HIPEC: HOPE or HYPE in the fight against advanced ovarian cancer?
Authors: C. Fotopoulou, J. Sehouli, S. Mahner, P. Harter, E. Van Nieuwenhuysen, A. Gonzalez-Martin, I. Vergote, L. Chiva, A. Du Bois
Journal: Annals of Oncology (2018)

Undergoing an era of revolutionary new knowledge and advances in the systemic and surgical treatment of peritoneally disseminated epithelial ovarian cancer (EOC), we never before have been confronted with such a plethora of novel targeted agents, genetically based treatment strategies and cutting edge surgical techniques that enrich our armamentarium in the fight against this deadly disease [1.Bowtell D.D. Böhm S. Ahmed A.A. et al.Rethinking ovarian cancer II: reducing mortality from high-grade serous ovarian cancer.Nat Rev Cancer. 2015; 15: 668-679Crossref PubMed Scopus (663) Google Scholar, 2.Ledermann J.A. Front-line therapy of advanced ovarian cancer: new approaches.Ann Oncol. 2017; 28: viii46-viii50Abstract Full Text Full Text PDF PubMed Scopus (39) Google Scholar, 3.Monk B.J. Facciabene A. Brady W.E. et al.Integrative development of a TLR8 agonist for ovarian cancer chemoimmunotherapy.Clin Cancer Res. 2017; 23: 1955-1966Crossref PubMed Scopus (25) Google Scholar]. Still, our art as clinicians is to put all this new body of knowledge into the right context so that we can help our patients without compromising their care through an enthusiastic effort of implementing new therapeutic approaches that are not yet sufficiently validated or confirmed. A characteristic example of such an enthusiastic endeavor is the incorporation of hyperthermic-intraperitoneal-chemotherapy (HIPEC) in the multimodal treatment concept of advanced EOC. It has already been implemented since years without any acceptable level of evidence from a controlled randomized trial. Has this gap now been closed and is HIPEC ready for prime time? HIPEC has been developed in an effort to combine the advantages of loco-regional delivery of chemotherapy with surgical radicality [4.Sugarbaker P.H. Surgical management of peritoneal carcinosis: diagnosis, prevention and treatment.Langenbecks Arch Chir. 1988; 373: 189-196Crossref PubMed Scopus (61) Google Scholar, 5.Spratt J.S. Adcock R.A. Muskovin M. et al.Clinical delivery system for intraperitoneal hyperthermic chemotherapy.Cancer Res. 1980; 40: 256-260PubMed Google Scholar]. Its application was first described in humans in 1979 in a 35-year-old man with pseudomyxoma peritonei [5.Spratt J.S. Adcock R.A. Muskovin M. et al.Clinical delivery system for intraperitoneal hyperthermic chemotherapy.Cancer Res. 1980; 40: 256-260PubMed Google Scholar]. The presumed benefit is that extensive peritonectomy allows macroscopic cytoreduction of peritoneal implants which, when combined with heated intraperitoneal chemotherapy, provides 'an avenue for further microscopic cytoreduction' as described by Sugarbaker three decades ago [4.Sugarbaker P.H. Surgical management of peritoneal carcinosis: diagnosis, prevention and treatment.Langenbecks Arch Chir. 1988; 373: 189-196Crossref PubMed Scopus (61) Google Scholar]. Up to now we did not have any high-quality evidence that HIPEC would positively affect survival in advanced EOC compared with surgery alone. The only prospective randomized trial in the recurrent setting has been widely criticized [6.Spiliotis J. Vaxevanidou A. Sergouniotis F. et al.The role of cytoreductive surgery and hyperthermic intraperitoneal chemotherapy in the management of recurrent advanced ovarian cancer: a prospective study.J Buon. 2011; 16: 74-79PubMed Google Scholar, 7.Harter P. Reuss A. Sehouli J. et al.Brief report about the role of hyperthermic intraperitoneal chemotherapy in a prospective randomized phase 3 Study in recurrent ovarian cancer from Spiliotis et al.Int J Gynecol Cancer. 2017; 27: 246-247Crossref PubMed Scopus (30) Google Scholar, 8.Sanz Rubiales Á Del Valle M.L. Survival analysis in a randomized trial of HIPEC in ovarian cancer.Ann Surg Oncol. 2017; 24: 631.Crossref PubMed Scopus (4) Google Scholar, 9.Batista T.P. Comment on: surgery and HIPEC in recurrent epithelial ovarian cancer: a prospective randomized phase III study.Ann Surg Oncol. 2017; 24: 630.Crossref PubMed Scopus (17) Google Scholar], while a large meta-analysis failed to identify any survival benefit [10.Chiva L.M. Gonzalez-Martin A. A critical appraisal of hyperthermic intraperitoneal chemotherapy (HIPEC) in the treatment of advanced and recurrent ovarian cancer.Gynecol Oncol. 2015; 136: 130-135Abstract Full Text Full Text PDF PubMed Scopus (67) Google Scholar]. For that reason, HIPEC data were not accepted within the scientific gynecologic oncology community [11.Harter P. du Bois A. Mahner S. et al.Statement of the AGO Kommission Ovar, AGO Study Group, NOGGO, AGO Austria and AGO Switzerland Regarding the Use of Hyperthermic Intraperitoneal Chemotherapy (HIPEC) in Ovarian Cancer.Geburtshilfe Frauenheilkd. 2016; 76: 147-149Crossref PubMed Scopus (11) Google Scholar]. At the fifth Ovarian Cancer Consensus Conference held in Tokyo, in November 2015, the recommendation of key opinion leaders was to conduct well-designed clinical trials on important topics in an attempt to establish—or not—any clinical rationale [12.Karam A. Ledermann J.A. Kim J.W. Participants of the 5th Ovarian Cancer Consensus Conference et al.Fifth Ovarian Cancer Consensus Conference of the Gynecologic Cancer InterGroup: first-line interventions.Ann Oncol. 2017; 28: 711-717Abstract Full Text Full Text PDF PubMed Scopus (96) Google Scholar]. van Driel and her team published in January 2018 a multicenter, open-label, phase III randomized trial, in which 245 patients with initially presumed inoperable EOC were randomly assigned to undergo or not undergo HIPEC at their interval debulking surgery (IDS), if not having progressed after three cycles of neoadjuvant chemotherapy (NAC) [13.van Driel W.J. Koole S.N. Sikorska K. et al.Hyperthermic intraperitoneal chemotherapy in ovarian cancer.N Engl J Med. 2018; 378: 230-240Crossref PubMed Scopus (786) Google Scholar]. The study reported a statistically significant progression-free survival (PFS) and overall survival (OS) benefit of HIPEC + IDS without significant increase of surgical morbidity and mortality. Even though these results appear very encouraging and would potentially prompt clinicians and patients to strive a combined maximal surgical effort with HIPEC in all settings of the disease, we agree with the authors of the editorial accompanying the original article [14.Spriggs D.R. Zivanovic O. Ovarian cancer treatment—are we getting warmer?.N Engl J Med. 2018; 378: 293-294Crossref PubMed Scopus (25) Google Scholar], that we need to exercise a high degree of caution not to extrapolate to all EOC patients positive data from a study that applies to only a rather small sub-cohort of EOC patients that has significant pitfalls. HIPEC is spreading currently in European and worldwide clinical practice in ovarian cancer without any robust evidence, possibly being harmful for a range of patients, so we need as body of experts to give an evaluation of its presumed merits. The following shortcomings must be considered: (1) Design of the study and end points. For this type of trial, the primary—or at least co-primary end point should have been OS, in which case the trial would have been larger and reliable enough to exclude significant bias. OS was analyzed at the time when the primary end point PFS was reached. At that time, 44% of the patients were still alive, resulting in 'only' 137 deaths (76 in the control arm and 61 in the HIPEC arm), with a clear imbalance in the PFS/OS improvement ratio: the median OS-benefit was 12 months versus only a 3.5-month PFS-benefit in favor of the HIPEC-arm. The investigators failed to report on other interesting outcome measures such as rates of complete and partial response and details of surgical procedures. We wonder whether the open label study has influenced the surgical quality that is hence difficult to be assessed. Inconsistencies in the determination and description of the actual study design shake additionally the credibility of the study's message: the recruitment database is indicated as closed on 31 March 2017 in the main publication, but on 5 April 2017 in the supplement, while the minimum number of events was reached in April 2016. These inconsistencies rely possibly on the fact that in 2016, directly after end of recruitment, the number of planned patients was decreased with no obvious reason from 280 to 242 [15.https://clinicaltrials.gov/archive/NCT00426257/2016_05_23/changes (23 May 2016, date last accessed).Google Scholar]. In the original sample size planning, the authors assumed a median PFS of 18 versus 27 months in the two arms. Even though at the final analysis HR was close to what the study investigators expected, the observed median PFS values (10.7 versus 14.2 months) were about half of the initially expected values. Interestingly, some randomizations took place before surgery; the large differences in bowel resection and stoma rates between both arms may therefore be due to a bias of the surgeon already knowing the randomization result. (2) Study design addressing only a small population of EOC patients. The mentioned study defined as eligible patients those with newly diagnosed stage III EOC that were referred for NAC + IDS± HIPEC in specialized centers in the Netherlands because 'their abdominal disease was too extensive for primary cytoreductive surgery or because incomplete surgery was carried out with residual disease >1 cm' [13.van Driel W.J. Koole S.N. Sikorska K. et al.Hyperthermic intraperitoneal chemotherapy in ovarian cancer.N Engl J Med. 2018; 378: 230-240Crossref PubMed Scopus (786) Google Scholar]. There is, however, no definition of the criteria of inoperability and how patients were allocated to NAC. So, looking at the bigger picture of all advanced EOC patients let us estimate how many of advanced EOC patients this study really addresses. The study excluded all stage IV patients, hence excluding at least one-third of all advanced EOC patients [16.Clamp A. McNeish I. Dean A. et al.ICON8: a GCIG phase III randomised trial evaluating weekly dose-dense chemotherapy integration in first-line epithelial ovarian/fallopian tube/primary peritoneal carcinoma (EOC) treatment: results of primary progression-free survival (PFS) analysis.Program and abstracts of the European Society for Medical Oncology 2017 Congress. 2017; Google Scholar]. The investigators did not clarify how they determined or even excluded stage IV disease. With preoperative imaging getting more refined, we diagnose today more commonly stage IV lesions than in the past, with the disease often remaining resectable after all, as for example in the case of extra-abdominal lymph nodes and parenchymatous liver- or spleen-metastases [17.Ataseven B. Chiva L.M. Harter P. et al.FIGO stage IV epithelial ovarian, fallopian tube and peritoneal cancer revisited.Gynecol Oncol. 2016; 142: 597-607Abstract Full Text Full Text PDF PubMed Scopus (52) Google Scholar, 18.Prader S. Harter P. Grimm C. et al.Surgical management of cardiophrenic lymph nodes in patients with advanced ovarian cancer.Gynecol Oncol. 2016; 141: 271-275Abstract Full Text Full Text PDF PubMed Scopus (39) Google Scholar]. From the two-thirds remaining patients; ∼10% will be fragile with a poor performance status unable to undergo radical surgical cytoreduction, even less with the addition of HIPEC [19.Heitz F. Harter P. Alesina P. et al.Pattern of and reason for postoperative residual disease in patients with advanced ovarian cancer following upfront radical debulking surgery.Gynecol Oncol. 2016; 141: 264-270Abstract Full Text Full Text PDF PubMed Scopus (38) Google Scholar]. That leaves us with less than ∼50% of all advanced EOC patients. From those, the majority can be cytoreduced to ≤10 mm residual disease in an upfront setting in appropriately trained and specialized cancer centers [19.Heitz F. Harter P. Alesina P. et al.Pattern of and reason for postoperative residual disease in patients with advanced ovarian cancer following upfront radical debulking surgery.Gynecol Oncol. 2016; 141: 264-270Abstract Full Text Full Text PDF PubMed Scopus (38) Google Scholar, 20.Chiva L. Lapuente F. Castellanos T. et al.What should we expect after a complete cytoreduction at the time of interval or primary debulking surgery in advanced ovarian cancer?.Ann Surg Oncol. 2016; 23: 1666-1673Crossref PubMed Scopus (41) Google Scholar, 21.Fotopoulou C. Jones B.P. Savvatis K. et al.Maximal effort cytoreductive surgery for disseminated ovarian cancer in a UK setting: challenges and possibilities.Arch Gynecol Obstet. 2016; 294: 607-614Crossref PubMed Scopus (24) Google Scholar], leaving us with <10% of all patients with advanced EOC that would theoretically fulfill the eligibility criteria of the van Driel study. The 'super-selection' of patients in this trial is reflected in the fact that even though mainly large volume and highly specialized cancer centers participated in this study, only an average of 3.5 patients per year per center were recruited [13.van Driel W.J. Koole S.N. Sikorska K. et al.Hyperthermic intraperitoneal chemotherapy in ovarian cancer.N Engl J Med. 2018; 378: 230-240Crossref PubMed Scopus (786) Google Scholar]. How justified would it be to extrapolate data that theoretically affect a minority of the entire patients' population to all EOC patients and generically claim that HIPEC has now an established value and survival benefit in the multimodal management of this challenging disease? (3) Heterogeneity of the results between the various study centers. A 43% of the patients were recruited by one center alone, namely the Netherlands Cancer Institute with the recruitment numbers of the remaining centers being comparatively small (see Figure 1). The study did not account for such small recruitment numbers and given the overall limited patients number, a spread within many small centers led to imbalances despite randomization. The fact that the study did not stratify for important prognosticators such as BRCA-status or histologic subtype further aggravate this. A forest plot for OS showed a favor of HIPEC in non-HGSOC with an HR of 0.31 as opposed to an HR of 0.76 in the HGSOC patients, which is of significant relevance since there is an imbalance of HGSOC and non-HGSOC in the two arms despite randomization. A further discrepancy we see are the outcomes per individual center reflecting the degree of expertise in a treatment modality not commonly familiar to gynecologic oncologists: the impact of HIPEC was lowest in the most actively recruiting center [13.van Driel W.J. Koole S.N. Sikorska K. et al.Hyperthermic intraperitoneal chemotherapy in ovarian cancer.N Engl J Med. 2018; 378: 230-240Crossref PubMed Scopus (786) Google Scholar]. In the small recruitment centers—where HR for survival seems more relevant, they did on average only one to two HIPEC cases per year within the study. It is unknown whether the same team would operate in both arms or whether 'HIPEC surgeons' had to step in after randomization to HIPEC. (4) Bias of evolving treatment strategies through slow recruitment. The study seemed to have large difficulties in recruiting since the team needed 9 years to recruit only 245 patients; as opposed to other recent surgical studies in EOC that successfully recruited considerable higher number of patients in shorter time periods; e.g. the AGO-DESKTOP-study (ENGOT-ov20; NCT01166737) recruited 408 patients within 4.5 years and the LION-study (AGO-OVAR OP3/ENGOT-ov31) 650 patients in only 3 years [22.Bois A.D. Vergote I. Ferron G. et al.Randomized controlled phase III study evaluating the impact of secondary cytoreductive surgery in recurrent ovarian cancer: AGO DESKTOP III/ENGOT ov20.J Clin Oncol. 2017; 35: 5501Crossref Google Scholar, 23.Harter P. Sehouli J. Lorusso D. et al.LION: lymphadenectomy in ovarian neoplasms—a prospective randomized AGO study group led gynecologic cancer intergroup trial.J Clin Oncol. 2017; 35: 5500Crossref Google Scholar]. This large discrepancy in recruitment and completion of the trial may be interpreted as surrogate marker for the quality of the study and the presence of strong selection bias. Most importantly, treatment modalities and surgical techniques change and evolve over the time period of a decade. (5) Underreported toxicity. Surprisingly, the authors report equivalent toxicity in both arms, even though the HIPEC patients received one additional course of cisplatin chemotherapy. Furthermore, the operation time was almost doubled in the HIPEC arm, with longer hospital stays and higher costs. A 4% of the patients in the HIPEC-arm underwent a gastrostomy; a very rare and morbid event in primary EOC-surgery. We wonder why no established surgical morbidity classification score (e.g. Clavien–Dindo) was used to report on these specific adverse events. Among patients who underwent a bowel resection, a stoma formation was carried out in 72% in the HIPEC-group as opposed to 43% in the surgery only group [13.van Driel W.J. Koole S.N. Sikorska K. et al.Hyperthermic intraperitoneal chemotherapy in ovarian cancer.N Engl J Med. 2018; 378: 230-240Crossref PubMed Scopus (786) Google Scholar]. The formation of a stoma is one of the main factors potentially affecting postoperative QoL. Furthermore, with stoma formation being associated with longer term complications such as herniation, fistulation, stenosis etc. [24.Tozzi R. Casarin J. Garruto-Campanile R. et al.Morbidity and reversal rate of ileostomy after bowel resection during Visceral-Peritoneal Debulking (VPD) in patients with stage IIIC-IV ovarian cancer.Gynecol Oncol. 2018; 148: 74-78Abstract Full Text Full Text PDF PubMed Scopus (21) Google Scholar] there is the risk of precluding those patients from receiving adjuvant treatment with antiangiogenetic targeted agents such as bevacizumab, which have been proved to significantly influence disease control in patients with high tumor load and residual disease [25.Perren T.J. Swart A.M. Pfisterer J. ICON7 Investigators et al.A phase 3 trial of bevacizumab in ovarian cancer.N Engl J Med. 2011; 365: 2484-2496Crossref PubMed Scopus (1601) Google Scholar]. Even though QoL-measurements did not seem to be overall negatively affected by the addition of HIPEC, we question why QoL and a surgical complication classification were not reported in detail in the van Driel study. The initially presumed survival benefit of intraperitoneal chemotherapy in EOC seem to have been over-ranked by newly emerging targeted therapies that are given systemically in a maintenance regimen. A good example is the GOG 252 study, where intraperitoneally applied cytotoxic chemotherapy failed to achieve any survival benefit in a multimodal treatment concept with systemic maintenance bevacizumab [26.Walker J.L. Brady M.F. DiSilvestro P.A. et al.A phase III trial of bevacizumab with IV versus IP chemotherapy in ovarian fallopian tube and peritoneal carcinoma NCI-supplied agent(s) a GOG/NRG trial (GOG 252).Society of Gynecologic Oncology Annual Meeting. 2016; Abstract Full Text Full Text PDF Google Scholar]. The results of the van Driel study are in contradiction with the recent results from the multicenter prospective randomized HIPEC-study by Lim and Bristow, which was also presented at ASCO 2017 and which was negative for both PFS and OS [27.Lim M.C. Chang S.-J. Yoo H.J. et al.Randomized trial of hyperthermic intraperitoneal chemotherapy (HIPEC) in women with primary advanced peritoneal, ovarian, and tubal cancer.J Clin Oncol. 2017; 35: 5520Crossref Google Scholar]. The difference between the two studies was that the Lim study had broader inclusion criteria allowing also upfront cytoreduction (only 39% received NAC), as long as postoperative residual disease was <1 cm. But even when evaluating the NAC patients separately, the median PFS for HIPEC- and control-group were 20 and 18 months (P = 0.137) with a median OS of 54 and 51 months (P = 0.407), respectively, and hence also not significantly different. The Lim study addressed a much larger patients' population than the van Driel one and was therefore much closer to the reality of the everyday treated EOC patients. Nevertheless, the colleagues who ran the Dutch HIPEC-trial in EOC deserve recognition for having conducted the first phase III randomized HIPEC-trial in a challenging patients' collective with initially inoperable stage III disease. We just need to be careful not to extrapolate these results to all advanced EOC patients. We must question ourselves as gynecologic oncology society whether the personal, financial and infrastructural resources that we are called to invest in an effort to maximize surgical benefit, is worth investing in broadly implementing HIPEC facilities or rather in training and implementing centralized centers and teams qualified to perform maximal effort cytoreductive surgery in and outside the peritoneal cavity in combination with novel systemic and maintenance regimens [28.Querleu D. Planchamp F. Chiva L. et al.European Society of Gynaecologic Oncology Quality Indicators for Advanced Ovarian Cancer Surgery.Int J Gynecol Cancer. 2016; 26: 1354-1363Crossref PubMed Scopus (79) Google Scholar]. This is an answer that we might obtain when the TRUST-trial (AGO-OVAR-OP.7, NCT02828618) will be reported [29.Mahner S. Heitz F. Burges A. et al.TRUST: trial of radical upfront surgical therapy in advanced ovarian cancer (ENGOT ov33/AGO‐OVAR OP7.J Clin Oncol. 2017; 35: TPS5602Crossref Google Scholar]. In the meantime, we cannot and should not as body of experts recommend implementation of HIPEC in the surgical treatment of all advanced EOC patients. None declared.