[Show abstract][Hide abstract] ABSTRACT: A multicenter phase II study was conducted to assess the efficacy of rituximab, methotrexate, procarbazine, and vincristine (R-MPV) followed by consolidation reduced-dose whole-brain radiotherapy (rdWBRT) and cytarabine in primary CNS lymphoma.
Patients received induction chemotherapy with R-MPV (five to seven cycles); those achieving a complete response (CR) received rdWBRT (23.4 Gy), and otherwise, standard WBRT was offered (45 Gy). Consolidation cytarabine was given after the radiotherapy. The primary end point was 2-year progression-free survival (PFS) in patients receiving rdWBRT. Exploratory end points included prospective neuropsychological evaluation, analysis of magnetic resonance imaging (MRI) white matter changes using the Fazekas scale, and evaluation of the apparent diffusion coefficient (ADC) as a prognostic factor.
Fifty-two patients were enrolled, with median age of 60 years (range, 30 to 79 years) and median Karnofsky performance score of 70 (range, 50 to 100). Thirty-one patients (60%) achieved a CR after R-MPV and received rdWBRT. The 2-year PFS for this group was 77%; median PFS was 7.7 years. Median overall survival (OS) was not reached (median follow-up for survivors, 5.9 years); 3-year OS was 87%. The overall (N = 52) median PFS was 3.3 years, and median OS was 6.6 years. Cognitive assessment showed improvement in executive function (P < .01) and verbal memory (P < .05) after chemotherapy, and follow-up scores remained relatively stable across the various domains (n = 12). All examined MRIs (n = 28) displayed a Fazekas score of ≤ 3, and no patient developed scores of 4 to 5; differences in ADC values did not predict response (P = .15), PFS (P = .27), or OS (P = .33).
R-MPV combined with consolidation rdWBRT and cytarabine is associated with high response rates, long-term disease control, and minimal neurotoxicity.
[Show abstract][Hide abstract] ABSTRACT: Reports suggest reasonable efficacy and minimal myelosuppression from combination imatinib and hydroxyurea for recurrent malignant glioma. We retrospectively reviewed 16 patients treated with this regimen who were evaluable for toxicity; 14 were also evaluable for response. The incidence of grade 3-4 hematologic toxicity was 25%. The best radiographic response, by Macdonald criteria, was partial response (PR) in three patients (21%), stable disease (SD) in four (29%), and progressive disease (PD) in seven (50%). One patient with a PR developed therapy-limiting hematologic toxicity on day 19 of treatment, progressing to grade 4 on day 64, and persisting until death on day 127 despite discontinuing both drugs. Another patient with PR and two of four patients with SD also developed grade 3 hematologic toxicity. All patients with grade 3-4 hematologic toxicity had disease control (PR or SD) as best radiographic response, whereas none with PD suffered grade 3-4 hematologic toxicity. Combining imatinib with hydroxyurea is effective in some patients with malignant glioma. However, myelosuppression can persist for months after discontinuing the regimen, precluding further chemotherapy. Disease control may also correlate with hematologic toxicity (p = 0.08), suggesting that glioma and marrow stem cells may share a common sensitivity to this chemotherapy regimen.
Journal of Neuro-Oncology 12/2007; 85(2):217-22. DOI:10.1007/s11060-007-9408-1 · 3.07 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Our goals were to evaluate the safety of adding rituximab to methotrexate (MTX)-based chemotherapy for primary CNS lymphoma, determine whether additional cycles of induction chemotherapy improve the complete response (CR) rate, and examine effectiveness and toxicity of reduced-dose whole-brain radiotherapy (WBRT) after CR.
Thirty patients (17 women; median age, 57 years; median Karnofsky performance score, 70) were treated with five to seven cycles of induction chemotherapy (rituximab, MTX, procarbazine, and vincristine [R-MPV]) as follows: day 1, rituximab 500 mg/m2; day 2, MTX 3.5 gm/m2 and vincristine 1.4 mg/m2. Procarbazine 100 mg/m2/d was administered for 7 days with odd-numbered cycles. Patients achieving CR received dose-reduced WBRT (23.4 Gy), and all others received standard WBRT (45 Gy). Two cycles of high-dose cytarabine were administered after WBRT. CSF levels of rituximab were assessed in selected patients, and prospective neurocognitive evaluations were performed.
With a median follow-up of 37 months, 2-year overall and progression-free survival was 67% and 57%, respectively. Forty-four percent of patients achieved a CR after five or fewer cycles, and 78% after seven cycles. The overall response rate was 93%. Nineteen of 21 CR patients received the planned 23.4 Gy WBRT. The most commonly observed grade 3 to 4 toxicities included neutropenia (43%), thrombocytopenia (36%), and leukopenia (23%). No treatment-related neurotoxicity has been observed.
The addition of rituximab to MPV increased the risk of significant neutropenia requiring routine growth factor support. Additional cycles of R-MPV nearly doubled the CR rate. Reduced-dose WBRT was not associated with neurocognitive decline, and disease control to date is excellent.
[Show abstract][Hide abstract] ABSTRACT: The purpose of this article was to review the current state of knowledge regarding the efficacy of adjuvant therapy for melanoma.
We reviewed the published literature, focusing on randomized clinical trials.
There have been no meaningful trials addressing adjuvant chemotherapy in melanoma because all trials have been underpowered. Adjuvant interferon-alpha has been tested both at high dose and at lower doses. None of the trials have shown a reproducible benefit in survival, although the high-dose trials and some of the low-dose trials have shown improvement in time to relapse. These experiences raise the question of whether chronic administration is more important than dose. An adjuvant pegylated interferon-alpha trial using a 5-year treatment period is currently under investigation. At least 7 randomized adjuvant vaccine trials have been published, but none have shown a beneficial effect on relapse-free or overall survival except in subset analyses.
To date, no adjuvant therapy has resulted in improved overall survival. To be attractive as an adjuvant therapy, experience from other tumor types indicates that a chemotherapy regimen should have a response rate of at least 20% in metastatic melanoma. Currently, biochemotherapy is being tested as an adjuvant treatment but other, less toxic, regimens should be sought. Once such a regimen with acceptable toxicity is identified, it would be reasonable to test it as an adjuvant therapy in a properly powered randomized trial. High-dose interferon-alpha for 1 year remains the only U.S. Food and Drug Administration-approved adjuvant therapy for melanoma, but long-term chronic dosing of interferon-alpha may prove more effective than short-term dose schedules. Development of melanoma vaccines remains an appealing and important goal. New technologies and understanding of the immune response against melanoma are leading to novel vaccine strategies designed to break immunologic tolerance against melanoma.
The Cancer Journal 05/2007; 13(3):217-22. DOI:10.1097/PPO.0b013e318074dfd4 · 4.24 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Greater than one-half of all intracranial tumors in adults represent metastases from disseminated systemic malignancies. Abundant
class I evidence has been accumulated for the past two decades that demonstrates improved survival and quality of life with
surgical resection or SRS for appropriate patients. In some tumor types, WBRT can effectively treat, prevent and/or delay
recurrences and improve survival as well. However, several factors may preclude either surgery or radiation therapy (e.g.,
number of metastases, co-existing medical or neurological conditions) and in such patients the mainstay of treatment is chemotherapy
or other biologic targeted therapy.
Cancer treatment and research 02/2007; 136:185-97. DOI:10.1007/978-0-387-69222-7_10
[Show abstract][Hide abstract] ABSTRACT: Treatment options for patients with recurrent central nervous system (CNS) metastases are limited. Rapid infusion of high-dose intravenous methotrexate (HD IV MTX) penetrates the blood-brain barrier (BBB) and has reported activity in leptomeningeal metastases.
Medical records were reviewed for all patients treated with HD IV MTX (3.5 g/m2) for CNS parenchymal or leptomeningeal metastases. Radiographic response rate, survival, and toxicity were determined.
Thirty-one women and one man with a median age of 52 years (range 33-76) were treated with a total of 141 cycles (median 4, range 1-13). Twenty-nine patients had breast cancer, and one each had cancer of unknown primary (CUP), squamous cell carcinoma of the head and neck, and non-small cell lung cancer (NSCLC). An objective radiographic response and stable disease were each observed in nine patients (28%), and 13 (44%) patients progressed. Prior treatment with low-dose MTX for systemic disease did not affect response (P = 0.8). The median overall survival (n = 32) was 19.9 weeks (range 2.9-135.4+) with one patient alive at 135.4 weeks. Myelosuppression and elevated serum hepatic transaminases were the most common acute toxicities (21% and 9% of HD IV MTX cycles, respectively).
HD IV MTX is effective in the treatment of CNS metastases with disease control (response or stable) as a best response in 56% of assessable patients. Further study is warranted.
Journal of Neuro-Oncology 08/2006; 78(3):255-60. DOI:10.1007/s11060-005-9044-6 · 3.07 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Primary central nervous system lymphoma (PCNSL) describes a malignant non-Hodgkin's lymphoma (NHL) whose sole site of involvement is the central nervous system (CNS). The diagnosis of PCNSL must be differentiated from systemic NHL with metastasis to the CNS, which usually occurs late in the course of systemic disease. PCNSL accounts for approximately 4% to 7% of primary brain tumors, and its incidence has been increasing since the mid-1970s. Compared with other more common malignant primary brain tumors, PCNSL tends to be more amenable to radiotherapeutic and chemotherapeutic intervention. In this article, the authors review the standard treatment for upfront and recurrent PCNSL.
Hematology/Oncology Clinics of North America 09/2005; 19(4):611-27, v. DOI:10.1016/j.hoc.2005.05.002 · 2.30 Impact Factor