Hyperthermic intraperitoneal chemotherapy for ovarian cancer: long-term findings from the OVHIPEC-1 trial

In 2018, data from the first randomised controlled trial (OVHIPEC-1 trial) on the use of hyperthermic intraperitoneal chemotherapy (HIPEC) in ovarian cancer showed that, among patients with FIGO stage III cancer treated with neoadjuvant chemotherapy and interval debulking surgery, those who additionally received HIPEC with cisplatin 100 mg/m2 had a significant benefit in progression-free and overall survival compared with those who did not after a median follow-up period of 4·7 years.1van Driel WJ Koole SN Sikorska K et al.Hyperthermic intraperitoneal chemotherapy in ovarian cancer.N Engl J Med. 2018; 378: 230-240Crossref PubMed Scopus (897) Google Scholar After publication of the study, aspects of the trial's methodology (eg, the small sample size and lack of stratification for FIGO stage and BRCA mutational status) and results (eg, the higher rate of stomas in the HIPEC group and the HIPEC toxicity profile) were widely criticised, which led to a non-universal agreement on the oncological benefit of HIPEC.2Kim SI Kim JH Lee S et al.Hyperthermic intraperitoneal chemotherapy for epithelial ovarian cancer: a meta-analysis.Gynecol Oncol. 2022; 167: 547-556Summary Full Text Full Text PDF Scopus (0) Google Scholar However, some of the concerns raised by the gynaecological oncology community have since been resolved or explained.3Koole SN Schouten PC Hauke J et al.Effect of HIPEC according to HRD/BRCAwt genomic profile in stage III ovarian cancer: results from the phase III OVHIPEC trial.Int J Cancer. 2022; 151: 1394-1404Crossref PubMed Scopus (0) Google Scholar, 4Ghirardi V Ronsini C Trozzi R et al.Hyperthermic intraperitoneal chemotherapy in interval debulking surgery for advanced epithelial ovarian cancer: a single-center, real-life experience.Cancer. 2020; 126: 5256-5262Crossref PubMed Scopus (24) Google Scholar S Lot Aronson and colleagues' Article in The Lancet Oncology5Aronson SL Lopez-Yurda M Koole SN et al.Cytoreductive surgery with or without hyperthermic intraperitoneal chemotherapy in patients with advanced ovarian cancer (OVHIPEC-1): final survival analysis of a randomised, controlled, phase 3 trial.Lancet Oncol. 2023; 10: 1109-1118Google Scholar shows that the survival benefit in patients treated with HIPEC within the OVHIPEC-1 trial is maintained after follow-up periods of 10·1 years (95% CI 8·4–12·9) in the surgery group (n=123) and 10·4 years (9·5–13·3) in the surgery-plus-HIPEC group (n=122), with 10-year progression-free survival being 6·6% (95% CI 3·4–13·0) versus 10·1% (5·8–19·7) and 10-year overall survival being 10·9% (6·5–18·0) versus 16·1% (10·3–25·2). Moreover, although the proportion of patients with platinum-resistant disease seemed to be lower in the surgery-plus-HIPEC group (32 [26%]) than in the surgery group (49 [40%]), probably due to the delayed recurrence in patients who received HIPEC, this difference cannot explain the differences in survival outcomes, because the frequencies of patients receiving platinum-based chemotherapy or secondary cytoreductive surgeries after study treatments did not differ. Indeed, because this study5Aronson SL Lopez-Yurda M Koole SN et al.Cytoreductive surgery with or without hyperthermic intraperitoneal chemotherapy in patients with advanced ovarian cancer (OVHIPEC-1): final survival analysis of a randomised, controlled, phase 3 trial.Lancet Oncol. 2023; 10: 1109-1118Google Scholar showed similar rates of maintenance or post-recurrence treatments between the two populations, it is reasonable to conclude that the survival gain is due to HIPEC itself. In the 15 years since the start of OVHIPEC-1 trial,1van Driel WJ Koole SN Sikorska K et al.Hyperthermic intraperitoneal chemotherapy in ovarian cancer.N Engl J Med. 2018; 378: 230-240Crossref PubMed Scopus (897) Google Scholar new therapies have been shown to significantly change patient outcomes, potentially framing the results of Aronson and colleagues' study5Aronson SL Lopez-Yurda M Koole SN et al.Cytoreductive surgery with or without hyperthermic intraperitoneal chemotherapy in patients with advanced ovarian cancer (OVHIPEC-1): final survival analysis of a randomised, controlled, phase 3 trial.Lancet Oncol. 2023; 10: 1109-1118Google Scholar in an outdated context. Specifically, only three patients received PARP inhibitors as front-line maintenance therapy as part of the SOLO-1 trial6Banerjee S Moore KN Colombo N et al.Maintenance olaparib for patients with newly diagnosed advanced ovarian cancer and a BRCA mutation (SOLO1/GOG 3004): 5-year follow-up of a randomised, double-blind, placebo-controlled, phase 3 trial.Lancet Oncol. 2021; 22: 1721-1731Summary Full Text Full Text PDF PubMed Scopus (118) Google Scholar (for which the final results were published in 2018 and which was enrolling patients in the same period as the OVHIPEC-1 trial). Additionally, in both treatment groups, only around 10% of patients received PARP inhibitors and 10% received secondary cytoreduction at the time of recurrence, which could affect the interpretation of the results in view of the available evidence.6Banerjee S Moore KN Colombo N et al.Maintenance olaparib for patients with newly diagnosed advanced ovarian cancer and a BRCA mutation (SOLO1/GOG 3004): 5-year follow-up of a randomised, double-blind, placebo-controlled, phase 3 trial.Lancet Oncol. 2021; 22: 1721-1731Summary Full Text Full Text PDF PubMed Scopus (118) Google Scholar, 7Harter P Sehouli J Vergote I et al.Randomized trial of cytoreductive surgery for relapsed ovarian cancer.N Engl J Med. 2021; 385: 2123-2131Crossref PubMed Scopus (102) Google Scholar However, this limitation is potentially applicable to all randomised trials and should not be sufficient to consider the effect of HIPEC negligible. We must acknowledge that these results are confined to a restricted population of patients with FIGO stage III ovarian cancer who had received up to four cycles of neoadjuvant chemotherapy. Data are needed on the morbidity and survival outcomes of patients with FIGO stage IV disease or patients who received more than four cycles of neoadjuvant chemotherapy (or both), and such findings could expand the application of HIPEC to a considerable number of patients. In an era in which medicine is moving towards personalisation of treatment, the identification of biomarkers predictive of HIPEC efficacy is of utmost importance. Indeed, evidence on the efficacy of HIPEC in relation to BRCA1/2 homologous recombination deficiency mutational status showed that patients with homologous recombination deficient tumours without pathogenic BRCA1/2 mutations might benefit the most from this treatment, in comparison to patients with BRCA1/2-mutated tumours.3Koole SN Schouten PC Hauke J et al.Effect of HIPEC according to HRD/BRCAwt genomic profile in stage III ovarian cancer: results from the phase III OVHIPEC trial.Int J Cancer. 2022; 151: 1394-1404Crossref PubMed Scopus (0) Google Scholar, 5Aronson SL Lopez-Yurda M Koole SN et al.Cytoreductive surgery with or without hyperthermic intraperitoneal chemotherapy in patients with advanced ovarian cancer (OVHIPEC-1): final survival analysis of a randomised, controlled, phase 3 trial.Lancet Oncol. 2023; 10: 1109-1118Google Scholar Ideally, translational studies aiming to clarify the biological basis underlying HIPEC activity will result in the identification of more specific predictive factors. Moreover, the role of PARP inhibitors in patients treated with HIPEC remains unclear; it is unknown whether the benefit of first-line treatment with PARP inhibitors6Banerjee S Moore KN Colombo N et al.Maintenance olaparib for patients with newly diagnosed advanced ovarian cancer and a BRCA mutation (SOLO1/GOG 3004): 5-year follow-up of a randomised, double-blind, placebo-controlled, phase 3 trial.Lancet Oncol. 2021; 22: 1721-1731Summary Full Text Full Text PDF PubMed Scopus (118) Google Scholar is so significant that the effect of HIPEC might become negligible and its administration thus potentially avoidable in some patients. Use of neoadjuvant chemotherapy and time between the last cycle of neoadjuvant chemotherapy and surgery have also shown associations with the effect of HIPEC, suggesting that recent chemotherapy exposure could positively affect HIPEC's efficacy.2Kim SI Kim JH Lee S et al.Hyperthermic intraperitoneal chemotherapy for epithelial ovarian cancer: a meta-analysis.Gynecol Oncol. 2022; 167: 547-556Summary Full Text Full Text PDF Scopus (0) Google Scholar This suggestion is supported by results from the CHIPOR trial,8Classe J-M Meeus P Leblanc E et al.Hyperthermic intraperitoneal chemotherapy in platinum-sensitive relapsed epithelial ovarian cancer: the CHIPOR randomized phase III trial.Proc Am Soc Clin Oncol. 2023; 41 (abstr).5510Google Scholar which showed an improvement in progression-free and overall survival in patients with platinum-sensitive recurrent ovarian cancer who received platinum-based chemotherapy followed by secondary cytoreduction plus HIPEC compared with patients who received chemotherapy and secondary cytoreduction only. By contrast, HIPEC was not effective when added to secondary cytoreduction alone, without previous chemotherapy, in the setting of platinum-sensitive recurrent ovarian cancer.9Zivanovic O Chi DS Zhou Q et al.Secondary cytoreduction and carboplatin hyperthermic intraperitoneal chemotherapy for platinum-sensitive recurrent ovarian cancer: an MSK team ovary phase II study.J Clin Oncol. 2021; 39: 2594-2604Crossref PubMed Scopus (50) Google Scholar Whether recent receipt of intravenous chemotherapy is able to increase the effect of HIPEC or whether HIPEC works to target microscopic disease left behind after surgery (which can occur due to difficulties in distinguishing between miliary or microscopic carcinomatosis and post-treatment tissue changes in patients recently exposed to chemotherapy) will deserve further investigation. We now have evidence that HIPEC with a specific drug (cisplatin) at a specific dose (100 mg/m2) given in a specific treatment setting (interval debulking surgery) does not increase patients' morbidity and provides a progression-free and overall survival benefits1van Driel WJ Koole SN Sikorska K et al.Hyperthermic intraperitoneal chemotherapy in ovarian cancer.N Engl J Med. 2018; 378: 230-240Crossref PubMed Scopus (897) Google Scholar, 4Ghirardi V Ronsini C Trozzi R et al.Hyperthermic intraperitoneal chemotherapy in interval debulking surgery for advanced epithelial ovarian cancer: a single-center, real-life experience.Cancer. 2020; 126: 5256-5262Crossref PubMed Scopus (24) Google Scholar that remains evident even after 10 years.5Aronson SL Lopez-Yurda M Koole SN et al.Cytoreductive surgery with or without hyperthermic intraperitoneal chemotherapy in patients with advanced ovarian cancer (OVHIPEC-1): final survival analysis of a randomised, controlled, phase 3 trial.Lancet Oncol. 2023; 10: 1109-1118Google Scholar While we await data from ongoing randomised trials (NCT05659381),10Koole S van Stein R Sikorska K et al.Primary cytoreductive surgery with or without hyperthermic intraperitoneal chemotherapy (HIPEC) for FIGO stage III epithelial ovarian cancer: OVHIPEC-2, a phase III randomized clinical trial.Int J Gynecol Cancer. 2020; 30: 888-892Crossref PubMed Scopus (43) Google Scholar and in view of what has been found so far, we believe that current guidelines should allow for some clinicians to consider the use of HIPEC as a treatment option in selected patients. We declare no competing interests. Cytoreductive surgery with or without hyperthermic intraperitoneal chemotherapy in patients with advanced ovarian cancer (OVHIPEC-1): final survival analysis of a randomised, controlled, phase 3 trialThese updated survival results confirm the long-term survival benefit of HIPEC in patients with primary stage III epithelial ovarian cancer undergoing interval cytoreductive surgery. Full-Text PDF