Three-dimensional Conformal External Beam Radiotherapy Research Articles

Methodological Comparison of Mapping the Expanded Prostate Cancer Index Composite to EuroQoL-5D-3L Using Cross-Sectional and Longitudinal Data: Secondary Analysis of NRG/RTOG 0415.

To compare the predictive ability of mapping algorithms derived using cross-sectional and longitudinal data. This methodological assessment used data from a randomized controlled noninferiority trial of patients with low-risk prostate cancer, conducted by NRG Oncology (ClinicalTrials.gov identifier: NCT00331773), which examined the efficacy of conventional schedule versus hypofractionated radiation therapy (three-dimensional conformal external beam radiation therapy/IMRT). Health-related quality-of-life data were collected using the Expanded Prostate Cancer Index Composite (EPIC), and health utilities were obtained using EuroQOL-5D-3L (EQ-5D) at baseline and 6, 12, 24, and 60 months postintervention. Mapping algorithms were estimated using ordinary least squares regression models through five-fold cross-validation in baseline cross-sectional data and combined longitudinal data from all assessment periods; random effects specifications were also estimated in longitudinal data. Predictive performance was compared using root mean square error. Longitudinal predictive ability of models obtained using baseline data was examined using mean absolute differences in the reported and predicted utilities. A total of 267 (and 199) patients in the estimation sample had complete EQ-5D and EPIC domain (and subdomain) data at baseline and at all subsequent assessments. Ordinary least squares models using combined data showed better predictive ability (lowest root mean square error) in the validation phase for algorithms with EPIC domain/subdomain data alone, whereas models using baseline data outperformed other specifications in the validation phase when patient covariates were also modeled. The mean absolute differences were lower for models using EPIC subdomain data compared with EPIC domain data and generally decreased as the time of assessment increased. Overall, mapping algorithms obtained using baseline cross-sectional data showed the best predictive performance. Furthermore, these models demonstrated satisfactory longitudinal predictive ability.

Accelerated partial breast irradiation by brachytherapy: present evidence and future developments.

Accelerated partial breast irradiation (APBI) delivers a short course of adjuvant RT after breast conserving surgery to only a limited part of the breast where the tumor was located. This procedure requires expertise, good communication, and close collaboration between specialized surgeons and attending radiation oncologists with adequate intraoperative tumor bed clip marking. However, APBI offers several intrinsic benefits when compared with whole breast irradiation (WBIR) including reduced treatment time (1 versus 4-6weeks) and better sparing of surrounding healthy tissues. The present publication reviews the APBI level 1-evidence provided with various radiation techniques supplemented by long-term experience obtained from large multi-institutional phase II studies. Additionally, it offers an outlook on recent research with ultra-short or single-fraction APBI courses and new brachytherapy sources. Mature data from three randomized controlled trials (RCTs) clearly prove the noninferiority of APBI with 'only two techniques-1/MIBT (multicatheter interstitial brachytherapy) (two trials) and 2/intensity modulated radiotherapy (one trial)'-in terms of equivalent local control/overall survival to the previous standard 'conventionally fractionated WBIR'. However, MIBT-APBI techniques were superior in both toxicity and patient-reported outcomes (PROs) versus WBIR at long-term follow-up. Currently, in RCT-setting, alternative APBI techniques such as intraoperative electrons, 50-kV x-rays and three-dimensional conformal external beam radiotherapy (3D-CRT) failed to demonstrate noninferiority to conventionally fractionated WBIR. However, 3D-CRT-APBI compared noninferior to hypo-fractionated WBIR in preventing ipsilateral breast tumor recurrence (randomized RAPID-trial) but was associated with a higher rate of late radiation toxicity. Ultimately, MIBT remains the only APBI modality with noninferior survival/superior toxicity/PROs at 10-years and therefore should be prioritized over alternative methods in patients with breast cancer considered at low-risk for local recurrence according to recent international guidelines.

Efficacy and safety of concurrent chemoradiotherapy in ECOG 2 patients with locally advanced non-small-cell lung cancer: a subgroup analysis of a randomized phase III trial

BackgroundThere is no consensus on the therapeutic approach to ECOG 2 patients with locally advanced non-small-cell lung cancer (LA-NSCLC), despite the sizable percentage of these patients in clinical practice. This study focused on the efficacy, toxicity and the optimal chemotherapy regimen of CCRT in ECOG 2 patients in a phase III trial.MethodsPatients capable of all self-care with bed rest for less than 50% of daytime were classified as ECOG 2 subgroup. A subgroup analysis was performed for ECOG 2 patients recruited in the phase III trial receiving concurrent EP (etoposide + cisplatin)/PC (paclitaxel + carboplatin) chemotherapy with intensity-modulated radiation therapy (IMRT) or three-dimensional conformal external beam radiation therapy (3D-CRT).ResultsA total of 71 ECOG 2 patients were enrolled into the study. Forty-six (64.8%) patients were treated with IMRT technique. The median overall survival (OS) and progression free survival (PFS) for ECOG 2 patients were 16.4 months and 9 months, respectively. No difference was observed in treatment compliance and toxicities between ECOG 2 patients and ECOG 0–1 patients. Within the ECOG 2 group (31 in the EP arm and 40 in the PC arm), median OS and 3-year OS were 15.7 months and 37.5% for the EP arm, and 16.8 months and 7.5% for the PC arm, respectively (p = 0.243). The incidence of grade ≥ 3 radiation pneumonitis was higher in the PC arm (17.5% vs. 0.0%, p = 0.014) with 5 radiation pneumonitis related deaths, while the incidence of grade 3 esophagitis was numerically higher in the EP arm (25.8% vs. 10.0%, p = 0.078).ConclusionsCCRT provided ECOG 2 patients promising outcome with acceptable toxicities. EP might be superior to PC in terms of safety profile in the setting of CCRT for ECOG 2 patients. Prospective randomized studies based on IMRT technique are warranted to validate our findings.Trial registrationClinicalTrials.gov registration number: NCT01494558. (Registered 19 December 2011).

IJU this issue

This issue deals with a wide range of clinical topics of urology, and contains three Review Articles, seven Original Articles and one Urological Note. Radiation cystitis is a specific type of iatrogenic injury to the bladder. Radiation cystitis can be a complication of radiation doses starting from 45 to 55 Gy, and the risk increases significantly at cumulative doses of ≥60 Gy. It is a potential, but often intractable, complication of pelvic radiation therapy for treatment of pelvic malignancies. Villeirs et al. (Ghent, Belgium) assessed the efficacy of hyperbaric oxygen therapy in reducing symptoms of radiation cystitis by systematic review of recent literature. Hyperbaric oxygen therapy was effective (the weighted average overall and complete response rates were 87.3% and 65.3%, respectively) in the treatment of radiation-induced cystitis, with minimal adverse events, but low availability and high cost. At present, as evidence is low, more prospective studies seem to be required. The term, bacillus Calmette–Guerin (BCG) failure, is ambiguous, and includes a very heterogeneous population of patients. By strictly focusing on patients who are unlikely to benefit from additional BCG therapy and who need to be treated with radical cystectomy, the new concept of “BCG unresponsive” was recently proposed. Kikuchi et al. (Kanagawa, Japan) demonstrated the definition of BCG unresponsive, and assessed the development of novel therapeutic options for BCG unresponsive disease. So far, the blockade of the programmed cell death-1/programmed cell death-ligand 1 pathway, which is considered to be activated by BCG therapy, is promising. Furthermore, clinical trials with other strategies, such as vaccines, gene therapy, and targeted and cytotoxic therapies, are ongoing. It is well known that cisplatin has various toxicities, including myelosuppression, gastrotoxicity and ototoxicity, and the main dose-limiting side-effect is nephrotoxicity. Shiraishi et al. (Kyoto, Japan) evaluated the safety and efficacy of the combined regimen of paclitaxel and ifosfamide plus nedaplatin for patients with refractory or relapsed germ cell tumors and impaired renal function. Their results showed that paclitaxel, ifosfamide and nedaplatin chemotherapy can be considered a safe and effective (overall response rate: 60%) regimen that results in less nephrotoxicity in germ cell tumor patients with renal dysfunction. In patients who show prostate-specific antigen failure after external beam radiotherapy for local or locally advanced prostate cancer, salvage therapy targeting the prostate is currently an option. Yamada et al. (Kyoto, Japan) examined the effect of permanent salvage brachytherapy in prostate cancer patients suffering recurrence after three-dimensional conformal external beam radiotherapy. Permanent salvage brachytherapy was carried out in 13 patients who suffered prostate-specific antigen failure. Their results showed that targeted fusion biopsy-based three-dimensional cancer mapping should be used for permanent salvage brachytherapy treatment planning to reduce the incidence of treatment-related adverse events while maintaining good oncological outcomes. In contrast, Takeda et al. (New York, USA) examined a set of proposed eligibility factors for hemi-ablative focal therapy in prostate cancer, and determined the likelihood of residual extensive disease. Hemi-ablative focal therapy, which involves ablation of an entire half of the prostate, is most frequently carried out now. They retrospectively analyzed data from 98 patients with the focal therapy consensus meeting the inclusion criteria who underwent radical prostatectomy. Their results showed that an important number of patients meeting the focal therapy consensus meeting the inclusion criteria can present extensive disease. Interestingly, their study also implied that targeted biopsies might provide more accurate information about the selection of focal therapy candidates. Until recently, there has been only limited information about the clinicopathological features of malignant urachal tumors (MUTs) from a large population-based study. Nagumo et al. (Ibaraki, Japan) used the hospital-based cancer registry data to extract 456 MUT cases. Their results showed that MUTs are quite rare (0.4% of all malignant bladder cancers) in Japan, and most of those without metastasis are likely to be treated with surgery alone, even at advanced stages. The necessity of establishing a standard of care for MUT patients at advanced stages or with metastasis is also reported. None declared.

Focal salvage low-dose-rate brachytherapy for recurrent prostate cancer based on magnetic resonance imaging/transrectal ultrasound fusion biopsy technique.

To examine the effect of permanent salvage brachytherapy in prostate cancer patients suffering recurrence after three-dimensional conformal external beam radiotherapy. The ultra-focal (target lesion alone), hemi-lobe (within a hemi-lobe) or focused whole-gland (focusing on the lesion, but extending into the whole gland) pattern was selected based on the Gleason score for the targeted biopsy, the numbers of positive cores in the targeted and systematic biopsies, and the locations of the positive cores. Novel dosimetry criteria derived from three-dimensional cancer mapping, which was based on targeted magnetic resonance imaging/transrectal ultrasound fusion biopsies, were used in these cases. Permanent salvage brachytherapy was carried out in 13 patients who suffered prostate-specific antigen failure (prostate-specific antigen 2.1-6.8ng/mL; age range 57-75years; Gleason score ≤7 [n=10], Gleason score ≥8 [n=2] and Gleason score not available [n=1]) since 2012. The targeted biopsy showed a single focus in three patients. The ultra-focal, hemi-lobe and focused whole-gland patterns were chosen in three, five and five patients, respectively. During the follow-up period (median duration 48months), prostate-specific antigen failure occurred in zero of three, one of five and three of five of the patients treated with the ultra-focal, hemi-lobe and focused whole-gland patterns, respectively. The 4-year biochemical recurrence-free survival rate was 74%. No grade3-4 adverse intestinal or urological events occurred. Targeted fusion biopsy-based three-dimensional cancer mapping should be used for permanent salvage brachytherapy treatment planning to reduce the incidence of treatment-related adverse events while maintaining good oncological outcomes.

Efficacy and Safety of Concurrent Chemoradiotherapy in ECOG 2 Patients with Locally Advanced Non-Small-Cell Lung Cancer: A Subgroup Analysis of a Randomized Phase III Trial

There is no consensus on the therapeutic approach to ECOG 2 patients with locally advanced non-small-cell lung cancer (LA-NSCLC), despite the sizable percentage of these patients in clinical practice. In recent years, the clinical benefit brought by utilization of modern radiotherapy technique such as intensity-modulated radiation therapy (IMRT) may bring opportunities of definitive treatment for ECOG 2 patients. This study focused on the efficacy, toxicity and the optimal chemotherapy regimen of CCRT in ECOG 2 patients in a phase III trial. Patients capable of all self-care with bed rest for less than 50% of daytime were classified as ECOG 2 subgroup. A subgroup analysis was performed for ECOG 2 patients recruited in the phase III trial receiving concurrent EP/PC chemotherapy with IMRT or three-dimensional conformal external beam radiation therapy (3D-CRT). A total of 71 ECOG 2 patients were enrolled into the study. Forty-six (64.8%) patients were treated with IMRT technique. The median overall survival (OS) and progression free survival (PFS) for ECOG 2 patients were 16.4 months and 9 months, respectively. No difference was observed in treatment compliance and toxicities between ECOG 2 patients and ECOG 0-1 patients. Within the ECOG 2 group (31 in the EP arm and 40 in the PC arm), median OS and 3-year OS were 15.7 months and 37.5% for the EP arm, and 16.8 months and 7.5% for the PC arm, respectively (p = 0.243). The incidence of grade≥3 radiation pneumonitis was higher in the PC arm (17.5% vs. 0.0%, p = 0.014) with 5 radiation pneumonitis related deaths, while the incidence of grade 3 esophagitis was numerically higher in the EP arm (25.8% vs. 10.0%, p = 0.078). CCRT provided ECOG 2 patients promising outcome with acceptable toxicities. EP might be superior to PC in terms of safety profile in the setting of CCRT for ECOG 2 patients. Prospective randomized studies based on IMRT technique are warranted to validate our findings.

Impact of Intensity Modulated Radiation Therapy on Acute Toxicity in Locally Advanced Lung Cancer: Results of a Large Statewide Multi-center Cohort

Secondary analysis of RTOG 0617 has shown lower rates of pneumonitis and less decline in patient quality of life with the use of intensity modulated radiation therapy (IMRT) versus three-dimensional conformal external beam radiation therapy (3D-CRT) in locally advanced non-small cell lung cancer patients undergoing definitive radiation therapy. In a large statewide radiation oncology quality consortium, we sought to evaluate impact of IMRT vs. 3D-CRT treatment technique on acute esophagitis and pneumonitis. From 2013 to 2017, 1919 patients with non-metastatic lung cancer were enrolled in the consortium. Physician reported toxicity by CTCAE and patient reported outcomes using FACT Lung Cancer Subscale (LCS) and FACT Trials Outcome Index (TOI) were collected at 1, 3 and 6 months from the end of radiation. We compared physician and patient reported quality of life by treatment technique. Normal tissue dose volume constraints and PTV objectives were not prospectively controlled. To account for differences in prognostic factors between IMRT and 3D-CRT patients, we performed inverse probability of treatment weighting (IPTW) via a propensity score. The propensity score was estimated via a logistic regression model and included age, smoking status, comorbidities, stage, PTV volume, chemotherapy, prescription dose, total number of structures and individual structures (e.g. esophagus, heart) within 2cm of the PTV. There were 1237 non-surgical locally advanced lung cancer patients met inclusion criteria. After excluding patients with missing variables, 1062 (86%) were included in the analysis. 31% were treated with 3D-CRT and 69% were treated with IMRT. Compared with 3D-CRT patients, IMRT patients had significantly larger PTVs (mean 370 vs 474cc) and were more likely to be stage IIIB (24% vs 32%). In logistic regression models using IPTW, there were no significant differences between 3D-CRT and IMRT in rates of esophagitis (Odds Ratio =0.95; 95% CI=0.70, 1.32; p=0.76) or pneumonitis (OR = 0.91; 95% CI:0.43, 1.92; p=0.80). At 6 months after completion of RT with a compliance of 45%, 3D-CRT and IMRT resulted in similar proportions of patient experiencing a decline of at least 2 points on LCS (38% vs 45%, p=0.33) and at least 5 points on TOI (48% vs 54%, p=0.72). In these data from a statewide consortium of academic and community radiation oncology practices, despite the PTV being larger among patients treated with IMRT vs 3D-CRT, no significant difference in acute esophagitis or pneumonitis by radiation treatment technique was found. Further analysis is underway seeking to use patient variables and dose relationships to identify a subgroup of patients in which IMRT may reduce toxicity relative to 3D-CRT.

Three-dimensional intrafractional internal target motions in accelerated partial breast irradiation using three-dimensional conformal external beam radiotherapy

PurposeWe evaluated three-dimensional intrafractional target motion, divided into respiratory-induced motion and baseline drift, in accelerated partial breast irradiation (APBI). MethodsPaired fluoroscopic images were acquired simultaneously using orthogonal kV X-ray imaging systems at pre- and post-treatment for 23 patients who underwent APBI with external beam radiotherapy. The internal target motion was calculated from the surgical clips placed around the tumour cavity. ResultsThe peak-to-peak respiratory-induced motions ranged from 0.6 to 1.5mm in all directions. A systematic baseline drift of 1.5mm towards the posterior direction and a random baseline drift of 0.3mm in the lateral-medial and cranial-caudal directions were observed. The baseline for an outer tumour cavity drifted towards the lateral and posterior directions, and that for an upper tumour cavity drifted towards the cranial direction. Moderate correlations were observed between the posterior baseline drift and the patients’ physical characteristics. The posterior margin for intrafractional uncertainties was larger than 5mm in patients with greater fat thickness due to the baseline drift. ConclusionsThe magnitude of the intrafractional motion was not uniform according to the direction, patients’ physical characteristics, or tumour cavity location due to the baseline drift. Therefore, the intrafractional systematic movement should be properly managed.

Preoperative treatment with radiochemotherapy for locally advanced gastroesophageal junction cancer and unresectable locally advanced gastric cancer.

Background.To purpose of the study was to analyze the results of preoperative radiochemotherapy in patients with unresectable gastric or locoregionally advanced gastroesophageal junction (GEJ) cancer treated at a single institution.Patients and methods.Between 1/2004 and 6/2012, 90 patients with locoregionally advanced GEJ or unresectable gastric cancer were treated with preoperative radiochemotherapy at the Institute of Oncology Ljubljana. Planned treatment schedule consisted of induction chemotherapy with 5-fluorouracil and cisplatin, followed by concomitant radiochemotherapy four weeks later. Three-dimensional conformal external beam radiotherapy was delivered by dual energy (6 and 15 MV) linear accelerator in 25 daily fractions of 1.8 Gy in 5 weeks with two additional cycles of chemotherapy repeated every 28 days. Surgery was performed 4–6 weeks after completing radiochemotherapy. Following the surgery, multidisciplinary advisory team reassessed patients for the need of adjuvant chemotherapy. The primary endpoints were histopathological R0 resection rate and pathological response rate. The secondary endpoints were toxicity of preoperative radiochemotherapy and survival.Results.Treatment with preoperative radiochemotherapy was completed according to the protocol in 84 of 90 patients (93.3%). Twenty patients (22.2%) did not undergo the surgery because of the disease progression, serious comorbidity, poor performance status or still unresectable tumour. In 13 patients (14.4%) only exploration was performed because the tumour was assessed as unresectable or diffuse peritoneal carcinomatosis was established. Fifty-seven patients (63.4%) underwent surgery with the aim of complete removal of the tumour. Radical resection was achieved in 50 (55.6%) patients and the remaining seven (7.8%) patients underwent non-radical surgery (R1 in five and R2 in two patients). In this group of patients (n = 57), pathological complete response of tumour was achieved in five patients (5.6% of all treated patients or 8.8% of all operated patients). Down-staging was recorded in 49 patients (86%), in one patient (1.8%) the stage after radiochemotherapy was unchanged while in seven patients (12.3%) the pathological stage was higher than clinical, mainly due to higher pN stage. No death was recorded during preoperative radiochemotherapy. Most grade 3 and 4 toxicities were due to vomiting, nausea and bone marrow suppression (granulocytopenia). Twenty-six (45.6%) patients died due to GEJ or gastric carcinoma, one died because of septic shock following the surgery and a reason for two deaths was unknown. Twenty-eight patients (49.1%) were disease free at the time of analysis, while 29 patients (50.9%) developed the recurrence, mostly as distant metastases. At two years, locoregional control, disease-free survival, disease-specific survival and overall survival were 82.9%, 43.9%, 56.9% and 53.9%, respectively.Conclusions.Preoperative radiochemotherapy was feasible in our group of patients and had acceptable toxicity. Majority of patients achieved down-staging, allowing greater proportion of radical resections (R0), which are essential for patients’ cure.

Active monitoring, radical prostatectomy, or radiotherapy for localised prostate cancer: study design and diagnostic and baseline results of the ProtecT randomised phase 3 trial

Prostate cancer is a major public health problem with considerable uncertainties about the effectiveness of population screening and treatment options. We report the study design, participant sociodemographic and clinical characteristics, and the initial results of the testing and diagnostic phase of the Prostate testing for cancer and Treatment (ProtecT) trial, which aims to investigate the effectiveness of treatments for localised prostate cancer. In this randomised phase 3 trial, men aged 50-69 years registered at 337 primary care centres in nine UK cities were invited to attend a specialist nurse appointment for a serum prostate-specific antigen (PSA) test. Prostate biopsies were offered to men with a PSA concentration of 3·0 μg/L or higher. Consenting participants with clinically localised prostate cancer were randomly assigned to active monitoring (surveillance strategy), radical prostatectomy, or three-dimensional conformal external-beam radiotherapy by a computer-generated allocation system. Randomisation was stratified by site (minimised for differences in participant age, PSA results, and Gleason score). The primary endpoint is prostate cancer mortality at a median 10-year follow-up, ascertained by an independent committee, which will be analysed by intention to treat in 2016. This trial is registered with ClinicalTrials.gov, number NCT02044172, and as an International Standard Randomised Controlled Trial, number ISRCTN20141297. Between Oct 1, 2001, and Jan 20, 2009, 228,966 men were invited to attend an appointment with a specialist nurse. Of the invited men, 100,444 (44%) attended their initial appointment and 82,429 (82%) of attenders had a PSA test. PSA concentration was below the biopsy threshold in 73,538 (89%) men. Of the 8566 men with a PSA concentration of 3·0-19·9 μg/L, 7414 (87%) underwent biopsies. 2896 men were diagnosed with prostate cancer (4% of tested men and 39% of those who had a biopsy), of whom 2417 (83%) had clinically localised disease (mostly T1c, Gleason score 6). With the addition of 247 pilot study participants recruited between 1999 and 2001, 2664 men were eligible for the treatment trial and 1643 (62%) agreed to be randomly assigned (545 to active monitoring, 545 to radiotherapy, and 553 to radical prostatectomy). Clinical and sociodemographic characteristics of randomly assigned participants were balanced across treatment groups. The ProtecT trial randomly assigned 1643 men with localised prostate cancer to active monitoring, radiotherapy, or surgery. Participant clinicopathological features are more consistent with contemporary patient characteristics than in previous prostate cancer treatment trials. UK National Institute for Health Research Health Technology Assessment Programme.

The Prevalence of Persistent Prostate Cancer after Radiotherapy Detected at Radical Cystoprostatectomy for Bladder Cancer

More than half of the men who receive treatment for prostate cancer elect radiotherapy. After radiotherapy recurrence is determined by an increase in prostate specific antigen and not usually by pathological confirmation. We describe the prevalence of persistent gradable prostate cancer in men treated with radiotherapy for prostate cancer at radical cystoprostatectomy for bladder cancer. A total of 78 patients underwent radiotherapy (brachytherapy and/or external beam radiation) before the development of bladder cancer requiring radical cystectomy at our institution. All tissues were evaluated by a specialized genitourinary pathologist. Median time from radiotherapy to radical cystoprostatectomy was 77 months. Gradable prostate cancer was identified in 45% of patients. Of the tumors 69% were Gleason score 7 or greater, 17% were pT3 or greater and 5% showed positive lymph nodes. Men treated more recently were less likely to have gradable prostate cancer, including 100% before 1980, 49% between 1980 and 2000 and 10% from 2000 to the present (p=0.002) as were those who received external beam radiation alone compared to brachytherapy and combined brachytherapy/external beam radiation (58% vs 27% and 14%, respectively, p=0.005). After radiotherapy 45% of men had persistent prostate cancer (37% of men with no evidence of disease). A decreased prostate cancer rate was associated with later treatment year and combined brachytherapy/external beam radiation regimens. Similar to men treated with radical cystoprostatectomy for muscle invasive bladder cancer, meticulous attention should be paid during prostate removal in men treated with radiotherapy because many may have persistent prostate cancer. In addition, markers other than prostate specific antigen should be studied in men treated with radiotherapy to better identify those with biochemical recurrence.

Abstract OT2-1-03: Preoperative accelerated partial breast irradiation trial (PAPBI); defining radiosensitivity

Abstract Background and aim of the study: A.The ongoing Preoperative Accelerated Partial Breast Irradiation (PAPBI) trial (NCT01024582) is based on the rationale that three-dimensional conformal external-beam radiation (3D-CRT) leads to more dose homogeneity compared with brachy-or intraoperative radiotherapy (RT). By irradiating preoperatively this can lead to more accurate tumor delineation and smaller irradiated volumes. As the tumor remains in situ during irradiation, more precise delivery of the radiation dose is guaranteed with CT cone beam linear accelerators, avoiding the uncertainties of the original tumor position in the operation cavity as is the case in postoperative RT. Tumor excision 6 weeks after RT removes the high dose volume tissue and can lead to better cosmesis. B. By assessing tumor response to radiotherapy, an additional goal of the study is to develop a gene expression profile that predicts breast cancer radiosensitivity. This gene signature of breast radiosensitivity would further design optimal treatment strategies for individual breast cancer patients treated with BCT. Inclusion citeria: Patients 60 years or older with a cT< = 3cm, ductal carcinoma (no in situ component), unifocal on mammogram and MRI, pN0(sn) (sentinel node procedure before RT), will be treated by preoperative RT (CTV = GTV + 2 cm, 10 × 4 Gy IMRT/VMAT over two weeks). Six weeks after pre-operative RT, a wide local excision will be performed. Skin toxicity and fibrosis is scored using EORTC/RTOG criteria. Patients are followed during RT and on a 3-monthly basis. Cosmesis is scored and photographs are taken for analysis (BCCT.core project score). To study radiosensit ivity, gene expression profiling from RNA and DNA isolated from biopsies (mRNA gene expression profiles, the miRNA expression profiles and the DNA copy number changes) taken of the tumor before radiotherapy and at time of surgery will be correlated with response to radiotherapy, defined as pathologic response at the time of the lumpectomy. Response of the tumor will be evaluated by MRI scan and PET (before radiotherapy and before surgery) and classical pathology. Endpoint : The main objective is to investigate the impact of a short fractionated schedule given preoperatively on cosmesis and breast fibrosis. Therefore, it is anticipated that the percentage of moderate or severe fibrosis will decrease from 27% as found in the boost arm of the EORTC boost-no boost trial to 15% (Collette et al EJC 2008). The total sample size of 120 patients will provide in excess of 80% power to detect the difference between the null hypotheses (a rate of fibrosis of 27%) and the alternative hypothesis (a rate of fibrosis of 15%) with an exact binomial test at 0.05 2-sided significance level. In addition, the 2-sided 95% confidence interval for the proportion of patients without local recurrence will extend 0.035 from the observed proportion for an expected proportion of 96%. An additional objective is to build a classifier (genomic or proteomic or any kind of molecular signature) to identify responders and non-responders. A total of 120 patients will be included in the study. The main analysis will include 60 patients in the training set and 60 in the validation set. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr OT2-1-03.

Abstract P5-14-05: Preoperative accelerated partial breast irradiation (PAPBI) trial: First results on acute toxicity, complications and cosmetic results

Abstract Background The ongoing Preoperative Accelerated Partial Breast Irradiation (PAPBI) trial (NCT01024582) was based on the rationale that three-dimensional conformal external-beam radiation (3D-CRT) leads to more dose homogeneity compared with brachy-or intraoperative radiotherapy (RT). By irradiating preoperatively this can lead to more accurate tumor delineation and smaller irradiated volumes. As the tumor remains in situ during irradiation, more precise delivery of the radiation dose is guaranteed with CT cone beam linear accelerators, avoiding the uncertainties of the original tumor position in the operation cavity as is the case in postoperative RT. Tumor excision 6 weeks after RT removes the high dose volume tissue and can lead to better cosmesis. Methods and materials Patients 60 years, T ≤ 3 cm, pN0(sn) (sentinel node procedure before RT), ductal carcinoma, unifocal on mammogram and MRI, undergo preoperative RT (CTV = GTV + 2 cm, 10 × 4 Gy IMRT/VMAT over two weeks); 6 weeks hereafter a wide local excision is performed. Skin toxicity and fibrosis is scored using EORTC/RTOG criteria. Patients are followed during RT and on a 3-monthly basis. Cosmesis is scored and photographs are taken for analysis (BCCT.core project score). Results From May 2010- 2013, 58 patients (pts) were included. For 52 pts follow up information is available up to at least 3 months after treatment; mean age 67.2 years (59-80); mean tumor size 1.4 cm (0.4-3.2); differentiation grade: grade 1 (n = 22), grade 2 (n = 28), unknown n = 8; mainly ER+PR + neu- (n = 50). 34 pts received hormonal therapy, none chemotherapy. Toxicity Acute RT toxicity grade 0 (23) grade 1(8). Postoperative complications were noted in 9/52 pts (17%): 2/52 had direct post-operative bleeding needing re-surgery; 1/52 developed a hematoma two months after surgery, needing re-surgery; 6/52 (11.5%) had a postoperative wound infection and received oral antibiotics. Of these 6; 1 wound abscess needing re-surgery; 1 small fistula closing within ten months. In the first year 9/52 pts developed localized oedema at the RT side fading away within 9 months. 4/53 pts developed hematoma post surgery. Fibrosis and cosmetic outcome Fibrosis score at 1 year (n = 35): grade 0 (9), grade 1 (21), grade 2 (4) grade 3 (1). Cosmetic outcome was scored at 1 year (n = 28): excellent/good (25; 89%), fair (3;11%). At 2 years follow up: 10/11 patients excellent/good and 1/11 patient fair. Fibrosis was noted in a limited volume. One ipsi-lateral breast tumor recurrence was diagnosed after 12 months at skin entry of the biopsy tract. Discussion The short term results of this PAPBI trial are promising in terms of acute treatment-related toxicities, complications and cosmetic outcome. Our complication rate of 17% (11% wound infection, 8% hematoma) is comparable with others*. Excellent or good cosmetic outcome was found in 90%, improving over time. Longer follow-up and increasing patient inclusion are needed to evaluate treatment efficacy, cosmetic results and toxicity on the longer term. *Mukesh et al (Eur J Surg Oncol 2012; 648 pts Cambridge IMRT trial), 18% infection, 8% hematoma. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P5-14-05.

Interim Cosmetic and Toxicity Results From RAPID: A Randomized Trial of Accelerated Partial Breast Irradiation Using Three-Dimensional Conformal External Beam Radiation Therapy

To report interim cosmetic and toxicity results of a multicenter randomized trial comparing accelerated partial-breast irradiation (APBI) using three-dimensional conformal external beam radiation therapy (3D-CRT) with whole-breast irradiation (WBI). Women age > 40 years with invasive or in situ breast cancer ≤ 3 cm were randomly assigned after breast-conserving surgery to 3D-CRT APBI (38.5 Gy in 10 fractions twice daily) or WBI (42.5 Gy in 16 or 50 Gy in 25 daily fractions ± boost irradiation). The primary outcome was ipsilateral breast tumor recurrence (IBTR). Secondary outcomes were cosmesis and toxicity. Adverse cosmesis was defined as a fair or poor global cosmetic score. After a planned interim cosmetic analysis, the data, safety, and monitoring committee recommended release of results. There have been too few IBTR events to trigger an efficacy analysis. Between 2006 and 2011, 2,135 women were randomly assigned to 3D-CRT APBI or WBI. Median follow-up was 36 months. Adverse cosmesis at 3 years was increased among those treated with APBI compared with WBI as assessed by trained nurses (29% v 17%; P < .001), by patients (26% v 18%; P = .0022), and by physicians reviewing digital photographs (35% v 17%; P < .001). Grade 3 toxicities were rare in both treatment arms (1.4% v 0%), but grade 1 and 2 toxicities were increased among those who received APBI compared with WBI (P < .001). 3D-CRT APBI increased rates of adverse cosmesis and late radiation toxicity compared with standard WBI. Clinicians and patients are cautioned against the use of 3D-CRT APBI outside the context of a controlled trial.

Late Toxicity and Patient Self-Assessment of Breast Appearance/Satisfaction on RTOG 0319: A Phase 2 Trial of 3-Dimensional Conformal Radiation Therapy-Accelerated Partial Breast Irradiation Following Lumpectomy for Stages I and II Breast Cancer

Late toxicities and cosmetic analyses of patients treated with accelerated partial breast irradiation (APBI) on RTOG 0319 are presented. Patients with stages I to II breast cancer ≤3 cm, negative margins, and ≤3 positive nodes were eligible. Patients received three-dimensional conformal external beam radiation therapy (3D-CRT; 38.5 Gy in 10 fractions twice daily over 5 days). Toxicity and cosmesis were assessed by the patient (P), the radiation oncologist (RO), and the surgical oncologist (SO) at 3, 6, and 12 months from the completion of treatment and then annually. National Cancer Institute Common Terminology Criteria for Adverse Events, version 3.0, was used to grade toxicity. Fifty-two patients were evaluable. Median follow-up was 5.3 years (range, 1.7-6.4 years). Eighty-two percent of patients rated their cosmesis as good/excellent at 1 year, with rates of 64% at 3 years. At 3 years, 31 patients were satisfied with the treatment, 5 were not satisfied but would choose 3D-CRT again, and none would choose standard radiation therapy. The worst adverse event (AE) per patient reported as definitely, probably, or possibly related to radiation therapy was 36.5% grade 1, 50% grade 2, and 5.8% grade 3 events. Grade 3 AEs were all skin or musculoskeletal-related. Treatment-related factors were evaluated to potentially establish an association with observed toxicity. Surgical bed volume, target volume, the number of beams used, and the use of bolus were not associated with late cosmesis. Most patients enrolled in RTOG 0319 were satisfied with their treatment, and all would choose to have the 3D-CRT APBI again.

Imaging Effects of Radiation Therapy in the Abdomen and Pelvis: Evaluating “Innocent Bystander” Tissues

Accurate interpretation of posttherapeutic images obtained in radiation oncology patients requires familiarity with modern radiation therapy techniques and their expected effects on normal tissues. Three-dimensional conformal external-beam radiation therapy techniques (eg, intensity-modulated radiation therapy, stereotactic body radiation therapy), although they are designed to reduce the amount of normal tissue exposed to high-dose radiation, inevitably increase the amount of normal tissue that is exposed to low-dose radiation, with the potential for resultant changes that may evolve over time. Currently available internal radiation therapy techniques (eg, arterial radioembolization for hepatic malignancies, brachytherapy for prostate cancer and gynecologic cancers) also carry risks of possible injury to adjacent nontargeted tissues. The sensitivity of tissues to radiation exposure varies according to the tissue type but is generally proportional to the rate of cellular division, with rapidly regenerating tissues such as intestinal mucosa being the most radiosensitive. The characteristic response to radiation-induced injury likewise varies according to tissue type, with atrophy predominating in epithelial tissue whereas fibrosis predominates in stromal tissue. Moreover, changes in irradiated tissues evolve over time: In the liver, decreased attenuation at computed tomography and increased signal intensity at T2-weighted magnetic resonance imaging reflect hyperemia and edema in the early posttherapeutic period; later, veno-occlusive changes alter the hepatic enhancement pattern; and finally, fibrosis develops in some patients. In the small bowel, wall thickening and mucosal hyperenhancement predominate initially, whereas luminal narrowing is the most prominent feature of chronic enteropathy. Correlation of posttherapeutic images with images used for treatment planning may be helpful when interpreting complex cases.

Tracking the dynamic seroma cavity using fiducial markers in patients treated with accelerated partial breast irradiation using 3D conformal radiotherapy

The purpose of the present study was to perform an analysis of the changes in the dynamic seroma cavity based on fiducial markers in early stage breast cancer patients treated with accelerated partial breast irradiation (APBI) using three-dimensional conformal external beam radiotherapy (3D-CRT). A prospective, single arm trial was designed to investigate the utility of gold fiducial markers in image guided APBI using 3D-CRT. At the time of lumpectomy, four to six suture-type gold fiducial markers were sutured to the walls of the cavity. Patients were treated with a fractionation scheme consisting of 15 fractions with a fractional dose of 333 cGy. Treatment design and planning followed NSABP∕RTOG B-39 guidelines. During radiation treatment, daily kV imaging was performed and the markers were localized and tracked. The change in distance between fiducial markers was analyzed based on the planning CT and daily kV images. Thirty-four patients were simulated at an average of 28 days after surgery, and started the treatment on an average of 39 days after surgery. The average intermarker distance (AiMD) between fiducial markers was strongly correlated to seroma volume. The average reduction in AiMD was 19.1% (range 0.0%-41.4%) and 10.8% (range 0.0%-35.6%) for all the patients between simulation and completion of radiotherapy, and between simulation and beginning of radiotherapy, respectively. The change of AiMD fits an exponential function with a half-life of seroma shrinkage. The average half-life for seroma shrinkage was 15 days. After accounting for the reduction which started to occur after surgery through CT simulation and treatment, radiation was found to have minimal impact on the distance change over the treatment course. Using the marker distance change as a surrogate for seroma volume, it appears that the seroma cavity experiences an exponential reduction in size. The change in seroma size has implications in the size of the CTV, PTV, and percent of normal breast tissue irradiated when using 3D-CRT.

Phase II Study of Docetaxel (AisuⓇ) Combined with Three-dimensional Conformal External Beam Radiotherapy in Treating Patients with Inoperable Esophageal Cancer

This study was designed to investigate treatment efficacy and side effects of concomitant Aisu® (docetaxel) with three-dimensional conformal external beam radiotherapy for the treatment of inoperable patients with esophageal cancer. Inoperable patients were treated with three-dimensional conformal external beam radiotherapy (5/week, 2 GY/day, and total dose 60GY) plus docetaxel (30-45 mg/m2, iv, d1, 8). Twenty eight patients met the study eligibility criteria and the response rate was evaluated according to RICIST guidelines. Among 28 patients, 2 achieved CR, 22 PR, 3 SD and 1 patient was documented PD. Mild gastrointestinal reaction and bone marrow suppression were also documented. All treatment related side effects were tolerable. Three-dimensional conformal external beam radiotherapy combined with docetaxel is an active and safe regimen for inoperable patients with esophageal cancer.

Prone Accelerated Partial Breast Irradiation After Breast-Conserving Surgery: Five-year Results of 100 Patients

To report the 5-year results of a prospective trial of three-dimensional conformal external beam radiotherapy (3D-CRT) to deliver accelerated partial breast irradiation in the prone position. Postmenopausal patients with Stage I breast cancer with nonpalpable tumors <2 cm, negative margins and negative nodes, positive hormone receptors, and no extensive intraductal component were eligible. The trial was offered only after eligible patients had refused to undergo standard whole-breast radiotherapy. Patients were simulated and treated on a dedicated table for prone setup. 3D-CRT was delivered at a dose of 30 Gy in five 6-Gy/day fractions over 10 days with port film verification at each treatment. Rates of ipsilateral breast failure, ipsilateral nodal failure, contralateral breast failure, and distant failure were estimated using the cumulative incidence method. Rates of disease-free, overall, and cancer-specific survival were recorded. One hundred patients were enrolled in this institutional review board-approved prospective trial, one with bilateral breast cancer. One patient withdrew consent after simulation, and another patient elected to interrupt radiotherapy after receiving two treatments. Ninety-eight patients were evaluable for toxicity, and, in 1 case, both breasts were treated with partial breast irradiation. Median patient age was 68 years (range, 53-88 years); in 55% of patients the tumor size was <1 cm. All patients had hormone receptor-positive cancers: 87% of patients underwent adjuvant antihormone therapy. At a median follow-up of 64 months (range, 2-125 months), there was one local recurrence (1% ipsilateral breast failure) and one contralateral breast cancer (1% contralateral breast failure). There were no deaths due to breast cancer by 5 years. Grade 3 late toxicities occurred in 2 patients (one breast edema, one transient breast pain). Cosmesis was rated good/excellent in 89% of patients with at least 36 months follow-up. Five-year efficacy and toxicity of 3D-CRT delivered in prone partial breast irradiation are comparable to other experiences with similar follow-up.

Later Outcomes and Alpha/Beta Estimate From Hypofractionated Conformal Three-Dimensional Radiotherapy Versus Standard Fractionation for Localized Prostate Cancer

Now that the follow-up time has exceeded 5 years, an estimate of the α/β ratio can be presented. The additional late outcomes in patients treated with three-dimensional conformal external beam radiotherapy for localized prostate cancer using a hypofractionated vs. a standard fractionation regimen are reported from this prospective nonrandomized contemporary comparison. A total of 114 nonrandomized patients chose hypofractionation delivered in 20 fractions of 3 Gy or 3.15 Gy (mean 3.06 Gy) for localized prostate cancer within a median overall time of 32 days (range, 29-49) using four fractions weekly. A total of 160 comparable patients were contemporarily treated within a median of 55 days (range 49-66). The median follow-up was 66 months (range, 24-95) for the hypofractionated arm and 63 months (range, 36-92) for the standard arm. The percentage of patients in the low-, medium-, and high-risk groups was 36%, 46%, and 18% in the hypofractionated arm and 44%, 50%, and 6% in standard arm (2 Gy), respectively. The 5-year actuarial biochemical absence of disease (prostate-specific antigen nadir+ 2 ng/mL) and disease-free survival rate was the same at 89% in both arms, making the α/β calculation unambiguous. The point ratio of α/β was 1.86 (95% confidence interval, 0.7-5.1 Gy). The 95% confidence interval was determined entirely by the binomial confidence limits in the numbers of patients. Rectal reactions of grade 3 and 4 occurred in 1 of 114 (hypofractionated) and 2 of 160 (standard) patients. The presented three-dimensional conformal regimen was acceptable, and the α/β value was 1.8, in agreement with other very recent low meta-analyses (reviewed in the "Discussion" section).