1 Service de Gastro-entérologie, Hôpital St Louis, Paris; 2 Centre Hépato-biliaire, Hôpital Paul Brousse, Villejuif; 3 Laboratoire de Pharmacologie Clinique, Center René Huguenin, St Cloud; 4 Service dOncologie Médicale, Hôpital St Louis, Paris; 5 Unité dOncologie Médicale, Service de Médecine Interne 1, Hôpital Cochin, Paris, France
Received 14 March 2002; accepted 25 March 2002
Abstract
Combination of chemotherapy and surgical resection of metastases is the most promising strategy to improve the fraction of long-term survivors and cured patients in metastatic colorectal cancer. We reproducibly observed evidence of exacerbation of the oxaliplatin-induced neurosensory toxicity following surgery. Total, protein-bound and intra-erythrocytic concentrations of oxaliplatin were measured, whenever possible, immediately prior to surgery and 4, 24 and 48 h following surgical resection. Among 12 patients, seven (58%) patients reported immediate post-operative aggravation of the pre-existing neurotoxicity. At the time of surgery, we detected high intra-erythrocytic platinum concentrations in all patients (median: 1365 µg/l, range: 8202968 µg/l). While ultrafilterable oxaliplatin was not detectable prior to surgery, it could be detected immediately after surgery and during 48 h. These results suggest that patients heavily pretreated with oxaliplatin may experience aggravation of neurotoxicity after surgery, probably through a redistribution of the pool of intra-erythrocytic oxaliplatin biotransformation products into the plasma. This clinical observation might be the consequence of peroperative hemolysis.
Key words: neurosensory toxicity, oxaliplatin, surgery
Introduction
The therapeutic possibilities in metastatic colorectal cancer (MCRC) patients have recently changed with the emergence of active chemotherapy combinations [1, 2]. Chemotherapy has prolonged survival up to 20 months [3]. Oxaliplatin, a new cytotoxic agent from the diaminocyclohexane platinum family, is a major drug with a large spectrum of antitumor activity differing from those of other platinum compounds. Experimental data showed its efficacy against cisplatin-resistant colon carcinoma cell lines and its synergistic activity when given in combination with 5-fluorouracil [4]. Oxaliplatin dose-limiting toxicity consists of a cumulative sensory peripheral neuropathy exacerbated by exposure to cold [5]. Its special characteristics have led to the development of a specific grading scale [2] that has been modified with increasing experience. However, this neurotoxicity is slowly but consistently reversible upon treatment discontinuation and is associated with minor hematotoxicity [57]. To date, two phase III randomized trials have shown that the addition of oxaliplatin to 5-fluorouracilleucovorin regimens result in significantly higher response rates [6, 7]. Combining oxaliplatin-based chemotherapy and surgical resection of metastases has become a prevalent therapeutic strategy to improve long-term survival in MCRC [8, 9]. The three-drug regimen of 5-fluorouracil, leucovorin and oxaliplatin may increase the prevalence of surgical resection of liver metastases [8]. These findings emphasize oxaliplatins role as a key agent in new therapeutic approaches for MCRC. We have noticed exacerbation of oxaliplatin neurosensory toxicity immediately following such surgery. We describe two case reports and a series of consecutively assessed patients who underwent surgical resection of metastases after oxaliplatin-based chemotherapy.
Patients
Case 1
A 60-year-old man with colonic adenocarcinoma developed liver metastases while on 5-fluorouracil/folinic acid adjuvant chemotherapy. From April to September 1998, he received 11 cycles of a combination regimen of oxaliplatin 85 mg/m2 and CPT-11 150175 mg/m2 every 2 weeks [9]. He achieved a partial response leading to a complete resection of the residual liver metastases 27 days after chemotherapy. Prior to surgery, the patient had a persistent between-cycles sensory loss of the extremities without functional impairment (grade 3 on Levis scale) [2] related to a cumulative dose of oxaliplatin of 935 mg/m2 and a dose-intensity of 47 mg/m2/week. Immediately following hepatectomy, he mentioned an acute aggravation of the neurosensory symptoms with loss of hand grip strength leading to dependence in dressing, eating and use of the toilet (grade 4). One year after the hepatectomy, an electromyogram showed moderate sensitive axonal neuropathy of the four members and he still had a moderately decreased acral sensitivity.
Case 2
A 51-year-old woman presented a right colonic cancer with synchronous bilateral hepatic localizations. From January to April 1999, she received five cycles of an every 2 weeks chronomodulated combination regimen with oxaliplatin 25 mg/m2/day, 5-fluorouracil 800 mg/m2/day and folinic acid 300 mg/m2/day from day 1 to 4 [2]. A grade 1 neuropathy was noted from cycle 3. A right colectomy with partial liver metastasectomy was performed 18 days after the end of chemotherapy without post-surgical complications. Three further cycles of the same regimen were administered. She presented only acral paresthesias without any functional impairment lasting less than 8 days after the last cycle of chemotherapy (grade 1). A second curative hepatectomy was made 18 days after chemotherapy with a cumulative oxaliplatin dose of 800 mg/m2 and a dose-intensity of 32 mg/m2/week. Immediately after hepatectomy, she complained of major exacerbation of neuropathy consisting of painful distal paresthesias and sole loss of sensitivity interfering with walking (grade 4). This toxicity decreased to grade 3 after 2 months. The same regimen with a low dose of oxaliplatin (20 mg/m2/day) was continued 1 month post-operatively for seven cycles. Eleven months after hepatectomy she still presented grade 3 neuropathy.
Results and discussion
These observations report for the first time reproducible evidence of exacerbation of the oxaliplatin-induced neurosensory toxicity following surgery. This led us to study the clinical outcome of patients under our care who underwent surgery following oxaliplatin-containing chemotherapy between April 1998 and June 2000, and who were available for such an evaluation. Twelve patients, including the two clinical cases described above, were prospectively analyzed. Patients characteristics are presented on Table 1. Total, protein-bound and intra-erythrocytic concentrations of oxaliplatin were measured, whenever possible, immediately prior to surgery and 4, 24 and 48 h following surgical resection.
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These results suggest that patients heavily pre-treated with oxaliplatin may experience aggravation of neurotoxicity after surgery, probably through a redistribution of the pool of intra-erythrocytic oxaliplatin biotransformation products into the plasma. We were able to detect this phenomenon in >50% of patients. Further studies are warranted to define more precisely the mechanism and the frequency of this exacerbation of oxaliplatin neurosensory toxicity. Our observation may be of importance as an increasing number of metastatic colorectal cancer patients may become candidates for surgical resection of metastases following oxaliplatin-containing first-line chemotherapy.
Footnotes
+ Correspondence to: Dr F. Goldwasser, Unité dOncologie Médicale, Service de Médecine Interne 1, Groupe Hospitalier Cochin, 27 Rue du Faubourg St Jacques 75679, Cedex 14, Paris, France. Tel: +33-1-58-41-17-47; Fax: +33-1-58-41-15-79; E-mail: francois.goldwasser@cch.ap-hop-paris.fr
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