A comparison of the efficacy of trastuzumab deruxtecan in advanced HER2-positive breast cancer: active brain metastasis versus progressive extracranial disease alone.

BACKGROUND: Trastuzumab deruxtecan (T-DXd) has demonstrated efficacy in patients with brain metastasis (BM), a group historically with poor outcomes. The prevalence of BMs in patients commencing T-DXd is currently unknown. No direct comparisons have been made of the activity of T-DXd in patients with active BM versus those with extracranial progression alone. This real-world study explored the prevalence of BMs in patients commencing T-DXd, the efficacy of T-DXd in active BM versus extracranial progression alone and the safety of T-DXd. PATIENTS AND METHODS: Patients with human epidermal growth factor receptor 2-positive advanced breast cancer treated with T-DXd between June 2021 and February 2023 at our specialist cancer hospital were identified and notes reviewed. Clinicopathological information, prior treatment, the presence or absence of central nervous system (CNS) disease, outcomes and treatment-emergent adverse events (TEAEs) were recorded. RESULTS: Twenty-nine female patients, with a median age of 52 years (interquartile range 44-62 years), were identified; the prevalence of BM was 41%. Median number of lines of prior therapy was 2 (range 2-6). At a median follow-up of 13.8 months, median progression-free survival (PFS) for the overall population was 13.9 months [95% confidence interval (CI) 12.4 months-not estimable (NE)], 16.1 months (95% CI 15.1 months-NE) for active BMs and 12.4 months (95% CI 8.3 months-NE) for progressive extracranial disease alone. The 12-month overall survival (OS) rate was 74% (95% CI 59% to 95%) in the overall population, and 83% (95% CI 58% to 100%) and 66% (95% CI 45% to 96%) for active BMs and extracranial disease only, respectively. Most common TEAEs were fatigue, alopecia, and constipation. In nine patients (31%, including two deaths), pneumonitis occurred. CONCLUSION: In this real-world population, we demonstrate T-DXd to be effective in patients with active BMs and those with progressive extracranial disease alone. PFS and OS were numerically longer in those with active BMs. These data demonstrate that patients with active BM treated with T-DXd have at least comparable outcomes to those with extracranial disease alone. The high rate of pneumonitis warrants further consideration.

Organ and Function Preservation in Gastrointestinal Malignancies.

Radiation plays an important role in organ preservation for gastrointestinal malignancies, with a watch and wait strategy enabling surgery to be avoided in patients who are not suitable or who are refusing surgery. Brachytherapy boost allows the radiation dose to be escalated, which plays a pivotal role in the successful outcome of achieving organ preservation. Here we describe the role of brachytherapy in two common gastrointestinal malignancies (oesophagus and rectum). Their indications and how the brachytherapy procedures are carried out, together with the dose and fractionation commonly used are discussed. The use of brachytherapy needs to be included in the training curriculum at all academic centres so that its use is developed by the newer generation of radiation oncologists. Its current non-use due to bias, lack of training and availability is no longer justified, given the overwhelming published evidence for the role of brachytherapy to improve organ preservation for both radical treatment and palliation in gastrointestinal malignancies.

Effect of prehabilitation on objectively measured physical fitness after neoadjuvant treatment in preoperative rectal cancer patients: a blinded interventional pilot study.

BACKGROUND: Patients requiring surgery for locally advanced rectal cancer often additionally undergo neoadjuvant chemoradiotherapy (NACRT), of which the effects on physical fitness are unknown. The aim of this feasibility and pilot study was to investigate the effects of NACRT and a 6 week structured responsive exercise training programme (SRETP) on oxygen uptake [Formula: see text] at lactate threshold ([Formula: see text]) in such patients. METHODS: We prospectively studied 39 consecutive subjects (27 males) with T3-4/N+ resection margin threatened rectal cancer who completed standardized NACRT. Subjects underwent cardiopulmonary exercise testing at baseline (pre-NACRT), at week 0 (post-NACRT), and week 6 (post-SRETP). Twenty-two subjects undertook a 6 week SRETP on a training bike (three sessions per week) between week 0 and week 6 (exercise group). These were compared with 17 contemporaneous non-randomized subjects (control group). Changes in [Formula: see text] at [Formula: see text] over time and between the groups were compared using a compound symmetry covariance linear mixed model. RESULTS: Of 39 recruited subjects, 22 out of 22 (exercise) and 13 out of 17 (control) completed the study. There were differences between the exercise and control groups at baseline [age, ASA score physical status, World Health Organisation performance status, and Colorectal Physiologic and Operative Severity Score for the Enumeration of Mortality and Morbidity (CR-POSSUM) predicted mortality]. In all subjects, [Formula: see text] at [Formula: see text] significantly reduced between baseline and week 0 [-1.9 ml kg(-1) min(-1); 95% confidence interval (CI) -1.3, -2.6; P<0.0001]. In the exercise group, [Formula: see text] at [Formula: see text] significantly improved between week 0 and week 6 (+2.1 ml kg(-1) min(-1); 95% CI +1.3, +2.9; P<0.0001), whereas the control group values were unchanged (-0.7 ml kg(-1) min(-1); 95% CI -1.66, +0.37; P=0.204). CONCLUSIONS: NACRT before rectal cancer surgery reduces physical fitness. A structured exercise intervention is feasible post-NACRT and returns fitness to baseline levels within 6 weeks. CLINICAL TRIAL REGISTRATION NCT: 01325909.

The effects of neoadjuvant chemoradiotherapy on physical fitness and morbidity in rectal cancer surgery patients.

BACKGROUND: Neoadjuvant chemoradiotherapy (NACRT) followed by surgery for resectable locally advanced rectal cancer improves outcome compared with surgery alone. Our primary hypothesis was that NACRT impairs objectively-measured physical fitness. We also wished to explore the relationship between fitness and postoperative outcome. METHOD: In an observational study, we prospectively studied 27 consecutive patients, of whom 25 undertook cardiopulmonary exercise testing (CPET) 2 weeks before and 7 weeks after standardized NACRT, then underwent surgery. In-hospital post-operative morbidity and mortality were recorded. Patients were followed up to 1 year for mortality. Data was analysed blind to clinical details. Receiver-operating characteristic (ROC) analysis defined the predictive value of CPET for in-hospital morbidity at day 5. RESULTS: Oxygen uptake ( [Formula: see text] in ml kg(-1) min(-1)) at estimated lactate threshold (θˆL) and at peak exercise ( [Formula: see text] at peak in ml kg(-1) min(-1)) both significantly decreased post-NACRT: [Formula: see text] at θˆL 12.1 (pre-NACRT) vs. 10.6 (post-NACRT), p < 0.001 (95%CI -1.7, -1.2); [Formula: see text] at peak 18.1 vs. 16.7, p < 0.001 (95%CI -3.1, -1.0). Optimal [Formula: see text] at θˆL and peak pre-NACRT for predicting postoperative morbidity were 12.0 and 18.1 ( [Formula: see text] at θˆL - AUC = 0.71, 77% sensitive and 75% specific; [Formula: see text] at peak - AUC = 0.75, 78% sensitive and 76% specific). Optimal [Formula: see text] at θˆL and peak post-NACRT for predicting postoperative morbidity were 10.7 and 16.7 ( [Formula: see text] at θˆL - AUC = 0.72, 77% sensitive and 83% specific; [Formula: see text] at peak - AUC = 0.80, 85% sensitive and 83% specific). CONCLUSION: NACRT before major rectal cancer surgery significantly decreased physical fitness as assessed by CPET. TRIALS REGISTRY NUMBER: NCT01334593.

Chronic radiation enteritis.

Chronic radiation enteritis is an increasing problem, as more patients receive radiotherapy as part of their cancer therapy and as the long-term survival of these patients improves. This review addresses the causes, investigation, treatment and prevention of this disease. A review of published studies was carried out using a variety of search terms, including radiation enteritis, investigation, treatment and prevention. Chronic radiation enteritis has been reported in up to 20% of patients receiving pelvic radiotherapy, although this may underestimate its true prevalence, as not all patients with gastrointestinal symptoms after radiotherapy will seek medical attention. Predisposing factors to chronic radiation enteritis include a low body mass index, previous abdominal surgery and the presence of co-morbid conditions; the radiation dose, fractionation and technique, as well as the concomitant use of chemotherapy, may also play a role. Clinical features of chronic radiation enteritis are multiple as the disease can affect any part of the gastrointestinal tract. Moreover, symptom aetiology within any one patient may be multifactorial and therefore it is important to adopt a structured approach when planning investigations. The evidence base for current therapies is limited, but nutrition, anti-diarrhoeals, anti-inflammatories, antibiotics, probiotics, pentoxifylline, tocopherol, cholestyramine, hyperbaric oxygen, endoscopic and surgical therapies have all received attention. Given the significant morbidity and mortality associated with chronic radiation enteritis, current available preventative strategies are reviewed, including tissue-sparing radiotherapy techniques. In conclusion, the evidence base for therapeutic and preventative strategies in treating chronic radiation enteritis is limited, but adopting a structured approach to investigating gastrointestinal symptoms after radiotherapy should allow better targeting of current therapies. Closer collaboration between oncologists and gastroenterologists will facilitate a more structured approach, not only in managing individual patients, but also in establishing clinical and research networks for this expanding disease, in order to improve the evidence base for its management.