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Simple Summary: Proton therapy is a highly effective type of radiotherapy that is used to treat cancer while minimizing damage to healthy tissue. In Switzerland, health insurance typically covers the cost of proton therapy. However, patients may still need to pay for their lodging and travel expenses during the treatment's 5–7 week duration. This can lead to financial stress, also known as financial toxicity. The present study is the first to measure patient-reported financial toxicity in a group of patients receiving proton therapy, including both patients and caregivers of pediatric cancer patients. It shows that many patients receiving proton therapy experience financial toxicity, which is measured by the COST score. Low income, long travel distances, and marriage can contribute to this financial burden. Patients often had to save money by cutting back on expenses in different areas. The study emphasizes the importance of considering financial aspects as part of cancer patients' overall care during proton therapy. Background: Proton therapy is indicated for cancers that would be difficult to treat with conventional radiotherapy. Compulsory healthcare insurance covers the costs of this therapy in Switzerland, but this does not mean that proton therapy is cost-neutral for every cancer patient. Significant out-of-pocket (OOP) costs may arise due to expenses associated with proton therapy, and patients may experience treatment-related financial distress—an effect known as "financial toxicity." This study investigates the financial toxicity of patients undergoing proton therapy in a high-income country with a compulsory health insurance policy. Methods: Between September 2019 and November 2021, 146 Swiss cancer patients treated with proton therapy participated in this study, of whom 90 (62%) were adults and 56 (38%) were caregivers of child cancer patients. Financial toxicity was assessed using the FACIT Comprehensive Score for Financial Toxicity (COST). OOP costs during proton therapy were recorded weekly, and financial coping strategies were captured at the end of treatment. Findings: The median COST score, indicating financial toxicity, was 29.9 (IQR 21.0; 36.0) for all patients, 30.0 (IQR 21.3; 37.9) for adults, and 28.0 (IQR 20.5; 34.0) for children's caregivers. Higher income (estimate 8.1, 95% CI 3.7 to 12.4, p ≤ 0.001) was significantly associated with higher COST scores, indicating less financial toxicity. Further distance from home to the treatment centre per 100 km (estimate −3.7, 95% CI −5.7 to −1.9, p ≤ 0.001) was significantly associated with lower COST scores, indicating increased financial toxicity. Married adult patients had substantially lower COST scores than single patients (estimate: −9.1, 95% CI −14.8 to −3.4, p ≤ 0.001). The median OOP cost was 2050 Swiss francs (CHF) and was spent mainly on travel, accommodation, and eating out. Sixty-three (43%) patients used their savings; 54 (37%) cut spending on leisure activities; 21 (14.4%) cut living expenses; 14 (9.6%) borrowed money; nine (6.2%) worked more; and four (2.7%) sold property. Patients with high COST scores used significantly fewer coping strategies such as saving on leisure activities (estimate −9.5, 95% CI −12.4 to −6.6, p ≤ 0.001), spending savings (estimate −3.9, 95% CI −6.3 to −1.4, p = 0.002), borrowing money (estimate −6.3, 95% CI −10.4 to −2.2, p = 0.003), and increasing workload (estimate −5.5, 95% CI −10.5 to −0.4, p = 0.035). Interpretation: A substantial number of cancer patients treated with proton therapy experience financial toxicity in Switzerland. Long travel distances to the proton therapy centre and low income negatively affect the financial well-being of these patients during proton therapy. [ABSTRACT FROM AUTHOR]

Simple Summary: Most patients with skull base tumors require radiation therapy as part of their overall treatment, preferably with protons. However, vital and healthy organs, such as the cochlea, are often located in the immediate anatomical vicinity of the tumor. Despite the high precision of the proton beam, irradiating the cochlea is often unavoidable, resulting in an increased risk of hearing loss. To assess the frequency and severity of changes in hearing after proton therapy, we performed a retrospective study in a cohort of 51 patients undergoing proton therapy for skull base tumors. We observed that a hearing threshold shift correlates to the applied radiation dose intensity to the cochlea. In addition, advancing age, hearing sensitivity before proton therapy, and the time elapsed after the end of proton therapy are independently associated with the deterioration of the hearing threshold after proton therapy. These results are essential to adequately inform patients about the treatment's impact and side effects. To assess the incidence and severity of changes in hearing threshold in patients undergoing high-dose pencil-beam-scanning proton therapy (PBS-PT). This retrospective cohort study included fifty-one patients (median 50 years (range, 13–68)) treated with PBS-PT for skull base tumors. No chemotherapy was delivered. Pure tone averages (PTAs)were determined before (baseline) and after PBS-PT as the average hearing thresholds at frequencies of 0.5, 1, 2, and 4 kHz. Hearing changes were calculated as PTA differences between pre-and post-PBS-PT. A linear mixed-effects model was used to assess the relationship between the PTA at the follow-up and the baseline, the cochlea radiation dose intensity, the increased age, and the years after PBS-PT. Included patients were treated for chordoma (n = 24), chondrosarcoma (n = 9), head and neck tumors (n = 9), or meningioma (n = 3), with a mean tumor dose of 71.1 Gy (RBE) (range, 52.0–77.8), and a mean dose of 37 Gy (RBE) (range, 0.0–72.7) was delivered to the cochleas. The median time to the first follow-up was 11 months (IQR, 5.5–33.7). The PTA increased from a median of 15 dB (IQR 10.0–25) at the baseline to 23.8 (IQR 11.3–46.3) at the first follow-up. In the linear mixed-effect model, the baseline PTA (estimate 0.80, 95%CI 0.64 to 0.96, p ≤ 0.001), patient's age (0.30, 0.03 to 0.57, p = 0.029), follow-up time (2.07, 0.92 to 3.23, p ≤ 0.001), and mean cochlear dose in Gy (RBE) (0.34, 0.21 to 0.46, p ≤ 0.001) were all significantly associated with an increase in PTA at follow-up. The applied cochlear dose and baseline PTA, age, and time after treatment were significantly associated with hearing loss after proton therapy. [ABSTRACT FROM AUTHOR]

Objective: Peripheral nerve sheath tumors (PNSTs) commonly arise from peripheral nerve roots and grow locally invasive. Malignant PNSTs (mPNSTs) represent aggressive sarcomas of neural origin that can originate from PNSTs. Radiation therapy is commonly used as part of the required multimodal treatment. However, both entities tend to occur early in life and are associated with the genetic disorder neurofibromatosis type 1 (NF-1), which is known to cause increased radiosensitivity. Pencil beam scanning proton therapy (PBSPT) allows for a minimization of the dose delivered to organs at risk and the integral dose and, thus, potentially also a reduction of radiation-induced adverse events. We report the clinical outcome and toxicity rates of patients with (m)PNSTs treated with PBSPT. Methods: We retrospectively reviewed 36 patients who received PBSPT (median dose, 64 GyRBE) with curative intent for (m)PNSTs between 1999 and 2020 at our institute. Twenty-eight (78%) and 8 (22%) patients were treated at diagnosis and for tumor recurrence/progression, respectively. The median age was 32 years (range, 3–75), and 25 (69%) patients were male. mPNST and PNST were diagnosed in 31 (86%) and 5 (14%) patients, respectively. Underlying NF-1 disease was found in 8 (22%) patients. Acute and late toxicities were recorded according to Common Terminology Criteria for Adverse Events, version 4.1 (CTCAE v4.1). Overall survival (OS), local control (LC), and distant control (DC) were estimated using the Kaplan–Meier method. Results: With a median follow-up time of 31 months (range, 4–194), 13 (36%) patients died from a progressive disease, 8 (22%) experienced local failure, and 14 (39%) experienced distant failure after PBSPT. Estimated 2-year OS, LC, and DC were 75.5%, 73.5%, and 61.2%, respectively. Acute grade 3 toxicity (dermatitis, mucositis, and pain) was observed in 5 (14%) patients. Late grade 3 cataract and osteonecrosis were both observed in 1 (3%) patient at 34 and 194 months after PBSPT, respectively. There was no late grade >3 toxicity or radiation-induced secondary cancer. Conclusion: To our knowledge, this is the first study to analyze the outcome of (m)PNSTs treated with proton therapy using a PBS delivery paradigm. In our cohort, consisting mainly of patients with mPNSTs, we report reasonable oncological outcomes and low toxicity rates after PBSPT. [ABSTRACT FROM AUTHOR]

Background. The aim of this pilot study was to assess tumour hypoxia in patients with cervical cancer before, during and after combined radio-chemotherapy and Magnetic Resonance Imaging (MRI) guided brachytherapy (BT) by use of the hypoxia Positron Emission Tomography (PET) tracer 18F-fluoroazomycin-arabinoside (18FAZA ). Material and methods. Fifteen consecutive patients with locally advanced cervical cancer referred for definitive radiotherapy (RT) were included in an approved clinical protocol. Stage distribution was 3 IB1, 1 IB2, 10 IIB, 1 IIIB, tumour volume was 55 cm3 (+/− 67, SD). Dynamic and static 18FAZA -PET scans were performed before, during and after external beam therapy (EBRT) and image guided BT +/− concomitant cisplatin. Dose was prescribed to the individual High Risk Clinical Target Volume (HR CTV) taking into account the dose volume constraints for adjacent organs at risk. Results. Five patients had visually identifiable tumours on 18FAZA -PET scans performed prior to radio-chemotherapy and four patients before brachytherapy. One of five 18FAZA PET positive patients had incomplete remission three months after RT, one had regional recurrence. Four of ten 18FAZA-PET negative patients developed distant metastases. The one patient with incomplete remission received 69 Gy (D90) in the HR CTV, whereas all other patients received mean 99 Gy (+/−12, SD). Conclusion. PET imaging with 18FAZA is feasible in patients with cancer of the uterine cervix. However, its predictive and prognostic value remains to be clarified. This applies in particular for the additional value of 18FAZA-PET compared to morphologic repetitive MRI within the setting of image guided high dose radiotherapy which may contribute to overcome hypoxia related radioresistance. [ABSTRACT FROM AUTHOR]

Purpose: To compare survival and severe late radiation toxicity between patients who received continuous low-dose-rate (LDR) brachytherapy (BT) and pulsed-dose-rate (PDR) BT for cervical cancer. Methods and Materials: A retrospective review of cervical cancer patients who underwent primary radiotherapy with or without concurrent cisplatin was performed. Late Grade 3 or worse toxicities were assessed using the National Cancer Institute Common Toxicity Criteria. The study endpoints were overall and disease-free survival and the probability of severe late toxicity. Results: A total of 109 patients (65.7%) received LDR BT and 57 (34.3%) received PDR BT. Seventy patients received concurrent chemotherapy with cisplatin. The 3-year overall survival and disease-free survival rate was 70% and 57% for the LDR group and 82% and 70% for the PDR group, respectively (p = 0.25 and p = 0.19). The 3-year probability rate for late Grade 3 or worse toxicity was 7.4% for LDR BT patients and 7.6% for PDR BT patients, respectively (p = 0.69) and 6.9% and 7.6%, respectively, for concurrent chemotherapy vs. none (p = 0.69). Conclusion: No difference was found in severe late toxicity, overall survival, or disease-free survival between the LDR and PDR groups. [Copyright &y& Elsevier]

Vascular endothelial growth factor (VEGF) plays an important role in the regulation of tumour growth and metastasis. It was the aim of this study to examine the impact of serum VEGF levels on the likelihood of response to radiotherapy and on the disease-free survival in patients with cervical cancer. Blood was taken before commencing treatment and serum VEGF was assessed by quantitative ELISA in 23 patients with cervical cancer stage IB–IVA undergoing primary radiotherapy. Serum VEGF levels were correlated with clinical and histopathologic factors as well as with response to radiotherapy and time to progression. Nineteen of the 23 patients had a complete response and four patients had persistent disease at 3 months. The median follow-up was 25 months (95% confidence interval: 23.5–26.5 months). At the time of analysis, eight patients were tumour-free and 15 patients had tumour progression; 12 of these 15 patients died of disease. Overall, the median serum VEGF level was 244 pg/ml (range 31.9–817.6 pg/ml). All four patients with local failure had VEGF levels >244 pg/ml, whereas 11 of the 19 patients with complete response had serum VEGF of ≤244 pg/ml (P=0.035). The median time to progression was 5 months in patients with VEGF of >244 pg/ml compared to 19 months in patients with VEGF of ≤244 pg/ml (log rank, P=0.003). In multivariate analysis, serum VEGF, tumour size and histological type, but not the patient's age, stage and grade of histological differentiation influenced the progression-free survival. Elevated pre-therapeutic serum VEGF levels are associated with poor response and a shorter time to progression in patients with cervical cancer undergoing primary radiotherapy. [Copyright &y& Elsevier]

Simple Summary: Patients with complex brain tumors are regularly treated with proton therapy (PT) to obtain an optimal curative treatment with limited toxicity. Value-based oncological medicine is increasingly important, particularly when long-term survival is to be expected. The aim of our prospective study was to evaluate health-related quality of life (HRQOL) and patient reported outcomes (PROs) in patients treated with PT for brain tumors. PT only temporarily influences PROs and QoL directly following PT and lower QoL and PROs were mostly reported by patients who were already in a worse condition with symptoms related to the tumor and previous treatment, before the start of PT. This study assists in improving patient support in patients with brain tumors receiving PT. Proton therapy (PT) is delivered to complex brain tumors to obtain an optimal curative treatment with limited toxicity. Value-based oncological medicine is increasingly important, particularly when long-term survival is to be expected. This study aims to evaluate health-related quality of life (HRQOL) and patient reported outcomes (PROs) in patients treated with PT for brain tumors. Adult patients with brain tumors treated with PT filled out the EORTC-QLQ-C30 and BN20 questionnaires up to three years following PT. Toxicity was scored using the CTCAE v4.03. QoL and PRO were correlated to clinical factors. Three-year overall survival, distant brain control and local control rates were 98%, 97% and 84%, respectively. No ≥G3 acute toxicity was observed. Late PT-related ≥G3 severe toxicity occurred in seven patients (5.7%). Lower global QoL scores after PT were significantly correlated to low Karnofsky performance status (KPS) before PT (p = 0.001), surgical complications before PT (p = 0.04) and progressive disease (p = 0.017). A low QLQ-30 summary score at one year follow-up was correlated to sex (p = 0.015), low KPS before PT (p < 0.001), and central nervous system symptoms before PT (p = 0.018). Reported QLQ-BN20 neurological symptoms were correlated to lower KPS at baseline (p < 0.001) and surgical complications before PT (p = 0.03). PT-related toxicity only influenced reported symptoms directly following PT, but not QoL. Although global QoL temporarily decreased after treatment, it improved again from one year onwards. Global QoL and reported symptoms over time were not correlated with the proton therapy and were more related to preexisting symptoms and progressive disease. This study assists in improving patient support in patients with brain tumors receiving PT. [ABSTRACT FROM AUTHOR]

Large inoperable sacral chordomas show unsatisfactory local control rates even when treated with high dose proton therapy (PT). The aim of this study is assessing feasibility and reporting early results of patients treated with PT and concomitant hyperthermia (HT). Patients had histologically proven unresectable sacral chordomas and received 70 Gy (relative biological effectiveness) in 2.5 Gy fractions with concomitant weekly HT. Toxicity was assessed according to CTCAE_v4. A volumetric tumor response analysis was performed. Five patients were treated with the combined approach. Median baseline tumor volume was 735 cc (range, 369–1142). All patients completed PT and received a median of 5 HT sessions (range, 2–6). Median follow-up was 18 months (range, 9–26). The volumetric analysis showed an objective response of all tumors (median shrinkage 46%; range, 9–72). All patients experienced acute Grade 2–3 local pain. One patient presented with a late Grade 3 iliac fracture. Combining PT and HT in large inoperable sacral chordomas is feasible and causes acceptable toxicity. Volumetric analysis shows promising early results, warranting confirmation in the framework of a prospective trial. This is an encouraging first report of the feasibility and early results of concomitant HT and PT in treating inoperable sacral chordoma. [ABSTRACT FROM AUTHOR]

Proton therapy (PT) has been administered for many years to a number of cancers, including brain tumours. Due to their remarkable physical properties, delivering their radiation to a very precise brain volume with no exit dose, protons are particularly appropriate for these tumours. The decrease of the brain integral dose may translate with a diminution of neuro-cognitive toxicity and increase of quality of life, particularly so in children. The brain tumour patient's access to PT will be substantially increased in the future, with many new facilities being planned or currently constructed in Europe, Asia and the United States. Although approximately 150'000 patients have been treated with PT, no level I evidence has been demonstrated for this treatment. As such, it is this necessary to generate high-quality data and some new prospective trials will include protons or will be activated to compare photons to protons in a randomized design. PT comes however with an additional cost factor that may contribute to the ever-growing health's expenditure allocated to cancer management. These additional costs and financial toxicity will have to be analysed in the light of a more conformal radiation delivery, non-target brain irradiation and lack of potential for dose escalation when compared to photons. The latter is due to the radiosensitivity of organs at risk in vicinity of the brain tumour, that photons cannot spare optimally. Consequentially, radiation-induced toxicities and tumour recurrences, which are cost-intensive, may decrease with PT resulting in an optimized photon/proton financial ratio in the end. This review details the indication of brain tumors for proton therapy and give a list of the open prospective trials for these challenging tumors. [ABSTRACT FROM AUTHOR]

Abstract: Purpose: To determine the efficacy and feasibility of induction chemotherapy (ICT) with docetaxel, cisplatin and 5-fluorouracil followed by radiotherapy and cetuximab (C) in patients with locally advanced head and neck cancer. Patients and methods: Forty-nine previously untreated patients with local advanced stage III and IV squamous cell carcinoma of the head and neck (SCCHN) received three courses of ICT consisting of docetaxel 75mg/m2 day 1, cisplatin 75mg/m2 day 1 and infusional 5-fluorouracil 750mg/m2/day on days 1–5 followed by radiotherapy plus C at 250mg/m2/week (after an initial loading dose of 400mg/m2). Results: After completion of ICT 44 of 49 patients received radiotherapy plus C. Three months after therapy completion tumour response was observed in 33 patients and after two years, 25 patients were in complete remission (CR). The most common grade 4 toxicity during the whole treatment period was dermatitis (30%), followed by mucositis (27%) and neutropenia (17%) without fever. One toxic related death was observed during ICT. Two-year progression-free survival (PFS) rate was 59% and two-year overall survival (OS) rate was 63%, respectively. Conclusion: Concurrent radiotherapy plus C after three courses of ICT was feasible and was associated with promising CR, PFS and OS rates. Further optimisation of dose and sequence is warranted. [Copyright &y& Elsevier]

Objective: This study presents the first clinical implementation of an efficient online daily adaptive proton therapy workflow (DAPT).&#xD;Approach: The DAPT workflow includes a pre-treatment phase, where a template and a fallback plan are optimized on the planning CT. In the online phase, the adapted plan is re-optimized on daily images from an in-room CT. Daily structures are rigidly propagated from the planning CT. Automated quality assurance (QA) involves geometric, sanity checks and an independent dose calculation from the machine files. &#xD;Differences from the template plan are analyzed field-by-field, and clinical plan is assessed by reviewing the achieved clinical goals using a traffic light protocol. If the daily adapted plan fails any QA or clinical goals, the fallback plan is used. In the offline phase the delivered dose is recalculated from log-files onto the daily CT, and a gamma analysis is performed (3%/3mm). The DAPT workflow has been applied to selected adult patients treated in rigid anatomy for the last serie of the treatment between October 2023 and April 2024.&#xD;&#xD;Main Results: DAPT treatment sessions averaged around 23 minutes [range: 15-30 min] and did not exceed the typical 30-minute time slot. Treatment adaptation, including QA and clinical plan assessment, averaged just under 7 minutes [range: 3:30-16 min] per fraction. All plans passed the online QAs steps. In the offline phase a good agreement with the log-files reconstructed dose was achieved (minimum gamma pass rate of 97.5 %). The online adapted plan was delivered for > 85% of the fractions. In 92% of total fractions, adapted plans exhibited improved individual dose metrics to the targets and/or organs at risk.&#xD;Significance: This study demonstrates the successful implementation of an online daily DAPT workflow. Notably, the duration of a DAPT session did not exceed the time slot typically allocated for non-DAPT treatment. As far as we are aware, this is a first clinical implementation of daily online adaptive proton therapy.&#xD., (Creative Commons Attribution license.)

Background: The use of magnetic resonance (MR) imaging for proton therapy treatment planning is gaining attention as a highly effective method for guidance. At the core of this approach is the generation of computed tomography (CT) images from MR scans. However, the critical issue in this process is accurately aligning the MR and CT images, a task that becomes particularly challenging in frequently moving body areas, such as the head-and-neck. Misalignments in these images can result in blurred synthetic CT (sCT) images, adversely affecting the precision and effectiveness of the treatment planning., Purpose: This study introduces a novel network that cohesively unifies image generation and registration processes to enhance the quality and anatomical fidelity of sCTs derived from better-aligned MR images., Methods: The approach synergizes a generation network (G) with a deformable registration network (R), optimizing them jointly in MR-to-CT synthesis. This goal is achieved by alternately minimizing the discrepancies between the generated/registered CT images and their corresponding reference CT counterparts. The generation network employs a UNet architecture, while the registration network leverages an implicit neural representation (INR) of the displacement vector fields (DVFs). We validated this method on a dataset comprising 60 head-and-neck patients, reserving 12 cases for holdout testing., Results: Compared to the baseline Pix2Pix method with MAE 124.95 ± $\pm$ 30.74 HU, the proposed technique demonstrated 80.98 ± $\pm$ 7.55 HU. The unified translation-registration network produced sharper and more anatomically congruent outputs, showing superior efficacy in converting MR images to sCTs. Additionally, from a dosimetric perspective, the plan recalculated on the resulting sCTs resulted in a remarkably reduced discrepancy to the reference proton plans., Conclusions: This study conclusively demonstrates that a holistic MR-based CT synthesis approach, integrating both image-to-image translation and deformable registration, significantly improves the precision and quality of sCT generation, particularly for the challenging body area with varied anatomic changes between corresponding MR and CT., (© 2024 The Author(s). Medical Physics published by Wiley Periodicals LLC on behalf of American Association of Physicists in Medicine.)

Background and Purpose: Imaging of respiration-induced anatomical changes is essential to ensure high accuracy in radiotherapy of lung cancer. We expanded here on methods for retrospective reconstruction of time-resolved volumetric magnetic resonance (4DMR) of the thoracic region and benchmarked the results against 4D computed tomography (4DCT)., Materials and Method: MR data of six lung cancer patients were collected by interleaving cine-navigator images with 2D data frame images, acquired across the thorax. The data frame images have been stacked in volumes based on a similarity metric that considers the anatomical deformation of lungs, while addressing ambiguities in respiratory phase detection and interpolation of missing data. The resulting images were validated against cine-navigator images and compared to paired 4DCTs in terms of amplitude and period of motion, assessing differences in internal target volume (ITV) margin definition., Results: 4DMR-based motion amplitude was on average within 1.8 mm of that measured in the corresponding 2D cine-navigator images. In our dataset, the 4DCT motion and the 4DMR median amplitude were always within 3.8 mm. The median period was generally close to CT references, although deviations up to 24 % have been observed. These changes were reflected in the ITV, which was generally larger for MRI than for 4DCT (up to 39.7 %)., Conclusions: The proposed algorithm for retrospective reconstruction of time-resolved volumetric MR provided quality anatomical images with high temporal resolution for motion modelling and treatment planning. The potential for imaging organ motion variability makes 4DMR a valuable complement to standard 4DCT imaging., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2023 The Author(s).)

Objective: To assess the radiation-induced optic neuropathy (RION) prevalence, following high dose pencil beam scanning proton therapy (PBSPT) to skull base and head and neck (H&N) tumours., Methods: Between 1999 and 2014, 216 adult patients, median age 47 years (range, 18-77), were treated with PBS PT for skull base or H&N malignancies, delivering ≥45 Gy RBE to the optic nerve(s) (ON) and/or optic chiasma (OC). The median administered dose to the planning target volume was 74.0 Gy RBE (range, 54.0-77.4). The median follow-up was 5.3 years (range, 0.8-15.9)., Results: RION was observed in 14 (6.5%) patients at a median time of 13.2 months (range, 4.8-42.6) following PBSPT. Most (92.9%) of RION were symptomatic. Most affected patients (11/14; 79%) developed unilateral toxicity. Grade 4, 3, 2 and 1 toxicity was observed in 10, 2, 1 and 1 patients, respectively. On univariate analyses, age (<70  vs ≥70 years; p < 0.0001), hypertension ( p = 0.0007) and tumour abutting the optic apparatus ( p = 0.012) were associated with RION. OC's V60 Gy RBE was of border line significance ( p = 0.06). None of the other evaluated OC-ON dose/volume metrics (Dmax, Dmean, V40-60) were significantly associated with this complication., Conclusion: These data suggest that high-dose PBS PT for skull base and H&N tumours is associated with a low prevalence of RION. Caution should be however exercised when treating elderly/hypertensive patients with tumours abutting the optic apparatus., Advances in Knowledge: This is the first study reporting the risk of developing RION following proton therapy with PBS technique, demonstrating the safety of this treatment.

Background: The aim of this pilot study was to assess tumour hypoxia in patients with cervical cancer before, during and after combined radio-chemotherapy and Magnetic Resonance Imaging (MRI) guided brachytherapy (BT) by use of the hypoxia Positron Emission Tomography (PET) tracer (18)F-fluoroazomycin-arabinoside ((18)FAZA )., Material and Methods: Fifteen consecutive patients with locally advanced cervical cancer referred for definitive radiotherapy (RT) were included in an approved clinical protocol. Stage distribution was 3 IB1, 1 IB2, 10 IIB, 1 IIIB, tumour volume was 55 cm(3) (+/- 67, SD). Dynamic and static (18)FAZA -PET scans were performed before, during and after external beam therapy (EBRT) and image guided BT +/- concomitant cisplatin. Dose was prescribed to the individual High Risk Clinical Target Volume (HR CTV) taking into account the dose volume constraints for adjacent organs at risk., Results: Five patients had visually identifiable tumours on (18)FAZA -PET scans performed prior to radio-chemotherapy and four patients before brachytherapy. One of five (18)FAZA PET positive patients had incomplete remission three months after RT, one had regional recurrence. Four of ten (18)FAZA-PET negative patients developed distant metastases. The one patient with incomplete remission received 69 Gy (D90) in the HR CTV, whereas all other patients received mean 99 Gy (+/-12, SD)., Conclusion: PET imaging with (18)FAZA is feasible in patients with cancer of the uterine cervix. However, its predictive and prognostic value remains to be clarified. This applies in particular for the additional value of (18)FAZA-PET compared to morphologic repetitive MRI within the setting of image guided high dose radiotherapy which may contribute to overcome hypoxia related radioresistance.

Purpose: To explore intratumor heterogeneity in gene expression profiles from patients with cervical cancer., Experimental Design: A total of 33 biopsies were obtained from 11 patients, sampling between two and five different areas for each tumor. The extracted RNA was hybridized onto the Affymetrix U133 Plus 2.0 oligonucleotide chip. The variance of expression within a patient (W), between patients (B) and the total variance (T = W + B) were calculated for each ProbeSet, and the ratio W/T was used as a measure of intratumor heterogeneity. Gene Ontology functional analysis was done to assess the function of genes that had high W/T (top 10%) and low W/T (bottom 10%) values., Results: In total, 448 ProbeSets (2.2% of the total) had W/T < 0.10, indicating low intratumor heterogeneity, and 537 ProbeSets (2.7% of the total) had W/T > 0.90, indicating high intratumor heterogeneity. In total 14,473 ProbeSets (72.4%) had higher intertumor than intratumor heterogeneity (W/T < 0.5). Genes with low intratumor heterogeneity were characterized by a statistically significant enrichment of immune-related functions (P < 0.0001). Genes with high intratumor heterogeneity were characterized by a significant tendency towards nuclear localization and nucleic acid binding (both P < 0.0001). For genes with W/T > 0.5, more than six biopsies would be required to minimize the intratumoral heterogeneity to <0.15; if W/T is 0.3 to 0.4, four biopsies are required; and for low W/T of 0.16 to 0.3, only two to three biopsies would be needed., Conclusion: Although the intratumor heterogeneity was low for the majority of the tested ProbeSets, for many genes, multiple biopsies are required to obtain a reliable estimate of gene expression.

Background: The impact of radiotherapy alone (RT-alone) and radiotherapy plus concurrent chemotherapy with cisplatin (RT-CHT) was determined for lymphocyte subpopulations in cervical cancer patients., Materials and Methods: Thirty-four women were treated either with RT-alone (n=14) or RT-CHT (n=20). Peripheral lymphocytes were collected before, immediately after and 6, 12 and 24 weeks after completion of treatment. Flow cytometric analysis included total T-cells, T-helper-cells, T-suppressor-cells, T-cytotoxic-cells, NK-cells, B-cells and the CD4+/CD8+ratio., Results: Twenty-four weeks after treatment, B-cells had recovered to pretreatment levels whereas total lymphocyte counts, T-helper and T-cytotoxic-cells were still significantly reduced in both groups. In contrast, T-suppressor-cells and NK-cells had recovered to pretreatment levels only in patients who received RT-alone and were still significantly reduced in patients who received RT-CHT., Conclusion: RT-alone and RT-CHT induce a significant and prolonged suppression of all lymphocyte subpopulations. RT-CHT, but not RT-alone, causes a prolonged suppression of NK-cells and T-suppressor cells.

Purpose: The purpose is to investigate the impact of hypoxia-inducible factor (HIF)-1alpha expression on response to radiotherapy and prognosis of patients with primary irradiated cervical cancer. Because human papillomavirus (HPV) oncoprotein E6 might interact with HIF-1alpha in various pathways, we also investigated the relation of HIF-1alpha and HPV status., Experimental Design: Expression of HIF-1alpha was investigated by immunohistochemistry in 67 specimens of patients who had received radical radiotherapy for cervical cancer stages IB-IIIB. HPV analysis was performed using type-specific PCR, cloning, and sequencing. Survival analysis was performed using univariate and multivariate analysis., Results: Immunohistochemistry revealed expression of HIF-1alpha in 72.1% of the tumor samples. In 16 (23.9%) cases, there was a weak expression, in 25 (37.3%) a moderate expression, and in 7 cases (10.4%) a strong expression of HIF-1alpha. Nineteen samples (28.4%) were considered negative for HIF-1alpha expression. Strong/moderate expression of HIF-1alpha was associated with only partial response to radiotherapy (P = 0.037, chi(2) test). Strong/moderate expression of HIF-1alpha was also an independent prognostic factor for shorter progression-free survival (P = 0.036, Cox regression) and cervical cancer-specific survival (P = 0.04, Cox regression). No association between HIF-1alpha expression and infection with different HPV types could be found., Conclusions: Overexpression of HIF-1alpha has predictive and prognostic significance in cervical cancer patients receiving curative radiation therapy. Possibly, expression of HIF-1alpha could serve as intrinsic marker of hypoxia in cervical cancer.