Circulating DNA in patients undergoing loco-regional treatment of colorectal cancer metastases: a systematic review and meta-analysis.

Background: Loco-regional treatment strategies of colorectal cancer (CRC) metastases are evolving, but biological markers that can benefit patients and assist physicians in clinical decisions are lacking. The primary objective of this systematic review and meta-analysis is to investigate the current knowledge on circulating DNA and its clinical utility in predicting outcomes in patients undergoing loco-regional treatment of CRC metastases. Methods: A systematic search of PubMed, Embase, and Cochrane Central Register of Controlled Trials was conducted on March 22, 2022. We included studies on patients undergoing loco-regional treatment of CRC metastases reporting the predictive or prognostic value of circulating DNA in the blood. Hazard ratios (HR) were pooled in separate random-effects meta-analyses to investigate if pre- or post-ablation measurements of circulating DNA were associated with survival. The risk of bias was assessed according to the Quality in Prognosis Studies tool. Results: Twenty-eight studies with 2868 patients were included, of which 16 studies were eligible for meta-analyses. As expected in this new research field, a majority of included studies (n = 21/28) had a high risk of bias in at least one domain. Circulating DNA above the cutoff in a plasma sample taken before loco-regional treatment was associated with a short recurrence-free survival [pooled HR = 2.8, 95% confidence interval (CI) 1.4-5.7, n = 162] and overall survival (pooled HR = 4.7, 95% CI 1.1-20.6, n = 105). Circulating DNA above the cutoff in a plasma sample taken after loco-regional treatment was associated with a short recurrence-free survival (pooled HR = 4.5, 95% CI 3.4-6.1, n = 569) and overall survival (pooled HR = 7.5, 95% CI 2.0-27.3, n = 161). There was limited data on the association between dynamics in circulating DNA and outcome. Conclusions: Measurements of circulating DNA can be valuable when selecting and monitoring patients undergoing loco-regional treatment of CRC metastases. Studies designed to investigate the true clinical utility of circulating DNA in the context of various ablation modalities are warranted.The review has been registered at PROSPERO (ID: CRD42022320032).

Hypofractionation with simultaneous integrated boost after breast-conserving surgery: Long term results of two phase-II trials.

PURPOSE: To analyze long-term results of two multicenter prospective single-arm trials (ARO-2010-01 and ARO-2013-04) investigating adjuvant hypofractionated radiotherapy (HF) with simultaneous integrated boost (SIB) after breast-conserving surgery (BCS). METHODS: Eligible patients had histopathologically confirmed unifocal breast cancer planned for whole breast irradiation plus boost radiotherapy to the tumor bed. In both studies, a total dose of 40 Gy was applied to the whole breast and of 48 Gy to the tumor bed in 16 fractions of 2.5 and 3.0 Gy. Radiotherapy could be given either as three-dimensional conformal radiotherapy (3D-CRT) or as intensity-modulated radiotherapy (IMRT). The primary study objectives were feasibility and security within an observation period of six months. The current investigation focuses on long-term efficacy and toxicities. RESULTS: Between 2011 and 2014, both trials enrolled 300 patients in total. Data from 274 of these patients could be used for the current analysis. The median follow-up time was 60 months and the 5-year disease-free survival 92.1%. Three patients suffered a local recurrence (after 36-72 months) while a regional recurrence occurred in one patient (after 17 months). The 5-year local control rate in the breast was 99.6%. 63.5% of all patients did not report any late radiation-related toxicity, 28.5% reported grade 1 and 7.3% grade 2 toxicities. The highest late toxicity was grade 3 in 2 women (0.7%, telangiectasia and lymphedema of the breast). CONCLUSION: Our analysis demonstrates favorable efficacy and low rates of long-term side effects of HF with SIB after BCS. Randomized controlled phase III trials are ongoing.

Stereotactic body radiotherapy of adrenal metastases-A dose-finding study.

Optimal doses for the treatment of adrenal metastases with stereotactic radiotherapy (SBRT) are unknown. We aimed to identify dose-volume cut-points associated with decreased local recurrence rates (LRR). A multicenter database of patients with adrenal metastases of any histology treated with SBRT (biologically effective dose, BED10 ≥50 Gy, ≤12 fractions) was analyzed. Details on dose-volume parameters were required (planning target volume: PTV-D98%, PTV-D50%, PTV-D2%; gross tumor volume: GTV-D50%, GTV-mean). Cut-points for LRR were optimized using the R maxstat package. One hundred and ninety-six patients with 218 lesions were included, the largest histopathological subgroup was adenocarcinoma (n = 101). Cut-point optimization resulted in significant cut-points for PTV-D50% (BED10: 73.2 Gy; P = .003), GTV-D50% (BED10: 74.2 Gy; P = .006), GTV-mean (BED10: 73.0 Gy; P = .007), and PTV-D2% (BED10: 78.0 Gy; P = .02) but not for the PTV-D98% (P = .06). Differences in LRR were clinically relevant (LRR ≥ doubled for cut-points that were not achieved). Further dose-escalation was not associated with further improved LRR. PTV-D50%, GTV-D50%, and GTV-mean cut-points were also associated with significantly improved LRR in the adenocarcinoma subgroup. Separate dose optimizations indicated a lower cut-point for the PTV-D50% (BED10: 69.1 Gy) in adenocarcinoma lesions, other values were similar (<2% difference). Associations of cut-points with overall survival (OS) and progression-free survival were not significant but durable freedom from local recurrence was associated with OS in a landmark model (P < .001). To achieve a significant improvement of LRR for adrenal SBRT, a moderate escalation of PTV-D50% BED10 >73.2 Gy (adenocarcinoma: 69.1 Gy) should be considered.

Trends in radiotherapy inpatient admissions in Germany: a population-based study over a 10-year period.

OBJECTIVE: With the increasing complexity of oncological therapy, the number of inpatient admissions to radiotherapy and non-radiotherapy departments might have changed. In this study, we aim to quantify the number of inpatient cases and the number of radiotherapy fractions delivered under inpatient conditions in radiotherapy and non-radiotherapy departments. METHODS: The analysis is founded on data of all hospitalized cases in Germany based on Diagnosis-Related Group Statistics (G-DRG Statistics, delivered by the Research Data Centers of the Federal Statistical Office). The dataset includes information on the main diagnosis of cases (rather than patients) and the performed procedures during hospitalization based on claims of reimbursement. We used linear regression models to analyze temporal trends. The considered data encompass the period from 2008 to 2017. RESULTS: Overall, the number of patients treated with radiotherapy as inpatients remained constant between 2008 (N = 90,952) and 2017 (N = 88,998). Starting in January 2008, 48.9% of 4000 monthly cases received their treatment solely in a radiation oncology department. This figure decreased to 43.7% of 2971 monthly cases in October 2017. We found a stepwise decrease between December 2011 and January 2012 amounting to 4.3%. Fractions received in radiotherapy departments decreased slightly by 29.3 (95% CI: 14.0-44.5) fractions per month. The number of days hospitalized in radiotherapy departments decreased by 83.4 (95% CI: 59.7, 107.0) days per month, starting from a total of 64,842 days in January 2008 to 41,254 days in 2017. Days per case decreased from 16.2 in January 2008 to 13.9 days in October 2017. CONCLUSION: Our data give evidence to the notion that radiotherapy remains a discipline with an important inpatient component. Respecting reimbursement measures and despite older patients with more comorbidities, radiotherapy institutions could sustain a constant number of cases with limited temporal shifts.

Stereotactic or conformal radiotherapy for adrenal metastases: Patient characteristics and outcomes in a multicenter analysis.

To report outcome (freedom from local progression [FFLP], overall survival [OS] and toxicity) after stereotactic, palliative or highly conformal fractionated (>12) radiotherapy (SBRT, Pall-RT, 3DCRT/IMRT) for adrenal metastases in a retrospective multicenter cohort within the framework of the German Society for Radiation Oncology (DEGRO). Adrenal metastases treated with SBRT (≤12 fractions, biologically effective dose [BED10] ≥ 50 Gy), 3DCRT/IMRT (>12 fractions, BED10 ≥ 50 Gy) or Pall-RT (BED10 < 50 Gy) were eligible for this analysis. In addition to unadjusted FFLP (Kaplan-Meier/log-rank), we calculated the competing-risk-adjusted local recurrence rate (CRA-LRR). Three hundred twenty-six patients with 366 metastases were included by 21 centers (median follow-up: 11.7 months). Treatment was SBRT, 3DCRT/IMRT and Pall-RT in 260, 27 and 79 cases, respectively. Most frequent primary tumors were non-small-cell lung cancer (NSCLC; 52.5%), SCLC (16.3%) and melanoma (6.7%). Unadjusted FFLP was higher after SBRT vs Pall-RT (P = .026) while numerical differences in CRA-LRR between groups did not reach statistical significance (1-year CRA-LRR: 13.8%, 17.4% and 27.7%). OS was longer after SBRT vs other groups (P < .05) and increased in patients with locally controlled metastases in a landmark analysis (P < .0001). Toxicity was mostly mild; notably, four cases of adrenal insufficiency occurred, two of which were likely caused by immunotherapy or tumor progression. Radiotherapy for adrenal metastases was associated with a mild toxicity profile in all groups and a favorable 1-year CRA-LRR after SBRT or 3DCRT/IMRT. One-year FFLP was associated with longer OS. Dose-response analyses for the dataset are underway.

[Myocardial infarction in a young patient with seminoma during chemotherapy with cisplatinum, etoposide, and bleomycin]. / Myokardinfarkt bei jungem Seminompatient während Chemotherapie mit Cisplatin, Etoposid und Bleomycin (PEB-Schema).

INTRODUCTION: More than 90 % of all patients with testicular germ cell tumours can be cured effectively. The mainstay of treatment is chemotherapy with cisplatin, etoposide and bleomycin (PEB). This regimen is usually well tolerated and does not lead to serious adverse events. Cardiovascular complications are encountered very rarely, but have gained increasing attention in recent years. CASE DESCRIPTION: A 33-year-old man with a testicular seminoma, clinical stage 2b, was subjected to PEB chemotherapy. At the end of the first treatment course, he had an acute ST-elevation myocardial infarction. Coronary angiography revealed a circumscribed stenosis of the left circumflex branch of the left coronary artery with intima dissection and thrombotic deposits. No atherosclerotic changes were found. Management consisted of placement of a drug-eluting coronary stent. Chemotherapy was discontinued and the seminoma treatment completed by radiotherapy with 30 Gy applied to the retroperitoneal mass and a paraaortic template. Complete remission was achieved. 6 months thereafter, the patient was doing well and was disease-free. COMMENT: About 0.3 % of all testis cancer patients undergoing cisplatin-based chemotherapy develop cardiovascular complications. Cisplatin-related endothelial damage with secondary thrombotic clotting is assumed to be etiologic in these cases. As there is little comorbidity, the prognostic outlook is favourable in most cases. Caregivers in charge of testis cancer management should be vigilant regarding cardiovascular complications to ensure immediate diagnostic and therapeutic measures in incident cases.

Adjuvant hypofractionated radiotherapy with simultaneous integrated boost after breast-conserving surgery: results of a prospective trial.

PURPOSE: We report results of a multicenter prospective single-arm phase II trial (ARO-2013-04, NCT01948726) of moderately accelerated hypofractionated radiotherapy with a simultaneous integrated boost (SIB) in patients with breast cancer receiving adjuvant radiotherapy after breast-conserving surgery. METHODS: The eligibility criteria included unifocal breast cancer with an indication for adjuvant radiotherapy to the whole breast and boost radiotherapy to the tumor bed. The whole breast received a dose of 40 Gy and the tumor bed a total dose of 48 Gy in 16 fractions of 2.5 and 3 Gy, respectively. Radiotherapy could be given either as 3D conformal RT (3D-CRT) or as intensity-modulated radiotherapy (IMRT). The study was designed as a prospective single-arm trial to evaluate the acute toxicity of the treatment regimen. The study hypothesis was that the frequency of acute skin reaction grade ≥2 would be 20% or less. RESULTS: From November 2013 through July 2014, 149 patients were recruited from 12 participating centers. Six patients were excluded, leaving 143 patients for analysis. Eighty-four patients (58.7%) were treated with 3D-CRT and 59 (41.3%) with IMRT. Adherence to the treatment protocol was high. The rate of grade ≥2 skin toxicity was 14.7% (95% confidence interval 9.8-21.4%). The most frequent grade 3 toxicity (11%) was hot flashes. CONCLUSION: This study demonstrated low toxicity of and high treatment adherence to hypofractionated adjuvant radiotherapy with SIB in a multicenter prospective trial, although the primary hypothesis was not met.

Clinical relevance of metal artefact reduction in computed tomography (iMAR) in the pelvic and head and neck region: Multi-institutional contouring study of gross tumour volumes and organs at risk on clinical cases.

INTRODUCTION: Artefacts caused by dental implants and hip replacements may impede target volume definition and dose calculation accuracy. The iterative metal artefact reduction (iMAR) algorithm can provide a solution for this problem. The present study compares delineation of gross tumour volumes (GTVs) and organs at risk (OARs) in the pelvic and the head and neck (H & N) regions using computed tomography (CT) with and without iMAR, and thus the practical applicability of iMAR for routine clinical use. METHODS: The native planning CT and CT-iMAR data of two typical clinical cases with image-distorting artefacts were used for multi-institutional contouring and analysis using the Dice similarity coefficient (DSC). GTV/OAR contours were compared with an intraobserver approach and compared to predefined reference structures. RESULTS: Mean volume for GTVprostate in the intraobserver approach decreased from 87 ± 44 cm3 (native CT) to 75 ± 22 cm3 (CT-iMAR) (P = 0.168). Compared to the reference, DSC values for GTVP rostate increased from 0.68 ± 0.15 to 0.78 ± 0.07 (CT vs. iMAR) (P < 0.05). In the H & N region, the reference for GTVT ongue (34 cm3 ) was underestimated on both data sets. No significant improvement in DSC values (0.83 ± 0.06 (native CT) versus 0.86 ± 0.06 (CT-iMAR)) was observed. CONCLUSION: The use of iMAR improves the anatomical delineation at the transition of prostate and bladder in cases of bilateral hip replacement. In the H & N region, anatomical residual structures and experience were apparently sufficient for precise contouring.

Radiological Patterns of Brain Metastases in Breast Cancer Patients: A Subproject of the German Brain Metastases in Breast Cancer (BMBC) Registry.

Evidence about distribution patterns of brain metastases with regard to breast cancer subtypes and its influence on the prognosis of patients is insufficient. Clinical data, cranial computed tomography (CT) and magnetic resonance imaging (MRI) scans of 300 breast cancer patients with brain metastases (BMs) were collected retrospectively in four centers participating in the Brain Metastases in Breast Cancer Registry (BMBC) in Germany. Patients with positive estrogen (ER), progesterone (PR), or human epidermal growth factor receptor 2 (HER2) statuses, had a significantly lower number of BMs at diagnosis. Concerning the treatment mode, HER2-positive patients treated with trastuzumab before the diagnosis of BMs showed a lower number of intracranial metastases (p < 0.001). Patients with a HER2-positive tumor-subtype developed cerebellar metastases more often compared with HER2-negative patients (59.8% vs. 44.5%, p = 0.021), whereas patients with triple-negative primary tumors had leptomeningeal disease more often (31.4% vs. 18.3%, p = 0.038). The localization of Brain metastases (BMs) was associated with prognosis: patients with leptomeningeal disease had shorter survival compared with patients without signs of leptomeningeal disease (median survival 3 vs. 5 months, p = 0.025). A shorter survival could also be observed in the patients with metastases in the occipital lobe (median survival 3 vs. 5 months, p = 0.012). Our findings suggest a different tumor cell homing to different brain regions depending on subtype and treatment.

Treatment of breast cancer with simultaneous integrated boost in hybrid plan technique : Influence of flattening filter-free beams.

OBJECTIVE: The present study compares in silico treatment plans using hybrid plan technique during hypofractionated radiation of mammary carcinoma with simultaneous integrated boost (SIB). The influence of 6 MV photon radiation in flattening filter free (FFF) mode against the clinical standard flattening filter (FF) mode is to be examined. PATIENTS AND METHODS: RT planning took place with FF and FFF radiation plans for 10 left-sided breast cancer patients. Hybrid plans were realised with two tangential IMRT fields and one VMAT field. The dose prescription was in line with the guidelines in the ARO-2010-01 study. The dosimetric verification took place with a manufacturer-independent measurement system. RESULTS: Required dose prescriptions for the planning target volumes (PTV) were achieved for both groups. The average dose values of the ipsi- and contralateral lung and the heart did not differ significantly. The overall average incidental dose to the left anterior descending artery (LAD) of 8.24 ± 3.9 Gy in the FFF group and 9.05 ± 3.7 Gy in the FF group (p < 0.05) were found. The dosimetric verifications corresponded to the clinical requirements. FFF-based RT plans reduced the average treatment time by 17 s/fraction. CONCLUSION: In comparison to the FF-based hybrid plan technique the FFF mode allows further reduction of the average LAD dose for comparable target volume coverage without adverse low-dose exposure of contralateral structures. The combination of hybrid plan technique and 6 MV photon radiation in the FFF mode is suitable for use with hypofractionated dose schemes. The increased dose rate allows a substantial reduction of treatment time and thus beneficial application of the deep inspiration breath hold technique.

Heart dose reduction in breast cancer treatment with simultaneous integrated boost: Comparison of treatment planning and dosimetry for a novel hybrid technique and 3D-CRT.

OBJECTIVE: The present study compares in silico treatment plans of clinically established three-dimensional conformal radiotherapy (3D-CRT) with a hybrid technique consisting of intensity-modulated radiotherapy (IMRT) and volumetric modulated arc radiotherapy (VMAT) during normally fractionated radiation of mammary carcinomas with simultaneous integrated boost on the basis of dose-volume histogram (DVH) parameters. PATIENTS AND METHODS: Radiation treatment planning was performed with a hybrid and a 3D-CRT treatment plan for 20 patients. Hybrid plans were implemented with two tangential IMRT fields and a VMAT field in the angular range of the tangents. Verification of the plan was performed with a manufacturer-independent measurement system consisting of a detector array and rotation unit. RESULTS: The mean values of the heart dose for the entire patient collective were 3.6 ± 2.5 Gy for 3D-CRT and 2.9 ± 2.1 Gy for the hybrid technique (p < 0.01). For the left side (n = 10), the mean values for the left anterior descending artery were 21.8 ± 7.4 Gy for 3D-CRT and 17.6 ± 7.4 Gy for the hybrid technique (p < 0.01). The mean values of the ipsilateral lung were 11.9 ± 1.6 Gy for 3D-CRT and 10.5 ± 1.3 Gy for the hybrid technique (p < 0.01). Calculated dose distributions in the hybrid arm were in good accordance with measured dose (on average 95.6 ± 0.5 % for γ < 1 and 3 %/3 mm). The difference of the mean treatment time per fraction was 7 s in favor of 3D-CRT. CONCLUSION: Compared with the established 3D-CRT technique, the hybrid technique allows for a decrease in dose, particularly of the mean heart and lung dose with comparable target volume acquisition and without disadvantageous low-dose load of contralateral structures. Uncomplicated implementation of the hybrid technique was demonstrated in this context. The hybrid technique combines the advantages of tangential IMRT with the superior sparing of organs at risk by VMAT.

Incidental dose to coronary arteries is higher in prone than in supine whole breast irradiation. A dosimetric comparison in adjuvant radiotherapy of early stage breast cancer.

PURPOSE: Sparing of normal lung is best achieved in prone whole breast irradiation (WBI). However, exposure of the heart and coronary arteries might increase due to anterior movement of the heart in prone WBI. PATIENTS AND METHODS: Treatment plans of 46 patients with large breasts irradiated for mammary cancer after breast-conserving surgery were retrospectively analyzed. The average treated breast volume of right-sided breasts (n = 33) was 1,804 ccm and 1,500 ccm for left-sided breasts (n = 13). The majority had invasive cancer (96 %) of which 61 % were pT1 and 39 % pT2 tumors. All patients received radiation therapy to the breast only. For three-dimensional (3D) treatment planning, all patients underwent a noncontrast-enhanced CT in the supine position with a wingboard and a second CT in the prone position using a prone breastboard. Nontarget volumes of the lung, heart, and coronary arteries were contoured. A total dose of 50.4 Gy was prescribed to the breast only. Differences were calculated for each patient and compared using the Wilcoxon signed-rank test. RESULTS: Treatment of left-sided breasts resulted in similar average mean heart doses in prone versus supine WBI (4.16 vs. 4.01 Gy; p = 0.70). The left anterior descending artery (LAD) had significantly higher dose exposure in left versus right WBI independent of position. Prone WBI always resulted in significantly higher exposures of the right circumflex artery (RCA) and LAD as compared to supine WBI. In left WBI, the mean LADprone was 33.5 Gy vs. LADsupine of 25.6 Gy (p = 0.0051). The V20prone of the LAD was 73.6 % vs. V20supine 50.4 % (p = 0.0006). CONCLUSION: The heart dose is not different between supine and prone WBI. However, in left WBI the incidental dose to the LAD with clinically relevant doses can be significantly higher in prone WBI. This is discussed controversially in the literature as it might depend on contouring and treatment techniques. We recommend contouring of LAD if patients are treated in prone WBI and evaluation of alternative treatment techniques for optimal sparing of coronary arteries.

The impact of flattening-filter-free beam technology on 3D conformal RT.

BACKGROUND: The removal of the flattening filter (FF) leads to non-uniform fluence distribution with a considerable increase in dose rate. It is possible to adapt FFF beams (flattening-filter-free) in 3D conformal radiation therapy (3D CRT) by using field in field techniques (FiF). The aim of this retrospective study is to clarify whether the quality of 3D CRT plans is influenced by the use of FFF beams. METHOD: This study includes a total of 52 CT studies of RT locations that occur frequently in clinical practice. Dose volume targets were provided for the PTV of breast (n=13), neurocranium (n=11), lung (n=7), bone metastasis (n=10) and prostate (n=11) in line with ICRU report 50/62. 3D CRT planning was carried out using FiF methods. Two clinically utilized photon energies are used for a Siemens ARTISTE linear accelerator in FFF mode at 7MVFFF and 11MVFFF as well as in FF mode at 6MVFF and 10MVFF. The plan quality in relation to the PTV coverage, OAR (organs at risk) and low dose burden as well as the 2D dosimetric verification is compared with FF plans. RESULTS: No significant differences were found between FFF and FF plans in the mean dose for the PTV of breast, lung, spine metastasis and prostate. The low dose parameters V5Gy and V10Gy display significant differences for FFF and FF plans in some subgroups. The DVH analysis of the OAR revealed some significant differences. Significantly more fields (1.9-4.5) were necessary in the use of FFF beams for each location (p<0.0001) in order to achieve PTV coverage. All the tested groups displayed significant increases (1.3-2.2 times) in the average number of necessary MU with the use of FFF beams (p<0.001). CONCLUSIONS: This study has shown that the exclusive use of a linear accelerator in FFF mode is feasible in 3D CRT. It was possible to realize RT plans in comparable quality in typical cases of clinical radiotherapy. The 2D dosimetric validation of the modulated fields verified the dose calculation and thus the correct reproduction of the characteristic FFF parameters in the planning system that was used.

Phase II trial of preoperative radiochemotherapy with concurrent bevacizumab, capecitabine and oxaliplatin in patients with locally advanced rectal cancer.

BACKGROUND: Preoperative radiochemotherapy (RCT) with 5-FU or capecitabine is the standard of care for patients with locally advanced rectal cancer (LARC). Preoperative RCT achieves pathological complete response rates (pCR) of 10-15%. We conducted a single arm phase II study to investigate the feasibility and efficacy of addition of bevacizumab and oxaliplatin to preoperative standard RCT with capecitabine. METHODS: Eligible patients had LARC (cT3-4; N0/1/2, M0/1) and were treated with preoperative RCT prior to planned surgery. Patients received conventionally fractionated radiotherapy (50.4 Gy in 1.8 Gy fractions) and simultaneous chemotherapy with capecitabine 825 mg/m2 bid (d1-14, d22-35) and oxaliplatin 50 mg/m2 (d1, d8, d22, d29). Bevacizumab 5 mg/kg was added on days 1, 15, and 29. The primary study objective was the pCR rate. RESULTS: 70 patients with LARC (cT3-4; N0/1, M0/1), ECOG < 2, were enrolled at 6 sites from 07/2008 through 02/2010 (median age 61 years [range 39-89], 68% male). At initial diagnosis, 84% of patients had clinical stage T3, 62% of patients had nodal involvement and 83% of patients were M0. Mean tumor distance from anal verge was 5.92 cm (± 3.68). 58 patients received the complete RCT (full dose RT and full dose of all chemotherapy). During preoperative treatment, grade 3 or 4 toxicities were experienced by 6 and 2 patients, respectively: grade 4 diarrhea and nausea in one patient (1.4%), respectively, grade 3 diarrhea in 2 patients (3%), grade 3 obstipation, anal abscess, anaphylactic reaction, leucopenia and neutropenia in one patient (1.4%), respectively. In total, 30 patients (46%) developed postoperative complications of any grade including one gastrointestinal perforation in one patient (2%), wound-healing problems in 7 patients (11%) and bleedings in 2 patients (3%). pCR was observed in 12/69 (17.4%) patients. Pathological downstaging (ypT < cT and ypN ≤ cN) was achieved in 31 of 69 patients (44.9%). All of the 66 operated patients had a R0 resection. 47 patients (68.1%) underwent sphincter preserving surgery. CONCLUSIONS: The addition of bevacizumab and oxaliplatin to RCT with capecitabine was well tolerated and did not increase perioperative morbidity or mortality. However, the pCR rate was not improved in comparison to other trials that used capecitabine or capecitabine/oxaliplatin in preoperative radiochemotherapy.

The impact of direct aperture optimization on plan quality and efficiency in complex head and neck IMRT.

BACKGROUND: Conventional step&shoot intensity modulated radio therapy (IMRT) approaches potentially lead to treatment plans with high numbers of segments and monitor units (MU) and, therefore, could be time consuming at the linear accelerator. Direct optimization methods are able to reduce the complexity without degrading the quality of the plan. The aim of this study is the evaluation of different IMRT approaches at standardized conditions for head and neck tumors. METHOD: For 27 patients with carcinomas in the head and neck region a planning study with a 2-step-IMRT system (KonRad), a direct optimization system (Panther DAO) and a mixture of both approaches (MasterPlan DSS) was created. In order to avoid different prescription doses for boost volumes a simple standardization was realized. The dose was downscaled to 50 Gy to the planning target volume (PTV) which included the primary tumor as well as the bilateral lymphatic drainage (cervical and supraclavicular). Dose restrictions for the organs at risk (OAR) were downscaled to this prescription from high dose concepts up to 72 Gy. Those limits were defined as planning objectives while reaching definable PTV coverage with a standardized field setup. The parameters were evaluated from the corresponding dose volume histogram (DVH). Special attention was paid to the efficiency of the method, measured by means of calculated MU and required segments. Statistical tests of significance were applied to quantify the differences between the evaluated systems. RESULTS: PTV coverage for all systems in terms of V90% and V95% fell short of the requested 100% and 95%, respectively, but were still acceptable (range: 98.7% to 99.1% and 94.2% to 94.7%). Overall for OAR sparing and the burden of healthy tissue with low doses no technique was superior for all evaluated parameters. Differences were found for the number of segments where the direct optimization systems generated less segments. Lowest average numbers of MU were 308 by Panther DAO calculated for 2 Gy fractions. Based on these findings the treatment time at the linear accelerator is the lowest for Panther DAO. CONCLUSIONS: All IMRT approaches implemented in the different treatment planning systems (TPS) generated clinically acceptable and comparable plans. No superior system in terms of PTV coverage and OAR sparing was found. Major differences in efficiency of the method in terms of calculated MU and treatment times were found.

Randomized phase III trial of sequential adjuvant chemoradiotherapy with or without erythropoietin Alfa in patients with high-risk cervical cancer: results of the NOGGO-AGO intergroup study.

PURPOSE: This open-label, randomized phase III study was designed to investigate the effects of erythropoietin alfa (EPO) in addition to adjuvant chemotherapy and pelvic radiotherapy (CRT) in patients with stage IB to II cervical cancer who had undergone radical hysterectomy. PATIENTS AND METHODS: Two hundred fifty-seven patients were randomly assigned to four cycles of carboplatin/ifosfamide chemotherapy followed by external-beam pelvic radiotherapy (CRT group) or four cycles of carboplatin/ifosfamide chemotherapy and EPO followed by pelvic radiotherapy and EPO (CRT + EPO group). The primary end point was recurrence-free survival (RFS). Secondary end points included overall survival (OS), change in hemoglobin levels, and safety, including thromboembolic events. RESULTS: The estimated 5-year RFS rates were 78% for patients receiving CRT + EPO and 70% for patients receiving CRT. There was no statistically significant difference in RFS, although a trend favoring patients treated with CRT + EPO was observed (hazard ratio [HR], 0.66; 95% CI, 0.39 to 1.12; log-rank P = .06). Exploratory analyses suggest a benefit with CRT + EPO for patients with stage IB to IIA disease (HR, 0.39; 95% CI, 0.18 to 0.85; P = .014) or patients with complete resection (HR, 0.55; 95% CI, 0.31 to 0.98; P = .039). OS was similar in both groups (HR, 0.88; 95% CI, 0.51 to 1.50; log-rank P = .63). Patients treated with EPO maintained higher hemoglobin levels throughout CRT. No significant differences in safety profiles were observed between the two groups. Incidence of thrombovascular events was low (2%) and comparable between both groups. CONCLUSION: This study confirms that EPO can be added safely to CRT in patients with cervical cancer, but it failed to demonstrate a significant benefit in RFS and OS.

[18F]fluoroethylcholine-PET/CT imaging for radiation treatment planning of recurrent and primary prostate cancer with dose escalation to PET/CT-positive lymph nodes.

BACKGROUND: At present there is no consensus on irradiation treatment volumes for intermediate to high-risk primary cancers or recurrent disease. Conventional imaging modalities, such as CT, MRI and transrectal ultrasound, are considered suboptimal for treatment decisions. Choline-PET/CT might be considered as the imaging modality in radiooncology to select and delineate clinical target volumes extending the prostate gland or prostate fossa. In conjunction with intensity modulated radiotherapy (IMRT) and imaged guided radiotherapy (IGRT), it might offer the opportunity of dose escalation to selected sites while avoiding unnecessary irradiation of healthy tissues. METHODS: Twenty-six patients with primary (n = 7) or recurrent (n = 19) prostate cancer received Choline-PET/CT planned 3D conformal or intensity modulated radiotherapy. The median age of the patients was 65 yrs (range 45 to 78 yrs). PET/CT-scans with F18-fluoroethylcholine (FEC) were performed on a combined PET/CT-scanner equipped for radiation therapy planning. The majority of patients had intermediate to high risk prostate cancer. All patients received 3D conformal or intensity modulated and imaged guided radiotherapy with megavoltage cone beam CT. The median dose to primary tumours was 75.6 Gy and to FEC-positive recurrent lymph nodal sites 66,6 Gy. The median follow-up time was 28.8 months. RESULTS: The mean SUV(max) in primary cancer was 5,97 in the prostate gland and 3,2 in pelvic lymph nodes. Patients with recurrent cancer had a mean SUV(max) of 4,38. Two patients had negative PET/CT scans. At 28 months the overall survival rate is 94%. Biochemical relapse free survival is 83% for primary cancer and 49% for recurrent tumours. Distant disease free survival is 100% and 75% for primary and recurrent cancer, respectively. Acute normal tissue toxicity was mild in 85% and moderate (grade 2) in 15%. No or mild late side effects were observed in the majority of patients (84%). One patient had a severe bladder shrinkage (grade 4) after a previous treatment with TUR of the prostate and seed implantation. CONCLUSIONS: FEC-PET/CT planning could be helpful in dose escalation to lymph nodal sites of prostate cancer.

Late Toxicity of Radiotherapy: A Problem or a Challenge for the Radiation Oncologist?

BACKGROUND: Large randomized clinical trials have established radiotherapy in conjunction with adjuvant systemic treatment as standard treatment in breast cancer after both mastectomy and lumpectomy. Although standard radiation therapy is well tolerated by the majority of patients, some patients might suffer from late normal tissue effects. METHODS: The literature on radiotherapy following surgery of breast cancer was reviewed with regard to late toxicity. RESULTS: Radiotherapy may, to some degree, cause persistent pain in the breast, arm and shoulder in up to 30-50% of patients after 3-5 years, lymphedema in 15-25%, and restriction of arm and shoulder movement in 35%. Awareness of cardiotoxicity is needed since anthracyclines, trastuzumab, and radiotherapy may cause damage to the heart. However, using modern radiotherapy techniques, the available evidence does not suggest a higher incidence of cardiac mortality. CONCLUSIONS: This review updates the database on toxicity from radiation in breast cancer. Advances in research of radiation-induced late effects may lead to improved treatment choices for breast cancer patients including radiotherapy and may improve quality of life after surviving breast cancer.