Systematic risk analysis of radiation pneumonitis in breast cancer: role of cotreatment with chemo-, endocrine, and targeted therapy.

PURPOSE: A major complication of sequential and concomitant chemoradiation in breast cancer treatment is interstitial pneumonitis induced by radiation therapy (RT), systemic therapy, or a combination of both. Dose and volume of co-irradiated lung tissue directly correlate with the risk of radiation pneumonitis. Especially in case of combined treatment, it is often unclear which of the used therapeutic agents promote pneumonitis. METHODS: This was a prospective monocentric study including 396 breast cancer patients. A systematic analysis of single and combined therapeutic measures was performed in order to identify treatment-related factors enhancing the risk of pneumonitis post RT. RESULTS: Overall incidence of pneumonitis of any grade was 38%; 28% were asymptomatic (grade 1) and 10% were symptomatic (> grade 1). Pneumonitis > grade 2 did not occur. Beside age, smoking status, and mean lung dose, the combined treatment with goserelin and tamoxifen significantly enhanced the risk of pneumonitis in a supra-additive pattern (odds ratio [OR] 4.38), whereas each agent alone or combined with other drugs only nonsignificantly contributed to a higher pneumonitis incidence post RT (OR 1.52 and OR 1.16, respectively). None of the other systemic treatments, including taxanes, increased radiation pneumonitis risk in sequential chemoradiation. CONCLUSION: Common treatment schedules in sequential chemoradiation following breast-conserving surgery only moderately increase lung toxicity, mainly as an asymptomatic complication, or to a minor extent, as transient pneumonitis ≤ grade 2. However, combined treatment with tamoxifen and the LHRH analog goserelin significantly increased the risk of pneumonitis in breast cancer patients after chemoradiation. Thus, closer surveillance of involved patients is advisable.

Tumor DNA-methylome derived epigenetic fingerprint identifies HPV-negative head and neck patients at risk for locoregional recurrence after postoperative radiochemotherapy.

Biomarkers with relevance for loco-regional therapy are needed in human papillomavirus negative aka HPV(-) head and neck squamous cell carcinoma (HNSCC). Based on the premise that DNA methylation pattern is highly conserved, we sought to develop a reliable and robust methylome-based classifier identifying HPV(-) HNSCC patients at risk for loco-regional recurrence (LR) and all-event progression after postoperative radiochemotherapy (PORT-C). The training cohort consisted of HPV-DNA negative HNSCC patients (n = 128) homogeneously treated with PORT-C in frame of the German Cancer Consortium-Radiation Oncology Group (DKTK-ROG) multicenter biomarker trial. DNA Methylation analysis was performed using Illumina 450 K and 850 K-EPIC microarray technology. The performance of the classifier was integrated with a series of biomarkers studied in the training set namely hypoxia-, 5-microRNA (5-miR), stem-cell gene-expression signatures and immunohistochemistry (IHC)-based immunological characterization of tumors (CD3/CD8/PD-L1/PD1). Validation occurred in an independent cohort of HPV(-) HNSCC patients, pooled from two German centers (n = 125). We identified a 38-methylation probe-based HPV(-) Independent Classifier of disease Recurrence (HICR) with high prognostic value for LR, distant metastasis and overall survival (P < 10-9 ). HICR remained significant after multivariate analysis adjusting for anatomical site, lymph node extracapsular extension (ECE) and size (T-stage). HICR high-risk tumors were enriched for younger patients with hypoxic tumors (15-gene signature) and elevated 5-miR score. After adjustment for hypoxia and 5-miR covariates, HICR maintained predicting all endpoints. HICR provides a novel mean for assessing the risk of LR in HPV(-) HNSCC patients treated with PORT-C and opens a new opportunity for biomarker-assisted stratification and therapy adaptation in these patients.

Radiotherapy for hormone-sensitive prostate cancer with synchronous low burden of distant metastases.

PURPOSE: The DEGRO Expert Commission on Prostate Cancer has revised the indication for radiation therapy of the primary prostate tumor in patients with synchronous distant metastases with low metastatic burden. METHODS: The current literature in the PubMed database was reviewed regarding randomized evidence on radiotherapy of the primary prostate tumor with synchronous low metastatic burden. RESULTS: In total, two randomized trials were identified. The larger study, the STAMPEDE trial, demonstrated an absolute survival benefit of 8% after 3 years for patients with low metastatic burden treated with standard of care (SOC) and additional radiotherapy (RT) (EQD2 ≤ 72 Gy) of the primary tumor. Differences in the smaller Horrad trial were not statistically significant, although risk reduction in the subgroup (< 5 bone metastases) was equal to STAMPEDE. The STOPCAP meta-analysis of both trials demonstrated the benefit of local radiotherapy for up to 4 bone lesions and an additional subanalysis of STAMPEDE also substantiated this finding in cases with M1a-only metastases. CONCLUSION: Therefore, due to the survival benefit after 3 years, current practice is changing. New palliative SOC is radiotherapy of the primary tumor in synchronously metastasized prostate cancer with low metastatic burden (defined as ≤ 4 bone metastases, with or without distant nodes) or in case of distant nodes only detected by conventional imaging.

Outcome after PSMA-PET/CT-based salvage radiotherapy for nodal recurrence after radical prostatectomy.

PURPOSE: Nodal recurrent prostate cancer (PCa) represents a common state of disease, amenable to local therapy. PSMA-PET/CT detects PCa recurrence at low PSA levels. The aim of this study was to evaluate the outcome of PSMA-PET/CT-based salvage radiotherapy (sRT) for lymph node (LN) recurrence. METHODS: A total of 100 consecutive patients treated with PSMA-PET/CT-based salvage elective nodal radiotherapy (sENRT) for LN recurrence were retrospectively examined. Patients underwent PSMA-PET/CT scan due to biochemical persistence (bcP, 76%) or biochemical recurrence (bcR, 24%) after radical prostatectomy (RP). Biochemical recurrence-free survival (BRFS) defined as PSA < post-RT nadir + 0.2 ng/ml and distant metastasis-free survival (DMFS) were calculated using the Kaplan-Meier method and uni- and multivariate analysis was performed. RESULTS: Median follow-up was 37 months. Median PSA at PSMA-PET/CT was 1.7 ng/ml (range 0.1-40.1) in patients with bcP and 1.4 ng/ml (range 0.3-5.1) in patients with bcR. PSMA-PET/CT detected 1, 2, and 3 or more LN metastases in 35%, 23%, and 42%, respectively. Eighty-three percent had only pelvic, 2% had only paraaortic, and 15% had pelvic and paraaortic LN metastases. Cumulatively, a total dose converted to EQD21.5 Gy of 66 Gy (60-70 Gy) was delivered to the prostatic fossa, 70 Gy (66-72 Gy) to the local recurrence, if present, 65.1 Gy (56-66 Gy) to PET-positive lymph nodes, and 47.5 Gy (42.4-50.9 Gy) to the lymphatic pathways. Concomitant androgen deprivation therapy (ADT) was administered in 83% of patients. One-, 2-, and 3-year BRFS was 80.7%, 71.6%, and 65.8%, respectively. One-, 2-, and 3-year DMFS was 91.6%, 79.1%, and 66.4%, respectively. In multivariate analysis, concomitant ADT, longer ADT duration (≥ 12 vs. < 12 months) and LN localization (pelvic vs. paraaortic) were associated with improved BRFS and concomitant ADT and lower PSA value before sRT (< 1 vs. > 1 ng/ml) with improved DMFS, respectively. No such association was seen for the number of affected lymph nodes. CONCLUSIONS: Overall, the present analysis shows that the so far, unmatched sensitivity and specificity of PSMA-PET/CT translates in comparably high BRFS and DMFS after PSMA-PET/CT-based sENRT for patients with PCa LN recurrence. Concomitant ADT, duration of ADT, PSA value before sRT, and localization of LN metastases were significant factors for improved outcome.

Moderately hypofractionated radiotherapy as definitive treatment for localized prostate cancer: Pattern of practice in German-speaking countries : A survey of the Prostate Cancer Expert Panel of the German Society of Radiation Oncology (DEGRO) and the Working Party on Radiation Oncology of the German Cancer Society (DKG-ARO).

PURPOSE: Various randomized phase III clinical trials have compared moderately hypofractionated to normofractionated radiotherapy (RT). These modalities showed similar effectiveness without major differences in toxicity. This project was conducted by the Prostate Cancer Expert Panel of the German Society of Radiation Oncology (DEGRO) and the Working Party on Radiation Oncology of the German Cancer Society. We aimed to investigate expert opinions on the use of moderately hypofractionated RT as a definitive treatment for localized prostate cancer in German-speaking countries. METHODS: A 25-item, web-based questionnaire on moderate-hypofractionation RT was prepared by an internal committee. The experts of the DEGRO were asked to complete the questionnaire. RESULTS: Fourteen active members of DEGRO completed the questionnaire. The questions described indications for selecting patients eligible to receive moderate hypofractionation based on clinical and pathological factors such as age, urinary symptoms, and risk-group. The questions also collected information on the technical aspects of selection criteria, including the definition of a clinical target volume, the use of imaging, protocols for bladder and rectal filling, the choice of a fractionation schedule, and the use of image guidance. Moreover, the questionnaire collected information on post-treatment surveillance after applying moderately hypofractionated RT. CONCLUSION: Although opinions varied on the use of moderate-hypofractionation RT, the current survey reflected broad agreement on the notion that moderately hypofractionated RT could be considered a standard treatment for localized prostate cancer in German-speaking countries.

Ultrahypofractionation of localized prostate cancer : Statement from the DEGRO working group prostate cancer.

Due to its low fractionation sensitivity, also known as "alpha/beta ratio," in relation to its surrounding organs at risk, prostate cancer is predestined for hypofractionated radiation schedules assuming an increased therapeutic ratio compared to normofractionated regimens. While moderate hypofractionation (2.2-4 Gy) has been proven to be non-inferior to normal fractionation in several large randomized trials for localized prostate cancer, level I evidence for ultrahypofractionation (>4 Gy) was lacking until recently. An accumulating body of non-randomized evidence has recently been strengthened by the publication of two randomized studies comparing ultrahypofractionation with a normofractionated schedule, i.e., the Scandinavian HYPO-RT trial by Widmark et al. and the first toxicity results of the PACE­B trial. In this review, we aim to give a brief overview of the current evidence of ultrahypofractionation, make an overall assessment of the level of evidence, and provide recommendations and requirements that should be followed before introducing ultrahypofractionation into routine clinical use.

PSMA-positive nodal recurrence in prostate cancer : Salvage radiotherapy is superior to salvage lymph node dissection in retrospective analysis.

PURPOSE: This analysis compares salvage lymph node dissection (SLND) to salvage lymph node radiotherapy (SLNRT) of 68Ga-PSMA PET-positive nodal recurrences after radical prostatectomy (RPE). METHODS: A total of 67 SLNRT and 33 SLND consecutive patients with pelvic and/or para-aortic nodal recurrences after RPE were retrospectively analyzed. Biochemical recurrence-free survival rates (bRFS; PSA <0.2 ng/mL) were calculated according to Kaplan-Meier and survival curves were compared using the log rank test. For multivariable analysis, binary logistic regression analysis was performed (p < 0.05). RESULTS: Median follow-up was 17 months (range, 6-53 months) in SLND patients and 31 months (range, 3-56 months) in SLNRT patients (p = 0.027). SLNRT patients had significantly more tumours of pT3 and pT4 category (82% vs. 67%; p = 0.006), pathologically involved lymph nodes (45% vs. 27%; p = 0.001) and positive surgical margins (54% vs. 12%; p = 0.001) at time of RPE than SLND patients. PSA persistence after RPE was significantly more frequently observed in the SLNRT cohort (73% vs. 27%; p = 0.001). There was no significant difference in the distribution of PET-positive lymph nodes. Median PSA before SLND was higher than before SLNRT (3.07 ng/ml vs. 1.3 ng/ml; p = 0.393). The 2­year bRFS was significantly higher in the SLNRT vs. the SLND cohort (92% vs. 30%; p = 0.001) with lower rates of distant metastases (21% vs. 52%; p = 0.002) and secondary treatments (5% vs. 39%; p = 0.011) irrespective of ongoing androgen deprivation therapy at last contact. In multivariable analysis, SLNRT was significantly associated with prolonged bRFS (regression coefficient 1.436, hazard ratio 4.204, 95% CI 1.789-9.878; p = 0.001). CONCLUSION: Based on this retrospective study SLNRT might be the preferred treatment option for patients with nodal recurrence after previous RPE.

Treatment strategies to prevent and reduce gynecomastia and/or breast pain caused by antiandrogen therapy for prostate cancer : Statement from the DEGRO working group prostate cancer.

AIM: To provide an overview on the available treatments to prevent and reduce gynecomastia and/or breast pain caused by antiandrogen therapy for prostate cancer. METHODS: The German Society of Radiation Oncology (DEGRO) expert panel summarized available evidence published and assessed the validity of the information on efficacy and treatment-related toxicity. RESULTS: Eight randomized controlled trials and one meta-analysis were identified. Two randomized trials demonstrated that prophylactic radiation therapy (RT) using 1â€¯× 10 Gy or 2â€¯× 6 Gy significantly reduced the rate of gynecomastia but not breast pain, as compared to observation. A randomized dose-finding trial identified the daily dose of 20 mg tamoxifen (TMX) as the most effective prophylactic dose and another randomized trial described that daily TMX use was superior to weekly use. Another randomized trial showed that prophylactic daily TMX is more effective than TMX given at the onset of gynecomastia. Two other randomized trials described that TMX was clearly superior to anastrozole in reducing the risk for gynecomastia and/or breast pain. One comparative randomized trial between prophylactic RT using 1â€¯× 12 Gy and TMX concluded that prophylactic TMX is more effective compared to prophylactic RT and furthermore that TMX appears to be more effective to treat gynecomastia and/or breast pain when symptoms are already present. A meta-analysis confirmed that both prophylactic RT and TMX can reduce the risk of gynecomastia and/or breast pain with TMX being more effective; however, the rate of side effects after TMX including dizziness and hot flushes might be higher than after RT and must be taken into account. Less is known regarding the comparative effectiveness of different radiation fractionation schedules and more modern RT techniques. CONCLUSIONS: Prophylactic RT as well as daily TMX can significantly reduce the incidence of gynecomastia and/or breast pain. TMX appears to be an effective alternative to RT also as a therapeutic treatment in the presence of gynecomastia but its side effects and off-label use must be considered.

Role of combined radiation and androgen deprivation therapy in intermediate-risk prostate cancer : Statement from the DEGRO working group on prostate cancer.

OBJECTIVE: This article aims to provide an overview of the role of combined radiation and androgen deprivation (ADT) therapy in patients with intermediate-risk prostate cancer. MATERIALS AND METHODS: The current German, European, and NCCN (National Comprehensive Cancer Network) guidelines as well as relevant literature in the PubMed database which provide information on sub-classification within the intermediate-risk group and the use of ADT in terms of oncological outcome were reviewed. RESULTS: Different recommendations for risk-group assessment of patients with localized prostate cancer are available. Subdivision of intermediate risk into a favorable and an unfavorable group seems to be justified to allow for a more individualized therapy in a quite heterogenous group of patients. So far, multiple randomized trials have shown a benefit when radiation therapy (RT) is combined with ADT. The use of dose-escalated RT without ADT also appears to be an adequate therapy associated with a very low rate of cancer-specific deaths. Therefore, taking into account the increased rate of toxicity associated with ADT, dose-escalated RT alone might be justified, especially in favorable intermediate-risk patients. CONCLUSION: Dose-escalated RT alone appears to be an appropriate treatment in favorable intermediate-risk patients. Addition of short course ADT (4-6 months) might improve outcomes in unfavorable intermediate-risk patients.

Measures of infection prevention and incidence of SARS-CoV-2 infections in cancer patients undergoing radiotherapy in Germany, Austria and Switzerland.

PURPOSE: COVID-19 infection has manifested as a major threat to both patients and healthcare providers around the world. Radiation oncology institutions (ROI) deliver a major component of cancer treatment, with protocols that might span over several weeks, with the result of increasing susceptibility to COVID-19 infection and presenting with a more severe clinical course when compared with the general population. The aim of this manuscript is to investigate the impact of ROI protocols and performance on daily practice in the high-risk cancer patients during this pandemic. METHODS: We addressed the incidence of positive COVID-19 cases in both patients and health care workers (HCW), in addition to the protective measures adopted in ROIs in Germany, Austria and Switzerland using a specific questionnaire. RESULTS: The results of the questionnaire showed that a noteworthy number of ROIs were able to complete treatment in SARS-CoV­2 positive cancer patients, with only a short interruption. The ROIs reported a significant decrease in patient volume that was not impacted by the circumambient disease incidence, the type of ROI or the occurrence of positive cases. Of the ROIs 16.5% also reported infected HCWs. About half of the ROIs (50.5%) adopted a screening program for patients whereas only 23.3% also screened their HCWs. The range of protective measures included the creation of working groups, instituting home office work and protection with face masks. Regarding the therapeutic options offered, curative procedures were performed with either unchanged or moderately decreased schedules, whereas palliative or benign radiotherapy procedures were more often shortened. Most ROIs postponed or cancelled radiation treatment for benign indications (88.1%). The occurrence of SARS-CoV­2 infections did not affect the treatment options for curative procedures. Non-university-based ROIs seemed to be more willing to change their treatment options for curative and palliative cases than university-based ROIs. CONCLUSION: Most ROIs reported a deep impact of SARS-CoV­2 infections on their work routine. Modification and prioritization of treatment regimens and the application of protective measures preserved a well-functioning radiation oncology service and patient care.

Therapy resistance mediated by cancer stem cells.

Cancer stem cells (CSC) possess abilities generally associated with embryonic or adult stem cells, especially self-renewal and differentiation. The CSC model assumes that this subpopulation of cells sustains malignant growth, which suggests a hierarchical organization of tumors in which CSCs are on top and responsible for the generation of intratumoral heterogeneity. Effective tumor therapy requires the eradication of CSC as they can support regrowth of the tumor resulting in recurrence. However, eradication of CSC is difficult because they frequently are therapy resistant. Therapy resistance is mediated by the acquisition of dormancy, increased DNA repair and drug efflux capacity, decreased apoptosis as well as the interaction between CSC and their supporting microenvironment, the CSC niche. This review highlights the role of CSC in chemo- and radiotherapy resistance as well as possible ways to overcome CSC mediated therapy resistance.

Therapy resistance mediated by exosomes.

Therapy resistance can arise within tumor cells because of genetic or phenotypic changes (intrinsic resistance), or it can be the result of an interaction with the tumor microenvironment (extrinsic resistance). Exosomes are membranous vesicles 40 to 100 nm in diameter constitutively released by almost all cell types, and mediate cell-to-cell communication by transferring mRNAs, miRNAs, DNAs and proteins causing extrinsic therapy resistance. They transfer therapy resistance by anti-apoptotic signalling, increased DNA-repair or delivering ABC transporters to drug sensitive cells. As functional mediators of tumor-stroma interaction and of epithelial to mesenchymal transition, exosomes also promote environment-mediated therapy resistance.Exosomes may be used in anticancer therapy exploiting their delivery function. They may effectively transfer anticancer drugs or RNAs in the context of gene therapy reducing immune stimulatory effects of these drugs and hydrophilic qualities facilitating crossing of cell membranes.

Shorter treatment times reduce the impact of intra-fractional motion : A real-time 4DUS study comparing VMAT vs. step-and-shoot IMRT for prostate cancer.

PURPOSE: To evaluate the impact of shorter treatment times on intra-fractional motion of the prostate during external beam radiotherapy. METHODS: 53 h of intra-fractional motion of the prostate were recorded in real-time by 4D ultrasound (4DUS) during 720 fractions in 28 patients, 14 of which whom treated with step-and-shoot intensity-modulated radiotherapy (IMRT) and 14 of whom were treated with volumetric arc therapy (VMAT). RESULTS: The average VMAT fraction was recorded for 2 min 43 s and was substantially shorter than the average step-and-shoot IMRT fraction at 6 min 13 s. Average radial displacement of the prostate per fraction was substantially and significantly reduced from 1.31 ± 1.28 mm (n = 357 step-and-shoot IMRT fractions) to 0.96 ± 1.04 mm (n = 363 VMAT fractions), p = 0.00004. Radial, vertical, and longitudinal root-mean-square (r. m. s.) error per fraction was reduced from 1.55 to 1.12 mm (-28%, p < 0.0001), from 1.16 to 0.77 mm (-34%, p < 0.0001), and from 0.79 to 0.56 mm (-29%, p = 0.0002), respectively. Lateral intra-fractional motion was generally small and did not differ significantly. The prostate remained during 95% of fraction time within 4.55 mm of the isocenter in case of step-and-shoot IMRT and within 2.45 mm in case of VMAT. The variance of displacements increased linearly with time, and the rate was the same for both step-and-shoot IMRT and VMAT patients. CONCLUSIONS: The position of the prostate changed less during shorter fractions, limiting fraction-average and end-of-fraction variance. This substantially and significantly reduced the impact of intra-fractional motion during shorter VMAT fractions as compared to longer step-and-shoot IMRT fractions.

Left-sided breast cancer and risks of secondary lung cancer and ischemic heart disease : Effects of modern radiotherapy techniques.

PURPOSE: Modern breast cancer radiotherapy techniques, such as respiratory-gated radiotherapy in deep-inspiration breath-hold (DIBH) or volumetric-modulated arc radiotherapy (VMAT) have been shown to reduce the high dose exposure of the heart in left-sided breast cancer. The aim of the present study was to comparatively estimate the excess relative and absolute risks of radiation-induced secondary lung cancer and ischemic heart disease for different modern radiotherapy techniques. METHODS: Four different treatment plans were generated for ten computed tomography data sets of patients with left-sided breast cancer, using either three-dimensional conformal radiotherapy (3D-CRT) or VMAT, in free-breathing (FB) or DIBH. Dose-volume histograms were used for organ equivalent dose (OED) calculations using linear, linear-exponential, and plateau models for the lung. A linear model was applied to estimate the long-term risk of ischemic heart disease as motivated by epidemiologic data. Excess relative risk (ERR) and 10-year excess absolute risk (EAR) for radiation-induced secondary lung cancer and ischemic heart disease were estimated for different representative baseline risks. RESULTS: The DIBH maneuver resulted in a significant reduction of the ERR and estimated 10-year excess absolute risk for major coronary events compared to FB in 3D-CRT plans (p = 0.04). In VMAT plans, the mean predicted risk reduction through DIBH was less pronounced and not statistically significant (p = 0.44). The risk of radiation-induced secondary lung cancer was mainly influenced by the radiotherapy technique, with no beneficial effect through DIBH. VMAT plans correlated with an increase in 10-year EAR for radiation-induced lung cancer as compared to 3D-CRT plans (DIBH p = 0.007; FB p = 0.005, respectively). However, the EARs were affected more strongly by nonradiation-associated risk factors, such as smoking, as compared to the choice of treatment technique. CONCLUSION: The results indicate that 3D-CRT plans in DIBH pose the lowest risk for both major coronary events and secondary lung cancer.

Dose optimization of total or partial skin electron irradiation by thermoluminescent dosimetry.

BACKGROUND: Due to the complex surface of the human body, total or partial skin irradiation using large electron fields is challenging. The aim of the present study was to quantify the magnitude of dose optimization required after the application of standard fields. METHODS: Total skin electron irradiation (TSEI) was applied using the Stanford technique with six dual-fields. Patients presenting with localized lesions were treated with partial skin electron irradiation (PSEI) using large electron fields, which were individually adapted. In order to verify and validate the dose distribution, in vivo dosimetry with thermoluminescent dosimeters (TLD) was performed during the first treatment fraction to detect potential dose heterogeneity and to allow for an individual dose optimization with adjustment of the monitor units (MU). RESULTS: Between 1984 and 2017, a total of 58 patients were treated: 31 patients received TSEI using 12 treatment fields, while 27 patients underwent PSEI and were treated with 4-8 treatment fields. After evaluation of the dosimetric results, an individual dose optimization was necessary in 21 patients. Of these, 7 patients received TSEI (7/31). Monitor units (MU) needed to be corrected by a mean value of 117 MU (±105, range 18-290) uniformly for all 12 treatment fields, corresponding to a mean relative change of 12% of the prescribed MU. In comparison, the other 14 patients received PSEI (14/27) and the mean adjustment of monitor units was 282 MU (±144, range 59-500) to single or multiple fields, corresponding to a mean relative change of 22% of the prescribed MU. A second dose optimization to obtain a satisfying dose at the prescription point was need in 5 patients. CONCLUSIONS: Thermoluminescent dosimetry allows an individual dose optimization in TSEI and PSEI to enable a reliable adjustment of the MUs to obtain the prescription dose. Especially in PSEI in vivo dosimetry is of fundamental importance.

Correction to: Left-sided breast cancer and risks of secondary lung cancer and ischemic heart disease-Effects of modern radiotherapy techniques.

Correction to: Strahlenther Onkol 2017 https://doi.org/10.1007/s00066-017-1213-y Unfortunately, during copy editing, the titles of Fig. 2a and 2b were removed.The correct Fig. 2a and 2b are shown below. The original article has been corrected ….

Use of androgen deprivation and salvage radiation therapy for patients with prostate cancer and biochemical recurrence after prostatectomy.

AIM: Overview on the use of androgen deprivation therapy (ADT) added to salvage radiation therapy (SRT) for prostate cancer patients with biochemical recurrence after prostatectomy. METHODS: The German Society of Radiation Oncology (DEGRO) expert panel summarized available evidence published between January 2009 and May 2017, and assessed the validity of the information on outcome parameters including overall survival (OS) and treatment-related toxicity. RESULTS: Two randomized controlled trials and nine relevant retrospective analyses were identified. The RTOG 9601 trial showed an OS improvement for the combination of 2 years of bicalutamide and SRT compared to SRT alone after a median follow-up of 13 years. This improvement appeared to be restricted to those patients with a prostate specific antigen (PSA) level before SRT of ≥0.7 ng/mL. The GETUG AFU-16 trial showed that after a median follow-up of 5 years, the addition of 6 months of goserelin to SRT improved progression-free survival (PFS; based on biochemical recurrence) as compared to SRT alone. ADT in both trials was not associated with increased major late toxicities. Results of retrospective series were inconsistent with a suggestion that the addition of ADT improved biochemical PFS especially in patients with high-risk factors such as Gleason Score ≥8 and in the group with initially negative surgical margins. CONCLUSIONS: ADT combined with SRT appears to improve OS in patients with a PSA level before SRT of ≥0.7 ng/mL. In patients without persistent PSA after prostatectomy and PSA levels of <0.7 ng/mL, ADT should not routinely be used, but may be considered in patients with additional risk factors such as Gleason Score ≥8 and negative surgical margins.

The PD-1/PD-L1 axis and human papilloma virus in patients with head and neck cancer after adjuvant chemoradiotherapy: A multicentre study of the German Cancer Consortium Radiation Oncology Group (DKTK-ROG).

We examined the prognostic role of PD-1+ and CD8+ tumor infiltrating lymphocytes (TILs), and PD-L1+ cells in patients with squamous cell carcinoma of the head and neck (SCCHN) treated with surgery and postoperative chemoradiotherapy (CRT). FFPE samples from 161 patients were immunohistochemically stained for PD-1, CD8 and PD-L1. The immune marker expression was correlated with clinicopathologic characteristics, and overall survival (OS), local progression-free survival (LPFS) and distant metastases free-survival (DMFS), also in the context of HPV16 DNA/p16 status. The median follow-up was 48 months (range: 4-100). The 2-year-OS was 84.1% for the entire cohort. High PD-1 and PD-L1 expression were more common in patients with positive HPV16 DNA (p < 0.001 and p = 0.008, respectively) and high infiltration by CD8+ TILs (p < 0.001 for both markers). High PD-L1 expression correlated with superior OS (p = 0.025), LPFS (p = 0.047) and DMFS (p = 0.048) in multivariable analysis, whereas no significance could be demonstrated for PD-1. Patients with CD8high /PD-L1high expression had favorable outcome (p < 0.001 for all endpoints) compared to other groups. We validated the superior OS data on CD8high /PD-L1high using the Cancer Genome Atlas TCGA dataset (n = 518; p = 0.032). High PD-L1 expression was a favorable prognostic marker in HPV16-negative but not HPV16-positive patients. In conclusion, HPV-positive tumors showed higher expression of immune markers. PD-L1 expression constitutes an independent prognostic marker in SCCHN patients post-adjuvant CRT. In conjunction with CD8 status, these data provide an important insight on the immune contexture of SCCHN and are directly relevant for future treatment stratification with PD-1/PD-L1 immune checkpoint inhibitors to complement CRT.

Prefraction displacement and intrafraction drift of the prostate due to perineal ultrasound probe pressure.

OBJECTIVE: In image-guided EBRT of the prostate, transperineal ultrasound (US) probes exert pressure on the perineum both during planning and treatment. Through tissue deformation and relaxation, this causes target and risk organ displacement and drift. In this study, prefraction shift and intrafraction drift of the prostate are quantified during robotic transperineal 4DUS. METHODS: The position of the prostate was recorded for different positions of the probe before treatment in 10 patients (16 series of measurements). During treatment (15 patients, 273 fractions), intrafraction motion of the prostate was tracked (total of 27 h and 24 min) with the transperineal probe in place. RESULTS: Per 1 mm shift of the US probe in the cranial direction, a displacement of the prostate by 0.42 ± 0.09 mm in the cranial direction was detected. The relationship was found to be linear (R² = 0.97) and highly significant (p < 0.0001). After initial contact of the probe and the perineum (no pressure), a shift of the probe of about 5-10 mm was typically necessary to achieve good image quality, corresponding to a shift of the prostate of about 2-4 mm in the cranial direction. Tissue compression and prostate displacement were well visible. During treatment, the prostate drifted at an average rate of 0.075 mm/min in the cranial direction (p = 0.0014). CONCLUSION: The pressure applied by a perineal US probe has a quantitatively similar impact on prostate displacement as transabdominal pressure. Shifts are predominantly in the cranial direction (typically 2-4 mm) with some component in the anterior direction (typically <1 mm). Slight probe pressure can improve image quality, but excessive probe pressure can distort the surrounding anatomy and potentially move risk organs closer to the high-dose area.

Comparison of prostate positioning guided by three-dimensional transperineal ultrasound and cone beam CT.

OBJECTIVE: The accuracy of a transperineal three-dimensional ultrasound system (3DUS) was assessed for prostate positioning and compared to fiducial- and bone-based positioning in kV cone beam computed tomography (CBCT) during definitive radiotherapy of prostate cancer. METHODS: Each of the 7 patients had three fiducial markers implanted into the prostate before treatment. Prostate positioning was simultaneously measured by 3DUS and CBCT before each fraction. In total, 177 pairs of 3DUS and CBCT scans were collected. Bone-match and seed-match were performed for each CBCT. Using seed-match as a reference, the accuracy of 3DUS and bone-match was evaluated. Systematic and random errors as well as optimal setup margins were calculated for 3DUS and bone-match. RESULTS: The discrepancy between 3DUS and seed-match in CBCT (average ± standard deviation) was 0.0 ± 1.7 mm laterally, 0.2 ± 2.0 mm longitudinally, and 0.3 ± 1.7 mm vertically. Using seed-match as a reference, systematic errors for 3DUS were 1.2 mm, 1.1 mm, and 0.9 mm; and random errors were 1.4 mm, 1.8 mm, and 1.6 mm, on lateral, longitudinal, and vertical axes, respectively. By analogy, the difference of bone-match to seed-match was 0.1 ± 1.1 mm laterally, 1.3 ± 3.8 mm longitudinally, and 1.3 ± 4.5 mm vertically. Systematic errors were 0.5 mm, 2.2 mm, and 2.6 mm; and random errors were 1.0 mm, 3.1 mm, and 3.9 mm on lateral, longitudinal, and vertical axes, respectively. The accuracy of 3DUS was significantly higher than that of bone-match on longitudinal and vertical axes, but not on the lateral axis. CONCLUSION: Image-guided radiotherapy of prostate cancer based on transperineal 3DUS was feasible, with overall small discrepancy to seed-match in CBCT in this retrospective study. Compared to bone-match, transperineal 3DUS achieved higher accuracy on longitudinal and vertical axes.