Adherence to hepatitis B screening and prophylactic lamivudine for prevention of rituximab-associated hepatitis B reactivation.

PURPOSE: Treatment with rituximab can be associated with hepatitis B reactivation leading to fulminant hepatitis and sometimes fatal hepatitis. The manufacturer has recommended screening the high-risk patients and monitoring hepatitis B virus carriers during and several months after the therapy. Prophylaxis with lamivudine has been recommended to prevent reactivation in hepatitis B virus carriers receiving rituximab. An institutional guideline was developed and implemented. This study evaluated the adherence to these clinical guidelines of hepatitis B screening in patients receiving rituximab-based treatment, the use of lamivudine prophylaxis, and the prevalence of positive hepatitis B virus surface antigen in this patient population in southeast Michigan. METHODS: A retrospective chart review of patients begun on rituximab therapy from January 2009 through June 2010 was conducted. RESULTS: Two hundred and eighty patients who received rituximab were identified. Approximately 70% of patients had hepatitis B virus surface antigen screening test prior to rituximab therapy. Antibody to hepatitis B virus core antigen was detected in 11.1% of patients, although the hepatitis B virus surface antigen positive rate was only 0.6%. One patient had hepatitis B virus reactivation despite lamivudine prophylaxis, but fully recovered after antiviral therapy was changed to tenofovir. CONCLUSION: The prevalence of hepatitis B virus surface antigen positivity is low in this study; however, antibody to hepatitis B virus core antigen positivity is high. Education to clinicians is warranted to increase awareness and further improve adherence to the clinical guidelines.

Possible case of levofloxacin-induced thrombocytopenia.

PURPOSE: A possible case of levofloxacin-induced thrombocytopenia is reported. SUMMARY: A 73-year-old Caucasian woman with stage IV squamous cell cancer of the oral cavity arrived at the hospital with a 6-day history of epistaxis; petechiae over her arms, legs, and abdomen; and bruises over her forearms. Her comorbidities included hypertension, type 2 diabetes mellitus, and coronary artery disease. Two weeks before arrival at the hospital, the patient had been admitted to the hospital with community-acquired pneumonia (CAP) and given a 10-day course of levofloxacin 500 mg daily, which she completed 4 days before this admission. Her platelet count was 7,000 cells/mm(3) on admission. Her home medications included aspirin 325 mg daily, ranitidine 150 mg twice daily, alprazolam 0.25 mg daily, and methadone 10 mg twice daily. She last received cetuximab six weeks before this hospital admission. No other new medications were recently introduced. She had no known drug allergies and no recent heparin exposure. The patient was given a platelet transfusion and treated empirically with prednisone for possible immune thrombocytopenic purpura, though drug-induced thrombocytopenia (DIT) was also suspected. She was restarted on her home medications except for aspirin. She was discharged with a 7-day course of oral corticosteroids. At discharge, her platelet count was 38,000 cells/mm(3). Corticosteroids were discontinued when DIT was established to be the most likely diagnosis. CONCLUSION: A 73-year-old woman with stage IV squamous cell cancer of the oral cavity developed a possible case of levofloxacin-induced thrombocytopenia after receiving the drug for 10 days for treatment of CAP.

Retrospective evaluation of venous thromboembolism prophylaxis in the adult cancer population.

STUDY OBJECTIVES: Hospitalized cancer patients are at an increased risk for venous thromboembolism (VTE) and it is recommended they receive pharmacologic prophylaxis unless otherwise contraindicated. The majority of data supporting this recommendation comes from sub-group analyses and extrapolation of data gathered in general medical/surgical patients. This study seeks to assess the safety and efficacy of VTE prophylaxis in cancer patients admitted to our institution. METHODS: Charts of patients 18-89 years of age receiving VTE prophylaxis with unfractionated heparin, low molecular weigh heparin, or fondaparinux while admitted to Karmanos Cancer Center between September and October 2007 were retrospectively reviewed. Risk factors for VTE were assessed and the efficacy/safety of the prophylactic agents was compared. RESULTS: One-hundred and eighty consecutive patients were identified. The average number of risk factors for developing VTE was 3-4 per hospital admission in addition to an active cancer diagnosis. Three VTEs occurred in the heparin group with two patients experiencing a VTE during their admission and one experiencing a VTE within 1 month after discharge. Four (2.6%) patients receiving heparin had a major bleeding event. Minor bleeding occurred in 14.3, 11.5, and 22.2% of patients receiving heparin, enoxaparin, and fondaparinux, respectively. CONCLUSIONS: This retrospective study showed cancer patients are at increased risk for VTE, typically with 3-4 risk factors per admission. VTEs were uncommon; however, three patients receiving heparin experienced a VTE and four had a major bleeding event. Minor bleeding rates were similar among groups.

Fatal liver failure in a patient on acetaminophen treated with sunitinib malate and levothyroxine.

OBJECTIVE: To report the occurrence of fatal acute liver failure following addition of levothyroxine to a regimen of sunitinib and acetaminophen. CASE SUMMARY: A 57-year-old woman who started sunitinib treatment for relapsed metastatic gastrointestinal stromal tumor after imatinib failure had disease stabilization and normal liver function through 8 cycles of sunitinib 50 mg/day for 4 weeks, followed by 2 weeks off treatment. Her continuing medications included acetaminophen approximately 4.5 g/wk, as well as standard medications for asthma. In cycle 8, she received oral levothyroxine 50-150 microg/day for approximately 30 days to control hypothyroidism before beginning cycle 9 of sunitinib. On day 4 of cycle 9, she was hospitalized with progressively rising circulating liver enzyme levels. She died 4 days postadmission despite discontinuation of sunitinib and initiation of intensive supportive treatment. At autopsy, her liver showed severe centrilobular necrosis with moderate-to-severe steatosis and minimal parenchymal invasion by the neoplasm. Viral stains were negative. DISCUSSION: Hepatic failure has been reported rarely in patients receiving sunitinib. Autopsy results excluded neoplastic disease progression and viral infection in the etiology of the event, and the patient may have died of the combined interaction of sunitinib, acetaminophen, and levothyroxine. Although sunitinib was not more than a possible hepatotoxin (Roussel Uclaf Causality Assessment Method) and may even have been hepatoprotective over a 48-week period against chronic intake of acetaminophen (probable hepatotoxin) by producing regional hypothyroidism within the liver, it is hypothesized that correction of the putative hepatic hypothyroidism with oral levothyroxine (possible hepatotoxin) and reinitiation of sunitinib treatment may have triggered hepatic necrosis. CONCLUSIONS: Acetaminophen should be used with particular caution in patients receiving sunitinib. In sunitinib-treated patients who also require levothyroxine therapy, increased caution in restarting subsequent sunitinib treatment and discontinuation of acetaminophen, if possible, is advisable. Further evaluation of this potential interaction is warranted.

Treatment of metastatic renal cell carcinoma.

PURPOSE: To review the treatment of metastatic renal cell carcinoma (RCC), including the use of new targeted therapies. METHODS: A search of MEDLINE (1966 to August 2008) and American Society of Clinical Oncology Meeting abstracts (2005 to May 2008) was preformed using the search terms bevacizumab, everolimus, interferon-alfa (IFN-alpha), interleukin-2 (IL-2), sorafenib, sunitinib, temsirolimus, and RCC. Articles most pertinent to the treatment of metastatic RCC are reviewed. RESULTS: The treatment of metastatic RCC has undergone a paradigm shift over the past 5 years from biologic response modifiers to new targeted therapies. Historically, response rates for the biological response modifiers, aldesleukin (IL-2), and IFN-alpha were approximately 15%. Recently, three targeted agents, sorafenib, sunitinib, and temsirolimus have been approved for the treatment of RCC. Additionally, bevacizumab has been investigated and shown to increase progression free survival in RCC. IL-2 remains the only agent to induce complete, durable remissions; however, many patients are not eligible for this therapy. Newer agents (sorafenib, sunitinib, and temsirolimus) have shown to be superior to IFN-alpha or placebo and bevacizumab combined with IFN-alpha has shown activity when compared to IFN-alpha alone. Unlike IL-2, the greatest benefit obtained with targeted therapies is in achieving stable disease (SD). Despite their benefit, targeted therapies have never been compared with each other in clinical trials and choosing the most appropriate agent remains challenging. To date, the optimal sequence or combination of treatments has not been defined; however, everolimus has recently demonstrated activity in patients progressing on targeted therapy. CONCLUSIONS: IL-2 remains the most active regimen in inducing complete responses; however, its use is accompanied by substantial morbidity and is limited to those with a good performance status. Targeted therapies are also efficacious in the treatment of RCC, with the major benefit being induction of SD. Future research will better define the sequencing of therapies, as well as, explore the activity of novel combination regimens.

Influence of plasma exchange on the disposition of the fourth generation cephalosporin cefepime.

Cefepime, a fourth generation cephalosporin, is widely used in hematology and oncology patients. These patients may require plasma exchange (PE) for indications such as chemotherapy- or cancer-induced thromobotic thrombocytopenic purpura to name a few. To date, no pharmacokinetic evaluation has been conducted assessing cefepime's disposition during PE. A 2 g IV cefepime single dose was given to patients undergoing therapeutic PE. Two hours from cefepime dose administration, plasma concentration was measured. PE was then instituted and cefepime plasmapheresate concentration was measured at the completion of the PE session. Cefepime levels were measured using HPLC. The percentage removed by PE was calculated as: amount removed/2 g dose. Ten adult patients were analyzed: median age (range): 52 years (33-67) and median weight (range); 82.85 kg (47-120). PE indications were: myasthenia gravis (n = 3), transverse myelitis (n = 2), multiple sclerosis (n = 1), chronic inflammatory demyelinating polyneuropathy (n = 1), idiopathic thrombocytopenic purpura (n = 1), thrombotic thrombocytopenic purpura (n = 1), and humoral rejection post cadaveric renal allograft (n = 1). All patients except one had a creatinine clearance >60 mL/min. One patient was excluded from the pharmacokinetic analysis owing to loss of venous access during PE. For the remaining nine patients, total plasma volume removed was 3.5 L (range: 2.5-3.5) and duration of PE was 120 min (range: 94-209). The cefepime removed by PE was 3.7% (range: 2.1-6.7). A strong correlation was found between cefepime plasma concentration prior to PE and the amount of drug removed (r = 0.96, r(2) = 0.92; p<0.05). The above results suggest that, under the studied conditions, cefepime removal by PE is clinically insignificant (approximately 4% of total 2 g dose).

Trastuzumab-induced hepatotoxicity.

OBJECTIVE: To report a case of probable trastuzumab-induced hepatotoxicity. CASE SUMMARY: A 54-year-old African American woman presented with locally advanced right-sided breast cancer that was found to be strongly positive for human epidermal growth factor receptor 2 (HER2) by fluorescence in situ hybridization. She was treated with neoadjuvant chemotherapy with 4 cycles of dose-dense doxorubicin and cyclophosphamide. Laboratory test results, including liver function tests (LFTs), were normal at that time. Therapy consisting of weekly doses of paclitaxel 80 mg/m(2) and a loading dose of trastuzumab 4 mg/kg for the first week and 2 mg/kg weekly thereafter was started. Alanine aminotransferase, aspartate aminotransferase, and alkaline phosphatase levels began to increase after the initial dose; the levels were significantly elevated after the fifth cycle. Paclitaxel was withheld, and trastuzumab was continued, as there were no prior reported cases of trastuzumab-induced hepatotoxicity at that time. Other possible etiologies for the elevated enzyme levels, including metastasis to the liver, were excluded. The patient continued to receive trastuzumab for a total of 8 weeks; it was discontinued at that time because enzyme levels continued to increase. When trastuzumab was discontinued, enzyme levels returned to normal. Subsequently, surgical resection of the cancer was performed. The patient's lymph nodes were found to be involved and, because of the high risk of disease recurrence, she was rechallenged with trastuzumab. LFTs showed enzyme levels rising again and trastuzumab was discontinued after 2 cycles, with subsequent normalization of the levels. She was then treated with weekly paclitaxel and her LFT values continued to be in the near-normal range. DISCUSSION: There were no comorbidities in this patient and, on initiation of trastuzumab, her liver enzyme levels were normal. The levels became elevated after initiation of trastuzumab, normalized after its discontinuation, and increased upon rechallenge. According to a validated drug-induced hepatotoxicity scale, trastuzumab was the probable cause of hepatotoxicity in this patient. CONCLUSIONS: Liver enzyme levels must be closely monitored in patients receiving trastuzumab. To our knowledge, this is the first report of trastuzumab-induced hepatotoxicity requiring discontinuation of the drug.

A single dose of rasburicase is sufficient for the treatment of hyperuricemia in patients receiving chemotherapy.

Hydration, urinary alkalization, and allopurinol are the standard of care in the treatment and prevention of hyperuricemia. Rasburicase is a new alternative for the management of hyperuricemia in cancer patients. Criteria for the use of rasburicase were developed by the Hematology/Oncology Pharmacy and Therapeutics Subcommittee of the Detroit Medical Center and implemented in 2003. The guidelines limit rasburicase use to one dose, with additional doses as needed, compared to the five doses recommended by the manufacturer, in cancer patients with hyperuricemia and bulky tumor who require immediate chemotherapy. During the period of March to September 2003, eight patients received rasburicase, according to the guidelines, for the management of hyperuricemia. One dose of rasburicase produced a rapid and sustained therapeutic effect of lowering the plasma uric acid levels in all patients. The levels remained below 4 mg/dL throughout the administration of chemotherapy for up to 96 h. Utilizing the guidelines resulted in a significant cost savings of 100,000 US dollars.

Efficacy and safety of reteplase for central venous catheter occlusion in patients with cancer.

PURPOSE: To evaluate the efficacy and safety of reteplase for central venous catheter (CVC) occlusion in patients with cancer. MATERIALS AND METHODS: An open-label, single-arm, prospective study was conducted. Reteplase (0.4 U) was instilled into each catheter lumen with a dwell time of 30 minutes in patients with cancer with a dysfunctional CVC. If the function of the catheter was not restored in 30 minutes, an additional dwell time of 30 minutes was allowed (a total of 60 minutes possible dwell time for the first dose). A second dose was repeated at 60 minutes after the first dose if catheter function was not restored (a total of 120 minutes for up to two doses). The primary efficacy outcome was the restoration of CVC function. RESULTS: Of 139 patients who received reteplase, the first-attempt success rate after a 30-minute dwell time was 66.9%. The cumulative success rates at 60, 90, and 120 minutes were 88.5%, 94.7%, and 94.7%, respectively. The variation of patient age, catheter age, CVC occlusion age, CVC type, number of lumen, or occlusion type was not associated with the efficacy of reteplase. There were no treatment-associated adverse events reported during the study period. CONCLUSION: Reteplase at 0.4-U dosing per catheter lumen is an effective and safe alternative that rapidly restores the patency of occluded CVCs in patients with cancer.

Gefitinib therapy for advanced non-small-cell lung cancer.

OBJECTIVE: To review the pharmacology, pharmacokinetics, clinical efficacy, and toxicity of gefitinib in non-small-cell lung cancer (NSCLC). DATA SOURCES: Primary literature search through MEDLINE and CANCERLIT, and abstract presentations (1966-May 2003). STUDY SELECTION AND DATA EXTRACTION: All published trials and abstracts citing gefitinib were evaluated, and all information deemed relevant was included in this article. DATA SYNTHESIS: NSCLC is known to overexpress epidermal growth factor receptor (EGFR). Gefitinib is a selective EGFR tyrosine kinase inhibitor. Based on the Phase I/II trial results, the optimal dose is 250 mg/d orally. It is well tolerated, with minimal and reversible toxicity. Skin rash and diarrhea are the most common adverse effects. Recent trials have shown that gefitinib provided a 10% tumor response rate and improved disease-related symptoms in patients with refractory, advanced NSCLC. CONCLUSIONS: Gefitinib, with a unique mechanism of action and favorable toxicity profile, has demonstrated clinical activity in NSCLC patients with chemotherapy-refractory disease. It provides a valuable addition to the treatment options as monotherapy in patients with advanced NSCLC after failure of both platinum-based and docetaxel chemotherapies. Further research is required to evaluate the use of gefitinib in different clinical settings.

Fluorouracil for allergic reactions to capecitabine.

OBJECTIVE: To report the safe use of fluorouracil in a patient with breast cancer who had allergic reactions to capecitabine. CASE SUMMARY: A 42-year-old African American woman with metastatic breast cancer developed progressive disease. Capecitabine 1500 mg taken by mouth twice daily was prescribed as the salvage chemotherapy. She developed a generalized rash and itching, sore throat, and dizziness approximately 4 hours after the first dose of capecitabine. These reactions recurred immediately after the second dose. Capecitabine was discontinued and the allergic reactions resolved after the woman took diphenhydramine for 1 week. In view of limited therapeutic options for her progressive disease, a trial of fluorouracil 300 mg/m(2)/d continuous intravenous infusion over 5 days was initiated without any premedications. She did not experience any reactions. The dose of fluorouracil in the second cycle was increased to 400 mg/m(2)/d continuous infusion over 5 days. DISCUSSION: Capecitabine is not intrinsically cytotoxic, but is converted to fluorouracil in tumor tissues via a 3-step enzymatic pathway. Capecitabine reaches peak blood concentrations in about 1.5 hours, with peak fluorouracil concentrations occurring at 2 hours. The elimination half-life of both drugs is 0.5-0.7 hours. The patient tolerated the rechallenge with fluorouracil without complications. Objective causality assessment revealed that the adverse event was probably drug induced. It was postulated that the allergic reaction was most likely caused by capecitabine or the intermediate metabolites based on the immediate reappearance of symptoms from the rechallenge, pharmacokinetic data, and well-tolerance of fluorouracil. CONCLUSIONS: The use of fluorouracil treatment with careful monitoring can be considered in a patient with mild allergic reactions to capecitabine.