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Optimization of Hyperthermic Intraperitoneal Chemotherapy With Oxaliplatin Plus Irinotecan at 43°C After Compete Cytoreductive Surgery: Mortality and Morbidity in 106 Consecutive Patients

¹ Department of Surgical Oncology, Institut Gustave Roussy, 39 Rue Camille Desmoulins, 94805 Villejuif, Cedex, France
² Intensive Care Unit, Institut Gustave Roussy, 39 Rue Camille Desmoulins, 94805 Villejuif, Cedex, France
³ Department of Anesthesiology, Institut Gustave Roussy, 39 Rue Camille Desmoulins, 94805 Villejuif, Cedex, France

Correspondence: Address correspondence and reprint requests to: D. Elias, MD, Phd; E-mail: elias{at}igr.fr

	ABSTRACT

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Background: Peritoneal carcinomatosis (PC), which has hitherto been regarded as a lethal entity, can now be cured with surgery (treating macroscopic tumor seeding) combined with hyperthermic intraperitoneal chemotherapy (HIPEC) (treating residual microscopic disease). The purpose of this study was to analyze the morbidity and mortality of a particular approach associating optimal (R0–R1) cytoreduction, optimal HIPEC combining oxaliplatin and irinotecan, and an optimal homogeneous intraperitoneal temperature of 43°C.

Methods: A total of 106 consecutive patients were included in this prospective phase 2 study. After complete resection of the PC, HIPEC was performed by the Coliseum technique with oxaliplatin (360 mg/m²) combined with irinotecan (360 mg/m²) in 2 L/m² of 5% dextrose, over 30 minutes at a real intraperitoneal temperature of 43°C. During the hour preceding HIPEC, patients received 5-fluorouracil (400 mg/m²) and leucovorin (20 mg/m²) intravenously, resulting in tritherapy.

Results: Postoperative mortality and morbidity rates were 4% and 66%, respectively. The most frequent complications were digestive fistula (24%), lung infection (16%), and severe hematological toxicity (11%). Statistical correlation was evidenced between morbidity and the carcinomatosis score (P = .0008), the number of resected organs (P = .0001), the duration of surgery (P = .0001), and blood loss (P = .0001).

Conclusions: This new approach, optimized in three respects (complete cytoreduction, combination oxaliplatin with irinotecan, and high temperature) has resulted in a relatively high but acceptable incidence of adverse events considering the expected advantage for survival.

Key Words: Morbidity • Mortality • Peritoneal carcinomatosis • Intraperitoneal chemotherapy • Hyperthermia • Cytoreductive surgery • Oxaliplatin • Irinotecan

	INTRODUCTION

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Peritoneal carcinomatosis (PC) is one of the most common causes of incurability of intra-abdominal cancers. Surgery or chemotherapy alone is not able to cure these patients. However, a new therapeutic concept¹ has already led to definitive cure of some cases of PC.^2–4 This concept is to treat macroscopic PC with complete cytoreductive surgery and residual microscopic PC with hyperthermic intraperitoneal chemotherapy (HIPEC). Complete cytoreductive surgery is necessary because experimental studies show that drug penetration is limited to a few cell layers under the surface of the tumor.⁵ Intraperitoneal chemotherapy must be immediate so that residual tumor cells do not get trapped in the postoperative fibrin adhesions.^6,7 HIPEC leads to a high local concentration of antineoplastic agents^8,9 whose cytotoxicity is enhanced by hyperthermia.^8–10 As a result of this approach, we recently published a 5-year survival rate of 48% in 30 patients with colorectal PC treated more than 5 years ago with heated intraperitoneal oxaliplatin.¹¹

Oxaliplatin is an interesting agent for HIPEC in colorectal PC.^12–14 It belongs to the family of platins, which are frequently used in HIPEC.^8,9,15–17 It does not cause renal or hepatic toxicity. In a previous trial, we performed a pharmacokinetic study of heated intraperitoneal oxaliplatin in humans. We established that 460 mg/m² of oxaliplatin in 2 L/m² of isoosmotic 5% dextrose, at 42–44°C over 30 minutes, administered intraperitoneally after an intravenous (IV) perfusion of 5-fluorouracil (5-FU) (400 mg/m²) with folinic acid (20 mg/m²), was well tolerated.¹⁸ It was also pharmacologically interesting, with intratumor penetration 17.8-fold higher than in nonbathed tissue.¹⁸ 5-FU was provided to potentiate the effect of oxaliplatin^12–15 but could not be mixed intraperitoneally with it because of pH incompatibility. Moreover, it is widely recognized that chemotherapy regimens including multiple agents are more potent than single-agent regimens.

Recently, an in vitro study about chemohyperthermia showed that the cytotoxic effect of combining of two drugs (irinotecan and mitomycin C) was higher than the use of a single agent (irinotecan) and that 42.5°C was more efficient than 39°C.¹⁹ Irinotecan is considered the second most potent agent after oxaliplatin for colorectal cancers,^20,21 yielding a high rate of tumor responses when administered intravenously with oxaliplatin and 5-FU. Combining oxaliplatin with irinotecan during HIPEC was the next logical step, particularly when we consider that this new therapeutic approach is the last resort for these patients. In our opinion, cytoreductive surgery plus HIPEC cannot be repeated many times in a patient, so it must be as efficient as possible when performed. To achieve this efficacy, the drug concentration and the level of hyperthermia must be increased, which may lead to the risk of postoperative complications. This is why we added irinotecan to oxaliplatin during HIPEC and published in 2004 the first pharmacokinetic and phase 1 study in humans.²² We also demonstrated that SN-38, the active metabolite of irinotecan, appeared inside the peritoneal cavity as soon as HIPEC began. Our phase 1 study enabled us to define the appropriate doses of oxaliplatin and irinotecan to use during HIPEC. Subsequently, we initiated a phase 2 prospective study that used these defined doses, which were identical for all patients.

In this study, we report the mortality and morbidity of this phase 2 clinical study of an optimized approach with HIPEC combining oxaliplatin plus irinotecan and intravenous 5-FU and leucovorin after complete cytoreduction in all patients, with a real intraperitoneal temperature of 43°C.

	PATIENTS AND METHODS

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Patient Eligibility
From June 2003 to December 2005, a total of 106 consecutive patients with preoperatively identified PC were eligible for this prospective phase 2 trial. The protocol was reviewed and approved both by our institutional review board and by an independent ethics committee. All patients provided written informed consent for participation in the study. Eligibility criteria were as follows: detectable PC, a good general status, age <66 years, no extra-abdominal extension, no evidence of bowel obstruction, no abundant ascites, and no bulky clinical or radiological PC. The presence of one or two easily resectable liver metastases was not a contraindication for inclusion.²³ All patients had already received miscellaneous regimens of IV chemotherapy during at least 2 months (according to the origin of the PC), except for those with peritoneal pseudomyxoma. Rapid progression of the PC under IV chemotherapy was a contraindication.²⁴ The preoperative workup included a clinical rectal examination, a computed tomographic scan of the thorax and abdomen, a complete colonoscopy, and tumor marker determination. Positron emission tomography was not performed in a systematic manner. The primary tumor was always resected first (except for pseudomyxoma and mesothelioma), and the mean interval between resection and HIPEC was 12.2 ± 4.2 months. The mean number of laparotomies per patient before HIPEC was 1.7 ± .9 (median, 2; range, 0–6).

The origin of the PC is reported in Table 1; it was mostly colorectal (45%) or pseudomyxoma from the appendix (39%).

Surgical Procedures
One hundred six patients were thus included in the study, 42 men and 64 women, with a mean age of 48 ± 12.4 years (range, 14–65 years). Resection of PC obeyed principles described elsewhere.²⁵ Intestinal anastomoses were delayed until after HIPEC was performed to treat the bowel margins.

Intraperitoneal Chemohyperthermia
We performed HIPEC with a continuous closed circuit by 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 homogeneity¹⁷ (Sunchip Gamidatech, Eaubonne, France). HIPEC was performed with the abdomen open and the skin pulled upward. We previously demonstrated in our institution that this was the only technique able to ensure temperature homogeneity and complete spatial diffusion of the peritoneal instillation in the whole peritoneal cavity.¹⁷ The flow rate was 1 L/min for each pump (total, 2 L/min). Four thermal probes inside the peritoneal cavity provided continuous temperature feedback, and we monitored the whole process and recorded it on a computer. The mean intra-abdominal temperature was 43°C during HIPEC; the temperature maintained throughout the abdominal cavity was between 42°C and 45°C.

The duration of the perfusion was 30 minutes from the time when the four thermic probes had reached the minimal temperature of 42°C. Usually, less than 5 minutes were required to obtain a high homogeneous temperature, leading to a total peritoneal infusion duration of approximately 35 minutes. The infusion was then completely evacuated. The total oxaliplatin and irinotecan doses were administered as a bolus mixed with 5% dextrose at the beginning of the procedure. The oxaliplatin and the irinotecan doses were identical (360 mg/m²), as recommended in our previous study in humans.²² The total amount of peritoneal liquid used was based on the body surface area (2 L/m²), as is the case for chemotherapy. We used measurement of the body surface area (m²) to determine the instillation volume and the oxaliplatin dose; this resulted in a similar intraperitoneal concentration of the drug in each patient, as proven by ourselves¹⁸ and later by Sugarbaker.²⁶ One hour before HIPEC, we administered systemic IV leucovorin, 20 mg/m², and 5-FU, 400 mg/m², because 5-FU potentiates the action of oxaliplatin and irinotecan^12,20 and because 5-FU cannot be mixed with oxaliplatin in the peritoneal cavity because of pH incompatibility. Thus, after this systemic perfusion, tumor and healthy tissue were soaked with 5-FU before the beginning of the HIPEC.

Postoperative Morbidity
Complications were graded on a scale of 1–5 according to a previously published grading system.²⁷ Grade 0 represents cases with no complications. Grade 1 complications are those requiring no intervention or minor interventions such as oral antibiotics, bowel rest, or basic monitoring. Grade 2 complications are those requiring moderate interventions such intravenous medications (e.g., antibiotics or antiarrhythmics), prolonged tube feeding, or chest tube insertion. Grade 3 complications are those requiring hospital readmission, surgical intervention, or radiological intervention. Grade 4 complications are those producing chronic disability, organ resection, or enteral diversion. Grade 5 complications result in death.

Grades 1 and 2 are grouped as minor, and grades 3–5 are considered major complications for the purpose of the analysis. Severe aplasia was defined as follows: a leukocyte count of <500/mL, platelets <50,000/mL, and hemoglobin <6.5 Hb/dL.

Statistics
Patients were recorded prospectively in a specific database. Postoperative mortality was analyzed during the 30 days after HIPEC and until the patient was discharged from the hospital. The ² test or the Fisher exact test, when appropriate, were used for univariate comparisons. Differences were considered statistically significant at P = .05.

	RESULTS

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Intraoperative Data
Intraoperative data are reported in Table 2 (the number of invaded peritoneal areas among the 13 areas described by Sugarbaker, peritoneal index, resected organs, digestive anastomoses, duration of surgery, and blood loss). Before resection, the maximal size of tumor nodules was >5 cm in diameter (or lesions were diffuse in one whole area) in 57 patients, between 5 cm and 5 mm in 39, and <5 mm in 10. After resection, the size of residual tumor seeding was 0 mm in 86 patients (81%), 1 mm in 18, and 2 mm in 2 (19%). There were 42 (40%) low rectal anastomoses, below the Douglas pouch (four of them were protected with a transient ileostomy), and 10 total colectomies. Urinary sutures (ureter or bladder) were required in 15 patients. A partial gastrectomy was performed in eight patients, and resection resulted in a small bowel (length >2 m) in four patients. Twenty-three patients (22%) had associated extraperitoneal metastases (including a boy aged 14 whose primary hepatocellular carcinoma was in the liver), which were resected at the same time (liver, 9; ovary, 12; spleen, 2). Liver resections never involved more than one-third of the liver mass. The mean duration of cytoreductive surgery plus HIPEC was 8 hours, and the mean blood loss was approximately 900 mL (Table 2).

Morbidity
Complications were assessed until patients were discharged from the hospital. Only 36 patients (34%) did not experience complications. Complications occurred in 70 patients (66%), and were intra- (n = 26) or extra- (n = 62) abdominal complications, or both (n = 18) (Table 3). Details on complications and their treatment are reported in Table 4. The most frequent were digestive fistula (23%), lung infection (16%), and grade 4 neutropenia or thrombocytopenia (11%). The mean time of onset of severe aplasia was day 7 after surgery (range, 4–12 days). The mean duration of severe aplasia was 3.4 days (range, 1–9 days). Among grade 2 complications, transient diarrhea and delayed restoration of intestinal transit were the most frequent and affected 86% of the patients. Finally, grade 0–2, grade 3–4, and grade 5 complications were observed in 34%, 66%, and 4% of our patients, respectively.

Parameters Correlated With Grade 3–5 Complications
Age was not statistically significantly correlated with the occurrence of intra-abdominal complications (P = .2), but it affected extra-abdominal complications (P = .01). Two types of primary disease (colorectal and peritoneal pseudomyxoma) were almost statistically significantly correlated (P = .06) with intra-abdominal complications. The occurrence of intra-abdominal complications was probably correlated with the number of resected organs (P = .07), but not with the number of digestive anastomoses (P = .54), peritoneal score (P = .49), duration of surgery (P = .10), or the amount of blood loss (P = .55). In contrast, the occurrence of extra-abdominal complications (which occurred more frequently) was highly correlated with the number of resected organs (P = .001) and the peritoneal score (P = .0008), two parameters that are strongly associated. The occurrence of extra-abdominal complications was also highly correlated with the duration of surgery (P = .0001) and the amount of blood loss (P = .0001).

Severe neutropenia was correlated with lung infection (P = .007), but not with digestive fistula (P = .62) or deep-seated abscess (P = .73).

	DISCUSSION

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Complete cytoreductive surgery plus HIPEC is becoming a new standard of treatment for selected patients with peritoneal tumor seeding, according to the results of the randomized trial by Verwaal et al.,²⁸ which compared standard treatment to cytoreductive surgery with HIPEC using mitomycin C in colorectal patients, and according to the 48% 5-year survival rate we obtained in 30 consecutive colorectal patients using heated intraperitoneal oxaliplatin.¹¹ The completeness of the cytoreduction has the strongest impact on survival^29,30 and is the first way to optimize our results, even if this leads to an increase in adverse events.

Mitomycin C (which is widely used for HIPEC ) is not considered a very active drug for digestive cancers, unlike oxaliplatin and irinotecan.^{12–14,20,21} Multiagent chemotherapy is more potent than single-agent chemotherapy. There is therefore a solid rationale for combining oxaliplatin with irinotecan during HIPEC. We successively conducted a phase 1 trial combining oxaliplatin with irinotecan during HIPEC in humans to determine the best dose to use,²² followed by a phase 2 study with the recommended dose defined in the phase 1 study. Admittedly, the main risk when using a tritherapy (oxaliplatin, irinotecan, and 5-FU) is increased toxicity. We also used hyperthermia at the maximal tolerable temperature known in animals³¹ (the maximal tolerable temperature in humans is not known), and this can also increase the morbidity of this combined treatment.

This study reports on the mortality and morbidity of 106 consecutive patients treated with an optimized combination of intraperitoneal oxaliplatin (360 mg/ m²) plus irinotecan (360 mg/m²) in 2 L/m² of 5% dextrose, at 43°C over 30 minutes. Just before HI-PEC, the patients underwent complete cytoreductive surgery and received an intravenous 1-hour infusion of leucovorin (20 mg/m²) and 5-FU (400 mg/m²).

Mortality was 4% and was mainly due to lung infection, which seemed to be correlated with inhalation during vomiting, which was the result of premature ablation of the gastric tube. Two of these patients also had severe neutropenia. The extent of surgery, particularly in the small omentum, with frequent resection of the nerves leading to the pylorus should lead us to systematically maintain the gastric tube throughout the first week after HIPEC.

Grade 3–5 morbidity was 66%, with most complications being extra-abdominal (58%)—predominantly lung infections (16%)—and with severe (World Health Organization grade 4) hematological toxicity (11%). The mean time of onset of this severe aplasia was day 7 postoperatively and lasted 3.5 days. Intra-abdominal complications were less frequent (25%), mainly digestive fistula (24%), which led to a repeat laparotomy and transient stomia. The occurrence of complications was correlated with age, extent of the peritoneal disease, number of resected organs, duration of surgery, blood loss, and type of primary disease. For statistical reasons, this is seen more clearly with extra-abdominal complications, which were more numerous (n = 62) than were intra-abdominal complications (n = 26). Grade 2 morbidity was mainly represented by transient diarrhea and delayed digestive transit, which were the main causes of a deteriorated quality of life during the postoperative course. We have still not found an efficient way to treat these adverse events.

The results of the largest series in the literature are presented in Table 5. They concern teams who have completed their learning curve with this new treatment. Even if the rate of the completeness of cytoreduction, the rate of peritoneal pseudomyxomas, and the chemotherapy regimen are quite different, results show that mortality ranges 1%–4% and morbidity 25%–66%. Like us, all these authors underlined that toxicity and mortality are associated with the tumor load, the extent of the surgery, its duration, and blood loss.^32–34 The series by Stephens et al.,³² which comprised 150 pseudomyxomas, showed that this type of tumor was associated with greater morbidity, and the series by Smeenk et al.,³⁴ which only concerned pseudomyxomas, linked morbidity and mortality with the completeness of cytoreduction. These divergences in the primaries, in the completeness of cytoreductive surgery, and also the different systems used to stage morbidity, make it difficult to compare series. In addition, we could be criticized for the higher incidence of adverse effects with this new approach. However, this must be weighed against the fact that the prognosis of PC is poor when treated with chemotherapy alone. Most of the other teams use a less aggressive approach during HIPEC, probably with a lower rate of adverse effects. However, because complete cytoreduction is more efficient than incomplete cytoreduction, because multiagent chemotherapy is more efficient than single-agent chemotherapy, and because a higher temperature is more efficient than a lower one, we can logically postulate that we will increase the survival rate of our patients, even if this is at the expense of slightly increasing the adverse effects.

In conclusion, the morbidity and mortality of this optimized combination of intraperitoneal oxaliplatin plus irinotecan at 43°C and systemic 5-FU after complete cytoreduction is relatively high but acceptable, considering the expected survival benefit.

	ACKNOWLEDGMENTS

 
We acknowledge Lorna Saint Ange for editing.

Received for publication October 13, 2006. Accepted for publication December 19, 2006.

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