Concurrent Olaparib and Radiation Therapy in Older Patients With Newly Diagnosed Glioblastoma: The Phase 1 Dose-Escalation PARADIGM Trial.

PURPOSE: Patients with glioblastoma who are older or have poor performance status (PS) experience particularly poor clinical outcomes. At the time of study initiation, these patients were treated with short-course radiation therapy (40 Gy in 15 fractions). Olaparib is an oral inhibitor of the DNA repair enzyme poly (ADP-ribose) polymerase (PARP) that is well tolerated as a single agent but exacerbates acute radiation toxicity in extracranial sites. Preclinical data predicted that PARP inhibitors would enhance radiosensitivity in glioblastoma without exacerbating adverse effects on the normal brain. METHODS AND MATERIALS: Phase 1 of the PARADIGM trial was a 3+3 dose-escalation study testing olaparib in combination with radiation therapy (40 Gy 15 fractions) in patients with newly diagnosed glioblastoma who were unsuitable for radical treatment either because they were aged 70 years or older (World Health Organization PS 0-1) or aged 18 to 69 years with PS 2. The primary outcome was the recommended phase 2 dose of olaparib. Secondary endpoints included safety and tolerability, overall survival, and progression-free survival. Effects on cognitive function were assessed via the Mini Mental State Examination. RESULTS: Of 16 eligible patients (56.25% male; median age, 71.5 years [range, 44-78]; 75% PS 0-1), 1 dose-limiting toxicity was reported (grade 3 agitation). Maximum tolerated dose was not reached and the recommended phase 2 dose was determined as 200 mg twice daily. Median overall survival and progression-free survival were 10.8 months (80% CI, 7.3-11.4) and 5.5 months (80% CI, 3.9-5.9), respectively. Mini Mental State Examination plots indicated that cognitive function was not adversely affected by the olaparib-radiation therapy combination. CONCLUSIONS: Olaparib can be safely combined with hypofractionated brain radiation therapy and is well tolerated in patients unsuitable for radical chemoradiation. These results enabled initiation of a randomized phase 2 study and support future trials of PARP inhibitors in combination with radiation therapy for patients with brain tumors.

Pre-diagnostic blood biomarkers for adult glioma.

Glioma is one of the most common malignant primary brain tumours in adults, of which, glioblastoma is the most prevalent and malignant entity. Glioma is often diagnosed at a later stage of disease progression, which means it is associated with significant mortality and morbidity. Therefore, there is a need for earlier diagnosis of these tumours, which would require sensitive and specific biomarkers. These biomarkers could better predict glioma onset to improve diagnosis and therapeutic options for patients. While liquid biopsies could provide a cheap and non-invasive test to improve the earlier detection of glioma, there is little known on pre-diagnostic biomarkers which predate disease detection. In this review, we examine the evidence in the literature for pre-diagnostic biomarkers in glioma, including metabolomics and proteomics. We also consider the limitations of these approaches and future research directions of pre-diagnostic biomarkers for glioma.

Delphi panel for consensus on the optimal management of dabrafenib plus trametinib-related pyrexia in patients with melanoma.

Purpose: Dabrafenib and trametinib combination therapy (dab + tram) is indicated to treat BRAF V600 mutation-positive unresectable/metastatic melanoma and as adjuvant treatment for resected stage III disease. Dab + tram-related pyrexia may require early therapy discontinuation. A modified Delphi panel was conducted to develop consensus on the optimal management of dab + tram-related pyrexia in patients with melanoma. Methods: In all, 10 UK oncologists experienced in melanoma management participated in a three-round modified Delphi study (Round 1: one-to-one interview; Rounds 2 and 3: email survey). In each round, participants rated the extent of their agreement with statements about defining and managing dab + tram-related pyrexia. Consensus was defined as >80% agreement for critical management (CM) and >60% for non-critical management (NCM) statements. Results: All 10 participants completed Round 1; 9 completed Rounds 2 and 3. Consensus was reached on 42/66 statements (20 CM and 22 NCM). Drug-related pyrexia was agreed as being strictly an elevation of body temperature, although other symptoms may be present (89% agreement). Panelists agreed on the need for simple and generic guidance on dab + tram-related pyrexia management that does not differentiate between patient groups (100%), and that management of first and second dab + tram-related pyrexia episodes should be the same regardless of treatment intent (100%). Regarding CM, participants agreed that both dab and tram should be interrupted for pyrexia (100%) without considering the use of steroids (89%); patients on dab + tram presenting to non-oncology services with pyrexia should be directed to an oncology-specific service as soon as possible and assessed for infection (100%). NCM statements on steroid use following dab + tram interruption and when to restart dab + tram did not reach consensus. Conclusions: These consensus statements provide a framework on optimal management of dab + tram-related pyrexia in patients with melanoma which should inform future guidelines.

Treating brain metastases in melanoma: What is the optimal CNS-directed and systemic management?

Treatments for melanoma have significantly advanced with the approval of targeted treatments against the BRAF/MEK pathway and immunotherapy in the form of checkpoint inhibitors. Studies have shown the effectiveness of these treatments against brain metastases. However, the optimum treatment strategy utilising CNS-directed treatments such as stereotactic radiosurgery (SRS) and neurosurgical resection is less clear. Over six years, 70 patients with metastatic melanoma were treated for brain metastases at a tertiary treatment centre. The median overall survival (OS) for all patients was 10.2 months. 51 patients received localised treatment; 7 resection (median OS 10 months), 11 resection and SRS (median OS 17.3 months) and 33 SRS alone (median OS 17.4 months). For patients treated with SRS those who had <2 cm3 treated had a better median OS (20.5 months) compared to those who had >2 cm3 treated (12 months). 69 Patients received systemic treatment. The median OS of patients who did not have CNS-directed treatment was poor (median OS 1.2 months). Patients treated with first line dual immunotherapy had the best median OS (26.7 months), compared to anti-PD-1 (14.1 months), ipilimumab (14.3 months) and kinase inhibitors (10.9 months). Despite advancements in treatment, the development of brain metastases in melanoma is associated with worse outcomes. A combination of CNS-directed and systemic treatment is important to improve survival. Dual immunotherapy appears to be the most effective systemic treatment and the use of SRS improved outcomes. As metastatic melanoma treatments evolve there need to be an ongoing focus to ensure these strategies adequately treat intracranial disease.

Sequential immunotherapy in melanoma: is it a realistic alternative to dual immunotherapy?

The treatment of metastatic melanoma has been revolutionised with the emergence of checkpoint inhibitors. The combination of Ipilimumab and Nivolumab offers the longest overall survival but is considerably more toxic than single-agent therapy. For patients who received single-agent immunotherapy it is unclear whether second-line immunotherapy is efficacious or tolerable. This study looked at outcomes for patients treated with sequential immunotherapy and compared them to patients who received dual immunotherapy. Fifty-eight patients received both Ipilimumab and an anti-PD-1 agent during the 5-year period, twenty-seven received dual immunotherapy, twenty received first-line Ipilimumab and eleven received an anti-PD-1 agent first line. The median overall survival (OS) was 24.8 months. The 5 year survival was greatest in patients treated with dual immunotherapy (42%) compared to first-line anti-PD-1 (33.3%) and first-line Ipilimumab (0%). As second-line treatments, anti-PD-1 agents had a median OS of 16.5 months compared to Ipilimumab at 3.4 months. 77.8% of patients had grade 3/4 toxicity with dual immunotherapy compared to 10% of patients treated with first-line Ipilimumab and 0% with anti-PD-1 agents. In the second line, 72.7% of patients treated with Ipilimumab experienced grade 3/4 toxicity, compared to 20% of patients treated with second-line anti-PD-1 agents. This study suggests Ipilimumab is not efficacious in patients who progress after anti-PD-1 agents, and this sequential approach does not avoid toxicity. The emergence of new checkpoint inhibitors will hopefully provide more efficacious treatment options for patients unable to tolerate Ipilimumab.

Health-related quality of life in patients with fully resected BRAFV600 mutation-positive melanoma receiving adjuvant vemurafenib.

AIM OF STUDY: The aim of the study was to assess the impact of treatment with adjuvant vemurafenib monotherapy on health-related quality of life (HRQOL) in patients with resected stage IIC-IIIC melanoma. METHODS: The phase 3 BRIM8 study (NCT01667419) randomised patients with BRAFV600 mutation-positive resected stage IIC-IIIC melanoma to 960 mg of vemurafenib twice daily or matching placebo for 52 weeks (13 × 28-day cycles). Patients completed the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) version 3 at baseline, cycle 1 (days 1, 15 and 22), cycle 2 (days 1 and 15), day 1 of every subsequent 4-week cycle, the end-of-treatment visit and each visit during the follow-up period. RESULTS: Completion rates for the EORTC QLQ-C30 questionnaire were high (>80%). There was a mean decline in the global health status (GHS)/quality of life (QOL) score of 17.4 (±22.9) and 17.3 (±24.1) points at days 15 and 22 of cycle 1, respectively, among vemurafenib-treated patients who recovered to approximately 10 points below baseline for the remainder of the treatment period. A similar trend was observed in all functional scales except for cognitive function (<10-point change from baseline at all visits) and in the symptom scores for appetite loss, fatigue and pain. As observed for the GHS/QOL score, all scores rapidly returned to baseline after completion of planned vemurafenib treatment or treatment discontinuation. CONCLUSIONS: The schedule of HRQOL assessments allowed for an accurate and complete evaluation of the impact of acute treatment-related symptoms. Vemurafenib-treated patients experience clinically meaningful moderate worsening in some treatment- or disease-related symptoms and GHS/QOL that resolve over time.

Adjuvant vemurafenib in resected, BRAFV600 mutation-positive melanoma (BRIM8): a randomised, double-blind, placebo-controlled, multicentre, phase 3 trial.

BACKGROUND: Systemic adjuvant treatment might mitigate the high risk of disease recurrence in patients with resected stage IIC-III melanoma. The BRIM8 study evaluated adjuvant vemurafenib monotherapy in patients with resected, BRAFV600 mutation-positive melanoma. METHODS: BRIM8 was a phase 3, international, double-blind, randomised, placebo-controlled study that enrolled 498 adults (aged ≥18 years) with histologically confirmed stage IIC-IIIA-IIIB (cohort 1) or stage IIIC (cohort 2) BRAFV600 mutation-positive melanoma that was fully resected. Patients were randomly assigned (1:1) by an interactive voice or web response system to receive twice-daily adjuvant oral vemurafenib 960 mg tablets or matching placebo for 52 weeks (13 × 28-day cycles). Randomisation was done by permuted blocks (block size 6) and was stratified by pathological stage and region in cohort 1 and by region in cohort 2. The investigators, patients, and sponsor were masked to treatment assignment. The primary endpoint was disease-free survival in the intention-to-treat population, evaluated separately in each cohort. Hierarchical analysis of cohort 2 before cohort 1 was prespecified. This trial is registered with ClinicalTrials.gov, number NCT01667419. FINDINGS: The study enrolled 184 patients in cohort 2 (93 were assigned to vemurafenib and 91 to placebo) and 314 patients in cohort 1 (157 were assigned to vemurafenib and 157 to placebo). At the time of data cutoff (April 17, 2017), median study follow-up was 33·5 months (IQR 25·9-41·6) in cohort 2 and 30·8 months (25·5-40·7) in cohort 1. In cohort 2 (patients with stage IIIC disease), median disease-free survival was 23·1 months (95% CI 18·6-26·5) in the vemurafenib group versus 15·4 months (11·1-35·9) in the placebo group (hazard ratio [HR] 0·80, 95% CI 0·54-1·18; log-rank p=0·26). In cohort 1 (patients with stage IIC-IIIA-IIIB disease) median disease-free survival was not reached (95% CI not estimable) in the vemurafenib group versus 36·9 months (21·4-not estimable) in the placebo group (HR 0·54 [95% CI 0·37-0·78]; log-rank p=0·0010); however, the result was not significant because of the prespecified hierarchical prerequisite for the primary disease-free survival analysis of cohort 2 to show a significant disease-free survival benefit. Grade 3-4 adverse events occurred in 141 (57%) of 247 patients in the vemurafenib group and 37 (15%) of 247 patients in the placebo group. The most common grade 3-4 adverse events in the vemurafenib group were keratoacanthoma (24 [10%] of 247 patients), arthralgia (17 [7%]), squamous cell carcinoma (17 [7%]), rash (14 [6%]), and elevated alanine aminotransferase (14 [6%]), although all keratoacanthoma events and most squamous cell carcinoma events were by default graded as grade 3. In the placebo group, grade 3-4 adverse events did not exceed 2% for any of the reported terms. Serious adverse events were reported in 40 (16%) of 247 patients in the vemurafenib group and 25 (10%) of 247 patients in the placebo group. The most common serious adverse event was basal cell carcinoma, which was reported in eight (3%) patients in each group. One patient in the vemurafenib group of cohort 2 died 2 months after admission to hospital for grade 3 hypertension; however, this death was not considered to be related to the study drug. INTERPRETATION: The primary endpoint of disease-free survival was not met in cohort 2, and therefore the analysis of cohort 1 showing a numerical benefit in disease-free survival with vemurafenib versus placebo in patients with resected stage IIC-IIIA-IIIB BRAFV600 mutation-positive melanoma must be considered exploratory only. 1 year of adjuvant vemurafenib was well tolerated, but might not be an optimal treatment regimen in this patient population. FUNDING: F Hoffman-La Roche Ltd.

Outcomes following iodine-125 brachytherapy in patients with Gleason 7, intermediate risk prostate cancer: a population-based cohort study.

BACKGROUND AND PURPOSE: To evaluate outcome in patients with Gleason 7 prostate cancer treated with iodine-125 brachytherapy at the British Columbia Cancer Agency. MATERIALS AND METHODS: Between 20th July 1998 and 7th February 2006, 1500 patients underwent I-125 prostate brachytherapy without supplemental external beam radiation therapy. Of these, 439 had Gleason 7 disease; 362 had Gleason 3+4 and 77 had 4+3 disease. Generally, patients received 6 months of androgen suppression. We compared biochemical no evidence of disease (bNED) between patients with Gleason ≤ 6 and Gleason 7 and between Gleason 3+4 and 4+3 using the Phoenix definition of biochemical recurrence. RESULTS: Median follow-up was 60 months. Estimated 5 year bNED was 97% for patients with Gleason score ≤ 6 and 94% for patients with Gleason 7 disease (p=0.037). Estimated bNED was 95% and 94% for 3+4 and 4+3, respectively (p=0.791). There was no difference in bNED between implants achieving D90 ≥ versus

Factors predictive of symptomatic radiation injury after linear accelerator-based stereotactic radiosurgery for intracerebral arteriovenous malformations.

PURPOSE: To investigate predictive factors in the development of symptomatic radiation injury after treatment with linear accelerator-based stereotactic radiosurgery for intracerebral arteriovenous malformations and relate the findings to the conclusions drawn by Quantitative Analysis of Normal Tissue Effects in the Clinic (QUANTEC). METHODS AND MATERIALS: Archived plans for 73 patients who were treated at the British Columbia Cancer Agency were studied. Actuarial estimates of freedom from radiation injury were calculated using the Kaplan-Meier method. Univariate and multivariate Cox proportional hazards models were used for analysis of incidence of radiation injury. Log-rank test was used to search for dosimetric parameters associated with freedom from radiation injury. RESULTS: Symptomatic radiation injury was exhibited by 14 of 73 patients (19.2%). Actuarial rate of symptomatic radiation injury was 23.0% at 4 years. Most patients (78.5%) had mild to moderate deficits according to Common Terminology Criteria for Adverse Events, version 4.0. On univariate analysis, lesion volume and diameter, dose to isocenter, and a V(x) for doses ≥8 Gy showed statistical significance. Only lesion diameter showed statistical significance (p < 0.05) in a multivariate model. According to the log-rank test, AVM volumes >5 cm(3) and diameters >30 mm were significantly associated with the risk of radiation injury (p < 0.01). The V(12) also showed strong association with the incidence of radiation injury. Actuarial incidence of radiation injury was 16.8% if V(12) was <28 cm(3) and 53.2% if >28 cm(3) (log-rank test, p = 0.001). CONCLUSIONS: This study confirms that the risk of developing symptomatic radiation injury after radiosurgery is related to lesion diameter and volume and irradiated volume. Results suggest a higher tolerance than proposed by QUANTEC. The widely differing findings reported in the literature, however, raise considerable uncertainties.

Biochemical control with radiotherapy improves overall survival in intermediate and high-risk prostate cancer patients who have an estimated 10-year overall survival of >90%.

PURPOSE: To identify subgroups of patients with carcinoma of the prostate treated with radical radiotherapy that have improved overall survival when disease is biochemically controlled. METHODS AND MATERIALS: A cohort of 1,060 prostate cancer patients treated with radical radiotherapy was divided into nine subgroups based on National Comprehensive Cancer Network risk category and estimated 10-year overall survival (eOS 10y) derived from the age adjusted Charlson Comorbidity Index. Patients with and without biochemical control were compared with respect to overall survival. Actuarial estimates of overall survival were calculated using the Kaplan-Meier method. Univariate and multivariate Cox proportional hazards models were used for analysis of overall survival. RESULTS: Median follow-up was 125 months (range, 51-176 months). Only the subgroups with high or intermediate risk disease and an eOS 10y of >90% had a statistically significantly improved overall survival when prostate cancer was biochemically controlled. In all other groups, biochemical control made no significant difference to overall survival. In the subgroup with high-risk disease and eOS 10y >90%, actuarial overall survival was 86.3% (95% confidence interval [CI] 78.5%-94.1%) and 62.1% (95% CI 52.9%-71.3%) for patients with biochemical control and biochemical relapse respectively (p = 0.002). In the intermediate risk group with eOS >90%, actuarial overall survival was 95.3% (95% CI 89.0%-100%) and 79.8% (95% CI 68.0%-91.6%) for biochemically controlled and biochemically relapsed patients (p = 0.033). On multivariate analysis, National Comprehensive Cancer Network risk group (p = 0.005), biochemical control (p = 0.033) and eOS 10y (p < 0.001) were statistically significant. CONCLUSION: Biochemical control translates into improved overall survival in patients with high or intermediate risk disease and an estimated 10-year overall survival of >90%.

The impact of hypofractionated whole breast radiotherapy on local relapse in patients with Grade 3 early breast cancer: a population-based cohort study.

PURPOSE: To determine whether patients with Grade 3 early breast cancer have an inferior rate of local disease control at 10 years with hypofractionated radiotherapy compared with more conventionally fractionated schedules. METHODS AND MATERIALS: Local relapse rates were compared between patients receiving hypofractionated radiotherapy or conventionally fractionated radiotherapy to the whole breast in a population-based cohort of women with early-stage (T1-T2, N0, M0) Grade 3 breast cancers diagnosed between 1990 and 2000 and referred to the British Columbia Cancer Agency. Cumulative rates of local relapse were estimated using a competing risk method, and factors significant on univariate analysis were included with fractionation group in a multivariate model. The primary end point was local control at 10 years. RESULTS: A total of 1,335 patients with Grade 3 tumors were treated with adjuvant radiotherapy, 252 with conventional fractionation, and 1,083 with a hypofractionated schedule. The 10-year cumulative incidence of local relapse was 6.9% in the hypofractionated group and 6.2% in the conventionally fractionated group (p = 0.99). CONCLUSIONS: There is no evidence that hypofractionation is inferior to conventional fractionation for breast conserving therapy in patients with Grade 3 breast cancer in this large population-based series after 10 years of follow-up.

Nucleocytoplasmic shuttling of Ssd1 defines the destiny of its bound mRNAs.

Mechanisms that control mRNA metabolism are critical for cell function, development and stress response. The Saccharomyces cerevisiae mRNA-binding protein Ssd1 has been implicated in mRNA processing, ageing, stress response and maintenance of cell integrity. Ssd1 is a substrate of the LATS/NDR tumour suppressor orthologue Cbk1 kinase. Previous data indicate that Ssd1 localizes to the cytoplasm; however, biochemical interactions suggest that Ssd1 at least transiently localizes to the nucleus. We therefore explored whether nuclear localization is important for Ssd1 cytoplasmic functions. We identified a functional NLS in the N-terminal domain of Ssd1. An Ssd1-derived NLS-GFP fusion protein and several C-terminally truncated Ssd1 proteins, which presumably lack nuclear export sequences, accumulate in the nucleus. Alanine substitution of the Ssd1 NLS prevents Ssd1 nuclear entry, mRNA binding and disrupts Srl1 mRNA localization. Moreover, Ssd1-NLS mutations abolish Ssd1 toxicity in the absence of Cbk1 phosphorylation and cause Ssd1 to localize prominently to cytoplasmic puncta. These data indicate that nuclear shuttling is critical for Ssd1 mRNA binding and Ssd1-mRNA localization in the cytoplasm. Collectively these data support the model that Ssd1 functions analogously to hnRNPs, which bind mRNA co-transcriptionally, are exported to the cytoplasm and target mRNAs to sites of localized translation and P-bodies.

The effect of loose versus stranded seeds on biochemical no evidence of disease in patients with carcinoma of the prostate treated with iodine-125 brachytherapy.

PURPOSE: The British Columbia Cancer Agency has been performing iodine-125 prostate brachytherapy since 1998, initially using loose seeds and phasing into the exclusive use of RAPIDStrand (RS) (Oncura Inc., Plymouth Meeting, PA) by November 2000. The aim of this study was to investigate rates of biochemical no evidence of disease (bNED) in patients treated with loose seeds compared with RS from this population-based cohort. METHODS AND MATERIALS: Between July 1998 and February 2006, 1500 implants were performed (327 loose and 1173 RS). Biochemical failure is reported using the Phoenix definition and prostate-specific antigen (PSA) >0.4ng/mL at ≥48 months postimplant. Actuarial estimates were calculated by the Kaplan-Meier method. Analysis was repeated with the first 100 loose and stranded implants excluded to assess the learning curve effect. Log-rank test was used to evaluate differences in bNED. Variables showing association with bNED were included in a multivariate model. RESULTS: There was no difference between loose and stranded seeds. Estimated rate of bNED was 93.5% (95% confidence interval [CI], 90.6-96.4) at 7 years for patients treated with loose seeds and 94.0% (95% CI, 91.8-96.2) for patients treated with RS according to Phoenix definition (p=0.846). Using the PSA >0.4ng/mL definition, estimated rates were 91.3% (95% CI, 88.0-94.6) and 91.9% (95% CI, 89.7-94.1) for loose and stranded seeds, respectively (p=0.871). Exclusion of the first 100 loose and stranded implants also revealed no difference in bNED. CONCLUSION: This study of 1500 patients treated with iodine-125 brachytherapy demonstrates no difference in bNED between loose and stranded seeds, using either Phoenix or PSA >0.4ng/mL definitions of biochemical failure.

Aerobic and anaerobic NAD+ metabolism in Saccharomyces cerevisiae.

In Saccharomyces cerevisiae the nicotinic acid moiety of NAD+ can be synthesized from tryptophan using the kynurenine pathway or incorporated directly using nicotinate phosphoribosyl transferase (NPT1). We have identified the genes that encode the enzymes of the kynurenine pathway and for BNA5 (YLR231c) and BNA6 (YFR047c) confirmed that they encode kynureninase and quinolinate phosphoribosyl transferase respectively. We show that deletion of genes encoding kynurenine pathway enzymes are co-lethal with the Deltanpt1, demonstrating that no other pathway for the synthesis of nicotinic acid exists in S. cerevisiae. Also, we show that under anaerobic conditions S. cerevisiae is a nicotinic acid auxotroph.