Radiotherapy induces an increase in serum antioxidant capacity reflecting tumor response.

Background and purpose: Radiotherapy (RT) is a mainstay component of treatment for patients with head and neck squamous cell carcinoma (HNSCC), but responses vary. As RT relies upon oxidative damage, antioxidant expression in response to RT-induced reactive oxygen species (ROS) could compromise treatment response. We aimed to examine local and systemic antioxidant responses to increased RT-induced ROS in relation to treatment success. Materials and methods: Nuclear factor erythroid 2-related factor 2 (NRF2), the main antioxidant transcription factor, was immunofluorescently stained in FaDu cells and in tumor biopsies of patients with oral cavity/oropharynx HNSCC before and after five fractions of RT. Besides, total antioxidant capacity (TAC) was analyzed in HNSCC tumor cells in vitro and in serum of HNSCC patients before, during, and after RT. Results: Data revealed an increase in NRF2 expression and TAC in head and neck cancer cells in vitro over the course of 5 daily fractions of 2 Gy. In accordance, also in patients' tumors NRF2 expression increased, which was associated with increased serum TAC during RT. Increasing serum TAC was related to impaired local tumor control. Conclusion: Radiation induced NRF2 expression and upregulated TAC, which may compromise the effect of RT-induced ROS. Changes in serum TAC during RT could serve as a novel predictor of treatment outcome in HNSCC patients.Medical Ethics Review Committee (CMO) approval - CMO number: 2007/104.

Personalized neck irradiation guided by sentinel lymph node biopsy in patients with squamous cell carcinoma of the oropharynx, larynx or hypopharynx with a clinically negative neck: (Chemo)radiotherapy to the PRIMary tumor only. Protocol of the PRIMO study.

Background: Elective neck irradiation (ENI) is performed in head and neck cancer patients treated with definitive (chemo)radiotherapy. The aim is to eradicate nodal metastases that are not detectable by pretreatment imaging techniques. It is conceivable that personalized neck irradiation can be performed guided by the results of sentinel lymph node biopsy (SLNB). It is expected that ENI can be omitted to one or both sides of the neck in 9 out of 10 patients, resulting in less radiation side effects with better quality of life. Methods/design: This is a multicenter randomized controlled trial aiming to compare safety and efficacy of treatment with SLNB guided neck irradiation versus standard bilateral ENI in 242 patients with cN0 squamous cell carcinoma of the oropharynx, larynx or hypopharynx for whom bilateral ENI is indicated. Patients randomized to the experimental-arm will undergo SLNB. Based on the histopathologic status of the SLNs, patients will receive no ENI (if all SLNs are negative), unilateral neck irradiation only (if a SLN is positive at one side of the neck) or bilateral neck irradiation (if SLNs are positive at both sides of the neck). Patients randomized to the control arm will not undergo SLNB but will receive standard bilateral ENI. The primary safety endpoint is the number of patients with recurrence in regional lymph nodes within 2 years after treatment. The primary efficacy endpoint is patient reported xerostomia-related quality of life at 6 months after treatment. Discussion: If this trial demonstrates that the experimental treatment is non-inferior to the standard treatment in terms of regional recurrence and is superior in terms of xerostomia-related quality of life, this will become the new standard of care.

Future steps in cardio-oncology-a national multidisciplinary survey among healthcare professionals in the Netherlands.

BACKGROUND: The awareness of cancer therapy-related adverse cardiac effects is fueled by recent literature on cardiotoxicity incidence and detection strategies. Although this influences the sense of urgency, in current practice, cardiotoxicity monitoring and treatment is not structurally performed. With this study, we aimed to evaluate current perspectives on cardio-oncology and to assess needs, ultimately to determine an agenda for improvements in current practice. MATERIAL AND METHODS: A national multidisciplinary 36-question survey was conducted. The survey was developed by a multidisciplinary team, theoretically based on an implementation checklist and distributed by email, through cardiology and oncology societies as well as social media. RESULTS: One hundred ninety professionals completed the survey, of which 66 were cardiologists, 66 radiation oncologists, and 58 medical oncologists and hematologists. Many professionals were unaware of their specialisms' cardio-oncology guidelines: 62.1% of cardiologists and 29.3% of the hematologists and medical oncologists respectively. Many cardiologists (N = 46; 69.7%), radiation oncologists (N = 45; 68.2%), and hematologists and medical oncologists (N = 38; 65.5%) expressed that they did not have sufficient knowledge to treat cardio-oncology patients and would either refer a patient or aspire to gain more knowledge on the topic. CONCLUSION: The field of cardio-oncology is advancing rapidly, with progress in stratification and detection strategies leading to the development of new guidelines and consensus statements. However, the application of these guidelines in current practice appears to be lagging. Professionals express a need for additional training and a practical guideline including risk stratification, monitoring, and treatment strategies. Multidisciplinary discussion and consensus on cardio-oncology care is vital to improve implementation of cardio-oncology guidelines, ultimately to improve cardiac care for oncology patients.

Considerations for radiotherapy in Bloom Syndrome: A case series.

Bloom Syndrome (BS) is a genetic DNA repair disorder, caused by mutations in the BLM gene. The clinical phenotype includes growth retardation, immunodeficiency and a strong predisposition to different types of malignancies. Treatment of malignancies in BS patients with radiotherapy or chemotherapy is believed to be associated with increased toxicity, but clinical and laboratory data are lacking. We collected clinical data of two Dutch BS patients with solid tumors. Both were treated with radiotherapy before the diagnosis BS was made and tolerated this treatment well. In addition, we collected fibroblasts from BS patients to perform in vitro clonogenic survival assays to determine radiosensitivity. BS fibroblasts showed less radiosensitivity than the severely radiosensitive Artemis fibroblasts. Moreover, studies of double strand break kinetics by counting 53BP1 foci after irradiation showed similar patterns compared to healthy controls. In combination, the clinical cases and laboratory experiments are valuable information in the discussion whether radiotherapy is absolutely contraindicated in BS, which is the Case in other DNA repair syndromes like Ataxia Telangiectasia and Artemis.

Imaging angiogenesis in patients with head and neck squamous cell carcinomas by [68Ga]Ga-DOTA-E-[c(RGDfK)]2 PET/CT.

PURPOSE: Angiogenesis plays an important role in the growth and metastatic spread of solid tumours and is characterised by the expression of integrins on the cell surface of endothelial cells. Radiolabelled RGD peptides specifically target angiogenesis-related αvß3 integrins, expressed on the activated endothelial cells of sprouting blood vessels. Here, we validated the feasibility of 68Ga[Ga]-DOTA-E-[c(RGDfK)]2 (68Ga-RGD) PET/CT to visualise angiogenesis in patients with oral squamous cell carcinoma (OSCC). METHODS: Ten patients with OSCC and scheduled for surgical resection including elective neck dissection received an intravenously administration of 68Ga-RGD (42 ± 8 µg; 214 ± 9 MBq). All patients subsequently underwent dynamic (n = 5) or static PET/CT imaging (n = 5) for 60 min or for 4 min/bed position at 30, 60 and 90 min after injection, respectively. Quantitative tracer uptake in tumour lesions was expressed as standardised uptake values (SUV). Additionally, tumour tissue was immunohistochemically stained for αvß3 integrin to assess the expression pattern. RESULTS: 68Ga-RGD tumour accumulation was observed in all patients. At 60 min post injection, tumour SUVmax ranged between 4.0 and 12.7. Tracer accumulation in tumour tissue plateaued at 10 min after injection. Uptake in background tissue did not change over time, resulting in tumour-to-muscle tissue of 6.4 ± 0.7 at 60 min post injection. CONCLUSIONS: 68Ga-RGD PET/CT of αvß3 integrin expression in OSCC patients is feasible with adequate tumour-to-background ratios. It will provide more insight in angiogenesis as a hallmark of the head and neck squamous cell carcinomas' tumour microenvironment. TRIAL REGISTRATION: https://eudract.ema.europa.eu no. 2015-000917-31.

Clinicopathological characteristics and outcome of 31 patients with ETV6-NTRK3 fusion gene confirmed (mammary analogue) secretory carcinoma of salivary glands.

OBJECTIVES: In 2010, a new subtype of salivary gland cancer (SGC), (mammary analogue) secretory carcinoma (SC), was defined, characterized by the ETV6-NTRK3 fusion gene. As clinical behavior and outcome data of this histological subtype tumor are still sparse, we aimed to describe the clinicopathological course and outcome of a series of translocation positive SC patients. PATIENT AND METHODS: We re-evaluated the pathological diagnosis of a subset of SGCs, diagnosed in 4 of 8 Dutch head and neck centers. Subsequently, tumors with a morphological resemblance to SC were tested for the ETV6-NTRK3 fusion gene using RT-PCR. Furthermore, patients prospectively diagnosed with SC were included. The clinical characteristics and outcomes were retrieved from the patient files. RESULTS: Thirty-one patients with ETV6-NTRK3 fusion gene positive SC were included. The median age was 49 years, 17 patients (55%) were male. Eighteen tumors (58%) arose in the parotid gland. One patient presented with lymph node metastasis. All patients underwent tumor resection and 4 patients had a neck dissection. Four patients had re-resection and 15 patients (48%) received postoperative radiotherapy. One patient developed a local recurrence, no regional recurrences or distant metastases were observed. After a median follow-up of 49 months the 5- and 10-year overall survival were 95%, the 5- and 10-year disease free survival were 89%. CONCLUSION: The clinical course of SC is favorable with a low rate of locoregional recurrence and excellent survival. Given the low incidence of nodal metastases, elective neck treatment, i.e. surgery and/or radiotherapy, does not seem to be indicated.

A meta-analysis on the surgical management of paraganglioma of the carotid body per Shamblin class.

OBJECTIVE: The aim of this study was to evaluate the risk associated with different types of surgery for carotid body paraganglioma of different Shamblin class. A meta-analysis was conducted to evaluate per tumour class, the local control, cranial nerve damage and complication rates of different techniques using internal carotid artery (ICA) and external carotid artery (ECA) ligation, clamping or bypassing, as well as the craniocaudal vs caudocranial techniques. DESIGN: A meta-analysis is conducted after a systematic search in PubMed and the Cochrane library, in accordance with the PRISMA guidelines. MAIN OUTCOME MEASURES: Local control, cranial nerve damage, complications, function recovery. RESULTS: Out of 3565 articles, 27 were selected. The overall quality of evidence of studies was low. Cranial nerve damage (3%, 17% and 39%) and complication rates (0%, 1% and 10%) were significantly related to Shamblin class (class 1, 2 and 3, respectively, P < .01). For class 3 tumours, an increased risk of complications was found associated with routine ICA manipulation/reconstruction (RR 3.12 with a 95% CI of 1.29-7.59), as well as a trend towards enhanced risk of routine ECA ligation (RR 3.48 with a 95% CI of 0.88-13.81). CONCLUSIONS: For class 1 and 2 tumours, surgery seems a viable treatment option. For class 3 tumours, morbidity in terms of cranial nerve deficit and complications is considerable; particularly, the use of ICA manipulation/reconstruction and potentially ECA ligation seem to be accompanied by high stroke incidence.

Results of a systematic literature review of treatment modalities for jugulotympanic paraganglioma, stratified per Fisch class.

OBJECTIVE: Key for successful jugulotympanic paraganglioma management is a personalised approach aiming for the best practice for each individual patient. To this end, a systematic review is performed, evaluating the local control and complication rates for the different treatment modalities stratified by the broadly accepted Fisch classification. DESIGN: A systematic literature review according to the PRISMA statement was performed. A detailed overview of individual treatment outcomes per Fisch class is provided. MAIN OUTCOME MEASURES: Local control, cranial nerve damage, complications, function recovery. RESULTS: Eighteen studies were selected, resembling 83 patients treated with radiotherapy and 299 with surgery. Excellent local control was found post-surgery for class A and B tumours, and risk of cranial nerve damage was <1%. For class C1-4 tumours, local control was 80%-95% post-surgery (84% post-radiotherapy), and cranial nerve damage was found in 71%-76% (none post-radiotherapy; P < .05). There was no difference in treatment outcomes between tumours of different C class. For class C1-4De/Di tumours, local control was 38%-86% (98% post-radiotherapy; P < .05) and cranial nerve damage/complication rates were 67%-100% (3% post-radiotherapy; P < .05). C1-4DeDi tumours showed lesser local control and cranial nerve damage rates when compared to C1-4De tumours. CONCLUSIONS: An individual risk is constituted for surgery and radiotherapy, stratified per Fisch class. For class A and B tumours, surgery is a suitable treatment option. For class C and D tumours, radiotherapy results in lower complication rates and similar or better local control rates when compared to the surgical group.

Correction to: Automated IMRT planning in Pinnacle-A study in head-and-neck cancer.

Correction to: Strahlenther Onkol 2017 https://doi.org/10.1007/s00066-017-1187-9 Unfortunately, parts of the 'Materials and Methods section' and a sentence in the 'Discussion section' had to be corrected.On page 3, left column, the complete first paragraph was corrected and now reads as follows:Auto-P.

Automated IMRT planning in Pinnacle : A study in head-and-neck cancer.

PURPOSE: This study evaluates the performance and planning efficacy of the Auto-Planning (AP) module in the clinical version of Pinnacle 9.10 (Philips Radiation Oncology Systems, Fitchburg, WI, USA). METHODS AND MATERIALS: Twenty automated intensity-modulated radiotherapy (IMRT) plans were compared with the original manually planned clinical IMRT plans from patients with oropharyngeal cancer. RESULTS: Auto-Planning with IMRT offers similar coverage of the planning target volume as the original manually planned clinical plans, as well as better sparing of the contralateral parotid gland, contralateral submandibular gland, larynx, mandible, and brainstem. The mean dose of the contralateral parotid gland and contralateral submandibular gland could be reduced by 2.5 Gy and 1.7 Gy on average. The number of monitor units was reduced with an average of 143.9 (18%). Hands-on planning time was reduced from 1.5-3 h to less than 1 h. CONCLUSIONS: The Auto-Planning module was able to produce clinically acceptable head and neck IMRT plans with consistent quality.

Prediction of local and metastatic recurrence in solitary fibrous tumor: construction of a risk calculator in a multicenter cohort from the French Sarcoma Group (FSG) database.

BACKGROUND: Solitary fibrous tumors (SFT) are rare unusual ubiquitous soft tissue tumors that are presumed to be of fibroblastic differentiation. At present, the challenge is to establish accurate prognostic factors. PATIENTS AND METHODS: A total of 214 consecutive patients with SFT diagnosed in 24 participating cancer centers were entered into the European database (www.conticabase.org) to perform univariate and multivariate analysis for overall survival (OS), local recurrence incidence (LRI) and metastatic recurrence incidence (MRI) by taking competing risks into account. A prognostic model was constructed for LRI and MRI. Internal and external validations of the prognostic models were carried out. An individual risk calculator was carried out to quantify the risk of both local and metastatic recurrence. RESULTS: We restricted our analysis to 162 patients with local disease. Twenty patients (12.3%) were deceased at the time of analysis and the median OS was not reached. The LRI rates at 10 and 20 years were 19.2% and 38.6%, respectively. The MRI rates at 10 and 20 years were 31.4% and 49.8%, respectively. Multivariate analysis retained age and mitotic count tended to significance for predicting OS. The factors influencing LRI were viscera localization, radiotherapy and age. Mitotic count, tumor localization other than limb and age had independent values for MRI. Three prognostic groups for OS were defined based on the number of unfavorable prognostic factors and calculations were carried out to predict the risk of local and metastatic recurrence for individual patients. CONCLUSION: LRI and MRI rates increased between 10 and 20 years so relapses were delayed, suggesting that long-term monitoring is useful. This study also shows that different prognostic SFT sub-groups could benefit from different therapeutic strategies and that use of a survival calculator could become standard practice in SFTs to individualize treatment based on the clinical situation.

The efficacy of hyperbaric oxygen therapy related to the clinical stage of osteoradionecrosis of the mandible.

This study aimed to evaluate the success of hyperbaric oxygen therapy (HBOT) and surgery in the treatment of mandibular osteoradionecrosis (ORN) in relation to the extent of the ORN. Twenty-seven patients with ORN were identified from a total of 509 patients with a history of primary oral or base of the tongue cancer; these patients had been treated with radiation therapy with curative intent between 1992 and 2006, with a radiation dose to the mandible of ≥50Gy. The ORN was staged according to the classification of Notani et al. The time from completion of radiation therapy to the development of ORN varied (median 3 years). Forty HBOT sessions were offered. After HBOT alone, 3 of 11 stage I lesions, 0 of 8 stage II lesions, and 0 of 8 stage III lesions had healed (P=0.0018). An absolute incidence of 5.3% ORN was found in this population. Of all sites irradiated in this study, the floor of the mouth was most associated with ORN (8.6%), whereas the cheek was least associated (0%). Based on the results of this study, HBOT can be recommended for stage I and II ORN and for selected cases of stage III ORN.

Induction chemotherapy with docetaxel/cisplatin/5-fluorouracil followed by randomization to two cisplatin-based concomitant chemoradiotherapy schedules in patients with locally advanced head and neck cancer (CONDOR study) (Dutch Head and Neck Society 08-01): A randomized phase II study.

PURPOSE: To study the feasibility of induction chemotherapy added to concomitant cisplatin-based chemoradiotherapy (CRT) in patients with locally advanced head and neck cancer (LAHNC). PATIENTS AND METHODS: LAHNC patients were treated with 4 courses of docetaxel/cisplatin/5-fluorouracil (TPF) followed by randomization to either cisplatin 100 mg/m(2) with conventional radiotherapy (cis100 + RT) or cisplatin 40 mg/m(2) weekly with accelerated radiotherapy (cis40 + ART). Primary endpoint was feasibility, defined as receiving ≥ 90% of the scheduled total radiation dose. Based on power analysis 70 patients were needed. RESULTS: 65 patients were enrolled. The data safety monitoring board advised to prematurely terminate the study, because only 22% and 41% (32% in total) of the patients treated with cis100 + RT (n = 27) and cis40 + ART (n = 29) could receive the planned dose cisplatin during CRT, respectively, even though the primary endpoint was reached. Most common grade 3-4 toxicity was febrile neutropenia (18%) during TPF and dehydration (26% vs 14%), dysphagia (26% vs 24%) and mucositis (22% vs 57%) during cis100 + RT and cis40 + ART, respectively. For the patients treated with cis100 + RT and cis40 + ART, two years progression free survival and overall survival were 70% and 78% versus 72% and 79%, respectively. CONCLUSION: After TPF induction chemotherapy, cisplatin-containing CRT is not feasible in LAHNC patients, because the total planned cisplatin dose could only be administered in 32% of the patients due to toxicity. However, all but 2 patients received more than 90% of the planned radiotherapy. Clinical Trials Information: NCT00774319.

18F-FLT PET changes during radiotherapy combined with cetuximab in head and neck squamous cell carcinoma patients.

AIM: Early treatment response of head and neck cancer to radiotherapy concomitant with cetuximab was monitored by repetitive PET imaging with the proliferation tracer 18F-FLT. PATIENTS, METHODS: Five head and neck cancer patients, treated with radiotherapy and concomitant cetuximab following cetuximab induction, received four 18F-FLT PET-CT scans before and during treatment. Changes in SUVpeak, SUVmean and CT- and PET-segmented gross tumour volumes were evaluated, as were correlations with immunohistochemical staining for Epidermal Growth Factor Receptor (EGFR) and Ki-67 (proliferation marker) in pre-treatment tumour biopsies. RESULTS: 18F-FLT PET measured tumor responses to the induction dose of cetuximab varied from 43% SUVpeak decrease to 47% increase. After start of radiotherapy 18F-FLT PET parameters decreased significantly in all patients. No associations were found between PET parameters and EGFR or Ki-67 expression levels. CONCLUSION: Proliferation of head and neck carcinomas shows a varying response to cetuximab induction, but consistently decreases after addition of radiotherapy.

EGFR-inhibition enhances apoptosis in irradiated human head and neck xenograft tumors independent of effects on DNA repair.

Epidermal growth factor receptor (EGFR) inhibition using cetuximab improves the efficacy of radiotherapy in only a subgroup of head and neck squamous cell carcinoma (HNSCC) patients. Therefore, to improve patient selection a better understanding of tumor characteristics that affect treatment is necessary. Here, we investigated the effect of cetuximab on repair of radiation-induced DNA damage in a HNSCC xenograft model, which shows a synergistic effect to cetuximab and radiotherapy (SCCNij185) and a HNSCC model, which shows no additive effect of cetuximab to radiotherapy (SCCNij153). In both tumor models, clear increases were seen in the number of 53BP1 and Rad51 foci after irradiation. 53BP1 foci were present at comparable levels in hypoxic and normoxic tumor areas of the tumor xenografts, while the number of Rad51 foci was significantly higher in normoxic areas compared to hypoxic areas (P < 0.05). In both SCCNij185 and SCCNij153 xenografts an increased number of 53BP1 foci was observed in tumors treated with cetuximab and radiotherapy compared to radiotherapy alone. In SCCNij185 this increase was statistically significant in normoxic tumor areas (P = 0.04) and in SCCNij153 in both hypoxic and normoxic areas (P = 0.007 and P = 0.02, respectively). The number of Rad51 foci was not significantly different when cetuximab was added to radiotherapy compared to radiotherapy alone. Levels of pEGFR and pERK1/2 were decreased when cetuximab was added to radiotherapy in SCCNij185, but not in SCCNij153. Apoptosis was also only increased in SCCNij185 tumors at 4 days after cetuximab and radiotherapy treatment (P < 0.01). In conclusion, cetuximab inhibited DNA repair in both HNSCC models, but this effect was not predictive for the radiosensitizing effect of cetuximab in vivo. This lack of correlation may be related to differential effects of cetuximab and radiotherapy on ERK1/2 signaling and a decreased induction of apoptosis by cetuximab and radiotherapy in the resistant model.

Interforaminal implant placement in oral cancer patients: during ablative surgery or delayed? A 5-year retrospective study.

In a retrospective study, two mandibular prosthetic rehabilitation strategies supported by implants in oral cancer patients were evaluated: implants placed in the non-resected edentulous symphyseal area during ablative surgery (DAS implants); or at a later stage (postponed (P) implants). Medical files of patients from two head-neck oncology groups from 2000 to 2005 were screened for study inclusion. DAS protocol was used in one group and P protocol in the other. After a 5 year follow-up of 261 edentulous patients with oral cancer in the second group, P implants were placed in 27 patients to support an overdenture. Of the 249 edentulous patients in the first group, 82 patients were given an implant supported overdenture using the DAS implant protocol. Regarding implant loss, no statistically significant differences were seen between the DAS and P implants. In the DAS group, more patients benefited from an implant-supported lower overdenture (39 versus 11%, respectively), and they received their overdenture on average 20.0 months sooner (sd=11.01, p<0.001) after ablative surgery. 17.1% of DAS implants and 4.6% of P implants were never loaded due to tumour and patient related factors including unfavourable implant soft tissue, tumour recurrence near the implant, or radiotherapy induced trismus.

[A young woman with progressive cerebral atrophy]. / Een jonge vrouw met progressieve cerebrale atrofie.

A 21-year-old patient suffering from neurofibromatosis type 1 had received radiotherapy for a chiasm glioma 17 years ago. Fourteen years later, there was progressive deterioration of several neurological functions. MRI scans showed a progressively increasing volume loss of the left hemisphere and stenoses around the circle of Willis with secondary parenchymal effects. Based on conventional cerebral angiography, the diagnosis 'moyamoya syndrome' was made.

FDG-PET/CT in radiation treatment planning of head and neck squamous cell carcinoma.

Advances in the field of radiation oncology in the last decade resulted in an increasing number of opportunities to optimize therapy. Increased accuracy to deliver the dose to tumors while sparing normal tissues demands more precise delineation of the tumors. When considering to deliver a boost to more aggressive parts of tumors, intratumoral heterogeneity needs to be assessed accurately. Adaptive radiotherapy demands evaluation of response during the course of radiotherapy, in terms of both volumetric and functional changes. Molecular imaging with fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT) has found its way into clinical practice for various indications in head and neck cancer and new applications are under investigation. In this review, an overview is provided of the current status and developments of the use of FDG-PET/CT in radiation oncology, describing the current status in radiation treatment planning, adaptation of therapy and the position compared to other imaging techniques.