cardiovascular-agents and Neoplasm-Metastasis

Approximately 25,000 patients have been treated to date with the humanized anti-HER2 monoclonal antibody, Herceptin. This therapy has proved effective and well tolerated in patients with HER2-positive metastatic breast cancer; adverse events were generally infusion-related fever and chills of mild-to-moderate severity. Cardiotoxicity and infusion-related reactions emerged as the two main safety concerns with the use of Herceptin. Retrospective analysis revealed a higher incidence of heart failure when Herceptin was combined with anthracyclines than that expected with anthracyclines alone. Age, anthracycline exposure and cardiac risk factors were found to be predictors of cardiac adverse events. Patients experiencing cardiac dysfunction responded well to standard cardiac medication and the majority improved. Cardiac function should be monitored regularly and Herceptin should be discontinued if significant heart failure develops unless the benefits for an individual patient outweigh the risks. Of 25,000 patients, 74 (0.3%) were reported to have experienced a serious infusion-related reaction. The majority occurred during or shortly after the first infusion and were characterized by respiratory symptoms. Most patients were successfully treated; a total of 33 patients continued Herceptin therapy with no recurrence of infusion reactions. Although the benefit to risk ratio of Herceptin remains favorable, physicians must be vigilant and aggressive in managing cardiotoxicity and infusion-related reactions.

Topics: Animals; Antibiotics, Antineoplastic; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Cardiovascular Agents; Chills; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Drug Interactions; Female; Fever; Heart Diseases; Heart Failure; Humans; Immunotherapy; Infusions, Intravenous; Neoplasm Metastasis; Pain; Palliative Care; Respiratory Insufficiency; Retrospective Studies; Risk Factors; Safety; Salvage Therapy; Trastuzumab; Treatment Outcome

Two large multicenter placebo controlled trials (088001 and 088006) in metastatic breast cancer found a significant cardioprotective effect of dexrazoxane when administered with doxorubicin. A delayed dose analysis found a protective effect even after a cumulative dose of doxorubicin of 300 mg/m2. Exploratory analysis combing the arms on the two studies found a cardioprotective effect of dexrazoxane either initially or after 300 mg/m2 when administered in patients older than 65 years, compared to patients receiving only placebo. Also, patients with an ejection fraction within 10% above the lower limit of normal were protected with dexrazoxane. Objective response rates were borderline significantly lower for patients receiving dexrazoxane. Recommendations are to administer dexrazoxane after 300 mg/m2.

Topics: Adult; Aged; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Cardiovascular Agents; Dose-Response Relationship, Drug; Doxorubicin; Female; Heart Diseases; Humans; Multicenter Studies as Topic; Neoplasm Metastasis; Randomized Controlled Trials as Topic; Razoxane

Anthracyclines are highly effective and widely used cytotoxic agents, but their application is often limited by cumulative dose-dependent cardiotoxicity. Dexrazoxane has been shown in several clinical trials to prevent the development of this serious toxicity. The aim of our study was to analyze the incidence of cardiac dysfunction over a 10-year period in patients with breast cancer who were treated with anthracycline-based regimens with addition of dexrazoxane, mainly in an adjuvant setting.. We conducted a retrospective analysis on a population of women with breast cancer treated at our institution between January 1993 and October 2003. We reviewed patients' medical records and data on patient characteristics, treatment history, and adverse events that were collected, starting from the time of first visit before starting therapy, with the use of software created and designed for clinical records management in our institution (1999 OK-DH). Patients underwent an ECG assessment prior to starting chemotherapy, and were clinically monitored for cardiac failure. Those who developed signs and symptoms suggestive of cardiac dysfunction underwent further ECG. If clinical findings indicated, echocardiography and further cardiologic investigations were performed. The main outcome measure was the development of signs and symptoms indicative of congestive heart failure (CHF).. A total of 318 female patients were treated with an anthracycline (doxorubicin or epirubicin)-based combination chemotherapy regimen during this time, in most cases in the adjuvant setting (n = 285). Most patients (n = 302) had early-stage disease and only 16 women presented with metastatic disease with good life expectancy (at least 1 year). All patients received dexrazoxane 1000 mg/m(2) intravenously prior to anthracycline administration during each chemotherapy cycle. The median follow-up duration was 35 months. During this time, five patients (1.57%) developed signs and symptoms of CHF. No patient at our institution died of heart failure during the period analyzed. Dexrazoxane was well tolerated, with no reports of adverse events associated with this drug.. The reported incidence of cardiotoxicity in this study represents a marked reduction compared with historical data for patients receiving anthracycline-based chemotherapy without dexrazoxane. Dexrazoxane appears to have a cardioprotective effect in women with early-stage or advanced breast cancer treated with anthracycline-based combination chemotherapy, mainly as an adjuvant treatment. Prospective, randomized, controlled clinical trials in adjuvant setting should be performed to confirm these results.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Cardiovascular Agents; Dose-Response Relationship, Drug; Doxorubicin; Electrocardiography; Epirubicin; Female; Follow-Up Studies; Heart Failure; Humans; Incidence; Life Expectancy; Middle Aged; Neoplasm Metastasis; Razoxane; Retrospective Studies

The recognition of the activity of paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) in metastatic breast cancer led to attempts to combine this drug with other active agents. Two agents that have received particular attention are doxorubicin and cisplatin. Initial pilot and phase I trials by the Eastern Cooperative Oncology Group (ECOG) led to the development of a three-arm, prospective randomized trial comparing single-agent doxorubicin, single-agent paclitaxel, and the combination of doxorubicin and paclitaxel (E 1193). This trial is currently closed to accrual and the initial results are being analyzed. Based on data from Gianni et al (J Clin Oncol 13:2688-2699, 1995), the ECOG is currently involved in two trials attempting both to confirm the superior activity of the regimen used by Gianni et al and, in a phase I/II trial, to ameliorate its cardiac toxicity through the addition of dexrazoxane. Similarly, both the ECOG and the Hoosier Oncology Group were unable to confirm the strikingly positive results obtained by the Vancouver group when cisplatin was combined with paclitaxel (Semin Oncol 22:108-111, 1995 [suppl 6]: Proc Am Soc Clin Oncol 13:71, 1994 [abstr 88]). Indiana University investigators are currently involved in a phase I trial attempting to combine carboplatin and paclitaxel in a biweekly schedule.

Topics: Antibiotics, Antineoplastic; Antineoplastic Agents; Antineoplastic Agents, Phytogenic; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Cardiovascular Agents; Cisplatin; Clinical Trials, Phase I as Topic; Clinical Trials, Phase II as Topic; Doxorubicin; Female; Heart; Humans; Multicenter Studies as Topic; Neoplasm Metastasis; Paclitaxel; Pilot Projects; Prospective Studies; Randomized Controlled Trials as Topic; Razoxane