Arthur D. Forman

Persistent neurotoxicity of systemically administered interferon‐alpha

Fourteen cancer patients had evidence of persistent neurotoxicity of interferon‐alpha therapy long after their treatment was discontinued. Although most of the cognitive symptoms were mild to moderate in severity, they were incapacitating to these individuals in their usual work. The neuropsychological test abnormalities were not attributable to subsequent therapy, disease status, or other medical problems. The pattern of deficits was consistent with frontal‐subcortical dysfunction. Of the four patients who had follow‐up assessment, two had improved and two had deteriorated. These findings suggest that in some cases interferon neurotoxicity is not reversible. NEUROLOGY 1991;41:672‐676

Tacrolimus-associated posterior reversible encephalopathy syndrome after allogeneic haematopoietic stem cell transplantation

Summary. Neurotoxicity is a significant complication of the use of tacrolimus. From April 1998 to December 2001, we identified 10 patients (six women, four men) who developed 11 episodes of tacrolimus‐associated posterior reversible encephalopathy syndrome (PRES) after allogeneic haematopoietic stem cell transplantation for haematological malignancies. The diagnosis was made by characteristic clinical findings (mental status changes, seizures, neurological deficits) with the exclusion of other causes and characteristic imaging findings. The median age was 35·5 years (range 19–57 years). Seven patients received a matched‐unrelated donor transplant and three received a cord blood transplant. The overall incidence of PRES was 1·6%, while the incidence in matched‐unrelated, mismatched‐related and cord blood transplants was 3·5%, 4·9% and 7·1% respectively. Mental status changes, cognitive deficits, seizures and lethargy were the most common clinical findings. Eight of 10 patients had characteristic findings of hyperintensity of the white matter on T2‐weighted images and FLAIR (fluid‐attenuated inversion recovery) sequence on magnetic resonance imaging of the brain. Serum tacrolimus levels were within the therapeutic range in most patients. Tacrolimus treatment was continued (n = 4) or temporarily withheld (n = 7) for 1–14 d. One patient was changed to cyclosporine. In most patients, subsequent treatment with tacrolimus was well tolerated without recurrence of neurotoxicity.

A Prospective Randomized Trial of Perioperative Seizure Prophylaxis in Patients with Intraparenchymal Brain Tumors.

OBJECT Seizures are a potentially devastating complication of resection of brain tumors. Consequently, many neurosurgeons administer prophylactic antiepileptic drugs (AEDs) in the perioperative period. However, it is currently unclear whether perioperative AEDs should be routinely administered to patients with brain tumors who have never had a seizure. Therefore, the authors conducted a prospective, randomized trial examining the use of phenytoin for postoperative seizure prophylaxis in patients undergoing resection for supratentorial brain metastases or gliomas. METHODS Patients with brain tumors (metastases or gliomas) who did not have seizures and who were undergoing craniotomy for tumor resection were randomized to receive either phenytoin for 7 days after tumor resection (prophylaxis group) or no seizure prophylaxis (observation group). Phenytoin levels were monitored daily. Primary outcomes were seizures and adverse events. Using an estimated seizure incidence of 30% in the observation arm and 10% in the prophylaxis arm, a Type I error of 0.05 and a Type II error of 0.20, a target accrual of 142 patients (71 per arm) was planned. RESULTS The trial was closed before completion of accrual because Bayesian predictive probability analyses performed by an independent data monitoring committee indicated a probability of 0.003 that at the end of the study prophylaxis would prove superior to observation and a probability of 0.997 that there would be insufficient evidence at the end of the trial to choose either arm as superior. At the time of trial closure, 123 patients (77 metastases and 46 gliomas) were randomized, with 62 receiving 7-day phenytoin (prophylaxis group) and 61 receiving no prophylaxis (observation group). The incidence of all seizures was 18% in the observation group and 24% in the prophylaxis group (p = 0.51). Importantly, the incidence of early seizures (< 30 days after surgery) was 8% in the observation group compared with 10% in the prophylaxis group (p = 1.0). Likewise, the incidence of clinically significant early seizures was 3% in the observation group and 2% in the prophylaxis group (p = 0.62). The prophylaxis group experienced significantly more adverse events (18% vs 0%, p < 0.01). Therapeutic phenytoin levels were maintained in 80% of patients. CONCLUSIONS The incidence of seizures after surgery for brain tumors is low (8% [95% CI 3%-18%]) even without prophylactic AEDs, and the incidence of clinically significant seizures is even lower (3%). In contrast, routine phenytoin administration is associated with significant drug-related morbidity. Although the lower-than-anticipated incidence of seizures in the control group significantly limited the power of the study, the low baseline rate of perioperative seizures in patients with brain tumors raises concerns about the routine use of prophylactic phenytoin in this patient population.

A multicenter phase II trial of intrathecal topotecan in patients with meningeal malignancies

To determine the therapeutic efficacy (13-week and 26-week CNS progression-free survival [PFS], response rate, and overall survival) and safety of intraventricular (IVent) topotecan in patients with neoplastic meningitis (NM), we conducted a phase II, open-label, nonrandomized, single-arm trial of IVent topotecan in patients with NM using 400 mug of topotecan IVent twice weekly for 6 weeks, followed by evaluation with imaging, cerebrospinal fluid (CSF), and physical examinations. In the absence of disease progression, patients were then treated with IVent topotecan weekly for 6 weeks, twice monthly for 4 months, and monthly thereafter. Sixty-two patients (23 males and 39 females) were enrolled from April 2001 through March 2006. Median age and KPS at enrollment were 56 (range 5-83) and 80 (range 60-100), respectively. Primary cancers included breast (19), lung (13), CNS (14), and others (16). Forty patients (65%) completed the 6-week induction period, among whom 13 (21%) had CSF clearance of malignant cells. Kaplan-Meier estimates of PFS at 13 and 26 weeks were 30% (95% confidence interval [CI], 20%-45%) and 19% (95% CI, 11%-34%). Overall median survival (50 deaths) was 15 weeks (95% CI, 13-24 weeks). The most common side effect was chemical meningitis in 32% of patients (5% grade 3); 32% experienced no drug side effects. IVent topotecan is well tolerated, but provides no added benefit over other IVent therapies. Because of its modest side effect profile, combining IVent topotecan with other IVent or systemic interventions should be considered.

Phase I/II clinical trial of didemnin B in non-small-cell lung cancer: neuromuscular toxicity is dose-limiting

SummaryDidemnin B (NSC 325319), a cyclic depsipeptide isolated from a Caribbean tunicate, exhibits potent preclinical antitumor activity. In previous phase I studies, 3.47 mg/m2 was the maximally tolerated dose, with nausea and vomiting being the dose-limiting toxicity. The drug was given in a single bolus infusion over 30 min every 28 days. In the current study, 30 patients presenting with previously treated non-small-cell lung cancer (NSCLC) received 46 courses of the drug at doses ranging from 3.47 to 9.1 mg/m2. Neuromuscular toxicity was dose-limiting. Neusea and vomiting appeared to be correlated with dose levels and were ameliorated by a combination of antiemetics including dexamethasone. Other side effects included a mild rise in hepatic enzymes and an allergic reaction that was preventable by the addition of corticosteroids to the premedication regimen. In all, 2 minor responses were seen among 24 evaluable patients. Because neuromuscular toxicity is dose-limiting, we recommend that routine measurements of creatine kinase and aldolase, a careful neurologic evaluation, and electromyography and muscle biopsy (if indicated) be incorporated into phase II trials. The recommended dose for phase II studies using a single bolus schedule is 6.3 mg/m2, following the premedication of patients with antiemetics.

Phase II clinical trial of didemnin B in previously treated small cell lung cancer

SummaryDidemnin B (NSC 325319), a cyclic depsipeptide isolated from a Carribean sea tunicate, exhibited potent antitumor activity in preclinical studies. After determining the maximum tolerated dose in our previous phase I/II trial, we conducted a phase II study of this drug in patients with previously treated small cell lung cancer; the starting dose was 6.3 mg/m2 intravenously over 30 min every 28 days. The major side effects were in the neuromuscular system and included severe muscle weakness, myopathy and/or myotonia by electromyography, and elevation of creatine phosphokinase and aldolase levels. We also observed modest increases in bilirubin and alkaline phosphatase levels. There were minimal hematologic toxic effects. No response was observed among 15 evaluable patients, leading us to conclude that didemnin B was toxic but inactive in patients with previously treated small cell lung cancer at the stated dose and schedule. A review of the literature revealed no significant antitumor activity in cancers of the colon, breast, ovaries, cervix, or lung (non-small cell) or in renal cell carcinoma. Further clinical trials for didemnin B may not be warranted at the stated dose and schedule.

Phase II trial and pharmacokinetic evaluation of cytosine arabinoside for leptomeningeal metastases from breast cancer

Purpose: To determine the efficacy and pharmacokinetics of intraventricular cytosine arabinoside (Ara-C) as front-line treatment for leptomeningeal metastases from breast cancer. Methods: Ten patients newly diagnosed with leptomeningeal metastases (LMM) from breast cancer were treated with 100 mg intraventricular cytosine arabinoside (IVT Ara-C) via an Ommaya reservoir. Treatment was administered three times a week for 2 weeks, then once a week for 4 weeks, and then once every 6 weeks for four cycles to responding patients. Nine patients were evaluable clinically, and seven patients underwent testing to determine the pharmacokinetic profile of Ara-C in the cerebrospinal fluid (CSF). Results: Two patients had partial responses lasting 9 and 40 weeks, respectively. Two other patients had stable disease. The median survival duration was 30 weeks (range: 5–58 weeks). Seven patients died from LMM. Acute toxic effects associated with IVT Ara-C included meningismus, nausea, vomiting, and myelosuppression. The median peak Ara-C level in CSF was 16.69 ± 6.30 mM (SD). The half life for elimination was 1.45 ± 0.61 h (SD) There was no drug accumulation between courses. Neuropsychological evaluations were completed in eight patients, six (75%) of whom had preexisting cognitive deficits. Their condition generally improved over the course of treatment until the LMM progressed. No neurotoxic side effects of IVT Ara-C were observed in the two patients who had normal baseline cognitive assessments. Conclusions: IVT Ara-C at this dose and schedule has minimal activity as initial treatment for LMM from breast cancer despite achievement of high peak levels of the drug in the cerebrospinal fluid. A liposomal Ara-C formulation is currently under investigation.

Multiple myeloma, painful neuropathy, acupuncture?

Thalidomide and bortezomib are remarkably efficacious in the treatment of multiple myeloma. Unfortunately, their use can cause sensory neuropathy, a common and serious adverse event that frequently limits dose and duration of treatment. Although the relationship between peripheral neuropathy and therapeutic dose is controversial, many authors have demonstrated a positive correlation between neuropathy and cumulative dose, dose intensity, and length of therapy. Peripheral neuropathic pain is the most troublesome symptom of neuropathy. Spontaneous pain, allodynia, hyperalgesia, and hyperpathia are often associated with decreased physical activity, increased fatigue, mood, and sleep problems. Symptoms are often difficult to manage, and available treatment options rarely provide total relief. Moreover, the adverse effects of these treatments often limit their use. Several studies have demonstrated the efficacy of acupuncture, with fewer adverse effects than analgesic drugs, in the treatment of painful diabetic and human immunodeficiency virus-related neuropathy. However, the effectiveness of acupuncture in treating toxic neuropathy has not been assessed. Although its putative mechanisms remain elusive, acupuncture has strong potential as an adjunctive therapy in thalidomide- or bortezomib-induced painful neuropathy, and a better understanding might guide its use in the management of chemotherapy-induced neuropathic pain. Well-designed clinical trials with adequate sample size and power are warranted.

Progressive Multifocal Leukoencephalopathy with Concurrent Richter's Syndrome

Progressive multifocal leukoencephalopathy (PML) is a demyelinating infectious disease caused by the JC virus. It was originally described in patients with chronic lymphocytic leukemia (CLL). Richters syndrome, or transformation to large cell lymphoma, occurs in approximately 3% of patients with CLL, and carries a poor prognosis. We report a patient with documented PML and concurrent Richters transformation outside the central nervous system. Before establishing a definitive diagnosis of PML, radiation therapy to the presumed lymphomatous brain lesion had been considered, raising the issue of whether stereotactic brain biopsy should be considered in every patient in a similar situation. Although this is likely a rare occurrence, patients with Richters transformation documented at an extra-neural site and a brain lesion may benefit from the establishment of an infectious diagnosis which would influence therapy.

Long term results of a phase 2 study of vincristine sulfate liposome injection (Marqibo®) substituted for non-liposomal vincristine in cyclophosphamide, doxorubicin, vincristine, prednisone with or without rituximab for patients with untreated aggressive non-Hodgkin lymphomas

Vincristine sulfate liposome injection (VSLI; Marqibo®; M) is active in relapsed and refractory lymphomas, and approved in the United States for relapsed and refractory adult acute lymphocytic leukaemia. We evaluated VSLI (2·0 mg/m2 without dose cap) substituted for non‐liposomal vincristine (VCR) in a cyclophosphamide, doxorubicin, vincristine, prednisone ± ritiximab (CHOP±R) regimen, creating CHMP±R in 72 untreated, aggressive non‐Hodgkin lymphoma patients, including 60 with diffuse large B‐cell lymphoma (DLBCL). The overall response rate was 96% (69/72) including complete response (CR) in 65 (90%) and unconfirmed CR in 2 (3%). Median progression‐free survival (PFS) and overall survival (OS) were not reached at median follow‐up of 8 and 10·2 years, respectively. The 5‐ and 10‐year PFS and OS were 75%, 63%, 87%, and 77%, respectively. Despite VSLI exposure of up to 35 mg, the safety profile of CHMP±R was comparable to that reported for CHOP±R. Grade 3 peripheral neuropathy was reported in 2 (3%) patients; there was no reported Grade 3/4 constipation. CHMP±R was highly active, generally well tolerated, and compared favourably to historical trials with R‐CHOP in DLBCL. This enhanced activity probably reflects VCR dose intensification, pharmacokinetic optimization, and enhanced delivery afforded by VSLI. A Phase 3 trial of R‐CHMP versus R‐CHOP in elderly patients with untreated DLBCL is ongoing.