Robust treatment planning of dose painting for prostate cancer based on ADC-to-Gleason score mappings - what is the potential to increase the tumor control probability?

BACKGROUND AND PURPOSE: The aim of this study was to evaluate the potential to increase the tumor control probability (TCP) with 'dose painting by numbers' (DPBN) plans optimized in a treatment planning system (TPS) compared to uniform dose plans. The DPBN optimization was based on our earlier published formalism for prostate cancer that is driven by dose-responses of Gleason scores mapped from apparent diffusion coefficients (ADC). MATERIAL AND METHODS: For 17 included patients, a set of DPBN plans were optimized in a TPS by maximizing the TCP for an equal average dose to the prostate volume (CTVT) as for a conventional uniform dose treatment. For the plan optimizations we applied different photon energies, different precisions for the ADC-to-Gleason mappings, and different CTVT positioning uncertainties. The TCP increasing potential was evaluated by the DPBN efficiency, defined as the ratio of TCP increases for DPBN plans by TCP increases for ideal DPBN prescriptions (optimized without considering radiation transport phenomena, uncertainties of the CTVT positioning, and uncertainties of the ADC-to-Gleason mapping). RESULTS: The median DPBN efficiency for the most conservative planning scenario optimized with a low precision ADC-to-Gleason mapping, and a positioning uncertainty of 0.6 cm was 10%, meaning that more than half of the patients had a TCP gain of at least 10% of the TCP for an ideal DPBN prescription. By increasing the precision of the ADC-to-Gleason mapping, and decreasing the positioning uncertainty the median DPBN efficiency increased by up to 40%. CONCLUSIONS: TCP increases with DPBN plans optimized in a TPS were found more likely with a high precision mapping of image data into dose-responses and a high certainty of the tumor positioning. These findings motivate further development to ensure precise mappings of image data into dose-responses and to ensure a high spatial certainty of the tumor positioning when implementing DPBN clinically.

Does exercise intensity matter for fatigue during (neo-)adjuvant cancer treatment? The Phys-Can randomized clinical trial.

Exercise during cancer treatment improves cancer-related fatigue (CRF), but the importance of exercise intensity for CRF is unclear. We compared the effects of high- vs low-to-moderate-intensity exercise with or without additional behavior change support (BCS) on CRF in patients undergoing (neo-)adjuvant cancer treatment. This was a multicenter, 2x2 factorial design randomized controlled trial (Clinical Trials NCT02473003) in Sweden. Participants recently diagnosed with breast (n = 457), prostate (n = 97) or colorectal (n = 23) cancer undergoing (neo-)adjuvant treatment were randomized to high intensity (n = 144), low-to-moderate intensity (n = 144), high intensity with BCS (n = 144) or low-to-moderate intensity with BCS (n = 145). The 6-month exercise intervention included supervised resistance training and home-based endurance training. CRF was assessed by Multidimensional Fatigue Inventory (MFI, five subscales score range 4-20), and Functional Assessment of Chronic Illness Therapy-Fatigue scale (FACIT-F, score range 0-52). Multiple linear regression for main factorial effects was performed according to intention-to-treat, with post-intervention CRF as primary endpoint. Overall, 577 participants (mean age 58.7 years) were randomized. Participants randomized to high- vs low-to-moderate-intensity exercise had lower physical fatigue (MFI Physical Fatigue subscale; mean difference -1.05 [95% CI: -1.85, -0.25]), but the difference was not clinically important (ie <2). We found no differences in other CRF dimensions and no effect of additional BCS. There were few minor adverse events. For CRF, patients undergoing (neo-)adjuvant treatment for breast, prostate or colorectal cancer can safely exercise at high- or low-to-moderate intensity, according to their own preferences. Additional BCS does not provide extra benefit for CRF in supervised, well-controlled exercise interventions.

Effects of a nutrition intervention on acute and late bowel symptoms and health-related quality of life up to 24 months post radiotherapy in patients with prostate cancer: a multicentre randomised controlled trial.

PURPOSE: Radiotherapy to the prostate gland and pelvic lymph nodes may cause acute and late bowel symptoms and diminish quality of life. The aim was to study the effects of a nutrition intervention on bowel symptoms and health-related quality of life, compared with standard care. METHODS: Patients were randomised to a nutrition intervention (n = 92) aiming to replace insoluble fibres with soluble and reduce intake of lactose, or a standard care group (n = 88) who were recommended to maintain their habitual diet. Bowel symptoms, health-related quality of life and intake of fibre and lactose-containing foods were assessed up to 24 months after radiotherapy completion. Multiple linear regression was used to analyse the effects of the nutrition intervention on bowel symptoms during the acute (up to 2 months post radiotherapy) and the late (7 to 24 months post radiotherapy) phase. RESULTS: Most symptoms and functioning worsened during the acute phase, and improved during the late phase in both the intervention and standard care groups. The nutrition intervention was associated with less blood in stools (p = 0.047), flatulence (p = 0.014) and increased loss of appetite (p = 0.018) during the acute phase, and more bloated abdomen in the late phase (p = 0.029). However, these associations were clinically trivial or small. CONCLUSIONS: The effect of the nutrition intervention related to dietary fibre and lactose on bowel symptoms from pelvic RT was small and inconclusive, although some minor and transient improvements were observed. The results do not support routine nutrition intervention of this type to reduce adverse effects from pelvic radiotherapy.

Prospective observational study of 177Lu-DOTA-octreotate therapy in 200 patients with advanced metastasized neuroendocrine tumours (NETs): feasibility and impact of a dosimetry-guided study protocol on outcome and toxicity.

PURPOSE: Peptide receptor radionuclide therapy in patients with neuroendocrine tumours has yielded promising results. This prospective study investigated the feasibility of dosimetry of the kidneys and bone marrow during therapy and its impact on efficacy and outcome. METHODS: The study group comprised 200 consecutive patients with metastasized somatostatin receptor-positive neuroendocrine tumours progressing on standard therapy or not suitable for other therapeutic options. A treatment cycle consisted of 7.4 GBq 177Lu-DOTA-octreotate with co-infusion of a mixed amino acid solution, and cycles were repeated until the absorbed dose to the kidneys reached 23 Gy or there were other reasons for stopping therapy. The Ki-67 index was ≤2% in 47 patients (23.5%), 3-20% in 121 (60.5%) and >20% in 16 (8%). RESULTS: In 123 patients (61.5%) the absorbed dose to the kidneys reached 23 Gy with three to nine cycles during first-line therapy; in no patient was a dose to the bone marrow of 2 Gy reached. The best responses (according to RECIST 1.1) were a complete response (CR) in 1 patient (0.5%), a partial response (PR) in 47 (23.5%), stable disease (SD) in 135 (67.5%) and progressive disease (PD) in 7 (3.5%). Median progression-free survival was 27 months (95% CI 22-30 months) in all patients, 33 months in those in whom the absorbed dose to the kidneys reached 23 Gy and 15 months in those in whom it did not. Median overall survival (OS) was 43 months (95% CI 39-53 months) in all patients, 54 months in those in whom the absorbed dose to the kidneys reached 23 Gy and 25 months in those in whom it did not. Median OS was 60 months in patients with a best response of PR or CR, 42 months in those with SD and 16 months in those with PD. Three patients (1.5%) developed acute leukaemia, 1 patient (0.5%) chronic leukaemia (unconfirmed) and 30 patients (15%) grade 3 or 4 bone marrow toxicity. Eight patients (4%) developed grade 2 kidney toxicity and one patient (0.5%) grade 4 kidney toxicity. CONCLUSIONS: Dosimetry-based therapy with 177Lu-DOTA-octreotate is feasible. Patients in whom the absorbed dose to the kidneys reached 23 Gy had a longer OS than those in whom it did not. Patients with CR/PR had a longer OS than those with SD. Bone marrow dosimetry did not predict toxicity.

Dose painting of prostate cancer based on Gleason score correlations with apparent diffusion coefficients.

BACKGROUND: Gleason scores for prostate cancer correlates with an increased recurrence risk after radiotherapy (RT). Furthermore, higher Gleason scores correlates with decreasing apparent diffusion coefficient (ADC) data from diffusion weighted MRI (DWI-MRI). Based on these observations, we present a formalism for dose painting prescriptions of prostate volumes based on ADC images mapped to Gleason score driven dose-responses. METHODS: The Gleason score driven dose-responses were derived from a learning data set consisting of pre-RT biopsy data and post-RT outcomes for 122 patients treated with a homogeneous dose to the prostate. For a test data set of 18 prostate cancer patients with pre-RT ADC images, we mapped the ADC data to the Gleason driven dose-responses by using probability distributions constructed from published Gleason score correlations with ADC data. We used the Gleason driven dose-responses to optimize dose painting prescriptions that maximize the tumor control probability (TCP) with equal average dose as for the learning sets homogeneous treatment dose. RESULTS: The dose painting prescriptions increased the estimated TCP compared to the homogeneous dose by 0-51% for the learning set and by 4-30% for the test set. The potential for individual TCP gains with dose painting correlated with increasing Gleason score spread and larger prostate volumes. The TCP gains were also found to be larger for patients with a low expected TCP for the homogeneous dose prescription. CONCLUSIONS: We have from retrospective treatment data demonstrated a formalism that yield ADC driven dose painting prescriptions for prostate volumes that potentially can yield significant TCP increases without increasing dose burdens as compared to a homogeneous treatment dose. This motivates further development of the approach to consider more accurate ADC to Gleason mappings, issues with delivery robustness of heterogeneous dose distributions, and patient selection criteria for design of clinical trials.

Kidney dosimetry during 177Lu-DOTATATE therapy in patients with neuroendocrine tumors: aspects on calculation and tolerance.

BACKGROUND: Fractionated therapy with 177Lu-DOTATATE has been reported to be an effective treatment for patients with metastasized neuroendocrine tumors. To optimize the treatment, absorbed doses to risk organs are calculated for the individual patient. For each organ, absorbed dose due to activity in the organ itself (self-dose) and that originating from other organs (cross-dose) are calculated from serial measurements to obtain the activity distribution following treatment. The main aim of the present work were to calculate the cross-dose contribution to the total absorbed kidney dose. METHODS: Five hundred patients with neuroendocrine tumors undergoing therapy with 177Lu-DOTATATE were included. Scintigraphic planar whole body images and single photon emission computed tomography/computed tomography (SPECT/CT) over the abdomen were acquired at 1, 4 and 7 days after treatment. Kidney self-dose was calculated based on radioactivity distribution obtained from SPECT/CT. Cross-dose to kidneys was estimated using organ-based analysis of planar whole body images and cross-fire dose factors from Olinda/EXM 1.1. RESULTS: Cross-dose to kidneys in the majority of patients were less than 2% and almost all cross-doses were less than 10%. Cross-dose exceeded 10% only in rare cases of patients with high tumor burden and low absorbed doses to kidneys. CONCLUSIONS: The absorbed dose from 177Lu-octreotate to solid organs due to cross-fire is generally low and can usually be neglected.

Malignant lipogenesis defined by 11C-acetate PET/CT predicts prostate cancer-specific survival in patients with biochemical relapse after prostatectomy.

PURPOSE: Malignant de novo lipogenesis is strongly linked to the aggressiveness of prostate cancer (PCa) under experimental conditions. 11C-Acetate PET/CT is a potential noninvasive biomarker of malignant lipogenesis in PCa, but its prognostic value is not known. The objective of this study was to analyse 11C-acetate PET/CT image metrics in relation to survival. METHODS: All patients undergoing 11C-acetate PET/CT in one university hospital from 2005 to 2011 due to PSA relapse after previous prostatectomy were retrospectively evaluated. Two groups of patients were compared: those who died from PCa and those who were censored. All previously reported findings of local recurrence, regional or distal lymph node metastases and bone metastases were counted and evaluated regarding 11C-acetate uptake intensity (SUVmax) and tumour volume. Total tumour volume and total lipogenic activity (TLA, summed SUVmax × TV) were calculated. Survival analysis in the entire study population was followed by Cox proportional hazards ratio (HR) analysis. RESULTS: A total of 121 patients were included, and 22 PCa-specific deaths were recorded. The mean PSA level at the time of PET was 2.69 ± 4.35 ng/mL. The median follow-up of the study population was 79 ± 28 months. PET identified at least one PCa lesion in 53 % of patients. Five-year PCa-specific survival after PET was 80 % and 100 % in patients with a positive and a negative PET scan, respectively (p < 0.001). Time-to-death was linearly correlated with highest SUVmax (r = -0.55, p = 0.01) and nonlinearly with TLA (r = -0.75, p < 0.001). Multivariate analysis showed statistical significance for number of bone metastases (HR 1.74, p = 0.01), tertile of TLA (HR 5.63, p = 0.029) and postoperative Gleason score (HR 1.84, p = 0.045). CONCLUSION: Malignant 11C-acetate accumulation measured with PET/CT is a strong predictor of survival in the setting of PSA relapse after prostatectomy. The study provides further evidence for a quantitative relationship between malignant de novo lipogenesis and early death. 11C-Acetate PET/CT might be useful for identifying a high-risk population of relapsing patients in which therapies targeting malignant lipogenesis might be of particular benefit.

Regional distribution and kinetics of [18F]fluciclovine (anti-[18F]FACBC), a tracer of amino acid transport, in subjects with primary prostate cancer.

PURPOSE: [(18)F]Fluciclovine (anti-[(18)F]FACBC) is a synthetic amino acid developed for PET assessment of the anabolic component of tumour metabolism in clinical routine. This phase 1 trial evaluated the safety, tracer stability and uptake kinetics of [(18)F]fluciclovine in patients. METHODS: Six patients with biopsy-proven prostate cancer were investigated with 3-T MRI and PET/CT. All underwent dynamic [(18)F]fluciclovine PET/CT of the pelvic area for up to 120 min after injection of 418 ± 10 MBq of tracer with simultaneous blood sampling of radioactivity. The kinetics of uptake in tumours and normal tissues were evaluated using standardized uptake values (SUVs) and compartmental modelling. RESULTS: Tumour deposits as defined by MRI were clearly visualized by PET. Urine excretion was minimal and normal tissue background was low. Uptake of [(18)F]fluciclovine in tumour from the blood was rapid and the tumour-to-normal tissue contrast was highest between 1 and 15 min after injection with a 65 % reduction in mean tumour uptake at 90 min after injection. A one-compartment model fitted the tracer kinetics well. Early SUVs correlated well with both the influx rate constant (K (1)) and the volume of distribution of the tracer (V (T)). There were no signs of tracer metabolite formation. The product was well tolerated in all patients without significant adverse events. CONCLUSION: [(18)F]Fluciclovine shows high uptake in prostate cancer deposits and appears safe for use in humans. The production is robust and the formulation stable in vivo. An early imaging window seems to provide the best visual results. SUV measurements capture most of the kinetic information that can be obtained from more advanced models, potentially simplifying quantification in future studies.

The clinical safety, biodistribution and internal radiation dosimetry of [¹8F]fluciclovine in healthy adult volunteers.

PURPOSE: We report on the biodistribution and internal radiation dosimetry in humans of [(18)F]fluciclovine, a synthetic L-leucine analogue being investigated as a potential diagnostic biomarker for neoplasia. METHODS: Whole-body positron emission tomography (PET) scans of 6 healthy volunteers were acquired at up to 16 time points up to about 5 h after a bolus administration of [(18)F]fluciclovine (153.8 ± 2.2 MBq). Venous blood samples were taken up to about 4 h post-injection from which (18)F activity concentrations in whole blood and plasma were measured. Urine was collected as voided up to 4 h post-injection, from which the excreted (18)F activity was measured. Absolute values of the (18)F activity contained in up to 11 source regions (brain, salivary glands, lung, heart, pancreas, spleen, liver, red bone marrow, kidneys, uterus and urinary bladder contents) were determined directly from quantitative analysis of the images. For each source region, the (18)F activity decay-corrected and normalised to that injected, as a function of time, was fit by an analytical function which was subsequently integrated to yield the cumulated activity normalised to the injected activity. These normalised cumulated activities were then used as input to the Organ Level INternal Dose Assessment/EXponential Modelling (OLINDA/EXM) package to calculate the internal radiation dosimetry of each subject following the Medical Internal Radiation Dose (MIRD) schema. An effective dose was then estimated for each subject. RESULTS: [(18)F]Fluciclovine was clinically well tolerated in this study. Very little (18)F was excreted with only a mean value of 3.3% present in the urine at about 4 h post-injection; no activity within the intestinal contents was noted. The highest mean initial uptakes were measured in the liver (13.8%), red bone marrow (11.1%) and lung (7.1%). The highest mean radiation absorbed doses per unit administered activity were received by the pancreas (102.2 µGy/MBq), the cardiac wall (51.7 µGy/MBq) and the uterine wall (44.6 µGy/MBq). The mean effective dose per unit administered activity was 22.1 µSv/MBq. CONCLUSION: The internal radiation dosimetry of [(18)F]fluciclovine appears acceptable for PET imaging.

Plan robustness and RBE influence for proton dose painting by numbers for head and neck cancers.

PURPOSE: To investigate the feasibility of dose painting by numbers (DPBN) with respect to robustness for proton therapy for head and neck cancers (HNC), and to study the influence of variable RBE on the TCP and OAR dose burden. METHODS AND MATERIALS: Data for 19 patients who have been scanned pretreatment with PET-FDG and subsequently treated with photon therapy were used in the study. A dose response model developed for photon therapy was implemented in a TPS, allowing DPBN plans to be created. Conventional homogeneous dose and DPBN plans were created for each patient, optimized with either fixed RBE = 1.1 or a variable RBE model. Robust optimization was used to create clinically acceptable plans. To estimate the maximum potential loss in TCP due to actual SUV variations from the pre-treatment imaging, we applied a test case with randomized SUV distribution. RESULTS: Regardless of the use of variable RBE for optimization or evaluation, a statistically significant increase (p < 0.001) in TCP was found for DPBN plans as compared to homogeneous dose plans. Randomizing the SUV distribution decreased the TCP for all plans. A correlation between TCP increase and variance of the SUV distribution and target volume was also found. CONCLUSION: DPBN for protons and HNC is feasible and could lead to a TCP gain. Risks associated with the temporal variation of SUV distributions could be mitigated by imposing minimum doses to targets. The correlation found between TCP increase and SUV variance and target volume may be used for patient selection.

Whole-body diffusion-weighted MRI compared with (18)F-NaF PET/CT for detection of bone metastases in patients with high-risk prostate carcinoma.

OBJECTIVE: The purpose of this study was to evaluate the accuracy of whole-body diffusion-weighted MRI (DWI) and (18)F-NaF PET/CT for detection of bone metastases in patients with high-risk prostate cancer. SUBJECTS AND METHODS: Both patient- and lesion-based analyses were performed on 49 consecutive patients (median age, 67 years; age range, 57-80 years) with recently diagnosed high-risk prostate cancer. All patients underwent bone scintigraphy, whole-body MRI including DWI and (18)F-NaF PET/CT before treatment. Bone scintigraphy, conventional MR images, and follow-up images were used as the standard of reference to evaluate (18)F-NaF PET/CT and DWI. RESULTS: On patient-based analysis, five patients had skeletal metastases on reference imaging that both DWI and (18)F-NaF PET/CT could verify, and (18)F-NaF PET/CT and DWI showed false-positive findings in four and one patient, respectively. With lesion-based analysis, (18)F-NaF PET/CT and DWI showed nine and five true-positive lesions, zero and four false-negative lesions, and seven and two false-positive lesions, respectively. Two patients with uncountable bone metastases were analyzed separately. In these patients, (18)F-NaF PET/CT showed more bone metastases than did DWI. CONCLUSION: We believe (18)F-NaF PET/CT is a sensitive modality for detection of bone metastases caused by prostate cancer. Whole-body DWI shows a higher specificity but lower sensitivity than (18)F-NaF PET/CT. Future studies with a larger patient cohort along with analyses of costs and clinical availability are needed before implementation of these methods can be considered.

Minor changes in effective half-life during fractionated 177Lu-octreotate therapy.

AIMS: Fractionated (177)Lu-DOTA-octreotate therapy has been reported to be an effective treatment option for patients with generalized neuroendocrine tumors. In our clinic, full individual dosimetry is performed during the first therapy cycle, while dosimetry at later cycles is based on the 24 h uptake measurement assuming an unchanged effective half-life. Our aim was to evaluate this assumption and the variation in the 24 h uptake during therapy. PATIENTS: Thirty patients, 13 women and 17 men, were included in the study. METHODS: During the first therapy cycle the (177)Lu-concentration was measured with SPECT/CT over the abdomen at 24 h, 96 h and 168 h after infusion. The effective half-life was determined for the kidneys, liver and spleen. The procedure was repeated at cycle 4 or 5. RESULTS: The median ratio between the effective half-lives of the latter and the first cycle was 0.97 and 1.01 for the right and left kidney, with a range of 0.89-1.01 (1st-3rd quartile) and 0.93-1.05, respectively. DISCUSSION: The mean value of the ratios was slightly lower than one, indicating a tendency towards increased activity elimination during therapy. In individual patients, significant changes were found for all organs, often when a large tumor burden reduction occurred during treatment. Possible contributing factors appeared to be larger amounts of non-tumor bound tracer, improved organ function (kidneys), decrease of vessel obstruction (spleen), less scatter from large tumors and reduction of small metastases (liver and spleen). CONCLUSION: With most patients it is safe to estimate absorbed doses to kidneys, liver and spleen from 24 h activity concentration assuming an unchanged effective half-life during therapy. Patients with risk factors for kidney dysfunction need to be monitored in more detail. Simplified dosimetry based on the assumption of unchanged effective half-life can function as guidance to the number of therapy cycles an individual patient can tolerate.

Comparison of 68Ga-PSMA PET/CT with fluoride PET/CT for detection of bone metastatic disease in prostate cancer.

BACKGROUND: 18F-NaF positron emission tomography/computed tomography (fluoride PET/CT) is considered the most sensitive technique to detect bone metastasis in prostate cancer (PCa). 68Ga-PSMA-11 (PSMA) PET/CT is increasingly used for staging of PCa. This study primarily aimed to compare the diagnostic performance of fluoride PET/CT and gallium-based PSMA PET/CT in identifying bone metastasis followed by a comparison of PSMA PET/CT with contrast-enhanced CT (CE-CT) in identifying soft tissue lesions as a secondary objective. METHODS: Twenty-eight PCa patients with high suspicion of disseminated disease following curative treatment were prospectively evaluated. PET/CT examinations using fluoride and PSMA were performed. All suspicious bone lesions were counted, and the tracer uptake was measured as standardized uptake values (SUV) for both tracers. In patients with multiple findings, ten bone lesions with highest SUVmax were selected from which identical lesions from both scans were considered for direct comparison of SUVmax. Soft tissue findings of local and lymph node lesions from CE-CT were compared with PSMA PET/CT. RESULTS: Both scans were negative for bone lesions in 7 patients (25%). Of 699 lesions consistent with skeletal metastasis in 21 patients on fluoride PET/CT, PSMA PET/CT identified 579 lesions (83%). In 69 identical bone lesions fluoride PET/CT showed significantly higher uptake (mean SUVmax: 73.1 ± 36.8) compared to PSMA PET/CT (34.5 ± 31.4; p < 0.001). Compared to CE-CT, PSMA PET/CT showed better diagnostic performance in locating local (96% vs 61%, p = 0.004) and lymph node (94% vs 46%, p < 0.001) metastasis. CONCLUSION: In this prospective comparative study, PSMA PET/CT detected the majority of bone lesions that were positive on fluoride PET/CT. Further, this study indicates better diagnostic performance of PSMA PET/CT to locate soft tissue lesions compared to CE-CT.

Comparison of 68Ga-PSMA-11 PET/CT with 11C-acetate PET/CT in re-staging of prostate cancer relapse.

Positron emission tomography (PET) imaging is used to localize recurrent disease in prostate cancer (PCa). The tracer 68Ga-PSMA-11 visualizes lesions overexpressing prostate-specific membrane antigen (PSMA), while 11C-acetate visualizes lesions with increased anabolic metabolism. The aim of this study was to compare the performance of PSMA-PET and acetate-PET in re-staging patients with biochemical relapse. Thirty PCa patients with prostate-specific antigen (PSA) relapse after primary curative therapy were prospectively evaluated. PET/CT examinations using 11C-acetate and 68Ga-PSMA-11 were performed. Identified lesions were categorized according to anatomical location and PET measurements were correlated with PSA at time of scan. Tumour lesions showed higher semi-quantitative uptake values on PSMA-PET than acetate-PET. PSMA-PET identified more lesions in 11 patients, fewer lesions in eight patients, and identical number of lesions in 11 patients. This study indicates better diagnostic performance of PSMA-PET, particularly in detecting lymph node (81% vs 60%, p = 0.02) and bone metastasis (95% vs 61%, p = 0.0001) compared to acetate-PET. However, 38% of PSMA-expressing metastases appear to be metabolically inactive and 15% of metabolically active metastases lack PSMA expression. Addition of PET with a metabolic tracer, such as 11C-acetate, might be beneficial before making treatment decisions.

Cancer of the parotid gland; long-term follow-up. A single centre experience on recurrence and survival.

BACKGROUND: The aim of the study was to investigate the results of treatment of malignant parotid gland tumours at a single centre during a 56 year period, focusing on tumour control and survival. PATIENTS AND METHODS: At Uppsala University Hospital, Sweden, 144 patients (73 male and 71 female) with parotid cancer were treated between 1948 and 2004. The mean and median ages were 62 and 65 years, respectively (range 16-89 years). Surgery was the primary treatment in 113 (78%) patients followed by radiotherapy in 81. Postoperative radiotherapy in doses of 64-66 Gy, where the intention was curative and delivered with either split course or not, was administered to a majority of patients after 1970. The split-course mode was practised between 1970 and 1989. The median follow-up time was 8.3 years for patients still alive. There were 57 (40%) relapses, of which 40 were local recurrences with 26 inside the treatment volume. RESULTS: The overall 5-year survival was 53%. The majority of tumour-related deaths appeared in the first 3-5 years after diagnosis. Age, co-morbidity, the presence of lymph node metastases, adenoid cystic carcinoma and extent of disease were important for outcome; gender, however, was not. We found no difference in the survival between patients following split course therapy versus continuous fractionation. No difference could be seen in the survival of patients treated in the 1970s versus the 1990s. CONCLUSIONS: Age, nodal engagement, a higher T-stage, adenoid cystic carcinoma histopathology, facial palsy and intercurrent disease worsen the outcome of patients, whereas gender does not. Treatment principles at our hospital have been surgery followed by radiotherapy since the early 1970s even though a split course technique was practised during a part of this period. Survival has not improved markedly. Thus, there is scope for improvement for this group of patients.

High efficacy of hypofractionated proton therapy with 4 fractions of 5 Gy as a boost to 50 Gy photon therapy for localized prostate cancer.

PURPOSE: We report the outcome of hypofractionated proton boost as an alternative to high dose-rate brachytherapy boost, aimed at an equivalent dose exceeding 86 Gy in 2 Gy fractions, for patients with localized prostate cancer and all risk groups. METHODS: Proton boost of 20 Gy given in 4 daily fractions to the prostate was followed after a one-week rest by photon therapy to 50 Gy in 2 Gy fractions. Outcomes are presented per risk group according to both NCCN and ISUP classifications. Advanced imaging was performed for adequate staging, and at an early stage of rising PSA, to identify the relapse site. Endpoints were PSA relapse-free-, locoregional relapse-free-, and distant metastasis-free- survival. Prostate cancer-specific-, metastasis-free-, and overall survival were also estimated. Genitourinary (GU) and gastrointestinal (GI) toxicity were based on patients' questionnaires and physicians' records. RESULTS: We treated 531 patients between 2002 and 2015; 504 had localized disease. The cohort included 180 patients with T3/T4 disease (36%). The majority of the 50% with high-/very high-risk disease received ADT, 9-24 months; 92 had adjuvant pelvic node treatment. Median follow-up was 113 months (43-193). For low-, intermediate-, high-, and very high-risk patients, the 5-year PSA relapse-free survival was 100%, 94%, 82%, and 72%, respectively. Prolonged ADT improved biochemical control and nodal treatment regional control. The NCCN classification had higher predictive discrimination than the ISUP classification. The 5-year prevalence grade 3+ was 2% for GU and 0% for GI toxicity in pre-treatment symptom-free patients, and not worsened by nodal treatment. CONCLUSION: Dose escalation with hypofractionated proton boost was as effective as reported with high dose-rate brachytherapy boost, and the GU and GI toxicity profile was very similar. The proton boost was also appropriate for patients with larger prostate volume, higher T-stage, and high-risk disease encompassing elective regional node photon therapy.

Robust maximization of tumor control probability for radicality constrained radiotherapy dose painting by numbers of head and neck cancer.

BACKGROUND AND PURPOSE: Radiotherapy with dose painting by numbers (DPBN) needs another approach than conventional margins to ensure a geometrically robust dose coverage for the tumor. This study presents a method to optimize DPBN plans that as opposed to achieve a robust dose distribution instead robustly maximize the tumor control probability (TCP) for patients diagnosed with head and neck cancer. MATERIAL AND METHODS: Volumetric-modulated arc therapy (VMAT) plans were optimized with a robust TCP maximizing objective for different dose constraints to the primary clinical target volume (CTVT) for a set of 20 patients. These plans were optimized with minimax optimization together with dose-responses driven by standardized uptake values (SUV) from 18F-fluorodeoxyglucose positron emission tomography (18FDG-PET). The robustness in TCP was evaluated through sampling treatment scenarios with isocenter displacements. RESULTS: The average increase in TCP with DPBN compared to a homogeneous dose treatment ranged between 3 and 20 percentage points (p.p.) which depended on the different dose constraints for the CTVT. The median deviation in TCP increase was below 1p.p. for all sampled treatment scenarios versus the nominal plans. The standard deviation of SUV multiplied by the CTVT volume were found to correlate with the TCP gain with R 2 ≥ 0.9. CONCLUSIONS: Minimax optimization of DPBN plans yield, based on the presented TCP modelling, a robust increase of the TCP compared to homogeneous dose treatments for head and neck cancers. The greatest TCP gains were found for patients with large and SUV heterogeneous tumors, which may give guidance for patient selection in prospective trials.

Repeatability of quantitative parameters of 18F-fluoride PET/CT and biochemical tumour and specific bone remodelling markers in prostate cancer bone metastases.

PURPOSE: 18F-fluoride PET/CT exhibits high sensitivity to delineate and measure the extent of bone metastatic disease in patients with prostate cancer. 18F-fluoride PET/CT could potentially replace traditional bone scintigraphy in clinical routine and trials. However, more studies are needed to assess repeatability and biological uptake variation. The aim of this study was to perform test-retest analysis of quantitative PET-derived parameters and blood/serum bone turnover markers at the same time point. Ten patients with prostate cancer and verified bone metastases were prospectively included. All underwent two serial 18F-fluoride PET/CT at 1 h post-injection. Up to five dominant index lesions and whole-body 18F-fluoride skeletal tumour burden were recorded per patient. Lesion-based PET parameters were SUVmax, SUVmean and functional tumour volume applying a VOI with 50% threshold (FTV50%). The total skeletal tumour burden, total lesion 18F-fluoride (TLF), was calculated using a threshold of SUV of ≥15. Blood/serum biochemical bone turnover markers obtained at the time of each PET were PSA, ALP, S-osteocalcin, S-beta-CTx, 1CTP and BAP. RESULTS: A total of 47 index lesions and a range of 2-122 bone metastases per patient were evaluated. Median time between 18F-fluoride PET/CT was 7 days (range 6-8 days). Repeatability coefficients were for SUVmax 26%, SUVmean 24%, FTV50% for index lesions 23% and total skeletal tumour burden (TLF) 35%. Biochemical bone marker repeatability coefficients were for PSA 19%, ALP 23%, S-osteocalcin 18%, S-beta-CTx 22%, 1CTP 18% and BAP 23%. CONCLUSIONS: Quantitative 18F-fluoride uptake and simultaneous biochemical bone markers measurements are reproducible for prostate cancer metastases and show similar magnitude in test-retest variation.

Dose painting by numbers based on retrospectively determined recurrence probabilities.

BACKGROUND AND PURPOSE: The aim of this study is to derive "dose painting by numbers" prescriptions from retrospectively observed recurrence volumes in a patient group treated with conventional radiotherapy for head and neck squamous cell carcinoma. MATERIALS AND METHODS: The spatial relation between retrospectively observed recurrence volumes and pre-treatment standardized uptake values (SUV) from fluorodeoxyglucose positron emission tomography (FDG-PET) imaging was determined. Based on this information we derived SUV driven dose-response functions and used these to optimize ideal dose redistributions under the constraint of equal average dose to the tumor volumes as for a conventional treatment. The response functions were also implemented into a treatment planning system for realistic dose optimization. RESULTS: The calculated tumor control probabilities (TCP) increased between 0.1-14.6% by the ideal dose redistributions for all included patients, where patients with larger and more heterogeneous tumors got greater increases than smaller and more homogeneous tumors. CONCLUSIONS: Dose painting prescriptions can be derived from retrospectively observed recurrence volumes spatial relation to pre-treatment FDG-PET image data. The ideal dose redistributions could significantly increase the TCP for patients with large tumor volumes and large spread in SUV from FDG-PET. The results yield a basis for prospective studies to determine the clinical value for dose painting of head and neck squamous cell carcinomas.

Assessment of Whether Patients' Knowledge, Satisfaction, and Experience Regarding Their 18F-Fluoride PET/CT Examination Affects Image Quality.

UNLABELLED: The aim of this study was to investigate patients' previous knowledge, satisfaction, and experience regarding an (18)F-fluoride PET/CT examination and to explore whether any discomfort or pain during the examination was associated with reduced image quality. A further aim was to explore whether patients' health-related quality of life (HRQoL) was associated with their satisfaction and experience regarding the examination. METHODS: Between November 2011 and April 2013, 50 consecutive patients with a histopathologic diagnosis of prostate cancer who were scheduled for (18)F-fluoride PET/CT were asked to participate in the study. A questionnaire was used to collect information on the patients' previous knowledge and experience regarding the examination. Image quality was assessed according to an arbitrary scale. The European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ-C30) and the prostate cancer-specific module (QLQ-PR25) were used to assess HRQoL. RESULTS: Forty-six patients (96%) completed the questionnaire. Twenty-six percent did not at all know what a (18)F-fluoride PET/CT examination was. Most (52%-70%) were satisfied to a very high degree with the care provided by the nursing staff but were less satisfied with the information given before the examination. Image quality was similar between patients who were exhausted or claustrophobic during the examination and those who were not. No correlations between HRQoL and the patients' experience regarding (18)F-fluoride PET/CT were found. CONCLUSION: Most patients were satisfied with the care provided by the nursing staff, but there is still room for improvement, especially regarding the information provided before the examination. A long examination time may be strenuous for the patient, but there was no difference in image quality between patients who felt discomfort or pain during the examination and those who did not.