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

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.


Introduction
Peritoneal metastasis (PM) can originate from a heterogeneous group of malignant tumors and frequently remains restricted to the peritoneal cavity. In the past, this condition was considered generally incurable and therefore as a palliative disease stage [1]. However, current multimodal treatment strategies comprising CytoReductive Surgery (CRS) and Hyperthermic IntraPEritoneal Chemotherapy (HIPEC) offer a promising therapy approach for selected patients. Depending on the extent of intra-abdominal tumor load, considerable survival benefits have been reported when compared to systemic chemotherapy alone, including a randomized controlled trial (RCT) [1,2].
This multimodal approach includes an ancillary treatment added to surgery, where a heated solution containing cytotoxic drugs is applied directly to the peritoneal cavity. This procedure called HIPEC is intended to destroy any remaining tumor cells after tumor removal. The underlying rationale is based on three theoretical considerations: (1) Surgical tumor debulking to expose residual tumor cells, due to poor tissue penetration of most cytotoxic drugs, (2) direct local administration of chemotherapy to the peritoneal cavity for homogeneous drug distribution, and (3) heated chemotherapy to enhance cytotoxicity [3].
In clinical practice, following CRS, the peritoneal cavity is filled with a heated carrier solution (CS) and cytotoxic drugs are subsequently added. A theoretical justification for this treatment is a compartmental effect termed "peritoneal-plasma barrier", suggesting that peritoneal malignancies are only insufficiently reachable by intravenous chemotherapy [4], such as a pharmacokinetic advantage assumed through high local drug concentrations combined with limited systemic exposure [5]. Hence, local administration of high-dosed cytotoxic drugs has been introduced to directly expose the peritoneal cavity, causing only confined systemic adverse effects. In colorectal cancer (CRC), the first formal RCT assessing the benefit added to surgery by using 30 min of oxaliplatin-based HIPEC, failed to show improved survival (PRODIGE 7; NCT00769405) [6,7]. In contrast, a current RCT in PM from ovarian cancer could establish improved survival, employing cisplatin HIPEC for 60 min in patients responding to carboplatin/paclitaxel [8]. Against this background, HIPEC is currently being reassessed, demanding comprehensive structured knowledge on respective treatment protocols published.
Hitherto, HIPEC was conducted with varying drugs, drug dosages and exposure times. Since this fact has been identified as a potential key issue and various calls for standardization in HIPEC are imminent [9][10][11][12], we performed a first of its kind comprehensive systematic literature review of the current state of the art in HIPEC for PM from CRC.
We identified 397 publications, which were screened for suitability. From the remaining articles, 66 publications were excluded (due to being review type articles, non-English language, or describing animal models). The remaining 125 articles were individually assessed and screened for relevant information (i.e., any reports describing the clinical use of HIPEC after CRS in humans with PM of CRC origin) and another 38 publications were excluded due to a lack of relevance. Ultimately, 87 articles were included into subsequent evaluations and complemented by 48 additional publications, identified by screening review type articles and reference lists. This resulted in 135 publications in total, encompassing 171 reports on HIPEC conduct for CRC.
A PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) flow diagram detailing the literature research strategy is provided in Figure 1. therapy"(All Fields) OR "chemotherapy"(All Fields) OR "drug therapy"(MeSH Terms) OR ("drug"(All Fields) AND "therapy"(All Fields)) OR "chemotherapy"(All Fields)) AND ("colorectal neoplasms"(MeSH Terms) OR ("colorectal"(All Fields) AND "neoplasms"(All Fields)) OR "colorectal neoplasms"(All Fields) OR ("colorectal"(All Fields) AND "cancer"(All Fields)) OR "colorectal cancer"(All Fields))). We identified 397 publications, which were screened for suitability. From the remaining articles, 66 publications were excluded (due to being review type articles, non-English language, or describing animal models). The remaining 125 articles were individually assessed and screened for relevant information (i.e., any reports describing the clinical use of HIPEC after CRS in humans with PM of CRC origin) and another 38 publications were excluded due to a lack of relevance. Ultimately, 87 articles were included into subsequent evaluations and complemented by 48 additional publications, identified by screening review type articles and reference lists. This resulted in 135 publications in total, encompassing 171 reports on HIPEC conduct for CRC.
A PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) flow diagram detailing the literature research strategy is provided in Figure 1.  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.

Quality Assessment
Quality assessment of the studies included was intentionally refrained from, since a meta-analysis of data was neither within the scope, nor considered appropriate based on the substantial differences observed. We instead intended to provide a systematic overview and description of the available literature on HIPEC treatment in CRC.

Data Extraction
Data was systematically extracted from all included publications, compiling the following information on HIPEC treatment when disclosed: Drug used (international nonproprietary name; INN, if applicable); drug dosage; type of matrix (diluent; carrier solution) used for peritoneal perfusion; volume of diluent in L; duration (min) and temperature of HIPEC in • C; number of patients treated; and duration of study (year (initiation) to year (end)), date of publication (month/year), and concomitant treatments (EPIC, i.v. chemotherapy). Authors of primary research articles were not contacted in case of missing information. Respective compiled data is provided in Tables S1-S9.

Data Synthesis
Data synthesis was performed using narrative methods. Further, data was compiled, tabulated, and outlined using suitable software (Microsoft Office; Microsoft, Redmond, WA, USA), according to the terms given under data extraction. For representation purposes, basic descriptive statistics were employed where appropriate. For depiction of geographical locations, an amMap JavaScript Maps was used (www.amcharts.com). Further statistical analyses were performed using the R software in the version 3.5.1 [13] as well as the packages dplyr in the version 0.7.6 [14], ggplot2 in the version 3.0.0 [15], tidyverse in the version 1.2.1 [16], plyr in the version 1.8.4 [17], ggpubr in the version 0.1.8 [18] and figures were created. Restrictions of data included may apply, as mentioned in respective figure captions.

Compliance with Applicable Guidelines
When applicable and appropriate to the scope of this review, respective guidelines were adhered to [19]. PRISMA guidelines have been consulted and transparent and reproducible methodology was implemented ( Figure 1) [20]. Basic data assessed for the purposes of this review can be obtained in Tables S1-S9. A PRISMA checklist is provided in Table S10. A formal registration and systematic review protocol were omitted.

Literature Search and Evaluation
Our search strategy identified 397 publications of which about 70% were initially excluded due to insufficiently matching our search criteria and another 38 articles after accessing the full text. Altogether, 135 publications, comprising articles identified by systematic as well as manual search were compiled from the scientific literature, adding up to 171 reports on HIPEC conduct performed for PM of CRC origin (Figure 1; Tables S1-S9).
Already at first examination, the obtained results concerning HIPEC drugs, drug dosage, duration, and diluents showed considerable heterogeneity and lacking consistency ( Figure 2). Clinical conduct of HIPEC further demonstrated clearly discernible dependencies in various instances. For example, the lead off protocol establishing a dosage benchmarked in mg/m 2 with mitomycin (MMC), published in 2001 by Witkamp et al., introduced a trend-setting practice (Table S1) [21]. Of note, this protocol administered 35 mg/m 2 MMC fractionated over 90 min and was featured in the first ever RCT testing CRS and HIPEC versus systemic chemotherapy [2].
The basic reported parameters, describing HIPEC conduct, were mainly the administered drugs and their dosage (using different ways of benchmarking), as well as the diluent/carrier solution (CS) used for peritoneal perfusion, respective volumes, and target temperatures as well as treatment duration. However, frequently reports on HIPEC conduct were fragmentary and relevant variables remained undisclosed (Tables S1-S8).
Overall, we compiled descriptions of no less than 60 different HIPEC protocols, accounting only for drug choice and/or dosages administered, among the 171 descriptions of HIPEC conduct published over a 25-year period (1992-2017) (Tables S1-S8). Only two publications reported a CDDP-monotherapy described by two different treatment protocols (Table S6) [108,147]. Approaches using either Melphalan (L-PAM) [151], 5-FU [152,153], or IRI [139] as a monotherapy were also very uncommon and have been reported only once or twice (Table S8). Furthermore, a single account describing a triple drug combination of MMC with CDDP and DOX in patients with disease refractory to prior HIPEC treatment was described [127].

Drugs Used for HIPEC in Peritoneal Metastasis from Colorectal Cancer
Overall, we compiled descriptions of no less than 60 different HIPEC protocols, accounting only for drug choice and/or dosages administered, among the 171 descriptions of HIPEC conduct published over a 25-year period (1992-2017) (Tables S1-S8).
For a rough estimate of actual drug concentrations used during HIPEC, we imputed respective values if unavailable to us. Based on presumed average patient characteristics and assuming maximum concentrations, we estimated HIPEC drug concentrations and categorized the results according to drug solvents. In MMC, respective median concentrations resulted in about 7-13 µg/mL ( Figure 5). Another practice distinctive for MMC single-agent use was adjusting the drug dosage according to sex. Here, a dosage of 12.5 mg/m 2 for men and a slightly lower dosage of 10.0 mg/m 2 for women was employed, which was described in about 10% of reports (Table S1) [23][24][25]28,30,40,50,52,59,68]. More importantly in the publications actually reporting diluent amounts, once 1.0 L was reported [52], twice 2.0 L [25,59], and in two further publications 2.0 L/m 2 [23,68], which affects the resulting drug concentrations more relevantly than, for instance, the comparably modest sex specific adaptations suggested.
For a rough estimate of actual drug concentrations used during HIPEC, we imputed respective values if unavailable to us. Based on presumed average patient characteristics and assuming maximum concentrations, we estimated HIPEC drug concentrations and categorized the results according to drug solvents. In MMC, respective median concentrations resulted in about 7-13 µg/mL ( Figure 5). Another practice distinctive for MMC single-agent use was adjusting the drug dosage according to sex. Here, a dosage of 12.5 mg/m 2 for men and a slightly lower dosage of 10.0 mg/m 2 for women was employed, which was described in about 10% of reports (Table S1) [23][24][25]28,30,40,50,52,59,68]. More importantly in the publications actually reporting diluent amounts, once 1.0 L was reported [52], twice 2.0 L [25,59], and in two further publications 2.0 L/m 2 [23,68], which affects the resulting drug concentrations more relevantly than, for instance, the comparably modest sex specific adaptations suggested.
For a rough estimate of actual drug concentrations used during HIPEC, we imputed respective values if unavailable to us. Based on presumed average patient characteristics and assuming maximum concentrations, we estimated HIPEC drug concentrations and categorized the results according to drug solvents. In MMC, respective median concentrations resulted in about 7-13 µg/mL ( Figure 5). Another practice distinctive for MMC single-agent use was adjusting the drug dosage according to sex. Here, a dosage of 12.5 mg/m 2 for men and a slightly lower dosage of 10.0 mg/m 2 for women was employed, which was described in about 10% of reports (Table S1) [23][24][25]28,30,40,50,52,59,68]. More importantly in the publications actually reporting diluent amounts, once 1.0 L was reported [52], twice 2.0 L [25,59], and in two further publications 2.0 L/m 2 [23,68], which affects the resulting drug concentrations more relevantly than, for instance, the comparably modest sex specific adaptations suggested.
For a rough estimate of actual drug concentrations used during HIPEC, we imputed respective values if unavailable to us. Based on presumed average patient characteristics and assuming maximum concentrations, we estimated HIPEC drug concentrations and categorized the results according to drug solvents. In MMC, respective median concentrations resulted in about 7-13 µg/mL ( Figure 5). Another practice distinctive for MMC single-agent use was adjusting the drug dosage according to sex. Here, a dosage of 12.5 mg/m 2 for men and a slightly lower dosage of 10.0 mg/m 2 for women was employed, which was described in about 10% of reports (Table S1) [23][24][25]28,30,40,50,52,59,68]. More importantly in the publications actually reporting diluent amounts, once 1.0 L was reported [52], twice 2.0 L [25,59], and in two further publications 2.0 L/m 2 [23,68], which affects the resulting drug concentrations more relevantly than, for instance, the comparably modest sex specific adaptations suggested.
For a rough estimate of actual drug concentrations used during HIPEC, we imputed respective values if unavailable to us. Based on presumed average patient characteristics and assuming maximum concentrations, we estimated HIPEC drug concentrations and categorized the results according to drug solvents. In MMC, respective median concentrations resulted in about 7-13 µg/mL ( Figure 5). Another practice distinctive for MMC single-agent use was adjusting the drug dosage according to sex. Here, a dosage of 12.5 mg/m 2 for men and a slightly lower dosage of 10.0 mg/m 2 for women was employed, which was described in about 10% of reports (Table S1) [23][24][25]28,30,40,50,52,59,68]. More importantly in the publications actually reporting diluent amounts, once 1.0 L was reported [52], twice 2.0 L [25,59], and in two further publications 2.0 L/m 2 [23,68], which affects the resulting drug concentrations more relevantly than, for instance, the comparably modest sex specific adaptations suggested.
For a rough estimate of actual drug concentrations used during HIPEC, we imputed respective values if unavailable to us. Based on presumed average patient characteristics and assuming maximum concentrations, we estimated HIPEC drug concentrations and categorized the results according to drug solvents. In MMC, respective median concentrations resulted in about 7-13 µg/mL ( Figure 5).
predominantly reported the use of lower amounts of L-OHP [55,65,66,69,127,134,139,142,143,145,147]. Of note, only one single publication reported administering an amount of 460 mg/m 2 /L, adding up to a substantially increased concentration of L-OHP compared to most other protocols [121], yielding a concentration 795 µg/mL and resulting in an outlier. In the PRODIGE7 trial, L-OHP has been used with adjustments of the drug dosage according to the open or closed technique of HIPEC (360 mg/m 2 or 460 mg/m 2 in 2 L/m 2 body surface area, respectively) [7], yielding a drug concentration of 180 µg/mL and 230 µg/mL L-OHP, respectively.  Another practice distinctive for MMC single-agent use was adjusting the drug dosage according to sex. Here, a dosage of 12.5 mg/m 2 for men and a slightly lower dosage of 10.0 mg/m 2 for women was employed, which was described in about 10% of reports (Table S1) [23][24][25]28,30,40,50,52,59,68]. More importantly in the publications actually reporting diluent amounts, once 1.0 L was reported [52], twice 2.0 L [25,59], and in two further publications 2.0 L/m 2 [23,68], which affects the resulting drug concentrations more relevantly than, for instance, the comparably modest sex specific adaptations suggested.
For a rough estimate of actual drug concentrations used during HIPEC, we imputed respective values if unavailable to us. Based on presumed average patient characteristics and assuming maximum concentrations, we estimated HIPEC drug concentrations and categorized the results according to drug solvents. In MMC, respective median concentrations resulted in about 7-13 µg/mL ( Figure 5). Another practice distinctive for MMC single-ag to sex. Here, a dosage of 12.5 mg/m 2 for men and a was employed, which was described in about 10% More importantly in the publications actually rep [52], twice 2.0 L [25,59], and in two further publica drug concentrations more relevantly than, for adaptations suggested.
For a rough estimate of actual drug concentra values if unavailable to us. Based on presumed maximum concentrations, we estimated HIPEC d according to drug solvents. In MMC, respective me ( Figure 5).

HIPEC Protocols Describing Combined Drug Use
A substantial proportion of HIPEC protocols reported using cytotoxic drugs combined within the same solution (

Differences in Exposure Times to Cytotoxic Drugs
The overall exposure time of the peritoneum to cytotoxic drugs ranged between 20 min and 120 min [67,152]. A relatively short duration of 30 min was very common for L-OHP (Figure 2b, Tables S4 and S5). This was the case both in L-OHP single-agent HIPEC (80%) [ (Figure 2b, Table S5). This differs with MMC single-agent  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: C single-agent use was adjusting the drug dosage according r men and a slightly lower dosage of 10.0 mg/m 2 for women about 10% of reports (Table S1) [23][24][25]28,30,40,50,52,59,68]. ctually reporting diluent amounts, once 1.0 L was reported ther publications 2.0 L/m 2 [23,68], which affects the resulting than, for instance, the comparably modest sex specific g concentrations used during HIPEC, we imputed respective n presumed average patient characteristics and assuming ed HIPEC drug concentrations and categorized the results spective median concentrations resulted in about 7-13 µg/mL Another practice distinctive for MMC single-agent use was adjusting the drug dos to sex. Here, a dosage of 12.5 mg/m 2 for men and a slightly lower dosage of 10.0 mg/m was employed, which was described in about 10% of reports (Table S1) [23][24][25]28,30,4 More importantly in the publications actually reporting diluent amounts, once 1.0 L [52], twice 2.0 L [25,59], and in two further publications 2.0 L/m 2 [23,68], which affect drug concentrations more relevantly than, for instance, the comparably modes adaptations suggested.
For a rough estimate of actual drug concentrations used during HIPEC, we impu values if unavailable to us. Based on presumed average patient characteristics a maximum concentrations, we estimated HIPEC drug concentrations and categoriz according to drug solvents. In MMC, respective median concentrations resulted in abou ( Figure 5).

Differences in Benchmarking Applied Drug Dosages
The publications included in our survey originated from four continents (Europe, Asia, North America, and Australia) and included at least 23 different countries, featuring roughly ten thousand CRC patients (Figure 9a). J. Clin. Med. 2018, 7, 567 12 of 32 exposure times of 1 h and beyond were mostly reported in dose finding studies, with treatments lasting for up to 2 h [146]. Particularly with infrequently employed drugs (Tables S6 and S8) [108,139,147,[151][152][153] or in respective drug combinations (Table S7) [119,[125][126][127], a considerable variability and ambiguity prevailed, suggesting a particularly experimental setting.

Differences in Benchmarking Applied Drug Dosages
The publications included in our survey originated from four continents (Europe, Asia, North America, and Australia) and included at least 23 different countries, featuring roughly ten thousand CRC patients (Figure 9a).

HIPEC Protocols Describing the Use of an Open and Closed Technique
A further varying factor is the practice of performing HIPEC in a closed or open abdominal cavity (also called coliseum technique) [155,156]. Each procedure has their respective set of advantages and disadvantages, the latter for instance allowing manipulation during the procedure, whereas the closed technique may entail less drug exposure of the personnel [156]. Further diverse technical solutions of combining a closed circuit with the option of manipulation during drug perfusion have been suggested [157,158]. It has been assumed that there might be an influence of those technical aspects on the outcome of the procedure, but this has never been clinically proven [156,159]. Some HIPEC protocols even entail changes in drug dosage, accounting for the open or closed technique used [7]. We therefore assessed all the included reports of HIPEC (n = 171), considering whether the open (44%) or closed (25%) technique was performed. The remainder of publications entailed mainly cases, where the used technique was not reported, but also comprised a choice according to surgeons' preference or further technical variations. The differences in fluid volumes used for dilution of drugs, when categorizing the HIPEC protocols according to the three mentioned categories previously mentioned, were rather low and varied between 3.0 L and 3.5 L in median (Figure 12a). However, for the open technique, some outliers were observed that had already been observed previously ( Figure 11). This situation therefore also resulted in relatively limited fluctuations in drug dosage, particularly for L-OHP (Figure 12b

Hyperthermia
Since hyperthermia is a defining feature of HIPEC, temperatures used were unanimously reported above physiological levels of 37 • C. It has to be noted that many different techniques and approaches were used to measure temperatures, impairing their comparability. For instance, there are publications where inflow temperatures amount to up to 48 • C [48], whereas in other publications, temperatures in the abdomen were reported ranging from 38.5 • C [79] to 44 • C [73]. Most frequently target temperatures were reported at 42.0 • C, but often a temperature range was given ( Figure 13).

Discussion
This comprehensive review on HIPEC conduct in peritoneal metastases (PM) from colorectal cancer (CRC) adds tangible evidence to the notion of heterogeneity and lacking uniformity in perioperative intraperitoneal drug administration [9,12,161]. We identified at least 60 different HIPEC protocols regarding different drugs used and their concentrations among 171 reports about HIPEC conduct, mentioned in 135 publications and included in this systematic review. Since relevant information was frequently lacking, those accounts may rather underestimate the true heterogeneity. Surprisingly, there was also uniformity within subareas, as evidenced with L-OHP use. On the downside, frequently HIPEC procedures are only vaguely described, omitting relevant information and focusing on other aspects of the procedure. This factor may even contribute to unintentional arbitrariness in subsequent research conduct and patient treatment, when aiming to reproduce protocols described in the literature.
A cursory examination already revealed that drug use has been inconsistent and included many different cytotoxic agents, foremost MMC and L-OHP, which are established to exert synergistic effects with heat, potentially a crucial factor for their choice in the first place [162]. MMC was the most commonly used drug in HIPEC, which was also found by a recent international survey [163], followed by L-OHP, both for single-agent use and drug combinations. Even though monotherapies prevail for HIPEC, there is a variety of drug combinations, comprising one fifth of the evaluated protocols, while for CRC the choice of the most suitable drug or drug combination remains currently unsettled. The first protocol established by RCT and therefore best evidence for many years used MMC [2], but tested CRS and HIPEC vs. palliative chemotherapy. Recent RCT results in CRC failed to show an improved survival, when assessing the survival benefit added by HIPEC with L-OHP (460 mg/m 2 for 30 min in the PRODIGE 7 trial (NCT00769405)) [6,7]. Therefore, whereas surgery resulted in impressively improved survival, the role of HIPEC generally remains heavily disputed [164]. On the other side, current RCT data are available for ovarian cancer, establishing a survival benefit for HIPEC with CDDP (100 mg/m 2 for 60 min in patients responsive to carboplatin/paclitaxel) [8].
These very topical results underscore the need to critically reassess HIPEC and its conduct, supporting the notion that a systematic overview of the status quo is a valuable attempt to complete the picture, providing further evidence in addition to consensus statements, and global surveys on this topic already published [155,163].
Against this background, a highly relevant aspect is the cytotoxic profile of drugs used, which is very difficult to control even when disregarding potential drug interactions and applying single drugs only, since the diluent itself may already influence drug effects (i.e., the matrix/ carrier solution drugs are diluted in for peritoneal perfusion). Further drug properties matter, for example with IRI, which needs to be enzymatically biotransformed for activation [165]. This step may certainly take place in malignant cells, but it is neither established whether an exposure time of 30 min for HIPEC with IRI would suffice for the activation nor if similar pharmacokinetics for i.v. and i.p. application can be assumed [166]. Therefore, the application of HCPT, an active metabolite of IRI, seems consequential [126].
Beyond this, for a long-time L-OHP has been administered with glucose containing solutions only, based on the understanding that the drug remains stable under such conditions [167]. However, since L-OHP probably requires transformation to gain cytotoxic properties, chloride containing solutions promoting activation may even be more advantageous. Unfortunately, many active metabolites of L-OHP and their kinetics are hardly evaluated thus far [168]. Therefore, respective investigations clarifying under which conditions drug bioactivity is optimal appear crucial [167,168]. According to our overview, a combination of glucose-based solutions with L-OHP (65%) generally prevailed, but also chloride-containing solutions have been employed [121,139]. Interestingly with MMC containing HIPEC protocols, respective information was much more frequently provided.
Additional heterogeneity is introduced in protocols that partition drug administrations into multiple fractionated applications during HIPEC or apply sex-adapted regimens [30,50,59]. It is an interesting fact that both practices are common with MMC, whereas for other drugs or drug combinations this was never observed by us.
Generally, drug dosing seems a particularly complex and error-prone aspect in HIPEC, as drug amounts are usually reported either as drug amount (in mg) or amount per m 2 (body surface area) and at times as concentrations administered in mg per L adapted to the body surface area (m 2 ). Accordingly, HIPEC protocols are not (easily) comparable, not even on a quantitative level, regardless of any other factors. Only very few reports exist, where a drug concentration in mg/L is indicated, which is particularly the case for early publications on HIPEC with MMC [22,42,43,47,48,57,58,78]. To cope with this, we assumed a virtual average patient enabling comparisons and providing drug concentrations employed for HIPEC, which may aid in establishing the status quo. Such knowledge is particularly relevant and will be required for any attempts of modeling HIPEC. Based on our survey, we may advice caution with regard to dosing drugs, since we witnessed a statement that HIPEC was performed with 460 mg/m 2 /L L-OHP [121], accounting for a substantially increased final drug concentration compared to previous work [131]. Giving these authors the benefit of a doubt by assuming that there was a mistake and 460 mg/m 2 was meant instead, the drug concentration (about 200 µg/mL L-OHP) would result similar to most other protocols. A clear sign for subjectivity in HIPEC conduct was mentioned in a report from 2011, where investigators frankly admitted that either MMC or L-OHP were chosen "according to surgeon´s preference" [169], which may be supposed for handling other aspects of HIPEC as well, since basic research and firm evidence is frequently missing.
Frequently, the procedure is not restricted to HIPEC only but also features concomitant intravenous drug application. This approach of (simultaneous) bidirectional treatment has been theoretically supported by the hypothesis that long-term survival may be improved in patients with higher systemic drug levels [162]. To our knowledge, however, there is no convincing evidence so far supporting concomitant i.v. drug administration during HIPEC [170]. Of note, according to our data, this practice is restricted to L-OHP single-agent or combination HIPEC treatments together with i.v. 5-FU +/− leucovorin. Speculatively, more complex therapy regimens may result more error prone and even entail an increased morbidity risk.
Another observation is that the volumes used for dilution of HIPEC drugs vary substantially from 0.5 L to 12 L. Of course, the latter does not refer to the volumes applied to the abdomen but rather a water bath used for heating [126] and the former speculatively refers to the volume the drug was initially solved in. Nevertheless, respective practices can influence final drug concentrations substantially. Interestingly, the practice of performing open and closed HIPEC procedures affected the resulting median drug concentrations only slightly, due to comparable volumes used for diluting drugs in both groups. We concur with preceding authors that reporting definite concentrations of drugs employed during HIPEC should be best practice and a standard measure is urgently needed to introduce comparability in this regard [171].
Further aspects complicate the picture, namely exposure times of peritoneal surfaces to respective drugs and hyperthermia. Whereas there are natural limits to applying heat to the peritoneum, restricted to a window of about 7 • C between 37 • C and 44 • C, the duration of HIPEC seems limited by practical aspects such as additional costs of prolonged procedures and missing evidence for the time needed. The rationale for using hyperthermia is based on basic research and is theoretically plausible, as for instance 40 • C has been proposed as a critical threshold in vitro [172], while resulting clinical effects ultimately remain unproven [162]. Against this background, it seems quite surprising to us that with MMC predominantly 90 min exposure was chosen, whereas the duration for L-OHP was mainly restricted to only 30 min.

Conclusions
Our literature survey provides a comprehensive systematic overview of about 35 years of clinical experience in HIPEC (1981-2016), reported in scientific articles published between 1992 and 2017. Since current RCT findings have raised critical questions that need to be addressed, it seems sensible to revisit HIPEC conduct in CRC comprehensively. As HIPEC is associated with specific risks that would otherwise be negligible, including spontaneous bowel perforations [173,174] or electrolyte imbalances due to using dextrose-based perfusion solutions as a matrix [175], as well as considerably increased rates of acute renal impairment and bleeding complications in platinum-based HIPEC, respectively, critical questions must be addressed [176]. Based on our survey, HIPEC does not appear as a single treatment, but as an array thereof with many identifiable specific, potentially critical aspects that warrant critical assessment.
The fact that clear standards in reporting HIPEC conduct are lacking prevents definite comparisons between published protocols and hinders a comprehensive assessment of data. The introduction of standardized reporting for HIPEC drug dosage using concentrations instead of being defined by body surface area has been requested on pharmacological grounds for many years [171], and we may provide a status quo here, necessary for basic research and modeling. However, attempts at standardizing HIPEC ad libitum, without sufficient scientific evidence seem misleading to us and may suggest false security, whereas the general concept is laudable [11,142]. We agree that the introduction of standards may reduce the margin of error and promote routines, thereby increasing patient security, as proven in the past [9]. Nevertheless, we frequently missed crucial information on many aspects of HIPEC, therefore efforts implementing standards in reporting HIPEC procedures are critical to reach better comparability.