIPEC, but retrospective cohort studies do not indicate a clear survival advantage compared with current treatment in the first- or second-line setting. Results of at least some of these studies are confounded by prognostic factors (completeness of cytoreduction, extent of peritoneal carcinomatosis, chemosensitivity to platinum). Well-designed, randomized trials are needed to control for potential covariates and to demonstrate improvements in net health outcomes compared with current treatment approaches (CRS with systemic chemotherapy). Such trials are currently in progress (see Ongoing and Unpublished Trials section). CRS/HIPEC is therefore investigational for the treatment of ovarian cancer.

Miscellaneous Tumors

Evidence for CRS/HIPEC in patients with goblet cell carcinoid tumors of the appendix comprises a single retrospective cohort study that did not show increased survival compared with published survival estimates. CRS/HIPEC is therefore investigational for this indication.

Practice Guidelines and Position Statements

National Comprehensive Cancer Network

  • National Comprehensive Cancer Network (NCCN) clinical practice guidelines in oncology for colon cancer (version 2.2015) and for rectal cancer (version 2.2015) consider the treatment of disseminated carcinomatosis with CRS and HIPEC to be investigational and do not endorse such
    therapy outside of a clinical trial.(81,82)
  • NCCN guidelines for gastric cancer (version 1.2014) and for uterine cancer (version 2.2015) do not include CRS/HIPEC.(83,84)
  • NCCN guidelines for ovarian cancer (version 3.2014) include recommendations for intraperitoneal chemotherapy in patients with optimally debulked (<1 cm) stage 2 (Category 2A recommendation) or stage 3 (Category 1 recommendation) disease.(85) Use of hyperthermic
    chemotherapy is not specified.
  • NCCN guidelines that specifically address the treatment of appendiceal tumors, pseudomyxoma peritonei, and peritoneal mesothelioma were not identified.

American Society of Colon and Rectal Surgeons

A 2012 practice parameter on the management of colon cancer by the American Society of Colon and Rectal Surgeons stated that treatment of patients with peritoneal carcinomatosis may include surgical cytoreduction. The role of HIPEC was “insufficiently defined.”(86)

Society of Surgical Oncology

In 2007, the Society of Surgical Oncology issued a consensus statement on CRS and HIPEC in the management of peritoneal surface malignancies of colonic origin.(87) Their recommendation is that patients with peritoneal carcinomatosis without distant disease, in whom complete cytoreduction is possible, undergo HIPEC before systemic therapy. As of January 2015, an updated consensus statement has not
been published.

U.S. Preventive Services Task Force Recommendations

The U.S. Preventive Services Task Force does not address CRS and Intraperitoneal chemotherapy.

Medicare National Coverage

There is no national coverage determination (NCD) for cytoreductive surgery or hyperthermic intraperitoneal chemotherapy. In the absence of an NCD, coverage decisions are left to the discretion of local Medicare carriers.

References:

  1. Glockzin G, Ghali N, Lang SA, et al. Results of cytoreductive surgery and hyperthermic intraperitoneal chemotherapy for peritoneal carcinomatosis from colorectal cancer. J Surg Oncol. 2009;100(4):306-310.
  2. Maggiori L, Elias D. Curative treatment of colorectal peritoneal carcinomatosis: current status and future trends. Eur J Surg Oncol. 2010;36(7):599-603.
  3. Elias D, Honore C, Ciuchendea R, et al. Peritoneal pseudomyxoma: results of a systematic policy of complete cytoreductive surgery and hyperthermic intraperitoneal chemotherapy. Br J Surg. 2008;95(9):1164-1171.
  4. Chua TC, Moran BJ, Sugarbaker PH, et al. Early- and long-term outcome data of patients with pseudomyxoma peritonei from appendiceal origin treated by a strategy of cytoreductive surgery and hyperthermic intraperitoneal chemotherapy. J Clin Oncol. Jul 10 2012;30(20):2449-2456. PMID 22614976
  5. Nakakura EK. Pseudomyxoma peritonei: more questions than answers. J Clin Oncol. Jul 10 2012;30(20):2429- 2430. PMID 22614983
  6. Yonemura Y, Kawamura T, Bandou E, et al. Advances in the management of gastric cancer with peritoneal dissemination. Recent Results Cancer Res. 2007;169:157-164. PMID 17506258
  7. Yonemura Y, Endou Y, Shinbo M, et al. Safety and efficacy of bidirectional chemotherapy for treatment of patients with peritoneal dissemination from gastric cancer: Selection for cytoreductive surgery. J Surg Oncol. Sep 15 2009;100(4):311-316. PMID 19697437
  8. Delotte J, Desantis M, Frigenza M, et al. Cytoreductive surgery with hyperthermic intraperitoneal chemotherapy for the treatment of endometrial cancer with peritoneal carcinomatosis. Eur J Obstet Gynecol Reprod Biol. Jan 2014;172:111-114. PMID 24300558
  9. Baratti D, Kusamura S, Deraco M. Diffuse malignant peritoneal mesothelioma: systematic review of clinical management and biological research. J Surg Oncol. Jun 2011;103(8):822-831. PMID 21283990
  10. MD Anderson Cancer Center. Appendix cancer: basics, © 2015. http://www.mdanderson.org/patient-and-cancerinformation/cancer-information/cancer-types/appendix-cancer/index.html. Accessed January 2, 2015.
  11. Abu-Zaid A, Azzam AZ, AlOmar O, et al. Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy for managing peritoneal carcinomatosis from endometrial carcinoma: a single-center experience of 6 cases. Ann Saudi Med. Mar-Apr 2014;34(2):159-166. PMID 24894786
  12. Armstrong DK, Bundy B, Wenzel L, et al. Intraperitoneal cisplatin and paclitaxel in ovarian cancer. N Engl J Med. Jan 5 2006;354(1):34-43. PMID 16394300
  13. Cannistra SA. Intraperitoneal chemotherapy comes of age. N Engl J Med. Jan 5 2006;354(1):77-79. PMID 16394306
  14. Yan TD, Cao CQ, Munkholm-Larsen S. A pharmacological review on intraperitoneal chemotherapy for peritoneal malignancy. World J Gastrointest Oncol. Feb 15 2010;2(2):109-116. PMID 21160929
  15. U.S. Food and Drug Administration. Devices@FDA. RanD S.R.L. Performer HT/Hang & Go HT Basic. 510(k) number K120026. 05/08/2012.
    http://www.accessdata.fda.gov/scripts/cdrh/devicesatfda/index.cfm?db=pmn&id=K120026. Accessed January 2, 2015.
  16. U.S. Food and Drug Administration (FDA). Warning letter: Therma Solutions, Inc., 05/07/2012. http://www.fda.gov/ICECI/EnforcementActions/WarningLetters/2012/ucm307258.htm. Accessed January 2, 2015.
  17. U.S. Food and Drug Administration (FDA). Warning letter: Belmont Instrument Corporation, 05/07/2012. http://www.fda.gov/iceci/enforcementactions/warningletters/2012/ucm306771.htm. Accessed January 2, 2015.
  18. Jimenez W, Sardi A, Nieroda C, et al. Predictive and prognostic survival factors in peritoneal carcinomatosis from appendiceal cancer after cytoreductive surgery with hyperthermic intraperitoneal chemotherapy. Ann Surg Oncol. Dec 2014;21(13):4218-4225. PMID 24986239
  19. Marcotte E, Dube P, Drolet P, et al. Hyperthermic intraperitoneal chemotherapy with oxaliplatin as treatment for peritoneal carcinomatosis arising from the appendix and pseudomyxoma peritonei: a survival analysis. World J Surg Oncol. 2014;12:332. PMID 25380618
  20. Glehen O, Gilly FN, Boutitie F, et al. Toward curative treatment of peritoneal carcinomatosis from nonovarian origin by cytoreductive surgery combined with perioperative intraperitoneal chemotherapy. Cancer. 2010;116(24):5608-5618.
  21. Chua TC, Yan TD, Smigielski ME, et al. Long-term survival in patients with pseudomyxoma peritonei treated with cytoreductive surgery and perioperative intraperitoneal chemotherapy: 10 years of experience from a single institution. Ann Surg Oncol. 2009;16(7):1903-1911.
  22. Vaira M, Cioppa T, de Marco G, et al. Management of pseudomyxoma peritonei by cytoreduction + HIPEC (hyperthermic intraperitoneal chemotherapy): results analysis of a twelve-year experience. In Vivo. 2009;23(4):639-644.
  23. Yan TD, Black D, Savady R, et al. A systematic review on the efficacy of cytoreductive surgery and perioperative intraperitoneal chemotherapy for pseudomyxoma peritonei. Ann Surg Oncol. 2007;14(2):484-492.
  24. Sardi A, Jimenez WA, Nieroda C, et al. Repeated cytoreductive surgery and hyperthermic intraperitoneal chemotherapy in peritoneal carcinomatosis from appendiceal cancer: analysis of survival outcomes. Eur J Surg Oncol. Nov 2013;39(11):1207-1213. PMID 24007834
  25. Elias D, Gilly F, Quenet F, et al. Pseudomyxoma peritonei: a French multicentric study of 301 patients treated with cytoreductive surgery and intraperitoneal chemotherapy. Eur J Surg Oncol. 2010;36(5):456-462. PMID
  26. Lord AC, Shihab O, Chandrakumaran K, et al. Recurrence and outcome after complete tumour removal and hyperthermic intraperitoneal chemotherapy in 512 patients with pseudomyxoma peritonei from perforated appendiceal mucinous tumours. Eur J Surg Oncol. Sep 2 2014. PMID 25216980
  27. Elias D, Mariani A, Cloutier AS, et al. Modified selection criteria for complete cytoreductive surgery plus HIPEC based on peritoneal  cancer index and small bowel involvement for peritoneal carcinomatosis of colorectal origin. Eur J Surg Oncol. Nov 2014;40(11):1467-1473. PMID 25086990
  28. Nikolic S, Dzodic R, Zegarac M, et al. Survival prognostic factors in patients with colorectal peritoneal carcinomatosis treated with cytoreductive surgery and intraoperative hyperthermic intraperitoneal chemotherapy: a single institution experience. J BUON. Jan-Mar 2014;19(1):66-74. PMID 24659645
  29. Tabrizian P, Shrager B, Jibara G, et al. Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy for peritoneal carcinomatosis: outcomes from a single tertiary institution. J Gastrointest Surg. May 2014;18(5):1024-1031. PMID 24577736
  30. Vallicelli C, Cavaliere D, Catena F, et al. Management of peritoneal carcinomatosis from colorectal cancer: review of the literature. Int J Colorectal Dis. Aug 2014;29(8):895-898. PMID 24915844
  31. Levine EA, Stewart JHt, Shen P, et al. Intraperitoneal chemotherapy for peritoneal surface malignancy: experience with 1,000 patients. J Am Coll Surg. Apr 2014;218(4):573-585. PMID 24491244
  32. Teo MC, Tan GH, Tham CK, et al. Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy in Asian patients: 100 consecutive patients in a single institution. Ann Surg Oncol. Sep 2013;20(9):2968-2974. PMID 23504144
  33. Esquivel J, Lowy AM, Markman M, et al. The American Society of Peritoneal Surface Malignancies (ASPSM) Multiinstitution Evaluation of the Peritoneal Surface Disease Severity Score (PSDSS) in 1,013 Patients with Colorectal Cancer with Peritoneal Carcinomatosis. Ann Surg Oncol. Dec 2014;21(13):4195-4201. PMID 24854493
  34. Baratti D, Kusamura S, Iusco D, et al. Postoperative complications after cytoreductive surgery and hyperthermic intraperitoneal chemotherapy affect long-term outcome of patients with peritoneal metastases from colorectal cancer: a two-center study of 101 patients. Dis Colon Rectum. Jul 2014;57(7):858-868. PMID 24901687
  35. Huang CQ, Feng JP, Yang XJ, et al. Cytoreductive surgery plus hyperthermic intraperitoneal chemotherapy improves survival of patients with peritoneal carcinomatosis from colorectal cancer: a case-control study from a Chinese center. J Surg Oncol. Jun 2014;109(7):730-739. PMID 24374987
  36. de Cuba EM, Kwakman R, Knol DL, et al. Cytoreductive surgery and HIPEC for peritoneal metastases combined with curative treatment of colorectal liver metastases: Systematic review of all literature and meta-analysis of observational studies. Cancer Treat Rev. Jun 2013;39(4):321-327. PMID 23244778
  37. Klaver YL, Chua TC, Verwaal VJ, et al. Secondary cytoreductive surgery and peri-operative intraperitoneal chemotherapy for peritoneal recurrence of colorectal and appendiceal peritoneal carcinomatosis following prior primary cytoreduction. J Surg Oncol. May 2013;107(6):585-590. PMID 23280508
  38. Rampone B, Schiavone B, Martino A, et al. Current role of hyperthermic intraperitoneal chemotherapy in the treatment of peritoneal carcinomatosis from colorectal cancer. World J Gastroenterol. Mar 21 2010;16(11):1299-1302. PMID 20238394
  39. Elias D, Lefevre JH, Chevalier J, et al. Complete cytoreductive surgery plus intraperitoneal chemohyperthermia with oxaliplatin for peritoneal carcinomatosis of colorectal origin. J Clin Oncol. 2008;27(5):681-685. PMID 
  40. van Leeuwen BL, Graf W, Pahlman L, et al. Swedish experience with peritonectomy and HIPEC. HIPEC in peritoneal carcinomatosis. Ann Surg Oncol. Mar 2008;15(3):745-753. PMID 18057988
  41. Glehen O, Kwiatkowski F, Sugarbaker PH, et al. Cytoreductive surgery combined with perioperative intraperitoneal chemotherapy for the management of peritoneal carcinomatosis from colorectal cancer: a multiinstitutional study. J Clin Oncol. 2004;22(16):3284-3292.
  42. Verwaal VJ, van Ruth S, de Bree E, et al. Randomized trial of cytoreduction and hyperthermic intraperitoneal chemotherapy versus systemic chemotherapy and palliative surgery in patients with peritoneal carcinomatosis of colorectal cancer. J Clin Oncol. 2003;21(20):3737-3743.
  43. Williams BH, Alzahrani NA, Chan DL, et al. Repeat cytoreductive surgery (CRS) for recurrent colorectal peritoneal metastases: yes or no? Eur J Surg Oncol. Aug 2014;40(8):943-949. PMID 24378009
  44. Turaga K, Levine E, Barone R, et al. Consensus Guidelines from The American Society of Peritoneal Surface Malignancies on Standardizing the Delivery of Hyperthermic Intraperitoneal Chemotherapy (HIPEC) in Colorectal Cancer Patients in the United States. Ann Surg Oncol. Jun 21 2013. PMID 23793364
  45. Verwaal VJ, Bruin S, Boot H, et al. 8-year follow-up of randomized trial: cytoreduction and hyperthermic intraperitoneal chemotherapy versus systemic chemotherapy in patients with peritoneal carcinomatosis of colorectal cancer. Ann Surg Oncol. 2008;5(9):2426-2432.
  46. Mahteme H, Hansson J, Berglund A, et al. Improved survival in patients with peritoneal metastases from colorectal cancer: a preliminary study. Br J Cancer. 2004;90(2):403-407. 
  47. Levine EA. The randomized trial of cytoreductive surgery with hyperthermic intraperitoneal chemoperfusion: what it does and does not tell us. Ann Surg Oncol. 2008;15(10):2633-2635.
  48. Markman M. Intraperitoneal hyperthermic chemotherapy as treatment of peritoneal carcinomatosis of colorectal cancer. Letter to the editor. J Clin Oncol. 2004;22(8):1527.
  49. Tsilimparis N, Bockelmann C, Raue W, et al. Quality of life in patients after cytoreductive surgery and hyperthermic intraperitoneal chemotherapy: is it worth the risk? Ann Surg Oncol. Jan 2013;20(1):226-232. PMID 22868919
  50. McQuellon RP, Loggie BW, Fleming RA, et al. Quality of life after intraperitoneal hyperthermic chemotherapy (IPHC) for peritoneal carcinomatosis. Eur J Clin Oncol. 2001;27(1):65-73.
  51. Shan LL, Saxena A, Shan BL, et al. Quality of life after cytoreductive surgery and hyperthermic intra-peritoneal chemotherapy for peritoneal carcinomatosis: A systematic review and meta-analysis. Surg Oncol. Oct 28 2014;23(4):199-210. PMID 25466850
  52. Seretis C, Youssef H. Quality of life after cytoreductive surgery and intraoperative hyperthermic intraperitoneal chemotherapy for peritoneal surface malignancies: A systematic review. Eur J Surg Oncol. Dec 2014;40(12):1605-1613. PMID 25242382
  53. Passot G, Bakrin N, Roux AS, et al. Quality of life after cytoreductive surgery plus hyperthermic intraperitoneal chemotherapy: a prospective study of 216 patients. Eur J Surg Oncol. May 2014;40(5):529-535. PMID 24370285
  54. Rudloff U, Langan RC, Mullinax JE, et al. Impact of maximal cytoreductive surgery plus regional heated intraperitoneal chemotherapy (HIPEC) on outcome of patients with peritoneal carcinomatosis of gastric origin: results of the GYMSSA trial. J Surg Oncol. Sep 2014;110(3):275-284. PMID 25042700
  55. Yarema RR, Ohorchak MA, Zubarev GP, et al. Hyperthermic intraperitoneal chemoperfusion in combined treatment of locally advanced and disseminated gastric cancer: results of a single-centre retrospective study. Int J Hyperthermia. May 2014;30(3):159-165. PMID 24641798
  56. Kim KW, Chow O, Parikh K, et al. Peritoneal carcinomatosis in patients with gastric cancer, and the role for surgical resection, cytoreductive surgery, and hyperthermic intraperitoneal chemotherapy. Am J Surg. Jan 2014;207(1):78-83. PMID 24157224
  57. Yang XJ, Huang CQ, Suo T, et al. Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy improves survival of patients with peritoneal carcinomatosis from gastric cancer: final results of a phase III randomized clinical trial. Ann Surg Oncol. Jun 2011;18(6):1575-1581. PMID 21431408
  58. Coccolini F, Cotte E, Glehen O, et al. Intraperitoneal chemotherapy in advanced gastric cancer. Meta-analysis of randomized trials. Eur J Surg Oncol. Jan 2014;40(1):12-26. PMID 24290371
  59. Bakrin N, Cotte E, Sayag-Beaujard A, et al. Cytoreductive surgery with hyperthermic intraperitoneal chemotherapy for the treatment of recurrent endometrial carcinoma confined to the peritoneal cavity. Int J Gynecol Cancer. Jul 2010;20(5):809-814. PMID 20973274
  60. Robella M, Vaira M, Mellano A, et al. Treatment of diffuse malignant peritoneal mesothelioma (DMPM) by cytoreductive surgery and HIPEC. Minerva Chir. Feb 2014;69(1):9-15. PMID 24675242
  61. Alexander HR, Jr., Bartlett DL, Pingpank JF, et al. Treatment factors associated with long-term survival after cytoreductive surgery and regional chemotherapy for patients with malignant peritoneal mesothelioma. Surgery. Jun 2013;153(6):779-786. PMID 23489943
  62. Yan TD, Deraco M, Baratti D, et al. Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy for malignant peritoneal mesothelioma: multi-institutional experience. J Clin Oncol. 2009;27(36):6237-6242. PMID
  63. Shetty SJ, Bathla L, Govindarajan V, et al. Comparison of cytoreductive surgery and hyperthermic intraperitoneal chemotherapy with mitomycin or carboplatin for diffuse malignant peritoneal mesothelioma. Am Surg. Apr 2014;80(4):348-352. PMID 24887664
  64. Helm JH, Miura JT, Glenn JA, et al. Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy for Malignant Peritoneal Mesothelioma: A Systematic Review and Meta-analysis. Ann Surg Oncol. Aug 15 2014. PMID 25124472
  65. Massari R, Barone M, Basilico R, et al. Peritonectomy and hyperthermic chemotherapy in patients with advanced or recurrent ephitelial ovarian cancer: a single center cohort study. Minerva Chir. Feb 2014;69(1):17-26. PMID 24675243
  66. Robella M, Vaira M, Marsanic P, et al. Treatment of peritoneal carcinomatosis from ovarian cancer by surgical cytoreduction and hyperthermic intraperitoneal chemotherapy (HIPEC). Minerva Chir. Feb 2014;69(1):27-35. PMID 24675244
  67. Konigsrainer I, Horvath P, Struller F, et al. Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy in recurrent epithelial ovarian cancer with peritoneal metastases: a single centre experience. Langenbecks Arch Surg. Jun 2014;399(5):589-594. PMID 24817542
  68. Chiva LM, Gonzalez-Martin A. A critical appraisal of hyperthermic intraperitoneal chemotherapy (HIPEC) in the treatment of advanced and recurrent ovarian cancer. Gynecol Oncol. Nov 28 2014. PMID 25434634
  69. Bakrin N, Classe JM, Pomel C, et al. Hyperthermic intraperitoneal chemotherapy (HIPEC) in ovarian cancer. J Visc Surg. Oct 2014;151(5):347-353. PMID 25168575
  70. Spiliotis J, Halkia E, Lianos E, et al. Cytoreductive Surgery and HIPEC in Recurrent Epithelial Ovarian Cancer: A Prospective Randomized Phase III Study. Ann Surg Oncol. Nov 13 2014. PMID 25391263
  71. Fagotti A, Costantini B, Petrillo M, et al. Cytoreductive surgery plus HIPEC in platinum-sensitive recurrent ovarian cancer patients: a case-control study on survival in patients with two year follow-up. Gynecol Oncol. Dec 2012;127(3):502-505. PMID 23022234
  72. Spiliotis J, Vaxevanidou A, Sergouniotis F, et al. The role of cytoreductive surgery and hyperthermic intraperitoneal chemotherapy in the management of recurrent advanced ovarian cancer: a prospective study. J BUON. Jan-Mar 2011;16(1):74-79. PMID 21674853
  73. Munoz-Casares FC, Rufian S, Rubio MJ, et al. The role of hyperthermic intraoperative intraperitoneal chemotherapy (HIPEC) in the treatment of peritoneal carcinomatosis in recurrent ovarian cancer. Clin Transl Oncol. Nov 2009;11(11):753-759. PMID 19917539
  74. Helm CW, Richard SD, Pan J, et al. Hyperthermic intraperitoneal chemotherapy in ovarian cancer: first report of the HYPER-O registry. Int J Gynecol Cancer. Jan 2010;20(1):61-69. PMID 20130504
  75. Le Brun JF, Campion L, Berton-Rigaud D, et al. Survival benefit of hyperthermic intraperitoneal chemotherapy for recurrent ovarian cancer: a multi-institutional case control study. Ann Surg Oncol. Oct 2014;21(11):3621-3627. PMID 24819120
  76. Cascales-Campos PA, Gil J, Feliciangeli E, et al. The Role of Hyperthermic Intraperitoneal Chemotherapy Using Paclitaxel in Platinum-Sensitive Recurrent Epithelial Ovarian Cancer Patients with Microscopic Residual Disease after Cytoreduction. Ann Surg Oncol. Sep 12 2014. PMID 25212832
  77. Coccolini F, Campanati L, Catena F, et al. Hyperthermic intraperitoneal chemotherapy with cisplatin and paclitaxel in advanced ovarian cancer: a multicenter prospective observational study. J Gynecol Oncol. Nov 3 2014. PMID 25376916
  78. Cascales-Campos P, Gil J, Gil E, et al. Cytoreduction and HIPEC after neoadjuvant chemotherapy in stage IIIC- IV ovarian cancer. Critical analysis in elderly patients. Eur J Obstet Gynecol Reprod Biol. Aug 2014;179:88-93. PMID 24965986
  79. Roy P, Chetty R. Goblet cell carcinoid tumors of the appendix: An overview. World J Gastrointest Oncol. Jun 15 2010;2(6):251-258. PMID 21160637
  80. McConnell YJ, Mack LA, Gui X, et al. Cytoreductive surgery with hyperthermic intraperitoneal chemotherapy: an emerging treatment option for advanced goblet cell tumors of the appendix. Ann Surg Oncol. Jun 2014;21(6):1975-1982. PMID 24398544
  81. National Comprehensive Cancer Network (NCCN). Clinical practice guidelines in oncology: colon cancer, version 2.2015. http://www.nccn.org/professionals/physician_gls/PDF/colon.pdf. Accessed January 2, 2015.
  82. National Comprehensive Cancer Network (NCCN). Clinical practice guidelines in oncology: rectal cancer, version 2.2015. http://www.nccn.org/professionals/physician_gls/pdf/rectal.pdf. Accessed January 2, 2015.
  83. National Comprehensive Cancer Network (NCCN). Clinical practice guidelines in oncology: gastric cancer, version 1.2014. http://www.nccn.org/professionals/physician_gls/pdf/gastric.pdf. Accessed January 2, 2015.
  84. National Comprehensive Cancer Network (NCCN). Clinical practice guidelines in oncology: uterine neoplasms, version 2.2015. http://www.nccn.org/professionals/physician_gls/pdf/uterine.pdf. Accessed January 2, 2015.
  85. National Comprehensive Cancer Network (NCCN). Clinical practice guidelines in oncology: ovarian cancer including fallopian tube cancer and primary peritoneal cancer, version 3.2014. http://www.nccn.org/professionals/physician_gls/pdf/ovarian.pdf. Accessed January 2, 2015.
  86. Chang GJ, Kaiser AM, Mills S, et al. Practice parameters for the management of colon cancer. Dis Colon Rectum. Aug 2012;55(8):831-843. PMID 22810468
  87. Esquivel J, Sticca R, Sugarbaker P, et al. Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy in the management of peritoneal surface malignancies of colonic origin: a consensus statement. Society of Surgical Oncology. Ann Surg Oncol. Jan 2007;14(1):128-133. PMID 17072675

  88.  

Codes

Number

Description

CPT 

 

See Policy Guidelines section 

ICD-9 

197.6 

Secondary malignant neoplasm of retroperitoneum and peritoneum 

  158.8-158.9 Malignant neoplasm of retroperitoneum and peritoneum code range (to report diffuse malignant peritoneal mesothelioma)
ICD-9-CM Procedure     No specific code for cytoreductive surgery; coding would be based on what is excised.  
    99.85 Hyperthermia for treatment of cancer  
ICD-10-CM (effective 10/1/15) C45.1 Mesothelioma of peritoneum
  C78.6 Secondary malignant neoplasm of retroperitoneum and peritoneum
ICD-10-PCS (effective 10/1/15)    No specific code for cytoreductive surgery; coding would be based on what is excised.  
    DWY38ZZ Radiation oncology, anatomic regions, other radiation, abdomen, hyperhthermia  
    DWY68ZZ Radiation oncology, anatomic regions, other radiation, pelvic region, hyperhthermia 

 


Index

Cytoreduction and Hyperthermic Intraperitoneal Chemotherapy
Hyperthermic Intraperitoneal Chemotherapy
Intraperitoneal Hyperthermic Chemotherapy


Policy History

Date

Action

Reason

06/27/05

Add policy to Medicine section, Oncology subsection

New policy

04/17/07 Replace Policy  Policy updated with literature search through February 2007; no changes in policy statement. Reference numbers 6–9 added 
06/12/08 Replace policy
Policy updated with literature search, reference numbers 10 and 11 added. Policy statement unchanged.
06/11/09 Replace policy Policy updated with literature search, reference numbers 11 through 13 added. Policy statement unchanged
10/08/10 Replace policy Policy updated with literature search; Rationale and Background sections revised extensively. Policy statement added that cytoreduction and hyperthermic intraperitoneal chemotherapy for the treatment of pseudomyxoma peritonei may be considered medically necessary; investigational policy statement clarified to specify that the indication considered is peritoneal carcinomatosis from colorectal cancer. The term, “pseudomyxoma peritonei” was added to the policy title. References 1-8, 10-12, and 17 added; reference 18 updated
10/04/11 Replace policy Policy updated with literature search. References 2, 4 and 20 added; references renumbered. Title changed to include peritoneal mesothelioma. Policy statement added that cytoreductive surgery and perioperative intraperitoneal chemotherapy for the treatment of peritoneal mesothelioma may be considered medically necessary. Use of the term “hyperthermic” changed to “perioperative” in the title and policy statements to include early postoperative intraperitoneal chemotherapy. Use of the term “cytoreduction” changed to “cytoreductive surgery” to be more specific.
10/11/12 Replace Policy Policy updated with literature search. No references added. No change to policy statements.
1/15/15 Replace policy Policy updated with literature review through January 2, 2015 references 4-8, 10-14, 18-19, 24, 26-35, 43, 51-61, 63-80, and 83-85 added; references 14 and 23-24 deleted. Investigational policy statement for ovarian cancer, peritoneal carcinomatosis due to gastric cancer or  endometrial cancer, and for all other indications added. Medically necessary policy statement unchanged. Title changed to “Select Intra-Abdominal and Pelvic Malignancies” to include the additional indications.