Management of nonfunctioning pituitary tumors: radiotherapy.

External beam radiotherapy (RT) is an essential part of the management of intracranial tumors and has been used in treating pituitary adenomas for more than five decades. It has been demonstrated that conventional RT for postoperative residual or progressive nonfunctioning pituitary adenomas (NFAs) present an excellent long-term local tumor control, although its use has been limited because of the potential late toxicity related to radiation treatments. Recent advances in radiation techniques have led to more accurate treatments, rendering obsolete many commonly held views of the "old" radiotherapy. New techniques include intensity modulated radiotherapy, volumetric-modulated arc therapy, and stereotactic techniques, either stereotactic radiosurgery or fractionated stereotactic radiotherapy. New techniques allow the delivering of higher radiation doses to the target with rapid dose fall-off in the surrounding normal tissues, and potentially limiting the long term toxicity of radiation. In this review, we present a critical analysis of the most recent available literature on the use of radiation in patients with NFAs, focusing particularly on the efficacy and safety of radiation stereotactic techniques.

Standard or hypofractionated radiotherapy in the postoperative treatment of breast cancer: a retrospective analysis of acute skin toxicity and dose inhomogeneities.

BACKGROUND: To identify predictive factors of radiation-induced skin toxicity in breast cancer patients by the analysis of dosimetric and clinical factors. METHODS: 339 patients treated between January 2007 and December 2010 are included in the present analysis. Whole breast irradiation was delivered with Conventional Fractionation (CF) (50 Gy, 2.0/day, 25 fractions) and moderate Hypofractionated Schedule (HS) (44 Gy, 2.75 Gy/day, 16 fractions) followed by tumour bed boost. The impact of patient clinical features, systemic treatments and, in particular, dose inhomogeneities on the occurrence of different levels of skin reaction has been retrospectively evaluated. RESULTS: G2 and G3 acute skin toxicity were 42% and 13% in CF patients and 30% and 7.5% in HS patients respectively. The retrieval and revaluation of 200 treatment plans showed a strong correlation between areas close to the skin surface, with inhomogeneities >107% of the prescribed dose, and the desquamation areas as described in the clinical records. CONCLUSIONS: In our experience dose inhomogeneity underneath G2 - G3 skin reactions seems to be the most important predictor for acute skin damage and in these patients more complex treatment techniques should be considered to avoid skin damage. Genetic polymorphisms too have to be investigated as possible promising candidates for predicting acute skin reactions.

Initial Experience With Single-Isocenter Radiosurgery to Target Multiple Brain Metastases Using an Automated Treatment Planning Software: Clinical Outcomes and Optimal Target Volume Margins Strategy.

PURPOSE: Our purpose was to assess the clinical outcomes and target positioning accuracy of frameless linear accelerator single-isocenter multiple-target (SIMT) dynamic conformal arc (DCA) stereotactic radiosurgery (SRS) for multiple brain metastases (BM). METHODS AND MATERIALS: Between October 2016 and September 2018, 31 consecutive patients ≥18 years old with 204 BM <3 cm in maximum size receiving SIMT DCA SRS were retrospectively evaluated. All plans were created using a dedicated automated treatment planning software (Brainlab, Munich, Germany), and treatments were performed with a Truebeam STx or a Novalis Tx (Brainlab and Varian Medical Systems, CA). The accuracy of setup and interfraction patient repositioning was assessed by Brainlab ExacTrac radiograph 6-dimensional image system and the risk of compromised target dose coverage evaluated. Brain control and overall survival were estimated by Kaplan-Meier method calculated from the time of SRS. RESULTS: Fourteen patients were treated for 4 to 6 and 17 patients for 7 to 10 BM. The mean gross tumor volume (GTV) was 0.65 cm3 and the mean planning target volume (PTV) was 0.89 cm3. Mean V95 (the volume of the PTV covered by 95% of the prescription dose) and D95 (the prescription dose covering 95% of the PTV) were 99.5% and 21.1 Gy, respectively. With a median clinical follow-up of 11 months (range, 4-26 months), the 1-year survival was 68% and local control was 89%. As a consequence of plan isocenter residual errors, a loss of target coverage, defined as V95 < 95%, occurred in 28 PTVs (10 patients); using a 1 mm GTV-to-PTV margin, adequate dose coverage was maintained for all lesions. CONCLUSIONS: SIMT DCA SRS represents a fast and effective approach for patients with up to 10 BM. The dosimetric effects of residual set-up and intrafraction positioning errors are modest, although a GTV-to-PTV margin of 1 mm is recommended.

A new standardized data collection system for brain stereotactic external radiotherapy: the PRE.M.I.S.E project.

BACKGROUND: In recent years, novel radiation therapy techniques have moved clinical practice toward tailored medicine. An essential role is played by the decision support system, which requires a standardization of data collection. The Aim of the Prediction Models In Stereotactic External radiotherapy (PRE.M.I.S.E.) project is the implementation of systems that analyze heterogeneous datasets. This article presents the project design, focusing on brain stereotactic radiotherapy (SRT). MATERIALS & METHODS: First, raw ontology was defined by exploiting semiformal languages (block and entity relationship diagrams) and the natural language; then, it was transposed in a Case Report Form, creating a storage system. RESULTS: More than 130 brain SRT's variables were selected. The dedicated software Beyond Ontology Awareness (BOA-Web) was set and data collection is ongoing. CONCLUSION: The PRE.M.I.S.E. project provides standardized data collection for a specific radiation therapy technique, such as SRT. Future aims are: including other centers and validating an extracranial SRT ontology.

Long-term favorable results by arteriovenous graft with Omniflow II prosthesis for hemodialysis.

AIMS AND METHODS: In order to decrease arteriovenous graft (AVG) failure and improve long-term patency, we used Omniflow II to perform AVG for hemodialysis access in 38 patients with very compromised vessels who were not suitable for other forms of AVG. RESULTS: At a median follow-up of 38 (range 6-55) months, 31/38 (81%) patients were still alive. At 6, 12, 18 and 24 months, the primary patency was 83, 80, 68 and 60%, whereas the secondary patency was 92, 83, 78 and 75%,respectively [corrected].The cumulative 38-month prosthetic AVG patency was 70%. No infective event related to the vascular prosthesis occurred. Neither AVG thrombosis nor modifications in thrombophilic pattern were observed; these findings confirm the high hemocompatibility of this prosthetic vascular device. CONCLUSION: Our experience is extremely encouraging for the use of new biosynthetic devices such as Omniflow II.

Comparative effectiveness of multi-fraction stereotactic radiosurgery for surgically resected or intact large brain metastases from non-small-cell lung cancer (NSCLC).

PURPOSE: to investigate clinical outcomes in patients with large brain metastases from non-small-cell lung cancer (NSCLC) who received surgical resection and postoperative stereotactic radiosurgery or SRS alone. PATIENTS AND METHODS: Two hundred and twenty-two patients with 241 large brain metastases (2-4 cm in size) who received surgery and multi-fraction SRS (mfSRS) to the resection cavity or mfSRS alone were analyzed. For all lesions the delivered dose was 3 x 9 Gy over three consecutive days. Primary endpoint of the study was local control (LC). Secondary endpoints included early improvement of neurological deficits, changes in performance status, treatment-related toxicity, radiation-induced brain necrosis (RN), distant brain failure (DBF), and overall survival (OS). Kaplan-Meier analysis and cumulative incidence function were used for comparing the probability of failure. RESULTS: At a median follow-up of 13 months, median OS times and 1-year survival rates were comparable: 13.5 months and 59% for patients receiving surgery and postoperative mfSRS to the resection cavity and 15.2 months and 68% for those treated with mfSRS alone (p = 0.2). Median DBF did not differ significantly between groups (surgery and mfSRS,12 months; mfSRS,14 months). Eighteen patients receiving surgery and mfSRS and 17 patients treated with mfSRS alone recurred locally (p = 0.2); respective 6-month and 12-month LC rates were 87% and 83% and 96% and 91% (p = 0.15). The 1-year cumulative incidence rates of RN were 15% and 7% after postoperative mfSRS and mfSRS alone (p = 0.03), respectively. CONCLUSIONS: In conclusion, mfSRS is an effective treatment for patients with large brain metastases from NSCLC resulting in equivalent LC and lower RN and risk of leptomeningeal spread compared to surgery and mf-SRS to the resection cavity. Surgery is an effective treatment option for patients with large symptomatic brain metastases who require rapid relief of neurological symptoms caused by tumor mass effect.

Stereotactic ablative radiation therapy as a potential curative treatment in duodenal adenocarcinoma: a case report.

PURPOSE: One of the rarest gastrointestinal neoplasm is small bowel cancer. Experience with its treatment modalities is limited. Stereotactic ablative radiation therapy (SABR) has improved, with image-guided radiation therapy becoming a curative option in many tumors. Especially when surgery cannot be performed due to comorbidities, SABR provides a good toxicity profile and an excellent tumor control rate owing to its specific schedule: high dose on a limited and well-defined area. METHODS: An 83-year-old man had arterial hypertension and congestive cardiomyopathy, with recent history of upper abdominal pain, weight loss over 10 kg, and progressive severe fatigue. The patient underwent endoscopy that showed a large mass partially obstructing the second part of the duodenum; a biopsy revealed a moderately differentiated adenocarcinoma. A staging CT scan confirmed localized disease. Due to the patient's age and comorbidities, a SABR was proposed as the preferred treatment. In order to localize the tumor during radiotherapy sessions, surgical clips were placed endoscopically next to the lesion as fiducial markers. The patient received 25 Gy in 5 fractions on alternate days. RESULTS: Resolution of duodenal obstruction and bleeding lasted for 14 months. The patient died of myocardial infarction. CONCLUSIONS: This case suggests that SABR could have a role in the palliative treatment of small bowel cancers, with good toxicity profile, particularly in patients for whom surgical treatment is not a viable option.

Ku70, Ku80, and sClusterin: A Cluster of Predicting Factors for Response to Neoadjuvant Chemoradiation Therapy in Patients With Locally Advanced Rectal Cancer.

PURPOSE: The identification of predictive biomarkers for neoadjuvant chemoradiation therapy (CRT) is a current clinical need. The heterodimer Ku70/80 plays a critical role in DNA repair and cell death induction after damage. The aberrant expression and localization of these proteins fail to control DNA repair and apoptosis. sClusterin is the Ku70 partner that sterically inhibits Bax-dependent cell death after damage in some pathologic conditions. This study sought to evaluate the molecular relevance of Ku70-Ku80-Clu as a molecular cluster predicting the response to neoadjuvant CRT in patients with locally advanced rectal cancer (LARC). METHODS AND MATERIALS: Patients enrolled in this study underwent preoperative CRT followed by surgical excision. A retrospective study based on individual response, evaluated by computed tomography and diffusion-weighted magnetic resonance imaging, identified responder (56%) and no-responder patients (44%). Ku70/80 and Clu expression were observed in biopsy specimens obtained before and after treatment with neoadjuvant CRT from the same LARC patients. In vitro studies before and after irradiation were also performed on radioresistant (SW480) and radiosensitive (SW620) colorectal cancer cell lines, mimicking sensitive or resistant tumor behavior. RESULTS: We found a conventional nuclear localization of Ku70/80 in pretherapeutic tumor biopsies of responder patients, in agreement with their role in DNA repair and regulating apoptosis. By contrast, in the no-responder population we observed an unconventional overexpression of Ku70 in the cytoplasm (P<.001). In this context we also overexpression of sClu in the cytoplasm, which accorded with its role in stabilizing of Bax-Ku70 complex, inhibiting Bax-dependent apoptosis. Strikingly, Ku80 in these tumor tissues was lost (P<.005). In vitro testing of colon cancer cells finally confirmed the results observed in tumor biopsy specimens, proving that Ku70/80-Clu deregulation is extensively involved in the resistance mechanism. CONCLUSION: These results strongly suggest a potential role of these proteins as a new prognostic tool to predict the response to chemoradiation in LARC.

Technical solutions to reduce mediastinal irradiation in young patients undergoing treatment for lymphomas: Preliminary experience.

This study aims at optimizing treatment planning in young patients affected by lymphoma (Stage II to III) by using an inclined board (IB) that allows reducing doses to the organs at risk. We evaluated 19 young patients affected by stage I to III lymphomas, referred to our Department for consolidation radiotherapy (RT) treatment on the mediastinum. Patients underwent 2 planning computed tomography (CT) scans performed in different positions: flat standard position and inclined position. A direct comparison between the different treatment plans was carried out analyzing dosimetric parameters obtained from dose-volume histograms generated for each plan. Comparison was performed to evaluate the sparing obtained on breast and heart. Dosimetric evaluation was performed for the following organs at risk (OARs): mammary glands, lungs, and heart. A statistically significant advantage was reported for V5, V20, and V30 for the breast when using the inclined board. A similar result was obtained for V5 and V10 on the heart. No advantage was observed in lung doses. The use of a simple device, such as an inclined board, allows the optimization of treatment plan, especially in young female patients, by ensuring a significant reduction of the dose delivered to breast and heart.

Dosimetric effect of Elekta Beam modulator micromultileaf in three-dimensional conformal radiotherapy and intensity-modulated radiotherapy for prostate cancer.

The purpose of this study is to analyze the dosimetric effect of Elekta Beam Modulator in 3-dimensional conformal radiation therapy (3DCRT) and in intensity-modulated radiation therapy (IMRT) for localized prostate cancer. We compared treatment plans developed with 2 different Elekta multileaf collimators (MLC): Beam Modulator micro-MLC (mMLC) (4-mm leaf width at the isocenter) and standard MLC (10-mm leaf width at the isocenter). The comparison was performed for 15 patients with localized prostate cancer in 3DCRT and IMRT delivery; a total of 60 treatment plans were processed. The dose-volume histograms were used to provide the quantitative comparison between plans. In particular, we analyzed differences between rectum and bladder sparing in terms of a set of appropriate Vx (percentage of organ at risk [OAR] volume receiving the x dose) and differences between target conformity and coverage in terms of coverage factor and conformation number. Our analysis demonstrates that in 3DCRT there is an advantage in the use of Elekta Beam Modulator mMLC in terms of organ sparing; in particular, a significant decrease in rectal V60 and V50 (p = 0.001) and in bladder V70 and V65 (p = 0.007 and 0.002, respectively) was found. Moreover, a better target dose conformity was obtained (p = 0.002). IMRT plans comparison demonstrated no significant differences between the use of the 4 or 10-mm MLCs. Our analysis shows that in 3DCRT the use of the Elekta Beam Modulator mMLC gives a gain in target conformity and in OARs dose sparing whereas in IMRT plans there is no advantage.

Is the in vivo dosimetry with the OneDosePlusTM system able to detect intra-fraction motion? A retrospective analysis of in vivo data from breast and prostate patients.

BACKGROUND: The OneDosePlusTM system, based on MOSFET solid-state radiation detectors and a handheld dosimetry reader, has been used to evaluate intra-fraction movements of patients with breast and prostate cancer. METHODS: An Action Threshold (AT), defined as the maximum acceptable discrepancy between measured dose and dose calculated with the Treatment Planning System (TPS) (for each field) has been determined from phantom data. To investigate the sensitivity of the system to direction of the patient movements, fixed displacements have been simulated in phantom. The AT has been used as an indicator to establish if patients move during a treatment session, after having verified the set-up with 2D and/or 3D images. Phantom tests have been performed matching different linear accelerators and two TPSs (TPS1 and TPS2). RESULTS: The ATs have been found to be very similar (5.0% for TPS1 and 4.5% for TPS2). From statistical data analysis, the system has been found not sensitive enough to reveal displacements smaller than 1 cm (within two standard deviations). The ATs applied to in vivo treatments showed that among the twenty five patients treated for breast cancer, only four of them moved during each measurement session. Splitting data into medial and lateral field, two patients have been found to move during all these sessions; the others, instead, moved only in the second part of the treatment. Patients with prostate cancer have behaved better than patients with breast cancer. Only two out of twenty five moved in each measurement session. CONCLUSIONS: The method described in the paper, easily implemented in the clinical practice, combines all the advantages of in vivo procedures using the OneDosePlusTM system with the possibility of detecting intra-fraction patient movements.

Palifermin in the management of mucositis in hematological malignancies: current evidences and future perspectives.

BACKGROUND: In the management of hematological malignancies, chemotherapy-induced mucositis is an increasingly recognized problem, leading to potentially severe clinical complications, treatment delays, increased costs and impairment of patient's quality of life. Many forms of cytotoxic treatments given in this setting may induce several degrees of mucositis. In particular, conditioning therapy with hematopoietic stem cell transplantation (HSCT) induces a disruption of the mucosal barrier function throughout the entire gastrointestinal tract facilitating the spreading of bacteria and endotoxin with subsequent increased risk of septicemia and, in the allogeneic setting, a worsening of Graft Versus Host Disease (GVHD). OBJECTIVES: To review the role of palifermin and of other existing and potential treatments for chemotherapy-induced mucositis in the context of current knowledge of pathobiology in the setting of hematological malignancies. METHODS: We searched for palifermin and mucositis of any region of the gastrointestinal tract using Medline; the abstract books of the most important hematological and oncological meetings were also reviewed. RESULTS/CONCLUSIONS: The pathobiology of mucositis is complex, and agents that target mechanisms to prevent mucositis or accelerate healing are highly required. In this regard, palifermin (recombinant human keratinocyte growth factor) has been demonstrated to reduce the severity and the duration of oral mucositis and to significantly improve several treatment outcomes in patients submitted to autologous HSCT; data are insufficient to recommend its use in the non-autologous HSCT settings, although interesting properties of this agent deserves other investigations in order to explore other possible indications.

Case reports: zoster pain in haematological malignancies: effective pain relief with oxycodone in patients unresponsive to other analgesic measures.

Varicella zoster virus (VZV) outbreak is a significant cause of morbidity in patients suffering from blood-related malignancies, occurring mostly among those affected by lymphoproliferative disorders and in those receiving haematopoietic stem-cell transplantation. The elucidated pathological mechanisms of VZV-related painful complications have provided the rationale for acute zoster pain (AZP) and post-herpetic neuralgia (PHN) treatment with antiviral therapy combined with neuroactive agents, such as tricyclic or anticonvulsant agents. The role of opioids in this setting is less clearly established. We successfully treated (with oxycodone) 12 consecutive patients suffering from AZP and long-lasting PHN resistant to several agents, including anticonvulsants and analgesics. Our experience is reported together with a brief overview of the management of these often distressing and intractable complications.