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.
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.
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.
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.
Cancer Research UK.
Somatostatin receptor-2 (SSTR2) is expressed on cell surface of neuroendocrine neoplasias; its presence is exploited for the delivery of peptide receptor radionuclide therapy (PRRT). Patients with no ...or low expression of SSTR2 are not candidates for PRRT. SSTR2 promotor undergoes epigenetic modification, known to regulate gene expression. We investigated whether the demethylation agent, guadecitabine, could enhance the expression of SSTR2 in NET models, using radioligand uptake/PET imaging as a biomarker of epigenetic modification.
The effects of guadecitabine on the transcriptional, translational, and functional regulation of SSTR2 both in vitro and in vivo using low (QGP-1) and high (BON-1) methylated neuroendocrine neoplasia models was characterised. Promotor region methylation profiling of clinical samples (n = 61) was undertaken. Safety of combination guadecitabine and PRRT was assessed in vivo.
Pyrosequencing of cell lines illustrated differential methylation indices – BON: 1 94%, QGP: 1 21%. Following guadecitabine treatment, a dose-dependent increase in SSTR2 in BON-1 at a transcriptional, translational, and functional levels using the SSTR2-directed radioligand, 18F-FET-βAG-TOCA (18F-FETO) (150% increase 18F-FETO uptake, p < 0.05) was observed. In vivo, guadecitabine treatment resulted in a 70% increase in 18F-FETO uptake in BON-1 tumour models compared models with low baseline percentage methylation (p < 0.05). No additive toxicity was observed with the combination treatment of PRRT and guadecitabine in vivo. Methylation index in clinical samples was 10.5% compared to 5.2% in controls (p = 0.03) and correlated with SSTR2 expression (Wilcoxon rank sign −3.75,p < 0.01).
Guadecitabine increases SSTR2 expression both in vitro and in vivo. The combination of demethylation agents with PRRT warrants further investigation.
•Transcriptional silencing of SSTR2 can be reversed using the DNA hypomethylating agents.•Reversal of methylation can be visualised using PET imaging.•DNA hypomethylating agents & peptide receptor radionuclide therapy should be investigated.
Abstract Purpose To determine whether voluntary deep-inspiratory breath-hold (v_DIBH) and deep-inspiratory breath-hold with the active breathing coordinator™ (ABC_DIBH) in patients undergoing left ...breast radiotherapy are comparable in terms of normal-tissue sparing, positional reproducibility and feasibility of delivery. Methods Following surgery for early breast cancer, patients underwent planning-CT scans in v_DIBH and ABC_DIBH. Patients were randomised to receive one technique for fractions 1–7 and the second technique for fractions 8–15 (40 Gy/15 fractions total). Daily electronic portal imaging (EPI) was performed and matched to digitally-reconstructed radiographs. Cone-beam CT (CBCT) images were acquired for 6/15 fractions and matched to planning-CT data. Population systematic ( Σ ) and random errors ( σ ) were estimated. Heart, left-anterior-descending coronary artery, and lung doses were calculated. Patient comfort, radiographer satisfaction and scanning/treatment times were recorded. Within-patient comparisons between the two techniques used the paired t -test or Wilcoxon signed-rank test. Results Twenty-three patients were recruited. All completed treatment with both techniques. EPI-derived Σ were ⩽1.8 mm (v_DIBH) and ⩽2.0 mm (ABC_DIBH) and σ ⩽2.5 mm (v_DIBH) and ⩽2.2 mm (ABC_DIBH) (all p non-significant). CBCT-derived Σ were ⩽3.9 mm (v_DIBH) and ⩽4.9 mm (ABC_DIBH) and σ ⩽ 4.1 mm (v_DIBH) and ⩽ 3.8 mm (ABC_DIBH). There was no significant difference between techniques in terms of normal-tissue doses (all p non-significant). Patients and radiographers preferred v_DIBH ( p = 0.007, p = 0.03, respectively). Scanning/treatment setup times were shorter for v_DIBH ( p = 0.02, p = 0.04, respectively). Conclusions v_DIBH and ABC_DIBH are comparable in terms of positional reproducibility and normal tissue sparing. v_DIBH is preferred by patients and radiographers, takes less time to deliver, and is cheaper than ABC_DIBH.
Whether the severity and mortality of COVID-19 in patients with cancer have improved in terms of disease management and capacity is yet to be defined.
To test whether severity and mortality from ...COVID-19 among patients with cancer have improved during the course of the pandemic.
OnCovid is a European registry that collects data on consecutive patients with solid or hematologic cancer and COVID-19. This multicenter case series study included real-world data from 35 institutions across 6 countries (UK, Italy, Spain, France, Belgium, and Germany). This update included patients diagnosed between February 27, 2020, and February, 14, 2021. Inclusion criteria were confirmed diagnosis of SARS-CoV-2 infection and a history of solid or hematologic cancer.
SARS-CoV-2 infection.
Deaths were differentiated at 14 days and 3 months as the 2 landmark end points. Patient characteristics and outcomes were compared by stratifying patients across 5 phases (February to March 2020, April to June 2020, July to September 2020, October to December 2020, and January to February 2021) and across 2 major outbreaks (February to June 2020 and July 2020 to February 2021).
At data cutoff, 2795 consecutive patients were included, with 2634 patients eligible for analysis (median IQR age, 68 18-77 years ; 52.8% men). Eligible patients demonstrated significant time-dependent improvement in 14-day case-fatality rate (CFR) with estimates of 29.8% (95% CI, 0.26-0.33) for February to March 2020; 20.3% (95% CI, 0.17-0.23) for April to June 2020; 12.5% (95% CI, 0.06-22.90) for July to September 2020; 17.2% (95% CI, 0.15-0.21) for October to December 2020; and 14.5% (95% CI, 0.09-0.21) for January to February 2021 (all P < .001) across the predefined phases. Compared with the second major outbreak, patients diagnosed in the first outbreak were more likely to be 65 years or older (974 of 1626 60.3% vs 564 of 1008 56.1%; P = .03), have at least 2 comorbidities (793 of 1626 48.8% vs 427 of 1008 42.4%; P = .001), and have advanced tumors (708 of 1626 46.4% vs 536 of 1008 56.1%; P < .001). Complications of COVID-19 were more likely to be seen (738 of 1626 45.4% vs 342 of 1008 33.9%; P < .001) and require hospitalization (969 of 1626 59.8% vs 418 of 1008 42.1%; P < .001) and anti-COVID-19 therapy (1004 of 1626 61.7% vs 501 of 1008 49.7%; P < .001) during the first major outbreak. The 14-day CFRs for the first and second major outbreaks were 25.6% (95% CI, 0.23-0.28) vs 16.2% (95% CI, 0.13-0.19; P < .001), respectively. After adjusting for country, sex, age, comorbidities, tumor stage and status, anti-COVID-19 and anticancer therapy, and COVID-19 complications, patients diagnosed in the first outbreak had an increased risk of death at 14 days (hazard ratio HR, 1.85; 95% CI, 1.47-2.32) and 3 months (HR, 1.28; 95% CI, 1.08-1.51) compared with those diagnosed in the second outbreak.
The findings of this registry-based study suggest that mortality in patients with cancer diagnosed with COVID-19 has improved in Europe; this improvement may be associated with earlier diagnosis, improved management, and dynamic changes in community transmission over time.
IntroductionIt has been recognized that increasing body mass index (BMI) is associated with improved outcome from immune checkpoint inhibitors (ICIs) in patients with various malignancies including ...non-small cell lung cancer (NSCLC). However, it is unclear whether baseline BMI may influence outcomes from first-line chemoimmunotherapy combinations.MethodsIn this international multicenter study, we evaluated the association between baseline BMI, progression-free survival (PFS) and overall survival (OS) in a cohort of patients with stage IV NSCLC consecutively treated with first-line chemoimmunotherapy combinations. BMI was categorized according to WHO criteria.ResultsAmong the 853 included patients, 5.3% were underweight; 46.4% were of normal weight; 33.8% were overweight; and 14.5% were obese. Overweight and obese patients were more likely aged ≥70 years (p=0.00085), never smokers (p<0.0001), with better baseline Eastern Cooperative Oncology Group—Performance Status (p=0.0127), and had lower prevalence of central nervous system (p=0.0002) and liver metastases (p=0.0395). Univariable analyses showed a significant difference in the median OS across underweight (15.5 months), normal weight (14.6 months), overweight (20.9 months), and obese (16.8 months) patients (log-rank: p=0.045, log rank test for trend: p=0.131), while no difference was found with respect to the median PFS (log-rank for trend: p=0.510). Neither OS nor PFS was significantly associated with baseline BMI on multivariable analysis.ConclusionsIn contrast to what was observed in the context of chemotherapy-free ICI-based regimens, baseline BMI does not affect clinical outcomes from chemoimmunotherapy combinations in patients with advanced NSCLC.
Abstract Purpose To compare mean heart and left anterior descending coronary artery (LAD) doses (NTDmean ) and positional reproducibility in larger-breasted women receiving left breast radiotherapy ...using supine voluntary deep-inspiratory breath-hold (VBH) and free-breathing prone techniques. Materials and methods Following surgery for early breast cancer, patients with estimated breast volumes >750 cm3 underwent planning-CT scans in supine VBH and free-breathing prone positions. Radiotherapy treatment plans were prepared, and mean heart and LAD doses were calculated. Patients were randomised to receive one technique for fractions 1–7, before switching techniques for fractions 8–15 (40 Gy/15 fractions total). Daily electronic portal imaging and alternate-day cone-beam CT (CBCT) imaging were performed. The primary endpoint was the difference in mean LAD NTDmean between techniques. Population systematic ( Σ ) and random errors ( σ ) were estimated. Within-patient comparisons between techniques used Wilcoxon signed-rank tests. Results 34 patients were recruited, with complete dosimetric data available for 28. Mean heart and LAD NTDmean doses for VBH and prone treatments respectively were 0.4 and 0.7 ( p < 0.001) and 2.9 and 7.8 ( p < 0.001). Clip-based CBCT errors for VBH and prone respectively were ⩽3.0 mm and ⩽6.5 mm ( Σ ) and ⩽3.5 mm and ⩽5.4 mm ( σ ). Conclusions In larger-breasted women, supine VBH provided superior cardiac sparing and reproducibility than a free-breathing prone position.
The first calpain protease was discovered over 40 years ago now, yet despite the vast amount of literature that has subsequently emerged detailing their involvement in the pathophysiology of a ...variety of human diseases, it is only in the last decade that calpain-mediated actions along the secretory pathway have begun to emerge. However, the number of secretory pathway substrates identified and their diversity of function continues to grow. This review summarizes our current knowledge of calpain-mediated mechanisms of action that are pertinent to synaptic vesicle assembly and budding, cytoskeletal organization, endosomal recycling, and exocytotic membrane fusion.
Abstract Background Large breast size is associated with increased risk of late adverse effects after surgery and radiotherapy for early breast cancer. It is hypothesised that effects of radiotherapy ...on adipose tissue are responsible for some of the effects seen. In this study, the association of breast composition with late effects was investigated along with other breast features such as fibroglandular tissue distribution, seroma and scar. Methods The patient dataset comprised of 18 cases with changes in breast appearance at 2 years follow-up post-radiotherapy and 36 controls with no changes, from patients entered into the FAST-Pilot and UK FAST trials at The Royal Marsden. Breast composition, fibroglandular tissue distribution, seroma and scar were assessed on planning CT scan images and compared using univariate analysis. The association of all features with late-adverse effect was tested using logistic regression (adjusting for confounding factors) and matched analysis was performed using conditional logistic regression. Results In univariate analyses, no statistically significant differences were found between cases and controls in terms of breast features studied. A statistically significant association (p < 0.05) between amount of seroma and change in photographic breast appearance was found in unmatched and matched logistic regression analyses with odds ratio (95% CI) of 3.44 (1.28–9.21) and 2.57 (1.05–6.25), respectively. Conclusions A significant association was found between seroma and late-adverse effects after radiotherapy although no significant associations were noted with breast composition in this study. Therefore, the cause for large breast size as a risk factor for late effects after surgery and optimally planned radiotherapy remains unresolved.
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