The Palliative Radiotherapy and Inflammation Study (PRAIS) - protocol for a longitudinal observational multicenter study on patients with cancer induced bone pain

BackgroundRadiation therapy (RT) results in pain relief for about 6 of 10 patients with cancer induced bone pain (CIBP) caused by bone metastases. The high number of non-responders, the long median time from RT to pain response and the risk of adverse effects, makes it important to determine predictors of treatment response. Clinical features such as cancer type, performance status and pain intensity, and biomarkers for osteoclast activity are proposed as predictors of response to RT. However, results are inconsistent and there is a need for better predictors of RT response. A similar argument can be stated for the development of cachexia; there are currently no predictors that can identify patients who will develop cachexia later in the cancer disease trajectory. Experimental and preclinical studies show that pain, depression and cachexia are related to inflammation. However, it is not known if inflammatory biomarkers can predict CIBP, depression or development of cachexia.MethodsThis multicenter, multinational longitudinal observational study will include 600 adult patients receiving RT for CIBP. Demographic data, clinical variables, osteoclast and inflammatory biomarkers will be assessed before start of RT, and 3, 8, 16, 24 and 52 weeks after last course of RT. The primary aim of the study is to identify potential predictors for pain relief from RT. Secondary aims are to explore potential predictors for development of cachexia, the longitudinal relationship between pain intensity and depression, and if inflammatory biomarkers are associated with changes in pain intensity, cachexia and depression during one-year follow up.DiscussionThe immediate clinical implication of the PRAIS study is to identify potential predictive factors for a RT response on CIBP, and thereby reduce non-efficacious RT. Patient benefits are fewer hospital visits, reduced risk of adverse effects and more individualized pain treatment. The long-term clinical implication of the PRAIS study is to improve the knowledge about inflammation in relation to CIBP, cachexia and depression and potentially identify associations and mechanisms that can be targeted for treatment.Trial registrationClinicalTrials.gov NCT02107664, date of registration April 8, 2014 (retrospectively registered).Trial sponsorThe European Palliative Care Research Centre (PRC), Department of Clinical and Molecular Medicine, NTNU, Faculty of medicine and Health Sciences, Trondheim, N-7491, Norway

Development of a deep inspiration breath-hold system for radiotherapy utilizing a laser distance measurer

Deep inspiration breath‐hold (DIBH) is a technique for treating left‐sided breast cancer (LSBC). In modern radiotherapy, one of the main aims is to exclude the heart from the beam aperture with an individualized beam design for LSBC. A deep inhalation will raise the chest wall while the volume of the lungs increase, this will again push the heart away from the breast to be treated. There are a few commercial DIBH systems, both invasive and noninvasive. We present an alternative noninvasive DIBH system based upon an industrial laser distance measurer. This system can be installed in a treatment room at a low cost; it is very easy to use and requires limited amount of training for the personnel and the patient. The system is capable of measuring the position of the chest wall with high frequency and precision in real time. The patient views its breathing curve through video glasses, and gets instructions during the treatment session. The system is well tolerated by test subjects due to its noninvasiveness

Monitoring deep inspiration breath hold for left-sided localized breast cancer radiotherapy with an in-house developed laser distance meter system

Deep inspiration breath hold (DIBH) in left‐sided breast cancer radiotherapy is a technique to reduce cardiac and pulmonary doses while maintaining target coverage. This study aims at evaluating an in‐house developed DIBH system. Free‐breathing (FB) and DIBH plans were generated for 22 left‐sided localized breast cancer patients who had radiation therapy (RT) after breast‐conserving surgery. All patients were treated utilizing an in‐house laser distance measuring system. 50 Gy was prescribed, and parameters of interest were target coverage, left anterior descending coronary artery, (LAD) and heart doses. Portal images were acquired and the reproducibility and stability of DIBH treatment were compared to FB. The comparing result shows there is a significant reduction in all LAD and heart dose statistics for DIBH compared to FB plans without compromising the target coverage. The maximum LAD dose was reduced from 43.7 Gy to 29.0 Gy and the volume of the heart receiving >25 Gy was reduced from 3.3% to 1.0% using the in‐house system, both statistically significant. The in‐house system gave a reproducible and stable DIBH treatment where the systematic error ∑, and random error σ, were less than 2.2 mm in all directions, but were not significantly better than at FB. The system was well tolerated and all patients completed their treatment sessions with DIBH

Robustness of VMAT and 3DCRT plans toward setup errors in radiation therapy of locally advanced left-sided breast cancer with DIBH

Purpose The aim of our study was to evaluate and compare the robustness of treatment plans produced using the volumetric modulated arc-therapy (VMAT) and the standard three-dimensional conformal radiotherapy (3DCRT) techniques by estimating perturbed doses induced by localization offsets for deep inspiration breath-hold (DIBH) in locally advanced breast cancer radiation therapy. Methods Twenty patients with left breast carcinoma requiring radiation therapy were analysed in this planning study. Robust VMAT plans regarding minimum CTV doses and standard 3DCRT plans were produced, and perturbed doses were calculated in accordance with localization values from the weekly offline imaging protocol. Offsets from 5 weeks were summed to a perturbed overall treatment plan. Dose criteria for evaluation were coverage and homogeneity of the target, as well as doses to organs at risk. Results VMAT plans resulted in significantly better target coverage compared to 3DCRT, as well as lowered doses to heart and left anterior descending artery, while the perturbed doses were less variable for VMAT than 3DCRT plans. Homogeneity was significantly improved in VMAT plans. The statistical analysis taking all organs into account found that VMAT plans were more robust than 3DCRT to localization offsets (p = .001). The overall mean setup-deviation for the DIBH-patients was less than 2 mm in all directions. Conclusions VMAT plans were more robust on average than conventional 3DCRT plans for DIBH when localization errors were taken into consideration. The combination of robust VMAT planning and DIBH generally improves the homogeneity and target doses

Rectal volume variations and estimated rectal dose during 8 weeks of image-guided radical 3D conformal external beam radiotherapy for prostate cancer

The introduction of modern image-guided radiotherapy (IGRT) has given new insight regarding organ motion in radiotherapy (RT), both in general and in treatment for prostate cancer (PC) [1]. IGRT with daily Cone-beam computed tomography (CBCT) is now considered as part of standard external beam radiotherapy (EBRT) in an increasingly number of cancer patients. Interfraction displacement of the prostate gland during RT is often observed in response to the variations in rectum and bladder filling, and can range from 0 to 20 mm [1], [2], [3], [4], [5], [6], [7]. Accordingly, rectal volume variation (RVV) during RT may increase the risk of biochemical and local failure [8], [9], [10], [11], [12], [13]. Moreover, the rectal volume (RV) receiving ≥ 60 Gy is associated with increased risk of grade ≥ 2 late rectal toxicity or rectal bleeding and can be a limiting factor for dose escalation [14], [15], [16], [17], [18], [19]. Some small sample-size studies have reported variable rectal dose distribution due to RVV during RT [2], [20], [21]. In order to minimize RVV, some authors advocate rectum emptying using an enema eventually combined with laxatives and dietary measures at the time of the initial planning computed tomography (CT) and during the treatment period, especially if daily IGRT is not applied [22], [23]. Consequently, studies on radiation dose distribution and variations in Organs at Risk during the total treatment period are essential to gain knowledge about the accuracy of dose delivery to the tumor and the surrounding normal tissue. The aim of this study was to answer the following research question: Are rectal volumes reduced or increased, and are rectal doses consequently reduced or increased during eight weeks of radical 3D conformal CBCT-IGRT in patients treated for PC

Intrafractional baseline drift during free breathing breast cancer radiation therapy

<p><b>Background:</b> Intrafraction motion in breast cancer radiation therapy (BCRT) has not yet been thoroughly described in the literature. It has been observed that baseline drift occurs as part of the intrafraction motion. This study aims to measure baseline drift and its incidence in free-breathing BCRT patients using an in-house developed laser system for tracking the position of the sternum.</p> <p><b>Materials and methods:</b> Baseline drift was monitored in 20 right-sided breast cancer patients receiving free breathing 3D-conformal RT by using an in-house developed laser system which measures one-dimensional distance in the AP direction. A total of 357 patient respiratory traces from treatment sessions were logged and analysed. Baseline drift was compared to patient positioning error measured from in-field portal imaging.</p> <p><b>Results:</b> The mean overall baseline drift at end of treatment sessions was −1.3 mm for the patient population. Relatively small baseline drift was observed during the first fraction; however it was clearly detected already at the second fraction. Over 90% of the baseline drift occurs during the first 3 min of each treatment session. The baseline drift rate for the population was −0.5 ± 0.2 mm/min in the posterior direction the first minute after localization. Only 4% of the treatment sessions had a 5 mm or larger baseline drift at 5 min, all towards the posterior direction. Mean baseline drift in the posterior direction in free breathing BCRT was observed in 18 of 20 patients over all treatment sessions.</p> <p><b>Conclusions:</b> This study shows that there is a substantial baseline drift in free breathing BCRT patients. No clear baseline drift was observed during the first treatment session; however, baseline drift was markedly present at the rest of the sessions. Intrafraction motion due to baseline drift should be accounted for in margin calculations.</p

Second cancers in radically treated Norwegian prostate cancer patients

Introduction: The aim of this registry-based cohort study was to estimate second cancer (SC) risk following radical prostate cancer (PC) treatment and evaluate if the risk was influenced by radiotherapy. Materials and methods: We collected data from the Cancer Registry of Norway on all patients with PC as first cancer diagnosis, from 1997 to 2014. Standardized incidence ratios (SIRs) for SC were calculated by comparing our cohort to the standard male population. Subdistribution hazard ratios were estimated in treatment groups, using patients treated with radical prostatectomy (RP) as reference. Results: We analyzed 24,592 radically treated PC patients. The median follow-up was 7.75 and 6.25 years in the external beam radiotherapy (EBRT) and RP-groups, respectively. SIR for SC was indifferent from the reference population in 24,592 radically treated patients, higher following EBRT, SIR 1.12 (1.07–1.17), and lower following RP, SIR 0.93 (0.87–0.99). EBRT treated patients had higher rectal and urinary bladder cancer incidences, SIR 1.38 (1.16–1.64) and 1.49 (1.31–1.69), respectively. The EBRT patients and the patients treated with radiation after RP (RT after RP) had 38 and 27% higher risk of any SC. We found higher risk of bladder cancer for all treatment groups as compared to RP patients. Only EBRT treated patients showed higher risk of rectal and lung cancer. Discussion/conclusions: In our study, we found that PC patients treated with EBRT had an increased incidence of SC compared to the general population. Patients treated with EBRT and RT after RP were found to have increased risk of SCs, using RP patients as reference. The risks of rectal and urinary bladder cancer in patients receiving EBRT were higher compared to both the general population and to patients treated with radical prostatectomy. The risk of SC should be taken into account when discussing treatment for patients and designing follow-up

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