HIPEC

ROLE AND
INDICATIONS
Presenter: Dr. Prasanth Narayanan J
Moderator: Dr. Phanindra Kumar
Swain
 What is HIPEC and its origin

 Why HIPEC- the rationale

 When HIPEC- Indications

SYNOPSIS
 When not- Contra indications

 Which all malignancies- Role - System wise

WHAT IS HIPEC
And the Origin
 4
• HIPEC- Hyperthermic Intraperitoneal Chemotherapy

• Involves administering cytotoxic agents into the peritoneal cavity at an

elevated temperature (41 to 43 degrees C) to promote their absorption by
neoplastic nodules- Peritoneal surface malignancies at fixed flow rate of
30-120 mins

• PSM- Primary or secondary. Primary- Mesothelioma and serous

carcinoma of peritoneum. Secondary- from other abdominal organs-
Ovary, CRC, Stomach and Appendix

• Peritoneal metastasis- Poorer prognosis than other metastatic sites, Less

responsive to systemic therapies

Ben Aziz M, Di Napoli R. Hyperthermic Intraperitoneal Chemotherapy. [Updated 2023 Jul

31]. In: StatPearls [Internet].
• Introduced in the 1980s by Spratt in animal experiments- “Thermal
Transfusion Infiltration system”

• HIPEC- almost always preceded by Cytoreductive surgery- Removal of all

macroscopic disease in the abdominal cavity

• CRS/HIPEC has grown, modelled and remodelled over the next decades to
become an integral part of the management of primary and secondary
peritoneal malignancies

Ben Aziz M, Di Napoli R. Hyperthermic Intraperitoneal Chemotherapy. [Updated 2023 Jul 31].
In: StatPearls [Internet].

Brind'Amour A, Dubé P. Canadian guidelines on the management of colorectal peritoneal

metastases. Curr Oncol. 2020 Dec;27(6):e621-e631.
WHY HIPEC
The Rationale
 PERITONEUM 7

ANATOMY AND PHYSIOLOGY

• Largest serous membrane of the humanbody. Surface area of approximately 1.8 m2

• Arterial supply- to parietal peritoneum- abdominal wall arteries and parietal pelvic arteries; to visceral
peritoneum- mesenteric, celiac and visceral pelvic arteries

• Venous drainage- parietal peritoneum  Systemic veins  IVC; visceral peritoneum  Poral
vein (80% drainage)

• Lymphatics – mainly subdiaphragmatic peritoneum, greater omentum Thoracic duct

• Three layered structure- mesothelium,basal lamina and submesothelial stroma

• Tight junctions, desmosomes and hemidesmosomes form the Peritoneal-Plasma Barrier  Basis of
pharmacokinetics of HIPEC
Jacquet P, Sugarbaker PH. Peritoneal-plasma barrier. Cancer Treat Res. 1996;82:53-63. doi: 10.1007/978-1-4613-1247-5_4.
 PERITONEUM 8

ANATOMY AND PHYSIOLOGY

van Baal JO, Van de Vijver KK, Nieuwland R, van Noorden CJ, van Driel WJ, Sturk A, Kenter GG, Rikkert LG, Lok CA. The histophysiology
and pathophysiology of the peritoneum. Tissue Cell. 2017 Feb;49(1):95-105. doi: 10.1016/[Link].2016.11.004.
PERITONEAL-PLASMA BARRIER
9

• Drugs of larger molecular weight- cleared at

much slower rate from the peritoneal cavity

• Drug concentration through intraperitoneal

route- several logs higher than same drug
through intra venous route

• Systemically administered drug  rapid

distribution, inversely proportional to blood
supply

• Low peritoneal blood perfusion rate  lower

concentration of IV drug in peritoneum

Jacquet P, Sugarbaker PH. Peritoneal-plasma barrier. Cancer Treat Res. 1996;82:53-63. doi:
10.1007/978-1-4613-1247-5_4.
 10

Jacquet P, Sugarbaker PH. Peritoneal-plasma barrier. Cancer Treat Res. 1996;82:53-63. doi:
10.1007/978-1-4613-1247-5_4.
 RATIONALE OF HIPEC 11

• Pharmacokinetic advantage of IP therapy because of PPB  high concentration gradient of drug in the
peritoneal cavity

• Effective peneteration of drug through peritoneum is 1mm. Surprisingly the peneteration remains the same after
peritonectomy too

• First pass metabolism in to the portal system  very minimal systemic concentration of drug and consequent
toxicity

• Micormetastasis in liver is being taken care by the first pass metabolism

• Propensity of peritoneal mets of certain primaries to remain confined to peritoneum- for longer period of time

Ben Aziz M, Di Napoli R. Hyperthermic Intraperitoneal Chemotherapy. [Updated 2023 Jul 31]. In: StatPearls [Internet]

Bhatt A, editor. Management of peritoneal metastases-cytoreductive surgery, HIPEC and beyond. Springer; 2018 Apr 2.
 12

• Hyperthermia 41 to 43 degree  accelerated cell death

• Complete vascular stasis of Micorcirculation of peritoneal tumour- in response to hyperthermia

• Increased membrane permeability due to hyperthermia and vascular stasis Increased drug absorption

• Synergistic cytotoxic effects with Doxorubicin and with cytostatics such as Platinum agents, Mitomycin C,
Melphalan, Docetaxel, Irinotecan, Gemcitabine.

• Prevents Tumour cell entrapment in the scars and suturelines

• Critical residual tumour size ~ 2.5mm (CC0-CC1)

Ben Aziz M, Di Napoli R. Hyperthermic Intraperitoneal Chemotherapy. [Updated 2023 Jul 31]. In: StatPearls [Internet]

Bhatt A, editor. Management of peritoneal metastases-cytoreductive surgery, HIPEC and beyond. Springer; 2018 Apr 2.
 13

Dellinger TH, Han ES. State of the Science: The role of HIPEC in the treatment of ovarian cancer.
Gynecol Oncol. 2021 Feb;160(2):364-368
 14

WHEN AND WHEN

NOT
Indications and Contra indications
 INDICATIONS
• Removal of all visible metastases or residual tumour size <2.5mm
• ASA grade < 3 with preserved renal, hepatic and cardiac functions
• PCI cutoffs depending on the primary malignancy (will be dealt separately)

CONTRA-INDICATIONS
• Extra abdominal metastases
Absolute Contra indications :
• Infiltration of root of mesentery
• Biopsy proven extra abdominal disease
• Massive involvement of retroperitoneum
• More than 3 liver metastases
• Massively involved pancreatic capsule
• N3 lymph nodes
• Expected small bowel resection for more than
• Unknown primary tumour
one third of the whole length
• Unresectable liver metastasis

Brind'Amour A, Dubé P. Canadian guidelines on the management of colorectal peritoneal metastases. Curr Oncol. 2020 Dec;27(6):e621-
e631.
 16

Bhatt A, editor. Management of peritoneal metastases-cytoreductive surgery, HIPEC and beyond. Springer;
2018 Apr 2.
 17

Bhatt A, editor. Management of peritoneal metastases-cytoreductive

surgery, HIPEC and beyond. Springer; 2018 Apr 2.
 18

WHICH ALL
MALIGNANCIES

Role- System wise

 19

OVARIAN
• 75% of ovarian cancer patients - advanced setting with disease already predominantly spread in the peritoneal
cavity.
• In primary stage III ovarian cancer - cytoreductive surgery (CRS) is established - proven to provide curative,
overall and progression-free survival (PFS) benefits.
HIPEC in Primary CRS:
• Addition of HIPEC to CRS in frontline/upfront setting – No real benefit
• Evidences in upfront- Retrospective single and multi institutional studies
• OVIHIPEC 2- first phase III RCT to investigate role of HIPEC in upfront CRS of ovarian cancer
• Results are expected in 2025

Auer RC, Sivajohanathan D, Biagi J, Conner J, Kennedy E, May T. Indications for hyperthermic intraperitoneal chemotherapy with
cytoreductive surgery: a systematic review. Eur J Cancer. 2020
Bhatt A, editor. Management of peritoneal metastases-cytoreductive surgery, HIPEC and beyond. Springer; 2018 Apr 2.
 20

Interval CRS:
• Most promising results for the use of HIPEC- in interval setup
• Supported by Study by Van driel et al, Lim et al
• NCCN- mentions HIPEC as an option during interval CRS. Not a standard of care yet
• Needs more phase III RCT to support findings of Van driel et al

Recurrent Ovarian cancer:

• Benefit of CRS/HIPEC in recurrent setup – through retrospective and case control studies
• In Platinum sensitive recurrence- when optimal cytoreduction is possible
• In Platinum resistant recurrence- when patients had incomplete CRS in primary setting or had good response to
chemotherapy. In both cases optimal cytoreduction is must.
• CHIPOR trial is a phase III RCT investigating the role of HIPEC in recurrent ovarian cancer- Recruitment phase

Auer RC, Sivajohanathan D, Biagi J, Conner J, Kennedy E, May T. Indications for hyperthermic intraperitoneal chemotherapy with
cytoreductive surgery: a systematic review. Eur J Cancer. 2020
Bhatt A, editor. Management of peritoneal metastases-cytoreductive surgery, HIPEC and beyond. Springer; 2018 Apr 2.
 21

•
22
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COLORECTAL
• Peritoneal mets are the second most common cause of death in CRC after liver mets

• 10% have PM at presentation; 25% after treatment of primary

• After CRS/HIPEC about 70-80% have peritoneal recurrence

• CRS/HIPEC in CRC is found to be beneficial in only selected group of patients

• HIPEC is also investigated as a prophylactic procedure for patient with increased risk of PM(T4 tumours,
tumour perforation and ovarian metastasis)- PROPHYLOCHIP

• RCTs comparing CRS/HIPEC vs CRS alone have not been very encouraging

Auer RC, Sivajohanathan D, Biagi J, Conner J, Kennedy E, May T. Indications for hyperthermic intraperitoneal chemotherapy with
cytoreductive surgery: a systematic review. Eur J Cancer. 2020
Bhatt A, editor. Management of peritoneal metastases-cytoreductive surgery, HIPEC and beyond. Springer; 2018 Apr 2.
 24

Auer RC, Sivajohanathan D, Biagi J, Conner J, Kennedy E, May T. Indications for hyperthermic intraperitoneal chemotherapy with
cytoreductive surgery: a systematic review. Eur J Cancer. 2020
 PRODIGE 7 TRIAL: 25

• France, multicentric (17), RCT

• P – CRC with mets, 18-70 years, ECOG 0-1. PCI <25, Which subset of CRC benefitted?
complete macroscopic resection, <1mm residual tumour
• However no stratification done on the basis of PCI • In a subgroup analysis of patients with medium-
• range PCI (>11 to 15)
I – CRS + HIPEC (n=133)
• 5 FU + Oxaliplatin • The median OS was 32.7 months(Non HIPEC) Vs
• C – CRS alone (n=132) 41.6 months in the HIPEC arm (p Z 0.0209)

• O – no benefit on peritoneal free survival (median f/u 64

m)
• 41.7 m vs 41.2 m (p 0.99)
• 30 day Complication rate was same
• 60 day complication rate (grade 3 & above) was more
in HIPEC arm
 GASTRIC
26

• Synchronous PM in 14-43%; metachronous in 10-46% in gastric cancer

• HIPEC in Gastric cancer-

• Therapeutic – Gastric Ca with PM
• Prophylactic – High risk Gastric cancer without PM( Stage IIIA, IIIB, poorly differentiated histology, mucinous variety)
• Palliative – with intractable ascites

• Level I evidence in utility of HIPEC in Gastric PM- Japanese studies

• Currently recommended for limited peritoneal disease- PCI <13 with CC0
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GASTRIC (CONTD)

• One RCT by Yang et al. -CRS plus HIPEC (cisplatin and MMC) Vs CRS alone in patients with gastric
peritoneal carcinomatosis.

• The median PCI score was 15 in both arms

• OS- CRS plus HIPEC (11.0 months; 95% CI,10.0-11.9) and the non-HIPEC arm (6.5 months; 95%,CI, 4.8-8.2;
p Z 0.046) in case of CC0 and CC1

• In case of incomplete cytoreduction- OS in HIPEC arm-8.2 months; non-HIPEC arm, 4.0 months (p Z 0.024)

• Higher PCI faired better with HIPEC

• NCCN mentions HIPEC as an alternative treatment for Stage IV disease – still under trials
 MESOTHELIOMA
29

• Mesotheliomas can affect any of the serosal surfaces – pleura, pericardium, peritoneum, or tunica vaginalis

• Systemic chemotherapy and radiation have failed in altering the disease course

• No available RCTs to support benefit of HIPEC in mesothelioma

• Select patients- HIPEC  durable control of ascites and better survival (based on Retrospective study)

• Epithelial subtype, lymphnode negative status, CC 0/CC1 and use of HIPEC  independent prognostic
factors on multivariate analysis.
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 PSEUDOMYXOMA PERITONEI FROM 31

APPENDICEAL NEOPLASM
• Biologically heterogenous group- From DPAM(Low grade Diffuse Peritoneal Adenomucinosis-60%) to
PMCA(Peritoneal Mucinous Carcinoma-28%)

• No RCTs. Only comparative and retrospective studies investigating role of HIPEC

• Most of them- heterogenous studies

• Sugarbaker reported 5yr survival of 86% in low grade neoplasm undergoing complete cytoreduction

• The most important prognostic factors - the completeness of cytoreduction, a low PCI, and low-grade PMP, no
regional nodal metastases and no prior non-definitive surgery or chemotherapy
Presentation title 32
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WHAT NEXT
Future perspectives
 ERAS IN CRS/HIPEC
Enhanced Recovery After Surgery (ERAS) Society guideline 2020:
• Preop counselling – to improve QOL, Somatic and psychological outcomes

• Nutritional screening – at risk/malnourished patients – 1.2g/Kg/day x 14days protein supplementation

(Oral>enteral>parenteral)

• At least two antiemetics (Ondansetaron, Dexamethasone, Droperidol) – to prevent PONV

• Total intravenous anaesthesia > Inhalational anaesthesia – to prevent PONV

• Pre op antibiotic – one hour before incision – with no further antibiotics

• Pre op bowel preparation – not recommended for colectomy alone – but indicated for rectal resection – to reduce
post op SSI and anastomotic leak

• Epidural anaesthesia (T5-T11), local anaesthetics or opioids x 72hrs – for pain relief, spare opioids – early
resumption of bowel function

• Limited IV fluid usage – target post op weight gain < 3.5Kg on POD - 3
 BIDIRECTIONAL INTRA-OPERATIVE 35

CHEMOTHERAPY
• IP and IV chemotherapy utilized simultaneously

• Creates a bidirectional diffusion gradient to tackle cancer nodules in intermediate tissue layers

• IV drug – multiple boluses or infusion through or just before surgery

• Introduced by Elias

• Augmentation of IP Oxaliplatin by IV 5 FU/Leucovorin infusion 1 hour before surgery

• Augmentation of IP Doxorubicin or Cisplatin by IV Ifosfamide – enhanced by hyperthermia

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BIDIRECTIONAL
INTRA-
OPERATIVE
CHEMOTHERAPY
WHAT HAS RETAINED- 37

SUMMARY
• HIPEC utilizes pharmacokinetic advantage of PPB and potentiation
through hyperthemia

• Different indications for different malignancies

• Level I evidence of HIPEC in Interval CRS in

ovarian malignancy, Gastric malignancies

• Others are investigational

• Prophylactic HIPEC are underway

• Need multicentric huge RCTs in every secondary PSM to establish

the role of HIPEC in day to day practice – which is in progress

• Judicial use of HIPEC in current practice – Proper counselling –

medicolegal litigations
THANK YOU