Efficacy of venlafaxine for the prevention and relief of oxaliplatin-induced acute neurotoxicity: results of EFFOX, a randomized, double-blind, placebo-controlled phase III trial.

BACKGROUND: Oxaliplatin neurosensory toxicity is dose limiting and may present as acute symptoms and/or cumulative peripheral neuropathy. PATIENTS AND METHODS: From October 2005 to May 2008, patients with oxaliplatin-induced acute neurotoxicity were randomized into a double-blind study, to receive either venlafaxine 50 mg 1 h prior oxaliplatin infusion and venlafaxine extended release 37.5 mg b.i.d. from day 2 to day 11 or placebo. Neurotoxicity was evaluated using numeric rating scale (NRS) for pain intensity and experienced relief under treatment, the Neuropathic Pain Symptom Inventory and the oxaliplatin-specific neurotoxicity scale. The primary end point was the percentage of patients with a 100% relief under treatment. RESULTS: Forty-eight patients were included (27 males, median age: 67.6 years). Most patients had colorectal cancer (72.9%). Median number of cycles administered at inclusion was 4.5 (mean cumulative oxaliplatin dose: 684.6 mg). Twenty out of 24 patients in arm A (venlafaxine) and 22 out of 24 patients in arm B (placebo) were assessable for neurotoxicity. Based on the NRS, full relief was more frequent in the venlafaxine arm: 31.3% versus 5.3% (P=0.03). Venlafaxine side-effects included grade 1-2 nausea (43.1%) and asthenia (39.2%) without grade 3-4 events. CONCLUSION: Venlafaxine has clinical activity against oxaliplatin-induced acute neurosensory toxicity.

Phase II randomised trial of chemoradiotherapy with FOLFOX4 or cisplatin plus fluorouracil in oesophageal cancer.

BACKGROUND: Concurrent chemoradiotherapy is a valuable treatment option for localised oesophageal cancer (EC), but improvement is still needed. A randomised phase II trial was initiated to assess the feasibility and efficacy in terms of the endoscopic complete response rate (ECRR) of radiotherapy with oxaliplatin, leucovorin and fluorouracil (FOLFOX4) or cisplatin/fluorouracil. METHODS: Patients with unresectable EC (any T, any N, M0 or M1a), or medically unfit for surgery, were randomly assigned to receive either six cycles (three concomitant and three post-radiotherapy) of FOLFOX4 (arm A) or four cycles (two concomitant and two post-radiotherapy) of cisplatin/fluorouracil (arm B) along with radiotherapy 50 Gy in both arms. Responses were reviewed by independent experts. RESULTS: A total of 97 patients were randomised (arm A/B, 53/44) and 95 were assessable. The majority had squamous cell carcinoma (82%; arm A/B, 42/38). Chemoradiotherapy was completed in 74 and 66%. The ECRR was 45 and 29% in arms A and B, respectively. Median times to progression were 15.2 and 9.2 months and the median overall survival was 22.7 and 15.1 months in arms A and B, respectively. CONCLUSION: Chemoradiotherapy with FOLFOX4, a well-tolerated and convenient combination with promising efficacy, is now being tested in a phase III trial.

An open phase II trial of gemcitabine, oxaliplatin and vinorelbine combination as first-line therapy in advanced non-small cell lung cancer patients.

The purpose of this multicentric Phase II study was to evaluate the safety and efficacy of a gemcitabine/oxaliplatin/vinorelbine combination as first-line therapy in advanced non-small cell lung cancer patients. Patients followed a fortnightly drug schedule, receiving on day 1, vinorelbine 25mg/m(2) (20-min infusion); gemcitabine 700 mg/m(2) (70-min infusion, fixed 10mg/m(2)/min); and on day 2, oxaliplatin 85 mg/m(2) (2-h infusion). Thirty-nine patients with a median age of 58 years received a total of 306 cycles (median 8 cycles); 67% were males. Most had adenocarcinoma (51%), large-cell (23%) and squamous cell carcinoma (21%); 15% had stage IIIB and 85% stage IV. There was one complete response (3%; 95% CI: 0.1-13%), 15 partial responses (PR) (38%; 95% CI: 23-55%), and 13 patients with stable disease (33%; 95% CI: 19-50%) of at least 2 months duration, for an overall non-progression rate of 74%. Median progression-free survival (PFS) was 4.1 months (95% CI: 3.1-8.7) and overall survival was 11.7 months (95% CI: 7.7-19.4). No treatment-related deaths occurred and very few grade 3-4 events were observed. Overall, the regimen was well tolerated and the planned recommended dose intensity was safely delivered to more than 95% of patients. This triple combination therapy study yielded favourable efficacy and toxicity results, which merit further evaluation in prospective randomised trials.

Phase I trial of oxaliplatin with fluorouracil, folinic acid and concurrent radiotherapy for oesophageal cancer.

This dose escalation study was designed to determine the maximum tolerated dose (MTD) and recommended doses (RDs) of 5-fluorouracil (5FU), folinic acid and oxaliplatin (FOLFOX) with concomitant radiotherapy in inoperable/metastatic oesophageal squamous cell carcinoma or adenocarcinoma. Patients received three courses of LV5FU2 regimen (folinic acid 200 mg m(-2), bolus 5FU 300-400 mg/m(2), continuous infusion 5FU 400-600 mg m(-2) on days 1 and 2) and escalating doses of oxaliplatin 50 to 100 mg m(-2) on day 1 (FOLFOX). This regimen was repeated every 2 weeks, concomitant to a 50-gray radiotherapy per 5 weeks. Three more cycles were delivered after completion of radiation therapy. Three to six patients were allocated to each of the five dose levels until MTD was reached. Thirty-three patients were enroled and 21 had metastatic disease. Maximum tolerated dose was oxaliplatin 100 mg m(-2), and continuous infusion 5FU was 600 mg m(-2) day(-) (level 5). The most common toxicities were neutropenia, dysphagia and oesophagitis. The RDs were those of FOLFOX-4 regimen (oxaliplatin 85 mg m(-2) and full doses of LV5FU2). The overall response was 48.5%, including 12% complete response. Response rate on primary tumour was 62.9%. This FOLFOX-4 regimen was reasonably well tolerated and effective in inoperable/metastatic oesophageal carcinoma and warrants additional investigation.

Oxaliplatin plus vinorelbine in advanced non-small-cell lung cancer: final results of a multicenter phase II study.

BACKGROUND: Oxaliplatin and vinorelbine are both active agents against non-small-cell lung cancer (NSCLC). In a previous phase I trial, we showed that oxaliplatin (130 mg/m2, day 1) and vinorelbine (26 mg/m2/day, days 1 and 8) can be safely combined when given every 21 days. We completed the evaluation of this new platinum-based doublet in advanced NSCLC patients in a multicenter phase II study. PATIENTS AND METHODS: Twenty-eight chemotherapy-naïve patients (22 men and six women: median age 58 years, range 33-70), including 20 with stage IV disease, received this out-patient combination, with 5-hydroxytryptamine-3-receptor agonists as the only prophylactic measure. RESULTS: A total of 117 cycles were given, for a median of three per patient (range 1-8). Of 26 eligible patients, nine achieved a partial response (WHO criteria), giving an objective response rate of 35% [95% confidence interval (CI) 17% to 56%]. The median progression free survival was 5.0 months (95% CI 3.1 to 6.9), median overall survival was 9.8 months (95% CI 2.2 to 17.5) and the 1-year survival rate was 37%. Neutropenia was the principal toxicity, grade 4 occurring in 11 patients (39%) and 25 cycles (22%). Four patients (14%) experienced one episode of febrile neutropenia each. Acute oxaliplatin-related neurosensory toxicity was prevalent, but was mild to moderate in the majority of patients (82%) and reversible. Grade 1/2 vomiting (65% of patients) and diarrhea (32% of patients) were easily managed. CONCLUSIONS: The oxaliplatin-vinorelbine doublet is a safe and active out-patient combination. It may represent an interesting alternative in the management of patients with NSCLC, and serve as a new doublet to which other active agents could be added.

[Treatment using concomitant radiochemotherapy of N+ M0 stage urothelial tumors of the bladder]. / Traitement par radiochimiothérapie concomitante des tumeurs urothéliales de vessie N+ M0.

Seventeen patients with N+ urothelial bladder tumours were treated by a combination of deep endoscopic resection and concomitant radiochemotherapy (5FU cisplatin). 15 patients completed their course of treatment. 52.9% of these 17 patients are in complete remission at 6 months, 35.2% are in complete remission at 1 year, 30% of patients in complete remission developed distant metastases, 52.9% developed local progression and 40% developed distant metastases. This protocol of deep resection combined with radiochemotherapy can therefore be effective in the local control of the tumour and can allow preservation of the bladder in the case of complete remission. However, it is insufficient to prevent the development of distant metastases. It is therefore preferable to intensify this treatment by performing complete endoscopic resection, by increasing the radiotherapy dose rate and by intensifying the chemotherapy protocol.

[Cancer of the kidney, prognostic value of nuclear grading for the early diagnosis of metastasis]. / Cancer du rein, valeur pronostique du grade nucléaire pour le diagnostic précoce de métastase.

OBJECTIVES: Since immunotherapy or surgery can sometimes lead to remission of metastatic renal cell carcinoma, it is important to recognize factors predicting metastasis. We therefore evaluated the usefulness of nuclear grading in predicting metastasis of renal cell carcinoma. METHODS: We retrospectively reviewed 95 patients (69 males, 26 females; mean age 63.9 years) who successively underwent surgical exeresis of a renal cell carcinoma. The TNM classification was established on the basis of preoperative work-up (thoraco-abdominal computed tomography, bone scintigraphy) and pathology examination of the surgical specimen. Nuclear grading was performed by a pathologist who was unaware of the histology results. Outcome was evaluated on the basis of physical examination and computed tomography results 6 months after surgery. RESULTS: There were 34 cases of clear cell carcinoma, 10 granulosus tumours, 2 oncocyte tumours and 16 renal cell carcinomas of undetermined type. Mean tumour diameter was 70.3 +/- 37.8 cm. Tumour classification gave (< 5 cm, n = 23; > 5 cm, n = 26; local invasion, n = 28; invasion of neighbouring organs, n = 2). Metastases had been identified in 11 patients before surgery. Nuclear grading according to the Führman scale gave F1 (n = 3), F2 (n = 28), F3 (n = 34) and F4 (n = 24). Tumour size and the TNM classification were correlated with the observed nuclear grading scores. Within one year of surgery, metastasis was observed in 6 patients whose Führman grades were F3 (n = 1) and F4 (n = 5). Metastasis occurred in 26% of the patients with a Führman grade 4. CONCLUSION: Nuclear grading can be used to identify patients who should be closely followed after surgical removal of renal cell carcinoma in order to improve early diagnose of metastasis.

[Acute pyelonephritis in women. Short-term hospitalization]. / Pyélonéphrite aiguë de la femme. Hospitalisation de courte durée.

One-hundred women suffering from acute pyelonephritis were hospitalized for less than 4 days on average, in order to make a diagnosis based on bacteriology and computerized tomography (CT) and to bring fever down with a 21-day antibiotic therapy. In cases of acute pyelonephritis due to a urinary tract obstacle, endoscopic uereteral drainage was added to the antibiotic treatment. In the absence of obstacle, medical treatment was sufficient to obtain apyrexia. Fluoroquinolone therapy made it possible to reduce the hospital stay to 2 or 3 days, depending on whether the lesions observed at CT were triangular or round.

Percutaneous antegrade dilation of ureteral strictures in kidney transplants.

Transplant ureteral stricture can be treated by either incisional surgery or percutaneous endoluminal dilation. We present 17 cases of percutaneous antegrade endoluminal dilation. The results of this procedure were satisfactory, with a 70% success rate that seems to be maintained during long-term followup. The results were better if dilation was done on a short and recent juxta-anastomotic stricture stented with a 10F Double-J* catheter for 2 months.