Linda R. Bressler

Controlled-release oxycodone compared with controlled-release morphine in the treatment of cancer pain: a randomized, double-blind, parallel-group study.

Controlled‐release oral formulations of oxycodone and morphine are both suitable analgesics for moderate to severe pain. They were compared in cancer‐pain patients randomized to double‐blind treatment with controlled‐release oxycodone (n = 48) or controlled‐release morphine (n = 52) every 12 h for up to 12 days. Stable analgesia was achieved by 83% of controlled‐release oxycodone and 81% of controlled‐release morphine patients in 2 days (median). Following titration to stable analgesia, pain intensity (0/none to 3/severe) decreased from baseline within each group (p≤ 0.005), from 1.9 (0.1) to 1.3 (0.1), mean (SE), with controlled‐release oxycodone, and from 1.6 (0.1) to 1.0 (0.1) with controlled‐release morphine (no significant between‐group differences). Typical opioid adverse experiences were reported in both groups. Hallucinations were reported only with controlled‐release morphine (n = 2). Visual analog scores (VAS) for ‘itchy’ and ‘scratching’ were lower with controlled‐release oxycodone (p≤ 0.044), as was peak‐to‐trough fluctuation in steady‐state plasma concentration (p = 0.004). The correlation between plasma concentration and dose was stronger (p = 0.026) for oxycodone (0.7) than morphine (0.3). The relationship between pain intensity (VAS) and plasma concentration was more positive for oxycodone (p = 0.046). There was a positive relationship between morphine‐6‐glucuronide concentrations and urea nitrogen and creatinine levels (p = 0.0001). Controlled‐release oxycodone was as effective as controlled‐release morphine in relieving chronic cancer‐related pain, and as easily titrated to the individuals need for pain control. While adverse experiences were similar, controlled‐release oxycodone was associated with less itching and no hallucinations. Controlled‐release oxycodone provides a rational alternative to controlled‐release morphine for the management of moderate to severe cancer‐related pain.

Temozolomide in malignant gliomas: current use and future targets

Temozolomide (TMZ) is an oral alkylating agent that is regarded as a tolerable and effective drug. When combined with radiotherapy in patients with newly diagnosed glioblastoma, survival is significantly prolonged. This finding has led to widespread use of TMZ for patients with this disease. We summarize developing concerns regarding the use of TMZ, imaging of malignant gliomas, and the pharmacology of TMZ—mechanism of action, scheduling and strategies for overcoming resistance.

Understanding and managing the possible adverse effects associated with bevacizumab

PURPOSE The adverse events associated with bevacizumab therapy are characterized, and the underlying pathophysiology, risk factors, frequency, and management of these events are described. SUMMARY The adverse events associated with bevacizumab include hypertension, proteinuria, thromboembolism, impaired wound healing, bleeding, perforation, reversible leukoencephalopathy syndrome, skin rash, and infusion-related hypersensitivity reactions. Patients should be monitored for these events throughout the course of bevacizumab therapy. Hypertension is by far the most common adverse event associated with bevacizumab. Blood pressure should be routinely monitored, and hypertension should be medically managed with antihypertensive drugs as deemed appropriate during bevacizumab therapy. Patients should be monitored for proteinuria every three to four weeks, and bevacizumab should be discontinued with persistent proteinuria of >2+. Thromboembolic events, impaired wound healing, bowel and nasal septum perforation, and bleeding share similar pathophysiology. Thromboembolic events should be managed in accordance with guidelines established by the American College of Chest Physicians, and bevacizumab should be discontinued for new life-threatening venous or arterial thromboembolism. To minimize the risk of bleeding or impaired wound healing, bevacizumab should be started at least four weeks after surgery or discontinued for at least six to eight weeks before elective surgery. The management of other adverse events is more anecdotal, with relatively few reports of their occurrence with bevacizumab. CONCLUSION Many of the potential serious complications of bevacizumab can be averted by close monitoring of patient-specific variables, which should be measured at baseline and then at predetermined intervals throughout the course of therapy to maximize patient safety.

Misperceptions and Inadequate Pain Management in Cancer Patients

This article examines misperceptions and barriers to adequate pain relief in cancer patients. Healthcare professionals have gaps in their knowledge of opioid drugs as well as misconceptions concerning tolerance, physical dependence, and addiction that often lead to the underprescribing of these agents. The pervasiveness of the “say no to drugs” message in our society and the fear of addiction on the part of patients and their families creates yet another barrier to the legitimate use of opioids to treat cancer pain. Legal and regulatory documents filled with arbitrary and ill-defined labels meant to promote the legitimate use of these drugs and curtail their misuse may instead intimidate healthcare professionals and negatively influence prescribing habits. Increased educational efforts for pharmacists and other healthcare professionals as well as the development of clinical role models and state cancer pain initiatives are cited as means to break down these barriers in order to achieve adequate pain relief for all cancer patients.

Use of clonidine to treat hot flashes secondary to leuprolide or goserelin.

Objective To determine the effects of clonidine, a centrally acting adrenergic agonist, in abating symptoms of hot flashes in men receiving either leuprolide or goserelin for prostate cancer. Design Patients were administered transdermal or oral clonidine 0.1–0.2 mg/d. Dosages were increased in increments of 0.1–0.3 mg/d every two to four weeks if symptoms persisted or until adverse effects developed. Setting Medical oncology clinic at the University of Illinois and the hypertension clinic at the Veterans Affairs West Side Medical Center. Participants Consenting male patients were eligible for the study if they were receiving leuprolide or goserelin for prostate cancer and were experiencing hot flashes. Exclusion criteria included diastolic blood pressure of 75 mm Hg or below or a history of adverse reactions to clonidine. Main Outcome Measures Effectiveness of clonidine was determined by questioning patients about frequency, severity, and duration of hot flashes at baseline and at two- to four-week intervals. Results All four patients receiving clonidine experienced a partial response within two weeks of starting treatment. No dose-dependent response was observed. Adverse effects were noted in one patient but did not result in discontinuation. Conclusions Our results document the first report of the use of clonidine to treat hot flashes secondary to leuprolide or goserelin therapy. Symptomatic improvement was noted in all four patients. Further evaluation of clonidine as well as other centrally acting adrenergic agonists is needed.

Phase I trial of p28 (NSC745104), a non-HDM2-mediated peptide inhibitor of p53 ubiquitination in pediatric patients with recurrent or progressive central nervous system tumors: A Pediatric Brain Tumor Consortium Study.

BACKGROUND p53 is a promising target in human cancer. p28 is a cell-penetrating peptide that preferentially enters cancer cells and binds to both wild-type and mutant p53 protein, inhibiting COP1-mediated ubiquitination and proteasomal degradation. This results in increased levels of p53, which induces cell cycle arrest at G2/M. We conducted a phase I study to determine the maximum-tolerated dose (MTD) and describe the dose-limiting toxicities (DLTs) and pharmacokinetics (PKs) of p28 in children. METHODS Children aged 3-21 years with recurrent or progressive central nervous system tumors were eligible. Intravenous p28 was administered 3 times weekly for 4 consecutive weeks of a 6-week cycle at 4.16 mg/kg/dose (the adult recommended phase II dose) using a rolling-6 study design. Expression status of p53 was characterized by immunohistochemistry, and serum PK parameters were established on the second dose. RESULTS Of the 18 eligible patients enrolled in the study, 12 completed the DLT monitoring period and were evaluable for toxicity. p28 was well-tolerated; 7 participants received ≥2 courses, and the most common adverse event attributed to the drug was transient grade 1 infusion-related reaction. PK analysis revealed a profile similar to adults; however, an increased area under the curve was observed in pediatric patients. High p53 expression in tumor cell nuclei was observed in 6 of 12 available tissue samples. There were no objective responses; 2 participants remained stable on the study for >4 cycles. CONCLUSIONS This phase I study demonstrated that p28 is well-tolerated in children with recurrent CNS malignancies at the adult recommended phase II dose.

Evaluation of the Modified Diet in Renal Disease Equation for Calculation of Carboplatin Dose

Background: Serum creatinine (SCr)-based formulas are used to estimate glomerular filtration rate (GFR) when calculating a dosage for carboplatin using the Calvert equation, but these formulas often underestimate measured GFR. The Modified Diet in Renal Disease (MDRD) equation appears to be a more accurate estimate of GFR in patients with chronic kidney disease, but this equation has not been studied extensively in patients with cancer. Objective: To determine the absolute difference between the dose of carboplatin administered (traditional SCr-based formulas used to estimate GFR) and the dose calculated using the MDRD equation to estimate GFR and compare the frequencies of thrombocytopenia, neutropenia, and dosage modifications between subjects in whom the difference in dose was 20% or more (divergent) or less than 20% (nondivergent). Methods: A retrospective analysis was conducted using data from patients who received carboplatin. Inclusion criteria were receipt of at least 2 doses of carboplatin, either as monotherapy or combination therapy, and documentation of desired area under the concentration-time curve (AUC). Patients were excluded if the baseline values needed to estimate GFR using the MDRD equation were not available. The absolute difference between the dose of carboplatin administered and that calculated using the MDRD equation was determined and, from this comparison, the subjects were divided into 2 groups (divergent vs nondivergent). Results: The medical records of 186 adults who received more than 2 doses of carboplatin were included in the analysis. The doses were divergent in 89 (48%) patients. The mean target AUC values were 5.3 mg/mUmin and 5.1 mg/mL/min in the divergent and nondivergent groups, respectively, and most patients received cytotoxic regimens with a relatively low risk of febrile neutropenia. The frequencies of neutropenia, thrombocytopenia, and dosage modifications were similar between the 2 groups. Use of the MDRD equation to calculate the carboplatin dosage did not appear to result in a change in the frequency of myelosuppression or the need for dose modifications compared with traditional SCr-based formulas. Conclusions: The traditional SCr-based formulas for the calculation of carboplatin dosage should be used to estimate carboplatin dose until more data become available regarding the use of the MDRD equation in this population.

Cyclophosphamide-Induced Facial Discomfort:

OBJECTIVE: To report the occurrence of cyclophosphamide-induced facial discomfort in patients at our institution, to review previous literature reports, and to discuss possible methods of prevention. SETTING: An oncology clinic in a university teaching hospital. PATIENTS: From January 1990 to March 1993, 14 patients experienced uncomfortable sensations of the skin or mucous membranes associated with cyclophosphamide administration. Details pertaining to each patient are described. INTERVENTIONS: Initial interventions included changing the duration of infusion or concentration of cyclophosphamide. We postulated that an anticholinergic medication such as ipratropium bromide may prevent cyclophosphamide-induced facial discomfort. MAIN OUTCOME MEASURES: Changing the infusion duration or cyclophosphamide concentration or administering ipratropium bromide intranasally resulted in variable degrees of improvement. CONCLUSIONS: The number of cyclophosphamide reactions seen at our institution indicates that facial or scalp burning, oropharyngeal tingling, nasal congestion, rhinorrhea, sneezing, and/or lacrimation may occur more frequently than previously noted. Thus, careful questioning is necessary to determine whether these clinical symptoms are present and bothersome in patients treated with cyclophosphamide. Intranasal ipratropium bromide, as well as other measures to prevent or decrease the intensity of cyclophosphamide-induced facial discomfort should be investigated.

Going past the data for temozolomide.

The benefit of six cycles of adjuvant temozolomide was documented in a randomized phase III (EORTC-NCIC CE.3) trial, and this therapy, following combined temozolomide and radiation, is the standard of care for patients with newly diagnosed glioblastoma. We comment on the differences in the length of adjuvant therapy in both clinical practice and national studies (e.g. RTOG 0825), usually doubling the length in the EORTC/NCIC study, and relate to historic adjuvant trials for solid tumors.

Fixed-interval v as-needed analgesics in cancer outpatients

Abstract Many health professionals advocate medicating cancer patients in pain with fixed-interval analgesic schedules, but there is little research to support this approach. A pilot study in cancer outpatients was conducted to test the hypothesis that patients randomized to fixed-interval schedules of oral narcotic analgesics would report lower pain intensity than patients randomized to as-needed schedules. Twelve patients were randomized to fixed-interval and eight to as-needed schedules. They were followed for five consecutive days, recording amount and time they took analgesics, and rating pain intensity three times daily on a 10 cm visual analogue scale. A one-way repeated measures analysis of variance revealed no differences between the two groups of patients. Possible explanations for the findings include small sample size, unreliable measures of pain intensity, inadequate analgesic doses or intervals, or individual characteristics of the pain experience. Further research must address methodologic and measurement problems involved in the study of pain and its management to clarify the issue of analgesic scheduling in cancer outpatients.