Acute Toxicity of Hypofractionated and Conventionally Fractionated (Chemo)Radiotherapy Regimens for Bladder Cancer: An Exploratory Analysis from the RAIDER Trial.

AIMS: Adding concurrent (chemo)therapy to radiotherapy improves outcomes for muscle-invasive bladder cancer patients. A recent meta-analysis showed superior invasive locoregional disease control for a hypofractionated 55 Gy in 20 fractions schedule compared with 64 Gy in 32 fractions. In the RAIDER clinical trial, patients undergoing 20 or 32 fractions of radical radiotherapy were randomised (1:1:2) to standard radiotherapy or to standard-dose or escalated-dose adaptive radiotherapy. Neoadjuvant chemotherapy and concomitant therapy were permitted. We report exploratory analyses of acute toxicity by concomitant therapy-fractionation schedule combination. MATERIALS AND METHODS: Participants had unifocal bladder urothelial carcinoma staged T2-T4a N0 M0. Acute toxicity was assessed (Common Terminology Criteria for Adverse Events) weekly during radiotherapy and at 10 weeks after the start of treatment. Within each fractionation cohort, non-randomised comparisons of the proportion of patients reporting treatment emergent grade 2 or worse genitourinary, gastrointestinal or other adverse events at any point in the acute period were carried out using Fisher's exact tests. RESULTS: Between September 2015 and April 2020, 345 (163 receiving 20 fractions; 182 receiving 32 fractions) patients were recruited from 46 centres. The median age was 73 years; 49% received neoadjuvant chemotherapy; 71% received concomitant therapy, with 5-fluorouracil/mitomycin C most commonly used: 44/114 (39%) receiving 20 fractions; 94/130 (72%) receiving 32 fractions. The acute grade 2+ gastrointestinal toxicity rate was higher in those receiving concomitant therapy compared with radiotherapy alone in the 20-fraction cohort [54/111 (49%) versus 7/49 (14%), P < 0.001] but not in the 32-fraction cohort (P = 0.355). Grade 2+ gastrointestinal toxicity was highest for gemcitabine, with evidence of significant differences across therapies in the 32-fraction cohort (P = 0.006), with a similar pattern but no significant differences in the 20-fraction cohort (P = 0.099). There was no evidence of differences in grade 2+ genitourinary toxicity between concomitant therapies in either the 20- or 32-fraction cohorts. CONCLUSION: Grade 2+ acute adverse events are common. The toxicity profile varied by type of concomitant therapy; the gastrointestinal toxicity rate seemed to be higher in patients receiving gemcitabine.

Correlation of Clinician- and Patient-Reported Outcomes in the BC2001 Trial.

AIMS: To evaluate whether there is sufficient correlation between patient-reported outcomes (PROs) and clinician-reported outcomes (CROs) in bladder cancer follow-up post-radiotherapy to streamline data collection and to reduce trial follow-up burden on patients, clinicians and trial programmes. MATERIALS AND METHODS: PROs data were collected within the BC2001 trial using the Functional Assessment of Cancer Therapy specific to bladder cancer (FACT-BL) questionnaire. CROs data were collected by clinicians using Late Effects in Normal Tissues Subjective, Objective and Management (LENT/SOM). Data were collected at baseline, post-treatment, at 6 and 12 months post-randomisation and then annually to 5 years. The percentage agreement between CROs and PROs measures was evaluated at 2 and 5 years post-randomisation. Concordance was tested using the weighted Kappa statistic with 95% confidence intervals. RESULTS: Correlation was evaluated between six categories of the FACT-BL and LENT/SOM scores. At 2 years the percentage agreement across these domains ranged from 45 to 78%, with the weighted Kappa statistic between 0.07 and 0.35. Results were similar in year 5 with 48-83% agreement and kappa statistics between -0.02 and 0.21. CONCLUSION: The correlation between CROs and PROs in patients treated with radiotherapy for bladder cancer were generally poor. PROs appear to be more sensitive, with higher grade events reported. Further work is needed to evaluate whether PROs alone can be used to evaluate toxicity-related outcomes in randomised controlled trials.

Differences in Quality of Life and Toxicity for Male and Female Patients following Chemo(radiotherapy) for Bladder Cancer.

AIMS: BC2001, a randomised trial of treatment for muscle-invasive bladder cancer, demonstrated no difference in health-related quality of life (HRQoL) or late toxicity between patients receiving radical radiotherapy with and without chemotherapy. This secondary analysis explored sex-based differences in HRQoL and toxicity. MATERIALS AND METHODS: Participants completed the Functional Assessment of Cancer Therapy Bladder (FACT-BL) HRQoL questionnaires at baseline, end of treatment, 6 months and annually until 5 years. Clinicians assessed toxicity with the Radiation Therapy Oncology Group (RTOG) and Late Effects in Normal Tissues Subjective, Objective and Management (LENT/SOM) scoring systems at the same timepoints. The impact of sex on patient-reported HRQoL was evaluated using multivariate analyses of change in FACT-BL subscores from baseline to the timepoints of interest. For clinician-reported toxicity, differences were compared by calculating the proportion of patients with grade 3-4 toxicities occurring over the follow-up period. RESULTS: For both males and females, all FACT-BL subscores had a reduction in HRQoL at the end of treatment. For males, the mean bladder cancer subscale (BLCS) score remained stable through to year 5. For females, there was a decline in BLCS from baseline at years 2 and 3 with a return to baseline at year 5. At year 3, females had a statistically significant and clinically meaningful worsening of mean BLCS score (-5.18; 95% confidence interval -8.37 to -1.99), which was not seen in males (0.24; -0.76 to 1.23). RTOG toxicity was more frequent in females than males (27% versus 16%, P = 0.027). CONCLUSION: Results suggest that female patients treated with radiotherapy ± chemotherapy for localised bladder cancer report worse treatment-related toxicity in post-treatment years 2 and 3 than males.

Neutrophil-Lymphocyte Ratio and Absolute Lymphocyte Count as Prognostic Markers in Patients Treated with Curative-intent Radiotherapy for Non-small Cell Lung Cancer.

AIMS: The neutrophil-lymphocyte ratio (NLR) and the absolute lymphocyte count (ALC) have been proposed as prognostic markers in non-small cell lung cancer (NSCLC). The objective of this study was to examine the association of NLR/ALC before and after curative-intent radiotherapy for NSCLC on disease recurrence and overall survival. MATERIALS AND METHODS: A retrospective study of consecutive patients who underwent curative-intent radiotherapy for NSCLC across nine sites in the UK from 1 October 2014 to 1 October 2016. A multivariate analysis was carried out to assess the ability of pre-treatment NLR/ALC, post-treatment NLR/ALC and change in NLR/ALC, adjusted for confounding factors using the Cox proportional hazards model, to predict disease recurrence and overall survival within 2 years of treatment. RESULTS: In total, 425 patients were identified with complete blood parameter values. None of the NLR/ALC parameters were independent predictors of disease recurrence. Higher pre-NLR, post-NLR and change in NLR plus lower post-ALC were all independent predictors of worse survival. Receiver operator curve analysis found a pre-NLR > 2.5 (odds ratio 1.71, 95% confidence interval 1.06-2.79, P < 0.05), a post-NLR > 5.5 (odds ratio 2.36, 95% confidence interval 1.49-3.76, P < 0.001), a change in NLR >3.6 (odds ratio 2.41, 95% confidence interval 1.5-3.91, P < 0.001) and a post-ALC < 0.8 (odds ratio 2.86, 95% confidence interval 1.76-4.69, P < 0.001) optimally predicted poor overall survival on both univariate and multivariate analysis when adjusted for confounding factors. Median overall survival for the high-versus low-risk groups were: pre-NLR 770 versus 1009 days (P = 0.34), post-NLR 596 versus 1287 days (P ≤ 0.001), change in NLR 553 versus 1214 days (P ≤ 0.001) and post-ALC 594 versus 1287 days (P ≤ 0.001). CONCLUSION: NLR and ALC, surrogate markers for systemic inflammation, have prognostic value in NSCLC patients treated with curative-intent radiotherapy. These simple and readily available parameters may have a future role in risk stratification post-treatment to inform the intensity of surveillance protocols.

Predicting the Risk of Disease Recurrence and Death Following Curative-intent Radiotherapy for Non-small Cell Lung Cancer: The Development and Validation of Two Scoring Systems From a Large Multicentre UK Cohort.

AIMS: There is a paucity of evidence on which to produce recommendations on neither the clinical nor the imaging follow-up of lung cancer patients after curative-intent radiotherapy. In the 2019 National Institute for Health and Care Excellence lung cancer guidelines, further research into risk-stratification models to inform follow-up protocols was recommended. MATERIALS AND METHODS: A retrospective study of consecutive patients undergoing curative-intent radiotherapy for non-small cell lung cancer from 1 October 2014 to 1 October 2016 across nine UK trusts was carried out. Twenty-two demographic, clinical and treatment-related variables were collected and multivariable logistic regression was used to develop and validate two risk-stratification models to determine the risk of disease recurrence and death. RESULTS: In total, 898 patients were included in the study. The mean age was 72 years, 63% (562/898) had a good performance status (0-1) and 43% (388/898), 15% (134/898) and 42% (376/898) were clinical stage I, II and III, respectively. Thirty-six per cent (322/898) suffered disease recurrence and 41% (369/898) died in the first 2 years after radiotherapy. The ASSENT score (age, performance status, smoking status, staging endobronchial ultrasound, N-stage, T-stage) was developed, which stratifies the risk for disease recurrence within 2 years, with an area under the receiver operating characteristic curve (AUROC) for the total score of 0.712 (0.671-0.753) and 0.72 (0.65-0.789) in the derivation and validation sets, respectively. The STEPS score (sex, performance status, staging endobronchial ultrasound, T-stage, N-stage) was developed, which stratifies the risk of death within 2 years, with an AUROC for the total score of 0.625 (0.581-0.669) and 0.607 (0.53-0.684) in the derivation and validation sets, respectively. CONCLUSIONS: These validated risk-stratification models could be used to inform follow-up protocols after curative-intent radiotherapy for lung cancer. The modest performance highlights the need for more advanced risk prediction tools.

The diabetic pregnancy and offspring blood pressure in childhood: a systematic review and meta-analysis.

AIMS/HYPOTHESIS: Offspring of diabetic mothers have increased risk of the metabolic syndrome in adulthood. Studies examining BP in offspring of diabetic mothers have conflicting conclusions. We performed a systematic review and meta-analysis of studies reporting offspring BP in children born to diabetic mothers. METHODS: Citations were identified in PubMed. Authors were contacted for additional data. Systolic and diastolic BP in offspring of diabetic mothers and controls were compared. Subgroup analysis of type of maternal diabetes and offspring sex were performed. Fixed-effects models were used, and random-effects models where significant heterogeneity was present. Meta-regression was used to test the relationship between offspring systolic BP and prepregnancy BMI. RESULTS: Fifteen studies were included in the review and 13 in the meta-analysis. Systolic BP was higher in offspring of diabetic mothers (mean difference 1.88 mmHg [95% CI 0.47, 3.28]; p = 0.009). Offspring of mothers with gestational diabetes had similar diastolic BP to controls, but higher systolic BP (1.39 mmHg [95% CI 0.00, 2.77]; p = 0.05); results for type 1 diabetes were inconclusive and there were no separate data available on offspring of type 2 diabetic mothers. Male offspring of diabetic mothers had higher systolic BP (2.01 mmHg [95% CI 0.93, 3.10]; p = 0.0003) and diastolic BP (1.12 mmHg [95% CI 0.36, 1.88]; p = 0.004) than controls; in female offspring there was no difference (systolic: 0.54 mmHg [95% CI -1.83, 2.90], p = 0.66; diastolic: 0.51 mmHg [95% CI -1.07, 2.09], p = 0.52). The correlation between offspring systolic BP and maternal prepregnancy BMI was not significant (p = 0.37). CONCLUSIONS/INTERPRETATION: Offspring of diabetic mothers have higher systolic BP than controls. Differences related to sex and type of maternal diabetes require further investigation.

The diabetic pregnancy and offspring BMI in childhood: a systematic review and meta-analysis.

AIMS/HYPOTHESIS: Offspring of mothers with diabetes are at increased risk of metabolic disorders in later life. Increased offspring BMI is a plausible mediator. We performed a systematic review and meta-analysis of studies examining offspring BMI z score in childhood in relation to maternal diabetes. METHODS: Papers reporting BMI z scores for offspring of diabetic (all types, and pre- and during-pregnancy onset) and non-diabetic mothers were included. Citations were identified in PubMed; bibliographies of relevant articles were hand-searched and authors contacted for additional data where necessary. We compared offspring BMI z score with and without adjustment for maternal pre-pregnancy BMI. We performed fixed effect meta-analysis except where significant heterogeneity called for use of a random effects analysis. RESULTS: Data were available from nine studies. In the diabetic group unadjusted mean offspring BMI z score was 0.28 higher (all diabetic mothers vs controls (95% CI 0.09, 0.47; p = 0.004; nine studies; offspring of diabetic mothers n = 927, controls n = 26,384) and with adjustment for maternal pre-pregnancy BMI, 0.07 higher (95% CI -0.15, 0.28; p = 0.54; three studies; offspring of diabetic mothers n = 244, controls n = 11,206). There was no evidence of a difference in offspring BMI z score in relation to type of diabetes (gestational vs type 1, p = 0.95). CONCLUSIONS/INTERPRETATION: Maternal diabetes is associated with increased offspring BMI z score, although this is no longer apparent after adjustment for maternal pre-pregnancy BMI in the limited number of studies in which this is reported. Causal mediators of the effect of maternal diabetes on offspring outcomes remain to be established; we recommend that future research includes adjustment for maternal pre-pregnancy BMI.

Prospective study of postpartum depression: 4 1/2-year follow-up of women and children.

The consequences of maternal postpartum depression for mothers and children were investigated in a 4 1/2-year follow-up study, which included 70 of 99 women who had participated in an earlier study of postpartum depression. Information about maternal adjustment and depression during the follow-up period and child adjustment at age 4 1/2 years was obtained. Women who had experienced a postpartum depression were predicted to be at increased risk for subsequent depression and poor adjustment of their child. Postpartum depression was directly related to subsequent depression but not child problems. Later depression was related to child problems at 4 1/2 years. We concluded that postpartum depression may increase risk for later maternal depression and in turn increases risk for child behavior problems. Intervening with women who have experienced a postpartum depression may reduce likelihood of future depressions and child behavior problems.

Controlled prospective study of postpartum mood disorders: comparison of childbearing and nonchildbearing women.

A controlled prospective study was undertaken to determine the extent to which pregnancy and the puerperium are associated with increased risk for minor and major depression, depressive symptom-atology, and poor social adjustment. A large sample of childbearing (CB) women were recruited during the second trimester of pregnancy along with an equal sized, matched sample of nonchild-bearing (NCB) women. Ss were assessed multiple times during pregnancy and after delivery by questionnaire and through personal interview on measures of depression and other mood states and marital and social adjustment. There were no differences between CB and NCB Ss with respect to rates of minor and major depression during pregnancy or after delivery. However, CB women experienced significantly higher levels of depressive symptomatology and poor social adjustment than NCB women during late pregnancy and the early puerperium.