Systematic Review of Variations in Hyperthermic Intraperitoneal Chemotherapy (HIPEC) for Peritoneal Metastasis from Colorectal Cancer

Abstract

Background: Cytoreductive surgery (CRS), followed by hyperthermic intraperitoneal chemotherapy (HIPEC), combines radical surgery with abdominal heated chemotherapy, constituting a multimodal treatment approach. Since clear standards for HIPEC conduct in colorectal carcinoma (CRC) are lacking, we aimed to provide a comprehensive structured survey. Data sources and study eligibility criteria: A systematic literature search was performed in PubMed, with keywords "HIPEC" and "colorectal cancer", according to established guidelines. Articles were systematically screened, selecting 87 publications complemented by 48 publications identified through extended search for subsequent synthesis and evaluation, extracting inter alia details on used drugs, dosage, temperature, exposure times, and carrier solutions.

Results: Compiled publications contained 171 reports on HIPEC conduct foremost with mitomycin C and oxaliplatin, but also other drugs and drug combinations, comprising at least 60 different procedures. We hence provide an overview of interconnections between HIPEC protocols, used drugs and carrier solutions as well as their volumes. In addition, HIPEC temperatures and dosing benchmarks, as well as an estimate of in vivo resulting drug concentrations are demonstrated.

Conclusions and implications: Owing to recent developments, HIPEC conduct and practices need to be reassessed. Unfortunately, imprecise and lacking reporting is frequent, which is why minimal information requirements should be established for HIPEC and the introduction of final drug concentrations for comparability reasons seems sensible.

Keywords: PRISMA; colorectal carcinoma; cytoreductive surgery; hyperthermic intraperitoneal chemotherapy; peritoneal metastasis; systematic review.

Figure 1

PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) flow diagram illustrating the literature search strategy: It maps the number of records identified, screened, included as well as excluded with respective reasons, conforming to PRISMA guidelines available at http://prisma-statement.org. This systematic search was complemented by 48 manuscripts identified through manual search of review type articles and back searches from reference lists of included articles, resulting in 135 articles in total, containing 171 reports on HIPEC conduct.

Figure 2

Drug use: (a) Bar chart of HIPEC (hyperthermic intraperitoneal chemotherapy) reports (n = 171) with respective drugs or drug combinations. (b) Percentages of included reports on selected drugs and drug combinations plotted against HIPEC duration in minutes (x-axis). (c) Percentages of drugs and drug combinations among reports. (d) Percentages of drug mono- and combination therapies. Drug combinations were further subdivided into protocols using a drug combination with MMC or L-OHP. Abbreviations used: CDDP (cisplatin); DOX (doxorubicin); IRI (irinotecan); L-OHP (oxaliplatin); and MMC (mitomycin c).

Figure 3

Trial conduct: The Lollipop plot depicts HIPEC clinical trials performed between 1981 and 2016 and published from 1994 to 2017 with different cytostatic drugs (only reports with n > 4 patients and protocols containing MMC or L-OHP single drug or combinations were included). Green dots signify year of trial initiation, blue dots end of recruitment, red crossed markers point to publication dates. Symbols are lg scaled according to number of patients included in the respective study. Publications conform to annotations given in Tables S1–S5, with Arabic letters marking chronological order (if required). Abbreviations used: CDDP (cisplatin); DOX (doxorubicin); IRI (irinotecan); L-OHP (oxaliplatin); and MMC (mitomycin c).

Figure 4

Overview of HIPEC protocols using MMC: Depiction of different drug dosages and measures thereof (pie chart with percentages) among protocols using MMC (n = 86). Connections and circle sizes are arbitrary and protocols were compiled manually, according to respective similarities. Related publications are annotated by superscript numbers, conforming to annotations given in Table S1. Publications reporting different protocols are shown multiple times, those without specific information (NR; not reported) are omitted. RCTs are marked in blue. Abbreviations and symbols: EPIC (Early postoperative intraperitoneal chemotherapy); f (fractionated, indicating shares of total dosage administered); MMC (mitomycin c); RCT (randomized controlled trial); (amount of diluent); (HIPEC duration); (male) and (female).

Figure 5

Drug concentration of MMC: The violin plot depicts concentrations of MMC as used in different HIPEC protocols. Protocols were categorized according to the matrix used to dilute drugs (crystalloid, dextrose, PDS or NR). Since there is lacking uniformity and for comparative reasons, we imputed data to a presumed average patient (with characteristics of 1.7 m height, 70 kg weight and 1.73 m² body surface area). Further in the case of ambiguity values were maximized using the maximal drug amounts and the minimum diluent volumes reported. The red bars mark medians and white boxes interquartile range. Protocols with missing data or reporting ≤4 patients were omitted. (Median drug concentrations (µg/mL): crystalloid: 13.3; Dextrose: 7.2; PDS: 10.8; NR: 10). Abbreviations used: MMC (mitomycin c); PDS (peritoneal dialysis solution); and NR (not reported).

Figure 6

Overview of HIPEC protocols using L-OHP: Depiction of different drug dosages and measures thereof (pie chart with percentages) among protocols using L-OHP (n = 44). Connections and circle sizes are arbitrary and protocols were compiled manually, according to respective similarities. Related publications are annotated by superscript numbers, conforming to annotations in Table S4. Abbreviations and symbols: 5-FU (5-fluorouracil i.v.); (amount of diluent); (duration of HIPEC); * (bidirectional protocol with 5-FU/Leucovorin); and L-OHP (oxaliplatin).

Figure 7

Drug concentration of L-OHP: The violin plot depicts concentrations of L-OHP, as used in different HIPEC protocols. Protocols were categorized according to the matrix used to dilute drugs (crystalloid, dextrose, PDS or NR). Since there is lacking uniformity and for comparative reasons, we imputed data to a presumed average patient (with characteristics of 1.7 m height, 70 kg weight and 1.73 m² body surface area). Further, in case of ambiguity values were maximized using the maximal drug amounts and the minimum diluent volumes reported. The red bars mark medians and white boxes interquartile range. Protocols with missing data or reporting ≤4 patients and the outlier [121] were omitted. (Median drug concentrations (µg/mL): crystalloid: 173; Dextrose: 230; PDS: 133; NR: 230). Abbreviations used: L-OHP (oxaliplatin); PDS (peritoneal dialysis solution); and NR (not reported).

Figure 8

Overview of HIPEC protocols using drug combinations: (a) Depiction of different drug dosages and measures thereof (double pie chart with percentages) among protocols using CDDP/MMC combinations (n = 20). Related publications are annotated by superscript numbers, conforming to annotations in Table S2; further in (b) protocols using L-OHP combined with IRI (n = 7) are annotated conforming to superscript numbers in Table S5; as well as in (c) protocols using MMC combined with DOX (n = 4) conforming to superscript numbers in Table S3. All connections and circle sizes are arbitrary and protocols were compiled manually, according to respective similarities. Abbreviations and symbols: (amount of diluent); and (HIPEC duration).

Figure 9

Overview of manuscript provenience, dosage specifications, and volumes of diluents: (a) Provenience of authors reporting HIPEC conduct in PM from CRC (b) Designations used for benchmarking drug dosages. (c) Volumes of diluents used for abdominal perfusion in L (x-axis) plotted against the number of mentions in publications (y-axis). The pie chart depicts percentages of HIPEC reports mentioning diluent volumes in L, L/m², or with no further specification (NR). (d) Volumes of diluent used in L/m² (x-axis) plotted against the number of mentions in publications (y-axis). Numbers were rounded to one half of a percent. Abbreviations used: NR (not reported).

Figure 10

Overview of drug diluents: (a) Bar chart of records reporting the use of crystalloid, dextrose and peritoneal dialysis solutions during HIPEC or else with lacking information (NR). Detailed information on perfusion solutions is available in Tables S1–S8. (b) Percentages of records among L-OHP single-agent or combination treatments. (c) Percentages of records among MMC single-agent or combination treatments. Abbreviations used: L-OHP (oxaliplatin); MMC (mitomycin c); PDS (peritoneal dialysis solution); and NR (not reported).

Figure 11

Overview on drug diluent volumes: The violin plots depict volumes of solutions used to dilute drugs employed for HIPEC with protocols categorized according to (a) solvent characteristics or (b) drugs used for HIPEC (reported volumes of ≤0.5 L were omitted). (Median volumes (L): crystalloid: 3.0; Dextrose: 3.5; PDS: 3.0; NR: 4.0/MMC: 3.0; MMC + CDDP: 4.0; MMC + DOX: 3.2; L-OHP: 3.5; and L-OHP + IRI: 3.5). The red bars mark medians and white boxes interquartile range. Abbreviations used: CDDP (cisplatin); DOX (doxorubicin); IRI (irinotecan); MMC (mitomycin c); PDS (peritoneal dialysis solution); L-OHP (oxaliplatin); and NR (not reported).

Figure 12

Overview on drug diluent volumes and drug concentrations for L-OHP and MMC according to open and closed HIPEC technique: The violin plots depict protocols categorized according to open/closed or missing/ambiguous information (NA), reporting (a) volumes of solutions used to dilute drugs employed for HIPEC (Median volumes (L): open: 3.2; closed: 3.0; NA: 3.5) or (b) the resulting concentrations of L-OHP (Median drug concentrations (µg/mL): open: 230; closed: 202; NA: 230) and (c) MMC (Median drug concentrations (µg/mL): open: 7.2; closed: 10; NA: 10). Since there is lacking uniformity and for comparative reasons, we imputed data to a presumed average patient (with characteristics of 1.7 m height, 70 kg weight and 1.73 m² body surface area). Further, in case of ambiguity values were maximized using the maximal drug amounts and the minimum volumes reported. The red bars mark medians and white boxes interquartile range. Protocols with missing data or reporting ≤4 patients and the outlier [121] were omitted. Abbreviations used: L-OHP (oxaliplatin); MMC (mitomycin c); NA (not assigned).

Figure 13

Temperatures during HIPEC: The Lollipop plot depicts temperatures (in °C) reported for HIPEC protocols described in the literature (only reports with n > 4 patients and protocols containing MMC or L-OHP single drug or in combinations were included; temperatures ≥46 °C were assigned 46 °C). Green dots signify minimum temperature and purple dots maximum temperatures in case a range was reported. Symbols are lg scaled according to number of patients included. Publications conform to annotations given in Tables S1–S5, with Arabic letters marking chronological order (if required). Abbreviations used: CDDP (cisplatin); DOX (doxorubicin); IRI (irinotecan); L-OHP (oxaliplatin); and MMC (mitomycin c).