The feasibility and acceptability of an app-based intervention with brief behavioural support (APPROACH) to promote brisk walking in people diagnosed with breast, prostate and colorectal cancer in the UK.

INTRODUCTION: Increased moderate to vigorous physical activity (MVPA) can improve clinical and psychosocial outcomes for people living with and beyond cancer (LWBC). This study aimed to assess the feasibility and acceptability of trial procedures in a pilot randomised controlled trial (RCT) of a theory-driven app-based intervention with behavioural support focused on promoting brisk walking (a form of MVPA) in people LWBC (APPROACH). METHODS: Participants diagnosed with breast, prostate or colorectal cancer were recruited from a single UK hospital site. Assessments at baseline and 3 months included online questionnaires, device-measured brisk walking (activPAL accelerometer) and self-reported weight and height. Participants were randomised to intervention or control (care as usual). The intervention comprised a non-cancer-specific app to promote brisk walking (National Health Service 'Active 10') augmented with print information about habit formation, a walking planner and two behavioural support telephone calls. Feasibility and acceptability of trial procedures were explored. Initial estimates for physical activity informed a power calculation for a phase III RCT. A preliminary health economics analysis was conducted. RESULTS: Of those medically eligible, 369/577 (64%) were willing to answer further eligibility questions and 90/148 (61%) of those eligible were enrolled. Feasibility outcomes, including retention (97%), assessment completion rates (>86%) and app download rates in the intervention group (96%), suggest that the trial procedures are acceptable and that the intervention is feasible. The phase III RCT will require 472 participants to be randomised. As expected, the preliminary health economic analyses indicate a high level of uncertainty around the cost-effectiveness of the intervention. CONCLUSIONS: This pilot study demonstrates that a large trial of the brisk walking intervention with behavioural support is both feasible and acceptable to people LWBC. The results support progression onto a confirmatory phase III trial to determine the efficacy and cost-effectiveness of the intervention.

Long-term outcomes by bone marrow B-cell depletion from the R2W trial of bortezomib with cyclophosphamide and rituximab in Waldenstrom macroglobulinaemia.

There remains a lack of consensus as to the most appropriate primary therapy in Waldenstrom macroglobulinemia (WM). We evaluated a novel bortezomib-based combination and developed a sensitive WM-specific flow cytometry assay (limit of detection 0.004% of leucocytes) to assess bone marrow (BM) response. Sixty treatment-naïve WM patients were enroled into this phase II trial and randomised (2:1) to receive cyclophosphamide and rituximab with either bortezomib (BRC) or fludarabine (FCR). The primary objective was to assess the overall response rate (ORR) in eligible patients receiving BRC (N = 41). An ORR of 97.6% (95%CI:87.1-99.9) was observed; 27 (65.9%) patients remain alive without progression after 62.6 months median follow-up, with 2-, 3- and 5-year progression-free survival (PFS) rates of 92.7% (95%CI:79.0-97.6), 80.5% (95%CI:64.8-89.7) and 65.5% (95%CI:48.8-77.9). Persistent WM B-cells were demonstrable in 19/38 patients at the end of treatment (median 0.24%, range 0.02-11.2%). PFS was markedly longer in patients with BM B-cell depletion (<0.004%) compared to those who had persistent BM B-cells detectable at end of treatment (HR = 0.06, 95%CI:0.01-0.47, p < 0.001), and remained independently associated after adjusting for baseline risk stratification or investigator-assessed response. BRC is a tolerable, highly efficacious regimen for treatment-naïve WM patients. BM B-cell depletion is independently associated with patient outcomes.

International Multicenter Study of Clinical Outcomes of Sinonasal Melanoma Shows Survival Benefit for Patients Treated with Immune Checkpoint Inhibitors and Potential Improvements to the Current TNM Staging System.

Objectives Sinonasal mucosal melanoma (SNMM) is an extremely rare and challenging sinonasal malignancy with a poor prognosis. Standard treatment involves complete surgical resection, but the role of adjuvant therapy remains unclear. Crucially, our understanding of its clinical presentation, course, and optimal treatment remains limited, and few advancements in improving its management have been made in the recent past. Methods We conducted an international multicenter retrospective analysis of 505 SNMM cases from 11 institutions across the United States, United Kingdom, Ireland, and continental Europe. Data on clinical presentation, diagnosis, treatment, and clinical outcomes were assessed. Results One-, three-, and five-year recurrence-free and overall survival were 61.4, 30.6, and 22.0%, and 77.6, 49.2, and 38.3%, respectively. Compared with disease confined to the nasal cavity, sinus involvement confers significantly worse survival; based on this, further stratifying the T3 stage was highly prognostic ( p < 0.001) with implications for a potential modification to the current TNM staging system. There was a statistically significant survival benefit for patients who received adjuvant radiotherapy, compared with those who underwent surgery alone (hazard ratio [HR] = 0.74, 95% confidence interval [CI]: 0.57-0.96, p = 0.021). Immune checkpoint blockade for the management of recurrent or persistent disease, with or without distant metastasis, conferred longer survival (HR = 0.50, 95% CI: 0.25-1.00, p = 0.036). Conclusions We present findings from the largest cohort of SNMM reported to date. We demonstrate the potential utility of further stratifying the T3 stage by sinus involvement and present promising data on the benefit of immune checkpoint inhibitors for recurrent, persistent, or metastatic disease with implications for future clinical trials in this field.

Relapse patterns in early-PET negative, limited-stage Hodgkin lymphoma (HL) after ABVD with or without radiotherapy-a joint analysis of EORTC/LYSA/FIL H10 and NCRI RAPID trials.

In the H10 and RAPID randomised trials, chemotherapy+radiotherapy (combined modalities treatment, CMT) was compared with chemotherapy (C) in limited-stage Hodgkin lymphoma (HL), with negative early positron emission tomography (ePETneg). We analysed patterns of relapses in the H10 trial, validated findings in the RAPID trial and performed a combined analysis stratified by trial. The impact of radiotherapy (RT) on risk of relapse was studied using adjusted Cox models, with time-varying effects. In H10, 1,059 ePETneg patients were included (465 European Organisation for Research and Treatment of Cancer (EORTC) favourable [F], 594 unfavourable [U]). Among the F patients, 2/227 (1%) relapsed after CMT, 30/238 (13%) after C: of these relapses, 21/30 (70%) occurred in less than 2 years and 25/30 (83%) affected originally involved areas. Among the U group, 16/292 (5%) relapsed after CMT: 8/16 (50%) in less than 2 years, 11/16 (69%) in originally involved areas. After C 30/302 (10%) relapsed: 27/30 (90%) in less than 2 years, and 26/30 (87%) in originally involved areas. Similar results were observed in 419 ePETneg RAPID patients (241 F, 128 U, 50 unclassified): among F patients, 6/118 (5%) relapsed after CMT; 13/123 (11%) after C: 11/13 (85%) in less than 2 years and 11/13 (85%) affecting originally involved areas. In U patients, 3/65 (5%) relapsed after CMT and 5/63 (8%) after C. In both trials, omitting RT in ePETneg HL resulted in more early relapses, mainly affecting originally involved areas. RT significantly reduced risk of early relapses in the combined stratified analysis.

Phase 0 Study of Vandetanib-Eluting Radiopaque Embolics as a Preoperative Embolization Treatment in Patients with Resectable Liver Malignancies.

PURPOSE: To assess the safety and tolerability of a vandetanib-eluting radiopaque embolic (BTG-002814) for transarterial chemoembolization (TACE) in patients with resectable liver malignancies. MATERIALS AND METHODS: The VEROnA clinical trial was a first-in-human, phase 0, single-arm, window-of-opportunity study. Eligible patients were aged ≥18 years and had resectable hepatocellular carcinoma (HCC) (Child-Pugh A) or metastatic colorectal cancer (mCRC). Patients received 1 mL of BTG-002814 transarterially (containing 100 mg of vandetanib) 7-21 days prior to surgery. The primary objectives were to establish the safety and tolerability of BTG-002814 and determine the concentrations of vandetanib and the N-desmethyl vandetanib metabolite in the plasma and resected liver after treatment. Biomarker studies included circulating proangiogenic factors, perfusion computed tomography, and dynamic contrast-enhanced magnetic resonance imaging. RESULTS: Eight patients were enrolled: 2 with HCC and 6 with mCRC. There was 1 grade 3 adverse event (AE) before surgery and 18 after surgery; 6 AEs were deemed to be related to BTG-002814. Surgical resection was not delayed. Vandetanib was present in the plasma of all patients 12 days after treatment, with a mean maximum concentration of 24.3 ng/mL (standard deviation ± 13.94 ng/mL), and in resected liver tissue up to 32 days after treatment (441-404,000 ng/g). The median percentage of tumor necrosis was 92.5% (range, 5%-100%). There were no significant changes in perfusion imaging parameters after TACE. CONCLUSIONS: BTG-002814 has an acceptable safety profile in patients before surgery. The presence of vandetanib in the tumor specimens up to 32 days after treatment suggests sustained anticancer activity, while the low vandetanib levels in the plasma suggest minimal release into the systemic circulation. Further evaluation of this TACE combination is warranted in dose-finding and efficacy studies.

Clinical outcomes, Kadish-INSICA staging and therapeutic targeting of somatostatin receptor 2 in olfactory neuroblastoma.

INTRODUCTION: Olfactory neuroblastoma (ONB) is a rare cancer of the sinonasal region. We provide a comprehensive analysis of this malignancy with molecular and clinical trial data on a subset of our cohort to report on the potential efficacy of somatostatin receptor 2 (SSTR2)-targeting imaging and therapy. METHODS: We conducted a retrospective analysis of 404 primary, locally recurrent, and metastatic olfactory neuroblastoma (ONB) patients from 12 institutions in the United States of America, United Kingdom and Europe. Clinicopathological characteristics and treatment approach were evaluated. SSTR2 expression, SSTR2-targeted imaging and the efficacy of peptide receptor radionuclide therapy [PRRT](177Lu-DOTATATE) were reported in a subset of our cohort (LUTHREE trial; NCT03454763). RESULTS: Dural infiltration at presentation was a significant predictor of overall survival (OS) and disease-free survival (DFS) in primary cases (n = 278). Kadish-Morita staging and Dulguerov T-stage both had limitations regarding their prognostic value. Multivariable survival analysis demonstrated improved outcomes with lower stage and receipt of adjuvant radiotherapy. Prophylactic neck irradiation significantly reduces the rate of nodal recurrence. 82.4% of the cohort were positive for SSTR2; treatment of three metastatic cases with SSTR2-targeted peptide-radionuclide receptor therapy (PRRT) in the LUTHREE trial was well-tolerated and resulted in stable disease (SD). CONCLUSIONS: This study presents pertinent clinical data from the largest dataset, to date, on ONB. We identify key prognostic markers and integrate these into an updated staging system, highlight the importance of adjuvant radiotherapy across all disease stages, the utility of prophylactic neck irradiation and the potential efficacy of targeting SSTR2 to manage disease.

Associations between cardiac irradiation and survival in patients with non-small cell lung cancer: Validation and new discoveries in an independent dataset.

INTRODUCTION: In 'IDEAL-6' patients (N = 78) treated for locally-advanced non-small-cell lung cancer using isotoxically dose-escalated radiotherapy, overall survival (OS) was associated more strongly with VLAwall-64-73-EQD2, the left atrial (LA) wall volume receiving 64-73 Gy equivalent dose in 2 Gy fractions (EQD2), than with whole-heart irradiation measures. Here we test this in an independent cohort 'OX-RT' (N = 64) treated routinely. METHODS: Using Cox regression analysis we assessed how strongly OS was associated with VLAwall-64-73-EQD2, with whole-heart volumes receiving 64-73 Gy EQD2 or doses above 10-to-70 Gy thresholds, and with principal components of whole-heart dose-distributions. Additionally, we tested associations between OS and volumes of cardiac substructures receiving dose-ranges described by whole-heart principal components significantly associated with OS. RESULTS: In univariable analyses of OX-RT, OS was associated more strongly with VLAwall-64-73-EQD2 than with whole-heart irradiation measures, but more strongly still with VAortV-29-38-EQD2, the volume of the aortic valve region receiving 29-38 Gy EQD2. The best multivariable OS model included LA wall and aortic valve region mean doses, and the aortic valve volume receiving ≥38 Gy EQD2, VAortV-38-EQD2. In a subsidiary analysis of IDEAL-6, the best multivariable model included VLAwall-64-73-EQD2, VAortV-29-38-EQD2, VAortV-38-EQD2 and mean aortic valve dose. CONCLUSION: We propose reducing heart mean doses to the lowest levels possible while meeting protocol dose-limits for lung, oesophagus, proximal bronchial tree, cord and brachial plexus. This in turn achieves large reductions in VAortV-29-38-EQD2 and VLAwall-64-73-EQD2, and we plan to closely monitor patients with values of these measures still >0% (their median value in OX-RT) following reduction.

An Evaluation of the Tolerability and Feasibility of Combining 5-Amino-Levulinic Acid (5-ALA) with BCNU Wafers in the Surgical Management of Primary Glioblastoma.

Background Glioblastoma (GBM) is the commonest primary malignant brain tumour in adults and effective treatment options are limited. Combining local chemotherapy with enhanced surgical resection using 5-aminolevulinic acid (5-ALA) could improve outcomes. Here we assess the safety and feasibility of combining BCNU wafers with 5-ALA-guided surgery. Methods We conducted a multicentre feasibility study of 5-ALA with BCNU wafers followed by standard-of-care chemoradiotherapy (chemoRT) in patients with suspected GBM. Patients judged suitable for radical resection were administered 5-ALA pre-operatively and BCNU wafers at the end resection. Post-operative treatment continued as per routine clinical practice. The primary objective was to establish if combining 5-ALA and BCNU wafers is safe without compromising patients from receiving standard chemoRT. Results Seventy-two patients were recruited, sixty-four (88.9%) received BCNU wafer implants, and fifty-nine (81.9%) patients remained eligible following formal histological diagnosis. Seven (11.9%) eligible patients suffered surgical complications but only two (3.4%) were not able to begin chemoRT, four (6.8%) additional patients did not begin chemoRT within 6 weeks of surgery due to surgical complications. Eleven (18.6%) patients did not begin chemoRT for other reasons (other toxicity (n = 3), death (n = 3), lost to follow-up/withdrew (n = 3), clinical decision (n = 1), poor performance status (n = 1)). Median progression-free survival was 8.7 months (95% CI: 6.4-9.8) and median overall survival was 14.7 months (95% CI: 11.7-16.8). Conclusions Combining BCNU wafers with 5-ALA-guided surgery in newly diagnosed GBM patients is both feasible and tolerable in terms of surgical morbidity and overall toxicity. Any potential therapeutic benefit for the sequential use of 5-ALA and BCNU with chemoRT requires further investigation with improved local delivery technologies.

Prognostic indices in diffuse large B-cell lymphoma in the rituximab era: an analysis of the UK National Cancer Research Institute R-CHOP 14 versus 21 phase 3 trial.

We compared the International Prognostic Index (IPI), Revised (R)-IPI and age-adjusted (aa)-IPI as prognostic indices for patients with diffuse large B-cell lymphoma (DLBCL) in the UK National Cancer Research Institute (NCRI) R-CHOP 14 versus 21 trial (N = 1080). The R-IPI and aa-IPI showed no marked improvement compared to the IPI for overall and progression-free survival, in terms of model fit or discrimination. Similar results were observed in exploratory analyses incorporating the Grupo Español de Linfomas/Transplante de Médula Ósea (GELTAMO)-IPI, where baseline ß2-microglobulin data were available (N = 655). Although our findings support current use of the IPI, a novel prognostic tool to better delineate a high-risk DLBCL group in the rituximab era is needed.

ICON 9-an international phase III randomized study to evaluate the efficacy of maintenance therapy with olaparib and cediranib or olaparib alone in patients with relapsed platinum-sensitive ovarian cancer following a response to platinum-based chemotherapy.

BACKGROUND: Two novel biological agents-cediranib targeting angiogenesis, and olaparib targeting DNA repair processes-have individually led to an improvement in ovarian cancer control. The aim of ICON9 is to investigate the combination of cediranib and olaparib maintenance in recurrent ovarian cancer following platinum-based therapy. PRIMARY OBJECTIVE: To assess the efficacy of maintenance treatment with olaparib in combination with cediranib compared with olaparib alone following a response to platinum-based chemotherapy in women with platinum-sensitive ovarian, fallopian tube or peritoneal cancer during first relapse. STUDY HYPOTHESIS: Maintenance therapy with cediranib and olaparib in combination is associated with improved patient outcomes compared with olaparib alone. TRIAL DESIGN: International phase III randomized controlled trial. Following a response to platinum-based chemotherapy patients are randomized 1:1 to either oral olaparib and cediranib (intervention arm) or oral olaparib alone (control arm). MAJOR INCLUSION CRITERIA: Patients with a known diagnosis of high grade serous or endometrioid carcinoma of the ovary, fallopian tube or peritoneum, progressing more than 6 months after first-line platinum-based chemotherapy, who have responded to second-line platinum-based chemotherapy. PRIMARY ENDPOINTS: Progression-free and overall survival. Co-primary endpoints to be assessed using a fixed-sequence gatekeeping approach: (1) progression-free survival, all patients; (2) progression-free survival, BRCA wild type; (3) overall survival, all patients; (4) overall survival, BRCA wild type. SAMPLE SIZE: 618 patients will be recruited. ESTIMATED DATES FOR COMPLETING ACCRUAL AND PRESENTING RESULTS: Accrual is expected to be completed in 2024 with presentation of results in 2025. TRIAL REGISTRATION: ClinicalTrials.gov: NCT03278717.

FDG-PET/CT after two cycles of R-CHOP in DLBCL predicts complete remission but has limited value in identifying patients with poor outcome - final result of a UK National Cancer Research Institute prospective study.

The UK National Cancer Research Institute initiated a prospective study (UKCRN-ID 1760) to assess the prognostic value of early fluorodeoxyglucose (FDG)-positron emission tomography (PET)/computed tomography (CT) in diffuse large B-cell lymphoma (DLBCL). In total, 189 patients with DLBCL treated with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone) had baseline and post-cycle-2 PET (PET2) within a quality assurance framework. Treatment decisions were based on CT; PET2 was archived for central blinded reporting after treatment completion. The association of PET2 response with end-of-treatment CT, progression-free (PFS) and overall survival (OS) was explored. The end-of-treatment complete response rate on CT was 83·9%, 75·0%, 70·5%, 40·4% and 36·4% for Deauville score (DS) 1 (n = 34), 2 (n = 39), 3 (n = 46), 4 (n = 56) and 5 (n = 14) (P < 0·001); and 64·1% and 50·0% for the maximum standardised uptake value (∆SUVmax ) of ≥66% (n = 168) and <66% (n = 21), respectively (P = 0·25). After a median 5·4 years of follow-up, the 5-year PFS was 69·4%, 72·8%, 76·7%, 71·2% and 47·6% by DS 1-5 (P = 0·01); and 72·6% and 57·1% by ∆SUVmax of ≥66% and <66% (P = 0·03), respectively. The association with DS remained in multivariable analyses, and was consistent for OS. Early complete metabolic response (DS 1-3) at interim PET/CT after two cycles of R-CHOP in DLBCL was associated with a higher end-of-treatment complete and overall response rate; however, only DS-5 patients had inferior PFS and OS.

Long-Term Results from the IDEAL-CRT Phase 1/2 Trial of Isotoxically Dose-Escalated Radiation Therapy and Concurrent Chemotherapy for Stage II/III Non-small Cell Lung Cancer.

PURPOSE: The IDEAL-CRT phase 1/2 multicenter trial of isotoxically dose-escalated concurrent chemoradiation for stage II/III non-small cell lung cancer investigated two 30-fraction schedules of 5 and 6 weeks' duration. We report toxicity, tumor response, progression-free survival (PFS), and overall survival (OS) for both schedules, with long-term follow-up for the 6-week schedule. METHODS AND MATERIALS: Patients received isotoxically individualized tumor radiation doses of 63 to 71 Gy in 5 weeks or 63 to 73 Gy in 6 weeks, delivered concurrently with 2 cycles of cisplatin and vinorelbine. Eligibility criteria were the same for both schedules. RESULTS: One-hundred twenty patients (6% stage IIB, 68% IIIA, 26% IIIB, 1% IV) were recruited from 9 UK centers, 118 starting treatment. Median prescribed doses were 64.5 and 67.6 Gy for the 36 and 82 patients treated using the 5- and 6-week schedules. Grade ≥3 pneumonitis and early esophagitis rates were 3.4% and 5.9% overall and similar for each schedule individually. Late grade 2 esophageal toxicity occurred in 11.1% and 17.1% of 5- and 6-week patients. Grade ≥4 adverse events occurred in 17 (20.7%) 6-week patients but no 5-week patients. Four adverse events were grade 5, with 2 considered radiation therapy related. After median follow-up of 51.8 and 26.4 months for the 6- and 5-week schedules, median OS was 41.2 and 22.1 months, respectively, and median PFS was 21.1 and 8.0 months. In exploratory analyses, OS was significantly associated with schedule (hazard ratio [HR], 0.56; 95% confidence interval [CI], 0.32-0.98; P = .04) and fractional clinical/internal target volume receiving ≥95% of the prescribed dose (HR, 0.88; 95% CI, 0.77-1.00; P = .05). PFS was also significantly associated with schedule (HR, 0.53; 95% CI, 0.33-0.86; P = .01). CONCLUSIONS: Toxicity in IDEAL-CRT was acceptable. Survival was promising for 6-week patients and significantly longer than for 5-week patients. Survival might be further lengthened by following the 6-week schedule with an immune agent, motivating further study of such combined optimized treatments.