Feasibility and early toxicity of intraoperative radiotherapy for breast cancer using the papillon + system: First results.

Background and Purpose: Breast intra operative radiation therapy has been evaluated with different systems delivering 20-21 Gy with treatment times around 30 min. Papillon + TM Contact X-ray machine was designed to produce a 50 kVp beam with a high dose rate ≥ 15 Gy/minute. A pilot study with the first prototype was conducted in Nice. Materials and methods: The inclusion criteria were age ≥ 60 years, unifocal ductal breast adenocarcinoma ≤ 2.5 cm, grade 1-2. Surgical local excision with sentinel node dissection was performed and the applicator was placed in the tumor bed after excision with a prescribed dose of 20 Gy. The main end point of the study was the doses measured with the Gafchromic films; two were located at the skin surface and two in the excision cavity. Secondary endpoints were early toxicity and relapse free survival. Results: Between 10/2018 and 09/2019, 26 patients were included. Mean Gafchromic doses were 18.8 Gy ± 2 Gy at the south pole, 15.6 Gy ± 2.81 Gy at the equator and 2.5 Gy ± 1.67 Gy at the skin. With a median follow-up time of 12 months, no skin or subcutaneous toxicity > grade 2, no local relapse and no metastasis were observed. Conclusion: This is the first phase II study testing the Papillon + tm system for breast IORT with in vivo dosimetry measurements and reassuring clinical data.

Single fraction of HDR brachytherapy for prostate cancer: Results of the SiFEPI phase II prospective trial.

Purpose: To report the results of the Single Fraction Early Prostate Irradiation (SiFEPI) phase 2 prospective trial. Materials/Methods: The SiFEPI trial (NCT02104362) evaluated a single fraction of high-dose rate brachytherapy (HDB) for low- (LR) and favorable-intermediate (FIR) risk prostate cancers. After rectal spacer placement, a single fraction of 20 Gy was delivered to the prostate. Oncological outcome (biochemical (bRFS) and local (lRFS) relapses, disease-free (DFS) and overall (OS) survivals and toxicity (acute/late genito-urinary (GU), gastro-intestinal (GI) and sexual (S) toxicities were investigated. Results: From 03/2014 to 10/2017, 35 pts were enrolled, of whom 33 were evaluable. With a median age of 66 y [46-79], 25 (76 %) and 8 (24 %) pts were LR and FIR respectively. With a MFU of 72.8 months [64-86], 6y-bRFS, lRFS and mRFS were 62 % [45-85], 61 % [44-85] and 93 % [85-100] respectively while 6y-DFS, CSS and OS were 54 % [37-77], 100 % and 89 % [77-100] respectively. Late GU, GI and S toxicities were observed in 11 pts (33 %;18G1), 4 pts (12 %;4G1) and 7 pts (21 %;1G1,5G2,1G3) respectively. Biochemical relapse (BR) was observed in 11 pts (33 %;7LR,4FIR) with a median time interval between HDB and BR of 51 months [24-69]. Nine of these pts (82 %) presented a histologically proven isolated local recurrence. Conclusions: Long-term results of the SiFEPI trial show that a single fraction of 20 Gy leads to sub-optimal biochemical control for LR/FIR prostate cancers. The late GU and GI toxicity profile is encouraging, leading to consideration of HDB as a safe irradiation technique.

High-dose-rate brachytherapy boost for elderly patients with intermediate to high-risk prostate cancer: 5-year clinical outcome of the PROSTAGE cohort.

Purpose: To analyze the oncological outcome in elderly (>70 years) prostate cancer after high-dose rate brachytherapy (HDB) boost. Materials/methods: In this retrospective study, patients with intermediate (IR) and high-risk (HR) prostate cancer underwent external beam radiation therapy (EBRT) followed by HDB boost with/without androgen deprivation therapy (ADT). The impact of age (≤70y vs. > 70y) was investigated. Oncological outcome focused on biochemical relapse-free survival (bRFS), cause-specific (CSS) and overall survival (OS). Late genito-urinary (GU) and gastro-intestinal (GI) toxicities were investigated. Results: From 07/08 to 01/22, 518 pts received a HDB boost, and 380 were analyzed (≤70y:177pts [46.6%] vs. > 70y:203pts [53.4%]). Regarding NCCN classification, 98 pts (≤70y: 53pts; >70y: 45pts; p = 0.107) and 282 pts (≤70y: 124pts; >70y: 158pts; p = NS) were IR and HR pts respectively. Median EBRT dose was 46 Gy [37.5-46] in 23 fractions [14-25]. HDB boost delivered a single fraction of 14/15 Gy (79%). ADT was used in 302 pts (≤70y: 130pts; >70y: 172pts; p = 0.01). With MFU of 72.6 months [67-83] for the whole cohort, 5-y bRFS, 5-y CSS and 5-y OS were 88% [85-92], 99% [97-100] and 94% [92-97] respectively; there was no statistical difference between the two age groups except for 5-y CSS (p = 0.05). Late GU and GI toxicity rates were 32.4% (G ≥ 3 7.3%) and 10.1% (no G3) respectively. Conclusions: For IR and HR prostate cancers, HDB boost leads to high rates of disease control with few late G ≥ 3 GU/GI toxicities. For elderly pts, HDB boost remains warranted mainly in HR pts, while competing comorbidity factors influence OS.

Irradiation of localized prostate cancer in the elderly: A systematic literature review.

Purpose: To analyze the literature that addresses radiation therapy for intermediate and high-risk prostate cancer (PC) in the elderly. Patients and methods: A PubMed literature search was conducted including articles from 01/01/2000 to 30/06/21, with the following keywords: PC, radiotherapy/brachytherapy and elderly. The analysis mainly focused on the issue of under-treatment in the elderly and the benefit/risk balance of irradiation. Results: Of the 176 references analyzed, 24 matched the selection criteria. The definition of "elderly patient" varied from 70 to 80 years. The analysis was impacted by the inhomogeneous primary end points used in each cohort. Age was often an obstacle to radical treatment, with a subsequent risk of under-treatment, particularly in patients with a poorer prognosis. However, comparable elderly oncological outcomes were compared to younger patients, both with external beam radiotherapy alone or combined with brachytherapy boost. Late toxicity rates are low and most often comparable to younger populations. However, a urinary over- toxicity was observed in the super-elderly (>80 years) after brachytherapy boost. The use of ADT should be considered in light of comorbidities, and may even be deleterious in some patients. Conclusion: Due to the increase in life expectancy, the management of PC in the elderly is a challenge for patients, clinicians and health insurance payers. Except for unfit men, elderly patients remain candidates for optimal curative treatment (i.e. regardless of age) after oncogeriatric assessment. More solid data from prospective trials conducted specially in this population will provide better guidance in our daily clinical practice.

Abiraterone plus prednisone added to androgen deprivation therapy and docetaxel in de novo metastatic castration-sensitive prostate cancer (PEACE-1): a multicentre, open-label, randomised, phase 3 study with a 2 × 2 factorial design.

BACKGROUND: Current standard of care for metastatic castration-sensitive prostate cancer supplements androgen deprivation therapy with either docetaxel, second-generation hormonal therapy, or radiotherapy. We aimed to evaluate the efficacy and safety of abiraterone plus prednisone, with or without radiotherapy, in addition to standard of care. METHODS: We conducted an open-label, randomised, phase 3 study with a 2 × 2 factorial design (PEACE-1) at 77 hospitals across Belgium, France, Ireland, Italy, Romania, Spain, and Switzerland. Eligible patients were male, aged 18 years or older, with histologically confirmed or cytologically confirmed de novo metastatic prostate adenocarcinoma, and an Eastern Cooperative Oncology Group performance status of 0-1 (or 2 due to bone pain). Participants were randomly assigned (1:1:1:1) to standard of care (androgen deprivation therapy alone or with intravenous docetaxel 75 mg/m2 once every 3 weeks), standard of care plus radiotherapy, standard of care plus abiraterone (oral 1000 mg abiraterone once daily plus oral 5 mg prednisone twice daily), or standard of care plus radiotherapy plus abiraterone. Neither the investigators nor the patients were masked to treatment allocation. The coprimary endpoints were radiographic progression-free survival and overall survival. Abiraterone efficacy was first assessed in the overall population and then in the population who received androgen deprivation therapy with docetaxel as standard of care (population of interest). This study is ongoing and is registered with ClinicalTrials.gov, NCT01957436. FINDINGS: Between Nov 27, 2013, and Dec 20, 2018, 1173 patients were enrolled (one patient subsequently withdrew consent for analysis of his data) and assigned to receive standard of care (n=296), standard of care plus radiotherapy (n=293), standard of care plus abiraterone (n=292), or standard of care plus radiotherapy plus abiraterone (n=291). Median follow-up was 3·5 years (IQR 2·8-4·6) for radiographic progression-free survival and 4·4 years (3·5-5·4) for overall survival. Adjusted Cox regression modelling revealed no interaction between abiraterone and radiotherapy, enabling the pooled analysis of abiraterone efficacy. In the overall population, patients assigned to receive abiraterone (n=583) had longer radiographic progression-free survival (hazard ratio [HR] 0·54, 99·9% CI 0·41-0·71; p<0·0001) and overall survival (0·82, 95·1% CI 0·69-0·98; p=0·030) than patients who did not receive abiraterone (n=589). In the androgen deprivation therapy with docetaxel population (n=355 in both with abiraterone and without abiraterone groups), the HRs were consistent (radiographic progression-free survival 0·50, 99·9% CI 0·34-0·71; p<0·0001; overall survival 0·75, 95·1% CI 0·59-0·95; p=0·017). In the androgen deprivation therapy with docetaxel population, grade 3 or worse adverse events occurred in 217 (63%) of 347 patients who received abiraterone and 181 (52%) of 350 who did not; hypertension had the largest difference in occurrence (76 [22%] patients and 45 [13%], respectively). Addition of abiraterone to androgen deprivation therapy plus docetaxel did not increase the rates of neutropenia, febrile neutropenia, fatigue, or neuropathy compared with androgen deprivation therapy plus docetaxel alone. INTERPRETATION: Combining androgen deprivation therapy, docetaxel, and abiraterone in de novo metastatic castration-sensitive prostate cancer improved overall survival and radiographic progression-free survival with a modest increase in toxicity, mostly hypertension. This triplet therapy could become a standard of care for these patients. FUNDING: Janssen-Cilag, Ipsen, Sanofi, and the French Government.

Preoperative high-dose-rate brachytherapy for high-risk early-stage cervical cancer: Long-term clinical outcome analysis.

OBJECTIVE: To report long-term oncological and toxicity outcomes after high-dose-rate brachytherapy (HDB) followed by oncologic surgery for patients with early-stage cervical cancer. METHODS AND MATERIALS: From 2005 to 2019, all patients treated with preoperative HDB at Antoine Lacassagne Cancer Center for early-stage (IB1-IB2-IIA - FIGO 2018) cervical cancer with local relapse risk factors were included. HDB was performed followed by hysterectomy. Oncological and toxicity outcomes were evaluated prospectively. RESULTS: We identified 61 patients, with a median follow-up of 84 months. Posthysterectomy complete pathological response was observed in 46 patients (75.4%). Six patients (9.8%) experienced recurrence, including 4 local relapses (6.6%), and 2 deaths (3.3%) due to cervical cancer. Five-year local, nodal and metastatic relapse-free survivals were 94% (95% CI 87-100%), 96% (95% CI 90-100%) and 93% (95% CI 86-100%) respectively. Five-year overall survival was 98% (95% CI 95-100%). No grade ≥ 3 acute toxicity was observed, and 3 patients (4.9%) experienced grade 2 acute toxicity. One patient presented grade 4 late digestive toxicity, and 6 patients had grade 2 late toxicity. Only 1 patient still had grade 2 toxicity, after 9 years follow-up. CONCLUSIONS: To our knowledge, we are reporting the longest follow-up of a preoperative HDB cohort. With similar oncological outcomes and less morbidity compared to primary surgery treatment followed more or less by adjuvant radiotherapy, HDB followed by hysterectomy could be a promising therapeutic option for early-stage cervical cancers with poor prognostic factors.

High-dose-rate brachytherapy boost for locally advanced cervical cancer: Oncological outcome and toxicity analysis of 4 fractionation schemes.

PURPOSE: Brachytherapy (BT) boost after radio-chemotherapy (RCT) is a standard of care in the management of locally advanced cervical cancer (LACC). As there is no consensus on high-dose-rate (HDR) BT fractionation schemes, our aim was to report the oncological outcome and toxicity profile of four different schemes using twice-a-day (BID) HDR-BT. PATIENTS AND METHODS: This was an observational, retrospective, single institution study for patients with LACC receiving a HDR-BT boost. The latter was performed with a single implant and single imaging done on day 1. The different fractionation schemes were: 7 Gy + 4x3.5 Gy (group 1); 7 Gy + 4x4.5 Gy (group 2); 3x7Gy (group 3) and 3x8Gy (group 4). Local (LFS), nodal (NFS) and metastatic (MFS) recurrence-free survival as well as progression-free survival (PFS) and overall survival (OS) were analyzed. Acute (≤6 months) and late toxicities (>6 months) were reported. RESULTS: From 2007 to 2018, 191 patients were included. Median follow-up was 57 months [45-132] and median EQD210D90CTVHR was 84, 82 and 90 Gy for groups 2, 3 and 4 respectively (dosimetric data missing for group 1). The 5-year LFS, NFS, MFS, PFS and OS were 85% [81-90], 83% [79-86], 70% [67-73], 61% [57-64] and 75% [69-78] respectively, with no significant difference between the groups. EQD210D90CTVHR < 85 Gy was a prognostic factor for local recurrence in univariate analysis (p = 0.045). The rates of acute/late grade ≥ 2 urinary, digestive and gynecological toxicities were 9%/15%, 3%/15% and 9%/25% respectively. CONCLUSION: Bi-fractionated HDR-BT boost seems feasible with good oncological outcome and slightly more toxicity after dose escalation.

Concomitant cervical and transperineal parametrial high-dose-rate brachytherapy boost for locally advanced cervical cancer.

PURPOSE: There is no consensus for parametrial boost technic while both transvaginal and transperineal approaches are discussed. A prototype was developed consisting of a perineal template, allowing transperineal needle insertion. This study analyzed acute toxicity of concomitant cervical and transperineal parametrial high-dose-rate brachytherapy (HDRB) boost for locally advanced cervical cancer. MATERIAL AND METHODS: From 01.2011 to 12.2014, 33 patients (pts) presenting a locally advanced cervical cancer with parametrial invasion were treated. After the first course of external beam radiation therapy with cisplatinum, HDRB was performed combining endocavitary and interstitial technique for cervical and parametrial disease. Post-operative delineation (CTV, bladder, rectum, sigmoid) and planification were based on CT-scan/MRI. HDRB was delivered in 3-5 fractions over 2-3 consecutive days. Acute toxicities occurring within 6 months after HDRB were retrospectively reviewed. RESULTS: Median age was 56.4 years (27-79). Clinical stages were: T2b = 23 pts (69.7%), T3a = 1 pt (3%), T3b = 6 pts (18.2%), and T4a = 3 pts (9.1%). Median HDRB prescribed dose was 21 Gy (21-27). Median CTVCT (16 pts) and HR-CTVMRI (17 pts) were 52.6 cc (28.5-74.3), 31.9 cc (17.1-58), respectively. Median EQD2αß10 for D90CTV and D90HR-CTV were 82.9 Gy (78.2-96.5), 84.8 Gy (80.6-91.4), respectively. Median EQD2αß3 (CT/MRI) for D2cc bladder, rectum and sigmoid were 75.5 Gy (66.6-90.9), 64.4 Gy (51.9-77.4), and 60.4 Gy (50.9-81.1), respectively. Median follow-up was 14 months (ranged 6-51). Among the 24 pts with MFU = 24 months, 2-year LRFS rate, RRFS, and OS were 86.8%, 88.8%, and 94.1%, respectively. The rates of acute genitourinary and gastrointestinal toxicities were 36% (G1 dysuria = 8 pts, G2 infection = 2 pts, G3 infection = 2 pts), and 27% (G1 diarrhea = 9 pts), respectively. One patient presented vaginal bleeding at the time of applicator withdrawal (G3-blood transfusion); no bleeding was observed due to the parametrial implant. CONCLUSIONS: Concomitant cervical and transperineal parametrial HDRB boost for locally advanced cervical cancer appears feasible and safe with no specific acute toxicity compare to cervical HDRB alone. Longer follow-up and larger patient cohort will be needed.

Interstitial preoperative high-dose-rate brachytherapy for early stage cervical cancer: dose-volume histogram parameters, pathologic response and early clinical outcome.

PURPOSE: To analyze dose-volume histogram parameters and pathologic response after preoperative high-dose-rate brachytherapy (HDRB) for high-risk early stage cervical cancers (ESCCs). METHODS AND MATERIALS: From June 2007 to December 2011, 32 patients with a histologically proven invasive cervical cancer with high risk of local recurrence (size >2cm, adenocarcinoma type, perineural and/or lymphovascular invasion) underwent a preoperative HDRB, which delivered a total dose of 39Gy in nine fractions over 5 days. All the patients underwent hysterectomy after HDRB. RESULTS: With a median clinical target volume of 50cc (minimum-maximum, 42-74), the median V100 was 49cc (minimum-maximum, 42-50). Median D90 was 45Gy (equivalent dose at 2Gy per fraction, 56Gyαß10). Median D2cc was 34Gy, 31Gy, 28Gy, and 38Gyαß3 for bladder, rectum, sigmoid, and vagina, respectively. Twenty-eight patients (88.5%) achieved a complete histologic response after surgery, whereas for the 4 remaining patients, residual tumor cells (3 patients) and gross residual disease (1 patient) were observed in the pathologic specimen. With a median followup of 24 months (minimum-maximum, 5-48), no local recurrence was observed; 1 patient died of intercurrent cause. Early toxicity occurred within the 30 days after HDRB (Common Terminology Criteria for Adverse Events v3.0) was G1 diarrhea for 15 patients (47%) and G1 urinary frequency or urgency for 13 patients (40.6%). No G2-G3 toxicities were noticed. CONCLUSIONS: Preoperative HDRB for high-risk ESCCs represents a well-tolerated procedure, which leads to a high rate of postoperative pathologic response. Dose-volume histogram parameters were at least equivalent to those obtained with a low-dose-rate procedure. Long-term results will help to analyze the place of preoperative brachytherapy in the management of high-risk ESCCs.

Dose gradient impact on equivalent dose at 2 Gy for high dose rate interstitial brachytherapy.

PURPOSE: To evaluate a new calculation model estimating the equivalent dose at 2 Gy (EQD2) taking into account dose gradient in high dose rate interstitial brachytherapy (HDRIB). MATERIAL AND METHODS: Forty dose-volume histograms (DVHs) of breast (20 pts) and prostate (20 pts) cancer dose distributions were reviewed. Physical prescribed doses (PPD) were 34 Gy (10f/5d) and 18 Gy (6f/2d) for breast (partial irradiation protocol) and prostate (boost after external irradiation) treatment, respectively. For each DVH, clinical target volume (CTV), V100, V150, V200, D90 and D100 were determined. Based on DVH segmentation, elementary doses (d) delivered to elementary volumes were determined, then multiplied by C (% of CTV receiving d). According to the linear quadratic model, EQD2 was calculated for different α/ß ratios. RESULTS: For breast implant, median EQD2 (α/ß = 4) was 42 Gy and 76 Gy (66-85) without and with dose gradient consideration, respectively. For prostate implant, median EQD2 (α/ß = 1.5) was 39 Gy and 98 Gy (90-103) whether dose gradient was not or was taken into account, respectively. CONCLUSIONS: This study pointed out that for brachytherapy, EQD2 calculation must take into account the dose gradient. Because this model is a mathematical one, it has to be cautiously applied. Nevertheless, it appears as a useful tool for EQD2 comparison between the same PPD delivered through EBRT or brachytherapy regarding trial result interpretation.