Development and benchmarking of a Deep Learning-based MRI-guided gross tumor segmentation algorithm for Radiomics analyses in extremity soft tissue sarcomas.

BACKGROUND: Volume of interest (VOI) segmentation is a crucial step for Radiomics analyses and radiotherapy (RT) treatment planning. Because it can be time-consuming and subject to inter-observer variability, we developed and tested a Deep Learning-based automatic segmentation (DLBAS) algorithm to reproducibly predict the primary gross tumor as VOI for Radiomics analyses in extremity soft tissue sarcomas (STS). METHODS: A DLBAS algorithm was trained on a cohort of 157 patients and externally tested on an independent cohort of 87 patients using contrast-enhanced MRI. Manual tumor delineations by a radiation oncologist served as ground truths (GTs). A benchmark study with 20 cases from the test cohort compared the DLBAS predictions against manual VOI segmentations of two residents (ERs) and clinical delineations of two radiation oncologists (ROs). The ROs rated DLBAS predictions regarding their direct applicability. RESULTS: The DLBAS achieved a median dice similarity coefficient (DSC) of 0.88 against the GTs in the entire test cohort (interquartile range (IQR): 0.11) and a median DSC of 0.89 (IQR 0.07) and 0.82 (IQR 0.10) in comparison to ERs and ROs, respectively. Radiomics feature stability was high with a median intraclass correlation coefficient of 0.97, 0.95 and 0.94 for GTs, ERs, and ROs, respectively. DLBAS predictions were deemed clinically suitable by the two ROs in 35% and 20% of cases, respectively. CONCLUSION: The results demonstrate that the DLBAS algorithm provides reproducible VOI predictions for radiomics feature extraction. Variability remains regarding direct clinical applicability of predictions for RT treatment planning.

Radiotherapy concepts for spinal metastases-results from an online survey among radiation oncologists of the German Society for Radiation Oncology.

PURPOSE: Spinal metastases (SM) are a common radiotherapy (RT) indication. There is limited level I data to drive decision making regarding dose regimen (DR) and target volume definition (TVD). We aim to depict the patterns of care for RT of SM among German Society for Radiation Oncology (DEGRO) members. METHODS: An online survey on conventional RT and Stereotactic Body Radiation Therapy (SBRT) for SM, distributed via e­mail to all DEGRO members, was completed by 80 radiation oncologists between February 24 and April 29, 2022. Participation was voluntary and anonymous. RESULTS: A variety of DR was frequently used for conventional RT (primary: n = 15, adjuvant: n = 14). 30 Gy/10 fractions was reported most frequently. TVD in adjuvant RT was heterogenous, with a trend towards larger volumes. SBRT was offered in 65% (primary) and 21% (adjuvant) of participants' institutions. A variety of DR was reported (primary: n = 40, adjuvant: n = 27), most commonly 27 Gy/3 fractions and 30 Gy/5 fractions. 59% followed International Consensus Guidelines (ICG) for TVD. CONCLUSION: We provide a representative depiction of RT practice for SM among DEGRO members. DR and TVD are heterogeneous. SBRT is not comprehensively practiced, especially in the adjuvant setting. Further research is needed to provide a solid data basis for detailed recommendations.

The importance of planning CT-based imaging features for machine learning-based prediction of pain response.

Patients suffering from painful spinal bone metastases (PSBMs) often undergo palliative radiation therapy (RT), with an efficacy of approximately two thirds of patients. In this exploratory investigation, we assessed the effectiveness of machine learning (ML) models trained on radiomics, semantic and clinical features to estimate complete pain response. Gross tumour volumes (GTV) and clinical target volumes (CTV) of 261 PSBMs were segmented on planning computed tomography (CT) scans. Radiomics, semantic and clinical features were collected for all patients. Random forest (RFC) and support vector machine (SVM) classifiers were compared using repeated nested cross-validation. The best radiomics classifier was trained on CTV with an area under the receiver-operator curve (AUROC) of 0.62 ± 0.01 (RFC; 95% confidence interval). The semantic model achieved a comparable AUROC of 0.63 ± 0.01 (RFC), significantly below the clinical model (SVM, AUROC: 0.80 ± 0.01); and slightly lower than the spinal instability neoplastic score (SINS; LR, AUROC: 0.65 ± 0.01). A combined model did not improve performance (AUROC: 0,74 ± 0,01). We could demonstrate that radiomics and semantic analyses of planning CTs allowed for limited prediction of therapy response to palliative RT. ML predictions based on established clinical parameters achieved the best results.

Incidental nodal irradiation in patients with esophageal cancer undergoing (chemo)radiation with 3D-CRT or VMAT.

The extent of elective nodal irradiation (ENI) in patients undergoing definitive chemoradiotherapy (dCRT) for esophageal squamous cell carcinoma (ESCC) remains unclear. The aim of this dosimetric study was to evaluate the extent of incidental nodal irradiation using modern radiation techniques. A planning target volume (PTV) was generated for 30 patients with node-negative esophageal carcinoma (13 cervical/upper third, 7 middle third, 10 lower third/abdomen). Thereby, no elective nodal irradiation (ENI) was intended. Both three-dimensional conformal radiotherapy (3D-CRT) and volumetric-modulated arc therapy (VMAT) treatment plans (50 Gy in 25 fractions) were calculated for all patients. Fifteen nodal stations were contoured according to the definitions of the AJCC and investigated in regard to dosimetric parameters. Compared to 3D-CRT, VMAT was associated with lower dose distribution to the organs at risk (lower Dmean, V20 and V30 for the lungs and lower Dmean and V30 for the heart). For both techniques, the median Dmean surpassed 40 Gy in 12 of 15 (80%) nodal stations. However, VMAT resulted in significantly lower Dmeans and equivalent uniform doses (EUD) compared to 3D-CRT for eight nodal stations (1L, 2L, 2R, 4L, 7, 8L, 10L, 15), while differences did not reach significance for seven nodal station (1R, 4R, 8U, 8M, 10R, 16). For dCRT of ESCC, the use of VMAT was associated with significantly lower median (incidental) doses to eight of 15 regional lymph node areas compared to 3D-CRT. However, given the small absolute differences, these differences probably do not impair (regional) tumor control rates.

Influence of radiation treatment technique (IMRT vs. 3D-RT) on acute toxicity and prognostic factors for survival for anal cancer.

We compared our institutional experience with intensity-modulated radiotherapy (IMRT) and 3D-conformal radiotherapy (3D-RT) for definitive treatment of primary anal cancer. We performed a single-institution retrospective review of all patients with anal squamous cell carcinoma treated with definitive (chemo) radiotherapy with curative intent from 2004 through 2018. We assessed several prognostic factors in respect to relevant survival endpoints. In addition, acute toxicities were determined and compared between IMRT and 3D-RT patients. This study included 94 patients (58 IMRT, 36 3D-RT). Mean follow up for all patients, for IMRT and 3D-RT patients was 61 months (range 6-176), 46 months (range 6-118), and 85 months (range 6-176), respectively. 5-year overall survival (OS) was 86%, disease-free survival (DFS) was 72%, and colostomy-free survival (CFS) was 75% in the IMRT cohort. In the 3D-RT cohort, OS was 87%, DFS was 71%, and CFS was 81% (all p > 0.05). Male gender and Karnofsky Index (KI) were revealed as independent prognostic factors for 5-year OS (p = 0.017; p = 0.023). UICC stage was an independent prognostic factor for DFS and CFS (p = 0.023; p = 0.042). In addition, the pre-treatment leukocyte count was an independent prognostic factor for CFS (p = 0.042). Acute grade ≥ 3 toxicity was not significantly different between IMRT and 3D-RT patients, but the IMRT cohort had favorable outcomes. This study confirmed IMRT as the primary definitive treatment of anal cancer. With similar survival rates, IMRT had the potential to reduce acute toxicity by sparing organs at risk. Promising prognostic factors such as BMI, KI, and leucocyte and hemoglobin levels should be further investigated.

As Easy as 1, 2, 3? How to Determine CBCT Frequency in Adjuvant Breast Radiotherapy.

The current study aims to assess the suitability of setup errors during the first three treatment fractions to determine cone-beam computed tomography (CBCT) frequency in adjuvant breast radiotherapy. For this, 45 breast cancer patients receiving non-hypofractionated radiotherapy after lumpectomy, including a simultaneous integrated boost (SIB) to the tumor bed and daily CBCT imaging, were retrospectively selected. In a first step, mean and maximum setup errors on treatment days 1-3 were correlated with the mean setup errors during subsequent treatment days. In a second step, dose distribution was estimated using a dose accumulation workflow based on deformable image registration, and setup errors on treatment days 1-3 were correlated with dose deviations in the clinical target volumes (CTV) and organs at risk (OAR). No significant correlation was found between mean and maximum setup errors on treatment days 1-3 and mean setup errors during subsequent treatment days. In addition, mean and maximum setup errors on treatment days 1-3 correlated poorly with dose coverage of the CTVs and dose to the OARs. Thus, CBCT frequency in adjuvant breast radiotherapy should not be determined solely based on the magnitude of setup errors during the first three treatment fractions.

Predictive value of clinical and 18F-FDG-PET/CT derived imaging parameters in patients undergoing neoadjuvant chemoradiation for esophageal squamous cell carcinoma.

Aim of this study was to validate the prognostic impact of clinical parameters and baseline 18F-FDG-PET/CT derived textural features to predict histopathologic response and survival in patients with esophageal squamous cell carcinoma undergoing neoadjuvant chemoradiation (nCRT) and surgery. Between 2005 and 2014, 38 ESCC were treated with nCRT and surgery. For all patients, the 18F-FDG-PET-derived parameters metabolic tumor volume (MTV), SUVmax, contrast and busyness were calculated for the primary tumor using a SUV-threshold of 3. The parameter uniformity was calculated using contrast-enhanced computed tomography. Based on histopathological response to nCRT, patients were classified as good responders (< 10% residual tumor) (R) or non-responders (≥ 10% residual tumor) (NR). Regression analyses were used to analyse the association of clinical parameters and imaging parameters with treatment response and overall survival (OS). Good response to nCRT was seen in 27 patients (71.1%) and non-response was seen in 11 patients (28.9%). Grading was the only parameter predicting response to nCRT (Odds Ratio (OR) = 0.188, 95% CI: 0.040-0.883; p = 0.034). No association with histopathologic treatment response was seen for any of the evaluated imaging parameters including SUVmax, MTV, busyness, contrast and uniformity. Using multivariate Cox-regression analysis, the heterogeneity parameters busyness (Hazard Ratio (HR) = 1.424, 95% CI: 1.044-1.943; p = 0.026) and contrast (HR = 6.678, 95% CI: 1.969-22.643; p = 0.002) were independently associated with OS, while no independent association with OS was seen for SUVmax and MTV. In patients with ESCC undergoing nCRT and surgery, baseline 18F-FDG-PET/CT derived parameters could not predict histopathologic response to nCRT. However, the PET/CT derived features busyness and contrast were independently associated with OS and should be further investigated.

Quality of life in patients treated with radiochemotherapy for primary diagnosis of anal cancer.

Anal cancer and the related treatment are generally known to affect patients' quality of life. The aim of this study was to assess self-reported quality of life (QoL) of anal cancer patients after combined radiation and chemotherapy, and to identify patient-, disease-, and therapy-related factors associated with QoL. A total of 94 patients treated with definitive chemoradiation for anal cancer at our institution in the period from 2004 to 2018 were identified from our database. QoL was assessed in the remaining 52 patients using the EORTC QLQ-C30 questionnaire (cancer-specific QoL) and the newly developed anal cancer module QLQ-ANL27 (site-specific QoL). Differences in QoL between anal cancer patients and a German age and sex adjusted reference population were examined. The median follow-up was 71 months (range, 7-176). In the cancer-specific QoL module, the anal cancer cohort presented with significantly lower scores in role (- 12.2 points), emotional (- 6.6 points), and social functioning (- 6.8 points), but higher scores in diarrhea (+ 36.3 points) and constipation (+ 13.3 points) than the German reference population. There were no significant differences in disease- or therapy-related factors, but age greater than 70 years and a follow-up time greater than 71 months had a negative impact on global QoL. As for the site-specific QoL, patients with a tumor relapse showed significantly higher symptom scores than patients with a complete clinical remission in all scales except of micturition frequency. Compared to 3D conformal radiotherapy, IMRT treatment seemed to improve non-stoma bowel function (+ 23.3 points), female sexual functioning (+ 24.2 points), and came along with less scores in the symptom scales pain (- 35.9 points), toilet proximity (- 28.6 points), and cleanliness (- 26.2 points). Most of the functional scores of anal cancer patients were lower compared to the general German population, but did not seem to affect the general QoL. Fatigue, physical, and role functioning had the strongest impact on global QoL causing psychological symptoms as important as physical.

Impact of CBCT frequency on target coverage and dose to the organs at risk in adjuvant breast cancer radiotherapy.

The current study aims to assess the effect of cone beam computed tomography (CBCT) frequency during adjuvant breast cancer radiotherapy with simultaneous integrated boost (SIB) on target volume coverage and dose to the organs at risk (OAR). 50 breast cancer patients receiving either non-hypofractionated or hypofractionated radiotherapy after lumpectomy including a SIB to the tumor bed were selected for this study. All patients were treated in volumetric modulated arc therapy (VMAT) technique and underwent daily CBCT imaging. In order to estimate the delivered dose during the treatment, the applied fraction doses were recalculated on daily CBCT scans and accumulated using deformable image registration. Based on a total of 2440 dose recalculations, dose coverage in the clinical target volumes (CTV) and OAR was compared depending on the CBCT frequency. The estimated delivered dose (V95%) for breast-CTV and SIB-CTV was significantly lower than the planned dose distribution, irrespective of the CBCT-frequency. Between daily CBCT and CBCT on alternate days, no significant dose differences were found regarding V95% for both, breast-CTV and SIB-CTV. Dose distribution in the OAR was similar for both imaging protocols. Weekly CBCT though led to a significant decrease in dose coverage compared to daily CBCT and a small but significant dose increase in most OAR. Daily CBCT imaging might not be necessary to ensure adequate dose coverage in the target volumes while efficiently sparing the OAR during adjuvant breast cancer radiotherapy with SIB.

High rate of complete histopathological response in hepatocellular carcinoma patients after combined transarterial chemoembolization and stereotactic body radiation therapy.

BACKGROUND: Liver transplantation (LT) presents a curative treatment option in patients with early stage hepatocellular carcinoma (HCC) who are not eligible for resection or ablation therapy. Due to a risk of up 30% for waitlist drop-out upon tumor progression, bridging therapies are used to halt tumor growth. Transarterial chemoembolization (TACE) and less commonly stereotactic body radiation therapy (SBRT) or a combination of TACE and SBRT, are used as bridging therapies in LT. However, it remains unclear if one of those treatment options is superior. The analysis of explant livers after transplantation provides the unique opportunity to investigate treatment response by histopathology. AIM: To analyze histopathological response to a combination of TACE and SBRT in HCC in comparison to TACE or SBRT alone. METHODS: In this multicenter retrospective study, 27 patients who received liver transplantation for HCC were analyzed. Patients received either TACE or SBRT alone, or a combination of TACE and SBRT as bridging therapy to liver transplantation. Liver explants of all patients who received at least one TACE and/or SBRT were analyzed for the presence of residual vital tumor tissue by histopathology to assess differences in treatment response to bridging therapies. Statistical analysis was performed using Fisher-Freeman-Halton exact test, Kruskal-Wallis and Mann-Whitney-U tests. RESULTS: Fourteen patients received TACE only, four patients SBRT only, and nine patients a combination therapy of TACE and SBRT. There were no significant differences between groups regarding age, sex, etiology of underlying liver disease or number and size of tumor lesions. Strikingly, analysis of liver explants revealed that almost all patients in the TACE and SBRT combination group (8/9, 89%) showed no residual vital tumor tissue by histopathology, whereas TACE or SBRT alone resulted in significantly lower rates of complete histopathological response (0/14, 0% and 1/4, 25%, respectively, P value < 0.001). CONCLUSION: Our data suggests that a combination of TACE and SBRT increases the rate of complete histopathological response compared to TACE or SBRT alone in bridging to liver transplantation.

Craniospinal irradiation(CSI) in patients with leptomeningeal metastases: risk-benefit-profile and development of a prognostic score for decision making in the palliative setting.

BACKGROUND: The aim of our study was to assess the feasibility and oncologic outcomes in patients treated with spinal (SI) or craniospinal irradiation (CSI) in patients with leptomeningeal metastases (LM) and to suggest a prognostic score as to which patients are most likely to benefit from this treatment. METHODS: Nineteen patients treated with CSI at our institution were eligible for the study. Demographic data, primary tumor characteristics, outcome and toxicity were assessed retrospectively. The extent of extra-CNS disease was defined by staging CT-scans before the initiation of CSI. Based on outcome parameters a prognostic score was developed for stratification based on patient performance status and tumor staging. RESULTS: Median follow-up and overall survival (OS) for the whole group was 3.4 months (range 0.5-61.5 months). The median overall survival (OS) for patients with LM from breast cancer was 4.7 months and from NSCLC 3.3 months. The median OS was 7.3 months, 3.3 months and 1.5 months for patients with 0, 1 and 2 risk factors according to the proposed prognostic score (KPS < 70 and the presence of extra-CNS disease) respectively. Nonhematologic toxicities were mild. CONCLUSION: CSI demonstrated clinically meaningful survival that is comparable to the reported outcome of intrathecal chemotherapy. A simple scoring system could be used to better select patients for treatment with CSI in this palliative setting. In our opinion, the feasibility of performing CSI with modern radiotherapy techniques with better sparing of healthy tissue gives a further rationale for its use also in the palliative setting.

Impact of 18F-FDG-PET/CT on the identification of regional lymph node metastases and delineation of the primary tumor in esophageal squamous cell carcinoma patients.

PURPOSE: In patients undergoing chemoradiation for esophageal squamous cell carcinoma (ESCC), the extent of elective nodal irradiation (ENI) is still discussed controversially. This study aimed to analyze patterns of lymph node metastases and their correlation with the primary tumor using 18F­fludeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT) scans. METHODS: 102 ESCC patients with pre-treatment FDG-PET/CT scans were evaluated retrospectively. After exclusion of patients with low FDG uptake and patients without FDG-PET-positive lymph node metastases (LNM), 76 patients were included in the final analysis. All LNM were assigned to 16 pre-defined anatomical regions and classified according to their position relative to the primary tumor (above, at the same height, or below the primary tumor). In addition, the longitudinal distance to the primary tumor was measured for all LNM above or below the primary tumor. The craniocaudal extent (i.e., length) of the primary tumor was measured using FDG-PET imaging (LPET) and also based on all other available clinical and imaging data (endoscopy, computed tomography, biopsy results) except FDG-PET (LCT/EUS). RESULTS: Significantly more LNM were identified with 18F­FDG-PET/CT (177 LNM) compared to CT alone (131 LNM, p < 0.001). The most common sites of LNM were paraesophageal (63% of patients, 37% of LNM) and paratracheal (33% of patients, 20% of LNM), while less than 5% of patients had supraclavicular, subaortic, diaphragmatic, or hilar LNM. With regard to the primary tumor, 51% of LNM were at the same height, while 25% and 24% of lymph node metastases were above and below the primary tumor, respectively. For thirty-three LNM (19%), the distance to the primary tumor was larger than 4 cm. No significant difference was seen between LCT/EUS (median 6 cm) and LPET (median 6 cm, p = 0.846) CONCLUSION: 18F­FDG-PET can help to identify subclinical lymph node metastases which are located outside of recommended radiation fields. PET-based involved-field irradiation might be the ideal compromise between small treatment volumes and decreasing the risk of undertreatment of subclinical metastatic lymph nodes and should be further evaluated.

Dosimetric comparison of organs at risk using different contouring guidelines for definition of the clinical target volume in anal cancer.

BACKGROUND: There are different contouring guidelines for definition of the clinical target volume (CTV) for intensity-modulated radiation therapy (IMRT) of anal cancer (AC). We conducted a planning comparison study to evaluate and compare the dose to relevant organs at risk (OARs) while using different CTV definitions. METHODS: Twelve patients with a primary diagnosis of anal cancer, who were treated with primary chemoradiation (CRT), were selected. We generated four guideline-specific CTVs and subsequently planned target volumes (PTVs) on the planning CT scan of each patient. An IMRT plan for volumetric arc therapy (VMAT) was set up for each PTV. Dose parameters of the planned target volume (PTV) and OARs were evaluated and compared, too. RESULTS: The mean volume of the four PTVs ranged from 2138 cc to 2433 cc. The target volumes contoured by the authors based on the recommendations of each group were similar in the pelvis, while they differed significantly in the inguinal region. There were no significant differences between the four target volumes with regard to the dose parameters of the cranially located OARs. Conversely, some dose parameters concerning the genitals and the skin varied significantly among the different guidelines. CONCLUSION: The four contouring guidelines differ significantly concerning the inguinal region. In order to avoid inguinal recurrence and to protect relevant OARs, further investigations are needed to generate uniform standards for definition of the elective clinical target volume in the inguinal region.

Pre-operative cellular dissociation grading in biopsies is highly predictive of post-operative tumour stage and patient outcome in head and neck squamous cell carcinoma.

BACKGROUND: Pre-operative treatment planning in head and neck squamous cell carcinoma (HNSCC) is mainly dictated by clinical staging, which has major shortcomings. Histologic grading is irrelevant due to its lack of prognostic impact. Recently, a novel grading termed Cellular Dissociation Grade (CDG) based on Tumour Budding and Cell Nest Size was shown to be highly prognostic for resected HNSCC. We aimed to probe the predictive and prognostic impact of CDG in the pre-operative biopsies of HNSCC. METHODS: We evaluated CDG in n = 160 pre-therapeutic biopsies from patients who received standardised treatment following German guidelines, and correlated the results with pre- and post-therapeutic staging data and clinical outcome. RESULTS: Pre-operative CDG was highly predictive of post-operative tumour stage, including the prediction of occult lymph node metastasis. Uni- and multivariate analysis revealed CDG to be an independent prognosticator of overall, disease-specific and disease-free survival (p < 0.001). Hazard ratio for disease-specific survival was 6.1 (11.1) for nG2 (nG3) compared with nG1 tumours. CONCLUSIONS: CDG is a strong outcome predictor in the pre-treatment scenario of HNSCC and identifies patients with nodal-negative disease. CDG is a purely histology-based prognosticator in the pre-therapeutic setting that supplements clinical staging and may aide therapeutic stratification of HNSCC patients.

Post-neoadjuvant cellular dissociation grading based on tumour budding and cell nest size is associated with therapy response and survival in oesophageal squamous cell carcinoma.

BACKGROUND: Cellular Dissociation Grade (CDG) composed of tumour budding and cell nest size has been shown to independently predict prognosis in pre-therapeutic biopsies and primary resections of oesophageal squamous cell carcinoma (ESCC). Here, we aimed to evaluate the prognostic impact of CDG in ESCC after neoadjuvant therapy. METHODS: We evaluated cell nest size and tumour budding activity in 122 post-neoadjuvant ESCC resections, correlated the results with tumour regression groups and patient survival and compared the results with data from primary resected cases as well as pre-therapeutic biopsies. RESULTS: CDG remained stable when results from pre-therapeutic biopsies and post-therapeutic resections from the same patient were compared. CDG was associated with therapy response and a strong predictor of overall, disease-specific (DSS) and disease-free (DFS) survival in univariate analysis and-besides metastasis-remained the only significant survival predictor for DSS and DFS in multivariate analysis. Multivariate DFS hazard ratios reached 3.3 for CDG-G2 and 4.9 for CDG-G3 neoplasms compared with CDG-G1 carcinomas (p = 0.016). CONCLUSIONS: CDG is the only morphology-based grading algorithm published to date, which in concert with regression grading, is able to contribute relevant prognostic information in the post-neoadjuvant setting of ESCC.

Outcomes of immediate oncoplastic surgery and adjuvant radiotherapy in breast cancer patients.

BACKGROUND: Oncoplastic surgery techniques lead to a rearrangement of the breast tissue and impede target definition during adjuvant radiotherapy (RT). The aim of this study was to assess local control rates after immediate oncoplastic surgery and adjuvant RT. METHODS: This study comprises 965 patients who underwent breast-conserving therapy and adjuvant RT between 01/2000 and 12/2005. 288 patients received immediate oncoplastic surgery (ONC) and 677 patients breast-conserving surgery only (NONC). All patients were treated with adjuvant external tangential-beam RT (total dose: 50/50.4 Gy; fraction dose 1.8/2.0 Gy). An additional boost dose of 10-16 Gy to the primary tumor bed was given in 900 cases (93.3%). Local control rates (LCR), Progression free survival (PFS) and overall survival (OS) were assessed retrospectively after a median follow-up period of 67 (Q25-Q75: 51-84) months. RESULTS: No significant difference was found between ONC and NONC in regard to LCR (5-yr: ONC 96.8% vs. NONC 95.3%; p = 0.25). This held also true for PFS (5-yr: ONC 92.1% vs. NONC 89.3%; p = 0.09) and OS (5-yr: ONC 96.0% vs. NONC 94.8%; p = 0.53). On univariate analyses G2-3 (p = 0.04), a younger age (p = 0.01), T-stage (p < 0.01) lymph node involvement (p < 0.01) as well as triple negative tumors (p < 0.01) were identified as risk factors for local recurrence. In a propensity score stratified Cox-regression model no significant impact of oncoplastic surgery on local control rate was found (HR: 2.05, 95% CI [0.93; 4.51], p = 0.08). CONCLUSION: Immediate oncoplastic surgery seems not to affect the effectiveness of adjuvant whole breast RT on local control rates in breast cancer patients.

Have we achieved adequate recommendations for target volume definitions in anal cancer? A PET imaging based patterns of failure analysis in the context of established contouring guidelines.

BACKGROUND: There are different contouring guidelines for the clinical target volume (CTV) in anal cancer (AC) which vary concerning recommendations for radiation margins in different anatomical regions, especially on inguinal site. PET imaging has become more important in primary staging of AC as a very sensitive method to detect lymph node (LN) metastases. Using PET imaging, we evaluated patterns of LN spread, and examined the differences of the respective contouring guidelines on the basis of our results. METHODS: We carried out a retrospective study of thirty-seven AC patients treated with chemoradiation (CRT) who underwent FDG-PET imaging for primary staging in our department between 2011 and 2018. Patients showing PET positive LN were included in this analysis. Using a color code, LN metastases of all patients were delineated on a template with "standard anatomy" and were divided indicating whether their location was in- or out-field of the standard CTV as recommended by the Radiation Therapy Oncology Group (RTOG), the Australasian Gastrointestinal Trials Group (AGITG) or the British National Guidance (BNG). Furthermore, a detailed analysis of the location of LN of the inguinal region was performed. RESULTS: Twenty-two out of thirty-seven AC patients with pre-treatment PET imaging had PET positive LN metastases, accumulating to a total of 154 LN. The most commonly affected anatomical region was inguinal (49 LN, 32%). All para-rectal, external/internal iliac, and pre-sacral LN were covered by the recommended CTVs of the three different guidelines. Of forty-nine involved inguinal LN, fourteen (29%), seven (14%) and five (10%) were situated outside of the recommended CTVs by RTOG, AGITG and BNG. Inguinal LN could be located up to 5.7 cm inferiorly to the femoral saphenous junction and 2.8 cm medial or laterally to the big femoral vessels. CONCLUSION: Pelvis-related, various recommendations are largely consistent, and all LN are covered by the recommended CTVs. LN "misses" appear generally cranially (common iliac or para-aortic) or caudally (inguinal) to the recommended CTVs. The established guidelines differ significantly, particular regarding the inguinal region. Based on our results, we presented our suggestions for CTV definition of the inguinal region. LN involvement of a larger number of patients should be investigated to enable final recommendations.

Neoadjuvant versus definitive chemoradiation in patients with squamous cell carcinoma of the esophagus.

BACKGROUND: Multimodal treatment with neoadjuvant chemoradiation followed by surgery (nCRT + S) is the treatment of choice for patients with locally advanced or node-positive esophageal squamous cell carcinoma (E-SCC). Those who are unsuitable or who decline surgery can be treated with definitive chemoradiation (dCRT). This study compares the oncologic outcome of nCRT + S and dCRT in E-SCC patients. METHODS: Between 2011 and 2017, 95 patients with E-SCC were scheduled for dCRT or nCRT+ S with IMRT at our department. Patients undergoing dCRT received at least 50 Gy and those undergoing nCRT + S received at least 41.4 Gy. All patients received simultaneous chemotherapy with either carboplatin and paclitaxel or cisplatin and 5-fluoruracil. We retrospectively compared baseline characteristics and oncologic outcome including overall survival (OS), progression-free survival (PFS) and site of failure between both treatment groups. RESULTS: Patients undergoing dCRT were less likely to have clinically suspected lymph node metastases (85% vs. 100%, p = 0.019) than patients undergoing nCRT + S and had more proximally located tumors (median distance from dental arch to cranial tumor border 20 cm vs. 26 cm, p < 0.001). After a median follow up of 25.6 months for surviving patients, no significant differences for OS and PFS were noticed comparing nCRT + S and dCRT. However, the rate of local tumor recurrence was significantly higher in patients treated with dCRT than in those treated with nCRT + S (38% vs. 10%, p = 0.002). Within a multivariate Cox regression model, age, tumor location, and tumor grading were the only independent parameters affecting OS and PFS. In addition to that, proximal tumor location was the only parameter independently associated with an increased risk for local treatment failure. CONCLUSION: In E-SCC patients treated with either dCRT or nCRT + S, a higher rate of local tumor recurrence was seen in patients treated with dCRT than in patients treated with nCRT + S. There was at least a trend towards an improved OS and PFS in patients undergoing nCRT + S. However, this should be interpreted with caution, because proximal tumor location was the only parameter independently affecting the risk of local tumor recurrence.

Cellular Dissociation Grading Based on the Parameters Tumor Budding and Cell Nest Size in Pretherapeutic Biopsy Specimens Allows for Prognostic Patient Stratification in Esophageal Squamous Cell Carcinoma Independent From Clinical Staging.

Initial treatment planning in esophageal squamous cell carcinoma mainly relies on clinical staging. Recently, a highly prognostic grading system based on the cellular dissociation parameters Tumor Budding and Cell Nest Size has been proposed for resected esophageal squamous cell carcinoma. To probe for the transferability and relevance of this established novel grading system in the pretreatment setting, we evaluated Tumor Budding/Cell Nest Size in pretherapeutic biopsies of either primarily resected (cohort 1, n=80) or neoadjuvantly treated (cohort 2, n=75) esophageal squamous cell carcinoma. Grading data were correlated with clinicopathologic and survival parameters. High Tumor Budding Activity and small Cell Nest Size in pretherapeutic biopsies were strongly associated with shortened overall survival, disease-free survival, and disease-specific survival in both cohorts. A modified histopathologic grading system incorporating both factors termed "Cellular Dissociation Grade" showed excellent prognostic demarcation between well (G1), moderately (G2), and poorly differentiated (G3) carcinomas in both scenarios (overall survival: cohort 1: P<0.001; cohort 2: P=0.009) and was predictive for a high pathologic tumor stage and the presence of nodal metastases in primarily resected patients. Multivariate analyses revealed the Cellular Dissociation Grade to be a predictor of poor outcome in the pretherapeutic setting independent of clinical stage (overall survival, disease-free survival, and disease-specific survival: P<0.001). Hazard ratio for disease-free survival was 3.19 for G2 and 5.66 for G3 carcinomas compared with G1 neoplasms. Our data not only prove the transferability of histopathologic grading based on Tumor Budding/Cell Nest Size to biopsy specimens in esophageal squamous cell carcinoma, but also demonstrate that the Cellular Dissociation Grade is a strong outcome predictor in this entity even in the pretreatment scenario. Therefore, we believe that this novel type of grading has the ability to serve as a powerful histology-based pretherapeutic biomarker, that might supplement clinical staging for choosing the most suitable therapy decision.

Impact of VMAT-IMRT compared to 3D conformal radiotherapy on anal sphincter dose distribution in neoadjuvant chemoradiation of rectal cancer.

BACKGROUND: Neoadjuvant radio- or chemoradiation (nIRT) therapy is the standard treatment for loco-regional advanced rectal cancer patients of the lower or middle third. Currently, intensity modulated radiation therapy (IMRT) is not the recommended radiation technique even though IMRT has advantages compared to 3D-radiation regarding dose sparing to organs at risk like small bowel and urinary bladder. So far, the benefit of IMRT concerning the anal sphincter complex is not examined. With this study we intended to evaluate the dose distribution on the anal sphincters of rectal cancer patients treated with IMRT in comparison with 3D-techniques. METHODS: We selected 16 patients for the IMRT-group and 16 patients for the 3D-group with rectal cancer of the middle third who were treated in our institute. All patients received 45 Gy in a chemoradiation protocol. Patients in both groups were matched regarding stage, primary tumor distance to the anal verge and size of the tumor. We delineated the internal and external anal sphincters, the addition of both sphincters and the levator ani muscle in all patients. Subsequently, we evaluated and compared dose parameters of the different sphincters in both groups and analysed the configuration of the isodoses in the area of the caudal radiation field, respectively. RESULTS: Most of the relevant dose parameters of the caudal sphincters (Dmean, Dmedian, V10-V40) were significantly reduced in the IMRT-group compared to the 3D-group. Accordingly, the isodoses at the caudal edge of the target volume in the IMRT group demonstrated a steep dose fall. The levator ani muscle always was included into the planned target volumes and received the full dose in both groups. CONCLUSIONS: The modern VMAT-IMRT can significantly reduce the dose to the anal sphincters for rectal cancer patients of the middle third who were treated with conventional chemoradiation therapy.