sign in sign up
<<
Home , Thrombocytopenia

ANTICANCER RESEARCH 28 : 3115-3118 (2008)

Fatal Thrombocytopenia after Oxaliplatin-based YU-YUN SHAO and RUEY-LONG HONG

Department of , National Taiwan University Hospital, Taipei, Taiwan, R.O.C.

Abstract. Oxaliplatin-related thrombocytopenia is Case Report considered rare and mostly self-limited. We present the first reported fatal case due to this complication. A 64-year-old A 64-year-old man with metastatic colon cancer had received patient with metastatic colon cancer was admitted for his eight months of chemotherapy with oxaliplatin and 24-hour 24th course of chemotherapy with oxaliplatin and 24-hour infusion of and leucovorin. Computed infusion of fluorouracil and leucovorin. Consciousness tomography revealed complete response, so chemotherapy changed on the next evening and deteriorated to deep coma was halted. Fifteen months later, tumor recurrence with within hours. Computed tomography revealed large new lung metastases developed. Salvage chemotherapy with with brain herniation. Hemogram the same regimen was resumed. From that time, a total of showed severe thrombocytopenia, which was considered to five episodes of grade 1 to 2 reaction be associated with oxaliplatin. The patient died six days occurred during infusion. The manifestations included skin later. The incidence of oxaliplatin-related thrombo- rash, tremor and chills. Notably, mild occurred cytopenia may have been underestimated and its severity during the 22nd and 23rd infusions. Hemogram was not long neglected. Other hypersensitivity reactions may examined because the symptoms were self-limited. precede its onset. Early hemogram examination during The patient was admitted for the 24th course. Hemogram hypersensitivity reaction to oxaliplatin may provide early on admission revealed normal results (hemoglobin 15 g/d l, diagnosis and the prevention of the possible fatal 163,000/μ l and leukocyte 5,300 /μ l). Chemotherapy consequences. was administered after adequate premedication, including antihistamines and steroids. One hour after the start of Oxaliplatin has been extensively applied worldwide for oxaliplatin infusion, the patient complained of acute back colorectal cancer and other malignancies. Due to its good soreness without cutaneous symptoms or hemoptysis. The safety profile, most patients receive in out-patient symptoms subsided after prolonging the infusion time. settings. Common toxicities include peripheral neuropathy, However, hematemesis developed on the next evening. Half diarrhea and mild myelosuppression. Hypersensitivity an hour later, the patient became lethargic and the pupils were reactions to oxaliplatin infusion have been reported, with an anisocoric. His consciousness soon deteriorated to coma. occurrence rate of 10-20% (1-3). Most manifestations were Emergent head CT revealed a large intracerebral mild and self-limited, but severe thrombocytopenia after of the left frontal lobe with mass effect and midline shift. No repeated administrations may develop (4-10). Most reported brain tumors were identified. The patient was intubated and events were self-limited within days. We here describe a transferred to an intensive care ward. Immediate follow-up patient with colorectal cancer who developed fatal hemogram showed a markedly decreased platelet count oxaliplatin-related thrombocytopenia. (4,000/μ l), while there was little change in the leukocyte count (3,880/μ l). The international normalized ratio was normal, so thromb otic thrombocytopenic or disseminated intravascular was less likely. A very low haptoglobin level (<18 mg/d l, normal range 30-178 mg/d l) revealed the possibility of concomitant intravascular Correspondence to: Ruey-Long Hong, National Taiwan University . A direct antiglobulin test result was Hospital, No. 7, Chung-Shan South Rd, Taipei 10016, Taiwan, strongly positive, so an immune-related process was favored. R.O.C. Tel: +886 223123456 ext. 67510, Fax: +886 223711174, e-mail: [email protected] Despite aggressive , the patient remained in deep coma without brainstem reflexes, and eventually died Key Words: Colorectal cancer, hypersensitivity reaction, intracranial of multi-organ failure six days after the onset of intracranial hemorrhage, oxaliplatin, thrombocytopenia. hemorrhage.

0250-7005/2008 $2.00+.40 3115 ANTICANCER RESEARCH 28 : 3115-3118 (2008)

Table I. Oxaliplatin-related thrombocytopenia.

Hemolysis Infusion Onset Preceding symptoms Treatment Result number (hours)

Earle et al. (4) Yes N.A. 5 Not mentioned Steroid, transfusion Recovery Sørbye et al. (5) Yes 9 1 day Back pain Transfusion Recovery Dold et al. (6) No 19 4 Skin rash Transfusion Recovery Koutras et al. (7)* Yes 14 1 Fever, chills, nausea, vomiting and back pain Steroid, transfusion Recovery No 13 1 day Back pain No Recovery Taleghani et al. (8) Yes 15 4 Not mentioned Steroid, transfusion Recovery Curtis et al. (9) No 17 2 days Abdominal pain Transfusion Recovery No 10 24 Not mentioned Transfusion Recovery Pavic et al. (10) No 20 8 Not mentioned Steroid, transfusion Recovery

N.A.: Not available. *Steroid was also used as a premedication.

Discussion The mechanism of oxaliplatin-related thrombocytopenia is considered immune-related. Prior case reports described We present a case with fatal intracranial hemorrhage due to positive direct antiglobulin test result (4, 5, 7, 8), which was oxaliplatin-related thrombocytopenia. To our knowledge, this also positive in our patient. Immunoglobulin G is the first example of a patient to die of this complication. against in the presence of oxaliplatin were indeed Oxaliplatin is generally used in many malignancies, identified in four patients (8-10). By monoclonal - especially colorectal cancer. Severe oxaliplatin-related specific immunomobilization of platelet antigen assay, GPIIb- thrombocytopenia is rare. In literature, most patients IIIa had the only or strongest reaction with the patients’ serum recovered after platelet transfusions or steroid use (Table I). compared to the other platelet antigens. However, how Thrombocytopenia may be associated with hemolytic oxaliplatin facilitates the reaction between the antibodies and anemia, but not always (4, 5, 7, 8). All the events recorded platelets remains unknown. The preference of this immune developed after repeated infusions; the earliest episode reaction to GPIIb-IIIa also mandates further exploration. occurred during the ninth infusion (5). The onset is various: Due to the considered immune-related nature of oxaliplatin- it could be as fast as one hour after the start of oxaliplatin related thrombocytopenia, steroid was sometimes used as a (7), but might be delayed to a few days after (5). treatment. Nonetheless, several patients recovered solely by Other hypersensitivity reactions frequently preceded transfusion (Table I). Although used as a premedication, our manifestations of thrombocytopenia, with back pain most patient and another described by Koutras et al . still developed commonly described (5-7, 9). Three out of the nine patients thrombocytopenia (7). These cases imply steroid had limited previously reported suffered from acute back pain, an effect in preventing allergic events to oxaliplatin. unusual manifestation of oxaliplatin-related hypersensitivity In summary, we describe a case with oxaliplatin-related reactions (11). The first discomfort in our patient was also thrombocytopenia which resulted in fatal intracranial back soreness, which had never happened during the prior hemorrhage. Immune-related thrombocytopenia may develop infusions. The explanation of this unique association needs after repeated oxaliplatin exposure. Its onset is frequently more investigation. preceded by other allergic reactions. should be Moreover, these preceding symptoms imply that cautious when patients have repeated symptoms or signs of physicians should be cautious with oxaliplatin-related allergic reaction to oxaliplatin because severe thrombocyto- allergic reactions. Although most are self-limited, penia may follow. Early hemogram examination may provide they may suggest a higher possibility of subsequent severe early diagnosis and the prevention of the possible fatal thrombocytopenia. In one retrospective study, 7.1% of consequences. patients with allergic reaction to oxaliplatin developed thrombocytopenia (12). The occurrence rate is probably References underestimated because hemograms are not routinely 1 Brandi G, Pantaleo MA, Galli C, Falcone A, Antonuzzo A, examined during allergic reactions and thrombocytopenia Mordenti P, Di Marco MC and Biasco G: Hypersensitivity may resolve within days. Our patient deteriorated very fast reactions related to oxaliplatin (OHP). Br J Cancer 89 : 477-481, after hemoptysis. In prevention, hemogram examination 2003. during hypersensitivity reactions to oxaliplatin should be 2 Andre T, Boni C, Mounedji-Boudiaf L, Navarro M, Tabernero J, considered for those patients with repeated episodes. Hickish T, Topham C, Zaninelli M, Clingan P, Bridgewater J,

3116 Shao and Hong : Fatal Oxaliplatin-related Thrombocytopenia

Tabah-Fisch I and de Gramont A: Oxaliplatin, fluorouracil, and 9 Curtis BR, Kaliszewski J, Marques MB, Saif MW, Nabelle L, leucovorin as adjuvant treatment for colon cancer. N Engl J Med Blank J, McFarland JG and Aster RH: Immune-mediated 350 : 2343-2351, 2004. thrombocytopenia resulting from sensitivity to oxaliplatin. Am J 3 Gowda A, Goel R, Berdzik J, Leichman CG and Javle M: Hematol 81 : 199-201, 2006. Hypersensitivity reactions to oxaliplatin: incidence and 10 Pavic M, Moncharmont P, Seve P, Rigal D and Broussolle C: management. Oncology (Williston Park) 18 : 1671-1675, 2004. Oxaliplatin-induced immune thrombocytopenia. Gastroenterol 4 Earle CC, Chen WY, Ryan DP and Mayer RJ: Oxaliplatin- Clin Biol 30 : 797-798, 2006. induced Evan's syndrome. Br J Cancer 84 : 441, 2001. 11 Siu SW, Chan RT and Au GK: Hypersensitivity reactions to 5 Sorbye H, Bruserud Y and Dahl O: Oxaliplatin-induced oxaliplatin: experience in a single institute. Ann Oncol 17 : 259- haematological emergency with an immediate severe thrombo- 261, 2006. cytopenia and haemolysis. Acta Oncol 40 : 882-883, 2001. 12 Maindrault-Goebel F, Andre T, Tournigand C, Louvet C, Perez- 6 Dold FG and Mitchell EP: Sudden-onset thrombocytopenia with Staub N, Zeghib N and De Gramont A: Allergic-type reactions to oxaliplatin. Ann Intern Med 139 : E156-E157, 2003. oxaliplatin: retrospective analysis of 42 patients. Eur J Cancer 7 Koutras AK, Makatsoris T, Paliogianni F, Kopsida G, 41 : 2262-2267 , 2005. Onyenadum A, Gogos CA, Mouzaki A and Kalofonos HP: Oxaliplatin-induced acute-onset thrombocytopenia, hemorrhage and hemolysis. Oncology 67 : 179-182, 2004. 8 Taleghani BM, Meyer O, Fontana S, Ahrens N, Novak U, Borner Received May 6, 2008 MM and Salama A: Oxaliplatin-induced immune . Revised July 15, 2008 Transfusion 45 : 704-708, 2005. Accepted August 4, 2008

3117