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      Biochemotherapy for Metastatic Melanoma with Limited Central Nervous System Involvement

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          Abstract

          Objectives: Biochemotherapy outcomes were examined in stage IV melanoma patients with previously treated or active central nervous system (CNS) metastases prior to systemic therapy. Patients and Methods: Patients who received biochemotherapy for metastatic melanoma with active or pretreated CNS metastases were compared to patients without evidence of CNS metastases in terms of response, time to progression (TTP), overall survival (OS), and treatment toxicity. Results: Twenty-six (16%) of 159 total patients began biochemotherapy with previously treated or active CNS metastases (group I), compared to 133 (84%) who were radiographically free of CNS involvement (group II). A partial or complete response to biochemotherapy was seen in 13 (50%) group I patients, compared to 56 (42%) group II patients (p = 0.243). The median TTP and median survival were 5.5 and 7.0 months, respectively, for group I patients and 6.0 and 9.9 months, respectively, for group II patients (p = 0.222 and 0.434 for TTP and OS, respectively). Five (19%) group I patients survived longer than 24 months. Gamma Knife radiosurgery or surgical resection of CNS disease prior to biochemotherapy improved survival versus delayed treatment (p = 0.017 and 0.005, respectively). Conclusion: Patients with limited CNS metastases and widespread systemic disease can achieve prolonged survival with targeted treatment of CNS lesions and aggressive systemic therapy.

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          Temozolomide and whole brain irradiation in melanoma metastatic to the brain: a phase II trial of the Cytokine Working Group.

          To evaluate the antitumor effects and toxicities of whole brain irradiation (WBI) with temozolomide (TMZ) administered by prolonged oral dosing in patients with melanoma metastatic to the brain. Patients with melanoma metastatic to the central nervous system (CNS) have an extremely poor prognosis and appear to benefit little from WBI. TMZ is an alkylating agent chemically similar to dacarbazine (DTIC) with good oral bioavailability and CNS penetration. TMZ has broad preclinical antitumor activity which in melanoma is comparable to that of DTIC. The combination of TMZ and WBI may provide enhanced antitumor activity against CNS metastasis from melanoma. Patients with measurable CNS metastases with or without systemic disease were treated with WBI, 30 Gray over ten fractions (days 1-5 and 8-12). TMZ, 75 mg small middle dotm(2 small middle dot)day, was started on day 1, continued daily for 6 weeks and repeated every 10 weeks. Thirty-one patients were treated. There was one CNS complete response of 4.5 months and two CNS partial responses of 2 months and 7 months duration; the latter patient also had a 4-month complete remission of systemic metastases. Toxicities were limited to a single episode of grade 3 transaminase elevation and two episodes of grade 3 neutropenia, one complicated by fatal sepsis. The median progression-free interval for both CNS and extracranial sites was 2 months (range 1 week-11 months), and median survival 6 months (range 2-12 months). WBI has lower than expected activity in CNS metastasis of malignant melanoma. Although TMZ can be safely administered with WBI, the combination has limited anti-tumor activity.
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            Treatment of brain metastases of malignant melanoma with temozolomide.

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              Multi-objective optimization in radiotherapy: applications to stereotactic radiosurgery and prostate brachytherapy.

              Treatment planning for radiation therapy is a multi-objective optimization process. Here we present a machine intelligent scheme for treatment planning based on multi-objective decision analysis (MODA) and genetic algorithm (GA) optimization. Multi-objective ranking strategies are represented in the L(p) metric under the displaced ideal model. Goal setting, protocol satisficing and fuzzy ranking of objective importance can be incorporated into the decision scheme to assimilate clinical decision making. For distance measures in the L(p) metric, a dynamic gauge function is defined based on the state energy of the decision system, which is assumed to undergo thermodynamic cooling with iteration time. The MODA scheme interacts with a robust GA engine, which adaptively evolves in the multi-modal landscape that defines the treatment plan quality. A conventionally challenging case of stereotactic radiosurgery of a brain lesion was selected for GA optimization. The resulting dose distributions are compared to human-developed plans, which are commonly regarded as clinically relevant and empirically optimal. The GA-optimized plans achieve substantially better sparing of critical normal neuroanatomy surrounding the brain lesion while respecting the preset constraints on tumor dose uniformity. In addition, machine optimization tends to produce novel treatment strategies which complements expert knowledge. The run time for producing an optimal plan is considerably shorter than the typical planning time for human experts, thus GA can also be used to aid the human treatment planning process. In prostate brachytherapy, MODA-GA was specifically applied to non-ideal conditions in which typical surgical uncertainties in seed implant positioning occur, where noisy objectives were introduced into the optimization scheme. The noisy system is found to be manageable by MODA-GA at uncertainty levels corresponding to reasonably proficient surgery teams. In contrast, noisy objectives would be very difficult to explore by human expert planners. Potential use of noisy optimization with time series analysis is being explored for error-corrective computer guidance in the operating room for prostate seed implantation. In conclusion, the combination of MODA and GA optimization offers both a solution to practical treatment planning tasks and the potential for real time applications in radiotherapy.
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                Author and article information

                Journal
                OCL
                Oncology
                10.1159/issn.0030-2414
                Oncology
                S. Karger AG
                0030-2414
                1423-0232
                2003
                May 2003
                16 May 2003
                : 64
                : 4
                : 328-335
                Affiliations
                aDivision of Medical Oncology, John Wayne Cancer Institute, Saint John’s Health Center, Santa Monica, Calif., and bUniversity of Southern California, Keck School of Medicine, Los Angeles, Calif., USA
                Article
                70289 Oncology 2003;64:328–335
                10.1159/000070289
                12759528
                19c359fc-cc3b-471c-8629-ba1116cd95c1
                © 2003 S. Karger AG, Basel

                Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher. Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug. Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

                History
                Page count
                Figures: 2, Tables: 3, References: 19, Pages: 8
                Categories
                Clinical Study

                Oncology & Radiotherapy,Pathology,Surgery,Obstetrics & Gynecology,Pharmacology & Pharmaceutical medicine,Hematology
                Gamma Knife radiosurgery,Central nervous system metastases,Biochemotherapy,Melanoma

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