EGFR mutation positive stage IV non small-cell lung cancer: treatment beyond progression

Non-small-cell lung cancer (NSCLC) is the leading cause of death from cancer for both men en women. Chemotherapy is the mainstay of treatment in advanced disease, but is only marginally effective. In about 30% of patients with advanced NSCLC in East Asia and in 10-15% in Western countries, EGFR mutations are found. In this population, first-line treatment with the tyrosine kinase inhibitors (TKI) erlotinib, gefitinib or afatinib is recommended. The treatment beyond progression is less well-defined. In this paper we present 3 patients, EGFR mutation positive, with local progression after an initial treatment with TKI. These patients were treated with local radiotherapy. TKI was temporarily stopped and restarted after radiotherapy. We give an overview of the literature and discuss the different treatment options in case of progression after TKI: TKI continuation with or without chemotherapy, TKI continuation with local therapy, alternative dosing or switch to next-generation TKI or combination therapy. There are different options for treatment beyond progression in EGFR mutation positive metastatic NSCLC, but the optimal strategy is still to be defined. Further research on this topic is ongoing

Neo-adjuvant treatment of adenocarcinoma and squamous cell carcinoma of the cervix results in significantly different pathological complete response rates

Abstract Background Previous studies on cervical cancer reported a worse outcome for adenocarcinoma (AC) compared with squamous cell carcinoma (SCC). Nevertheless, standard treatment remains identical. Insight in the impact of histological types on biological behavior and pathological complete response rates might result in a treatment paradigm shift. Methods Clinicopathological characteristics, survival rates and relapse patterns were compared between AC (n = 36) and SCC (n = 143) cervical cancer patients. Pathological response to treatment was evaluated in the patient subgroup treated with neo-adjuvant chemoradiation followed by surgery (NA-CRT group; n = 84). Results In the entire cohort, 5y Disease Specific Survival (DSS) was 97.1 and 84% for AC and SCC respectively (p = 0.150). In the NA-CRT group 5y DSS was 100 and 75.5% for AC and SCC respectively (p = 0.059). Relapse patterns did not differ significantly between AC and SCC in the entire cohort, or in the NA-CRT group. Adenocarcinoma patients treated with NA-CRT showed significantly less pathological complete response compared with SCC patients (AC = 7%, SCC = 43%, p = 0.027). Conclusions There were no statistically significant differences regarding relapse and DSS rates between SCC and AC in the entire cohort, or the NA-CRT group. However, a trend to better 5y DSS of AC in the NA-CRT group was observed. This analysis showed significant differences in treatment responses after NA-CRT: patients with AC responded remarkably less to chemoradiation, resulting in a significantly lower pathological complete response rate. These findings imply a need for a paradigm shift in the treatment of cervical AC patients

PRIMMO study protocol : a phase II study combining PD-1 blockade, radiation and immunomodulation to tackle cervical and uterine cancer

Background: Immunotherapeutic approaches have revolutionized oncological practice but are less evaluated in gynecological malignancies. PD-1/PD-L1 blockade in gynecological cancers showed objective responses in 13-17% of patients. This could be due to immunosuppressive effects exerted by gynecological tumors on the microenvironment and an altered tumor vasculature.In other malignancies, combining checkpoint blockade with radiation delivers benefit that is believed to be due to the abscopal effect. Addition of immune modulation agents has also shown to enhance immune checkpoint blockade efficacy. Therefore we designed a regimen consisting of PD-1 blockade combined with radiation, and different immune/environmental-targeting compounds: repurposed drugs, metronomic chemotherapy and a food supplement.We hypothesize that these will synergistically modulate the tumor microenvironment and induce and sustain an anti-tumor immune response, resulting in tumor regression. Methods: PRIMMO is a multi-center, open-label, non-randomized, 3-cohort phase 2 study with safety run-in in patients with recurrent/refractory cervical carcinoma, endometrial carcinoma or uterine sarcoma.Treatment consists of daily intake of vitamin D, lansoprazole, aspirin, cyclophosphamide and curcumin, starting 2weeks before the first pembrolizumab dose. Pembrolizumab is administered 3-weekly for a total of 6cycles. Radiation (3x8Gy) is given on days 1, 3 and 5 of the first pembrolizumab dose.The safety run-in consists of 6 patients. In total, 18 and 25 evaluable patients for cervical and endometrial carcinoma respectively are foreseen to enroll. No sample size is determined for uterine sarcoma due to its rarity.The primary objective is objective response rate at week 26 according to immune-related response criteria.Secondary objectives include safety, objective response rate at week 26 according to RECIST v1.1, best overall response, progression-free survival, overall survival and quality of life.Exploratory, translational research aims to evaluate immune biomarkers, extracellular vesicles, cell death biomarkers and the gut microbiome. Discussion: In this study, a combination of PD-1 blockade, radiation and immune/environmental-targeting compounds is tested, aiming to tackle the tumor microenvironment and induce anti-tumor immunity. Translational research is performed to discover biomarkers related to the mode of action of the combination. Trial registration: EU Clinical Trials Register: EudraCT 2016-001569-97, registered on 19-6-2017. Clinicaltrials.gov: NCT03192059, registered on 19-6-2017

Adoption of single fraction radiotherapy for uncomplicated bone metastases in a tertiary centre

Background: Single-fraction radiotherapy (SFRT) offers equal pain relief for uncomplicated painful bone metastases as compared to multiple-fraction radiotherapy (MFRT). Despite this evidence, the adoption of SFRT has been poor with published rates of SFRT for uncomplicated bone metastases ranging from <10% to 70%. We aimed to evaluate the adoption of SFRT and its evolution over time following the more formal endorsement of the international guidelines in our centre starting from 2013. Materials and methods: We performed a retrospective review of fractionation schedules at our centre for painful uncomplicated bone metastases from January 2013 until December 2017. Only patients treated with 1 x 8 Gy (SFRT-group) or 10 x 3 Gy (MFRT-group) were included. We excluded other fractionation schedules, primary cancer of the bone and post-operative radiotherapy. Uncomplicated was defined as painful but not associated with impending fracture, existing fracture or existing neurological compression. Temporal trends in SFRT/MFRT usage and overall survival were investigated. We performed a lesion-based patterns of care analysis and a patient-based survival analysis. Mann-Whitney U and Chisquare test were used to assess differences between fractionation schedules and temporal trends in prescription, with Kaplan-Meier estimates used for survival analysis (p-value <0.05 considered significant). Results: Overall, 352 patients and 594 uncomplicated bone metastases met inclusion criteria. Patient characteristics were comparable between SFRT and MFRT, except for age. Overall, SFRT was used in 92% of all metastases compared to 8% for MFRT. SFRT rates increased throughout the study period from 85% in 2013 to 95% in 2017 (p = 0.06). Re-irradiation rates were higher in patients treated with SFRT (14%) as compared to MFRT (4%) (p = 0.046). Four-week mortality and median overall survival did not differ significantly between SFRT and MFRT (17% vs 18%, p = 0.8 and 25 weeks vs 38 weeks, p = 0.97, respectively). Conclusions: Adherence to the international guidelines for SFRT for uncomplicated bone metastasis was high and increased over time to 95%, which is the highest reported rate in literature. (C)2021 The Authors. Published by Elsevier B.V. on behalf of European Society for Radiotherapy and Oncology

Ionizing radiation results in a mixture of cellular outcomes including mitotic catastrophe, senescence, methuosis, and iron-dependent cell death

Radiotherapy is commonly used as a cytotoxic treatment of a wide variety of tumors. Interestingly, few case reports underlined its potential to induce immune-mediated abscopal effects, resulting in regression of metastases, distant from the irradiated site. These observations are rare, and apparently depend on the dose used, suggesting that dose-related cellular responses may be involved in the distant immunogenic responses. Ionizing radiation (IR) has been reported to elicit immunogenic apoptosis, necroptosis, mitotic catastrophe, and senescence. In order to link a cellular outcome with a particular dose of irradiation, we performed a systematic study in a panel of cell lines on the cellular responses at different doses of X-rays. Remarkably, we observed that all cell lines tested responded in a similar fashion to IR with characteristics of mitotic catastrophe, senescence, lipid peroxidation, and caspase activity. Iron chelators (but not Ferrostatin-1 or vitamin E) could prevent the formation of lipid peroxides and cell death induced by IR, suggesting a crucial role of iron-dependent cell death during high-dose irradiation. We also show that in K-Ras-mutated cells, IR can induce morphological features reminiscent of methuosis, a cell death modality that has been recently described following H-Ras or K-Ras mutation overexpression

Acute toxicity and health-related quality of life after accelerated whole breast irradiation in 5 fractions with simultaneous integrated boost

Introduction: Acceleration of radiotherapy in 5 fractions for breast cancer can reduce the burden of treatment. We report on acute toxicity after whole-breast irradiation with a simultaneous integrated boost in 5 fractions over 10-12 days. Material and methods: Acute toxicity and health-related quality of life (HRQoL) of 200 patients, randomized between a 15or 5-fractions schedule, were collected, using the CTCAE toxicity scoring system, the Multidimensional Fatigue Inventory, EORTC QLQ-C30 and BR23 and the BREAST-Q questionnaire. The prescribed dose to the breast was either 15*2.67 Gy (40.05 Gy) or 5*5.7 Gy (28.5 Gy). 90% of patients received a SIB to a cumulative dose of 46.8 Gy (15*3.12 Gy) or 31 Gy (5*6.2 Gy). Results: Physician-assessed toxicity was lower for the 5-fractions group. A significant difference was observed for breast pain (p = 0.002), fatigue (p < 0.0001), breast edema (p = 0.001) and dermatitis (p = 0.003). Patients treated in 5 fractions reported better mean HRQoL scores for breast symptoms (p = 0.001) and physical well-being (p = 0.001). A clinically important deterioration in HRQoL of 10 points or more was also less frequently observed in the latter group for physical functioning (p = 0.0005), social functioning (p = 0.0007), fatigue (p = 0.003), breast symptoms (p = 0.0002) and physical wellbeing (p = 0.002). Conclusion: In this single institute study, acute toxicity of accelerated breast radiotherapy in 5 fractions over 10-12 days seems to compare favourably to hypofractionated breast radiotherapy in 15 fractions. Less breast edema, dermatitis, desquamation, breast pain and fatigue are seen. Social and physical functioning are also less disturbed and patients have a better future perspective