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Simple Summary: A cohort of 123 women with stage I-II breast cancer enrolled in a prospective clinical trial of adjuvant radiotherapy who were followed for over 10 years. Year 2020 was associated with excess mortality. The number of deaths (n = 5) in that single year represented a third of all deaths (n = 15) in the full decade before. There was in that year a significant increase in lung-heart toxicity and a significant decline in lung-heart function as measured by left ventricular ejection fraction, forced vital capacity and carbon-monoxide diffusing capacity. We investigated lung-heart toxicity and mortality in 123 women with stage I-II breast cancer enrolled in 2007–2011 in a prospective trial of adjuvant radiotherapy (TomoBreast). We were concerned whether the COVID-19 pandemic affected the outcomes. All patients were analyzed as a single cohort. Lung-heart status was reverse-scored as freedom from adverse-events (fAE) on a 1–5 scale. Left ventricular ejection fraction (LVEF) and pulmonary function tests were untransformed. Statistical analyses applied least-square regression to calendar-year aggregated data. The significance of outliers was determined using the Dixon and the Grubbs corrected tests. At 12.0 years median follow-up, 103 patients remained alive; 10-years overall survival was 87.8%. In 2007–2019, 15 patients died, of whom 11 were cancer-related deaths. In 2020, five patients died, none of whom from cancer. fAE and lung-heart function declined gradually over a decade through 2019, but deteriorated markedly in 2020: fAE dipped significantly from 4.6–4.6 to 4.3–4.2; LVEF dipped to 58.4% versus the expected 60.3% (PDixon = 0.021, PGrubbs = 0.054); forced vital capacity dipped to 2.4 L vs. 2.6 L (PDixon = 0.043, PGrubbs = 0.181); carbon-monoxide diffusing capacity dipped to 12.6 mL/min/mmHg vs. 15.2 (PDixon = 0.008, PGrubbs = 0.006). In conclusion, excess non-cancer mortality was observed in 2020. Deaths in that year totaled one-third of the deaths in the previous decade, and revealed observable lung-heart deterioration. [ABSTRACT FROM AUTHOR]

Purpose: Previous studies in patients with breast cancer have shown acute radiation therapy-induced reductions of pulmonary diffusing capacity, essentially owing to lung volume restriction. We aimed to assess the long-term effect of 2 radiation therapy regimens, which differed in terms of radiation technique and dose fractionation, on lung function.Methods and Materials: From a randomized controlled trial comparing conventional 3-dimensional conformal radiation therapy (CR) and hypofractionated tomotherapy (TT), 84 patients with breast cancer (age at inclusion 54 ± 10 [standard deviation] years) could be assessed at baseline, after 3 months, and after 1, 2, 3, and 10 years. Measurements included forced vital capacity, total lung capacity (TLC), and diffusing capacity (TLco).Results: Radiation therapy-induced lung function changes over 10 years (Δ) were similar for both treatment arms, and in a patient subgroup with negligible history of respiratory disease or smoking (n = 57) these averaged: Δ forced vital capacity = -13 (± 9) percent predicted; ΔTLco = -14 (± 12) percent predicted; and ΔTLC = -11 (± 9) percent predicted. The only significant correlation was between V20 (lung volume exposed to dose exceeding 20 Gy) and ΔTLco (rho = -0.36; P = .007). In this subgroup, as well as in the entire patient cohort, the incurred pulmonary restriction in terms of TLC and TLco showed a greater decline at 3 months for CR versus TT. However, at 10 years, no significant difference could be detected between CR and TT (P = .9 for TLC and P = .2 for TLco in the entire patient cohort). Of the patients with normal TLC and TLco at baseline (ie, above lower limits of normal), respectively 94% and 96% were still normal 10 years later.Conclusions: In women with breast cancer, conventional 3-dimensional conformal radiation therapy and hypofractionated tomotherapy induce similar restrictive lung patterns during the course of a 10-year period, despite some treatment-dependent differences in the first 3 months. The large majority of women with normal lung function at baseline maintained a normal lung function status 10 years after radiation therapy, irrespective of treatment arm. [ABSTRACT FROM AUTHOR]

Purpose To optimize the local control of stereotactic body radiotherapy (SBRT) using the Vero-SBRT system and respiratory motion management in patients with oligometastatic cancer. Materials and methods Patients with five or less metastases were eligible. In metastases with significant motion, a fiducial was implanted for Vero dynamic tracking. For other metastases an internal target volume (ITV) was defined to encompass the respiratory tumor trajectory. A dose of 50 Gy in 10 fractions was prescribed on the 80% isodose line. Results We treated 87 metastases in 44 patients, with colorectal cancer as the most common primary origin (65.9%). Metastatic sites were mainly lung ( n = 62) and liver ( n = 17). Twenty-seven metastases were treated with dynamic tracking, the remaining 60 using the ITV-concept. Three patients (7%) experienced grade ⩾3 toxicity. After a median follow-up of 12 months, the overall one-year local control (LC) amounted to 89% (95% CI 77–95%), with corresponding values of 90% and 88% for the metastases irradiated with the ITV-approach and dynamic tracking, respectively. Median progression-free survival reached 6.5 months, one-year overall survival 95%. Conclusions SBRT with proper respiratory motion management resulted in a high LC and an acceptable toxicity profile in oligometastatic cancer patients. [ABSTRACT FROM AUTHOR]

Purpose A head-to-head comparison of two clinical correlation models with a focus on geometrical accuracy for internal tumor motion estimation during real-time tumor tracking (RTTT). Methods and materials Both the CyberKnife (CK) and the Vero systems perform RTTT with a correlation model that is able to describe hysteresis in the breathing motion. The CK dual-quadratic (DQ) model consists of two polynomial functions describing the trajectory of the tumor for inhale and exhale breathing motion, respectively. The Vero model is based on a two-dimensional (2D) function depending on position and speed of the external breathing signal to describe a closed-loop tumor trajectory. In this study, 20 s of internal motion data, using an 11 Hz (on average) full fluoroscopy (FF) sequence, was used for training of the CK and Vero models. Further, a subsampled set of 15 internal tumor positions (15p) equally spread over the different phases of the breathing motion was used for separate training of the CK DQ model. Also a linear model was trained using 15p and FF tumor motion data. Fifteen liver and lung cancer patients, treated on the Vero system with RTTT, were retrospectively evaluated comparing the CK FF, CK 15p and Vero FF models using an in-house developed simulator. The distance between estimated target position and the tumor position localized by X-ray imaging was measured in the beams-eye view (BEV) to calculate the 95th percentile BEV modeling errors (ME 95,BEV ). Additionally, the percentage of ME 95,BEV smaller than 5 mm (P 5mm ) was determined for all correlation models. Results In general, no significant difference ( p > 0.05, paired t -test) was found between the CK FF and Vero models. Based on patient-specific evaluation of the geometrical accuracy of the linear, CK DQ and Vero correlation models, no statistical necessity ( p > 0.05, two-way ANOVA) of including hysteresis in correlation models was proven, although during inhale breathing motion, the linear model resulted in a decreased P 5mm with 5–6% compared to both the DQ CK and Vero models. Conclusion Dual-quadratic CyberKnife and 2D Vero correlation models were interchangeable in terms of geometrical accuracy with the CK linear ME 95,BEV = 4.1 mm, CK dual-quadratic ME 95,BEV = 3.9 mm and Vero ME 95,BEV = 3.7 mm, when modeled with FF sequence. CK DQ modeling based on 15p acquired in 20 s may lead to problems for internal motion estimation. [ABSTRACT FROM AUTHOR]

Background and purpose For tumor tracking, a correlation model is used to estimate internal tumor position based on external surrogate motion. When patients experience an internal/external surrogate drift, an update of the correlation model is required to continue tumor tracking. In this study, the accuracy of the internal tumor position estimation for both the clinical available update at discrete points in time (rebuild) and an in-house developed non-clinical online update approach was investigated. Methods A dynamic phantom with superimposed baseline drifts and 14 SBRT patients, treated with real-time tumor tracking (RTTT) on the Vero system, were retrospectively simulated for three update scenarios, respectively no update, clinical rebuild and 0.5 Hz automated online update of the correlation model. By comparing the target positions based on 0.5 Hz verification X-ray images with the estimated internal tumor positions regarding all three update scenarios, 95th percentile modeling errors (ME 95 ), incidences of full geometrical coverage of the CTV by a 5 mm extended PTV ( P 5mm ) and population-based PTV margins were calculated. Further, the treatment time reduction was estimated when switching from the clinical rebuild approach to the online correlation model update. Results For dynamic phantom motion with baseline drifts up to 0.4 mm/min, a 0.5 Hz intra-fraction update showed a similar accuracy in terms of ME 95 and P 5mm compared to clinical rebuild. For SBRT patients treated on Vero with RTTT, accuracy was improved by 0.5 Hz online update compared to the clinical rebuild protocol, yielding smaller PTV margins (from 3.2 mm to 2.7 mm), reduced ME 95,3D (from 4.1 mm to 3.4 mm) and an increased 5th percentile P 5mm (from 90.7% to 96.1%) for the entire patient group. Further, 80% of treatment sessions were reduced in time with on average 5.5 ± 4.1 (1 SD) min. Conclusion With a fast (0.5 Hz) automated online update of the correlation model, an efficient RTTT workflow with improved geometrical accuracy was obtained. [ABSTRACT FROM AUTHOR]

Purpose To report on the first clinical application of a real-time tumor tracking (RTTT) solution based on the Vero SBRT gimbaled linac system for treatment of moving tumors. Methods and materials A first group of 10 SBRT patients diagnosed with NSCLC or oligometastatic disease in lung or liver was treated with the RTTT technique. The PTV volumes and OAR exposure were benchmarked against the widely used ITV approach. Based on data acquired during execution of RTTT treatments, a first review was performed of the process. Results The 35% PTV volume reduction with RTTT of the studied single lesions SBRT irradiations of small target volumes is expected to result in a small (<1%) reduction of lung or liver NTCP. A GTV–PTV margin of 5.0 mm was applied for treatment planning of RTTT. From patient data on residual geometric uncertainties, a CTV–PTV margin of 3.2 mm was calculated. Reduction of the GTV–PTV margin below 5.0 mm without better understanding of biological definition of tumor boundaries was discouraged. Total treatment times were reduced to 34.4 min on average. Conclusion A considerable PTV volume reduction was achieved applying RTTT and time efficiency for respiratory correlated SBRT was reestablished with Vero RTTT. [ABSTRACT FROM AUTHOR]

Background: The α/β ratio for prostate cancer is postulated being in the range of 0.8 to 2.2 Gy, giving rise to the hypothesis that there may be a therapeutic advantage to hypofractionation. To do so, we carried out a randomized trial comparing hypofractionated and conventionally fractionated image-guided intensity modulated radiotherapy (IG-IMRT) in high-risk prostate cancer. Here, we report on acute toxicity and quality of life (QOL) for the first 124 randomized patients.Methods: The trial compares 76 Gy in 38 fractions (5 fractions/week) (Arm 1) to 63 Gy in 20 fractions (4 fractions/week) (Arm 2) (IG-IMRT). Prophylactic pelvic lymph node irradiation with 46 Gy in 23 fractions sequentially (Arm 1) and 44 Gy in 20 fractions simultaneously (Arm 2) was applied. All patients had long term androgen deprivation therapy (ADT) started before RT. Both physician-rated acute toxicity and patient-reported QOL using EPIC questionnaire are described.Results: There were no differences in overall maximum acute gastrointestinal (GI) or genitourinary (GU) toxicity. Compared to conventional fractionation (Arm 1), GI and GU toxicity both developed significantly earlier but also disappeared earlier in the Arm 2, reaching significant differences from Arm 1 at week 8 and 9. In multivariate analyses, only parameter shown to be related to increased acute Grade ≥1 GU toxicity was the study Arm 2 (p = 0.049). There were no statistically significant differences of mean EPIC scores in any domain and sub-scales. The clinically relevant decrease (CRD) in EPIC urinary domain was significantly higher in Arm 2 at month 1 with a faster recovery at month 3 as compared to Arm 1.Conclusions: Hypofractionation at 3.15 Gy per fraction to 63 Gy within 5 weeks was well tolerated. The GI and GU physician-rated acute toxicity both developed earlier but recovered faster using hypofractionation. There was a correlation between acute toxicity and bowel and urinary QOL outcomes. Longer follow-up is needed to determine the significance of these associations with late toxicity. [ABSTRACT FROM AUTHOR]

Abstract: Background and purpose: Investigation of the use of TomoTherapy and TomoDirect versus conventional radiotherapy for the treatment of post-operative breast carcinoma. This study concentrates on the evaluation of the planning protocol for the TomoTherapy and TomoDirect TPS, dose verification and the implementation of in vivo dosimetry. Materials and methods: Eight patients with different breast cancer indications (left/right tumor, axillary nodes involvement (N+)/no nodes (N0), tumorectomy/mastectomy) were enrolled. TomoTherapy, TomoDirect and conventional plans were generated for prone and supine positions leading to six or seven plans per patient. Dose prescription was 42Gy in 15 fractions over 3weeks. Dose verification of a TomoTherapy plan is performed using TLDs and EDR2 film inside a home-made wax breast phantom fixed on a rando-alderson phantom. In vivo dosimetry was performed with TLDs. Results: It is possible to create clinically acceptable plans with TomoTherapy and TomoDirect. TLD calibration protocol with a water equivalent phantom is accurate. TLD verification with the phantom shows measured over calculated ratios within 2.2% (PTV). An overresponse of the TLDs was observed in the low dose regions (<0.1Gy). The film measurements show good agreement for high and low dose regions inside the phantom. A sharp gradient can be created to the thoracic wall. In vivo dosimetry with TLDs was clinically feasible. Conclusions: The TomoTherapy and TomoDirect modalities can deliver dose distributions which the radiotherapist judges to be equal to or better than conventional treatment of breast carcinoma according to the organ to be protected. [Copyright &y& Elsevier]

Purpose: Preoperative (chemo)radiotherapy is considered to be standard of care in locally advanced rectal cancer, but is associated with significant small-bowel toxicity. The aim of this study was to explore to what extent helical tomotherapy and daily megavolt (MV) CT imaging may reduce the irradiated volume of small bowel. Methods and Materials: A 3D-conformal radiotherapy (3D-CRT) plan with CTV-PTV margins adjusted for laser-skin marks (15, 15, and 10 mm for X, Y, and Z directions, respectively) was compared with helical tomotherapy (IMRT) using the same CTV-PTV margins, and to helical tomotherapy with margins adapted to daily MV-CT imaging (IMRT/IGRT; 8, 11, 7, and 10 mm for X, Yant, Ypost and Z resp.) for 11 consecutive patients. The planning goals were to prescribe 43.7 Gy to 95% of the PTV, while minimizing the volume of small bowel receiving more than 15 Gy (V15 SB). Results: The mean PTV was reduced from 1857.4 ± 256.6 cc to 1462.0 ± 222.3 cc, when the CTV-PTV margins were adapted from laser-skin marks to daily MV-CT imaging (p < 0.01). The V15 SB decreased from 160.7 ± 102.9 cc to 110.9 ± 74.0 cc with IMRT and to 81.4 ± 53.9 cc with IMRT/IGRT (p < 0.01). The normal tissue complication probability (NTCP) for developing Grade 2+ diarrhea was reduced from 39.5% to 26.5% with IMRT and to 18.0% with IMRT/IGRT (p < 0.01). Conclusion: The combination of helical tomotherapy and daily MV-CT imaging significantly decreases the irradiated volume of small bowel and its NTCP. [Copyright &y& Elsevier]

Purpose: To explore the efficacy and toxicity profile of helical tomotherapy in the preoperative treatment of patients with rectal cancer. Patients and Methods: Twenty-four patients with T3/T4 rectal cancer were included in this nonrandomized noncontrolled study. A dose of 46 Gy in daily fractions of 2 Gy was delivered to the presacral space and perineum if an abdominoperineal resection was deemed necessary. This dose was increased by a simultaneous integrated boost to 55.2 Gy when the circumferential resection margin was less than 2 mm on magnetic resonance imaging. Acute toxicity was evaluated weekly. Metabolic response was determined in the fifth week after the end of radiotherapy by means of fluorodeoxyglucose-positron emission tomography scan. A metabolic response was defined as a decrease in maximal standardized uptake value of more than 36%. Results: The mean volume of small bowel receiving more than 15 Gy and mean bladder dose were 227 ml and 20.8 Gy in the no-boost group and 141 ml and 21.5 Gy in the boost group. Only 1 patient developed Grade 3 enteritis. No other Grade 3 or 4 toxicities were observed. Two patients developed an anastomotic leak within 30 days after surgery. The metabolic response rate was 45% in the no-boost group compared with 77% in the boost group. All except 1 patient underwent an R0 resection. Conclusions: Helical tomotherapy may decrease gastrointestinal toxicity in the preoperative radiotherapy of patients with rectal cancer. A simultaneous integrated radiation boost seems to result in a high metabolic response rate without excessive toxicity. [Copyright &y& Elsevier]

Abstract: Background and purpose: The purpose of this study is to assess retrospectively secondary patient motion induced by 6D patient setup correction. Materials and methods: For 104 patients, treated with Novalis®, 6D setup correction prior to treatment was performed by ExacTrac5.0/NovalisBody® in combination with the Robotic Tilt Module™ mounted underneath the Exact Couch® top. This 6D correction might induce additional setup errors due to patient reaction against the rotations. To evaluate induced secondary motion, the 6D setup correction is verified and evaluated with respect to the tolerance limits. Results: The majority of measured secondary motions are found within the tolerance limits. Detected secondary motions are mostly found in longitudinal shifts and lateral rotations, and mainly found in only 1 dimension during the same verification. The verifications indicate that the patient population can be divided into a group that hardly moves and a group that moves throughout all 6D setup corrections. The patient’s behavior can be predicted by the evaluation of the first five fractions as none of the patients demonstrate a learning curve during the treatment. Conclusions: 6D setup correction does not induce secondary motion for the majority of the patients and can therefore be applied for all treatment indications. [Copyright &y& Elsevier]

Background: Modeling the relationship between age and mortality for breast cancer patients may have important prognostic and therapeutic implications. Methods: Data from 9 registries of the Surveillance, Epidemiology, and End Results Program (SEER) of the United States were used. This study employed proportional hazards to model mortality in women with T1-2 breast cancers. The residuals of the model were used to examine the effect of age on mortality. This procedure was applied to node-negative (N0) and node-positive (N+) patients. All causes mortality and breast cancer specific mortality were evaluated. Results: The relationship between age and mortality is biphasic. For both N0 and N+ patients among the T1-2 group, the analysis suggested two age components. One component is linear and corresponds to a natural increase of mortality with each year of age. The other component is quasiquadratic and is centered around age 50. This component contributes to an increased risk of mortality as age increases beyond 50. It suggests a hormonally related process: the farther from menopause in either direction, the more prognosis is adversely influenced by the quasi-quadratic component. There is a complex relationship between hormone receptor status and other prognostic factors, like age. Conclusion: The present analysis confirms the findings of many epidemiological and clinical trials that the relationship between age and mortality is biphasic. Compared with older patients, young women experience an abnormally high risk of death. Among elderly patients, the risk of death from breast cancer does not decrease with increasing age. These facts are important in the discussion of options for adjuvant treatment with breast cancer patients. [ABSTRACT FROM AUTHOR]

Background and purpose: Recent and large trials of adjuvant radiotherapy for breast cancer have shown an overall survival benefit in favour of radiotherapy. However, with longer follow-up the late lethal toxicity of radiotherapy might reduce the overall survival benefits. In this paper we investigate more deeply this hypothesis.Patients and methods: Overviews of the Early Breast Cancer Trialists’ Collaborative Group provide uniform data on more than 50 unconfounded trials on adjuvant radiotherapy for early breast cancer. These data were published at regular intervals: 1987, 1990, 1995, and 2000. The odds ratios (death of any cause) were borrowed to compare the benefits of adjuvant radiotherapy between the early publications and the more mature data of the same trials. Statistical significance is calculated following logrank statistics.The comparison of odds ratios (radiotherapy versus surgery only) was done for the whole group of trials, for the older (patients accrual started in 1970 or earlier) and the more recent trials (patient accrual started after 1970), and for the large (≥600 patients) and the small trials (<600 patients).Results: Comparison of early with more mature data reveals that the odds ratios for overall survival remain stable as data become more mature. The analyses of trials’ age and trials’ size, as predictors of overall survival benefit, indicate that these factors become statistically more significant with increasing maturity of the trials.In the large recent trials an overall survival benefit due to radiotherapy (odds reduction) of 10, 10, 12 and 13%, respectively P<0.3, 0.2, 0.005 and 0.00005 is found in the successive publications. The difference in survival benefit of radiotherapy between the group of large recent trials and group of old or small trials becomes more significant at the successive updates: 10 via 9% and 12 to 13% (odds reductions), with respectively P=0.2, 0.2, 0.004 and 0.00005.Conclusions: These results support the hypothesis that the survival benefit in the recent trials is an inherent characteristic of the recent and large trials, not influenced by follow-up duration. The effect of radiotherapy as performed in the large recent trials is clinically and statistically significantly different from the effect of radiotherapy in the old or small trials. As a consequence, predictions based on pooled data including old radiotherapy trials should not be extrapolated to modern radiotherapy. [Copyright &y& Elsevier]

Abstract: We evaluated setup accuracy of NovalisBody stereoscopic X-ray positioning with automated correction for rotational errors with the Robotics Tilt Module in patients treated with conformal arc radiotherapy for prostate cancer. The correction of rotational errors was shown to reduce random and systematic errors in all directions. (NovalisBody™ and Robotics Tilt Module™ are products of BrainLAB A.G., Heimstetten, Germany). [Copyright &y& Elsevier]

Purpose: To evaluate early side effects in prostate cancer patients treated with image-guided conformation arc therapy (IGCAT) using a minimultileaf collimator and daily X-ray–assisted patient positioning. Methods and Materials: Between May 2000 and November 2004, 238 cT1-T3N0M0 tumors were treated with doses of 70 or 78 Gy. Seventy patients also received neoadjuvant or concurrent hormonal treatment. Median follow-up is 18 months (range, 4–55 months). The Radiation Therapy Oncology Group and the European Organization for Research and Treatment of Cancer toxicity scoring system was used to evaluate early side effects. Results: Grade 1, 2, and >2 acute side effects occurred in 19, 6, and 0% (gastrointestinal) and 37, 16, and 0% (genitourinary) of the patients. No relation between radiation dose and early side effects was observed. Conclusion: Patients treated with image-guided conformation arc therapy experience a low rate of Grade 2 (i.e., requiring medication) early side effects. The definitive evaluation of late side effects and biochemical control requires further follow-up. [Copyright &y& Elsevier]

Background: We conducted a randomized, prospective trial comparing external irradiation with external irradiation plus goserelin (an agonist analogue of gonadotropin-releasing hormone that reduces testosterone secretion) in patients with locally advanced prostate cancer. Methods: From 1987 to 1995, 415 patients with locally advanced prostate cancer were randomly assigned to receive radiotherapy alone or radiotherapy plus immediate treatment with goserelin. The patients had a median age of 71 years (range, 51 to 80). Patients in both groups received 50 Gy of radiation to the pelvis over a period of five weeks and an additional 20 Gy over an additional two weeks as a prostatic boost. Patients in the combined-treatment group received 3.6 mg of goserelin (Zoladex) subcutaneously every four weeks starting on the first day of irradiation and continuing for three years; those patients also received cyproterone acetate (150 mg orally per day) during the first month of treatment to inhibit the transient rise in testosterone associated with the administration of goserelin. Results: Data were available for analysis on 401 patients. The median follow-up was 45 months. Kaplan–Meier estimates of overall survival at five years were 79 percent (95 percent confidence interval, 72 to 86 percent) in the combined-treatment group and 62 percent (95 percent confidence interval, 52 to 72 percent) in the radiotherapy group (P = 0.001). The proportion of surviving patients who were free of disease at five years was 85 percent (95 percent confidence interval, 78 to 92 percent) in the combined-treatment group and 48 percent (95 percent confidence interval, 38 to 58 percent) in the radiotherapy group (P<0.001). Conclusions: Adjuvant treatment with goserelin, when started simultaneously with external irradiation, improves local control and survival in patients with locally advanced prostate cancer. (N Engl J Med 1997;337:295-300.) [ABSTRACT FROM AUTHOR]