Mary G. Quinn

Acute Oxaliplatin-Induced Peripheral Nerve Hyperexcitability

PURPOSE Oxaliplatin is a novel platinum compound with clinical activity in several malignancies. Neurotoxicity is dose-limiting and occurs in two distinct forms, an acute neurologic symptom complex that occurs within hours or days of therapy and a chronic, cumulative sensory neuropathy. PATIENTS AND METHODS Patients were treated in a phase I study designed to establish the maximum-tolerated dose of capecitabine given with oxaliplatin. Because of the unusual neurosensory toxicity of oxaliplatin, detailed neurologic examination, needle electromyography (EMG), and nerve conduction studies (NCS) were performed before and the day after oxaliplatin in a subset of 13 patients. Carbamazepine therapy was tried in 12 additional patients to determine whether the neurologic effects might be relieved. RESULTS All patients experienced acute, reversible neurotoxicities with oxaliplatin. Symptoms included paresthesias, dysesthesias, cold hypersensitivity, jaw pain, eye pain, pain in the arm used for drug infusion, ptosis, leg cramps, and visual and voice changes. Serial EMG and NCS revealed striking signs of hyperexcitability in motor nerves after oxaliplatin. In patients who achieved therapeutic levels, carbamazepine did not alter the clinical or electromyographic abnormalities. CONCLUSION The acute neurotoxicity seen with oxaliplatin is characterized by peripheral-nerve hyperexcitability, and the findings are similar to the clinical manifestations of neuromyotonia. Carbamezepine, which provides symptomatic relief in acquired neuromytonia, did not seem to be beneficial. Efforts to identify a successful neuroprotectant strategy would have a major impact on improving patient quality of life and the ability to deliver full doses of oxaliplatin.

Survey of oxaliplatin-associated neurotoxicity using an interview-based questionnaire in patients with metastatic colorectal cancer

BackgroundNew chemotherapy regimens for patients with colorectal cancer have improved survival, but at the cost of clinical toxicity. Oxaliplatin, an agent used in first-line therapy for metastatic colorectal cancer, causes acute and chronic neurotoxicity. This study was performed to carefully assess the incidence, type and duration of oxaliplatin neurotoxicity.MethodsA detailed questionnaire was completed after each chemotherapy cycle for patients with metastatic colorectal cancer enrolled in a phase I trial of oxaliplatin and capecitabine. An oxaliplatin specific neurotoxicity scale was used to grade toxicity.ResultsEighty-six adult patients with colorectal cancer were evaluated. Acute neuropathy symptoms included voice changes, visual alterations, pharyngo-laryngeal dysesthesia (lack of awareness of breathing); peri-oral or oral numbness, pain and symptoms due to muscle contraction (spasm, cramps, tremors). When the worst neurotoxicity per patient was considered, grade 1/2/3/4 dysesthesias and paresthesias were seen in 71/12/5/0 and 66/20/7/1 percent of patients. By cycles 3, 6, 9, and 12, oxaliplatin dose reduction or discontinuation was needed in 2.7%, 20%, 37.5% and 62.5% of patients.ConclusionOxaliplatin-associated acute neuropathy causes a variety of distressing, but transient, symptoms due to peripheral sensory and motor nerve hyperexcitability. Chronic neuropathy may be debilitating and often necessitates dose reductions or discontinuation of oxaliplatin. Patients should be warned of the possible spectrum of symptoms and re-assured about the transient nature of acute neurotoxicity. Ongoing studies are addressing the treatment and prophylaxis of oxaliplatin neurotoxicity.

Phase I and Pharmacokinetic Trial of Weekly Oral Fluorouracil Given With Eniluracil and Low-Dose Leucovorin to Patients With Solid Tumors

PURPOSE Fluorouracil (5-FU) given as a weekly, high-dose 24-hour infusion is active and tolerable. We evaluated an oral regimen of eniluracil (which inactivates dihydropyrimidine dehydrogenase [DPD]), 5-FU, and leucovorin to simulate this schedule. PATIENTS AND METHODS Patients received a single 24-hour infusion of 5-FU (2,300 mg/m(2) on day 2) with leucovorin (15 mg orally [PO] bid on days 1 through 3) to provide reference pharmacokinetic data. Two weeks later, patients began treatment with eniluracil (20 mg) and leucovorin (15 mg) (PO bid on days 1 through 3) and 5-FU (10 to 15 mg/m(2) PO bid on day 2). RESULTS Dose-limiting toxicity (diarrhea, neutropenia, and fatigue) was seen with 5-FU 15 mg/m(2) PO bid on day 2 given weekly for either 6 of 8 weeks or 3 of 4 weeks, whereas five of seven patients tolerated 5-FU 10 mg/m(2) PO bid given weekly for 3 of 4 weeks. Eniluracil led to a 35-fold reduction in 5-FU clearance. Fluoro-beta-alanine, a 5-FU catabolite, was not detected in plasma during oral 5-FU-eniluracil therapy. DPD activity was markedly suppressed in all patients during eniluracil therapy; the inactivation persisted after the last eniluracil dose; percentages of baseline values were 1.8% on day 5, 4.5% on day 12, and 23.6% on day 19. CONCLUSION The recommended oral dosage of 5-FU (10 mg/m(2) PO bid) given with eniluracil and leucovorin is approximately 115-fold lower than the reference dosage for 24-hour infusional 5-FU. This difference is greater than expected given the reduction in 5-FU clearance. DPD inactivation persisted for several weeks after completion of eniluracil therapy.

Cardiac toxicity associated with capecitabine therapy

Capecitabine (N-pentyloxycarbonyl-5?-deoxy-5-fluorocytidine) is a novel fluoropyrimidine carbamate that is orally administered and absorbed through the intestinal mucosa as an intact molecule (1). A series of three enzymatic steps are required to convert this prodrug to 5-fluorouracil (5-FU). The parent compound reaches the liver through the portal circulation, where it is metabolized to 5?-deoxy5-fluorocytidine by a 60 kDa carboyxlesterase. The latter compound is converted to 5?-deoxy-5 /fluorouridine by cytidine deaminase, which is widely distributed throughout the body and in plasma. Finally, 5-FU is released within the cell through the action of thymidine phosphorylase, and the plasma levels of 5-FU are relatively low. Since many tumor tissues contain higher levels of this enzyme compared to normal tissues, formation of 5-FU may occur preferentially within tumor tissue. The recommended schedule for capecitabine is 1 250 mg/m twice daily (morning and evening, equivalent to 2 500 mg/m total daily dose) dosing for 2 weeks followed by a one-week rest period every 3 weeks. Capecitabine was first given approval by the Food and Drug Administration for the treatment of patients with breast cancer whose disease has progressed on prior therapy (2). Two large PhaseIII trials comparing capecitabine with IV bolus 5-FU/leucovorin in patients with metastatic colorectal cancer have shown the oral drug has similar efficacy, with a reduction in mucositis and neutropenia (3, 4). Clinical safety data from patients included in these trials with either breast or colorectal cancer indicates that the most common toxicities include hand-foot syndrome, diarrhea, nausea and vomiting. Although cardiac symptoms have been reported with 5FU given alone or with other agents, cardiac toxicity in patients receiving capecitabine has only rarely been reported. We describe a patient who developed recurrent episodes of chest pain after 3 /5 doses of capecitabine while participating in a clinical trial of oxaliplatin in combination with capecitabine. Case report. The patient, a 54-year-old Caucasian male, was diagnosed with rectal cancer one year before entry in this clinical trial. He had initially undergone a diverting colostomy, with low anterior resection of the primary tumor. The patient received adjuvant chemoradiation with infusional fluorouracil, followed by 4 cycles of 5-FU, leucovorin and irinotecan given weekly for 4 out of 6 weeks. A CT scan taken after completion of this regimen revealed new metastatic disease involving the liver and diaphragm. The patient’s main symptom was mild fatigue. He had a 70-pack/ year history of smoking but had given up the habit the year before, and had alcohol only on occasion. There was no family history of cardiac disease, and he did not have any known cardiac risk factors. His medications at the time of enrolment in the study were terazosin hydrochloride, citalopram hydrobromide, enteric-coated aspirin, oxazepam, ranitidine, and celecoxib. The patient was enrolled in an Institutional Review Boardapproved Phase I study evaluating escalating doses of capecitabine given twice daily on days 1 /5 and 8 /12 in combination with oxaliplatin 130 mg/m infused IV over 2 h every 3 weeks. For the first cycle, the patient received oxaliplatin 130 mg/m on day 1; capecitabine 1 350 mg/m was given twice daily morning and evening starting the next day (total daily dose 2 700 mg/m). On day 4, the patient was referred to the Oncology Clinic complaining of mild substernal pressure while walking, but without shortness of breath. This occurred about 12 h after the dose of capecitabine the previous evening. The symptoms improved when he lay down, and lasted for about 30 min. An electrocardiogram (ECG) done in the clinic showed no acute ischemic changes. An echocardiogram showed an ejection fraction of 50 /70%, with normal left ventricular size and function. Cardiac enzymes and troponin levels were unremarkable, and no ECG changes were noted by telemetry throughout the next 24 h. The patient underwent a stress test the next day (about 26 h after the episode of chest pain); the examination was terminated during stage 2 (maximum workload 7 METS) because of fatigue. During the recovery period, the patient complained of chest pain, but no clear-cut signs of ischemia were seen on the ECG. Cardiac catheterization, performed on day 6, showed left dominant coronary circulation with non-obstructive coronary artery disease. The cardiologist suspected that the chest pain was not cardiac in origin, and a trial with prilosec was recommended for detection of possible esophageal reflux. No additional capecitabine therapy was given during that cycle, and no further episodes of chest pain occurred. When the patient returned for the start of cycle 2, a repeat stress test was terminated during stage 3 (10 METS) because of fatigue; the patient had no chest pain and the ECG was normal. He received oxaliplatin and capecitabine the next day. On day 3, about 3 h after the fifth dose of capecitabine, the patient experienced another episode of chest pain while walking to the clinic. The ECG was normal. A repeat stress test performed 4 h after the symptoms had resolved was stopped after reaching 7 METS owing to chest pain and fatigue. Nifedepine was prescribed for a possible capecitabine-associated coronary spasm. CASE REPORT

A Phase I Pharmacologic and Pharmacogenetic Trial of Sequential 24-Hour Infusion of Irinotecan Followed by Leucovorin and a 48-Hour Infusion of Fluorouracil in Adult Patients with Solid Tumors

Purpose: In preclinical studies, sequential exposure to irinotecan (CPT-11) then fluorouracil (5-FU) is superior to concurrent exposure or the reverse sequence; a 24-hour infusion of CPT-11 may be better tolerated than shorter infusions. Experimental Design: CPT-11 was first given at four levels (70-140 mg/m2/24 hours), followed by leucovorin 500 mg/m2/0.5 hours and 5-FU 2,000 mg/m2/48 hours on days 1 and 15 of a 4-week cycle. 5-FU was then increased in three cohorts up to 3,900 mg/m2/48 hours. Results: Two patients had dose-limiting toxicity during cycle 1 at 140/3,900 of CPT-11/5-FU (2-week delay for neutrophil recovery; grade 3 nausea despite antiemetics); one of six patients at 140/3,120 had dose-limiting toxicity (grade 3 diarrhea, grade 4 neutropenia). Four of 22 patients with colorectal cancer had partial responses, two of which had prior bolus CPT-11/5-FU. The mean 5-FU plasma concentration was 5.1 μmol/L at 3,900 mg/m2/48 hours. The end of infusion CPT-11 plasma concentration averaged 519 nmol/L at 140 mg/m2/24 hours. Patients with UDP-glucuronosyltransferase (UGT1A1; TA)6/6 promoter genotype had a lower ratio of free to glucuronide form of SN-38 than in patients with ≥1 (TA)7 allele. Thymidylate synthase genotypes for the 28-base promoter repeat were 2/2 (13%), 2/3 (74%), 3/3 (13%); all four responders had a 2/3 genotype. Conclusions: Doses (mg/m2) of CPT-11 140/24 hours, leucovorin 500/0.5 hours and 5-FU 3,120/48 hours were well tolerated.

PARP Inhibition to Enhance Response to Chemotherapy

Abstract The inhibition of poly(ADP-ribose) polymerase (PARP) enzymes is a relatively new anticancer therapeutic strategy designed to impair the ability of tumor cells to repair DNA damage. PARP inhibitors induce synthetic lethality in cells lacking the ability to repair DNA breaks through homologous recombination, such as those with mutations in BRCA1/2 genes. Furthermore, the combination of DNA-damaging chemotherapies with PARP inhibitors may potentiate the DNA damage caused by these agents and lead to enhanced antitumor activity. An additional mechanism of action of PARP inhibitors, known as PARP trapping, has been shown to result in double-strand breaks in DNA, further expanding the potential of these drugs in causing DNA damage accumulation and ultimately apoptosis. While clinical trials testing the combination of PARP inhibitors with chemotherapeutic agents have been challenging due to enhanced toxicity, a number of studies have demonstrated clinical benefits using this strategy. This chapter will review the current status of PARP inhibitor development and discuss the lessons that have been learned from novel chemotherapy combination studies.

Incidence of long-term hair loss (LHL) following docetaxel (D)-containing non-anthracycline (A) adjuvant chemotherapy (Adj) of early stage breast cancer (ESB).

e12522Background: Taxane-containing Adj is an accepted life-prolonging component of modern multi-modal ESB therapy. One of the most distressing complications of Adj is alopecia. While patients (pts) are usually reassured that this is temporary, there have been troubling reports of LHL, generally with regimens that include D and A. We attempted to define the incidence of LHL in a large cohort of patients who received Adj which contained D without A. Methods: Pts who received Adj/neo-Adj which contained D but not A for ESB in clinical trials, or as standard of care in our single academic institution were identified. Pts had completed Adj more than one year. Trials pts were contacted directly, non-trials pts assessed during clinic visits. LHL was graded as 0,1 or 2 (CTCAE). Results: We identified 368 pts, with a median follow-up of >5 years. Pts received DC4 or DC6 (D/cyclophosphamide 75/600 mg/2 iv 3-weekly 4 or 6 times); or DPH (D 75 mg/m2, carboplatin AUC 6 and trastuzumab given 3-weekly iv). LHL occurred...