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

Immunological correlates of treatment and response in stage IV malignant melanoma patients treated with Ipilimumab

Introduction: Ipilimumab is effective in the treatment of metastatic malignant melanoma, but few biomarkers reliably predict treatment response. Methods: Patients were treated with Ipilimumab for metastatic malignant melanoma. Blood and serum samples were collected before and during treatment. Mononuclear cells in peripheral blood were subjected to immune phenotypic analyses and cytokine levels were measured in serum samples. Results were correlated with clinical data. Results: A total of 40 patients were included in the analyses. Clinical response were associated with an increase after one series of treatment in absolute lymphocyte count (ALC) (p = 0.008), absolute T cell count (p = 0.02) and the absolute number of activated T cells in peripheral blood (p = 0.003). A high frequency of myeloid derived suppressor cells (MDSC) and a higher level of IL6 were associated with treatment failure, though not significantly. Levels of IL6 in serum above the median showed a tendency to associate with reduced survival by the 4th treatment series. Finally, treatment with Ipilimumab led to a decreased frequency of FOXP3+ regulatory T cells (p = 0.009). Conclusion: Ipilimumab leads to increased ALC, T cell count and T cell activation in malignant melanoma patients responding to treatment. A high baseline frequency of myeloid-derived suppressor cells and high levels of IL6 is associated with a reduced chance of responding to therapy

Serum IL-6 as a prognostic biomarker in patients with stage IIB-III melanoma.

8545 Background: Interleukin (IL)-6 is an immunomodulatory cytokine produced by cancer cells and different immune cells. The specific function of IL-6 in cancer is unknown. Serum IL-6 is elevated in patients with different types of cancer. Elevated serum concentration of IL-6 is related to short survival in patients with stage IV melanoma. Methods: IL-6 was measured by ELISA (R&amp;D) in pretreatment serum samples from 435 patients with stage IIB-III melanoma (151 women and 284 men, median age 51 years, range 18-77). After surgery patients were treated in a randomized study (The Nordic IFN trial) with either adjuvant interferon for 1 or 2 years, or observation. Results: Median serum concentration of IL-6 after surgery and before treatment was 1.8 ng/l, range 0.23-24 ng/l. Patients with serum IL-6 above the median had shorter overall survival (OS) compared to patients with serum IL-6 below the median (p=0.004). Median OS was 4.5 years in patients with serum IL-6 above the median (95% confidence interval (CI): 3.05-7.60). In patients with serum IL-6 below the median, median OS was not reached at the last survival-update. Multivariate Cox analysis including serum IL-6, ulceration in primary melanoma, LDH, white blood cells, lymph node metastases and Breslow thickness of primary melanoma showed that only serum IL-6 (hazard ratio (HR) = 1.48, 95% confidence interval (CI) : 1.13-1.94, p=0.004) was an independent prognostic factor for OS. In subgroup analysis of the control group and the two treatment groups, serum IL-6 demonstrated a negative prognostic impact in the control group (HR = 1.62, 95% CI: 1.02-2.57, p=0.04) and in the group treated with 2 years interferon HR = 1.69, 95% CI: 1.06-2.7, p=0.03). In the group treated with 1 year interferon this negative impact was not significant (HR = 1.15, 95% CI: 0.71-1.85, p=0.58). An interaction between IL-6 and treatment arm was not significant (p=0.45), suggesting that the negative prognostic effect of elevated pretreatment serum IL-6 is independent of treatment. Conclusions: Serum IL-6 above the median is an independent prognostic biomarker of short OS in patients operated for stage IIB-III melanoma. </jats:p