[18F]FDG-PET accurately identifies pathological response early upon neoadjuvant immune checkpoint blockade in head and neck squamous cell carcinoma

Purpose To investigate the utility of [18F]FDG-PET as an imaging biomarker for pathological response early upon neoadjuvant immune checkpoint blockade (ICB) in patients with head and neck squamous cell carcinoma (HNSCC) before surgery. Methods In the IMCISION trial (NCT03003637), 32 patients with stage II‒IVb HNSCC were treated with neoadjuvant nivolumab with (n = 26) or without (n = 6) ipilimumab (weeks 1 and 3) before surgery (week 5). [18F]FDG-PET/CT scans were acquired at baseline and shortly before surgery in 21 patients. Images were analysed for SUVmax, SUVmean, metabolic tumour volume (MTV), and total lesion glycolysis (TLG). Major and partial pathological responses (MPR and PPR, respectively) to immunotherapy were identified based on the residual viable tumour in the resected primary tumour specimen (≤ 10% and 11–50%, respectively). Pathological response in lymph node metastases was assessed separately. Response for the 2 [18F]FDG-PET-analysable patients who did not undergo surgery was determined clinically and per MR-RECIST v.1.1. A patient with a primary tumour MPR, PPR, or primary tumour MR-RECIST-based response upon immunotherapy was called a responder. Results Median ΔSUVmax, ΔSUVmean, ΔMTV, and ΔTLG decreased in the 8 responders and were significantly lower compared to the 13 non-responders (P = 0.05, P = 0.002, P < 0.001, and P < 0.001). A ΔMTV or ΔTLG of at least − 12.5% detected a primary tumour response with 95% accuracy, compared to 86% for the EORTC criteria. None of the patients with a ΔTLG of − 12.5% or more at the primary tumour site developed a relapse (median FU 23.0 months since surgery). Lymph node metastases with a PPR or MPR (5 metastases in 3 patients) showed a significant decrease in SUVmax (median − 3.1, P = 0.04). However, a SUVmax increase (median + 2.1) was observed in 27 lymph nodes (in 11 patients), while only 13 lymph nodes (48%) contained metastases in the corresponding neck dissection specimen. Conclusions Primary tumour response assessment using [18F]FDG-PET-based ΔMTV and ΔTLG accurately identifies pathological responses early upon neoadjuvant ICB in HNSCC, outperforming the EORTC criteria, although pseudoprogression is seen in neck lymph nodes. [18F]FDG-PET could, upon validation, select HNSCC patients for response-driven treatment adaptation in future trials. Trial registration https://www.clinicaltrials.gov/, NCT03003637, December 28, 2016.

334. Impact of Overall Dexamethasone Exposure on Development of Invasive Pulmonary Aspergillosis in Hospitalized Patients with COVID-19

Background Abbreviated courses of corticosteroids, such as dexamethasone, have demonstrated significant improvements in clinical outcomes among patients infected with COVID-19, although chronic corticosteroid use can predispose patients to opportunistic infections. The RECOVERY trial investigators showed reduced 28-day mortality among patients treated with 6 mg/day dexamethasone for up to 10 days, however in clinical practice the dosage and duration of dexamethasone therapy can vary widely based on severity of disease and provider discretion. Upon observing an anecdotal increase in the number of patients presenting with potential invasive aspergillosis during the third wave of COVID-19, we sought to evaluate the impact of overall dexamethasone exposure on the development of invasive pulmonary aspergillosis. Methods Patients presenting to our institution from Dec. 2020 – Jan. 2021 with positive PCR for SARS-CoV-2 were screened for dexamethasone therapy. Assignment of high vs low dose dexamethasone groups were retrospectively made based on overall dexamethasone exposure. Low dose dexamethasone assignment was restricted to a total exposure of no more than 78 mg during a patient’s hospitalization. Adjudication of invasive pulmonary aspergillosis was made based on criteria that included host factors, radiologic findings, clinical factors, and mycological evidence. Results Dexamethasone therapy was provided to 202 patients admitted to the hospital with COVID-19. Invasive pulmonary aspergillosis was determined to be probable in n=7 patients based on European Organization for Research and Treatment of Cancer (EORTC) criteria, and in n=13 patients based on expanded criteria. Patients in the low dose dexamethasone group were less likely to be diagnosed with probable IPA based on EORTC criteria (n=0, 0% on low dose vs. n=7, 11% on high dose) as well as expanded criteria (n=9, 5% on low dose vs. n=11, 17% on high dose), p&lt; 0.001. Conclusion Patients hospitalized with COVID-19 receiving high-dose dexamethasone may be at a higher risk of opportunistic infections such as invasive pulmonary aspergillosis compared to patients who receive low-dose dexamethasone therapy. Further investigation is needed to obtain higher certainty of IPA diagnosis. Disclosures All Authors: No reported disclosures

P14.78 Comparison of progression-free survival after reirradiation of local and distant glioblastoma’s relapses

BACKGROUND Despite using of modern comprehensive approaches to the treatment of patients with glioblastomas (GB) it invariably recur after a median interval of less than 7 months. Relapses are inevitable and is often the leading cause of death in patients. About 80–90% of recurrences are local, distant relapses are 5–20%. The optimal treatment strategy of recurrent GB have not yet been determined. MATERIAL AND METHODS The analysis included 130 patients with 160 lesions after primary combined treatment. Progression was assessed based on the RANO criteria. All patients have been re-irradiated in various regimens: 26 pts with median dose 60 Gy/30 fr, 20 pts with median dose 45 Gy/15 fr, 74 pts with dose 24-35Gy for 3–7 fr., 10 pts with median dose 22Gy/1fr. The scheme and regimen of fractionation were determined by tumor volume, localization and functional status of patient. Chemotherapy was changed to a regimen with Bevacizumab (BVZ) before the re-irradiation. According to the EORTC criteria lesions were divided as local (n=112) and distant (n=48) progression with median volume 23.6 cc and 14.7 cc respectively. RESULTS The median progression-free survival in the whole group was 8.2 months(95% CI 7–8.7). Progression-free survival at 6; 12 and 24 months was 65.8%; 21.9% and 4% respectively. Progression-free median survival after treatment of local and distant glioblastoma recurrences was different: 7.6 and 9.2 months, respectively (p = 0.048). In 17.4% radiation necrosis was detected according to MRI and 11C-methionine PET-CT data. Steroid and BVZ therapy were effective in these cases, no one of them was reoperated. CONCLUSION Re-irradiation for GB recurrences is effective and safe way for improvement of outcomes in patients with progression. In the group of patients with local relapses, local control is lower than in the group of distant ones. It may associated with the increasing of the radioresistance of tumor cells after the initial combined treatment. Further studies are needed to compare and assess the role of radiobiological and others factors in the development of local and distant recurrence.The research was supported financially by RFBR (Project No. 18-29-01061).

Profile of Mucormycosis Cases from a Network of Hospitals in North India Amidst COVID-19 Pandemic

Incidence of mucormycosis suddenly surged in India after the second wave of COVID-19. This is a crippling disease and needs to be studied in detail to understand the disease, its course, and the outcomes. Between 1st March and 15th July 2021, our network of hospitals in North India received a total of 155 cases of COVID-associated mucormycosis cases as all of them reported affliction by COVID-19 earlier or concurrent. Their records were retrieved from the Electronic Health Records system of the hospitals and their demographics, clinical features, treatments, and outcomes were studied. More than 80% (125 cases) had proven disease and the remaining 30 were categorized as possible mucormycosis as per the EORTC criteria. More than two-thirds (69.0%) of the cases were males and the mean age was 53 years for either sex. Nearly two-thirds (64.5%) had symptoms of nose and jaws and 42.6% had eye involvement. Some had multiple symptoms. As many as 78.7% had diabetes and 91.6% gave history of use of steroids during COVID-19 treatment. The primary surgery was functional endoscopic sinus surgery (FESS) (83.9%). Overall mortality was 16.8%, which is one-and-a-half times the mortality in hospitalized COVID-19 patients in the corresponding population. Occurrence of mucormycosis was associated with diabetes and use of steroids, but mortality was not associated with either of them. Cases undergoing surgery and on antifungal had steeply lower mortality (11.9% vs. 50.0%, P < 0.001) than those who were exclusively on antifungal drugs. Treatment by different drugs did not make much of a difference in mortality.

Evaluation of treatment-associated eye toxicity after irradiation in childhood and adolescence—results from the Registry of the Evaluation of Side Effects after Radiotherapy in Childhood and Adolescence (RiSK)

Purpose The aim of the study is to evaluate treatment-related acute and late eye toxicity associated with radiation therapy in childhood and adolescence as correlated with RT (radiotherapy) doses. Methods From 2001 to 2016, a total of 1725 children and adolescents undergoing radiation therapy were prospectively documented in the Registry of the Evaluation of Side Effects after Radiotherapy in Childhood and Adolescence (RiSK). The RTOG/EORTC criteria were used to classify ocular acute and late effects. Uni- and multivariate analyses were carried out to evaluate the impact of patient age, pre-existing impairments, and radiation dose on ocular toxicity. Results Of all documented patients, 593 received dose to the eye and formed the basis of this analysis. In 435 patients, information on acute reaction was available and graded 1, 2, 3, and 4 in 49, 17, 0, and 2 patients, respectively. Information on late toxicity was available in 268 patients and graded 1, 2, 3, and 4 in 15, 11, 11, and 5 patients, respectively. The acute toxicity rate was significantly higher in children who received a maximum dose > 50 Gy to the eye (p < 0.001) and who had a pre-existing eye impairment (p < 0.001 in multivariate analysis). The development of late toxicity was significantly higher for patients experiencing acute toxicity and having received a radiation dose > 50 Gy. Conclusion Acute and late toxicity both correlate with high radiation dose to the eye (> 50 Gy) and acute toxicity additionally with pre-existing eye impairments.

Efficacy and safety of JMT103 in patients with giant cell tumor of bone: A multicenter, single-arm, open-label, phase Ib/II study.

11526 Background: JMT103 is a novel, fully humanized IgG4 monoclonal antibody targeting RANKL, inhibiting osteoclastogenesis and osteoclast-mediated bone resorption. A multicenter, single-arm, open-label, phase Ib/II study was conducted to evaluate the efficacy and safety of JMT103 in patients (pts) with Giant cell tumor of bone (GCTB). Methods: Eligible pts (ECOG: 0-2) were adults with pathologically confirmed unresectable GCTB or their planned surgery is associated with severe morbidity. Pts with active dental or jaw condition requiring oral surgery, other anti-tumor therapies, anti-RANKL antibody or concurrent use of bisphosphonates were excluded. 2 mg/kg JMT103 was administrated subcutaneously every 4 weeks with a loading dose on days 8 and day 15 of the first 4 week of therapy. The primary endpoint was tumor response, defined as elimination of at least 90% giant cells or objective response of the target lesion assessed by radiologic imaging as per Modified Inverse Choi density/size (ICDS) or the Modified European Organization for Research and Treatment of Cancer (EORTC) criteria within 12 weeks. Secondary endpoints included safety profile, change of pain score using Brief Pain Inventory-Short Form, and suppression of bone-resorption biomarkers. Results: 38 pts (14 males) were enrolled between June 3 and December 24, 2020. The median age was 31 years (range 18-57). Lesions sites included lower extremities (39.5%), upper extremities (31.6%), spine (21.1%) and pelvis (13.2%). Among 32 pts with at least 1 efficacy evaluation within 12 weeks, 26 (81.3%, 95% CI: 63.6-92.8) had a tumor response by at least one response criteria. All 7 pts who underwent histological assessments had a tumor response. 25 of 32 pts assessed by radiology had a tumor response. As per ICDS criteria, 23 of 32 (71.9%) had a response; as per EORTC criteria, 15 of 17 (88.2%) had a response. 21 of 26 (80.8%) pts who complained of pain at baseline experienced reduced pain during the treatment. The median reductions in bone-resorption biomarkers were 71.8% (IQR 67.7-82.4) for uNTx/Cr (p < 0.001) and 81.4% (IQR 68.3-84.7) for sCTx (p < 0.001) at day 8. Of all 38 pts who were included in safety analyses, treatment-related adverse events (TRAEs) occurred in 14 pts. The most common TRAEs were hypophosphatemia (18.4%), hypocalcemia (7.9%) and blood bilirubin increased (7.9%). 1 patient (2.6%) was reported a grade 3 AE but it was not related to the treatment; other AEs were grade 1–2. Conclusions: JMT103 demonstrated encouraging anti-tumor efficacy and manageable safety profile in pts with unresectable GCTB or at high risk of severe morbidity after surgery. Clinical trial information: NCT04255576.

Toxicity Reduction after Craniospinal Irradiation via Helical Tomotherapy in Patients with Medulloblastoma: A Unicentric Retrospective Analysis

Objectives: Recent trials with craniospinal irradiation (CSI) via helical Tomotherapy (HT) demonstrated encouraging medulloblastoma results. In this study, we assess the toxicity profile of different radiation techniques and estimate survival rates. Materials and Methods: We reviewed the records of 46 patients who underwent irradiation for medulloblastoma between 1999 and 2019 (27 conventional radiotherapy technique (CRT) and 19 HT). Patient, tumor, and treatment characteristics, as well as treatment outcomes—local control rate (LCR), event-free survival (EFS), and overall survival (OS)—were reviewed. Acute and late adverse events (AEs) were evaluated according to the Radiation Therapy Oncology Group and the European Organization for Research and Treatment of Cancer (RTOG/EORTC) criteria. Results: In total, 43 courses of CSI and three local RT were administered to the 46 patients: 30 were male, the median age was 7 years (range 1–56). A median total RT dose of 55 Gy (range 44–68) and a median CSI dose of 35 Gy (range, 23.4–40) was delivered. During follow-up (median, 99 months), six patients (13%) developed recurrence. The EFS rate after 5 years was 84%. The overall OS rates after 5 and 10 years were 95% and 88%, respectively. There were no treatment-related deaths. Following HT, a trend towards lower grade 2/3 acute upper gastrointestinal (p = 0.07) and subacute CNS (p = 0.05) toxicity rates was detected compared to CRT-group. The risk of late CNS toxicities, mainly grade 2/3, was significantly lower following HT technique (p = 0.003). Conclusion: CSI via HT is an efficacious treatment modality in medulloblastoma patients. In all, we detected a reduced rate of several acute, subacute, and chronic toxicities following HT compared to CRT.

Interim [18F]FDG PET/CT can predict response to anti-PD-1 treatment in metastatic melanoma

Purpose In an attempt to identify biomarkers that can reliably predict long-term outcomes to immunotherapy in metastatic melanoma, we investigated the prognostic role of [18F]FDG PET/CT, performed at baseline and early during the course of anti-PD-1 treatment. Methods Twenty-five patients with stage IV melanoma, scheduled for treatment with PD-1 inhibitors, were enrolled in the study (pembrolizumab, n = 8 patients; nivolumab, n = 4 patients; nivolumab/ipilimumab, 13 patients). [18F]FDG PET/CT was performed before the start of treatment (baseline PET/CT) and after the initial two cycles of PD-1 blockade administration (interim PET/CT). Seventeen patients underwent also a third PET/CT scan after administration of four cycles of treatment. Evaluation of patients’ response by means of PET/CT was performed after application of the European Organization for Research and Treatment of Cancer (EORTC) 1999 criteria and the PET Response Evaluation Criteria for IMmunoTherapy (PERCIMT). Response to treatment was classified into 4 categories: complete metabolic response (CMR), partial metabolic response (PMR), stable metabolic disease (SMD), and progressive metabolic disease (PMD). Patients were further grouped into two groups: those demonstrating metabolic benefit (MB), including patients with SMD, PMR, and CMR, and those demonstrating no MB (no-MB), including patients with PMD. Moreover, patterns of [18F]FDG uptake suggestive of radiologic immune-related adverse events (irAEs) were documented. Progression-free survival (PFS) was measured from the date of interim PET/CT until disease progression or death from any cause. Results Median follow-up from interim PET/CT was 24.2 months (19.3–41.7 months). According to the EORTC criteria, 14 patients showed MB (1 CMR, 6 PMR, and 7 SMD), while 11 patients showed no-MB (PMD). Respectively, the application of the PERCIMT criteria revealed that 19 patients had MB (1 CMR, 6 PMR, and 12 SMD), and 6 of them had no-MB (PMD). With regard to PFS, no significant difference was observed between patients with MB and no-MB on interim PET/CT according to the EORTC criteria (p = 0.088). In contrary, according to the PERCIMT criteria, patients demonstrating MB had a significantly longer PFS than those showing no-MB (p = 0.045). The emergence of radiologic irAEs (n = 11 patients) was not associated with a significant survival benefit. Regarding the sub-cohort undergoing also a third PET/CT, 14/17 patients (82%) showed concordant responses and 3/17 (18%) had a mismatch of response assessment between interim and late PET/CT. Conclusion PET/CT-based response of metastatic melanoma to PD-1 blockade after application of the recently proposed PERCIMT criteria is significantly correlated with PFS. This highlights the potential ability of [18F]FDG PET/CT for early stratification of response to anti-PD-1 agents, a finding with possible significant clinical and financial implications. Further studies including larger numbers of patients are necessary to validate these results.

Predicting tumor response and outcome of second-look surgery with 18F-FDG PET/CT: insights from the GINECO CHIVA phase II trial of neoadjuvant chemotherapy plus nintedanib in stage IIIc-IV FIGO ovarian cancer

Background This ancillary study aimed to evaluate 18F-FDG PET parameter changes after one cycle of treatment compared to baseline in patients receiving first-line neoadjuvant anti-angiogenic nintedanib combined to paclitaxel-carboplatin chemotherapy or chemotherapy plus placebo and to evaluate the ability of 18F-FDG PET parameters to predict progression-free survival (PFS), overall survival (OS), and success of second-look surgery. Materials and methods Central review was performed by two readers blinded to the received treatment and to the patients’ outcome, in consensus, by computing percentage change in PET metrics within a volume of interest encompassing the entire tumor burden. EORTC and PERCIST criteria were applied to classify patients as responders (partial metabolic response and complete metabolic response) or non-responders (stable metabolic disease and progressive metabolic disease). Also analyzed was the percentage change in metabolic active tumor volume (MATV) and total lesion glycolysis (TLG). Results Twenty-four patients were included in this ancillary study: 10 received chemotherapy + placebo and 14 chemotherapy + nintedanib. PERCIST and EORTC criteria showed similar discriminative power in predicting PSF and OS. Variation in MATV/TLG did not predict PFS or OS, and no optimal threshold could be found for MATV/TLG for predicting survival. Complete cytoreductive surgery (no residual disease versus residual disease < 0.25 cm/0.25–2.5 cm/> 2.5 cm) was more frequent in responders versus non-responders (P = 0.002 for PERCIST and P = 0.02 for EORTC criteria). No correlation was observed between the variation of PET data and the variation of CA-125 blood level between baseline sample and that performed contemporary to the interim PET, but a statistically significant correlation was observed between ΔSULpeak and ΔCA-125 between baseline sample and that performed after the second cycle. Conclusion 18F-FDG PET using EORTC or PERCIST criteria appeared to be a useful tool in ovarian cancer trials to analyze early tumor response, and predict second-look surgery outcome and survival. An advantage of PERCIST is the correlation of ΔSULpeak and ΔCA-125, PET response preceding tumor markers response by 1 month. Neither MATV nor TLG was useful in predicting survival. Trial registration NCT01583322 ARCAGY/ GINECO GROUP GINECO-OV119, 24 April 2012

Proton re-irradiation of unresectable recurrent head and neck cancers

Purpose: This study presents a retrospective analysis (efficacy and toxicity) of outcomes in patients with unresectable recurrence of previously irradiated head and neck cancers, treated with proton therapy.Methods: From November 2015 to January 2020, 30 patients with in-field recurrence of head and neck cancer, who were not suitable for surgery, due to medical contraindications, tumor localization or extent, received re-irradiation with intensity-modulated proton therapy (IMPT). Sites of retreatment included the aerodigestive tract (60%) and base of the skull (40%). The median total dose of prior radiotherapy was 55.0 Gy. The median time to the second course was 38 months. The median re-irradiated tumor volume was 158.1 cm3. Patients were treated with 2.0, 2.4 and 3.0 GyRBE per fraction, with a median EQD2 of 57.6 Gy (α/β=10). Radiation-induced toxicity was recorded according to the RTOG/EORTC criteria.Results: The 1- and 2-years LC, RFS, and OS were 52.6/21.0, 21.9/10.9 and 73.4/8.4%, respectively, with a median follow-up time of 21 months. The median overall survival was 16 months. Acute grade 3 toxicity was observed in 1 patient (3.3%). There were 5 late severe side effects (16.6%), with one death associated with re-irradiation.Conclusion: Re-irradiation with a proton beam can be considered a safe and efficient treatment even for a group of patients with unresectable recurrent H&N cancers.