Management of cardiac health in trastuzumab-treated patients with breast cancer: updated United Kingdom National Cancer Research Institute recommendations for monitoring.

More women are living with and surviving breast cancer, because of improvements in breast cancer care. Trastuzumab (Herceptin) has significantly improved outcomes for women with HER2-positive tumours. Concerns about the cardiac effects of trastuzumab (which fundamentally differ from the permanent myocyte loss associated with anthracyclines) led to the development of cardiac guidelines for adjuvant trials, which are used to monitor patient safety in clinical practice. Clinical experience has shown that the trial protocols are not truly applicable to the breast cancer population as a whole, and exclude some women from receiving trastuzumab, even though they might benefit from treatment without long-term adverse cardiac sequelae. Consequently, five oncologists who recruited patients to trastuzumab trials, some cardiologists with whom they work, and a cardiovascular lead general practitioner reviewed the current cardiac guidelines in the light of recent safety data and their experience with adjuvant trastuzumab. The group devised recommendations that promote proactive pharmacological management of cardiac function in trastuzumab-treated patients, and that apply to all patients who are likely to receive standard cytotoxic chemotherapy. Key recommendations include: a monitoring schedule that assesses baseline and on-treatment cardiac function and potentially reduces the overall number of assessments required; intervention strategies with cardiovascular medication to improve cardiac status before, during, and after treatment; simplified rules for starting, interrupting and discontinuing trastuzumab; and a multidisciplinary approach to breast cancer care.

Expert opinion on the use of anthracyclines in patients with advanced breast cancer at cardiac risk.

Anthracyclines are considered to be among the most active agents for the treatment of breast cancer. However, their use is limited by cumulative, dose-related cardiotoxicity. Such cardiotoxicity results in a permanent loss of cardiac myocytes and a progressive reduction in cardiac function following each subsequent dose of anthracycline. Initially, damage to the heart is subclinical; however, increasingly impaired cardiac function can result in cardiovascular symptoms, with serious cardiac injury resulting in chronic heart failure. Since the early detection and treatment of cardiotoxicity can reduce its clinical effects, it is important that oncologists are aware of these adverse effects and manage them appropriately. This review examines the risk factors for anthracycline-associated cardiotoxicity and offers recommendations on strategies to reduce the cardiotoxicity of anthracyclines in the management of patients with advanced breast cancer.

Phase I study of carboplatin, doxorubicin and weekly paclitaxel in patients with advanced ovarian carcinoma.

BACKGROUND: Doxorubicin is an active compound in epithelial ovarian cancer (EOC), but adding it to carboplatin-paclitaxel causes toxicity. Toxicity can be reduced by weekly administration. We examined the tolerability of weekly paclitaxel in combination with carboplatin and doxorubicin. PATIENTS AND METHODS: Chemotherapy naïve patients with EOC were treated with doxorubicin (50 mg/m(2) day 1), carboplatin (AUC 6 day 1) and paclitaxel (days 1, 8, 15, 21), 28-day cycle. Three patients were treated at each paclitaxel dose level, starting at 60, 75 and 90 mg/m(2)/week. If more than two patients in a cohort experienced dose-limiting toxicity (DLT) three more patients were treated at the dose level below. RESULTS: Twelve patients with advanced EOC received a median of six cycles (range 2-6) of the three-drug combination. DLT occurred at dose level 3: prolonged grade 4 febrile neutropenia, 1 patient; grade 3 peripheral neuropathy, 1 patient. All six patients treated at dose level 2 experienced short-lived grade 4 neutropenia, which led to dose modifications resulting in an actual delivered dose of paclitaxel of 64 mg/m(2)/week. Eight out of 12 patients had measurable disease on CT scan: four obtained a partial remission; three had stable disease. CONCLUSIONS: The combination of carboplatin, doxorubicin and paclitaxel in patients with EOC is active and its main toxicity is myelosuppression. Dose intensity of paclitaxel can be maintained in a three-drug combination through weekly administration (65 mg/m(2)).

Incidence of P-glycoprotein overexpression and multidrug resistance (MDR) reversal in adult soft tissue sarcoma.

Multidrug resistance (MDR) is a widespread problem in the treatment of neoplastic diseases and may limit the effectiveness of treatment of adult soft tissue sarcomas (STS). We examined the levels of expression of the MDR marker P-glycoprotein (Pgp) in fresh, surgical material and matched paraffin-embedded tissue using MRK-16 and JSB-1 monoclonal antibodies. Using fresh tumour material in short-term culture an assessment of doxorubicin sensitivity (MTT assay) and MDR modulation using PSC-833 in daunorubicin (DNR) accumulation experiments (FACS analysis) was carried out. 44 patients were studied at various disease stages with a mean follow-up duration of 487 days (range: 45-1095 days). Immunocytochemistry and immunohistochemistry showed 62% and 58%, respectively, of STS samples were positive for Pgp. Patients showing negative Pgp expression had a median survival of 544 days versus 431 days for Pgp-positive patients (P=0.311), with disease-free survival medians of 508 and 355 days, respectively (P=0.203). In vitro doxorubicin sensitivity was not informative in this respect and there was no apparent relationship between this and Pgp expression. Eleven out of 29 samples evaluated for MDR modulation showed enhanced tumour cell DNR accumulation. However, the effects of PSC-833 on drug accumulation in clinical material were modest compared with those seen for MDR cell lines, with a maximum of only 20% enhancement. Moreover, there was no relationship between the extent of PSC-833 effects on accumulation and the levels of Pgp seen in the STS samples. Nevertheless, we show evidence that a proportion of cases of STS express moderate to high levels of Pgp. There may be a role for MDR modulating agents in association with doxorubicin in the treatment of these tumours, either in the adjuvant setting or at first relapse.

Continuous infusional combination chemotherapy in inflammatory breast cancer: a phase II study.

Despite the introduction of systemic chemotherapy, inflammatory breast cancer (IBC) remains a disease with a poor prognosis. We performed this phase II study to evaluate the efficacy of infusional chemotherapy as initial treatment in patients with IBC. Fifty-four patients with newly diagnosed IBC were offered infusional chemotherapy and 34 accepted. The schedule consisted of continuous infusional ECF (bolus epirubicin and cisplatin, substituted by carboplatin or cyclophosphamide in some patients) plus continuous 5-FU, given three weekly for six cycles. Following chemotherapy patients went on to have surgery and/or radiotherapy. The chemotherapy was well tolerated and resulted in an overall response rate of 79% with 35% of patients achieving a complete clinical response. The median response duration, time to progression and overall survival were 12 months (4-89+ months), 12 months (4-89+ months) and 23 months (7-89+ months), respectively. Patients had a 5 year disease free and overall survival of 11% and 29%, respectively. Infusional ECF is well tolerated and achieves a high clinical response rate in patients with IBC, but survival results do not appear to be superior to those achieved with conventional bolus chemotherapy schedules.

Susceptibility of fibromatosis cells in short-term culture to Ifosfamide: a possible experimental treatment in clinically aggressive cases.

Purpose. Deep fibromatoses are large, often rapidly growing but benign soft tissue tumours. Although surgery is the mainstay of treatment, in unremitting and aggressive cases the use of cytotoxic chemotherapy may produce objective tumour responses. Fresh tumour samples from four patients with fibromatosis were investigated as part of a study of drug resistance in soft tissue tumours.Methods. Following short-term culture of fibromatosis cells in vitro , chemosensitivity to 4-hydroperoxy-ifosfamide, the active form of ifosfamide and doxorubicin was tested. Following 72-h continuous exposure to each drug, surviving cell fraction was assessed using the lactate dehydrogenase assay.Results. Mean IC(50) values for ifosfamide and doxorubicin were 6.2 and 0.35 micromol/l, respectively. In samples of soft tissue sarcoma (STS) from the same study the mean IC(50) values for ifosfamide and doxorubicin were 14.8 and 1.69 micromol. The difference in mean ifosfamide IC(50) values for fibromatosis and STS samples was statistically significant.Discussion. We are not aware of any other report suggesting the use of ifosfamide in this condition. These observations suggest that, for patients with inoperable or progressive lesions of fibromatosis causing significant morbidity, it may be valuable to include ifosfamide in experimental treatment regimens.

Ewing's sarcoma and primitive neuroectodermal tumor in adults: are they different from Ewing's sarcoma and primitive neuroectodermal tumor in children?

PURPOSE: To determine whether age at diagnosis influences the behavior of Ewing's sarcoma and primitive neuroectodermal tumor (PNET). PATIENTS AND METHODS: We reviewed the clinical features, treatment, and outcome of 59 consecutive patients with Ewing's sarcoma and PNET treated on the Adult Sarcoma Unit at our institution from 1980 to 1995. RESULTS: The 37 male and 22 female patients had a median age of 24 years. Lower limb was the most common primary tumor site. Fifteen patients had nonmetastatic tumor less than 100-mL volume, 27 had nonmetastatic disease greater than 100-mL volume, and 17 had evidence of metastatic disease at presentation. The origin of the primary tumor was soft tissue in 28 cases, bone in 30, and uncertain in one. The Kaplan-Meier estimate of 5-year overall survival (OS) in all patients was 38% and of progression-free survival (PFS), 27%. When patients with metastatic disease at presentation were excluded, these figures increased to 52% and 34%, respectively. Bulk of disease at presentation and response to primary treatment were statistically highly significant predictors of both PFS and OS. Age and tissue of origin of the tumor did not influence outcome. CONCLUSION: The behavior of Ewing's sarcoma and PNET in adults is no different from its behavior in children. We feel the way forward in the treatment of adults with Ewing's sarcoma and PNET is for them to be included in the current multicenter trials of multidisciplinary treatment directed at children.

Quantification of phosphorus metabolites in human calf muscle and soft-tissue tumours from localized MR spectra acquired using surface coils.

Metabolite concentrations determined from MR spectra provide more specific information than peak area ratios. This paper presents a method of quantification that allows metabolite concentrations to be determined from in vivo 31P MR spectra acquired using a surface coil and ISIS localization. Corrections for the effects of B1 field inhomogeneity produced by surface coils are based on a measured and calibrated spatial sensitivity field map for the coil. Account is taken of imperfections in pulse performance, coil loading effects and relaxation effects, the latter making use of published metabolite relaxation times. The technique is demonstrated on model solutions. The concentrations of the main 31P metabolites in normal human calf muscle measured using this method are [PCr] = 26.9 +/- 4.1 mM; [Pi] = 3.6 +/- 1.2 mM; [NTP] = 6.8 +/- 1.8 mM. Quantification of spectra acquired from soft-tissue tumours in patients both pre- and post-treatment showed that changes in metabolite concentrations are more sensitive to metabolic changes than changes in peak area ratios.

Chemosensitivity testing of fresh and continuous tumor cell cultures using lactate dehydrogenase.

We have examined the use of the LDH (lactate dehydrogenase) assay for chemosensitivity testing in established and primary cultures of sarcoma, leukaemia and ovarian cancer in parallel with the MTT assay. The method we describe is rapid, sensitive and ideal for 96-well plate assays using adherent or suspension cultures. Excellent agreement between the two methods was observed (r = 0.936) using a variety of antitumour agents, with some notable exceptions. In the Bax (human synovial sarcoma) cell line MTT colour production by control cells was very low, thus MTT-->formazan production could not be relied upon as a definitive end point equating with cell number. In contrast, colour production of control cells using the LDH assay was significantly greater and all cultures tested were suitable for titration of chemosensitivity. There was a discrepancy between IC50 values obtained either by cell counting or MTT in the HTB88 (human leiomyosarcoma) line treated with 5-FU (59.9 microM vs > 200 microM, respectively). However, cell counting agreed well with the LDH assay (IC50 47.3 microM). Whilst the MTT assay remains a reliable method for chemosensitivity testing, the LDH assay may prove more appropriate in certain experimental settings.

The use of paediatric chemotherapy protocols at full dose is both a rational and feasible treatment strategy in adults with Ewing's family tumours.

BACKGROUND: Ewing's sarcoma and primitive neuroectodermal tumour (ES/PNET) are rare, limiting opportunities for therapy studies in adults. Chemotherapy regimens adapted from paediatric studies are often used for adults but concerns about poor outcome and treatment toxicity may adversely affect drug dose intensity. We present our experience using a paediatric protocol at full dose. PATIENTS AND METHODS: Records of 34 patients with ES/PNET who received the IVAD chemotherapy regimens were reviewed. Received drug dose intensity, toxicity and survival data were collected. RESULTS: Received dose intensity in 30 evaluable patients was 0.92 compared to the standard IVAD schedule. Myelosuppression was the major toxicity, 83% of patients experienced grade 4 neutropenia. There was no major renal or cardiac toxicity. In patients without metastases at presentation, five-year overall survival was 63% and progression free survival was 39%. Tumour burden at presentation was statistically significantly associated with survival (P = 0.002). The five-year survival rate of 80% in patients presenting with low volume non metastatic disease was equivalent to published paediatric series. CONCLUSIONS: Although the IVAD chemotherapy regimens are myelotoxic in adults, they can be given safely. We recommend that adults with ES/PNET should be included in current multicentre, multidisciplinary treatment studies directed at children.