Search

Abstract Background In early-phase studies with targeted therapeutics and radiotherapy, it may be difficult to decide whether an adverse event should be considered a dose-limiting toxicity (DLT) of the investigational systemic agent, as acute normal tissue toxicity is frequently encountered with radiation alone. We have reanalyzed the toxicity data from a recently conducted phase 1 study on vorinostat, a histone deacetylase inhibitor, in combination with pelvic palliative radiotherapy, with emphasis on the dose distribution within the irradiated bowel volume to the development of DLT. Findings Of 14 eligible patients, three individuals experienced Common Terminology Criteria of Adverse Events grade 3 gastrointestinal and related toxicities, representing a toxicity profile vorinostat has in common with radiotherapy to pelvic target volumes. For each study patient, the relative volumes of small bowel receiving radiation doses between 6 Gy and 30 Gy at 6-Gy intervals (V6-V30) were determined from the treatment-planning computed tomography scans. The single patient that experienced a DLT at the second highest dose level of vorinostat, which was determined as the maximum-tolerated dose, had V6-V30 dose-volume estimates that were considerably higher than any other study patient. This patient may have experienced an adverse radiation dose-volume effect rather than a toxic effect of the investigational drug. Conclusions When reporting early-phase trial results on the tolerability of a systemic targeted therapeutic used as potential radiosensitizing agent, radiation dose-volume effects should be quantified to enable full interpretation of the study toxicity profile. Trial registration ClinicalTrials.gov: NCT00455351

Abstract Background The tumor response to preoperative radiotherapy of locally advanced rectal cancer varies greatly, warranting the use of experimental models to assay the efficacy of molecular targeting agents in rectal cancer radiosensitization. Histone deacetylase (HDAC) inhibitors, agents that cause hyperacetylation of histone proteins and thereby remodeling of chromatin structure, may override cell cycle checkpoint responses to DNA damage and amplify radiation-induced tumor cell death. Methods Human colorectal carcinoma cell lines were exposed to ionizing radiation and HDAC inhibitors, and cell cycle profiles and regulatory factors, as well as clonogenicity, were analyzed. Results In addition to G2/M phase arrest following irradiation, the cell lines displayed cell cycle responses typical for either intact or defective p53 function (the presence or absence, respectively, of radiation-induced expression of the cell cycle inhibitor p21 and subsequent accumulation of G1 phase cells). In contrast, histone acetylation was associated with complete depletion of the G1 population of cells with functional p53 but accumulation of both G1 and G2/M populations of cells with defective p53. The cellular phenotypes upon HDAC inhibition were consistent with the observed repression of Polo-like kinase-1, a regulatory G2/M phase kinase. Following pre-treatment with HDAC inhibitors currently undergoing clinical investigation, the inhibitory effect of ionizing radiation on clonogenicity was significantly amplified. Conclusion In these experimental models, HDAC inhibition sensitized the tumor cells to ionizing radiation, which is in accordance with the concept of increased probability of tumor cell death when chromatin structure is modified.

Objective  Squamous cell carcinoma (SCC) of the paranasal sinuses is usually diagnosed at an advanced stage, making curative therapy difficult. The goal of this study was to evaluate the management and outcomes of patients with SCC treated at our institution. Methods  In a population-based consecutive prospective cohort, we conducted an analysis of all patients treated for SCC between 1988 and 2017. Results  A total of 72 patients were included, follow-up was 100%. Mean follow-up was 57 months for the entire cohort, and 108 months for patients with no evidence of disease. Eighty-two percent of all patients had high-stage (T4) disease. Fifty-seven patients underwent treatment with curative intent; consisting of surgery with or without oncologic treatment in 34, and of oncologic treatment only in 23 cases. Fifteen patients received palliative treatment. The rates of overall survival for the entire cohort were 55% at 2, 41% at 5, and 32% at 10 years, and corresponding disease-specific survival (DSS) rates were 55, 45, and 34%, respectively. DSS rates after surgical treatment with curative intent were 81% at 2, 65% at 5, and 54% at 10 years. Retromaxillary involvement and nonradical surgery were negative prognostic factors. Best survival was achieved with the combination of radical surgery and adjuvant oncologic treatment. Conclusion  Surgical resection with a curative intent yielded 65% at 5-year DSS even in this cohort of patients with high-stage SCC and is still considered as the treatment of choice, preferably in combination with adjuvant radiation therapy and chemotherapy. [ABSTRACT FROM AUTHOR]

Objectives  Sinonasal adenocarcinoma (AC) is a potentially curable disease despite being an aggressive malignancy. Long-term survival can be achieved with early diagnosis and adequate multidisciplinary treatment. Our goal was to evaluate outcomes for patients with AC treated at our institution. Design  In a population-based consecutive prospective cohort, we conducted an analysis of all patients treated for surface epithelial AC between 1995 and 2018. Results  Twenty patients were included, and follow-up was 100%. The mean follow-up time was 89 months for the entire cohort (112 months for patients with no evidence of disease). Intestinal-type AC was found in 65%, whereas nonintestinal-type AC was found in 35% of all cases; 75% had stage T3/4 disease. Tumor grade was intermediate/high in 65%. Eighteen patients underwent treatment with curative intent (craniofacial resection [CFR] in 61%, transfacial approach in 39%, adjuvant radiotherapy in 89%), achieving negative margins in 56% of cases. Overall survival (OS) rates were 90, 68, and 54% after 2, 5, and 10 years of follow-up, respectively, and the corresponding disease-specific survival (DSS) rates were 90, 73, and 58%. Age over 60 years, tumor with a maxillary origin, and microscopic bone invasion were negative prognostic factors. Radical CFR was correlated with better OS and DSS. Conclusion  The high probability of achieving radicality with CFR, the low complication rate, the acceptable toxicity of modern irradiation modalities, and the promising survival rates indicate that this strategy might be considered a safe and an effective option for treating patients with very advanced sinonasal AC. [ABSTRACT FROM AUTHOR]

Background: Tumors originating from the craniofacial region usually present in a locally advanced stage with frequent involvement of adjacent sites and have a strong tendency for local recurrence in the absence of adjuvant therapy, even when the original surgical resection was presumed to be radical. In the past decades, several advances in the radiological diagnosis and treatment of craniofacial malignancies have been introduced. There are, however, no randomized trials that define the optimal multimodal treatment of these tumors because of their rarity as well as heterogeneity in both histology and site of origin. The aim of this study was to conduct a critical review of the role of adjuvant therapy in the treatment of craniofacial malignancy. Method: We conducted a critical review of the past and contemporary literature available, focusing on adjuvant oncological treatments of the most common craniofacial malignancies. Results: Preoperative radiotherapy can have a documented role in the treatment of olfactory neuroblastoma and soft tissue sarcoma, while preoperative chemotherapy can be advocated in the treatment of sinonasal undifferentiated carcinoma, neuroendocrine carcinoma, olfactory neuroblastoma, and craniofacial sarcoma (both soft-tissue and high-grade osteosarcoma). Postoperative radiotherapy has a well-established role in the treatment of most craniofacial malignancies. The role of postoperative chemotherapy is unclear in most histologies, but is commonly used during the treatment of well-selected cases of paranasal sinus carcinoma, olfactory neuroblastoma, mucosal melanoma, soft tissue sarcoma and high-grade craniofacial osteosarcoma. Discussion: Alongside developments in surgery, there have also been improvements in diagnostics, radiotherapy, and chemotherapy. Implementation of novel radiation techniques allows delivery of higher radiation doses while minimizing irradiation-related morbidity. Better understanding of tumor biology allows the construction of more complex treatment strategies, incorporating adjuvant chemotherapy either pre- or postoperatively. In the era of personalized targeted therapy, rapid strides are being made to identify specific tumor-targets for use of novel biologic agents, with the potential to change current management paradigms., (Copyright © 2020 König, Osnes, Bruland, Sundby Hall, Bratland and Meling.)

Gorlin syndrome is a rare genetic condition in which patients may develop medulloblastomas, jaw cysts and basal cell carcinomas and show congenital skeletal malformations. If left undiagnosed, Gorlin syndrome can have a number of negative consequences. Early diagnosis and good follow-up is important for all patients with rare disorders. We wish to make doctors and dentists aware of Gorlin syndrome so that, whenever the syndrome is suspected or a patient has been diagnosed, the patient is referred for assessment, treatment and follow-up by specialists who know the disorder well. Dermatology departments at university hospitals and departments of medical genetics have a key role to play in assessment and follow-up. A national support group for Gorlin syndrome has been established, consisting of a dermatologist, oncologist, geneticist, paediatrician, specialist dentist, ophthalmologist, orthopaedic surgeon, plastic surgeon, oral and maxillofacial surgeon and counsellors. Patients, relatives and health professionals can contact the Centre for Rare Disorders directly for information about Gorlin syndrome, or to be put in touch with members of the group.

Background: Cardiac dysfunction in the form of reduced systolic and/or diastolic left ventricular function after adjuvant cancer therapy has recently attracted increasing attention. The best-known cardiotoxic agents are anthracyclines and the recombinant antibody trastuzumab. Patients treated with radiotherapy to the thorax are liable to develop coronary artery disease. There are no official guidelines for the preventive treatment of cardiac dysfunction induced by chemotherapy, antibody therapy or radiotherapy. The purpose of this article is to provide an overview of cardiac dysfunction caused by adjuvant cancer therapies and to review possible preventive therapeutic principles., Material and Method: This article is based on a review of the literature derived from a search in PubMed., Results: 27% of those treated with anthracyclines and trastuzumab may develop some degree of cardiac dysfunction. The figure for patients receiving radiotherapy to the thorax is more uncertain. Small-scale studies suggest that anthracycline-induced cardiac dysfunction can be prevented wholly or partially by blocking the renin-angiotensin-aldosterone system and by beta-adrenergic blockade. As yet, there are no results of prospective studies on cardiopreventive treatment during trastuzumab therapy or thoracic radiotherapy., Interpretation: There is a need for randomised, placebo-controlled studies of homogeneous groups of patients in order to determine whether treatment with cardioprotective medication in parallel with chemotherapy, antibody therapy or radiotherapy can prevent or reduce cardiac dysfunction.