Overall survival after reirradiation of spinal metastases – independent validation of predictive models

Background: It is unknown if survival prediction tools (SPTs) sufficiently predict survival in patients who undergo palliative reirradiation of spinal metastases. We therefore set out to clarify if SPTs can predict survival in this patient population. Methods: We retrospectively analyzed spinal reirradiations performed (n = 58, 52 patients, 44 included in analysis). SPTs for patients with spinal metastases were identified and compared to a general palliative score and to a dedicated SPT to estimate prognosis in palliative reirradiation independent of site (SPT-Nieder). Results: Consistently in all tests, SPT-Nieder showed best predictive performance as compared to other tools. Items associated with survival were general condition (KPS), liver metastases, and steroid use. Other factors like primary tumor site, pleural effusion, and bone metastases were not correlated with survival. We adapted an own score to the data which performed comparable to SPT-Nieder but avoids the pleural effusion item. Both scores showed good performance in identifying long-term survivors with late recurrences. Conclusions: Survival prediction in case of spinal reirradiation is possible with sufficient predictive separation. Applying SPTs in case of reirradiation helps to identify patients with good life expectancy who might benefit from dose escalation or longer treatment courses

Comparison of breast simultaneous integrated boost (SIB) radiotherapy techniques

Purpose: To dosimetrically evaluate different breast SIB techniques with respect to target coverage and organs at risk (OARs) doses. Methods: Four IMRT techniques were compared in 12 patients. Three techniques employ tangential whole breast irradiation with either two coplanar fields (T-2F), or four non-coplanar fields (T-NC), or one Volumetric Modulated Arc Therapy (T-VMAT) for the boost volume. The fourth technique is a fully-modulated VMAT technique (f-VMAT). Dosimetric parameters were compared for the boost and breast target volumes as well as OARs. Delivery efficiency was analysed based on number of monitor units (MUs) and estimated delivery time. Results: T-VMAT and f-VMAT ranked highest with respect to integral assessment of boost and breast treatment quality measures. T-VMAT significantly outperformed f-VMAT with respect to ipsi-lateral lung and left-sided patients’ heart volumes ≥ 5 Gy (35 % ± 5 % vs. 52 % ± 6 % and 11 % ± 5 % vs. 22 % ± 6 %, respectively). f-VMAT significantly outperformed T-VMAT with respect to ipsi-lateral lung volume ≥ 20 Gy (13 % ± 2 % vs. 15 % ± 3 %) and heart volume ≥ 30 Gy in left breast cancer (0 % ± 0 % vs. 1 % ± 1 %). T-VMAT and f-VMAT needed 442 ± 58 and 1016 ± 152 MUs, respectively. Conclusions: The hybrid T-VMAT is considered the technique of choice due to its balance of quality, efficiency and dose to OARs

Knowledge-based radiation therapy (KBRT) treatment planning versus planning by experts: validation of a KBRT algorithm for prostate cancer treatment planning

Background: A knowledge-based radiation therapy (KBRT) treatment planning algorithm was recently developed. The purpose of this work is to investigate how plans that are generated with the objective KBRT approach compare to those that rely on the judgment of the experienced planner. Methods: Thirty volumetric modulated arc therapy plans were randomly selected from a database of prostate plans that were generated by experienced planners (expert plans). The anatomical data (CT scan and delineation of organs) of these patients and the KBRT algorithm were given to a novice with no prior treatment planning experience. The inexperienced planner used the knowledge-based algorithm to predict the dose that the OARs receive based on their proximity to the treated volume. The population-based OAR constraints were changed to the predicted doses. A KBRT plan was subsequently generated. The KBRT and expert plans were compared for the achieved target coverage and OAR sparing. The target coverages were compared using the Uniformity Index (UI), while 5 dose-volume points (D10, D30, D50, D70 and D90) were used to compare the OARs (bladder and rectum) doses. Wilcoxon matched-pairs signed rank test was used to check for significant differences (p < 0.05) between both datasets. Results: The KBRT and expert plans achieved mean UI values of 1.10 ± 0.03 and 1.10 ± 0.04, respectively. The Wilcoxon test showed no statistically significant difference between both results. The D90, D70, D50, D30 and D10 values of the two planning strategies, and the Wilcoxon test results suggests that the KBRT plans achieved a statistically significant lower bladder dose (at D30), while the expert plans achieved a statistically significant lower rectal dose (at D10 and D30). Conclusions: The results of this study show that the KBRT treatment planning approach is a promising method to objectively incorporate patient anatomical variations in radiotherapy treatment planning

O6-methylguanine-DNA methyltransferase (MGMT) Promoter methylation is a rare event in soft tissue sarcoma

BACKGROUND: Gene silencing of O6-methylguanine–DNA methyltransferase (MGMT) by promoter methylation improves the outcome of glioblastoma patients after combined therapy of alkylating chemotherapeutic agents and radiation. The purpose of this study was to assess the frequency of MGMT promoter methylation in soft tissue sarcoma to identify patients eligible for alkylating agent chemotherapy such as temozolomide. FINDINGS: Paraffin tumor blocks of 75 patients with representative STS subtypes were evaluated. The methylation status of the MGMT promoter was assessed by methylation-specific polymerase-chain-reaction analysis (PCR). Furthermore, immunohistochemistry was applied to verify expression of MGMT. MGMT gene silencing was assumed if MGMT promoter methylation was present and the fraction of tumor cells expressing MGMT was 20% or less. Methylation specific PCR detected methylated MGMT promoter in 10/75 cases. Immunohistochemical staining of nuclear MGMT was negative in 15/75 cases. 6/75 tumor samples showed MGMT promoter methylation and negative immunohistochemical nuclear staining of MGMT. In none of the tested STS subtypes we found a fraction of tumors with MGMT silencing exceeding 22%. CONCLUSION: MGMT gene silencing is a rare event in soft tissue sarcoma and cannot be recommended as a selection criterion for the therapy of STS patients with alkylating agents such as temozolomide

Comparison of breast sequential and simultaneous integrated boost using the biologically effective dose volume histogram (BEDVH)

Purpose: A method is presented to radiobiologically compare sequential (SEQ) and simultaneously integrated boost (SIB) breast radiotherapy. Methods: The method is based on identically prescribed biologically effective dose (iso-BED) which was achieved by different prescribed doses due to different fractionation schemes. It is performed by converting the calculated three-dimensional dose distribution to the corresponding BED distribution taking into consideration the different number of fractions for generic α/β ratios. A cumulative BED volume histogram (BEDVH) is then derived from the BED distribution and is compared for the two delivery schemes. Ten breast cancer patients (4 right-sided and 6 left-sided) were investigated. Two tangential intensity modulated whole breast beams with two other oblique (with different gantry angles) beams for the boost volume were used. The boost and the breast target volumes with either α/β = 10 or 3 Gy, and ipsi-lateral and contra-lateral lungs, heart, and contra-lateral breast as organs at risk (OARs) with α/β = 3 Gy were compared. Results: Based on the BEDVH comparisons, the use of SIB reduced the biological breast mean dose by about 3%, the ipsi-lateral lung and heart by about 10%, and contra-lateral breast and lung by about 7%. Conclusion: BED based comparisons should always be used in comparing plans that have different fraction sizes. SIB schemes are dosimetrically more advantageous than SEQ in breast target volume and OARs for equal prescribed BEDs for breast and boost

Genital invasion or perigenital spread may pose a risk of marginal misses for Intensity Modulated Radiotherapy (IMRT) in anal cancer

Background: While intensity modulated radiotherapy (IMRT) in anal cancer is feasible and improves high-dose conformality, the current RTOG/AGITG contouring atlas and planning guidelines lack specific instructions on how to proceed with external genitalia. Meanwhile, the RTOG-Protocol 0529 explicitly recommends genital sparing on the basis of specific genital dose constraints. Recent pattern-of-relapse studies based on conventional techniques suggest that marginal miss might be a potential consequence of genital sparing. Our goal is to outline the potential scope and increase the awareness for this clinical issue. Methods: We present and discuss four patients with perigenital spread in anal cancer in both early and advanced stages (three at time of first diagnosis and one in form of relapse). Genital/perigenital spread was observed once as direct genital infiltration and thrice in form of perigenital lymphatic spread. Results: We review the available data regarding the potential consequences of genital sparing in anal cancer. Pattern-of-relapse studies in anal cancer after conventional radiotherapy and the current use of IMRT in anal cancer are equivocal but suggest that genital sparing may occasionally result in marginal miss. An obvious hypothesis suggested by our report is that perigenital lymphovascular invasion might be associated with manifest inguinal N+ disease. Conclusions: Local failure has low salvage rates in recent anal cancer treatment series. Perigenital spread may pose a risk of marginal misses in IMRT in anal cancer. To prevent marginal misses, meticulous pattern-of-relapse analyses of controlled IMRT-series are warranted. Until their publication, genital sparing should be applied with caution, PET/CT should be used when possible and meeting genital dose constraints should not be prioritized over CTV coverage, especially (but not only) in stage T3/4 and N+ disease

Detection of local recurrence with 3-tesla MRI after radical prostatectomy: A useful method for radiation treatment planning?

Background/Aim: Salvage radiotherapy improves biochemical control in patients with recurrence of prostate cancer after prostatectomy. Radiotherapy target volumes of the prostatic fossa are based on empirical data and differ between different guidelines. Localization of recurrence with multiparametric magnetic resonance imaging (MRI) might be a feasible approach to localize recurrent lesions. Patients and Methods: Twenty-one patients with biochemical recurrence after radical prostatectomy were included (median prostate-specific antigen (PSA) =0.17 ng/ml). Multi-parametric MRI was performed using a 3-T MR system. Results: Lesions were detected in seven patients with a median PSA of 0.86 ng/ml (minimum= 0.31 ng/ml). Patients without detectable recurrence had a median PSA of 0.12 ng/ml. All patients with detectable lesions responded to radiotherapy. Eleven out of 14 patients without detectable recurrence also responded. Plasma flow in suspicious lesions was correlated with PSA level. Conclusion: Detection of recurrence at the prostatic fossa with our approach was possible in a minority of patients with a low PSA level. Clinical relevance of plasma flow in suspicious lesions should be further investigated

Phantom-based evaluation of dose exposure of ultrafast combined kV-MV-CBCT towards clinical implementation for IGRT of lung cancer

Purpose: Combined ultrafast 90\ub0+90\ub0 kV-MV-CBCT within single breath-hold of 15s has high clinical potential for accelerating imaging for lung cancer patients treated with deep inspiration breath-hold (DIBH). For clinical feasibility of kV-MV-CBCT, dose exposure has to be small compared to prescribed dose. In this study, kV-MV dose output is evaluated and compared to clinically-established kV-CBCT. Methods: Accurate dose calibration was performed for kV and MV energy; beam quality was determined. For direct comparison of MV and kV dose output, relative biological effectiveness (RBE) was considered. CT dose index (CTDI) was determined and measurements in various representative locations of an inhomogeneous thorax phantom were performed to simulate the patient situation. Results: A measured dose of 20.5mGE (Gray-equivalent) in the target region was comparable to kV-CBCT (31.2mGy for widely-used, and 9.1mGy for latest available preset), whereas kVMV spared healthy tissue and reduced dose to 6.6mGE (30%) due to asymmetric dose distribution. The measured weighted CTDI of 12mGE for kV-MV lay in between both clinical presets. Conclusions: Dosimetric properties were in agreement with established imaging techniques, whereas exposure to healthy tissue was reduced. By reducing the imaging time to a single breathhold of 15s, ultrafast combined kV-MV CBCT shortens patient time at the treatment couch and thus improves patient comfort. It is therefore usable for imaging of hypofractionated lung DIBH patients

A fast radiotherapy paradigm for anal cancer with volumetric modulated arc therapy (VMAT)

Background/Purpose: Radiotherapy (RT) volumes for anal cancer are large and of moderate complexity when organs at risk ( OAR) such as testis, small bowel and bladder are at least partially to be shielded. Volumetric intensity modulated arc therapy (VMAT) might provide OAR-shielding comparable to step-and-shoot intensity modulated radiotherapy (IMRT) for this tumor entity with better treatment efficiency. Materials and methods: Based on treatment planning CTs of 8 patients, we compared dose distributions, comformality index (CI), homogeneity index ( HI), number of monitor units (MU) and treatment time (TTT) for plans generated for VMAT, 3D-CRT and step-and-shoot-IMRT (optimized based on Pencil Beam (PB) or Monte Carlo ( MC) dose calculation) for typical anal cancer planning target volumes (PTV) including inguinal lymph nodes as usually treated during the first phase (0-36 Gy) of a shrinking field regimen. Results: With values of 1.33 +/- 0.21/1.26 +/- 0.05/1.3 +/- 0.02 and 1.39 +/- 0.09, the CI's for IMRT (PB-Corvus/PB-Hyperion/MC-Hyperion) and VMAT are better than for 3D-CRT with 2.00 +/- 0.16. The HI's for the prescribed dose (HI36) for 3D-CRT were 1.06 +/- 0.01 and 1.11 +/- 0.02 for VMAT, respectively and 1.15 +/- 0.02/1.10 +/- 0.02/1.11 +/- 0.08 for IMRT (PB-Corvus/PB-Hyperion/MCHyperion). Mean TTT and MU's for 3D-CRT is 220s/225 +/- 11MU and for IMRT (PB-Corvus/PBHyperion/MC-Hyperion) is 575s/1260 +/- 172MU, 570s/477 +/- 84MU and 610s748 +/- 193MU while TTT and MU for two-arc-VMAT is 290s/268 +/- 19MU. Conclusion: VMAT provides treatment plans with high conformity and homogeneity equivalent to step-and-shoot-IMRT for this mono-concave treatment volume. Short treatment delivery time and low primary MU are the most important advantages

Clinical outcome of hypofractionated breath-hold image-guided SABR of primary lung tumors and lung metastases

Background: Stereotactic Ablative RadioTherapy (SABR) of lung tumors/metastases has been shown to be an effective treatment modality with low toxicity. Outcome and toxicity were retrospectively evaluated in a unique single-institution cohort treated with intensity-modulated image-guided breath-hold SABR (igSABR) without external immobilization. The dose–response relationship is analyzed based on Biologically Equivalent Dose (BED). Patients and methods: 50 lesions in 43 patients with primary NSCLC (n = 27) or lung-metastases of various primaries (n = 16) were consecutively treated with igSABR with Active-Breathing-Coordinator (ABC®) and repeat-breath-hold cone-beam-CT. After an initial dose-finding/-escalation period, 5x12 Gy for peripheral lesions and single doses of 5 Gy to varying dose levels for central lesions were applied. Overall-survival (OS), progression-free-survival (PFS), progression pattern, local control (LC) and toxicity were analyzed. Results: The median BED2 was 83 Gy. 12 lesions were treated with a BED2 of &lt;80 Gy, and 38 lesions with a BED2 of <80 Gy. Median follow-up was 15 months. Actuarial 1- and 2-year OS were 67% and 43%; respectively. Cause of death was non-disease-related in 27%. Actuarial 1- and 2-year PFS was 42% and 28%. Progression site was predominantly distant. Actuarial 1- and 2 year LC was 90% and 85%. LC showed a trend for a correlation to BED2 (p = 0.1167). Pneumonitis requiring conservative treatment occurred in 23%. Conclusion: Intensity-modulated breath-hold igSABR results in high LC-rates and low toxicity in this unfavorable patient cohort with inoperable lung tumors or metastases. A BED2 of <80 Gy was associated with reduced local control