Insular Decision Criteria in Clinical Practice: Analysis of Decision-Making in Oncology.

BACKGROUND: Medical decision-making is complex and involves a variety of decision criteria, many of which are universally recognised. However, decision-making analyses have demonstrated that certain decision criteria are not used uniformly among clinicians. AIM: We describe decision criteria, which for various contexts are only used by a minority of decision makers. For these, we introduce and define the term "insular criteria". METHODS: 19 studies analysing clinical decision-making based on decision trees were included in our study. All studies were screened for decision-making criteria that were mentioned by less than three local decision makers in studies involving 8-26 participants. RESULTS: 14 out of the 19 included studies reported insular criteria. We identified 42 individual insular criteria. They could be intuitively allocated to seven major groups, these were: comorbidities, treatment, patients' characteristics/preferences, caretaker, scores, laboratory and tumour properties/staging. CONCLUSION: Insular criteria are commonly used in clinical decision-making, yet, the individual decision makers may not be aware of them. With this analysis, we demonstrate the existence of insular criteria and their variety. In daily practice and clinical studies, awareness of insular criteria is important.

Long-term oncological and functional follow-up in low-dose-rate brachytherapy for prostate cancer: results from the prospective nationwide Swiss registry.

OBJECTIVE: To evaluate the long-term oncological, functional and toxicity outcomes of low-dose-rate brachytherapy (LDR-BT) in relation to risk factors and radiation dose in a prospective multicentre cohort. PATIENTS AND METHODS: Data of patients from 12 Swiss centres undergoing LDR-BT from September 2004 to March 2018 were prospectively collected. Patients with a follow-up of ≥3 months were analysed. Functional and oncological outcomes were assessed at ~6 weeks, 6 and 12 months after implantation and annually thereafter. LDR-BT was performed with 125 I seeds. Dosimetry was done 6 weeks after implantation based on the European Society for Radiotherapy and Oncology recommendations. The Kaplan-Meier method was used for biochemical recurrence-free survival (BRFS). A prostate-specific antigen (PSA) rise above the PSA nadir + 2 was defined as biochemical failure. Functional outcomes were assessed by urodynamic measurement parameters and questionnaires. RESULTS: Of 1580 patients in the database, 1291 (81.7%) were evaluable for therapy outcome. The median (range) follow-up was 37.1 (3.0-141.6) months. Better BRFS was found for Gleason score ≤3+4 (P = 0.03, log-rank test) and initial PSA level of <10 ng/mL (P < 0.001). D'Amico Risk groups were significantly associated with BRFS (P < 0.001), with a hazard ratio of 2.38 for intermediate- and high-risk patients vs low-risk patients. The radiation dose covering 90% of the prostate volume (D90) after 6 weeks was significantly lower in patients with recurrence. Functional outcomes returned close to baseline levels after 2-3 years. A major limitation of these findings is a substantial loss to follow-up. CONCLUSION: Our results are in line with other studies showing that LDR-BT is associated with good oncological outcomes together with good functional results.

[Modern Treatment Concepts in Radiation Oncology]. / Moderne Behandlungskonzepte in der Radio-Onkologie.

Modern Treatment Concepts in Radiation Oncology Abstract. Radiotherapy is a widely used form of therapy that is used in half of all cancer patients. Advances in understanding the fundamentals of tumor and radiation biology, in medical physics and computer science as well as technical developments have continuously improved the effectiveness and healing success of radiotherapy. Patients benefit from new treatment concepts such as hypofractionated radiotherapy for breast and prostate cancer, leading to a reduction in the duration of treatment by several weeks. Selected patients with early stages of breast cancer can be treated with partial breast irradiation with focus on the tumor bed after breast conserving surgery increasing tolerability and comfort. High dose stereotactic radiotherapy over five to six sessions of radiation or only one fraction (radiosurgery) have expanded treatment options for common tumor entities leading to long-lasting tumor control resulting in improved survival and quality of life for those affected. In early lung cancer stereotactic radiotherapy is an alternative to primary tumor surgery. For patients with oligometastatic tumor disease stereotactic radiotherapy allows a curative approach by effectively treating metastases. In patients with brain metastases whole-brain irradiation is replaced by stereotactic irradiation of the individual metastases with fewer side effects. Recently, promising results for improved tumor control with the combination of radiotherapy and immunotherapy have been presented. Radioimmunotherapy represents a new therapy combination. However, final assessment of its efficacy and side effects profile is still missing. In order to gain therapeutic certainty, further prospective study data are necessary.

Applied Swarm-based medicine: collecting decision trees for patterns of algorithms analysis.

BACKGROUND: The objective consensus methodology has recently been applied in consensus finding in several studies on medical decision-making among clinical experts or guidelines. The main advantages of this method are an automated analysis and comparison of treatment algorithms of the participating centers which can be performed anonymously. METHODS: Based on the experience from completed consensus analyses, the main steps for the successful implementation of the objective consensus methodology were identified and discussed among the main investigators. RESULTS: The following steps for the successful collection and conversion of decision trees were identified and defined in detail: problem definition, population selection, draft input collection, tree conversion, criteria adaptation, problem re-evaluation, results distribution and refinement, tree finalisation, and analysis. CONCLUSION: This manuscript provides information on the main steps for successful collection of decision trees and summarizes important aspects at each point of the analysis.

Haemoglobin and creatinine values as prognostic factors for outcome of concurrent radiochemotherapy in locally advanced head and neck cancers : Secondary results of two European randomized phase III trials (ARO 95-06, SAKK 10/94).

BACKGROUND: To determine the influence of baseline laboratory values on treatment outcome in patients with locally advanced head and neck cancer (HNSCC). METHODS: Data of the randomized trials ARO 95 -06 (n = 384) and SAKK 10 /94 (n = 224) were pooled for a total sample size of 608 patients. Haemoglobin (Hb) and creatinine (Cr) were available at baseline and their association with locoregional recurrence-free survival (LRRFS), distant metastasis-free survival (DMFS), cancer-specific survival (CSS), and overall survival (OS) was analyzed using univariable and multivariable Cox regression models. RESULTS: A total of 580 and 564 patients were available with baseline Hb and Cr values in the pooled analysis. Univariable analyses revealed that lower baseline Hb values were significantly associated with decreased LRRFS, DMFS, CSS and OS. This effect remained significant for OS when the treatment arms (radiotherapy [RT] alone vs. chemoradiation [CRT]) were analyzed separately. Higher baseline Cr was associated with improved OS in the pooled analysis. Interestingly, the prognostic value of baseline Cr appeared to be limited to the subgroup of 284 patients who were treated with CRT. In the multivariable Cox regression model lower baseline Hb remained associated with decreased OS both in the patients who received CRT (HR 0.79, 95 % CI 0.66-0.94, p = 0.009) and in those patients who underwent RT alone (HR 0.67, 95 % CI 0.58-0.78, p < 0.001). Increased baseline Cr remained significantly associated with improved OS in patients who underwent CRT (HR 0.79, 95 % CI 0.69-0.92, p = 0.002) but not in those patients who underwent RT alone. CONCLUSIONS: An association between lower baseline Hb and inferior treatment outcome was confirmed. Baseline Cr was introduced as a prognosticator of outcome after CRT for locally advanced HNSCC.

Volumetric regression ratio of the primary tumor and metastatic lymph nodes after induction chemotherapy predicts overall survival in head and neck squamous cell carcinoma: a retrospective analysis.

PURPOSE: We looked for any predictive value of change in primary tumor and metastatic lymph node volumes after induction chemotherapy (IC) on oncologic outcome in head and neck squamous cell carcinoma (HNSCC). METHODS: Nineteen patients with stage IVA/B HNSCC treated between 2004 and 2010 with at least one cycle of IC (docetaxel, cisplatin and 5-fluorouracil/TPF) and concomitant chemoradiotherapy (CRT) with cisplatin were retrospectively analyzed. Volumes were calculated separately for primary tumor (Vtm), lymph node metastases (Vln) and their sum (Vsum) on computed tomography (CT) images before and after IC. The effect of volumetric changes on locoregional failure (LRF), distant metastasis (DM) and overall survival (OS) was assessed. P values <0.05 were considered as statistically significant. RESULTS: The median follow-up of surviving patients was 25 months (range: 10.7-83.3). The median number of cycles and duration of TPF was 3 (range: 1-4) and 44 days (range: 4-116), respectively. Empirical area under the curve (AUC) analyses for death, LRF and DM revealed optimal cut-off values of Vtm diminution (30.54%, AUC: 87%) and Vsum decrease (35.45%, AUC: 64.55%) only for OS (p <0.05). Among those, a reduction in Vsum more than 35.4% between pre- and post-IC was significantly correlated with better OS (100 vs 43% at 2 years, p <0.05). CONCLUSION: Volumetric shrinkage of the tumor load after IC assessed with CT seems to predict OS. The assessment of volumetric shrinkage upon IC might be used to decide whether to offer patients alternative strategies like palliative/de-intensified treatments or more aggressive combined modalities after IC.

Design and implementation of a "cheese" phantom-based Tomotherapy TLD dose intercomparison.

BACKGROUND: The unique beam-delivery technique of Tomotherapy machines (Accuray Inc., Sunnyvale, Calif.) necessitates tailored quality assurance. This requirement also applies to external dose intercomparisons. Therefore, the aim of the 2014 SSRMP (Swiss Society of Radiobiology and Medical Physics) dosimetry intercomparison was to compare two set-ups with different phantoms. MATERIALS AND METHODS: A small cylindrical Perspex phantom, which is similar to the IROC phantom (Imaging and Radiation Oncology Core, Houston, Tex.), and the "cheese" phantom, which is provided by the Tomotherapy manufacturer to all institutions, were used. The standard calibration plans for the TomoHelical and TomoDirect irradiation techniques were applied. These plans are routinely used for dose output calibration in Tomotherapy institutions. We tested 20 Tomotherapy machines in Germany and Switzerland. The ratio of the measured (Dm) to the calculated (Dc) dose was assessed for both phantoms and irradiation techniques. The Dm/Dc distributions were determined to compare the suitability of the measurement set-ups investigated. RESULTS: The standard deviations of the TLD-measured (thermoluminescent dosimetry) Dm/Dc ratios for the "cheese" phantom were 1.9 % for the TomoHelical (19 measurements) and 1.2 % (11 measurements) for the TomoDirect irradiation techniques. The corresponding ratios for the Perspex phantom were 2.8 % (18 measurements) and 1.8 % (11 measurements). CONCLUSION: Compared with the Perspex phantom-based set-up, the "cheese" phantom-based set-up without individual planning was demonstrated to be more suitable for Tomotherapy dose checks. Future SSRMP dosimetry intercomparisons for Tomotherapy machines will therefore be based on the "cheese" phantom set-up.

PSA bounce after ¹²5I-brachytherapy for prostate cancer as a favorable prognosticator.

BACKGROUND: Permanent low-dose-rate brachytherapy (BT) with iodine 125 is an established curative treatment for localized prostate cancer. After treatment, prostate-specific antigen (PSA) kinetics may show a transient rise (PSA bounce). Our aim was to investigate the association of PSA bounce with biochemical control. PATIENTS AND METHODS: Patients treated with BT in Switzerland were registered in a prospective database. Only patients with a follow-up of at least 2 years were included in our analysis. Clinical follow-up and PSA measurements were assessed after 1.5, 3, 6, and 12 months, and annually thereafter. If PSA increased, additional follow-up visits were scheduled. Cases of PSA bounce were defined as a rise of at least 0.2 ng/ml above the initial PSA nadir with a subsequent decline to or below the initial nadir without treatment. Biochemical failure was defined as a rise to nadir + 2 ng/ml. RESULTS: Between March 2001 and November 2010, 713 patients with prostate cancer undergoing BT with at least 2 years of follow-up were registered. Median follow-up time was 41 months. Biochemical failure occurred in 28 patients (3.9 %). PSA bounce occurred in 173 (24.3 %) patients; only three (1.7 %) patients with PSA bounce developed biochemical failure, in contrast to 25 (4.6 %) patients without previous bounce (p < 0.05). The median time to bounce was 12 months, the median time to biochemical failure was 30 months. The median bounce increase was 0.78 ng/ml. Twenty-eight patients with bounce (16.5 %) had a transient PSA rise of + 2 ng/ml above the nadir. CONCLUSION: In most cases, an early increase in PSA after BT indicates PSA bounce and is associated with a lower risk of biochemical failure.

Consensus and differences in primary radiotherapy for localized and locally advanced prostate cancer in Switzerland: A survey on patterns of practice.

INTRODUCTION: External beam radiotherapy (EBRT), with or without androgen deprivation therapy (ADT), is an established treatment option for nonmetastatic prostate cancer. Despite high-level evidence from several randomized trials, risk group stratification and treatment recommendations vary due to contradictory or inconclusive data, particularly with regard to EBRT dose prescription and ADT duration. Our aim was to investigate current patterns of practice in primary EBRT for prostate cancer in Switzerland. MATERIALS AND METHODS: Treatment recommendations on EBRT and ADT for localized and locally advanced prostate cancer were collected from 23 Swiss radiation oncology centers. Written recommendations were converted into center-specific decision trees, and analyzed for consensus and differences using a dedicated software tool. Additionally, specific radiotherapy planning and delivery techniques from the participating centers were assessed. RESULTS: The most commonly prescribed radiation dose was 78 Gy (range 70-80 Gy) across all risk groups. ADT was recommended for intermediate-risk patients for 6 months in over 80 % of the centers, and for high-risk patients for 2 or 3 years in over 90 % of centers. For recommendations on combined EBRT and ADT treatment, consensus levels did not exceed 39 % in any clinical scenario. Arc-based intensity-modulated radiotherapy (IMRT) is implemented for routine prostate cancer radiotherapy by 96 % of the centers. CONCLUSION: Among Swiss radiation oncology centers, considerable ranges of radiotherapy dose and ADT duration are routinely offered for localized and locally advanced prostate cancer. In the vast majority of cases, doses and durations are within the range of those described in current evidence-based guidelines.

Surface dose characterisation of the Varian Ir-192 HDR conical surface applicator set with a vertically orientated source.

BACKGROUND: Conical surface applicators with an Ir-192 high-dose-rate brachytherapy source are a common modality for the treatment of non-melanomatous skin cancer with high tumour control rates. Surface dose characterisation of the Varian Varisource GammaMed+ IX afterloader vertical type surface applicators is performed two dimensionally using high-resolution film dosimetry. AIM: The focus of this study was to determine if Varian surface applicators with a vertical source suffer from the dose distribution irregularities reported for comparable applicators. Our goal was to evaluate if the irregularities found affected treatment and dose output verification procedures. METHODS: Ionisation chamber-based verification of applicator output was established according to guidelines provided by the manufacturer. For additional measurement of surface dose Gafchromic EBT3 film dosimetry was used. The term "therapeutic dose" was defined as 85% of the prescribed dose level. RESULTS: For the 10 different applicator inserts evaluated, cold spots were observed. Mean cold spot size was 2.0 mm × 3.6 mm (± 0.6 mm). The cold spots were dosimetrically well below 85% of the prescribed dose. The cold spot was situated 2.2 mm (1.4-2.7 mm) unilaterally from the central axis and caused general asymmetry in the dose profiles intersecting the cold spot area. A source tilt of approximately 8° (± 1°) was determined for the source used for irradiation. CONCLUSIONS: A central underdosed area exceeding 15 % of the prescribed dose has not been previously reported. Source tilt was observed and found to affect clinical use and possibly treatment outcome in applicators using a vertically arranged source. Surface applicators with a vertically orientated source were subject to dose irregularities that could impact on chamber-based applicator output verification procedures. We recommend film dosimetry-backed applicator commissioning to avoid systematic errors.

Re-irradiation with and without bevacizumab as salvage therapy for recurrent or progressive high-grade gliomas.

The optimal treatment for recurrent high-grade gliomas is unknown and a standard of care does not exist. Re-irradiation with concomitant bevacizumab represents an option. Retrospectively, we analyzed a cohort of heavily pretreated patients (n = 14) with relapsing HGGs who underwent re-irradiation with conventional 3D-conformal or intensified modulated radiotherapy (IMRT). Ten of them received re-irradiation in combination with bevacizumab. The study population consisted of eight GBMs and six anaplastic gliomas. All patients had previously undergone irradiation for first-line therapy, including seven patients with radiochemotherapy with temozolomide. Patients without contraindications started with two infusions of bevacizumab (10 mg/kg of body weight every other week) prior to re-irradiation and continued through re-irradiation until progression. The median patient age was 45 years with a median Karnofsky performance scale of 70. The median dose of re-irradiation was 41.6 Gy [39-55 Gy]. The median physical cumulative radiation dose was 101.6 Gy [65-110.4 Gy]. The median PFS from re-irradiation was 5.1 months [1.6-17.4] based on clinical and RANO criteria. Median OS from re-irradiation was 9.0 months [6.4-17.8]. We detected radionecrosis due to advanced imaging in one patient. Other toxicities were expected and attributable well known side effects of bevacizumab. This retrospective study provides additional feasibility and safety data of conventional 3D-conformal re-irradiation and IMRT in combination with bevacizumab in relapsing high-grade gliomas.

Relevance of incidental colorectal FDG-PET/CT-enhanced lesions.

INTRODUCTION: Positron emission tomography/computed tomographies (PET/CTs) may result in incidental findings of fluorodeoxyglucose (FDG)-avid lesions in the colon. The aim of this study was to assess the relevance of a colonoscopic workup of such lesions. PATIENTS AND METHODS: We retrospectively analysed all PET/CT reports (n = 4,973) generated in our nuclear medicine department between May 2006 and May 2011; in 69 cases a colonoscopic evaluation was recommended for incidental FDG-avid lesions. RESULTS: Of these 69 cases, 51 underwent colonoscopy because of the potential need for further treatment. The maximum standardized uptake values (SUVmax) ranged from 5.0 to 42.0 with an average of 10.9. In 44 of the 51 patients, a histopathological abnormality was found on colonoscopy, 44 in the location described by PET/CT. A further 38 lesions were identified that were not visible on PET/CT. The histopathological evaluation in the 51 patients revealed 14 hyperplastic polyps, 27 adenomas with low-grade and 4 with high-grade dysplasia, 3 adenocarcinomas and 1 neuro-endocrine tumour. CONCLUSION: Incidental findings of focal colorectal FDG uptake should lead to further workup with colonoscopy. The SUVmax was not predictive for higher grade histologies. With an SUV of 5 the yield was high for colonic premalignant and malignant lesions. However, malignancy cannot be ruled out in focal lesions with an SUV of less than 5, and for individual patients a colonoscopy should not be ruled out.

Role of Adjuvant Radiotherapy in Non-Small Cell Lung Cancer-A Review.

BACKGROUND: For patients with completely resected non-small cell lung cancer (NSCLC) with ipsilateral mediastinal lymph node involvement (pN2), the administration of adjuvant chemotherapy is the standard of care. The role of postoperative radiation therapy (PORT) is controversial. METHODS: We describe the current literature focusing on the role of PORT in completely resected NSCLC patients with pN2 involvement and reflect on its role in current guidelines. RESULTS: Based on the results of the recent Lung ART and PORT-C trials, the authors conclude that PORT cannot be generally recommended for all resected pN2 NSCLC patients. A substantial decrease in the locoregional relapse rate without translating into a survival benefit suggests that some patients with risk factors might benefit from PORT. This must be balanced against the risk of cardiopulmonary toxicity with potentially associated mortality. Lung ART has already changed the decision making for the use of PORT in daily practice for many European lung cancer experts, with lower rates of recommendations for PORT overall. CONCLUSIONS: PORT is still used, albeit decreasingly, for completely resected NSCLC with pN2 involvement. High-level evidence for its routine use is lacking. Further analyses are required to identify patients who would potentially benefit from PORT.

Catalytic activity imperative for nanoparticle dose enhancement in photon and proton therapy.

Nanoparticle-based radioenhancement is a promising strategy for extending the therapeutic ratio of radiotherapy. While (pre)clinical results are encouraging, sound mechanistic understanding of nanoparticle radioenhancement, especially the effects of nanomaterial selection and irradiation conditions, has yet to be achieved. Here, we investigate the radioenhancement mechanisms of selected metal oxide nanomaterials (including SiO2, TiO2, WO3 and HfO2), TiN and Au nanoparticles for radiotherapy utilizing photons (150 kVp and 6 MV) and 100 MeV protons. While Au nanoparticles show outstanding radioenhancement properties in kV irradiation settings, where the photoelectric effect is dominant, these properties are attenuated to baseline levels for clinically more relevant irradiation with MV photons and protons. In contrast, HfO2 nanoparticles retain some of their radioenhancement properties in MV photon and proton therapies. Interestingly, TiO2 nanoparticles, which have a comparatively low effective atomic number, show significant radioenhancement efficacies in all three irradiation settings, which can be attributed to the strong radiocatalytic activity of TiO2, leading to the formation of hydroxyl radicals, and nuclear interactions with protons. Taken together, our data enable the extraction of general design criteria for nanoparticle radioenhancers for different treatment modalities, paving the way to performance-optimized nanotherapeutics for precision radiotherapy.

Role of Brachytherapy in the Postoperative Management of Endometrial Cancer: Decision-Making Analysis among Experienced European Radiation Oncologists.

BACKGROUND: There are various society-specific guidelines addressing adjuvant brachytherapy (BT) after surgery for endometrial cancer (EC). However, these recommendations are not uniform. Against this background, clinicians need to make decisions despite gaps between best scientific evidence and clinical practice. We explored factors influencing decision-making for adjuvant BT in clinical routine among experienced European radiation oncologists in the field of gynaecological radiotherapy (RT). We also investigated the dose and technique of BT. METHODS: Nineteen European experts for gynaecological BT selected by the Groupe Européen de Curiethérapie and the European Society for Radiotherapy & Oncology provided their decision criteria and technique for postoperative RT in EC. The decision criteria were captured and converted into decision trees, and consensus and dissent were evaluated based on the objective consensus methodology. RESULTS: The decision criteria used by the experts were tumour extension, grading, nodal status, lymphovascular invasion, and cervical stroma/vaginal invasion (yes/no). No expert recommended adjuvant BT for pT1a G1-2 EC without substantial LVSI. Eighty-four percent of experts recommended BT for pT1a G3 EC without substantial LVSI. Up to 74% of experts used adjuvant BT for pT1b LVSI-negative and pT2 G1-2 LVSI-negative disease. For 74-84% of experts, EBRT + BT was the treatment of choice for nodal-positive pT2 disease and for pT3 EC with cervical/vaginal invasion. For all other tumour stages, there was no clear consensus for adjuvant treatment. Four experts already used molecular markers for decision-making. Sixty-five percent of experts recommended fractionation regimens of 3 × 7 Gy or 4 × 5 Gy for BT as monotherapy and 2 × 5 Gy for combination with EBRT. The most commonly used applicator for BT was a vaginal cylinder; 82% recommended image-guided BT. CONCLUSIONS: There was a clear trend towards adjuvant BT for stage IA G3, stage IB, and stage II G1-2 LVSI-negative EC. Likewise, there was a non-uniform pattern for BT dose prescription but a clear trend towards 3D image-based BT. Finally, molecular characteristics were already used in daily decision-making by some experts under the pretext that upcoming trials will bring more clarity to this topic.

Extrapulmonary small cell carcinoma: An indication for prophylactic cranial irradiation? A single center experience.

BACKGROUND: Information about extrapulmonary small cell carcinoma (EPSCC) is limited and the role of prophylactic cranial irradiation (PCI) is unknown. PATIENTS AND METHODS: Disease presentation and outcome of all EPSCC at our hospital between 1990 and 2009 were retrospectively analyzed. RESULTS: Of 30 EPSCC, the male:female ratio was 58%:42%; 83% had a performance status of 0-2. Median age was 71 years (32-80). Seventeen (57%) had limited stage (LS), 13 (43%) extensive stage (ES). The location of the primary tumor was gastrointestinal (n = 8), unknown (6), gynecological (6), urogenital (5), and ear nose throat (5). Four (13%) developed brain metastases (2 ES, 2 LS). In ES, first line chemotherapy (CT) was given in 85%, mostly platinum-etoposide (64%). Response rate was 90%. In LS, CT and radiotherapy (RT) ± resection resulted in persistent remissions in 67% of patients. Median survival was 16 months (1-107 months), 18 months (1-107 months), and 9 months (0.4-25 months) for LS + ES, LS, and ES, respectively. Weight loss ≥5 % and ECOG performance status 3 + 4 were associated with poorer survival (p < 0.001 and p < 0.01, respectively). CONCLUSION: The incidence of brain metastases was relatively low (13%). More studies are necessary, before routinely offering PCI to patients with EPSCC. Best survival outcomes in LS were achieved with multimodality treatment including CT and RT. Prognosis was poor in patients with ES.

High-dose methotrexate with or without whole brain radiotherapy for primary CNS lymphoma (G-PCNSL-SG-1): a phase 3, randomised, non-inferiority trial.

BACKGROUND: High-dose methotrexate is the standard of care for patients with newly diagnosed primary CNS lymphoma. The role of whole brain radiotherapy is controversial because delayed neurotoxicity limits its acceptance as a standard of care. We aimed to investigate whether first-line chemotherapy based on high-dose methotrexate was non-inferior to the same chemotherapy regimen followed by whole brain radiotherapy for overall survival. METHODS: Immunocompetent patients with newly diagnosed primary CNS lymphoma were enrolled from 75 centres and treated between May, 2000, and May, 2009. Patients were allocated by computer-generated block randomisation to receive first-line chemotherapy based on high-dose methotrexate with or without subsequent whole brain radiotherapy, with stratification by age (<60 vs ≥60 years) and institution (Berlin vs Tübingen vs all other sites). The biostatistics centre assigned patients to treatment groups and informed local centres by fax; physicians and patients were not masked to treatment group after assignment. Patients enrolled between May, 2000, and August, 2006, received high-dose methotrexate (4 g/m(2)) on day 1 of six 14-day cycles; thereafter, patients received high-dose methotrexate plus ifosfamide (1·5 g/m(2)) on days 3-5 of six 14-day cycles. In those assigned to receive first-line chemotherapy followed by radiotherapy, whole brain radiotherapy was given to a total dose of 45 Gy, in 30 fractions of 1·5 Gy given daily on weekdays. Patients allocated to first-line chemotherapy without whole brain radiotherapy who had not achieved complete response were given high-dose cytarabine. The primary endpoint was overall survival, and analysis was per protocol. Our hypothesis was that the omission of whole brain radiotherapy does not compromise overall survival, with a non-inferiority margin of 0·9. This trial is registered with ClinicalTrials.gov, number NCT00153530. FINDINGS: 551 patients (median age 63 years, IQR 55-69) were enrolled and randomised, of whom 318 were treated per protocol. In the per-protocol population, median overall survival was 32·4 months (95% CI 25·8-39·0) in patients receiving whole brain radiotherapy (n=154), and 37·1 months (27·5-46·7) in those not receiving whole brain radiotherapy (n=164), hazard ratio 1·06 (95% CI 0·80-1·40; p=0·71). Thus our primary hypothesis was not proven. Median progression-free survival was 18·3 months (95% CI 11·6-25·0) in patients receiving whole brain radiotherapy, and 11·9 months (7·3-16·5; p=0·14) in those not receiving whole brain radiotherapy. Treatment-related neurotoxicity in patients with sustained complete response was more common in patients receiving whole brain radiotherapy (22/45, 49% by clinical assessment; 35/49, 71% by neuroradiology) than in those who did not (9/34, 26%; 16/35, 46%). INTERPRETATION: No significant difference in overall survival was recorded when whole brain radiotherapy was omitted from first-line chemotherapy in patients with newly diagnosed primary CNS lymphoma, but our primary hypothesis was not proven. The progression-free survival benefit afforded by whole brain radiotherapy has to be weighed against the increased risk of neurotoxicity in long-term survivors.

Radiotherapy or Surgery? Comparative, Qualitative Assessment of Online Patient Education Materials on Prostate Cancer.

As multiple different treatment options are available for prostate cancer (PCa) and YouTube is commonly used as a source for medical information, we performed a systematic and comparative assessment of available videos guiding patients on their choice for the optimal treatment. An independent search for surgical therapy or radiotherapy of PCa on YouTube was performed and the 40 most viewed videos of both groups were analyzed. The validated DISCERN questionnaire and PEMAT were utilized to evaluate their quality and misinformation. The median overall quality of the videos was found to be low for surgery videos, while radiotherapy videos results reached a moderate quality. The median PEMAT understandability score was 60% (range 0-100%) for radiotherapy and 75% (range 40-100) for surgery videos. The radiotherapy videos contained less misinformation and were judged to be of higher quality. Summarized, the majority of the provided videos offer insufficient quality of content and are potentially subject to commercial bias without reports on possible conflict of interest. Thus, most of available videos on YouTube informing PCa patients about possible treatment methods are not suited for a balanced patient education or as a basis for the patient's decision.

Dose-intensified Versus Conventional-dose Salvage Radiotherapy for Biochemically Recurrent Prostate Cancer After Prostatectomy: The SAKK 09/10 Randomized Phase 3 Trial.

BACKGROUND: Salvage radiotherapy (SRT) is utilized for biochemical progression of prostate cancer after radical prostatectomy (RP). OBJECTIVE: To report the outcomes of the SAKK 09/10 trial comparing conventional and dose-intensified SRT. DESIGN, SETTING, AND PARTICIPANTS: SAKK 09/10 was a randomized, multicenter, phase 3 trial that recruited men with biochemical progression after RP. INTERVENTION: Patients were randomly assigned to conventional-dose (64 Gy) or dose-intensified SRT (70 Gy) to the prostate bed without hormonal therapy. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The primary endpoint was freedom from biochemical progression (FFBP). Secondary endpoints included clinical progression-free survival (PFS), time to hormonal treatment, overall survival (OS), acute and late toxicity (Common Terminology Criteria for Adverse Events v4.0), and quality of life (QoL). RESULTS AND LIMITATIONS: Between February 2011 and April 2014, 350 patients were randomly assigned to 64 Gy (n = 175) or 70 Gy (n = 175). Median prostate-specific antigen at randomization was 0.3 ng/ml. After median follow-up of 6.2 yr, the median FFBP was 8.2 yr in the 64 Gy arm and 7.6 in the 70 Gy arm (log-rank p = 0.4), with a hazard ratio of 1.14 (95% confidence interval 0.82-1.60). The 6-year FFBP rates were 62% and 61%, respectively. No significant differences in clinical PFS, time to hormonal treatment, or OS were observed. Late grade 2 and 3 genitourinary toxicity was observed in 35 (21%) and 13 (7.9%) patients in the 64 Gy arm, and 46 (26%) and seven (4%) in the 70 Gy arm, respectively (p = 0.8). Late grade 2 and 3 gastrointestinal toxicity was observed in 12 (7.3%) and seven patients (4.2%) in the 64 Gy arm, and 35 (20%) and four (2.3%) in the 70 Gy arm, respectively (p = 0.009). There were no significant differences in QoL. CONCLUSIONS: Conventional-dose SRT to the prostate bed is sufficient in patients with early biochemical progression of prostate cancer after RP. PATIENT SUMMARY: The optimal radiation therapy dose for patients who have increased tumor markers after surgery for prostate cancer is unclear. We found that administering a higher dose only increased the gastrointestinal side effects without providing any benefits to the patient. This clinical trial is registered on ClinicalTrials.gov as NCT01272050.

Radiotherapy for lentigo maligna and lentigo maligna melanoma - a systematic review.

Lentigo maligna (LM) is the most common subtype of in situ melanoma und occurs frequently in the sun-exposed head and neck region in elderly patients. The therapeutic "gold standard" is surgical excision, as there is the risk of progression to invasive (lentigo maligna) melanoma (LMM). However, surgery is not feasible in certain patients due to age, comorbidities or patient preference. Radiotherapy using Grenz rays or superficial X-rays has been established as non-invasive alternative for the treatment of LM and LMM. We performed a systematic literature search of MEDLINE and Embase databases in September 2019 and identified 14 patient series using radiotherapy for LM or LMM. No prospective trials were found. The 14 studies reported a total of 1243 lesions (1075 LM and 168 LMM) treated with radiotherapy. Local recurrence rates ranged from 0 to 31% and were comparable to surgical series in most of the reports on radiotherapy. Superficial radiotherapy was prescribed in 5-23 fractions with a total dose of 35-57 Gy. Grenz ray therapy was prescribed in 42-160 Gy in 3-13 fractions with single doses up to 20 Gy. Cosmetic results were reported as "good" to "excellent" for the majority of patients.In conclusion, the available low-level evidence suggests that radiotherapy may be a safe and effective treatment for LM and LMM. Data from prospective trials such as the phase 3 RADICAL trial are needed to confirm these promising findings and to compare radiotherapy to other non-surgical therapies and to surgery.