Drugs, doses, and durations of intraperitoneal chemotherapy: standardising HIPEC and EPIC for colorectal, appendiceal, gastric, ovarian peritoneal surface malignancies and peritoneal mesothelioma

Figures & data

Table 1. Overview of pharmacologic properties of the chemotherapy drugs most frequently selected for IP application.

Drug	Type	Molecular weight (Daltons)	Dose	Exposure time	AUC-ratio	Penetration depth	Thermal augmentation	Remarks
Cisplatin	Alkylator	300.1	50 mg/m^2–250 mg/m^2	30 min–20 h	7.8–21	1–5 mm	Yes	Dose limiting nephrotoxicity
Carboplatin	Alkylator	371.25	200 mg/m^2–800 mg/m^2	30 min–20 h	1.9–10	0.5–9 mm	Yes
Oxaliplatin	Alkylator	397.3	200 mg/m^2–460 mg/m^2	30 min–20 h	3.5–16	1–2 mm	Yes
Melphalan	Alkylator	305.2	50 mg/m^2–70 mg/m^2	90 min–120 min	93		Yes	Rapid degradation
Mitomycin C	Antitumor antibiotic	334.3	15 mg/m^2–35 mg/m^2	90 min–150 min	10–23.5	2 mm	Yes
Doxorubicin	Antitumor antibiotic	579.99	15 mg/m^2–75 mg/m^2	90 min	162–579	4–6 cell layers	Yes
Docetaxel	Antimicrotubuli agent	861.9	45 mg/m^2–150 mg/m^2	30 min–23 h	552	NA	Conflicting data	Cell-cycle specific
Paclitaxel	Antimicrotubuli agent	853.9	20 mg/m^2–180 mg total dose	30 min–23 h	1000	>80 cell layers	Conflicting data	Cell-cycle specific
5-fluorouracil	Antimetabolite	130.08	650 mg/m^2 for 5 days (EPIC)	23 h	250	0.2 mm	Yes (mild)	Cell-cycle specific
Gemcitabine	Antimetabolite	299.5	50 mg/m^2–1000 mg/m^2	60 min–24 h	500	NA	NA	Cell-cycle specific
Pemetrexed	Antimetabolite	471.4	500 mg/m^2	24 h	19.2	NA	NA	Cell-cycle specific

AUC: Area-under-the-curve; thermal augmentation: cytotoxicity of the chemotherapeutic agent is enhanced by hyperthermia.

Table 2. Hyperthermic intraperitoneal peroperative chemotherapy (HIPEC) and bidirectional intraoperative chemotherapy (BIC) regimens.

Cisplatin-based regimens
Sugarbaker regimen
1. Add cisplatin to 2 L 1.5% dextrose peritoneal dialysis solution
2. Add doxorubicin to the same 2 L 1.5% peritoneal dialysis solution
3. Dose of cisplatin is 50 mg/m^2 and doxorubicin is 15 mg/m^2 for 90-min HIPEC treatment
Intravenous chemotherapy
4. Add ifosfamide 1300 mg/m^2 to 1 L 0.9% sodium chloride. Begin continuous IV infusion over 90 minutes simultaneous with intraperitoneal chemotherapy
5. Add mesna disulphide 260 mg/m^2 in 100 mL 0.9% sodium chloride to be given IV as a bolus 15 min prior to ifosfamide infusion
6. Add mesna disulphide 260 mg/m^2 in 100 mL 0.9% sodium chloride to be given IV as a bolus 4 hours after ifosfamide infusion
7. Add mesna disulphide 260 mg/m^2 in 100 mL 0.9% sodium chloride to be given IV as a bolus 8 h after ifosfamide infusion
National Cancer Institute Milan regimen
1. 15.25 mg/L of doxorubicin and 43 mg/L of cisplatin for 90-min HIPEC treatment
2. Chemotherapy solution 4–6 litres based on capacity of the peritoneal space
Oxaliplatin-based regimens
Elias high-dose oxaliplatin regimen
1. Add oxaliplatin to 2 L/m2 5% dextrose solution
2. Dose of oxaliplatin is 460 mg/m2
3. 30-minute HIPEC treatment
Intravenous component
4. Add 5-fluorouracil 400 mg/m^2 and leucovorin 20 mg/m^2 to separate bags of 250 mL normal saline. Begin rapid intravenous infusion of both drugs one hour before intraperitoneal chemotherapy
Glehen medium dose oxaliplatin regimen
1. Add oxaliplatin to 2 L/m^2 5% dextrose solution
2. Dose of oxaliplatin is 360 mg/m^2
3. 30-min HIPEC treatment
Intravenous component
4. Add 5-fluorouracil 400 mg/m^2 and leucovorin 20 mg/m^2 to separate bags of 250 mL normal saline. Begin rapid intravenous infusion of both drugs one hour before intraperitoneal chemotherapy
Wake Forest University oxaliplatin regimen
1. Add oxaliplatin to 3 L 5% dextrose solution
2. Dose of oxaliplatin is 200 mg/m^2
3. Two hour HIPEC treatment
Mitomycin C-based regimens
Sugarbaker regimen
1. Add mitomycin C to 2 L 1.5% dextrose peritoneal dialysis solution
2. Add doxorubicin to the same 2 L 1.5% peritoneal dialysis solution
3. Dose of mitomycin C and doxorubicin is 15 mg/m^2 for each chemotherapy agent
4. Add 5-fluorouracil (400 mg/m^2) and leucovorin (20 mg/m^2) to separate bags of 250 mL normal saline. Begin rapid intravenous infusion of both drugs simultaneous with intraperitoneal chemotherapy
Dutch high-dose mitomycin C Regimen: ‘triple dosing regimen’
1. Add mitomycin C to 3 L 1.5% dextrose peritoneal dialysis solution
2. Add mitomycin C to the 1.5% peritoneal dialysis solution at a dose of 17.5 mg/m^2 followed by 8.8 mg/m^2 at 30 min and 8.8 mg/m^2 at 60 min
3. Total dose of mitomycin C 35 mg/m^2 for 90-min HIPEC treatment
American Society of Peritoneal Surface Malignancy Low-Dose Mitomycin C Regimen: ‘concentration-based regimen’
1. Add mitomycin C to 3 L 1.5% dextrose peritoneal dialysis solution
2. Add mitomycin C to the 1.5% peritoneal dialysis solution at a dose of 30 mg/3 L followed by 10 mg at 60 min
3. Dose of mitomycin C 40 mg/3 L for 901-min HIPEC treatment

Figure 1. Pharmacologic concept of bidirectional intravenous and intraperitoneal chemotherapy. (Credit: Fujiware et al. [139], with permission.)

Table 3. Early postoperative intraperitoneal chemotherapy (EPIC)-regimens.

Early postoperative intraperitoneal chemotherapy with 5-fluorouracil on postoperative days 1 through 4 for adenocarcinoma from appendiceal, colonic, and gastric cancer

1. 5-Fluorouracil _________ mg (400 mg/m^2 for females and 600 mg/m^2 for males, maximum dose =1400 mg) and 50 meq sodium bicarbonate in _________ mL 1.5% dextrose peritoneal dialysis solution via the Tenckhoff catheter daily for 4 days: start date _________, stop date _________ .

2. The intraperitoneal fluid volume is 1 L for patients ≤2.0 m^2 and 1.5 L for those >2.0 m^2.

3. Drain all fluid from the abdominal cavity prior to instillation, then clamp abdominal drains.

4. Run the chemotherapy solution into the abdominal cavity through the Tenckhoff catheter as rapidly as possible. Dwell for 23 h and drain for 1 h prior to next instillation.

5. Use gravity to maximise intraperitoneal distribution of the 5-fluorouracil. Instill the chemotherapy with the patient in a full right lateral position. After 30 min, direct the patient to turn to the full left lateral position. Change position right to left every 30 min. Continue turning for the first 6 h after instillation of chemotherapy solution.

6. Monitor with pulse oximeter during the first 6 hours of intraperitoneal chemotherapy.

7. Continue to drain abdominal cavity after final dwell until Tenckhoff catheter is removed.

Early postoperative intraperitoneal chemotherapy with paclitaxel on postoperative days 1–5 for peritoneal mesothelioma and ovarian cancer

1. Paclitaxel _________ mg (20 to 40 mg/m^2 × _________ m^2) (maximum dose =80 mg) in 1000 mL 6% Hespan^® (B. Braun, Irvine, CA) via Tenckhoff catheter daily: start date _________, stop date _________ .

2. Instill as rapidly as possible via Tenckhoff catheter. Dwell for 23 h. Drain from Jackson-Pratt drains for one hour prior to next instillation.

3. During the initial 6 h after chemotherapy infusion, the patient’s bed should be kept flat. The patient should be on the right side during instillation. Turn at 30 min post-instillation onto the left side and continue to change sides at 30-min intervals for 6 h.

4. Monitor with pulse oximeter during the first 6 hours of intraperitoneal chemotherapy.

5. Continue to drain abdominal cavity by Jackson-Pratt drains after the last dose of intraperitoneal chemotherapy.

Fujiware K, Armstrong D, Morgan M, et al. (2007). Principles and practice of intraperitoneal chemotherapy for ovarian cancer. Int J Gynecol Cancer 17:1–20.

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