Hyperthermic Intraperitoneal Chemotherapy
(HIPEC) in Epithelial Ovarian Cancer
Pro
Georgia Cintra, MD
Diretoria Grupo Brasileiro de Tumores Ginecológicos
IGCS International Mentor
Comissão Nacional de Ginecologia Oncologica da Federação Brasileira de Ginecologia
Conflict of Interests
• None to declare
HIPEC
Why Intraperitoneal
Chemotherapy?
• Most recurrences of EOC occur in the peritoneal cavity.
• Direct exposure of chemotherapy has cytotoxic effects
due to alterations in the cell membrane and nucleus,
protein denaturation and changes in calcium
permeability.
• Allows higher concentrations of antitumor agents while
normal tissues, such as the bone marrow, are relatively
spared.
Koole SN Cancer 2019 Armstrong DK NEJM 2006 Zivanovic O Gynecol Oncol 2018
Why Heat?
• Enhances the penetration of chemotherapy at the peritoneal
surface and increases the cytotoxic effect of chemotherapy.
• Increases the sensitivity of cancer cells to chemotherapy by
impairing DNA repair.
• Mild hyperthermia degrades the BRCA gene leading to a
transient impairment of homologous recombination in tumor
cells, restricting the cells’ ability to repair double strand breaks
in DNA.
• Hyperthermia induces the activation of the systemic immune
response by activating heat-shock proteins
Koole SN Cancer 2019 Graham R Obst Gynecol 2024 Zivanovic O Gynecol Oncol 2018
Why Heat?
• Enhances the penetration of chemotherapy at the peritoneal surface and
increases the cytotoxic effect of chemotherapy.
• Increases the sensitivity of cancer cells to chemotherapy by impairing
DNA repair.
• Mild hyperthermia degrades the BRCA gene leading to a transient
impairment of homologous recombination in tumour cells, restricting the
cells’ ability to repair double strand breaks in DNA.
• Hyperthermia induces the activation of the systemic immune response
by activating heat-shock proteins
Cisplatin-DNA intrastrand adducts within the tumor sample
Koole SN Cancer 2019 Graham R Obst Gynecol 2024 Zivanovic O Gynecol Oncol 2018
When?
Primary Interval
debulking debulking Recurrence
surgery surgery
When?
Primary Interval
debulking debulking Recurrence
surgery surgery
PDS
• 1 RCT which included 107 patients who underwent PCS
• 58 HIPEC/49 non-HIPEC
• 1 meta-analysis with 1861 patients
• 1057 HIPEC / 804 non-HIPEC
• NO ONCOLOGICAL BENEFIT OF HIPEC IN THE SETTING OF
PRIMARY DEBULKING SURGERY (Prospective trials ongoing)
Kim SI Gynecol Oncol 2022 Lim MC JAMA Surgery 2022
When?
Primary Interval
debulking debulking Recurrence
surgery surgery
IDS
Van Driel W NEJM 2018 Aronson SL Lancet Oncology 2023
IDS
Median PFS was 14.2 months vs. 10.7 Median OS was 45.7 months vs. 33.9
months (HIPEC vs no HIPEC group) months (HIPEC vs no HIPEC group)
p = 0.003 p= 0.02
Van Driel W NEJM 2018 Aronson SL Lancet Oncology 2023
IDS
Safety / Toxicity
• Longer surgical time in the HIPEC arm
• Toxicity was not increased by HIPEC administration
• 1 death (surgery alone arm)
• The time between surgery and the start of adjuvant
chemotherapy did not differ between arms
• The number of patients completing 6 cycles of
chemotherapy were similar
Van Driel W NEJM 2018
IDS
Subgroup Analysis - IDS
Median Overall Survival:
- HIPEC: 61.8m
- No HIPEC: 48.2m
(HR 0.53 p=0.4)
Lim MC JAMA Surgery 2022
IDS
Among the 393 patients who underwent neoadjuvant
chemotherapy followed by interval CRS, the use of
HIPEC significantly improved 5-year OS (RR = 0.77; 95%
CI 0.67-0.90; P = 0.001)
Filis P, ESMO Open 2022
When?
Primary Interval
debulking debulking Recurrence
surgery surgery
Recurrence
• Similar toxicicity - HIPEC WELL TOLERARATED
• “Our study does not support the use of HIPEC
with carboplatin at 800 mg/m2 during secondary
cytoreduction”.
Zivanovic O, JCO 2021
GUIDELINES
GUIDELINES
DEBATE
“THE MORBIDITY IS TOO HIGH”
“The rate of complications for cytoreductive surgery and HIPEC in the setting of advanced
ovarian cancer is not negligible, and has not varied over the years”
Navarro BS Int J Gynecol Cancer 2024
“THE MORBIDITY IS TOO HIGH”
“The rate of complications for cytoreductive surgery and
HIPEC in the setting of advanced ovarian cancer is not
negligible, and has not varied over the years”
Despite more aggressive cytoreductive surgeries
over time, the addition of HIPEC didn’t increase
morbidity!
Navarro BS Int J Gynecol Cancer 2024
“THE MORBIDITY IS TOO HIGH”
Adding Sodium Thiosulfate protects
against renal toxicity
“The risk for occurrence of grade 3 adverse events (of any type) was similar between the intervention and control
groups (143/ 308 patients in the HIPEC group and 130/309 patients in the control group)”
Filis P, ESMO Open 2022
“THE MORBIDITY IS TOO HIGH”
Koole SN, Eur J Surg Oncol 2021
“IT’S TOO EXPENSIVE”
Koole SN, JCO 2019
Why it only works at IDS?
• PDS: Lim et al:
• Included Stage IV
• Lower dose of Cisplatin (75mg/m2)
• Recurrent disease: Zivanovic O:
• Carboplatin
• 5 cycles of chemo in HIPEC arm vs 6 cycles in non-HIPEC arm
• Fewer CC-0 in the HIPEC arm
• IDS:
• Hyperthermia might mitigate chemo-resistance
• Shorter gap between chemotherapy treatments
Zivanovic O, JCO 2021 Lim MC JAMA Surgery 2022 Graham R, The Obstetrician & Gynaecologist 2024
OVHIPEC-1 MAJOR CRITICISMS
• Timing of randomization → before surgery
• Selection of centres → Expertise in HIPEC
• Recruitment was too long → Overselection of patients?
• Number of ostomies → Different surgeries?
• Differences in histology → Differences in Survival?
OVHIPEC-1 MAJOR CRITICISMS
• Timing of randomization → before surgery
• Selection of centres → Expertise in HIPEC
• Recruitment was too long → Overselection of patients?
• Number of ostomies → Different surgeries?
• Differences in histology → Differences in Survival?
OVHIPEC-1 MAJOR CRITICISMS
• Recruitment was too long → Overselection of patients?
• Nationwide comparative cohort study (all patients who fullfilled OVHIPEC-1 eligibility criteria between
2007 and 2016 - n = 1376)
• Trial patients had a better performance status, higher socioeconomic status, and underwent bowel
surgery more often
• The difference in OS between the trial and the real-world populations was not statistically significant
OVHIPEC-1 MAJOR CRITICISMS
• Timing of randomization → before surgery
• Selection of centres → Expertise in HIPEC
• Recruitment was too long → Overselection of patients?
• Number of ostomies → Different surgeries?
• Differences in histology → Differences in Survival?
OVHIPEC-1 MAJOR CRITICISMS
• Timing of randomization
CC-0 and CC-1 before
→were surgery
comparable
• Selection of centresin→both
Expertise
groupsin HIPEC
• Recruitment was too long → Overselection of patients?
• Number of ostomies → Different surgeries?
• Differences in histology → Differences in Survival?
OVHIPEC-1 MAJOR CRITICISMS
• Timing of randomization → before surgery
• Selection of centres → Expertise in HIPEC
• Recruitment was too long → Overselection of patients?
• Number of ostomies → Different surgeries?
• Differences in histology → Differences in Survival?
OVHIPEC-1 MAJOR CRITICISMS
• Differences in histology → Differences in Survival?
OVHIPEC-1 DESKTOP III
OVHIPEC-1 MAJOR CRITICISMS
• Differences in histology → Differences in Survival?
DESKTOP III
OVHIPEC-1
CONCLUSIONS
HIPEC is a safe and validated treatment that adds oncological benefits
in the setting of patients undergoing interval cytoreduction.
The main treatment still remains surgery – with the aim of complete
cytoredution
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¡Gracias!
