Heated intra-operative intraperitoneal oxaliplatin alone and in combination with intraperitoneal irinotecan: Pharmacologic studies
Introduction
Cisplatin is one of the antineoplastic agents most frequently used in intraperitoneal chemo-hyperthermia (IPCH).1–4 The rationale for its intraoperative use is potentiation at high temperatures and the ability to act at any stage of malignant cell replication.1 This drug has a proven activity in the treatment of intraperitoneal malignancies such as gastric and ovarian carcinomas but not for colorectal or appendix adenocarcinomas.5–7#
Oxaliplatin (LOHP) is a third generation platinum complex. It induces no renal or hepatic toxicity, but may cause a cumulative sensory neuropathy. It gives high response rates and improves survival in metastatic colorectal cancer patients. The objective response rate was 24% as a single agent in second-line intravenous chemotherapy and around 55% in first line treatment when combined with 5-fluorouracil (5-FU) and leucovorin at a dose intensity of 40–50mg/m2 per week.8–10#
A new therapeutic concept11 has led to a long-term survival of some cases of peritoneal carcinomatosis (PC).51213 This concept is to treat macroscopic PC with complete cytoreductive surgery and residual microscopic PC with IPCH. Complete cytoreductive surgery is necessary because experimental studies show that drug penetration is limited to a few cell layers beneath the surface of the tumor.14 Intraperitoneal chemotherapy must be used concomitantly with surgery in order to prevent trapping of residual tumor cells in the post-operative fibrin adhesions.15 IPCH leads to a high local concentration of antineoplastic agents,1 and their cytotoxicity is improved by hyperthermia,1 that of LOHP being increased by 180%.16#
LOHP should be a more interesting agent for IPCH in colorectal carcinomatosis than currently used drugs, such as mitomycin,124–6 which has a limited efficacy on such tumors, and 5-FU, which is a long-acting drug not potentiated by hyperthermia.17#
In this article, we report the results of four consecutive prospective trials of IPCH with LOHP following complete cytoreductive surgery for PC, the last one with the addition of irinotecan.#
Patient eligibility and surgical procedures
Patients in good general status with established PC were included in consecutive trials reviewed and approved both by our institution's clinical trial review board and by an independent ethics committee. All patients gave their written informed consent for participation in the studies. In these trials, patients with extraperitoneal metastases could be enrolled, provided the disease was completely resectable.#
At laparotomy, we confirmed the diagnosis of PC by frozen section and scored the extent of PC according to Sugarbaker's peritoneal cancer index.2 Macroscopically detectable disease had to be completely resected before including the patient in the trial. Resection of PC obeyed principles described elsewhere.18 During each procedure, we chose one 5-mm-sized tumor nodule (or 2–3 nodules of 2–3mm each), marked it, and left it in place during IPCH. We then resected it after IPCH to analyze intratumoral oxaliplatin penetration.#
Intraperitoneal chemohyperthermia
We performed IPCH with a continuous closed circuit using four 36-French drains (two inlets and two outlets) connected to two pumps. We used one heating unit and two heat exchangers to eliminate a Y-connector that could reduce flow rates and heat homogeneity.4 IPCH was performed with the abdomen open, skin pulled upwards, after demonstrating that this technique was the only one to allow temperature homogeneity and complete spatial diffusion of the peritoneal instillation in the whole peritoneal cavity.4 Flow rate was 1l/min for each pump. Four thermal probes inside the peritoneal cavity gave continuous temperature feedback, and we monitored the whole process and stored data in a computer. The intra-abdominal temperature was maintained between 42°C and 44°C during IPCH. Perfusion duration was exactly 30min from the time when optimal temperature (>42°C) was reached. The rationale for this short duration of IPCH were: (1) the high cost of time in the operating room, (2) the marked increase in tumor oxygenation occurring mainly during the first 30min at 42.5°C19 and (3) an assumption that increased drug concentration was more effective than long exposure in an optimal IPCH. Usually, 5–10min were necessary to reach a high homogeneous temperature, leading to total peritoneal infusion duration of approximately 40min. Afterwards, we completely evacuated the infusion.#
We delivered the total oxaliplatin dose (also for irinotecan) as a bolus mixed with a 5% dextrose solution at the beginning of the IPCH. The total amount of peritoneal liquid used was based on the body surface area (2l/m2) and the fact that the dimension of the abdominal cavity varies with size and weight. This strategy produced the same intraperitoneal drug concentration in all patients. One hour before IPCH, we delivered systemic intravenous leucovorin 20mg/m2 and 5-FU 400mg/m2, because 5-FU potentiates the action of oxaliplatin and irinotecan.9 However, as 5-FU cannot be mixed with oxaliplatin in the peritoneal cavity due to pH incompatibility, it was delivered intravenously.#
Pharmacokinetic studies
We collected from each patient 14 heparinized blood samples (5ml), the first one being taken just before IPCH, and then for 24h after IPCH. Also, five 5ml peritoneal fluid samples 37°C at the beginning of the procedure, at 42°C when the target temperature was reached, and then every 10min until the end of IPCH (which lasted 30min). For tissue concentration, we studied three types of solid tissues for each patient: a 5mm diameter tumoral nodule, a 5cm diameter piece of normal peritoneal tissue, both treated with IPCH, and one piece of parietal muscle, which was not in contact with IPCH. We performed the platinum assay by using flameless atomic absorption spectrophotometry and irinotecan and SN38 assay by simultaneous determination of CPT-11 and SN 38 by high performance thin layer chromatography (HPLC). We used the Micropharm® software to analyze pharmacokinetic results.#
First trial: pharmacokinetics of heated intraperitoneal oxaliplatin in humans20
From December 1998 to March 2000, we included 20 patients (mean age 44.5±9.1years).#
The first dose level of LOHP was 260mg/m2 (twice the 3-weekly intravenous dosage). Dose escalation was in 50mg/m2, increasing to a maximum of 460mg/m2. Before moving to the next dose level, we had to treat at least three patients at each level without any of them presenting any severe chemotherapy-related toxicity or unexplained post-operative complication. Should one of these complications occur, two more patients had to be treated at the same dose level without any incident before escalating to the next dose. At 410mg/m2, following a protocol amendment, we treated three patients with our standard instillation volume (2l/m2) and three with 2.5l/m2, to evaluate the effect of dilution on pharmacokinetics. The study included a total of 20 patients in this study.#
Results
Intraoperative parameters
Mean duration of surgery, including IPCH, was 8.4±2.7h, mean blood loss 1138±930ml (range 700–3000), and mean number of intestinal anastomoses 1.5±1.1 per patient (range 0–4). Mean peritoneal cancer index (reflecting the extent of PC) was 19.6±2.2 (median 21, range 4–31).#
Postoperative toxicity
There was no hospital mortality. Two intestinal fistulas (10%) occurred during the postoperative course at the first and last dose levels. Other complications occurred in 8 patients at all dose levels: 3 abscesses drained percutaneously, 3 pneumonias, 3 urinary tract infections and 2 central venous catheter infections. There was no renal failure, no neutropenia and no neurotoxicity. Mean hospital stay was 24.8±15days (median 21, range 11–71).#
Pharmacokinetics
There was a rapid, constant and exponential decrease of platinum concentration in the peritoneal perfusion during the procedure. Half the drug was absorbed during the 40min of the procedure. Maximum concentration (Cmax) was 25 times higher in the peritoneal instillation than in plasma at the 460mg/m2 dose level (peritoneal fluid platinum 330μg/ml and plasma platinum 3.2μg/ml).#
Effect of dose escalation
Cmax and AUC increased progressively at each step, suggesting a dose-related effect. At the maximal dose of 460mg /m2, maximal peritoneal concentration and maximal plasma AUC were obtained with no deleterious clinical effect. In addition, mean plasma AUC of ultrafiltered platinum (14.8μg/ml per h) was slightly less than that obtained with systemic intravenous LOHP over 2h at 130mg/m2 (19μg/ml per h).21#
Tissue concentration
Ultrafilterable platinum concentrations in solid tissues (tumor, peritoneum in contact with the drug and distant muscle) are reported in Table 1. Concentrations were higher in bathed tissues than in non-bathed ones. The drug concentration in tumor tissue increased while increasing the dose in the instillation. At the last dose level, it was 17.8 times higher in bathed tissue than in non-bathed tissue.#
Effect of instillation volume on concentration and pharmacokinetics
In patients treated with 410mg/m2 of oxaliplatin, pharmacokinetic results differed dramatically when the total volume of the instillation was changed from 2l/m2 to 2.5l/m2. Platinum intraperitoneal Cmax decreased by 20% in the 2.5l/m2 group. When we used 410mg/m2 of oxaliplatin in 2.5l/m2, Cmax and AUC resembled those observed with 310mg/m2 in 2l/m2 (Table 2), indicating that volume and relative concentration of peritoneal perfusions are very important variables for IPCH.#
Discussion
Oxaliplatin is currently a promising drug for intraperitoneal use with hyperthermia for colorectal carcinomas.16 It is derived from cisplatinum, which acts through the formation of DNA adducts in malignant cells whatever the cell cycle phase. Platinum compounds cytotoxic activity, especially oxaliplatin, is potentiated by hyperthermia.1622 Our trial is the first one to study the pharmacokinetics and tolerance of oxaliplatin administered intraperitonally with hyperthermia in humans. We proved that during IPCH, oxaliplatin was rapidly absorbed, half the dose administered during the 30min of the procedure disappeared.#
We recommend using 460mg/m2 of oxaliplatin with concomitant intravenous 5-FU (400mg/m2) and leucovorin (20mg/m2). Finally, at the 460mg/m2 level, Cmax was 25 times greater in the peritoneum, where we want the drug to be active, than in blood, and the concentration was 17.8 times higher in tissues directly in contact with the drug than in more distant tissues, like muscle. Also, it appears that the volume of instillation must be adapted to each individual by using the body surface area in accordance with the oxaliplatin dose calculation. We suggest that a volume of 2l/m2 is preferable with our IPCH methodology.#
Second trial: pharmacokinetics of heated intraperitoneal oxaliplatin in hypo-osmotic solutions in humans23
Experimentally, intraperitoneal hypotonic solutions increase platinum accumulation in tumor cells and enhance its cytotoxicity in vitro.2425 Experiments with rats showed that the amount of platinum taken up by solid tumors on the peritoneum from a hypotonic solution of 103mosm/l was about twice that taken up from isotonic solutions.26 As a result of these laboratory investigations we conducted a phase I clinical study of LOHP administered by IPCH with increasingly hypotonic solutions, following complete cytoreductive surgery for PC. Our goal was to test the possibility that hypotonic intraperitoneal LOHP might be preferable to and cheaper than intraperitoneal LOHP dose escalation.#
From January 2001 to July 2001, we enrolled 16 consecutive patients.#
Experimental design
The total amount of peritoneal liquid used was based, as for LOHP, on the body surface area, and set at 2l/m2. The dose of LOHP was 460mg/m2, as defined in our previous clinical study.20 One hour before IPCH, we delivered leucovorin 20mg/m2 and 5-FU 400mg/m2. Four solutions with osmolarities of 300, 200, 150, and 100mosm/l were prepared by diluting 5% dextrose solutions in sterilized distilled water. Three patients were treated with 300mosm/l, four with 200mosm/l (a mistake was made in the pharmacokinetic study, necessitating the inclusion of a fourth patient), four with 150mosm/l, and five with 100mosm/l (only four valid pharmacokinetic datasets were obtained at this level).#
Results
Intraoperative parameters
Mean duration of the procedure, including surgery and IPCH, was 7.7±2.6hours, mean blood losses were 959±728ml (range 100–4000ml), and mean number of intestinal sutures was 2.9±2.1 per patient (range 1–7). Mean peritoneal index (reflecting the extent of PC) was 17.6±2.3 (median 19, range 4–35).#
Postoperative toxicity
There was one in-hospital death (6.2%). A patient free of complications died suddenly on day 7 after rupture of an undiagnosed intracranial arterial aneurysm. Two intestinal anastomotic fistulae occurred postoperatively in patients treated with solutions of 300 and 100mosm/l, representing a fistula rate of 12.5% for 16 patients and 4.3% for 46 anastomoses. Diffuse peritoneal hemorrhage occurred in 5 patients (31.2%), necessitating repeated laparotomies mainly in patients treated with solutions of 150 or 100mosm/l, and the site of bleeding was not found. There was no neurotoxicity. No noteworthy modification of plasmatic osmolarity and no evidence of cytolysis (LDH increase) were detected. The overall morbidity rate (including all types of complications, even minimal) was 56.2%, only 6 patients (37.5%) having an uneventful postoperative course. The mean hospital stay was 28.7±14days (median 27days, range 12–65days).#
Pharmacokinetics
Half the drug dose was absorbed during the 35-min IPCH procedure. There was no significant difference in LOHP absorption according to the osmolarity of the solution (Table 3). There was no significant difference in the AUC or Cmax of total LOHP or ultrafiltered LOHP according to the osmolarity of the solution. The use of increasingly hypotonic solutions did not yield higher concentrations of total LOHP or ultrafilterable LOHP in bathed tissues (peritoneum and tumor nodules), as shown in Table 4.#
Discussion
This trial is the first clinical study of the pharmacokinetics and safety of LOHP administered intraperitoneally with hyperthermia in increasingly hypotonic solutions. Although experimental studies showed kinetic advantages in using intraperitoneal platinum in hypotonic solutions, our clinical trial did not confirm the results of these experimental studies.24–26 LOHP disappearance from the intraperitoneal solution was similar whatever the osmolarity. In contrast, very hypotonic solutions (150 and 100mosm/l) induced local and systemic toxicity, reflected by diffuse intraperitoneal hemorrhage (31.2% of patients), and more frequent severe thrombocytopenia than observed in our previous trial with isotonic solutions, in which no postoperative hemorrhage occurred in the 20 patients studied.20#
In conclusion, contrary to experimental studies, this phase I clinical trial suggests that the use of hypotonic intraperitoneal solutions during IPCH with LOHP does not increase tumor or systemic penetration of LOHP, but it induces a high incidence of intraperitoneal hemorrhage and thrombocytopenia.#
Third trial: A phase II study with intraperitoneal LOHP in colorectal cancer patients27
Between June 1998 and February 2001, 24 patients with an evident PC of colorectal origin were treated with intraperitoneal LOHP according to the results of our phase I pharmacokinetic study. They underwent complete resection of the PC and of associated metastases (liver 4, ovary 2, spleen 1), followed by IPCH performed in an open abdominal cavity. Dose of LOHP was 460mg/m2, in 2l/m2 of dextrose 5% so the intraperitoneal concentration was the same for each patient during 30min at 42–44°C, with a flow rate of 2l/min. During the hour preceding IPCH, they received an intravenous administration of 5-FU (400mg/m2) and leucovorin (20mg/m2).#
Median age was 50±9.3years, mean peritoneal cancer index, 16.9 (SD 9.5, median 13.5, range 4–35), median operative duration, 490min, and median blood loss, 965ml. Two postoperative deaths (8%) occurred by intracerebral hemorrhage (one due to a severe thrombocytopenia, and one due to a ruptured aneurysm), and grade 2–3 morbidity rate was 37.5% (with two grade 3 aplasias). Median hospital stay was 21days. All the patients had a minimal follow-up of 18months. Median follow-up was 27.4months (range 18.3–49.6). One patient committed suicide at 8months without any evidence of recurrence.#
At 1, 2 and 3years, global survival and disease-free survival rates were respectively 83%, 74%, 65% and 70%, 50%, 50% (Fig. 1). Only 32% of the 22 postoperative living patients presented a peritoneal recurrence. In this small series, the presence of extraperitoneal metastases had no significant impact on recurrences (p=0.49), but a peritoneal cancer index greater than 24 did (p=0.005).#
Discussion
With an overall survival rate of 74%, a disease-free survival rate of 50%, and an incidence of peritoneal recurrence of 32% at 2years, the results of this series are encouraging, and one may predict a 5-year survival rate close to 40%. Also, the 2-year overall survival rate of 74% is superior to the 60% that we obtained earlier without hyperthermia and without LOHP in similar patients.28 However, more extensive data are necessary to confirm these options.#
Fourth trial: Pharmacokinetics of heated intraperitoneal oxaliplatin in combination with irinotecan in humans29
Its purpose was to report the pharmacokinetics and tolerance profile of heated intraoperative intraperitoneal oxaliplatin combined with irinotecan. Both of these drugs are potentiated by hyperthermia. In 2002, 39 consecutive patients with peritoneal carcinomatosis underwent complete cytoreductive surgery followed by intra-operative IPCH with a fixed dose of oxaliplatin (460mg/m2), and one of the seven increasing doses of irinotecan (from 300 to 700mg/m2). IPCH was performed with the abdomen open, for 30min at 43°C, with 2l/m2 of a 5% dextrose instillation in a closed continuous circuit. Patients received intravenous leucovorin (20mg/m2) and 5-fluorouracil (400mg/m2) just before IPCH.#
Results
The hospital mortality rate was 2.5% and the non-hematological complication rate was 25%. However, grade 3–4 hematological toxicity rate was 58%. The mean delay for aplasia appearance was postoperative day 7 (range 3–12). It was 8.7days for the lower doses of irinotecan (300–450mg/m2) and 5.2days for the higher doses (500–700mg/m2). Mean duration of hematologic toxicity was 2.7±1.6days. The hematological toxicity was correlated with the peritoneal cancer index ≥20 (p=0.017) and with a long duration of surgery (p=0.046). There was no neurotoxicity, but a grade 3 diarrhea (>7 stools/day) occurred in 81% of patients. The mean hospital stay was 28.1±8.3days (median 21, range 13–103).#
Pharmacokinetics
The results were exactly similar to those reported previously when oxaliplatin was the sole molecule in the peritoneal instillation:20 the addition of increasing doses of irinotecan in the peritoneal perfusion did not modify its pharmacokinetics.#
The intraperitoneal concentration of irinotecan presented a rapid, constant and exponential decrease during the procedure. At the end of IPCH, 45–50% of the molecule was absorbed (Table 5). Irinotecan is a pro-drug that exerts its anticancer activity after transformation into SN-38 by carboxylesterases. SN-38 is 100–1000-fold more cytotoxic than irinotecan. The effect of dose escalation resulted in increasing concentrations of irinotecan and SN-38 in peritoneum as in plasma.#
Tissue concentration of irinotecan
The drug concentration in tumor tissue progressively increased with doses from 300 to 400mg/m2, but seemed to stay constant for doses higher than 400. The different concentration ratios between the tumor (bathed with IPCH) and the muscle (not bathed tissue) are reported in Table 6. They were 16–23 times higher in bathed tissues than in non-bathed tissues, and not significantly different according to the dosages of intraperitoneal irinotecan.#
Discussion
This trial is the first to report the intraperitoneal pharmacokinetics and tolerance of irinotecan plus oxaliplatin administered intraperitonally, along with hyperthermia, in humans. SN-38 is 100–1000-fold more cytotoxic than irinotecan. However, a recent study reported carboxylesterases to be minimally present in the peritoneum. Our findings showed rapid conversion of irinotecan to SN-38 in that SN-38 was detected in the peritoneal instillation in the first minutes of IPCH and remained at a high constant level during the whole procedure. Furthermore, we demonstrated that the intra-tumoral penetration of irinotecan was important and effective after tissue bathing, and that the tissue concentration ratio between bathed and non-bathed tissues ranged from 17 to 23, close to the ratio of 17.8 obtained with oxaliplatin. The conclusion of this phase I trial was to recommend the doses of 460mg/m2 for intraperitoneal oxaliplatin, and 400mg/m2 for irinotecan in a 2l/m2 instillation over 30min at 43°C. In January 2004 a phase II study with this dosage was initiated. A high rate of hematological complications was observed, causing us to reduce the dose of both drugs to 360mg/m2.#
Conclusion
These trials studied pharmocokinetic, tolerance and efficiency of heated intraperitoneal oxaliplatin and intraperitoneal irinotecan. These molecules are currently the most interesting drugs for colorectal carcinomas. Their association with intravenous 5-fluorouracil and leucovorin result in a synergistic tri-therapy, which is an association most likely to eradicate minute deposits of tumor. This aggressive treatment of PC with a combination of cytoreductive surgery and regional hyperthermic chemotherapy creates an opportunity to cure an otherwise terminal illness. It is a new frontier of treatment that one should not overlook. In such conditions, it is justified to accept a high-risk treatment if proven to be effective.#
Acknowledgements
This work was supported in part by the Association de Recherche Contre le Cancer (grant nos. 9744 and 5660). Oxaliplatin was kindly supplied by Sanofi-Synthelab, and Irinotecan by Aventis.#
Figures and Tables
Table 1
| IP level (mg/m2) | Tumor nodule(s) | Peritoneum | Musclea |
| 260 | 228 | 230 | 29 |
| 310 | 248 | 273 | 31 |
| 360 | 327 | 296 | 20 |
| 410 | 323 | 287 | 21 |
| 460 | 339 | 392 | 19 |
| ip, intraperitoneal. |
Table 2
| Dose (mg/m2) | ||||
| 410 | 410 | 360 | 310 | |
| Volume (l/m2) | 2 | 2.5 | 2 | 2 |
| Instillation | 205 | 164 | 180 | 155 |
| Plasma | 14.1 | 9.1 | 12.4 | 8.4 |
Table 3
| Step (mosm/l) | ||||
| 300 | 200 | 150 | 100 | |
| Beginning | 173 | 182.3 | 171 | 169.3 |
| End | 68.6 | 77.3 | 76 | 78.5 |
| Absorption (%) | 60 | 57.6 | 55.5 | 53.6 |
Table 4
| Osmolarity of solution (mosm/l) | ||||
| 300 | 200 | 150 | 100 | |
| Number of cases | 3 (+3)b | 3 | 4 | 4 |
| Unbathed tissuea | 10.4 (2.7) | 15.6 (3.4) | 11.6 (3.1) | 17.7 (3.6) |
| Peritoneum | 338.6 (92.2) | 313.6 (101.2) | 449.2 (83.2) | 396.3 (72.8) |
| Tumor nodule | 298.5 (87.2) | 322 (76.4) | 440.1 (108.1) | 479.6 (81.7) |
| Ratio bathed/unbathed | 30.6 | 20.4 | 38.3 | 24.7 |
| Standard deviations are in parentheses. |
Table 5
| IP irinotecan (mg/m2) | At the beginning of IPCHa | At the end of IPCHb | % of absorption |
| 300 | 81.6 | 45.1 | 44.7 |
| 350 | 133.2 | 74.4 | 44.3 |
| 400 | 97.4 | 53.6 | 44.9 |
| 450 | 151.7 | 81 | 46.7 |
| 500 | 155.6 | 79.8 | 48.7 |
| 600 | 164.8 | 91.8 | 44.5 |
| 700 | 209.8 | 108.8 | 48.3 |
| ip, intraperitoneal; IPCH, intraperitoneal chemohyperthermia. |
Table 6
| Dosage of intraperitoneal irinotecan (mg/m2) | |||||||
| 300 | 350 | 400 | 450 | 500 | 600 | 700 | |
| Ratio tumor/muscle | 15.9 | 15.8 | 20.9 | 23.2 | 22.1 | 16.8 | 18.8 |
References
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