Phase I and Pharmacologic Studies of Topotecan in Patients With Impaired Hepatic Function

O’Reilly, Seamus; Rowinsky, Eric K.; Slichenmyer, William J.; Donehower, Ross C.; Forastiere, Arlene A.; Ettinger, David S.; Chen, Tian Ling; Sartorius, S E; Bowling, Katherine; Smith, J.; Brubaker, Abe; Lubejko, Barbara; Ignacio, Virna; Grochow, Louise B.

doi:10.1093/jnci/88.12.817

Cited by 64 publications

(33 citation statements)

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“…We used all three agents at dosages identified in phase I-II studies as safe and effective: thiotepa achieved significantly better results at X900 mg/m 2 , with doselimiting CNS toxicity at 1125 mg/m 2 ; 27 carboplatin had impressive antitumor activity at X1200 mg/m 2 and was safe in dosages up to 2000 mg/m 2 ; 29 and topotecan 10 mg/m 2 divided over 5 days became a commonly used salvage treatment because of impressive anticancer activity and modest toxicity, 11,13 though lower dosages were used in conventional combination chemotherapy regimens. [30][31][32][33][34] The 3 days of thiotepa preceded the 3 days of carboplatin, and the 5 days of topotecan were completed before the last dose of carboplatin.…”

Section: Discussionmentioning

confidence: 99%

“…As an alternative, we chose topotecan because this topoisomerase-I inhibitor may be less affected by the most common multidrug resistance mechanisms, 3,4 can potentiate antitumor effects of alkylating agents, 5 has good CNS penetration, 6 is active against NB, [7][8][9][10] and causes little extramedullary toxicity. [7][8][9][10][11][12] We now present our experience in NB patients treated with a myeloablative regimen that includes topotecan. We previously reported preliminary results with the same regimen, used against a variety of solid tumors.…”

Section: Introductionmentioning

confidence: 99%

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Topotecan, thiotepa, and carboplatin for neuroblastoma: failure to prevent relapse in the central nervous system

Kushner

Krämer

Modak

et al. 2006

Bone Marrow Transplant

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We report on a three-drug myeloablative regimen designed to consolidate remission and to prevent central nervous system (CNS) relapse of high-risk neuroblastoma (NB). Sixty-six NB patients received topotecan 2 mg/m 2 / day, Â 4 days; thiotepa 300 mg/m 2 /day, Â 3 days; and carboplatin B500 mg/m 2 /day, Â 3 days. Post-SCT treatments included radiotherapy, immunotherapy, 13-cisretinoic acid, 7oral etoposide. Significant nonhematologic toxicities were mucositis and skin-related in all patients, convulsions in three patients, and cardiac failure and venocclusive disease of liver in one patient each. Grade 2 hepatotoxicity led to truncating cytoreduction in two patients; both later relapsed in brain. Among 46 patients transplanted in first complete/very good partial remission (CR/VGPR), event-free survival is 54% (s.e.78%) at 36 months post-SCT; notable events were three non-NB-related deaths (adenovirus on day þ 9, bowel necrosis at 5 months, multiorgan failure at seven months) and four relapses in brain. Of 12 patients transplanted with evidence of NB, two became long-term event-free survivors and two relapsed in the brain. Of eight patients transplanted in second or greater CR/VGPR, one became a long-term event-free survivor and seven relapsed though not in the CNS. This regimen has manageable toxicity but does not prevent CNS relapse.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Topotecan, thiotepa, and carboplatin for neuroblastoma: failure to prevent relapse in the central nervous system

Kushner

Krämer

Modak

et al. 2006

Bone Marrow Transplant

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“…Armstrong et al [58] have proposed modified dosing guidelines to limit topotecaninduced toxicity in patients with impaired renal function ( Table 2) [59]. Although the liver also contributes to the clearance of topotecan, no dose modifications are necessary in patients with impaired hepatic function [60].…”

Section: Topotecanmentioning

confidence: 99%

Management of Treatment-Related Toxicity in Advanced Ovarian Cancer

Dunton

2002

The Oncologist

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Recognition of recurrent ovarian cancer as a disease with significant secondary responses and remissions has led to an increase in the need for oncologists to plan for the long-term therapy of patients. However, many of the currently available front-line and salvage agents used in advanced ovarian cancer are associated with cumulative and/or irreversible toxicities that pose challenges in longterm planning. The irreversible effects associated with some of these therapies may render patients less tolerant to subsequent treatments and lead to a cycle of diminishing treatment options with each remission and disease relapse. Additionally, the potential for patients to experience cumulative toxicity must be carefully weighed against the goals of prolonging the disease-free interval and improving patient quality of life. A number of agents are available in the treatment armamentarium (platinum, paclitaxel, gemcitabine, etoposide, liposomal doxorubicin, and topotecan), many, but not all of which are associated with cumulative toxicity. For instance, cumulative neurotoxicity associated with cisplatin as first-line therapy may diminish the option for retreatment with platinum at first relapse. In contrast, the main toxicity associated with topotecan is noncumulative, manageable myelosuppression. In this review, the major toxicities associated with the predominant chemotherapy agents used in advanced ovarian cancer are discussed along with selected management approaches in the context of long-term treatment planning and sequencing.

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“…No dose adjustment is recommended in patients with impaired liver function based on a case cohort study (bilirubin 1.7-4.9 mg/dl) [24].…”

Section: Topotecanmentioning

confidence: 99%

Commentary: Oncologic Drugs in Patients with Organ Dysfunction: A Summary

2007

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After completing this course, the reader will be able to:1. Describe the currently recommended dose adjustments for common chemotherapeutics in oncology patients with organ dysfunction.2. Explain the rationale for using phase I dose-escalation studies to determine appropriate chemotherapy dosing in patients with organ dysfunction.3. Discuss the limitations of the currently available studies to guide chemotherapy dose adjustment in patients with organ dysfunction.Access and take the CME test online and receive 1 AMA PRA Category 1 Credit ™ at CME.TheOncologist.com CME CME ABSTRACTThere are few prospective data regarding the pharmacokinetics and clinical toxicity of commonly used chemotherapeutics in cancer patients with organ dysfunction. Although increasing numbers of studies are investigating newer chemotherapeutics in patients with liver or kidney dysfunction, most guidelines for dosing, especially for established agents, remain empiric. This review describes the available data (both prospective and case study) evaluating the impact of renal and hepatic dysfunction on toxicity and dosing of commonly used chemotherapeutics and provides a practical summary for their use in this setting.

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Phase I and Pharmacologic Studies of Topotecan in Patients With Impaired Hepatic Function

Abstract: Cancer patients with hepatic injury can be treated with topotecan at a starting dose of 1.5 mg/m2, given daily for 5 days and administered every 3 weeks. Topotecan dose modifications do not appear to be required for patients with hepatic dysfunction and normal renal function.

Cited by 64 publications

References 0 publications

Topotecan, thiotepa, and carboplatin for neuroblastoma: failure to prevent relapse in the central nervous system

Topotecan, thiotepa, and carboplatin for neuroblastoma: failure to prevent relapse in the central nervous system

Management of Treatment-Related Toxicity in Advanced Ovarian Cancer

Commentary: Oncologic Drugs in Patients with Organ Dysfunction: A Summary

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