Salvage Radiation Therapy After Radical Prostatectomy: Analysis of Toxicity by Dose-Fractionation in the RADICALS-RT Trial.

PURPOSE: Emerging data indicate comparable disease control and toxicity of normal postoperative fractionation and moderate hypofractionation radiation therapy (RT) in prostate cancer. In RADICALS-RT, patients were planned for treatment with either 66 Gy in 33 fractions (f) over 6.5 weeks or 52.5 Gy in 20f over 4 weeks. This non-randomized, exploratory analysis explored the toxicity of these 2 schedules in patients who had adjuvant RT. METHODS AND MATERIALS: Information on RT dose was collected in all patients. The Radiation Therapy Oncology Group toxicity score was recorded every 4 months for 2 years, every 6 months until 5 years, then annually until 15 years. Patient-reported data were collected at baseline and at 1, 5, and 10 years using standard measures, including the Vaizey fecal incontinence score (bowel) and the International Continence Society Male Short-Form questionnaire (urinary incontinence). The highest event grade was recorded within the first 2 years and beyond 2 years and compared between treatment groups using the χ² test. RESULTS: Of 634 patients, 217 (34%) were planned for 52.5 Gy/20f and 417 (66%) for 66 Gy/33f. In the first 2 years, grade 1 to 2 cystitis was reported more frequently among the 66 Gy/33f group (52.5 Gy/20f: 20% vs 66 Gy/33f: 30%; P = .04). After 2 years, grade 1 to 2 cystitis was reported in 16% in the 66-Gy group and 9% in the 52.5-Gy group (P = .08). Other toxic effects were similar in the 2 groups, and very few patients had any grade 3 to 4 toxic effects. Patients reported slightly higher urinary and fecal incontinence scores at 1 year than at baseline, but no clinically meaningful differences were reported between the 52.5 Gy/20f and 66 Gy/33f groups. Patient-reported health was similar at baseline and at 1 year and similar between the 52.5 Gy/20f and 66 Gy/33f groups. CONCLUSIONS: Severe toxic effects were rare after prostate bed radiation therapy with either 52.5 Gy/20f or 66 Gy/33f. Only modest differences were recorded in toxic effects or in patient-reported outcomes between these 2 schedules.

A phase 2 trial of deep-inspiration breath hold in radiotherapy of gastric lymphomas.

Background and purpose: Radiotherapy (RT) is an important part in the treatment of gastric lymphomas and the prognosis after radiotherapy is very good with a good chance of long-term survival, so prevention of long-term adverse effects is important. In patients with gastric lymphomas cardiac late effects are of most concern. The aim of this study was to assess if the dose to the heart could be reduced with deep inspiration breath-hold (DIBH) without compromising the dose to the target or increasing the risk of other late effects. Methods and patients: Fifteen patients with gastric lymphoma were included. RT plans were made using DIBH and Free breathing (FB) scans. Clinical target volume (CTV) was the stomach plus 1 cm margin. The heart and surrounding organs at risk (OAR) were contoured. Two sets of plan comparisons were made, one with 1 cm CTV to planning target volume (PTV) margin in both DIBH and FB and one set with an additional 5 mm CTV to PTV margin in cranio-caudal direction with FB. Datasets were analysed with Wilcoxon signed rank test for non-parametric paired data. Results: All patients tolerated the procedures and were treated with volumetric arc therapy technique in DIBH. Target coverage was kept equal between FB and DIBH, while a statistically significant reduction of the estimated does to the heart was seen with DIBH. Median mean heart dose was reduced from 7.1 Gy (5.7-12) to a median of 3.2 Gy (1.2-7.0) and heart V20 from a median of 54 (17-106) cm3 to 15. (0.0-78) cm3. The estimated mean doses to the liver, duodenum, pancreas and spinal cord were at the same level. Conclusion: This clinical trial of RT with DIBH for gastric lymphomas showed that the heart dose could be reduced without compromising PTV coverage. The doses to abdominal OARs were similar with FB and DIBH.

Effectiveness of Docetaxel for Metastatic Hormone-sensitive Prostate Cancer in Clinical Practice.

BACKGROUND: Addition of docetaxel to androgen deprivation therapy (ADT) for the treatment of metastatic hormone-sensitive prostate cancer (mHSPC) has been proved to be effective with an overall survival (OS) benefit in phase III clinical trials. The effectiveness of docetaxel with ADT in the general patient population remains unknown. OBJECTIVE: The purpose of this study is to report the clinical experience in mHSPC patients treated with 3rd-weekly docetaxel plus ADT in routine practice at two Danish institutions. DESIGN SETTING AND PARTICIPANTS: A two-center retrospective study including consecutive mHSPC patients treated with 3rd-weekly docetaxel plus ADT was conducted. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Outcomes of interest were OS, and biochemical and clinical progression-free survival. RESULTS AND LIMITATIONS: A total of 173 consecutive patients with mHSPC who received docetaxel every 3rd week plus ADT between June 2015 and February 2018 were included. Most patients had high-volume disease (85%). All six planned docetaxel cycles were delivered in 149 cases (86%). Of the patients, 106 (61%) were alive at the last follow-up. At a median follow-up of 42 (37.8-58.6) mo, the median OS was 51.6 (41.5-56.3) mo. Castration-resistant prostate cancer (CRPC) developed in 46% within 1 yr, with a median time to CRPC of 15.6 (13.0-18.1) mo. Prostate-specific antigen nadir ≤0.2 ng/l was achieved in 15% of patients after 6 mo of ADT and in 19% after 12 mo. CONCLUSIONS: The effect of docetaxel for mHSPC patients treated in routine practice appears comparable with the overall efficacy reported in the literature. Selection of patients will influence the results in clinical practice and clinical studies. PATIENT SUMMARY: In this report, we looked at the clinical effectiveness of docetaxel combined with androgen deprivation therapy in men with metastatic hormone-sensitive prostate cancer (mHSPC) in a Danish population. We found the effect of docetaxel treatment for mHSPC in the general population to be comparable with the overall efficacy reported in published studies.

Harnessing benefit of highly conformal RT techniques for lymphoma patients.

This status article describes current state-of-the-art radiotherapy for lymphomas and new emerging techniques. Current state-of-the-art radiotherapy is sophisticated, individualised, CT-based, intensity-modulated treatment, using PET/CT to define the target. The concept of involved site radiotherapy should be used, delineating the target using the exact same principles as for solid tumours. The optimal treatment delivery includes motion management and online treatment verification systems, which reduce intra- and interfractional anatomical variation. Emerging radiotherapy techniques in lymphomas include adaptive radiotherapy in MR- and CT-based treatment systems and proton therapy. The next generation linear accelerators have the capability to deliver adaptive treatment and allow relatively quick online adaptation to the daily variations of the anatomy. The computer systems use machine leaning to facilitate rapid automatic contouring of the target and organs-at-risk. Moreover, emerging MR-based planning and treatment facilities allow target definition directly from MR scans and allow intra-fractional tracking of structures recognisable on MR. Proton facilities are now being widely implemented. The benefits of proton therapy are due to the physical properties of protons, which in many cases allow sparing of normal tissue. The variety of techniques in modern radiotherapy means that the radiation oncologist must be able to choose the right technique for each patient. The choice is mainly based on experience and standard protocols, but new systems calculating risks for the patients with a specific treatment plan and also systems integrating clinical factors and risk factors into the planning process itself are emerging.

uPAR PET/CT for Prognostication and Response Assessment in Patients with Metastatic Castration-Resistant Prostate Cancer Undergoing Radium-223 Therapy: A Prospective Phase II Study.

The aim of this Phase II study was to investigate the potential for response assessment and prognostication of positron emission tomography (PET) using the ligand 68Ga-NOTA-AE105 targeting the urokinase-type plasminogen activator receptor (uPAR) in patients receiving Radium-223-dichloride therapy (223RaCl2). A combined whole-body uPAR PET and computed tomography (CT) was performed before initiation of 223RaCl2 and after two cycles of therapy. Standardized uptake value (SUV) in selected bone metastases was measured and the lesion with the highest SUVmax was considered the index lesion. Clinical outcomes were overall survival (OS), radiographic progression free survival (rPFS) and occurrence of symptomatic skeletal event (SSE). A total of 17 patients were included and 14 patients completed both baseline and follow-up uPAR-PET/CT. Baseline SUVmax of the index lesion was associated with OS; hazard ratio 2.51 (95% CI: 1.01-6.28, p = 0.05) per unit increase in SUVmax. No association between changes in SUVmax from baseline to follow-up and OS, progression during therapy, or rPFS was found. Baseline SUVmax was a significant predictor of SSE with receiver operating characteristics (ROC) area under the curve (AUC) = 0.81 (95% CI: 0.58-1.00, p = 0.034). A cut-off for tumor SUVmax could be established with an odds ratio of 14.0 (95% CI: 1.14-172.6, p = 0.023) for occurrence of SSE within 12 months. Although based on a small number of patients, uPAR-PET SUVmax in bone metastases was predictive for OS and risk of SSE in mCRPC patients receiving 223RaCl2. However, a relatively low uptake of the uPAR ligand in bone metastases impedes visual evaluation and requires another modality for lesion delineation.

Urokinase-Type Plasminogen Activator Receptor (uPAR) PET/MRI of Prostate Cancer for Noninvasive Evaluation of Aggressiveness: Comparison with Gleason Score in a Prospective Phase 2 Clinical Trial.

The aim of this study was to evaluate the correlation between uptake of the PET ligand 68Ga-NOTA-AE105, targeting the urokinase-type plasminogen activator receptor (uPAR), and Gleason score in patients undergoing prostate biopsy. Methods: Patients with clinical suspicion of prostate cancer (PCa) or previously diagnosed with PCa were prospectively enrolled in this phase 2 trial. A combination of uPAR PET and multiparametric MRI (mpMRI) was performed, and the SUV in the primary tumor, as delineated by mpMRI, was measured by 2 independent readers. The correlation between the SUV and the Gleason score obtained by biopsy was assessed. Results: A total of 27 patients had histologically verified PCa visible on mpMRI and constituted the study population. There was a positive correlation between the SUVmax and the Gleason score (Spearman ρ = 0.55; P = 0.003). Receiver operating characteristic analysis showed an area under the curve of 0.88 (95% CI, 0.67-1.00) for discriminating a Gleason score of greater than or equal to 3 + 4 from a Gleason score of less than or equal to 3 + 3. A cutoff for the tumor SUVmax could be established with a sensitivity of 96% (79%-99%) and a specificity of 75% (30%-95%) for detecting a Gleason score of greater than or equal to 3 + 4. For discriminating a Gleason score of greater than or equal to 4 + 3 from a Gleason score of less than or equal to 3 + 4, a cutoff could be established for detecting a Gleason score of greater than or equal to 4 + 3 with a sensitivity of 93% (69%-99%) and a specificity of 62% (36%-82%). Conclusion: SUV measurements from uPAR PET in primary tumors, as delineated by mpMRI, showed a significant correlation with the Gleason score, and the tumor SUVmax was able to discriminate between low-risk Gleason score profiles and intermediate risk Gleason score profiles with a high diagnostic accuracy. Consequently, uPAR PET/MRI could be a promising method for the noninvasive evaluation of PCa and might reduce the need for repeated biopsies (e.g., in active surveillance).

Timing of radiotherapy after radical prostatectomy (RADICALS-RT): a randomised, controlled phase 3 trial.

BACKGROUND: The optimal timing of radiotherapy after radical prostatectomy for prostate cancer is uncertain. We aimed to compare the efficacy and safety of adjuvant radiotherapy versus an observation policy with salvage radiotherapy for prostate-specific antigen (PSA) biochemical progression. METHODS: We did a randomised controlled trial enrolling patients with at least one risk factor (pathological T-stage 3 or 4, Gleason score of 7-10, positive margins, or preoperative PSA ≥10 ng/mL) for biochemical progression after radical prostatectomy (RADICALS-RT). The study took place in trial-accredited centres in Canada, Denmark, Ireland, and the UK. Patients were randomly assigned in a 1:1 ratio to adjuvant radiotherapy or an observation policy with salvage radiotherapy for PSA biochemical progression (PSA ≥0·1 ng/mL or three consecutive rises). Masking was not deemed feasible. Stratification factors were Gleason score, margin status, planned radiotherapy schedule (52·5 Gy in 20 fractions or 66 Gy in 33 fractions), and centre. The primary outcome measure was freedom from distant metastases, designed with 80% power to detect an improvement from 90% with salvage radiotherapy (control) to 95% at 10 years with adjuvant radiotherapy. We report on biochemical progression-free survival, freedom from non-protocol hormone therapy, safety, and patient-reported outcomes. Standard survival analysis methods were used. A hazard ratio (HR) of less than 1 favoured adjuvant radiotherapy. This study is registered with ClinicalTrials.gov, NCT00541047. FINDINGS: Between Nov 22, 2007, and Dec 30, 2016, 1396 patients were randomly assigned, 699 (50%) to salvage radiotherapy and 697 (50%) to adjuvant radiotherapy. Allocated groups were balanced with a median age of 65 years (IQR 60-68). Median follow-up was 4·9 years (IQR 3·0-6·1). 649 (93%) of 697 participants in the adjuvant radiotherapy group reported radiotherapy within 6 months; 228 (33%) of 699 in the salvage radiotherapy group reported radiotherapy within 8 years after randomisation. With 169 events, 5-year biochemical progression-free survival was 85% for those in the adjuvant radiotherapy group and 88% for those in the salvage radiotherapy group (HR 1·10, 95% CI 0·81-1·49; p=0·56). Freedom from non-protocol hormone therapy at 5 years was 93% for those in the adjuvant radiotherapy group versus 92% for those in the salvage radiotherapy group (HR 0·88, 95% CI 0·58-1·33; p=0·53). Self-reported urinary incontinence was worse at 1 year for those in the adjuvant radiotherapy group (mean score 4·8 vs 4·0; p=0·0023). Grade 3-4 urethral stricture within 2 years was reported in 6% of individuals in the adjuvant radiotherapy group versus 4% in the salvage radiotherapy group (p=0·020). INTERPRETATION: These initial results do not support routine administration of adjuvant radiotherapy after radical prostatectomy. Adjuvant radiotherapy increases the risk of urinary morbidity. An observation policy with salvage radiotherapy for PSA biochemical progression should be the current standard after radical prostatectomy. FUNDING: Cancer Research UK, MRC Clinical Trials Unit, and Canadian Cancer Society.

DaPeCa-4: outcome in penile cancer patients with N3 disease due to extra nodal extension treated with surgery and chemo-irradiation.

Objective: The role of pelvic lymph node dissection (PLND) is still debated in patients with N3 stage penile cancer. In Denmark this subgroup of patients is in general managed with an inguinal lymphadenectomy (ILND) and adjuvant chemoradiation and PLND is not offered as a standard. The objective of this study was to report treatment outcomes of this regimen and compare this with existing literature.Materials and methods: We retrospectively reviewed records of patients with pT1-T4, N3, M0 penile cancer diagnosed between 1st January 2010 and 31th December 2014 in Denmark and treated with curative intend.Results: 21 patients were identified with a median follow up of 74 months (CI 54-94). Management of the penile lesion was local resection in 5 (23.8%), partial penectomy in 10 (47.6%), and total penectomy in 6 (28.6%) of patients. Regarding the most extensive lymph node (LN) surgery: 4 patients (23,8%) went directly to oncological treatment from sentinel node biopsy with no further LN dissection, 6 patients (28.6%) were treated with unilateral ILND, 10 patients (47.6%) with bilateral ILND and a single patient (4.8%) was treated with ILND and PLND. In the adjuvant setting patients were treated with external beam therapy of involved regions and cisplatin-based chemotherapy. Median overall survival was 84 months (CI 0-176). The 5-year probability of surviving penile cancer was 57.1% (CI 36.0-78.3).Conclusion: Treatment with surgery and chemo-irradiation in this national cohort does not show inferior survival outcomes compared to historical cohorts.

Involved node radiation therapy in the combined modality treatment for early-stage Hodgkin lymphoma: Analysis of relapse location and long-term outcome.

BACKGROUND AND PURPOSE: Involved node radiation therapy (INRT) in the combined modality treatment for early-stage Hodgkin lymphoma (ESHL) has reduced the irradiated volume dramatically. Limiting the irradiated volume further based on initial disease bulk, 18F-fluoro-deoxy-glucose (FDG)-avidity, or residual computed tomography (CT) abnormality after chemotherapy seems attractive. In a cohort of patients treated with INRT a meticulous pattern-of-relapse analysis was performed to examine these options. MATERIAL AND METHODS: Patients treated for ESHL in our institution from 2005 to 2014 who achieved complete remission with chemotherapy were included. Patient characteristics, treatment details and clinical outcome were registered. For relapsed patients, rigid co-registration of the positron emission tomography/computed tomography-scans from the time of diagnosis and at relapse was done to visually assess the relapse location relative to initial involvement and, if irradiated, the irradiated volume. Size and maximum Standardized Uptake Value of the initial node(s) with later relapse, and residual CT abnormalities after chemotherapy in those locations were measured. RESULTS: We included 182 patients. Twelve (6.6%) patients relapsed, five in previously involved nodes (two irradiated, three not irradiated). Relapses did not occur preferentially in initially bulky disease, in lymph node(s) with the highest FDG-uptake, or in residual CT abnormalities after chemotherapy. CONCLUSIONS: Modern treatment with brief chemotherapy and limited radiotherapy provides excellent long-term disease control in ESHL. Neither bulk, high FDG-uptake, nor residual CT abnormality after chemotherapy could predict initially involved lymph nodes with a high risk of relapse.

[Management of thymomas and thymic carcinomas].

This review summarises the diagnostics, staging and treatment of thymic epithelial tumours, of which CT is the current primary imaging. The International Association for the Study of Lung Cancer/International Thymic Malignancy Interest Group TNM staging and the WHO histological classifications are described. Surgery done as total thymectomy with video-assisted thoracoscopic surgery in stage I and open sternotomy in larger stages is the primary treatment if possible. Presurgical tumour reduction with chemotherapy and the possibility of adjuvant radiotherapy after R+ resection is described. Radiotherapy or chemotherapy can be considered, if definite surgery is not possible. Relapse is treated after the same principles as primary disease.

Interim analysis of the REASSURE (Radium-223 alpha Emitter Agent in non-intervention Safety Study in mCRPC popUlation for long-teRm Evaluation) study: patient characteristics and safety according to prior use of chemotherapy in routine clinical practice.

PURPOSE: REASSURE is a global, prospective, non-interventional study to assess long-term safety of radium-223 in patients with bone metastatic castration-resistant prostate cancer. Here we report an interim analysis of patients according to previous use of chemotherapy. METHODS: Radium-223 was administered in routine clinical practice. Interim safety analysis was planned after enrolment of the first 600 patients. Patient characteristics and safety data by previous administration of chemotherapy (docetaxel and/or cabazitaxel) were investigated. RESULTS: This interim analysis included 583 patients. Median duration of observation was 7 months (range, 0-20). Nineteen patients treated with concomitant chemotherapy were excluded, 564 (97%) were eligible for exploratory analysis according to prior use of chemotherapy; 190 (34%) had previously received and completed chemotherapy, and 374 (66%) had not. In the prior versus no prior chemotherapy group, a higher proportion of patients had an Eastern Cooperative Oncology Group performance status of ≥2 (22% vs 11%) and > 20 metastatic lesions (26% vs 15%), median alkaline phosphatase (162.0 vs 115.0 U/L) and prostate-specific antigen (132.0 vs 40.2 ng/mL) levels were higher, and a lower proportion completed 6 radium-223 injections (45% vs 63%). Drug-related treatment-emergent adverse events (TEAEs) occurred in 63 and 48%, and haematological drug-related TEAEs in 21 and 9% of patients who had or had not previously received chemotherapy. Four drug-related deaths were reported, all in the prior chemotherapy group. CONCLUSIONS: The short-term safety profile of radium-223 in routine clinical practice was comparable to other clinical studies, irrespective of prior chemotherapy use. Haematological TEAEs occurred more frequently in the prior chemotherapy group, presumably due to decreased bone marrow function as a consequence of more advanced disease and prior exposure to cytotoxic therapy. Patients who had not previously received chemotherapy appeared to have a lower burden of disease at baseline, and a lower proportion discontinued radium-223 treatment.

A step and shoot intensity modulated technique for total body irradiation.

INTRODUCTION: Total body irradiation (TBI) is a part of the conditioning regimen for bone marrow transplant.At the Royal Marsden (Sutton, UK) and Rigshospitalet (Copenhagen, Denmark), we introduced a step and shoot IMRT (SS IMRT) technique for TBI. This technique requires no equipment other than that used to deliver other external beam radiation. In this paper, we describe this technique and report on data from the two clinics. MATERIALS AND METHODS: The patients were positioned supine, supported by vacuum bag(s). The entire body of the patients were CT scanned with 5 mm slices. Multiple multi-leaf collimator (MLC) defined fields were used.In-vivo dosimetry was performed at the Royal Marsden for 113 patients.Calculated doses for 18 adult and 4 paediatric patients from Rigshospitalet were extracted. RESULTS: The in-vivo data from the Royal Marsden showed that the mean TLD measured dose difference was -1.9% with a standard deviation of 4.5%.SS IMRT plans for 22 patients from Rigshospitalet resulted in mean doses to the brain, lungs and kidneys all within the range of 11.1-11.8 Gy, while the V(12 Gy) was below 5% for the brain, 2% for the lungs and 0% for the kidneys. DISCUSSION: SS IMRT is feasible for TBI and can deliver targeted doses to the organs at risk.

223Ra Therapy of Advanced Metastatic Castration-Resistant Prostate Cancer: Quantitative Assessment of Skeletal Tumor Burden for Prognostication of Clinical Outcome and Hematologic Toxicity.

The aim of this study was to investigate the prognostic value of the quantitative assessment of skeletal tumor burden on bone scintigraphy (Bone Scan Index [BSI]) in patients who have advanced metastatic castration-resistant prostate cancer (mCRPC) and are receiving 223RaCl2 We hypothesized that the BSI can serve as a prognostic biomarker of overall survival (OS) and hematologic toxicity and as a tool for response assessment in patients with mCRPC treated with 223RaCl2Methods: This study was a retrospective investigation of a Danish cohort of mCRPC patients who received 223RaCl2 therapy between March 2014 and October 2015 and for whom baseline bone scintigraphy was available. Bone scintigraphy studies were reviewed and graded according to the extent of disease. Furthermore, an automated BSI (EXINI BoneBSI) was obtained for baseline scintigraphy studies and follow-up scans after 3 cycles as well as at the end of therapy. Clinical outcomes were OS and occurrence of hematologic toxicity of grades 2-5. Associations between the BSI and clinical outcomes were investigated in multivariate regression models including the visual assessment of bone scintigraphy and other relevant covariates. Results: A total of 88 patients were included. The median number of completed 223RaCl2 cycles was 4, and 27 patients (31%) completed 6 cycles. The BSI was significantly associated with OS in the multivariate analysis; the median OS for patients with a BSI of greater than 5 was 8.2 mo, and the median OS for patients with a BSI of less than or equal to 5 was 15.0 mo (hazard ratio, 2.65 [95% confidence interval, 1.5-4.71]; P = 0.001). Likewise, the baseline BSI was prognostic for the occurrence of hematologic toxicity; patients with a BSI of greater than 5 had an odds ratio of 3.02 (95% confidence interval, 1.2-7.8; P = 0.02) for toxicity. The BSI declined during therapy in 44% of the patients who completed 3 cycles of 223RaCl2 (n = 52) and in 84% of the patients after the end of therapy (n = 32). There was no significant association between a change in the BSI during therapy and OS. Conclusion: The BSI is a promising biomarker for prognostication of OS and hematologic toxicity in late-stage mCRPC patients receiving 223RaCl2 Further prospective studies are needed to evaluate the potential of the BSI for response assessment in 223RaCl2 therapy.

Impact of treatment delay in Radium-223 therapy of metastatic castration-resistant prostate cancer patients.

BACKGROUND: Radium-223-dichloride (Ra-223) is an alpha-emitting, bone seeking radionuclide therapy approved for patients with metastatic castration-resistant prostate cancer (mCRPC). In the fall of 2014, a global temporary shortage of Ra-223 occurred for 2 months due to production irregularities. The aim of this study was to assess whether prolonged interval between Ra-223 cycles to non-disease related causes had a negative impact on clinical outcome of therapy. MATERIALS AND METHODS: Retrospective single-center study of mCRPC patients who initiated Ra-223 therapy in the period from March 2014 to February 2015. End points were number of completed Ra-223 cycles, overall survival (OS) and radiographic progression-free survival (rPFS). Bone scintigraphy, CT of thorax and abdomen, hematological status, PSA and alkaline phosphatase were evaluated prior to first dose and after 3rd and 6th treatment, respectively. Follow-up period was 18 months after first Ra-223 cycle. RESULTS: A total of 50 consecutive patients initiated Ra-223 therapy in the time period. Seventeen of 50 patients (34%) had prolonged interval between cycles due to delivery problems. Median delay was 4 weeks (range 3-9 weeks). Patients with delayed treatment had significantly longer median rPFS [delayed patients: 7.1 months (95% CI 4.9-9.3) vs. 4.5 months (95% CI 2.8-6.3)]. There was no significant difference in number of completed cycles or median OS. CONCLUSION: We find no negative impact of prolonged interval between Ra-223 cycles due to non-disease related reasons on OS, rPFS or number of completed treatment cycles.

Life years lost attributable to late effects after radiotherapy for early stage Hodgkin lymphoma: The impact of proton therapy and/or deep inspiration breath hold.

BACKGROUND AND PURPOSE: Due to the long life expectancy after treatment, the risk of late effects after radiotherapy (RT) is of particular importance for patients with Hodgkin lymphoma (HL). Both deep inspiration breath hold (DIBH) and proton therapy have been shown to reduce the dose to normal tissues for mediastinal HL, but the impact of these techniques in combination is unknown. The purpose of this study was to compare the life years lost (LYL) attributable to late effects after RT for mediastinal HL using intensity modulated radiation therapy (IMRT) in free breathing (FB) and DIBH, and proton therapy in FB and DIBH. MATERIALS AND METHODS: Plans for each technique were created for 22 patients with HL. Doses were extracted and the risk of late effects and LYL were estimated. RESULTS: We found that the use of DIBH, proton therapy, and the combination significantly reduced the LYL compared to IMRT in FB. The lowest LYL was found for proton therapy in DIBH. However, when IMRT in DIBH was compared to proton therapy in FB, no significant difference was found. CONCLUSIONS: Patient-specific plan comparisons should be used to select the optimal technique when comparing IMRT in DIBH and proton therapy in FB.

Prospective assessment of the quality of life before, during and after image guided intensity modulated radiotherapy for prostate cancer.

BACKGROUND: Radiotherapy (RT) in combination with androgen deprivation therapy (ADT) for prostate cancer (PCa) carries a risk of gastrointestinal (GI) and genitourinary toxicity, which might affect the quality of life (QoL). The purpose of this study was to assess the QoL in patients with PCa before, during and after radiotherapy (RT) and to compare the QoL 1 year after RT to a normal population. METHODS: The QoL was evaluated prospectively by the self-administered questionnaire SF-36 in 87 patients with PCa. The SF-36 was completed before RT (baseline), at start of RT, at end of RT and 1 year after RT. A mixed model analysis was used to determine the changes in QoL at each time point compared to baseline. The patients' QoL 1 year after RT was compared to a normal population consisting of 462 reference subjects matched on age and education. RESULTS: One year after RT, patients reported significantly less pain and significantly fewer limitations due to their physical health compared to baseline. Compared to the normal population, patients reported significantly less pain 1 year after RT. However, patients also reported significantly less vitality, worse mental health as well as significantly more limitations due to physical and mental health 1 year after RT compared to the normal population. CONCLUSIONS: In this study, patients with PCa did not experience significant impairment in the QoL 1 year after RT compared to baseline. However, patients reported significantly worse mental health before, during and 1 year after RT compared to the normal population.

Low-dose (10-Gy) total skin electron beam therapy for cutaneous T-cell lymphoma: an open clinical study and pooled data analysis.

PURPOSE: Cutaneous T-cell lymphomas (CTCLs) are dominated by mycosis fungoides (MF) and Sézary syndrome (SS), and durable disease control is a therapeutic challenge. Standard total skin electron beam therapy (TSEBT) is an effective skin-directed therapy, but the possibility of retreatments is limited to 2 to 3 courses in a lifetime due to skin toxicity. This study aimed to determine the clinical effect of low-dose TSEBT in patients with MF and SS. METHODS AND MATERIALS: In an open clinical study, 21 patients with MF/SS stages IB to IV were treated with low-dose TSEBT over <2.5 weeks, receiving a total dose of 10 Gy in 10 fractions. Data from 10 of these patients were published previously but were included in the current pooled data analysis. Outcome measures were response rate, duration of response, and toxicity. RESULTS: The overall response rate was 95% with a complete cutaneous response or a very good partial response rate (<1% skin involvement with patches or plaques) documented in 57% of the patients. Median duration of overall cutaneous response was 174 days (5.8 months; range: 60-675 days). TSEBT-related acute adverse events (grade 1 or 2) were observed in 60% of patients. CONCLUSIONS: Low-dose (10-Gy) TSEBT offers a high overall response rate and is relatively safe. With this approach, reirradiation at times of relapse or progression is likely to be less toxic than standard dose TSEBT. It remains to be established whether adjuvant and combination treatments can prolong the beneficial effects of low-dose TSEBT.

Prospective assessment of urinary, gastrointestinal and sexual symptoms before, during and after image-guided volumetric modulated arc therapy for prostate cancer.

OBJECTIVE: The aim of this study was to prospectively assess the development of 24 urinary, gastrointestinal and sexual symptoms in patients with prostate cancer (PCa) during and after image-guided volumetric modulated arc therapy (IG-VMAT). MATERIAL AND METHODS: A total of 87 patients with PCa participated in this study. The patients were asked to complete a modified version of the Prostate Cancer Symptom Scale (PCSS) questionnaire before radiotherapy (RT) (baseline), at the start of RT, at the end of RT and 1 year after RT. Changes in symptoms at the start of RT, at the end of RT and 1 year after RT compared to baseline were analysed by a mixed model analysis of repeated measurements with the following covariates: age, comorbidity, smoking and androgen deprivation therapy (ADT). RESULTS: All urinary problems except for haematuria increased significantly at the end of RT compared to baseline. One year after RT, there was no longer any difference compared to baseline for any of the urinary symptoms. All gastrointestinal symptoms except for nausea increased significantly at the end of RT. One year after RT, patients also reported slightly higher degrees of stool frequency, bowel leakage, planning of toilet visits, flatulence, mucus, gastrointestinal bleeding and impact of gastrointestinal bother on daily activities compared to baseline. All sexual symptoms increased significantly at all times compared to baseline. The use of ADT was associated with worse sexual symptoms. CONCLUSIONS: IG-VMAT is a safe treatment for PCa, with few and mild changes in urinary and gastrointestinal symptoms 1 year after RT compared to baseline. Sexual symptoms deteriorated both during and after RT. The use of ADT was associated with worse sexual symptoms.

Improvement in toxicity in high risk prostate cancer patients treated with image-guided intensity-modulated radiotherapy compared to 3D conformal radiotherapy without daily image guidance.

BACKGROUND: Image-guided radiotherapy (IGRT) facilitates the delivery of a very precise radiation dose. In this study we compare the toxicity and biochemical progression-free survival between patients treated with daily image-guided intensity-modulated radiotherapy (IG-IMRT) and 3D conformal radiotherapy (3DCRT) without daily image guidance for high risk prostate cancer (PCa). METHODS: A total of 503 high risk PCa patients treated with radiotherapy (RT) and endocrine treatment between 2000 and 2010 were retrospectively reviewed. 115 patients were treated with 3DCRT, and 388 patients were treated with IG-IMRT. 3DCRT patients were treated to 76 Gy and without daily image guidance and with 1-2 cm PTV margins. IG-IMRT patients were treated to 78 Gy based on daily image guidance of fiducial markers, and the PTV margins were 5-7 mm. Furthermore, the dose-volume constraints to both the rectum and bladder were changed with the introduction of IG-IMRT. RESULTS: The 2-year actuarial likelihood of developing grade > = 2 GI toxicity following RT was 57.3% in 3DCRT patients and 5.8% in IG-IMRT patients (p < 0.001). For GU toxicity the numbers were 41.8% and 29.7%, respectively (p = 0.011). On multivariate analysis, 3DCRT was associated with a significantly increased risk of developing grade > = 2 GI toxicity compared to IG-IMRT (p < 0.001, HR = 11.59 [CI: 6.67-20.14]). 3DCRT was also associated with an increased risk of developing GU toxicity compared to IG-IMRT.The 3-year actuarial biochemical progression-free survival probability was 86.0% for 3DCRT and 90.3% for IG-IMRT (p = 0.386). On multivariate analysis there was no difference in biochemical progression-free survival between 3DCRT and IG-IMRT. CONCLUSION: The difference in toxicity can be attributed to the combination of the IMRT technique with reduced dose to organs-at-risk, daily image guidance and margin reduction.

[Treatment of adrenocortical carcinomas is challenging]. / Diagnose og behandling af binyrebarkkarcinom.

Adrenocortical carcinomas (ACC) are rare tumours responsible for only 0.02% of the total number of malignant diseases. However the ACC are aggressive with a mean fiveyears survival of 20-50% and are often associated with increased production of adrenocortical hormones. The effect of the treatment is controversial and often based on small retrospective series or expert opinions. Centralization, international attention and collaboration in the treatment of ACC are mandatory. Randomized clinical trials are needed to determine the best treatment strategy in order to increase survival in patients with ACC.