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BACKGROUND Many transanal platforms have been developed to address the challenge of reach and vision when operating transanally. The single-port robot was specifically designed for narrow-aperture surgery and is a promising platform for minimally invasive transanal surgery. OBJECTIVE The purpose of this phase II trial is to evaluate the safety and feasibility of the initial clinical experience with single-port robot transanal minimally invasive surgery. DESIGN In a prospective phase II trial, patients with rectal neoplasms eligible for local excision were enrolled for single-port robotic transanal minimally invasive surgery. SETTING The study was conducted between October 2018 and March 2020 at a tertiary referral hospital. PATIENTS/INTERVENTION Twenty-six consecutive patients underwent single-port robotic transanal minimally invasive surgery resection of rectal lesions. MAIN OUTCOME MEASURES The primary end point of the study was the efficacy and safety of single-port robotic transanal minimally invasive surgery. RESULTS There were 13 men and 13 women, with an average lesion size of 2.9 cm (range, 1.0-6.0 cm) and average level of 4.8 cm from the anorectal ring (range, 0-30 cm). Ten patients had a preoperative diagnosis of adenocarcinoma, 7 of whom received neoadjuvant chemoradiation (range, 4500-5580 cGy with concurrent oral capecitabine). Eighty-eight percent of cases were completed by single-port robotic transanal minimally invasive surgery; 2 were converted to transanal endoscopic microsurgery, and 1 patient underwent a low anterior resection. There were no piecemeal extractions, and all margins were negative on final pathology. There were no mortalities, and the morbidity rate was 15.4%. There have been no local recurrences, with a mean follow-up of 5.8 months (range, 0-15.9 months). LIMITATIONS The study was limited by small sample size, short-term follow up, and a single-surgeon experience. CONCLUSION Single-port robotic transanal minimally invasive surgery procedures are safe and feasible in patients with select benign and malignant rectal lesions. Future trials will need to evaluate the long-term safety and efficacy of single-port robotic transanal minimally invasive surgery. See Video Abstract at http://links.lww.com/DCR/B605. PRIMERA EXPERIENCIA CLNICA CON CIRUGA MNIMAMENTE INVASIVA TRANSANAL ROBTICA DE PUERTO NICO ENSAYO DE FASE II DE LOS CASOS INICIALES ANTECEDENTES:Se han desarrollado muchas plataformas transanales para abordar el desafio del alcance y la vision cuando se opera de manera transanal. El robot de un solo puerto fue disenado especificamente para la cirugia de apertura estrecha y es una plataforma prometedora para la cirugia transanal minimamente invasiva.OBJETIVO:El proposito de este ensayo de fase II es evaluar la seguridad y viabilidad de la experiencia clinica inicial con la cirugia minimamente invasiva transanal con robot de puerto unico.DISENO:En un ensayo prospectivo de fase II, los pacientes con neoplasias rectales elegibles para la escision local se inscribieron para la cirugia minimamente invasiva transanal robotica de puerto unico.AJUSTE:El estudio se realizo entre octubre de 2018 y marzo de 2020 en un hospital de referencia terciario.PACIENTES / INTERVENCION:Veintiseis pacientes consecutivos fueron sometidos a cirugia minimamente invasiva transanal robotica de puerto unico para reseccion de lesiones rectales.PRINCIPALES MEDIDAS DE RESULTADO:El criterio de valoracion principal del estudio fue la eficacia y seguridad de la cirugia minimamente invasiva transanal robotica de puerto unico.RESULTADOS:Hubo 13 hombres y 13 mujeres, con un tamano de lesion promedio de 2.9 cm (rango 1.0-6.0 cm) y un nivel promedio de 4.8 cm del anillo anorrectal (rango 0-30 cm). Diez pacientes tenian un diagnostico preoperatorio de adenocarcinoma, 7 de los cuales recibieron quimiorradiacion neoadyuvante (rango 4500-5580 cGy con capecitabina oral concurrente). El 88% de los casos se completaron mediante cirugia minimamente invasiva transanal robotica de puerto unico; 2 se convirtieron a microcirugia endoscopica transanal y 1 se sometio a una reseccion anterior baja. No hubo extracciones parciales y todos los margenes fueron negativos en la patologia final. No hubo mortalidad y una tasa de morbilidad del 15,4%. No ha habido recidivas locales, con un seguimiento medio de 5,8 meses (rango 0-15,9 meses).LIMITACIONES:El estudio estuvo limitado por un tamano de muestra pequeno, un seguimiento a corto plazo y la experiencia de un solo cirujano.CONCLUSION:Los procedimientos de cirugia minimamente invasiva transanal robotica de puerto unico son seguros y factibles en pacientes con lesiones rectales benignas y malignas seleccionadas. Los ensayos futuros deberan evaluar la seguridad y eficacia a largo plazo de la cirugia minimamente invasiva transanal robotica de puerto unico. Consulte Video Resumen en http://links.lww.com/DCR/B605. (Traduccion-Dr. Eduardo Londono-Schimmer).

Objetivo: Analisar o glicogênio muscular, o perfil hematológico e as alterações eletrocardiográficas de ratos tratados com o medicamento a base de capecitabina. Metodologia: Foram utilizados ratos da linhagem Wistar, com 3 a 4 meses de idade e peso de 180 a 200 gramas da ANILAB®, sem restrição alimentar, com temperatura constante de 23 ± 2ºC e ciclo normal de dia e noite, com 12 horas. O medicamento foi administrado por gavagem em uma dose de 359mg/kg, dissolvida em tampão de citrato 40mM, contendo 5% de goma arábica como transporte. Resultados: Foi obsrvado que ocorreu diferença entre os grupos experimentais, sendo que os animais tratados com capecitabina tiverem concentrações menores de glicogênio hepático e muscular, além do medicamento diminuir os parâmetros hematológicos, resultando em alterações eletrocardiográficas importantes. Conclusão: O medicamento modifica a homeostasia metabólica tecidual e altera a reatividade cardiovascular tanto no padrão adrenérgico quanto colinérgico.

Introdução: O uso de antineoplásicos tem sido uma das melhores escolhas de tratamento para o câncer. A capecitabina uma droga utilizada em pacientes com cânceres já metastáticos, tem induzido á reações adversas dermatológica como a SMP (síndrome mão pé). Objetivo: Relatar uma experiência vivenciada numa paciente na unidade de internação de um hospital particular do estado de São Paulo, mostrando a importância de novas pesquisas e novas publicações a respeito de como conduzir e proporcionar qualidade de vida para pacientes em situações semelhantes. Método: Relato de experiência sobre a síndrome mão pé em uma paciente internada na unidade de internação de hospital privado do estado de São Paulo, referenciando os cuidados adequados, e as possíveis condutas. Resultados: Percebe-se a importância da síndrome mão pé (SMP), para a qualidade de vida de pacientes oncológicos em uso de linhas de tratamento que utiliza antineoplásicos com dose acumulativa que pode causar sintomas iniciais, é necessário um olhar diferenciado para não agravar ao nível de comprometer atividade de vida diária do paciente. Conclusão: Através desse relato podemos analisar o tão quanto os ensaios clínicos, novos relatos de experiência e novas comprovações cientificas estão em falta, qual se relaciona a SMP, existe pouca comprovações cientificas a respeito do tema.

La quimioterapia metronómica es un tipo de quimioterapia cuya toxicidad es mínima. Consiste en administraragentes antineoplásicos habituales a intervalos muy próximos uno del otro y a dosis relativamente bajasdurante un tiempo prolongado y sin periodos de descanso farmacológico. Esta terapia reduce la toxicidady elimina la necesidad de tratamientos de soporte, por lo tanto, el empleo de esta modalidad de tratamientoen pacientes con enfermedad metastásica resulta de gran interés. Muchas investigaciones han evaluado laadministración de medicamentos antineoplásicos en esquemas metronómicos, tanto en monoterapia comoen combinación. Los fármacos mayormente estudiados son la ciclofosfamida, vinorelbina y capecitabina.Diversos estudios han mostrado la eficacia y tolerancia de esta terapia combinada con la hormonoterapiae inmunoterapia. Es necesaria mayor evidencia científica para definir cuestiones como: pacientes que másbeneficio puedan obtener y las combinaciones terapéuticas a emplear de acuerdo al tipo de paciente., Metronomic chemotherapy is a type of chemotherapy whose toxicity is minimal. It consists of administeringusual antineoplastic agents at intervals very close to each other and at relatively low doses for a prolonged timewithout periods of pharmacological rest. This therapy reduce toxicity and eliminates the need for supportivetreatments, therefore, the use of this treatment modality in patients with metastatic disease is of great interest.Many investigations have evaluated the administration of antineoplastic drugs in metronomic schemes,both in monotherapy and in combination. The most studied drugs are cyclophosphamide, vinorelbine andcapecitabine. Several studies have shown the efficacy and tolerance of this therapy combined with hormonetherapy and immunotherapy. More scientific evidence is needed to define issues such as: patients who canobtain more benefit and the therapeutic combinations to be used according to the type of patients.

We report the case of a patient with a stage IV ab initio HR-/HER2 positive breast cancer. The patient, treated with pertuzumab and trastuzumab for approximately 8 months, developed a progression of both systemic and cerebral disease. Subsequent treatment with T-DM1 obtained disease control for about 10 months. Afterwards we suggested a therapy based on lapatinib and capecitabine with a clear lasting response at encephalic level. This clinical case suggests that the combination of lapatinib + capecitabine is a valid option in case of double-block progression of HER2 and T-DM1. The interesting activity of lapatinib at encephalic level indicates the drug as one of the best therapeutic options available today in this patient setting (Oncology)

Capecitabine is a prodrug used primarily as a chemotherapeutic agent. Despite its good tolerance, it has several adverse effects, including the appearance of eruptive nevi. We present the case of a patient, with a history of EC IV breast adenocarcinoma and superficial extension melanoma, which developed 2 weeks after the start of therapy with capecitabine multiple eruptive palmoplantar pigmented lesions, with diverse benign dermatoscopic patterns. With the increasing incidence of solid tumors, these agents are being more used. It is important that the treating physician knows its adverse effects and apply non-invasive diagnostic tools like dermoscopy to avoid unnecessary biopsies.

espanolLas complicaciones cardiovasculares son efectos probables de la quimioterapia y pueden abarcar distintas manifestaciones. Para advertir del riesgo del uso de farmacos citotoxicos y de sus efectos adversos cardiovasculares, describimos el caso de una paciente que fue tratada con CPT 11 (irinotecan), capecitabina y bevacizumab, por un adenocarcinoma de colon en estadio avanzado y que desarrollo un sindrome coronario agudo sin elevacion del segmento ST. Consideramos como agente causal mas probable la capecitabina, que es un agente quimioterapico oral empleado como tratamiento de primera linea en el cancer de colon metastasico y de segunda linea en el cancer de mama. Son conocidos sus efectos adversos gastrointestinales, dermatologicos y sobre la medula osea; sin embargo, menos frecuente es la toxicidad cardiologica. EnglishCardiovascular toxicity is a potential complication of anticancer therapies and may include a wide range of manifestations. In order to create awareness of the risk of cytotoxic drugs use and their cardiac side-effects, we report the case of a patient who received treatment with CPT- 11 (irinotecan), capecitabine and bevacizumab due to an advanced- stage colon adenocarcinoma, who developed an acute coronary syndrome without ST elevation. We consider capecitabine as the most plausible inducement of this event, which is an oral chemotherapeutic drug used as first-line treatment in metastatic colon cancer and second-line in breast cancer. Gastrointestinal, cutaneous and hematological are established side effects of capecitabine. Cardiac toxicity is uncommon, even though its range of occurrence is increasing due to the ageing population.

Le Lupus erythemateux aigue(LEA) chimio-induit est une affection rare, quelques cas ont ete rapporte dans la litterature incriminant la capecitabine, le paclitaxel et le docetaxel. Nous rapportons le cas d’une patiente âgee de 64 ans suivie pour carcinome canalaire invasif du sein droit, d’emble metastatique au niveau hepatique et ganglionnaire, sans antecedents de maladies auto-immunes ou d’allergie medicamenteuse. Apres une premiere ligne de chimiotherapie type AC60 (6 cures au total), elle a recu le docetaxel a la dose de 100 mg/m2, apres 5 cures elle a presente des lesions erythemateuses diffuses au niveaux des deux mains, des avants bras, des deux joues et en peribuccale, elle a ete mise sous corticotherapie avec protection solaire, on a pu poursuivre la meme chimiotherapie jusqu’a la huitieme cure. L’evolution a ete marque par la progression de sa maladie elle a ete mise sous capecitabine a la dose de 1250 mg/m2 deux fois par jours, apres six cures elle a presente des plaques erythemateux-squameuse et prurigineuse du visage, disposee en aille de papillon avec ulceration buccale et pulpite des doigts (Panel C) faisant evoque en premier un lupus erythemateux cutane aigue chimio-induit. Une biopsie a ete realisee qui etait en faveur d’une toxidermie lichenoide. Un bilan immunologique a ete demande pour eliminer un LEA chimio-induit, objectivant des anticorps anti DNA natif et des anticorps anti-histones negatifs, les anticorps anti-nucleaires sont positives a 320, ces derniers peuvent etre positives dans 50 a 70% des cas de cancer mammaire, ORL ou lymphome. Au vu de ces resultats le diagnostic de toxidermie est le plus probable.

BACKGROUND: The CAIRO3 and AIO 0207 trials demonstrated the efficacy of fluoropyrimidine plus bevacizumab (FP+Bev) maintenance treatment in metastatic colorectal cancer (mCRC) patients. In this individual patient data meta-analysis with updated follow-up, we aim to provide more precise estimates of treatment effects and to identify subgroups that benefit most from maintenance treatment or observation. METHODS: In 871 patients, randomised to FP+Bev maintenance treatment or observation, we investigated whether treatment effect was modified by sex, age, performance status, response to induction treatment, primary tumour location, number of metastatic sites, disease stage and primary tumour resection, serum LDH, platelet count, CEA, and RAS/BRAF mutation status. Primary end point was time to second progression after reintroduction of the induction regimen (PFS2). Secondary end points were first progression-free survival (PFS1) and overall survival (OS). RESULTS: At a median follow-up of 68.5 months (IQR 54.6-87.0 months), maintenance treatment was more effective compared with observation in PFS1 (HR 0.40(95% CI 0.34-0.47)) and PFS2 (HR 0.70(0.60-0.81)). No subgroups were identified that did not benefit from maintenance treatment in PFS1 and PFS2; no clinically relevant subgroup effects were observed. Regarding OS, pooled results were not significant (HR 0.91(0.78-1.05)), and the trials showed marked heterogeneity in overall treatment effect and subgroup effects. CONCLUSIONS: FP+Bev maintenance treatment is effective in all patients, regardless of the investigated subgroups. info:eu-repo/semantics/publishedVersion

Background: Capecitabine is known to rarely cause raised serum triglycerides (TG). In our centre, several patients receiving capecitabine developed raised TG levels corresponding to the ‘very high risk' category for potentially serious acute pancreatitis. Methods: A fasting blood lipid screening protocol was introduced into clinical practice for patients receiving capecitabine. Patients with TGs >5 mmol l−1 were treated and followed up. An 18-month prospective audit was performed to establish the incidence and severity of capecitabine-induced hypertriglyceridaemia (CIHT). Results: A total of 304 patients received capecitabine for colorectal cancer between January 2008 and June 2009. Of these, 212 patients (70%) were screened and 8 (3.7%) developed clinically significant hypertriglyceridaemia requiring lipid-lowering therapy. Two of the eight patients had diabetes and one had pre-existing dyslipidaemia. One suffered cerebral infarction during chemotherapy. There were no cases of acute pancreatitis. Follow-up showed that serum TGs safely and rapidly returned to normal with appropriate treatment without discontinuation of capecitabine. Conclusions: This is the first prospective study evaluating CIHT. These results suggest that it should be classed as a ‘common' undesired effect of capecitabine. Despite this, the incidence does not justify routine screening in all patients. Targeted screening in those with diabetes or pre-existing hyperlipidaemia is recommended, together with adoption of a clear management policy.

The complexity of cancer chemotherapy requires pharmacists be familiar with the complicated regimens and highly toxic agents used. This column reviews various issues related to preparation, dispensing, and administration of antineoplastic therapy, and the agents, both commercially available and investigational, used to treat malignant diseases.

Actas Dermosifiliogr. 2009;100:329-43 338 7. Chen GY, Chen YH, Hsu NM, Tsao CJ, Chen WC. Onychomadesis and onycholisis associated with capecitabine. Br J Dermatol. 2001;145:521-2. 8. Vazquez-Bayo C, Rodriguez-Bujaldon AL, Jimenez-Puya R, Galan-Gutierrez M, Moreno-Gimenez JC. Hiperpigmentacion secundaria a capecitabina. Actas Dermosifiliogr. 2007; 98:491-3. 9. Pui JC, Meehan S, Moskovits T. Capecitabine induced cutaneous hyperpigmentation: report of a case. J Drug Dermatol. 2002;1:202-5. 10. Tavares-Bello R. Capecitabine-induced hand-foot syndrome and cutaneous hyperpigmentation in an elderly vitiligo patient. J Eur Acad Dermatol Venereol. 2007;21:1434-5.

Actas Dermosifiliogr. 2009;100:329-43 338 7. Chen GY, Chen YH, Hsu NM, Tsao CJ, Chen WC. Onychomadesis and onycholisis associated with capecitabine. Br J Dermatol. 2001;145:521-2. 8. Vazquez-Bayo C, Rodriguez-Bujaldon AL, Jimenez-Puya R, G a l a n G u t i e r r e z M , M o r e n o G i m e n e z J C . Hiperpigmentacion secundaria a capecitabina. Actas Dermosifiliogr. 2007;98:491-3. 9. Pui JC, Meehan S, Moskovits T. Capecitabine induced cutaneous hyperpigmentation: report of a case. J Drug Dermatol. 2002;1:202-5.

Capecitabine, a prodrug of 5-fluorouracil (5-FU), is rarely associated with severe hypertriglyceridemia. We present a patient with severe capcitabine-induced hypertriglyceridemia, with the literature review.A 50-year-old woman with metastatic breast carcinoma was treated with oral capecitabine. She was also receiving bezafibrate due to hyperglycenemia. Pretreatment lipid profile revealed slight elevation of serum triglycerides and total cholesterol. A repeat lipid profile performed 5 weeks after the start of capecitabine treatment revealed a marked increase in the serum triglyceride and cholesterol levels. The dose of bezafibrate was increased, atorvastatin was added, and the next cycle of capecitabine was withheld. When the triglyceride and cholesterol levels had decreased, capecitabine was started with reduced dose. However, at the end of this cycle, the triglyceride and the cholesterol levels increased again.Monitoring of the lipid profile should be considered in cancer patients receiving capecitabine, particularly those with a known diagnosis of dyslipidemia.

Im Rahmen von toxischen Arzneimittelreaktionen, insbesondere als Folge von Chemotherapien, zahlt die palmoplantare Erythrodysasthesie (PPE) mit einer Inzidenz von 6–64%, unter Capecitabine-Monotherapie von 10–24%, zu den haufigen unerwunschten Nebenwirkungen der Haut unter Chemotherapie. So sollte beim Auftreten von akralen Hauterscheinungen insbesondere unter Therapie mit Capecitabine (Xeloda®) differenzialdiagnostisch an eine PPE gedacht werden und eine Reduktion des Zytostatikums oder eine Anderung des Therapiemoduls veranlasst werden. In diesem Fallbericht wird erstmalig eine Patientin vorgestellt, die unter Capecitabine-Therapie das Krankheitsbild einseitiger akraler Nekrosen entwickelte, das als Abortivform einer PPE gewertet werden musste.

A 72-year-old patient with esophageal carcinoma developed a severe hand-foot syndrome during second-line therapy with the oral fluoropyrimidine capecitabine. We also summarize the current knowledge with regard to the hand-foot syndrome and distinguish it from palmoplantar erythrodysesthesia.

The aim of this study was to determine the dose-limiting toxicity (DLT) and establish the recommended dose for mitomycin C added every 3 weeks to the standard combination dose of capecitabine. Cohorts of at least three patients with pretreated gastrointestinal carcinoma received capecitabine 1000 mg m(-2) orally twice daily on days 1-14 plus i.v. bolus mitomycin C on day 1 at doses of 4, 6, 8 or 10 mg m(-2) (corresponding to dose levels I-IV). Cycles were repeated every 3 weeks. Two treatment cycles were considered for the evaluation of DLTs. Of the 53 patients enrolled, the majority had colorectal (n=27) or gastric (n=14) cancers. Patients had received a median of two lines of prior chemotherapy (34% with/=3 lines and 87% with prior 5-FU-based therapy). At the recommended dose level (IV, n=30), grade 3 adverse events during cycles 1 and 2 were: anaemia (10%); leukopenia (3%); thrombocytopenia (3%); stomatitis/mucositis (3%); hand-foot syndrome (3%). Two patients experienced DLTs (mucositis, n=1; neutropenic fever, n=1), but there were no grade 4 events. The median dose intensity for capecitabine and mitomycin C was 100% during cycles 1 and 2 and only four patients required postponement of therapy. Of the 43 patients evaluable for efficacy, seven achieved partial and minor remissions (16%; 95% CI, 5-28%), and 12 patients (28%) had stable disease. The favourable safety profile and promising activity of the capecitabine/mitomycin C combination, even in heavily pretreated patients, warrant further evaluation in patients with advanced colorectal and gastric cancers.

The goal in administering chemotherapeutics is to develop the ability to predict the outcome of therapy in terms of response and toxicity. Technology has been developed to allow tumor profiling with measurement of protein expression, gene expression levels of markers, and even genetic polymorphisms, which may predict response to particular chemotherapeutics. The chemotherapeutics for which particular markers have been shown to predict outcome include the fluoropyrimidines and platinums. The next step is to develop clinical trials that will assess prospectively the benefits of profiling a patient's particular tumor, which should translate into an improvement in response and toxicity.

Objectives: To evaluate the efficacy and safety of capecitabine in patients with advanced or recurrent gastric cancer, we conducted a pilot phase II study in Japan. Methods: Patients with advanced or recurrent gastric cancer were given oral capecitabine 828 mg/m2 twice daily for 3 weeks, followed by 1 week of no treatment. Two or more cycles were administered. From July 1996 to December 1997, 32 patients were enrolled in the study. The response to capecitabine was evaluated in 31 patients, excluding 1 found to be ineligible. Results: The overall response rate was 19.4% (6/31, 95% confidence interval: 7.5–37.5%). The median duration of response was 124.5 days, the median time to disease progression 85.0 days, and the median survival time 247.5 days. Drug-related adverse events of grade 3 or higher were infrequent: in 2 patients (6.3%) total bilirubin concentration increased, and 1 patient (3.1%) each had elevation of GOT, anemia, lymphopenia, increased creatinine, and hand-foot syndrome. No patient had gastrointestinal toxicity of grade 3 or higher. Conclusion: Capecitabine was suggested to be safe and effective in the treatment of advanced or recurrent gastric cancer. Further phase II studies of capecitabine on a large scale are warranted.

Cette session de l’ASCO a confirme le role croissant des therapies ciblees dans le traitement du cancer du seinmetastatique.Mais, une fois n’est pas coutume, la presentation « vedette » concernait les patientes HER2-negatives, avec l’etude AVADO (Abstract LB 1011), testant la place du bevacizumab (B) en association au docetaxel (D) en premiere ligne metastatique. Le benefice de l’association bevacizumab et paclitaxel avait ete presente a l’ASCO 2005 (et publie en decembre dernier) conduisant a l’attribution d’une autorisation de mise sur marche (AMM) en 2007. Les resultats d’un schema incorporant ledocetaxel,plusclassiquedansnos protocoles, etaient tres attendus. Dans l’etude AVADO, 736 patientes ont ete randomisees pour recevoir, soit D 100 mg/m + placebo (P), soit D 100 + B 7,5 mg/kg, soit D 100 + B 15 mg/kg (schema j1-j21). Les patientes pouvaient recevoir au maximum neuf cycles de D, le bevacizumab etait poursuivi jusqu’a progression. Les caracteristiques des patientes etaient bien equilibrees dans les trois bras (environ 55 % de chimiotherapie adjuvante dont 15 % de taxanes, 41/49/49 % de patientes presentant trois sites metastatiques ou plus, 50/40/ 46 % de metastases hepatiques). L’objectif principal etait la mediane de survie sans progression (SSP), avec l’hypothese d’un gain de 2,6 mois (6 versus 8,6). Avec un suivi median de 10,2 mois, la SSP est significativement amelioree dans les deux bras incorporant le bevacizumab (hasard ratio [HR] respectif de 0,79 et 0,72), avec une mediane de 8 mois pour le bras placebo versus 8,7 et 8,8 mois pour les bras B 7,5 et B 15. On observe aussi une amelioration significative du taux de reponse objective (RO) ; lasurvieglobalen’estpas evaluable, puisque 80 % des patientes sont encore en vie dans chaque bras. Le benefice en SSP est retrouve pour tous les sous-groupes prevus dans l’analyse. L’administration de bevacizumab n’entraine pas de majoration significative de la toxicite (HTA, hemorragie, neutropenie...). Au total, meme si l’amplitude du benefice obtenu par l’adjonction de bevacizumab au docetaxel parait moindre qu’avec le paclitaxel, l’etudeAVADOconfirmecebenefice sur le taux de reponse et la survie sans progression. Ces deux etudes concordantes positionnent donc le bevacizumab comme une option possible en premiere lignemetastatique si le choixde la chimiotherapie s’est porte sur un taxane en monotherapie.

Background: Onycholysis, which is separation of the nail plate from the nail bed at its distal and lateral attachments, can cause pain and impair function and is a well-known side effect of traditional chemotherapeutic agents. Objectives: We present two cases of onycholysis associated with capecitabine in women with advanced breast cancer, who were initially referred for evaluation of onychomycosis and review the literature on capecitabine. Conclusion: Owing to the increased frequency of use of capecitabine for different cancers, physicians should be aware of this side effect.

For over four decades, 5-fluorouracil (5-FU) has been the mainstay of therapy for colorectal cancer and a major cytotoxic agent for treating gastrointestinal tumors and a variety of others, including breast and head and neck cancers. Xeloda® (capecitabine) is a new drug that is administered orally and has been rationally designed to generate 5-FU selectively within solid tumors. Theoretically, it has two major advantages, which should translate into an improved therapeutic index: firstly, enhanced drug concentration at the cancer site and therefore greater anti-tumor activity and secondly, reduced drug levels in non-tumor tissues, with a consequent reduction in systemic toxicity. After promising preclinical studies, phase I clinical trials of Xeloda have been performed with a variety of schedules, both with and without the oral biomodulator leucovorin. Anti-tumor activity has been observed with all regimens tested. In the setting of colorectal cancer, a randomized phase II study substantiated the phase I reports of activity and established the most promising regimen for phase III clinical trials. Patients in the phase II trial were randomly selected to receive either continuous Xeloda, intermittent Xeloda or intermittent Xeloda plus leucovorin. There were complete or partial responses in 21% of patients in the continuous arm, 24% in the intermittent arm, and 23% in the arm with intermittent Xeloda plus leucovorin. In addition, 51–63% of patients in each arm achieved stable disease. Therapy was well tolerated in all three arms. The intermittent regimen of Xeloda alone was associated with a longer time to disease progression and offered a one-week rest period to the patient. It was therefore selected for subsequent studies. Two randomized phase III trials of Xeloda versus the ’Mayo’ regimen in patients with advanced colorectal cancer have completed recruitment. They are designed to demonstrate at least equivalent efficacy, with important secondary endpoints of comparisons of toxicity, medical care utilization, and quality of life. No formal results are yet available from these studies. The same regimen of Xeloda is now being evaluated in a large scale adjuvant study, which is expected to recruit approximately 1,700 Dukes’ C colonic cancer patients (X-ACT study). The modest toxicity of Xeloda (particularly its low incidence of neutropenia) makes it a suitable candidate for novel combination therapies involving other agents that are active in colorectal cancer, including camptothecin and its analogues, oxaliplatin and radiotherapy. Further studies of Xeloda can be expected with other diseases known to be responsive to fluoropyrimidines, together with diseases traditionally thought to be resistant.

5-Fluorouracil (5-FU) plays an important role in the treatment of several tumor types, particularly colorectal cancer and breast cancer. Xeloda® (capecitabine; 5′-deoxy-5-fluoro-N-[(pentyloxy)carbonyl-cytidine]) is a new rationally designed fluoropyrimidine carbamate. It is administrated orally and after absorption it is first metabolized to 5′-deoxy-5-fluorocytidine (5′-DFCR) by carboxylesterase from the liver and then converted to 5′-deoxy-5-fluorouridine (5′-DFUR) by cytidine deaminase from the liver and tumor tissues. Finally, thymidine phosphorylase (TP) converts 5′-DFUR to 5-FU. TP is more active in tumor tissues than in normal tissue. This tissue localization pattern results in preferential metabolism and generates higher levels of 5-FU in malignant tissue, thus enhancing efficacy but minimizing side effects. The tumor tissue selectivity was confirmed in a study of 19 patients with colorectal cancer. After Xeloda administration, concentrations of 5-FU were 2.5 times higher in the primary tumor compared with adjacent healthy tissue. Xeloda was highly active in human tumor xenografts. It was more active than 5-FU, 5′-DFUR and tegafur plus uracil (UFT) and had a better therapeutic index. Xeloda also demonstrated synergistic or additive activity when used in combination with cyclophosphamide, methotrexate, doxorubicin, paclitaxel and docetaxel. This may be in part a result of up-regulation of TP by the cytotoxic agents. Phase I and II clinical trials have shown that Xeloda is active across a range of tumor types, and phase III studies are ongoing.

Capecitabine is used to treat advanced breast and gastrointestinal malignancies. A single case of encephalopathy and three cases of peripheral neuropathy are the only neurotoxicities reported. The authors report five additional cases of capecitabine-induced multifocal leukoencephalopathy.

Background: This phase 1 study evaluated the maximum tolerated dose (MTD), safety, and efficacy of bosutinib (competitive Src/Abl tyrosine kinase inhibitor) plus capecitabine. Methods: Patients with locally advanced/metastatic breast, pancreatic, or colorectal cancers; cholangiocarcinoma; or glioblastoma received bosutinib plus capecitabine at eight of nine possible dose combinations using an ‘up-down' design to determine the toxicity contour of the combination. Results: Among 32 enrolled patients, none of the 9 patients receiving MTD (bosutinib 300 mg once daily plus capecitabine 1000 mg m−2 twice daily) experienced dose-limiting toxicities (DLTs). Overall, 2 out of 31 (6%) evaluable patients experienced DLTs (grade 3 neurologic pain (n=1); grade 3 pruritus/rash and increased alanine aminotransferase (n=1)). Most common treatment-related adverse events (AEs) were diarrhoea, nausea, vomiting, palmar-plantar erythrodysesthesia (PPE), fatigue; most frequent grade 3/4 AEs: PPE, fatigue, and increased alanine/aspartate aminotransferase. Although diarrhoea was common, 91% of affected patients experienced maximum grade 1/2 events that resolved. Best overall confirmed partial response or stable disease >24 weeks (all tumour types) was observed in 6 and 13% of patients. Conclusions: In this population of patients with advanced solid tumours, bosutinib plus capecitabine demonstrated a safety profile similar to that previously reported for bosutinib or capecitabine monotherapy; limited efficacy was observed.

Purpose: To determine the dose-limiting toxicities (DLTs) and the maximum-tolerated doses of the paclitaxel, oxaliplatin (LOHP) and capecitabine combination in patients with advanced solid tumors. Patients and Methods: Patients received escalating doses of paclitaxel (starting dose 100 mg/m2) and LOHP (starting dose 40 mg/m2) on days 1 and 15 and capecitabine (starting dose 800 mg/m2/day) on days 1–7 and 15–21 every 28 days. DLTs were evaluated in the first cycle. Results: Sixteen patients were treated at four dose-escalating levels. Eleven (68.7%) patients had received two or more prior chemotherapy regimens. The DLT level was reached at paclitaxel 110 mg/m2, LOHP 50 mg/m2 and capecitabine 1,000 mg/m2/day. DLTs due to grade 2–3 neutropenia resulted in treatment delays. No febrile neutropenia or treatment-related death occurred. Grade 2–3 neutropenia occurred in 3 (19%) patients each, grade 2–4 fatigue affected 6 (37.5%) patients, and grade 2–3 neurotoxicity was observed in 2 (12.5%) and 1 (6%) patients, respectively. Two partial responses and four disease stabilizations were achieved. Conclusion: The recommended doses for phase II studies are paclitaxel 100 mg/m2 and LOHP 50 mg/m2 on days 1 and 15 and capecitabine 1,000 mg/m2/day on days 1–7 and 15–21 every 4 weeks. This regimen is well tolerated and merits further evaluation.

The authors report the case of a 70-year-old man with metastatic colon cancer and no known history of coronary disease or major risk factors who developed coronary vasospasm after the initiation of capecitabine (Xeloda®). Although coronary vasospasm has been associated with another older fluoropyrimidine compound, 5-fluorouracil, this is the first reported occurrence with this relatively newer cancer drug.

Objectives: Capecitabine (CAP) and oxaliplatin (OX) have shown interesting activity in a wide range of solid tumors. A phase I study was conducted in order to determine the maximum tolerated dose (MTD) and dose-limiting toxicity (DLT) of their combination in patients with refractory solid tumors. Patients and Methods: Thirty-three pretreated patients with histologically confirmed inoperable neoplasms were enrolled. The patients’ median age was 64 years, 21 were males, and 27 had a WHO performance status of 0–1. OX was administered on days 1 and 8, as a 3-hour intravenous infusion, at escalated doses ranging from 50 to 70 mg/m2. CAP was administered orally for 14 consecutive days, at escalated doses ranging from 1,200 to 2,100 mg/m2/day. Treatment was repeated every 3 weeks. Results: At the dose of 2,100 mg/m2 (Xeloda) and 70 mg/m2 (OX), all 3 enrolled patients presented DLT (grade 3 diarrhea, grade 3 asthenia and grade 3 neurotoxicity, respectively), and, thus, the recommended MTD for future phase II studies are 2,000 mg/m2 for CAP and 70 mg/m2 for OX. A total of 145 treatment cycles were administered. Toxicity was very mild. Grade 2/3 neutropenia was observed in 4 (3%) treatment cycles. The main nonhematologic toxicities were grade 2/3 nausea/vomiting (7 cycles; 5%), grade 2/3 neurotoxicity (10 cycles; 7%), grade 2/3 asthenia (8 cycles; 5.5%) and grade 2/3 diarrhea (6 cycles; 4%). There was no treatment-related death. One (4%) complete remission, 2 (8%) partial remissions, and 9 (36%) cases of stable disease were observed among 25 evaluable patients. Conclusions: The results demonstrate that CAP and OX can be safely combined at clinically relevant doses and that this regimen merits further evaluation.