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Prevention of Oxaliplatin-Induced Peripheral Sensory Neuropathy by Carbamazepine in Patients with Advanced Colorectal Cancer
Brief
Communication Prevention of Oxaliplatin-Induced Peripheral Sensory Neuropathy by Carbamazepine in Patients with Advanced Colorectal Cancer Christian Lersch,1 Renate Schmelz,1 Florian Eckel,1 Johannes Erdmann,1 Martina Mayr,1 Ewert Schulte-Frohlinde,1 Stefan Quasthoff,2 Julian Grosskreutz,2 Helmuth Adelsberger3 Abstract Oxaliplatin plays a key role in the treatment of advanced colorectal cancer. The dose-limiting side effect of this platinum analogue is neurotoxicity. Significant efforts have been undertaken in an attempt to prevent and/or circumvent the development of neurotoxicity. Sodium channel inactivation kinetics on rat sensory sural nerve preparations are altered after exposure to oxaliplatin. Carbamazepine antagonizes this effect in vitro. Results from preliminary clinical studies indicate that the sodium channel blockers carbamazepine and gabapentin may be effective in preventing neurotoxicity. The role of amifostine is not yet clear. Randomized clinical studies are necessary to confirm the potential benefit of carbamazepine and other sodium channel blockers in preventing and/or overcoming the development of oxaliplatin-induced neurotoxicity. Clinical Colorectal Cancer, Vol. 2, No. 1, 54-58, 2002 Key words: Oxaliplatin, Chemotherapy, Neurotoxicity, Carbamazepine, 5-Fluorouracil, Folinic acid
Introduction Colorectal cancer is estimated to claim the lives of at least 500,000 people in the world each year,1 with higher mortality rates in industrialized countries. A significant number of patients either present with and/or recur with disease spread to the liver,2 and approximately 50% of patients will eventually die from progressive disease. The long-term outcome for patients with metastatic disease is extremely poor, as most tumors are resistant to current treatment options. For more than 50 years, the fluoropyrimidine 5-fluorouracil (5-FU) has been used in the management of metastatic colorectal cancer. Objective response rates to 5-FU monotherapy are typically in the 10%-20% range, with a median survival duration of approximately 10 months. While the addition of biochemical modulating agents (eg, leucovorin) may nearly 1II.
Medical Hospital and Health Center, Technischen Universität Munich, Germany 2Neurological Hospital, Karl-Franzens Universität Graz, Austria 3Zoological Institute, Ludwig-Maximilians Universität, Munich, Germany Submitted: Jan. 15, 2002; Revised: April 17, 2002; Accepted: April 25, 2002 Address for correspondence: Christian Lersch, MD, PhD, II. Medical Hospital and Health Center, Technischen Universität München, Klinikum rechts der Isar, Ismaninger St 22, 81675 Munich, Germany Fax: 49-89-4140-4968; e-mail: [email protected]
54 • Clinical Colorectal Cancer May 2002
double the response rate, little improvement in overall survival has been observed. New agents in first- and second-line chemotherapy include the oral 5-FU prodrugs, the topoisomerase I inhibitor irinotecan, and the thymidylate synthase inhibitor raltitrexed. The platinum analogue oxaliplatin, which was initially identified in the early 1970s, has received renewed attention over the past few years.3
Oxaliplatin Oxaliplatin is a third-generation platinum analogue that exerts its cytotoxic action by causing interstrand and intrastrand cross-links between 2 adjacent guanine bases or 2 adjacent guanine-adenine bases in DNA. The formation of DNA adducts results in the inhibition of DNA biosynthesis and DNA repair mechanisms.4 The end result is apoptosis. The bulky 1,2-diaminocyclohexane (DACH) carrier ligand of oxaliplatin is generally associated with greater cytotoxicity and inhibition of DNA synthesis than the DNA adducts formed by either cisplatin or carboplatin. Of note, there appears to be no cross-resistance between oxaliplatin and cisplatin/carboplatin, and oxaliplatin is active against human colon cancer cell lines that are defective in mismatched repair genes.
Oxaliplatin-Induced Neurotoxicity In up to 15% of patients, the dose-limiting toxicity of oxaliplatin is a transient, acute, and predominantly peripheral
sensory neuropathy that is cumulative in nature.5 It is associated with sensory ataxia and dysesthesia of the limbs, mouth, throat, and larynx, and is sometimes associated with muscular cramps or spasms. Of note, the laryngopharyngeal dysesthesias are frequently exacerbated by exposure to cold.6,7 Symptoms develop in up to 97% of patients8 within a few minutes after the start of the infusion and spontaneously disappear after a few minutes or up to several days later. Grade 3/4 neurotoxicity occurs in approximately 10% of patients after 6 cycles of treatment and in up to 50% of patients after 9 cycles, when oxaliplatin is given at a dose of 130 mg/m2 every 3 weeks.9 Neurosensory toxicity is dependent on the cumulative dose of oxaliplatin. Patients affected are usually those who receive doses ≥ 540 mg/m2 over ≥ 4 cycles of therapy.10 Cumulative neurotoxicity is manifested by an increased difficulty in performing normal activities of daily living, including writing, holding things, or closing shirts and jackets. In most patients, this adverse event is reversible within a few months after the end of therapy. Seventy-four percent of patients have a regression of World Health Organization (WHO) grade 3 neuropathy within 13 weeks. Moreover, central neurotoxicity (ie, Lhermitte’s sign), genitosphincteral deficiency, and proprioception deficit after cumulative doses of oxaliplatin > 1000 mg has been reported in 4 patients.11 Nausea, vomiting, diarrhea, and myelosuppression are additional, albeit minor, side effects of oxaliplatin. Oxaliplatin lacks the nephrotoxicity of cisplatin and the myelosuppressive effects of carboplatin. From their preliminary study of 17 patients, Shifflet et al12 concluded that pharmacokinetic monitoring may not identify and/or predict for those patients at risk for developing neurotoxicity. They measured the levels of oxaliplatin and its biotransformation product Pt (DACH) C12 (DACH) in patients’ blood using high performance liquid chromatography and atomic absorption spectrometry. At steady state, the ratios of oxaliplatin to DACH did not correlate with neurotoxicity. This finding suggests that the levels of DACH, which were shown to be 3.8-fold more neurotoxic in the rat model, may not be a reliable pharmacodynamic marker that can predict for neurotoxicity.
Oxaliplatin-Induced Morphologic Changes in Nerves In an in vitro study, oxaliplatin reduced the growth of neurites of explanted rats’ dorsal root ganglia in tissue cultures.13 Cavaletti et al14,15 treated 4 groups of female Wistar rats with different doses and schedules of oxaliplatin intraperitoneally. They found the least toxic effects when giving 4 mg/kg/day (24 mg/m2) biweekly for 9 weeks. Conduction velocity in the tail nerve was significantly reduced in all animals at the end of treatment with no difference between the groups, and partial recovery occurred after 5 weeks of follow-up. Morphometry of dorsal root ganglia revealed significant differences in the oxaliplatin-treated groups versus the untreated control. Nucleolar, nuclear, and somatic areas were reduced, with nucleolar segregation in all treated animals. Morphometric changes completely recovered after 5 weeks of follow-up.
Table 1
Morphological Changes in Rats’ Dorsal Root Ganglia After Oxaliplatin Exposure
• Reduced growth of neurites • Reduced nucleolar, nuclear, and somatic areas, with nucleolar segregation
Mild secondary axonopathy occurred in sciatic nerves. In contrast, Holmes et al16 observed reduced cell and nuclear areas in the neuronal cell bodies of rat dorsal root ganglia L4L6 when compared with control animals after an 8-week recovery period. Neurotoxicity correlated with a greater retention of platinum by the dorsal root ganglia. Morphological changes in nerves of rats after oxaliplatin exposure are summarized in Table 1.
Neurotoxicity Mechanisms Underlying Neurotoxicity In rodents, cisplatin is preferentially toxic to large diameter neurons and proprioceptive sensory modalities. In contrast, it appears that motor neurons are spared from toxicity.17 Storage of platinum drugs in sensory neurites is associated with reduced cellular metabolism and axoplasmatic transport.18 The hydrophilicity of platinum drugs correlates with platinum sequestration in the peripheral nervous system but not with neurotoxicity detected by measuring sensory nerve conduction velocity in Wistar rats. Differences in the reactivity of platinum complexes obviously account for some of the variation in their neurotoxicity.19 Screnci et al20 concluded from their studies that Pt (DACH) derivatives exhibit enantiomeric-selective peripheral neurotoxicity during repeated dosing in rats. Grolleau et al21 employed the whole cell patch-clamp technique to investigate the oxaliplatin effects on the electrophysiological properties of short-term cultured dorsal unpaired median neurons isolated from the central nervous system of the cockroach, Periplaneta americana. After an intracellular application of up to 500 μmol of oxaliplatin and its metabolite oxalate, the amplitude of the voltage-gated sodium current was decreased, thereby reducing the amplitude of the action potential by one-half. The effect of oxaliplatin could be mimicked by 10 mmol bis-(o-aminophenoxy)-N, N, N´, N´tetraacetic acid, known as a chelator of calcium ions. Since oxalate immobilizes calcium ions as well as bis-(oaminophenoxy)-N, N, N´, N´-tetraacetic acid, this study suggests a pathway involving calcium ions. Therefore, it may be useful to increase calcium blood levels to decrease oxaliplatin-induced neurotoxicity. Alteration of sodium channel inactivation kinetics on rat sensory sural nerve preparations were observed 5-10 minutes after the application of oxaliplatin 250 μmol.22 Na+ influx was increased due to prolonged opening of Na+ channels. The size and the duration of the action potentials in myelinated Afibres, elicited by supramaximal stimulation, dramatically increased. Electrotonic responses showed enhanced and persistent repetitive firing for several hundred milliseconds. The
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Prevention of Oxaliplatin-Induced Neuropathy Preliminary data from 4 patients receiving oxaliplatin 130 mg/m2 every 3 weeks suggested a dramatic improvement in acute neurotoxicity with the administration of intravenous • Increased Na+ influx due to prolonged opening of Na+ channels calcium gluconate 1 g and magnesium sulfate 1 g.27 In con• Increased size and duration of the action potentials in myelinated A-fibres, trast, treatment with magnesium citrate 1 g die by mouth elicited by supramaximal stimulation combined with oxaliplatin therapy did not result in any bene• Enhanced and persistent repetitive firing for several hundred milliseconds fit on neurotoxicity. This effect was tested by measuring vibratory sensibility at the plantar surfaces of the feet as well as • Lengthening of the refractory period at the palmar surfaces of the hands by a tuning fork and a de• No blockage of potassium channels tailed questioning of patients for symptoms (Lersch et al, unpublished data). • No effect on Na+ currents of hippocampal neurons Patients with metastatic colorectal cancer treated with either raltitrexed 3 mg/m2 plus oxaliplatin 130 mg/m2, every refractory period of peripheral nerves was lengthened. There 3 weeks (n = 9) or irinotecan 175 mg/m2 plus oxaliplatin 85 was absolutely no effect on Na+ currents of hippocampal neumg/m2 every 2 weeks (n = 6) received the thiophosphate cyrons, suggesting that the interaction of oxaliplatin is restricttoprotectant agent amifostine at a dose of 500 mg, subcutaed to one or more channel isoforms. The in vitro results are neously 20 minutes prior to administration of the anticancer summarized in Table 2. The effect of oxaliplatin could be anagents.28,29 All patients experienced ≥ grade 2 polyneuropatagonized by 1 mmol Na+ channel blocker carbamazepine.23 thy upon receiving a cumulative oxaliplatin dose of 390 High concentrations of Ca2+ > 10 mmol antagonized the efmg/m2. Neurologic symptoms improved immediately in 10 fect of oxaliplatin on nerve excitability. Gabapentin failed to patients, while 5 patients did not respond. affect Na+ current in isolated cortical neurons of rats,24 but it Similar results were reported by Rudolph et al.30 Patients was not tested in the presence of oxaliplatin. The underlying received oxaliplatin 85 mg/m2 on day 1, folinic acid 500 mg/m2 mechanism for the clinical benefit of gabapentin is not yet evon days 1 and 2, and 5-FU 4000 mg/m2 as a 48-hour continident and needs to be further elucidated. uous infusion every 2 weeks. Half of the patients also received amifostine at a dose of 910 mg/m2 as a 10-minute Studies to Prevent Neurotoxicity intravenous infusion just prior to chemotherapy. The inciPatients who are receiving oxaliplatin-based chemotherapy dence of peripheral neurotoxicity was significantly reduced must be warned to avoid drinking cold liquids and/or ingest(P = 0.048) in the amifostine group. ing cold foods for a few days following treatment. In addition, Mariani et al31 treated 15 colorectal cancer patients with patients should be advised to avoid going out in the cold oxaliplatin 85 mg/m2 on days 1 and 15 and folinic acid 60 weather after therapy with oxaliplatin. If necessary, patients mg/m2 together with 5-FU 500 mg/m2 on days 1, 2, and 15. should wear protection around the face and, in particular, The mean cumulative dose of oxaliplatin was 255 mg/m2 around the nose and mouth areas to avoid the possibility of (range, 85-1190 mg/m2). Patients received gabapentin at the difficult breathing and/or swallowing. Of note, acute neudose of 100 mg twice a day immediately after the onset of rosensory symptoms usually disappear after the discontinuaneuropathic symptoms. The dosage was increased by an adtion of the drug.25 To date, the neurotoxicity resulting from ditional 100 mg per day if symptoms continued for 3 days. platinum exposure has not been prevented by treatment with Symptoms disappeared in all patients treated and recurred in a number of agents including thiols, neurotrophic factors, or 2 patients who discontinued their gabapentin treatment. calcium channel blockers.26 Carbamazepine is one of the most commonly prescribed Drugs Used to Prevent Oxaliplatin-Induced Neuropathy Table 3 anticonvulsant drugs, which exerts its pharmacological efPatients No. of Whose Neurotoxicity fect by binding to the receptor Drug, Dose, Route of Application Patients Was Improved (%) sites associated with the activation of voltage-sensitive Calcium gluconate 1 g I.V. and magnesium sulfate 1 g I.V. 4 100% sodium channels.32 Based on 27 die just after the onset of symptoms during oxaliplatin infusion this mechanism, it is predicted Magnesium citrate 1 g p.o. die (Lersch et al, unpublished data) 13 0 to be a potential candidate as a protective agent against oxaliAmifostine 500 mg subcutaneously just before oxaliplatin infusion28,29 15 67% platin-induced neurotoxicity. Amifostine 910 mg/m2 I.V. just before oxaliplatin infusion30 15 not indicated In a nonrandomized pilot study, 40 pretreated patients Gabapentin 100 mg b.i.d. immediately after the onset of neuropathic 15 100% suffering from advanced colsymptoms31 orectal cancer received oxali33 10 100% Carbamazepine doses p.o. adapted to a serum level of 3-6 mg/L platin 85 mg/m2 on days 1, 15, Table 2
In Vitro Effects of Oxaliplatin on Rat Sural Nerves
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Christian Lersch et al and 29 and folinic acid 500 mg/m2 plus 5-FU 2000 mg/m2 on days 1, 8, 15, 22, 29, and 36 repeated every day as secondline therapy. Ten patients also received carbamazepine 200600 mg by mouth at doses adapted to serum levels of 3-6 mg/L. Dosage was started with 200 mg beginning 1 week before the first dose of oxaliplatin. Two days later, the dose was increased to 400 mg. Carbamazepine was continuously given to the patients until the end of chemotherapy with oxaliplatin. In case of ongoing neuropathological symptoms, carbamazepine was further prescribed for a maximum of 3 weeks until symptoms had disappeared. The median cumulative dose of oxaliplatin was 722 mg/m2. Neurological examinations were performed weekly, mainly by measuring the vibratory sensibility at the plantar surfaces of the feet and the palmar surfaces of the hands by a tuning fork and the documentation of side effects (ie, hyperpathic symptoms induced by cold and treatment-related toxicities). Grade 2-4 neuropathy, as outlined by the modified WHO scale, did not occur in any patient. In contrast, this toxicity was observed in 30% of an historical control group (n = 30) who had received an even lower cumulative dose of oxaliplatin (510 mg/m2).33 At present, a controlled multicenter trial has been initiated to further evaluate the efficacy and toxicity of carbamazepine in oxaliplatin-treated patients with advanced colorectal cancer. A summary of the preliminary data cited above is reported in Table 3.
Conclusion Oxaliplatin-induced neurotoxicity appears to be most likely due to alterations in the kinetics of sodium channel inactivation. Carbamazepine is the only substance that has proven to antagonize this effect in vitro. Several pilot clinical studies have shown that carbamazepine, gabapentin, and amifostine can reduce the severity of neurotoxicity in patients. However, the in vitro preclinical data suggests that carbamazepine may be the most promising substance to prevent neurotoxicity. Randomized controlled trials are necessary to further evaluate the neuroprotective effect of carbamazepine and perhaps other sodium channel blockers in oxaliplatin-treated patients. Given the potentially increased role of oxaliplatin in the treatment of advanced colorectal cancer, such studies are critically important as they may help improve the safety profile of this interesting agent.
References 01. Comparison of fluorouracil with additional levamisole, higher-dose folinic acid, or both, as adjuvant chemotherapy for colorectal cancer: a randomised trial. QUASAR Collaborative Group. Lancet 2000; 355:1588-1596. 02. Seifert JK, Junginger T, Morris DL. A collective review of the world literature on hepatic cryotherapy. J R Coll Surg Edinb 1998; 43:141154. 03. Wiseman LR, Adkins JC, Plosker GL, et al. Oxaliplatin: a review of its use in the management of metastatic colorectal cancer. Drugs Aging 1999; 14:459-475. 04. Raymond E, Chaney SG, Taamma A, et al. Oxaliplatin: a review of preclinical and clinical studies. Ann Oncol 1998; 9:1053-1071. 05. Soulie P, Raymond E, Misset JL, et al. Oxaliplatin: update on an active and safe DACH platinum complex. In: Pinedo HM, Schornagel JH, eds. Platinum and Other Metal Coordination Compounds in
Cancer Chemotherapy, 1996:165-174. 06. Misset JL. Oxaliplatin in practice. Br J Cancer 1998; 77 (suppl 4):47. 07. Norum J. Oxaliplatin in colorectal cancer patients living in an arctic or subarctic area: significant cold-triggered dysesthesias and laryngeal reactions. J Chemother 2000; 12:525-529. 08. Machover D, Diaz-Rubio E, de Gramont A, et al. Two consecutive phase II studies of oxaliplatin (L-OHP) for treatment of patients with advanced colorectal carcinoma who were resistant to previous treatment with fluoropyrimidines. Ann Oncol 1996; 7:95-98. 09. Krikorian A, Vignoud J, Brienza S, et al. Oxaliplatin: global safety. 5th International Congress on Anti-Cancer Chemotherapy, Paris, January 31-February 3, 1995. 10. Extra JM, Marty M, Brienza S, et al. Pharmacokinetics and safety profile of oxaliplatin. Semin Oncol 1998; 25:13-22. 11. Tabieb S, Freyer G, Rambaud L, et al. Central neurotoxicity induced by oxaliplatin: report on 4 cases. Proc Am Soc Clin Oncol 2000; 19:312a (Abstract #1234). 12. Shifflet SL, Bernard SA, Lindley C, et al. Preliminary analysis of possible relationship of oxaliplatin and its biotransformation products to neurotoxicity. Proc Am Assoc Cancer Res 2000; 41:706 (Abstract #4487). 13. Luo FR, Wyrick SD, Chaney SG. Comparative neurotoxicity of oxaliplatin, ormaplatin, and their biotransformation products utilizing a rat dorsal root ganglia in vitro explant culture model. Cancer Chemother Pharmacol 1999; 44:29-38. 14. Cavaletti G, Tredici G, Petruccioloi MG, et al. Neurotoxicity of oxaliplatin (I-OHP) in rats and influence of scheduling. Clin Cancer Res 2000; 6 (suppl):4537s (Abstract #4356). 15. Cavaletti G, Tredici G, Petruccioli MG, et al. Effects of different schedules of oxaliplatin treatment on the peripheral nervous system of the rat. Eur J Cancer 2001; 37:2457-2463. 16. Holmes J, Stanko J, Varchenko M, et al. Comparative neurotoxicity of oxaliplatin, cisplatin, and ormaplatin in a Wistar rat model. Toxicol Sci 1998; 46:342-351. 17. McKeage MJ, Boxall FE, Jones M, et al. Lack of neurotoxicity of oral bisacetatoamminedichlorocyclohexylamine-platinum(IV) in comparison to cisplatin and tetraplatin in the rat. Cancer Res 1994; 54:629-631. 18. Quasthoff S, Brosskreutz J. Chemotherapy-induced peripheral neuropathy. Med Welt 2000; 51:10-14. 19. Screnci D, McKeage MJ, Galettis P, et al. Relationships between hydrophobicity, reactivity, accumulation and peripheral nerve toxicity of a series of platinum drugs. Br J Cancer 2000; 82:966-972. 20. Screnci D, Er HM, Hambley TW, et al. Stereoselective peripheral sensory neurotoxicity of diaminocyclohexane platinum enantiomers related to ormaplatin and oxaliplatin. Br J Cancer 1997; 76:502-510. 21. Grolleau F, Gamelin L, Boisdron-Celle M, et al. A possible explanation for a neurotoxic effect of the anticancer agent oxaliplatin on neuronal voltage-gated sodium channels. J Neurophysiol 2001; 85:22932297. 22. Adelsberger H, Quasthoff S, Grosskreutz J, et al. Alteration of sodium channel inactivation kinetics on rat sural nerve by the chemotherapeutic agent oxaliplatin. Biol Chem 1999; 380S:123. 23. Adelsberger H, Quasthoff S, Grosskreutz J, et al. The chemotherapeutic oxaliplatin alters voltage-gated Na(+) channel kinetics on rat sensory neurons. Eur J Pharmacol 2000; 406:25-32. 24. Stefani A, Spadoni F, Giacomini P, et al. The effects of gabapentin on different ligand- and voltage-gated currents in isolated cortical neurons. Epilepsy Res 2001; 43:239-248. 25. Haller DG. Safety of oxaliplatin in the treatment of colorectal cancer. Oncology (Huntingt) 2000; 14:15-20. 26. Screnci D, McKeage MJ. Platinum neurotoxicity: clinical profiles, experimental models and neuroprotective approaches. J Inorg Biochem 1999; 77:105-110. 27. Laine-Cessac P, Boisdron-Celle M, Girault C, et al. Acute oxaliplatin neurotoxicity dramatically improved with intravenous calcium and magnesium salts. Therapie (Paris) 1998; 53:183 (Abstract #132). 28. Penz M, Kornek GV, Raderer M, et al. Subcutaneous administration of amifostine: a promising therapeutic option in patients with oxaliplatin-related peripheral sensitive neuropathy. Ann Oncol 2001; 12:421-422. 29. Fiebiger W, Penz M, Raderer M, et al. A new therapeutic option in patients with oxaliplatin-related peripheral neuropathy. Onkologie
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Prevention of Oxaliplatin-Induced Neuropathy 2000; 23:67 (Abstract #248). 30. Rudolph S, Fahlke J, Kuhn R, et al. Randomised trial with or without amifostine to reduce neurotoxic side effects under chemotherapy with oxaliplatin (L-OHP), FA/5-FU. Proc Am Soc Clin Oncol 2001; 20:302b (Abstract #2958). 31. Mariani G, Garrone O, Granetto C, et al. Oxaliplatin induced neuropathy: could gabapentin be the answer? Proc Am Soc Clin Oncol 2000; 19:609a (Abstract #2397).
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32. Willow M, Kuenzel EA, Catterall WA. Inhibition of voltage-sensitive sodium channels in neuroblastoma cells and synaptosomes by the anticonvulsant drugs diphenylhydantoin and carbamazepine. Mol Pharmacol 1984; 25:228-234. 33. Eckel F, Schmelz R, Adelsberger H, et al. Prevention of oxaliplatininduced neuropathy by carbamazepine, a pilot study. Dtsch Med Wochenschr 2002; 127:78-82.
Communication Prevention of Oxaliplatin-Induced Peripheral Sensory Neuropathy by Carbamazepine in Patients with Advanced Colorectal Cancer Christian Lersch,1 Renate Schmelz,1 Florian Eckel,1 Johannes Erdmann,1 Martina Mayr,1 Ewert Schulte-Frohlinde,1 Stefan Quasthoff,2 Julian Grosskreutz,2 Helmuth Adelsberger3 Abstract Oxaliplatin plays a key role in the treatment of advanced colorectal cancer. The dose-limiting side effect of this platinum analogue is neurotoxicity. Significant efforts have been undertaken in an attempt to prevent and/or circumvent the development of neurotoxicity. Sodium channel inactivation kinetics on rat sensory sural nerve preparations are altered after exposure to oxaliplatin. Carbamazepine antagonizes this effect in vitro. Results from preliminary clinical studies indicate that the sodium channel blockers carbamazepine and gabapentin may be effective in preventing neurotoxicity. The role of amifostine is not yet clear. Randomized clinical studies are necessary to confirm the potential benefit of carbamazepine and other sodium channel blockers in preventing and/or overcoming the development of oxaliplatin-induced neurotoxicity. Clinical Colorectal Cancer, Vol. 2, No. 1, 54-58, 2002 Key words: Oxaliplatin, Chemotherapy, Neurotoxicity, Carbamazepine, 5-Fluorouracil, Folinic acid
Introduction Colorectal cancer is estimated to claim the lives of at least 500,000 people in the world each year,1 with higher mortality rates in industrialized countries. A significant number of patients either present with and/or recur with disease spread to the liver,2 and approximately 50% of patients will eventually die from progressive disease. The long-term outcome for patients with metastatic disease is extremely poor, as most tumors are resistant to current treatment options. For more than 50 years, the fluoropyrimidine 5-fluorouracil (5-FU) has been used in the management of metastatic colorectal cancer. Objective response rates to 5-FU monotherapy are typically in the 10%-20% range, with a median survival duration of approximately 10 months. While the addition of biochemical modulating agents (eg, leucovorin) may nearly 1II.
Medical Hospital and Health Center, Technischen Universität Munich, Germany 2Neurological Hospital, Karl-Franzens Universität Graz, Austria 3Zoological Institute, Ludwig-Maximilians Universität, Munich, Germany Submitted: Jan. 15, 2002; Revised: April 17, 2002; Accepted: April 25, 2002 Address for correspondence: Christian Lersch, MD, PhD, II. Medical Hospital and Health Center, Technischen Universität München, Klinikum rechts der Isar, Ismaninger St 22, 81675 Munich, Germany Fax: 49-89-4140-4968; e-mail: [email protected]
54 • Clinical Colorectal Cancer May 2002
double the response rate, little improvement in overall survival has been observed. New agents in first- and second-line chemotherapy include the oral 5-FU prodrugs, the topoisomerase I inhibitor irinotecan, and the thymidylate synthase inhibitor raltitrexed. The platinum analogue oxaliplatin, which was initially identified in the early 1970s, has received renewed attention over the past few years.3
Oxaliplatin Oxaliplatin is a third-generation platinum analogue that exerts its cytotoxic action by causing interstrand and intrastrand cross-links between 2 adjacent guanine bases or 2 adjacent guanine-adenine bases in DNA. The formation of DNA adducts results in the inhibition of DNA biosynthesis and DNA repair mechanisms.4 The end result is apoptosis. The bulky 1,2-diaminocyclohexane (DACH) carrier ligand of oxaliplatin is generally associated with greater cytotoxicity and inhibition of DNA synthesis than the DNA adducts formed by either cisplatin or carboplatin. Of note, there appears to be no cross-resistance between oxaliplatin and cisplatin/carboplatin, and oxaliplatin is active against human colon cancer cell lines that are defective in mismatched repair genes.
Oxaliplatin-Induced Neurotoxicity In up to 15% of patients, the dose-limiting toxicity of oxaliplatin is a transient, acute, and predominantly peripheral
sensory neuropathy that is cumulative in nature.5 It is associated with sensory ataxia and dysesthesia of the limbs, mouth, throat, and larynx, and is sometimes associated with muscular cramps or spasms. Of note, the laryngopharyngeal dysesthesias are frequently exacerbated by exposure to cold.6,7 Symptoms develop in up to 97% of patients8 within a few minutes after the start of the infusion and spontaneously disappear after a few minutes or up to several days later. Grade 3/4 neurotoxicity occurs in approximately 10% of patients after 6 cycles of treatment and in up to 50% of patients after 9 cycles, when oxaliplatin is given at a dose of 130 mg/m2 every 3 weeks.9 Neurosensory toxicity is dependent on the cumulative dose of oxaliplatin. Patients affected are usually those who receive doses ≥ 540 mg/m2 over ≥ 4 cycles of therapy.10 Cumulative neurotoxicity is manifested by an increased difficulty in performing normal activities of daily living, including writing, holding things, or closing shirts and jackets. In most patients, this adverse event is reversible within a few months after the end of therapy. Seventy-four percent of patients have a regression of World Health Organization (WHO) grade 3 neuropathy within 13 weeks. Moreover, central neurotoxicity (ie, Lhermitte’s sign), genitosphincteral deficiency, and proprioception deficit after cumulative doses of oxaliplatin > 1000 mg has been reported in 4 patients.11 Nausea, vomiting, diarrhea, and myelosuppression are additional, albeit minor, side effects of oxaliplatin. Oxaliplatin lacks the nephrotoxicity of cisplatin and the myelosuppressive effects of carboplatin. From their preliminary study of 17 patients, Shifflet et al12 concluded that pharmacokinetic monitoring may not identify and/or predict for those patients at risk for developing neurotoxicity. They measured the levels of oxaliplatin and its biotransformation product Pt (DACH) C12 (DACH) in patients’ blood using high performance liquid chromatography and atomic absorption spectrometry. At steady state, the ratios of oxaliplatin to DACH did not correlate with neurotoxicity. This finding suggests that the levels of DACH, which were shown to be 3.8-fold more neurotoxic in the rat model, may not be a reliable pharmacodynamic marker that can predict for neurotoxicity.
Oxaliplatin-Induced Morphologic Changes in Nerves In an in vitro study, oxaliplatin reduced the growth of neurites of explanted rats’ dorsal root ganglia in tissue cultures.13 Cavaletti et al14,15 treated 4 groups of female Wistar rats with different doses and schedules of oxaliplatin intraperitoneally. They found the least toxic effects when giving 4 mg/kg/day (24 mg/m2) biweekly for 9 weeks. Conduction velocity in the tail nerve was significantly reduced in all animals at the end of treatment with no difference between the groups, and partial recovery occurred after 5 weeks of follow-up. Morphometry of dorsal root ganglia revealed significant differences in the oxaliplatin-treated groups versus the untreated control. Nucleolar, nuclear, and somatic areas were reduced, with nucleolar segregation in all treated animals. Morphometric changes completely recovered after 5 weeks of follow-up.
Table 1
Morphological Changes in Rats’ Dorsal Root Ganglia After Oxaliplatin Exposure
• Reduced growth of neurites • Reduced nucleolar, nuclear, and somatic areas, with nucleolar segregation
Mild secondary axonopathy occurred in sciatic nerves. In contrast, Holmes et al16 observed reduced cell and nuclear areas in the neuronal cell bodies of rat dorsal root ganglia L4L6 when compared with control animals after an 8-week recovery period. Neurotoxicity correlated with a greater retention of platinum by the dorsal root ganglia. Morphological changes in nerves of rats after oxaliplatin exposure are summarized in Table 1.
Neurotoxicity Mechanisms Underlying Neurotoxicity In rodents, cisplatin is preferentially toxic to large diameter neurons and proprioceptive sensory modalities. In contrast, it appears that motor neurons are spared from toxicity.17 Storage of platinum drugs in sensory neurites is associated with reduced cellular metabolism and axoplasmatic transport.18 The hydrophilicity of platinum drugs correlates with platinum sequestration in the peripheral nervous system but not with neurotoxicity detected by measuring sensory nerve conduction velocity in Wistar rats. Differences in the reactivity of platinum complexes obviously account for some of the variation in their neurotoxicity.19 Screnci et al20 concluded from their studies that Pt (DACH) derivatives exhibit enantiomeric-selective peripheral neurotoxicity during repeated dosing in rats. Grolleau et al21 employed the whole cell patch-clamp technique to investigate the oxaliplatin effects on the electrophysiological properties of short-term cultured dorsal unpaired median neurons isolated from the central nervous system of the cockroach, Periplaneta americana. After an intracellular application of up to 500 μmol of oxaliplatin and its metabolite oxalate, the amplitude of the voltage-gated sodium current was decreased, thereby reducing the amplitude of the action potential by one-half. The effect of oxaliplatin could be mimicked by 10 mmol bis-(o-aminophenoxy)-N, N, N´, N´tetraacetic acid, known as a chelator of calcium ions. Since oxalate immobilizes calcium ions as well as bis-(oaminophenoxy)-N, N, N´, N´-tetraacetic acid, this study suggests a pathway involving calcium ions. Therefore, it may be useful to increase calcium blood levels to decrease oxaliplatin-induced neurotoxicity. Alteration of sodium channel inactivation kinetics on rat sensory sural nerve preparations were observed 5-10 minutes after the application of oxaliplatin 250 μmol.22 Na+ influx was increased due to prolonged opening of Na+ channels. The size and the duration of the action potentials in myelinated Afibres, elicited by supramaximal stimulation, dramatically increased. Electrotonic responses showed enhanced and persistent repetitive firing for several hundred milliseconds. The
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Prevention of Oxaliplatin-Induced Neuropathy Preliminary data from 4 patients receiving oxaliplatin 130 mg/m2 every 3 weeks suggested a dramatic improvement in acute neurotoxicity with the administration of intravenous • Increased Na+ influx due to prolonged opening of Na+ channels calcium gluconate 1 g and magnesium sulfate 1 g.27 In con• Increased size and duration of the action potentials in myelinated A-fibres, trast, treatment with magnesium citrate 1 g die by mouth elicited by supramaximal stimulation combined with oxaliplatin therapy did not result in any bene• Enhanced and persistent repetitive firing for several hundred milliseconds fit on neurotoxicity. This effect was tested by measuring vibratory sensibility at the plantar surfaces of the feet as well as • Lengthening of the refractory period at the palmar surfaces of the hands by a tuning fork and a de• No blockage of potassium channels tailed questioning of patients for symptoms (Lersch et al, unpublished data). • No effect on Na+ currents of hippocampal neurons Patients with metastatic colorectal cancer treated with either raltitrexed 3 mg/m2 plus oxaliplatin 130 mg/m2, every refractory period of peripheral nerves was lengthened. There 3 weeks (n = 9) or irinotecan 175 mg/m2 plus oxaliplatin 85 was absolutely no effect on Na+ currents of hippocampal neumg/m2 every 2 weeks (n = 6) received the thiophosphate cyrons, suggesting that the interaction of oxaliplatin is restricttoprotectant agent amifostine at a dose of 500 mg, subcutaed to one or more channel isoforms. The in vitro results are neously 20 minutes prior to administration of the anticancer summarized in Table 2. The effect of oxaliplatin could be anagents.28,29 All patients experienced ≥ grade 2 polyneuropatagonized by 1 mmol Na+ channel blocker carbamazepine.23 thy upon receiving a cumulative oxaliplatin dose of 390 High concentrations of Ca2+ > 10 mmol antagonized the efmg/m2. Neurologic symptoms improved immediately in 10 fect of oxaliplatin on nerve excitability. Gabapentin failed to patients, while 5 patients did not respond. affect Na+ current in isolated cortical neurons of rats,24 but it Similar results were reported by Rudolph et al.30 Patients was not tested in the presence of oxaliplatin. The underlying received oxaliplatin 85 mg/m2 on day 1, folinic acid 500 mg/m2 mechanism for the clinical benefit of gabapentin is not yet evon days 1 and 2, and 5-FU 4000 mg/m2 as a 48-hour continident and needs to be further elucidated. uous infusion every 2 weeks. Half of the patients also received amifostine at a dose of 910 mg/m2 as a 10-minute Studies to Prevent Neurotoxicity intravenous infusion just prior to chemotherapy. The inciPatients who are receiving oxaliplatin-based chemotherapy dence of peripheral neurotoxicity was significantly reduced must be warned to avoid drinking cold liquids and/or ingest(P = 0.048) in the amifostine group. ing cold foods for a few days following treatment. In addition, Mariani et al31 treated 15 colorectal cancer patients with patients should be advised to avoid going out in the cold oxaliplatin 85 mg/m2 on days 1 and 15 and folinic acid 60 weather after therapy with oxaliplatin. If necessary, patients mg/m2 together with 5-FU 500 mg/m2 on days 1, 2, and 15. should wear protection around the face and, in particular, The mean cumulative dose of oxaliplatin was 255 mg/m2 around the nose and mouth areas to avoid the possibility of (range, 85-1190 mg/m2). Patients received gabapentin at the difficult breathing and/or swallowing. Of note, acute neudose of 100 mg twice a day immediately after the onset of rosensory symptoms usually disappear after the discontinuaneuropathic symptoms. The dosage was increased by an adtion of the drug.25 To date, the neurotoxicity resulting from ditional 100 mg per day if symptoms continued for 3 days. platinum exposure has not been prevented by treatment with Symptoms disappeared in all patients treated and recurred in a number of agents including thiols, neurotrophic factors, or 2 patients who discontinued their gabapentin treatment. calcium channel blockers.26 Carbamazepine is one of the most commonly prescribed Drugs Used to Prevent Oxaliplatin-Induced Neuropathy Table 3 anticonvulsant drugs, which exerts its pharmacological efPatients No. of Whose Neurotoxicity fect by binding to the receptor Drug, Dose, Route of Application Patients Was Improved (%) sites associated with the activation of voltage-sensitive Calcium gluconate 1 g I.V. and magnesium sulfate 1 g I.V. 4 100% sodium channels.32 Based on 27 die just after the onset of symptoms during oxaliplatin infusion this mechanism, it is predicted Magnesium citrate 1 g p.o. die (Lersch et al, unpublished data) 13 0 to be a potential candidate as a protective agent against oxaliAmifostine 500 mg subcutaneously just before oxaliplatin infusion28,29 15 67% platin-induced neurotoxicity. Amifostine 910 mg/m2 I.V. just before oxaliplatin infusion30 15 not indicated In a nonrandomized pilot study, 40 pretreated patients Gabapentin 100 mg b.i.d. immediately after the onset of neuropathic 15 100% suffering from advanced colsymptoms31 orectal cancer received oxali33 10 100% Carbamazepine doses p.o. adapted to a serum level of 3-6 mg/L platin 85 mg/m2 on days 1, 15, Table 2
In Vitro Effects of Oxaliplatin on Rat Sural Nerves
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Christian Lersch et al and 29 and folinic acid 500 mg/m2 plus 5-FU 2000 mg/m2 on days 1, 8, 15, 22, 29, and 36 repeated every day as secondline therapy. Ten patients also received carbamazepine 200600 mg by mouth at doses adapted to serum levels of 3-6 mg/L. Dosage was started with 200 mg beginning 1 week before the first dose of oxaliplatin. Two days later, the dose was increased to 400 mg. Carbamazepine was continuously given to the patients until the end of chemotherapy with oxaliplatin. In case of ongoing neuropathological symptoms, carbamazepine was further prescribed for a maximum of 3 weeks until symptoms had disappeared. The median cumulative dose of oxaliplatin was 722 mg/m2. Neurological examinations were performed weekly, mainly by measuring the vibratory sensibility at the plantar surfaces of the feet and the palmar surfaces of the hands by a tuning fork and the documentation of side effects (ie, hyperpathic symptoms induced by cold and treatment-related toxicities). Grade 2-4 neuropathy, as outlined by the modified WHO scale, did not occur in any patient. In contrast, this toxicity was observed in 30% of an historical control group (n = 30) who had received an even lower cumulative dose of oxaliplatin (510 mg/m2).33 At present, a controlled multicenter trial has been initiated to further evaluate the efficacy and toxicity of carbamazepine in oxaliplatin-treated patients with advanced colorectal cancer. A summary of the preliminary data cited above is reported in Table 3.
Conclusion Oxaliplatin-induced neurotoxicity appears to be most likely due to alterations in the kinetics of sodium channel inactivation. Carbamazepine is the only substance that has proven to antagonize this effect in vitro. Several pilot clinical studies have shown that carbamazepine, gabapentin, and amifostine can reduce the severity of neurotoxicity in patients. However, the in vitro preclinical data suggests that carbamazepine may be the most promising substance to prevent neurotoxicity. Randomized controlled trials are necessary to further evaluate the neuroprotective effect of carbamazepine and perhaps other sodium channel blockers in oxaliplatin-treated patients. Given the potentially increased role of oxaliplatin in the treatment of advanced colorectal cancer, such studies are critically important as they may help improve the safety profile of this interesting agent.
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