Nivolumab in patients with advanced renal cell carcinoma in France: interim results of the observational, real-world WITNESS study.

BACKGROUND: Nivolumab is the first immune checkpoint inhibitor approved in Europe for the treatment of advanced renal cell carcinoma (aRCC) in patients resistant to prior antiangiogenic therapy. WITNESS is an ongoing, prospective, observational study designed to evaluate the effectiveness and safety of nivolumab in patients with aRCC treated in real life (or routine practice) in France (ClinicalTrials.gov identifier: NCT03455452). PATIENTS AND METHODS: This study includes adult patients with a confirmed diagnosis of aRCC who have initiated nivolumab after 1-2 prior lines of antiangiogenic therapy. Endpoints include overall survival (OS), progression-free survival (PFS), duration of treatment (DOT), duration of response (DOR), overall response rate (ORR), subgroup analyses, and treatment-related adverse events (TRAEs). Results after a median follow-up of 12.3 months are presented here. RESULTS: A total of 325 patients with aRCC were included, of whom 38.2% had a Karnofsky score <80, 77.8% received nivolumab as second-line therapy, and 69.5% had undergone a previous nephrectomy. In the overall population, median OS was 20.5 [95% confidence interval (CI) 17.6-25.0] months and median PFS was 5.2 (95% CI 4.5-5.9) months. ORR was 34.5%, median DOT was 3.8 months, and median DOR was 16.5 months. Nivolumab was effective in different subgroups including patients with bone or glandular metastases and those receiving baseline corticosteroids. Moreover, effectiveness was observed irrespective of prior nephrectomy and line of treatment. No new safety signals were identified; TRAEs of any grade were reported in 32.0% of patients, grade ≥3 and serious TRAEs in 11.1% each, and TRAEs leading to discontinuation in 8.9%. CONCLUSIONS: Preliminary results of the ongoing WITNESS study confirm the real-world effectiveness and safety of nivolumab monotherapy in previously treated patients with aRCC. Treatment benefits were similar to those observed in the pivotal phase III CheckMate 025 randomized clinical trial, despite a broader, real-life study population.

A phase III adjuvant randomised trial of 6 cycles of 5-fluorouracil-epirubicine-cyclophosphamide (FEC100) versus 4 FEC 100 followed by 4 Taxol (FEC-T) in node positive breast cancer patients (Trial B2000).

BACKGROUND: Standard adjuvant chemotherapy regimens for patients with node positive (N+) breast cancer consisted of anthracycline followed by taxane. The European Association for Research in Oncology embarked in 2000 on a phase III trial comparing 6 cycles of FEC100 versus 4 FEC100 followed by 4 Taxol. Primary end-point was disease free survival. Secondary end-points were overall survival, local recurrence free interval, metastases free interval and safety. PATIENTS AND METHODS: Between March 2000 and December 2002, 837 patients were randomised between 6FEC100 for 6 cycles (417patients) or FEC100 for 4 cycles then Taxol 175mg/m(2)/3 weeks for 4 cycles (4FEC100-4T) (420 patients). One thousand patients had been planned initially but the trial was closed earlier due to slow accrual. RESULTS: Hazard ratios (HRs) were 0.99 for disease-free survival (DFS) (95%CI: 0.77-1.26; p=0.91), and 0.85 for overall survival (OS) (95%CI: 0.62-1.15; p=0.29). Nine-year DFS were 62.9% versus 62.5% for 6FEC100 and 4FEC100-4T, respectively. Nine-year OS were 73.9% versus 77% for 6FEC100 and 4FEC100-4T, respectively. Toxicity analyses based on 803 evaluable patients showed that overall grade 3-4 toxicities were similar in both arms (63% versus 58% for 6FEC100 arm and 4FEC100-4T arm, respectively; p=0.16). CONCLUSION: In this trial replacing the last 2 FEC100 cycles of 6FEC100 regimen by 4 Taxol does not lead to a discernable DFS or OS advantage. The lack of a significant difference between the randomised treatment arms may however be due to a lack of power of this trial to detect small, yet clinically worthwhile, treatment benefits.

Cisplatin-docetaxel induction plus concurrent 3-D conformal radiotherapy and weekly chemotherapy for locally advanced non-small cell lung cancer patients: a phase II trial.

Concurrent chemoradiotherapy (CHRT) is the standard of care for unresectable locally advanced stage III non-small cell lung cancer. However, the optimal combination remains unclear. The aim of this study was to evaluate the efficacy of 2 induction chemotherapy cycles (days 1 and 22) with docetaxel 75 mg/m(2) and cisplatin 75 mg/m(2) followed by concurrent chemotherapy (weekly docetaxel-cisplatin, 20 mg/m(2)) and 3-D conformal radiotherapy for 6 weeks (66 Gy/5 fractions per week/2 Gy per fraction). The primary endpoint was the response rate. Secondary objectives were toxicity, time to progression, and overall survival. Forty-four patients were included and 40 were eligible. The mean age was 60.5 years (range 40.7-72.1), and 75% had stage IIIB disease. Six patients underwent complete R0 resection including 2 pathologic complete responses after a planned intermediate evaluation. Thirty-three patients completed CHRT. The objective response rate was 65% (95% CI 50.2-79.8). Grade 3-4 hematologic and digestive toxicities were observed mainly during the induction phase. Grade 3 esophagitis (5%) was experienced during CHRT. With a median follow-up of 38.7 months, the median progression-free survival was 28.3 months (95% CI 11.0-35.0) and the median survival rate was 31.4 months. Cisplatin-docetaxel induction followed by concurrent 3-D conformal radiotherapy and weekly chemotherapy is a feasible protocol associated with a promising response rate and acceptable toxicity.

Dose-dense adjuvant chemotherapy in node-positive breast cancer: docetaxel followed by epirubicin/cyclophosphamide (T/EC), or the reverse sequence (EC/T), every 2 weeks, versus docetaxel, epirubicin and cyclophosphamide (TEC) every 3 weeks. AERO B03 randomized phase II study.

BACKGROUND: Adding a taxane to anthracycline-based adjuvant chemotherapy prolongs survival in node-positive patients but optimal dose and schedule remain undetermined. This study aimed to select a dose-dense regimen for further assessment in phase III studies. PATIENTS AND METHODS: Ninety-nine patients with node-positive invasive breast adenocarcinoma were randomly assigned to docetaxel (Taxotere) (T) 75 mg/m2, epirubicin (E) 75 mg/m2 and cyclophosphamide (C) 500 mg/m2 (TEC)x6, every 3 weeks; E 100 mg/m2, C 600 mg/m2 x 4, then T 100 mg/m2 x 4 (EC-->T) or the reverse sequence (T-->EC), every 2 weeks, with pegfilgrastim support. The primary end point was the incidence of grade 4 toxicity. RESULTS: Dose intensity was almost doubled with dose-dense regimens, compared with TEC. Twenty-seven patients experienced grade 4 toxicity: 26%, 40% and 18% with TEC, EC-->T and T-->EC, respectively, mainly neutropenia, but febrile neutropenia occurred only in 11%, 10% and 3%. Grade 3-4 nail disorders, hand-foot syndrome and peripheral neuropathy occurred in 46%, 73% and 68% of patients with TEC, EC-->T and T-->EC, respectively. CONCLUSIONS: Dose-dense regimens yield more frequent and severe nonhematological toxic effects than standard dose TEC regimen. Though grade 4 toxicity rates appear acceptable with the T-->EC regimen, the incidence of grade 3-4 events makes it difficult to recommend either dose-dense regimen for further investigation.

[Tolerance and feasibility of adjuvant treatment of stage II malignant melanoma with high-dose interferon-alpha]. / Tolérance et faisabilité du traitement adjuvant du mélanome malin stade II par interféron alpha à fortes doses.

BACKGROUND: The use of high-dose interferon alpha as adjuvant therapy has been shown for the first time to improve recurrence-free and overall survival in stage II malignant melanoma. The aim of our work was to evaluate the toxicity of this therapeutic scheme during a 1-year period in 13 patients with malignant melanoma. PATIENTS AND METHODS: Thirteen patients, mean age 56 years, with stage II melanoma were included. Interferon alpha was administered at the dose of 20 MU per m2 body surface area five days per week for four weeks during the induction phase and at the dose of 10 MU subcutaneously three times a week for 48 weeks in the maintenance phase. Patients underwent clinical assessment daily and had blood tests twice a week during the induction phase. Weekly blood tests and monthly examinations were then performed during the maintenance phase. Clinical and biological toxicity was evaluated in accordance with the WHO scores. Grade 3 toxicity led to a 30 p. 100 dose reduction and treatment was interrupted in case of grade 4 toxicity. RESULTS: A flu-like syndrome (grade 1-2) and digestive disorders, nausea, anorexia related to dysgeusia or dry mouth were observed in most of the patients during the induction phase and persisted in 30% of the patients during the maintenance phase. Six patients developed a state of depression (grade 2-3) which persisted during the maintenance phase, inciting us to prescribe an antidepressor regimen for all our patients. One patient developed major reversible alopecia at dose reduction. Nine patients had grade 1 or grade 2 neutropenia and four had grade 3 neutropenia. Seven patients developed grade 1-2 thrombocytopenia, six had elevated transaminase levels (grade 1-2) and two moderately elevated CPK. CONCLUSION: At the end of the induction phase of interferon alpha therapy in 13 patients with malignant melanoma, 8/13 had received 100 p. 100 of the theoretical dose and 11/13 had received 80 p. 100. At the end of the treatment protocol, 5/10 patients had received 100 p. 100 of the theoretical dose and 8/10 more than 80 p. 100. The proposed protocol appears to be feasible without major risk. Rigorous clinical and biological surveillance is mandatory.

Outpatient treatment with subcutaneous interleukin-2 and interferon alfa administration in combination with fluorouracil in patients with metastatic renal cell carcinoma: results of a sequential nonrandomized phase II study. Subcutaneous Administration Propeukin Program Cooperative Group.

PURPOSE: We report the results of the Subcutaneous Administration Propeukin Program (SCAPP) II trial of an outpatient treatment in renal cell carcinoma using interleukin-2 (IL-2) and interferon alfa-2a (IFN-alpha) administered subcutaneously in combination with fluorouracil (5-FU). The objective of this multicenter trial was to confirm that the combination of IL-2, IFN-alpha, and 5-FU leads to a response rate greater than 20%. PATIENTS AND METHODS: Patients with metastatic renal cell carcinoma were included in this study. During the induction phase of the treatment, which lasted 10 weeks, IL-2 and IFN-alpha were administered subcutaneously three times a week for 8 weeks at doses of 18 MIU and 9 MIU, respectively. During these 8 weeks, every Monday, 5-FU was administered at a dose of 750 mg by intravenous infusion over 30 minutes. After evaluation, responding patients or patients with stable disease (SD) were given maintenance treatment, until disease progression (PD) or the appearance of unacceptable toxicity. Each maintenance cycle consisted of a 2-week treatment followed by a three-week rest period. During treatment, IL-2 and IFN-alpha were administered subcutaneously three times a week at doses of 18 MIU and 9 MIU, respectively. Every Monday, 5-FU was administered at a dose of 750 mg by intravenous infusion over 30 minutes. RESULTS: This trial was closed when the sixth sequential analysis showed the lack of benefit from this combination. At the end of the induction period, of 62 patients, 12 (19%; 95% confidence interval [CI], 10% to 31%) reached an objective response, including one complete response (CR), 16 presented with SD, and 27 showed PD. Twenty-seven patients (43%) developed severe toxicity that required reduction of the planned doses (13 patients), delayed treatment (eight patients), or treatment termination (six patients). Seventeen patients were given maintenance treatment. One- and 2-year survival rates were estimated at 55% and 33%, respectively. The 2-year survival rate was 15% in 11 patients who presented with three poor-prognosis factors and 41% in 51 patients who initially presented with no, one, or two poor-prognosis factors (P = .04). CONCLUSION: As in other recently published studies that used 5-FU, IL-2, and IFN-alpha, the multicenter SCAPP II trial in patients with metastatic renal cell carcinoma generated severe toxicity. This sequential trial failed to confirm the favorable results previously obtained by Atzpodien and Sella with this combination of three drugs. Its efficacy, assessed on the response and survival rates, is near to the results observed in programs that used IL-2 alone given subcutaneously.

[Systemic signs of primary Gougerot-Sjögren syndrome. 48 cases]. / Signes systémiques du syndrome de Goujerot-Sjögren primitif. 48 observations.

Forty-eight patients with primary Sjögren syndrome are documented together with the results of their baseline investigations. The majority of patients were female (44 out of 48) and mean age was 63.2 years. Common clinical features included 20 parenchymal lung disease, among which 4 had interstitial pulmonary fibrosis and 2 lymphocytic interstitial pneumonitis, 12 neurologic manifestations, 16 Raynaud's phenomenon, 12 arthritis, and 3 gastrointestinal involvement. Haematological features occurred in 15 patients and another autoimmune disease was encountered in 13 cases. These extraglandular manifestations were the dominating reasons for hospital referral in 43.5% of cases, the sicca syndrome were most often only mentioned by the patients after special questioning which explain considerable delay before the diagnosis.

[Clinical course of Horton disease. Apropos of 42 cured patients]. / Evolution de la maladie de Horton. A propos de 42 malades guéris.

We report a prospective study of 42 patients with biopsy-proven giant cell arteritis (CGA) who recovered for more than one year (mean follow up of 71 months since withdrawal of steroid treatment). It was used the same regimen of prednisone and well closely monitored along the whole treatment. In 22 patients, dapsone was given concomitantly with prednisone. Mean duration of steroid therapy was 23.1 months (range: 6-57 months); it was significantly decreased with treatment by dapsone (12 months and 12 days). Age, sex, initial clinical and biological (acute phase reactants) findings did not provide useful information for predicting steroid treatment needed for recovery. Thirty-six relapses were observed in 22 patients (60%) during treatment or after its withdrawal. Incidence of relapses declined during steroid treatment and relapses were (only) observed over first 6 months after steroid withdrawal. Three amaurosis fugax occurred at the beginning of treatment and an axillar bilateral stenosis was also observed. Forty-eight side effects of corticosteroids were recorded in 26 patients (63%): myopathy (n = 12), bone complications (n = 11), metabolic complications (n = 9). Twelve patients (63%) had experienced side effects of dapsone. This study emphasized the difficulty in treating CGA. Close monitoring is required. A steroid regimen is recommended.

[Autoimmune thyroid diseases and Horton disease]. / Thyréopathies autoimmunes et maladie de Horton.

In a retrospective study of 115 patients with giant cell arteritis, 5 clinically patent autoimmune diseases were recorded; including 2 patients (1.8%) with Grave's disease and 1 with hypothyroidism. Among these patients, 46 had systematic assays of blood thyroid hormones and 39 were systematically investigated for anti-thyroid antibodies (ATAb):3 (6.5%) had biological hypothyroidism and 4 (10.3%) had ATAb. These findings were not significantly different from those of a control group of 39 age and sex matched patients.

[Multiple autoimmune syndrome]. / Syndrome auto-immun multiple.

Report a case of multiple auto-immune syndrome with auto-immune thyroiditis, Sjögren's syndrome, primary biliary cirrhosis. Moreover the patient suffered from neuropsychiatric symptoms and anti-cardiolipid antibodies were significantly elevated.

Osteosarcoma with calcified regional lymph nodes.

A case of osteosarcoma of osteoblastic type with inguinal calcified lymphadenopathy is described. The primary lesion of the distal left femur was treated with limb-sparing surgery. Chemotherapy was given before and after the surgical procedure. Metachronous calcified lymph node metastases were seen on plain radiography, computed tomography and bone radionuclide scan. The patient is alive and free of disease more than 40 months after lymphadenectomy and radiotherapy of regional node metastases.

[Isolated inflammatory syndrome: think of benign tumors of the liver]. / Syndrome inflammatoire isolé: penser aux tumeurs bénignes du foie.

The authors report seven cases of benign tumors of the liver revealed by elevated acute phase reactants. They show that these elevated acute phase reactants are not linked with a particular histological diagnosis, the presence of tumor necrosis and that they disappear with the chirurgical cure of the tumor.

[Death in Horton disease. Prognostic factors]. / Les décès dans la maladie de Horton. Facteurs de pronostic.

The authors reported causes of death and searched for prognosis factors in Giant Cell Arteritis (GCA). The diagnosis was confirmed by temporal biopsy in all cases. Fourteen patients died during treatment; thirty-six patients had completely recovered (follow up > 6 months after withdrawal of steroid therapy). The commonest causes of death were cardiovascular (n = 7) and digestive (n = 4); they occurred after an average of 195 days of treatment, half of them during the first three months. One death was due to GCA (autopsy) and five deaths were attributed to the treatment with corticosteroids. The prognosis factors were searched for by comparing age, sex, clinical signs, laboratory data before treatment, past medical history in the both series; further more initial dose of Prednisone and the dose after 180 days of steroid therapy were compared in the two groups. The adverse prognosis factors revealed by this study were: advanced age (p < 0.01), previous ischaemic heart disease (p < 0.05) and higher dose of corticosteroids administered at 6 months of treatment (< 0.01).

[Possible value of variations in the serum alkaline DNAse activity in the prognosis of cancers of the upper respiratory-digestive tract treated by chemotherapy]. / Valeur prédictive des variations de l'activité sérique de la DNAse alcaline dans le pronostic des cancers des voies aérodigestives supérieures traités par chimiothérapie.

Variations in serum alkaline DNase activity before and repeatedly after standardized chemotherapy were examined in patients with head and neck carcinomas. The enzyme activity was measured by way of a modified spectrophotometric method. No variations of such activity observed in patients without therapeutic response or with minor response could be considered as a marker of primary or acquired resistance to chemotherapy. Distinct variations in serum alkaline DNase activity (a steep decrease after therapy followed a few weeks later by a regain of values higher than the initial value) correspond to complete or partial positive responses. Such observations of the variations in enzyme activity in relation to individual initial values measured before therapy could be considered as a reliable prognostic test for the therapy of many head and neck carcinomas.