Continuous versus intermittent extended adjuvant letrozole for breast cancer: final results of randomized phase III SOLE (Study of Letrozole Extension) and SOLE Estrogen Substudy.

BACKGROUND: Late recurrences in postmenopausal women with hormone receptor-positive breast cancers remain an important challenge. Avoidance or delayed development of resistance represents the main objective in extended endocrine therapy (ET). In animal models, resistance was reversed with restoration of circulating estrogen levels during interruption of letrozole treatment. This phase III, randomized, open-label Study of Letrozole Extension (SOLE) studied the effect of extended intermittent letrozole treatment in comparison with continuous letrozole. In parallel, the SOLE estrogen substudy (SOLE-EST) analyzed the levels of estrogen during the interruption of treatment. PATIENTS AND METHODS: SOLE enrolled 4884 postmenopausal women with hormone receptor-positive, lymph node-positive, operable breast cancer between December 2007 and October 2012 and among them, 104 patients were enrolled in SOLE-EST. They must have undergone local treatment and have completed 4-6 years of adjuvant ET. Patients were randomized between continuous letrozole (2.5 mg/day orally for 5 years) and intermittent letrozole treatment (2.5 mg/day for 9 months followed by a 3-month interruption in years 1-4 and then 2.5 mg/day during all of year 5). RESULTS: Intention-to-treat population included 4851 women in SOLE (n = 2425 in the intermittent and n = 2426 in the continuous letrozole groups) and 103 women in SOLE-EST (n = 78 in the intermittent and n = 25 in the continuous letrozole groups). After a median follow-up of 84 months, 7-year disease-free survival (DFS) was 81.4% in the intermittent group and 81.5% in the continuous group (hazard ratio: 1.03, 95% confidence interval: 0.91-1.17). Reported adverse events were similar in both groups. Circulating estrogen recovery was demonstrated within 6 weeks after the stop of letrozole treatment. CONCLUSIONS: Extended adjuvant ET by intermittent administration of letrozole did not improve DFS compared with continuous use, despite the recovery of circulating estrogen levels. The similar DFS coupled with previously reported quality-of-life advantages suggest intermittent extended treatment is a valid option for patients who require or prefer a treatment interruption.

[Demons-Meigs syndrome secondary to an ovarian Brenner tumour. Case report and literature survey]. / Syndrome de Demons-Meigs secondaire à une tumeur de Brenner. Présentation d'un cas clinique et revue de la littérature.

A 65-year old woman presents with a Demons-Meigs syndrome characterized by dyspnea resulting from a transsudative pleural effusion, an important unilateral right ovarian mass and ascites. The diagnosis of a Brenner type histology was obtained after complete surgical removal of ovarian tumor. After discharge the patient entered in a sustained complete response and thus potential cure. Brenner tumor is a rare and often benign ovarian affection. The clinical signs aren't generally much specific: pelvic pain or heaviness, metrorrhagia and menstrual irregularity may be observed. Brenner tumor may exceptionally induce a Demons-Meigs's syndrome. This syndrome associates one or more benign tumors of the female reproductive tract with pleural and peritoneal effusions. This could depict a rich but disturbing clinical picture. The prognosis and the regression of the symptomatology are nevertheless excellent after tumor surgical resection.

Les auteurs rapportent le cas d'une patiente de 65 ans admise pour un syndrome de Demons-Meigs caractérisé par une dyspnée sur épanchement pleural transsudatif, une masse ovarienne unilatérale volumineuse et de l'ascite. La résection complète de la masse tumorale permettra le diagnostic de tumeur de Brenner de l'ovaire droit et sera soldée par la disparition de tout signe clinique et, a priori, la guérison de la patiente. La tumeur de Brenner est une affection ovarienne rare et généralement bénigne. Les signes cliniques sont généralement peu spécifiques : douleurs ou pesanteurs pelviennes, métrorragies ou encore une irrégularité du cycle menstruel peuvent être observées. La tumeur de Brenner peut, exceptionnellement, s'inscrire dans un syndrome de Demons-Meigs. Ce syndrome, associant une ou plusieurs tumeurs bénignes de l'appareil génital féminin à un épanchement pleural et péritonéal, peut donner un tableau clinique plus riche, mais aussi plus alarmant. Le pronostic, avec la régression de la symptomatologie, est cependant excellent après exérèse chirurgicale de la tumeur.

[pericarditis following 5-fluorouracil administration]. / LE CAS CLINIQUE DU MOIS. Péricardite apràs administration de 5-fluorouracil.

We report a case of pericarditis supervening after 5-fluorouracil infusion in a 52-year-old patient suffering from metastatic rectal cancer. Besides its well-known side-effects (mucitis, diarrhea, nausea, hematotoxicity), this molecule sometimes induces cardio-toxicity, which can take different clinical forms, pericarditis being one of the most uncommon. Several risk factors have been described and have to be kept in mind when initiating this therapy. Prevention may consist of close monitoring of patients considered at risk. Treatment of 5-FU induced cardiotoxicity basically consists in stopping the use of this drug and replacing it with another chemotherapy agent.

[Cancer recurrence or sarcoidosis: the essential contribution of pathology]. / Récidive tumorale ou sarcoïdose: un rendez-vous en anatomo-pathologie à ne pas manquer.

The development of pulmonary nodules or lymph nodes in the course of a malignancy, in particular breast cancer, can sometimes correspond to the onset of sarcoidosis. Osteolytic lesions can simultaneously occur which further strengthens the impression of a metastatic disease. No particular test, biological markers or imaging technique, has a satisfactory discriminating power and a biopsy is needed to establish the correct diagnosis and decide on the adequate treatment. The concomitance of sarcoidosis and cancer raises the possibility of a granolumatous disease.

[A trans-hospital pilot programme for onco-geriatry. The experience of the CHC-Liege]. / Programme pilote trans-hospitalier d'onco-gériatrie.

The authors offered to 296 consecutive cancer patients aged > or = 70 to undergo a joint comprehensive geriatric and oncological assessment. After pluridisciplinary discussion, several reflections have emerged: the need in 15 - 32% of cases to reinforce the role of the paramedical staff; the correlation between age, low clinical indices, alteration of renal function as well as geriatric characteristics; 67% of evaluated cases presented a significant geriatric profile; recommendations for patients' management in relation to their pattern of frailty and health aging (standard, adapted or palliative treatment).

[Chronotherapy with 5-fluorouracil folinic acid and oxaliplatin delivered over 48 hours every second week in colorectal cancer. The CHC-Liège experience (Belgium)]. / Chronochimiothérapie à base de 5-fluorouracil, acide folinique et oxaliplatine administrée en deux jours toutes les deux semaines pour le cancer colorectal. L'expérience du CHC-Liège (Belgique).

One hundred and ten consecutive patients suffering from a colorectal cancer received chronotherapy infused over two days every two weeks. Each course comported 5 FU 3g/m(2), folinic acid (600 mg/m(2) - l. form or 1200 mg/m(2)--racemic form) and oxaliplatin (85/mg/m(2)--adjuvant indication or 100mg/m(2)--palliative indication). According to chronobiological concepts, 5 FU and folinic acid were infused from 10 pm to 10 am with a peak at 4 am while oxaliplatin was delivered from 10 am to 10 pm with a peak at 4 pm. The overall tolerance was excellent with a maximum of 17% patients experiencing a grade 3 toxicity. The toxicity was higher in women, in older patients (>=70) or in case of flat infusion. In adjuvant situation (60 cases), progression free and overall survivals established respectively at 76% (42+months) and 88% (45+months). Fifty-two percent response rate were recorded within the palliative group (50 cases) with an overall 68% disease control. Median progression free survival was seven months but median survival was not attained at 31+ months. Thirty percent patients could benefit from a curative surgery after chemotherapy. Older patients (>=70) experienced worsened survival. In conclusion, we think that our chrono-FOLFOX 2-12 should be proposed as standard treatment for colorectal cancer patients.

Phase I - II study to assess the feasibility and activity of the triple combination of 5-fluorouracil/folinic acid, carboplatin and irinotecan (CPT-11) administered by chronomodulated infusion for the treatment of advanced colorectal cancer. Final report of the BE-1603 study.

Thirty-six metastatic colorectal cancer patients received every 2 weeks, as first- (17) or second-line (19) treatment a combined chronotherapy with CPT-11 (infused at day 1 from 2 to 8 a.m.; peak at 5 a.m.), given with 5FU (700 mg/m(2) per day; days 2-5) and folinic acid (300 mg/m(2) per day; days 2-5) both infused from 10 p.m. to 10 a.m. with a peak at 4 a.m., and carboplatin (40 mg/m(2) per day; days 2-5; infused from 10 a.m. to 10 p.m.; peak at 4 p.m.). The doses of CPT11 could be easily pushed from 120 to 180 mg/m(2) in successive cohorts in the phase I part of the study (11 cases). Twenty-five patients were then treated in the phase II of the trial. The overall toxicity was mild leading to dose-reductions in only 11-13% courses. The tumoral activity was interesting with 81% responses and 94% tumour control. Also prolonged survivals were recorded with 8.8 months of progression free and 15.6 months overall survivals. More prolonged survivals were observed in chemotherapy naive patients. Seven patients (19%) could be reoperated from their residual disease.

[Hemolytic uremic syndrome induced by gemcitabine. A poorly recognized complication?]. / Syndrome hémolytique et urémique induit par la gemcitabine. Une complication méconnue?

This report is concerned with the development of an hemolytic uremic syndrome (HUS) in 6 patients (3 males, 3 females, aged 53 to 73) suffering from an advanced cancer and treated by protracted (>= 4 months) infusions of gemcitabine. Over 4 to 14 months, the patients received 13-34 infusions delivering a cumulative dose oscillating between 9 and 29 g/m2. A progressive alteration of renal function preceeded the acute syndrome. After interruption of gemcitabine and symptomatic treatment, the evolution of haemolytic anemia was generally favourable. This was not the case for renal dysfunction: 2 complete and 1 partial resolution of renal insufficiency were noted, but 1 case required chronic dialysis. Based on the authors experience, the frequency of an HUS complication after protracted gemcitabine treatment could be as high as 2.7 %.

[Interest of chronotherapy in multidisciplinary management of oesophageal and gastric cancers]. / Intérêt de la chronothérapie dans le traitement pluridisciplinaire des cancers de l'oesophage et de l'estomac.

The authors evaluated the impact of a chronotherapy with 5-FU, folinic acid and carboplatine (chronomodulated infusions by ambulatory pumps; 5/21 days) for the management of oesophagus (52 cases) and gastric (56 cases) cancer patients. The overall tolerance of treatment was gauged excellent (grade 3-4; % patients: mucitis: 11-23%; leucopenia 6-19%; thrombopenia 18-50%; almost no digestive disturbances nor alopecia). Also tumor outcome was considered interesting with major responses rate in 61% (gastric) to 79% (oesophagus) of patients. The median survival of oesophageal cancer was limited to 9.2 months; the one of disseminated gastric cancer was 12.7 months but 72% of curatively resected patients were alive at 5+ years.

[Chronotherapy combining 5-fluorouracil, folinic acid and carboplatin as first line treatment in metastatic colorectal cancer. A phase 2 study]. / Chronothérapie associant le 5-fluorouracile, l'acide folinique, et le carboplatine en première ligne thérapeutique dans le cancer colorectal métastatique. Une étude de phase 2.

Seventy-two patients suffering from a metastatic colorectal cancer received, as first line treatment, a combination chronotherapy with 5-FU and folinic acid (infused from 10 pm to 10 am with a peak at 4 am, respectively at doses of 700 and 300 mg/m2 per day) and carboplatin (infused at the dose of 40 mg/m2 per day from 10 am to 10 pm with a peak at 4 pm). The courses of four days were repeated every two weeks. A major tumoral response was observed in 60% cases (68% in those not previously treated with adjuvant chemotherapy). The median times to progression and overall survival established at 11 and 27 months. The clinical (grades 3-4 in maximum 5% cases) and hematological (grades 3-4 in maximum 10-29% cases) toxicities were quite limited. Our observations suggest the interest to incorporate carboplatin in the combined infusional treatment of colorectal cancer.

[Feasibility survey (Phase I-II) of a four drugs combination (5-fluorouracil, folinic acid, carboplatin and irinotecan) delivered using a chronomodulated infusion in the treatment of advanced colorectal cancer]. / Etude de faisabilité (Phase I-II) d'une quadruple combinaison associant le 5-fluorouracile, l'acide folinique et le carboplatine à de l'irinotecan administrés en infusion chronomodulée pour le traitement du cancer colorectal avancé.

Seventeen colorectal cancer patients received as first (12 cases) or second line (5 cases) treatment a combined chronotherapy with CPT 11 (infused at day 1 from 2 to 8 am; peak at 5 am), given with 5 FU (700 mg/m2 per day ; days 2-5) and folinic acid (300 mg/m2 per day, days 2-5) both infused from 10 pm to 10 am with a peak at 4 am, and carboplatin (40 mg/m3/day - days 2-5 ; infused from 10 am to 10 pm - peak at 4 pm). The doses of CPT 11 could be easily increased from 120 up to 180 mg/m2 in successive cohorts of four patients through acceptable toxicity. Thus, five patients have already been treated in the phase II part of the trial. An interesting tumoral outcome has been observed: 88% major responses with no progression; median time to progression: nine months and median survival: 19.7 months.

[Adjuvant chemotherapy for Dukes B2 and C colon cancer combining 5-fluorouracil and folinic acid with or without carboplatin. Feasibility and comparison between standard and chronomodulated deliveries]. / Chimiothérapie adjuvante pour le cancer du colon de stades Dukes B2 et C comportant du 5-fluorouracile et de l'acide folinique, avec ou sans carboplatine. Faisabilité et comparaison d'une administration standard à une administration chronomodulée.

Thirty-seven patients operated from a Dukes B2-C colon cancer were randomised to receive as adjuvant infusional chemotherapy, nine 5 FU and folinic acid courses with or without carboplatin, as standard (de Gramont; 2 days every 2 weeks) or chronomodulated administration (4 days every 2 weeks). The overall tolerance was judged excellent with less than 7% courses with dose-adaptations. The two carboplatin arms presented an enhanced haematological toxicity, while some more cutaneous toxicity was observed in the chronomodulated arm with the three drugs.

Sequential administration of epirubicin and paclitaxel for advanced breast cancer. A phase I randomised trial.

Forty-six previously untreated patients with advanced breast cancer were eligible for the present randomised phase I study. It aimed to evaluate the toxicity and activity of a therapeutic sequence with epirubicin on day 1 followed by paclitaxel on day 2 (sequence A) or the reverse sequence, ie., paclitaxel on day 1 followed by epirubicin on day 2 (sequence B). The starting doses of epirubicin and paclitaxel, administered either according to sequence A or B, (level 1 cohort) were 90 mg/m2 and 175 mg/m2, respectively. Per cohort of 3 patients, the dose of paclitaxel was increased by 25 mg/m2 (levels 2 and 4) and of epirubicin by 10 mg/m2 (levels 3 and 5). Treatment was repeated with 3-week intervals. The maximal tolerated dose (MTD) was achieved at level 1 in sequence B (paclitaxel first) and level 3 (epirubicin 100 mg/m2 followed by paclitaxel 200 mg m2) in sequence A. Dose limiting toxicity (DLT) was neutropenia (+/- febrile) in both sequences. Cardiac events occurred in 28% of the patients; significant decrease in left ventricular ejection function (LVEF) was observed in 8/33 and in 2/13 patients in sequence A and B, respectively. This was associated with 5 and 1 cardiac heart failure (CHF), respectively. In 43 evaluable patients, 10 CR and 25 PR were observed (overall response rate 81%). In the 20 patients with locally advanced disease (LABC), the respective numbers were 7 CR and 11 PR; in the 23 metastatic (MBC) patients, 3 CR and 14 PR were recorded. The median survival of the both groups was not reached at 33 + months. In conclusion , the combination of epirubicin and paclitaxel has significant activity in breast cancer. The recommended sequence of both drugs in combination therapy, mainly to avoid neutropenia, is epirubicin day 1 followed by paclitaxel on day 2. Cardiac toxicity remains problematic in either sequence of administration.

The sentinel lymph node biopsy in breast cancer.

OBJECTIVE: To evaluate the possibility and accuracy of this new diagnostic approach to the breast cancer disease in our centre. MATERIAL AND METHODS: Since March 1999, every patient presenting with a cT1-T2 N0 breast carcinoma was scheduled for a sentinel lymph node search. An injection of Tc-99 labelled nanocolloïd with a dose of 1 mCu was injected either intramammary or intradermally. The patients have been divided into two groups: in group I, they received their injection intramammarily the day before the operation; because of several failures in identifying the sentinel lymph node (SLN), the protocol was modified, the patients receiving their injection the day of operation, intradermally (group II). Once a lymphoscintigraphy done, the SLN was identified at operation using a detection probe, after the primary tumour had been removed. A routine axillary dissection was then performed to remove the rest of the lymph nodes. All the nodes were then checked routinely for metastatic cells. The SLN was also screened by semi-serial slides and by immuno-assay. RESULTS: From March 1999 till March 2001, sixty patients presented consecutively with a T1 or T2 biopsy proven breast carcinoma with no clinical lymph nodes. They were all scheduled for a sentinel lymph node search according to the protocol. Mean tumour size was 9.9 mm (ranging from 4 to 23 mm). Fourteen patients (group I) received their injection intramammarily but we failed to identify the sentinel node in five patients (35%). The remaining forty-two patients (group II) received their injection intradermally. Sentinel nodes were then identified in forty-three patients (93%). Positive SLN were discovered in eleven cases by routine examination (13 positive nodes among 104 harvested sentinel nodes, i.e. 13%). Micro metastases were discovered in three other SLN by immunohistology. In total, 605 lymph nodes were evaluated through the axillary dissection, representing a mean number of 10.08 lymph nodes per patient. For four patients, positive lymph node were discovered in the axillary dissection while SLN were negative (6.6% of false negative). CONCLUSIONS: During this learning curve period, it appears that the method for screening the SLN is reliable, since the figures encountered are similar to those of the literature. By adding a perioperative blue dye injection, it might be possible to reduce the percentage of false negative results. It is difficult to assess, at present, the impact SLN could have on survival.

[Clinical case of the month. Metastatic endocarditis: clinical observation and review of the literature]. / Le cas clinique du mois. L'endocardite métastatique: observation clinique et revue de la littérature.

The authors describe a case of metastatic endocarditis associated with a gastric carcinoma. The diagnosis was made early and the treatment by surgery and chemotherapy allowed a survival of 18 months, which is unusually long. The differential diagnosis is discussed and includes nonbacterial thrombotic endocarditis, infectious endocarditis and primary tumors of the heart.