Prognosis in young women less than 40 years of age with brain metastasis from breast cancer.

Background: Brain metastasis from breast cancer (bca) in young women is doubly devastating because both quality of life and life expectancy are significantly reduced. With new radiation technology and drugs that have emerged, survival is expected to increase for these young women. Methods: Using the oacis and sardo patient databases, we identified 121 patients diagnosed with bca and brain metastasis between 2006 and 2016 at the University of Montreal Hospital Centre. Those patients were divided into Group A, patients who developed brain metastasis during the evolution of metastatic bca, and Group B, patients whose first metastasis was to the brain. For each group, we compared young patients (<40 years of age) with older patients (≥40 years of age). Results: Among the 121 patients with brain metastasis, median overall survival (mos) was significantly longer for those less than 40 years of age than for those 40 or more years of age (18 months vs. 4 months, p < 0.001). With respect to the timing of brain metastasis, survival was significantly longer in Group B than in Group A (7 months vs. 4 months, p = 0.032). In Group A, mos was significantly longer for patients less than 40 years of age than for patients 40 or more years of age (18 months vs. 3 months, p = 0.0089). In Group B, the 2-year overall survival rate was 57% for patients less than 40 years of age and 12% for those 40 or more years of age (mos: not reached vs. 7 months; p = 0.259). Conclusions: In our single-centre retrospective cohort of women with brain metastasis from bca, prognosis was better for young women (<40 years) than for older women (≥40 years). Survival was also longer for patients whose initial metastasis was to the brain than for patients whose brain metastasis developed later in the disease course. In patients who received systemic treatment, median survival remained significantly higher in women less than 40 years of age. Further studies are needed to validate those results.

A global economic model to assess the cost-effectiveness of new treatments for advanced breast cancer in Canada.

Objective Considering the increasing number of treatment options for metastatic breast cancer (MBC), it is important to develop high-quality methods to assess the cost-effectiveness of new anti-cancer drugs. This study aims to develop a global economic model that could be used as a benchmark for the economic evaluation of new therapies for MBC. Methods The Global Pharmacoeconomics of Metastatic Breast Cancer (GPMBC) model is a Markov model that was constructed to estimate the incremental cost per quality-adjusted life years (QALY) of new treatments for MBC from a Canadian healthcare system perspective over a lifetime horizon. Specific parameters included in the model are cost of drug treatment, survival outcomes, and incidence of treatment-related adverse events (AEs). Global parameters are patient characteristics, health states utilities, disutilities, and costs associated with treatment-related AEs, as well as costs associated with drug administration, medical follow-up, and end-of-life care. The GPMBC model was tested and validated in a specific context, by assessing the cost-effectiveness of lapatinib plus letrozole compared with other widely used first-line therapies for post-menopausal women with hormone receptor-positive (HR+) and epidermal growth factor receptor 2-positive (HER2+) MBC. Results When tested, the GPMBC model led to incremental cost-utility ratios of CA$131 811 per QALY, CA$56 211 per QALY, and CA$102 477 per QALY for the comparison of lapatinib plus letrozole vs letrozole alone, trastuzumab plus anastrozole, and anastrozole alone, respectively. Results of the model testing were quite similar to those obtained by Delea et al., who also assessed the cost-effectiveness of lapatinib in combination with letrozole in HR+/HER2 + MBC in Canada, thus suggesting that the GPMBC model can replicate results of well-conducted economic evaluations. Conclusions The GPMBC model can be very valuable as it allows a quick and valid assessment of the cost-effectiveness of any new treatments for MBC in a Canadian context.

Temozolomide in metastatic breast cancer (MBC): a phase II trial of the National Cancer Institute of Canada - Clinical Trials Group (NCIC-CTG).

BACKGROUND: Temozolomide is an oral alkylating agent that crosses the blood-brain barrier, and has preclinical activity in breast cancer. This phase II trial sought to determine the activity and toxicity of temozolomide in metastatic breast cancer (MBC). Temozolomide was administered in a dose dense schedule of 150 mg/m(2) on days 1-7 and 15-21 in a 28-day cycle. MATERIALS AND METHODS: Patients had unidimensional disease for response assessment by RECIST criteria, up to two prior chemotherapy regimens for MBC, and may have had brain metastases if radiation was not expected to be required within 4 weeks. RESULTS: Nineteen women were entered on the study. All were evaluable for toxicity and 18 were evaluable for response. The median age was 54 years; 14 had prior chemotherapy for MBC and 12 had prior hormones. Sites of disease included bone, brain, liver and lung. Treatment was well tolerated with 14/19 receiving >90% planned dose intensity. Common grade 1-3 drug-related effects included nausea, fatigue, vomiting, anorexia and skin rash. Grade 3-4 hematologic toxicities included granulocytopenia and thrombocytopenia. Of the 18 evaluable patients, there were no objective responses; three had stable disease and 15 progressive disease. CONCLUSIONS: No responses to temozolomide were documented in these heavily pretreated women with extensive MBC including brain metastases.

Prospective randomized trial of docetaxel versus doxorubicin in patients with metastatic breast cancer.

PURPOSE: This phase III study compared docetaxel and doxorubicin in patients with metastatic breast cancer who had received previous alkylating agent-containing chemotherapy. PATIENTS AND METHODS: Patients were randomized to receive an intravenous infusion of docetaxel 100 mg/m(2) or doxorubicin 75 mg/m(2) every 3 weeks for a maximum of seven treatment cycles. RESULTS: A total of 326 patients were randomized, 165 to receive doxorubicin and 161 to receive docetaxel. Overall, docetaxel produced a significantly higher rate of objective response than did doxorubicin (47.8% v 33.3%; P =.008). Docetaxel was also significantly more active than doxorubicin in patients with negative prognostic factors, such as visceral metastases (objective response, 46% v 29%) and resistance to prior chemotherapy (47% v 25%). Median time to progression was longer in the docetaxel group (26 weeks v 21 weeks; difference not significant). Median overall survival was similar in the two groups (docetaxel, 15 months; doxorubicin, 14 months). There was one death due to infection in each group, and an additional four deaths due to cardiotoxicity in the doxorubicin group. Although neutropenia was similar in both groups, febrile neutropenia and severe infection occurred more frequently in the doxorubicin group. For severe nonhematologic toxicity, the incidences of cardiac toxicity, nausea, vomiting, and stomatitis were higher among patients receiving doxorubicin, whereas diarrhea, neuropathy, fluid retention, and skin and nail changes were higher among patients receiving docetaxel. CONCLUSION: The observed differences in activity and toxicity profiles provide a basis for therapy choice and confirms the rationale for combination studies in early breast cancer.

Two different schedules for integrating filgrastim as adjuvant therapy in the treatment of patients with advanced stage Hodgkin's lymphoma receiving MOPP/ABV hybrid chemotherapy.

PURPOSE: Management of advanced-stage Hodgkin's disease with a MOPP/ABV hybrid regimen (mechlorethamine, vincristine, procarbazine, prednisone, Adriamycin, bleomycin and vinblastine) has yielded a high complete response rate (75-85%). However, myelosuppression can limit delivery of treatment. Filgrastim has been shown to reduce chemotherapy-related neutropenia and allow for on-time administration of planned doses of chemotherapeutic agents. The objective of this study was to find the best way to integrate filgrastim with the MOPP/ABV hybrid regimen. METHODS: Enrolled in this study were 24 patients (aged 18-52 years) with newly diagnosed, histologically documented Hodgkin's disease. In schedule I, patients received filgrastim (5 microg/kg s.c. daily) beginning on day 9, 24 h after administration of ABV. In schedule II, patients received filgrastim concomitantly with procarbazine on days 2-7 (starting 24 h after day-1 MOPP administration and stopping 24 h before ABV administration) as well as after ABV beginning on day 9. Filgrastim after ABV administration was administered until two consecutive ANC readings of 10 x 10(9)/l were achieved. RESULTS: All patients were able to complete all six cycles of therapy. There was a trend to fewer dose reductions in schedule II (0.76%) as compared to schedule I (4.2%) with a P-value of 0.077 (chi-squared test). Specifically, 11.6% of MOPP courses and 5.5% of ABV courses were dose-reduced in schedule I versus 1.7% and 1.4%, respectively, in schedule II. CONCLUSION: In conclusion, filgrastim was effective in supporting the delivery of the MOPP/ABV chemotherapy. Concomitant administration of filgrastim with procarbazine (days 2-7) appears to be safe and allows the maximum dose intensity of this therapy.

A multicenter, double-blind comparison of i.v. and oral administration of ondansetron plus dexamethasone for acute cisplatin-induced emesis. Ondansetron Acute Emesis Study Group.

A total of 530 patients were treated in this multicenter, double-blind, double-dummy, parallel group study to compare the anti-emetic efficacy and safety of a once daily ondansetron oral regimen with a once daily i.v. dosing regimen over a 24 h period, administered to patients prior to receiving cisplatin (50 mg/m2 or greater) chemotherapy. Patients were randomized to receive a single dose of ondansetron plus dexamethasone given either orally (ondansetron 24 mg and dexamethasone 12 mg, n=262) or i.v. (ondansetron 8 mg and dexamethasone 20 mg, n=268). Complete control of emesis (i.e. no emetic episodes, no rescue and no premature withdrawal) was achieved for 85% of patients (224 of 262) in the oral group and 83% (223 of 268) in the i.v. group. No nausea was reported in 70% of patients in the oral group and 68% in the i.v. group. There were no statistically significant differences between the two groups for any of the assessments of efficacy, which included time to first emetic episode, number of emetic episodes and the worst grade of nausea occurring over the 24 h study period. Once daily ondansetron oral and i.v., in combination with dexamethasone, was well tolerated in this study. In conclusion, once daily oral ondansetron 24 mg plus dexamethasone is equally effective in the control of emesis and nausea induced by highly emetogenic chemotherapy as once daily ondansetron 8 mg i.v. plus dexamethasone.

The impact of postchemotherapy nausea and vomiting on quality of life after moderately emetogenic chemotherapy.

The purpose of the study was to assess the impact of postchemotherapy nausea and vomiting (PCNV) after moderately emetogenic chemotherapy on health-related quality of life (HRQOL) in patients with cancer being treated in a routine clinical practice setting. The European Organization for Research and Treatment in Cancer (EORTC) Quality of Life Questionnaire (QLQ-C30) was administered on day 2 and day 6 following moderately emetogenic chemotherapy to 119 patients with a variety of cancers. Patients kept daily diaries to record the occurrence and severity of nausea and vomiting. The QLQ-C30 questions were modified, for this study only, to assess the impact of nausea and vomiting on HRQOL in patients who experienced nausea and/or vomiting during the six days following chemotherapy. Those patients who experienced either nausea or vomiting experienced a decrease in HRQOL from prechemotherapy levels on six functioning and five symptom scales at day 2, and on four functioning and four symptom scales on day 6. Comparison of mean scores between the unmodified QLQ-30 and the nausea and vomiting versions demonstrated that the HRQOL rating attributed to nausea and vomiting accounted for much, but not all, of the deterioration in HRQOL scores in patients who experienced these symptoms. It can be concluded that patients who experience PCNV experience a significant negative impact on their HRQOL and that this impact can be attributed in large part to their experience of nausea and vomiting. However, since not all of the deterioration is attributable to these symptoms, other reasons for some of the decrease in HRQOL must also be identified in future studies.

Use of dexamethasone and granisetron in the control of delayed emesis for patients who receive highly emetogenic chemotherapy. National Cancer Institute of Canada Clinical Trials Group.

PURPOSE: To evaluate the roles of granisetron and dexamethasone for emesis control on days 2 through 7 after the administration of cisplatin in doses of 50 mg/m2 or greater to patients who had not previously received chemotherapy. PATIENTS AND METHODS: Four hundred thirty-five eligible and assessable patients were randomized to one of two arms in a double-blind fashion: arm A; granisetron 3 mg intravenous (i.v.) plus dexamethasone 10 mg i.v. prechemotherapy followed by granisetron 1 mg orally at 6 and 12 hours, then granisetron 1 mg orally and dexamethasone 8 mg orally twice daily on days 2 through 7 (219 patients); arm B; as in arm A but with placebo substituted for granisetron on days 2 through 7 (216 patients). All patients completed diaries in which episodes of emesis and severity of nausea were recorded. RESULTS: The addition of granisetron on days 2 through 7 had no discernable impact on nausea and vomiting during this period. CONCLUSION: The administration of a 5-hydroxytryptamine3, receptor (5-HT3) antagonist, in this case granisetron, after 24 hours conferred no benefit. This negative result needs to be assessed in light of conflicting literature, but at present it does not appear that the routine use of these drugs in this setting is justified.

Dexamethasone improves the efficacy of granisetron in the first 24 h following high-dose cisplatin chemotherapy.

The object of the study was to determine whether dexamethasone improved the efficacy of the serotonin receptor (5-HT3) antagonist granisetron in controlling acute (within 24 h) emesis in cancer patients receiving high-dose cisplatin chemotherapy and to ascertain whether continuation of granisetron after 24 h reduces the occurrence of delayed emesis. This randomised, double-blind, multicentre, three-arm study was conducted at 21 medical centres. A group of 292 nausea- and emesis-free patients with cancer, who had never had chemotherapy and were scheduled to receive at least 50 mg/m2 cisplatin, were given 3 mg granisetron i.v. in a 15-min infusion with or without 10 mg dexamethasone i.v. completed 5 min prior to high-dose cisplatin and 1 mg granisetron p.o. at +6 h and +12 h. Primary study end-points were control of emesis and nausea. Patients completed a self-report diary every 6 h for the first 24 h. At the end of the 24-h period, the patients who received dexamethasone had a significantly higher complete protection rate from emesis (64% compared to 39%) than those who received no steroid. Similarly, the dexamethasone-treated group had a significantly higher complete plus partial (0-2 emetic episodes) protection rate (84% compared to 64%). This study shows that dexamethasone markedly enhances the antiemetic efficacy of granisetron for acute-onset emesis in high-dose cisplatin chemotherapy.

The importance of dose scheduling with mitoxantrone, 5-fluorouracil and leucovorin in metastatic breast cancer.

We have studied a mitoxantrone, 5-fluorouracil (5-FU) and leucovorin chemotherapy regimen in metastatic breast cancer. 8 patients received mitoxantrone 10 mg/m2 on day 1, leucovorin 200 mg/m2 and 5-FU 300 mg/m2 on days 1-5 by intravenous bolus every 28 days in a pilot study. Grades 3-4 granulocytopenia followed 55% of the courses, with 2 patients admitted for febrile neutropenia. Only a 29% objective response rate was seen in a subsequent phase II trial using reduced mitoxantrone doses. Comparison with other trials suggested that 5-day bolus 5-FU administration adversely affects the combination's therapeutic index.

Ondansetron compared with dexamethasone and metoclopramide as antiemetics in the chemotherapy of breast cancer with cyclophosphamide, methotrexate, and fluorouracil.

BACKGROUND: Although ondansetron was found to be effective as an antiemetic in numerous clinical trials of highly emetogenic combination-chemotherapy regimens that included cisplatin, its role in milder emetogenic regimens has not been fully defined. To address its use with a widely used but less emetogenic regimen, we performed a double-blind, randomized clinical trial comparing ondansetron with dexamethasone and metoclopramide in patients with breast cancer receiving chemotherapy with cyclophosphamide, methotrexate, and fluorouracil. METHODS: A total of 165 women with breast cancer from 14 Canadian centers who were about to receive this chemotherapy for the first time were randomly assigned to receive either ondansetron (n = 85) or dexamethasone plus metoclopramide (n = 80), a widely used, standard antiemetic regimen. The patients recorded the incidence of nausea, emesis, and other side effects in diaries, and these data were compared in the two groups. RESULTS: The patients who received dexamethasone and metoclopramide had significantly less nausea during the first 24 hours after chemotherapy was begun. Otherwise, there were no statistically significant differences in efficacy between the regimens. The incidence of drowsiness and increased appetite was higher in the group given dexamethasone and metoclopramide. CONCLUSIONS: For women with breast cancer who are being treated with cyclophosphamide, methotrexate, and fluorouracil, the efficacy of dexamethasone and metoclopramide in controlling nausea and vomiting equaled or exceeded that of ondansetron.

Combined modality therapy of Hodgkin's disease: 10-year results of National Cancer Institute of Canada Clinical Trials Group multicenter clinical trial.

The purpose of this study was to compare four methods of treatment for stage III-IV Hodgkin's disease. Between January 1972 and September 1976, 266 patients with stage IIIB, IVA, and IVB Hodgkin's disease from 21 cancer treatment centers across Canada were registered as eligible; 40 were found to be ineligible. Of the 226 remaining patients, only seven were followed for less than 10 years. All patients received three courses of mechlorethamine, vincristine, procarbazine, and prednisone (MOPP) chemotherapy, which induced a complete response (CR) in 36%; an additional 42% obtained adequate disease control. Patients were randomly assigned to (1) treatment with radiation to the abdomen and mantle (group AX3, 62 patients) or (2) continue their treatment with an additional three courses of MOPP (group A, 105 patients). For the A group, a second randomization took place 3 months later (regardless of status at that time) to (1) no further treatment (AC6, 23 patients), (2) radiotherapy to the abdomen and mantle (AX6, 48 patients), or (3) maintenance chemotherapy at 3-month intervals for 1 year (AC10, 26 patients). The survival of AX3 patients was somewhat better than for the A group, but the difference was not significant (P = .0565). However, there was a significant interaction (P = .0029) between age and treatment, so that among patients less than 30 years of age, the survival of the A group was better, whereas for older patients, treatment with AX3 resulted in improved survival. Age itself remained a significant prognostic factor for survival after controlling for the amount of radiotherapy delivered to the abdomen and the dose intensity of vincristine for the first three courses of chemotherapy. The addition of radiation therapy to MOPP significantly reduced the frequency of nodal relapses. These results suggest that combined modality therapy may be beneficial for some patients with Hodgkin's disease and that age must be carefully considered in interpreting the results of clinical trials in Hodgkin's disease.

Influence of ethanol on hepatic glutathione content and on the activity of glutathione S-transferases and epoxide hydrase in the rat.

Chronic ethanol administration to female rats for 3 weeks was associated with a 60% increase in liver microsomal cytochrome P-450 content. This effect was accompanied by a similar increase in microsomal epoxide hydrase activity, in the presence of styrene oxide, and by significant increases in liver glutathione concentration and cytosolic glutathione S-transferase activities. A time-course study showed that the elevation of liver glutathione concentration seen after 3 weeks of ethanol consumption was a transient phenomenon, not observed after prolonged (23 weeks) ethanol intake and preceded, in the first 10-12 days of ethanol administration, by a decrease below control levels. The latter occurred at a time when the cytochrome P-450 content and the activity of glutathione S-transferases reached maximal increases to levels twice as high as those seen from 3 to 23 weeks of ethanol consumption. These observations show that chronic ethanol consumption may thus affect the hepatotoxicity of xenobiotics susceptible to cytochrome P-450-dependent bioactivation by influencing both this pathway and those involved in the inactivation of reactive metabolites. They also suggest that vulnerability of the liver to such hepatotoxins may be influenced by the duration of exposure to ethanol.

The oxidation of a steroidal bromohydrin revisited.

A comparative study was made of the reactions of 5-bromo-3 beta, 6 beta-dihydroxy-5 alpha-androstan-17-one 3-acetate (1) with lead tetraacetate alone and in the presence of iodine in both high intensity visible light and in total darkness using a variety of solvents. Markedly different product profiles were obtained under the different reaction conditions, making our results of both practical importance and theoretical interest.

Effect of family size and mother's longevity.

A prospective study of the mother's longevity and of her completed family size has been conducted on the basis of historical demographic records. We show that 1 to 5 pregnancies is associated with the greatest longevity in weakly inbred women and 11 pregnancies is associated with greatest longevity in more inbred women. Taking into account maternal inbreeding, completely sterile women and those who had a large number of pregnancies have an equal mean longevity. It is suggested that repeated pregnancies produce a cumulative hormonal effect, the distribution of which, following family size, should be bell-shaped.

PIP: A prospective study of the relationship between mother's longevity and her completed family size was undertaken using historical demographic records from the rural population of Isle-aux-Coudres, Quebec, where, because of its small size, entire civil records had been collected since colonization in 1728. The basic hypothesis was that a woman who had undergone the strains of childbirth and fully recovered would, at the end of her reproductive life, be stronger the more pregnancies she had had; i.e., that stress strengthened the organism. Consequently, longevity would increase as a function of the number of pregnancies. It was assumed, however, that there was no reason to believe that the relationship between family size and longevity would necessarily be linear. Rather, an optimal number of pregnancies was assumed, afterwhich number was reached maternal longevity would decrease. The curve expressing the overall relationship would, then, have the appearance of a bell shape. The women in the sample were all born between 1800-1880, were all dead at the time of the study, had all lived to be at least 47, all had husbands alive when they reached 47, were all married only once, and had exact birth dates known for each child. After a 2nd elimination process involving birth interval information, the sample size was reduced to 119. Secular trends in longevity and family size were accounted for. The curve depicting mean longevity per family size was bimodal suggesting there were 2 groups of women differentiated by number of children, i.e., 0-8 and 9-15. Mean inbreeding coefficients were obtained for both groups of mothers to clarify the situation. Indications were that 1-5 pregnancies were associated with the greatest longevity for slightly inbred women, and 11 pregnancies were associated with the greatest longevity in more inbred women. Taking maternal inbreeding into account, completely sterile women and those who had a large number of pregnancies had an equal mean longevity.