V. Girre

Management of breast cancer in elderly individuals: recommendations of the International Society of Geriatric Oncology.

Breast cancer is the most commonly diagnosed cancer and the leading cause of cancer mortality in women worldwide. Elderly individuals make up a large part of the breast cancer population, and there are important specific considerations for this population. The International Society of Geriatric Oncology created a task force to assess the available evidence on breast cancer in elderly individuals, and to provide evidence-based recommendations for the diagnosis and treatment of breast cancer in such individuals. A review of the published work was done with the results of a search on Medline for English-language articles published between 1990 and 2007 and of abstracts from key international conferences. Recommendations are given on the topics of screening, surgery, radiotherapy, (neo)adjuvant hormone treatment and chemotherapy, and metastatic disease. Since large randomised trials in elderly patients with breast cancer are scarce, there is little level I evidence for the treatment of such patients. The available evidence was reviewed and synthesised to provide consensus recommendations regarding the care of breast cancer in older adults.

Use of Geriatric Assessment for Older Adults in the Oncology Setting: A Systematic Review

Background Geriatric assessment is a multidisciplinary diagnostic process that evaluates the older adult’s medical, psychological, social, and functional capacity. No systematic review of the use of geriatric assessment in oncology has been conducted. The goals of this systematic review were: 1) to provide an overview of all geriatric assessment instruments used in the oncology setting; 2) to examine the feasibility and psychometric properties of those instruments; and 3) to systematically evaluate the effectiveness of geriatric assessment in predicting or modifying outcomes (including the impact on treatment decision making, toxicity of treatment, and mortality). Methods We searched Medline, Embase, Psychinfo, Cinahl, and the Cochrane Library for articles published in English, French, Dutch, or German between January 1, 1996, and November 16, 2010, reporting on cross-sectional, longitudinal, interventional, or observational studies that assessed the feasibility or effectiveness of geriatric assessment instruments. The quality of articles was evaluated using relevant quality assessment frameworks. Results We identified 83 articles that reported on 73 studies. The quality of most studies was poor to moderate. Eleven studies examined psychometric properties or diagnostic accuracy of the geriatric assessment instruments used. The assessment generally took 10–45min. Geriatric assessment was most often completed to describe a patient’s health and functional status. Specific domains of geriatric assessment were associated with treatment toxicity in 6 of 9 studies and with mortality in 8 of 16 studies. Of the four studies that examined the impact of geriatric assessment on the cancer treatment decision, two found that geriatric assessment impacted 40%–50% of treatment decisions. Conclusion Geriatric assessment in the oncology setting is feasible, and some domains are associated with adverse outcomes. However, there is limited evidence that geriatric assessment impacted treatment decision making. Further research examining the effectiveness of geriatric assessment on treatment decisions and outcomes is needed.

Pharmacokinetics and toxicity of docetaxel: Role of CYP3A, MDR1, and GST polymorphisms

Patients initiating docetaxel chemotherapy were genotyped for CYP3A4, CYP3A5, MDR1, GSTM1, GSTT1, GSTM3, and GSTP1 to identify variability factors of docetaxel pharmacokinetics and toxicity.

Phase I evaluation of seliciclib (R-roscovitine), a novel oral cyclin-dependent kinase inhibitor, in patients with advanced malignancies

AIM Phase I study of seliciclib (CYC202, R-roscovitine), an inhibitor of cyclin-dependent kinases 2, 7 and 9, causing cell cycle changes and apoptosis in cancer cells. PATIENTS AND METHODS This phase I trial aimed at defining the toxicity profile, the maximum tolerated dose (MTD), the recommended phase II dose (RD) and the main pharmacokinetic and pharmacodynamic parameters of oral seliciclib. Three schedules were evaluated: seliciclib given twice daily for 5 consecutive days every 3 weeks (schedule A), for 10 consecutive days followed by 2 weeks off (schedule B) and for 3d every 2 weeks (schedule C). RESULTS Fifty-six patients received a total of 218 cycles of seliciclib. Dose-Limiting Toxicities (DLT) consisting of nausea, vomiting, asthenia and hypokalaemia occurred at 1600 mg bid for schedule A and in schedule C, DLT of hypokalaemia and asthenia occurred at 1800 mg bid. The evaluation of longer treatment duration in schedule B was discontinued because of unacceptable toxicity at lower doses. Other adverse events included transient serum creatinine increases and liver dysfunctions. Pharmacokinetic data showed that exposure to seliciclib and its carboxylate metabolite increased with increasing dose. Soluble cytokeratin 18 fragments allowed monitoring of seliciclib-induced cell death in the blood of patients treated with seliciclib at doses above 800 mg/d. One partial response in a patient with hepatocellular carcinoma and sustained tumour stabilisations were observed. CONCLUSIONS The MTD and RD for seliciclib are 1250 mg bid for 5d every 3 weeks and 1600 mg bid for 3d every 2 weeks, respectively.

Survival of breast cancer patients with meningeal carcinomatosis

BACKGROUND Breast cancer is the leading nonhematologic cause of meningeal carcinomatosis (MC). The aim of this study was to report the outcome of patients diagnosed with breast cancer MC and treated in single institution by a high-dose intrathecal methotrexate (MTX) regimen. METHODS Ninety-one patients were diagnosed with breast cancer MC from 2000 to 2007. Intrathecal treatment was MTX 15 mg/day (days 1-5), hydrocortisone acetate (day 1) and oral folinic acid (days 1-5), repeated every 2 weeks. Patients and tumor characteristics were associated with the early clinical and biological outcome and with the overall survival (OS). RESULTS The median survival was 4.5 months (range 0-53). In multivariate analysis, adverse prognostic factors at diagnosis were performance status >2 [P = 0.006, response rate (RR) = 0.33 (0.15-0.71)], more than three chemotherapy regimens before MC diagnosis [P = 0.03, RR = 0.40 (0.19-0.93)], negative hormone receptor status [P = 0.02, RR = 0.4 (0.19-0.90)] and high Cyfra 21-1 level [P = 0.048, RR = (0.09-0.99)]. Clinical progression after one cycle and biological response after two cycles were independently associated with OS [P < 0.001, RR = 0.09 (0.02-0.37) and P = 0.003, RR = 3.6 (1.5-8.5), respectively]. We propose a prognostic score in order to define three distinct groups of prognosis. CONCLUSIONS MC presents a poor prognosis, but 1-year survival rate was 25%. This score may become a useful tool for treatment decision and clinical trials.

Phase II multicenter study of larotaxel (XRP9881), a novel taxoid, in patients with metastatic breast cancer who previously received taxane-based therapy

BACKGROUND Treatment options are limited for patients with refractory metastatic breast cancer (MBC). Larotaxel (XRP9881) is a novel taxoid with preclinical activity against taxane-resistant breast cancer. The current phase II trial of larotaxel was conducted in women with taxane-treated MBC. PATIENTS AND METHODS Patients were stratified by response to prior taxane therapy (resistant or nonresistant). Larotaxel 90 mg/m(2) was administered as a 1-h infusion every 3 weeks. Patients were evaluated for tumor response every two cycles. A blinded external response review committee determined the overall response rate (ORR), duration of response (DOR), and time to progression (TtP) of the disease. Median survival time (MST) and safety were also evaluated. RESULTS One hundred and thirty patients were treated. In the nonresistant group, the ORR was 42%; median DOR 5.3 months; median TtP 5.4 months; and MST 22.6 months. In the resistant group, the ORR was 19%; median DOR 5.0 months; median TtP 1.6 months; and MST 9.8 months. The most common grade 3/4 adverse events were neutropenia (82%), fatigue (15%), diarrhea (12%), febrile neutropenia (9%), neutropenic infection (8%), and sensory neuropathy (7%). CONCLUSIONS Larotaxel has good activity, manageable toxicity, and a favorable therapeutic index in women with taxane-pretreated MBC.

Cabazitaxel in patients with advanced solid tumours: results of a Phase I and pharmacokinetic study.

BACKGROUND Although the taxanes paclitaxel and docetaxel are among the most active agents for the treatment of a wide range of cancers, tumours often develop resistance to these treatments. Cabazitaxel is a novel taxane active in both preclinical models of chemotherapy-sensitive and -resistant human tumours and patients with advanced prostate cancer that progressed following docetaxel treatment. AIM To establish the maximum tolerated dose (MTD) and dose-limiting toxicities (DLTs) of cabazitaxel. PATIENTS AND METHODS Cabazitaxel was administered every 3 weeks to patients with advanced solid tumours. The design allowed intrapatient dose escalation. The primary objective was to determine the MTD. Secondary objectives were to describe the safety profile, establish an appropriate dose, determine the pharmacokinetic (PK) profile of cabazitaxel, and assess antitumour activity. RESULTS Twenty-one patients were recruited. The MTD was reached at 30 mg/m(2), at which three of five patients experienced haematologic DLTs during the first cycle. DLTs during subsequent cycles were mainly haematologic and reported at 25 and 30 mg/m(2) dosing levels. Nail disorders and severe alopecia were not reported, and neurotoxicity, fluid retention and hypersensitivity were mild and infrequent. Cabazitaxel demonstrated linear PK, a triphasic elimination profile, with a long half-life and high clearance. Of the 19 patients evaluable for response, one unconfirmed partial response and six occurrences of stable disease were reported. CONCLUSIONS The 25mg/m(2) dose of cabazitaxel was recommended for use in future clinical studies. In this study, cabazitaxel had an acceptable tolerability profile and activity in cervical, colorectal, endometrial and lung cancers.

Does frailty predict hospitalization, emergency department visits, and visits to the general practitioner in older newly-diagnosed cancer patients? Results of a prospective pilot study

Research on the use of health care by older newly-diagnosed cancer patients is sparse. We investigated whether frailty predicts hospitalization, emergency department (ED) and general practitioner (GP) visits in older cancer patients in a prospective pilot study. Newly-diagnosed cancer patients aged 65 years and over were recruited in the Segal Cancer Centre, Jewish General Hospital, Montreal, Canada. One hundred ten patients participated, mean age 74.1, 70% women. During 1 year follow-up, 52 patients (47.3%) had cancer-related hospitalizations, 23 patients (20.9%) had ED visit and 17 patients (15.5%) had GP visit. No frailty marker predicted hospitalization or visits to the GP. Cognitive impairment suspicion was the only frailty marker that predicted ED visits (odds ratio 4.97; 95%CI 1.14-21.69). Although health care use was considerable in this sample, most frailty markers were not associated with health care use in this pilot study.

Cost-Effectiveness Analysis of Trastuzumab (Herceptin) in HER2-Overexpressed Metastatic Breast Cancer

Objective:In women with Human Epidermal growth Receptor 2 (HER2)-positive metastatic breast cancer (MBC), Trastuzumab has become the standard of care but previous studies have raised doubts about its economic acceptability. We carried out the first cost-effectiveness study for Trastuzumab in MBC patients, in France, that is based on observed resource use and outcomes in clinical practice. Methods:We retrospectively analyzed 47 HER2-positive MBC patients in a before-and-after design study. Nineteen patients did not receive Trastuzumab (“before” Trastuzumab introduction in clinical practice) and 28 patients received Trastuzumab (the “after” population). Direct medical costs were estimated on the basis of the physical quantities reported in the patient medical records, for the period from first metastatic progression until death or date of patient last news. Monetary values (2002 French francs) were attributed to these quantities on the basis of unit costs and incremental cost-effectiveness ratios were calculated. Results:In the Trastuzumab group, median overall survival was significantly higher (37 months vs. 19 months in the non-Ttrastuzumab group, P = 0.001) but total treatment costs were 3 times higher (&U20AC;39,608 vs. &U20AC;12,795). The cost per additional life-year saved by Trastuzumab treatment was estimated to be &U20AC;27,492 (95% confidence interval: &U20AC;20,964-&U20AC;34,020/year of life [bootstrapped estimation]). Conclusions:Our data suggest that despite its high unit price, Trastuzumab should be considered cost-effective in MBC patients to the extent that its incremental cost per life-year saved remains lower than gross domestic product per capita in countries like France.

Potential drug interactions in elderly cancer patients

INTRODUCTION Drug interaction constitutes a major challenge in elderly cancer patients. This study investigated the number and types of medications patients and potential drug interactions in these patients. METHODS Treatments received by 105 cancer outpatients aged ≥70 years were analyzed using the French Thesaurus to identify drug-drug interactions according to four levels: contraindication, concomitant use not recommended, concomitant medications requiring precautions and concomitant medications to be taken into account. RESULTS The mean number of medications per patient was 4.7 (range: 0-14). Among 97 patients taking ≥2 drugs, 45 potential interactions were identified, occurring in 32 patients. No contraindication, 2 cases of concomitant use not recommended, 9 cases requiring precautions (20%) and 34 cases of concomitant medications to be taken into account were identified. Drug interactions caused respiratory distress and increased bleeding risk. CONCLUSION Drug interactions are common in the elderly, but almost half of interactions were moderate.