Combined use of radiotherapy and tyrosine kinase inhibitors in the management of metastatic non-small cell lung cancer: a literature review.

The approval of tyrosine kinase inhibitors (TKIs) as first-line agents has revolutionised treatment of patients diagnosed with advanced non-small cell lung cancer (NSCLC) harboring targetable mutations, adding substantial overall survival (OS) benefit, compared to chemotherapy. However, the efficacy of these agents is inevitably diminished at a point in the disease course, either because of cellular resistance-mechanisms or due to affected pharmacokinetics, like low-central nervous system penetration. The aim of this article is to review existing evidence on the combined use of EGFR (epidermal growth factor)- or ALK (anaplastic lymphoma kinase)-specific TKIs and radiotherapy (RT) in advanced NSCLC setting, as an attempt to delay or overcome TKI-resistance and thus, to expand the time period during which patients derive benefit from a given line of targeted therapy. At present, combining RT with EGFR- or ALK-TKIs in the management of advanced, oncodriver-mutated NSCLC has shown quite promising results, with regards to PFS and OS, rendering prolongation of the TKI-derived benefit feasible, with generally tolerable toxicity. Future studies to confirm the observed efficacy and clarify possible safety issues as well as the appropriate treatment sequence and target volumes are needed, especially in the rapidly-evolving era of newer-generation TKIs.

Radiotherapy and Testicular Function: A Comprehensive Review of the Radiation-Induced Effects with an Emphasis on Spermatogenesis.

This comprehensive review explores the existing literature on the effects of radiotherapy on testicular function, focusing mainly on spermatogenic effects, but also with a brief report on endocrine abnormalities. Data from animal experiments as well as results on humans either from clinical studies or from accidental radiation exposure are included to demonstrate a complete perspective on the level of vulnerability of the testes and their various cellular components to irradiation. Even relatively low doses of radiation, produced either from direct testicular irradiation or more commonly from scattered doses, may often lead to detrimental effects on sperm count and quality. Leydig cells are more radioresistant; however, they can still be influenced by the doses used in clinical practice. The potential resultant fertility complications of cancer radiotherapy should be always discussed with the patient before treatment initiation, and all available and appropriate fertility preservation measures should be taken to ensure the future reproductive potential of the patient. The topic of potential hereditary effects of germ cell irradiation remains a controversial field with ethical implications, requiring future research.

Anti-Tumor Immunity and Preoperative Radiovaccination: Emerging New Concepts in the Treatment of Breast Cancer.

Neoadjuvant chemotherapy (NACT) for certain breast cancer (BC) subtypes confers significant tumor regression rates and a survival benefit for patients with a complete pathologic response. Clinical and preclinical studies have demonstrated that immune-related factors are responsible for better treatment outcomes, and thus, neoadjuvant immunotherapy (IO) has emerged as a means to further improve patient survival rates. Innate immunological "coldness", however, of specific BC subtypes, especially of the luminal ones, due to their immunosuppressive tumor microenvironment, hinders the efficacy of immune checkpoint inhibitors. Treatment policies aiming to reverse this immunological inertia are, therefore, needed. Moreover, radiotherapy (RT) has been proven to have a significant interplay with the immune system and promote anti-tumor immunity. This "radiovaccination" effect could be exploited in the neoadjuvant setting of BC and significantly enhance the effects of the already established clinical practice. Modern stereotactic irradiation techniques directed to the primary tumor and involved lymph nodes may prove important for the RT-NACT-IO combination. In this review, we provide an overview and critically discuss the biological rationale, clinical experience, and ongoing research underlying the interplay between neoadjuvant chemotherapy, anti-tumor immune response, and the emerging role of RT as a preoperative adjunct with immunological therapeutic implications in BC.

Is anti-PD-1 immunotherapy a means for post-irradiation tumor clearance in head and neck cancer?

Chemo-radiotherapy is the standard treatment for locally advanced head-neck cancer (LA-HNC). However, about 30% of tumors do not respond or even progress shortly after the completion of radiotherapy. We investigated whether anti-PD1 immunotherapy can eradicate the irradiated tumor and reverse the ominous prognosis of these patients. We retrospectively analyzed a small series of 9 patients with LA-HNC who did not respond (6/9) or showed local disease progression (3/9) during chemo-radiotherapy and were treated with nivolumab anti-PD1 immunotherapy. Immunotherapy started 1.5 months after the end of radiotherapy. Out of 9 patients, 3 (33.3%) had a complete response and 3 (33.3%) partial response at 6 months after the onset of immunotherapy. Two patients are alive with no evidence of disease at 36 months. One more patient with partial response and without disease progression survived 16 months after therapy when he died from intercurrent disease. Immunotherapy showed an excellent tolerance profile. One patient developed an extensive skin rash on the 16th cycle. Anti-PD-1 immunotherapy after radiotherapy can lead to clearance of the remnant tumor and ameliorate the prognosis of patients. Randomized trials are necessary to establish post-irradiation immunotherapy as a standard of care in this ill-fated subgroup of HNC patients.