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Background: Soft tissue sarcomas (STS) represent a diverse group of rare malignant tumors. Currently, five to six weeks of preoperative radiotherapy (RT) combined with surgery constitute the mainstay of therapy for localized high-grade sarcomas (G2-G3). Growing evidence suggests that shortening preoperative RT courses by hypofractionation neither increases toxicity rates nor impairs oncological outcomes. Instead, shortening RT courses may improve therapy adherence, raise cost-effectiveness, and provide more treatment opportunities for a wider range of patients. Presumed higher rates of adverse effects and worse outcomes are concerns about hypofractionated RT (HFRT) for STS. This systematic review summarizes the current evidence on preoperative HFRT for the treatment of STS and discusses toxicity and oncological outcomes compared to normofractionated RT., Methods: We conducted a systematic review of clinical trials describing outcomes for preoperative HFRT in the management of STS using PubMed, the Cochrane library, the Cochrane Central Register of Controlled Trials, ClinicalTrials.gov, Embase, and Ovid Medline. We followed the 2020 Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Trials on retroperitoneal sarcomas, postoperative RT, and hyperthermia were excluded. Articles published until November 30th, 2021, were included., Results: Initial search yielded 94 articles. After removal of duplicate and ineligible articles, 13 articles qualified for analysis. Eight phase II trials and five retrospective analyses were reviewed. Most trials applied 5 × 5 Gy preoperatively in patients with high-grade STS. HFRT courses did not show increased rates of adverse events compared to historical trials of normofractionated RT. Toxicity rates were mostly comparable or lower than in trials of normofractionated RT. Moreover, HFRT achieved comparable local control rates with shorter duration of therapy. Currently, more than 15 prospective studies on HFRT + / - chemotherapy are ongoing., Conclusions: Retrospective data and phase II trials suggest preoperative HFRT to be a reasonable treatment modality for STS. Oncological outcomes and toxicity profiles were favorable. To date, our knowledge is mostly derived from phase II data. No randomized phase III trial comparing normofractionated and HFRT in STS has been published yet. Multiple ongoing phase II trials applying HFRT to investigate acute and late toxicity will hopefully bring forth valuable findings., (© 2022. The Author(s).)

Background: Proton beam therapy is a well-established treatment option for patients with uveal melanoma (UM). The treatment procedure, in general, includes placing radiopaque clips to ensure exact eye-positioning during radiotherapy, followed by the delivery of proton irradiation. The short-term burden associated with proton therapy in patients with UM has rarely been addressed. In this prospective study, we investigated the physiological and psychological aspects of proton therapy that might affect the well-being of patients during the different stages of treatment., Methods: During the treatment procedure, we conducted longitudinal assessments of the Quality of life (QOL), organ-specific symptoms, and psychological aspects in patients with UM with three questionnaires (EORTC QLQ-C30, EORTC QLQ-OPT30, and GAD-7). Patients completed questionnaires before clip surgery (T0), before proton therapy (T1), after completing treatment (T2), and three months after treatment completion (T3). We also collected data on tumor characteristics and socio-demographics to identify potential risk factors associated with high treatment burdens., Results: We prospectively included 131 consecutive patients. Questionnaire data showed a significant, temporary decline in global QOL and an increase in eye-related symptoms, as a result of the clip surgery (T0-T1). After treatment completion (T2), global QOL improved gradually, and none of the eye-related symptoms significantly deteriorated over the course of proton therapy. The global QOL returned to baseline levels three months after treatment (T3). We identified baseline anxiety as an independent risk factor for experiencing an acute treatment-related burden. Furthermore, we found interactions between GAD7 and patient sex showing that anxiety had a more pronounced effect on QOL outcome in female patients., Conclusion: The short-term treatment-related burden of ocular proton therapy appeared to be largely associated with the preceding clip surgery, rather than the irradiation procedure. We found that anxiety was strongly associated with experiencing QOL issues during the treatment procedure. Our findings could contribute to the development of future strategies for improving the treatment process and psycho-oncologic patient care., (© 2021. The Author(s).)

Background: Radiochemotherapy (RCT) has been shown to induce changes in immune cell homeostasis which might affect antitumor immune responses. In the present study, we aimed to compare the composition and kinetics of major lymphocyte subsets in the periphery of patients with non-locoregional recurrent (n = 23) and locoregional recurrent (n = 9) squamous cell carcinoma of the head and neck (SCCHN) upon primary RCT., Methods: EDTA-blood of non-locoregional recurrent SCCHN patients was collected before (t0), after application of 20-30 Gy (t1), in the follow-up period 3 (t2) and 6 months (t3) after RCT. In patients with locoregional recurrence blood samples were taken at t0, t1, t2 and at the time of recurrence (t5). EDTA-blood of age-related, healthy volunteers (n = 22) served as a control (Ctrl). Major lymphocyte subpopulations were phenotyped by multiparameter flow cytometry., Results: Patients with non-recurrent SCCHN had significantly lower proportions of CD19 + B cells compared to healthy individuals before start of any therapy (t0) that dropped further until 3 months after RCT (t2), but reached initial levels 6 months after RCT (t3). The proportion of CD3 + T and CD3 + /CD4 + T helper cells continuously decreased between t0 and t3, whereas that of CD8 + cytotoxic T cells and CD3 + /CD56 + NK-like T cells (NKT) gradually increased in the same period of time in non-recurrent patients. The percentage of CD4 + /CD25 + /FoxP3 + regulatory T cells (Tregs) decreased directly after RCT, but increased above initial levels in the follow-up period 3 (t2) and 6 (t3) months after RCT. Patients with locoregional recurrence showed similar trends with respect to B, T cells and Tregs between t0 and t5. CD4 + T helper cells remained stably low between t0 and t5 in patients with locoregional recurrence compared to Ctrl. NKT/NK cell subsets (CD56 + /CD69 + , CD3 - /CD56 + , CD3 - /CD94 + , CD3 - /NKG2D + , CD3 - /NKp30 + , CD3 - /NKp46 + ) increased continuously up to 6 months after RCT (t0-t3) in patients without locoregional recurrence, whereas in patients with locoregional recurrence, these subsets remained stably low until time of recurrence (t5)., Conclusion: Monitoring the kinetics of lymphocyte subpopulations especially activatory NK cells before and after RCT might provide a clue with respect to the development of an early locoregional recurrence in patients with SCCHN. However, studies with larger patient cohorts are needed., Trial Registration: Observational Study on Biomarkers in Head and Neck Cancer (HNprädBio), NCT02059668. Registered on 11 February 2014, https://clinicaltrials.gov/ct2/show/NCT02059668 ., (© 2021. The Author(s).)

Background: Liver compresses are frequently used in integrative medicine as supportive therapy during cancer treatment in order to reduce fatigue. We performed a pilot study to test whether the external application of yarrow liver compresses impacts fatigue in patients with metastatic cancer undergoing radiation therapy., Methods: A randomized prospective pilot trial was performed including patients with brain metastasis or bone metastasis of solid tumors. Patients underwent either palliative radiation therapy (RT) of the metastatic lesions (control group) over two weeks or the same RT with additional external application of yarrow liver compresses once daily during RT. The primary objective was improvement on the general fatigue subscale of the multidimensional fatigue inventory (MFI-20) at the end of treatment, where a mean difference of two points is considered clinically relevant. Secondary objectives included psychological distress, quality of life and qualitative analysis with self-established visual analogue scales (VAS). Mean differences in general fatigue at the end of treatment compared to baseline were analyzed using the ANCOVA test., Results: From 09/2017 to 08/2019 a total of 39 patients were randomized. Due to drop outs 24 patients (12 per group) were available for analysis. Patients in the intervention group received a mean number of 10.5 (range, 7-14) applications of yarrow liver compresses. The mean improvement at the end of therapy on the general fatigue subscale of the MFI-20 was 2 points in favor of the intervention group (p = 0.13), and all other MFI-20 subscales showed at least a trend towards improvement in favor of the intervention group. Likewise, psychological distress and VAS data was improved, the latter reaching statistical significance for the symptoms fatigue, tension and lack of drive. Major toxicities were not observed., Conclusions: External application of liver compresses appears to reduce fatigue within a clinical relevant range in patients with metastatic cancer undergoing radiation therapy., Trial Registration: ISRCTN, ICTRP DRKS00012999.

Background: Current guidelines for the treatment of anaplastic astrocytoma (AA) recommend maximal safe resection followed by radiotherapy and chemotherapy. Despite this multimodal treatment approach, patients have a limited life expectancy. In the present study, we identified variables associated with overall survival (OS) and constructed a model score to predict the OS of patients with AA at the time of their primary diagnosis., Methods: We retrospectively evaluated 108 patients with newly diagnosed AA. The patient and tumor characteristics were analyzed for their impact on OS. Variables significantly associated with OS on multivariable analysis were included in our score. The final algorithm was based on the 36-month survival rates corresponding to each characteristic., Results: On univariate analysis, age, Karnofsky performance status, isocitrate dehydrogenase status, and extent of resection were significantly associated with OS. On multivariable analysis all four variables remained significant and were consequently incorporated in the score. The total score ranges from 20 to 33 points. We designated three prognostic groups: A (20-25), B (26-29), and C (30-33 points) with 36-month OS rates of 23%, 71%, and 100%, respectively. The OS rate at 5 years was 8% in group A, 61% in group B and 88% in group C., Conclusions: Our model score predicts the OS of patients newly diagnosed with AA and distinguishes patients with a poor survival prognosis from those with a greater life expectancy. Independent and prospective validation is needed. The upcoming changes of the WHO classification of brain tumors as well as the practice changing results from the CATNON trial will most likely require adaption of the score.

Background: Stereotactic radiosurgery (SRS) has been increasingly applied for up to 10 brain metastases instead of whole brain radiation therapy (WBRT) to achieve local tumor control while reducing neurotoxicity. Furthermore, brain-metastasis incidence is rising due to the increasing survival of patients with cancer. Our aim was to analyze the efficacy and safety of CyberKnife (CK) radiosurgery for elderly patients., Methods: We retrospectively identified all patients with brain metastases ≥ 65 years old treated with CK-SRS at our institution since 2011 and analyzed data of primary diseases, multimodality treatments, and local therapy effect based on imaging follow-up and treatment safety. Kaplan-Meier analysis for local progression-free interval and overall survival were performed., Results: We identified 97 patients (233 lesions) fulfilling the criteria at the first CK-SRS. The mean age was 73.2 ± 5.8 (range: 65.0-87.0) years. Overall, 13.4% of the patients were > 80 years old. The three most frequent primary cancers were lung (40.2%), kidney (22.7%), and malignant melanoma (15.5%). In 38.5% (47/122 treatments) multiple brain metastases were treated with the CK-SRS, with up to eight lesions in one session. The median planning target volume (PTV) was 1.05 (range: 0.01-19.80) cm 3 . A single fraction was applied in 92.3% of the lesions with a median prescription dose of 19 (range: 12-21) Gy. The estimated overall survivals at 3-, 6-, and 12 months after SRS were 79, 55, and 23%, respectively. The estimated local tumor progression-free intervals at 6-, 12-, 24-, 36-, and 72 months after SRS were 99.2, 89.0, 67.2, 64.6, and 64.6%, respectively. Older age and female sex were predictive factors of local progression. The Karnofsky performance score remained stable in 97.9% of the patients; only one patient developed a neurological deficit after SRS of a cerebellar lesion (ataxia, CTCAE Grade 2)., Conclusions: SRS is a safe and efficient option for the treatment of elderly patients with brain metastases with good local control rates without the side effects of WBRT. Older age and female sex seem to be predictive factors of local progression. Prospective studies are warranted to clarify the role of SRS treatment for elderly patients.

Background: For loco-regionally advanced, but transorally resectable oropharyngeal cancer (OPSCC), the current standard of care includes surgical resection and risk-adapted adjuvant (chemo) radiotherapy, or definite chemoradiation with or without salvage surgery. While transoral surgery for OPSCC has increased over the last decade for example in the United States due to transoral robotic surgery, this treatment approach has a long history in Germany. In contrast to Anglo-Saxon countries, transoral surgical approaches have been used frequently in Germany to treat patients with oro-, hypopharyngeal and laryngeal cancer. Transoral laser microsurgery (TLM) has had a long tradition since its introduction in the early 70s. To date, the different therapeutic approaches to transorally resectable OPSCC have not been directly compared to each other in a randomized trial concerning disease control and survival. The goal of this study is to compare initial transoral surgery to definitive chemoradiation for resectable OPSCC, especially with regards to local and regional control., Methods: TopROC is a prospective, two-arm, open label, multicenter, randomized, and controlled comparative effectiveness study. Eligible patients are ≥18 years old with treatment-naïve, histologically proven OPSCC (T1, N2a-c, M0; T2, N1-2c, M0; T3, N0-2c, M0 UICC vers. 7) which are amenable to transoral resection. Two hundred eighty patients will be randomly assigned (1:1) to surgical treatment (arm A) or chemoradiation (arm B). Standard of care treatment will be performed according to daily routine practice. Arm A consists of transoral surgical resection with neck dissection followed by risk-adapted adjuvant therapy. Patients treated in arm B receive standard chemoradiation, residual tumor may be subject to salvage surgery. Follow-up visits for 3 years are planned. Primary endpoint is time to local or locoregional failure (LRF). Secondary endpoints include overall and disease free survival, toxicity, and patient reported outcomes. Approximately 20 centers will be involved in Germany. This trial is supported by the German Cancer Aid and accompanied by a scientific support program., Discussion: This study will shed light on an urgently-needed randomized comparison of the strategy of primary chemoradiation vs. primary surgical approach. As a comparative effectiveness trial, it is designed to provide data based on two established regimens in daily clinical routine., Trial Registration: NCT03691441 Registered 1 October 2018 - Retrospectively registered.

Background: Stereotactic radiosurgery (SRS) is an effective treatment for trigeminal neuralgia (TN). Nevertheless, a proportion of patients will experience recurrence and treatment-related sensory disturbances. In order to evaluate the predictors of efficacy and safety of image-guided non-isocentric radiosurgery, we analyzed the impact of trigeminal nerve volume and the nerve dose/volume relationship, together with relevant clinical characteristics., Methods: Two-hundred and ninety-six procedures were performed on 262 patients at three centers. In 17 patients the TN was secondary to multiple sclerosis (MS). Trigeminal pain and sensory disturbances were classified according to the Barrow Neurological Institute (BNI) scale. Pain-free-intervals were investigated using Kaplan Meier analyses. Univariate and multivariate Cox regression analyses were performed to identify predictors., Results: The median follow-up period was 38 months, median maximal dose 72.4 Gy, median target nerve volume 25 mm 3 , and median prescription dose 60 Gy. Pain control rate (BNI I-III) at 6, 12, 24, 36, 48, and 60 months were 96.8, 90.9, 84.2, 81.4, 74.2, and 71.2%, respectively. Overall, 18% of patients developed sensory disturbances. Patients with volume ≥ 30 mm 3 were more likely to maintain pain relief (p = 0.031), and low integral dose (< 1.4 mJ) tended to be associated with more pain recurrence than intermediate (1.4-2.7 mJ) or high integral dose (> 2.7 mJ; low vs. intermediate: log-rank test, χ 2  = 5.02, p = 0.019; low vs. high: log-rank test, χ 2  = 6.026, p = 0.014). MS, integral dose, and mean dose were the factors associated with pain recurrence, while re-irradiation and MS were predictors for sensory disturbance in the multivariate analysis., Conclusions: The dose to nerve volume ratio is predictive of pain recurrence in TN, and re-irradiation has a major impact on the development of sensory disturbances after non-isocentric SRS. Interestingly, the integral dose may differ significantly in treatments using apparently similar dose and volume constraints.

Background: Robotic stereotactic ablative radiotherapy (SABR) is currently under investigation as a noninvasive treatment option for patients with renal cell carcinoma (RCC). For radiation therapy of RCC, tumor motion and the need for high ablative doses while preserving the remaining renal parenchyma is a challenge. We aimed to analyze the safety and efficacy of robotic radiosurgery in RCC in a specific difficult subgroup of patients with impaired renal function., Methods: We retrospectively identified all patients with RCC, treated with robotic SABR and motion compensation in our institution between 2012 and 2017. Either single fraction SABR of 24 or 25 Gy or 3 fractions of 12 Gy prescribed to the 70% isodose line was applied. Local control, overall survival, radiation side effects were evaluated together with renal function and tumor motion., Results: We analyzed data of 13 lesions treated in 10 patients with clear cell RCC and a mean age of 70.5 ± 13.6 years (range: 48-87). Prior to SABR, 8 patients underwent previous complete and/or partial nephrectomy, 7 patients presented with chronic kidney disease ≥ stage 3. The median of minimum, mean and maximum planning target volume doses were 23.2, 29.5 and 35.0 Gy for single fraction and 24.4, 42.5 and 51.4 Gy for the three fractions regime. Persistent local control by robotic SABR was achieved in 9 out of 10 patients (92.3% of all lesions) within a median follow-up period of 27 month (range: 15-54). One patient underwent nephrectomy due to progressive disease and sufficient renal function of the contralateral kidney. Renal function remained stable with a mean estimated glomerular filtration rate (eGFR) of 51.3 ± 19.7 ml/min at baseline and 51.6 ± 25.8 ml/min at follow-up. The largest respiratory-induced tumor motion was seen in superior-inferior direction, compensated by the CyberKnife with mean targeting errors of maximal 2.2 mm., Conclusions: Robotic SABR is technically feasible for the treatment of RCC in preexisting kidney disease with good local tumor control at about 2 years follow-up. Robotic SABR with motion tracking offers a valid treatment option for patients, who are at increased risk for progression to end-stage renal disease due to partial nephrectomy or ablative techniques.

Background: Meningiomas are the most common primary tumors of the central nervous system. In patients with WHO grade I meningiomas no adjuvant therapy is recommended after resection. In case of anaplastic meningiomas (WHO grade III), adjuvant fractionated radiotherapy is generally recommended, regardless of the extent of surgical resection. For atypical meningiomas (WHO grade II) optimal postoperative management has not been clearly defined yet., Methods: We conducted a retrospective analysis of patients treated for intracranial atypical meningioma at Charité Universitätsmedizin Berlin from March 1999 to October 2018. Considering the individual circumstances (risk of recurrence, anatomical location, etc.), patients were either advised to follow a wait-and-see approach or to undergo adjuvant radiotherapy. Primary endpoint was progression-free survival (PFS)., Results: This analysis included 99 patients with atypical meningioma (WHO grade II). Nineteen patients received adjuvant RT after primary tumor resection (intervention group). The remaining 80 patients did not receive any further adjuvant therapy after surgical resection (control group). Median follow-up was 37 months. Median PFS after primary resection was significantly longer in the intervention group than in the control group (64 m vs. 37 m, p = 0.009, HR = 0.204, 95% CI = 0.062-0.668). The influence of adjuvant RT was confirmed in multivariable analysis (p = 0.041, HR = 0.192, 95% CI = 0.039-0.932)., Conclusions: Our study adds to the evidence that RT can improve PFS in patients with atypical meningioma.

Background: The dismal overall survival (OS) prognosis of glioblastoma, even after trimodal therapy, can be attributed mainly to the frequent incidence of intracranial relapse (ICR), which tends to present as an in-field recurrence after a radiation dose of 60 Gray (Gy). In this study, molecular marker-based prognostic indices were used to compare the outcomes of radiation with a standard dose versus a moderate dose escalation., Methods: This retrospective analysis included 156 patients treated between 2009 and 2016. All patients were medically fit for postoperative chemoradiotherapy. In the dose-escalation cohort a simultaneous integrated boost of up to 66 Gy (66 Gy RT) within small high-risk volumes was applied. All other patients received daily radiation to a total dose of 60 Gy or twice daily to a total dose of 59.2 Gy (60 Gy RT)., Results: A total of 133 patients received standard 60 Gy RT, while 23 received 66 Gy RT. Patients in the 66 Gy RT group were younger (p <  0.001), whereas concomitant temozolomide use was more frequent in the 60 Gy RT group (p <  0.001). Other intergroup differences in known prognostic factors were not observed. Notably, the median time to ICR was significantly prolonged in the 66 Gy RT arm versus the 60 Gy RT arm (12.2 versus 7.6 months, p = 0.011), and this translated to an improved OS (18.8 versus 15.3 months, p = 0.012). A multivariate analysis revealed a strong association of 66 Gy RT with a prolonged time to ICR (hazard ratio = 0.498, p = 0.01) and OS (hazard ratio = 0.451, p = 0.01). These differences remained significant after implementing molecular marker-based prognostic scores (ICR p = 0.008, OS p = 0.007) and propensity-scored matched pairing (ICR p = 0.099, OS p = 0.023)., Conclusion: Radiation dose escalation was found to correlate with an improved time to ICR and OS in this cohort of glioblastoma patients. However, further prospective validation of these results is warranted.

Background: Malignant melanoma brain metastases (MBM) are the third most common cause for brain metastases (BM). Historically Whole-brain radiotherapy (WBRT) was considered the goldstandard of treatment even though melanoma cells are regarded as very radioresistant. Therapeutic possibilities have fundamentally changed since the availability of stereotactic radiotherapy (SRT), where it is possible to apply high ablative doses in a very precise manner. In this work we analyze prognostic factors of overall survival (OS) after SRT in patients with MBM and evaluate the applicability of popular prognostic indices that mainly stem from the WBRT-era., Materials and Methods: This work is a retrospective analysis of OS of 80 malignant melanoma (MM) patients who received SRT for intracranial melanoma metastases between 2004 and 2014 who had not received prior treatment for MBM in terms of surgery or WBRT. Potential prognostic factors were analyzed using univariable and multivariable analysis. Existing prognostic scores [Graded Prognostic Assessment (GPA), Diagnosis-Specific-GPA (DS-GPA), Golden Grading System (GGS) and RADES] were calculated and tested using log-rank analysis., Results: Eighty patients, respectively 177 brain metastases, were irradiated. The median survival time from radiation was 7.06 months. Overall, GGS, GPA and DS-GPA were significant predictors of survival. The MM-specific index DS-GPA showed the best p-value but did not show adequate division when looking at the two intermediate risk subgroups. RADES did not show any statistically significant prognostic value. In univariable as well as in multivariable analyses a higher Karnofsky-Index, a single BM, and non nodular melanoma (NM) histology were positive predictors of survival., Conclusion: The existing prognostic scores do not seem to ideally fit for this special group of patients. Our results indicate that the histologic subtype of MM could add to the prognostic value of specialized future indices.

Background: By the use of PSMA positron emission tomography (PET) detection of prostate cancer lesions with a high sensitivity and specificity combined with a favorable lesion to background contrast is feasible. Therefore, PSMA-PET is increasingly used for planning of radiotherapy treatment; however, any data on intermediate-term outcome is missing so far., Methods: Patients with high-risk or very high risk prostate cancer, referred for salvage radiotherapy (SRT, n = 22) between 2013 and 2015, underwent PSMA-PET prior to therapy. Irradiation was planned on PET data with boost to macroscopic tumors/metastases. Treatment related toxicity was measured using Common Terminology Criteria for Adverse Events (CTCAE, v4.0)., Result: Findings in PSMA-PET led to treatment modifications in 77% of SRT patients compared to available CT information. One patient did not receive irradiation due to disseminated disease, the other patients received increased boost doses to macroscopic disease and/or inclusion of additional target volumes. Toxicity was low as only 2 patients reported toxicities > grade 1. With a Median follow-up time of 29 in patients that were not lost to follow-up, prolonged PSA responses below baseline were observed in the majority of patients (14 of 20). In hormone-naïve SRT patients (n = 11), radiotherapy led to prolonged PSA decrease in 8/11 patients, however with 3 of these 8 patients receiving repeated PSMA based irradiation of novel lesions during follow-up., Conclusion: PSMA-PET guided planning of radiotherapy led to change of treatment in the majority of patients. Treatment related toxicity was well tolerated and promising results regarding intermediate-term PSA decrease were observed., Trial Registration: No trial registration was performed due to retrospective evaluation.

Background: Postoperative adjuvant radiation therapy (ART) in T3 and R1 prostate cancer as well as salvage radiation therapy (SRT) in case of postoperative biochemical failure (BF) are established treatments. Dose-intensified postoperative radiation therapy (RT) schemes have shown superior biochemical control accompanied by increased toxicity rates. In our study we evaluate a novel risk adapted dose-intensified postoperative RT scheme., Methods: A consecutive series of prostate cancer patients receiving postoperative RT after radical prostatectomy using helical Tomotherapy between 04/2012 and 04/2015 was analyzed retrospectively. RT was administered using a simultaneous integrated boost (SIB) to the area at risk (37 fractions of 1.9 Gy, total dose: 70.3 Gy) being defined based on histopathological findings (T3/R1 region) and in few cases according to additional diagnostic imaging. The whole prostate bed was treated with a dose of 66.6 Gy (37 fractions of 1.8 Gy). Primary endpoints were acute and late genitourinary (GU) and gastrointestinal (GI) toxicities. Secondary endpoints included patient reported outcome as assessed by the International Prostate Symptom Score (IPSS), the International Consultation on Incontinence questionnaire (ICIQ) and prostate cancer specific Quality of Life questionnaire QLQ-PR25, as well as rates of BF., Results: A total of 69 patients were analyzed. Sixteen patients underwent ART and 53 patients SRT, respectively. The median follow-up was 20 months (range, 8-41 months). Seven (10.1%) and four (5.8%) patients experienced acute grade 2 GU and GI toxicity. Two patients (2.9%) had late grade 2 GU toxicity, whereas no late grade 2 GI nor any grade 3 acute or late GU or GI events were observed. When compared to the baseline IPSS scores (p = 1.0) and ICIQ scores (p = 0.87) were not significantly different at the end of follow-up. Patient reported Quality of life (QoL) showed also no significant difference. A total of seven patients (10.1%) experienced a biochemical recurrence with the 2-year biochemical progression-free survival (bPFS) being 91%., Conclusions: Postoperative RT for prostate cancer patients with a risk adapted dose-intensified SIB using helical tomotherapy is feasible and associated with favorable acute and late GU and GI toxicity rates, no significant change of IPSS-, ICIQ scores and patient reported QoL and results in promising bPFS rates.

Background: Treatment of locally advanced squamous cell carcinomas of the head and neck (SCCHN) remains unsatisfactory. Although the addition of concurrent radiochemotherapy (RCT) or the combination of radiotherapy with blockade of the epidermal growth factor receptor (EGFR) have improved outcomes over radiotherapy alone, further optimization is urgently needed. The introduction of immune checkpoint inhibitors is currently revolutionizing cancer treatment. Clinical evidence has recently been provided in melanoma that immune checkpoint blockade may cooperate with radiation. Therefore, we searched in the literature for the evidence of combining immune checkpoint inhibitors with radiotherapy in primary treatment of SCCHN., Discussion: A substantial amount of previous studies has dissected the molecular mechanisms of immune evasion in SCCHN. The biological effects of radio- and chemotherapy in tumor cells and the immune cell microenvironment were characterized in detail, revealing significant interference of both types of treatment with anti-tumor immunity. This extensive review of the literature revealed considerable amount of evidence that addition of immune checkpoint inhibitors might boost the immunomodulatory potential of radiotherapy and RCT regimens in SCCHN., Summary: Promising activity of immune checkpoint inhibitors has already been reported for metastatic/recurrent SCCHN. Given the immunogenic effect of radiotherapy and its enhancement by chemotherapy, combination of radiotherapy or RCT with this new type of immunotherapy might represent a valuable option for improvement of curative treatment modalities in SCCHN.

Introduction: Hyperfractionated (HFRT) or accelerated hyperfractionated radiotherapy (AHFRT) have been discussed as a potential treatment for glioblastoma based on a hypothesized reduction of late radiation injury and prevention of repopulation. HFRT and AHFRT have been examined extensively in the pre-Temozolomide era with inconclusive results. In this study we examined the role of accelerated hyperfractionation in the Temozolomide era., Materials and Methods: Sixty-four patients who underwent AHFRT (62 of which received Temozolomide) were compared to 67 patients who underwent normofractionated radiotherapy (NFRT) (64 of which received TMZ) between 02/2009 and 10/2014. Follow-up data were analyzed until 01/2015., Results: Median progression-free survival (PFS) was 6 months for the entire cohort. For patients treated with NFRT median PFS was 7 months, for patients treated with AHFRT median PFS was 6 months. Median overall survival (OS) was 13 months for all patients. For patients treated with NFRT median OS was 15 months, for patients treated with AHFRT median OS was 10 months. The fractionation regimen was not a predictor of PFS or OS in univariable- or multivariable analysis. There was no difference in acute toxicity profiles between the two treatment groups., Conclusions: Univariable and multivariable analysis did not show significant differences between NFRT and AHFRT fractionation regimens in terms of PFS or OS. The benefits are immanent: the regimen does significantly shorten hospitalization time in a patient collective with highly impaired life expectancy. We propose that the role of AHFRT + TMZ should be further examined in future prospective trials.

Here we evaluate the current status of clinical research on regional hyperthermia (RHT) in combination with chemotherapy or radiation therapy in paediatric oncology.Data were identified in searches of MEDLINE, Current Contents, PubMed, and references from relevant articles using medical subject headings including hyperthermia, cancer, paediatric oncology, children, radiation therapy and chemotherapy. Currently, only two RHT centres exist in Europe which treat children. Clinical RHT research in paediatric oncology has as yet been limited to children with sarcomas and germ cell tumours that respond poorly to or recur after chemotherapy. RHT is a safe and effective treatment delivering local thermic effects, which may also stimulate immunological processes via heat-shock protein reactions. RHT is used chiefly in children and adolescents with sarcomas or germ cell tumours located in the abdomino-pelvic region, chest wall or extremities to improve operability or render the tumour operable. It could potentially be combined with radiation therapy in a post-operative R1 setting where more radical surgery is not possible or combined with chemotherapy instead of radiation therapy in cases where the necessary radiation dose is impossible to achieve or would have mutilating consequences. RHT might also be an option for chemotherapy intensification in the neoadjuvant first-line treatment setting for children and adolescents, as was recently reflected in the promising long-term outcome data in adults with high-risk soft tissue sarcomas (EORTC 62961/ESHO trial).The limited data available indicate that combining RHT with chemotherapy is a promising option to treat germ cell tumours and, potentially, sarcomas. RHT may also be beneficial in first-line therapy in children, adolescents and young adults. The research should focus on optimising necessary technical demands and then initiate several clinical trials incorporating RHT into interdisciplinary treatment of children, adolescents and young adults that include translational research components exploring potential immunological mechanisms of action.

Background: Total body irradiation (TBI) has been part of standard conditioning regimens before allogeneic stem cell transplantation for many years. Its effect on normal tissue in these patients has not been studied extensively., Method: We studied the in vivo cytogenetic effects of TBI and high-dose chemotherapy on skin fibroblasts from 35 allogeneic stem cell transplantation (SCT) patients. Biopsies were obtained prospectively (n = 18 patients) before, 3 and 12 months after allogeneic SCT and retrospectively (n = 17 patients) 23-65 months after SCT for G-banded chromosome analysis., Results: Chromosomal aberrations were detected in 2/18 patients (11 %) before allogeneic SCT, in 12/13 patients (92 %) after 3 months, in all patients after 12 months and in all patients in the retrospective group after allogeneic SCT. The percentage of aberrant cells was significantly higher at all times after allogeneic SCT compared to baseline analysis. Reciprocal translocations were the most common aberrations, but all other types of stable, structural chromosomal aberrations were also observed. Clonal aberrations were observed, but only in three cases they were detected in independently cultured flasks. A tendency to non-random clustering throughout the genome was observed. The percentage of aberrant cells was not different between patients with and without secondary malignancies in this study group., Conclusion: High-dose chemotherapy and TBI leads to severe chromosomal damage in skin fibroblasts of patients after SCT. Our long-term data suggest that this damage increases with time, possibly due to in vivo radiation-induced chromosomal instability.

Background: Our purpose was to analyze the long-term clinical outcome and to identify prognostic factors after Linac-based stereotactic radiosurgery (SRS) or fractionated stereotactic radiotherapy (FSRT) on patients with brain metastases (BM) from non-small cell lung cancer (NSCLC)., Materials and Methods: We performed a retrospective analysis of survival on 90 patients who underwent SRS or FSRT of intracranial NSCLC metastases between 04/2004 and 05/2014 that had not undergone prior surgery or whole brain radiotherapy (WBRT) for BM. Follow-up data was analyzed until May 2015. Potential prognostic factors were examined in univariable and multivariable analyses. The Golden Grading System (GGS), the disease-specific graded prognostic assessment (DS-GPA), the RADES II prognostic index as well as the NSCLC-specific index proposed by Rades et al. in 2013 (NSCLC-RADES) were calculated and their predictive values were tested in univariable analysis., Results: The median follow-up time of the surviving patients was 14 months. The overall survival (OS) rate was 51 % after 6 months and 29.9 % after 12 months. Statistically significant factors of better OS after univariable analysis were lower International Union Against Cancer (UICC) stage at first diagnosis, histology of adenocarcinoma, prior surgery of the primary tumor and lower total BM volume. After multivariable analysis adenocarcinoma histology remained a significant factor; higher Karnofsky Performance Score (KPS) and the presence of extracranial metastases (ECM) were also significant. The RADES II and the NSCLC-RADES indices were significant predictors of OS. However, the NSCLC-RADES failed to differentiate between intermediate- and low-risk patients. The DS-GPA and GGS were not statistically significant predictors of survival in univariable analysis., Conclusion: The ideal prognostic index has not been defined yet. We believe that more specific indices will be developed in the future. Our results indicate that the histologic subtype of NSCLC could add to the prognostic value of specialized future indices. The RADES II index had the highest predictive value in the examined patient cohort.

Background: Glioblastoma multiforme is the most common and most aggressive malign brain tumor. The 5-year survival rate after tumor resection and adjuvant chemoradiation is only 10 %, with almost all recurrences occurring in the initially treated site. Attempts to improve local control using a higher radiation dose were not successful so that alternative additive treatments are urgently needed. Given the strong rationale for hyperthermia as part of a multimodal treatment for patients with glioblastoma, non-invasive radio frequency (RF) hyperthermia might significantly improve treatment results., Methods: A non-invasive applicator was constructed utilizing the magnetic resonance (MR) spin excitation frequency for controlled RF hyperthermia and MR imaging in an integrated system, which we refer to as thermal MR. Applicator designs at RF frequencies 300 MHz, 500 MHz and 1GHz were investigated and examined for absolute applicable thermal dose and temperature hotspot size. Electromagnetic field (EMF) and temperature simulations were performed in human voxel models. RF heating experiments were conducted at 300 MHz and 500 MHz to characterize the applicator performance and validate the simulations., Results: The feasibility of thermal MR was demonstrated at 7.0 T. The temperature could be increased by ~11 °C in 3 min in the center of a head sized phantom. Modification of the RF phases allowed steering of a temperature hotspot to a deliberately selected location. RF heating was monitored using the integrated system for MR thermometry and high spatial resolution MRI. EMF and thermal simulations demonstrated that local RF hyperthermia using the integrated system is feasible to reach a maximum temperature in the center of the human brain of 46.8 °C after 3 min of RF heating while surface temperatures stayed below 41 °C. Using higher RF frequencies reduces the size of the temperature hotspot significantly., Conclusion: The opportunities and capabilities of thermal magnetic resonance for RF hyperthermia interventions of intracranial lesions are intriguing. Employing such systems as an alternative additive treatment for glioblastoma multiforme might be able to improve local control by "fighting fire with fire". Interventions are not limited to the human brain and might include temperature driven targeted drug and MR contrast agent delivery and help to understand temperature dependent bio- and physiological processes in-vivo.

The introduction of next-generation sequencing (NGS) in the field of cancer research has boosted worldwide efforts of genome-wide personalized oncology aiming at identifying predictive biomarkers and novel actionable targets. Despite considerable progress in understanding the molecular biology of distinct cancer entities by the use of this revolutionary technology and despite contemporaneous innovations in drug development, translation of NGS findings into improved concepts for cancer treatment remains a challenge. The aim of this article is to describe shortly the NGS platforms for DNA sequencing and in more detail key achievements and unresolved hurdles. A special focus will be given on potential clinical applications of this innovative technique in the field of radiation oncology.

Background: Peritoneal carcinomatosis occurs in different cancer subtypes and is associated with a dismal prognosis. Some doubts remain whether the whole abdomen can be treated by regional hyperthermia, therefore we analyzed feasibility conducting a pilot study., Methods: A simulation of the abdominopelvic heat distribution in 11 patients with peritoneal carcinomatosis was done using the HyperPlan software and the SIGMA-60 and SIGMA-Eye applicators. Tissue-specific region-related electrical and thermal parameters were used to solve the Maxwell's equations and the bioheat-transfer equation. Three-dimensional specific absorption rate (SAR) distributions and, additionally, estimated region-related perfusion rates were used to solve the bioheat-transfer equation. The predicted SAR and temperature distributions were compared with minimally invasive measurements in pelvic reference points., Results: In 11 patients (7 of them treated in the SIGMA-60 and 4 in the SIGMA-Eye applicator) the measured treatment variables (SAR, temperatures in the pelvic reference points) indicated that the heated volumes were higher for the SIGMA-Eye applicator. The mean computed abdominal SARs were less for the SIGMA-Eye (33 versus 44 W/kg). Nevertheless, the temperature distributions in the abdomen (peritoneal cavity) were more homogeneous in the SIGMA-Eye applicator as compared to the SIGMA-60 as indicated by higher values of T90 (mean 40.2 versus 38.2 °C) and T50 (mean 41.1 versus 40.2 °C), while the maximum temperatures were similar (in the range 41 to 43 °C). Even though the mean abdominal SAR was lower in the SIGMA-Eye, the heat distribution covered a larger volume of the abdomen (in particular the upper abdomen). For the SIGMA-60 applicator the achieved T90 appeared to be limited between 41 and 42 °C, for the SIGMA Eye applicator more effective T90 in the range 42 to 43 °C were obtained., Conclusion: Our results suggest that an adequate heating of the abdomen and therefore abdominal regional hyperthermia in PC patients appears feasible. The SIGMA-Eye applicator appears to be superior compared to the SIGMA-60 applicator for abdominal hyperthermia.

Background: Current studies on salvage radiotherapy (sRT) investigate timing, dose-escalation and anti-hormonal treatment (ADT) for recurrent prostate cancer. These approaches could either be limited by radiation-related susceptibility of the anastomosis or by suspected side-effects of long-term ADT. A phase II protocol was developed to investigate the benefit and tolerability of regional hyperthermia with moderately dose-escalated radiotherapy., Methods: The study hypothesis is that radio-thermotherapy is a safe and feasible salvage treatment modality. The primary endpoint is safety measured by frequency of grade 3+ genitourinary (GU) and gastrointestinal (GI) adverse events (AE) according to Common Toxicity Criteria (CTC) version 4. Feasibility is defined by number of hyperthermia treatments (n ≥ 7) and feasibility of radiotherapy according to protocol. Target volume delineation is performed according to the EORTC guidelines. Radiation treatment is administered with single doses of 2 Gy 5×/week to a total dose of 70 Gy. Regional hyperthermia is given 2×/week to a total of 10 treatments., Results: European centres participate in the phase II trial using intensity modulated RT (IMRT) or volumetric modulated arc technique (VMAT). The initiating centres were participants of the SAKK 09/10 study, where the same patient criteria and target volume definition (mandatory successful performed dummy run) were applied insuring a high standardisation of the study procedures., Conclusions: The introduced phase II study implements highly precise image-guided radiotherapy and regional hyperthermia. If the phase II study is found to be safe and feasible, a multicenter phase III study is planned to test whether the addition of regional hyperthermia to dose-intensified sRT improves biochemical control.

Background: To compare highly sophisticated intensity-modulated radiotherapy (IMRT) delivered by either helical tomotherapy (HT), RapidArc (RA), IMRT with protons (IMPT) in patients with locally advanced cervical cancer., Methods and Materials: Twenty cervical cancer patients were irradiated using either conventional IMRT, VMAT or HT; ten received pelvic (PEL) and ten extended field irradiation (EFRT). The dose to the planning-target volume A (PTV&#95;A: cervix, uterus, pelvic ± para-aortic lymph nodes) was 1.8/50.4 Gy. The SIB dose for the parametrium (PTV&#95;B), was 2.12/59.36 Gy. MRI-guided brachytherapy was administered with 5 fractions up to 25 Gy. For EBRT, the lower target constraints were 95% of the prescribed dose in 95% of the target volume. The irradiated small bowel (SB) volumes were kept as low as possible. For every patient, target parameters as well as doses to the organs at risk (SB, bladder, rectum) were evaluated intra-individually for IMRT, HT, VMAT and IMPT., Results: All techniques provided excellent target volume coverage, homogeneity, conformity. With IMPT, there was a significant reduction of the mean dose (Dmean) of the SB from 30.2 ± 4.0 Gy (IMRT); 27.6 ± 5.6 Gy (HT); 34.1 ± 7.0 (RA) to 18.6 ± 5.9 Gy (IMPT) for pelvic radiation and 26.3 ± 3.2 Gy (IMRT); 24.0 ± 4.1 (HT); 25.3 ± 3.7 (RA) to 13.8 ± 2.8 Gy (IMPT) for patients with EFRT, which corresponds to a reduction of 38-52% for the Dmean (SB). Futhermore, the low dose bath (V10Gy) to the small bowel was reduced by 50% with IMPT in comparison to all photon techniques. Furthermore, Dmean to the bladder and rectum was decresed by 7-9 Gy with IMPT in patents with pelvic radiation and EFRT., Conclusion: All modern techniques (were proved to be dosimetrically adequate regarding coverage, conformity and homogeneity of the target. Protons offered the best sparing of small bowel and rectum and therefore could contribute to a significant reduction of acute and late toxicity in cervical cancer treatment.

Background: The mammalian target of rapamycin (mTOR) signaling pathway plays a pivotal role in numerous cellular processes involving growth, proliferation and survival. The purpose of this study was to investigate the anti-tumoral effect of the mTOR inhibitor (mTORi) CCI-779 in HNSCC cell lines and its potency in cisplatin- and cetuximab-resistant cells., Methods: A panel of 10 HNSCC cell lines with differences in TP53 mutational status and basal cisplatin sensitivity and two isogenic models of acquired resistance to cisplatin and cetuximab, respectively were studied. Cell survival after treatment with CCI-779, cisplatin and cetuximab alone or in combination was determined by MTT assays. Potential predictive biomarkers for tumor cell sensitivity to CCI-779 were evaluated., Results: We observed considerable heterogeneity in sensitivity of HNSCC cell lines to CCI-779 monotherapy. Sensitivity was observed in TP53 mutated as well as wild-type cell lines. Total and p-EGFR expression levels but not the basal activity of the mTOR and MAPK signaling pathways were correlated with sensitivity to CCI-779. Resistant cells with increased EGFR activation could be sensitized by the combination of CCI-779 with cetuximab. Interestingly, cell lines with acquired resistance to cisplatin displayed a higher sensitivity to CCI-779 whereas cetuximab-resistant cells were less sensitive to the drug, but could be sensitized to CCI-779 by EGFR blockade., Conclusions: Activity of CCI-779 in HNSCC cells harboring TP53 mutations and displaying a phenotype of cisplatin resistance suggests its clinical potential even in patients with dismal outcome after current standard treatment. Cetuximab/mTORi combinations might be useful for treatment of tumors with high expression of EGFR/p-EGFR and/or acquired cetuximab resistance. This combinatorial treatment modality needs further evaluation in future translational and clinical studies.

Young patients with cervical cancer who undergo chemoradiation might be interested in fertility preservation, not only dependent upon the use of a gestational carrier as maybe achieved by the use of ovarian transposition and cryo-conservation of oocytes or ovarian tissue, but may prefer to carry pregnancy to term after cancer treatment. The latter approach is a non-established concept needing both modern radiation therapy approaches as well as modifications -if at all possible- in current recommendations for target volume delineation to spare dose to the unaffected uterus. Future strategies to serve selected patients in this respect should only be conducted in prospective clinical evaluations and are critically discussed in this article.

Background: To analyze the impact of weight loss before and during chemoradiation on survival outcomes in patients with locally advanced head and neck cancer., Methods: From 07/1994-07/2000 a total of 224 patients with squamous cell carcinoma of the head and neck were randomized to either hyperfractionated radiation therapy alone or the same radiation therapy combined with two cycles of concomitant cisplatin. The primary endpoint was time to any treatment failure (TTF); secondary endpoints were locoregional recurrence-free survival (LRRFS), distant metastasis-free survival (DMFS) and overall survival (OS). Patient weight was measured 6 months before treatment, at treatment start and treatment end., Results: The proportion of patients with >5% weight loss was 32% before, and 51% during treatment, and the proportion of patients with >10% weight loss was 12% before, and 17% during treatment. After a median follow-up of 9.5 years (range, 0.1 - 15.4 years) weight loss before treatment was associated with decreased TTF, LRRFS, DMFS, cancer specific survival and OS in a multivariable analysis. However, weight loss during treatment was not associated with survival outcomes., Conclusions: Weight loss before and during chemoradiation was commonly observed. Weight loss before but not during treatment was associated with worse survival.

Background: It was our purpose to analyze long-term clinical outcome and to identify prognostic factors after Linac-based fractionated stereotactic radiotherapy (Linac-based FSRT) and stereotactic radiosurgery (SRS) in patients with intracranial meningiomas., Materials and Methods: Between 10/1995 and 03/2009, 297 patients with a median age of 59 years were treated with FSRT for intracranial meningioma. 50 patients had a Grade I meningioma, 20 patients had a Grade II meningioma, 12 patients suffered from a Grade III tumor, and in 215 cases no histology was obtained (Grade 0). Of the 297 patients, 144 underwent FSRT as their primary treatment and 158 underwent postoperative FSRT. 179 patients received normofractionated radiotherapy (nFSRT), 92 patients received hypofractionated FSRT (hFSRT) and 26 patients underwent SRS. Patients with nFSRT received a mean total dose of 57.31 ± 5.82 Gy, patients with hFSRT received a mean total dose of 37.6 ± 4.4 Gy and patients who underwent SRS received a mean total dose of 17.31 ± 2.58 Gy., Results: Median follow-up was 35 months. Overall progression free survival (PFS) was 92.3% at 3 years, 87% at 5 years and 84.1% at 10 years. Patients with adjuvant radiotherapy showed significantly better PFS-rates than patients who had been treated with primary radiotherapy. There was no significant difference between PFS-rates of nFSRT, hFSRT and SRS patients. PFS-rates were independent of tumor size. Patients who had received nFSRT showed less acute toxicity than those who had received hFSRT. In the Grade 0/I group the rate of radiologic focal reactions was significantly lower than in the atypical/malignant histology group., Conclusion: This large study showed that FSRT is an effective and safe treatment modality with high PFS-rates for intracranial meningioma. We identified "pathological grading" and and "prior surgery" as significant prognostic factors.

Background: To analyze setup deviations using daily megavoltage computed tomography (MVCT) and to evaluate three MVCT frequency reducing protocols for gynecologic cancer patients treated with helical tomotherapy., Methods: We recorded the setup errors of 56 patients with gynecological cancer observed throughout their whole course by matching their daily MVCT with the planning CT. Systematic and random errors were calculated on a patient and population basis. We defined three different protocols corresponding to MVCTs from the first five fractions (FFF), the first ten fractions (FTF) or from the first and third weeks (505). We compared theoretical. setup errors calculated using these 5 or 10 early MVCT scans with the actual errors found with the remaining fractions to to analyze the residual deviations., Results: The total systematic (random) deviations had means of -2.0 (3.8)mm, 0.5 (3.4)mm, 0.5 (6.1)mm and -0.5° (0.9°) in vertical (V), longitudinal (LO), lateral (LA), and roll (R) directions, respectively. The proposed three MVCT protocols resulted in minor residual deviations. In all three protocols, 95% of all calculated residual deviations were less than or equal to 5 mm in all 3 directions. When examining the additional minimal CTV-PTV setup margins that were calculated based on these residual deviations, the 505 protocol would have allowed smaller margins than the FFF and FTF protocol, particularly in the V direction., Conclusions: For patients with gynecologic cancer, the 505-protocol led to the lowest residual deviations and therefore might offer the best approach in reducing the frequency of pre-treatment MVCTs.

Purpose: To evaluate the technique, dosimetry, dose-volume-histograms (DVHs) and acute toxicity for CyberKnife® boost irradiation instead of intra-cervical brachytherapy in patients with cervical cancer., Methods and Materials: Eleven who were not suitable for brachytherapy with FIGO stage IIB-IIIB cervical cancer underwent primary chemoradiation. After fiducial implantation, T2 contrast-enhanced planning MRI and CT scans at 2-mm slice thickness were collected in the treatment position. The clinical target volume was defined as cervix + macroscopic residual tumour on MRI. Five fractions of 6 Gy each were prescribed to the target volume with a covering single dose 6 Gy. DVH parameters were evaluated for the target and organs at risk. Acute toxicity was documented once a week., Results: DmeanPTV ranged from 33.6-40 Gy, median 36.7 Gy with a coverage of the PTV calculated to 100% of the prescribed dose ranging from 93.0-99.3% (median 97.7%). For the PTV the median CN was 0.78 (range, 0.66 to 0.87) and the median CI was 1.28 (range 1.15 to 1.52). Gastrointestinal (GI) and genitourinary (GU) toxicity was mild. There was no grade 3 or higher GI and GU toxicity. After 6 months of follow up, there were no local recurrences. For the complete treatment, a median EQD2 to 1 cc and 2 cc of the bladder wall was 98.8 Gy and 87.1 Gy, respectively. Median EQD2 to 1 cc and 2 cc of the rectal wall was 72.3 Gy and 64 Gy, respectively, correlating with a risk < 10% for Grade 2-4 late toxicity., Conclusions: CyberKnife robotic radiosurgery in patients with cervical cancer provides excellent target coverage with steep dose gradients toward normal tissues and safe DVH parameters for bladder, rectum and sigmoid. Acute toxicity was mild. Longer follow-up is needed to evaluate the oncological equality.

Background: Establishing Total Body Irradiation (TBI) using Helical Tomotherapy (HT) to gain better control over dose distribution and homogeneity and to individually spare organs at risk. Because of their limited body length the technique seems especially eligible in juvenile patients., Patients and Methods: The cohort consisted of 10 patients, 6 female and 4 male, aged 4 - 22 y with acute lymphoblastic- (ALL) or acute myeloic leukemia (AML). All patients presented with high risk disease features. Body length in treatment position ranged from 110-180 cm. Two Gy single dose was applied BID to a total dose of 12 Gy. Dose volume constraint for the PTV was 95% dose coverage for 95% of the volume. The lungs were spared to a mean dose of [less than or equal to] 10 Gy. Patients were positioned in a vac-loc bag in supine position with a 3-point head mask., Results: Average D95 to the PTV was 11.7 Gy corresponding to a mean coverage of the PTV of 97.5%. Dmean for the lungs was 9.14 Gy. Grade 3-4 side effects were not observed., Conclusions: TBI using HT is feasible and well tolerated. A benefit could be demonstrated with regard to dose distribution and homogeneity and the selective dose-reduction to organs at risk.

Background: Interfraction prostate motion must be compensated by increased safety margins. If filling status of rectum and bladder is constant, motion should be reduced. We attempted to reduce interfraction motion errors by proper patient instruction., Method: In 38 patients pairs of radio-opaque fiducial markers were implanted prior to definitive radiotherapy. Patients were positioned either according to skin marks or infrared body marker. We measured prostate displacement, i.e. pelvic bones versus intraprostatic marker position, via ExacTrac (two orthogonal radiographies) in 1252 fractions. Systematic and random setup and displacement errors were determined and safety margins estimated., Results: In our study interfraction prostate displacement is < 1 mm in RL direction, and < 2 mm in AP and SI direction. Systematic errors are slightly below random errors (< 1.5 mm). Positioning according skin marks results in higher inaccuracies of ±1.5 - 2 mm in RL and ±2 - 2.5 mm in AP/SI direction., Conclusions: In case of appropriate patient instructions (constant organ filling) the positioning via bone fusion requires CTV-PTV margins of 2 mm in RL, 4 mm in AP, and 5 mm in SI direction. Studies without any description of patient instruction found much higher margins of > 1 cm in AP and SI direction.

Purpose: To proof feasibility of hydrogel application in patients with advanced cervical cancer undergoing chemo-radiation in order to reduce rectal toxicity from external beam radiation as well as brachytherapy., Material and Methods: Under transrectal sonographic guidance five patients with proven cervical cancer underwent hydro gel (20 cc) instillation into the tip of rectovaginal septum adherent to posterior part of the visible cervical tumor. Five days after this procedure all patients underwent T2 weighted transversal and sagittal MRI for brachytherapy planning. MRI protocol included T2 weighted fast spin echo (FSE) imaging in sagittal, coronal and para-axial orientation using an 1.5 Tesla MRI. Separation of anterior rectal wall and cervix was documented., Results: Hydrogel application was uneventful in all patients and no toxicity was reported. Separation ranged from 7 to 26 mm in width (median 10 mm). The length of the separation varied between 18 and 38 mm (median 32 mm). In all patients displacement was seen in the posterior vaginal fornix, and/or at the deepest part of uterine cervix depending on the extension of the cul-de-sac in correlation to the posterior wall of the uterus. In patients with bulky tumor and/or deep (vaginal) extend of peritoneal cavity tumour was seen mainly cranial from the rectovaginal space and therefore above the hydrogeI application. Only in the extra-peritoneal (lower) part of the cervix a good separation could be achieved between the rectum and cervix., Conclusion: Hydrgel instillation in patients with cervial cancer undergoing chemoradiation is safe and feasible. Because of the loose tissue of the cul-de-sac and its intra- and extraperitoneal part, hydrogel instillation of 20 cc did not result in a sufficient separation of the cervix from anterior wall.

Introduction: Magnetic resonance imaging (MRI) and computed tomography (CT) with (68)Ga-DOTATOC positron emission tomography ((68)Ga-DOTATOC-PET) were compared retrospectively for their ability to delineate infracranial extension of skull base (SB) meningiomas treated with fractionated stereotactic radiotherapy., Methods: Fifty patients with 56 meningiomas of the SB underwent MRI, CT, and (68)Ga-DOTATOC PET/CT prior to fractionated stereotactic radiotherapy. The study group consisted of 16 patients who had infracranial meningioma extension, visible on MRI ± CT (MRI/CT) or PET, and were evaluated further. The respective findings were reviewed independently, analyzed with respect to correlations, and compared with each other., Results: Within the study group, SB transgression was associated with bony changes visible by CT in 14 patients (81%). Tumorous changes of the foramen ovale and rotundum were evident in 13 and 8 cases, respectively, which were accompanied by skeletal muscular invasion in 8 lesions. We analysed six designated anatomical sites of the SB in each of the 16 patients. Of the 96 sites, 42 had infiltration that was delineable by MRI/CT and PET in 35 cases and by PET only in 7 cases. The mean infracranial volume that was delineable in PET was 10.1 ± 10.6 cm(3), which was somewhat larger than the volume detectable in MRI/CT (8.4 ± 7.9 cm(3))., Conclusions: (68)Ga-DOTATOC-PET allows detection and assessment of the extent of infracranial meningioma invasion. This method seems to be useful for planning fractionated stereotactic radiation when used in addition to conventional imaging modalities that are often inconclusive in the SB region.

Background: Chemoradiation for cervical cancer patients is associated with considerable gastrointestinal toxicity. Intensity-modulated radiotherapy (IMRT) has demonstrated superiority in terms of target coverage and normal tissue sparing in comparison to conventional 3D planning in gynaecological malignancies. Whether IMRT in prone (PP) or supine position (SP) might be beneficial for cervical cancer patients remains partially unanswered., Methods: 10 patients on FIGO stage IB-III cervical cancer, 6 patients for definitive and 4 patients for adjuvant external beam pelvic RT, were planned in PP and SP using a 7-field IMRT technique. IMRT plans for PP and SP (mean dose, Dmean 50.4 Gy) were optimized in terms of PTV coverage (1st priority) and small bowel sparing (2nd priority). A comparison of DVH parameters for PTV, small bowel, bladder, and rectum was performed., Results: The comparison showed a similar PTV coverage of 95% of the prescribed dose and for target conformity in IMRT plans (PP, SP). PTV, rectum and bladder volumes were comparable for PP and SP. Significantly larger volumes of small bowel were found in PP (436 cc, + 35%, p = 0.01). PP decreased the volume of small bowel at 20-50.4 Gy (p < 0.05) and increased the rectum volumes covered by doses from 10-40 Gy (p < 0.01), the V50.4 was < 5% in both treatment positions. Bladder sparing was significant better at 50.4 Gy (p = 0.03) for PP., Conclusion: In this dosimetric study, we demonstrated that pelvic IMRT in prone position for patients with cervical cancer seems to be beneficial in reducing small bowel volume at doses >or=20 Gy while providing similar target coverage and target conformity. The use of frequent image guidance with KV (kilovolt) or MV (megavolt) computer tomography can reduce set-up deviations, and treatment in prone position can be done with a higher set-up accuracy. Clinical outcome studies are needed to affirm lower toxicity.

Background: To evaluate the benefit of an on-line correction protocol based on implanted markers and weekly portal imaging in external beam radiotherapy of prostate cancer. To compare the use of bony anatomy versus implanted markers for calculation of setup-error plus/minus prostate movement. To estimate the error reduction (and the corresponding margin reduction) by reducing the total error to 3 mm once a week, three times per week or every treatment day., Methods: 23 patients had three to five, 2.5 mm Ø spherical gold markers transrectally inserted into the prostate before radiotherapy. Verification and correction of treatment position by analysis of orthogonal portal images was performed on a weekly basis. We registered with respect to the bony contours (setup error) and to the marker position (prostate motion) and determined the total error. The systematic and random errors are specified. Positioning correction was applied with a threshold of 5 mm displacement., Results: The systematic error (1 standard deviation [SD]) in left-right (LR), superior-inferior (SI) and anterior-posterior (AP) direction contributes for the setup 1.6 mm, 2.1 mm and 2.4 mm and for prostate motion 1.1 mm, 1.9 mm and 2.3 mm. The random error (1 SD) in LR, SI and AP direction amounts for the setup 2.3 mm, 2.7 mm and 2.7 mm and for motion 1.4 mm, 2.3 mm and 2.7 mm. The resulting total error suggests margins of 7.0 mm (LR), 9.5 mm (SI) and 9.5 mm (AP) between clinical target volume (CTV) and planning target volume (PTV). After correction once a week the margins were lowered to 6.7, 8.2 and 8.7 mm and furthermore down to 4.9, 5.1 and 4.8 mm after correcting every treatment day., Conclusion: Prostate movement relative to adjacent bony anatomy is significant and contributes substantially to the target position variability. Performing on-line setup correction using implanted radioopaque markers and megavoltage radiography results in reduced treatment margins depending on the online imaging protocol (once a week or more frequently).

Background: The additional use of radiotherapy has changed the treatment of locally advanced rectal cancer (LARC) dramatically. But a major achievement has been the development of total mesorectal excision (TME) as a surgical standard and the recognition that the surgeon is the predominant prognostic factor. The benefit of preoperative hypofractionated radiotherapy (SCRT; five fractions each of 5 Gy), initially established by the Swedish Rectal Cancer Trial, has been demonstrated in conjunction with TME by the Dutch Colorectal Cancer Group. The concept of combined neoadjuvant radiochemotherapy (conventional radiation of about 50 Gy with chemotherapy) has not been compared over surgery alone with TME. However, the German Rectal Cancer Study Group recently demonstrated that preoperative radiochemotherapy (RCT) was better than postoperative radiochemotherapy in terms of local control., Methods and Design: Patients with histological proven rectal cancer staged T2N+ or T3 are randomized to receive either SCRT (25 Gy in five fractions of 5 Gy) plus TME-surgery within 5 days or RCT (50.4 Gy in 28 fractions of 1.8 Gy, continuous infusion 5-fluorouracil) plus TME-surgery 4-6 weeks later. All patients receive adjuvant chemotherapy (12 weeks continuous infusional 5-FU) and are followed up for 5 years. TME-quality is independently documented by the surgeon and the pathologist. Hypothesis of the study is that RCT is superior to SCRT in terms of local recurrence after five years. Secondary endpoints are overall survival, disease-free survival, complete resection rate (R0 resection), rate of sphincter saving resection, acute and late toxicity (radiation related side effects), and quality of life (including long term bowel function)., Discussion: Similar long-term survival, local control and late morbidity have been reported for both concepts of preoperative therapy in non-comparative studies. In addition to other ongoing (and recently published) comparative trials we include a larger number of patients for adequate power, apply quality-controlled TME and try to avoid the adjuvant treatment bias by mandatory adjuvant chemotherapy in both groups. Further more, stratification of the initially planned surgical procedure and sphincter-preservation will generate valid evidence whether RCT will allow a less aggressive (sphincter saving) surgical approach.

Background: The application of induction chemotherapy failed to provide a consistent benefit for local control in primary treatment of advanced head and neck (H&N) cancers. The aim of this study was to compare the results of concomitant application of radiochemotherapy for treating locally advanced head-and-neck carcinoma in comparison with the former standard of sequential radiochemotherapy., Methods: Between 1987 and 1995 we treated 122 patients with unresectable (stage IV head and neck) cancer by two different protocols. The sequential protocol (SEQ; 1987-1992) started with two courses of neoadjuvant chemotherapy (cisplatin [CDDP] + 120-h continuous infusions (c.i.) of folinic acid [FA] and 5-fluorouracil [5-FU]), followed by a course of radiochemotherapy using conventional fractionation up to 70 Gy. The concomitant protocol (CON; since 1993) combined two courses of FA/5-FU c.i. plus mitomycin (MMC) concomitantly with a course of radiotherapy up to 30 Gy in conventional fractionation, followed by a hyperfractionated course up to 72 Gy. Results from the two groups were compared., Results: Patient and tumor characteristics were balanced (SEQ = 70, CON = 52 pts.). Mean radiation dose achieved (65.3 Gy vs. 71.6 Gy, p = 0.00), response rates (67 vs. 90 % for primary, p = 0.02), and local control (LC; 17.6% vs. 41%, p = 0.03), were significantly lower in the SEQ group, revealing a trend towards lower disease-specific (DSS; 19.8% vs. 31.4%, p = 0.08) and overall (14.7% vs. 23.7%, p = 0.11) survival rates after 5 years. Mucositis grades III and IV prevailed in the CON group (54% versus 44%). Late toxicity was similar in both groups., Conclusion: Concurrent chemotherapy seemed more effective in treating head and neck tumors than induction chemotherapy followed by chemoradiation, resulting in better local control and a trend towards improved survival.

Background: Former meta-analyses have shown a survival benefit for the addition of chemotherapy (CHX) to radiotherapy (RT) and to some extent also for the use of hyperfractionated radiation therapy (HFRT) and accelerated radiation therapy (AFRT) in locally advanced squamous cell carcinoma (SCC) of the head and neck. However, the publication of new studies and the fact that many older studies that were included in these former meta-analyses used obsolete radiation doses, CHX schedules or study designs prompted us to carry out a new analysis using strict inclusion criteria., Methods: Randomised trials testing curatively intended RT (> or =60 Gy in >4 weeks/>50 Gy in <4 weeks) on SCC of the oral cavity, oropharynx, hypopharynx, and larynx published as full paper or in abstract form between 1975 and 2003 were eligible. Trials comparing RT alone with concurrent or alternating chemoradiation (5-fluorouracil (5-FU), cisplatin, carboplatin, mitomycin C) were analyzed according to the employed radiation schedule and the used CHX regimen. Studies comparing conventionally fractionated radiotherapy (CFRT) with either HFRT or AFRT without CHX were separately examined. End point of the meta-analysis was overall survival., Results: Thirty-two trials with a total of 10 225 patients were included into the meta-analysis. An overall survival benefit of 12.0 months was observed for the addition of simultaneous CHX to either CFRT or HFRT/AFRT (p < 0.001). Separate analyses by cytostatic drug indicate a prolongation of survival of 24.0 months, 16.8 months, 6.7 months, and 4.0 months, respectively, for the simultaneous administration of 5-FU, cisplatin-based, carboplatin-based, and mitomycin C-based CHX to RT (each p < 0.01). Whereas no significant gain in overall survival was observed for AFRT in comparison to CFRT, a substantial prolongation of median survival (14.2 months, p < 0.001) was seen for HFRT compared to CFRT (both without CHX)., Conclusion: RT combined with simultaneous 5-FU, cisplatin, carboplatin, and mitomycin C as single drug or combinations of 5-FU with one of the other drugs results in a large survival advantage irrespective the employed radiation schedule. If radiation therapy is used as single modality, hyperfractionation leads to a significant improvement of overall survival. Accelerated radiation therapy alone, especially when given as split course radiation schedule or extremely accelerated treatments with decreased total dose, does not increase overall survival.