Milly Buwenge

A phase I study of short-course accelerated whole brain radiation therapy for multiple brain metastases

PURPOSE To define the maximum tolerated dose (MTD) of a SHort-course Accelerated whole brain RadiatiON therapy (SHARON) in the treatment of patients with multiple brain metastases. METHODS AND MATERIALS A phase 1 trial in 4 dose-escalation steps was designed: 12 Gy (3 Gy per fraction), 14 Gy (3.5 Gy per fraction), 16 Gy (4 Gy per fraction), and 18 Gy (4.5 Gy per fraction). Eligibility criteria included patients with unfavorable recursive partitioning analysis (RPA) class>or=2 with at least 3 brain metastases or metastatic disease in more than 3 organ systems, and Eastern Cooperative Oncology Group (ECOG) performance status≤3. Treatment was delivered in 2 days with twice-daily fractionation. Patients were treated in cohorts of 6-12 to define the MTD. The dose-limiting toxicity (DLT) was defined as any acute toxicity≥grade 3, according to the Radiation Therapy Oncology Group scale. Information on the status of the main neurologic symptoms and quality of life were recorded. RESULTS Characteristics of the 49 enrolled patients were as follows: male/female, 30/19; median age, 66 years (range, 23-83 years). ECOG performance status was <3 in 46 patients (94%). Fourteen patients (29%) were considered to be in recursive partitioning analysis (RPA) class 3. Grade 1-2 acute neurologic (26.4%) and skin (18.3%) toxicities were recorded. Only 1 patient experienced DLT (neurologic grade 3 acute toxicity). With a median follow-up time of 5 months (range, 1-23 months), no late toxicities have been observed. Three weeks after treatment, 16 of 21 symptomatic patients showed an improvement or resolution of presenting symptoms (overall symptom response rate, 76.2%; confidence interval 0.95: 60.3-95.9%). CONCLUSIONS Short-course accelerated radiation therapy in twice-daily fractions for 2 consecutive days is tolerated up to a total dose of 18 Gy. A phase 2 study has been planned to evaluate the efficacy on overall survival, symptom control, and quality of life indices.

Forward-planned intensity modulated radiation therapy using a cobalt source: A dosimetric study in breast cancer

This analysis evaluates the feasibility and dosimetric results of a simplified intensity-modulated radiotherapy (IMRT) treatment using a cobalt-therapy unit for post-operative breast cancer. Fourteen patients were included. Three plans per patient were produced by a cobalt-60 source: A standard plan with two wedged tangential beams, a standard tangential plan optimized without the use of wedges and a plan based on the forward-planned “field-in-field” IMRT technique (Co-FinF) where the dose on each of the two tangential beams was split into two different segments and the two segments weight was determined with an iterative process. For comparison purposes, a 6-MV photon standard wedged tangential treatment plan was generated. Dmean, D98%, D2%, V95%, V107%, homogeneity, and conformity indices were chosen as parameters for comparison. Co-FinF technique improved the planning target volume dose homogeneity compared to other cobalt-based techniques and reduced maximum doses (D2%) and high-dose volume (V110%). Moreover, it showed a better lung and heart dose sparing with respect to the standard approach. The higher dose homogeneity may encourage the adoption of accelerated-hypofractionated treatments also with the cobalt sources. This approach can promote the spread of breast conservative treatment in developing countries.

Robotic radiosurgery in pancreatic cancer: A systematic review.

AIM To present a systematic review of techniques and clinical results. METHODS A systematic review of published literature was performed. Only studies reporting patient outcome after radiosurgery (single fraction) delivered with robotic devices [i.e., robotic radiosurgery (RRS)] have been analyzed. RESULTS A total of 96 patients from 5 studies were included. The studies are characterized by small series and different methods in terms of dose, target definition, combination with chemotherapy and/or standard fractionated radiotherapy and evaluation modalities. Preliminary results are positive in terms of tumor response (ORR = 56%) and local control of the tumor (crude rate of local progressions: 19.5%). Results for median overall survival (11.4 mo) seem comparable with the ones of prolonged chemoradiation (range: 8.6-13.0 mo). However, gastrointestinal toxicity seems to be the main limitation of RRS, especially at the duodenal level. CONCLUSION RRS allows for local treatment in a shortened time (1 fraction) compared to traditional treatments (about 1 mo), providing the possibility for an easy integration with systemic therapies. Preliminary results did not show any outcome differences compared to standard chemoradiation. Thus, further efforts to reduce gastrointestinal toxicity are strongly needed.

Short course accelerated radiation therapy (SHARON) in palliative treatment of advanced solid cancer in older patients: A pooled analysis

OBJECTIVES To evaluate the efficacy and safety of a conformal Short Course Accelerated Radiation therapy (SHARON) for symptomatic palliation of locally advanced or metastatic cancers in older patients. MATERIALS AND METHODS This is a pooled analysis on patients aged ≥80 years selected between subjects enrolled in 3 phase I-II studies on a short course palliative treatment of advanced or metastatic cancer. The primary endpoint was to evaluate the symptoms response rate produced by accelerated radiotherapy delivered in 4 total fractions in twice a day. Total dose ranged between 14 Gy and 20 Gy while dose/fraction between 3.5 and 5 Gy. RESULTS A total of 48 patients were included in this analysis. Twenty-six patients (54.2%) had advanced primary or metastatic head and neck tumors, 11 (22.9%) locally advanced or metastatic thoracic cancers, 11 (22.9%) complicated bone metastases. The majority of patients presented pain (60.4%). With a median follow-up time of 5.5 months, no G4 acute and late toxicities were recorded. The overall palliative response rate was 91.7% with a median duration of palliation of 4 months. CONCLUSION Short course accelerated radiotherapy in locally advanced or metastatic cancers is effective in terms of symptom relief and well tolerated even in older patients.

Intensity modulated radiation therapy for breast cancer: current perspectives

Background Owing to highly conformed dose distribution, intensity modulated radiation therapy (IMRT) has the potential to improve treatment results of radiotherapy (RT). Postoperative RT is a standard adjuvant treatment in conservative treatment of breast cancer (BC). The aim of this review is to analyze available evidence from randomized controlled trials (RCTs) on IMRT in BC, particularly in terms of reduction of side effects. Methods A literature search of the bibliographic database PubMed, from January 1990 through November 2016, was performed. Only RCTs published in English were included. Results Ten articles reporting data from 5 RCTs fulfilled the selection criteria and were included in our review. Three out of 5 studies enrolled only selected patients in terms of increased risk of toxicity. Three studies compared IMRT with standard tangential RT. One study compared the results of IMRT in the supine versus the prone position, and one study compared standard treatment with accelerated partial breast IMRT. Three studies reported reduced acute and/or late toxicity using IMRT compared with standard RT. No study reported improved quality of life. Conclusion IMRT seems able to reduce toxicity in selected patients treated with postoperative RT for BC. Further analyses are needed to better define patients who are candidates for this treatment modality.

Adjuvant radiotherapy with brachytherapy boost in soft tissue sarcomas

Purpose The standard primary treatment for soft tissue sarcoma (STS) is a wide surgical resection, preceded or followed by radiotherapy. Purpose of this retrospective study was to assess the efficacy of perioperative brachytherapy (BRT) plus postoperative external beam radiation therapy (EBRT) in patients with intermediate-high risk STS. Material and methods BRT delivered dose was 20 Gy. External beam radiation therapy was delivered with 3D-technique using multiple beams. The prescribed dose was 46 Gy to the PTV. Neoadjuvant and adjuvant chemotherapy (CHT) was used in patients with potentially chemosensitive histological subtypes. The primary aim of the study was to analyze overall survival (OS) and local control (LC) in a large patient population treated with surgery, perioperative BRT, and adjuvant EBRT ± CHT. Secondary objective was to identify prognostic factors for patients outcome in terms of LC, disease-free survival (DFS), and OS. Results From 2000 to 2011, 107 patients presenting 2-3 grade (FNLCC) primary or recurrent STS were treated with surgery, perioperative BRT, and adjuvant EBRT ± CHT. Five-year LC and OS were 80.9% and 87.4%, respectively. At univariate analysis, a higher LC was recorded in primary vs. recurrent tumors (p = 0.015), and in lower limb tumors vs. other sites (p = 0.027). An improved DFS was recorded in patients with lower limb tumors vs. other sites (p = 0.034). Conclusions The combination of BRT and EBRT was able to achieve satisfactory results even in a patients population with intermediate-high risk STS. Patients with recurrent or other than lower limb sited tumors show a worse LC.

Brachytherapy in non melanoma skin cancer of eyelid: a systematic review.

Purpose Non melanoma skin cancers (NMSC) of eyelid are uncommon. Many treatments approach are available with surgery being considered as the gold standard. Radiotherapy is an effective alternative in patients unfit for surgery. Brachytherapy (BT) might be a better therapeutic option due high radiation dose concentration to the tumor and rapid dose fall-off resulting in normal tissues sparing. The aim of this review is to evaluate local control, toxicity, and functional cosmetic outcome of BT in NMSC of eyelid. Material and methods A systematic search of the bibliographic databases PubMed, Scopus, and Cochrane Library from the earliest possible date through October 2015 was performed. Only studies published in English were included. Results Six articles fulfilled the selection criteria and were included in our review. Due to high risk of bias, all studies were classified to provide a low level of evidence (according to Scottish Intercollegiate Guidelines Network Classification). No randomized controlled trials or case control studies were founded. Brachytherapy was well tolerated with acceptable toxicity and high local control rates (median: 95.2%). Functional and cosmetic outcome were reported in five study as acceptable good functional-cosmetic outcome (median: 100%). Conclusions To date, few evidences are available on the role of BT in eyelid NMSC, and they show satisfactory results in terms of local control and functional cosmetic outcome. Therefore, prospective controlled trials are justified.

Palliative two-dimensional radiotherapy of pancreatic carcinoma: a feasibility study.

AIMS AND BACKGROUND The aim of the study was to analyze the dose to be administered with two-dimensional involved-field palliative radiotherapy in advanced pancreatic carcinoma with respect to current dose-volume constraints (QUANTEC). METHODS AND STUDY DESIGN The following standard regimens were evaluated: 30 Gy at 3 Gy/fraction (regimen A), 36 Gy at 2.4 Gy/fraction (regimen B), 45 Gy at 1.8 Gy/fraction (regimen C), and 50 Gy at 2 Gy /fraction (regimen D). The following constraints were considered: spinal cord Dmax <50 Gy, duodenum Dmax <55 Gy, liver Dmean <30 Gy, kidneys Dmean <15 Gy. For dose/fraction different from 1.8-2 Gy, the correction of constraints using a value of alpha/beta = 3 for late effects was considered. The calculation of dose/volume constraints was repeated for three different radiation beams: cobalt unit, 6 MV photons, and 15 MV photons. Standard field sizes were used and adapted according to the different beam types, using the parameters of our previous study. Respect of dose-volume constraints was assessed for each type of beam and treatment (dose per fractionation) in all patients. Treatments were considered acceptable in case of: 1) respect of the constraints for spinal cord and duodenum in all patients; 2) respect in >10/15 patients of constraints for kidneys and liver. Therefore, minor violations (<10%) of the constraints for these organs were accepted (in less than 5/15 patients), in consideration of the palliative aim of treatment. RESULTS In regimen A (30 Gy, 3 Gy/fraction), evaluated constraints were respected in all patients, regardless of the type of energy. In regimen B (36 Gy, 2.4 Gy/fraction), constraints were met in all patients undergoing irradiation with 6 and 15 MV photons. However, using the cobalt unit, kidney constraint was respected only in 5 of 15 patients. In regimens C and D (45 Gy, 1.8 Gy/fraction and 50 Gy, 2 Gy/fraction, respectively), the constraint for the kidney was respected only in 2-5 patients, depending on the energy used. Furthermore, using 50 Gy, the spinal cord constraint was not respected in 2-3 patients, depending on the beam used. Therefore, only the following treatments were considered acceptable: 1) 30 Gy, 3 Gy/fraction, regardless of the energy used; 2) 36 Gy, 2.4 Gy/fraction, only for treatments performed with linear accelerator (6-15 MV). CONCLUSIONS The clinical benefits of radiotherapy in pancreatic tumors should not be withheld from patients treated in centers only with two-dimensional technology. Prospective trials, particularly in developing countries, would be useful to evaluate the efficacy in this setting of involved-field two-dimensional treatments using the dose and fractionation defined in this analysis.

Prognostic Impact of Presurgical CA19-9 Level in Pancreatic Adenocarcinoma: A Pooled Analysis

BACKGROUND: Presurgical carbohydrate antigen 19-9 (CA19-9) level predicts overall survival (OS) in resected pancreatic adenocarcinoma (PaC). The aim of this pooled analysis was to evaluate if presurgical CA19-9 level can also predict local control (LC) and distant metastasis-free survival (DMFS). METHODS: Seven hundred patients with PaC from eight institutions who underwent surgical resection ± adjuvant treatment between 2000 and 2014 were analyzed. Patients were divided based on four presurgical CA19-9 level cutoffs (5, 37, 100, 353 U/ml). Weibull regression model to identify independent predictors of OS on 404 patients with complete information was fitted. RESULTS: Median follow-up was 17 months (range: 2-225 months). Univariate analysis showed a better prognosis in pT1-2, pN0, diameter <30 mm, or grade 1 tumors and in patients undergoing R0 resection, distal pancreatectomy, or adjuvant chemotherapy and with lower CA19-9 levels. Five-year OS, LC, and DMFS were as follows: CA19-9 <5.0: 5.7%, 47.2%, 17.0%; CA19-9 5.1-37.0: 37.9%, 63.3%, 46.0%; CA19-9 37.1-100.0: 27.1%, 59.4%, 39.0%; CA19-9 100.1-353.0: 17.4%, 43.4%, 26.7%; CA19-9 >353.1: 10.9%, 50.2%, and 23.4%, respectively. At multivariate analysis, CA19-9 >100 and <353 level (P=.002), CA19-9 ≥353.1 (P<.001) level, G3 tumor (P=.002), and tumor diameter >30 mm (P<.001) correlated with worse OS. Patients treated with postoperative chemoradiation doses >50.0 Gy showed improved OS (P<.001). CONCLUSION: Presurgical CA19-9 predicts both OS and pattern of failure. Therefore, CA19-9 should be included in predictive models in order to customize treatments based on prognostic factors. Moreover, future studies should stratify patients according to presurgical CA19-9 level.

Feasibility of 2D‑conformal radiotherapy for pancreatic carcinoma

The purpose of the present study was to propose an optimized 2D technique (2D-conformal) for radiotherapy (RT) of pancreatic cancer (CaP). This technique is based on double simulation which resolves the problems of radiographic image distortion. Five patients with locally advanced CaP were identified and enrolled. Treatment planning was simulated in 3 different ways: Two dimensional-standard (2D-SRT), 2D-conformal (2D-CRT), and three dimensional-conformal (3D-CRT) techniques for 10 MV LINAC. Simulation for a cobalt machine was also performed using only the 2D techniques. 2D-SRT technique was planned with fields definition based on anatomical landmarks (bone and duodenum). 3D-CRT was planned with standard virtual simulation technique, and 3D dose evaluation and optimization. 2D-CRT technique was based on manual information transfer from a diagnostic CT-scan to simulation radiograms. To eliminate the X-ray image distortion, a double simulation was employed and the profile of the GTV was delineated on radiographs bearing the simulator isocenter into the target center. Concerning target irradiation of either LINAC (10 MV) or cobalt source, the PTV constraints (ICRU 62) were met in all patients (Dmin >95%, Dmax <107%) with all techniques (2D-SRT, 3D-CRT, 2D-CRT). For organs at risk irradiation, in terms of Dmax to both duodenum and spinal cord, similar results were recorded with all techniques using the LINAC (10 MV). Liver and kidneys Dmean gradually improved from 2D-SRT to 2D-CRT and 3D-CRT. The 2D-CRT compared to 2D-SRT technique, halved the average dose to the liver and reduced to about 1/3 the average dose to the kidneys. With the cobalt source, using the 2D-CRT produced a reduction of Dmean to the kidneys (median from 30.7 to 16.9%) and liver (median from 33.4 to 22.3%) compared to 2D-SRT. This analysis showed better planning results in RT treatment of CaP while using a 2D-CRT compared to 2D-SRT technique and therefore presents an example for optimized 2D RT use.