Safety and Efficacy of Cabozantinib in Metastatic Renal-Cell Carcinoma: Real-World Data From an Italian Managed Access Program.

BACKGROUND: The randomized phase 3 METEOR study confirmed a survival benefit of cabozantinib over everolimus in patients with metastatic renal-cell carcinoma (mRCC) with disease that progressed after treatment with at least one previous antiangiogenic inhibitor. The aim of this analysis was to evaluate the safety and activity of cabozantinib in an unselected population. METHODS: Data were collected across 24 Italian centers. Cabozantinib therapy was initiated at physician request between September and December 2016. Patients with mRCC with disease that progressed after one or more prior systemic treatment were evaluated. Cabozantinib 60 mg was administered orally once daily. Doses were reduced to 40 mg or 20 mg in patients experiencing grade 3 or intolerable grade 2 adverse events (AEs). RESULTS: Data from 96 patients were evaluated. Cabozantinib was administered as second-line therapy in 28 patients (29%) and as third-line therapy in 18 patients (19%), while the remaining 50 patients (52%) received cabozantinib in further treatment lines. Sixty-six patients began therapy with the full dose of 60 mg. Because of poor performance status, 29 patients began therapy with a reduced dose of 40 mg and 1 patient with 20 mg. At the time of our analysis, grade 3/4 AEs were observed in 35 patients (36%). Only 5 patients discontinued treatment as a result of AEs. Partial response was observed in 35 patients (36%), whereas 33 (34%) had stable disease and 28 (30%) progressive disease. Median progression-free survival was 8.0 months. CONCLUSION: Cabozantinib showed acceptable tolerability and activity in a large unselected population treated according to everyday clinical practice.

Predictive Role of ERCC1 Expression in Head and Neck Squamous Cell Carcinoma Patients Treated with Surgery and Adjuvant Cisplatin-Based Chemoradiation.

OBJECTIVE: ERCC1 (excision repair cross-complementation group 1) expression predicts survival in patients with locally advanced head and neck squamous cell carcinoma (HNSCC) treated with chemoradiation. In order to evaluate the predictive role in the adjuvant setting, we investigated ERCC1 expression in radically resected HNSCC patients who underwent surgery and cisplatin chemoradiation. METHODS: ERCC1 expression levels were determined by immunohistochemistry in primary tumor tissues from 48 patients with stage III-IV cancers. The median follow-up was 38.5 months (range: 5-121). RESULTS: High ERCC1 expression was observed in 36 (75%) patients. Univariate analysis showed that patients with high levels of ERCC1 had significantly worse disease-free survival and overall survival (OS) than patients with low levels (HR = 7.15; 95% CI, 1.68-30.35; p = 0.008 and HR = 9.90; 95% CI, 1.33-73.96; p = 0.025, respectively). In the multivariate analysis, high ERCC1 expression (HR = 7.36; 95% CI, 1.72-31.4; p = 0.007) together with high-risk category (HR = 2.69; 95% CI, 1.01-7.18; p = 0.048) were the best predictors for relapse. High ERCC1 expression was the only unfavorable independent determinant for OS (HR = 9.53; 95% CI, 1.27-71.35; p = 0.028). CONCLUSIONS: This investigation suggests that ERCC1 expression might be useful to predict prognosis in radically resected HNSCC patients treated with surgery and chemoradiation.

Conservative treatment of invasive bladder carcinoma by transurethral resection, protracted intravenous infusion chemotherapy, and hyperfractionated radiotherapy: long term results.

BACKGROUND: Organ preservation has been investigated in patients with muscle-invasive bladder carcinoma over the past decades as an alternative to radical cystectomy. The majority of studies reported that trimodal schedules, including transurethral resection of bladder tumor (TURB), radiotherapy (RT), and chemotherapy, are a feasible and safe organ-sparing approach without deferring the survival probability. However, to the authors' knowledge the best combination of RT and chemotherapy has yet to be well defined. The current study evaluated the long-term results of a schedule of concurrent cisplatin and 5-fluorouracil (5-FU) administered as protracted intravenous infusions (PVI) during hyperfractionated radiotherapy (HFRT) with organ-sparing intent in patients with infiltrating transitional cell carcinoma of the bladder (TCCB). METHODS: Seventy-seven patients with a classification of T2-T4aN0M0 TCCB were enrolled in the current study. After a complete TURB and bladder mapping, 42 of 77 patients underwent 2 cycles of induction chemotherapy. All 77 patients underwent HFRT and a schedule of cisplatin (4-6 mg/m(2) per day) and 5-FU (180-220 mg/m(2) per day) as concomitant PVI (radiochemotherapy [RCT]). Six to 8 weeks after RCT, patient response was evaluated by computed tomography scan, urine cytology, and TURB. Patients who achieved a complete response (CR) were followed at regular intervals. For patients with residual or recurrent invasive tumor, salvage cystectomy was recommended. RESULTS: Seventy-two patients were evaluable for response: 65 achieved a CR (90.3%) and 7 (9.7%) achieved a partial response. No significant difference was observed for the different prognostic factors with the exception of stage of disease (T2 [95.7%] vs. T3-T4a [80.0%]; P = 0.04). The observed toxicity, mainly hematologic, was higher among the patients who received induction chemotherapy compared with the patients who did not receive induction chemotherapy, even though the difference was not statistically significant. After a median follow-up of 82.2 months (range, 30-138 months), 44 of 65 (57.1%) patients who achieved a CR were alive. Of these 44 patients, 33 had tumor-free bladders. The 5-year overall, bladder-intact, tumor-specific, disease-free, and cystectomy-free survival rates for all 77 patients were 58.5%, 46.6%, 75.0%, 53.5%, and 76.1%, respectively. No associations were observed in overall and tumor-specific survival with different prognostic factors. CONCLUSIONS: Combined treatment appeared to provide high response rates and can be offered as an alternative option to radical cystectomy in selected patients who refuse or are unsuitable for surgery.

Accelerated hyperfractionated radiotherapy and concurrent protracted venous infusion chemotherapy in locally advanced head and neck cancer.

Concurrent radiotherapy and chemotherapy result in a significant benefit with respect to induction chemotherapy followed by radiotherapy or radiotherapy alone, although with a significant increase of toxicity. To discover a more tolerated and effective chemoradiation regimen, the feasibility and efficacy of a hyperfractionated accelerated irradiation with concurrent protracted venous infusion chemotherapy was investigated. Sixty-five patients with advanced head and neck cancer underwent a definitive (53 patients) or a postoperative adjuvant (12 patients) chemoradiation treatment. Chemotherapy consisted of an intravenous protracted infusion of 5 and 200 mg/m /d cisplatin and 5-fluorouracil, respectively. Radiotherapy consisted of a split-course accelerated hyperfractionation of two 150-cGy (split twice a day) or three 100-cGy fractions per day (split three times a day) at more than 6-hour intervals, for 2 weeks followed, after a 1-week interruption, by 2-to-3-week treatment, with the same fractionation schedule, to a total dose of 60 Gy to 69 Gy. Confluent mucositis was tolerable and was the cause of treatment delay of more than 10 days in only 20% of patients. Grade 3 or greater systemic toxicity occurred only in 9 of 65 (14%) patients and was never the cause of drug dose reduction. Complete responses were observed in 69% of patients with gross diseases. At a median follow-up of 43.5 months, 45% of patients were alive and free of disease and 38% died of cancer. The 5-year actuarial local regional failure was 35%. The 5-year actuarial disease-specific survival was 50%. Preservation of larynx function was achieved in 47% of living patients and in 74% of all patients, with advanced tumors of the laryngopharynx. The long-term results of this study suggest that this chemoradiation regimen has the potential of achieving a significant improvement over standard therapy while avoiding significant toxicity.