Multidisciplinary analysis of cancer-related fatigue at the time of diagnosis: preliminary results of the BIOCARE FActory cohort.

PURPOSE: Cancer-related fatigue (CRF) is a common side effect of cancer and cancer treatment that significantly impairs the quality of life and can persist for years after treatment completion. Although fatigue is often associated with cancer treatment, it is also a result of the disease itself, even before intervention. CRF at the time of diagnosis may affect treatment timing or completion and is a consistent predictor of post-treatment fatigue at any time. The mechanisms underlying CRF are multidimensional and not well understood, particularly at the time of diagnosis. METHODS: Sixty-five breast cancer patients at the time of diagnosis were included. The participants completed self-assessment questionnaires about CRF, sleep disturbances, and emotional symptoms and wore an accelerometer to assess levels of spontaneous physical activity and sleep quality. During the experimental session, the participants underwent cognitive, neuromuscular, and exercise metabolism evaluations. RESULTS: Using augmented backward elimination regression, this study found that emotional symptoms and perceived sleep disturbances were the strongest predictors of CRF (adjusted r2 = 0.51). Neuromuscular fatigability and sleep disturbance were also associated with physical dimensions, whereas cognitive performance was associated with cognitive dimensions. CONCLUSION: At the time of diagnosis, emotional and cognitive dimensions are over-represented compared to the general population, and specific subdimensions have specific predictors that support the idea of distinct mechanisms. Evaluating CRF subdimensions and their potential mechanisms at the time of diagnosis would be particularly relevant for identifying high-risk patients and offering them appropriate interventions. TRIAL REGISTRATION: This study was registered at ClinicalTrials.gov (NCT04391543) in May, 2020.

Building a biopsychosocial model of cancer-related fatigue: the BIOCARE FActory cohort study protocol.

BACKGROUND: Cancer-related fatigue (CRF) is the most common side effect of cancer and cancer treatment. CRF prevalence is up to 50% in breast cancer patients and can continue several years after cancer remission. This persistent subjective sense of exhaustion is multifactorial. Numerous parameters have been evidenced to be related to CRF across biological, physical, psychological, social and/or behavioral dimensions. Although CRF has been studied for many years, the majority of previous studies focused on only one dimension, i.e., physical function. Moreover, few studies investigated CRF longitudinally with repeated measures. These are the two main obstacles that limit the understanding of CRF mechanisms. The purpose of this study is to create a biopsychosocial model of CRF with simultaneous and longitudinal anthropometric, clinical, biological, physical, psychological and sociological parameters. METHODS: BIOCARE FActory is a multicentric prospective study that will consist of an 18-month follow-up of 200 women diagnosed with breast cancer. Four visits will be scheduled at diagnosis, after treatments, and 12 and 18 months after diagnosis. The same procedure will be followed for each visit. Each session will be composed of anthropometric data collection, a semi-structured interview, cognitive tests, postural control tests, neuromuscular fatigability tests and a cardiorespiratory fitness test. Clinical and biological data will be collected during medical follow-ups. Participants will also complete questionnaires to assess psychological aspects and quality of life and wear an actigraphy device. Using a structural equation modeling analysis (SEM), collected data will build a biopsychosocial model of CRF, including the physiological, biological, psychological, behavioral and social dimensions of CRF. DISCUSSION: This study aims to highlight the dynamics of CRF and its correlates from diagnosis to post treatment. SEM analysis could examine some relations between potential mechanisms and CRF. Thus, the biopsychosocial model will contribute to a better understanding of CRF and its underlying mechanisms from diagnosis to the aftermaths of cancer and its treatments. TRIAL REGISTRATION: This study is registered at ClinicalTrials.gov ( NCT04391543 ), May 2020.

Handgrip fatiguing exercise can provide objective assessment of cancer-related fatigue: a pilot study.

PURPOSE: As a subjective symptom, cancer-related fatigue is assessed via patient-reported outcomes. Due to the inherent bias of such evaluation, screening and treatment for cancer-related fatigue remains suboptimal. The purpose is to evaluate whether objective cancer patients' hand muscle mechanical parameters (maximal force, critical force, force variability) extracted from a fatiguing handgrip exercise may be correlated to the different dimensions (physical, emotional, and cognitive) of cancer-related fatigue. METHODS: Fourteen women with advanced breast cancer, still under or having previously received chemotherapy within the preceding 3 months, and 11 healthy women participated to the present study. Cancer-related fatigue was first assessed through the EORTC QLQ-30 and its fatigue module. Fatigability was then measured during 60 maximal repeated handgrip contractions. The maximum force, critical force (asymptote of the force-time evolution), and force variability (root mean square of the successive differences) were extracted. Multiple regression models were performed to investigate the influence of the force parameters on cancer-related fatigue's dimensions. RESULTS: The multiple linear regression analysis evidenced that physical fatigue was best explained by maximum force and critical force (r = 0.81; p = 0.029). The emotional fatigue was best explained by maximum force, critical force, and force variability (r = 0.83; p = 0.008). The cognitive fatigue was best explained by critical force and force variability (r = 0.62; p = 0.035). CONCLUSION: The handgrip maximal force, critical force, and force variability may offer objective measures of the different dimensions of cancer-related fatigue and could provide a complementary approach to the patient reported outcomes.

Open-label randomised phase III trial of vinflunine versus an alkylating agent in patients with heavily pretreated metastatic breast cancer.

Background: There is no standard treatment after progression on second-line chemotherapy for metastatic breast cancer (MBC). We compared vinflunine with physician's choice of alkylating agent (AA) for patients with heavily pretreated MBC. Patients and methods: In this open-label phase III trial, patients with MBC were included if they had received at least two prior chemotherapy regimens for MBC and had received anthracycline, taxane, antimetabolite and vinca alkaloid therapy. Patients were no longer candidates for these chemotherapies because of resistance and/or intolerance. Patients were randomised to either vinflunine 280 mg/m2 intravenously every 3 weeks (q3w) or AA monotherapy q3w. Stratification factors were performance status, number of prior chemotherapy lines for MBC, disease measurability and study site. The primary end point was overall survival (OS). Results: A total of 594 patients were randomised (298 to vinflunine, 296 to AA). There was no difference between treatment arms in OS (hazard ratio 1.04, P = 0.67; median 9.1 months for vinflunine versus 9.3 months for AA), progression-free survival (hazard ratio 0.94, P = 0.49; median 2.5 versus 1.9 months, respectively) or overall response rate (6% versus 4%, respectively). However, the disease control rate was significantly higher with vinflunine than AA (44% versus 35%, respectively; P = 0.04). The most common adverse events (any grade) were haematological and gastrointestinal disorders and asthenia in both arms. The most common grade 3/4 adverse events were neutropenia (19% versus 11% with vinflunine versus AA, respectively) and asthenia (10% versus 4%). Conclusions: Vinflunine 280 mg/m2 q3w did not improve OS compared with the physician's choice of AA as third- or later-line therapy for MBC. Vinflunine demonstrated an acceptable safety profile, suggesting that vinflunine 320 mg/m2 merits evaluation. ClinicalTrials.gov: NCT01091168.

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.

Prognostic nomogram to predict progression-free survival in patients with platinum-sensitive recurrent ovarian cancer.

BACKGROUND: Patients with platinum-sensitive recurrent ovarian cancer are a heterogeneous group, and it is not possible to accurately predict the progression-free survival (PFS) in these patients. We developed and validated a nomogram to help improve prediction of PFS in patients treated with platinum-based chemotherapy. METHODS: The nomogram was developed in a training cohort (n=955) from the CALYPSO trial and validated in the AGO-OVAR 2.5 Study (n=340). The proportional-hazards model (nomogram) was based on pre-treatment characteristics. RESULTS: The nomogram had a concordance index (C-index) of 0.645. Significant predictors were tumour size platinum-chemotherapy-free interval, CA-125, number of organ metastatic sites and white blood count. When the nomogram was applied without CA-125 (CA-125 was not available in validation cohort), the C-indices were 0.624 (training) and 0.594 (validation). When classification was based only on the platinum-chemotherapy-free interval, the indices were 0.571 (training) and 0.560 (validation). The calibration plot in the validation cohort based on four predictors (without CA-125) suggested good agreement between actual and nomogram-predicted 12-month PFS probabilities. CONCLUSION: This nomogram, using five pre-treatment characteristics, improves prediction of PFS in patients with platinum-sensitive ovarian cancer having platinum-based chemotherapy. It will be useful for the design and stratification of patients in clinical trials and also for counselling patients.

Weekly combination of topotecan and gemcitabine in early recurrent ovarian cancer patients: a French multicenter phase II study.

OBJECTIVES: The aim of this phase II study was to assess the benefits of a weekly administration of topotecan and gemcitabine in patients with ovarian carcinoma having relapsed after platinum/taxane-based first-line chemotherapy. METHODS: Seventy-seven patients with progression of disease /=2 cycles administered). The only major severe toxicity was neutropenia grades 3 (17%) and 4 (6%). Approximately 60% of the patients received the complete schedule of treatment, dose interruptions/delays being mainly due to moderate thrombocytopenia or neutropenia. The objective response rate was 14%, the values for patients having relapsed within 6 (n=30) and 6-12 (n=36) months being 7% and 20%, respectively. Median durations of response were 4.9 and 6.4 months and clinical benefit rates including stabilizations reached 63% and 69% in patients having relapsed within 6 or 6-12 months, respectively. Corresponding median overall survival was 7.5 and 15.6 months. Symptoms and pain were reduced in 64% and 39% of the patients concerned, respectively. CONCLUSION: In early relapse ovarian cancer, weekly combination of gemcitabine and topotecan has a modest objective response rate. However, a high proportion of patients experienced stable disease and symptom control leading to acceptable quality of life.

Evaluation of oral versus intravenous dose of vinorelbine to achieve equivalent blood exposures in patients with solid tumours.

Patient's preference is for oral chemotherapy when both oral and i.v. are available, provided that efficacy is equivalent. Reliable switch from oral to i.v. is possible if correspondence between respective doses has been established. Vinorelbine oral was developed as a line extension of VRL i.v. on the basis that similar AUCs result in similar activities. From a first crossover study on 24 patients receiving VRL 25 mg/m2 i.v. and 80 mg/m2 oral data extrapolation concluded on AUCs bioequivalence between Vinorelbine 30 mg/m2 i.v. and 80 mg/m2 oral. A new trial was performed to support this calculation. In a crossover design study on patients (PS 0-1) with advanced solid tumours (44% breast carcinoma), VRL was administered (30 mg/m2 i.v., 80 mg/m2 oral) with a standard meal and 5-HT3 antagonists, at 2 weeks interval. Pharmacokinetics was performed over 168 h and VRL was measured by LC-MS/MS. Statistics included bioequivalence tests. Forty-eight patients were evaluable for PK: median age 58 years (25-71), PS0/PS1: 20/28, M/F: 11/37. Mean AUCs were 1,230 +/- 290 and 1,216 +/- 521 ng/ml for i.v. and oral, respectively. The confidence interval of the AUC ratio (0.83-1.03) was within the required regulatory range (0.8-1.25) and proved the bioequivalence between the two doses. The absolute bioavailability was 37.8 +/- 16.0%, and close to the value from the first study (40%). Patient tolerability was globally comparable between both forms with no significant difference on either haematological or non-haematological toxicities (grade 3-4). This new study, conducted on a larger population, confirmed the reliable dose correspondence previously established between vinorelbine 80 mg/m2 oral and 30 mg/m2 i.v.

[Hospital pathway of patients with breast cancer]. / Trajectoires hospitalières des patientes atteintes de cancer du sein en Poitou-Charentes.

Health care network should promote better quality, equity and care efficacy. On the subject of breast cancer, literature has shown inequality in care depending on geographical areas and health centres locations. This article illustrates a method of analysis of female non in situ non metastatic breast cancer patients hospital care pathway, from the 2002 and 2003 Poitou-Charentes' county Diagnosis Related Groups (DRG's) data bases. The treatments several phases are described along with their combination. The number of chemotherapy and radiotherapy sessions per patient are each analysed for comparison between Health Centres, Health Centres Status, and in view of the referentials recommendations. Several health pathways options are quantified: Mono/pluri Health Centres sites, inside/outside a geographical department, inside/outside Poitou-Charentes county. Nine hundred and nine patients hospital care pathways are described. Surgery was more often partial (66%), with Health Centres variation between 17 and 68%. Among the 308 patients who had chemotherapy, 78% received between 4 and 6 sessions, with variation per Health Centre between 65 and 90%. Radiotherapy is difficult to trace because of the Health Centres non systematic radiotherapy sessions linkage, and private Health Centres lack of information (no DRG's). 91% of identified radiotherapy benefiting patients had 25 to 35 sessions, in conformation with recommendations depending on the surgery performed with Health Centres variation ratio between 76 and 96%. Hospital care pathways options between two type of treatments were identified. 90% of the hospital care pathways took place in the same geographical department, and 30% took place in public Health Centres alone. Despite radiotherapy tractability limits, proper DRG's data collection allows the description of health pathways between Health Centres and allows health practice disparity identification. Using this tool, in accordance with the Cancer Plan, can therefore help health networks in evaluating care pathway in cancer and many other fields.

Second-line chemotherapy with pegylated liposomal doxorubicin and carboplatin is highly effective in patients with advanced ovarian cancer in late relapse: a GINECO phase II trial.

BACKGROUND: Platinum-based chemotherapy is standard second-line treatment of patients with advanced ovarian cancer (AOC) in late relapse. Pegylated liposomal doxorubicin (PLD) has significant single-agent activity in this setting. Therefore, we evaluated the use of PLD plus carboplatin in this patient population. PATIENTS AND METHODS: PLD 30 mg/m(2) followed by carboplatin at area under the curve (AUC) 5 mg.min/ml, repeated every 28 days for a maximum of nine cycles, was administered to 104 women with AOC relapsing >or=6 months after completion of first- or second-line therapy with platinum-taxane-based regimens. RESULTS: Overall response was 63%, with a 38% complete response, median progression-free survival of 9.4 months, and median overall survival (OS) of 32 months. Grade 3 or 4 neutropenia occurred in 51% of patients, but febrile neutropenia in only 3%. Nonhematologic toxic effects were primarily grades 1 and 2, with low rates of alopecia and neurotoxicity. CONCLUSIONS: PLD plus carboplatin is highly effective, prolongs OS, and is well tolerated in women with AOC in late relapse previously treated with both platinum and taxanes. Evaluation of this regimen in phase III trials is warranted.

Efficacy and tolerability of the ifosfamide-epirubicin combination in relapsed ovarian cancer.

A retrospective study evaluating the efficacy and tolerability of epirubicin-ifosfamide (EI) in patients with relapsed advanced ovarian cancer (ROC) after prior chemotherapy was conducted. A total of 93 patients received epirubicin (50 mg/m(2), day 1), ifosfamide (1500 or 2500 mg/m(2), days 1-3), and mesna monthly. Thirty-five percent had received one line of chemotherapy (platinum 100%, taxanes 8%); 38%, two lines; and 27%, more than two lines. Fifty-three percent received 2500 mg/m(2)/day ifosfamide and 47% received 1500 mg/m(2)/day ifosfamide. Ifosfamide was administered by continuous infusion in 12 patients. Mean number of courses was 4 (1-12). Grade 4 toxicity was 69% neutropenia and 12% thrombocytopenia. Three patients on high-dose ifosfamide as a short infusion had central nervous system dysfunction resulting in death. There were 84 assessable patients: 7 (8%), complete responses; 13 (15%), partial responses; and 20 (24%), stable disease. Median time to progression was 5 months (3 days to 36 months). The EI combination appears to be effective in ROC. However, toxicity with high-dose ifosfamide administered by short infusion is not acceptable. Tolerability can be improved using ifosfamide at 1500 mg/m(2) by continuous infusion. The combination of ifosfamide with newer anthracycline agents such as liposomal doxorubicin may be an alternative and needs further evaluation for use after first-line taxane-based chemotherapy.

A phase II trial of raltitrexed (Tomudex) in advanced pancreatic and biliary carcinoma.

PURPOSE: To evaluate the impact of raltitrexed (Tomudex) on the quality of life in a multicenter, phase II study in advanced pancreatic and biliary carcinomas. PATIENTS AND METHODS: Forty-six patients with advanced, histologically proven pancreatic (n = 37, 80.4%) or biliary (n = 9, 19.6%) carcinoma received 3 mg/m2 raltitrexed intravenously once every 3 weeks. For the quality of life assessments, EORTC QLQ-C30 was used, and the evaluation of the clinical benefit was performed according to the 4 criteria of the clinical benefit response. All patients were assessed for safety, and 41 patients were evaluable for objective response. RESULTS: Patients (63% male/37% female) had a mean age of 61.2 years, 71.7% had a PS of 0-1, 78.3% had metastatic disease, and 63% had at least 2 tumoral sites. A total of 176 cycles were administered with a mean of 4 cycles per patient (range 1-12). Three out of 43 patients evaluable for EORTC QLQ-C30 (7.0%; CI(95%) 1.4-19.0%) had a quality of life improvement. Thirty-two patients fulfilled the 4 criteria required to evaluate the clinical benefit response; 5 were responders (15.6%; CI(95%) 5.3-32.8%); 1 patient was a good responder based on both the EORTC questionnaire and the clinical benefit response. Forty-one patients were assessable for response, 3 responded to treatment (response rate: 6.5 %; CI(95%) 1.3-17.9%). Median survival was 4.6 months (CI(95%) 2.9-8.2 months), the 1-year survival rate was 21.8%. The most common grade 3-4 toxicities were neutropenia (8%), leukopenia (8%), thrombopenia (6%), anemia (6%), liver enzyme elevations (11%), asthenia (9%), vomiting (9%), abdominal pain (7%), and phlebitis (6%). One treatment-related death occurred (neutropenic sepsis). CONCLUSION: Raltitrexed appeared to be generally well tolerated and showed a clinical benefit response and/or quality of life improvement in a limited number of patients.

Docetaxel plus 5-fluorouracil in locally recurrent and/or metastatic squamous cell carcinoma of the head and neck: a phase II multicenter study.

This phase II study evaluated docetaxel-5-fluorouracil (5-FU) in locally recurrent and/or metastatic squamous cell carcinoma of the head and neck (SCCHN). Patients were divided into 2 cohorts--those previously treated with chemotherapy and those nonpretreated--that received docetaxel 75 mg/m2 (day 1) plus 5-FU 1,000 mg/m2/day (days 1-5 every 3 weeks). Of 63 patients entered, 20 (31.7%) were pretreated and 43 (68.3%) were nonpretreated. Fifty-nine patients (93.7%) had received prior radiotherapy. After inclusion of 20 patients, the 5-FU dose was reduced to 750 mg/m2/day due to unacceptable toxicity. The overall response rate (ORR) was 20.6% on radiologic review (22.2%, investigator assessment). Pretreated patients achieved an ORR of 25.0% versus 18.6% for nonpretreated patients. This unexpected finding was partly attributed to differences in patient characteristics between the groups. Overall major grade 3 to 4 toxicities comprised neutropenia (66.6%), febrile neutropenia (31.7%), and mucositis (31.7%). Grade 3 to 4 toxicities were lower at the reduced 5-FU dose (750 mg/m2/day): Febrile neutropenia declined from 40.0% to 27.9%; mucositis declined from 55.0% to 20.9%. Three treatment-related deaths occurred (2 with 5-FU 750 mg/m2/day, 1 with 5-FU 1,000 mg/m2/day). Docetaxel-5-FU appears active in locally recurrent and/or metastatic SCCHN with acceptable toxicity at the dose of 5-FU 750 mg/m2.

Patient preference for either the EORTC QLQ-C30 or the FACIT Quality Of Life (QOL) measures: a study performed in patients suffering from carcinoma of an unknown primary site (CUP).

The objective of this study was to examine and compare two core measures of Quality Of Life (QOL) used in cancer clinical trials: the European Organisation for Research and Treatment of Cancer QOL Core Questionnaire 30 (EORTC QLQ-30) and the Functional Assessment of Chronic Illness Therapy (FACIT), in order to identify which one patients have the strongest preference for using. 68 patients suffering from Carcinomas of an Unknown Primary site (CUP) were recruited in a multicentric study; all of them completed both questionnaires, administered in a randomised manner. The criteria were the percentage of preferences, and four indicators of acceptability. The results indicated that an equal proportion of patients preferred the QLQ-C30 (19%) and FACIT (19%). 54% of patients felt both questionnaires were acceptable. All the indicators of acceptability favoured the QLQ-C30. Analysis of open-ended questions shed light on the difficulties encountered by the patients. As no significant preference was observed for one of the questionnaires, the QLQ-C30 was chosen on the basis of its significantly better acceptability criteria.

Phase II multicentre study of docetaxel plus 5-fluorouracil in patients with anthracycline-pretreated metastatic breast cancer.

The purpose of the study was to determine the efficacy and safety of docetaxel plus continuous infusion of 5-fluorouracil (5-FU) in patients with metastatic breast cancer previously treated with anthracyclines. A total of 41 patients with histologically proven metastatic breast cancer and performance status 0-2, who had received at least one anthracycline-containing regimen, received docetaxel 85 mg m(-2) followed by continuous infusion of 5-FU 750 mg m(-2) day(-1) for 5 days every 3 weeks for up to eight cycles. All patients received corticosteroid premedication, but there was no prophylactic colony-stimulating factor support. The most frequent metastatic sites were the liver (61%), bone (29%), and lung (29%). All 41 patients were assessable for toxicity and 30 were eligible and assessable for efficacy. The objective response rate was 70.0% (95% CI: 53.6-86.4%) for the per protocol group and 53.7% (95% CI: 38.4-68.9%) for the intent-to-treat (ITT) population. For the ITT population, median duration of response was 8.4 months (95% CI: 6.7-12.2 months), median time to progression was 6.7 months (95% CI 5.5-8.6 months), and median survival was 17 months (95% CI: 12.3-not recorded months). Grade 3/4 neutropenia occurred in 54% of patients, with febrile neutropenia in 24% of patients and 5% of cycles, but infections were rare. Stomatitis was frequent, grade 3 in 24% of patients and grade 4 in one patient (2%), but manageable. Diarrhoea was rare, grade 3 in 7% of patients and 1% of cycles. Other grade 3/4 nonhaematological toxicities were infrequent. In conclusion, this docetaxel/5-FU regimen is highly active and well tolerated in patients with anthracycline-pretreated metastatic breast cancer. The efficacy is particularly promising, as one-third of patients were either second-line and/or anthracycline-resistant/refractory.

[Pituitary germinoma presenting as a pseudotumoral lymphocytic hypophysitis in a man]. / Germinome hypophysaire révélé par une hypophysite lymphocytaire pseudo-tumorale chez un homme.

A 45-year-old man presented with headaches and extraocular muscle palsy due to a sellar mass extending into the right cavernous sinus. Hormonal determinations revealed a gonadotrophic insufficiency. A transsphenoidal surgical removal revealed a lymphocytic hypophysitis with fibrosis and necrosis. Rapid growth of the pseudotumor was noted despite a high dose steroid therapy (1 mg/kg/d) for a month. Further biological and histopathological investigations were performed. They showed a high cerebrospinal fluid (CSF) B-human chorionic gonadotropin (ss-HCG) level of 12 UI/L (normal<5 UI/L), normal plasma BHCG level, and undetectable CSF and plasma alpha-fetoprotein levels. The tumors cells showed a positive reactivity for placental alkaline phosphatase and for vimentin. These findings were consistent with an inflammatory lymphocytic process caused by an intrasellar germinoma. Chemotherapy was ill-tolerated and external radiotherapy was ineffective.

Dose-finding study of docetaxel and doxorubicin in first-line treatment of patients with metastatic breast cancer.

PURPOSE: To determine the maximum tolerated dose (MTD), the dose-limiting toxicity (DLT) and the recommended dose of docetaxel in combination with doxorubicin, and to evaluate the activity in patients with advanced breast cancer. PATIENTS AND METHODS: Forty-two women with untreated metastatic breast cancer (79% with visceral metastases; 52% with prior adjuvant anthracycline therapy) were treated with doxorubicin (40-60 mg/m2) i.v. bolus followed one hour later by docetaxel (50-85 mg/m2) one-hour i.v. infusion every three weeks, without G-CSF support. RESULTS: The MTD occurred at the dose level combining 85 mg/m2 of docetaxel and 50 mg/m2 of doxorubicin, with the DLT being neutropenic sepsis. Neutropenia and/or its complications were manageable and no grade 3-4 or severe non-hematological toxicities were observed. Fluid retention was frequent but never severe. With a median cumulative dose of doxorubicin of 392 mg/m2 (240-559 mg/m2) and a median follow-up time of 29 months (9(+)-41), no congestive heart failure was observed. High activity was observed at all dose levels, particularly the last four, with a response rate of 81% (95% confidence interval (95% CI): 62.5-92.5). Median time to progression was 46 weeks (6(+)-62). Two-year survival was 66%, and median survival has not yet been reached. CONCLUSIONS: Docetaxel-doxorubicin is feasible, safe and highly active. The incidence of febrile neutropenia without G-CSF requires careful monitoring but is acceptable in this setting. There does not appear to be an increase in the cardiac toxicity of doxorubicin. The recommended doses is either docetaxel 75 mg/m2 and doxorubicin 50 mg/m2 or docetaxel 60 mg/m2 and doxorubicin 60 mg/m2, administered every three weeks.

Efficacy and safety of docetaxel (Taxotere) in heavily pretreated advanced breast cancer patients: the French compassionate use programme experience.

The aim of this investigation was to assess retrospectively docetaxel safety and efficacy in advanced breast cancer patients in a French compassionate use programme. Patients had received > 1 prior chemotherapy regimen for advanced disease, were either anthracycline-resistant (that is progressed within 6 months after anthracycline-based chemotherapy) or had received the maximum cumulative dose. The recommended docetaxel dose was 100 mg/m2/cycle (75 mg/m2 in case of liver function impairment: transaminases > 1.5 x upper limit of normal (ULN), alkaline phosphatases > 3 x ULN). Between August 1993 and December 1995, 889 patients were treated in 67 French centres, of whom 870 were evaluable for safety and 825 were evaluable for patient and treatment characteristics and efficacy. 20.5% (of the 825 patients evaluable for baseline characteristics) had poor performance status (PS > or = 2), 49.3% liver metastasis and 9.6% biological liver dysfunction. 98.4% had been previously treated by anthracyclines, 50.8% had resistant disease and 37.1% had received > 2 prior palliative chemotherapy lines. The most frequent severe toxicity, febrile neutropenia (reported in 223/870 (25.6%) patients evaluable for safety), caused 10 deaths, 6 of these being patients with severe liver impairment before inclusion. Fluid retention syndrome and other common non-haematological toxicities were well tolerated. 3.1% (28/889) of all patients and 11.4% of those with liver dysfunction, died from treatment-related causes. The overall response rate in 825 assessable patients was 22.9% (95% confidence interval (CI): 20.2-26.2%). Median time to treatment failure was 4 months (95% CI: 3.6-4.3) and median survival was 9.8 months (95% CI: 8.8-10.7). This report on the largest series of unselected advanced breast cancer patients treated with docetaxel, supports previous phase II studies, confirming docetaxel's utility in patients relapsing after failing anthracycline-containing palliative chemotherapy.