Dose escalation of five-fraction SABR for prostate cancer: Biochemical outcome and toxicity comparison of two prospective trials.

2015 ◽  
Vol 33 (7_suppl) ◽  
pp. 224-224
Author(s):  
Hima Bindu Musunuru ◽  
Harvey Charles Quon ◽  
Liying Zhang ◽  
Patrick Cheung ◽  
Colin I Tang ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Intensity Modulated Radiotherapy ◽  
Psa Bounce ◽  
Stereotactic Ablative Body Radiotherapy ◽  
Gi Toxicity ◽  
Psa Nadir ◽  
Group 2 ◽  
Grade 3 ◽  
Group 1

224 Background: To compare the biochemical outcomes and toxicities of two different 5 fraction stereotactic ablative body radiotherapy (SABR) schedules for the treatment of localized prostate cancer. Methods: Two sequential phase I/II studies of 5-fraction SABR for the treatment of low and intermediate risk (LR and IR) prostate cancer have been conducted. In the first trial, 84 LR patients(pts) received 35 Gy in 5 fractions, once per week over 29 days (Group 1). In the second trial, 30 pts (18 LR, 11 IR) received 40 Gy in 5 fractions, once per week over 29 days (Group 2). Treatment was delivered to the prostate with intensity modulated radiotherapy using daily image guidance and a 4mm (Group 1) or 5 mm (Group 2) CTV-PTV margin. PSA nadir and bRFS(nadir+2 definition) were compared between the two groups. Acute (CTCv3.0), late (RTOG) and cumulative toxicity for late grade ≥ 2 GU/GI toxicities were also compared. Results: Median follow up was 74 (IQR 67-81) and 36 (IQR 32-39) months. Median PSA nadir was 0.4 ng/ml and 0.3 ng/ml. Time to PSA nadir was 54 and 32.5 months. 44.0% in group 1 and 30% in Group 2 experienced benign PSA bounce. There were 3 and 0 PSA failures in Groups 1 and 2. 2-, 4- and 6-year bRFS was 100%, 98.7% and 95.9% and 100%, 100% and not reached in groups 1 and 2, respectively (p=0.91). The only acute grade 3 toxicity was noticed in Group 1 (1 pt, GU). Late grade 4 GI toxicity was noted in Group 1 (1 pt, GI, fistula). Up to 4 years of follow-up, Group 2 pts have had a greater percentage of grade 2+ cumulative GU (5.0% vs 24.2%) and GI (7.6% vs 26.2%) toxicities. Conclusions: Pts receiving a dose escalated SABR had slightly lower PSA nadir and similar bRFS - longer follow up is needed to better estimate biochemical outcomes in Group 2. There seemed to be a greater risk of grade 2 toxicities in the higher dose cohort but grade 3+ toxicities were not increased. Quality of life analyses will be presented separately. Clinical trial information: NCT01578902 , NCT01146340 .[Table: see text]

Combined treatment image guided-intensity modulated radiotherapy (IG-IMRT) plus high-dose rate brachytherapy (HDR) and hormonotherapy (HT) as treatment for high-risk prostate cancer: Five-year result of a phase II study

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 15571-15571
Author(s):  
B. Guix ◽  
J. Bartrina ◽  
I. Henriquez ◽  
R. Serrate ◽  
P. Palombo ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
High Risk ◽  
Dose Rate ◽  
Late Effects ◽  
High Dose Rate ◽  
High Dose ◽  
Group 2 ◽  
Grade 3 ◽  
Group 1

15571 Background: To report early and late toxicity and preliminary biochemical outcome in 345 patients with high-risk (Gleason >=7; PSA>20 or T2c-T3) clinically localized prostate cancer treated with combined high-dose-rate brachytherapy and IMRT (IMRT-HDR) to the prostate and seminal vesicles with 24–36 months of hormononal treatment (goserelin+bicalutamide) (HT). Methods: Between 12/1999 and 10/2003, 345 patients with PSA>20, Gleason score>6 and/or T2c-T3 N0 M0 prostate cancer were treated with IG-IMRT followed by HDR implant to the prostate and HT. Patients were randomly assigned to receive HT for 24 (group 1, 172 patients) or 36 months (group 2, 173 patients). Acute and late toxicities were scored by the EORTC/RTOG morbidity grading scales. Special attention to local, regional or distant recurrence, survival, late effects, PSA and testosterone levels and quality of life was done. PSA failure was defined as nadir +2.0 ng/ml. Results: All patients completed treatment. One patient included in the group 1 and none of the group 2 experienced grade 3 rectal toxicity (rectal ulcer). Seven patients in each group (4.0%) developed acute Grade 2 urinary symptoms, and none experienced urinary retention. No patient (0%) developed Grade 4 rectal complications or grade 3 or 4 urinary complications. With a median follow-up of 44 months, the 5-year actuarial PSA relapse-free survival rates for the whole group of patients was 95.7 %. No statistical differences between group 1 and 2 patients were found. Conclusions: High-dose IG-IMRT+HDR and HT was a safe and effective method of escalating the dose to the prostate without increasing the risk of late effects. Acute and late rectal and urinary complications were significantly low, compared with what has been observed with high-dose conventional, 3D-conformal or IMRT-only. Short-term PSA control rates seem to be at least comparable to those achieved with 3D-EBRT or IMRT. Both treatment regimes were very effective. Longer follow-up is needed to know if better PSA control rate are achieved with longer HT. No significant financial relationships to disclose.

Clinical outcomes and late toxicity of hypofractionated intensity-modulated radiotherapy for high-risk prostate cancer.

2017 ◽  
Vol 35 (6_suppl) ◽  
pp. 56-56
Author(s):  
Michael Wang ◽  
Robert Pearcey ◽  
Nadeem Pervez ◽  
Don Yee ◽  
Alina Mihai ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
High Risk ◽  
Intensity Modulated Radiotherapy ◽  
Late Toxicity ◽  
Seminal Vesicles ◽  
High Risk Prostate Cancer ◽  
Risk Prostate Cancer ◽  
Gi Toxicity ◽  
Grade 3

56 Background: Since prostate cancer has intrinsic high radiation-fraction sensitivity, hypofractionated radiotherapy (HFRT) could offer treatment advantages. However, dose-escalated HFRT may increase risks of late genitourinary (GU) and gastrointestinal (GI) toxicity. Intensity-modulated radiotherapy (IMRT) can potentially deliver dose-escalated HFRT without increasing late toxicities. This study’s acute toxicity data was previously published. We now present five-year efficacy results and late toxicity data for prostate cancer patients treated with HFRT using IMRT. Methods: From 2005-2012, our Phase II prospective study enrolled one hundred patients with either high risk disease (one or more of: Stage ≥ T3, Gleason ≥ 8, or PSA ≥ 20 ng/mL) or high tier intermediate risk disease (Gleason 7 and PSA ≥ 15 ng/mL). All patients received HFRT using IMRT in 25 daily fractions. Sixty patients received 68 Gy to the prostate and proximal seminal vesicles, with simultaneous integrated boost (SIB) of 45 Gy to pelvic lymph nodes and distal seminal vesicles. Forty patients received 68 Gy to the prostate, and a SIB of 50 Gy to pelvic lymph nodes and seminal vesicles. Adjuvant hormonal therapy was given for two to three years. Biochemical failure was determined by the Phoenix definition. Late toxicity scores were recorded every 6 months after completing RT. Results: Median age of patients was 67 years. 33% had Stage ≥ T3, 52% had Gleason ≥ 8, and 44% had PSA ≥ 20 ng/mL. After a median follow-up of 5.4 years, median PSA at last follow-up was 0.10 ng/mL. Five-year biochemical control rate (BCR) was 91.8%, five-year progression-free survival (PFS) was 92.8%, and five-year overall survival (OS) was 88.7%. Five-year cumulative incidence of Grade ≥ 3 GU and GI toxicity were 13.0% and 16.7% respectively. At the five-year efficacy endpoint, ongoing Grade ≥ 3 GU and GI toxicity were 1.9% and 0% respectively. Conclusions: Dose-escalated HFRT using IMRT results in favourable five-year BCR, PFS, and OS for patients with localized high-risk prostate cancer, and is well-tolerated with acceptable late GU and GI toxicity. These findings support ongoing Phase III trials that are assessing the clinical use of IMRT-based HFRT. Clinical trial information: NCT00126802.

scholarly journals Relationship between two year PSA nadir and biochemical recurrence in prostate cancer patients treated with iodine-125 brachytherapy

2014 ◽  
Vol 47 (2) ◽  
pp. 89-93 ◽  
Author(s):  
Carlos Antônio da Silva Franca ◽  
Sérgio Lannes Vieira ◽  
Antonio Carlos Pires Carvalho ◽  
Antonio Jose Serrano Bernabe ◽  
Antonio Belmiro Rodrigues Campbell Penna
Keyword(s):  
Prostate Cancer ◽  
Cancer Patients ◽  
Biochemical Recurrence ◽  
Disease Free Survival ◽  
Disease Recurrence ◽  
Recurrence Rates ◽  
Psa Nadir ◽  
Group 2 ◽  
Iodine 125 ◽  
Group 1

Objective To evaluate the relationship between two year PSA nadir (PSAn) after brachytherapy and biochemical recurrence rates in prostate cancer patients. Materials and Methods In the period from January 1998 to August 2007, 120 patients were treated with iodine-125 brachytherapy alone. The results analysis was based on the definition of biochemical recurrence according to the Phoenix Consensus. Results Biochemical control was observed in 86 patients (71.7%), and biochemical recurrence, in 34 (28.3%). Mean PSAn was 0.53 ng/ml. The mean follow-up was 98 months. The patients were divided into two groups: group 1, with two year PSAn < 0.5 ng/ml after brachytherapy (74 patients; 61.7%), and group 2, with two year PSAn ≥ 0.5 ng/ml after brachytherapy (46 patients; 38.3%). Group 1 presented biochemical recurrence in 15 patients (20.3%), and group 2, in 19 patients (43.2%) (p < 0.02). The analysis of biochemical disease-free survival at seven years, stratified by the two groups, showed values of 80% and 64% (p < 0.02), respectively. Conclusion Levels of two year PSAn ≥ 0.5 ng/ml after brachytherapy are strongly correlated with a poor prognosis. This fact may help to identify patients at risk for disease recurrence.

scholarly journals Prostate-specific antigen bounce after 125I-brachytherapy for prostate cancer is a favorable prognosticator in patients who are biochemical recurrence-free at 4 years and correlates with testosterone

2019 ◽  
Vol 50 (1) ◽  
pp. 58-65 ◽  
Author(s):  
Yasushi Nakai ◽  
Nobumichi Tanaka ◽  
Isao Asakawa ◽  
Satoshi Anai ◽  
Makito Miyake ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Prostate Specific Antigen ◽  
Biochemical Recurrence ◽  
Specific Antigen ◽  
Testosterone Levels ◽  
Psa Bounce ◽  
125I Brachytherapy ◽  
Psa Nadir ◽  
Free Rate

Abstract Background Because patients with prostate-specific antigen (PSA) bounce do not experience biochemical recurrence (BCR) until PSA bounce occurs, the period until PSA bounce ends can be considered the so-called lead-time bias. Therefore, we evaluated differences in BCR-free rate in prostate cancer patients who were BCR-free 4 years after 125I-brachytherapy alone. Furthermore, we evaluated predictors for PSA bounce and the correlation between testosterone and PSA bounce. Methods From 2004 to 2012, 256 patients with prostate adenocarcinoma underwent 125I-brachytherapy alone. PSA and testosterone levels were monitored prior to 125I-brachytherapy, at 1, 3, 6, 12, 18, 24, 30, 36, 42, 48, 54 and 60 months after 125I-brachytherapy and yearly after 5-year follow-up. PSA bounce was defined as ≥0.2 ng/ml increase above the interval PSA nadir, followed by a decrease to nadir or below. Results BCR-free rate in patients with PSA bounce (100% 7-year BCR-free rate) was significantly better (P &lt; 0.044) than that in patients without PSA bounce (95.7% 7-year BCR-free rate) in patients who were BCR-free 4 years after 125I-brachytherapy alone (n = 223). Age was the only predictor (odds ratio: 0.93, 95% confidence interval: 0.88–0.98, P = 0.004) for PSA bounce (n = 177). The testosterone level at PSA bounce was significantly higher (P = 0.036) than that at nadir before PSA bounce (87 cases). Conclusions Patients with PSA bounce had good BCR-free rate even in patients who were BCR-free 4 years after 125I-brachytherapy alone. Testosterone levels were higher at PSA bounce; increased testosterone levels may be a cause of PSA bounce.

scholarly journals The effect of capped biparametric magnetic resonance imaging slots on weekly prostate cancer imaging workload

2020 ◽  
Vol 93 (1108) ◽  
pp. 20190929 ◽  
Author(s):  
Nikita Sushentsev ◽  
Iztok Caglic ◽  
Evis Sala ◽  
Nadeem Shaida ◽  
Rhys A Slough ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Mean Absolute Deviation ◽  
Resonance Imaging ◽  
Absolute Deviation ◽  
Intergroup Comparison ◽  
Before And After ◽  
Group 2 ◽  
Group 1

Objective: To introduce capped biparametric (bp) MRI slots for follow-up imaging of prostate cancer patients enrolled in active surveillance (AS) and evaluate the effect on weekly variation in the number of AS cases and total MRI workload. Methods: Three 20 min bpMRI AS slots on two separate days were introduced at Addenbrooke’s Hospital, Cambridge. The weekly numbers of total prostate MRIs and AS cases recorded 15 months before and after the change (Groups 1 and 2, respectively). An intergroup variation in the weekly scan numbers was assessed using the coefficient of variance (CV) and mean absolute deviation; the Mann–Whitney U test was used for an intergroup comparison of the latter. Results: In AS patients, a shift from considerable to moderate variation in weekly scan numbers was observed between the two groups (CV, 51.7 and 26.8%, respectively); mean absolute deviation of AS scans also demonstrated a significant decrease in Group 2 (1.28 vs 2.58 in Group 1; p < 0.001). No significant changes in the variation in total prostate MRIs were observed, despite a 10% increased workload in Group 2. Conclusion: A significant reduction in weekly variation of AS cases was demonstrated following the introduction of capped bpMRI slots, which can be used for more accurate long-term planning of MRI workload. Advances in knowledge: The paper illustrates the potential of introducing capped AS MRI slots using a bp protocol to reduce weekly variation in demand and allow for optimising workflow, which will be increasingly important as the demands on radiology departments increase worldwide.

Comparison of intermittent versus continuous methotrexate plus 6-mp in maintenance regimen for standard risk acute lymphoblastic leukemia in children (GBTLI ALL-99)

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 9512-9512 ◽  
Author(s):  
S. R. Brandalise
Keyword(s):  
Maintenance Therapy ◽  
Maintenance Treatment ◽  
Risk Group ◽  
Lymphoblastic Leukemia ◽  
Treatment Schedule ◽  
Group 2 ◽  
Grade 3 ◽  
Standard Risk ◽  
Group 1

9512 Objectives: To compare by randomization the conventional use of 6-MP (50 mg/m2 daily) / MTX (25 mg/m2/wk) regimen with the intermittent use of MTX (200 mg/m2/IV 6 h infusion each 21 days)/ 6-MP (100 mg/m2/day × 10) in maintenance therapy. Methods: Newly diagnosed ALL children up to 18 yrs of age registered in the GBTLI ALL-99 Protocol. The eligibility criteria for standard-risk group were age >1 <9 years and WBC count at diagnosis <50,000/mm3 and good responders at D7/D14. Randomization was made after the late consolidation phase (week 42) prior to the maintenance treatment. Treatment Schedule: Induction: [DX(Pred), DNM, VCR, L-ASP, CICLO, Ara-C, 6-MP], Intensification: (MTX 2 g/m2 6 h inf. × 4, 6-MP) Late Consolidation: (DX, VCR, DOXO, L-ASP, CICLO, ARA-C, 6-TG) plus prolonged triple intratecal therapy, were done previously to maintenance therapy. Total treatment duration was two years. No CNS radiation was done. Toxicities were defined according to NCI-version 2001 criteria. Results: 560 pts were enrolled in the study. 22 slow responders pts (4.1%) moved to high risk group. The total number of analyzed pts was 512. Two hundred and thirty pts entered group 1 [continuous (conventional) 6MP-MTX] and 230 pts entered group 2 (Intermittent MTX/6-MP). Remission rate was 95.3%. 439 pts (87.9%) are in CCR. The mean follow up period is 2.2 years. The estimated 5 years OS rate for both groups is 88.1% ± 2.1%. The estimated 5 years EFS for both groups is 80% ± 2.9%. According to maintenance regimen, the 5 years EFS rate is 80.2% ± 4.5% and 88.3% ± 3.7% for group 1 and group 2, respectively (p=0.048). Grade 3 and 4 hepatic toxicities were 254 episodes for group 1 and 144 episodes for group 2 (p=0.019). Grade 3 CNS toxicities were 13 episodes (group 1) and 5 in group 2. Grade 4 hematological toxicities were 254 episodes for group 1 and 144 episodes for group 2 (p=0.003). Conclusions: Despite the short mean time follow-up (2.2 years) the patients with the intermittent regimen (Group 2) had better EFS rate (p = 0.048) and less hematological, CNS and hepatic toxicities, comparing with patients that received conventional maintenance treatment (group 1). No significant financial relationships to disclose.

Carboplatin, ifosfamide, and mesna (CIM) for the treatment of gynecological carcinosarcoma

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. e16539-e16539
Author(s):  
N. Walji ◽  
A. Zachariah ◽  
C. Yap ◽  
S. A. Hussain ◽  
C. J. Poole ◽  
...  
Keyword(s):  
Complete Response ◽  
Kaplan Meier ◽  
Metastatic Setting ◽  
The Common ◽  
Group 2 ◽  
Grade 3 ◽  
Abdominal Irradiation ◽  
Toxicity Criteria ◽  
Group 1

e16539 Background: A GOG trial comparing cisplatin/ifosfamide/mesna chemotherapy versus whole abdominal irradiation for FIGO stages I-IV carcinosarcoma (CS) showed an estimated median survival (MS) of 50 months for chemotherapy but high toxicity. This study investigates the efficacy and tolerability of a novel regimen using carboplatin AUC 5, ifosfamide 3 g/m2 and mesna 1 g/m2 (CIM) in both the adjuvant and metastatic setting. Methods: Retrospective analysis of women with CS treated from May 1997-May 2007 with CIM (group 1) versus other chemotherapy regimens (group 2). Toxicity was graded according to the Common Toxicity Criteria and MS estimated using the Kaplan-Meier method. Results: Of 51 eligible women (median age 71 years) 35 (69%) had stage 3 or 4 disease. 35/51 (69%) received chemotherapy; 2 with stage 1c disease received pelvic radiotherapy (pRT) alone whilst the remaining 14 were unfit for any treatment. Median follow-up for the treated patients is 45 months. 11/35 patients (31%) received CIM as first-line chemotherapy. Other regimens included: carboplatin (n = 14); carboplatin/paclitaxel (n = 3); carboplatin/epirubicin (n = 3); carboplatin/doxorubicin (n = 2); doxorubicin/ifosfamide (n = 1); cisplatin/ifosfamide (n = 1). 20/35 (57%) received adjuvant chemotherapy (AC) of which 8 received CIM; 11/20 patients also received adjuvant pRT. MS in the CIM AC group is 54.7 months compared to 37.4 months for other regimens. 3/8 patients (37.5%) in the CIM arm developed recurrent disease compared to 9/12 (75%) for other regimens. 4/16 patients received CIM as first- or second-line palliative chemotherapy. All patients responded of whom 2 achieved clinical and radiological complete response (CR). One woman subsequently relapsed and achieved a second CR with CIM. MS for all chemotherapy-treated patients is 54.7 months (group 1) versus 20.6 months (group 2) (p = 0.07). No patients in group 1 experienced any grade 3/4 toxicity and all patients completed the prescribed treatment. There were 2 unexpected treatment-related deaths in group 2, one of whom received carboplatin/paclitaxel and the other carboplatin/epirubicin. Conclusions: CIM appears to be efficacious and well tolerated in the treatment of CS and merits further investigation in clinical trials. No significant financial relationships to disclose.

Experience with artificial urinary sphincter implantation in men who underwent prior pelvic radiation therapy for prostate cancer.

2014 ◽  
Vol 32 (4_suppl) ◽  
pp. 236-236
Author(s):  
Sameer G. Jhavar ◽  
Erin Bird ◽  
Gregory P. Swanson
Keyword(s):  
Prostate Cancer ◽  
Radiation Therapy ◽  
Artificial Urinary Sphincter ◽  
Pelvic Radiation ◽  
Urinary Sphincter ◽  
Prior Surgery ◽  
Group 3 ◽  
Group 2 ◽  
Group 1

236 Background: To assess outcomes after artificial urinary sphincter implantation in men who received prior pelvic radiation therapy. Methods: Between 1997 and 2012, 107 patients were identified from the Scott and White Hospital database who underwent artificial urinary sphincter implantation for urinary incontinence after prostate cancer treatment. Of these 17 were excluded for lack of follow-up data. Of the remaining 90 patients, 59 patients underwent prior surgery alone (group 1), 25 underwent prior surgery followed by pelvic radiation therapy (group 2); and 6 patients underwent prior radiation therapy alone. Results: Average ages at sphincter implantation were 69 yrs. (range 54 - 82), 73 yrs. (range 63 - 81), and 70 yrs. (range 60 - 80) respectively for groups 1, 2 and 3. Social continence rates were 80% (47/59) for group 1, 72% (18/25) for Group 2 and 50% (3/6) for group 3 at an average follow-up of 6 yrs. (range 0 - 17), 4 yrs. (range 1 - 12) and 3 yrs. (range 0 - 6) respectively. Average time between surgery and sphincter implantation was 5 yrs. (range 1-27) in group 1. Average time between radiation and sphincter implantation was 7 yrs. (range 1 - 18) and 6 yrs. (range 1 - 17) in Groups 2 and 3. Re-operation rates were 42% (25/59); 48% (12/25); and 50% (3/6) in groups 1, 2, and 3, respectively. In men who were incontinent at last follow-up, the average time between pelvic radiation and sphincter placement was relatively shorter as compared to those who were continent [5 yrs. (range 1 -11) vs. 7 yrs. (range 1 - 18) in Group 2; and 4 yrs. (range 1 -5) vs.10 yrs. (range 4 - 17) in group 3]. The rates of erosions were 10/59 (17%); 4/25 (16%); and 0/6 (0%) in groups 1, 2, and 3, respectively. The rates of infection were 5/59 (8%), 0/25 (0%), and 2/6 (33%) in groups 1, 2, and 3, respectively. Conclusions: Our experience with artificial urinary sphincter in men who underwent prior pelvic radiation therapy is comparable to that reported in the literature. Our results identify factors associated with worse continence after artificial urinary sphincter in men who underwent prior pelvic radiation therapy.

The prognostic value of mid-treatment prostate-specific antigen level in patients receiving salvage radiotherapy.

2019 ◽  
Vol 37 (7_suppl) ◽  
pp. 289-289
Author(s):  
Jason Homza ◽  
John T. Nawrocki ◽  
Harmar D. Brereton ◽  
Christopher A. Peters
Keyword(s):  
Prostate Cancer ◽  
Prostate Specific Antigen ◽  
Specific Antigen ◽  
Salvage Radiotherapy ◽  
Clinical Failure ◽  
Treatment Intensification ◽  
Significant Difference ◽  
Group 2 ◽  
Group 1

289 Background: Salvage radiotherapy (SRT) may be employed as a potentially curative intervention for patients experiencing biochemical failure (serum prostate-specific antigen [PSA] ≥ 0.2 ng/mL) after prostatectomy for localized prostate cancer. Patients not showing a favorable response to SRT alone may require additional therapies and may benefit from earlier identification of this need. Methods: 131 consecutive patients received SRT during the timeframe of this study. 76 were deemed eligible based on the following criteria: prostatic adenocarcinoma diagnosis receiving SRT, no clinical evidence of metastasis, no hormone use prior to/during SRT, serum PSA measurement halfway through SRT, and minimum follow-up time of 3 months. Median follow-up time was 51.6 months. Eligible patients were divided into three groups based on PSA response by the midpoint of treatment: no change, decrease, or increase in PSA. The primary endpoint of the study was clinical failure (measured from SRT completion), defined as serum PSA value ≥0.2ng/mL above the post-radiotherapy nadir, initiation of androgen deprivation therapy, development of bone metastasis, or death from prostate cancer. Results: 13.1% experienced no change in PSA halfway through SRT (group 0), 68.4% of patients experienced a decrease (group 1), 18.4% experienced an increase (group 2). Four-year freedom from clinical failure was 60.0% for group 0, 58.3% for group 1, and 41.7% for group 2. Median time to clinical failure was 71.7 months for group 1, 26.8 months for group 2, and was not reached for group 0. Pairwise multiple comparison demonstrated a significant difference in four-year freedom from clinical failure between groups 1 and 2 (p = 0.036). Conclusions: These data strongly suggest that changes in PSA are apparent midway through SRT and are associated with 4-year freedom from clinical failure. Further study is warranted to determine whether mid-treatment PSA during SRT may be used to identify a subset of patients that may benefit from treatment intensification.

scholarly journals Preliminary Safety and Efficacy Results with an Intermittent Schedule of the PI3kδ Inhibitor ME-401 Alone or in Combination with Rituximab for B-Cell Malignancies

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 2893-2893 ◽  
Author(s):  
Andrew D. Zelenetz ◽  
Jacob D. Soumerai ◽  
Deepa Jagadeesh ◽  
Nishitha Reddy ◽  
Anastasios Stathis ◽  
...  
Keyword(s):  
B Cell ◽  
Research Funding ◽  
Objective Response ◽  
Intermittent Schedule ◽  
Safety And Efficacy ◽  
Group 2 ◽  
Grade 3 ◽  
Expansion Cohort ◽  
Group 1

Abstract Background: ME-401, a potent and selective oral PI3kδ inhibitor, achieved a high rate of early and durable responses in patients with follicular lymphoma (FL), chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) when administered once daily in 28-day cycles on a continuous schedule (CS) in a dose escalation Phase 1b study (Soumerai et al, ASCO 2018:#7519). The most common adverse events (AEs) were the delayed onset (beyond Cycle 2) of grade 3 diarrhea and rash, which were reversible with drug interruption and/or corticosteroids. These delayed AEs were thought to be due to pathway inhibition in regulatory T cells (Treg) leading to a disruption in immune homeostasis. We hypothesized that an intermittent schedule (IS) beyond Cycle 2 might mitigate or reduce the incidence of significant delayed AEs. The IS tested was selected based on the kinetics of Treg repopulation, and consists of ME-401 administered on days 1-7 of a 28-day cycle. We report preliminary results of this strategy. Methods: Group 1 included 31 patients with relapsed FL (n = 22) or CLL/SLL (n = 9) who received ME-401 on a CS at doses ≥60 mg per day. 11/29 patients (38%) who received >2 cycles of therapy had developed delayed grade 3 AEs on CS and could be re-challenged with either the CS or IS (from December 2017 onward) following recovery from toxicity. The other 18/29 patients (62%) had not developed a grade 3 AEs of interest on CS and, beginning in December 2017, were switched to IS after a median of 26 weeks (range, 8-49) of daily dosing. Group 2 included 15 patients with relapsed FL (n = 9), diffuse large B-cell lymphoma (n = 4), marginal zone lymphoma (MZL, n = 1), and CLL (n = 1) who received rituximab 375 mg/m2 x 8 doses over 6 months and ME-401 at 60 mg daily x 2 cycles then switched to the IS. Group 3 includes 30 patients with relapsed FL/CLL/SLL enrolling in an expansion cohort of ME-401 alone at 60 mg daily x 2 cycles then switching to IS. Results: Group 1: Of the 11 patients who developed a delayed grade 3 AE on CS, 6 were never re-challenged, 2 were re-challenged with CS with recurrence of their AE, and 3 were re-challenged with IS without recurrence of their AE. Of the 18 patients switched to the IS, and with a median follow-up of 5.2 months (range, 2.3-6.6) on IS, 3 developed grade 3 diarrhea on IS, 2 in the first cycle and 1 in the second cycle after the switch to IS, of whom 2 have been re-treated with IS for 1+ and 5+ months without recurrence of the AE. One patient was not evaluable for response due to discontinuation on Day 28 for personal reasons and 27/30 (90%) evaluable patients achieved an objective response. With a median follow-up of 9.4 months (range, 2.2-17.5) from enrollment, only 2/27 (7%) responders had disease progression (PD) on CS and were discontinued. Of the 18 patients who were switched to IS, only 1 SLL patient with a partial response (PR) achieved on CS developed PD on IS and was successfully rescued with switch back to CS. Another CLL patient in PR on CS had 10% increase in SPD from nadir in Cycle 5 on the IS and was switched back to CS. Group 2: 10/15 patients have completed 2 cycles of daily dosing at the time of analysis and were systematically switched to IS. With a median follow-up of 3.4 months (range, 1.5-5.7) on IS, only 1/10 patients developed delayed grade 3 diarrhea in the first cycle after switch to IS. 7/10 patients (70%) with FL/MZL achieved an objective response and no PD was reported with a median follow-up of 5.2 months (range, 3.1-7.5) from enrollment. Conclusions: Preliminary data suggest that switching to an intermittent schedule consisting of ME-401 administered on days 1-7 of a 28-day cycle following 2 cycles of continuous daily dosing was associated with a low rate of delayed grade 3 AEs and was associated with preservation of response in the vast majority of patients. All delayed grade 3 AEs of interest on IS occurred within 1-2 cycles of switching from CS to IS, suggesting that these might have represented a delayed effect of daily dosing. IS may also be a suitable re-treatment strategy in patients with delayed AEs on CS. Safety and efficacy data for the expansion cohort of 30 patients treated with ME-401 at 60 mg for 2 cycles then switched to IS will be presented at the meeting. A randomized study comparing CS and IS in FL is planned. Disclosures Zelenetz: Abbvie: Research Funding; Celgene: Consultancy; AstraZeneca: Consultancy; Novartis/Sandoz: Consultancy; Amgen: Consultancy; Gilead: Consultancy, Research Funding; Genentech/Roche: Consultancy, Research Funding. Reddy:MEI Pharma: Research Funding. Stathis:Oncology Therapeutic Development: Research Funding. Ghalie:MEI Pharma: Employment, Equity Ownership; Viracta Therapeutics: Membership on an entity's Board of Directors or advisory committees. Pagel:Pharmacyclics, an AbbVie Company: Consultancy; Gilead: Consultancy.

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