Hyperthermic intraperitoneal chemotherapy with oxaliplatin for peritoneal carcinomatosis: a clinical pharmacological perspective on a surgical procedure

Abstract

Cytoreductive surgery combined with hyperthermic intraperitoneal chemotherapy (HIPEC) has become the standard of care in the treatment of patients with peritoneal carcinomatosis of colorectal origin. The use of oxaliplatin for HIPEC has gained popularity. Although the HIPEC procedure is adopted throughout the world, major differences exist between treatment protocols regarding the carrier solution, perfusate volume, use of an open or closed technique, duration of the perfusion and application of additional flushing. These differences can influence the pharmacokinetics and pharmacodynamics of oxaliplatin and might thereby have an impact on the efficacy and/or safety of the treatment. Clinicians should be aware of the clinical importance of oxaliplatin pharmacology when performing HIPEC surgery. This review adds new insights into the complex field of the pharmacology of HIPEC and highlights an important worldwide problem: the lack of standardization of the HIPEC procedure.

Introduction

Metastases to the peritoneal cavity, referred to as peritoneal carcinomatosis (PC), is a common phenomenon in distant metastatic colorectal cancer 1, 2, 3. Patients with isolated metastasis to the peritoneum who are treated with palliative surgery alone or with 5‐fluorouracil (5‐FU)‐based regimens have poor overall survival rates of approximately 6 months 4, 5, 6. As a result of the introduction of cytoreductive surgery (CRS) combined with hyperthermic intraperitoneal chemotherapy (HIPEC), median overall survival has significantly increased to 63 months, with a 5‐year survival rate of approximately 40% 7. The CRS‐HIPEC procedure has become the standard of care in the treatment of patients with PC of colorectal origin 8. Adequate patient selection remains one of the main challenges as CRS‐HIPEC is associated with approximately 1–3% mortality and significant morbidity in one‐third of patients 7. The most important prognostic factors that have been identified to influence the outcome after the CRS‐HIPEC procedure are the extent of the peritoneal disease, the completeness of cytoreduction and the histological subtype of the primary tumour 9.

Different chemotherapeutic drugs can be administered in HIPEC for colorectal PC. Traditionally, mitomycin C (MMC) was the most commonly used drug, but for the past few years oxaliplatin has been used more often worldwide. Oxaliplatin is the cornerstone in the systemic treatment of patients with colorectal cancer. Results on survival in HIPEC series for CRC are comparable for MMC and oxaliplatin 10, 11, 12, 13, 14, 15, 16, 17. No statistically significant differences were demonstrated in survival and postoperative morbidity after HIPEC with MMC or oxaliplatin 18, 19. As there has been no randomized phase III trial comparing MMC and oxaliplatin, there is no consensus on the intraperitoneal drug of choice. Based on the duration of the perfusion, 30 min for oxaliplatin vs. 90 min for MMC, oxaliplatin is the preferred drug in the CRS‐HIPEC procedure for colorectal PC in many centres.

The oxaliplatin dose used for HIPEC is 3.5–5.4 times the intravenous dose of a one‐off infusion delivered to patients with metastatic colorectal cancer in the various treatment regimens 20. Although CRS‐HIPEC is widely applied as the standard treatment for PC of colorectal origin, the exact procedure for HIPEC differs between institutions and surgeons. There is no consensus on the applied dose, duration, carrier solution, perfusate volume, perfusate concentration, use of an open vs. closed technique, or the usefulness of additional flushing with crystalloids at the end of the HIPEC procedure. These differences can play an important role in the pharmacokinetics (PK) of oxaliplatin and thereby might influence efficacy and/or safety of the HIPEC procedure. The present review provides an overview about the PK and pharmacodynamics (PD) of oxaliplatin during HIPEC procedures and the implications for clinical practice. It is surprising that a high‐risk procedure as HIPEC, with a great impact on survival, has not yet been standardized.

Analytical techniques

Oxaliplatin is highly reactive in the blood and forms a variety of hydrolysed intermediates after intravenous infusion, including monochloro‐ dichloro‐ and diaquo‐platinum species 21, 22. Up to 17 platinum‐containing derivatives have been observed in plasma ultrafiltrate (UF) samples from patients 23. These intermediates rapidly react with endogenous low‐molecular‐weight molecules such as glutathione, cysteine and methionine, and high‐molecular‐weight compounds such as albumin, globulin and haemoglobin 21, 24, 25. At the end of a 2‐h intravenous administration of oxaliplatin, approximately 40% of the administered platinum is bound to erythrocytes and approximately 33% is bound to plasma proteins 26. The unbound platinum is generally considered as the pharmacologically active moiety 21, 22, although the relationship between free platinum and the pharmacological activity and toxicity is not as clear as for carboplatin 27. Free platinum concentrations are a sum of active as well as inactive forms of free platinum. Some authors suggest that the parent drug oxaliplatin is the pharmacologically active moiety 24, 28, 29. Analysis of the free fraction of the parent drug oxaliplatin has revealed a very short terminal half‐life for intact oxaliplatin of only 14 min in blood 24.

Considering this, it is important to differentiate between the analytical techniques that are used for the detection of platinum derivatives when interpreting PK data. The majority of PK studies that have used the HIPEC procedure determined the platinum content by flameless atomic absorption spectrometry (AAS) 30, 31, 32, 33, 34, 35, 36, direct current plasma emission spectroscopy 37, inductively coupled plasma optical emission spectrometry 38, 39, 40 or inductively coupled plasma mass spectrometry 41, 42. These analytical techniques measure both the parent drug oxaliplatin and other active and inactive platinum‐containing complexes that are formed as a result of the high reactivity of oxaliplatin in vivo. This might lead to an overestimation of the concentration of active drug, as a result of nonspecificity. Two studies have investigated the PK of intact oxaliplatin during HIPEC 35, 43. Measurement of intact oxaliplatin and total platinum content can result in large differences in PK parameter estimation, such as an oxaliplatin plasma clearance of 28.4 l h⁻¹ m⁻² based on intact oxaliplatin 43 vs. 6.68 l h⁻¹ m⁻² based on AAS 33. However, the extent of drug absorbed during HIPEC (36–60% 43 vs. 40–68% 33) and the volume of distribution (0.294 l kg⁻¹ 44 vs. 0.235 l kg⁻¹ 33) seem to be consistent. To date, it is unknown which analytical measurement (intact oxaliplatin or the mixture of platinum derivatives) is the best surrogate marker to predict both the toxicity and efficacy of oxaliplatin‐based HIPEC. Future research should be performed to provide answers to this unresolved question.

Carrier solutions in HIPEC

The ideal carrier solution for HIPEC with oxaliplatin should provide a uniform distribution of the cytotoxic drug and heat, with minimal loss of volume during perfusion. This requires minimal transport of fluid and electrolytes from the peritoneal compartment to the plasma, and stability of the drug in the carrier solution. As oxaliplatin can react with chloride ions, causing degradation, dextrose 5% is often used as the carrier solution in oxaliplatin‐based HIPEC protocols 45. A disadvantage of the use of dextrose 5% is the inability to maintain a high intraperitoneal fluid volume, owing to rapid absorption 45. High intraperitoneal volumes of dextrose 5% require high doses of insulin to prevent severe hyperglycaemia, causing major electrolyte disturbances during perfusion 46, 47, 48, 49. Other carrier solutions that have been investigated are hypertonic solutions, hypotonic solutions and isotonic high molecular weight solutions. The main disadvantage of hypertonic solutions is dilution of the drug due to fluid shift towards the peritoneal cavity 45. Both in vitro and animal studies suggest that the use of hypotonic solutions can enhance platinum accumulation in tissue 50, 51. Nevertheless, this effect could not be replicated in humans and, because of an increased risk of haemorrhage and thrombocytopenia, the use of hypotonic solutions for HIPEC with oxaliplatin is discouraged 52. Some centres advise the use of high molecular weight solutions such as icodextrin 40, 53. The small differences that are found in the rate and extent of oxaliplatin absorption between glucose 5% and icodextrin 4% are deemed clinically irrelevant 53. Promising results have been seen with the use of the peritoneal dialysis fluids Physioneal 40 dextrose 2.27% solution 35 and Dianeal PD4 dextrose 1.36% solution 54, 55, showing minimal electrolyte and glycaemic disturbances during the HIPEC procedure. The cytotoxic properties of oxaliplatin in Physioneal 40 dextrose 2.27% solution remain unchanged during the HIPEC procedure 35. These findings support the use of perfusates containing lower concentrations of dextrose.

However, there is currently no consensus on the best type of carrier solution, showing the need for further research, as different carrier solutions might result in different outcomes.

Drug penetration in tumour tissue

The goal of intraperitoneal administration of oxaliplatin is to obtain high local concentrations and high penetration in tumour tissue to enhance efficacy. Although tissue penetration seems important, a relationship between tissue concentration and efficacy of the HIPEC procedure has not yet been described. Given the heterogeneity of colorectal carcinoma, the optimal tissue concentration might differ for each patient, or even in different tumours within the same patient. Drug penetration is limited to only a few cell layers under the tumour surface 56. This highlights the importance of complete cytoreduction to optimize the effect of intraperitoneally administered oxaliplatin. Elias et al. 30 showed that the concentration of platinum in healthy peritoneal tissue exposed to oxaliplatin solution during HIPEC is a good reflection of its concentration in peritoneal tumour tissue. A recent study collected tissue samples after HIPEC with oxaliplatin and demonstrated no significant difference (P = 0.38) between the platinum concentration in peritoneal tissue and in the subjacent fascia 35.

Table 1 provides an overview of human and animal studies in which platinum tissue concentrations during the HIPEC procedure with oxaliplatin were measured. As a result of major differences in the procedure, it is hard to compare the individual studies. Factors that have been identified to have an impact on the platinum concentration in tumour tissue are hyperthermia, pressure, dose, perfusate concentration, type of carrier solution and pretreatment with 5‐FU 30, 35, 36, 37, 38, 52, 57, 58.

Table 1.

Overview of human and animal studies measuring total platinum tissue exposure during the hyperthermic intraperitoneal chemotherapy procedure with oxaliplatin

Author/year	Subjects	Treatment strategy	Oxaliplatin dose (mg m −2 )	Carrier solution	Duration, flow rate	Temperature (˚C)	Flushing afterwards	Analytical method	Total platinum tissue concentration (ng mg −1 )
Human studies
Elias et al./2002 32	n = 5	Open coliseum technique	260	5% dextrose, 2 l m−2	30 min (+ approximately 10 min required to reach high homogeneous temperature), 2 l min−1	42–44	No	AAS	Tumour tissue: 228 μg g−1 dry tissue Normal peritoneum: 230 μg g−1 dry tissue
	n = 3		310						Tumour tissue: 248 μg g−1 dry tissue Normal peritoneum: 273 μg g−1 dry tissue
	n = 3		360						Tumour tissue: 327 μg g−1 dry tissue Normal peritoneum: 296 μg g−1 dry tissue
	n = 3 + 3		410	5% dextrose, 2.0 l m−2 and 2.5 l m−2					Tumour tissue: 323 μg g−1 dry tissue Normal peritoneum: 287 μg g−1 dry tissue
	n = 3		460	5% dextrose, 2 l m−2					Tumour tissue: 339 μg g−1 dry tissue Normal peritoneum: 392 μg g−1 dry tissue
Elias et al./2002 54	n = 4	Open coliseum technique	460	100 mosm l−1 dextrose, 2 l m−2	30 min (+ approximately 5 min required to reach high homogeneous temperature), 2 l min−1	42–44	No	AAS	Tumour tissue: 480 ± 82 μg g−1 dry tissue Normal peritoneum: 396 ± 73 μg g−1 dry tissue
	n = 4			150 mosm l−1 dextrose, 2 l m−2					Tumour tissue: 440 ± 108 μg g−1 dry tissue Normal peritoneum: 449 ± 83 μg g−1 dry tissue
	n = 3			200 mosm l−1 dextrose, 2 l m−2					Tumour tissue: 322 ± 76 μg g−1 dry tissue Normal peritoneum: 314 ± 101 μg g−1 dry tissue
	n = 3 (+3)			300 mosm l−1 dextrose, 2 l m−2					Tumour tissue: 299 ± 87 μg g−1 dry tissue Normal peritoneum: 339 ± 92 μg g−1 dry tissue
Stewart et al./2008 40	n = 12	Closed	200	5% dextrose, fixed volume of 3 l	120 min, 0.8–1 l min−1	40.6 ± 0.5	Yes, with 3 l of crystalloid	ICP‐OES	Tumour tissue: 15.9 ± 12.0 μg g−1 Normal peritoneum: 17.7 ± 10.8 μg g−1
	n = 3		250						Tumour tissue: 20.3 ± 9.7 μg g−1 Normal peritoneum: 26.3 ± 14.7 μg g−1
Löffler et al./2017 37	n = 9	Not mentioned	300	Physioneal 40 dextrose 2.27% w/v Clear‐Flex peritoneal dialysis solution, 5–6 l (different concentrations; 93.7 ± 12.2 [75.0–108.9] μg ml−1)	30 min, not mentioned	42	Not mentioned	AAS	Normal peritoneum: 50 μg g−1 dry tissue [range 5–203 μg g−1] Subjacent fascia: 70 μg g−1 dry tissue [range 0–103 μg g−1]
Animal studies
Facy et al./2012 38 (in pigs)	n = 5	Semi‐open	150 mg l−1	5% dextrose, 4 l	30 min, not mentioned	38	Yes, with 1 l of 5% dextrose	AAS	Parietal peritoneum: 35.62 ± 8.81 μg g−1 Visceral peritoneum: 5.48 ± 0.70 μg g−1
	n = 5					42			Parietal peritoneum: 38.73 ± 7.74 μg g−1 Visceral peritoneum: 7.99 ± 1.66 μg g−1
	n = 5	Semi‐open with high intra‐abdominal pressure		5% dextrose, 8 l		38			Parietal peritoneum: 53.61 ± 10.32 μg g−1 Visceral peritoneum: 6.95 ± 1.46 μg g−1
	n = 5					42			Parietal peritoneum: 66.16 ± 13.03 μg g−1 Visceral peritoneum: 10.39 ± 3.49 μg g−1
Piché et al./2011 59 (in rats)	n = 5	Closed	920	5% dextrose, 15 ml	25 min, 16 ml min−1	37	Yes, with 20 ml of 5% dextrose	HPLC with Phenomenex column and a precolumn of C18	Normal peritoneum: 5.7 ± 0.4 μg ml−1
	n = 7					40			Normal peritoneum: 6.5 ± 0.3 μg ml−1
	n = 13					43			Normal peritoneum: 7.9 ± 0.6 μg ml−1
	n = 6		460			40			Normal peritoneum: 2.4 ± 0.7 μg ml−1
	n = 6		1840						Normal peritoneum: 15.5 ± 0.6 μg ml−1
Pestieau et al./2001 39 (in rats)	n = 5	Closed	15 mg kg−1	5% dextrose, 150 ml	90 min, 80 ml min−1	35–37	Not mentioned	DC‐PES	Colonic tissue: 25 ± 9 μg ml−1
	n = 5					40–42			Colonic tissue: 28 ± 6 μg ml−1

AAS, atomic absorption spectrometry; DC‐PES = direct current plasma emission spectroscopy; ICP‐OES, inductively coupled plasma optical emission spectrometry; HPLC, high‐performance liquid chromatography

Effect of hyperthermia and pressure

The rationale for using hyperthermia in cancer treatment relates to tumour cells being more susceptible to heat than nonmalignant cells. Hyperthermia impairs DNA replication and disturbs multiple DNA repair pathways, and thus sensitizes cancer cells to cytotoxic agents, leading to increased cell death 59. Local heating of tumours also triggers multiple antitumour immune responses and facilitates increased trafficking of immune cells between tumours and draining lymph nodes 60.

Besides intrinsic antitumour activities, hyperthermia also enhances the cytotoxicity of oxaliplatin 57, 61. A study in rats showed that the peritoneal tissue concentration of oxaliplatin significantly increased with higher temperature 57. An animal study in a pig model using a semi‐open technique with a constant oxaliplatin concentration showed that hyperthermia (42°C) increased the tissue concentration of oxaliplatin in the visceral peritoneum compared with normothermia. High pressure also increased the oxaliplatin tissue concentration in both the visceral and parietal peritoneum compared with normal pressure 36. High intra‐abdominal pressure can be achieved using a HIPEC procedure with a closed abdominal wall 36, 62. However, higher tissue concentrations and a homogeneous distribution of oxaliplatin in the perfusate can be achieved using the open technique 63, 64.

Effect of dose and concentration

A study in rats showed that tissue distribution is significantly increased by the use of higher doses of oxaliplatin. A sixfold increase in tissue concentration was seen with a fourfold increase in dose 57. In a phase I clinical study, an increase in tumour platinum concentration was found with every dose escalation step of 50 mg m⁻². Tumour platinum exposure increased by a factor of 1.5 between the lowest and highest dose tested, which were 260 mg mg⁻² and 460 mg m⁻², respectively 30. HIPEC with oxaliplatin perfused at a temperature of 40°C over a period of 2 h showed a 1.3‐fold increase in tumour platinum exposure between a dose of 200 mg m⁻² and of 250 mg m⁻². Nevertheless, the maximum tolerated dose for a 2‐h perfusion of oxaliplatin was 200 mg m⁻² in that study 38.

Perfusate volume and perfusate concentration are important variables for PK during the HIPEC procedure. The diffusion of oxaliplatin from perfusate to peritoneal tissue and blood is driven by a concentration gradient. A higher perfusate volume of 2.5 l m⁻², instead of 2 l m⁻², decreases the intraperitoneal platinum concentration by 20% 30. The maximal plasma concentration (C_max) and systemic exposure are similar for a 410 mg m⁻² dose of oxaliplatin in 2.5 l m⁻² and a 310 mg m⁻² dose in 2 l m⁻². This indicates that the PK and tissue penetration of oxaliplatin are influenced more by the concentration in the perfusate than by the total dose administered 30, 57. Some publications describe the use of a standard perfusate volume of 2 l m⁻² with a fixed dose of 460 mg m⁻². In this case, all patients are treated with a fixed concentration of 230 mg l⁻¹ oxaliplatin in the perfusate at the beginning of the HIPEC procedure. Using perfusate volumes above 2 l m⁻², along with a fixed dose per m², might negatively influence efficacy because tumour exposure will be decreased. However, the use of fixed volumes of 2 l m⁻² can cause inadequate tissue contact time in patients with a relative large abdominal cavity. Some centres fill the abdominal cavity completely before the administration of oxaliplatin. This causes great variation in oxaliplatin concentrations and therefore is likely to influence tumour penetration and the systemic absorption of oxaliplatin, which might influence the efficacy and/or safety of the treatment.

PK of oxaliplatin during HIPEC

Table 2 provides an overview of PK studies of oxaliplatin in patients undergoing the HIPEC procedure.

Table 2.

Pharmacokinetic studies of oxaliplatin in patients undergoing the hyperthermic intraperitoneal chemotherapy procedure with oxaliplatin

Author/year	Subjects	Treatment strategy	Oxaliplatin dose (mg m −2 )	Carrier solution	Duration, flow rate	Temperature (°C)	Flushing afterwards	Analytical method	Pharmacokinetic parameters
									Total platinum half‐life in perfusate (min)	Total platinum		Ultrafilterable platinum
										C max (μg ml−1)	AUC (μg ml*h−1)	C max (μg ml−1)	AUC (μg ml*h−1)
Elias et al./2002 32	n = 5	Open coliseum technique	260	5% dextrose, 2 l m−2	30 min (+ approximately 10 min required to reach high homogeneous temperature), 2 l min−1	42–44	No	AAS	40	–	–		11
	n = 3		310							–	–		14
	n = 3		360							–	–		15
	n = 3 + 3		410	5% dextrose, 2 l m−2 and 2.5 l m−2						–	–		15
	n = 3		460	5% dextrose, 2 l m−2						13.2	–	8.5	17
Elias et al./2002 54	n = 4	Open coliseum technique	460	100 mosm l−1 dextrose, 2 l m−2	30 min (+ approximately 5 min required to reach high homogeneous temperature), 2 l min−1	42–44	No	AAS	35	15.0 ± 2.3	92.3 ± 10.1	8.7 ± 1.7	16.7 ± 2.3
	n = 4			150 mosm l−1 dextrose, 2 l m−2						13.6 ± 1.7	104.0 ± 12.1	9.1 ± 1.4	18.6 ± 2.6
	n = 3			200 mosm l−1 dextrose, 2 l m−2						10.4 ± 0.9	72.3 ± 6.3	7.6 ± 1.2	15.0 ± 1.7
	n = 3 (+3)			300 mosm l−1 dextrose (=iso‐osmotic), 2 l m−2						12.0 ± 1.8	81.6 ± 7.2	7.8 ± 1.1	17.6 ± 1.9
Mahteme et al./2008 45	n = 8	Open coliseum technique	427 ± 29	5% dextrose, 3.2 ± 0.7 l	30 min (+ time required to reach high homogeneous temperature), not mentioned	41.5–43	Yes, with an unknown amount of saline	LC with porous graphitic carbon and postcolumn derivation with sodium diethyldithiocarbamate in a microwave field followed by photometric detection	29.5 [21.1–41.2] a	–	–	8.3 ± 1.8a	26 220 ± 4290a
Ferron et al./2008 35	n = 24	Open coliseum technique	360 (n = 7) and 460 (n = 17)	5% dextrose, 2 l m−2	30 min (+ approximately 8–10 min required to reach high homogeneous temperature) (12×) and 30 min (12×), 2 l min−1	42–43	Yes, with an unknown amount of saline	AAS	29 [18–42]	–	–	–	13.7 [8.0–20.0]
Chalret du Rieu et al./2014 36	n = 58	Open coliseum technique	360	5% dextrose, 2 l m−2	30 min (+ approximately 8–10 min required to reach high homogeneous temperature) (12×) and 30 min (63×), 2 l min−1	42–43	Yes, with an unknown amount of saline	AAS	29.6 ± 6	–	–	–	16.1 ± 4.9
	n = 17		460										22.9 ± 4.7
Leinwand et al./2013 43	n = 10	Closed	250	5% dextrose, 2.7 ± 0.8 l	60 min, 1 l min−1	Not mentioned	Not mentioned	ICP‐MS	–	–	138.1 ± 33.1 mg*min l−1	–	–
Stewart et al./2008 40	n = 12	Closed	200	5% dextrose, fixed volume of 3 l	120 min, 0.8–1 l min−1	40.6 ± 0.5	Yes, with 3 l of crystalloid	ICP‐OES	70.1 ± 23.8	2.2 ± 0.77	23.2 ± 11.4	–	–
	n = 3		250						65.3 ± 10.3	3.2 ± 0.6	31.1 ± 3.0
Valenzuela et al./2011 41	n = 30	Open coliseum technique	360	4% icodextrin, 2.5–6 l	40 (range 30–60), 1 l min−1	42–43	Not mentioned	ICP‐OES	132	2.56 ± 0.9	87.20 ± 123.20	–	–
Pérez‐Ruixo et al./2012 42	n = 36	Open coliseum technique	364.5 ± 32.4	4% icodextrin, 3.9 ± 0.8 l	37.6 ± 8.3, 1 l min−1	42–43	Not mentioned	ICP‐OES	76.8 ± 21	20.5 ± 4.3	192 ± 45.3	–	–
	n = 13		399.5 ± 94.7	5% dextrose, 3.6 ± 0.6 l	33.8 ± 5.1, 1 l min−1				71.4 ± 29.4	22.3 ± 9.1	213 ± 72.4

AAS, atomic absorption spectrometry, AUC, area under the concentration–time curve; C_max, maximal plasma concentration; ICP‐MS, inductively coupled plasma mass spectrometry, ICP‐OES, inductively coupled plasma optical emission spectrometry; LC, liquid chromatography

^aUnbound oxaliplatin parent drug

Absorption of platinum from the peritoneal compartment

In the peritoneal compartment, the great majority of administered drug is present as unbound platinum, which is available for antitumour activity and transfer to the bloodstream. This indicates low platinum protein‐binding in the perfusate solution. Although unbound platinum in the perfusate has only been studied for intraperitoneal administration of cisplatin 65, 66, this might also apply to the administration of oxaliplatin. Given the high reactivity of oxaliplatin with serum proteins such as albumin, it can be speculated that extensive cytoreduction, bleeding or severed tissue surfaces will decrease the fraction of unbound platinum in the perfusate. No significant association has been found between oxaliplatin systemic exposure and the extent of the surgery or the peritoneal cancer index 34.

Oxaliplatin is rapidly absorbed from the peritoneal compartment, with reported mean peritoneal half‐lives (t_1/2s) of 29 min 33, 34, 35 min 52 and 40 min 30, indicating that approximately half of the dose is cleared from the peritoneal compartment during a 30‐min HIPEC procedure. Some studies have report much longer peritoneal t_1/2s of up to 2.2 h 38, 39, 40. The rate constant for the absorption of oxaliplatin from the peritoneal perfusate to the plasma is independent of the administered dose and shows low interpatient variability (with a coefficient of variation of 22%) 33. Furthermore, modifications to the osmolarity of the carrier solution (with a fixed oxaliplatin concentration) do not affect systemic oxaliplatin absorption 52. A positive correlation has been found between the percentage of systemic absorbed platinum and the body mass index (BMI) of patients 43. This might be due to a larger peritoneal surface area in patients with a higher BMI. This could not be replicated in another study using a closed HIPEC procedure 41. Nevertheless, it was shown that body surface area (BSA) is a predictor of systemic exposure to platinum. Patients with a higher BSA show a lower plasma oxaliplatin area under the concentration–time curve (AUC) over a 1‐h closed HIPEC procedure, possibly caused by lower drug concentrations in the perfusate in these patients 41. The peritoneal AUC and systemic AUC of oxaliplatin during HIPEC is not influenced by disease burden or the extent of peritonectomy, indicating that an intact peritoneum is not required to maintain the concentration differences between perfusate and plasma observed during HIPEC procedure 41, 67.

HIPEC performed with a sodium bicarbonate‐containing carrier solution shows a fast decline of free platinum compounds in the perfusate, with a recovery of only 50% at 5 min after the start of perfusion 35. This fast decline of free platinum compounds in the perfusate might not only be explained by absorption from the peritoneal compartment, but also by a reaction with solid tissues in the peritoneum and degradation in the perfusate solution, most probably caused by a reaction with erythrocytes and other cell types or debris circulating in the perfusate. Only a small percentage (10–15%) of the parent drug oxaliplatin is consistently detectable during 30‐min HIPEC with 300 mg m⁻² oxaliplatin. This can be the result of rapid nonenzymatic transformation into reactive compounds in the perfusate. Nevertheless, it was shown that bioactivity in the perfusate was preserved during the whole 300‐min HIPEC procedure 35. When dextrose 5% is used as a carrier solution, the parent drug oxaliplatin is more stable in the perfusate, with a degradation of only 5–10% at the end of the HIPEC procedure 43. These large differences in recovery of the parent drug oxaliplatin could be explained by different carrier solutions, given that there is a higher reactivity with sodium bicarbonate‐containing carrier solutions 35. However, both studies used different analytical methods, making it hard to compare these results adequately.

Systemic PK of oxaliplatin with HIPEC

One of the advantages of intraperitoneal administration of oxaliplatin is the use of high drug doses with relatively low systemic exposure. The interindividual variability of central volume of distribution and plasma clearance is larger than for peritoneal volume of distribution and peritoneal clearance 33. The C_max of platinum in the plasma is reached at the end of the HIPEC procedure 31, 52. After evacuation of the oxaliplatin solution from the abdominal cavity, the plasma concentration of platinum rapidly drops. Some studies showed a relatively small systemic exposure (AUC) that was comparable to AUC values observed after a 2‐h intravenous infusion of oxaliplatin at a dose of 130 mg m⁻² 30. Others found a twofold higher systemic exposure to the parent drug oxaliplatin after HIPEC compared with an intravenous infusion of 130 mg m⁻² oxaliplatin over 30 min 43. Systemic exposure to oxaliplatin increases with higher doses 30, 34. A study in rats showed that higher perfusion temperatures decreased the systemic exposure to oxaliplatin 57 and decreased drug absorption in kidney tissue 37. The reason for these findings is unknown, but might be associated with higher reactivity in the peritoneum.

High systemic exposure to oxalipatin during HIPEC can lead to thrombocytopenia and neutropenia. The most frequently reported toxicities after HIPEC with oxaliplatin are haemoperitoneum (23%), neuropathy (19%), thrombocytopenia (13%) and ascites (4%) 34. Although haemoperitoneum is a postoperative complication, high systemic oxaliplatin exposure can increase the risk of this condition. Neutropenia is rarely observed 34.

To date, only two studies have investigated the PK of intact oxaliplatin during HIPEC 35, 43. Huge differences were found between the plasma clearance of unbound intact oxaliplatin (28.4 l h⁻¹ m⁻²) 43 and total unbound platinum (6.68 l h⁻¹ m⁻²) 33. The systemic exposure to unbound intact oxaliplatin is about four times lower than the systemic exposure to total unbound platinum. This can be explained by the fact that, with time, the amount of intact oxaliplatin will constitute a gradually decreasing fraction of total unbound platinum as a result of reactivity with endogenous compounds 43.

Additional flushing

There is no consensus about the usefulness of flushing the abdominal cavity with crystalloids at the end of oxaliplatin administration. When flushing is performed, its purpose is to minimize systemic exposure to both patient and personnel, as well as to evacuate remaining debris and clots due to the surgery and resulting bleeding. However, HIPEC without flushing might increase tumour exposure because intraperitoneal tumour cells might be exposed to high concentrations of oxaliplatin for a longer period. Currently, there is a lack of knowledge on the effect of additional flushing on oxaliplatin PK.

PD of oxaliplatin during HIPEC

Few studies have investigated the PD of oxaliplatin during HIPEC 34, 39, 68, 69. These studies use PK/PD models to find associations between PK parameters and PD toxicities of the treatment. It has been demonstrated that HIPEC‐induced neutropenia largely depends on the duration of the HIPEC procedure and the oxaliplatin concentration in the perfusate, which is related to systemic concentrations 39. It has been predicted that each 400 mg l⁻¹ increase in initial oxaliplatin concentration causes a 28% decrease in the absolute neutrophil count (ANC) at day 7 69. Extending the duration of HIPEC from 30 min to 60 min is predicted to result in a 23% decrease in ANC at day 7 69. This is relevant because postoperative infectious complications can be expected within the first week after surgery. the main determinants for the duration and severity of HIPEC‐induced thrombocytopenia are the initial oxaliplatin concentration and the duration of the HIPEC procedure 69.

The systemic exposure to oxaliplatin is associated with the severity of thrombocytopenia and the occurrence of haemoperitoneum 34. An increase by approximately 20% in systemic oxaliplatin exposure resulted in a decrease in platelets and an increase in the chance of developing haemoperitoneum. No associations were found between either intraperitoneal or systemic oxaliplatin exposure and the onset of ascites or neuropathy 34.

The PK studies that have been performed so far suggest that higher doses of oxaliplatin could be used for the HIPEC procedure, without substantially increasing the risk of major haematological toxicity. Nevertheless, based on the data summarized above, this should be performed with great caution.

The rationale for administration of 5‐FU prior to administration of oxaliplatin

The combination of intravenous administration of oxaliplatin with 5‐FU–leucovorin significantly improves antitumour efficacy in patients with metastatic colorectal cancer 70. There is a synergistic effect of oxaliplatin and 5‐FU 71, but 5‐FU cannot be mixed with oxaliplatin because of incompatibility. This is the reason for the clinical use of intraoperative intravenous administration of 5‐FU and leucovorin in conjunction with intraperitoneal perioperative oxaliplatin 30. Although the peritoneum and abdominal cavity have an impaired blood supply, resulting in systemic therapy having limited efficacy, it has been demonstrated that 5‐FU administered intravenously penetrates rapidly into heated tumour nodules during HIPEC 72. The simultaneous administration of intravenous and intraperitoneal chemotherapy creates an ideal situation for enhancement of cytotoxicity in the heated tumour nodules. In a recent study in rats, intravenous administration of 5‐FU enhanced the peritoneal absorption of oxaliplatin 58. This highlights the importance of the administration of 5‐FU in the management of PC of gastrointestinal origin.

Knowledge gaps

Although several studies have investigated drug penetration in tumour tissue during the HIPEC procedure, no relationship has been found between tumour platinum exposure and clinical outcome yet. It can be assumed that tissue penetration is an important factor for optimal drug effect. However, the optimal drug concentration to attain complete tumour cell death remains unclear and might differ for individual patients and tumours. Higher tumour exposures can be achieved with the use of higher perfusate concentrations and a longer duration of procedure, but this will also cause an increased systemic absorption, which is related to toxicity. Future studies should investigate the relationship between tumour exposure and antitumour efficacy, and systemic exposure and toxicity. This will help to establish the optimal HIPEC procedure for each patient.

Future perspectives

For patients with advanced PC who are not eligible for HIPEC with curative intent, a novel treatment has recently been introduced, called ʻpressurized intraperitoneal aerosol chemotherapy (PIPAC). This technique is minimally invasive and combines the advantages of local administration with pressurized vaporization. Although no clear indication for PIPAC has yet been defined, the treatment has been reported to be feasible, well tolerated and safe 73. However, available data are limited by small sample sizes, heterogeneity and the lack of control groups.

New techniques, such as organoid technology 74, create great opportunities for future HIPEC research. Organoids are three‐dimensional stem cell cultures that self‐organize into ex vivo ‘mini‐organs’. Organoids generated from colorectal carcinomas can be used to test several cytotoxic agents, concentrations, durations, temperatures and frequencies, to optimize current intraperitoneal chemotherapy. The first study to use this approach showed that oxaliplatin was the most efficient cytotoxic agent in patients with PC of colorectal cancer origin 75. The use of organoids generated from colorectal carcinomas from individual patients will create opportunities to individualize HIPEC procedures. Future studies should investigate the opportunities that these individualized approaches may bring, which will theoretically create the optimal treatment, with high tumour exposure and efficacy and acceptable systemic exposure and toxicity.

Conclusions

Currently, there is a wide variety of procedures and a lack of PK data in HIPEC. Several important factors can influence the PK profile of oxaliplatin in HIPEC procedures. The variety of analytical techniques and HIPEC procedures makes it difficult to compare individual studies. Although HIPEC is now widely accepted as an effective curative treatment option, the exact procedure can differ between institutions. There is a need for standardization of the first‐line HIPEC procedure with oxaliplatin in patients with PC of colorectal origin. Given the complexity of the procedure, there is a need for a multidisciplinary approach, combining the expertise of surgeons, medical oncologists, perfusionists, anaesthetists and pharmacists.

Nomenclature of ligands

Key ligands in this article are hyperlinked to corresponding entries in http://www.guidetopharmacology.org, the common portal for data from the IUPHAR/BPS Guide to PHARMACOLOGY 76.

Competing Interests

There are no competing interests to declare.

de Jong, L. A. W. , Elekonawo, F. M. K. , de Reuver, P. R. , Bremers, A. J. A. , de Wilt, J. H. W. , Jansman, F. G. A. , ter Heine, R. , and van Erp, N. P. (2019) Hyperthermic intraperitoneal chemotherapy with oxaliplatin for peritoneal carcinomatosis: a clinical pharmacological perspective on a surgical procedure. Br J Clin Pharmacol, 85: 47–58. 10.1111/bcp.13773.