Safety profile of cyclin-dependent kinase (CDK) 4/6 inhibitors with concurrent radiation therapy: A systematic review and meta-analysis.

The cyclin-dependent kinase 4 and 6 inhibitors (CDK4/6i) have become the standard of care for hormone receptor-positive (HR + ) and human epidermal growth factor receptor 2-negative (HER2-) metastatic breast cancer, improving survival outcomes compared to endocrine therapy alone. Abemaciclib and ribociclib, in combination with endocrine therapy, have demonstrated significant benefits in invasive disease-free survival for high-risk HR+/HER2- early breast cancer patients. Each CDK4/6i-palbociclib, ribociclib, and abemaciclib-exhibits distinct toxicity profiles. Radiation therapy (RT) can be delivered with a palliative or ablative intent, particularly using stereotactic body radiation therapy for oligometastatic or oligoprogressive disease. However, pivotal randomized trials lack information on concomitant CDK4/6i and RT, and existing preclinical and clinical data on the potential combined toxicities are limited and conflicting. As part of a broader effort to establish international consensus recommendations for integrating RT and targeted agents in breast cancer treatment, we conducted a systematic review and meta-analysis to evaluate the safety profile of combining CDK4/6i with palliative and ablative RT in both metastatic and early breast cancer settings.

Can patient decision aids reduce decisional conflict in a de-escalation of breast radiotherapy clinical trial? The PRIMETIME Study Within a Trial implemented using a cluster stepped-wedge trial design.

BACKGROUND: For patients with early breast cancer considered at very-low risk of local relapse, risks of radiotherapy may outweigh the benefits. Decisions regarding treatment omission can lead to patient uncertainty (decisional conflict), which may be lessened with patient decision aids (PDA). PRIMETIME (ISRCTN 41579286) is a UK-led biomarker-directed study evaluating omission of adjuvant radiotherapy in breast cancer; an embedded Study Within A Trial (SWAT) investigated whether PDA reduces decisional conflict using a cluster stepped-wedge trial design. METHODS: PDA diagrams and a video explaining risks and benefits of radiotherapy were developed in close collaboration between patient advocates and PRIMETIME trialists. The SWAT used a cluster stepped-wedge trial design, where each cluster represented the radiotherapy centre and referring peripheral centres. All clusters began in the standard information group (patient information and diagrams) and were randomised to cross-over to the enhanced information group (standard information plus video) at 2, 4 or 6 months. Primary endpoint was the decisional conflict scale (0-100, higher scores indicating greater conflict) which was assessed on an individual participant level. Multilevel mixed effects models used a random effect for cluster and a fixed effect for each step to adjust for calendar time and clustering. Robust standard errors were also adjusted for the clustering effect. RESULTS: Five hundred twenty-one evaluable questionnaires were returned from 809 eligible patients (64%) in 24 clusters between April 2018 and October 2019. Mean decisional conflict scores in the standard group (N = 184) were 10.88 (SD 11.82) and 8.99 (SD 11.82) in the enhanced group (N = 337), with no statistically significant difference [mean difference - 1.78, 95%CI - 3.82-0.25, p = 0.09]. Compliance with patient information and diagrams was high in both groups although in the enhanced group only 121/337 (36%) reported watching the video. CONCLUSION: The low levels of decisional conflict in PRIMETIME are reassuring and may reflect the high-quality information provision, such that not everyone required the video. This reinforces the importance of working with patients as partners in clinical trials especially in the development of patient-centred information and decision aids.

Hypoxia and angiogenic biomarkers in prostate cancer after external beam radiotherapy (EBRT) alone or combined with high-dose-rate brachytherapy boost (HDR-BTb).

PURPOSE: To investigate angiogenic and hypoxia biomarkers to predict outcome in patients receiving external beam radiotherapy (EBRT) alone or combined with high-dose-rate brachytherapy boost (HDR-BTb) for localised prostate cancer. METHODS: Prostate biopsy samples were collected prospectively in patients entered into a phase 3 randomised controlled trial of patients receiving EBRT or EBRT + HDR-BTb. Univariate and multivariate analyses using Cox proportional hazards model were performed to identify associations between immunohistochemical staining of hypoxia inducible factor 1 alpha (HIF1α), glucose transporter 1 (GLUT1), osteopontin (OPN) and microvessel density (MVD) using CD-34 antibody with clinical outcome. The primary endpoint was biochemical relapse free survival (BRFS) and secondary endpoint was distant metastasis free survival (DMFS). RESULTS: Immunohistochemistry was available for 204 patients. Increased OPN (Hazard ratio [HR] 2.38, 95% Confidence Interval [CI] 1.06-5.34, p < 0.036) and GLUT1 (HR 2.36, 95%CI 1.39-4.01, p < 0.001) expression were predictive of worse BRFS. Increased GLUT1 expression (HR 2.22, 1.02-4.84, p = 0.045) was predictive of worse DMFS. Increased MVD (CD-34) (HR 1.82, 95%CI 1.06-3.14, p = 0.03) and OPN (HR 1.82, 95%CI 1.06-3.14, p = 0.03) but reduced GLUT1 expression (HR 0.40, 95%CI 0.20-0.79, p = 0.009) were predictive of improved BRFS in patients receiving EBRT + HDR-BTb. CONCLUSION: Our data suggest angiogenic and hypoxia biomarkers may predict outcome and benefit of dose escalation, however further validation in prospective studies including hypoxia modification is needed. Trial registration number ISRCTN98241100, registered with ISRCTN at http://www.controlled-trials.com/isrctn/.

Can patient-reported outcomes be used instead of clinician-reported outcomes and photographs as primary endpoints of late normal tissue effects in breast radiotherapy trials? Results from the IMPORT LOW trial.

BACKGROUND: In an era of low local relapse rates after adjuvant breast radiotherapy, risks of late normal-tissue effects (NTE) need to be balanced against risk of relapse. NTE are assessed using patient-reported outcome measures (PROMs), clinician-reported outcomes (CRO) and photographs. This analysis investigates whether PROMs can be used as primary NTE endpoints in breast radiotherapy trials. METHODS: Analyses were conducted within IMPORT LOW (ISRCTN12852634) at 2 and 5 years. NTE were recorded by CRO, photographs and PROMs. Measures of agreement tested concordance, risk ratios for radiotherapy groups were compared, and influence of baseline characteristics on concordance investigated. RESULTS: In 1095 patients who consented to PROMS and photographs, PROMs were available at 2 and/or 5 years for 976 patients, of whom 909 had CRO and 844 had photographs. Few patients had moderate/marked NTE, irrespective of method used (eg. 19% patients and 9% clinicians reported breast shrinkage at year-5). Patients reported more NTE than assessed from CRO or photographs (p < 0.001 for most NTE). Concordance between assessments was poor on an individual patient level; eg. for year-5 breast shrinkage, % agreement = 48% and weighted kappa = 0.17. Risk ratios comparing radiotherapy schedules were consistent between PROMs and CRO or photographs. CONCLUSIONS: Few patients had moderate/marked NTE irrespective of method used. Patients reported more NTE than CRO and photographs, therefore NTE may be underestimated if PROMs are not used. Despite poor concordance between methods, effect sizes from PROMs were consistent with CRO and photographs, suggesting PROMs can be used as primary NTE endpoints in breast radiotherapy trials.

Is breast seroma after tumour resection associated with patient-reported breast appearance change following radiotherapy? Results from the IMPORT HIGH (CRUK/06/003) trial.

BACKGROUND: Seroma describes a collection of serous fluid within a cavity, occurring following surgery. Seroma is associated with normal tissue effects (NTE) following breast radiotherapy, as reported by clinicians and on photographs. This study investigates the association between seroma and the NTE breast appearance change collected using patient-reported outcome measures (PROMs) in IMPORT HIGH, as well as investigating the association between breast appearance change and patient/tumour/treatment factors. METHODS: Case-control methodology was used for seroma analysis within IMPORT HIGH. Cases were patients reporting moderate/marked breast appearance change and controls reported none/mild changes at year-3. One control was selected at random for each case. Seromas were graded as not visible/subtle or visible/highly visible on CT radiotherapy planning scans. Logistic regression tested associations, adjusting for patient/tumour/treatment factors. RESULTS: 1078/1149 patients consented to PROMs, of whom 836 (78%) reported whether they had 3-year breast appearance change; 231 cases and 231 controls were identified. 304/462 (66%) patients received chemotherapy. Seroma prevalence was 20% (41/202) in cases and 16% (32/205) in controls, and less frequent in patients receiving adjuvant chemotherapy [10% (24/246) compared with 29% (40/138) without]. Visible seroma was not significantly associated with breast appearance change [OR 1.38 (95%CI 0.83-2.29), p = 0.219]. Larger tumour size, haematoma, current smoking and body image concerns at baseline were independent risk factors. CONCLUSIONS: Seroma was not associated with patient-reported breast appearance change, but haematoma and smoking were significant risk factors. Lack of association may be related to lower prevalence of seroma compared with previous reports, perhaps reflecting patients receiving adjuvant chemotherapy in whom seroma resolves prior to radiotherapy.

Patient-Reported Outcomes Over 5 Years After Whole- or Partial-Breast Radiotherapy: Longitudinal Analysis of the IMPORT LOW (CRUK/06/003) Phase III Randomized Controlled Trial.

PURPOSE: IMPORT LOW demonstrated noninferiority of partial-breast and reduced-dose radiotherapy versus whole-breast radiotherapy for local relapse and similar or reduced toxicity at 5 years. Comprehensive patient-reported outcome measures collected at serial time points are now reported. PATIENTS AND METHODS: IMPORT LOW recruited women with low-risk breast cancer after breast-conserving surgery. Patients were randomly assigned to 40 Gy whole-breast radiotherapy (control), 36 Gy whole-breast and 40 Gy partial-breast radiotherapy (reduced-dose), or 40 Gy partial-breast radiotherapy only (partial-breast) in 15 fractions. European Organisation for Research and Treatment of Cancer Quality of Life Questionnaires Core 30 and Breast Cancer-Specific Module, Body Image Scale, protocol-specific items, and the Hospital Anxiety and Depression Scale were administered at baseline, 6 months, and 1, 2, and 5 years. Patterns of moderate/marked adverse effects (AEs) were assessed using longitudinal regression models, and baseline predictors were investigated. RESULTS: A total of 41 of 71 centers participated in the patient-reported outcome measures substudy; 1,265 (95%) of 1,333 patients consented, and 557 (58%) of 962 reported no moderate/marked AEs at 5 years. Breast appearance change was most prevalent and persisted over time (approximately 20% at each time point). Prevalence of breast hardness, pain, oversensitivity, edema, and skin changes reduced over time ( P < .001 for each), whereas breast shrinkage increased ( P < .001). Analysis by treatment group showed average number of AEs per person was lower in partial-breast (incidence rate ratio, 0.77; 95% CI, 0.71 to 0.84; P < .001) and reduced-dose (incidence rate ratio, 0.83; 95% CI, 0.76 to 0.90; P < .001) versus whole-breast group and decreased over time in all groups. Younger age, larger breast size/surgical deficit, lymph node positivity, and higher levels of anxiety/depression were baseline predictors of subsequent AE reporting. CONCLUSION: Most AEs reduced over time, with fewer AEs in the partial-breast and reduced-dose groups. Baseline predictors for AE reporting were identified. These findings will facilitate informed discussion and shared decision making for future patients receiving moderately hypofractionated breast radiotherapy.

Partial-breast radiotherapy after breast conservation surgery for patients with early breast cancer (UK IMPORT LOW trial): 5-year results from a multicentre, randomised, controlled, phase 3, non-inferiority trial.

BACKGROUND: Local cancer relapse risk after breast conservation surgery followed by radiotherapy has fallen sharply in many countries, and is influenced by patient age and clinicopathological factors. We hypothesise that partial-breast radiotherapy restricted to the vicinity of the original tumour in women at lower than average risk of local relapse will improve the balance of beneficial versus adverse effects compared with whole-breast radiotherapy. METHODS: IMPORT LOW is a multicentre, randomised, controlled, phase 3, non-inferiority trial done in 30 radiotherapy centres in the UK. Women aged 50 years or older who had undergone breast-conserving surgery for unifocal invasive ductal adenocarcinoma of grade 1-3, with a tumour size of 3 cm or less (pT1-2), none to three positive axillary nodes (pN0-1), and minimum microscopic margins of non-cancerous tissue of 2 mm or more, were recruited. Patients were randomly assigned (1:1:1) to receive 40 Gy whole-breast radiotherapy (control), 36 Gy whole-breast radiotherapy and 40 Gy to the partial breast (reduced-dose group), or 40 Gy to the partial breast only (partial-breast group) in 15 daily treatment fractions. Computer-generated random permuted blocks (mixed sizes of six and nine) were used to assign patients to groups, stratifying patients by radiotherapy treatment centre. Patients and clinicians were not masked to treatment allocation. Field-in-field intensity-modulated radiotherapy was delivered using standard tangential beams that were simply reduced in length for the partial-breast group. The primary endpoint was ipsilateral local relapse (80% power to exclude a 2·5% increase [non-inferiority margin] at 5 years for each experimental group; non-inferiority was shown if the upper limit of the two-sided 95% CI for the local relapse hazard ratio [HR] was less than 2·03), analysed by intention to treat. Safety analyses were done in all patients for whom data was available (ie, a modified intention-to-treat population). This study is registered in the ISRCTN registry, number ISRCTN12852634. FINDINGS: Between May 3, 2007, and Oct 5, 2010, 2018 women were recruited. Two women withdrew consent for use of their data in the analysis. 674 patients were analysed in the whole-breast radiotherapy (control) group, 673 in the reduced-dose group, and 669 in the partial-breast group. Median follow-up was 72·2 months (IQR 61·7-83·2), and 5-year estimates of local relapse cumulative incidence were 1·1% (95% CI 0·5-2·3) of patients in the control group, 0·2% (0·02-1·2) in the reduced-dose group, and 0·5% (0·2-1·4) in the partial-breast group. Estimated 5-year absolute differences in local relapse compared with the control group were -0·73% (-0·99 to 0·22) for the reduced-dose and -0·38% (-0·84 to 0·90) for the partial-breast groups. Non-inferiority can be claimed for both reduced-dose and partial-breast radiotherapy, and was confirmed by the test against the critical HR being more than 2·03 (p=0·003 for the reduced-dose group and p=0·016 for the partial-breast group, compared with the whole-breast radiotherapy group). Photographic, patient, and clinical assessments recorded similar adverse effects after reduced-dose or partial-breast radiotherapy, including two patient domains achieving statistically significantly lower adverse effects (change in breast appearance [p=0·007 for partial-breast] and breast harder or firmer [p=0·002 for reduced-dose and p<0·0001 for partial-breast]) compared with whole-breast radiotherapy. INTERPRETATION: We showed non-inferiority of partial-breast and reduced-dose radiotherapy compared with the standard whole-breast radiotherapy in terms of local relapse in a cohort of patients with early breast cancer, and equivalent or fewer late normal-tissue adverse effects were seen. This simple radiotherapy technique is implementable in radiotherapy centres worldwide. FUNDING: Cancer Research UK.

Protons and more: state of the art in radiotherapy.

The purpose of modern radiotherapy is to deliver a precise high dose of radiation which will result in reproductive death of the cells. Radiation should transverse within the tumour volume whilst minimising damage to surrounding normal tissue. Overall 40% of cancers which are cured will have received radiotherapy. Current state of the art treatment will incorporate cross-sectional imaging and multiple high energy X-ray beams in processes called intensity modulated radiotherapy and image guided radiotherapy. Brachytherapy enables very high radiation doses to be delivered by the direct passage of a radiation source through or within the tumour volume and similar results can be achieved using rotational stereotactic X-ray beam techniques. Protons have the characteristics of particle beams which deposit their energy in a finite fixed peak at depth in tissue with no dose beyond this point - the Bragg peak. This has advantages in certain sites such as the spine adjacent to the spinal cord and particularly in children when the overall volume of tissue receiving radiation can be minimised.

A case of γ-butyrolactone associated with severe withdrawal delirium and acute renal failure.

γ-Butyrolactone (GBL) is a popular drug of abuse which is easily available over the internet. Following a UK classification change to a class C drug in January 2010, internet supply has become difficult. Some of the effects have resulted in sourcing GBL from industrial solvents. We report a case of a 24-year-old man who was admitted for detoxification from GBL. He reported having sourced the GBL by diluting the contents of nail varnish remover pads with water. During his admission he developed a severe withdrawal delirium and acute renal failure. He required admission to the intensive care unit. Physicians and psychiatrists should be aware of toxic sources of GBL leading to renal failure and consider GBL in those presenting with agitation, psychosis or coma.

Isolated ventricular noncompaction syndrome in a nigerian male: case report and review of the literature.

Isolated ventricular non-compaction cardiomyopathy (IVNC) is a rare, morphologically distinct primary genetic cardiomyopathy, which is now gaining prominence as an important differential diagnosis in patients presenting with cardiac failure. We describe a case report of a Nigerian male with facial dysmorphism presenting with cardiac failure. This is followed by a review of the literature with focus on the diagnosis of this condition, which may be difficult especially in non-Caucasian populations.