Innovative strategies for cisplatin desensitization in hyperthermic intraperitoneal chemotherapy of ovarian cancer

Introduction

Ovarian cancer includes a variety of histopathological subtypes, with epithelial ovarian cancer (EOC) representing approximately 90% of cases. EOC is the most lethal gynecological malignancy in the United States and the fifth leading cause of cancer-related death among women. In 2022, around 19,880 new cases and 12,810 deaths were projected. The five-year survival rate remains at approximately 49%, though it improves significantly in early-stage disease and certain histological variants. ¹

Platinum-based agents are standard in ovarian cancer treatment; however, hypersensitivity reactions (HSRs), particularly to carboplatin, occur in 8–16% of cases. Risk increases with cumulative exposure, rising to 27% after seven cycles. HSRs may involve type I hypersensitivity, cytokine release, or mixed mechanisms. BRCA mutations and specific regimens further elevate risk. Reactions typically occur during or shortly after infusion, with varying severity, including fever, chills, and skin rashes. ²

Hyperthermic intraperitoneal chemotherapy (HIPEC) enables effective drug delivery to poorly vascularized tumor tissue, while the peritoneal barrier limits systemic absorption and toxicity. Administered after complete cytoreductive surgery (CRS), HIPEC ensures uniform exposure of all peritoneal surfaces to high concentrations of chemotherapy. Hyperthermia (41–43 °C for 30–120 min) enhances cytotoxicity by increasing tissue penetration, exerting direct cytotoxic effects, and improving the oncological response of the drug agents such as cisplatin, and oxaliplatin.^3,4

Desensitization is a process employed to establish immunological tolerance to medication in cases of HSR, enabling the continuation of first-line treatment through incremental dose escalation. ⁵ Various protocols have been used to reintroduce these agents, with differences in dilution bags and infusion rates. ²

Case description

A 41-year-old woman patient was diagnosed with granulosa cell tumor EC IVB (stromal sex cord tumor) without other comorbidity or chronic drug use. Treatment is indicated by the oncologist with paclitaxel and carboplatin for 6 cycles every 21 days. Her condition began when she presented symptoms characterized by generalized rash with itching, nausea, chest pain, and dyspnea in the sixth cycle of carboplatin 750 mg 30 min after the infusion. For this reason, the infusion was suspended, and 0.50 mg of epinephrine was administered intramuscularly, 20 mg of chloropyramine intravenously and 250 ml of saline solution intravenously with resolution of symptoms.

Two weeks after the hypersensitivity reaction to carboplatin, platinum skin tests were performed: carboplatin prick test at a concentration of 10 mg/ml negative, intradermal tests at 0.1 mg/ml and 1 mg/ml negative; cisplatin prick test at 1 mg/ml negative, intradermal tests at 0.01 mg/ml and 0.1 mg/ml negative; oxaliplatin prick test at 5 mg/ml negative, intradermal tests at 0.05 mg/ml and 0.5 mg/ml negative. (Figure 1).

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Figure 1.

Skin prick and intradermal tests for platinum compounds (carboplatin, cisplatin, and oxaliplatin). Figure 1A. Skin prick tests: Positive control histamine 14 × 10 mm, Negative control (glycerin solution) 3 × 2 mm, Carboplatin concentration 10 mg/ml 3 × 2 mm, Cisplatin 1 mg/ml 4 × 3 mm, and Oxaliplatin 5 mg/ml 2 × 2 mm. Figure 2A. Intradermal tests: Negative control physiological solution 5 × 5 mm, Carboplatin concentration 0.1 mg/ml 10 × 5 mm, 1 mg/ml 7 × 6 mm; Cisplatin concentration 0.01 mg/ml 6 × 4 mm, 0.1 mg/ml 9 × 5 mm; and Oxaliplatin concentration 0.05 mg/ml 2 × 3 mm, 0.5 mg/ml 10 × 6 mm.

A multidisciplinary team from medical oncology, surgical oncology, and allergy and immunology reached consensus to proceed with cytoreductive surgery and intraperitoneal desensitization to cisplatin.

At the time of surgery, the peritoneal carcinomatosis index (PCI) was 17 points. The cytoreductive procedure included omentectomy, appendectomy, resection of mesenteric implants, diaphragmatic and parietal peritonectomy, along with end bloc resection of the uterus, bilateral salpingo-oophorectomy, and pelvic peritonectomy, achieving completeness of cytoreduction score of CC-0 (complete cytoreduction). The procedure lasted nine hours, with an estimated blood loss of 900 cc, without complications. (Figure 2).

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Figure 2.

Cisplatin hyperthermic intraperitoneal chemotherapy desensitization.

After the end of the surgery, HIPEC was performed using the closed technique, the total volume consisted of 4600 mL of 0.9% sodium chloride containing 180 mg of cisplatin at 42 °C for 140 min, concluding with the drainage phase without lavage. An intraperitoneal desensitization protocol of 180 mg of cisplatin in 1 bag in 8 steps in 140 min (Table 1). The desensitization was conducted in 8 sequential stages using a stepwise increase in perfusate volume and flow rate, manually titrated via syringe infusion into the circulating perfusate. This approach allowed precise control of the dose during the initial phases (e.g., 40 mL, 80 mL) prior to full recirculation. Premedication included dexamethasone (8 mg IV), chloropyramine (20 mg IV), and ondansetron (8 mg IV) administered one hour prior.

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Table 1.

Cisplatin desensitization protocol 1-bag, 8-step.

Desensitization protocol for Cisplatin with 1 bag
1 bag/ 8 steps	Volumen (mL) per bag	Concentration (mg/mL) per bag	Amount (mL) of bag infused	Infuse dose (mg) per bag
Solution 1	4600	0.039 mg/ml	4600	180 mg

Step	Time (min)	Volume infused (ml)	Administered dose per step (mg)	Cumulative percentage (%)	Cumulative volume infused (ml)	Cumulative dose (mg)
1	10	40 ml	1.5 mg	1%	40 ml	1.56 mg
2	10	80 ml	3 mg	2.5%	120 ml	4.5mg
3	10	150 ml	6 mg	6%	270 ml	10.5 mg
4	10	300 ml	12 mg	12.5%	570 ml	22.5 mg
5	10	580 ml	22.5 mg	25%	1150 ml	45 mg
6	30	1150 ml	45 mg	50%	2300 ml	90 mg
7	30	1150 ml	45 mg	75%	3450 ml	135 mg
8	30	1150 ml	45 mg	100%	4600 ml	180 mg
Time: 140 min Total dose: 180 mg

Discussion

Platinum-based agents are commonly used in cancer treatment but are associated with cumulative toxicity and hypersensitivity reactions, which increase with repeated exposure. HIPEC may reduce these risks through localized absorption. As of 2021, guidelines recommend this approach for select stage II–III epithelial cancers with optimal cytoreduction.^3,6

Cross-reactivity between platinum agents has been reported in several studies, with up to 35–45% of reactions between oxaliplatin and carboplatin, and 7–10% between cisplatin and carboplatin. Although cisplatin administration is generally safe after reactions to carboplatin and oxaliplatin, some reports suggest that anaphylaxis can still occur. ⁷ Unlike intravenous desensitization, where gradual systemic exposure promotes immunologic tolerance, intraperitoneal desensitization occurs within a closed cavity under hyperthermic conditions. Cisplatin remains confined to the peritoneal cavity for up to 140 min, with limited systemic absorption. This may reduce the risk of immediate systemic hypersensitivity reactions, although it also complicates detection of subtle reactions due to general anesthesia.

A 2020 case report documented the successful administration of HIPEC with cisplatin in a patient who had previously experienced an HSR to systemically administered oxaliplatin. This case is particularly relevant given the concern regarding potential cross-reactivity among platinum-based agents when delivered via distinct administration routes, such as systemic versus intraperitoneal infusion. ⁸

Although desensitization extended the duration of administration, cumulative exposure was preserved. More than 75% of the planned cisplatin dose was delivered over 60 min, which aligns with standard HIPEC exposure parameters. Further studies are needed to determine whether prolonged titration affects pharmacologic efficacy. Intraperitoneal cisplatin may offer a therapeutic alternative for patients with prior systemic platinum hypersensitivity. Additional research is necessary to clarify cross-reactivity between administration routes, the cumulative risk of HSR during HIPEC, and the role of skin testing and desensitization in ensuring safety.

Conclusion

To date, there are no documented cases of drug desensitization in the context of intraperitoneal HIPEC. This emphasizes the importance of further investigation into this approach, as demonstrated by the successful outcome in our patient. Such research is critical for developing management strategies for patients who experience severe allergic reactions to platinum-based agents, providing a potential alternative for sustaining effective therapeutic regimens.