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The standard of care for the first-line management of metastatic urothelial carcinoma has been recently challenged, with the combination of pembrolizumab and enfortumab vedotin (P-EV) strongly arising as a practice-changing option from classical platinum-based chemotherapies. With this paradigm shift on the horizon new questions, including the most suitable second line of treatment for these patients, and the role that the molecular characterization of these tumours will have when selecting these therapies will inevitably arise. Furthermore, after the negative results of the Keynote 361 and IMvigor 130 trials, the combination of nivolumab with platinum-based chemotherapy followed by nivolumab maintenance (Nivo GC-Nivo) has also shown positive results when compared with chemotherapy alone. Translational studies at a molecular, cellular, and functional level will be key to better explain these discordant results. In this Current Perspective, we discuss the potential impact of these results in clinical practice and propose specific guidance for prospective translational research. [ABSTRACT FROM AUTHOR]

Purpose To assess the safety, feasibility, and efficacy of free-hand intraoperative multicatheter breast implant (FHIOMBI) and perioperative high-dose-rate brachytherapy (PHDRBT) in early breast cancer. Methods and Materials Patients with early breast cancer candidates for breast conservative surgery (BCS) were prospectively enrolled. Patients suitable for accelerated partial breast irradiation (APBI) (low or intermediate risk according GEC-ESTRO criteria) received PHDRBT (3.4 Gy BID × 10 in 5 days). Patients not suitable for APBI (high risk patients according GEC-ESTRO criteria) received PHDRBT boost (3.4 Gy BID × 4 in 2 days) followed by whole breast irradiation. Results From June 2007 to November 2014, 119 patients were treated and 122 FHIOMBI procedures were performed. Median duration of FHIOMBI was 25 minutes. A median of eight catheters (range, 4–14) were used. No severe intraoperative complications were observed. Severe early postoperative complications (bleeding) were documented in 2 patients (1.6%), wound healing complications in 3 (2.4%), and infection (mastitis or abscess) in 2 (1.6%). PHDRBT was delivered as APBI in 88 cases (72.1%) and as a boost in 34 (27.8%). The median clinical target volume T was 40.8 cc (range, 12.3–160.5); median D 90 was 3.32 Gy (range, 3.11–3.85); median dose homogeneity index was 0.72 (range, 0.48–0.82). With a median followup of 38.4 months (range, 8.7–98.7) no local, elsewhere, or regional relapses were observed; there was only one distant failure in PHDRBT boost. No major (acute or late) RTOG grade 3 or higher were documented in any of the 119 patients treated with PHDRBT. Cosmetic outcome in APBI patients was excellent or good in (87.0%) and fair or poor in (11.9%) while in boost patients was excellent or good in (76.4%) and fair in (23.5%). Conclusion The FHIOMBI-PHDRBT program does not add complications to conservative surgery. It allows precise selection of APBI patients and offers excellent results in disease control and cosmetics. It also offers logistic advantages because it dramatically shortens the time of local treatment and avoids further invasive procedures. [ABSTRACT FROM AUTHOR]

Purpose To compare rectal toxicity, urinary toxicity, and nadir+2 PSA relapse-free survival (bRFS) in two consecutive Phase II protocols of high-dose-rate (HDR) brachytherapy used at the authors institution from 2001 to 2012. Methods and Materials Patients with National Comprehensive Cancer Network high risk and very high risk prostate cancer enrolled in studies HDR4 (2001–2007, n = 183) and HDR2 (2007–2012, n = 56) were analyzed. Patients received minipelvis external beam radiation therapy/intensity-modulated external radiotherapy to 54 Gy and 2 years of androgen blockade along with HDR brachytherapy. HDR4 protocol consisted of four 4.75 Gy fractions delivered in 48 hours; the HDR2 protocol delivered two 9.5 Gy fractions in 24 hours. Average 2-Gy equivalent dose (α/β = 1.2) prostate D 90 doses for the HDR4 and HDR2 groups were 89.8 Gy and 110.5 Gy, respectively ( p = 0.0001). Both groups were well balanced regarding risk factors. Prior transurethral resection of the prostate was more frequent in the HDR2 group ( p = 0.001). Results After a median followup of 7.4 years (range, 2–11.2), there was no difference in adverse grade ≥ 2 rectal events (HDR4 = 10.4% vs. HDR2 = 12.5%; p = ns) or grade ≥3 (HDR4 = 2.2% vs. HDR2 = 3.6%; p = ns). No differences in urinary grade ≥2 adverse events (HDR4 = 23% vs. HDR2 = 26.8%; p = ns) or grade ≥3 (HDR4 = 7.7% vs. HDR2 = 8.9%; p = ns) were detected. The 7-year bRFS for HDR4 and HDR2 protocols was 88.7% and 87.8%, respectively ( p = ns). Conclusions HDR4 and HDR2 protocols produce similar results in terms of toxicity and bRFS at the intermediate time point of 7 years. [ABSTRACT FROM AUTHOR]

Purpose To assess the toxicity and efficacy of salvage wide resection (SWR) with intraoperative electron beam radiation therapy (IOERT) or perioperative high-dose-rate brachytherapy (PHDRB) in previously unirradiated patients (PUP) vs. previously irradiated patients (PIP) with isolated local recurrence of soft tissue sarcomas (STS) of the extremities and the superficial trunk. Methods and Materials PUP received SWR and IOERT/PHDRB with external beam radiation therapy. PIP received SWR and IOERT/PHDRB only. Results Fifty patients were analyzed retrospectively. PUP ( n = 24; 48%) received IOERT ( n = 13) or PHDRB ( n = 11). PIP ( n = 26; 52%) received IOERT ( n = 10) or PHDRB ( n = 16). Reintervention because of complications was not required in PUP. Nine of 26 (34%) PIP required reintervention ( p = 0.01). After a median followup of 3.7 years (range, 0.2–18.3), the 5-year rates of locoregional control, distant control, and overall survival were 54%, 66%, and 56%, respectively. Five-year locoregional control was higher in PUP than in PIP (81% vs. 26%, p = 0.01) and in the extremity locations compared with trunk locations (68% vs. 28%, p = 0.001). Five-year overall survival was superior in unifocal vs. multifocal presentations (70% vs. 36%, p = 0.03) and for tumor sizes <4 vs. ≥4 cm (74% vs. 50%, p = 0.05). Conclusions Prior irradiation is the main determinant of locoregional control in patients with isolated local recurrence of STS. The locoregional control rates in PUP were similar to those described in primary STS. In PIP, SWR + IOERT/PHDRB reirradiation yielded modest locoregional control rates and was associated with significant morbidity, especially in PHDRB cases. [ABSTRACT FROM AUTHOR]

Purpose To determine whether perioperative high-dose-rate brachytherapy (PHDRB) implants with larger high-dose regions produce increased locoregional control. Methods and Materials Patients ( n = 166) enrolled in several PHDRB prospective studies conducted at the University of Navarre were analyzed. The PHDRB was given to total doses of 16 Gy/4 b.i.d. or 24 Gy/6 b.i.d. treatments for negative or close/positive margins along with 45 Gy/25 Rx of external beam radiation therapy. The histogram-based generalized equivalent uniform dose (EUD) formulism was used to quantify and standardize the dose–volume histogram into 2-Gy equivalents. The region of interest analyzed included: tissue volume encompassed by the prescription isodose of 4 Gy ( TV 100 ). Routine dose reporting parameters such as physical dose and single-point 2-Gy equivalent dose were used for reference. Results After a median followup of 7.4 years (range, 3–12+), 50 patients have failed, and 116 remain controlled at last followup. Overall, EUD was not different in the patients who failed compared with controls (89.1 Gy vs. 86.5 Gy; p = not significant). When patients were stratified by risk using the University of Navarre Predictive Model, very high-risk patients (i.e., tumors ≥3 cm resected with close <1 mm/positive margins) had an improved locoregional control with higher EUD values ( p = 0.028). This effect was not observed in low-, intermediate-, and high-risk University of Navarre Predictive Model categories. Conclusions In very high-risk patients, enlarged high-dose regions can produce a dose–response effect. Routine dose reporting methods such as physical dose and single-point 2-Gy equivalent dose may not show this effect, but it can be revealed by histogram-based EUD assessment. [ABSTRACT FROM AUTHOR]

Abstract: Purpose: To develop a simple clinical model predictive of locoregional failure after complete surgical resection followed by perioperative high-dose-rate brachytherapy (PHDRB) and external beam irradiation (EBRT). Patient and Methods: Patients (n =166) enrolled in several PHDRB prospective studies conducted at the University of Navarre were analyzed. PHDRB was given to total doses of 16 Gy/4 b.i.d. or 24 Gy/6 b.i.d. treatments for negative or close/positive margins along with 45Gy of EBRT. Results: After a median followup of 7.4 years (range, 3–12+), 50 patients have failed and 116 remain controlled at last followup. Tumor size, with a cutoff point set at 3cm (p =0.041) and margin status (positive and <1mm vs. negative ≥1mm, p =0.0001) were independent predictors of locoregional control. These two parameters were used to develop a four-tiered, hierarchical scoring system that stratified patients into low-risk (negative ≥1mm margins and size ≤3cm), intermediate-risk (negative ≥1mm margins, and size >3cm), high-risk (positive and <1mm margins and size ≤3cm), and very high–risk categories (positive and <1mm margins and size >3cm). This classification yields 5-year locoregional control rates of 92.3%, 78.0%, 65.5%, and 48.0% for low-, intermediate-, high-, and very high–risk categories, respectively. The predictive ability of the model is highly significant (p =0.0001) with an area under the curve of 0.72 (0.64–0.81). Conclusions: The risk of locoregional failure after combined surgical resection, PHDRB, and EBRT is mainly determined by the number of residual clonogens, which is inversely proportional to the status of the surgical margins and directly related to the size of the resected tumor. These two parameters generate a four-tiered predictive model that seems to be valid for a number of different common tumors and clinical settings. [Copyright &y& Elsevier]

Abstract: Purpose: To report the disease-free Grade ≥3 complication-free survival of a Phase II protocol of reirradiation with high-dose-rate (HDR) interstitial brachytherapy (ITB) in previously irradiated gynecologic cancer. Methods and Materials: Fifteen patients with previously irradiated cervical (n = 6), endometrial (n = 6), and vulvovaginal tumors (n = 3) were treated with HDR-ITB alone to a median dose of 38 Gy in 8 b.i.d. fractions over 4 consecutive days. Prior treatments included surgery (n = 12; 80%), external irradiation (n = 15; 100%), and brachytherapy (n = 9; 60%). Average clinical target volume Size was 60.9 cc (range, 14.8–165.3 cc), and median time to reirradiation was 3.9 years (range, 0.4–22.7 years). Results: With a median followup of 2.8 years (range, 1.2–9.2 years), 3 patients (20.0%) developed Grade ≥3 toxicity consisting of Grade 3 intestinal obstruction (n = 1), Grade 4 rectovesical fistula (n = 1), and Grade 5 intestinal obstruction (n = 1). Six patients remain alive and without evidence of disease at last followup. Two patients are alive with disease progression, and 7 patients have died, 4 of them from disease progression and 3 from other causes. The 2-year disease-free Grade ≥3 complication-free survival was 40%. Conclusions: HDR-ITB alone is a reasonable salvage treatment option in a significant number of patients with previously irradiated gynecologic tumors. [Copyright &y& Elsevier]

Abstract: Objective: To compare the biologic equivalence in terms of local control and toxicity of a short course of high-dose-rate intravaginal brachytherapy alone (IVBa) delivered over five consecutive days (25Gy/5Rx/5 days) to other more protracted classical schemes 21Gy/3Rx/14–28 days (Postoperative Radiation Therapy in Endometrial Carcinoma [PORTEC]-2/Memorial Sloan-Kettering Cancer Center). Methods and Materials: From February 2001 to May 2008, 122 patients with International Federation of Gynecology and Obstetrics Stage IaG3–IIIaG2 endometrial adenocarcinoma were treated with total abdominal hysterectomy and bilateral salpingo-oophorectomy followed by postoperative IVBa. Seventy-seven patients (63.1%) underwent surgical staging. Total IVBa dose was 25Gy in five consecutive daily fractions prescribed at 0.5-cm depth. Results: After a median followup of 4.1 years, the rates of Radiation Therapy Oncology Group Grades 1, 2, and ≥3 complications were 12.9%, 3.4%, and 0.8%, respectively. Five patients (4.1%) presented locoregional failures: two isolated nodal pelvic failures, one vaginal pelvic relapse (intra-abdominal lymph node metastases), one vaginal distant failure, and one combined locoregional and distant failure. The 8.5-year actuarial vaginal control rate was 97.5%, and the pelvic control rate was 94.3%. Six other patients developed distant metastases alone. The 8.5-year actuarial overall and disease-free survival rates were 90.3% and 87.2%, respectively. Univariate analysis revealed that histologic grade, deep myometrial invasion, advanced age, and categorization as high intermediate–risk patient according to the PORTEC-2 and the Gynecologic Oncology Group (GOG)-99 stratifications were statistically significant prognostic factors. After multivariate analysis, histologic grade (p =0.001) and high intermediate risk according to GOG-99 (p =0.004) and PORTEC-2 (p =0.001) remained significant. Conclusions: The proposed scheme reproduces the excellent results obtained with more protracted schemes and has the added advantage of shortened overall treatment time. [Copyright &y& Elsevier]

Purpose: To determine patient, tumor, and treatment factors predictive of local control (LC) in a series of patients treated with either perioperative high-dose-rate brachytherapy (PHDRB) alone (Group 1) or with PHDRB combined with external-beam radiotherapy (EBRT) (Group 2). Patient and Methods: Patients (n = 312) enrolled in several PHDRB prospective Phase I–II studies conducted at the Clínica Universidad de Navarra were analyzed. Treatment with PHDRB alone, mainly because of prior irradiation, was used in 126 patients to total doses of 32 Gy/8 b.i.d. or 40 Gy/10 b.i.d. treatments after R0 or R1 resections. Treatment with PHDRB plus EBRT was used in 186 patients to total doses of 16 Gy/4 b.i.d. or 24 Gy/6 b.i.d. treatments after R0 or R1 resections along with 45 Gy of EBRT with or without concomitant chemotherapy. Results: No dose–margin interaction was observed in Group 1 patients. In Group 2 patients there was a significant interaction between margin status and 2-Gy equivalent (Eq2Gy) dose (p = 0.002): (1) patients with negative margins had 9-year LC of 95.7% at Eq2Gy = 62.9Gy; (2) patients with close margins of >1 mm had 9-year LC of 92.4% at Eq2Gy = 72.2Gy, and (3) patients with positive/close <1-mm margins had 9-year LC of 68.0% at Eq2Gy = 72.2Gy. Conclusions: Two-gray equivalent doses ≥70 Gy may compensate the effect of close margins ≥1 mm but do not counterbalance the detrimental effect of unfavorable (positive/close <1 mm) resection margins. No dose–margin interaction is observed in patients treated at lower Eq2Gy doses ≤50 Gy with PHDRB alone. [ABSTRACT FROM AUTHOR]

Purpose: To determine the feasibility of combined long-term luteinizing hormone-releasing hormone agonist–based androgen suppressive therapy (AST) and dose escalation with high-dose-rate (HDR) brachytherapy for high-risk (HRPC) or very-high-risk prostate cancer (VHRPC). Methods and Materials: Between January 2001 and October 2006, 134 patients (median age, 70 years) with either National Comprehensive Cancer Network criteria–defined HRPC (n = 47, 35.1%) or VHRPC (n = 87, 64.9%) were prospectively enrolled in this Phase II trial. Tumor characteristics included a median pretreatment prostate-specific antigen level of 14.6 ng/mL, a median clinical stage of T2c, and a median Gleason score of 7. Three-dimensional conformal radiotherapy (54 Gy in 30 fractions) was followed by HDR brachytherapy (19 Gy in 4 b.i.d. treatments). Androgen suppressive therapy started 0–3 months before three-dimensional conformal radiotherapy and continued for 2 years. Results: One implant was repositioned with a new procedure (0.7%). Five patients (3.7%) discontinued AST at a median of 13 months (range, 6–18 months) because of disease progression (n = 1), hot flashes (n = 2), fatigue (n = 1), and impotence (n = 1). After a median follow-up of 37.4 months (range, 24–90 months), the highest Radiation Therapy Oncology Group–defined late urinary toxicities were Grade 0 in 47.8%, Grade 1 in 38.1%, Grade 2 in 7.5%, and Grade 3 in 6.7% of patients. Maximal late gastrointestinal toxicities were Grade 0 in 73.1%, Grade 1 in 16.4%, Grade 2 in 7.5%, and Grade 3 in 2.9% of patients. There were no Grade 4 or 5 events. Conclusions: Intermediate-term results show that dose escalation with HDR brachytherapy combined with long-term AST is feasible and has a toxicity profile similar to that reported by previous HDR brachytherapy studies. [Copyright &y& Elsevier]

Summary: Brachytherapy is a sophisticated radiation method in which radioisotopes are placed inside or at a short distance from the tumour. The volume of tissue that receives the prescribed dose of radiotherapy is therefore fairly small compared with that used in standard radiotherapy techniques. In paediatric oncology, this method of radiation delivery can have a favourable effect on several undesirable long-term side-effects that sometimes develop in children who receive radiotherapy, such as growth retardation and development of second primary tumours. Here, we describe the rationale for use of brachytherapy in children with cancer, the methods of the different brachytherapy techniques available, and the results obtained with several brachytherapy regimens in expert institutions throughout the world. [Copyright &y& Elsevier]

Purpose To determine the long-term results of a Phase II trial of perioperative high-dose-rate brachytherapy (PHDRB) in primary advanced or recurrent gynecological cancer. Methods and Materials Fifty patients with locally advanced and recurrent gynecological cancer suitable for salvage surgery were included. Unirradiated patients ( n = 25) received preoperative chemoradiation followed by surgery and PHDRB (16–24 Gy). Previously irradiated patients ( n = 25) received surgery and PHDRB alone (32–40 Gy). Results Median followup was 11.5 years. Eight unirradiated patients (32%) developed Grade ≥3 toxic events including two fatal events. Local and locoregional control rates at 16 years were 87.3% and 78.9%, respectively. Sixteen-year disease-free and overall survival rates were 42.9% and 46.4%, respectively. Ten previously irradiated patients (40.0%) developed Grade ≥3 adverse events, including four fatal events. Local and locoregional control rates at 14 years were 59.6% and 42.6%, respectively. Fourteen-year disease-free and overall survival rates were 16.0% and 19.2%, respectively. Conclusions PHDRB allows effective salvage of a subset of unfavorable gynecological tumors with high-risk surgical margins. Toxicity was unacceptable at the initial dose levels but deescalation resulted in the absence of severe toxicity without a negative impact on locoregional control. A substantial percentage of patients remain alive and controlled at >10 years including a few previously irradiated cases with positive margins. [ABSTRACT FROM AUTHOR]

To evaluate the feasibility, early toxicity, and clinical outcomes of early-breast cancer patients in a single-arm, phase I/II study of an ultra-accelerated, four-fraction schedule of minimal breast irradiation (4f-AMBI) using a multicatheter, minimally-invasive, intraoperative tumor bed implant (MITBI) during breast-conserving surgery (BCS). Eligible women aged >40 years with clinically and radiologically confirmed, unifocal invasive or in situ ≤3 cm tumors were considered as potential candidates for MITBI during BCS. After the pathology report, patients who met APBI criteria received ultra-accelerated four-fractions irradiation (6.2 Gy BID x 4fx over 2 days) with perioperative HDR-brachytherapy (PHDRBT). Early complications, toxicity, clinical outcomes, and cosmetic results were analyzed. Of 89 patients initially implanted, 60(67.4%) were definitively included in the 4f-AMBI-protocol. The median age was 64.4 years; the median CTV was 32.1 cc (6.9–75.4 cc), and the external-V 100 was 43.1 cc (12.87–107 cc), representing 5% of the breast tissue irradiated with a median CTV D 90 of 6.2 Gy (5.6–6.28 Gy). The entire local treatment (BCS& MITBI-4f-AMBI) was completed at a median of 8 days (4–10 days). The rate of early complications was 11%. There were no major complications. Acute skin-subcutaneous G1 toxicity was reported in 11.7%, and late G1 toxicity on 36.7%. After a median follow-up of 27 months (11–51 months), the local, elsewhere, locoregional and distant-control rates were 100%, 98.3%, 100%, and 100% respectively. The early-cosmetic evaluation was excellent-good in 94.5% of patients evaluated. Ultra-accelerated, four-fraction, minimal breast irradiation (4f-AMBI) using a minimally-invasive tumor bed implant procedure is safe, dosimetrically feasible, and shows small irradiated volumes. This program provides low toxicity rates and excellent short-term clinical and cosmesis outcomes. [ABSTRACT FROM AUTHOR]

Background: A joint analysis of data from centers involved in the Spanish Cooperative Initiative for Intraoperative Electron Radiotherapy was performed to investigate long-term outcomes of locally recurrent soft tissue sarcoma (LR-STS) patients treated with a multidisciplinary approach. Methods and Materials: Patients with a histologic diagnosis of LR-STS (extremity, 43%; trunk wall, 24%; retroperitoneum, 33%) and no distant metastases who underwent radical surgery and intraoperative electron radiation therapy (IOERT; median dose, 12.5 Gy) were considered eligible for participation in this study. In addition, 62% received external beam radiation therapy (EBRT; median dose, 50 Gy). Results: From 1986 to 2012, a total of 103 patients from 3 Spanish expert IOERT institutions were analyzed. With a median follow-up of 57 months (range, 2-311 months), 5-year local control (LC) was 60%. The 5-year IORT in-field control, disease-free survival (DFS), and overall survival were 73%, 43%, and 52%, respectively. In the multivariate analysis, no EBRT to treat the LR-STS (P=.02) and microscopically involved margin resection status (P=.04) retained significance in relation to LC. With regard to IORT in-field control, only not delivering EBRT to the LR-STS retained significance in the multivariate analysis (P=.03). Conclusion: This joint analysis revealed that surgical margin and EBRT affect LC but that, given the high risk of distant metastases, DFS remains modest. Intensified local treatment needs to be further tested in the context of more efficient concurrent, neoadjuvant, and adjuvant systemic therapy. [Copyright &y& Elsevier]

Abstract: Objectives: To determine the relationship between dosimetric parameters obtained on postimplantation Day 0 and biochemical relapse-free survival (bRFS) in patients treated with 125I transperineal interstitial permanent prostate brachytherapy (TIPPB). Methods: Two-hundred twenty men with low-risk (n =155, 70.4%), low-volume intermediate-risk (n =63, 28.7%), or high-risk (n =2, 0.9%) prostate cancer were treated with TIPPB between December 2000 and June 2006. Seventy-four (33.6%) patients received short-term (3–6 months) androgen suppression therapy before TIPPB. The median followup for patients free of biochemical failure was of 37.9 months (range, 24.0–84.5 months). Results: The receiver operating characteristic (ROC) analysis established a best-fit cutoff value for the quantifiers D 90 and V 100 of 147Gy and 92%, respectively. The Kaplan–Meier analysis of bRFS at the cutoff value of D 90 =147Gy using the ASTRO, nadir+2, and combined (ASTRO and nadir+2) definitions showed a trend toward statistical significance for the ASTRO (p =0.076) and nadir+2 (p =0.064) definitions and a statistically significant correlation for the combined definition (p =0.033). The corresponding 7-year bRFS for the D 90 >147Gy and D 90 ≤147Gy subsets using the ASTRO, nadir+2, and combined definitions were 96.5% vs. 89.7% (ASTRO, p =0.076); 93.7% vs. 70.5% (nadir+2, p =0.064); and 94.4 vs. 75.5% (combined, p =0.033). The V 100 (%) cutoff value of 92% predicted by the ROC analysis was not significant. Among other cutoff values, only D 90 =140Gy (p =0.050) and D 90 =160Gy (p =0.098) showed a trend toward statistical significance when the nadir+2 and the ASTRO definitions were used. The rest of dosimetric, tumor, and patient parameters did not show statistical correlation with bRFS in the Kaplan–Meier analysis. Conclusions: The cutoff value of D 90 =147Gy obtained on postimplantation Day 0 showed a trend toward significant correlation with bRFS when the standard ASTRO and nadir+2 definitions were used and a weak but statistically significant correlation with bRFS as per the nonstandard combined definition in a series of patients with predominantly low-risk disease (70.4%) treated at high radiation doses (median D 90 =152.9Gy, median V 100 =92.5%). [Copyright &y& Elsevier]

Abstract: Background: To determine the feasibility of combined perioperative high-dose-rate brachytherapy (PHDRB) and intermediate-dose external beam radiation therapy (EBRT) as an alternative to full-dose adjuvant EBRT in patients with unirradiated squamous cell cancer (SCC) of the oral cavity and oropharynx. Methods and Materials: Forty patients were treated with surgical resection and PHDRB. PHDRB dose was 4Gy b.i.d.×4 (16Gy) for R0 resections and 4Gy b.i.d.×6 (24Gy) for R1 resections, respectively. External beam radiotherapy (45Gy in 25 fractions) was added postoperatively. Patients with Stage III, IVa tumors, and some recurrent cases received concomitant cisplatin–paclitaxel chemotherapy during EBRT. Results: The rate of protocol compliance was 97.5%. Eleven patients (27.5%) developed RTOG Grade 3 or greater toxicity. Four patients (10%) presented complications requiring a major surgical procedure (RTOG 4), and one patient died of bleeding (RTOG 5). Three complications (7.5%) occurred in the perioperative period, and 8 (20.0%) occurred more than 3 months after the completion of the treatment program. Severe complications were more frequent in posteriorly located implants than in anterior implants (p =0.035). After a median follow-up of 50 months for living patients (range, 2.5–86.1+), the 7-year actuarial rates of local and locoregional control were 86% and 82%, respectively; and the 7-year disease-free survival and overall survival rates were 50.4% and 52.3%, respectively. Conclusions: PHDRB can be integrated into the management of patients with resected cancer of the oral cavity who are candidates to receive postoperative radiation or chemoradiation. The local control and toxicity rates were similar to those expected after standard chemoradiation. PHDRB was associated with high toxicity in posterior locations, and the scheduled PHDRB dose was shifted to the closest lower level. [Copyright &y& Elsevier]

Abstract: Purpose: To evaluate the feasibility and intermediate-term results of conservative surgery, adjuvant chemotherapy, and delayed accelerated partial breast irradiation (APBI) with high-dose-rate brachytherapy. Methods and Materials: Between 2000 and 2007, a total of 26 patients with a median age of 54 years were treated with conservative surgery followed by adjuvant chemotherapy and exclusive high-dose-rate brachytherapy. Inclusion criteria followed the Radiation Therapy Oncology Group 95-17 trial guidelines. The tumor bed was marked at the time of surgery (n =2) or before brachytherapy (n =24). The brachytherapy procedure was performed at a median of 22 weeks after surgery. A median of 14 brachytherapy catheters were placed in three to four parallel planes. A dose of 34.0Gy in 10 b.i.d. fractions given over 5 consecutive days was prescribed to the clinical target volume (CTV90). Results: After a median followup of 53 months (range, 6.8–81), Radiation Therapy Oncology Group Grade 1–2 events and Grade 3 events were observed in 10 (38.4%) patients and 3 (11.5%) patients, respectively. No Grade 4–5 events were observed. Patients rated their cosmetic result as excellent (37.5%), good (50.0%), fair (8%), or poor (4%) based on the Wazer''s Criteria. The 6-year actuarial local, elsewhere in the breast, and distant control rates were 100%, 96.2%, and 96.2%, respectively. Six-year disease-free survival and overall survival were 92.3% and 96.2%, respectively. Conclusions: Patients undergoing surgery and adjuvant chemotherapy can still be candidates for APBI. Optimal visualization of the internal lumpectomy scar before implantation is mandatory. Cosmetic results may be slightly worse due to the interaction between chemotherapy and APBI, and technical refinements may be needed in this group of patients. [Copyright &y& Elsevier]

Abstract: Objective: To evaluate the feasibility and intermediate-term results of a short course of high-dose-rate (HDR) intravaginal brachytherapy only after hysterectomy. Methods and materials: From December 1999 to February 2005, 50 patients with International federation of gynecology and obstetrics Stages IA–IIB endometrioid endometrial adenocarcinoma were treated with total abdominal hysterectomy and bilateral salpingo-oophorectomy followed by postoperative HDR brachytherapy alone. The mean age of the patients was 62.6 years (range 42–86). International federation of gynecology and obstetrics patient grouping included IaG3Nx (n =1), IbG1N0 (n =1), IbG1Nx (n =2), IbG2N0 (n =10), IbG2Nx (n =20), IbG3N0 (n =3), IbG3Nx (n =1), IcG1Nx (n =2), IcG2N0 (n =3), IcG3N0 (n =3), IIaG1Nx (n =2), IIaG2Nx (n =1), and IIbG1N0 (n =1). Twenty-one patients (42.0%) had been surgically staged. Four to 16 weeks after surgery (median 42d, range 28–112), all patients received HDR intravaginal brachytherapy to 25Gy in five consecutive 5-Gy daily fractions prescribed at 0.5-cm depth. Median HDR brachytherapy treatment duration was 5 days (range 5–12). Results: After a median followup of 37 months (range 12–80), the overall survival and disease-free survival were 96%. No vaginal or pelvic recurrences have been observed. One patient (2%) developed distant metastases. No late toxicities of Grade 3 or greater have been reported. Conclusions: The results reported in this study are in agreement with previous reports of postoperative HDR brachytherapy alone in early-stage endometrial cancer. HDR brachytherapy alone seems to provide adequate tumor control. The fractionation schedule proposed (25Gy in five consecutive daily treatments) was well tolerated and is convenient for patients living far from the radiation center. [Copyright &y& Elsevier]

Abstract: Background: This study was undertaken to determine the feasibility of perioperative high-dose-rate brachytherapy (PHDRB) as an adjunct to salvage surgery in primary advanced or recurrent gynecologic cancer. Methods: Twenty-five patients with either locally advanced (n =4) or recurrent (n =21) gynecologic cancer suitable for salvage surgery were included. Unirradiated patients were treated with preoperative chemoradiation followed by salvage surgery and PHDRB (R0 and R1 resections receiving 16 or 24Gy, respectively). Previously irradiated patients were treated with salvage surgery and PHDRB alone with 32 or 40Gy for R0 or R1 resections, respectively. Results: Resections were categorized as R0 in 9 patients (36.0%) and R1 in 16 (64.0%). Four previously irradiated patients suffered fatal pelvic bleeding between 8 and 13 months after surgery and PHDRB. After a median follow-up of 20 months (3–55+), the 4-year actuarial local and pelvic controls were 88.1% and 80.8%, respectively. The 4-year distant metastases-free survival was 40.9%. Four-year actuarial overall survival was 34.0%, with a median survival of 27.1 months (95% confidence interval: 17.5–36.8). Conclusions: Local and pelvic control results are excellent for this very high-risk-disease population. PHDRB dose in previously irradiated patients has been shifted to the closest lower level due to unacceptable vascular toxicity. [Copyright &y& Elsevier]

Abstract: Purpose: This study was undertaken to determine the feasibility of perioperative high-dose-rate brachytherapy (PHDRB) as an accelerated boost in patients with pediatric sarcomas. Methods and materials: Five pediatric patients (ages 7–16) with soft tissue sarcomas (STS) or soft tissue recurrences of previously treated osteosarcomas were treated with surgical resection and PHDRB (16–24 Gy) for R0-R1 resections. Patients with STS and osteosarcomas received 27 Gy and 45 Gy of EBRT postoperatively. Results: After a median follow-up of 27 months (range, 12–50) all the patients remain locally controlled. Only 1 patient developed regrowth of pulmonary metastases and died of distant disease at 16 months. Conclusions: The use of PHDRB is safe in the short-term in this pediatric population. Only 1 patient suffered a partial wound dehiscence that may not be entirely related to PHDRB. Patients with recurrent osteosarcomas can be treated in a fashion similar to their adult soft tissue counterparts and avoid limb amputation. Younger patients with STS may achieve local control and prevent growth retardation with a combination of PHDRB and moderate doses of EBRT. [Copyright &y& Elsevier]

Purpose To assess long-term outcomes and toxicity of adjuvant radiotherapy in the post-surgical management of patients with resected high-grade skeletal osteosarcomas. Methods and materials Seventy-two patients with primary resected osteosarcomas underwent adjuvant radiotherapy after neoadjuvant chemotherapy from December 1984 to December 2008. Local control (LC), overall survival (OS) and disease-free survival (DFS) were estimated using Kaplan–Meier methods. For survival outcomes potential associations were assessed in univariate and multivariate analyses using the Cox proportional hazards model. Results After a median follow-up of 174 months (range, 33–363 months), 10-year LC, DFS, and OS rates were 82%, 58%, and 73%, respectively. In the multivariate analysis only R1 margin status ( p = 0.02) remained significantly associated with LC. Patients with tumor necrosis <90% ( p = 0.04) and R1 resection margin ( p = 0.05) remained at a significantly higher risk of mortality on multivariate analysis. Six patients (8%) developed grade ⩾3 treatment-related chronic toxicity events. No grade 5 toxicities were reported. Conclusions A multimodal radiotherapy-containing approach is a well-tolerated component of treatment for patients with osteosarcomas undergoing programed resection, allowing low toxicity rates while maintaining high local control rates. [ABSTRACT FROM AUTHOR]

Purpose To assess long-term outcomes and toxicity of intraoperative electron-beam radiation therapy (IOERT) in the management of pediatric patients with Ewing sarcomas (EWS) and rhabdomyosarcomas (RMS). Methods and Materials Seventy-one sarcoma (EWS n=37, 52%; RMS n=34, 48%) patients underwent IOERT for primary (n=46, 65%) or locally recurrent sarcomas (n=25, 35%) from May 1983 to November 2012. Local control (LC), overall survival (OS), and disease-free survival were estimated using Kaplan-Meier methods. For survival outcomes, potential associations were assessed in univariate and multivariate analyses using the Cox proportional hazards model. Results After a median follow-up of 72 months (range, 4-310 months), 10-year LC, disease-free survival, and OS was 74%, 57%, and 68%, respectively. In multivariate analysis after adjustment for other covariates, disease status ( P =.04 and P =.05) and R1 margin status ( P <.01 and P =.04) remained significantly associated with LC and OS. Nine patients (13%) reported severe chronic toxicity events (all grade 3). Conclusions A multimodal IOERT-containing approach is a well-tolerated component of treatment for pediatric EWS and RMS patients, allowing reduction or substitution of external beam radiation exposure while maintaining high local control rates. [ABSTRACT FROM AUTHOR]

Purpose To determine whether the time to loading (TTL) affects locoregional control. Methods and Materials Locoregional control status was determined in 301 patients enrolled in several perioperative high-dose-rate brachytherapy (PHDRB) prospective studies conducted at the University of Navarre. The impact of the time elapsed from catheter implantation to the first PHDRB treatment (TTL) was analyzed. Patients treated with PHDRB alone ( n = 113), mainly because of prior irradiation, received 32 Gy in eight twice-a-day treatments or 40 Gy in 10 twice-a-day treatments for negative or close/positive margins, respectively. Patients treated with PHDRB + external beam radiation therapy (EBRT) ( n = 188) received 16 Gy in four twice-a-day treatments or 24 Gy in six twice-a-day treatments for negative or close/positive margins followed by 45 Gy of EBRT in 25 treatments. Results After a median followup of 6.5 years (range, 2–13.6+), 113 patients have failed (37.5%), 65 in the PHDRB-alone group (57.5%) and 48 in the combined PHDRB + EBRT group (25.5%). Patients who started PHDRB before Postoperative Day 5 had a 10-year locoregional control rate of 66.7% and patients who started PHDRB on Postoperative Day 5 or longer had a 10-year locoregional control rate of 51.8% ( p = 0.009). Subgroup analysis detected that this difference was only observed in the recurrent cases treated with PHDRB alone (Subset 2; n = 99; p = 0.004). No correlation could be detected between locoregional control rate and TTL in the other patient subsets although a trend toward a decreased locoregional control rate after a longer TTL was observed when they were grouped together ( p = 0.089). Conclusions Patients should start PHDRB as soon as possible to maximize locoregional control especially in those recurrent cases treated with PHDRB alone. The time effect in other disease scenarios is less clear. [ABSTRACT FROM AUTHOR]

Purpose To perform a joint analysis of data from 3 contributing centers within the intraoperative electron-beam radiation therapy (IOERT)-Spanish program, to determine the potential of IOERT as an anticipated boost before external beam radiation therapy in the multidisciplinary treatment of pediatric extremity soft-tissue sarcomas. Methods and Materials From June 1993 to May 2013, 62 patients (aged <21 years) with a histologic diagnosis of primary extremity soft-tissue sarcoma with absence of distant metastases, undergoing limb-sparing grossly resected surgery, external beam radiation therapy (median dose 40 Gy) and IOERT (median dose 10 Gy) were considered eligible for this analysis. Results After a median follow-up of 66 months (range, 4-235 months), 10-year local control, disease-free survival, and overall survival was 85%, 76%, and 81%, respectively. In multivariate analysis after adjustment for other covariates, tumor size >5 cm (P=.04) and R1 margin status (P=.04) remained significantly associated with local relapse. In regard to overall survival only margin status (P=.04) retained association on multivariate analysis. Ten patients (16%) reported severe chronic toxicity events (all grade 3). Conclusions An anticipated IOERT boost allowed for external beam radiation therapy dose reduction, with high local control and acceptably low toxicity rates. The combined radiosurgical approach needs to be tested in a prospective trial to confirm these results. [ABSTRACT FROM AUTHOR]

Purpose: The present study was undertaken to determine factors predictive of toxicity, patterns of failure, and survival in 60 adult patients with soft tissue sarcomas of the extremity and superficial trunk treated with combined perioperative high-dose-rate brachytherapy and external beam radiotherapy. Methods and Materials: The patients were treated with surgical resection and perioperative high-dose-rate brachytherapy (16 or 24 Gy) for negative and close/microscopically positive resection margins, respectively. External beam radiotherapy (45 Gy) was added postoperatively to reach a 2-Gy equivalent dose of 62.9 and 72.3 Gy, respectively. Adjuvant chemotherapy with ifosfamide and doxorubicin was given to patients with advanced high-grade tumors. Results: Grade 3 toxic events were observed in 18 patients (30%) and Grade 4 events in 6 patients (10%). No Grade 5 events were observed. A location in the lower limb was significant for Grade 3 or greater toxic events on multivariate analysis (p = .013), and the tissue volume encompassed by the 150% isodose line showed a trend toward statistical significance (p = .086). The local control, locoregional control, and distant control rate at 9 years was 77.4%, 69.5%, and 63.8%, respectively. On multivariate analysis, microscopically involved margins correlated with local control (p = .036) and locoregional control (p = .007) and tumor size correlated with distant metastases (p = .004). The 9-year disease-free survival and overall survival rate was 47.0% and 61.5%, respectively. Multivariate analysis showed poorer disease-free survival rates for patients with tumors >6 cm (p = .005) and microscopically involved margins (p = .043), and overall survival rates decreased with increasing tumor size (p = .011). Conclusions: Grade 3 or greater wound complications can probably be decreased using meticulous treatment planning to decrease the tissue volume encompassed by the 150% isodose line, especially in lower limb locations. Microscopically involved margins remain a predictor of local and locoregional failure, despite radiation doses >70 Gy. Patients with tumors ≥6 cm and microscopically involved margins are at high risk of treatment failure and death from the development of distant metastases. [ABSTRACT FROM AUTHOR]

Purpose: To determine the impact of a set of patient, tumor, and treatment factors on toxicity and outcome in patients with head-and-neck squamous cell cancer treated with surgical resection and perioperative high–dose rate brachytherapy (PHDRB) alone (single-modality [SM] group) (n = 46) or PHDRB combined with postoperative radiation or chemoradiation (combined-modality [CM] group) (n = 57). Methods and Materials: From 2000 to 2008, 103 patients received PHDRB after complete macroscopic resection. SM patients received 32 or 40 Gy of PHDRB in 8 or 10 twice-daily treatments for R0 and R1 resections. CM patients received 16 or 24 Gy of PHDRB in 4 or 6 twice-daily treatments for R0 and R1 resections, followed by external radiation of 45 Gy in 25 fractions with or without concomitant chemotherapy. Results: Grade ≥4 complications according to the Radiation Therapy Oncology Group were more frequent in the SM group than in the CM group (p = 0.024). Grade ≥3 and ≥4 complications increased with the antecedent of prior irradiation (p = 0.032 and p = 0.006, respectively) and with TV150 values of 13 mL or greater (p = 0.032 and p = 0.032, respectively). After a median follow-up of 34.8 and 60.8 months for SM and CM patients, respectively, patients with high-risk margins had a 9-year local control rate of 68.0% whereas patients with wider margins had a 9-year local control of 93.7% (p = 0.045). Patients with primary and recurrent tumors had 9-year actuarial locoregional control rates of 81.8% and 54.2%, respectively (p = 0.003). Patients with lymph–vascular space invasion (LVSI)–positive and LVSI-negative tumors had 9-year distant control rates of 62.8% and 81.6%, respectively (p = 0.034). Disease-free survival rates decreased in recurrent cases (p = 0.006) as well as in LVSI-positive patients (p = 0.035). Conclusions: The complications observed are largely attributable to the antecedent of prior irradiation but can possibly be minimized by meticulous mapping and exhaustive planning to reduce TV150 values. Patients with high-risk margins, LVSI-positive status, and recurrent disease have a higher risk of treatment failure, and therefore risk-directed treatment strategies are required. [ABSTRACT FROM AUTHOR]

Purpose: To validate tolerance and pathological complete response rate (pCR) of a 4-week preoperative course of intensity-modulated radiation therapy (IMRT) with concurrent capecitabine and oxaliplatin (CAPOX) in patients with locally advanced rectal cancer. Methods and Materials: Patients with T3 to T4 and/or N+ rectal cancer received preoperative IMRT (47.5 Gy in 19 fractions) with concurrent capecitabine (825 mg/m2 b.i.d., Monday to Friday) and oxaliplatin (60 mg/m2 on Days 1, 8, and 15). Surgery was scheduled 4 to 6 weeks after the completion of chemoradiation. Primary end points were toxicity and pathological response rate. Local control (LC), disease-free survival (DFS), and overall survival (OS) were also analyzed. Results: A total of 100 patients were evaluated. Grade 1 to 2 proctitis was observed in 73 patients (73%). Grade 3 diarrhea occurred in 9% of the patients. Grade 3 proctitis in 18% of the first 50 patients led to reduction of the dose per fraction to 47.5 Gy in 20 treatments. The rate of Grade 3 proctitis decreased to 4% thereafter (odds ratio, 0.27). A total of 99 patients underwent surgery. A pCR was observed in 13% of the patients, major response (96–100% of histological response) in 48%, and pN downstaging in 78%. An R0 resection was performed in 97% of the patients. After a median follow-up of 55 months, the LC, DFS, and OS rates were 100%, 84%, and 87%, respectively. Conclusions: Preoperative CAPOX-IMRT therapy (47.5 Gy in 20 fractions) is feasible and safe, and produces major pathological responses in approximately 50% of patients. [ABSTRACT FROM AUTHOR]

Abstract: Background: This study was undertaken to determine the feasibility of salvage surgery and perioperative high-dose-rate brachytherapy (PHDRB) at the dose/fractionation schedule proposed in patients with previously irradiated, recurrent head and neck cancer or second primary tumors arising in a previously irradiated field. Methods and materials: Twenty-five patients were treated with surgical resection and PHDRB. The PHDRB dose was 4Gy b.i.d.×8 (32Gy) for R0 resections and 4Gy b.i.d.×10 (40Gy) for R1 resections. Further external beam radiotherapy or chemotherapy was not given. Results: Resections were categorized as R0 (negative margins of at least 10mm) in 3 patients (12.0%) and R1 (negative margins of less than 10mm or microscopically positive margins) in 22 (88.0%). Twelve patients with R1 resections had microscopically positive margins (48%), and 10 patients had close margins (40%), with a median of 2.0mm. Ten patients (40.0%) developed Radiation Therapy Oncology Group Grade 3 or greater toxicity. Seven patients (28%) presented complications requiring a major surgical procedure. Four of these complications appeared in the immediate postoperative period and were surgical in nature (flap failure, n =2; fistula, n =2), and the other three were mainly related to the brachytherapy procedure (n =2) or the radiation dose delivered (n =1). One patient died on postoperative day 11 due to bleeding. After a median followup of 14 months, the 4-year local control rate and overall survival were 85.6% and 46.4%, respectively. Conclusions: Surgical salvage and PHDRB at the dose/fractionation proposed are feasible in this high-risk population. Toxicity is high, but not substantially different from other reirradiation series. Four-year local control results are encouraging taking into account that 22 of 25 patients (88%) had either close or microscopically positive margins. [Copyright &y& Elsevier]

Abstract: Purpose: This study was undertaken to determine the feasibility of perioperative high-dose-rate brachytherapy (PHDRB) as an alternative to standard low-dose-rate brachytherapy in adult patients with soft tissue sarcomas. Methods and materials: Twenty-five adult patients with soft tissue sarcomas of the extremities or the superficial trunk were treated with surgical resection and PHDRB (16, 24, or 32Gy) for negative, close/microscopically positive, or grossly involved surgical resection margins, respectively. External beam radiation therapy (45Gy) was added postoperatively. Adjuvant chemotherapy with ifosfamide and doxorubicin was given to patients with high-grade tumors. Results: Resection margins were negative in 6 patients (24.0%), close/microscopically positive in 18 (72.0%), and grossly involved in 1 (4.0%). One patient (4.0%) with wound dehiscence needed reoperation. Three patients failed in the anatomical region treated, but relapse sites were not adjacent to the area treated with PHDRB. After a median followup of 23.2 months (range 2.8–48.0), the 4-year local and regional control rates were 100% and 80.5%, respectively. Four-year overall survival was 78.2%. Conclusions: Locoregional control and survival results are encouraging for this high-risk patient population. PHDRB results seem to be similar to those obtained with low-dose-rate brachytherapy. [Copyright &y& Elsevier]

Purpose: To determine the feasibility of combined long-term androgen deprivation therapy (ADT) and dose escalation with high-dose-rate (HDR) brachytherapy. Methods and Materials: Between 2001 and 2007, 200 patients with high-risk prostate cancer (32.5%) or very high-risk prostate cancer (67.5%) were prospectively enrolled in this Phase II trial. Tumor characteristics included a median pretreatment prostate-specific antigen of 15.2 ng/mL, a clinical stage of T2c, and a Gleason score of 7. Treatment consisted of 54 Gy of external irradiation (three-dimensional conformal radiotherapy [3DCRT]) followed by 19 Gy of HDR brachytherapy in four twice-daily treatments. ADT started 0–3 months before 3DCRT and continued for 2 years. Results: One hundred and ninety patients (95%) received 2 years of ADT. After a median follow-up of 3.7 years (range, 2–9), late Grade ≥2 urinary toxicity was observed in 18% of the patients and Grade ≥3 was observed in 5%. Prior transurethral resection of the prostate (p = 0.013) and bladder D50 ≥1.19 Gy (p = 0.014) were associated with increased Grade ≥2 urinary complications; age ≥70 (p = 0.05) was associated with Grade ≥3 urinary complications. Late Grade ≥2 gastrointestinal toxicity was observed in 9% of the patients and Grade ≥3 in 1.5%. CTV size ≥35.8 cc (p = 0.007) and D100 ≥3.05 Gy (p = 0.01) were significant for increased Grade ≥2 complications. The 5-year and 9-year biochemical relapse-free survival (nadir + 2) rates were 85.1% and 75.7%, respectively. Patients with Gleason score of 7–10 had a decreased biochemical relapse-free survival (p = 0.007). Conclusions: Intermediate-term results at the 5-year time point indicate a favorable outcome without an increase in the rate of late complications. [ABSTRACT FROM AUTHOR]