Trastuzumab versus observation for HER2 nonamplified early breast cancer with circulating tumor cells (EORTC 90091-10093, BIG 1-12, Treat CTC): a randomized phase II trial.

Background: Trastuzumab improves the outcome of women with HER2 positive breast cancer. We aimed to assess whether trastuzumab decreases the detection rate of circulating tumor cells (CTCs) in women with high risk, HER2 nonamplified, early breast cancer. Patients and methods: The EORTC 90091-10093 BIG 1-12 Treat CTC is a phase II trial, conducted in 70 hospitals and 6 CTC laboratories across 5 European countries. Patients with centrally confirmed HER2 nonamplified breast cancer and ≥1 centrally confirmed CTC per 15 ml of blood by CellSearch® following surgery and (neo)adjuvant chemotherapy were randomized (1 : 1) to 6 cycles of trastuzumab intravenously versus 18 weeks of observation. Randomization was stratified for center, locally confirmed estrogen receptor status and adjuvant versus neoadjuvant chemotherapy. The primary end point was rate of detection of ≥1 CTC per 15 ml of blood at week 18. Secondary end points were invasive disease-free survival (iDFS) and cardiac safety. Results: Between 30 April 2013 and 17 October 2016, 1317 patients were screened; 95 (7.2%) had detectable CTC(s), and 63 (4.8%) were randomized to trastuzumab (n = 31) or observation (n = 32). Fifty-eight patients were assessable for the primary end point, 29 in each arm. In 9 of the 58 patients, CTC(s) were still detected at week 18 : 5 in the trastuzumab and 4 in the observation arm (one-sided Fisher's exact test, P = 0.765). An Independent Data Monitoring Committee recommended stopping further accrual for futility for the primary end point. Median follow-up at database lock was 13 months (IQR 4-16.5). The 1-year iDFS was 93.8% (95% CI 77.3-98.4) in the observation versus 84.8% (95% CI 63.4-94.2) in the trastuzumab arm. No grade 2-4 cardiac events were observed in the trastuzumab arm. Conclusion: Trastuzumab does not decrease the detection rate of CTCs in HER2 nonamplified, nonmetastatic breast cancer.

A phase III trial of exemestane plus bevacizumab maintenance therapy in patients with metastatic breast cancer after first-line taxane and bevacizumab: a GINECO group study.

BACKGROUND: Maintenance strategies beyond response or tumor stabilization with first-line chemotherapy in metastatic breast cancer (MBC) have not been extensively studied. Endocrine therapy combined with continued bevacizumab may be a helpful option for estrogen receptor (ER)-positive MBC. PATIENTS AND METHODS: In this prospective, open-label, phase III study, patients with histologically confirmed ER-positive, HER2-negative MBC and non-progressive disease after 16-24 weeks of taxane plus bevacizumab (T + BEV) were randomized to continuation of T + BEV or maintenance bevacizumab plus exemestane (E + BEV). The primary end point was progression-free survival (PFS) from randomization. To have 80% power to detect an improvement in the 6-month PFS rate (PFS6m) from 50% to 65%, 186 assessable patients were needed for a total of 141 PFS events. An interim analysis was planned after 40% of the required events. RESULTS: The interim analysis with 98 patients showed that the probability of reaching a statistically significant improvement in PFS by the end of the study was only 7%. This led the Independent Data and Monitoring Committee to recommend termination of patient enrollment. After a median of 21-month follow-up of all randomized patients (117 in total), PFS6m from randomization was 67.2% [95% confidence interval (CI) 53.6-77.7] with T + BEV and 55.2% (95% CI 41.5-66.9) with E + BEV [hazard ratio (HR): 1.0, 95% CI 0.7-1.5, P = 0.998]. Median PFS from BEV initiation was 12.5 and 12.3 months in the T + BEV and E + BEV arms, respectively. In the T + BEV arm, taxane was prematurely stopped for the majority of patients (94.9%), mainly due to toxicity (49.2%). Updated data after 35 months' median follow-up showed death rates of 44% and 55% in T + BEV and E + BEV arms, respectively. CONCLUSION: In this trial, maintenance therapy with E + BEV in ER-positive, HER2-negative MBC patients with no evidence of progression after first-line T + BEV did not achieve longer PFS compared with continuation of T + BEV. CLINICALTRIALSGOV: NCT01303679.

Experience of multidisciplinary assessment of elderly patients with cancer in a French general hospital during 1 year: a new model care study.

OBJECTIVES: Our main aim was to describe and explore a multidisciplinary approach to the management of elderly patients with cancer, who constitute a heterogeneous population. MATERIALS AND METHODS: This descriptive study was performed between October 2009 and September 2010. Patients with cancer ≥ 70 years of age were included. Some underwent a simplified multidimensional geriatric assessment with a Charlson score administered by an oncologist, and the evaluation was submitted to a geriatrician who decided whether or not a complete a comprehensive geriatric assessment (CGA) (n=54) should be done. Another group of patients directly underwent a CGA (n=49), and a few patients included in a specific trial underwent a geriatric assessment (n=8). Each patient was classified as fit, vulnerable, or frail by a multidisciplinary team. RESULTS: 111 patients were included (median age: 81 years [range: 65-96]; 60 males). The most frequent types of cancer were lung (n=29), gastrointestinal (n=20) and head and neck (n=14). Median Charlson score was 2.1 [range: 0-9]. Standard therapy was given to 37/41 (90%) fit, 19/41 (42%) vulnerable, and 6/29 (21%) frail patients. Thirteen frail patients received best supportive care. A social worker was mobilized for 2/41 (5%) fit, 14/41 (34%) vulnerable, and 11/29 (38%) frail patients. CONCLUSIONS: Our study outlines the possibilities of cooperation between geriatricians and oncologists in a general hospital. This collaboration could modify therapeutic schedules especially in frail and vulnerable patients.

Intraperitoneal clearance as a potential biomarker of cisplatin after intraperitoneal perioperative chemotherapy: a population pharmacokinetic study.

BACKGROUND: Intraperitoneal (IP) perioperative chemotherapy with cisplatin is an interesting option in ovarian cancer treatment. A combination of cisplatin with IP epinephrine (already shown to improve IP and decrease systemic platinum (Pt) exposure) was evaluated using a population pharmacokinetic analysis. METHODS: Data from 55 patients treated with cisplatin-based IP perioperative chemotherapy with (n=26) or without (n=29) epinephrine were analysed using NONMEM. RESULTS: Epinephrine halves clearance between peritoneum and serum (IPCL) and increases the Pt central volume of distribution, IP exposure and penetration in tissue. IPCL has a better predictive value than any other parameter with respect to renal toxicity. CONCLUSION: This confirms that IPCL could be useful in assessing renal toxicity. As IPCL is also linked to tissue penetration and IP exposure, it may be proposed as biomarker. In addition to a Bayesian estimation, we propose a single-sample calculation-way to assess it. Prospective studies are needed to validate IPCL as a biomarker in this context.

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.

Results of a randomised phase II study comparing docetaxel with methotrexate in patients with recurrent head and neck cancer.

We report the results of a randomised phase II trial of docetaxel tested as a single agent in patients with recurrent head and neck cancer using methotrexate as a control arm to validate the results. Eligibility criteria included: histologically-confirmed squamous cell carcinoma, measurable disease, adequate haematological, renal and hepatic functions, no prior chemotherapy for recurrent cancer, signed informed consent. 40 mg/m2 methotrexate was given as a short weekly bolus i.v. injection, and 40 mg/m2 docetaxel was administered as a one hour weekly infusion. A total of 57 patients were randomised based on a ratio of 2/1:37 and 20 patients received docetaxel and methotrexate, respectively. Patient characteristics included 49 males and 8 females; the median age was 59 years (range: 43-82 years). Twenty-eight patients had a local-regional relapse and 29 had distant metastasis, the median disease-free interval was 7.9 months (range: 0-165 months). For patients treated with docetaxel, the following grade 3-4 toxicities occurred: neutropenia (12.5%) with febrile neutropenia in one patient (1%), anaemia (19%) mucositis (9%) and ungueal toxicity (9%). In the methotrexate arm, the grade 3-4 toxicities were: anaemia (15%) and mucositis (5%). The response rate was significantly higher in the docetaxel arm with 27% (95% confidence interval (CI): 21.7-32.3%) of objective responses versus 15% (95% CI: 11.2-18.8%) in the methotrexate arm. Overall survival and time to progression were super-imposable between the docetaxel and methotrexate treatments. Docetaxel given as a weekly infusion has a high activity in patients with head and neck cancer. A phase III trial is needed to test if this translates into a survival benefit for docetaxel use.

Phase I and pharmacokinetic study of the association of capecitabine-cisplatin in head and neck cancer patients.

The combination of cisplatin and 5-fluorouracil (5-FU) is considered to be the standard treatment in induction chemotherapy for patients with squamous cell carcinoma of the head and neck. Capecitabine (Xeloda) is an oral fluoropyrimidine that is preferentially activated at the tumoral level, exploiting the higher thymidine phosphorylase activity in tumoral tissue. This phase I trial was conducted in patients with locally recurrent or metastatic head and neck carcinoma. The treatment plan included cisplatin on day 1 every 21 days, followed by capecitabine twice daily from day 2 to day 15, with a 1-week rest period. Pharmacokinetic investigations concerned plasma measurement of unchanged capecitabine, 5'-deoxy-5-fluorocytidine, 5'-doxifluridine and 5-FU using an optimized high performance liquid chromatography method, and cisplatin measurement in plasma using a limited sampling procedure. Twenty-one patients were included (mean age 61 years, range 46-76 years). Dose (mg/m(2)) increments for cisplatin and capecitabine (b.i.d.), respectively, were as follows: level 1, 80 and 1000 (three patients); level 2, 100 and 1000 (12 patients); and level 3, 100 and 1125 (five patients). Dose-limiting toxicities occurring during the first cycle (grade >/= 3) were observed on level 2 (one patient with diarrhea, nausea, vomiting, hand-foot syndrome, one toxic death due to renal failure and neutropenia, one patient with neutropenia) and on level 3 (one patient with diarrhea, one patient with hand-foot syndrome and one patient with neutrothrombocytopenia). Due to delayed side-effects, 14 patients (67%) had repeated cycles every 28 days instead of 21 days as initially planned. Objective response was obtained in seven patients (three complete responses and four partial responses). There was no evidence of pharmacokinetic-pharmacodynamic relationships with the drugs and metabolites investigated. Combination of capecitabine and cisplatin is feasible, with a very promising response rate. The recommended doses for further phase II studies are those of level 2 with cisplatin 100 mg/m(2) on day 1 and capecitabine 1000 mg/m(2) b.i.d. on days 1-14, every 28 days.

[Epidermal growth factor receptors (EGFR): a new target for anticancer therapy]. / Les récepteurs à epidermal growth factor (REGF), une nouvelle cible thérapeutique.

Epidermal Growth Factor receptor (EGFR) are a key factor for the tumoral proliferation and its tumoral over expression appears to be a powerful prognosis factor. Currently, 2 types of treatments are targeting EGFR: a monoclonal antibodies anti-EGFR and a specific inhibitors of the EGFR tyrosine kinase. The administration of these compound alone or in combination with chemotherapy gives some promising results. These targets as anti-cancer therapy had emerged to be a new perspective for oncology.

Pharmacokinetics of low-dose carboplatin and applicability of a method of calculation for estimating individual drug clearance.

BACKGROUND: Carboplatin is the only cancer drug for which conventional doses are individually adjusted according to estimated clearance and target area under the curve (AUC). The aim of this prospective study was (i) to evaluate intra- and interpatient variability of ultrafilterable (UF) carboplatin AUC(0-)(infinity) and (ii) to test whether the prediction of carboplatin clearance according to the Chatelut formula established for conventional carboplatin doses was accurate for low carboplatin doses. MATERIALS AND METHODS: Thirty-one head and neck cancer patients (29 men, two women, mean age 55.9 years) received concomitant radiotherapy (Rgamma 2 Gy/day) and chemotherapy (carboplatin 50 mg/m(2)/day i.v.) for 7 weeks: Rgamma was administered 5 days/week (days 1-5) and carboplatin 2 days/week (days 1 and 4). Pharmacokinetics was performed once per week. A limited sample strategy based on Bayesian analysis was first validated and blood was subsequently taken 1 and 4 h after the end of carboplatin administration. RESULTS: A total of 143 cycles was analyzed. Ultrafilterable carboplatin AUC(0-)(infinity) ranged from 0.360 to 4.200 mg.min/ml (mean 0.830, median 0.670). As a corollary, UF carboplatin clearance ranged from 19.1 to 244.7 ml/min. Ultrafilterable carboplatin concentrations were very stable over time: AUC(0-)(infinity) variability due to treatment duration contributed to <1% of the total variance, while interpatient variability contributed to 68.6%. Accordingly, intrasubject effect was not significant (P = 0.38) whereas intersubject effect was highly significant (P <0.001). These results suggest that optimal dosage for targeting a given AUC may vary within a 13-fold range between patients. The Chatelut formula, based on creatininemia, body weight, age and sex, over estimates carboplatin clearance by 40% on average (bias 95% CI 29.6% to 51.1%). No significant relationship was observed between either bone marrow toxicity or creatinine clearance decrease and carboplatin pharmacokinetics. CONCLUSIONS: The Chatelut carboplatin clearance model established for conventional carboplatin dosages (>100 mg/m(2)) is not applicable for targeting low AUC (<1 mg x min/ml).

Results of randomised phase II studies comparing S16020 with methotrexate in patients with recurrent head and neck cancer.

BACKGROUND: The purpose of this study was to carry out two randomised phase II trials of S16020, a new olivacine derivative, tested as a single agent in patients with recurrent head and neck cancer, using methotrexate as the control arm to validate the results. PATIENTS AND METHODS: S16020 at either 80 or 100 mg/m2 was administered as a 3-h infusion every 3 weeks. Methotrexate, 40 or 50 mg/m2, was given by bolus injection, weekly for a minimum of 6 weeks. In total, 36 patients were entered in the randomised studies (25 in an initial study, 11 in a confirmatory study) of whom 24 received S16020 and 12 received methotrexate. RESULTS: A scheduled interim analysis showed one patient having a non-confirmed objective response with S16020 and three patients having a confirmed objective response with methotrexate. In the methotrexate group, there were no patients with severe non-haematological toxicity. With S16020, there was a high incidence of severe non-haematological toxicities, including asthenia, oedema of the face, oedema and pain at the tumour sites and erythematous rash; consequently, both studies were stopped. CONCLUSIONS: Both studies were stopped due to the poor anticipated benefit/risk ratio for S16020, although time to progression and overall survival time were similar in both treatment arms.

The relationship of epidermal growth factor receptor levels to the prognosis of unresectable pharyngeal cancer patients treated by chemo-radiotherapy.

The aim of this study was to analyse prognostic factors for time to treatment failure (TTF) and overall survival (OS) in patients with unresectable cancer of the pharynx. A twice daily (b.i.d.) radiotherapy with concomitant cisplatin-5-fluorouracil chemotherapy was administered to 77 consecutive patients (68 males, 9 females; median age: 56 years). The studied factors were: age, gender, tumour differentiation, tumour volume, initial hemoglobin level, karnofsky index (KI), primary tumour location, T, N, epidermal growth factor receptor (EGFR) level in the tumour (fmol/mg protein). KI and EGFR level were significant predictors in a multivariate analysis for TTF (P=0.004 and P=0.0001) and OS (P=0.004 and P=0.0001). In order to select subgroups with different outcomes, a stratification of patients was performed based on the EGFR value: patients with tumour EGFR levels <35 fmol/mg protein, between 35 and 275 fmol/mg protein and >275 fmol/mg protein had 95%, 51% and 16% 3 year OS rates, respectively (log rank test; P=0.0001). Interestingly, for patients exhibiting a complete response (CR) after concomitant b.i.d. chemo-radiotherapy, patients with EGFR levels <35 fmol/mg protein were all alive at 3 years; in contrast, there was only 70 and 13% 3 year survival rates for patients with EGFR tumour levels between 35 and 275 fmol/mg protein and above 275 fmol/mg protein, respectively. EGFR determination appears to be a powerful prognostic parameter in unresectable pharyngeal cancer patients treated by concomitant chemo-radiotherapy.

Clinical prognostic factors for patients with recurrent head and neck cancer: implications for randomized trials.

The purpose of our study was to determine the clinical prognostic factors for the duration of the overall survival from recurrence (OSR) in patients with recurrent head and neck squamous-cell carcinoma. We performed a retrospective analysis on 496 patients treated between 1982 and 1993 at the Antoine Lacassagne Center. The significant favorable prognostic factors for the OSR were: initial T(1-2) (p = 0.008), no initial nodal involvement (p = 0.002), no initial chemotherapy exposure (p = 0.002), induction chemotherapy response (p = 0.001), duration of disease-free interval (DFI; p = 0.0001), performance status (PS) 0-1 (p = 0.004) and local-regional recurrence (p = 0.001). In the multivariate analysis, the apparent nonsignificance of all factors apart from the DFI suggested that relevant prognostic factors could be embedded in the DFI. Multivariate analysis was performed after excluding the DFI. The results indicated that local-regional recurrence, PS 0-1 and no initial chemotherapy exposure remained significant favorable prognostic factors for the OSR. The advantages of taking into account such prognostic factors are to eliminate the patient selection bias and to ensure a fairer comparative evaluation of new or already existing agents in recurrent head and neck cancer.

Combination of cisplatin-doxorubicin-cyclophosphamide in adenocarcinoma of unknown primary site: a phase II trial.

The purpose of this report is to evaluate toxicity, response, and survival of the cyclophosphamide-doxorubicin-cisplatin (CAP) chemotherapy regimen in patients with adenocarcinoma of unknown primary site (ACUP). Twenty-two patients with ACUP were eligible for this study between June 1992 and April 1999. There were 13 men (59%) and 9 women (41%) with a median age of 53.5 years (range: 29--78 years). Lung (seven), liver (six), vertebral bone site (six), and abdominal nodes (six) were the most common metastatic sites. Treatment consisted of doxorubicin 50 mg/m(2), cyclophosphamide 1,000 mg/m(2), and cisplatin 100 mg/m(2) (CAP), administered every 3 weeks; a total of six courses were planned. Twenty-two patients were assessable for toxicity and 20 patients were assessable for response. Grade III to IV neutropenia was observed in 14 patients (64%); febrile neutropenia occurred in 6 patients (27%) and in 10 cycles (12.5%). Grade III to IV anemia and thrombocytopenia were found in 12 (54.5%) and 9 patients (41%), respectively. Grade III to IV nausea and vomiting was observed in 9 patients (41%). Ten patients, 50% of the assessable population, obtained an objective response, including 3 complete (15%) and 7 partial (35%) responses. The median response duration was 3.9 months (range: 0.5--13.3 months). One patient (5%) had stable disease and 5 patients (25%) had progressive disease. The median overall survival and the median time to progression were 10.7 months (range: 0.4--56.9 months) and 8.8 months (range: 6.6--16.5 months), respectively. The CAP regimen in patients with ACUP had significant activity. This chemotherapy regimen induced a high level of grade III to IV toxicities and could not be considered as a treatment of reference. However, the emergence of long-term survivors among responder patients highlighted the need to search for an active treatment for patients with ACUP.

Concomitant twice-a-day radiotherapy and chemotherapy in unresectable head and neck cancer patients: A long-term quality of life analysis.

BACKGROUND: The purpose of this study is to make a comparative analysis between acute toxicity with late toxicity. This study is based upon a French quality of life (QoL) questionnaire in a cohort of advanced head and neck (H&N) cancer patients treated by concomitant twice-a-day continuous radiotherapy with no acceleration and chemotherapy with cisplatin and 5-fluorouracil. METHODS: From September 1992 to November 1997, a prospective data bank of 91 patients was constituted. In November 1999, 31 patients were still alive and followed for more than 3 years. All patients had stage IV strictly unresectable squamous cell carcinoma of oropharynx or hypopharynx. A French specific H&N cancer QoL questionnaire was used at the end of radiotherapy and at the last date of follow-up of each patient (during 1999). p values reflect comparison of percentages obtained at the end of treatment with percentages at long-term follow-up. Statistical analysis was performed using chi(2) test (p <.05 considered as significant). Percentages obtained by the QoL questionnaire correspond to moderate-severe problems only. RESULTS: Twenty-nine of 31 (94%) patients participated in the QoL study. Acute treatment toxicities were severe with declines in virtually all QoL and functional domains. Globally, with an average long-term follow-up of 4.5 years (range 3-7 years after treatment), there is a statistical improvement in the following symptoms: dry mouth and sticky saliva (97% versus 55%, p <.05); tasting problems (35% versus 21%, not significant); swallowing problems (77% versus 36%, p <.05); and H&N pain (86% versus 9%, p <.05). Financial problems were not improved (21% versus 14%, not significant), and psychological problems (59% versus 5%) were statistically significant. Fourteen of 29 (48%) patients were drinking and 8 of 29 (28%) were smoking at long-term follow-up; at the diagnosis they were 86% and 90%, respectively. At long-term follow-up 22 of 29 presented good or very good QoL, and 25 of 29 said they had improved their initial QoL. CONCLUSION: The interest of twice-a-day radiotherapy with concomitant chemotherapy is to increase total radiotherapy equivalent dose without increasing late toxicity and also to improve locoregional control, survival, and long-term QoL/effectiveness ratio. Best supportive care is recommended to obtain both good QoL and cancer control in a long-term follow-up.

Phase II trial of a paclitaxel-carboplatin combination in recurrent squamous cell carcinoma of the head and neck.

OBJECTIVE: Twenty-seven patients with recurrent squamous cell carcinoma of the head and neck were entered in a multicenter study to determine the efficacy of the paclitaxel-carboplatin association. METHODS: Standard eligibility criteria applied, i.e. measurable disease, and chemotherapy given as induction treatment or concomitant chemoradiotherapy was allowed if completed more than 6 months prior to the study. Every 21 days, paclitaxel 175 mg/m(2) and carboplatin AUC 6 were administered. The patient group included 3 females and 24 males with a median age of 61 years (range 39-75 years). RESULTS: All patients were assessable for toxicity and 24 for responses. Main grade 3-4 toxicities were: neutropenia (62.9%), febrile neutropenia (18.5%), anemia (11.1%), thrombocytopenia (14.8%), mucositis (7.4%) and vomiting (7.4%). Among the intent-to-treat population, 29.6% of patients had an objective response, with a median response duration of 4.2 months (range 1-5.7 months). Stable and progressive disease were observed in 11.1 and 48.1% of patients, respectively. The median overall survival was 7.2 months (range 0.5-10.9 months). CONCLUSION: From these data, paclitaxel-carboplatin seems to have an activity in recurrent squamous cell carcinoma of the head and neck, but the high level of toxicity highlights the need to search for a safer chemotherapy combination.

An analysis of potential factors allowing an individual prediction of cisplatin-induced anaemia.

Severe cisplatin (CP)-induced anaemia significantly impairs the patient's quality of life. Prevention based on erythropoietin (EPO) administration would be cost-effective providing that individual predictive factors of anaemia are identified. The aim of the present study was to identify parameters able to predict the occurrence of CP-related anaemia. This prospective study was conducted on 40 head and neck cancer patients receiving a CP (100 mg/m(2), intravenous (i. v.) on day 1) - 5-fluorouracil (5-FU, 1 g/m(2)/dx5 days by continuous infusion) induction chemotherapy. Three cycles were given at 3-weekly intervals. Platinum pharmacokinetics (total and ultrafilterable plasma platinum concentration measured 16 h after CP administration) and 5-FU pharmacokinetics (full-cycle plasma area under the curve, (AUC(0-105h)30 g/l) occurred in 15 patients (38%) and 3 of them also received a blood transfusion. Patient age, 5-FU AUC(0-105h) and total platinum concentration were unrelated to Hb loss. In contrast, ultrafilterable (UF) platinum concentration was significantly correlated to Hb loss: the higher the UF platinum concentration, the greater the Hb loss (P=0.015). A discriminant analysis allowed a cut-off value for UF platinum to be proposed to identify patients developing significant loss of Hb: 91% of patients exhibiting a UF platinum concentration above 50 ng/ml developed significant loss of Hb in contrast to 18% in the group of patients with a UF platinum concentration below 50 ng/ml (odds ratio (95% confidence interval, CI) of 46 (4.7-446)). In conclusion, the present platinum pharmacokinetic survey may be proposed as a valuable approach to identify patients at risk for developing severe anaemia.

[Books published in Spain on smoking]. / Libros publicados en Espanã sobre tabaquismo.

Tobacco dependence, considered for a long time as a habit and, more recently, as an addiction, has many bad effects in health. The objective of this study was to analyse books published in this field in Spain. Books indexed in the ISBN Spanish database in CD-ROM (updated to 1993) dealing with addiction to tobacco, that included one of the following words: tabac*, tabak*, tabaq*, fuma*, fumad*, nicotine*, alquitran*, antitabac*, antitabaq*, cigarro*, cigarri*, exfumad*, pipa*, puro*, picadura* or filtro, were included in the study. Authors, ISBN classification, year of publication, language (of publication and original) and publishers were descriptively analysed. One hundred and four books were analysed. The highest number was published during the period 1990-1993 (42%); being 1993 (n = 15) and 1991 (n = 14) the most productive years. A big increase was observed from 1985. A great number (76% of books, n = 79) was written by personal authors and the 14% (n = 14) by public organizations. Most of the books (n = 88; 85%); were published in Spanish, followed by Catalan (n = 13; 13%); 21 books (20%) were translations: most of them from English (n = 12; 60%) or from French (n = 3; 14%). Forty six per cent of books was published by trade publishers and 31% by public organizations. According to the ISBN classification, these books were grouped in 20 different topics; but, most of them (70%) were included in three of these topics: hygiene (n = 42, 40%), pharmacology-toxicology-drugs (n = 18, 17%) and pathology-diseases and medical/therapeutical clinical practice (n = 14; 13%). The number of books published in Spain dealing with tobacco dependence has increased very much from 1985; it suggests that interest in this area in SPain has also increased. Most of the books are published in Spanish, and the most frequently translated language is English. These books are basically published by trade publishers and public organizations. These results have to be considered taking into account that fighting against consumption of tobacco and tobacco dependence is a relatively new area of research and study.

[International diffusion of the Spanish research on pain. Analysis of the period 1981-1990]. / Difusión internacional de la investigación española en algología. Análisis del período 1981-1990.

BACKGROUND: The significance of pain in medical practice has excited considerable interest among both practicing physicians and researchers. In Spain, interest in this field has come late. OBJECTIVE: To analyze the international dissemination of Spanish pain research during the period from 1981 through 1990. METHODS: All articles reporting research carried out in Spain and published during the period under study were collected and analyzed if they included the term "pain" as a keyword. The data bases used for collection were CD-ROM versions of Excerpta Medica CD Drugs & Pharmacology and MEDLINE: RESULTS: Articles considering pain to be a main topic numbered 228. Spanish contributions to the field tripled in the period studied. Half the articles were generated by either Anesthesia and Intensive Care or Pharmacology departments and were published mainly in REVISTA ESPANOLA DE ANESTESIOLOGIA Y REANIMACION (51), Medicina Clínica (17) and Revista Clínica Española (10). Most of the published articles reported clinical research (192), particularly in the areas of cancer pain (29), trials (20), and postoperative (20), neurological (15) and joint (12) pain. Most (67.6%) were published in Spanish. Although most articles listed four or more authors, only 2.4% of the authors and 17.7% of the centers published more than three articles. Most studies were carried out in hospitals (69.1%) or universities (18.2%), principally in Catalonia (26.7%), Madrid (18.2%) and Andalusia (17%). CONCLUSIONS: In spite of increased research seen in recent years, the dissemination of Spanish science may be limited because of its publications mainly in Spanish. Research is scattered, with only a small number of authors following a continuous line of research.

[Effect of acarbose on glycemia and pancreatic hormone secretion induced by usual meals in Spain]. / Efecto de la acarbosa sobre la glucemia y la secreción de hormonas pancreáticas inducida por comidas habituales en España.

Acarbose is a pseudotetrasaccharide of bacterial origin which, in a competitive and reversible way, inhibits intestinal alphaglycosidase. Following such mechanism of action, carbohydrates are not split to monosaccharides and, therefore, cannot be absorbed as easily as in normal conditions. Controlled clinical trials have shown the therapeutic usefulness of Acarbose in the treatment of mon-insulin dependent as well as insulin dependent Diabetes, specially in reducing postprandial hyperglycemia and glycosylated hemoglobin levels. The objective of this study was to evaluate the effect of Acarbose when it is used in a diet with a time-schedule and calorie distribution typical of a Spanish environment. A cross-over simple-blind study design was followed, in which 8 healthy volunteers, with ages between 23 and 29 years, took at 8:30 a.m. a 530 Kcal breakfast (18% of the daily total), at 13:30 p.m. a 1.400 Kcal lunch (40%), and at 21:00 p.m. a 1.070 Kcal dinner (36%). Before each of the meals 100 mg of Acarbose (or placebo, following a randomized distribution) were administered, and blood samples were drawn-10, 0, 30, 60, 90, 120, 150 and 180 minutes, in which glucose levels, insulin, pancreatic polypeptide and glucagon were determined. When Acarbose was administered statistically significant differences in glycemia and insulin postprandial figures were observed. It is concluded that when Acarbose is administered at a 100 mg dose (t.i.d.) together with a diet with a typically spanish calorie distribution and time-schedule, it produces a significant lowering in the postprandial glucose and insulin raises.(ABSTRACT TRUNCATED AT 250 WORDS)