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Journal of Clinical Oncology, Vol 22, No 8 (April 15), 2004: pp. 1527-1529 © 2004 American Society of Clinical Oncology. DOI: 10.1200/JCO.2004.99.293
Hyperthermic Intraperitoneal Chemotherapy in Patients With Peritoneal Carcinosis
Medizinische Klinik Hämatologie and Onkologie, Campus Virchow Klinikum, Berlin, Germany To the Editor: Vic J. Vervaal and colleagues1 demonstrated that an improvement of survival is achieved in colorectal cancer patients with peritoneal carcinosis treated by surgical cytoreduction and hyperthermic intraperitoneal chemotherapy (HIPEC) when compared with schedules with palliative chemotherapy (with or without surgery) alone. This study, for the first time, demonstrated a survival benefit for adjunctive HIPEC in the scope of a randomized trial, but this result was counterbalanced by a 16% early death rate and an excessively high rate of severe side effects in the experimental arm (WHO 3: 65% of patients; WHO 4: 45% of patients). In our opinion, such high complication rates are hardly acceptable in a palliative treatment concept that yielded an overall survival benefit of 10 months for the entire patient population. In addition, there was virtually no clinically relevant improvement in subgroups of patients with far advanced disease. Indeed, a median survival of less than 6 months was reported in 33% of patients treated in the experimental arm. It is plausible that a number of side effects associated with surgery plus HIPEC have been caused or promoted by either the intraperitoneal application of mitomycin C or the hyperthermic conditions of its administration (eg, hematotoxicity, 27%; fistulae, 15%; infection, 6%; pancreatitis, 2% of patients treated). Certain other complications may rather be assigned to the surgical procedure or rapid disease progression (eg, pulmonary embolism within 3 months after surgery). However, 24% of patients treated with HIPEC suffered from severe or life-threatening complications that caused damage to vital organs (heart failure/arrhythmia, 14%; terminal renal failure, 6%; paresis: 4% of patients), and it is difficult to ascribe these events to any of the single modality applied. Therefore, these high rates of severe adverse events appear to result from the topical application of surgery and adjunctive chemotherapy under hyperthermic conditions. Unfortunately, the study was not designed to precisely define the role of HIPEC by comparing treatment with surgery alone with surgery plus HIPEC. We would like to emphasize that it is largely unknown if elevated (eg, > 37°C) temperatures actually contribute to the efficacy of intraperitoneal chemotherapy. On the one hand, 10 randomized trials on different locoregional hyperthermia approaches have already demonstrated a benefit when hyperthermia is added to standard radiotherapy and/or chemotherapy. Most of these studies have been performed with radiofrequency hyperthermia techniques in patients with superficial or pelvic tumors, and a number of concomitant analyses have revealed a clear-cut correlation between thermal dose and clinical outcome.2 On the other hand, such a dose-response relationship has never been duplicated for any of the "convective" hyperthermia techniques HIPEC or hyperthermic isolated limb perfusion (HILP), respectively. In addition, a randomized comparison on normothermic versus hyperthermic chemotherapy in the scope of HIPEC or HILP has never been performed. The occurrence of organ failure in the context of HIPEC raises suggestions on the experiences with chemotherapy and whole-body hyperthermia (WBH). In particular extracorporal WBH, in which the patient's core body temperature is raised by convective heating of blood, bears the risk of severe renal failure,3 but heart failure, arrhythmias, multiorgan failure, or pareses have also been reported with the use of modern radiant-heat WBH devices.4 In our opinion, it cannot be ruled out that intraoperative HIPEC may produce additional toxicity without being more effective than normothermic intraperitoneal chemotherapy. One strategy to resolve the question of whether the efficacy of intraperitoneal chemotherapy is actually enhanced by application as HIPEC may be a randomized comparison between normothermic and hyperthermic intraperitoneal drug application. Another policy may be the application of hyperthermic chemotherapy in the postoperative or palliative setting by employing novel regional radiofrequency hyperthermia (RHT) applicators that enable effective heat delivery to the entire abdomen ("part-body hyperthermia"). After a phase of preclinical evaluation, such magnetic resonance–guided RHT devices have recently been introduced into clinical practice in our institution, as well as a very few others (Fig 1). First clinical experience and phase I-data indicate that effective hyperthermia can be safely delivered to patients with peritoneal masses by this technology, with only little additional toxicity.5 A first phase II trial on intravenous chemotherapy (folinic acid/fluorouracil/oxaliplatin) plus RHT in patients with peritoneal carcinosis has recently been initiated.
Authors' Disclosures of Potential Conflicts of Interest The authors indicated no potential conflicts of interest.
REFERENCES
1. Verwaal VJ, van Ruth S, de Bree E, et al: Randomized trial of cytoreduction and hyperthermic intraperitoneal chemotherapy versus systemic chemotherapy and palliative surgery in patients with peritoneal carcinomatosis of colorectal cancer. J Clin Oncol 21:3737-3743, 2003 2. Wust P, Hildebrandt B, Sreenivasa G, et al: Hyperthermia in combined treatment of cancer. Lancet Oncol 3:487-497, 2002[CrossRef][Medline] 3. Wiedemann GJ, Robins HI, Gutsche S, et al: Ifosfamide, carboplatin and etoposide (ICE) combined with 41.8 degrees C whole body hyperthermia in patients with refractory sarcoma. Eur J Cancer 32A:888-892, 1996 4. Kerner T, Hildebrandt B, Ahlers O, et al: Anaesthesiological experiences with whole body hyperthermia. Int J Hyperthermia 19:1-12, 2003[Medline] 5. Gellermann J, Wlodarczyk W, Seebass M, et al: MR-thermometry during radiofrequeny hyperthermia (part-body hyperthermia) in pelvic tumors. Radiology 225(P):510, 2002 (abstr)
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Copyright © 2004 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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