Dose escalation of tolinapant (ASTX660) in combination with standard radical chemoradiotherapy in cervical cancer : a study protocol for a phase 1b TiTE-CRM clinical trial (CRAIN) in UK secondary care centres.

BACKGROUND: Cervical cancer is the fourth most common cancer in women, with an estimated 342,000 deaths worldwide in 2020. Current standard of care in the UK for locally advanced cervical cancer is concurrent chemoradiotherapy with weekly cisplatin, yet 5-year overall survival rates are only 65% with a distant relapse rate of 50%. Inhibitors of Apoptosis Proteins (IAPs) are often overexpressed in cancer cells and associated with tumour progression and resistance to treatment. Tolinapant, developed by Astex Pharmaceuticals, is an IAP antagonist with an additional mechanism of action via down-regulation of NF-kB, an important regulator in cervical cancer. Preclinical studies performed using tolinapant in combination with cisplatin and radiotherapy showed inhibition of tumour growth and enhanced survival. There is therefore a strong rationale to combine tolinapant with chemoradiotherapy (CRT). METHODS: CRAIN is a phase Ib open-label, dose escalation study to characterise the safety, tolerability and initial evidence for clinical activity of tolinapant when administered in combination with cisplatin based CRT. Up to 42 patients with newly diagnosed cervix cancer will be recruited from six UK secondary care sites. The number of participants and the duration of the trial will depend on toxicities observed and dose escalation decisions, utilising a TiTE-CRM statistical design. Treatment will constist of standard of care CRT with 45 Gy external beam radiotherapy given in 25 daily fractions over 5 weeks with weekly cisplatin 40mg/m2. This is followed by brachytherapy for which common schedules will be 28 Gy in 4 fractions high-dose-rate or 34 Gy in 2 fractions pulsed-dose-rate. Tolinapant will be administered in fixed dose capsules taken orally daily for seven consecutive days as an outpatient on alternate weeks (weeks 1, 3, 5) during chemoradiation. Dose levels for tolinapant which will be assessed are: 60 mg; 90 mg (starting level); 120 mg; 150 mg; 180 mg. Escalation will be guided by emerging safety data and decisions by the Safety Review Committee. DISCUSSION: If this trial determines a recommended phase II dose and shows tolinapant to be safe and effective in combination with CRT, it would warrant future phase trials. Ultimately, we hope to provide a synergistic treatment option for these patients to improve outcome. TRIAL REGISTRATIONS: EudraCT Number: 2021-006555-34 (issued 30th November 2021); ISRCTN18574865 (registered 30th August 2022).

Palliative radiotherapy in cancers of female genital tract: Outcomes and prognostic factors.

BACKGROUND AND PURPOSE: Metastatic and incurable cancers of the gynaecological tract (FGTC) represent a major global health burden. Systemic treatment has modest efficacy and radiotherapy is often used for local symptoms. This study combines experience from two large UK centres in palliative radiotherapy for gynaecological cancers. MATERIALS AND METHODS: Pooled data from two major centres was analysed. Advanced FGTC patients who received at least one fraction of palliative radiotherapy to the pelvis between 2013 and 2018 were included. Data collected included demographic and tumour details, radiotherapy dose fractionation and details of previous and subsequent treatment. Response was defined in terms of toxicity, symptomatic response and survival. Comorbidities were recorded using a modified ACE 27 score which is adjusted for the presence of uncontrolled FGTC in all the patients. RESULTS: A total of 184 patients were included for treatment response and toxicity; survival data was available for 165 patients. Subjective response in pre-radiotherapy symptoms was documented in 80.4%. Grade 3 or worse gastrointestinal, urinary and other (vomiting, fatigue, pain) toxicity incidence was 2.2%, 3.8%, and 2.7% respectively. No statistically significant correlation between the prescribed EQD210 and symptom control or toxicity was seen. 1 year overall survival was 25.1% (median 5.9 months). Absent distant metastases, completion of the intended course of radiotherapy, response to radiotherapy, and receipt of further lines of treatment were independent prognostic factors. CONCLUSION: Palliative radiotherapy is effective for symptoms of advanced FGTC with low toxicity. The absence of a dose response argues for short low dose palliative radiotherapy schedules to be used.

RadBone: bone toxicity following pelvic radiotherapy - a prospective randomised controlled feasibility study evaluating a musculoskeletal health package in women with gynaecological cancers undergoing pelvic radiotherapy.

INTRODUCTION: Patients receiving radiotherapy are at risk of developing radiotherapy-related insufficiency fractures, which are associated with increased morbidity and pose a significant burden to patients' quality of life and to the health system. Therefore, effective preventive techniques are urgently required. The RadBone randomised controlled trial (RCT) aims to determine the feasibility and acceptability of a musculoskeletal health package (MHP) intervention in women undergoing pelvic radiotherapy for gynaecological malignancies and to preliminary explore clinical effectiveness of the intervention. METHODS AND ANALYSIS: The RadBone RCT will evaluate the addition to standard care of an MHP consisting of a physical assessment of the musculoskeletal health, a 3-month prehabilitation personalised exercise package, as well as an evaluation of the fracture risk and if required the prescription of appropriate bone treatment including calcium, vitamin D and-for high-risk individuals-bisphosphonates. Forty participants will be randomised in each group (MHP or observation) and will be followed for 18 months. The primary outcome of this RCT will be feasibility, including the eligibility, screening and recruitment rate, intervention fidelity and attrition rates; acceptability and health economics. Clinical effectiveness and bone turnover markers will be evaluated as secondary outcomes. ETHICS AND DISSEMINATION: This study has been approved by the Greater Manchester East Research Ethics Committee (Reference: 20/NW/0410, November 2020). The results will be published in peer-reviewed journals, will be presented in national and international conferences and will be communicated to relevant stakeholders. Moreover, a plain English report will be shared with the study participants, patients' organisations and media. TRIAL REGISTRATION NUMBER: NCT04555317.

Isotoxic Intensity Modulated Radiation Therapy in Stage III Non-Small Cell Lung Cancer: A Feasibility Study.

PURPOSE: Not all patients with stage III non-small cell lung cancer (NSCLC) are suitable for concurrent chemoradiation therapy (CRT). Local failure rate is high for sequential concurrent CRT. As such, there is a rationale for treatment intensification. METHODS AND MATERIALS: Isotoxic intensity modulated radiation therapy (IMRT) is a multicenter feasibility study that combines different intensification strategies including hyperfractionation, acceleration, and dose escalation facilitated by IMRT. Patients with unresectable stage III NSCLC, Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 to 2, and unsuitable for concurrent CRT were recruited. A minimum of 2 cycles of platinum-based chemotherapy was compulsory before starting radiation therapy (RT). Radiation dose was increased until a maximum dose of 79.2 Gy was reached or 1 or more of the organs at risk met predefined constraints. RT was delivered in 1.8-Gy fractions twice daily, and an RT quality assurance program was implemented. The primary objective was the delivery of isotoxic IMRT to a dose >60 Gy equivalent dose in 2-Gy fractions (EQD2 assuming an α/ß ratio of 10 Gy for acute reacting tissues). RESULTS: Thirty-seven patients were recruited from 7 UK centers. Median age was 69.9 years (range, 46-86 years). The male-to-female ratio was 17:18. ECOG PS was 0 to 5 in 14.2% of patients; PS was 1 to 27 in 77.1% of patients; PS was 2 to 3 in 8.6% of patients. Stage IIIA:IIIB ratio was 22:13 (62.9%:37.1%). Of 37 patients, 2 (5.4%) failed to achieve EQD2 > 60 Gy. Median prescribed tumor dose was 77.4 Gy (range, 61.2-79.2 Gy). A maximum dose of 79.2Gy was achieved in 14 patients (37.8%). Grade 3 esophagitis was reported in 2 patients, and no patients developed grade 3 to 4 pneumonitis. There were 3 grade 5 events: acute radiation pneumonitis, bronchopulmonary hemorrhage, and acute lung infection. Median follow-up at time of analysis was 25.4 months (range, 8.0-44.2) months for 11 of 35 survivors. The median survival was 18.1 months (95% confidence interval [CI], 13.9-30.6), 2-year overall survival was 33.6% (95% CI, 17.9-50.1), and progression-free survival was 23.9% (95% CI, 11.3-39.1). CONCLUSIONS: Isotoxic IMRT is a well-tolerated and feasible approach to treatment intensification.

Post-treatment lymphocytopaenia, integral body dose and overall survival in lung cancer patients treated with radical radiotherapy.

INTRODUCTION: Post-treatment lymphocytopaenia is a recognized complication of thoracic radiotherapy likely due to irradiation of a large volume of circulatory blood. We hypothesize that post-treatment absolute lymphocyte count (ALC) is associated with integral body dose and overall survival (OS) in lung cancer patients treated with radical radiotherapy. MATERIALS AND METHODS: Data on clinicopathological variables, dosimetric parameters, and pre and post-treatment blood counts were collected retrospectively in 217 lung cancer patients (131 with non-small cell lung cancer and 86 with small cell lung cancer) treated with radical radiotherapy. Induction chemotherapy followed by radiotherapy and concurrent chemoradiotherapy were delivered in 89 (42%) and 99 (47%) patients respectively. Multiple stepwise regression analysis was performed separately for ALC and absolute neutrophil count (ANC) to derive a model for prediction of post-treatment count and multivariate analysis was performed for OS using a Cox regression model. RESULTS: There was a significant decline in post-treatment counts for both ANC and ALC (p < 0.001). Multiple stepwise linear regression analysis confirmed pre-treatment ALC, body integral dose and use of concurrent chemotherapy as significant predictors of post-treatment ALC (R2 = 0.33, F(4,212) = 26.6 p < 0.001). Pre-treatment ANC, integral heart dose and number of fractions were significant predictors of post-treatment ANC (R2 = 0.18, F(3,213) = 16.38 p < 0.001). Low post-treatment ALC, high pre-treatment ANC, high planning target volume integral dose and lower number of fractions were predictive of inferior OS. CONCLUSIONS: There is a negative correlation between integral body dose and post-treatment ALC which is an adverse prognostic factor in lung cancer patients treated with radical radiotherapy.

Short Communication: Management of patients with extensive-stage small-cell lung cancer treated with radiotherapy: A survey of practice.

OBJECTIVES: The results of the randomized phase 3 CREST trial evaluating the use of thoracic radiotherapy for extensive-stage small-cell lung cancer (ES-SCLC) were published in the Lancet in 2015. The primary endpoint (10% overall survival difference at 1-year) was not achieved, but there was significant improvement in 2-year overall survival (13% vs 3%; p = 0.004) and low toxicity rates, suggesting thoracic radiotherapy should be considered for ES-SCLC patients who respond to chemotherapy. Questions have been raised as to whether these results will lead to a change in practice. MATERIALS AND METHODS: We developed an electronic survey to determine the impact of the publication on clinical practice across some European countries. RESULTS AND CONCLUSION: We report the results of our survey, which suggest the CREST trial has changed practice, resulting in an increase in the use of thoracic radiotherapy amongst the surveyed centers from 25% to 85%. Furthermore the dose and fractionation schedule used in the trial has been widely adopted across Europe.

Cell Death, Inflammation, Tumor Burden, and Proliferation Blood Biomarkers Predict Lung Cancer Radiotherapy Response and Correlate With Tumor Volume and Proliferation Imaging.

INTRODUCTION: There is an unmet need to develop noninvasive biomarkers to stratify patients in drug-radiotherapy trials. In this pilot study we investigated lung cancer radiotherapy response and toxicity blood biomarkers and correlated findings with tumor volume and proliferation imaging. PATIENTS AND METHODS: Blood samples were collected before and during (day 21) radiotherapy. Twenty-six cell-death, hypoxia, angiogenesis, inflammation, proliferation, invasion, and tumor-burden biomarkers were evaluated. Clinical and laboratory data were collected. Univariate analysis was performed on small-cell and non-small-cell lung cancer (NSCLC) whereas multivariate analysis focused on NSCLC. RESULTS: Blood samples from 78 patients were analyzed. Sixty-one (78.2%) harbored NSCLC, 48 (61.5%) received sequential chemoradiotherapy. Of tested baseline biomarkers, undetectable interleukin (IL)-1b (hazard ratio [HR], 4.02; 95% confidence interval [CI], 2.04-7.93; P < .001) was the only significant survival covariate. Of routinely collected laboratory tests, high baseline neutrophil count was a significant survival covariate (HR, 1.07; 95% CI, 1.02-1.11; P = .017). Baseline IL-1b and neutrophil count were prognostic for survival in a multivariate model. The addition of day-21 cytokeratin-19 antigen modestly improved this model's survival prediction (concordance probability, 0.75-0.78). Chemotherapy (P < .001) and baseline keratinocyte growth factor (P = .019) predicted acute esophagitis, but only chemotherapy remained significant after Bonferroni correction. Baseline angioprotein-1 and hepatocyte growth factor showed a direct correlation with tumor volume whereas changes in vascular cell adhesion molecule 1 showed significant correlations with 18F-fluorothymidine (FLT) positron emission tomography (PET). CONCLUSION: Select biomarkers are prognostic after radiotherapy in this lung cancer series. The correlation between circulating biomarkers and 18F-FLT PET is shown, to our knowledge for the first time, highlighting their potential role as imaging surrogates.

Which patients with ES-SCLC are most likely to benefit from more aggressive radiotherapy: A secondary analysis of the Phase III CREST trial.

INTRODUCTION: In ES-SCLC patients with residual intrathoracic disease after first-line chemotherapy, the addition of thoracic radiotherapy reduces the risk of intrathoracic recurrence, and improves 2-year survival. To identify patient subgroups for future trials investigating higher dose (extra)thoracic radiotherapy, we investigated the prognostic importance of number and sites of metastases in patients included in the CREST trial. MATERIALS/ METHODS: Additional data on sites and numbers of metastases were collected from individual records of 260 patients from the top 9 recruiting centers in the randomized CREST trial (53% of 495 study patients), which compared thoracic radiotherapy (TRT) to no TRT in ES-SCLC patients after any response to chemotherapy. All patients received prophylactic cranial irradiation. RESULTS: The clinical characteristics and outcomes of the 260 patients analyzed here did not differ significantly from that of the other 235 patients included in the CREST trial, except that fewer patients had a WHO=0 performance status (24% vs 45%), and a higher proportion had WHO=2 (15% vs 5%; p<0.0001). No distant metastases were recorded in 5%, 39% had metastases confined to one organ, 34% to two, and 22% to three or more organ sites. Metastases were present in the liver (47%), bone (40%), lung (28%), extrathoracic (non-supraclavicular) lymph nodes (19%), supraclavicular nodes (18%), adrenals (17%) and other sites (12%). The OS (p=0.02) and PFS (p=0.04) were significantly better in patients with 2 or fewer metastases, with OS significantly worse if liver (p=0.03) and/or bone metastases (p=0.04) were present. DISCUSSION: This analysis of patients recruited from the top 9 accruing centers in the CREST trial suggests that future studies evaluating more intensive thoracic and extra-thoracic radiotherapy in ES-SCLC should focus on patients with fewer than 3 distant metastases.

Protocol for the isotoxic intensity modulated radiotherapy (IMRT) in stage III non-small cell lung cancer (NSCLC): a feasibility study.

INTRODUCTION: The majority of stage III patients with non-small cell lung cancer (NSCLC) are unsuitable for concurrent chemoradiotherapy, the non-surgical gold standard of care. As the alternative treatment options of sequential chemoradiotherapy and radiotherapy alone are associated with high local failure rates, various intensification strategies have been employed. There is evidence to suggest that altered fractionation using hyperfractionation, acceleration, dose escalation, and individualisation may be of benefit. The MAASTRO group have pioneered the concept of 'isotoxic' radiotherapy allowing for individualised dose escalation using hyperfractionated accelerated radiotherapy based on predefined normal tissue constraints. This study aims to evaluate whether delivering isotoxic radiotherapy using intensity modulated radiotherapy (IMRT) is achievable. METHODS AND ANALYSIS: Isotoxic IMRT is a multicentre feasibility study. From June 2014, a total of 35 patients from 7 UK centres, with a proven histological or cytological diagnosis of inoperable NSCLC, unsuitable for concurrent chemoradiotherapy will be recruited. A minimum of 2 cycles of induction chemotherapy is mandated before starting isotoxic radiotherapy. The dose of radiation will be increased until one or more of the organs at risk tolerance or the maximum dose of 79.2 Gy is reached. The primary end point is feasibility, with accrual rates, local control and overall survival our secondary end points. Patients will be followed up for 5 years. ETHICS AND DISSEMINATION: The study has received ethical approval (REC reference: 13/NW/0480) from the National Research Ethics Service (NRES) Committee North West-Greater Manchester South. The trial is conducted in accordance with the Declaration of Helsinki and Good Clinical Practice (GCP). The trial results will be published in a peer-reviewed journal and presented internationally. TRIAL REGISTRATION NUMBER: NCT01836692; Pre-results.

Hyperfractionated and accelerated radiotherapy in non-small cell lung cancer.

Radical radiotherapy plays a major role in the treatment of non-small cell lung cancer (NSCLC) due to the fact that many patients are medically or surgically inoperable. Advances in technology and radiotherapy delivery allow targeted treatment of the disease, whilst minimizing the dose to organs at risk. This in turn creates an opportunity for dose escalation and the prospect of tailoring radiotherapy treatment to each patient. This is especially important in patients deemed unsuitable for chemotherapy or surgery, where there is a need to increase the therapeutic gain from radical radiotherapy alone. Recent research into fractionation schedules, with hyperfractionated and accelerated radiotherapy regimes has been promising. How to combine these new fractionated schedules with dose escalation and chemotherapy remains open to debate and there is local, national and international variation in management with a lack of overall consensus. An overview of the current literature on hyperfractionated and accelerated radiotherapy in NSCLC is provided.

Early reduction in tumour [18F]fluorothymidine (FLT) uptake in patients with non-small cell lung cancer (NSCLC) treated with radiotherapy alone.

PURPOSE: Changes in tumour 3'-deoxy-3'-[(18)F]fluorothymidine (FLT) uptake during concurrent chemo-radiotherapy in patients with non-small cell lung cancer (NSCLC) have been reported, at variable time points, in two pilot positron emission tomography (PET) studies. The aim of this study was to assess whether FLT changes occur early in response to radiotherapy (RT) without concurrent chemotherapy and whether such changes exceed test-retest variability. METHODS: Sixteen patients with NSCLC, scheduled to have radical RT, underwent FLT PET once/twice at baseline to assess reproducibility and/or after 5-11 RT fractions to evaluate response. Primary and nodal malignant lesions were manually delineated on CT and volume, mean and maximum standardized uptake values (SUV(mean) and SUV(max)) estimated. Analysis included descriptive statistics and parameter fitting to a mixed-effects model accounting for patients having different numbers of evaluable lesions. RESULTS: In all, 35 FLT PET scans from 7 patients with a total of 18 lesions and 12 patients with a total of 30 lesions were evaluated for reproducibility and response, respectively. SUV(mean) reproducibility in primary tumours (SD 8.9%) was better than SUV(max) reproducibility (SD 12.6%). In nodes, SUV(mean) and SUV(max) reproducibilities (SD 18.0 and 17.2%) were comparable but worse than for primary tumours. After 5-11 RT fractions, primary tumour SUV(mean) decreased significantly by 25% (p = 0.0001) in the absence of significant volumetric change, whereas metastatic nodes decreased in volume by 31% (p = 0.020) with a larger SUV(mean) decrease of 40% (p < 0.0001). Similar changes were found for SUV(max). CONCLUSION: Across this group of NSCLC patients, RT induced an early, significant decrease in lesion FLT uptake exceeding test-retest variability. This effect is variable between patients, appears distinct between primary and metastatic nodal lesions, and in primary tumours is lower than previously reported for concurrent chemo-RT at a similar time point. These results confirm the potential for FLT PET to report early on radiation response and to enhance the clinical development of novel drug-radiation combinations by providing an interpretable, early pharmacodynamic end point.