Clinical outcomes of adapted hypofractionated radiotherapy for bladder cancer in elderly patients.

OBJECTIVE: To investigate the feasibility, efficacy, and safety of trimodal therapy (TMT) using a bifractionated split-course hypofractionated radiotherapy (RT) for non-metastatic muscle-invasive bladder cancer (MIBC) in elderly patients. PATIENTS AND METHODS: We retrospectively reviewed the characteristics and outcomes of patients aged >75 years with non-metastatic MIBC suitable or not for radical cystectomy (RC) and treated with transurethral resection of bladder tumour followed by concomitant radio-chemotherapy (platinum salt and 5-fluorouracil) at two institutions (Saint Louis Hospital, Paris, France and European Georges Pompidou Hospital, Paris, France) between 1990 and 2021. RT consisted of an adapted bifractionated split-course hypofractionated RT. Acute toxicities were reported according to Common Terminology Criteria for Adverse Events version 5.0 and late toxicities were reported according to the Radiation Therapy Oncology Group/European Organisation for Research and Treatment of Cancer late radiation morbidity scoring schema. The primary end-point was overall survival (OS). Secondary end-points included other survivals outcomes and safety. RESULTS: A total of 122 patients were identified, with a median (range) follow-up of 51.1 (0.5-210.8) months. In all, 83.5% of patients completed radio-chemotherapy. The OS rate was 61.7% at 3 years and 51.2% at 5 years. In multivariate analysis, the completion of RT and concomitant chemotherapy were significantly associated with better OS and cancer-specific survival. For patients fit for RC, a complete histological response was achieved for 77 patients (91.7%) with radio-chemotherapy and the bladder conservation rate was 90.5%. Acute and late Grade ≥3 toxicities were <5%. CONCLUSION: Bifractionated split-course hypofractionated RT with concomitant chemotherapy regimen appears to be well-tolerated and effective. Trimodal treatment seems to be a curative option for elderly patients unfit for radical surgery compared with palliative care and may contribute to improved survival in these patients.

Ten-Year Outcomes of Hypofractionated Postmastectomy Radiation Therapy of 26 Gy in 6 Fractions.

PURPOSE: To investigate the efficacy and long-term side effects of hypofractionated postmastectomy radiation therapy (HFRT-PM) of 26 Gy in 6 fractions over 5 weeks. METHODS AND MATERIALS: We retrospectively reviewed characteristics and outcomes of patients with stage I to III breast cancer treated with HFRT-PM between 2000 and 2009. Treatment provided 4 fractions of 4 Gy (days 1, 3, 15, 17) and then 2 fractions of 5 Gy (days 29 and 31) over 5 weeks. The treatment techniques were applied by using 3-dimensional conformal radiation therapy of the chest wall with regional nodal volume if required. RESULTS: We identified 454 patients with a median follow-up of 10.6 years (range, 0.5-22.9). Regional nodal irradiation was done in 84.1% of patients. At 10 years, the cumulative incidence of locoregional relapse was 15.1%. In multivariate analysis, regional lymph node involvement (≥4 nodes) was associated with worse locoregional control (hazard ratio, 1.68; 95% confidence interval, 1.06-2.67; P = .03) and overall survival (hazard ratio, 2.16; 95% confidence interval, 1.59-2.95; P < .001). The toxicities were acceptable. The incidence of cardiac disorders (3.3%), and symptomatic lung fibrosis (1.5%) was low during follow-up. At 10 years, the cumulative rate of arm lymphedema was 9.5% and considered severe in 20 patients (4.4%). CONCLUSIONS: The long-term results of this study show that HFRT-PM of 26 Gy in 6 fractions over 5 weeks seems safe, but locoregional recurrence seems slightly higher than that observed in the literature, highlighting the need for long-term follow-up and for randomized trials for hypofractionated radiation therapy postmastectomy.

Incorporating Magnetic Resonance Imaging (MRI) Based Radiation Therapy Response Prediction into Clinical Practice for Locally Advanced Cervical Cancer Patients.

In recent years, magnetic resonance imaging (MRI) has become one of the standard imaging tools to define the macroscopic gross tumor volume in locally advanced cervical cancer patients based on T2-weighted sequence. Recent data suggest that functional MRI could be used to potentially improve the delineation of target volumes based on physiologic features, defining radioresistant subvolumes that may require higher doses to achieve local cure. Functional imaging can be used to predict tumor biology and outcome, as well as for assessment of tumor response during radiotherapy. The concept of adaptive radiotherapy relies on the possibility of monitoring variations in target volumes structures to guide treatment-plan modification during radiotherapy, taking into account not only internal movements but also tumor response. With integrated MRI in radiotherapy linear accelerators, motion monitoring during treatment delivery has become available. MRI can be also used to accurately evaluate cervical tumor residual volume after chemoradiotherapy, and therefore allowing a personalized treatment planning for brachytherapy boost, based on tumor radiosensitivity. In this review, we discuss how MRI tumor response assessment could be included into clinical practice during radiation therapy in locally advanced cervical cancer patients.

Esophageal brachytherapy: Institut Gustave Roussy's experience.

PURPOSE: Esophageal cancer is characterized by its propension to local evolution, which conditions prognosis and quality of life. Brachytherapy may be a therapeutic option for all stages of esophageal cancer. METHODS AND MATERIALS: This retrospective unicentric study included all consecutive patients treated for an esophageal high-dose-rate brachytherapy in our institution from 1992 to 2018. RESULTS: Ninety patients were included. They were treated in four distinct indications: exclusive (7 patients), boost after external beam radiotherapy (41), reirradiation (36), or palliative aim (6). Most frequently prescribed schemes were 3 × 5 Gy (boost) or 6 × 5 Gy (exclusive treatment and reirradiation) at applicator's surface or at 5 mm. At the end of follow-up, 50% of patients had presented with local recurrence. Seventeen percent of patients had a metastatic relapse. Median overall survival was 15 months in the whole cohort: 22 months in the boost setting, 25 months for exclusive brachytherapy, 15 months for reirradiation, and only 2 months for palliative treatment. Tumor length at brachytherapy, brachytherapy dose, and interfraction response were significantly associated to overall survival. 40% of patients presented with grade 2+ toxicity, mostly esophagitis, including three toxic deaths. CONCLUSIONS: Although local control outcomes are still poor, one must remember that patients are unfit for any curative therapeutic option and that palliative chemotherapy offers mediocre results. The most promising setting probably is reirradiation because brachytherapy offers a remarkable dose gradient allowing best organ at risk sparing, with an encouraging rate of long survivors (19% at 2 years). Esophageal brachytherapy deserves to be further investigated because some patients, even unfit, may benefit from it, with acceptable toxicity.

Solitary Plasmacytoma Treated by Lenalidomide-Dexamethasone in Combination with Radiation Therapy: Clinical Outcomes.

PURPOSE: The study evaluates the results of the concurrent use of lenalidomide-dexamethasone with intensity modulated radiation therapy (IMRT) for solitary plasmacytoma in terms of toxicity and outcome. METHODS AND MATERIALS: Forty-six patients were treated for histologically proven solitary plasmacytoma (SP) between June 2007 and June 2018 in our Department (Curie Institute, Paris, France). All patients received IMRT. The median total dose was 40 Gy (range, 40-46). Prescription of concurrent lenalidomide-dexamethasone with radiation therapy was left to the discretion of the referring hematologist-oncologist and started the first day of radiation therapy for 4 cycles. RESULTS: Twenty-seven solitary plasmacytoma were treated with IMRT alone and 19 with lenalidomide-dexamethasone in association with IMRT. At 5 years, the local control, multiple myeloma-free survival (MMFS), and progression-free survival (PFS) rates were 96.3%, 85.4%, and 60%. MMFS and PFS were significantly higher in the IMRT plus lenalidomide-dexamethasone group compared with IMRT alone group (100% vs 77.1%, P = .02 and 81.7% vs 48.4%, P = .047, respectively). No major toxicity was found in either group. CONCLUSIONS: Lenalidomide-dexamethasone in association with IMRT in the treatment of solitary plasmacytoma is safe and improves MMFS and PFS. Further prospective and comparative studies are needed to confirm these results.

Increased bone marrow SUVmax on 18F-FDG PET is associated with higher pelvic treatment failure in patients with cervical cancer treated by chemoradiotherapy and brachytherapy.

The aim of this study was to evaluate if bone marrow (BM) SUVmax measured on pre-treatment 18F-FDG PET/CT predicts the clinical outcome of locally advanced cervical cancer (LACC). We recruited retrospectively patients with LACC who underwent staging 18F-FDG PET/CT and had baseline blood tests, then treated by chemoradiation therapy (CRT), followed by image-guided adaptive brachytherapy (IGABT). BM SUVmax was calculated and correlated to inflammatory blood markers. Tumor size and pelvic lymph node involvement were evaluated on baseline MRI. Prognostic value of SUV uptake and blood markers regarding overall survival (OS), pelvic and extra-pelvic recurrence-free survival (PRFS and EPRFS respectively) was assessed using Cox models with adjusted p-values. 116 patients with FIGO stage Ib-IVa cervical cancer, treated between 2005 and 2014, were analyzed. The median follow-up was 75.5 months. BM SUVmax was significantly correlated to tumor SUVmax. In multivariate analysis, PRFS was significantly poorer in patients with high BM SUVmax (>2.8) and neutrophilia (p < .05). Tumor size (>5 vs ≤5 cm) could predict PRFS, EPRFS and OS (p < .05). In our cohort, FIGO stage (I-II vs III-IV), pelvic lymph node involvement and tumor SUVmax (>12 vs ≤12) were not prognostic for OS or pelvic and extra-pelvic relapses. Patients with LACC and high BM SUVmax on 18F-FDG PET have worse PFRS following CRT plus IGABT. These results can be potentially explained by the pro-inflammatory role of the tumor microenvironment and G-CSF expressed by tumor cells. These data support the role of PET as a potential indicator of disease aggressiveness beyond tumor staging.

Radiobiological optimization comparison between pulse-dose-rate and high-dose-rate brachytherapy in patients with locally advanced cervical cancer.

PURPOSE: Only scarce data are available on the possibility to include radiobiological optimization as part of the dosimetric process in cervical cancer treated with brachytherapy (BT). We compared dosimetric outcomes of pulse-dose-rate (PDR) and high-dose-rate (HDR)-BT, according to linear-quadratic model. METHODS AND MATERIALS: Three-dimensional dosimetric data of 10 consecutive patients with cervical cancer undergoing intracavitary image-guided adaptive PDR-BT after external beam radiation therapy were examined. A new HDR plan was generated for each patient using the same method as for the PDR plan. The procedure was intended to achieve the same D90 high-risk clinical target volume with HDR as with PDR planning after conversion into dose equivalent per 2 Gy fractions (EQD2) following linear-quadratic model. Plans were compared for dosimetric variables. RESULTS: As per study's methodology, the D90 high-risk clinical target volume was strictly identical between PDR and HDR plans: 91.0 Gy (interquartile: 86.0-94.6 Gy). The median D98 intermediate-risk clinical target volume was 62.9 GyEQD2 with HDR vs. 65.0 GyEQD2 with PDR (p < 0.001). The median bladder D2cc was 65.6 GyEQD2 with HDR, vs. 62 GyEQD2 with PDR (p = 0.004). Doses to the rectum, sigmoid, and small bowel were higher with HDR plans with a median D2cc of 55.6 GyEQD2 (vs. 55.1 GyEQD2, p = 0.027), 67.2 GyEQD2 (vs. S 64.7 GyEQD2, p = 0.002), and 69.4 GyEQD2 (vs. 66.8 GyEQD2, p = 0.014), respectively. For organs at risk (OARs), the effect of radiobiological weighting depended on the dose delivered. When OARs BT contribution to D2cc doses was <20 GyEQD2, both BT modalities were equivalent. OARs EQD2 doses were all higher with HDR when BT contribution to D2cc was ≥20 GyEQD2. CONCLUSION: Both BT modalities provided satisfactory target volume coverage with a slightly higher value with the HDR technique for OARs D2cc while intermediate-risk clinical target volume received higher dose in the PDR plan. The radiobiological benefit of PDR over HDR was predominant when BT contribution dose to OARs was >20 Gy.

Disseminated Tumor Cells Predict Efficacy of Regional Nodal Irradiation in Early Stage Breast Cancer.

PURPOSE: Disseminated tumor cells (DTCs) collect in the bone marrow and indicate micrometastatic spread. We previously reported that DTCs could be a predictive factor for the efficacy of regional node irradiation (internal mammary nodes [IMNs]/supra- and infraclavicular nodes [SCNs]). In this article, we report the long-term results (>10 years) on the impact of DTC status in early stage breast cancer. METHODS AND MATERIALS: Patients with localized breast cancer were eligible for inclusion in this prospective cohort. DTCs were obtained from a medullary iliac crest sample performed before any primary therapy. DTC status was prospectively assessed by pathologists. Irradiation volumes were defined per standard of care. Cumulative incidence rates and hazard ratios were obtained using both Cox and Fine-Gray models. Interaction tests were performed to confirm the predictive value of DTC status in a multivariate analysis. RESULTS: Six hundred twenty patients with localized breast cancer were included. Overall, 94 patients (15.2%) were DTC-positive. After a median follow-up of 11.7 years, 47 patients (7.6%) experienced locoregional relapse. DTC detection was associated with a higher risk of locoregional relapse in univariate and multivariate analyses (Cox hazard ratio, 3.26; 95% confidence interval, 1.6-5.7; P = .001). In the multivariate subgroup analysis, IMN/SCN irradiation significantly reduced locoregional relapse among DTC-positive patients compared with DTC-negative patients (interaction test: hazard ratio, 0.3; 95% confidence interval, 0.1-0.9; P = .02). IMN/SCN was the only irradiation volume with an impact on locoregional relapse in patients according to DTC status, and the predictive value of DTC status for the benefit of locoregional irradiation was independent of locoregional nodal status. CONCLUSIONS: This long-term analysis confirms the predictive impact of DTC status on the efficacy of regional radiation therapy for locoregional relapse in early breast cancer. After further studies, DTC status could be used as a decision tool to better tailor adjuvant radiation therapy in patients with early stage breast cancer.

Tumor Shrinkage During Chemoradiation in Locally Advanced Cervical Cancer Patients: Prognostic Significance, and Impact for Image-Guided Adaptive Brachytherapy.

PURPOSE: To study the prognostic value of gross tumor volume (GTV) shrinkage and its dosimetric implication in a large cohort of patients with cervical cancer receiving definitive chemoradiotherapy plus image guided adaptive brachytherapy. METHODS AND MATERIALS: Clinical records of consecutive patients treated in our institution between February 2004 and November 2015 by concurrent chemoradiotherapy (45 Gy in 25 fractions ± lymph node boosts) followed by a magnetic resonance imaging-guided adaptive pulse-dose rate brachytherapy were included. The prognostic value of GTV and its evolution after chemoradiotherapy were examined first on initial staging magnetic resonance imaging and then at time of brachytherapy. All measures and measurement cutoffs were selected using time-dependent area under the curve for 3-year progression-free survival (PFS). RESULTS: GTV evolution between diagnosis and the time of brachytherapy was assessed in 247 patients. After chemoradiotherapy, complete response was observed in 75 patients (28%). Optimal cutoffs were GTV = 55 cm3 at diagnosis, GTV = 7.5 cm3 at brachytherapy, and GTV reduction ≥90%. All patients with volume above or reduction below these cutoffs had significant reduced overall survival, PFS, local control, and distant metastasis control (P < .001). Patients with anemia at diagnosis had a lower tumor volume response rate (P < .001). In multivariate analysis, incorporating the International Federation of Gynecology and Obstetrics stage, N+ stage, anemia, and dosimetric parameters for image guided adaptive brachytherapy, GTV optimal volume reduction after chemoradiotherapy was independently associated with improved overall survival, PFS, local control, and distant metastasis control (P < .001). CONCLUSIONS: These results could provide a rationale for dose de-escalation studies in brachytherapy for patients displaying optimal GTV volumetric reduction after chemoradiotherapy and may reinforce the need for dose escalation in poorly responding patients.

Concurrent administration of anti-HER2 therapy and radiotherapy: Systematic review.

BACKGROUND: Over the past few years, anti-HER2 targeted therapies have proven to be a key treatment in the management of human epidermal growth receptor 2 (HER2)-positive breast cancers, as well as gastrointestinal tract tumors and head and neck tumors. Anti-HER2 therapies administered alone or in combination with chemotherapy have been extensively studied, but only limited robust data are available concerning the safety and efficacy of anti-HER2 molecules in combination with radiotherapy. METHODS: We searched on Medline, Embase and Cochrane databases the articles providing data on the concomitant association between the antiHER2 therapies used in clinical practice (trastuzumab, pertuzumab, lapatinib and T-DM1) with radiotherapy. The articles were selected according to their pre-clinical and clinical relevance. RESULTS: The trastuzumab-irradiation combination is the most studied, with a focus on the cardiac toxicity. The combination of lapatinib-irradiation was particularly studied in the context of cerebral metastases of HER2-positive breast cancer. The data on pertuzumab and T-DM1 were poor and are mainly case reports. CONCLUSION: To date, reliable conclusions about the toxicity and/or efficacy of concomitant irradiation with anti-HER2 therapies are difficult to make due to the heterogeneity of the data in the literature and need to be confirmed on a larger scale and long term follow-up. Nevertheless, no serious adverse events are reported and the toxicity profile seems to be manageable.