Treating disease progression with osimertinib in EGFR-mutated non-small-cell lung cancer: novel targeted agents and combination strategies.

A precision medicine approach has been successfully applied in medical oncology for the treatment of non-small-cell lung cancer (NSCLC) through the identification of targetable driver molecular aberrations; activating mutations of epidermal growth factor receptor (EGFR) are the most common. Osimertinib, a third-generation, wild-type sparing, irreversible EGFR tyrosine kinase inhibitor (TKI), originally showed a striking activity after progression to first- and second-generation EGFR-TKIs when T790M resistance mutation was identified. Thereafter, upfront use of osimertinib became the standard of care based on overall survival benefit over first-generation TKIs erlotinib and gefitinib as reported in the FLAURA trial. For patients progressing on osimertinib, identification of resistance mechanisms is crucial to develop novel targeted therapeutic approaches. Moreover, innovative drugs or combination therapies are being developed for cases in which a specific resistance mechanism is not identifiable. In this review, the post-osimertinib treatment options for EGFR-mutated NSCLC are analyzed, with an outlook to ongoing clinical trials. An algorithm to guide clinicians in managing progression on osimertinib is proposed.

Salvage Low Dose Rate Brachytherapy For Recurrent Prostate Cancer After External Beam Radiotherapy: Results From A Single Institution With Focus On Toxicity And Functional Outcomes.

BACKGROUND/AIM: Low dose rate brachytherapy has been used as salvage therapy for locally recurrent prostate cancer (PC) after primary external beam radiation therapy (EBRT), along with surgery and cryotherapy. All these techniques, in particular, when applied to the whole gland, involve a relatively high risk of toxicity and may worsen the patient's quality of life. Our aim is to evaluate the results of whole-gland salvage brachytherapy (SBT) after primary EBRT in terms of toxicity, functional outcomes, and efficacy. MATERIALS AND METHODS: We retrospectively reviewed clinical data on 19 patients consecutively treated with SBT at our institution between June 2012 and November 2015. Local recurrences were identified with 11C-choline positron emission tomography/computed tomography and pelvic magnetic resonance imaging after biochemical recurrence according to Phoenix criteria (prostate-specific antigen nadir + 2). Low dose rate brachytherapy was performed by 125I permanent seeds implantation to the whole prostate gland, with a prescription dose of 130 Gy. At the time of SBT, only 2 patients were receiving androgen deprivation therapy. Acute and late toxicities were recorded using the CTCAE 4.0 scoring system. Quality of life was assessed using IPSS (International Prostate Symptoms Score) and IIEF (International Index of Erectile Function) questionnaires at baseline and 6, 12, and 24 months after SBT, and the respective mean values were compared using Student t test. Biochemical relapse-free survival (BRFS) was also calculated. RESULTS: Median follow-up after SBT was 24 months. Of 19 patients, 2 patients experienced a G3 cystitis (10.2%) and 1 patient experienced a G4 proctitis (5.3%), respectively. Mean pre-SBT IPSS scores and 6, 12, and 24 months after SBT were 5.84, 10.22, 15.72, and 8.10, respectively. Mean pre-SBT IIEF scores and 6, 12, and 24 months after SBT were 8.42, 3.55, 7.89, and 6.40, respectively. At the time of analysis, only 2 patients showed a biochemical relapse (3-year BRFS 85.2%). The Student t test demonstrated a worsening of functional outcome 6 months and 1 year after treatment but a subsequent improvement 2 years after SBT. CONCLUSIONS: Salvage brachytherapy for recurrent PC after primary EBRT seems to be a feasible treatment for selected patients. Our series revealed a severe toxicity peak 6 months and 1 year after local re-treatment and then they decrease. Early BRFS rates are good. However, these are very preliminary results so further patient accrual, long-term follow-up, and prospective trials are needed in the future.

Role of external beam radiotherapy in the treatment of relapsing meningioma.

The role of radiotherapy in the treatment of relapsing meningiomas is not well established. Data of patients treated with radiotherapy for a relapsing meningioma were retrospectively analyzed. Overall survival (OS) was the primary endpoint of the analysis. Local control and acute and late toxicity rates have been also reported. From April 1986 to February 2011, 37 patients with a diagnosis of recurrent meningioma were treated. Median age was 64 years (range 36-79). A total of 18, 10, 5 and 4 patients were affected by relapsing benign, atypical, malignant meningiomas and meningiosarcomas, respectively (WHO classification). Median dose was 60 Gy (range 46-66 Gy). The median follow-up was 42 months (range 3-300 months). OS at 1, 3, 5 and 8 years was 81, 55.6, 43.9 and 25.8%, respectively (median OS 45 months). A strong statistical trend was observed toward better OS rates in patients treated with radiotherapy at first recurrence compared to those treated at the second (or more) recurrence (OS 50.5 vs. 30.8%, p=0.055). A statistical impact of the histology (WHO I vs. II, III and IV) on 5-year OS was also observed (OS 60 vs. 30%, 0 and 0%, p=0.010). Radiotherapy has been well tolerated, with no G2-4 neurological toxicity (RTOG toxicity score). Conventional radiation therapy has an important role in multidisciplinary approach in the treatment of recurrence of meningiomas. The histological type and the timing of the radiotherapy are prognostic factors in terms of survival.