Analysis of the StoRM cohort reveals physical activity to be associated with survival in metastatic breast cancer.

Benefits of physical activity are widely demonstrated for early stage cancers but few studies have focused on metastatic disease. The purpose of this study was to determine the impact of physical activity on survival in patients with metastatic breast cancer. We conducted a secondary analysis of the national, multicentric, non-randomized, prospective cohort SNPs to Risk of Metastasis (StoRM) study. The level of physical activity was self-reported at inclusion and divided into three categories of physical activity: light level, moderate level, and vigorous level. Overall, 833 patients (56.2%) completed the physical activity questionnaire at baseline on average physical activity during the previous year: 11.6% had a light level of physical activity, 69.0% achieved moderate levels of physical activity and 19.3% reported vigorous levels of physical activity. After adjustment for confounding, physical activity was not statistically significantly associated with overall survival in the whole population. Subgroup analysis identified that both vigorous and moderate physical activity were associated with statistically significantly improved overall survival compared to light physical activity level only in the HER2 positive subgroup (HR 0.23; 95% CI 0.07-0.70, p = 0.01 and HR 0.38; 95% CI 0.15-0.96, p = 0.04). Physical activity done during the previous year was associated with survival in HER2 positive metastatic breast cancer patients. These results suggest that overall survival in metastatic breast cancer patients could be improved through physical activity which should be considered as a complementary intervention for these individuals. The study showed that moderate/vigorous levels of physical activity were associated with better overall survival, and that these associations remained statistically significant in multivariate analysis in the HER2 positive subgroup. These results have clinical relevance and justify the recommendations for physical activity interventions in metastatic breast cancer.

Prevention of 5-fluorouracil-induced early severe toxicity by pre-therapeutic dihydropyrimidine dehydrogenase deficiency screening: Assessment of a multiparametric approach.

5-Fluorouracil (5-FU)-based treatments can lead to early-onset severe (4%-5%) even fatal (0.3%) toxicities in patients with dihydropyrimidine dehydrogenase (DPD) deficiency. This multicenter prospective cohort study aimed to assess the clinical benefit of pretherapeutic screening for DPD deficiency using a multiparametric approach. Two parallel cohorts of patients treated with 5-FU-based chemotherapy for colorectal carcinoma were compared in a prospective nonrandomized study. In arm A, patients had DPD deficiency screening before treatment, whereas in arm B no pretherapy screening was performed. Dosing was based on 5-FU administration guidelines of each institution. DPD deficiency screening was performed using a combined multiparametric approach (5-FUODPM Tox). The frequency of early grade 4-5 toxic events potentially induced by 5-FU was compared in the two groups. At total of 1,142 patients (n = 1,116 evaluable) were enrolled. In arm A, out of 718 evaluable patients, nine grade 4 early toxicities potentially related to 5-FU were reported in nine patients (1.2%) with no toxic death despite one complete DPD deficiency and 24 partial deficiencies. The 24 patients with partial deficiency had safe pharmacokinetics (PK)-monitored 5-FU. In arm B, among 398 evaluable patients, 17 grade 4-5 toxic early events potentially related to 5-FU were reported in 12 patients (4.2%). The incidence of early severe toxicity was significantly higher in arm B (P = .0019), confirming the positive impact of pretherapeutic DPD assessment. The percent of patients with a toxicity grade 3 or higher observed in arm A was 10.8% (n = 78) compared to 17.55% (n = 69)  in arm B (P = .0497). The percentage of death was reduced from 2.5/1,000 in arm B to 0 in arm A. The time to occurrence of all grade ≥3 toxicities was determined in both arms and the difference between the two arms was significant (P = .047). Overall, one patient with complete DPD deficiency confirmed retrospectively died within 13 days from grade 5 multivisceral toxicity. Enrollment was prematurely closed after external experts' decision. In conclusion, multiparametric pretherapeutic DPD deficiency screening significantly lowered the risk of early severe toxicity and avoided an early toxic death. This approach should be used for safe administration of 5-FU-based treatments.

Safety and efficacy of single-agent bevacizumab-containing therapy in elderly patients with platinum-resistant recurrent ovarian cancer: Subgroup analysis of the randomised phase III AURELIA trial.

BACKGROUND: The AURELIA trial demonstrated significantly improved progression-free survival (PFS) with bevacizumab added to chemotherapy for platinum-resistant ovarian cancer (PROC). METHODS: Patients with PROC were randomised to receive investigator-selected single-agent chemotherapy alone or with bevacizumab. Post-hoc exploratory analyses assessed efficacy, safety and patient-reported outcomes according to age <65 versus ≥65years. RESULTS: In the 133 patients (37%) aged ≥65years, baseline hypertension was more frequent and ascites was less common than in patients <65years. The magnitude of PFS benefit from bevacizumab was similar in patients ≥65 versus <65years (hazard ratio 0.44 [95% CI, 0.31-0.64] versus 0.49 [95% CI, 0.37-0.64], respectively, treatment-age interaction p=0.58), with similar improvements in response rates. Grade≥3 hypertension was more common with bevacizumab than chemotherapy alone in both subgroups, and more common in older than younger patients irrespective of treatment. However, there was no excess of other adverse events of specific interest for bevacizumab, including venous thromboembolic events, in older patients. More patients receiving bevacizumab in the younger but not the older subgroup showed improved gastrointestinal/abdominal symptoms. CONCLUSION: In exploratory analyses, PFS and response rate improvement with bevacizumab were consistent in older and younger patients. Grade≥3 hypertension was more common in elderly bevacizumab-treated patients; careful monitoring is recommended. Overall, bevacizumab-containing therapy was well tolerated in a selected population aged ≥65years, suggesting a favourable benefit:risk profile. However, geriatric assessments are needed to improve selection of elderly patients potentially gaining symptom and quality of life improvements from bevacizumab-containing therapy. CLINICAL TRIALS REGISTRATION: ClinicalTrials.govNCT00976911.

A phase I/II trial of the safety and clinical activity of a HER2-protein based immunotherapeutic for treating women with HER2-positive metastatic breast cancer.

The objectives of this phase I/II study (NCT00140738) were to evaluate the safety and clinical activity of a cancer immunotherapeutic agent (recombinant HER2 protein (dHER2) and the immunostimulant AS15) in patients with HER2-overexpressing metastatic breast cancer (MBC). Forty HER2-positive MBC patients received up to 18 doses (12q2w, 6q3w) of dHER2 immunotherapeutic, as first- or second-line therapy following response to trastuzumab-based treatment as maintenance. Toxicity was graded by the Common Terminology Criteria for Adverse Events (CTCAE) and clinical activity was evaluated by target lesion assessment according to the Response Evaluation Criteria in Solid Tumors (RECIST). Immunogenicity was assessed. The dHER2 immunotherapeutic was well tolerated: grade 1/2 adverse events (AEs) were most common. No cardiac events were observed and one patient experienced an asymptomatic decrease of left ventricular ejection fraction below the normal range (47 %). Both humoral and cellular immunogenicity to the dHER2 antigen was observed. No patient discontinued the immunizations because of AEs but 35/40 withdrew prematurely, 34 because of disease progression (24/34 before or at the tumor assessment after dose 6). One patient achieved a complete response lasting 11 months and one patient had a partial response lasting 3.5 months. Ten patients experienced stable disease ≥26 weeks with 4/10 still in stable disease at the last tumor assessment after 47 weeks. Immunization of MBC patients with the dHER2 immunotherapeutic was associated with minimal toxicity and no cardiac events. Clinical activity was observed with two objective responses and prolonged stable disease for 10/40 patients.

Safety of subcutaneous clodronate and efficacy in hypercalcemia of malignancy: a novel route of administration.

Bisphosphonates have become standard treatment in management of malignancy-induced hypercalcemia and malignant bone pain. One obstacle to the routine use of bisphosphonates in palliative patients is that oral bisphosphonates have low bioavailability and a degree of gastrointestinal toxicity that may explain poor compliance. Intravenous administration can be cumbersome in patients admitted to long-term care settings or at home. We have developed and tested a new way of administering clodronate via subcutaneous infusion. This retrospective cohort study evaluated 150 patients admitted to a tertiary palliative care unit from May 1996 to May 2000 who received 254 subcutaneous infusions of clodronate for hypercalcemia or bony complications. Data were collected by chart review and specifically evaluated site toxicity and biochemistry. There was minimal local toxicity and only 2 infusions needed to be discontinued because of pain at the subcutaneous site. Clodronate showed efficacy in normalizing the serum calcium within 5 days post-infusion in 32 of 43 infusions given for hypercalcemia. This study shows that subcutaneous clodronate is safe and can lower serum calcium levels in malignant hypercalcemia.

[Bisphosphonates, pain and quality of life in metastatic breast cancer patients: a literature review]. / Bisphosphonates, douleurs et qualité de vie dans le cancer du sein métastatique : une revue de la littérature.

Bisphosphonates constitute the standard treatment for cancer hypercalcemia and prevention of complications of metastatic bone disease. Various clinical endpoints have been used to evaluate the impact of bisphosphonates on bone metastases. This literature review is focused on the analgesic effect of bisphosphonates and their impact on quality of life (QoL) in patients with bone metastases from breast cancer. Twenty-five randomized trials studying bisphosphonates with pain and/or QoL as primary or secondary endpoints were considered. These studies were analyzed with following criterias : study type, primary cancer, drug scheduling, number of patients included, associated specific treatment, primary and secondary endpoints, pain assessment, and QoL assessment. The results are in favor of an efficacy of bisphosphonates in bone pain, even when not always statistically significant and with an important variability in assessment criterias and tools. QoL assessment with validated, reliable scales (EORTC QLQ-C30, Rotterdam Symptom Checklist...) has been performed in 9 studies. The use of bisphosphonates with systemic and radiation therapy increases QoL or reduces QoL deterioration. Despite some methodological limitations, these studies indicate a beneficial effect on bone pain, and an improvement in the QoL of patients with metastatic bone disease of breast cancer. Because of a lack of systemic data, reliable analysis of the results is difficult. Several questions remain open about which bisphosphonates and route of administration to choose, and the variable effects on different primaries.

When midazolam fails.

Significant distress is experienced by patients, families, and caregivers when a symptom or disorder, such as an agitated delirium, becomes an intractable, or a catastrophic event, such as irreversible stridor. When palliative sedation is indicated for these patients, midazolam is usually the preferred drug. In some cases, however, midazolam fails to provide adequate sedation. Two cases are presented to illustrate this phenomenon and explore the possible mechanisms underlying this lack of response. These mechanisms appear to be multifaceted. The heterogeneity of the GABA(A) receptor complex and the alterations that this complex can undergo functionally can explain, to some degree, the diversity of the physiological and pharmacological outcomes. Other factors responsible for the diversity in response may include concomitant medications, age, concurrent disease, overall health status, alcohol use, liver disease, renal disease, smoking and hormonal status. Evidence-based guidelines on alternative treatment options should midazolam fail are required. In the interim, a lower threshold for adding an alternative drug, such as phenobarbital, or substituting midazolam with another drug, such as propofol, should be considered in these circumstances.