Randomized Phase II Study of Cabazitaxel Versus Methotrexate in Patients With Recurrent and/or Metastatic Squamous Cell Carcinoma of the Head and Neck Previously Treated With Platinum-Based Therapy.

LESSONS LEARNED: Cabazitaxel has activity in squamous cell carcinoma of the head and neck (SCCHN) and taxane-resistant cell lines. For the first time, cabazitaxel was investigated in incurable patients with recurrent SCCHN. Patients were randomly assigned to cabazitaxel every 3 weeks or weekly methotrexate.This phase II study did not meet its primary endpoint.Cabazitaxel has low activity in SCCHN.The toxicity profile in this population also was not favorable owing to the high rate of febrile neutropenia observed (17%). BACKGROUND: Cabazitaxel is a second-generation taxane that improves the survival of patients with metastatic castrate-resistant prostate cancer following docetaxel therapy. Cabazitaxel has activity in squamous cell carcinoma of the head and neck (SCCHN) and taxane-resistant cell lines. In this randomized phase II trial, we investigated cabazitaxel in patients with recurrent SCCHN. METHODS: Patients with incurable SCCHN with progression after platinum-based therapy were randomly assigned to cabazitaxel every 3 weeks (cycle 1, 20 mg/m2, increased to 25 mg/m2 for subsequent cycles in the absence of nonhematological adverse events [AEs] greater than grade 2 and hematological AEs greater than grade 3) or methotrexate (40 mg/m2/week). The patients were stratified according to their performance status and previous platinum-based chemotherapy for palliation versus curative intent. The primary endpoint was the progression-free survival rate (PFSR) at 18 weeks. RESULTS: Of the 101 patients, 53 and 48, with a median age of 58.0 years (range, 41-80), were randomly assigned to cabazitaxel or methotrexate, respectively. The PFSR at 18 weeks was 13.2% (95% confidence interval [CI], 5%-25%) for cabazitaxel and 8.3% (95% CI, 2%-20%) for methotrexate. The median progression-free survival was 1.9 months in both arms. The median overall survival was 5.0 and 3.6 months for cabazitaxel and methotrexate, respectively. More patients experienced serious adverse events with cabazitaxel than with methotrexate (54% vs. 36%). The most common drug-related grade 3-4 AE in the cabazitaxel arm was febrile neutropenia (17.3%). CONCLUSION: This study did not meet its primary endpoint. Cabazitaxel has low activity in recurrent SCCHN.

Phase II study of dual phosphoinositol-3-kinase (PI3K) and mammalian target of rapamycin (mTOR) inhibitor BEZ235 in patients with locally advanced or metastatic transitional cell carcinoma.

OBJECTIVE: To assess, in a multicentre phase II trial, the safety and efficacy of BEZ235, an oral pan-class I phosphoinositol-3-kinase (PI3K) and mammalian target of rapamycin (mTOR) complex1/2 inhibitor, in locally advanced or metastatic transitional cell carcinoma (TCC) after failure of platinum-based therapy. PATIENTS AND METHODS: Patients with locally advanced or metastatic TCC progressing after platinum therapy were prospectively stratified by PI3K/Akt/mTOR pathway alterations, defined as PTEN loss and PIK3CA mutation. All patients received BEZ235 until progressive disease or unacceptable toxicity. The primary endpoint was the progression-free survival (PFS) rate at 16 weeks. This study was, however, closed prematurely because BEZ235 was withdrawn from further development. RESULTS: A total of 20 patients (18 without and two with PI3K/Akt/mTOR alterations) were enrolled and received BEZ235. One partial response (5%) and two cases of stable disease (10%) were observed, all in patients without PI3K/mTOR pathway alterations. The PFS rate at 8 and 16 weeks was 15 and 10%, respectively; the median (range) PFS was 62 (38-588) days (95% confidence interval [CI] 53-110); and the median (range) overall survival was 127 (41-734) days (95% CI 58-309). Among the 90% of patients who experienced drug-related adverse events of any grade, 50% experienced grade 3-4 adverse events, including stomatitis (15%), fatigue (5%), nausea (5%), diarrhoea (5%), renal failure (5%), cutaneous rash (5%), hepatotoxicity (5%) and hypertension (5%). CONCLUSION: BEZ235 showed modest clinical activity and an unfavourable toxicity profile in patients with advanced and pretreated TCC; however, a minority of patients experienced a clinical benefit, suggesting that a complete blockade of the PI3K/mTOR axis could improve outcome in some specific patients. Furthermore, this study showed that molecular stratification of patients for personalized medicine before treatment is feasible.

Refractory insulin resistance and hemophagocytic lymphohistiocytosis following enfortumab vedotin treatment: A case report.

The increasing incidence of urothelial carcinoma, coupled with advancements in its therapeutic landscape, has resulted in improved survival rates for patients. This, in turn, has led to a growing population of patients requiring specialized oncological care, with Enfortumab vedotin (EV) emerging as a pivotal treatment for metastatic urothelial carcinoma. While EV is associated with hyperglycemia, ketoacidosis is exceedingly rare. To the best of our knowledge, the link between EV and hemophagocytic lymphohistiocytosis (HLH) has not yet been explored. A 56-year-old patient diagnosed with metastatic urothelial carcinoma underwent EV treatment as a third-line treatment after progression following treatment with cisplatin/gemcitabine and pembrolizumab. Notably, after receiving two doses of EV, the patient exhibited refractory insulin resistance, leading to ketoacidosis. Subsequently, HLH emerged, necessitating a treatment regimen involving dexamethasone and etoposide. Despite intensive efforts, the patient experienced septic shock, resulting in death. The present case report highlights refractory insulin resistance and ketoacidosis, followed by reactive HLH, in the context of EV therapy. The limited literature on these complications demonstrates the need for further research to improve the understanding of the underlying mechanisms. With growing evidence of the efficacy of EV and evolving survival rates in urothelial carcinoma, healthcare professionals must remain vigilant for potential adverse effects, ensuring early recognition and optimal patient care.

Patient-reported outcomes in terms of swallowing and quality of life after prophylactic versus reactive percutaneous endoscopic gastrostomy tube placement in advanced oropharyngeal cancer patients treated with definitive chemo-radiotherapy: Swall PEG study.

BACKGROUND: Percutaneous endoscopic gastrostomy (PEG) is often used to provide nutritional support in locally advanced head and neck cancer patients undergoing multimodality treatment. However, there is little published data on the impact of prophylactic versus reactive PEG. PEG placement may affect swallowing-related physiology, function, and quality of life. The Swall PEG study is a randomized controlled phase III trial testing the impact of prophylactic versus reactive PEG on patient-reported outcomes in terms of swallowing and quality of life in oropharyngeal cancer patients. METHODS: Patients with locally advanced oropharyngeal cancer receiving chemo-radiotherapy will be randomized to either the prophylactic or reactive PEG tube group. Randomization will be stratified by human papillomavirus (HPV) status and unilateral versus bilateral positive neck lymph nodes. The primary objective of the study is the patient's reported outcome in terms of swallowing (MD Anderson Dysphagia Inventory (MDADI)) at 6 months. Secondary objectives include health-related quality of life, dosimetric parameters associated with patient-reported outcomes, chemo-radiation toxicities, PEG tube placement complications, the impact of nutritional status on survival and toxicity outcomes, loco-regional control, overall survival, the impact of HPV and tobacco smoking on survival outcomes and toxicities, and the cost-effectiveness of each treatment strategy. DISCUSSION: Findings from this study will enhance clinical evidence regarding nutritional management in oropharyngeal cancer patients treated by concurrent chemo-radiation. TRIAL REGISTRATION: ClinicalTrials.gov NCT04019548, study protocol version 2.0_08/08/2019. Registered on 15 July 2019.