A new schedule of one week on/one week off temozolomide as second-line treatment of advanced neuroendocrine carcinomas (TENEC-TRIAL): a multicenter, open-label, single-arm, phase II trial.

BACKGROUND: There is no consensus on the second-line treatment of patients with progressive high-grade neuroendocrine neoplasms (NENs G3) and large-cell lung neuroendocrine carcinoma. These patients generally have poor performance status and low tolerance to combination therapy. In this trial, we aim to evaluate the efficacy and safety of temozolomide given every other week in patients with advanced platinum-pretreated NENs G3. PATIENTS AND METHODS: This trial is an open-label, non-randomized, phase II trial. Patients with platinum-pretreated metastatic neuroendocrine carcinoma were treated with 75 mg/m2/day of temozolomide for 7 days, followed by 7 days of no treatment (regimen one week on/one week off). The primary endpoint was the overall response rate. Secondary endpoints included progression-free survival (PFS), overall survival (OS), safety and tolerability. This study is registered with ClinicalTrials.gov, NCT04122911. RESULTS: From 2017 to 2020, 38 patients were enrolled. Among the patients with determined Ki67, 12 out of 36 (33.3%) had a Ki67 index <55% and the remaining 24 out of 36 (66.6%) had an index ≥55%. Overall response rate was 18% (7/38), including one complete response and six partial responses. The median PFS was 5.86 months [95% confidence interval (CI) 4.8 months-not applicable) and the median OS was 12.1 months (95% CI 5.6-20.4 months). The 1-year PFS rate was 37%. No statistically significant difference in median PFS [hazard ratio 1.3 (95% CI 0.6-2.8); P = 0.44] and median OS [hazard ratio 1.1 (95% CI 0.5-2.4); P = 0.77] was observed among patients with Ki67 <55% versus ≥55%. Only G1-G2 adverse events were registered, the most common being G1 nausea, diarrhea and abdominal pain. CONCLUSION: One week on/one week off temozolomide shows promising activity in patients with poorly differentiated NEN. The good safety profile confirmed the possibility of using this scheme in patients with poor performance status.

Management of recurrent nasopharyngeal carcinoma: current perspectives.

Nasopharyngeal carcinoma is a rare disease in Western countries. Nevertheless, its incidence in China, Singapore, and other Eastern countries reaches 20 cases per 100,000 people. Being an extremely chemo- and radiosensitive disease, upfront treatment often consists in the association of intensity-modulated radiation therapy and concurrent cisplatin. Unfortunately, about 20% of the patients suffer from a radioresistant disease which recurs after upfront therapy. For these patients, mainly available therapeutic options consist in systemic therapy, in particular poly-chemotherapy. In those showing a single locoregional recurrence, chemotherapy is not considered to be the preferred approach and other different strategies may be employed. Re-irradiation and surgery are strategies that are always used more often, albeit related to high risk of morbidity. Immunotherapy and targeted therapy, such as heavy ions-based re-irradiations, are experimental but very intriguing options.

Epigenetic control of gene expression: Potential implications for cancer treatment.

Epigenetic changes are defined as inherited modifications that are not present in DNA sequence. Gene expression is regulated at various levels and not only in response to DNA modifications. Examples of epigenetic control are DNA methylation, histone deacetylation and mi-RNA expression. Methylation of several tumor suppressor gene promoters is responsible for their silencing and thus potentially sustain cancerogenesis. Similarly, histone deacetylation can lead to oncogene activation. mi-RNA are small (18-20 nucleotides) non-coding RNA fragments capable of inhibiting other m-RNA, ultimately altering the balance in oncogene and tumor suppressor gene expression. It has been shown that growth of several tumor types can be stimulated by epigenetic changes in various phases of cancerogenesis, and drugs able to interfere with these mechanisms can have a positive impact on tumor progression. As matter of fact, epigenetic changes are dynamic and can be reversed by epigenetic inhibitors. Recently, methyltransferase and histone deacetylase inhibitors have attracted the attention of researchers and clinicians as they potentially provide alternative therapeutic options in some cancers. Drugs that inhibit DNA methylation or histone deacetylation have been studied for the reactivation of tumor suppressor genes and repression of cancer cell growth. Epigenetic inhibitors work alone or in combination with other therapeutic agents. To date, a number of epigenetic inhibitors have been approved for cancer treatment. The main challenge in the field of epigenetic inhibitors is their lack of specificity. In this review article we describe their mechanisms of action and potential in cancer treatment.