[Cervical CUP Syndrome: Diagnosis and Therapy]. / Zervikales CUP-Syndrom: Diagnostik und Therapie.

In CUP syndrome (CUP = cancer of unknown primary) there are 1 or more metastases of a primary tumor that cannot be localized despite extensive diagnostics. CUP syndrome accounts for 5% of all human malignancies, making it one of the 10 most common forms of cancer. In addition to inflammatory lymph node enlargement and benign changes such as cervical cysts, lymph node metastases are among the most common cervical masses. Cervical CUP syndrome is a histologically confirmed cervical lymph node metastasis with an unknown primary tumor. In addition to anamnesis, clinical examination and histological confirmation, diagnostics include radiological imaging using PET-CT and panendoscopy with histological primary tumor search. Treatment options include surgical therapy with neck dissection and chemoradiotherapy.

Long-term outcome after intraoperative radiotherapy as a boost in breast cancer.

PURPOSE: To investigate long-term oncological outcome and incidence of chronic side effects in patients with breast cancer and intraoperative radiotherapy given as an upfront boost (IORT boost). METHODS: Retrospective analysis of 400 patients with an IORT boost with low-energy X­rays (20 Gy), subsequent whole-breast irradiation (46-50 Gy), and annual oncological follow-up. Side effects were prospectively evaluated (LENT-SOMA scales) over a period of up to 15 years. Side effects scored ≥grade 2 at least three times during follow-up were judged to be chronic. RESULTS: The median age was 63 years (30-85) and the median follow-up was 78 months (2-180) after IORT boost. In 15 patients a local recurrence occurred, resulting in a local recurrence rate at 5, 10, and 15 years of 2.0%, 6.6%, and 10.1%, respectively. The overall survival rates at 5, 10, and 15 years were 92.1%, 81.8%, and 80.7%, respectively. The most common high-grade side effects were fibrosis (21%) and pain (8.6%). The majority of side effects occurred within the first 3 years. The actuarial rates of chronic fibrosis were 19.1% and 21.1% at 5 and ≥8 years, of chronic pain 8.6% at ≥4 years, of chronic edema of the breast 2.4% at ≥2 years, of chronic lymphedema 0.0% at 5 and 10 years, and of chronic hyperpigmentation 0.5% at ≥2 years. Side effects were similar or less than expected from an external beam boost. CONCLUSION: IORT boost appears to be a highly efficient and safe method for upfront delivery of the tumor bed boost in high-risk breast cancer patients.

Single-center long-term results from the randomized phase-3 TARGIT-A trial comparing intraoperative and whole-breast radiation therapy for early breast cancer.

PURPOSE: Partial breast irradiation using intraoperative radiotherapy (IORT) after breast-conserving surgery could be sufficient for a selected group of breast cancer patients. We report the results of a cohort of patients from a single center treated as part of the randomized phase-3 TARGIT-A trial. METHODS: Patients (≥50 years) with cT1 cN0 cM0 and invasive ductal histology on biopsy were randomized between IORT with 20 Gy (arm-A) or postoperative whole-breast RT (WBRT) up to 56 Gy in 2 Gy fractions (arm-B). Postoperatively, patients in arm-A with multifocality, lymphovascular invasion, nodal invasion, extensive intraductal component, invasive lobular carcinoma, or resection margins <1 cm received additional postoperative WBRT. RESULTS: Between 2002 and 2012, 184 patients were randomized, of whom 90 in arm-A and 90 in arm-B were evaluated. Median follow-up was 8.5 years. The 5­year overall survival was 94.4% in arm-A and 93.3% in arm-B (p = 0.73). Two local recurrences were observed: one at 70.3 months in an arm-A patient who received IORT + WBRT and another at 4.5 months in an arm-B patient who refused all forms of adjuvant treatment, thus resulting in a 5-year local recurrence of 0% in arm-A and 1.1% in arm-B. The 5­year in-breast recurrence (outside of the index quadrant) was 0% in arm-A and 1.2% in arm-B. Salvage mastectomy was performed successfully in all patients with relapse. CONCLUSION: Long-term follow-up of this single-center cohort consolidates the earlier reports of low local recurrence rates after single-dose IORT. Our results are in line with non-inferiority of risk-adapted IORT for selected patients with early breast cancer.

Combined kyphoplasty and intraoperative radiotherapy (Kypho-IORT) versus external beam radiotherapy (EBRT) for painful vertebral metastases - a randomized phase III study.

BACKGROUND: The spine is the most frequent location of bone metastases. Local treatment aims at palliation of pain and, given the increased likelihood of long-term cancer survival, at local control. Kyphoplasty and intraoperative radiotherapy (Kypho-IORT) provided instantaneous pain relief in 70% of patients at the first day after the intervention and resulted in local control rates of > 93% at 1 year in a recently conducted phase I/II trial. To assess its clinical value, we designed a phase III trial which tests Kypho-IORT against the most widespread standard-of-care, external beam radiotherapy (EBRT), in patients with painful vertebral metastases. METHODS: This phase III study includes patients ≥50 years of age with up to 4 vertebral metastases and a pain score of at least 3/10 points on the visual/numeric analogy scale (VAS). Patients randomized into the experimental arm (A) will undergo Kypho-IORT (Kyphoplasty plus IORT with 8 Gy prescribed to 13 mm depth). Patients randomized into the control arm (B) will receive EBRT with either 30 Gy in 10 fractions or 8 Gy as a single dose. The primary end point is pain reduction defined as at least - 3 points on the VAS compared to baseline at day 1. Assuming that 40% of patients in the Kypho-IORT arm and 5% of patients in the control arm will achieve this reduction and 20% will drop out, a total of 54 patients will have to be included to reach a power of 0.817 with a two-sided alpha of 0.05. Secondary endpoints are evaluation of the percentage of patients with a pain reduction of at least 3 points at 2 and 6 weeks, local tumor control, frequency of re-intervention, secondary fractures/sintering, complication rates, skin toxicity/wound healing, progression-free survival (PFS), overall survival (OS) and quality of life. DISCUSSION: This trial will generate level 1 evidence on the clinical value of a one-stop procedure which may provide instantaneous pain relief, long-term control and shortened intervals to further adjuvant (systemic) therapies in patients with spinal metastases. TRIAL REGISTRATION: Registered with ClinicalTrials.gov, number: NCT02773966 (Registration date: 05/16/2016).

Novel radiotherapy techniques for involved-field and involved-node treatment of mediastinal Hodgkin lymphoma: when should they be considered and which questions remain open?

PURPOSE: Hodgkin lymphoma (HL) is a highly curable disease. Reducing late complications and second malignancies has become increasingly important. Radiotherapy target paradigms are currently changing and radiotherapy techniques are evolving rapidly. DESIGN: This overview reports to what extent target volume reduction in involved-node (IN) and advanced radiotherapy techniques, such as intensity-modulated radiotherapy (IMRT) and proton therapy-compared with involved-field (IF) and 3D radiotherapy (3D-RT)- can reduce high doses to organs at risk (OAR) and examines the issues that still remain open. RESULTS: Although no comparison of all available techniques on identical patient datasets exists, clear patterns emerge. Advanced dose-calculation algorithms (e.g., convolution-superposition/Monte Carlo) should be used in mediastinal HL. INRT consistently reduces treated volumes when compared with IFRT with the exact amount depending on the INRT definition. The number of patients that might significantly benefit from highly conformal techniques such as IMRT over 3D-RT regarding high-dose exposure to organs at risk (OAR) is smaller with INRT. The impact of larger volumes treated with low doses in advanced techniques is unclear. The type of IMRT used (static/rotational) is of minor importance. All advanced photon techniques result in similar potential benefits and disadvantages, therefore only the degree-of-modulation should be chosen based on individual treatment goals. Treatment in deep inspiration breath hold is being evaluated. Protons theoretically provide both excellent high-dose conformality and reduced integral dose. CONCLUSION: Further reduction of treated volumes most effectively reduces OAR dose, most likely without disadvantages if the excellent control rates achieved currently are maintained. For both IFRT and INRT, the benefits of advanced radiotherapy techniques depend on the individual patient/target geometry. Their use should therefore be decided case by case with comparative treatment planning.

INTRAGO: intraoperative radiotherapy in glioblastoma multiforme­a phase I/II dose escalation study.

BACKGROUND: Glioblastoma multiforme (GBM) is the most frequent primary malignant brain tumor in adults. Despite multimodal therapies, almost all GBM recur within a narrow margin around the initial resected lesion. Thus, novel therapeutic intensification strategies must target both, the population of dispersed tumor cells around the cavity and the postoperative microenvironment. Intraoperative radiotherapy (IORT) is a pragmatic and effective approach to sterilize the margins from persistent tumor cells, abrogate post-injury proliferative stimuli and to bridge the therapeutic gap between surgery and radiochemotherapy. Therefore, we have set up INTRAGO, a phase I/II dose-escalation study to evaluate the safety and tolerability of IORT added to standard therapy in newly diagnosed GBM. In contrast to previous approaches, the study involves the application of isotropic low-energy (kV) x-rays delivered by spherical applicators, providing optimal irradiation properties to the resection cavity. METHODS/DESIGN: INTRAGO includes patients aged 50 years or older with a Karnofsky performance status of at least 50% and a histologically confirmed (frozen sections) supratentorial GBM. Safety and tolerability (i.e., the maximum tolerated dose, MTD) will be assessed using a classical 3 + 3 dose-escalation design. Dose-limiting toxicities (DLT) are wound healing deficits or infections requiring surgical intervention, IORT-related cerebral bleeding or ischemia, symptomatic brain necrosis requiring surgical intervention and early termination of external beam radiotherapy (before the envisaged dose of 60 Gy) due to radiotoxicity. Secondary end points are progression-free and overall survival. TRIAL REGISTRATION: The study is registered with clinicaltrials.gov, number: NCT02104882 (Registration Date: 03/26/2014).

A novel approach for superficial intraoperative radiotherapy (IORT) using a 50 kV X-ray source: a technical and case report.

The use of IORT as a treatment modality for patients with close or positive margins has increased over the past decade. For situations where a flat area (up to 6 cm in diameter) has to be treated intraoperatively, new applicators for superficial treatment with a miniature X-ray source (INTRABEAM system) were developed. Here we report our evaluation of the dosimetric characteristics of these new applicators and their first clinical use. Each of these flat and surface applicators consists of a radiation protective metal tube and a flattening filter, which converts the spherical dose distribution of the X-ray source into a flat one. The homogeneity of each dose distribution and depth-dose measurements were evaluated using film dosimetry in a solid water phantom and a soft X-ray ionization chamber in a water tank. The first patient was treated with 5 Gy delivered in 5 mm using a 4 cm FLAT applicator over 21 minutes. The flat applicators show the maximum homogeneity, with a uniformity ratio of 1.02-1.08 in certain depths. In 1 mm depth surface applicators show a uniformity ratio of 1.15-1.28. They also show a higher dose rate and a steeper dose gradient compared to the flat applicators. The results of this investigation demonstrated that the flat and surface applicators have unique dosimetric characteristics that need to be considered during the treatment planning stages. This work also showed that it is possible to perform a superficial localized IORT which provides new application possibilities for use of the INTRABEAM system.

Homogenous dose prescription in Gamma Knife Radiotherapy: Combining the best of both worlds.

PURPOSE: Stereotactic radiosurgery with linear accelerators (LINACs) or Leksell Gamma Knife® (LGK, Elekta AB) is an established treatment option for intracranial tumors. When those are involving/abutting organs at risk (OAR), homogenous and normofractionated treatments outmatch single fraction deliveries. In such situations, it would be desirable to balance LINAC's homogeneity benefits with LGK's dose gradient attributes. In this study, we determined homogeneity and OAR sparing ranges using a non-clinical, homogenous prototype version of LGK Lightning. METHODS: We retrospectively analyzed thirty fractionated LGK Icon in-house patients with acoustic neuromas, pituitary adenomas and meningiomas. Four treatment plans were generated (54 Gy,1.8 Gy/fx) per patient: one LINAC plan, one clinical Lightning plan ("LGK") and two prototype Lightning plans ("LGK Hom" and "LGK OAR"). We analyzed Dmean and D2% for different OAR, Gradient Index (GI), Paddick Conformity Index (PCI), Homogeneity Index (HI) and beam-on-time (BOT). RESULTS: While the LINAC vs. Lightning plans (LGK Hom|LGK OAR|LGK) boast better homogeneity (median: 1.08 vs. 1.18|1.24|1.35) and shorter BOT (median: 137 s vs. 432 s|510 s|510 s), Lightning plans show improved GI (median: 6.68 vs. 3.86|3.50|3.19), similar PCI (median: 0.75 vs. 0.76|0.75|0.82) and significantly reduced OAR doses. For in-tumor OAR, LGK Hom and LINAC plans achieves similar OAR sparing with improved GI for LGK Hom. CONCLUSIONS: This study is a preliminary attempt to combine the dosimetric advantages of LINAC and LGK treatment planning. We observed that LGK plan homogeneity can be improved toward LINAC standards while maintaining the LGK advantage of favorable OAR doses and GI. Additionally, in-tumor OAR hotspots can be considerably reduced.

Hypoxia as a stimulus for tissue formation: The concept of organogenesis in microsurgically vascularized tissue engineering constructs.

Axial vascularization of tissue constructs is essential to maintain an adequate blood supply for a stable regeneration of a clinically relevant tissue size. The versatility of the arterio-venous loop (AVL) has been previously shown in various small and large animal models as well as in clinical reports for bone regeneration. We have previously demonstrated the capability of the AVL to induce axial vascularization and to support the nourishment of tissue constructs in small animal models after applying high doses of ionizing radiation comparable to those applied for adjuvant radiotherapy after head and neck cancer. We hypothesize that this robust ability to induce regeneration after irradiation could be related to a state of hypoxia inside the constructs that triggers the HIF1 (hypoxia induced factor 1) - SDF1 (stromal derived factor 1) axis leading to chemotaxis of progenitor cells and induction of tissue regeneration and vascularization. We analyzed the expression of HIF1 and SDF1 via immunofluorescence in axially vascularized bone tissue engineering constructs in Lewis rats 2 and 5 weeks after local irradiation with 9Gy or 15Gy. We also analyzed the expression of various genes for osteogenic differentiation (collagen 1, RUNX, alkaline phosphatase and osteonectin) via real time PCR analysis. The expression of HIF1 and SDF1 was enhanced two weeks after irradiation with 15Gy in comparison to non-irradiated constructs. The expression of osteogenic markers was enhanced at the 5-weeks time point with significant results regarding collagen, alkaline phosphatase and osteonectin. These results indicate that the hypoxia within the AVL constructs together with an enhanced SDF1 expression probably play a role in promoting tissue differentiation. The process of tissue generation triggered by hypoxia in the vicinity of a definite vascular axis with enhanced tissue differentiation over time resembles hereby the well-known concept of organogenesis in fetal life.

Real-time definition of single seed placement sensitivity in low-dose-rate prostate brachytherapy.

PURPOSE: In low-dose-rate brachytherapy, iodine-125 seeds are implanted based on a treatment plan, generated with respect to different dose constraints. The quality of the dose distribution depends on a precise seed placement, however, during treatment planning the impact on the dose parameters when certain seeds fail to be placed precisely is not clear. METHODS AND MATERIALS: We developed a method using automatic differentiation to calculate gradients of dose parameters with regard to the seeds' positions. Thus, we understand their sensitivity with respect to the seed placement. A statistical analysis is performed on a data set with 35 prostate brachytherapy patients. RESULTS: The most sensitive seeds regarding the dosimetric parameters of both rectum and urethra are close to the corresponding organ. Their gradient directions are mainly orthogonal to their surfaces. However, not all seeds close to the surface are equally sensitive with regard to the dose parameter. The most sensitive seeds regarding the prostate's dose parameters are distributed throughout the prostate and the direction of the gradients are mainly parallel to its surface. A linear regression with respect to different patient parameters shows that dose constraints which are barely fulfilled have large gradients and thus are additionally sensitive to misplacement. CONCLUSION: Automatic differentiation can be used to analyze dose parameter sensitivity with respect to seed placement. Integrating this into treatment planning systems is valuable as it speeds up the planning procedure, making it more robust and less dependent on user experience while showing the operating physician which needle placements require greater accuracy than others.

Acute and Long-Term Toxicity after Planned Intraoperative Boost and Whole Breast Irradiation in High-Risk Patients with Breast Cancer-Results from the Targeted Intraoperative Radiotherapy Boost Quality Registry (TARGIT BQR).

In the context of breast cancer treatment optimization, this study prospectively examines the feasibility and outcomes of utilizing intraoperative radiotherapy (IORT) as a boost in combination with standard external beam radiotherapy (EBRT) for high-risk patients. Different guidelines recommend such a tumor bed boost in addition to whole breast irradiation with EBRT for patients with risk factors for local breast cancer recurrence. The TARGIT BQR (NCT01440010) is a prospective, multicenter registry study aimed at ensuring the quality of clinical outcomes. It provides, for the first time, data from a large cohort with a detailed assessment of acute and long-term toxicity following an IORT boost using low-energy X-rays. Inclusion criteria encompassed tumors up to 3.5 cm in size and preoperative indications for a boost. The IORT boost, administered immediately after tumor resection, delivered a single dose of 20 Gy. EBRT and systemic therapy adhered to local tumor board recommendations. Follow-up for toxicity assessment (LENT SOMA criteria: fibrosis, teleangiectasia, retraction, pain, breast edema, lymphedema, hyperpigmentation, ulceration) took place before surgery, 6 weeks to 90 days after EBRT, 6 months after IORT, and then annually using standardized case report forms (CRFs). Between 2011 and 2020, 1133 patients from 10 centers were preoperatively enrolled. The planned IORT boost was conducted in 90%, and EBRT in 97% of cases. Median follow-up was 32 months (range 1-120, 20.4% dropped out), with a median age of 61 years (range 30-90). No acute grade 3 or 4 toxicities were observed. Acute side effects included erythema grade 1 or 2 in 4.4%, palpable seroma in 9.1%, punctured seroma in 0.3%, and wound healing disorders in 2.1%. Overall, chronic teleangiectasia of any grade occurred in 16.2%, fibrosis grade ≥ 2 in 14.3%, pain grade ≥ 2 in 3.4%, and hyperpigmentation in 1.1%. In conclusion, a tumor bed boost through IORT using low-energy X-rays is a swift and feasible method that demonstrates low rates in terms of acute or long-term toxicity profiles in combination with whole breast irradiation.

Longitudinal cosmetic outcome after planned IORT boost with low kV X-rays-monocentric results from the TARGIT BQR registry.

Background: Intraoperative radiotherapy can serve as an anticipated boost (IORT boost) in combination with a subsequent external whole breast irradiation in high-risk breast cancer patients and is part of many guidelines. Nevertheless, there are only few prospective data available regarding cosmetic outcome after IORT boost using kV X-rays. The aim of this study was to evaluate the cosmetic outcome of patients treated within the prospective phase IV TARGeted Intraoperative radioTherapy (TARGIT) Boost Quality Registry (BQR) study (NCT01440010) in one center. Methods: In the context of the TARGIT BQR study standardized photos in three positions (arms down, arms up, from the side) were available for different time points. For this analysis a layperson, a radiation oncologist and a gynecologist evaluated available photos at different time points during follow-up with up to 4 years using the Harvard scale (comparison of treated and the untreated breast; rating: excellent, good, fair, poor). Longitudinal results were compared to preoperative results (baseline). Results: Seventy-three patients were available for the analysis. Baseline cosmetic assessment was excellent/good in 98.8% (mean value for all three positions). Postoperative cosmetic outcome (median) was good for all positions and remained constant for 4 years. Around 30% of the patients showed a constant or even improved cosmetic outcome compared to baseline. Only few patients showed a poor result at 4 years. The majority of patients showed an excellent or good cosmetic outcome at all time points. Conclusions: Patients from the prospective TARGIT BQR study treated with IORT boost and additional whole breast irradiation showed good or excellent cosmetic outcomes in most cases during 4 years of follow-up. These results add important information for shared decision making in breast cancer patients.

Prospective Comparison of Hypofractionated Versus Normofractionated Intensity-Modulated Radiotherapy in Breast Cancer: Late Toxicity Results of the Non-Inferiority KOSIMA Trial (ARO2010-3).

Purpose: To compare the late toxicity profile of hypofractionation and normofractionation for whole-breast radiotherapy in breast cancer (BC) patients after conserving surgery. Methods: Sixty-year-old or older patients with pTis-pT3, pN0-pN1a, M0 BC were recruited and stratified to hypofractionated (arm R-HF) or normofractionated (arm L-NF) intensity-modulated radiotherapy (IMRT), for right- and left-sided BC, respectively, in this single-center, non-randomized, non-inferiority trial. A boost was allowed if indicated. The primary outcome was the cumulative percentage of patients developing grade III fibrosis, grade I telangiectasia, and/or grade II hyperpigmentation after 2 years, with a pre-specified non-inferiority margin of 15% increase from an expected 2-year toxicity rate of 20%. Results: The Median follow-up was 4.93 (0.57-8.65) years for R-HF and 5.02 (0.65-8.72) years for L-NF (p=0.236). The median age was 68 (60-83 and 60-80) years, respectively. In total, 226 patients were recruited (107 for R-HF and 119 for L-NF), with 100 and 117 patients suitable for assessment, respectively. A boost was delivered in 51% and 53% of each arm, respectively. Median PTV volumes were 1013.6 (273-2805) cm3 (R-HF) and 1058.28 (315-2709) cm3 (L-NF, p=0.591). The 2-year primary endpoint rate was 6.1% (95% CI 1.3-11.7, n=5 of 82) and 13.3% (95% CI 7-20.2, n=14 of 105), respectively (absolute difference -7.2%, one-sided 95% CI ∞ to -0.26, favoring R-HF). No local recurrence-free- or overall-survival differences were found. Conclusion: In this prospective non-randomized study, hypofractionation did not have higher toxicity than normofractionated whole-breast IMRT.

Multiple direction needle-path planning and inverse dose optimization for robotic low-dose rate brachytherapy.

PURPOSE: Robotic systems to assist needle placements for low-dose rate brachytherapy enable conformal dose planning only restricted to path planning around risk structures. We report a treatment planning system (TPS) combining multiple direction needle-path planning with inverse dose optimization algorithms. METHODS: We investigated in a path planning algorithm to efficiently locate needle injection points reaching the target volume without puncturing risk structures. A candidate needle domain with all combinations of trajectories is used for the optimization process. We report a modular algorithm for inverse radiation plan optimization. The initial plan with V100>99% is generated by the "greedy optimizer". The "remove-seed algorithm" reduces the number of seeds in the high dose regions. The "depth-optimizer" varies the insertion depth of the needles. The "coverage-optimizer" locates under-dosed areas in the target volume and supports them with an additional amount of seeds. The dose calculation algorithm is benchmarked on an image set of a phantom with a liver metastasis (prescription dose Dpr=100Gy) and is re-planned in a commercial CE-marked TPS to compare the calculated dose grids using a global gamma analysis. The inverse optimizer is benchmarked by calculating 10 plans on the same phantom to investigate the stability and statistical variability of the dose parameters. RESULTS: The path planning algorithm efficiently removes 72.5% of all considered injection points. The candidate needle domain consists of combinations of 1971 tip points and 827 injection points. The global gamma analysis with gamma 1%=2.9Gy, 1mm showed a pass rate of 98.5%. The dose parameters were V100=99.1±0.3%, V150=76.4±2.5%, V200=44.5±5.5% and D90=125.9±3.6Gy and 10.7±1.3 needles with 34.0±0.8 seeds were used. The median of the TPS total running time was 4.4minutes. CONCLUSIONS: The TPS generates treatment plans with acceptable dose coverage in a reasonable amount of time. The gamma analysis shows good accordance to the commercial TPS. The TPS allows taking full advantage of robotic navigation tools to enable a new precise and safe method of minimally invasive low-dose-rate brachytherapy.

A knowledge-based quantitative approach to characterize treatment plan quality: Application to prostate VMAT planning.

PURPOSE: To characterize treatment plan (TP) quality, a quantitative quality control (QC) tool is proposed. The tool is validated using volumetric modulated arc therapy (VMAT) plans for treatment of prostate cancer by estimating the achievable organ at risk (OAR) sparing, based on the knowledge learned from prior plans. METHODS: Prostate TP quality was investigated by evaluating the achieved OAR sparing in the rectum and bladder, based on their proximity to target surface. The knowledge base used in this work comprises 450 plans, consisting of 181 homogenous prostate plans and 269 simultaneous integrated boost (SIB) prostate plans. A knowledge-based algorithm was used to relate the absorbed doses of the OARs (rectum and bladder) and their proximity to the planning target volume (PTV). A metric (Mq,r value) was calculated to characterize the OAR sparing based on the weighted differences of the mean doses at binned distances to the PTV surface. The 90% probability ellipse of the normally distributed OARs Mq,r values was considered to define a threshold above which the treatment plan was re-optimized. RESULTS: Following re-optimization, 8/11 of the homogenous plans and 6/13 of the SIB plans outside the 90% probability ellipse could be re-optimized to gain better OAR sparing while achieving the same or better target coverage. However, 3/4 of the homogenous TPs and 1/9 of the SIB TPs between 80% and 90% were improved. Mq,r values of bladder and rectum after re-optimizing the plans in both groups of homogenous and SIB showed lower values compared to the corresponding values before re-optimization, which implies that better OARs sparing was achieved. CONCLUSIONS: This work demonstrates an effective anatomy-specific QC tool for identifying suboptimal plans and determining the achievable OAR sparing for each individual patient anatomy.

Bone marrow-sparing intensity-modulated radiotherapy (IMRT) for neo-adjuvant therapy of inoperable cervical cancer in a patient with severe thrombocytopenia.

BACKGROUND: Therapy possibilities are limited in patients with cervix carcinoma and thrombocytopenia. CASE REPORT: We describe a 50-year-old woman with inoperable cervical carcinoma and chronic lymphatic B cell leukemia (B-CLL). Due to thrombocytopenia, a combined radiochemotherapy could not be performed. Intensitymodulated radiotherapy (IMRT) aiming at maximal bone sparing was planned. After a total dose of 45 Gy, a laparoscopic omentum plastic was performed to enable radiotherapy (RT) to full dose. 3 days later, an external beam boost was restarted to a cumulative dose of 50.4 Gy. Regular blood analysis showed low but stable blood counts. 4 weeks after RT, magnetic resonance imaging (MRI) showed a 30% regression of the tumor volume and, after transfusion of fresh-frozen plasma, a hysterectomy could be performed. 6 months after therapy, no recurrence or late toxicities had occurred. CONCLUSION: The clinical implementation of IMRT may potentially improve the therapeutic outcome of patients with cervix cancer, allowing dose escalation without increasing normal-tissue toxicity.

Accelerated Radiotherapy with Concurrent Chemotherapy in Locally Advanced Head and Neck Cancers: Evaluation of Response and Compliance.

PURPOSE: Concurrent chemo-radiotherapy (CCRT) is the primary treatment modality for locally advanced head and neck squamous cell cancer patients (LAHNSCC). Intensity modulated radiotherapy (IMRT) with simultaneous integrated boost (SIB) and concurrent chemotherapy is not broadly implicated in our region mainly because of the lack of experience. This study aims at evaluating the response and compliance of this approach in our patients. METHODS: Forty patients with LAHNSCC were included and 50% received induction chemotherapy. All the patients were treated with IMRT-SIB radiotherapy for 70Gy over 33 daily fractions. Weekly cisplatin (40mg/m2) was administered during the radiation course. RESULTS: With median follow-up of 1.5 years, LC was achieved in 82.5% of cases and distant control rate was 90%. More than 5 interrupted radiation sessions and GTV volume > 50 cc significantly affected LRC (P= 0.02 and 0.001 respectively). Eighty percent of cases experienced grade 3 or 4 toxicities. Induction chemotherapy and PTV-70 volume >150 cc significantly affected the degree of toxicities (P=0.018 and 0.0001 respectively).The 2 years disease free survival (DFS) was 77%. ECOG PS, large GTV volume (> 50 cc) and RT interruption (>5 sessions) had negative impact on DFS (P= 0.041, 0.002 and 0.001 respectively). The 2 years overall survival (OS) was 87%. Radiation interruption (> 5 sessions) was the only factor which had significant detrimental effect on OS (P= 0.001). CONCLUSION: Induction chemotherapy seems to have a negative impact on patient's compliance to CCRT. Bulky tumors and prolonged radiation interruptions were associated with significantly lower LRC, DFS and OS.

Adjuvant electronic brachytherapy for endometrial carcinoma: A 4-year outcomes report.

PURPOSE: The purpose of the study was to report the outcomes of a single-center adjuvant electronic brachytherapy (e-BT) experience for patients with endometrial carcinoma. METHODS AND MATERIALS: Patients were retrospectively assessed. Intracavitary e-BT was applied through a cylindrical applicator (diameters 2.5-3.5 cm). e-BT single doses ranged between 4 and 7 Gy (EQD2 ∼ 6-12, α/ß of 10 Gy and an relative biological effectiveness of 1.3) at 5-mm depth. Adverse events are reported at first week, 1-3 months, 3-12 months, 12-24 months, and >24 months. The overall survival, disease-free survival, distant disease control rate, and local control rate were estimated using the Kaplan-Meier method. RESULTS: Twenty-nine patients were assessed. The median age was 68 [48-86] years. External beam radiotherapy was added in n = 8 (27.6%) patients. Staging was 13.8% for T1a, 51.7% for T1b, 24.1% for T2, 6.9% for T3a, and 3.4% for T3b. Grading was G3 in 51.7% (n = 15), G2 in 20.7% (n = 6), and G1 in 27.6% (n = 8). Median followup was 47 months [5-88]. Overall Grade 1, 2, and 3 toxicity was 89.7% (n = 26), 17.2% (n = 5), and 6.9% (n = 2), respectively. No Grade 3 cystitis or proctitis or any Grade 4 or 5 toxicity occurred during followup. No local recurrences were detected. Estimated distant disease control rate was 92.1% (n = 2, distant metastasis at 7 and 11 months). Estimated 4-year overall survival was 84.8% (n = 4 events, two unrelated to disease) and disease-free survival was 84.6%. CONCLUSIONS: Our data suggest that e-BT resembles a very-low-toxicity profile and a high local control rate in the adjuvant scenario for patients with endometrial carcinoma.

Intraoperative radiotherapy with low energy x-rays for primary and recurrent soft-tissue sarcomas.

BACKGROUND: Soft tissue sarcomas (STS) treatment remains a therapeutic challenge. Intraoperative radiotherapy (IORT) resembles a safe and efficient for STS treatment. The first data on electronic-IORT (eIORT) using low-energy photons is herein presented. METHODS: Thirty-one patients with newly and recurrent STS were retrospectively assessed. EIORT was applied with low-energy photons during surgery. The dose was either prescribed to the applicator surface (spherical applicators) or 5 mm depth (flat applicators). Overall progression-free survival (O-PFS), local progression-free survival (L-PFS), overall survival (OS) and adverse events were evaluated. RESULTS: Median follow-up was 4.88 (1.0-8.95) years. Twenty-five patients (80.6%) had recurrent STS with prior treatment. The resection status was R1 in 25.8% and R2 in 6.5%. The distribution was 51.7% for extremities, 35.5% for abdomen and pelvis, 9.7% for thorax and 3.2% for head and neck tumors. The median O-PFS was 11.0 months, with 42.6% 5-year estimated O-PFS. The only local recurrence in the primary setting occurred after 22 months. Median L-PFS in recurrent STS was 12.5 months, with 65.5% 5-year estimated L-PFS. The 5-year OS estimated rate was 94.7% (3 events after 7 years). No G3 toxicity related to eIORT was observed. Two patients exhibited G2 acute neuropathic pain. Late neuropathic pain was seen in 6 patients being 3 graded as G1 and 3 as G2. No wound-related toxicity was found. CONCLUSION: Electronic IORT with low-energy photons is a safe treatment option for STS, yielding similar outcomes as historical series reporting IORT with electrons or HDR brachytherapy.

Feasibility of interstitial stepping-source electronic brachytherapy to locally inoperable tumors.

PURPOSE: Radiotherapy is the mainstay in the treatment of locally inoperable tumors. Interstitial electronic needle-based kilovoltage brachytherapy (EBT) could be an economic alternative to high-dose-rate (HDR) brachytherapy or permanent seed implantation (PSI). In this work, we evaluated if locally inoperable tumors treated with PSI at our institution may be suitable for EBT. MATERIAL AND METHODS: A total of 10 post-interventional computed tomography (CT) scans of patients, who received PSI and simulated stepping-source EBT applied with Intrabeam system and needle applicator were used. EBT treatment planning software with 3-dimensional image and projection of applicator were applied for designing trajectories and establishing dwell positions. Dwell position doses were summarized, and doses covering 90% of the target volume (D90) achieved with stepping-source EBT were compared to those of PSI. Additionally, conformality of dose distributions and total irradiation time were assessed using conformation number (CN) or conformal index (COIN). RESULTS: In all patients, D90 of EBT exceeded the prescribed dose or D90 of PSI on average by 4.7% or 21.3% relative to the prescribed dose, respectively. Mean number of trajectories was 5.0 for EBT and 6.9 for PSI. Average CN/COIN for EBT was 0.69, with a mean irradiation time of 27.8 minutes for standardized dose of 13 Gy. CONCLUSIONS: Stepping-source EBT allowed for a conformal treatment of inoperable interstitial tumors with similar D90. Fewer trajectories were required for EBT in majority of cases.