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Review

Current Research and Development in Hyperthermic Intraperitoneal Chemotherapy (HIPEC)—A Cross-Sectional Analysis of Clinical Trials Registered on ClinicalTrials.gov

1
Department of Surgery, Kantonsspital St. Gallen, 9007 St. Gallen, Switzerland
2
Department of Visceral and Transplant Surgery, University Hospital Zurich, 8091 Zurich, Switzerland
3
Department of Radiation Oncology, Kantonsspital St. Gallen, 9007 St. Gallen, Switzerland
4
Department of Radiation Oncology, Inselspital, University of Bern, 3010 Bern, Switzerland
*
Author to whom correspondence should be addressed.
These authors contributed equally to this work.
Cancers 2023, 15(7), 1926; https://doi.org/10.3390/cancers15071926
Submission received: 9 February 2023 / Revised: 17 March 2023 / Accepted: 21 March 2023 / Published: 23 March 2023
(This article belongs to the Section Cancer Therapy)

Abstract

:

Simple Summary

Peritoneal metastases have a poor prognosis, and one potential treatment option is cytoreductive surgery (CRS) with hyperthermic intraperitoneal chemotherapy (HIPEC). The specific role of HIPEC is still poorly defined. In this cross-sectional study, we systematically analyzed all HIPEC trials registered on ClinicalTrials.gov to identify current research areas and to provide a perspective on expected outcomes. Only 11% (n = 26) of HIPEC trials registered on ClinicalTrials.gov (n = 234) have been published. The registered trials are very heterogeneous regarding methodological approaches and study designs. Currently, research is being conducted on 20 different drugs. The most studied cancers in HIPEC trials are peritoneal metastatic colorectal tumors, gastric cancer, and ovarian cancer.

Abstract

Introduction: Over the past two decades, cytoreductive surgery and HIPEC has improved outcomes for selected patients with peritoneal metastasis from various origins. This is a cross-sectional study with descriptive analyses of HIPEC trials registered on ClinicalTrials.gov. This study aimed to characterize clinical trials on HIPEC registered on ClinicalTrials.gov with the primary objective of identifying a trial focus and to examine whether trial results were published. Methods: The search included trials registered from 1 January 2001 to 14 March 2022. We examined the associations of exposure variables and other trial features with two primary outcomes: therapeutic focus and results reporting. Results: In total, 234 clinical trials were identified; 26 (11%) were already published, and 15 (6%) trials have reported their results but have not been published as full papers. Among ongoing nonpublished trials, 81 (39%) were randomized, 30 (14%) were blinded, n = 39 (20%) were later phase trials (i.e., phases 3 and 4), n = 152 (73%) were from a single institution, and 91 (44%) had parallel groups. Most of the trials were recruiting at the time of this analysis (75, 36%), and 39 (20%) were completed but had yet to publish results. In total, 68% of the trials focused on treatment strategies, and 53% investigated the oncological outcome. The most studied neoplasms for HIPEC trials were peritoneally metastasized colorectal cancer (32%), gastric cancer (29%), and ovarian cancer (26%). Twenty different drugs were analyzed in these clinical trials. Conclusions: Many study results are awaited from ongoing HIPEC trials. Most HIPEC trials focused on gastric, colorectal, or ovarian cancer. Many clinical trials were identified involving multiple entities and chemotherapeutic agents.

1. Introduction

Peritoneal metastasis has a dismal prognosis despite systemic treatment [1]. Treatment options for peritoneal malignancy include systemic chemotherapy and, in selected cases, cytoreductive surgery (CRS), with hyperthermic intraperitoneal chemotherapy (HIPEC) providing excellent outcomes in several cohort studies [2,3,4,5]. In theory, CRS is performed to treat macroscopic tumor lesions, and HIPEC is used to treat microscopic residual tumors within a curative treatment regimen [5,6,7,8,9,10]. Despite excellent results for CRS/HIPEC, the specific role of HIPEC remains poorly defined, and recent publications have fueled the ongoing debates about CRS and HIPEC [11,12,13,14,15].
To the best of our knowledge, no published study has empirically analyzed registered clinical trials examining HIPEC. ClinicalTrials.gov was created due to the Food and Drug Administration Modernization (FDAMA) Act of 1997 and was made available to the public in February 2000. The use of registries such as ClinicalTrials.gov has been embraced by the International Committee of Medical Journal Editors (ICMJE). Since 2005, the ICMJE has required trial registration before participant enrollment as a prerequisite for publication in any of its member journals [16]. ClinicalTrials.gov is the largest clinical trial registry, and the registration process and its potential for an analysis of the landscape of clinical trials are well described [17,18,19]. Herein, we quantify the characteristics of HIPEC trials registered on ClinicalTrials.gov to identify the current research fields, identify early discontinuation, report results, and generate an outlook on expected future results.

2. Materials and Methods

2.1. Selection of Clinical Trials

We downloaded an XML data set comprising all 408,263 clinical trials registered with ClinicalTrials.gov on March 14th, 2022. Our analysis was restricted to HIPEC trials. To identify potential HIPEC trials, we searched for the terms: “intraperitoneal chemotherapy”, “hipec”, “hyperthermic intraperitoneal chemotherapy”, “peritoneal metastases”, “peritoneal carcinomatosis”, “peritoneal malignancy”, and “cytoreductive surgery”. This search strategy resulted in 487 (100%) trials for manual review and classification. All trials addressing diseases other than cancer, treatment with pressurized intraperitoneal aerosol chemotherapy (PIPAC), intraperitoneal chemotherapy (IP) delivery via a catheter, or different types of therapy were excluded from this analysis. The remaining 234 (48%) trials were included in our analysis. The trial selection process is shown in Figure 1.

2.2. Data from ClinicalTrials.gov

Data on the trial characteristics, registration, completion of the trials, study design, enrollment characteristics, funding source, and number of study sites for all clinical trials were extracted from the ClinicalTrials.gov.
Included trials were divided classified by (1, 1/2, 2, 2/3, 3, 4, NA): the number of participants; allocation status (randomized vs. nonrandomized); trial start year; region; intervention type (drug, procedure, biological, behavioral, device, dietary supplement, diagnostic test, radiation, combination product, other); primary purpose (treatment, prevention, diagnostic, supportive care, other); overall status and primary outcome (efficacy, safety, feasibility, pharmacodynamics/pharmacokinetics, quality of life, other).
To determine the trial focus, each included clinical trial was classified according to its primary disease origins: peritoneal metastases from gastric cancer, colorectal cancer, cancer from the hepatopancreatic origin, ovarian cancer, primary peritoneal malignancy, etc. Each trial was assigned to 1 or multiple appropriate categories of disease origin.
All clinical trials on solid-organ tumors were manually reviewed to evaluate the therapeutic focus, and each trial was assigned to one or more appropriate drug categories. One or more therapeutic foci per study were accepted. For the analyses, each therapeutic focus was treated as a binary variable. All reported interventions were evaluated and classified into the following therapeutic groups: experimental and approved drugs, based on the development status of the specific therapy. Experimental drugs were annotated as such if no previous indication was approved for commercial use by the United States Food and Drug Administration
The trials were classified according to the reported experimental intervention types. If randomization was not explicitly defined, a manual review of the trial entries was performed to determine the study design.
Funding sources include foundations (e.g., National Institutes of Health, government networks), industry, and academic institutions (e.g., universities, hospitals, foundations, and other nonprofit organizations).
Frequencies and percentages were provided for categorical characteristics; medians and interquartile ranges (IQRs) were provided for continuous characteristics.

2.3. Search for Publications of Trial Results

To identify if trials registered at ClinicalTrials.gov were published, the electronic databases EMBASE, MEDLINE (via PubMed), and Cochrane Central Register of Controlled Trials were searched. We included the trial registration number (NCT number) in the search for publications searching for given trial characteristics. If more than one publication was identified, we chose the publication that most closely fit the study described in the record. We then searched an online result registry ClinicalStudyResults.org (accessed on 25 October 2022) and result reports available through company Web pages for references to publications [20,21].
We defined a trial as published if the primary outcome(s) results were published in a peer-reviewed journal. We also recorded whether the trial was reported elsewhere in other publication types, such as articles without results presentation, conference abstracts, clinical study reports, and records in trial registries.
Bibliometric data of the journals where the HIPEC trials were published were found in the Journal Citation Reports of the ISI Web of Knowledge [22]. Citation reports were extracted for the individual papers from the Web of Science for the main publication from each trial [23].

2.4. Outcome Parameters

The primary outcomes were the trial’s focus (colorectal carcinoma, ovarian carcinoma, appendiceal carcinoma, etc.) and trial completion. The study completion date is defined by ClinicalTrials.gov as the date when participants are no longer being examined or treated (last patient’s final visit). Each record was classified as including study results in links to PubMed abstracts, links to unpublished result reports, or actual study results.
Secondary outcomes were characteristics of registered clinical trials. Data on characteristics of the trials and their registration include registration date, start date, completion date, condition treated, funding source, trial phase, primary outcome, anticipated enrolment number, age group of participants, and elements of the study design. Two authors (K.U., M.G.) independently performed the literature search and data extraction, and consensus resolved disagreements.

2.5. Ethical Statement

This study was reviewed by the Ethical Committee of the Cantonal Hospital St. Gallen and was exempt from oversight and informed consent because all data are publicly available. Our findings are reported in accordance with the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guidelines.

3. Results

The characteristics of all trials for HIPEC registered in ClinicalTrials.gov are shown in Table 1. In total, 64% of the clinical trials were small in terms of the number of participants (100 or fewer). Overall, 96% of these trials had an anticipated enrollment of 500 or fewer participants, and the median number of participants per trial was n = 60 (IQR, 1–15,000). Most trials (n = 158, 68%) focused on treatment strategies, n = 123 (53%) trials investigated the overall survival, and n = 130 (56%) trials analyzed drugs. Most of the trials received academic funding (195, 83%). Most trials were performed at single sites (n = 170, 73%); n = 64 (27%) were multisite trials. Most trials were initiated in a European or North American research site (n = 34% vs. 32%). A few trials (n = 52, 22%) were restricted to women, a difference mainly attributable to ovarian cancer trials. There were also differences in age distribution among the three categories. Most trials included only adult patients. Eight trials had been withdrawn: four were withdrawn because of poor accrual rate, two were withdrawn because the study was not funded, and two were withdrawn because of logistical problems before the recruitment phase.
Several missing data elements exist for some characteristics: 19% of the trials were missing data regarding the primary purpose; 5% of the trials did not report the intervention type; 9% of the trials did not report the number of institutions or the region; 34% of the trials did not report the randomization method or trial phase; and 15% of the trials did not report the overall status.
Of the 234 clinical trials we reviewed, n = 26 (11%) were already published, and n = 15 (6%) trials had reported their results elsewhere. Some studies were published in high-ranked journals, such as The New England Journal of Medicine (NCT00426257) [24], JAMA Surgery (NCT01091636) [25], Lancet Oncology (NCT00769405, NCT01226394, NCT01835041) [26,27,28], or the Lancet Gastroenterology Hepatology (NCT02231086) [29]. Most trials were published in the Annals of Surgical Oncology (NCT00458809, NCT02891447, NCT03230240, NCT02575859, NCT02863471) [30,31,32,33,34].
The cancer entity involved in the trial had a significant impact on citation scores: papers on ovarian cancer and colorectal cancer research resulted in many more citations than those on other cancer types. European countries consistently published the most articles (n = 14), followed by the United States (n = 7), which had a relatively high commitment to surgical oncology research. The output of East Asian countries (China, Republic of Korea, Singapore, Taiwan) has been increasing rapidly over time but is still below that of the larger European countries. Some data elements for some characteristics are missing or not added or updated in a total of 23% of published trials reported the incorrect overall recruitment status; 31% of published trials did not report the randomization methods; 31% of trials did not report the phase; and 26% of trials did not report their primary endpoint.
Among ongoing nonpublished trials, n = 170 (82%) were interventional trials, n = 81 (39%) were randomized, n = 30 (14%) were blinded, n = 39 (20%) were later-phase trials (i.e., phases 3 and 4), n = 152 (73%) were from a single institution, and n = 91 (44%) had parallel groups. Most of the trials were recruiting at the time of this analysis (75, 36%), and 39 (20%) were completed but had not published results on the primary endpoint (shown in Supplementary Table S1).
A detailed analysis of the relative commitment to ongoing HIPEC research at cancer sites and an analysis of the investigated agents are displayed in Table 2. Multiple tumor types were analyzed in n = 90 of 208 ongoing trials. Thirty-three of the n = 208 ongoing trials included patients with either primary or secondary peritoneal metastases, regardless of the primary tumor (colorectal carcinoma, ovarian carcinoma, appendiceal carcinoma, etc.). The most widely studied neoplasms for HIPEC trials were peritoneal metastasized colorectal cancer (n = 67, 32%), peritoneal metastasized ovarian cancer (n = 61, 29%), and peritoneal metastasized gastric cancer (n = 54, 26%). Neoplasia sites with smaller percentages of HIPEC clinical trials were peritoneal metastasized liver cancer, peritoneal metastasized gallbladder cancer, and peritoneal metastasized bladder cancer (n = 1 (0.4%), n = 1 (0.4%), and n = 1 (0.4%), respectively).
Twenty different drugs (cisplatin, mitomycin- C, irinotecan, doxorubicin, paclitaxel, oxaliplatin, 5-fluorouracil, docetaxel, lobaplatin, carboplatin, anti-PD-1 antibody, thalidomide, leucovorin, melphalan, MOC31PE immunotoxin, capecitabine, raltitrexed, pasireotide, gemcitabine, and cantrixil) were analyzed in these clinical trials. The drugs with the highest proportions of clinical tests were cisplatin (n = 78 (33%)), mitomycin C (n = 69 (29%)), and oxaliplatin (n = 37 (17%)) (shown in Table 2).
The phase III trial characteristics are shown in Table 3. Thirty-nine phase III and one phase IV ongoing trials are registered at ClinicalTrials.gov. Of the 20 different tumor entities analyzed in the ongoing trials, the phase III and phase IV trials focus on gastric carcinoma (n = 13), ovarian carcinoma (n = 12), and colon carcinoma (n = 11).
Fourteen ongoing later-phase clinical trials (i.e., phases II/III and III) evaluated the efficacy and safety of HIPEC in the treatment of patients with peritoneal metastases of gastric origin (shown in Table 2). HIPEC is analyzed for two indications in gastric cancer: first, as a definitive treatment in established peritoneal metastases (NCT03348150, NCT03179579, NCT03023436, NCT02356276, NCT02158988, NCT00052962); second, as an adjuvant therapy after curative surgery for patients with locally advanced gastric cancer and a high risk of developing peritoneal metastases (NCT04597294, NCT04447352, NCT03917173, NCT02960061, NCT02381847, NCT02240524, NCT01882933, NCT01683864) (shown in Table 3).
Three phase III ongoing clinical trials (NCT01628380, NCT03772028, NCT03842982) evaluated the efficacy of HIPEC for advanced-stage ovarian cancer used in an adjuvant setting and one phase III clinical trial (NCT03180177) in neoadjuvant setting patients. HIPEC was analyzed in two phase III trials (NCT03373058 and NCT02328716) as a definitive treatment in ovarian cancer with established peritoneal metastases. Three phase III clinical trials (NCT01376752, NCT03220932, NCT03371693) have the primary objective of comparing the efficacy and safety of CRS alone versus CRS plus HIPEC of first or second platinum-resistant ovarian cancer recurrence (shown in Table 3).
Fourteen ongoing later-phase research clinical trials (i.e., phases II/III, III and IV) evaluated the efficacy and safety of HIPEC in the treatment of patients with peritoneal metastases of colorectal origin (shown in Table 2). Six randomized phase III trials studied HIPEC for patients with locally advanced colorectal cancer and a high risk of developing peritoneal metastases in an adjuvant mode in addition to standard treatment to prevent the development of peritoneal metastasis (NCT02179489, NCT02965248, NCT02974556, NCT03221608, NCT03914820 and NCT04370925). One phase IV clinical trial (NCT05250648) evaluated the effectiveness of HIPEC with high-dose mytomicin-C in preventing the development of peritoneal recurrence in patients with limited peritoneal metastasis from colon cancer (not rectal) after CRS (shown in Table 3).
The annual number of clinical trials in the field of HIPEC that started per year worldwide or reported results to ClinicalTrials.gov is shown in Figure 2. The three curves are almost parallel. Reporting trial results (journal publications and other reports included) was more common after 2010. The number of trials submitted for registration in ClinicalTrials.gov increased over the two periods: from n = 25 in 1997–2009 to n = 203 in 2010–2021. The mean time between the estimated end of the study and the first publication of results was four years (range 0.1–15 years). However, the end of each survey could not be analyzed herein.

4. Discussion

4.1. Main Findings

In this study, we estimated that only 11% of HIPEC trials registered at ClinicalTrials.gov were published. Compared to other research fields, CRS/HIPEC is poorly represented. Between 1997 and 2022, only 234 clinical trials examining HIPEC were registered. Many publications on HIPEC are expected in the following years. HIPEC trials increased at a significant rate from 2010. Registered trials are highly heterogeneous in terms of methodological approaches and study designs. Research is currently being performed with 20 different drugs, including experimental drugs. Small, single-center clinical trials on HIPEC dominate the ClinicalTrials.gov database, but most are funded by academic institutions or cancer foundations. The most studied cancer entities in HIPEC trials are peritoneal metastasized colorectal, gastric and ovarian cancers.

4.2. Results in Context

With the concept of CRS combined with HIPEC, many encouraging results were found in randomized controlled trials and large cohort studies. The introduction of CRS and HIPEC in the 1990s, but especially after 2000, has obtained unprecedented results in patients with peritoneal metastases of colorectal cancer; thus, it has gradually been accepted, even being considered the best treatment for these patients [35,36,37,38,39]. In the following years, more trials were registered. Clinical research on HIPEC represents a key component of the multiple efforts needed to reduce the disease burden in patients and to advance the treatment of peritoneal metastases. The progress of the field warrants and partially depends on a greater commitment of resources and funding by all clinical trial sponsors. In addition to increasing the number of HIPEC clinical trials, improvement in HIPEC trial completion and dissemination is important. We found a mean delay of 4 years between study completion and publication. Scarce reports of study results, particularly in academic-funded trials, may reflect relatively limited resources in academia. Although federal statutes require many clinical trials to report their results within one year with the option to delay for 2 years [40], the parameters of the statutes have evolved over the past decade, and barriers exist to consistent results reporting [41,42,43,44]. A lack of results can bias the literature, squander limited resources, and hinder medical innovation. Greater results reporting within HIPEC trials continues to be a relevant goal, with implications for all physicians who treat patients with peritoneal metastases.
In treating primary peritoneal cancer and the pseudomyxoma peritonei and the treatment of peritoneal metastasized colorectal, ovarian, or gastric cancer, the addition of HIPEC has been used in specialized centers worldwide. HIPEC was introduced and performed for peritoneal malignancies worldwide. However, despite its proliferation, the procedure still needs to be better studied, and execution of solid large multicentric randomized trials remains difficult. Many scientific projects were terminated early because of difficulties in recruiting. Heterogeneity in chemotherapeutics and technical aspects of HIPEC, as well as many different therapeutic concepts, have hindered the comparability of studies.
The French PRODIGE-7 trial (NCT00769405) [26] has most recently cast doubt on the benefit of HIPEC. The authors found no overall survival benefit by adding HIPEC to cytoreductive surgery and more frequent postoperative late complications, suggesting that CRS alone should be the cornerstone of therapeutic strategies. These study results are still controversial today. Additionally, prophylactic HIPEC in so-called high-risk situations in patients with colorectal cancer has lost popularity after the Dutch and French RCTs were published. In ovarian cancer, a Dutch study by Van Driel et al. [24] showed promising results in patients with stage III epithelial ovarian cancer with more prolonged recurrence-free survival and overall survival than surgery alone. Despite an unclear picture after the publication of the most recent trials, the rationale of CRS and HIPEC remains logical to many surgeons and medical oncologists. The ongoing studies, hopefully, provide more clarity in the field. Six ongoing randomized, phase III trials studied HIPEC for patients with locally advanced colorectal cancer and a high risk of developing peritoneal metastases in an adjuvant mode in addition to standard treatment to prevent the development of peritoneal metastasis (NCT02179489, NCT02965248, NCT02974556, NCT03221608, NCT03914820 and NCT04370925). Probably the most important ongoing study on this topic is the GECOP-MMC-Trial (NCT05250648). It is a prospective, open-label, randomized, multicenter phase IV clinical trial that evaluates the effectiveness of HIPEC with high-dose mytomicin-C in preventing the development of peritoneal recurrence in patients with limited peritoneal metastasis from colon cancer (not rectal), after CRS [45].

4.3. Strengths/Limitations

Our analysis uniquely examines the therapeutic focus of HIPEC trials, publication status, and study characteristics. This analysis allows for extrapolation of factors that may contribute to the low number of HIPEC trials and increased risk of premature discontinuation in HIPEC trials. We present novel assessments of temporal trends that are only possible with a large sample and a longer period. This study examines the drugs used to treat peritoneal metastases and reviews and compares reporting of results from ongoing trials.
The present cross-sectional analysis has some limitations. First, the ClinicalTri-als.gov registry represents only a sample of all global clinical trials; there are several other registries (e.g., European Union Clinical Trials Registry (EudraCT) or Clinical Trials Registry India (CTRI)) that can also be used worldwide. Trials are registered in one of the other registries and therefore were not examined in our study. However, a study found that ClinicalTrials.gov contains the greatest number of trials compared with other data-bases [46].
Second, there were changes in the data collected, the definitions used, and the rigor with which missing data were tracked. Due to practical or logistical limitations, some data elements needed to be included or available.
Third, because this analysis involves multiple testing, it is possible that the strength of association seen for some trial features may be the result of chance.
Fourth, the data sets for all problems in the database are probably only sometimes complete and up to date. Some of these trials may have been in the pre-commercialization phase or were early negative studies for which plans for commercialization were withdrawn. Because sponsors submit study characteristics, verifying their accuracy is impossible.
Fifth, during data collection, certain data may have needed to be misclassified during selection and classification or some studies were registered incorrectly. We greatly minimized these limitations: Two authors (K.U. and M.G.) cross-checked all identified studies and the selection steps. Finally, the limitations of ClinicalTrials.gov have been described in other studies and applied to this analysis [47,48].

4.4. Implications for Future Research

Based on our results, we identified a broad heterogeneity of drugs used for HIPEC for different tumor entities, which hinders the development of comparable study designs. Inclusion criteria for patients in future studies should be defined very clearly. Otherwise, study results may be flawed, as in the abovementioned French study by Quenet et al. [26]. The range of primary tumor types for peritoneal metastases and additional histologic subtypes in general is too broad and therefore does not allow for the generalization of treatment options and indications for HIPEC. This applies under the study conditions.
A critical implication for future research is clearly the need for better multicentric studies in the field of HIPEC. Such studies should be performed according to study parameters and stratifications that need to be better defined and yet to be developed.

4.5. Implications for the Practice

It is essential to participate in ongoing and future multicentric trials rather than performing another large cohort trial over a long period with different HIPEC drug regimens or heterogeneous patient groups. Systematic chemotherapies have developed dramatically over the past years with excellent results. Therefore, the benefit of HIPEC might have been shrinking in parallel, making it more challenging to detect the solid survival advantages of HIPEC. HIPEC should be performed in experienced centers and whenever possible under study conditions. Sixty-seven ongoing clinical trials are evaluating the efficacy and safety of HIPEC in treating patients with peritoneal metastases of colorectal origin. Most likely, the most important ongoing study on this topic is the GECOP-MMC-Trial (NCT05250648). This prospective, open-label, randomized, multicenter phase IV clinical trial evaluates the effectiveness of HIPEC with high-dose mitomycin C in preventing the development of peritoneal recurrence in patients with limited peritoneal metastasis from colon cancer (not rectal) after CRS [45]. There is a broad heterogeneity of drugs used for different tumor entities of up to twenty different chemotherapeutics used for HIPEC in ovarian cancer. There is an urgent need for clinical guidelines on the administration and type of drugs to be used.
On the other hand, clinicians should, whenever possible, adopt existing clinical recommendations; an early example is the ASPSM scheme published in 2013 [49].
Currently, 39 phase III and one phase IV ongoing trials are registered on ClinicalTrials.gov. Of the more than 20 tumor entities analyzed in ongoing trials, phase III and IV trials focus mainly on colonic, gastric, and ovarian cancers. Twenty-eight ongoing randomized controlled phase III trials and one phase IV trial evaluated the efficacy and safety of HIPEC in an adjuvant setting for cancer patients with peritoneal dissemination. The primary aim of this study was to compare the overall survival and disease-free survival between cancer patients with limited peritoneal carcinomatosis and/or tumor-positive peritoneal cytology treated with cytoreductive surgery and HIPEC and those treated with the current standard treatment.
To date, there is also a discrepancy in how patients with ovarian cancer recurrence should be treated. Most patients with recurrences are currently treated with new combinations of systemic chemotherapy. Repeated laparotomy with complete cytoreduction is an option. Two phase III prospective randomized trials (NCT04473339, NCT01376752) compared cytoreductive surgery with or without HIPEC, and one phase III trial (NCT03220932) compared cytoreductive surgery with HIPEC versus chemotherapy alone.
Neoadjuvant therapy concepts with HIPEC were recently discussed, and one phase III multicenter, prospective, randomized controlled clinical trial evaluated the efficacy of HIPEC used in the neoadjuvant setting for advanced-stage epithelial ovarian cancer patients eligible for CRS before planned surgery (NCT03180177). Two phase II (NCT04308837, NCT05095467) and one phase III (NCT03179579) trials evaluated the efficacy of a multimodality approach to treating patients with locally advanced gastric cancer by incorporating diagnostic laparoscopy with HIPEC in a neoadjuvant setting followed by surgical resection and adjuvant chemotherapy. The trial aims of studies with a multimodality approach are inducing pathological complete response; rates of disease progression during neoadjuvant therapy; and overall, disease-free and peritoneal disease-free survival. A phase II single-center, prospective proof-of-concept study (NCT02850874) evaluated the surgical outcomes and clinicopathologic results of neoadjuvant HIPEC in conjunction with perioperative systemic chemotherapy (neoadjuvant and adjuvant) and pancreaticoduodenectomy in a small cohort of patients having T1-T3 resectable pancreatic ductal adenocarcinoma with one or more high-risk clinical features.

5. Conclusions

Many study results from ongoing HIPEC trials are expected because only a small percentage of HIPEC trials registered at ClinicalTrials.gov have been published. Most trials on HIPEC are focused on gastric, colorectal, or ovarian cancers. A large heterogeneity in terms of methodological approaches and study designs of clinical trials was identified involving multiple entities and chemotherapeutic agents.

Supplementary Materials

The following supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/cancers15071926/s1, Table S1: Characteristics of HIPEC Trials already completed but not yet published results.

Author Contributions

K.U.: study design, data analysis, data analysis interpretation, literature search, figures, manuscript writing, and manuscript review. M.G.: study design, data analysis, data analysis interpretation, literature search, figures, manuscript writing, and manuscript review. K.L.: study design, interpretation of the data analysis, literature search, manuscript writing, and manuscript review. P.M.P.: interpretation of the data and review of the manuscript. K.S.: interpretation of the data and review of the manuscript. N.C.: study design, interpretation of the data analysis, literature search, manuscript writing, and manuscript review. T.S.: study design, data analysis, data analysis interpretation, literature search, figures, manuscript writing, and manuscript review of the manuscript. All authors have read and agreed to the published version of the manuscript.

Funding

This study did not receive any specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

Institutional Review Board Statement

The authors confirm that this study complies with the guidelines for human studies and that the research was conducted ethically following the World Medical Association Declaration of Helsinki. The paper is exempt from ethical committee approval. According to Swiss law and the local ethics committee, no further ethical approvals are needed in a low-risk study of category A.

Informed Consent Statement

Not applicable.

Data Availability Statement

The authors confirm that the data supporting the findings of this study are available within the article and its Supplementary Materials.

Conflicts of Interest

N.C. works as a medical advisor for Wemedoo AG, Sumpfstrasse 24, 6312 Steinhausen, Switzerland. The authors have no conflict of interest to declare.

References

  1. Franko, J.; Shi, Q.; Meyers, J.P.; Maughan, T.S.; Adams, R.A.; Seymour, M.T.; Saltz, L.; Punt, C.J.; Koopman, M.; Tournigand, C.; et al. Prognosis of patients with peritoneal metastatic colorectal cancer given systemic therapy: An analysis of individual patient data from prospective randomised trials from the analysis and research in cancers of the digestive system (ARCAD) database. Lancet Oncol. 2016, 17, 1709–1719. [Google Scholar] [CrossRef]
  2. Lambert, L.A. Looking up: Recent advances in understanding and treating peritoneal carcinomatosis. CA Cancer J. Clin. 2015, 65, 284–298. [Google Scholar] [CrossRef]
  3. Glehen, O.; Kwiatkowski, F.; Sugarbaker, P.H.; Elias, D.; Levine, E.A.; De Simone, M.; Barone, R.; Yonemura, Y.; Cavaliere, F.; Quenet, F.; et al. Cytoreductive surgery combined with perioperative intraperitoneal chemotherapy for the management of peritoneal carcinomatosis from colorectal cancer: A multi-institutional study. J. Clin. Oncol. 2004, 22, 3284–3292. [Google Scholar] [CrossRef] [Green Version]
  4. Jayne, D.G.; Fook, S.; Loi, C.; Seow-Choen, F. Peritoneal carcinomatosis from colorectal cancer. Br. J. Surg. 2002, 89, 1545–1550. [Google Scholar] [CrossRef]
  5. Sadeghi, B.; Arvieux, C.; Glehen, O.; Beaujard, A.C.; Rivoire, M.; Baulieux, J.; Fontaumard, E.; Brachet, A.; Caillot, J.L.; Faure, J.L.; et al. Peritoneal carcinomatosis from non-gynecologic malignancies: Results of the EVOCAPE 1 multicentric prospective study. Cancer 2000, 88, 358–363. [Google Scholar] [CrossRef]
  6. Sugarbaker, P.H. New standard of care for appendiceal epithelial neoplasms and pseudomyxoma peritonei syndrome? Lancet Oncol. 2006, 7, 69–76. [Google Scholar] [CrossRef]
  7. Yan, T.D.; Welch, L.; Black, D.; Sugarbaker, P.H. A systematic review on the efficacy of cytoreductive surgery combined with perioperative intraperitoneal chemotherapy for diffuse malignancy peritoneal mesothelioma. Ann. Oncol. 2007, 18, 827–834. [Google Scholar] [CrossRef]
  8. Friedrich, M.; Zinn, W.; Kolnsberg, L.; Kraft, C.; Kuhn, W. Hyperthermic Intraperitoneal Chemotherapy (HIPEC) for Ovarian Cancer: Evaluation of Side Effects in a Single Institution Cohort. Anticancer Res. 2020, 40, 1481–1486. [Google Scholar] [CrossRef]
  9. Spratt, J.S.; Adcock, R.A.; Muskovin, M.; Sherrill, W.; McKeown, J. Clinical delivery system for intraperitoneal hyperthermic chemotherapy. Cancer Res. 1980, 40, 256–260. [Google Scholar]
  10. Girshally, R.; Demtroder, C.; Albayrak, N.; Zieren, J.; Tempfer, C.; Reymond, M.A. Pressurized intraperitoneal aerosol chemotherapy (PIPAC) as a neoadjuvant therapy before cytoreductive surgery and hyperthermic intraperitoneal chemotherapy. World J. Surg. Oncol. 2016, 14, 253. [Google Scholar] [CrossRef] [Green Version]
  11. Sugarbaker, P.H.; Ryan, D.P. Cytoreductive surgery plus hyperthermic perioperative chemotherapy to treat peritoneal metastases from colorectal cancer: Standard of care or an experimental approach? Lancet Oncol. 2012, 13, e362–e369. [Google Scholar] [CrossRef]
  12. van Driel, W.J.; Koole, S.N.; Sonke, G.S. Hyperthermic Intraperitoneal Chemotherapy in Ovarian Cancer. N. Engl. J. Med. 2018, 378, 1363–1364. [Google Scholar] [CrossRef]
  13. Verwaal, V.J.; van Ruth, S.; de Bree, E.; van Sloothen, G.W.; van Tinteren, H.; Boot, H.; Zoetmulder, F.A. 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, 3737–3743. [Google Scholar] [CrossRef]
  14. Chua, T.C.; Yan, T.D.; Saxena, A.; Morris, D.L. Should the treatment of peritoneal carcinomatosis by cytoreductive surgery and hyperthermic intraperitoneal chemotherapy still be regarded as a highly morbid procedure?: A systematic review of morbidity and mortality. Ann. Surg. 2009, 249, 900–907. [Google Scholar] [CrossRef]
  15. Quere, P.; Facy, O.; Manfredi, S.; Jooste, V.; Faivre, J.; Lepage, C.; Bouvier, A.M. Epidemiology, Management, and Survival of Peritoneal Carcinomatosis from Colorectal Cancer: A Population-Based Study. Dis. Colon. Rectum. 2015, 58, 743–752. [Google Scholar] [CrossRef]
  16. DeAngelis, C.D.; Drazen, J.M.; Frizelle, F.A.; Haug, C.; Hoey, J.; Horton, R.; Kotzin, S.; Laine, C.; Marusic, A.; Overbeke, A.J.; et al. Clinical trial registration: A statement from the International Committee of Medical Journal Editors. JAMA 2004, 292, 1363–1364. [Google Scholar] [CrossRef]
  17. Califf, R.M.; Zarin, D.A.; Kramer, J.M.; Sherman, R.E.; Aberle, L.H.; Tasneem, A. Characteristics of clinical trials registered in ClinicalTrials.gov, 2007-2010. JAMA 2012, 307, 1838–1847. [Google Scholar] [CrossRef] [Green Version]
  18. Cihoric, N.; Tsikkinis, A.; van Rhoon, G.; Crezee, H.; Aebersold, D.M.; Bodis, S.; Beck, M.; Nadobny, J.; Budach, V.; Wust, P.; et al. Hyperthermia-related clinical trials on cancer treatment within the ClinicalTrials.gov registry. Int. J. Hyperthermia 2015, 31, 609–614. [Google Scholar] [CrossRef]
  19. Hartung, D.M.; Zarin, D.A.; Guise, J.M.; McDonagh, M.; Paynter, R.; Helfand, M. Reporting discrepancies between the ClinicalTrials.gov results database and peer-reviewed publications. Ann. Intern. Med. 2014, 160, 477–483. [Google Scholar] [CrossRef] [Green Version]
  20. AstraZeneca Clinical Trials. Available online: www.astrazenecaclinicaltrials.com (accessed on 25 October 2022).
  21. GlaxoSmithKline Clinical Study Register. Available online: www.gsk-clinicalstudyregister.com (accessed on 25 October 2022).
  22. ISI Web of Knowledge, Journal Citation Reports, Thomson Reuters. Available online: https://jcr.clarivate.com/ (accessed on 14 October 2022).
  23. ISI Web of Science, Thomson Reuters. Available online: http://www.isiknowledge.com (accessed on 25 October 2022).
  24. van Driel, W.J.; Koole, S.N.; Sikorska, K.; Schagen van Leeuwen, J.H.; Schreuder, H.W.R.; Hermans, R.H.M.; de Hingh, I.; van der Velden, J.; Arts, H.J.; Massuger, L.; et al. Hyperthermic Intraperitoneal Chemotherapy in Ovarian Cancer. N. Engl. J. Med. 2018, 378, 230–240. [Google Scholar] [CrossRef]
  25. Lim, M.C.; Chang, S.J.; Park, B.; Yoo, H.J.; Yoo, C.W.; Nam, B.H.; Park, S.Y.; Collaborators, H.f.O.C. Survival After Hyperthermic Intraperitoneal Chemotherapy and Primary or Interval Cytoreductive Surgery in Ovarian Cancer: A Randomized Clinical Trial. JAMA Surg. 2022, 157, 374–383. [Google Scholar] [CrossRef]
  26. Quenet, F.; Elias, D.; Roca, L.; Goere, D.; Ghouti, L.; Pocard, M.; Facy, O.; Arvieux, C.; Lorimier, G.; Pezet, D.; et al. Cytoreductive surgery plus hyperthermic intraperitoneal chemotherapy versus cytoreductive surgery alone for colorectal peritoneal metastases (PRODIGE 7): A multicentre, randomised, open-label, phase 3 trial. Lancet Oncol. 2021, 22, 256–266. [Google Scholar] [CrossRef]
  27. Goere, D.; Glehen, O.; Quenet, F.; Guilloit, J.M.; Bereder, J.M.; Lorimier, G.; Thibaudeau, E.; Ghouti, L.; Pinto, A.; Tuech, J.J.; et al. Second-look surgery plus hyperthermic intraperitoneal chemotherapy versus surveillance in patients at high risk of developing colorectal peritoneal metastases (PROPHYLOCHIP-PRODIGE 15): A randomised, phase 3 study. Lancet Oncol. 2020, 21, 1147–1154. [Google Scholar] [CrossRef]
  28. Alistar, A.; Morris, B.B.; Desnoyer, R.; Klepin, H.D.; Hosseinzadeh, K.; Clark, C.; Cameron, A.; Leyendecker, J.; D’Agostino, R., Jr.; Topaloglu, U.; et al. Safety and tolerability of the first-in-class agent CPI-613 in combination with modified FOLFIRINOX in patients with metastatic pancreatic cancer: A single-centre, open-label, dose-escalation, phase 1 trial. Lancet Oncol. 2017, 18, 770–778. [Google Scholar] [CrossRef]
  29. Klaver, C.E.L.; Wisselink, D.D.; Punt, C.J.A.; Snaebjornsson, P.; Crezee, J.; Aalbers, A.G.J.; Brandt, A.; Bremers, A.J.A.; Burger, J.W.A.; Fabry, H.F.J.; et al. Adjuvant hyperthermic intraperitoneal chemotherapy in patients with locally advanced colon cancer (COLOPEC): A multicentre, open-label, randomised trial. Lancet Gastroenterol. Hepatol. 2019, 4, 761–770. [Google Scholar] [CrossRef]
  30. Stewart, J.H.t.; Shen, P.; Russell, G.; Fenstermaker, J.; McWilliams, L.; Coldrun, F.M.; Levine, K.E.; Jones, B.T.; Levine, E.A. A phase I trial of oxaliplatin for intraperitoneal hyperthermic chemoperfusion for the treatment of peritoneal surface dissemination from colorectal and appendiceal cancers. Ann. Surg. Oncol. 2008, 15, 2137–2145. [Google Scholar] [CrossRef] [Green Version]
  31. Badgwell, B.; Ikoma, N.; Murphy, M.B.; Wang, X.; Estrella, J.; Roy-Chowdhuri, S.; Das, P.; Minsky, B.D.; Lano, E.; Song, S.; et al. A Phase II Trial of Cytoreduction, Gastrectomy, and Hyperthermic Intraperitoneal Perfusion with Chemotherapy for Patients with Gastric Cancer and Carcinomatosis or Positive Cytology. Ann. Surg. Oncol. 2021, 28, 258–264. [Google Scholar] [CrossRef]
  32. Franko, J.; Brahmbhatt, R.; Tee, M.; Raman, S.; Ferrel, B.; Gorvet, M.; Andres, M. Cellular Immunoprofile of Peritoneal Environment During a HIPEC Procedure. Ann. Surg. Oncol. 2020, 27, 5005–5013. [Google Scholar] [CrossRef]
  33. Baratti, D.; Kusamura, S.; Iusco, D.; Gimondi, S.; Pietrantonio, F.; Milione, M.; Guaglio, M.; Bonomi, S.; Grassi, A.; Virzi, S.; et al. Hyperthermic Intraperitoneal Chemotherapy (HIPEC) at the Time of Primary Curative Surgery in Patients with Colorectal Cancer at High Risk for Metachronous Peritoneal Metastases. Ann. Surg. Oncol. 2017, 24, 167–175. [Google Scholar] [CrossRef]
  34. Yurttas, C.; Horvath, P.; Fischer, I.; Meisner, C.; Nadalin, S.; Konigsrainer, I.; Konigsrainer, A.; Beckert, S.; Loffler, M.W. A Prospective, Phase I/II, Open-Label Pilot Trial to Assess the Safety of Hyperthermic Intraperitoneal Chemotherapy After Oncological Resection of Pancreatic Adenocarcinoma. Ann. Surg. Oncol. 2021, 28, 9086–9095. [Google Scholar] [CrossRef]
  35. Chua, T.C.; Morris, D.L.; Saxena, A.; Esquivel, J.; Liauw, W.; Doerfer, J.; Germer, C.T.; Kerscher, A.G.; Pelz, J.O. Influence of modern systemic therapies as adjunct to cytoreduction and perioperative intraperitoneal chemotherapy for patients with colorectal peritoneal carcinomatosis: A multicenter study. Ann. Surg. Oncol. 2011, 18, 1560–1567. [Google Scholar] [CrossRef] [PubMed]
  36. Goere, D.; Malka, D.; Tzanis, D.; Gava, V.; Boige, V.; Eveno, C.; Maggiori, L.; Dumont, F.; Ducreux, M.; Elias, D. Is there a possibility of a cure in patients with colorectal peritoneal carcinomatosis amenable to complete cytoreductive surgery and intraperitoneal chemotherapy? Ann. Surg. 2013, 257, 1065–1071. [Google Scholar] [CrossRef] [PubMed]
  37. Klaver, C.E.; Groenen, H.; Morton, D.G.; Laurberg, S.; Bemelman, W.A.; Tanis, P.J.; Research Committee of the European Society of Coloproctology. Recommendations and consensus on the treatment of peritoneal metastases of colorectal origin: A systematic review of national and international guidelines. Color. Dis. 2017, 19, 224–236. [Google Scholar] [CrossRef]
  38. Li, Y.; Yu, Y.; Liu, Y. Report on the 9(th) International Congress on Peritoneal Surface Malignancies. Cancer Biol. Med. 2014, 11, 281–284. [Google Scholar]
  39. Quenet, F.; Goere, D.; Mehta, S.S.; Roca, L.; Dumont, F.; Hessissen, M.; Saint-Aubert, B.; Elias, D. Results of two bi-institutional prospective studies using intraperitoneal oxaliplatin with or without irinotecan during HIPEC after cytoreductive surgery for colorectal carcinomatosis. Ann. Surg. 2011, 254, 294–301. [Google Scholar] [CrossRef]
  40. General Definition of Institution of Higher ed- Ucation, 20 USC ch 28, x1001 (2012). Available online: https://www.law.cornell.edu/uscode/text/ (accessed on 14 March 2023).
  41. Tse, T.; Fain, K.M.; Zarin, D.A. How to avoid common problems when using ClinicalTrials.gov in research: 10 issues to consider. BMJ 2018, 361, k1452. [Google Scholar] [CrossRef] [Green Version]
  42. Zarin, D.A.; Tse, T.; Williams, R.J.; Carr, S. Trial Reporting in ClinicalTrials.gov—The Final Rule. N. Engl. J. Med. 2016, 375, 1998–2004. [Google Scholar] [CrossRef] [Green Version]
  43. Anderson, M.L.; Chiswell, K.; Peterson, E.D.; Tasneem, A.; Topping, J.; Califf, R.M. Compliance with results reporting at ClinicalTrials.gov. N. Engl. J. Med. 2015, 372, 1031–1039. [Google Scholar] [CrossRef] [Green Version]
  44. DeVito, N.J.; Bacon, S.; Goldacre, B. Compliance with legal requirement to report clinical trial results on ClinicalTrials.gov: A cohort study. Lancet 2020, 395, 361–369. [Google Scholar] [CrossRef]
  45. Pereira, F.; Serrano, A.; Manzanedo, I.; Pérez-Viejo, E.; González-Moreno, S.; González-Bayón, L.; Arjona-Sánchez, A.; Torres, J.; Ramos, I.; Barrios, M.E.; et al. GECOP-MMC: Phase IV randomized clinical trial to evaluate the efficacy of hyperthermic intraperitoneal chemotherapy (HIPEC) with mytomicin-C after complete surgical cytoreduction in patients with colon cancer peritoneal metastases. BMC Cancer 2022, 22, 536. [Google Scholar] [CrossRef]
  46. Zarin, D.A.; Tse, T.; Williams, R.J.; Rajakannan, T. Update on Trial Registration 11 Years after the ICMJE Policy Was Established. N. Engl. J. Med. 2017, 376, 383–391. [Google Scholar] [CrossRef] [Green Version]
  47. Chan, A.W.; Altman, D.G. Epidemiology and reporting of randomised trials published in PubMed journals. Lancet 2005, 365, 1159–1162. [Google Scholar] [CrossRef] [PubMed]
  48. Meinert, C.L.; Tonascia, S.; Higgins, K. Content of reports on clinical trials: A critical review. Control Clin. Trials 1984, 5, 328–347. [Google Scholar] [CrossRef] [PubMed]
  49. Turaga, K.; Levine, E.; Barone, R.; Sticca, R.; Petrelli, N.; Lambert, L.; Nash, G.; Morse, M.; Adbel-Misih, R.; Alexander, H.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. 2014, 21, 1501–1505. [Google Scholar] [CrossRef] [PubMed]
Figure 1. Flow diagram of search for trials from ClinicalTrials.gov, adapted from the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement.
Figure 1. Flow diagram of search for trials from ClinicalTrials.gov, adapted from the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement.
Cancers 15 01926 g001
Figure 2. Cumulative number of clinical trials that started per year, that reported results to ClinicalTrials.gov, or that were published.
Figure 2. Cumulative number of clinical trials that started per year, that reported results to ClinicalTrials.gov, or that were published.
Cancers 15 01926 g002
Table 1. Characteristics of HIPEC trials registered in ClinicalTrials.gov.
Table 1. Characteristics of HIPEC trials registered in ClinicalTrials.gov.
CharacteristicsAll Trials Journal Publications Not Published in Journals
n = 234 (100%)n = 26 (11%)n = 208 (89%)
Results Reported Elsewhere No Results Available
n = 15 (6%)n = 193 (83%)
Primary purpose of trial
Treatment1581812128
Prevention131012
Diagnostic5005
Supportive care5005
Other a9126
Missing446137
Intervention type b
Drug1301610104
Procedural11413992
Biological3003
Behavioral5104
Device9009
Dietary supplement1001
Diagnostic Test6006
Radiation3003
Combination Product3012
Other334524
Missing120012
Funding b
Academic1951711167
Industry5005
Cancer foundation 4811631
Missing1001
Region b
Africa2002
Australia1001
Europe7914659
North America767960
Central and South America2101
Asia and Pacific534049
Middle East1001
Missing220022
Number of institutions/Collaboration
11701813139
29018
3–10203116
>10151014
Missing204016
Anticipated enrollment, No. of patients
1–94004
10–498812670
50–99577248
100–499757662
500–9997007
>10002011
Missing1001
Sex
Female only524444
Male only0000
Both1822211149
Age of study population
Children only1001
Children and adults180216
Adults only2152613176
Study type
Interventional1902014156
Observational446137
Allocation status c
Randomized909774
Nonrandomized203116
Missing808666
Interventional group
Single group8710671
Parallel10110883
Sequential1001
Missing1001
Blinding c
None (open label)1571812127
Single blind142111
Double blind9009
Triple blind6015
Quadruple blind3003
Missing1001
Trial phase
Phase I252023
Phase I/II10208
Phase II698655
Phase II/III5122
Phase III445336
Phase IV1001
Missing808468
Overall status
Not yet recruiting210021
Recruiting750372
Completed6318639
Suspended1001
Terminated15258
Withdrawn8008
Active, not recruiting143011
Enrolling by invitation1001
Unknown status363132
Length of study conduct
<1 y143011
1–2 y294025
2–5 y937680
5–10 y7911860
>10 y161114
Missing3003
Primary Outcome d
Efficacy123149100
Safety7912463
Feasibility211416
Pharmacodynamics/pharmacokinetics294025
Quality of life of patients9108
Other e373331
a Includes health services research and basic science. b Percentages may not add up to 100%, as categories are not mutually exclusive. c Only collected for interventional studies. d Trials could have >1 therapeutic focus. For analysis, each therapeutic focus was treated as a binary variable. e Includes lab draws (inflammatory parameters, biomarkers etc.), tumoral biopsy tissue, microbiome, and diagnostic.
Table 2. Number of clinical trials involving different drugs by neoplasia site.
Table 2. Number of clinical trials involving different drugs by neoplasia site.
Colorectal a
(n = 67)
Ovarian a
(n = 61)
Gastric a
(n = 54)
Primary Peritoneal a
(n = 35)
From Each Origin a,b
(n = 33)
Appendiceal a
(n = 21)
Fallopian Tube a
(n = 20)
Non-Carcinoma Tumors a,c
(n = 8)
Pancreatic a
(n = 7)
Uterine a
(n = 5)
Cervical a
(n = 3)
Bile Duct Cancer a,d
(n = 2)
Small Intestine a
(n = 1)
Bladder a
(n = 1)
Used drugs, n (%) e
Cisplatin4 (6)20 (33)16 (30)11 (31)5 (15)1 (5)9 (45)3 (38)2 (29)1 (20)0 (0)0 (0)0 (0)0 (0)
Mitomycin C 18 (27)7 (11)15 (28)7 (20)2 (6)7 (33)4 (20)2 (25)2 (29)3 (60)3 (100)1 (50)1 (100)1 (100)
Irinotecan3 (4)0 (0)3 (6)1 (3)0 (0)0 (0)0 (0)0 (0)0 (0)0 (0)0 (0)0 (0)0 (0)0 (0)
Doxorubicin1 (1)5 (8)3 (6)1 (3)0 (0)1 (0)3 (15)3 (38)1 (14)2 (40)2 (67)1 (50)1 (100)0 (0)
Paclitaxel1 (1)8 (13)18 (33)2 (6)1 (3)0 (0)3 (15)0 (0)0 (0)0 (0)0 (0)0 (0)0 (0)0 (0)
Oxaliplatin13 (19)2 (3)6 (11)4 (11)0 (0)3 (14)0 (0)0 (0)0 (0)0 (0)0 (0)0 (0)0 (0)0 (0)
5-Fluorouracil3 (4)0 (0)3 (6)1 (3)1 (3)0 (0)0 (0)0 (0)0 (0)0 (0)0 (0)0 (0)0 (0)0 (0)
Docetaxel0 (0)3 (5)3 (6)1 (3)0 (0)0 (0)1 (5)0 (0)0 (0)0 (0)0 (0)0 (0)0 (0)0 (0)
Lobaplatin2 (3)1 (2)2 (4)0 (0)0 (0)0 (0)0 (0)0 (0)0 (0)0 (0)0 (0)0 (0)0 (0)0 (0)
Carboplatin1 (1)12 (20)1 (2)6 (17)1 (3)0 (0)8 (40)0 (0)0 (0)1 (20)0 (0)0 (0)0 (0)0 (0)
Anti-PD-1 antibody0 (0)0 (0)1 (2)0 (0)0 (0)0 (0)0 (0)0 (0)0 (0)0 (0)0 (0)0 (0)0 (0)0 (0)
Thalidomide2 (3)0 (0)0 (0)0 (0)0 (0)1 (5)0 (0)0 (0)0 (0)0 (0)0 (0)0 (0)0 (0)0 (0)
Leucovorin1 (1)0 (0)0 (0)0 (0)0 (0)1 (5)0 (0)0 (0)0 (0)0 (0)0 (0)0 (0)0 (0)0 (0)
Melphalan1 (1)0 (0)0 (0)0 (0)0 (0)1 (5)0 (0)0 (0)0 (0)0 (0)0 (0)0 (0)0 (0)0 (0)
MOC31PE1 (1)0 (0)0 (0)0 (0)0 (0)0 (0)0 (0)0 (0)0 (0)0 (0)0 (0)0 (0)0 (0)0 (0)
Capecitabine1 (1)0 (0)0 (0)0 (0)0 (0)0 (0)0 (0)0 (0)0 (0)0 (0)0 (0)0 (0)0 (0)0 (0)
Raltitrexed2 (3)0 (0)0 (0)0 (0)0 (0)0 (0)0 (0)0 (0)0 (0)0 (0)0 (0)0 (0)0 (0)0 (0)
Pasireotide1 (1)1 (2)0 (0)1 (3)0 (0)0 (0)0 (0)0 (0)0 (0)0 (0)0 (0)0 (0)0 (0)0 (0)
Gemcitabine0 (0)1 (2)1 (2)1 (3)0 (0)0 (0)1 (5)1 (13)3 (42)1 (20)0 (0)1 (50)0 (0)0 (0)
Cantrixil0 (0)1 (2)0 (0)0 (0)0 (0)0 (0)1 (5)0 (0)0 (0)0 (0)0 (0)0 (0)0 (0)0 (0)
Missing2 (3)1 (2)0 (0)1 (3)24 (75)11 (52)0 (0)1 (13)1 (14)1 (20)0 (0)0 (0)0 (0)0 (0)
Allocation status
Randomized27 (40)22 (36)21 (39)10 (29)12 (36)6 (29)5 (25)0 (0)2 (29)0 (0)0 (0)1 (50)0 (0)0 (0)
Nonrandomized5 (8)9 (15)1 (2)3 (8)2 (6)3 (14)2 (10)2 (25)3 (42)2 (40)2 (67)1 (50)1 (100)0 (0)
Missing35 (52)30 (49)32 (59)22 (63)19 (58)12 (57)13 (65)6 (75)2 (29)3 (60)1 (33)0 (0)0 (0)1 (100)
Trial phase, n (%)
Phase I7 (10)11 (18)4 (7)7 (20)1 (3)2 (10)5 (25)3 (37.5)1 (14)1 (20)0 (0)0 (0)0 (0)0 (0)
Phase I/II4 (6)2 (3)3 (6)3 (8)0 (0)0 (0)1 (5)0 (0)0 (0)0 (0)0 (0)0 (0)0 (0)0 (0)
Phase II17 (25)19 (31)21 (39)12 (35)5 (15)8 (38)8 (40)3 (37.5)4 (58)2 (40)2 (67)2 (100)1 (100)0 (0)
Phase II/III2 (3)0 (0)1 (2)0 (0)0 (0)1 (5)0 (0)0 (0)1 (14)0 (0)0 (0)0 (0)0 (0)0 (0)
Phase III11 (17)12 (20)13 (24)3 (8)3 (9)0 (0)3 (15)0 (0)0 (0)0 (0)0 (0)0 (0)0 (0)0 (0)
Phase IV1 (1)0 (0)0 (0)0 (0)0 (0)0 (0)0 (0)0 (0)0 (0)0 (0)0 (0)0 (0)0 (0)0 (0)
Missing25 (38)17 (28)12 (22)10 (29)24 (73)10 (47)3 (15)2 (25)1 (14)2 (40)1 (33)0 (0)0 (0)1 (100)
a The number of trials indicates in how many of the 208 ongoing trials the tumor entity was analyzed, if this is comprehensible. Number of trials may not add up to 208 because trials could use >1 type of neoplasia. For analysis, each type of neoplasia was treated as a binary variable. b These trials did not differentiate which neoplasia types were involved. c Histologically proven diffuse peritoneal or retroperitoneal tumor from the following histology: desmoplastic round cell tumor, ovarian germ cell, sarcoma, rhabdomyosarcoma, Wilms’ tumor, late-stage neuroblastoma, or other non-carcinoma tumors. d Include Gallbladder cancer and cholangiocarcinoma of the extrahepatic bile duct or liver e Percentages may not add up to 100% because trials could have used >1 drug. For analysis, each drug was treated as a binary variable.
Table 3. Ongoing phase III and IV trials.
Table 3. Ongoing phase III and IV trials.
ClinicalTrials.Gov Trial ID PhaseTreatment Allocation Number of ParticipantsPrimary Purpose of TrialCondition or DiseaseChemotherapy DrugsTrial Status
NCT00052962Phase IIIRandomized30TreatmentPeritoneal carcinomatosis from each originCisplatinCompleted
NCT04981639Phase IIIRandomized72Supportive carePeritoneal carcinomatosis from each originN/ARecruiting
NCT03359811Phase IIIRandomized75TreatmentPeritoneal carcinomatosis from each originN/ACompleted
NCT03180177Phase IIIRandomized263TreatmentPrimary peritoneal carcinoma AND Ovarian AND Tube carcinomaPaclitaxel AND/OR cisplatinNot yet recruiting
NCT03373058Phase IIIRandomized310TreatmentPrimary peritoneal carcinoma AND Ovarian AND Tube carcinomaDocetaxel AND/OR Cisplatin Recruiting
NCT02328716Phase IIIRandomized32OtherPrimary peritoneal carcinoma AND Ovarian AND Tube carcinomaCisplatinUnknown status
NCT01628380Phase IIIRandomized94TreatmentOvarian cancerCisplatin AND Paclitaxel Unknown status
NCT02681432Phase IIIRandomized60TreatmentOvarian cancerPaclitaxel Unknown status
NCT03220932Phase IIIRandomized132TreatmentOvarian cancerCisplatinNot yet recruiting
NCT03371693Phase IIIRandomized112TreatmentOvarian cancerLobaplatin Active, not recruiting
NCT03717610Phase IIIN/A10TreatmentOvarian cancerMitomycin CRecruiting
NCT03842982Phase IIIRandomized362TreatmentOvarian cancerN/ARecruiting
NCT04473339Phase IIIRandomized280TreatmentOvarian cancerN/ARecruiting
NCT04111978Phase IIIRandomized540TreatmentOvarian cancerN/ARecruiting
NCT01376752Phase IIIRandomized415TreatmentRecurrent ovarian cancerCisplatinActive, not recruiting
NCT02158988Phase IIIRandomized105TreatmentGastric cancerMitomycin C AND/OR CisplatinCompleted
NCT02240524Phase IIIRandomized582TreatmentGastric cancerPaclitaxelUnknown status
NCT02356276Phase IIIRandomized584TreatmentGastric cancerPaclitaxelUnknown status
NCT02381847Phase IIIRandomized60TreatmentGastric cancerCisplatinUnknown status
NCT02960061Phase IIIRandomized640TreatmentGastric cancerPaclitaxel Unknown status
NCT03179579Phase IIIRandomized88TreatmentGastric cancerPaclitaxel AND/OR CisplatinNot yet recruiting
NCT03917173Phase IIIRandomized240TreatmentGastric cancerMitomycin C AND CisplatinRecruiting
NCT04447352Phase IIIRandomized200TreatmentGastric cancerCisplatinRecruiting
NCT04597294Phase IIIRandomized600PreventionGastric cancerIrinotecanRecruiting
NCT03772028Phase IIIRandomized538TreatmentGastric cancerMitomycin CRecruiting
NCT01882933Phase IIIRandomized367TreatmentGastric cancerOxaliplatinActive, not recruiting
NCT03023436Phase IIIN/A220TreatmentGastric cancerCisplatinRecruiting
NCT03348150Phase IIIRandomized182TreatmentGastric cancerOxaliplatin AND DocetaxelRecruiting
NCT02614534Phase IIIRandomized200TreatmentColorectal cancerMitomycin CActive, not recruiting
NCT02179489Phase IIIRandomized300TreatmentColorectal cancerMitomycin CRecruiting
NCT02965248Phase IIIRandomized147TreatmentColorectal cancerOxaliplatinRecruiting
NCT02974556Phase IIIRandomized140PreventionColorectal cancerOxaliplatin Not yet recruiting
NCT03028155Phase IIIRandomized60TreatmentColorectal cancerOxaliplatinUnknown status
NCT03221608Phase IIIRandomized300PreventionColorectal cancerLobaplatinNot yet recruiting
NCT03413254Phase IIIRandomized389DiagnosticColorectal cancerN/ARecruiting
NCT03914820Phase IIIRandomized330TreatmentColorectal cancerMitomycin CRecruiting
NCT04370925Phase IIIRandomized688TreatmentColorectal cancerMitomycin CRecruiting
NCT04861558Phase IIIRandomized356TreatmentColorectal cancer5 Fluorouracil AND/OR Irinotecan AND/OR OxaliplatinRecruiting
NCT03733184Phase IIIN/A200N/AColorectal cancerMitomycin CUnknown status
NCT05250648Phase IVRandomized216TreatmentColorectal cancerMytomicin CNot yet recruiting
NR/NA: not reported or not applicable. Peritoneal metastases from each origin (from gastric, colorectal, appendiceal, hepatopancreatic, uterine or ovarian cancers or primary peritoneal tumors). Data gathered on 1 October 2022.
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MDPI and ACS Style

Ukegjini, K.; Guidi, M.; Lehmann, K.; Süveg, K.; Putora, P.M.; Cihoric, N.; Steffen, T. Current Research and Development in Hyperthermic Intraperitoneal Chemotherapy (HIPEC)—A Cross-Sectional Analysis of Clinical Trials Registered on ClinicalTrials.gov. Cancers 2023, 15, 1926. https://doi.org/10.3390/cancers15071926

AMA Style

Ukegjini K, Guidi M, Lehmann K, Süveg K, Putora PM, Cihoric N, Steffen T. Current Research and Development in Hyperthermic Intraperitoneal Chemotherapy (HIPEC)—A Cross-Sectional Analysis of Clinical Trials Registered on ClinicalTrials.gov. Cancers. 2023; 15(7):1926. https://doi.org/10.3390/cancers15071926

Chicago/Turabian Style

Ukegjini, Kristjan, Marisa Guidi, Kuno Lehmann, Krisztian Süveg, Paul Martin Putora, Nikola Cihoric, and Thomas Steffen. 2023. "Current Research and Development in Hyperthermic Intraperitoneal Chemotherapy (HIPEC)—A Cross-Sectional Analysis of Clinical Trials Registered on ClinicalTrials.gov" Cancers 15, no. 7: 1926. https://doi.org/10.3390/cancers15071926

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