Long-term fatigue and quality of life among epithelial ovarian cancer survivors: a GINECO case/control VIVROVAIRE I study.

BACKGROUND: Few data are available on long-term fatigue (LTF) and quality of life (QoL) among epithelial ovarian cancer survivors (EOCS). In this case-control study, we compared LTF, symptoms and several QoL domains in EOCS relapse-free ≥3 years after first-line treatment and age-matched healthy women. PATIENTS AND METHODS: EOCS were recruited from 25 cooperative GINECO centers in France. Controls were randomly selected from the electoral rolls. All participants completed validated self-reported questionnaires: fatigue (FACIT-F), QoL (FACT-G/O), neurotoxicity (FACT-Ntx), anxiety/depression (HADS), sleep disturbance (ISI), and physical activity (IPAQ). Severe LTF (SLTF) was defined as a FACIT-F score <37/52. Univariate and multivariate logistic regressions were conducted to analyze SLTF and its influencing factors in EOCS. RESULTS: A total of 318 EOCS and 318 controls were included. EOCS were 63-year-old on average, with FIGO stage I/II (50%), III/IV (48%); 99% had received platinum and taxane chemotherapy, with an average 6-year follow-up. There were no differences between the two groups in socio-demographic characteristics and global QoL. EOCS had poorer FACIT-F scores (40 versus 45, P < 0.0001), lower functional well-being scores (18 versus 20, P = 0.0002), poorer FACT-O scores (31 versus 34 P < 0.0001), and poorer FACT-Ntx scores (35 versus 39, P < 0.0001). They also reported more SLTF (26% versus 13%, P = 0.0004), poorer sleep quality (63% versus 47%, P = 0.0003), and more depression (22% versus 13%, P = 0.01). Fewer than 20% of EOCS and controls exercised regularly. In multivariate analyses, EOCS with high levels of depression, neurotoxicity, and sleep disturbance had an increased risk of developing SLTF (P < 0.01). CONCLUSION: Compared with controls, EOCS presented similar QoL but persistent LTF, EOC-related symptoms, neurotoxicity, depression, and sleep disturbance. Depression, neuropathy, and sleep disturbance are the main conditions associated with severe LTF.

Clinical validation of a prognostic tool in a population of outpatients treated for incurable cancer undergoing anticancer therapy: PRONOPALL study.

BACKGROUND: In 2008, a study of the characteristics of hospitalised patients led to the development of a prognostic tool that distinguished three populations with significantly different 2-month survival rates. The goal of our study aimed at validating prospectively this prognostic tool in outpatients treated for cancer in terminal stage, based on four factors: performance status (ECOG) (PS), number of metastatic sites, serum albumin and lactate dehydrogenase. PATIENTS AND METHODS: PRONOPALL is a multicentre study of current care. About 302 adult patients who met one or more of the following criteria: life expectancy under 6 months, performance status ≥ 2 and disease progression during the previous chemotherapy regimen were included across 16 institutions between October 2009 and October 2010. Afterwards, in order to validate the prognostic tool, the score was ciphered and correlated to patient survival. RESULTS: Totally 262 patients (87%) were evaluable (27 patients excluded and 13 unknown score). Median age was 66 years [37-88], and women accounted for 59%. ECOG PS 0-1 (46%), PS 2 (37%) and PS 3-4 (17%). The primary tumours were: breast (29%), colorectal (28%), lung (13%), pancreas (12%), ovary (11%) and other (8%). About 32% of patients presented one metastatic site, 35% had two and 31% had more than two. The median lactate dehydrogenase level was 398 IU/l [118-4314]; median serum albumin was 35 g/l [13-54]. According to the PRONOPALL prognostic tool, the 2-month survival rate was 92% and the median survival rate was 301 days [209-348] for the 130 patients in population C, 66% and 79 days [71-114] for the 111 patients in population B, and 24% and 35 days for [14-56] the 21 patients in population A. These three populations survival were statistically different (P <0.0001). CONCLUSION: PRONOPALL study confirms the three prognostic profiles defined by the combination of four factors. This PRONOPALL score is a useful decision-making tool in daily practice.

A phase II trial of abiraterone acetate plus prednisone in patients with triple-negative androgen receptor positive locally advanced or metastatic breast cancer (UCBG 12-1).

BACKGROUND: Several expression array studies identified molecular apocrine breast cancer (BC) as a subtype that expresses androgen receptor (AR) but not estrogen receptor α. We carried out a multicentre single-arm phase II trial in women with AR-positive, estrogen, progesterone receptor and HER2-negative (triple-negative) metastatic or inoperable locally advanced BC to assess the efficacy and safety of abiraterone acetate (AA) plus prednisone. PATIENTS AND METHODS: Patients with a metastatic or locally advanced, centrally reviewed, triple-negative and AR-positive (≥10% by immunohistochemistry, IHC) BC were eligible. Any number of previous lines of chemotherapy was allowed. AA (1000 mg) was administered once a day with prednisone (5 mg) twice a day until disease progression or intolerance. The primary end point was clinical benefit rate (CBR) at 6 months defined as the proportion of patients presenting a complete response (CR), partial response (PR) or stable disease (SD) ≥6 months. Secondary end points were objective response rate (ORR), progression-free survival (PFS) and safety. RESULTS: One hundred and forty-six patients from 27 centres consented for IHC central review. Of the 138 patients with sufficient tissue available, 53 (37.6%) were AR-positive and triple-negative, and 34 of them were included from July 2013 to December 2014. Thirty patients were eligible and evaluable for the primary end point. The 6-month CBR was 20.0% [95% confidence interval (CI) 7.7%-38.6%], including 1 CR and 5 SD ≥6 months, 5 of them still being under treatment at the time of analysis (6.4+, 9.2+, 14.5+, 17.6+, 23.4+ months). The ORR was 6.7% (95% CI 0.8%-22.1%). The median PFS was 2.8 months (95% CI 1.7%-5.4%). Fatigue, hypertension, hypokalaemia and nausea were the most common drug-related adverse events; the majority of them being grade 1 or 2. CONCLUSIONS: AA plus prednisone treatment is beneficial for some patients with molecular apocrine tumours and five patients are still on treatment. CLINICALTRIALSGOV: NCT01842321.

Translational studies within the TAMRAD randomized GINECO trial: evidence for mTORC1 activation marker as a predictive factor for everolimus efficacy in advanced breast cancer.

BACKGROUND: Everolimus is an agent frequently associated with specific toxicities. Predictive markers of efficacy are needed to help define which patients could benefit from it. The goal of this exploratory study was to identify potential predictive biomarkers in the mammalian target of rapamycin (mTOR) complex 1 (mTORC1) activation pathway using primary tumor samples collected during the phase II tamoxifen plus everolimus (TAMRAD) trial. PATIENTS AND METHODS: Tumor tissues were collected retrospectively from the TAMRAD trial. Immunohistochemistry was carried out using specific antibodies directed toward proteins that result in mTORC1 activation [canonical phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt)/mTOR or alternative pathways]. DNA was extracted from the tumor tissue; mutation screening in the PIK3CA gene (exons 9 and 20) and the KRAS gene (exons 2 and 3) was first carried out using Sanger direct sequencing, and then completed by next-generation sequencing for PIK3CA. An exploratory analysis of everolimus efficacy in terms of a time-to-progression (TTP) increase was carried out in each biomarker subgroup (high versus low expression referring to the median percentage of marked cells). RESULTS: A total of 55 primary tumor samples from the TAMRAD trial­25 from the tamoxifen-alone group and 30 from the tamoxifen/everolimus group­were evaluated for biomarkers. The subgroups most likely to have an improvement in TTP with tamoxifen/everolimus therapy, compared with tamoxifen alone, were patients with high p4EBP1, low 4EBP1, low liver kinase B1, low pAkt, and low PI3K. Among the 45 samples screened for mutation status, nine samples (20%; 95% CI 9.6-34.6) had a PIK3CA mutation. KRAS mutation was observed in one patient. CONCLUSIONS: A positive correlation between late effectors of mTORC1 activation, a positive correlation between Akt-independent mTORC1 activation, and an inverse correlation between canonical PI3K/Akt/mTOR pathway and everolimus efficacy were observed in this exploratory analysis. However, these correlations need to be validated in larger studies before applying the findings to routine clinical practice.

Fracture incidence after 3 years of aromatase inhibitor therapy.

BACKGROUND: The purpose of this study was to describe the fracture incidence and bone mineral density (BMD) evolution in a large cohort of post-menopausal women with breast cancer after 3 years of aromatase inhibitor (AI) therapy. PATIENTS AND METHODS: A prospective, longitudinal study in real-life setting. Each woman had an extensive medical assessment, a biological evaluation, a BMD measurement, and systematic spinal X-rays at baseline and after 3 years of AI therapy. Women with osteoporosis at baseline (T-score < -2.5 and/or non-traumatic fracture history) were treated by oral weekly bisphosphonates. RESULTS: Among 497 women (mean age 63.8 ± 9.6 years) included in this study, 389 had a bone evaluation both at baseline and after 3 years of AI therapy: 267 women (mean age 61.2 ± 8.6) with no osteoporosis at baseline and 122 women (mean age 67.2 ± 9.1) with osteoporosis at baseline justifying a weekly oral bisphosphonate treatment. Women without bisphosphonates had a significant decrease in spine BMD (-3.5%, P < 0.01), neck BMD (-2.0%, P < 0.01), and total hip BMD (-2.1%, P < 0.01) over the 3 years but only 15 of them (5.6%) presented an incident vertebral or non-vertebral fracture. In osteoporotic women treated with bisphosphonates, spine and hip BMD were maintained at 3 years but 12 of them (9.8%) had an incident fracture. These fractured women were significantly older (74.1 ± 9.8 versus 66.5 ± 8.8) but also presented BMD loss during treatment suggesting poor adherence to bisphosphonate treatment. CONCLUSION: This real-life study confirmed that AIs induced moderate bone loss and low fracture incidence in post-menopausal women without initial osteoporosis. In women with baseline osteoporosis and AI therapy, oral bisphosphonates maintain BMD but were associated with a persistent fracture risk, particularly in older women.

Use of liposomal doxorubicin-cyclophosphamide combination in breast cancer patients with brain metastases: a monocentric retrospective study.

Brain metastases (BM) can affect up to 45 % of a high-risk breast cancer (BC) population. Liposomal doxorubicin (LD)-based chemotherapy has demonstrated efficacy in the treatment of BC and LD crosses the blood-brain barrier. The aim of this retrospective study is to evaluate the efficacy of the LD-cyclophosphamide (CTX) combination in BM related to BC. Patients diagnosed with BM related to BC and treated with the LD-CTX combination were eligible. BM objective response rate (BM-ORR), BM disease control rate (BM-DCR), BM progression-free survival, overall survival (OS) and safety were analyzed. 29 patients were eligible. The median time from metastatic diagnosis to brain involvement was 12 months. BM was more frequently observed in HER2+ patients. On average, three courses of chemotherapy were administered without grade 3-4 limiting adverse events. After three cycles, BM-ORR and BM-DCR were 41.4 and 58.6 % respectively versus 50 and 62.5 % when no prior radiotherapy was administered. From BM diagnosis, OS was 23 months. A high BM-ORR is observed with the LD-CTX combination in patients with BM related to BC. This is an attractive therapeutic option for these patients, especially when no prior whole brain radiotherapy has been administered.

[Evaluation of the management of metastatic renal cell carcinoma in the era of targeted therapies. retrospective clinical study over six years]. / Évaluation de la prise en charge du cancer du rein métastatique à l'ère des thérapies ciblées. Étude clinique rétrospective sur six ans.

OBJECTIVE: To evaluate the outcomes following targeted therapies in the management of metastatic renal cell carcinoma (mRCC), through the study of overall survival (OS) and progression-free (PFS). PATIENTS AND METHODS: We retrospectively included 78 patients treated with targeted therapies for mRCC at the Paul Papin Cancer Institute from 2004 to 2009. Overall survival (OS), progression free survival (PFS), response to treatment, occurrence of grade III and IV side effects, were analyzed following first and second line treatments. RESULTS: Median follow-up was 33 months [5-236], and 41 patients died (52.6%). Median OS was 36 months [95% CI 29-43]. The median PFS was 14 months [95% CI 6.71-21.29] for sunitinib, 38 months [95% CI 11.41-64.59] for bevacizumab with interferon (IFN), and 8 months [95% CI 0-17.03] for IFN alone. A partial reduction, stabilization or increase in tumor size was observed for 19.2%, 47.4% and 25.6% of cases. A second line treatment was given for 53 patients. They received either sunitinib (n=20, 37.8%), bevacizumab with IFN (n=7, 13.2%), sorafenib (n=17, 32.2%), temsirolimus (n=3, 5.6%) or other molecules (n=6 11.2%). Grade III or IV side effects were observed for 14.1%, 28.3% and 18.2% of the patients following first, second and third line treatment, respectively. CONCLUSION: Outcomes of targeted therapies in our center upheld the literature data. These therapies allow a benefit survival versus immunotherapy, with sometimes large side-effect.

High prevalence of vertebral fractures in women with breast cancer starting aromatase inhibitor therapy.

BACKGROUND: The purpose of this study was to describe bone status in a large cohort of postmenopausal women with nonmetastatic breast cancer, at the initiation of aromatase inhibitor therapy. PATIENTS AND METHODS: A prospective, transversal and clinical study was conducted. Each woman had an extensive medical history, a biological evaluation, a bone mineral density (BMD) measurement and spinal X-rays. RESULTS: Four hundred and ninety-seven women aged 63.8 ± 9.6 years were included in this study. Eighty-five percent of these women had a 25-OH vitamin D concentration <75 nmol/l. One hundred and fifty-six women (31.4%) had a T-score < -2 at one of the three site measurements. Ninety-five women (19.1%) had a history of nonvertebral fracture with a total of 120 fractures. Spine X-rays evaluation revealed that 20% of the women had at least one vertebral fracture. The presence of vertebral fracture was associated with nonvertebral fracture history [odds ratio (OR) 1.6, 95% confidence interval (CI) 1.1-2.4] and with spine BMD (OR 1.4, 95% CI 1.1-1.7). The prevalence of vertebral fracture reached 62.9% in women with age above 70 years and femoral T-score < -2.5. CONCLUSION: Before starting aromatase inhibitor therapy for breast cancer, a large proportion of women had a vitamin D insufficiency and vertebral fractures.

The influence of fluorouracil outcome parameters on tolerance and efficacy in patients with advanced colorectal cancer.

The purpose of this study was to determine simple genetic factors helpful to tailor 5-FU administration and determine strategy in first-line chemotherapy of advanced colorectal cancer. In 76 patients initially treated by 5-FU, thymidylate synthase, dihydropyrimidine dehydrogenase and methylene tetrahydrofolate reductase germinal polymorphisms, dihydrouracil/uracil plasma ratio and 5-FU plasma clearance were investigated and correlated for tolerance (10.5% grade 3 and 4 toxicity) and efficacy (32.9% objective response rate and 20 months median overall survival time). Toxicity was linked to performance status >2 (P=0.004), low UH2/U ratio, 2846 A>T, IVS 14+1G>A for DPD (P=0.031), and homozygoty C/C for MTHFR 1298 A>C (P=0.0018). The overall survival of the patients with a 3R/3R TS genotype associated with C/C for 677 C>T or A/A for 1298 A>C was statistically shorter (log-rank test P=0.0065). Genetic factors permit the tailoring of 5-FU treatment. They should occupy center stage in future clinical trials for specifically designing treatment for patients with a given biologic feature.

Osteoporosis treatment and 10 years' oestrogen receptor+ breast cancer outcome in postmenopausal women treated with aromatase inhibitors.

BACKGROUND: Risk factors for breast cancer relapse are well-known, such as large tumour size or lymph node involvement. The aim of our study was to analyse the influence of bone mineral density, fractures and bisphosphonate or vitamin D prescription on 10 years' breast cancer outcome. PATIENTS AND METHODS: This is a longitudinal and prospective cohort of 450 postmenopausal women with local oestrogen receptor (ER)+ breast cancer. For every patient, we analysed tumour characteristics, bone status at the beginning of aromatase inhibitor treatment and 10 years' cancer outcome with Cox model. RESULTS: Mean follow-up was 10.3 ± 3.0 years. Seventy nine women died, and 75 had a relapse; 30.7% had a history of fracture, 16.9% had a T-score ≤ -2.5 and 11.3% had vitamin D deficiency. Bisphosphonates were prescribed to 35.3% women for osteoporosis for a mean duration of 5 ± 1.7 years. Tumour size (hazard ratio [HR] = 1.32, P ≤ 0.01) and the number of lymph nodes involved (HR = 1.07, P = 0.03) were significantly associated with relapse. Bisphosphonate treatment was significantly associated with a decreased risk of relapse (HR = 0.51, P = 0.03). Age at cancer diagnosis (HR = 1.07, P ≤ 0.01) and vitamin D deficiency (HR = 1.85, P = 0.04) were significantly associated with an increased risk of death, whereas bisphosphonate treatment was associated with a decreased risk of death (HR = 0.46, P = 0.01). CONCLUSION: Osteoporosis treatment, including vitamin D and bisphosphonates, is associated with a 50% reduction of relapse and death in women treated with aromatase inhibitors for ER+ breast cancer.

[Low-grade endometrial stromal sarcoma: contribution of hormone therapy and etoposide]. / Sarcome du chorion cytogène de bas grade. Mise au point sur l'intérêt de l'hormonothérapie et de l'étoposide à partir de 4 cas.

Endometrial stromal sarcoma is a rare malignant uterine tumor. We report 4 cases of low-grade endometrial stromal sarcoma, corresponding to the form with a mitotic index at less than 10 mitoses per 10 high power fields (HPF), from which we carried out a review of the literature and defined the potential interest of hormone therapy and chemotherapy by etoposide. Generally diagnosed in pre-menopause, the main clinical signs, which are not very specific, are metrorrhagia and pelvic pain. The etiologic diagnosis is established from the pathology analysis. Intravascular extension, which is observed in nearly 50% of patients, should evoke the disease. The initial treatment is mainly based open surgery, generally total hysterectomy with annexectomy. There is no effective adjuvant treatment. The potential of reccurences remains around 50% with a 34-month median. Several therapeutic options are possible after recurrence but no standard treatment has been established. We are mainly interested in three medical options but the surgery remains an alternative of choice. Chemotherapy by oral etoposide offers easy administration, good compliance and acceptable toxicity with median 20-month remission in 3 patients before progression. Hormone therapy with progestogens (hormone receptor expression of the tumor is 71% for estrogens and 95% for progesterone) is widely studied in the literature with a 46% response rate and 46% rate of disease stabilization. Hormone therapy with an anti-aromatase appears to be a promising treatment according to the bibliographic references on this subject. Overall, prognosis of low-grade endometrial sarcoma is relatively good with 100% survival at 5 years. The progression pattern is slow, requiring regular and prolonged surveillance.

[Cytolytic hepatitis and esomeprazole during chemotherapy]. / Hépatite cytolytique due à l'ésoméprazole au cours d'une chimiothérapie anticancéreuse.

INTRODUCTION: Esomeprazole, the pure S isomer form of omeprazole, is indicated for the treatment of peptic esophagitis. We report here a major episode of cytolytic hepatitis following a single administration. CASE: A 41-year-old woman with infiltrating ductal carcinoma of the breast was undergoing chemotherapy with paclitaxel and trastuzumab. On the fourth day of the second course, she took 1 tablet of esomeprazole 20 mg for epigastric pain. Liver pain and asthenia followed, and liver function tests showed substantial cytolysis. These tests returned to normal levels despite continuation of the chemotherapy. DISCUSSION: This cytolytic hepatitis is very probably imputable to esomeprazole, but a synergistic hepatic toxicity of the chemotherapy with esomeprazole cannot be ruled out.

[Cancers of unknown origin: 311 cases]. / Cancers d'origine indéterminée: à propos de 311 cas.

Carcinoma of unknown primary site has been defined as a metastatic disease without known primary site (upon clinical, radiological or endoscopic examination) at the initial therapeutic decision. The incidence of such carcinomas is between 1.6 and 15% of all adult's tumors. The goals of this retrospective and monocentric study were 1) the incidence of these carcinoma; 2) the utility to identify the primary site; 3) the efficacy of treatment in terms of survival; and 4) the prognostic factors to optimize strategic choices. Between January 1980 to December 1995, 311 cases were identified; this represents 1.6% of all cases treated in our center. Histological analyses of metastases revealed adenocarcinoma: 164 cases (92 males, 72 females; 29 well differentiated, 11 poorly differentiated and 41 undifferentiated); squamous cell carcinoma: 90 cases (78 males, 12 females); undifferentiated carcinoma: 27 cases (21 males, 6 females); neuro-endocrine tumor: 10 cases; and others: 20 cases. Median age was 61.1 years (30-94). Half of the patients had a PS between 0 and 1. The carcinoma was revealed by only one site of metastases in 35% of the cases (lymph node 72.9%, bone 35.5%, liver 19.4% and lung 16.5%). The primary carcinoma was found in only 6% of the cases. Median survival of all patients was only 9 months. Multivariate analyses by the Cox method show four positive prognostic factors: sex (female), performance status (PS < 2), histological analyses (squamous cell carcinoma), only one site of metastases.

Impact of geriatric risk factors on pegylated liposomal doxorubicin tolerance and efficacy in elderly metastatic breast cancer patients: final results of the DOGMES multicentre GINECO trial.

BACKGROUND: Metastatic breast cancer chemotherapy in the elderly is considered effective in carefully selected patients, but there is little data regarding its effect in vulnerable patients. METHODS: We evaluated tumour response (primary endpoint), feasibility and outcomes after six courses of an adapted dose of pegylated liposomal doxorubicin (PLD) (40 mg/m(2) every 28 days) as first-line chemotherapy for hormone-resistant MBC. RESULTS: Of 60 patients >70 years (median 77 years), 15% had performance status ≥2 and 73% had visceral metastases. Geriatric assessment included: ≥2 comorbidities, 42%; ≥1 deficiency in Activities of Daily Living (ADL), 10% and Instrumental ADL (IADL), 82%; living in residential homes, 12%; albumin <35 g/L, 17%; body mass index (BMI) <21, 20%; depression, 17%; and lymphocytes ≤1 × 10(3)/mm(3), 27%. Complete response, partial response and stable disease were observed in 5%, 15% and 60%, respectively, but only 48% completed six cycles. Treatment discontinuations were mostly due to disease progression (18%) and non-haematological (NH) toxicities (22%). Eight patients died during treatment (three possibly related to PLD), and 15 had unplanned hospital admissions. Exploratory analyses to identify geriatric covariates associated with treatment outcomes revealed severe haematological toxicities significantly correlated with lymphocytes ≤1 × 10(3)/mm(3). NH toxicities correlated with age ≥80 years and living in residential homes. Progression-free survival (median 6.1 months) decreased with age, deficiency in IADL, cardiac dysfunction and living in residential homes. Overall survival (median 15.7 months) also decreased with living in residential homes. CONCLUSION: Despite manageable haematological toxicities and expected response rates, PLD feasibility was poor in unselected elderly patients.

Impact of an all-oral capecitabine and vinorelbine combination regimen on functional status of elderly patients with advanced solid tumours: A multicentre pilot study of the French geriatric oncology group (GERICO).

BACKGROUND: Elderly metastatic cancer patients typically have short life expectancy and frequently suboptimal treatment. Goals of therapy should include preservation of functional status as well as clinical response. For elderly patients, oral chemotherapy could be a valuable strategy, avoiding the constraints and risks of intravenous drugs. METHODS: This study assessed effect of an all-oral combination of capecitabine and vinorelbine on functional status (measured by basic Activities of Daily Living [ADL]), toxicity, efficacy and compliance in patients ≥70 years with advanced breast, prostate or lung cancer. RESULTS: Eighty patients were enrolled. After three cycles, 81.8% of patients had stabilised or improved ADL, and 8.6% and 42.9% had a response or stabilised disease. Compliance was excellent (68.8%). The most common grade 3-4 toxicities were haematological (17.9%) and gastrointestinal (7.7%). CONCLUSION: In elderly cancer patients, an all-oral combination of capecitabine and vinorelbine maintains functional status, is well tolerated, and provides good disease control.