Image guided radiotherapy in curative treatment for prostate cancer. 5-year results from a randomized controlled trial (RIC-trial).

BACKGROUND: Between 2012 and 2015 we conducted a randomized controlled trial in prostate cancer patients comparing weekly 2-D portal imaging versus daily 3-D verification. AIM: To evaluate the clinical outcomes of image guided radiotherapy by presenting rectal and urinary side effects, health related quality of life and progression free survival after 5-years follow up of a randomized controlled trial. METHODS: We randomized 260 men with intermediate or high-risk prostate cancer to weekly 2-D portal imaging with 15 mm margin from CTV to PTV (Arm A) or daily 3-D cone-beam computer tomography with 7 mm margins (Arm B). Prescribed doses were 78 Gy/39 fractions. All patients received hormonal therapy. Primary end point was patient reported bowel symptoms and secondary outcomes were patient reported urinary symptoms, health- related quality of life and progression free survival. RESULTS: Of the 216 patients available for analyses at 5 years more than 90 % completed patient reported outcome measures. There were no significant differences between study arms for any single items nor scales evaluating bowel symptoms. There were also no differences in self-reported urinary symptoms nor in health-related quality of life. Symptom scores were low in both study arms. Progression free survival was similar in Arm B as compared to arm A (Hazard ratio 1.01; 95 % CI 0.57 to 1.97). CONCLUSIONS: Our results support that both 2-D weekly and 3-D daily image guided radiotherapy are safe and efficient treatments for PC and emphasize the need to evaluate technological progress in clinical trials with long follow-up.

Training, validation, and clinical implementation of a deep-learning segmentation model for radiotherapy of loco-regional breast cancer.

AIM: To train and validate a comprehensive deep-learning (DL) segmentation model for loco-regional breast cancer with the aim of clinical implementation. METHODS: DL segmentation models for 7 clinical target volumes (CTVs) and 11 organs at risk (OARs) were trained on 170 left-sided breast cancer cases from two radiotherapy centres in Norway. Another 30 patient cases were used for validation, which included the evaluation of Dice similarity coefficient and Hausdorff distance, qualitative scoring according to clinical usability, and relevant dosimetric parameters. The manual inter-observer variation (IOV) was also evaluated and served as a benchmark. Delineation of the target volumes followed the ESTRO guidelines. RESULTS: Based on the geometric similarity metrics, the model performed significantly better than IOV for most structures. Qualitatively, no or only minor corrections were required for 14% and 71% of the CTVs and 72% and 26% of the OARs, respectively. Major corrections were required for 15% of the CTVs and 2% of the OARs. The most frequent corrections occurred in the cranial and caudal parts of the structures. The dose coverage, based on D98 > 95%, was fulfilled for 100% and 89% of the breast and lymph node CTVs, respectively. No differences in OAR dose parameters were considered clinically relevant. The model was implemented in a commercial treatment planning system, which generates the structures in 1.5 min. CONCLUSION: Convincing results from the validation led to the decision of clinical implementation. The clinical use will be monitored regarding applicability, standardization and efficiency.

Dose to penile bulb is not associated with erectile dysfunction 18 months post radiotherapy: A secondary analysis of a randomized trial.

BACKGROUND: Erectile dysfunction is a common side effect of prostate cancer (PC) therapy. In this randomized study (The RIC-study) we used patient reported outcomes to evaluate sexual function 18 months after combined endocrine therapy and radical radiotherapy (RT) given with either wide or tight planning target volume (PTV) margins. We also analyzed the impact of radiation dose to penile bulb on sexual function. METHODS: The RIC-study included 257 men with intermediate and high-risk PC. All patients received 6 months of total androgen blockage started 3 months prior to randomization. In high-risk patients, an oral anti-androgen (Bicalutamide) was administered for an additional 2.5 years. Patients were randomized to receive 78 Gy in 39 fractions guided either by weekly offline orthogonal portal imaging or by daily online cone beam computed tomography image-guided RT. Sexual function was evaluated at 18 months after start of RT using the Questionnaire Umeå Fransson Widmark 1994. Ability to have an erection was assessed on an 11-point scale numerical rating scale (0 = no and 10 = very much) as the primary outcome. In addition, the association between penile bulb (PB) radiation dose and erectile function was analyzed. FINDINGS: Of 250 evaluable patients, 228 (mean age 71.8 years) returned the questionnaires. The patients reported a high degree of sexual related problems with mean scores to the primary outcome question (221 respondents) of 7.44 and 7.39 in the 2D weekly IGRT-arm and 3D daily IGRT-arm (p = 0.93) respectively. For four additional questions (scale 0-10) regarding sexual function resulted in mean scores >6.5 with no difference between study arms. The mean dose to PB was substantially larger in the 2D weekly IGRT-arm vs the 3D daily IGRT-arm (mean 59.8 Gy vs mean 35.1 Gy).We found no effect of mean PB-dose on the primary outcome adjusted for study-site, risk-group and age. When adjusting for serum-testosterone level at 18 months in addition, the effect of mean PB-dose remained insignificant. INTERPRETATION: IGRT protocol or PB dose had no effect on ED 18 months after RT in this study population. The low potency rates can partly be explained by the prolonged use of anti-androgen in high risk patients. Longer follow-up is needed to confirm the results from the RIC-study.

Radiotherapy for prostate cancer - Does daily image guidance with tighter margins improve patient reported outcomes compared to weekly orthogonal verified irradiation? Results from a randomized controlled trial.

BACKGROUND: Novel cancer drugs are subject to strict scientific evaluation of safety and efficacy and usually undergo a cost effectiveness analysis before approval for use in clinical practice. For new techniques in radiotherapy (RT) such as image-guided radiotherapy (IGRT), this is often not the case. We performed a randomized controlled trial to compare daily cone beam computer tomography (CBCT) IGRT with reduced planning target volume (PTV) margins vs weekly orthogonal portal imaging with conventional PTV margins. The primary aim of the study was to investigate the effect of two different image guidance techniques on patient reported outcome (PRO) using early side effects as proxy outcome of late rectal side effects in patients receiving curative RT for prostate cancer. METHODS: This open label, phase 3 trial conducted at two RT centers in Norway enrolled men aged 18 years or older with previously untreated histologically proven intermediate or high-risk adenocarcinoma of the prostate. Patients eligible for radical RT received it after 3 months of total androgen blockage and were randomly assigned to 78 Gy in 39 fractions guided either by weekly offline orthogonal portal imaging (15 mm margins to PTV) or by daily online CBCT IGRT (7 mm margins to PTV). Based on previous results indicating that acute rectal side effects are a valid proxy outcome for late rectal side effects, the primary outcome was acute rectal toxicity at end of RT as evaluated by rectal bother scale (five of the items from PRO's QUFW94). The RIC-trial is registered with ClinicalTrials.gov, number NCT01550237. FINDINGS: Between October 2012 and June 2015, 257 patients were randomly assigned to weekly offline portal imaging (n = 129) or daily online CBCT IGRT (n = 128). Out of 250 evaluable patients, 96% completed PROs at baseline and 97% at end of RT. Baseline analyses demonstrated balance between groups for baseline characteristics as well as for PROs. In general, patients reported a small degree of side effects at end of RT, and there was no difference between groups for primary outcome (rectal bother scale of QUFW94 1.871 vs 1.884, p = 0.804). In addition, there were no significant differences between groups for any other gastrointestinal or urinary symptom as reported by QUFW94. Health related quality of life analyses (EORTC QLQ 30) demonstrated no differences between groups. INTERPRETATION: In radical RT for prostate cancer, daily CBCT IGRT with reduced PTV margins demonstrated no advantage with respect to patient reported side effects at end of RT as compared to weekly orthogonal offline portal imaging with standard PTV margins.

Radiobiological treatment planning evaluation of inverse planning simulated annealing for cervical cancer high-dose-rate brachytherapy.

AIM: To compare five inverse treatment plans with one conventional manually-optimized plan for cervical cancer brachytherapy (BT) using radiobiological parameters combined with dosimetric and volumetric parameters. MATERIALS AND METHODS: Five inverse treatment plans were calculated using an inverse planning simulated annealing (IPSA) algorithm for each of four fractions for 12 cervical cancer patients treated with high-dose-rate (HDR) brachytherapy. The inverse treatment plans were compared to a manually-optimized plan used for the actual treatment of the patients. The comparison of the plans was performed with respect to the probability of cure without complication (P+). RESULTS: Overall, the manually optimized plan scored the best results; however, the probability of cure without complication is within an acceptable clinical range for all the plans. CONCLUSION: Although there are still considerable uncertainties in the radiobiological parameters, the radiobiological plan evaluation method presents itself as a potential complement to physical dosimetric methods.

Dosimetric evaluation of manually and inversely optimized treatment planning for high dose rate brachytherapy of cervical cancer.

BACKGROUND: To compare five inverse treatment planning methods with the conventional manually optimized planning approach for brachytherapy of cervical cancer with respect to dosimetric parameters. MATERIAL AND METHODS: Eighteen cervical cancer patients treated with magnetic resonance imaging (MRI)-guided high dose rate (HDR) brachytherapy were included in this study. Six plans were created for each of the 4 HDR brachytherapy fractions for each patient: 1 manually optimized and 5 inversely planned. Three of these were based on inverse planning simulated annealing (IPSA) with and without extra constraints on maximum doses of the target volume, and different constraints on doses to the organs at risk (OARs). In addition there were two plans based on dose to target surface points. The resulting dose-volume histograms were analyzed and compared from the dosimetric point of view by quantifying specific dosimetric parameters, such as clinical target volume (CTV) D90, CTV D100, conformal index (COIN), and D2cm3 for rectum, bladder and the sigmoid colon. RESULTS: Manual optimization led to a mean target coverage of 78.3% compared to 87.5%, 91.7% and 82.5% with the three IPSA approaches (p < 0.001). Similar COIN values for manual and inverse optimization were found. The manual optimization led to better results with respect to the dose to the OARs expressed as D2cm3. Overall, the best results were obtained with manual optimization and IPSA plans with volumetric constraints including maximum doses to the target volume. CONCLUSIONS: Dosimetric evaluation of manual and inverse optimization approaches is indicating the potential of IPSA for brachytherapy of cervical cancer. IPSA with constraints of maximum doses to the target volume is closer related to manual optimization than plans with constraints only to minimum dose to the target volume and maximum doses to OARs. IPSA plans with proper constraints performed better than those based on dose to target surface points and manually optimized plans.

Adaptive brachytherapy of cervical cancer, comparison of conventional point A and CT based individual treatment planning.

BACKGROUND: Locally advanced cervical cancer is commonly treated with external radiation therapy combined with local brachytherapy. The brachytherapy is traditionally given based on standard dose planning with prescription of dose to point A. Dosimetric aspects when changing from former standard treatment to individualized treatment plans based on computed tomography (CT) images are here investigated. MATERIAL AND METHODS: Brachytherapy data from 19 patients with a total of 72 individual treatment fractions were retrospectively reviewed. Standard library plans were analyzed with respect to doses to organs at risk (OARs), and the result was compared to corresponding delivered individualized plans. The theoretical potential of further optimization based on prescription to target volumes was investigated. The treatments were performed with a Fletcher applicator. RESULTS: For standard treatment planning, the tolerance dose limits were exceeded in the bladder, rectum and sigmoid in 26%, 4% and 15% of the plans, respectively. This was observed most often for the smallest target volumes. The individualized planning of the delivered treatment gave the possibility of controlling the dose to critical organs to below certain limits. The dose was still prescribed to point A. An increase in target dose coverage was achieved when additional individual optimization was performed, while still keeping the dose to the OARs below predefined limits. Relatively low average target coverage, especially for the largest volumes was however seen. CONCLUSION: The individualized delivered treatment plans ensured that doses to OARs were within acceptable limits. This was not the case in 42% of the corresponding standard plans. Further optimized treatment plans were found to give an overall better dose coverage. In lack of MR capacity, it may be favorable to use CT for planning due to possible protection of OARs. The CT based target volumes were, however, not equivalent to the volumes described in magnetic resonance imaging (MRI) based recommendations. Prescription and assessment of dose, when introducing such target volumes, should be evaluated and preferably compared to well known treatment regimens.

Effects of growth factors on growth and radiation sensitivity of the human breast cancer cell line T-47D.

Different growth factors are supposed to be involved in evolution of breast cancer. Radiation therapy is used in treatment of breast cancer patients, and the possible relationships between the influence of growth factors on cells and their radiation sensitivity are therefore of interest. Cell growth and radiation sensitivity of the human oestrogen and progesterone receptor positive cell line T-47D were investigated following exposure to the growth factors IGF-1, TGF-alpha and TGF-beta. Experiments were done with standard medium and in growth factor defined medium. Changes in cell cycle distribution were investigated by flow cytometry. The cell growth was significantly decreased by removal of growth factors in the culture medium, an effect which partly could be reversed by supplementation of growth factors. The growth factors decreased the cellular doubling time in standard medium, but to a smaller extent than seen in growth factor defined medium. The radiation sensitivity and plating efficiency were slightly affected by growth factor defined versus standard growth conditions. Additional growth factor exposure was able to some extent to change the radiation sensitivity, mainly by effects due to changes in repair of sublethal damage. Only minor changes were seen in phase distribution of these cells. Cellular growth was dependent on presence of different growth factors, and changes in growth factor conditions greatly influenced the cellular doubling time in vitro. Corresponding changes in radiation sensitivity were minor for doses relevant for radiation therapy.