Comparison between site and central radiological assessments for patients with recurrent glioblastoma on a clinical trial.

AIM: Assessment of magnetic resonance imaging (MRI) in glioblastoma can be challenging. For patients with recurrent glioblastoma managed on the CABARET trial, we compared disease status assessed at hospitals and subsequent blinded central expert radiological review. METHODS: MRI results and clinical status at specified time points were used for site and central assessment of disease status. Clinical status was determined by the site. Response Assessment in Neuro-Oncology (RANO) criteria were used for both assessments. Site and central assessments of progression-free survival (PFS) and response rates were compared. Inter-rater variability for central review progression dates was assessed. RESULTS: Central review resulted in shorter PFS in 45% of 89 evaluable patients (n = 40). Median PFS was 3.6 (central) versus 3.9 months (site) (hazard ratio 1.5, 95% confidence interval 1.3-1.8, P < 0.001). Responses were documented more frequently by sites (n = 16, 18%) than centrally (n = 11, 12%). Seven of 120 patients continued on trial without site-determined progression for more than 6 months beyond the central review determination of progression. Of scans reviewed by all three central reviewers, 33% were fully concordant for progression date. CONCLUSION: While the difference between site and central PFS dates was statistically significant, the 0.3-month median difference is small. The variability within central review is consistent with previous studies, highlighting the challenges in MRI interpretation in this context. A small proportion of patients benefited from treatment well beyond the centrally determined progression date, reinforcing that clinical status together with radiology results are important determinants of whether a therapy is effective for an individual.

The role of early magnetic resonance imaging in predicting survival on bevacizumab for recurrent glioblastoma: Results from a prospective clinical trial (CABARET).

BACKGROUND: Bevacizumab has been associated with prolonged progression-free survival for patients with recurrent glioblastoma; however, not all derive a benefit. An early indicator of efficacy or futility may allow early discontinuation for nonresponders. This study prospectively assessed the role of early magnetic resonance imaging (eMRI) and its correlation with subsequent routine magnetic resonance imaging (MRI) results and survival. METHODS: Patients were part of a randomized phase 2 clinical trial (CABARET) comparing bevacizumab with bevacizumab plus carboplatin for recurrent glioblastoma. eMRI was conducted after 4 weeks in the trial (after 2 treatments with bevacizumab [10 mg/kg every 2 weeks]). The results were compared with the results of the subsequent 8-week MRI standard. RESULTS: For 119 of 122 patients, eMRI was available, and 111 had subsequent MRI for comparison. Thirty-six (30%) had an early radiological response, and 17 (14%) had progressive disease. The concordance between eMRI and 8-week MRI was moderate (κ = 0.56), with most providing the same result (n = 79 [71%]). There was strong evidence that progression-free survival and overall survival were predicted by the eMRI response (both P values < .001). The median survival was 8.6 months for an eMRI response, 6.6 months for stable disease, and 3.7 months for progressive disease; the hazard ratio (progressive disease vs stable disease) was 3.4 (95% confidence interval, 1.9-6.0). Landmark analyses showed that eMRI progression was a strong predictor of mortality independent of other potential baseline predictors. CONCLUSIONS: In this study, early progression on MRI appears to be a robust marker of a poor prognosis for patients on bevacizumab. Cancer 2017;123:3576-82. © 2017 American Cancer Society.

Health-related quality of life outcomes from CABARET: a randomized phase 2 trial of carboplatin and bevacizumab in recurrent glioblastoma.

In recurrent glioblastoma, health-related quality of life (HRQL) is a crucial trial endpoint. We examined HRQL outcomes as a secondary endpoint for patients in the CABARET randomized phase 2 trial. 122 patients were randomly allocated to bevacizumab monotherapy or bevacizumab plus carboplatin. We calculated change scores from baseline for each HRQL measure on the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) and the Brain Cancer Module (QLQ-BN20), together with time to deterioration in HRQL, and the proportion of participants with clinically meaningful improvements in specific disease-related symptoms. At baseline, 117 of 122 randomized patients (96%) attempted questionnaires. Questionnaire participation rates were >90% for patients continuing on treatment, however at the end-of-treatment visit only 72 (64% of eligible participants) returned a form. There were no differences between arms in change scores over the treatment period. Time to ≥10 point deterioration in scores from baseline was also similar between arms. HRQL deterioration occurred largely before progression for the domains tested, but scores in HRQL domains specifically relevant to symptoms of recurrent glioblastoma also improved for about 50% of patients with symptoms at baseline. Neither detrimental nor beneficial effects on HRQL were seen with carboplatin added to bevacizumab, with a proportion of patients on both arms experiencing symptomatic benefit. Given the reduced questionnaire completion at end of treatment, time to HRQL deterioration is a feasible and robust clinical trial endpoint in this patient population. Clinical trials registration number: ACTRN12610000915055.

Continuing or ceasing bevacizumab beyond progression in recurrent glioblastoma: an exploratory randomized phase II trial.

BACKGROUND: In patients with recurrent glioblastoma, the benefit of bevacizumab beyond progression remains uncertain. We prospectively evaluated continuing or ceasing bevacizumab in patients who progressed while on bevacizumab. METHODS: CABARET, a phase II study, initially randomized patients to bevacizumab with or without carboplatin (Part 1). At progression, eligible patients underwent a second randomization to continue or cease bevacizumab (Part 2). They could also receive additional chemotherapy regimens (carboplatin, temozolomide, or etoposide) or supportive care. RESULTS: Of 120 patients treated in Part 1, 48 (80% of the anticipated 60-patient sample size) continued to Part 2. Despite randomization, there were some imbalances in patient characteristics. The best response was stable disease in 7 (30%) patients who continued bevacizumab and 2 (8%) patients who stopped receiving bevacizumab. There were no radiological responses. Median progression-free survival was 1.8 vs 2.0 months (bevacizumab vs no bevacizumab; hazard ratio [HR], 1.08; 95% CI, .59-1.96; P = .81). Median overall survival was 3.4 vs 3.0 months (HR, .84; 95% CI, .47-1.50; P = .56 and HR .70; 95% CI .38-1.29; P = .25 after adjustment for baseline factors). Quality-of-life scores did not significantly differ between arms. While the maximum daily steroid dose was lower in the continuation arm, the difference was not statistically significant. CONCLUSIONS: Patients who continued bevacizumab beyond disease progression did not have clear survival improvements, although the study was not powered to detect other than very large differences. While these data provide the only randomized evidence related to continuing bevacizumab beyond progression in recurrent glioblastoma, the small sample size precludes definitive conclusions and suggests this remains an open question.

Validating self-report and proxy reports of the Dexamethasone Symptom Questionnaire -Chronic for the evaluation of longer-term corticosteroid toxicity.

PURPOSE: In brain tumours, brain metastases or advanced cancer; treatment with corticosteroids, side effects can add to symptoms. These are best assessed by patients, complementing clinical assessment. We assessed the feasibility and validity of the Dexamethasone Symptom Questionnaire-Chronic (DSQ-Chronic), patient and caregiver versions. METHODS: A longitudinal cohort study was conducted, collecting clinician-rated toxicity, performance status, dexamethasone dose and DSQ-Chronic (patient and caregiver versions) at baseline, then 2, 4 and 8 weeks later. Patients had a primary malignant brain tumour, brain metastases, or advanced cancer; Karnofsky Performance Status ≥40 and predicted survival ≥8 weeks. Analysis included questionnaire completion rates, frequency and severity of dexamethasone-attributable side effects, agreement between patient and caregiver ratings, comparison with clinician-rated toxicity and correlation with performance status. RESULTS: Sixty-six patients were recruited (mean age 60 years), with their caregivers. Completion of questionnaires was over 90% for the dyad at baseline but dropped over time, with caregiver completion rates higher at all timepoints. Agreement between patients and proxies was fair to moderate, and while proxies systematically overestimated symptom severity on DSQ-chronic total scores, the bias was less than 10 points. Patient and clinician agreement was higher for more objective symptoms. CONCLUSION: The DSQ-Chronic is feasible when the patient is relatively well. As capacity to complete the DSQ-Chronic diminishes, caregivers can be proxy-raters. Clinicians capture corticosteroid toxicities, which may not be obvious to the patient. The DSQ-Chronic, patient and caregiver versions, are useful tools to be used with clinician assessment.

Randomized phase 2 study of carboplatin and bevacizumab in recurrent glioblastoma.

BACKGROUND: The optimal use of bevacizumab in recurrent glioblastoma (GBM), including the choice of monotherapy or combination therapy, remains uncertain. The purpose of this study was to compare combination therapy with bevacizumab monotherapy. METHODS: This was a 2-part randomized phase 2 study. Eligibility criteria included recurrent GBM after radiotherapy and temozolomide, no other chemotherapy for GBM, and Eastern Cooperative Oncology Group performance status 0-2. The primary objective (Part 1) was to determine the effect of bevacizumab plus carboplatin versus bevacizumab monotherapy on progression-free survival (PFS) using modified Response Assessment in Neuro-Oncology criteria. Bevacizumab was given every 2 weeks, 10 mg/kg; and carboplatin every 4 weeks, (AUC 5). On progression, patients able to continue were randomized to continue or cease bevacizumab (Part 2). Secondary endpoints included objective radiological response rate (ORR), quality of life, toxicity, and overall survival (OS). RESULTS: One hundred twenty-two patients (median age, 55y) were enrolled to Part 1 from 18 Australian sites. Median follow-up was 32 months, and median on-treatment time was 3.3 months. Median PFS was 3.5 months for each arm (hazard ratio [HR]: 0.92, 95% CI: 0.64-1.33, P = .66). ORR was 14% (combination) versus 6% (monotherapy) (P = .18). Median OS was 6.9 (combination) versus 7.5 months (monotherapy) (HR: 1.18, 95% CI: 0.82-1.69, P = .38). The incidence of bevacizumab-related adverse events was similar to prior literature, with no new toxicity signals. Toxicities were higher in the combination arm. Part 2 data (n = 48) will be reported separately. CONCLUSIONS: Adding carboplatin resulted in more toxicity without additional clinical benefit. Clinical outcomes in patients with recurrent GBM treated with bevacizumab were inferior to those in previously reported studies. CLINICAL TRIALS REGISTRATION NR: ACTRN12610000915055.

Culturally and linguistically diverse patient participation in glioma research.

Marginal communities, such as culturally and linguistically diverse (CALD) patients, have significantly lower rates of recruitment, accrual, and retention in cancer clinical trials. A combination of language and cultural barriers means that trial participation from CALD communities remains at suboptimal levels, which in turn favors research findings that are biased towards therapeutic effects or toxicities within the context of non-CALD populations. Here we outline some key challenges and implications for CALD patient participation in glioma research in countries such as Australia, where English is the language of governance and health services implementation. We highlight multistakeholder interventions to improve both investigator recruitment and participation of CALD communities in future glioma research, particularly in this era when global migration has come of age. Enhancing research participation of CALD communities ensures not only wider understanding of genetic heterogeneity to improve glioma outcomes but also equity in access to care.

Prevention of osteoporosis as a consequence of aromatase inhibitor therapy in postmenopausal women with early breast cancer: rationale and design of a randomized controlled trial.

BACKGROUND: Aromatase inhibitors (AIs) have improved the prognosis for breast cancer survivors and are now standard of care for postmenopausal women with hormone receptor positive early stage breast cancer. One side-effect, however, is a decrease in bone mineral density (BMD) and increased fracture risk. Since hormone replacement therapy (HRT) is contraindicated in these women, one prevention option is exercise combined with vitamin D and calcium. The effect of this intervention on drug-induced osteoporosis is unknown. METHODS: A single-blind randomized controlled trial will be undertaken to test the hypothesis that exercise combined with vitamin D and calcium can prevent the decrease in BMD associated with the use of AIs. Sixty postmenopausal women prescribed an AI for the treatment of breast cancer will be randomized into either an exercise or control group. Participants randomized to the exercise group will undertake a 12-month gym-based exercise program, 3 times per week involving resistance and impact training. Participants in the control group will be advised on the benefits of exercise for preventing osteoporosis, but not prescribed exercise. Both groups will receive vitamin D and calcium supplements. The primary outcome will be total hip bone mineral density measured via dual energy X-ray absorptiometry (DXA). Study outcomes will be compared between groups at baseline, 6months and 12months. SUMMARY: This study will investigate the effect of exercise in combination with vitamin D and calcium on prevention of drug-induced osteoporosis in postmenopausal women prescribed AIs for the treatment of breast cancer.

The placebo effect of ankle taping in ankle instability.

PURPOSE: Recurrence of ankle sprains is common among athletes. Although ankle taping reduces the risk of injury, the mechanism underlying its effectiveness remains unclear. Anecdotal reports suggest a role of the belief among athletes that taping will protect them from injury. That is, taping may have a placebo effect. The purpose of the present study was to determine whether there was a placebo effect with ankle taping in individuals with ankle instability. METHODS: Thirty participants with ankle instability completed a hopping test and a modified star excursion balance test under three conditions: (i) real tape, (ii) placebo tape, and (iii) control (no tape). Participants were blinded to the purpose of the study and were informed that the study aimed to compare two methods of ankle taping referred to as mechanical (real) and proprioceptive (placebo). The order of testing the three conditions and the two functional tests was randomized. RESULTS: There was no significant difference in performance among the three conditions for the hopping test (P = 0.865) or the modified star excursion balance test (P = 0.491). However, a secondary exploratory analysis revealed that participants' perceptions of stability, confidence, and reassurance increased with both real and placebo ankle taping when performing the functional tasks. CONCLUSION: The role of the placebo effect of ankle taping in individuals with ankle instability remains unclear. Clinicians should, therefore, continue to use ankle-taping techniques of known efficacy. They should, however, focus on maximizing patients' beliefs in the efficacy of ankle taping, because its application reassured participants and improved their perceived stability and confidence. The effect of ankle taping on participants' perceptions may contribute to its effectiveness in preventing injury.