CCC publication: Patient choice in the NHS: capturing "decision regret".

Citation: BMJ. 2019, 366, l5363
Author: Myint AS

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CCC publication: A phase II trial of cabazitaxel as second line chemotherapy in relapsed locally advanced and/or metastatic carcinoma of the penis

Citation: The Journal of International Medical Research. 2019, 47(10), 4664-72 Epub 2019 Sep 10
Author: Challapalli A, Pearson S, Mitra AV, Coe M, Thomson A, Elliott T, Kirkbride P, Pickering L, Kirk H, Foulstone E, Evans H, Bravo A, Bahl AK
Abstract: KEYWORDS: Advanced penile cancer; cabazitaxel; metastasis; objective response rate; overall survival; progression-free survival; second line chemotherapy

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CCC publication: Intensity-modulated fractionated radiotherapy versus stereotactic body radiotherapy for prostate cancer (PACE-B): acute toxicity findings from an international, randomised, open-label, phase 3, non-inferiority trial

Citation: The Lancet. Oncology. 2019, 20(11), 1531-43
Author: Brand DH1, Tree AC2, Ostler P3, van der Voet H4, Loblaw A5, Chu W5, Ford D6, Tolan S7, Jain S8, Martin A9, Staffurth J10, Camilleri P11, Kancherla K12, Frew J13, Chan A14, Dayes IS15, Henderson D6, Brown S16, Cruickshank C16, Burnett S16, Duffton A17, Griffin C16, Hinder V16, Morrison K2, Naismith O18, Hall E16, van As N19; PACE Trial Investigators
Abstract: BACKGROUND: Localised prostate cancer is commonly treated with external-beam radiotherapy. Moderate hypofractionation has been shown to be non-inferior to conventional fractionation. Ultra-hypofractionated stereotactic body radiotherapy would allow shorter treatment courses but could increase acute toxicity compared with conventionally fractionated or moderately hypofractionated radiotherapy. We report the acute toxicity findings from a randomised trial of standard-of-care conventionally fractionated or moderately hypofractionated radiotherapy versus five-fraction stereotactic body radiotherapy for low-risk to intermediate-risk localised prostate cancer.
METHODS: PACE is an international, phase 3, open-label, randomised, non-inferiority trial. In PACE-B, eligible men aged 18 years and older, with WHO performance status 0-2, low-risk or intermediate-risk prostate adenocarcinoma (Gleason 4 + 3 excluded), and scheduled to receive radiotherapy were recruited from 37 centres in three countries (UK, Ireland, and Canada). Participants were randomly allocated (1:1) by computerised central randomisation with permuted blocks (size four and six), stratified by centre and risk group, to conventionally fractionated or moderately hypofractionated radiotherapy (78 Gy in 39 fractions over 7·8 weeks or 62 Gy in 20 fractions over 4 weeks, respectively) or stereotactic body radiotherapy (36·25 Gy in five fractions over 1-2 weeks). Neither participants nor investigators were masked to allocation. Androgen deprivation was not permitted. The primary endpoint of PACE-B is freedom from biochemical or clinical failure. The coprimary outcomes for this acute toxicity substudy were worst grade 2 or more severe Radiation Therapy Oncology Group (RTOG) gastrointestinal or genitourinary toxic effects score up to 12 weeks after radiotherapy. Analysis was per protocol. This study is registered with ClinicalTrials.gov, NCT01584258. PACE-B recruitment is complete and follow-up is ongoing.
FINDINGS: Between Aug 7, 2012, and Jan 4, 2018, we randomly assigned 874 men to conventionally fractionated or moderately hypofractionated radiotherapy (n=441) or stereotactic body radiotherapy (n=433). 432 (98%) of 441 patients allocated to conventionally fractionated or moderately hypofractionated radiotherapy and 415 (96%) of 433 patients allocated to stereotactic body radiotherapy received at least one fraction of allocated treatment. Worst acute RTOG gastrointestinal toxic effect proportions were as follows: grade 2 or more severe toxic events in 53 (12%) of 432 patients in the conventionally fractionated or moderately hypofractionated radiotherapy group versus 43 (10%) of 415 patients in the stereotactic body radiotherapy group (difference -1·9 percentage points, 95% CI -6·2 to 2·4; p=0·38). Worst acute RTOG genitourinary toxicity proportions were as follows: grade 2 or worse toxicity in 118 (27%) of 432 patients in the conventionally fractionated or moderately hypofractionated radiotherapy group versus 96 (23%) of 415 patients in the stereotactic body radiotherapy group (difference -4·2 percentage points, 95% CI -10·0 to 1·7; p=0·16). No treatment-related deaths occurred.
INTERPRETATION: Previous evidence (from the HYPO-RT-PC trial) suggested higher patient-reported toxicity with ultrahypofractionation. By contrast, our results suggest that substantially shortening treatment courses with stereotactic body radiotherapy does not increase either gastrointestinal or genitourinary acute toxicity.
FUNDING: Accuray and National Institute of Health Research.
Copyright © 2019 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.

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CCC publication: Putting patients first: an inventive service delivering cancer treatment at home

Citation: Journal of Comparative Effectiveness Research. 2019, 8(12), 951-60
Author: Yip, Frances; Zavery, Burhan; Poulter-Clark, Helen; Spencer, Joan
Abstract: Aim: This study evaluated the patient experience of receiving subcutaneous chemotherapy at home via a unique 'Cancer Treatment at Home' outreach service adapted by the UK Clatterbridge Cancer Centre NHS Foundation Trust. Patients & methods: The service involved using highly trained nurses to deliver cancer treatments to patients in their own homes. Patient outcomes were monitored over 12 months via the Systemic Anti-Cancer Therapy at Home (SACT) survey using handheld electronic devices. Results: Of the 56 participating cancer patients, 53 provided responses. Patients received subcutaneous trastuzumab, denosumab, pembrolizumab, fulvestrant and goserelin. Overall, 96% of respondents were 'very satisfied' and 4% 'satisfied' with the service. All respondents would recommend the service to others. Conclusion: The 'Cancer Treatment at Home' service has improved the patient experience for cancer care and has been recognized nationally for its achievements.
KEYWORDS: denosumab; home care service; oncology; questionnaire; survey; trastuzumab

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WUTH publication: Application of artificial intelligence (AI) in Radiotherapy workflow: Paradigm shift in Precision Radiotherapy using Machine Learning

Citation: The British Journal of Radiology. 2019,  92 (1103), 20190716 Epub ahead of print]
Author: Boon IS, Au Yong TPT, Boon CS

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WUTH publication: Insidious onset of headache, diplopia and Horner's syndrome: a rare case of petrous bone osteomyelitis

Citation: BMJ Case reports. 2019, 12(9), e231062
Author: Biart S, Panicker J
Abstract: We present an unusual case of skull base osteomyelitis in an 88-year-old woman. She presented with gradual onset unilateral headache and diplopia. On examination, there was evidence of a left-sided Horner's and ipsilateral sixth nerve palsy. In addition to persistent raised inflammatory markers, an MRI neck identified signal change in the petrous bone confirming a diagnosis of skull base osteomyelitis. Skull base osteomyelitis should be considered in presentations of subacute raised inflammatory markers in the context of ipsilateral cranial nerve signs.
© BMJ Publishing Group Limited 2019. No commercial re-use. See rights and permissions. Published by BMJ.
KEYWORDS: cranial nerves; headache (including migraines); infection (neurology)

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WUTH publication: Development and Maintenance of a Pleural Disease Service: Role of the "Pleurologist"

Citation: Seminars in respiratory and critical care medicine. 2019, 40(3), 297-304
Author: Cameron K, Teodoro D, Kasis A, Evison M
Abstract: Changes in the health care environment, increasing specialization, and the use of ultrasound have led to pleural diseases being managed by a select few. This article aims to look at the impact of current medical education paradigms, service structure, procedural education and role of the "pleurologist" in providing care to patients with pleural disease.
Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

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CCC publication: (P097) Cutaneous toxicity from immune checkpoint inhibitors: Experience from a specialist dermatology unit

Citation: British Journal of Dermatology. 2019, 181, 136
Author: Yip V.; Olsson-Brown A.; Pirmohamed M.; Hindle E.
Abstract: Immune checkpoint inhibitors (ICIs) are immunomodulatory agents used in the treatment of an increasing number of malignancies. They inhibit tumour-induced immunosuppression and reactivate tumour-specific cytotoxic T lymphocytes resulting in control of malignant disease (Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer 2012; 12: 25264). However, off-target tissue effects can lead to immune-related adverse effects (irAEs), most commonly in the skin (Sibaud V. Dermatologic reactions to immune checkpoint inhibitors: skin toxicities and immunotherapy. Am J Clin Dermatol 2018; 19: 34561). From May 2014 to July 2018, all cases of immunotherapy-induced cutaneous irAEs referred to a specialist dermatology unit were reviewed. Demographics, clinical features, investigations and outcomes for patients were recorded. Sixteen patients were referred with ICI-induced cutaneous toxicity. Nine (56%) were female and seven (44%) male. Their mean age was 67.8 years (range 4881). The mean time to reaction was 3.6 months after starting ICI treatment (range 18). Melanoma (n = 11) was the most common indication for ICI therapy, followed by nonsmall-cell lung cancer (n = 5). Eleven patients experienced irAEs secondary to pembrolizumab, three to combination ipilimumab/nivolumab therapy and one to ipilimumab and nivolumab, respectively. The most common cutaneous irAEs were eczema (n = 9) and lichenoid reactions (n = 3). Individual cases of psoriasis, inflammatory rash, petechiae and telogen effluvium were reported. No cases of severe cutaneous adverse reactions (e.g. tevensJohnson syndrome) were reported. Treatment with oral (n = 9) or topical (n = 4) corticosteroids was most often prescribed. Intravenous corticosteroids, combination topical corticosteroidantiinfective, acitretin and methotrexate were prescribed to individual patients. Eight patients required a protracted course of treatment. Cutaneous toxicities resulted in discontinuation of ICI therapy in one patient
and delayed treatment in two cases, and led to modification of combination therapy in one case. Cutaneous irAEs most commonly manifested as an itchy erythematous rash clinically consistent with eczema. Corticosteroids were required in the majority of cases. In some cases, cutaneous irAEs resulted in delay or discontinuation of ICI therapy. As ICI usage expands, cutaneous adverse events will become an increasing issue, requiring further research to elucidate pathogenic mechanisms in order to improve clinical management.

CCC publication: Patient Reported Acute Toxicity in PACE-B, an International Phase III Randomised Controlled Trial Comparing Stereotactic Body Radiotherapy to Conventionally Fractionated or Moderately Hypofractionated Radiotherapy (CFMHRT) for Localised Prostate Cancer

Citation: International Journal of Radiation Oncology Biology Physics. 2019, 105(1)
Author: Brand D.H.; Tree A.; Morrison K.; Naismith O.; van As N.; Ostler P.; van der Voet H.; Loblaw D.A.; Chu W.; Ford D.;Tolan S.; Jain S.; Martin A.; Staffurth J.; Brown S.; Burnett S.; Griffin C.; Hinder V.; Hall E.; Duffton A.
Abstract: Purpose/Objective(s): External beam radiotherapy (EBRT) is one of several curative treatment options for localised prostate cancer (LPCa). Moderate hypofractionation of EBRT (2.5-3Gy per fraction (f)) has been shown non-inferior to conventional 2 Gy/f by multiple large randomised controlled trials (RCTs). Low and comparable rates of clinician reported acute toxicity have been reported in the Stereotactic Body Radiotherapy (SBRT) and CFMHRT treated groups in PACE-B. This study reports patient reported outcomes (PRO) for
bladder and bowel, related to acute toxicity. Materials/Methods: PACE (NCT01584258) is a phase III, openlabel, multiple-cohort RCT. Patients eligible for the PACE-B cohort had LPCa, stage T1-T2, <= Gleason 3 + 4, PSA <= 20 ng/mL and were either unsuitable for surgery or chose EBRT. Randomisation was 1:1 between SBRT (36.25Gy/5f over 1-2 weeks (wks)) or CFMHRT (78Gy/39f over 7.5 wks or 62Gy/20f over 4 wks, determined by centre's standard schedule). Androgen deprivation therapy was not allowed. PRO metrics included: Expanded Prostate Cancer Index Composite 26 (EPIC-26) at baseline, 2, 4, 12 wks post radiotherapy (RT); International Prostate Symptom Score (IPSS) at baseline, 2, 4, 8, 12 wks post-RT. The proportion of patients with EPIC-26 change scores (baseline to 12 wks) greater than minimum clinically important differences (MCID) in each subdomain (urinary incontinence (UI) 8 points, urinary obstructive (UO) 6 points, bowel 5 points) are reported. IPSS total scores were categorised as none, mild, moderate, severe and compared between SBRT and CFMHRT at 12 weeks. Comparisons between SBRT and CFMHRT were based on chi-squared tests with p < 0.01 considered statistically significant.
Result(s): Between 07/12/2012 and 04/01/18, 38 centres randomised 874 pts: 431 received CFMHRT; 414 SBRT. Patient and disease characteristics were similar between CFMHRT and SBRT: mean age: 69.5 vs 69.3 years; Intermediate risk: 91.4% vs 92.5%; T-stage >=T2b: 51.7% vs 56.6%; Gleason Score 3+4: 80.7% vs 85.5%; PSA 10-20 ng/mL: 30.9% vs 31.6%. EPIC MCID deteriorations, for CFMHRT vs SBRT, occurring by subdomain were: UI 67/326 (20.6%) vs 51/323 (15.8%), p=0.12; UO 108/313 (34.5%) vs 105/306 (34.3%), p=0.96; bowel
91/322 (28.2%) vs 90/323 (27.9%), p=0.91. Proportion of patients with baseline none/mild/moderate/severe IPSS symptoms were CFMHRT: 5.4%/51.1%/37.3%/6.2% and SBRT: 4.5%/54.5%/35.6%/5.4%. At 12 weeks no differences were seen in IPSS scores between CFMHRT and SBRT: 2.8%/57.9%/36.8%/2.5% vs 3.4%/54.8%/36.7%/5.1% (p=0.34, test for trend).
Conclusion(s): These data corroborate the prior clinician-reported acute toxicity findings for bladder and bowel outcomes, with no significant differences in key PRO measures.
Copyright © 2019

CCC publication: Pharmacodynamic and Clinical Results from a Phase I/II Study of the HSP90 Inhibitor Onalespib in Combination with Abiraterone Acetate in Prostate Cancer

Citation: Clinical Cancer Research. 2019, 25(15), 4624-633
Author: Slovin, Susan; Hussain, Syed; Saad, Fred; Garcia, Jorge; Picus, Joel; Ferraldeschi, Roberta; Crespo, Mateus; Flohr,
Abstract: PURPOSE: Onalespib is a potent, fragment-derived second-generation HSP90 inhibitor with preclinical activity in castration-resistant prostate cancer (CPRC) models. This phase I/II trial evaluated onalespib in combination with abiraterone acetate (AA) and either prednisone or prednisolone (P) in men with CRPC progressing on AA/P.
PATIENTS AND METHODS: Patients with progressing CRPC were randomly assigned to receive 1 of 2 regimens of onalespib combined with AA/P. Onalespib was administered as intravenous infusion starting at 220 mg/m2 once weekly for 3 of 4 weeks (regimen 1); or at 120 mg/m2 on day 1 and day 2 weekly for 3 of 4 weeks (regimen 2). Primary endpoints were response rate and safety. Secondary endpoints included evaluation of androgen receptor (AR) depletion in circulating tumor cells (CTC) and in fresh tumor tissue biopsies.
RESULTS: Forty-eight patients were treated with onalespib in combination with AA/P. The most common ≥grade 3 toxicities related to onalespib included diarrhea (21%) and fatigue (13%). Diarrhea was dose limiting at 260 and 160 mg/m2 for regimens 1 and 2, respectively. Transient decreases in CTC counts and AR expression in CTC were observed in both regimens. HSP72 was significantly upregulated following onalespib treatment, but only a modest decrease in AR and GR was shown in paired pre- and posttreatment tumor biopsy samples. No patients showed an objective or PSA response.
CONCLUSIONS: Onalespib in combination with AA/P showed mild evidence of some biological effect; however, this effect did not translate into clinical activity, hence further exploration of this combination was not justified.
©2019 American Association for Cancer Research.

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