Prophylaxis of catheter-related deep vein thrombosis in cancer patients with low-dose warfarin, low molecular weight heparin, or control: a randomized, controlled, phase III study.

PURPOSE: Whether an anticoagulant prophylaxis is needed for patients with cancer with a central venous catheter is a highly controversial subject. We designed a study to compare different prophylactic strategies over 3 months of treatment. METHODS: We performed a phase III prospective, open-label randomized trial. After the insertion of a central venous access device, consecutive patients with planned chemotherapy for cancer were randomized to no anticoagulant prophylaxis, low molecular weight heparin [low molecular weight heparin (LMWH); with isocoagulation doses], or warfarin 1 mg/day. Treatments were given over the first 3 months. Doppler ultrasound and venographies were performed on days 1 and 90, respectively, or sooner in case of clinical presumption of thrombosis. RESULTS: A total of 420 patients were randomized, and 407 were evaluable. Forty-two catheter-related deep vein thrombosis (DVT) occurred (10.3 %), 20 in those with no anticoagulation, 8 in those receiving warfarin, and 14 in those receiving LMWH. Nine additional non-related catheter deep vein thrombosis (CDVT) occurred. Anticoagulation significantly reduced the incidence of catheter-related DVT (p = 0.035) and catheter non-related DVT (p = 0.007), with no difference between warfarin and LMWH. Safety was good (3.4 % of attributable events) but compliance with randomized prophylaxis was lower than expected. CONCLUSIONS: Prophylaxis showed a benefit regarding catheter-related and non-catheter-related DVT with no increase in serious side effects.

Effects of a home-based walking training program on cardiorespiratory fitness in breast cancer patients receiving adjuvant chemotherapy: a pilot study.

BACKGROUND: Breast cancer treatment is associated with a decline in measured cardiorespiratory fitness and increased fatigue. There is accumulating evidence that exercise training during adjuvant chemotherapy may contribute to prevent these changes. Additional studies are needed to explore the effectiveness of home-based walking interventions among this population. AIM: The aim of this study was to investigate the effects of a 12-week adapted home-based walking training program (WTP) on clinical rehabilitation in breast cancer patients receiving adjuvant chemotherapy. DESIGN: This was a pilot study using a single-group design. SETTING: Unit Department of Physiology and Medical Oncology, Limoges University Hospital, France. POPULATION: Thirty-nine outpatients predominantly with stage II breast cancer. METHODS: Participants performed 3 home ambulatory aerobic walking sessions per week at 50-60% of their maximum heart rate for 12 weeks. Functional capacity was assessed with an incremental cardiopulmonary exercise test during which peak oxygen consumption (VO(2peak)) was measured. A six-minute walking test (6 MWT) was performed to evaluate physical function. The revised Piper Fatigue Scale (PFS-R) was used to measure self-reported fatigue. RESULTS: Thirty-four patients (87%) completed all study procedures. Per Protocol (PP) analysis indicated that VO(2peak) recorded both before and after a 12-week adapted home-based WTP increased significantly by 2.21 mL.kg-1.min-1 (P=0.008) and 6 MWT distance increased significantly by 42 m (P=0.04). PFS-R score increased by 0.4 points, but not significantly. CONCLUSION: In breast cancer patients receiving adjuvant chemotherapy, home-based WTP is feasible and associated with significant improvements in VO(2peak), with no significant effect on fatigue score. Larger randomized trials are necessary to confirm these findings.

Use of darbepoetin alfa in European clinical practice for the management of chemotherapy-induced anaemia in four tumour types: final data from the CHOICE study.

OBJECTIVES: The CHOICE study was a prospective, multicentre, observational study designed to assess levels of adherence in current clinical practice to the European product label and EORTC guidelines for the treatment of chemotherapy-induced anaemia (CIA) with darbepoetin alfa (DA). Here we present data split by tumour types: breast, colorectal, ovarian and lung. METHODS: Haemoglobin (Hb) levels and red blood cell transfusion requirements were evaluated among patients with solid tumours in 11 European countries. The primary outcome measure was the proportion of patients with a target Hb level of ≥10-≤12 g/dL. RESULTS: The full analysis set included 1887 patients (mean ± SD 62.4 ± 11.4 years); 1585 (84%) had a current disease stage of ≥3. Common chemotherapy regimens were non-platinum + non-taxane based (n = 696 [37%]) or platinum + non-taxane based (n = 660 [35%]). Breast cancer (n = 575): The mean ± SD Hb level at baseline was 9.9 ± 0.8 g/dL (n = 568). Target Hb level was reached by 187 (55%) patients. Colorectal cancer (n = 310): At baseline the mean ± SD Hb level was 9.8 ± 0.8 g/dL (n = 306). Target Hb level was reached by 107 patients (56%). Ovarian cancer (n = 301): The mean ± SD Hb level at baseline was 9.7 ± 0.8 g/dL (n = 294). Target Hb level was reached by 81 patients (44%). Lung cancer (n = 701): At baseline the mean ± SD Hb level was 9.8 ± 0.9 g/dL (n = 692). Target Hb level was reached by 142 patients (39%). SAFETY: Five severe or life-threatening adverse drug reactions were seen (three patients with breast cancer, one patient with colorectal cancer and one patient with ovarian cancer). LIMITATIONS: Potential bias could not be excluded due to the study's observational nature. CONCLUSIONS: This study demonstrates that the recommendations are adhered to in clinical practice, with the mean starting Hb level <10 g/dL irrespective of tumour type. Furthermore, DA is likely to be effective and well tolerated for the treatment of CIA in patients with breast, colorectal, ovarian or lung cancer.

A final analysis from the CHOICE study examining darbepoetin alfa use for chemotherapy-induced anaemia in current European clinical practice.

OBJECTIVES: The CHOICE study was a prospective, multicentre, observational study designed to assess the level of adherence in current clinical practice to the European product label and the EORTC guidelines for the treatment of chemotherapy-induced anaemia with darbepoetin alfa (DA). METHODS: Hb levels and red blood cell (RBC) transfusion requirements were evaluated among 1900 patients with solid tumours in 11 European countries. The primary outcome measure was the proportion of patients with a target Hb level of ≥10-≤12 g/dL after 9 weeks' DA treatment. RESULTS: The full analysis set (FAS) comprised 1887 patients (mean ± SD age 62.4 ± 11.4 years) divided into categories by baseline Hb < 9 g/dL (n = 281); 9-<10 g/dL (n = 770); 10-<11 g/dL (n = 695); ≥11 g/dL (n = 114). The proportion of patients who remained on the study at week 9 achieving the target Hb level was 37% (n = 60), 48% (n = 217), 54% (n = 210) and 38% (n = 23) in the subgroups with a baseline Hb level of <9 g/dL, 9-<10 g/dL, 10-<11 g/dL and ≥11 g/dL, respectively. In the <9 g/dL, 9-<10 g/dL, 10-<11 g/dL and ≥11 g/dL subgroups of the FAS, the number of patients maintaining Hb levels ≥10 g/dL after their first achievement of an Hb value of 10 g/dL was 95 (34%), 372 (48%), 476 (68%) and 87 (76%), respectively. The Kaplan-Meier percentages of patients who required an RBC transfusion from week 5 until end of treatment period were: 29%, 20%, 12% and 17% in the <9 g/dL, 9-<10 g/dL, 10-<11 g/dL and ≥11 g/dL subgroups, respectively. Kaplan-Meier percentages of patients reaching an Hb level of >13 g/dL were 10%, 9%, 21% and 29%, respectively. Potential bias could not be excluded due to the study's observational nature. CONCLUSIONS: DA initiation and target Hb ranges adhered to current guidelines in the majority of patients. Furthermore, this study demonstrates faster achievement of the target range and reduced transfusion requirements are associated with initiation of DA at Hb levels of 9-<10 g/dL and 10-<11 g/dL rather than <9 g/dL.

Current practice of darbepoetin alfa in the management of haemoglobin levels in cancer patients undergoing chemotherapy - data from the CHOICE study.

OBJECTIVE: To evaluate adherence to European Organisation for Research and Treatment of Cancer (EORTC) and European Summary of Product Characteristic (SmPC) guidance on recommended haemoglobin (Hb) values in routine clinical practice use of darbepoetin alfa (DA) in cancer patients internationally. METHODS: This multicentre, prospective, observational study assessed DA use in 11 European countries. This interim analysis (IA) included ∼1300 breast, colorectal, ovarian or lung cancer patients receiving DA during any chemotherapy cycle. Hb level and red blood cell (RBC) transfusion requirement data were collected. RESULTS: Of the 1290 patients (mean [SD] age 62.5 [11.1] years) included in this IA full analysis set, 499 had lung, 387 breast, 192 colorectal and 212 ovarian cancer. Mean baseline Hb levels were <10 g/dL. At week 9, 426 (33%) patients had a Hb level of 10-12 g/dL, 165 (13%) of >12 g/dL, 226 (18%) of <10 g/dL and 473 (37%) had missing Hb values. 54% of the 672 patients still on the study at week 9 with available Hb values had Hb values of 10-12 g/dL. For patients with a baseline Hb of <10 g/dL, the Kaplan-Meier (K-M) percentage of patients with Hb levels ≥10 g/dL from week 1 to end of treatment period (EOTP) was 86%. For these patients, the K-M% of patients with Hb levels >13 g/dL from week 1 to EOTP was 10%. The K-M% of patients requiring RBC transfusions from week 5 to EOTP was 26% for all patients. Seven patients reported treatment-related non-serious adverse drug reactions, four were thromboses. CONCLUSIONS: This IA suggests most patients were treated according to European SmPC guidance. Hb evolution during the study is consistent with data from clinical trials, implying DA is effective in increasing Hb levels in chemotherapy-induced anaemia patients. Hb levels >13 g/dL were infrequent. Limitations are related to the observational nature of this study.

Expression levels of thymidylate synthase, thymidylate phosphorylase and dihydropyrimidine dehydrogenase in head and neck squamous cell carcinoma: preliminary study.

INTRODUCTION: Pharyngo-laryngeal tumors classified as T3-4, N0-3, M0, are conventionally treated by mutilating surgery (total (pharyngo)-laryngectomy). Neo-adjuvant chemotherapy with 5-FU/platinum salt can be proposed in an attempt to preserve the larynx. The level of the response to chemotherapy ranges from 36 to 54% of cases. Thus, a large number of patients receive chemotherapy that is ineffective and not free from adverse effects. Three main enzymes are involved in the metabolism of 5-FU: thymidylate synthase (TS), thymidylate phosphorylase (TP) and dihydropyrimidine dehydrogenase (DPD). Several studies suggest that a high level of expression of these three genes correlates with a poor clinical response to 5-FU. The main purpose of our study was to look for a correlation between the levels of expression of the genes for sensitivity to 5-FU (TS, TP, DPD) within the tumor and the clinical response observed after three courses of chemotherapy combining 5-FU/platinum salt in patients presenting with advanced cancer of the pharyngo-larynx. METHODS: This was a prospective genetic study that had required approval from the Ethics Committee. The main assessment criterion was based on the assessment of the clinical response by an ENT panendoscopy and a cervical CT scan, after three courses of chemotherapy. The expression of the genes was determined by quantitative RT-PCR, using total RNA extracted from tumor biopsies taken during the initial panendoscopy. RESULTS: The means calculated, in our study, for the three genes of interest (TS, TP, DPD) were lower in the responder group than those in the non-responder group. DISCUSSION: Our preliminary findings reveal trends that confirm the hypothesis that the lower the level of expression of the sensitivity genes, the better the clinical response to chemotherapy. They now form part of a larger study that is currently in progress.

Concomitant intensive chemoradiotherapy induction in non-metastatic inflammatory breast cancer: long-term follow-up.

The aim of this study was to evaluate with a long follow-up the efficacy of concomitant chemoradiotherapy in non-metastatic inflammatory breast cancer (IBC) and to evaluate the breast conservation rate. Between 1990 and 2000, 66 non-metastatic patients with IBC were treated with chemotherapy and concomitant irradiation. The induction chemotherapy consisted of epirubicine, cyclophosphamide and vindesine, in association with split-course bi-fractionated irradiation to a total dose of 65 Gy with concomitant cisplatin and 5-fluorouracil. Maintenance chemotherapy consisted of high-dose methotrexate and six cycles of epirubicine, cyclophosphamide and fluorouracil. Hormonal treatment was given if indicated. Mastectomy was not systemic. Among 65 evaluable patients, 57 (87.6%) achieved a complete clinical response and had a breast conservation. Only six loco regional relapses were noted in six patients with a delay of 20 months and with concomitant metastatic dissemination in four cases. Median disease-free survival (DFS) was 28 months. Median overall survival (OS) was 63 months and median follow-up was 55.5 months. Induction chemotherapy and concomitant irradiation is feasible in patients with IBC, permitting a breast conservation with a high rate of local control with an OS comparable to that of the best recent series.

Physical activity in the management of cancer-related fatigue induced by oncological treatments.

OBJECTIVE: We aimed to review the literature on physical activity in the management of cancer-related fatigue. MATERIALS AND METHODS: A search of PubMed for English- or French-language articles using the keywords fatigue, cancer, exercise, physical activity, sport, randomized, and controlled. RESULTS: We found reports of 11 randomized or controlled studies, all of them in English. Most involved small numbers of patients. Four of the studies reported that physical exercise had an effect on the fatigue: three a positive effect and one a negative effect. One of these four studies was carried out in patients still undergoing treatment (hormone therapy). Of the three post-treatment studies, the two finding positive effect involved breast cancer patients quite a while after the end of treatment (chemotherapy and/or radiotherapy), whereas the study finding a negative effect involved patients 1 month after treatment, all with chemotherapy. CONCLUSION: Physical activity appears to be a good way of combating fatigue induced by various cancer therapies. However, many questions remain, which highlights the need for randomized studies with sufficient numbers of patients.

[MRI evaluation of primary chemotherapy response in breast cancer]. / Evaluation par IRM de la réponse à la chimiothérapie d'induction dans les cancers du sein.

The aim of this work was to evaluate the value of contrast enhanced MRI for determination of response to neoadjuvant chemotherapy (type FEC) in breast cancer according to two parameters: size of the enhancing tumor and the maximum relative enhancement curve (MRC) in the same tumor area. Twenty women with breast cancer (15 invasive ductal carcinomas and 5 invasive lobular carcinomas) T2 (n = 8) or T3 (n = 12) were evaluated by physical examination and MRI after a minimal of three courses of FEC and prior to surgery. Data from physical examination and imaging studies were compared to histopathological findings. Physical examination estimated correctly the residual tumor size in 45% of cases and MRI in 60% with 3 false negative cases. Among evaluated patients with MRI measurable residual tumor, tumor size was underestimated in 69% of the cases and overestimated in 31% of the cases. A MRC flattening was observed in 5 cases among the patients with a partial response or clinical stable disease correlated with a poor cellular density in the microscopic findings. MRI monitoring of chemotherapy response can be useful for guiding surgery. Therefore, underestimation of the residual tumor size and false negative rate are remaining problems.

Pre-irradiation chemotherapy for newly diagnosed high grade astrocytoma.

The purpose of this work was to determine the response rate and toxicity of a combination of Carmustine and Cisplatin administered before radiation in patients with newly diagnosed high grade astrocytoma. A good response rate has been published with this association in primary cerebral high grade tumor. This protocol was administered in a homogeneous population of 37 adult patients with measurable tumor on magnetic resonance imaging (MRI) or CT scan. After biopsy or subtotal resection, the patients received BCNU 40 mg/m2/d and CODP 40 mg/m2/d, for 3 days every 28 days for 3 cycles. Evaluation was performed before each cycle. Radiation therapy began 4 weeks after completing the chemotherapy or immediately if there was evidence of tumor progression on chemotherapy. Seven out of 37 (19%) demonstrated tumor regression with a median duration to progression of 11 months. Median survival was 6 months. Myelosuppression was the predominant but manageable toxicity. This work indicated that the first chemotherapy protocol gave poor results in a homogeneous group of patients, with bad prognosis.

Thrombotic microangiopathy and digital necrosis: two unrecognized toxicities of gemcitabine.

We report one new case of hemolytic-uremic syndrome (HUS) and one case of digital necrosis after treatment with gemcitabine (Gemzar). Case 1, a 34-year-old man, was given first-line metastatic treatment with gemcitabine for a adenocarcinoma of the pancreas. After a cumulative dose of 10 000 mg/m2 gemcitabine, the onset of subacute renal failure associated with hemolytic anemia of mechanical origin was observed. A diagnosis of probable gemcitabine-induced thrombotic microangiopathy was arrived at. Symptoms resolved after stopping the chemotherapy, in spite of the progression of the disease. Case 2, a 61-year-old man, was administered a combination of gemcitabine and a platinum salt as first-line metastatic treatment for carcinoma of the bladder urothelium. Following a cumulative dose of 10 000 mg/m2 of gemcitabine, the patient suffered from bilateral peripheral vascular disease of somewhat acute onset with hemorrhagic lesions of the finger pads that became necrotic. The work-up was negative and a causal relationship was attributed to gemcitabine. The patient made good progress when given an i.v. infusion of Ilomedine (iloprost trometamol) and chemotherapy was withdrawn. We conclude that gemcitabine must be added to the list of drugs that cause HUS and necrotizing vasculitis.