Successful desensitization with cetuximab after an infusion reaction to panitumumab in patients with metastatic colorectal cancer.

BACKGROUND: Cetuximab and panitumumab are chimeric and fully human monoclonal antibodies, respectively, against epidermal growth factor receptor used in the treatment of metastatic colorectal cancer (mCRC). Incidence of documented infusion reaction (IR) is more common with cetuximab (all grades [g]: 15-21%, g 3/4: 2-5%) than panitumumab (all g: 4%, g 3/4: 1%). Anecdotal reports suggest successful challenge with panitumumab following IR with cetuximab (Saif et al. in Cancer Chemother Pharmacol 63(6):1017-1022, 2009). However, safety of cetuximab after IR with panitumumab is not known. We report two patients successfully desensitized with cetuximab after IR with panitumumab. PATIENTS AND METHODS: A 42-year-old female with mCRC received panitumumab as a third-line agent. She developed severe chest tightness, pain, and shortness of breath (SOB), 5 min after first panitumumab infusion. A second 70-year-old male with mCRC developed severe facial flushing, back pain, SOB, tachycardia and hypotension, 5 min after second dose of panitumumab plus irinotecan as a second-line therapy. These two patients received desensitization protocol for cetuximab after a test dose of 20 mg IV over 10 min followed by a slow infusion 10% of original rate in 0-2 h, 25% of original rate in 2-2.5 h, 50% reduced rate in 2.5-3 h, and then 100% infusion rate after 3 h. Patients were observed 4 h after completion of infusion. RESULTS: First patient received a total of 12 cycles of cetuximab with stable disease, no recurrence of IR, and grade 1-2 acniform rash that first developed after third cycle. Second patient received a total of eight cycles uneventfully without IR. CONCLUSIONS: To our knowledge, this is the first report of two patients with documented IR with panitumumab being desensitized successfully with cetuximab. Though anecdotal reports suggest safety of panitumumab in patients following IR with cetuximab, panitumumab can also cause severe IR. Our experience suggests that in case of limited options, such patients can be successfully challenged with cetuximab in a hospital after appropriate desensitization and premedication. Further studies focusing on desensitization and identifying hypersensitivity profile of different anti-epidermal growth factor receptor antibodies are warranted.

Effect of etoposide on the pharmacokinetics of methotrexate in vivo.

The effect of etoposide on the pharmakokinetics of methotrexate (MTX) was examined in vivo. High-dose (5g/m2/24 h) MTX therapy was combined with two etoposide (100mg/m2/ 1 h) infusions as a part of the medulloblastoma protocol developed in our department. Vepesid therapy was administered in two different schedules. The first group of patients received etoposide immediately before and at the end (24 h) of MTX treatment. The second group was treated with etoposide at 24 and at 48 h after starting MTX infusion. In this latter group both treatment-related grade III and grade IV toxicity developed more frequently than in the first group (58.6 versus 29.2%, for grade 3 toxicity p=0.019, for grade 4 toxic signs p=0.040, respectively). We observed that after the second dose of etoposide given at 48 h (second group) both total and unbound serum MTX levels (determined by high-performance liquid chromatography) were elevated by 53-109 and 26-65%, respectively, by the third hour after completion of Vepesid infusion. This effect was detectable for 6 h. All the liver and kidney functions of the patients were within the normal range. These results suggest the possibility of partial recirculation of extra/intracellular MTX into the blood after etoposide administration. Based on these results, the therapeutic protocol has been modified, and Vepesid is given prior to and at the end (24 h) of high-dose MTX treatment. Under these conditions only a slight decrease of MTX elimination has been detected between 25 and 28 h. These results emphasize the role of possible schedule-dependent interactions of cytostatic drugs.

Recombinant human erythropoietin in the prevention of chemotherapy-induced anaemia in children with malignant solid tumours.

This prospective, randomised pilot study was designed to evaluate safety, feasibility and efficacy of recombinant human erythropoietin (rhEPO) in the prevention and treatment of chemotherapy-induced anaemia in children with solid tumours. 20 children (age 4-18 years) undergoing cyclic combination chemotherapy were randomised either to a control group or to receive rhEPO at a dose of 150 U/kg/dose subcutaneously three times/week for a minimum of 12 weeks or three chemotherapy cycles. Of 15 evaluable patients, 8 were randomised to the rhEPO group and 7 to the control group. RhEPO-treated patients showed an increase in the haematocrit over the first 8 weeks of therapy, with a significantly higher mean haematocrit at week 8 (33.2 +/- 2.1% versus 39.3 +/- 4.2% in the control and rhEPO groups, respectively, P < 0.05). Similarly, significantly higher haemoglobin concentrations could be demonstrated in the rhEPO group by week 8 (11.06 +/- 1.35 g/dl versus 13.11 +/- 1.13 g/dl in the control and rhEPO groups, respectively, P < 0.05), with higher precycle haemoglobin before chemotherapy cycles 3 and 4 and higher midcycle haemoglobin between cycles 3 and 4. There was a trend towards a reduction of transfusion requirements during the 3rd month of therapy in rhEPO patients. The results of this pilot study indicate a significant benefit of rhEPO in children treated with intensive combination chemotherapy regimens. Further studies should target issues such as appropriate dosing, timing and duration of rhEPO therapy in children with cancer.

[In vivo effect of etoposide on the pharmacokinetics of methotrexate]. / Az etoposid hatása a metotrexát farmakokinetikájára in vivo.

High dose (5 g/m2/24 h) methotrexate therapy was combined two times with etoposide (100 mg/m2/1h) infusions as a part of the Medulloblastoma protocol developed in our Department Vepesid therapy was administered in two different schedules. The first group of the patients have received etoposide immediately before and at the end (24th h) of methotrexate treatment. The second group was treated with etoposide at 24 h and at 48 hour after starting methotrexate infusion. In this latter group treatment related grade 3-4 toxicity developed more frequently than in the first group (58.6% vs 33.3%). The authors observed that after the second dose of etoposide given at 48 h (second group) both total and unbound serum methotrexate levels (determined by high performance liquid chromatography) were elevated by 53.14-109.19%, and 25.86-64.95%, respectively by the third hour after completion of Vepesid infusion. This effect was detectable for 6 hours. All the liver and kidney functions of the patients were in the normal range. These results suggest the possibility of partial recirculation of extra/intracellular methotrexate into the blood after etoposide administration. Based on these results the therapeutic protocol has been modified and Vepesid is given prior to and at the end (24 h) of high dose methotrexate treatment. Under these conditions only a slight decrease of methotrexate elimination has been detected between the 25-28th h. These results emphasize the role of possible schedule dependent interactions of cytostatic drugs.

Diffuse plasmacytosis in a child with brainstem glioma following multiagent chemotherapy and intensive growth factor support.

The use of granulocyte colony-stimulating factor (G-CSF) or granulocyte-macrophage colony-stimulating factor (GM-CSF) in order to abrogate chemotherapy-induced neutropenia has become a routine part of many cancer treatment regimes. However, there are still very few data available about possible complications related to repeated or prolonged use of these agents in patients with malignant solid tumors. The authors report a child with brainstem glioma who received repeated cycles of multiagent chemotherapy with G- or GM-CSF support. During this period of 10 months, no clinical side effects were observed that could have been attributed to growth factor administration. However, postmortem histological examination revealed the presence of diffuse plasmacytosis, a rare hematological disorder in childhood. Undifferentiated plasma cells of nonmonoclonal origin could be demonstrated infiltrating bone marrow, lungs, and lymph nodes of the patient. Based on previously published in vitro and in vivo evidence on the interleukin-6 (IL-6)-mediated stimulatory effect of G- and GM-CSF on myeloma cell proliferation, the authors suggest a possible link between extensive growth factor support and the development of plasmacytosis in this patient.

Administration of Ethyol (amifostine) to a child with medulloblastoma to ameliorate hematological toxicity of high dose carboplatin.

The first report on the administration of the chemoprotective agent Ethyol (amifostine) in conjunction with high dose carboplatin to a patient in the pediatric/adolescent age group is presented. A 17 year old teenager with recurrent cerebellar medulloblastoma received a total of five courses of high dose carboplatin 2 x 600 mg/m2 (1200 mg/m2 total) in each cycle. A complete response has been observed following the third treatment cycle. However, cumulative grade IV hematological toxicity developed following each of the first four treatments. Therefore, the fifth treatment was administered in conjunction with amifostine, at a dose of 2 x 740 mg/m2. Time to complete hematological recovery (Hb > 100 g/l, granulocytes > 2.0 G/l, platelets > 100 G/l) was 52, 58, 72, 78 and 50 days, respectively, following treatments nos 1, 2,,3, 4 and 5. The duration of grade III-IV neutropenia (< 1.0 G/l) was 3, 7, 8, 10 and 5 days, respectively. The duration of grade II-IV thrombocytopenia (platelets < 75 G/l) was 10, 25, 35, 40 and 32 days, respectively. Grade IV thrombocytopenia (platelets < 25 G/l) lasted for 5, 10, 12, 18 and 3 days, respectively, after each consecutive treatment. The total number of platelet transfusions was 1, 2, 2, 3 and 1, with the transfusion of 6, 9, 11, 11 and 5 units of platelets. The administration of amifostine has not been accompanied by any serious side effect. A short decrease in body temperature and a transient drop of blood pressure have been observed. Although hematological toxicity of high dose carboplatin has not been eliminated by amifostine, we conclude that significant protection was achieved in this situation of progressive bone marrow exhaustion.

[Pharmacokinetic study of dibromodulcitol in children with brain tumors]. / A dibrómdulcit farmakokinetikai vizsgálata agytumoros gyermekekben.

Systemic pharmacokinetics of high-dose (500 mg/m2), orally administered dibromodulcitol (Elobromol) were studied in 16 chemotherapeutic courses administered to 5 patients. Cerebrospinal fluid dibromodulcitol levels were also analysed in two patients. Bromoepoxydulcitol, dianhydrodulcitol are cytotoxic, whereas bromoanhydrodulcitol, andhydroepoxydulcitol are inactive metabolites detectable during the biotransformation of dibromodulcitol. The HPLC method, developed by our team, is suitable for the determination of both dibromodulcitol and its main metabolites (dianhydrodulcitol and bromoanhydrodulcitol). Our publication is the first in the literature to describe the pharmacokinetic properties of these three hexite-derivatives in pediatric patients. With the exception of one patient, concentration-time curves were analysed by the one-compartment model. From the 30th minute following administration, dibromodulcitol was detectable in all plasma samples for at least 12 hours, its concentration however was usually undetectable by the 24th hour. Though highly variable in value, dianhydrodulcitol concentrations were detectable during all but one therapeutic courses. The following peak concentrations were observed: dibromodulcitol: 3.46-30.63 microM; dianhydroldulcitol: 1.70-6.17 microM; bromoanhydrodulcitol: 0-5.63 microM. The correlation of area under the curve for bromoanhydrodulcitol and dibromodulcitol was exponential up to 200 microMxh with no additional increase detectable above this limit; the distribution of dianhydrodulcitol values were described by a maximum-curve. The possibility of enterohepatic recirculation could not be excluded for any of the compounds studied. Each of the three hexitol derivatives were detectable in the cerebrospinal fluid even if the concentration of the individual metabolite remained undetectable in plasma. The cerebrospinal fluid concentrations of dibromodulcitol were almost constant in the period from 2.5 to 8 hours following administration.(ABSTRACT TRUNCATED AT 250 WORDS)

Pharmacokinetic studies on Elobromol in children with brain tumors.

Systemic pharmacokinetics of high dose (500 mg/m2), orally administered Elobromol (dibromodulcitol, DBD) were studied in 16 chemotherapeutic courses administered to five patients. Cerebrospinal fluid (CSF) DBD levels were also analyzed in two patients. Bromoepoxydulcitol (BED), dianhydrodulcitol (DAD) are cytotoxic, whereas bromoanhydrodulcitol (BAD) and anhydroepoxydulcitol (AED) are inactive metabolites detectable during the biotransformation of DBD. The HPLC method, developed by our team, is suitable for the determination of both DBD and its main metabolites (DAD and BAD). Our publication is the first in the literature to describe the pharmacokinetic properties of these three hexitol derivatives in pediatric patients. With the exception of one patient, concentration time curves were analyzed by the one-compartment model. From 30 min following administration, DBD was detectable in all plasma samples for at least 12 h; its concentration, however, was usually undetectable by 24 h. Though highly variable in value, DAD concentrations were detectable during all but one of the therapeutic courses. The following peak concentrations were observed: DBD = 3.46-30.63 microM, DAD = 1.70-6.17 microM and BAD = 0-5.63 microM. The correlation of AUCBAD and AUCDBD values were exponential up to 200 microM h with no additional increase detectable above this limit: the distribution of AUCBAD and AUCDBD was described by a maximum curve. The possibility of enterohepatic recirculation could not be excluded for any of the compounds studied. Each of the three hexitol derivatives was detectable in CSF even if the concentration of the individual metabolite remained undetectable in plasma. DBD CSF concentrations were almost constant in the period from 2.5 to 8 h following administration.(ABSTRACT TRUNCATED AT 250 WORDS)

Human recombinant granulocyte-macrophage colony-stimulating factor in pediatric oncology practice.

This paper reports preliminary experiences with human recombinant granulocyte-macrophage colony-stimulating factor (GM-CSF) in children with malignant diseases administered for three indications: (1) chemotherapy-induced neutropenia and sepsis, (2) prolonged neutropenia decreasing dose intensity, and (3) prevention of neutropenia after sublethal doses of chemotherapy. It was concluded that in the daily dose of 5 micrograms/kg subcutaneously, GM-CSF is capable of reducing the duration of chemotherapy-induced neutropenia and may be an effective tool in maintaining dose intensity and achieving dose escalation.

[Poly-electrolyte fractionated porcine factor VIII in the treatment of hemophilia A]. / Polielektrolit-frakcionált porcin VIII. faktor egy esetben való alkalmazásáról gátlótestes haemophiliában.

In approximately 10 to 15 percent of congenital hemophilia A patients circulating antibodies to factor VIII appear in the blood that poses a serious problem in their treatment. A number of methods and preparations are used in the clinical practice to overcome this problem. Authors report their favourable clinical experience with the administration of polyelectrolyte-fractionated porcine factor VIII. concentrate in a hemophiliac child for the first time in Hungary and a brief review of the clinical methods in use in the management of factor VIII. inhibitors.

[First experience with the use of granulocyte-macrophage colony stimulating factor in pediatric oncology]. / Elsö tapasztalataink a granulocita-makrofág kolóniastimuláló faktor alkalmazásáról a gyermekgyógyászati onkológiában.

Authors report their first experiences with the application of granulocyte-macrophage colony stimulating factor in 12 pediatric cancer patients (14 cases). The drug was given in a 5 micrograms/kg single daily dose subcutaneously. Patients were divided into three main indication groups: 1. Severe neutropenia (white blood cell count < 1.0 G/l) and sepsis (6 patients); 2. Prolonged neutropenia (white blood cell count: 1.0-2.0 G/l) and delay in treatment (3 patients); 3. Dose-escalation of chemotherapy in therapy-resistant cases (4 patients). Authors report that in all cases a substantial raise in white blood cell count could be achieved after 5-6 days of granulocyte-macrophage colony stimulating factor treatment. No side effects were detected except of a moderate local pain at the site of the injection. Authors suggest that in the above described dose and way of administration granulocyte-macrophage colony stimulating factor can be an effective agent in the treatment of chemotherapy-induced neutropenia in paediatric oncology.

[Use of ondansetron, a 5-HT3 receptor antagonist, as a new type of antiemetic in pediatric oncology]. / Egy új típusú antiemetikum, az 5-HT3 receptor antagonista ondansetron alkalmazása gyermekonkológiában.

The effectiveness of the new antiemetic drug, the 5-hydroxytryptamin (5-HT) receptor antagonist ondansetron was evaluated in paediatric cancer patients. 5-HT3 antagonists represent a new class of drugs effective in the control of chemo- and radiotherapy-induced emesis. Based on their selectivity 5-HT3 antagonist are free from extrapyramidal side effects, a major problem in children in the case of currently used dopamine receptor antagonists (e.g. metoclopramide). In this study ondansetron was tested as antiemetic in 33 children with malignant disease (132 chemotherapy cycles) treated with: 1. high-dose cisplatin (120 mg/m2), 2. intermediate-dose cisplatin (60 mg/m2) and 3. no cisplatin-containing, combined high-dose chemotherapy. Ondansetron was found to be safe and effective in the control of acute and delayed emesis in all treatment groups. Its effectiveness was superior to the currently used antiemetic drugs in the period of acute emesis.