Background Surgery is the main modality of cure for solid cancers and was prioritised to continue during COVID-19 outbreaks. This study aimed to identify immediate areas for system strengthening by comparing the delivery of elective cancer surgery during the COVID-19 pandemic in periods of lockdown versus light restriction. Methods This international, prospective, cohort study enrolled 20 006 adult (≥18 years) patients from 466 hospitals in 61 countries with 15 cancer types, who had a decision for curative surgery during the COVID-19 pandemic and were followed up until the point of surgery or cessation of follow-up (Aug 31, 2020). Average national Oxford COVID-19 Stringency Index scores were calculated to define the government response to COVID-19 for each patient for the period they awaited surgery, and classified into light restrictions (index <20), moderate lockdowns (20–60), and full lockdowns (>60). The primary outcome was the non-operation rate (defined as the proportion of patients who did not undergo planned surgery). Cox proportional-hazards regression models were used to explore the associations between lockdowns and non-operation. Intervals from diagnosis to surgery were compared across COVID-19 government response index groups. This study was registered at ClinicalTrials.gov , NCT04384926 . Findings Of eligible patients awaiting surgery, 2003 (10·0%) of 20 006 did not receive surgery after a median follow-up of 23 weeks (IQR 16–30), all of whom had a COVID-19-related reason given for non-operation. Light restrictions were associated with a 0·6% non-operation rate (26 of 4521), moderate lockdowns with a 5·5% rate (201 of 3646; adjusted hazard ratio [HR] 0·81, 95% CI 0·77–0·84; p<0·0001), and full lockdowns with a 15·0% rate (1775 of 11 827; HR 0·51, 0·50–0·53; p<0·0001). In sensitivity analyses, including adjustment for SARS-CoV-2 case notification rates, moderate lockdowns (HR 0·84, 95% CI 0·80–0·88; p<0·001), and full lockdowns (0·57, 0·54–0·60; p<0·001), remained independently associated with non-operation. Surgery beyond 12 weeks from diagnosis in patients without neoadjuvant therapy increased during lockdowns (374 [9·1%] of 4521 in light restrictions, 317 [10·4%] of 3646 in moderate lockdowns, 2001 [23·8%] of 11 827 in full lockdowns), although there were no differences in resectability rates observed with longer delays. Interpretation Cancer surgery systems worldwide were fragile to lockdowns, with one in seven patients who were in regions with full lockdowns not undergoing planned surgery and experiencing longer preoperative delays. Although short-term oncological outcomes were not compromised in those selected for surgery, delays and non-operations might lead to long-term reductions in survival. During current and future periods of societal restriction, the resilience of elective surgery systems requires strengthening, which might include...

Tumor treating fields (TTFields) is a new modality used for the treatment of glioblastoma. It is based on antineoplastic low-intensity electric fields induced by two pairs of electrode arrays placed on the patient’s scalp. The layout of the arrays greatly impacts the intensity (dose) of TTFields in the pathology. The present study systematically characterizes the impact of array position on the TTFields distribution calculated in a realistic human head model using finite element methods. We investigate systematic rotations of arrays around a central craniocaudal axis of the head and identify optimal layouts for a large range of (nineteen) different frontoparietal tumor positions. In addition, we present comprehensive graphical representations and animations to support the users’ understanding of TTFields. For most tumors, we identified two optimal array positions. These positions varied with the translation of the tumor in the anterior-posterior direction but not in the left-right direction. The two optimal directions were oriented approximately orthogonally and when combining two pairs of orthogonal arrays, equivalent to clinical TTFields therapy, we correspondingly found a single optimum position. In most cases, an oblique layout with the fields oriented at forty-five degrees to the sagittal plane was superior to the commonly used anterior-posterior and left-right combinations of arrays. The oblique configuration may be used as an effective and viable configuration for most frontoparietal tumors. Our results may be applied to assist clinical decision-making in various challenging situations associated with TTFields. This includes situations in which circumstances, such as therapy-induced skin rash, scar tissue or shunt therapy, etc., require layouts alternative to the prescribed. More accurate distributions should, however, be based on patient-specific models. Future work is needed to assess the robustness of the presented results towards variations in conductivity.

Background Preclinical studies suggest that skull remodeling surgery (SR-surgery) increases the dose of tumor treating fields (TTFields) in glioblastoma (GBM) and prevents wasteful current shunting through the skin. SR-surgery introduces minor skull defects to focus the cancer-inhibiting currents towards the tumor and increase the treatment dose. This study aimed to test the safety and feasibility of this concept in a phase 1 setting. Methods 15 adult patients with first recurrence of GBM were treated with personalized SR-surgery, TTFields and physician’s choice oncological therapy. The primary endpoint was toxicity and secondary endpoints included standard efficacy outcomes. Results SR-surgery resulted in a mean skull defect area of 10.6 cm 2 producing a median TTFields enhancement of 32% (range 25-59%). The median TTFields treatment duration was 6.8 months and the median compliance rate 90%. Patients received either bevacizumab, bevacizumab/irinotecan, or temozolomide rechallenge. We observed 71 adverse events (AEs) of grades 1 (52%), 2 (35%), and 3 (13%). There were no grade 4 or 5 AEs or intervention-related serious AEs. Six patients experienced minor TTFields-induced skin rash. The median progression-free survival (PFS) was 4.6 months and the PFS rate at 6 months was 36%. The median overall survival (OS) was 15.5 months and the OS rate at 12 months was 55%. Conclusions TTFields therapy combined with SR-surgery and medical oncological treatment is safe and non-toxic and holds potential to improve the outcome for GBM patients through focal dose enhancement in the tumor.

Background OptimalTTF-2 is a randomized, comparative, multi-center, investigator-initiated, interventional study aiming to test skull remodeling surgery in combination with Tumor Treating Fields therapy (TTFields) and best physicians choice medical oncological therapy for first recurrence in glioblastoma patients. OptimalTTF-2 is a phase 2 trial initiated in November 2020. Skull remodeling surgery consists of five burrholes, each 15 mm in diameter, directly over the tumor resection cavity. Preclinical research indicates that this procedure enhances the effect of Tumor Treating Fields considerably. We recently concluded a phase 1 safety/feasibility trial that indicated improved overall survival and no additional toxicity. This phase 2 trial aims to validate the efficacy of the proposed intervention. Methods The trial is designed as a comparative, 1:1 randomized, minimax two-stage phase 2 with an expected 70 patients to a maximum sample size of 84 patients. After 12-months follow-up of the first 52 patients, an interim futility analysis will be performed. The two trial arms will consist of either a) TTFields therapy combined with best physicians choice oncological treatment (control arm) or b) skull remodeling surgery, TTFields therapy and best practice oncology (interventional arm). Major eligibility criteria include age ≥ 18 years, 1st recurrence of supratentorial glioblastoma, Karnofsky performance score ≥ 70, focal tumor, and lack of significant co-morbidity. Study design aims to detect a 20% increase in overall survival after 12 months (OS12), assuming OS12 = 40% in the control group and OS12 = 60% in the intervention group. Secondary endpoints include hazard rate ratio of overall survival and progression-free survival, objective tumor response rate, quality of life, KPS, steroid dose, and toxicity. Toxicity, objective tumor response rate, and QoL will be assessed every 3rd month. Endpoint data will be collected at the end of the trial, including the occurrence of suspected unexpected serious adverse reactions (SUSARs), unacceptable serious adverse events (SAEs), withdrawal of consent, or loss-to-follow-up. Discussion New treatment modalities are highly needed for first recurrence glioblastoma. Our proposed treatment modality of skull remodeling surgery, Tumor Treating Fields, and best practice medical oncological therapy may increase overall survival significantly. Trial registration ClinicalTrials.gov Identifier: NCT0422399, registered 13. January 2020.