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1 w wz 9«y Kor. J. Clin. Pharm., Vol. 9, No w y Oxaliplatin n w m B Á½ B Á B Áùx BC B ƒm w C ƒm w w w (009 3 Á009 6 Á ) Oxaliplatin-induced Peripheral Neuropathy in Patients with Advanced or Metastatic Gastric Cancer Ae-Ryoung Park a, Soon-Joo Kim a, Joon Seok Bang a, and Hyen-Oh La a,b* a Department of Pharmacy, Seoul St. Mary s Hospital, The Catholic University of Korea b Department of Pharmacology, College of Medicine, The Catholic University of Korea (Received March, 009ÁRevised June, 009ÁAccepted June 0, 009) Oxaliplatin is a tolerable and effective drug of choice in the treatment of advanced or metastatic gastric cancer. However, it has many dose-limiting neurotoxicities. This study was performed to assess the incidence and types of oxaliplatin-related neurotoxicities. Sixty-four patients receiving oxaliplatin-involved regimen as salvage therapy on metastatic gastric cancer or as the first-line therapy on advanced gastric cancer were evaluated during the period between September, 006 and February 9, 008. The patients were treated with oxaliplatin 00 mg/m and leucovorin 00 mg/m simultaneously as -hour-lasting infusion on Day- followed by 5-FU 00 mg/m as a -hour-lasting continuous infusion both on Day- and Day- by every other week. We developed questionnaires to evaluate patient-recognized neurotoxic symptoms rather than the observer-described events. Surveys were completed at bedside or via telephone interview. Acute and chronic neurotoxicities were graded according to the National Cancer Institute Common Toxicity Criteria (NCI-CTC, version 3) as well as the Oxaliplatin-specific Neurotoxicity Scale. The Grade-3 neuropathy was reported in 9% of the patients (n=) and grade-/ neuropathy occurred in 70% (n=45). The most common symptom was cold-related dysesthesia (83%) regarded as nociperception by the patients. Some patients (9%) experienced functional impairment affecting activities of daily living such as writing, buttoning, and walking. Even though 74% of the patients (4/57) were prescribed with gabapentin to reduce these peripheral symptoms, it did not appear to derive any benefit from this medication. It is suggested that notify the patients about their oxaliplatin-associated, debilitating symptoms, and educate them any self-care strategy at the initiating phase of the chemotherapy. Moreover, it needs to design the intervention studies regarding the prevention and management of the peripheral neuropathy. Key words - gastric cancer, oxaliplatin, peripheral neuropathy, modified FOLFOX-6 ù (8.3%), w 3 (6.4%) w. û s,, 5.5% w. ) y ƒ ü w 3» 4»¾ w š, 5 5~5% zƒ., w yw ww Correspondence to : ùx ƒm w w w (37-70) s 505, w 00y Tel: , Fax: hola@catholic.ac.kr y w j wš, mw 7.5~».,3) w t w yw w regimen y, oxaliplatin leucovorin, 5-fluorouracil profile wš, Al-Batran w 34% overall response rate e z ½w. 4-6) Oxaliplatin,-diaminocyclohexane (DACH) ligand sww 3 yw yw cisplatin w x w, w p, w ùkü. Oxaliplatin w w 8

2 w y Oxaliplatin n w m 9 ƒ ù ƒ m p y n ww» w. w w, w ƒ, p, oxaliplatin n z ü w» w. x ƒ m e» 7,8) w ƒ p ü ƒw. 9) Oxaliplatin w w wš, n y w sƒ» w w w. 0) w sƒ y w sƒ mw y m w œwš, w v w l ¾ ƒm w w, š (palliative therapy) oxaliplatin sww w yw y w. w yw regimen( w modified FOLFOX-6 ) n ú oxaliplatin 00 mg/m leucovorin 00 mg/m n w z 5-fluorouracil 00 mg/m ƒƒ w, ú 5- fluorouracil 4 w. 4) y ƒ m sƒw w w l ¾, y ƒ w l mw š, n w ù w m e y y w. w ƒ w,», m ƒ w 9 w w, ƒ w w y w w š, š w ƒ w, t»w (Table ). m sƒ» National Cancer Institute Common Toxicity Criteria (NCI- CTC) version 3 oxaliplatin ƒ w Oxaliplatinspecific neurotoxicity scale ww Grade 0 l 4¾ 5 w NCI-Sanofi criteria sƒ w (Table ). m sƒ n» Grade ùkù ù Grade 3 z ùkú n v w, Grade 3 ù Grade 4 x n ƒ «š. 0) Table. Categorized questions ƒ» m ü. ƒ ù ò ö ¾?. ƒ ù ò ö ¾? 3. rw ù yñ ø ¾? 4. rw ù yñ ø ¾? 5. z m ö ¾?.» ö ¾?. ö ¾? 3. ö ö ¾?. ù ƒ ƒ ù ø ¾? Table. NCI-Sanofi criteria for measuring the neuro-sensory toxicities Scale Grade 0 Grade Grade Grade 3 Grade 4 Definition No symptoms Paresthesias or dysesthesias of short duration that resolve and do not interfere with function Paresthesias or dysesthesias interfering with function but not activities of daily living Paresthesias or dysesthesias with pain or functional impairment that also interfere with activities of daily living Persistent paresthesias or dysesthesias that are disabling or life threatening

3 0 Kor. J. Clin. Pharm., Vol. 9, No., 009 y p» w, š y 75, m w ƒ ƒ w 64, sƒw. ú y w y 6 (9.4%). s û ƒ 47 (73%) (7, 7%) w, s³ 6.7±.4 š k ww ƒ 8 (3%) š, 56 (87%) w. e» ƒ 0 (3%) ƒ š, 9 (30%), š, v, (Table 3). y 64 modified FOLFOX-6 regimen wš w yw ww ù e (conservative therapy) š y 55 š, ù 9 modified FOLFOX-6 regimen w. Modified Folfox-6 w 48»(cycle) w ww š, s³ n» 8.8±3.9 (range: -), w 07» n w, s³.9±.4(range: 9-7)» w yw ww. Table 3. Demographic characteristics of the study subjects Variables N % Total patients Sex Male Female Age(years) Disease status Locally advanced Metastatic Organs involved Liver Peritoneum Pancreas Nodes Colon Rectum Bone Breast Ovary Duodenum Lung * Median±S.D ±.4* Table 4. Neurotoxic events graded by the NCI-Sanofi Criteria Scale Number of patients suffering from toxic events Grade 0 Grade Grade Grade 3 Grade Number of patients (%) 57 (89) 7 () (34) 3 (36) (9) 35 (55) m y NCI-Sanofi criteria w w w Grade ùkü y ƒ (34%) š, Grade ƒ 3 (36%), Grade 3 y ƒ (9%)., Grade y 55% w (Table 4). Grade y s³ oxaliplatin 070 mg/m (range: mg/m ) š, s³ 0.7»(range: 3-») w yw ww. Grade 3 y s³ oxaliplatin 00 mg/m (range: mg/ m ), s³ 0.»(range: 4-8») w yw ww. m ùkù ƒ ƒ w, y 83%ƒ y w. ƒ ù ò y w ƒ 5% š, ƒ 48% ùkû.» ö ù» rw ö, y w» 9% w, 58%ƒ m Grade 3 ùkûš, s³» w yw ww., w» y y j w oxaliplatin sw w yw y r. y y ƒ œ j w ƒ, š ƒ, ƒ w ƒ. ƒ ù z m ö %, rw ù yñ ƒƒ 5 9% ùkû (Fig. ). m y w γ- aminobutyric acid (GABA) gabapentin n w, m y w 57 4 (74%) gabapentin n w m y w.

w y Oxaliplatin n w m Fig.. Neurotoxic events in the patients with oxaliplatin (recipients-responded) š Oxaliplatin w m oxaliplatin oxalate w calcium ion voltage-gated Na + channel w w š.

4 w y Oxaliplatin n w m Fig.. Neurotoxic events in the patients with oxaliplatin (recipients-responded) š Oxaliplatin w m oxaliplatin oxalate w calcium ion voltage-gated Na + channel w w š.,) m n w, n wš 3 w 3% y ƒ š ƒ ùkþ šƒ. 3) m j» w GABA gabapentin n w ù, n y wš y, Mitchell oxaliplatin w x û š, jš gabapentin n w ù, z w û. Calcium 4) magnesium, carbamazepine ù gabapentin w, alpha-lipoic acid, glutathione oxaliplatin m e z š, ³ y w k, m w ƒ y e ¾ ³. 5,6) w, oxaliplatin 6 w n w Petrioli n w 6 n Grade ùkû ù(8.% vs. 59.3%: P=0.0), 6 n w y ù r wš, ew ƒ ƒ v w w ƒ. 7) Oxaliplatin n w, w y m x w, 89% y ƒ Grade w ùkþ, Grade x 55% w. Grade 3 ùkù 9%( ) w, s³ oxaliplatin 00 mg/m (range: mg/m ) š, s³ 0.»(range: 4-8») w yw ww. ƒ w m, 85%ƒ y w š, 9% y»,» y» y rw y w, 58%ƒ m sƒ Grade 3 ùkû. w š w sww» y s³» w yw ww. w, y w Folfox-6 regimen x, m 87% ùkûš, Grade 3 m % š 4), j. w, Gramont w 3 x, w y oxaliplatin 85 mg/m, leucovorin 00 mg/m 5-fluorouracil 000 mg/m n» m 00 mg/m (») 5% ùkû š šw. 7) oxaliplatin m w ƒ w,», m w y 9 w w sƒw ƒ. Oxaliplatin m sƒ w y sƒ w sƒ ww Land y sƒ w w w

5 Kor. J. Clin. Pharm., Vol. 9, No., 009 w š, w sƒ ƒ» w., w sƒƒ y sƒ w y sƒ ww w ƒ š, w e» Grade 3 ƒ» ƒƒ.6% 0.4% ù kù (9%) w û ùkû., Land y w sƒ w, w e m ƒ ƒƒ 64.9% 83% š, ƒ ù ò ƒƒ 56.% 5%, r ù ò ƒƒ 5.% 48% ƒ w. 0) ó, modified FOLFOX-6 w yw w y 9 sw ù e ƒ z m w w w recall biasƒ w ƒ ¾ w w w w. š x m ƒ, w ( cancer.go.kr/cms/statics/survival_rate/index.html).. Glimelius B, Ekstrom K, Hoffman K, et al. Randomized comparison between chemotherapy plus best supportive care with best supportive care in advanced gastric cancer. Ann Oncol 997; 8: Hill ME, Cunningham D. Medical management of advanced gastric cancer. Cancer Treat Rev 998; 4: Louvet C, Andre T, Tigaud JM, et al. Phase II study of oxaliplatin, fluorouracil, and folinic acid in locally advanced or metastatic gastric cancer patients. J Clin Oncol 004; 0: Al-Batran SE, Atmaca A, Hegewisch-Becker S, et al. Phase II trial of biweekly infusional fluorouracil, folinic acid, and oxaliplatin in patients with advanced gastric cancer. J Clin Oncol 004; : Leong T. Chemotherapy and radiotherapy in the management of gastric cancer. Curr Opin Gastroenterol 005; : De Gramont A, Figer A, Seymour M, et al. Leucovorin and fluorouracil with or without oxaliplatin as first-line treatment in advanced colorectal cancer. J Clin Oncol 000; 8: Wilson RH, Lehky T, Thomas RR, et al. Acute oxaliplatin-induced peripheral nerve hyperexcitability. J Clin Oncol 00; 0: Cassidy J, Misset JL. Oxaliplatin-related side effects: characteristics and management. Semin Oncol 00; 9: Land SR, Kopec JA. Neurotoxicity from oxaliplatin combined with weekly bolus fluorouracil and leucovorin as surgical adjuvant chemotherapy for stage II and III colon cancer: NSABP C-07. J Clin Oncol 007; 5: Gamelin L, Capitain O, Gamelin E, et al. Predictive factors of oxaliplatin neurotoxicity: the involvement of the oxalate outcome pathway. Clin Cancer Res 007; 3: Grolleau F, Gamelin L, Gamelin E, et al. A possible explanation for a neurotoxic effect of the anticancer agent oxaliplatin on neuronal voltage-gated sodium channels. J Neurophysiol 00; 85: Nordlinger B, Sorbye H, Glimelius B, et al. Perioperative chemotherapy with FOLFOX4 and surgery versus surgery alone for respectable liver metastases from colorectal cancer: a randomized controlled trial. Lancet 008; 37: Mitchell PL, Goldstein D, Michael M, et al. Addition of gabapentin to a modified FOLFOX regimen does not reduce oxaliplatin-induced neurotoxicity. Clin Colorectal Cancer 006; 6: Grothey A. Oxaliplatin-safety profile: neurotoxicity. Semin Oncol 003; 30: Gamelin L, Boisdron-Celle, Delva R, et al. Prevention of oxaliplatin-related neurotoxicity by calcium and magnesium infusions: a retrospective study of 6 patients receiving oxaliplatin combined with 5-fluorouracil and leucovorin for advanced colorectal cancer. Clin Cancer Res 004; 0: Petrioli R, Pascucci A, Francini G, et al. Neurotoxicity of FOLFOX-4 as adjuvant treatment for patients with colon and gastric cancer: a randomized study of two different schedules of oxaliplatin. Cancer Chemother Pharmacol 008; 6: Cavanna L, Artioli F, Zaniboni A, et al. Oxaliplatin in combination with 5-fluorouracil and leucovorin in patients with metastatic gastric cancer. Am J Clin Oncol 006; 9: Leonard G, Wright MA, Grem JL, et al. Survey of oxaliplatin-associated neurotoxicity using an interviewbased questionnaire in patients with metastatic colorectal cancer. BMC Cancer 005; 5: Pietrangeli A, Leandri M, Garufi C, et al. Persistence of high-dose oxaliplatin-induced neuropathy at long-term follow-up. Eur Neurol 006; 56: 3-6.

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16(2)-7(p ).fm w wz 16«2y Kor. J. Clin. Pharm., Vol. 16, No. 2. 2006 ü t xy y w tœ ½ BÁ x BC B y w w w C y w w w Current Status and Expectations of Orphan Drugs in Korea -In point of supplying medicines for the rare