Duration of androgen deprivation therapy with postoperative radiotherapy for prostate cancer: a comparison of long-course versus short-course androgen deprivation therapy in the RADICALS-HD randomised trial.

BACKGROUND: Previous evidence supports androgen deprivation therapy (ADT) with primary radiotherapy as initial treatment for intermediate-risk and high-risk localised prostate cancer. However, the use and optimal duration of ADT with postoperative radiotherapy after radical prostatectomy remains uncertain. METHODS: RADICALS-HD was a randomised controlled trial of ADT duration within the RADICALS protocol. Here, we report on the comparison of short-course versus long-course ADT. Key eligibility criteria were indication for radiotherapy after previous radical prostatectomy for prostate cancer, prostate-specific antigen less than 5 ng/mL, absence of metastatic disease, and written consent. Participants were randomly assigned (1:1) to add 6 months of ADT (short-course ADT) or 24 months of ADT (long-course ADT) to radiotherapy, using subcutaneous gonadotrophin-releasing hormone analogue (monthly in the short-course ADT group and 3-monthly in the long-course ADT group), daily oral bicalutamide monotherapy 150 mg, or monthly subcutaneous degarelix. Randomisation was done centrally through minimisation with a random element, stratified by Gleason score, positive margins, radiotherapy timing, planned radiotherapy schedule, and planned type of ADT, in a computerised system. The allocated treatment was not masked. The primary outcome measure was metastasis-free survival, defined as metastasis arising from prostate cancer or death from any cause. The comparison had more than 80% power with two-sided α of 5% to detect an absolute increase in 10-year metastasis-free survival from 75% to 81% (hazard ratio [HR] 0·72). Standard time-to-event analyses were used. Analyses followed intention-to-treat principle. The trial is registered with the ISRCTN registry, ISRCTN40814031, and ClinicalTrials.gov, NCT00541047. FINDINGS: Between Jan 30, 2008, and July 7, 2015, 1523 patients (median age 65 years, IQR 60-69) were randomly assigned to receive short-course ADT (n=761) or long-course ADT (n=762) in addition to postoperative radiotherapy at 138 centres in Canada, Denmark, Ireland, and the UK. With a median follow-up of 8·9 years (7·0-10·0), 313 metastasis-free survival events were reported overall (174 in the short-course ADT group and 139 in the long-course ADT group; HR 0·773 [95% CI 0·612-0·975]; p=0·029). 10-year metastasis-free survival was 71·9% (95% CI 67·6-75·7) in the short-course ADT group and 78·1% (74·2-81·5) in the long-course ADT group. Toxicity of grade 3 or higher was reported for 105 (14%) of 753 participants in the short-course ADT group and 142 (19%) of 757 participants in the long-course ADT group (p=0·025), with no treatment-related deaths. INTERPRETATION: Compared with adding 6 months of ADT, adding 24 months of ADT improved metastasis-free survival in people receiving postoperative radiotherapy. For individuals who can accept the additional duration of adverse effects, long-course ADT should be offered with postoperative radiotherapy. FUNDING: Cancer Research UK, UK Research and Innovation (formerly Medical Research Council), and Canadian Cancer Society.

Adding 6 months of androgen deprivation therapy to postoperative radiotherapy for prostate cancer: a comparison of short-course versus no androgen deprivation therapy in the RADICALS-HD randomised controlled trial.

BACKGROUND: Previous evidence indicates that adjuvant, short-course androgen deprivation therapy (ADT) improves metastasis-free survival when given with primary radiotherapy for intermediate-risk and high-risk localised prostate cancer. However, the value of ADT with postoperative radiotherapy after radical prostatectomy is unclear. METHODS: RADICALS-HD was an international randomised controlled trial to test the efficacy of ADT used in combination with postoperative radiotherapy for prostate cancer. Key eligibility criteria were indication for radiotherapy after radical prostatectomy for prostate cancer, prostate-specific antigen less than 5 ng/mL, absence of metastatic disease, and written consent. Participants were randomly assigned (1:1) to radiotherapy alone (no ADT) or radiotherapy with 6 months of ADT (short-course ADT), using monthly subcutaneous gonadotropin-releasing hormone analogue injections, daily oral bicalutamide monotherapy 150 mg, or monthly subcutaneous degarelix. Randomisation was done centrally through minimisation with a random element, stratified by Gleason score, positive margins, radiotherapy timing, planned radiotherapy schedule, and planned type of ADT, in a computerised system. The allocated treatment was not masked. The primary outcome measure was metastasis-free survival, defined as distant metastasis arising from prostate cancer or death from any cause. Standard survival analysis methods were used, accounting for randomisation stratification factors. The trial had 80% power with two-sided α of 5% to detect an absolute increase in 10-year metastasis-free survival from 80% to 86% (hazard ratio [HR] 0·67). Analyses followed the intention-to-treat principle. The trial is registered with the ISRCTN registry, ISRCTN40814031, and ClinicalTrials.gov, NCT00541047. FINDINGS: Between Nov 22, 2007, and June 29, 2015, 1480 patients (median age 66 years [IQR 61-69]) were randomly assigned to receive no ADT (n=737) or short-course ADT (n=743) in addition to postoperative radiotherapy at 121 centres in Canada, Denmark, Ireland, and the UK. With a median follow-up of 9·0 years (IQR 7·1-10·1), metastasis-free survival events were reported for 268 participants (142 in the no ADT group and 126 in the short-course ADT group; HR 0·886 [95% CI 0·688-1·140], p=0·35). 10-year metastasis-free survival was 79·2% (95% CI 75·4-82·5) in the no ADT group and 80·4% (76·6-83·6) in the short-course ADT group. Toxicity of grade 3 or higher was reported for 121 (17%) of 737 participants in the no ADT group and 100 (14%) of 743 in the short-course ADT group (p=0·15), with no treatment-related deaths. INTERPRETATION: Metastatic disease is uncommon following postoperative bed radiotherapy after radical prostatectomy. Adding 6 months of ADT to this radiotherapy did not improve metastasis-free survival compared with no ADT. These findings do not support the use of short-course ADT with postoperative radiotherapy in this patient population. FUNDING: Cancer Research UK, UK Research and Innovation (formerly Medical Research Council), and Canadian Cancer Society.

Evaluation of Immunophenotypic and Molecular Biomarkers for Sézary Syndrome Using Standard Operating Procedures: A Multicenter Study of 59 Patients.

Differentiation between Sézary syndrome and erythrodermic inflammatory dermatoses can be challenging, and a number of studies have attempted to identify characteristic immunophenotypic changes and molecular biomarkers in Sézary cells that could be useful as additional diagnostic criteria. In this European multicenter study, the sensitivity and specificity of these immunophenotypic and recently proposed but unconfirmed molecular biomarkers in Sézary syndrome were investigated. Peripheral blood CD4(+) T cells from 59 patients with Sézary syndrome and 19 patients with erythrodermic inflammatory dermatoses were analyzed for cell surface proteins by flow cytometry and for copy number alterations and differential gene expression using custom-made quantitative PCR plates. Experiments were performed in duplicate in two independent centers using standard operating procedures with almost identical results. Sézary cells showed MYC gain (40%) and MNT loss (66%); up-regulation of DNM3 (75%), TWIST1 (69%), EPHA4 (66%), and PLS3 (66%); and down-regulation of STAT4 (91%). Loss of CD26 (≥80% CD4(+) T cells) and/or CD7 (≥40% CD4(+) T cells) and combination of altered expression of STAT4, TWIST1, and DNM3 or PLS3 could distinguish, respectively, 83% and 98% of patients with Sézary syndrome from patients with erythrodermic inflammatory dermatoses with 100% specificity. These additional diagnostic panels will be useful adjuncts in the differential diagnosis of Sézary syndrome versus erythrodermic inflammatory dermatoses.

Temozolomide for central nervous system involvement in mycosis fungoides.

BACKGROUND: The central nervous system (CNS) is one of the most commonly involved sites in the systemic progression of primary cutaneous T cell lymphomas (CTCLs) such as mycosis fungoides (MF). There is no consensus on the treatment of CNS progression in CTCL, but survival of 3-6 months is suggested when methotrexate-based chemotherapy and/or CNS irradiation is used. Temozolomide is active in earlier stages of MF and readily crosses the blood-brain barrier. There are no published data on its use in MF patients with CNS involvement. METHODS: Four MF patients were treated with oral temozolomide (200 mg/m(2) per day for 5 d on a 28-day cycle) for CNS progression. Two patients received temozolomide with low-dose CNS irradiation as initial treatment, and two received temozolomide following disease progression after methotrexate-based chemotherapy and CNS irradiation. All patients received dexamethasone. RESULTS: Temozolomide was well tolerated; there were no treatment withdrawals or dose reductions caused by toxicity. Patient 1 had an excellent partial response in pre-irradiated disease. Patient 2 showed disease stabilization following irradiation. Patient 3 showed a complete response after a partial response to irradiation. Patient 4 demonstrated continued stabilization after a partial response to irradiation. Overall survival ranged from 10 to 33 months. Patient 3 remains alive and symptom-free at 23 months following treatment. CONCLUSIONS: Temozolomide following low-dose CNS irradiation appears to be well tolerated and effective in MF patients with CNS progression. It may represent a less toxic alternative to chemotherapy containing methotrexate or an option for second-line therapy.

An unusual case of granulomatous slack skin disease with necrobiosis.

Granulomatous slack skin disease (GSS) is a very rare form of T-cell lymphoma, with only 52 cases reported in the literature. In the recent World Health Organization-European Organization for Research and Treatment of Cancer consensus classification GSS is considered to be a variant of mycosis fungoides. We describe a patient with GSS and histologic evidence of necrobiosis, which has not been previously reported.

Dynamic dose-feedback prostate brachytherapy in patients with large prostates and/or planned transurethral surgery before implantation.

OBJECTIVE: To compare the quality of permanent prostate brachytherapy (PPB) implants, dosimetric outcomes and urinary morbidity between patients with large (>50 mL) and those with smaller prostates, treated with a dynamic dose-feedback technique as monotherapy for localized prostate cancer. PATIENTS AND METHODS: The series included patients with pre-existing bladder outlet obstruction managed with planned transurethral resection or incision of the prostate; 155 consecutive men had PPB implants as monotherapy for localized prostate cancer using a dynamic dose-feedback approach. Dosimetric variables assessed included the implant volume, the minimum dose to 90% of the prostate (D90), and the volumes of prostate receiving 100% and 150% of the prescribed dose as a percentage of the total volume (V100 and V150), during and after implantation. Urinary morbidity was recorded in terms of acute urinary retention (AUR), the need for surgical intervention after implantation and the American Urologic Association (AUA) symptom score at baseline, 1.5, 3, 6, 9, 12 and 18 months. RESULTS: In all, 38 patients had prostate volumes of >or=50 mL; prostate volume had no influence on any dosimetric variable assessed. Two patients with large prostates (>or=50 mL) had AUR and required delayed surgery. Three patients with small prostates (<50 mL) had transient retention; the differences were not statistically significant (Fisher's exact test). AUA symptom scores peaked at 6 weeks and returned to baseline within a year; there were no statistically significant differences between the groups. Eight patients had planned transurethral surgery at >or=4 months before implantation; they all had D90s of >130 Gy and had no incontinence. CONCLUSION: Using the dynamic feedback technique, there was no adverse dosimetric and urinary morbidity in men having PPB and with prostates of >50 mL. Likewise, there were no impediments, e.g. pubic arch interference, which precluded a favourable dosimetric implant in men with a large prostate. Large prostates should not be a contraindication to PPB and require no hormonal cytoreduction. Patients with obstructive lower urinary tract symptoms can be managed with planned transurethral prostatic surgery before implantation, without compromising implant quality or morbidity.