Targeting Treatment Resistance in Head and Neck Squamous Cell Carcinoma – Proof of Concept for CT Radiomics-Based Identification of Resistant Sub-Volumes

PurposeRadiomics has already been proposed as a prognostic biomarker in head and neck cancer (HNSCC). However, its predictive power in radiotherapy has not yet been studied. Here, we investigated a local radiomics approach to distinguish between tumor sub-volumes with different levels of radiosensitivity as a possible target for radiation dose intensification.Materials and MethodsOf 40 patients (n=28 training and n=12 validation) with biopsy confirmed locally recurrent HNSCC, pretreatment contrast-enhanced CT images were registered with follow-up PET/CT imaging allowing identification of controlled (GTVcontrol) vs non-controlled (GTVrec) tumor sub-volumes on pretreatment imaging. A bi-regional model was built using radiomic features extracted from pretreatment CT in the GTVrec and GTVcontrol to differentiate between those regions. Additionally, concept of local radiomics was implemented to perform detection task. The original tumor volume was divided into sub-volumes with no prior information on the location of recurrence. Radiomic features from those sub-volumes were then used to detect recurrent sub-volumes using multivariable logistic regression.ResultsRadiomic features extracted from non-controlled regions differed significantly from those in controlled regions (training AUC = 0.79 CI 95% 0.66 - 0.91 and validation AUC = 0.88 CI 95% 0.72 – 1.00). Local radiomics analysis allowed efficient detection of non-controlled sub-volumes both in the training AUC = 0.66 (CI 95% 0.56 – 0.75) and validation cohort 0.70 (CI 95% 0.53 – 0.86), however performance of this model was inferior to bi-regional model. Both models indicated that sub-volumes characterized by higher heterogeneity were linked to tumor recurrence.ConclusionLocal radiomics is able to detect sub-volumes with decreased radiosensitivity, associated with location of tumor recurrence in HNSCC in the pre-treatment CT imaging. This proof of concept study, indicates that local CT radiomics can be used as predictive biomarker in radiotherapy and potential target for dose intensification.

Efficacy of dose intensification in induction therapy for localized Ewing sarcoma: Italian Sarcoma Group (ISG) and Associazione Italiana Ematologia ed Oncologia Pediatrica (AIEOP) ISG/AIEOP EW-1 study.

11501 Background: The role of dose intensification of chemotherapy in Ewing sarcoma (ES) is under evaluation in prospective trials. This is a controlled, randomized phase III study evaluating the impact on event-free survival (EFS) of two arms at different intensity of induction therapy in localized ES at onset. Methods: Newly diagnosed localized ES patients aged 2-40 were eligible. They were randomized to receive 4-courses induction therapy - 1 every 21 days - either with a standard arm (arm A) as per ISG/SSGIII protocol (Ferrari S, et at, Ann Oncol. 2011;22(5):1221) or with an intense arm B, consisting of vincristine 1,5mg/sqm+ doxorubicin 80mg/sqm+ifosfamide 9g/sqm for each course. After induction, patients underwent surgery and/or radiotherapy,followed by an adaptive treatment. Good responders received standard courses chemotherapy: arm A pts received 9 courses, while arm B pts received 5 courses. Poor responders in both arms received 4 courses followed by high-dose busulfan/melphalan+autologous stem cell rescue. The primary outcome measure was EFS for the 2 arms in the intention-to-treat population. Kaplan-Meier curves compared with log-rank test and Cox model were performed to assess differences between study arms. A secondary outcome was toxicity differences, assessed by means of the Fisher’s exact test. Initial sample size was 230 pts, type I error rate 5%, power 80%. Results: Between 2009 and 2019, 234 patients were randomized (arm A-115; arm B-119). M:F ratio was 1.8; median age 14 years (range 2-40); tumour site extremity in 55%, axial/pelvis in 45%; tumour volume < 200ml in 31% and ≥200ml in 69%. A good response was obtained in 56% in arm A and 60% in arm B. Median follow-up was 68 months. EFS was not significantly different between arms; HR: 0.85; 95% CI: 0,51-1,41, 5-year EFS (95% CI) was 73% (64-82%) in arm A and 75% (67-83%) in arm B ( p = 0.526). Good responders in arm A and in arm B and poor responders in arm B had comparable results: 5-year EFS (95% CI) was 80% (71-91%), 77% (67-88%), and 72% (59-86%), respectively, while poor responders in arm A showed a worse, not statistically significant (p = 0.164) performance (63%; 50-78%). Subgroup analyses showed similar outcome for age, tumour site and volume in both arms. Hematological, gastrointestinal, and cardiovascular grade ≥3 toxicities were more pronounced in arm B (p < 0.05). Conclusions: Intense induction therapy with arm B did not improve 5-year EFS when compared with the standard arm A. The higher toxicity observed in arm B than in arm A was counterbalanced, in good responders, by a similar outcome with a shorter treatment plan. For poor responders, with almost 30 patients per arm event-free and with < 48-month FUP, better 5-year EFS in arm B than in arm A was observed but needs further observation. Clinical trial information: NCT02063022.

Frequency and Effectiveness of Empirical Anti-TNF Dose Intensification in Inflammatory Bowel Disease: Systematic Review with Meta-Analysis

Loss of response to antitumor necrosis factor (anti-TNF) therapies in inflammatory bowel disease occurs in a high proportion of patients. Our aim was to evaluate the loss of response to anti-TNF therapy, considered as the need for dose intensification (DI), DI effectiveness and the possible variables influencing its requirements. Bibliographical searches were performed. Selection: prospective and retrospective studies assessing DI in Crohn’s disease and ulcerative colitis patients treated for at least 12 weeks with an anti-TNF drug. Exclusion criteria: studies using anti-TNF as a prophylaxis for the postoperative recurrence in Crohn’s disease or those where DI was based on therapeutic drug monitoring. Data synthesis: effectiveness by intention-to-treat (random effects model). Data were stratified by medical condition (ulcerative colitis vs. Crohn’s disease), anti-TNF drug and follow-up. Results: One hundred and seventy-three studies (33,241 patients) were included. Overall rate of the DI requirement after 12 months was 28% (95% CI 24–32, I2 = 96%, 41 studies) in naïve patients and 39% (95% CI 31–47, I2 = 86%, 18 studies) in non-naïve patients. The DI requirement rate was higher both in those with prior anti-TNF exposure (p = 0.01) and with ulcerative colitis (p = 0.02). The DI requirement rate in naïve patients after 36 months was 35% (95% CI 28–43%; I2 = 98%; 18 studies). The overall short-term response and remission rates of empirical DI in naïve patients were 63% (95% CI 48–78%; I2 = 99%; 32 studies) and 48% (95% CI: 39–58%; I2 = 92%; 25 studies), respectively. The loss of response to anti-TNF agents―and, consequently, DI―occurred frequently in inflammatory bowel disease (approximately in one-fourth at one year and in one-third at 3 years). Empirical DI was a relatively effective therapeutic option.

P277 Frequency and effectiveness of empirical anti-TNF dose intensification in Inflammatory Bowel Disease: systematic review with meta-analysis

Background Loss of response to anti-TNF (tumor necrosis factor) therapies in inflammatory bowel disease occurs in a high proportion of patients. However, the precise incidence of dose intensification (DI) and its effectiveness remains unclear. Our aims were: 1) To evaluate the need of DI of anti-TNF therapy either by increasing the dose or decreasing doses’ interval; 2) To evaluate possible variables influencing its requirement; 3) To assess the effectiveness of empirical DI. Methods Bibliographical searches were performed in Pubmed, Embase, the Cochrane Library and CINAHL. Selection: prospective and retrospective studies assessing loss of response to anti-TNF therapy, considered as the need of DI, in Crohn’s disease (CD) and ulcerative colitis (UC) patients treated for at least 12 weeks with an anti-TNF drug [infliximab (IFX), adalimumab (ADA), certolizumab or golimumab]. Exclusion criteria: studies using anti-TNF as prophylaxis for postoperative recurrence in CD or those where DI was based on therapeutic drug monitoring. Data synthesis: Effectiveness by intention-to-treat (random effects model). Data were stratified by medical condition (UC vs. CD), anti-TNF drug and follow-up. Subgroup analyses were performed to explore heterogeneity. Results In total, 174 studies (32,031 patients) were included. The overall rate of DI requirement after 12 months follow-up was 27% (95%CI 23-31, I2=96%, 51 studies) in naïve patients and 38% (95%CI 31-46, I2=87%, 18 studies) in non-naïve patients. The rate of DI requirement was higher in patients with prior anti-TNF exposure (c²=6.5, P=0.01) and in UC patients (c²=4.7, P=0.03). The rate of DI requirement in naïve patients after 36 months follow-up was 35% (95%CI 27-43%; I2=98%; 22 studies). The overall short-term response and remission rates to empirical DI in naïve patients were 66% (95%CI 61-71%; I2=81%; 35 studies) and 48% (95%CI 35-62%; I2=97%; 27 studies), respectively. Subgroup analyses are presented in the tables. Conclusion Loss of response to anti-TNF agents ―and consequent DI― occur frequently in IBD (approximately in 1/4 at one year and in 1/3 at 3 years). DI requirement is higher in UC patients and in those with prior anti-TNF exposure. Empirical DI is a relatively effective therapeutic option.

P441 Clinical efficacy, drug sustainability and results from therapeutic drug monitoring in Crohn’s disease patients treated with ustekinumab – 1-year follow-up of a prospective, nationwide, multicenter cohort from Hungary

Background Although efficacy and safety of ustekinumab (UST) in the treatment of inflammatory bowel disease have been demonstrated through randomized trials, data from real-life prospective cohorts are still of great interest. Our aim was to evaluate the clinical efficacy, drug sustainability, frequency of dose intensification, and results from therapeutic drug monitoring in UST treated Crohn’s disease (CD) patients using a prospective, nationwide, multicenter cohort from Hungary. Methods Patients were consecutively enrolled in this cohort between 2019 January and 2020 May from 5 academic centers and 5 county hospitals. Data from patient demographics, disease phenotype, treatment history (surgical history, prior and present medical therapies), clinical disease activity (using the Crohn’s Disease Activity Index (CDAI), Harvey Bradshaw Index (HBI)), biomarkers (C-reactive protein – CRP), and therapeutic drug monitoring were captured. Evaluations were performed at week8 (post-induction), w16-20, w32-36, and w52-56 follow-up visits. Results N=142 CD patients were included with a median follow-up time of 60 weeks (IQR:47.5–79.5w) [57.4% female; age 38.4±13.0 years]. Based on the Montreal classification, complicated disease behavior (B2orB3) was 48.2%, whereas ileocolonic disease location(L3) 55.7%. Perianal manifestation was present in 46.8% of the patients. Previous anti-TNF exposition was 97.2%, while previous vedolizumab failure was 25.5%. 66.2%/ 66.9% of the patients had moderate-to-sever clinical disease activity at baseline (CDAI&gt;220/HBI&gt;7). Clinical response and remission rates were 78.1% and 57.7% using CDAI, and 82.5% and 51.8% based on HBI scores after induction treatment (w8). One year clinical remission rates were 58% / 57.3% (CDAI/HBI) Composite clinical and biomarker remission (CDAI&lt;150 and CRP&lt;10mg/L) rates were 35.4%; 33.3%; 38.6% and 36.6% at w8/w16-20/w32-36 and w52-56. Parallel corticosteroid use was 34%/26.3%/16.5%/21%/16.9% at baseline and w8/w16-20/w32-36/w52-56. Drug sustainability was high with 81.9% (SD: 3.4) of patients remaining on treatment at one year.(Figure1) Probability of dose intensification was high and introduced early in the treatment, 42.2% (SD: 4.2) at ~w32 and 51.9% (SD: 4.4%) at 1y.(Figure2) Patients with complex disease phenotype (B2/B3) had higher probability for dose intensification (log-rank: p=0.042). Mean serum trough levels of UST were 4,28±3,35/ 1,35±1,42/ 0,82±0,65 and 1,13±0,74µg/mL measured at w8/w16-20/w32-36 and w52-56. ADAs were exceeding 1AU/mL in only 2 patients. Conclusion Ustekinumab showed good drug sustainability and clinical efficacy in a population with severe disease phenotype and high rates of previous anti-TNF failure, however frequent and early dose intensification was required.

P483 Infliximab but not adalimumab drug levels predict faecal calprotectin response in Inflammatory Bowel Disease patients on dose-intensified anti-TNF therapy

Background Secondary loss of response (SLOR) to infliximab (IFX) and adalimumab (ADA) is common and dose intensification is effective in a proportion of patients. Drug level targets associated with response as measured by faecal calprotectin (FCP) after anti-TNF intensification have not been well established. Methods Retrospective observational study of consecutive adult patients with Crohn’s disease (CD) or ulcerative colitis (UC) with SLOR commenced on dose-intensified IFX (5mg/kg 6 weekly) or ADA (40mg weekly) between May 2013-August 2020. Patients were managed via a protocolised virtual clinic. Trough anti-TNF drug levels and FCP were measured at baseline, and at 6 and 12 months post dose intensification. FCP response was defined as ≤150μg/g. Inter-group and longitudinal comparisons used Mann-Whitney U and Wilcoxon signed-rank tests, respectively. ROC curves evaluated anti-TNF drug levels predictive of FCP response. Results Of 78 patients (56% male, median age 40 years), 60 had CD (58% on IFX) and 18 had UC (100% on IFX). There were no significant differences in patient or disease demographics between FCP responders and non-responders at 6 or 12 months. At 6 months, median IFX level and increment in level from baseline were higher in FCP responders than non-responders in both CD and UC (Table 1). At 6 months, achieving an IFX level ≥5.7μg/mL in CD (AUC 0.82, sensitivity 88%, specificity 65%, p=0.012; Figure 1A) and an IFX level ≥5.2μg/mL in UC (AUC 0.89, sensitivity 100%, specificity 73%, p=0.015; Figure 1B) best predicted FCP response. ADA levels at 6 months and both IFX and ADA levels at 12 months were not predictive of FCP response in any cohort. Conclusion After dose-intensified IFX, CD and UC patients achieving FCP response had greater absolute and increment in drug levels than those with elevated FCP. IFX levels ≥5.7μg/mL and ≥5.2μg/mL at 6 months are predictive of FCP response in CD and UC, respectively. ADA levels were not predictive of FCP response.

P412 Effectiveness of ustekinumab in fistulising perianal Crohn′s disease refractory or intolerant to anti-TNF

Background The management of fistulising perianal Crohn′s disease (pCD) is a challenging problem for patients and physicians. New therapeutic alternatives are needed, particularly in anti-TNF refractory patients. Data regarding ustekinumab (UST) effectiveness in pCD are scarce. Our aim was to evaluate the clinical and radiologic effectiveness of UST in pCD patients refractory or intolerant to anti-TNF. Methods We conducted a multi-center retrospective observational study. All patients with anti-TNF refractory pCD treated with UST were evaluated. Demographic and clinical variables including concomitant drugs were registered. Clinical response was evaluated at 16 weeks and 12 months and was defined as a reduction of 50% of draining fistulas or a marked reduction in fistula drainage. In patients with a magnetic resonance imaging (MRI) before and after treatment initiation, radiologic response was defined according to Ng Score (healed, partial response, unchanged, deterioration). Results Thirty-two patients were included, 68.8% female, median age 44,11 (IQR 36.28-48.56). Median time from diagnosis to UST initiation was 12.94 years (IQR 7.52-19.52), 90.6% had received previously 2 anti-TNF (37.5% also vedolizumab) and 46.9% had more than 2 fistulas. In 22 patients (68.8%) pCD was the main indication for UST treatment while in the remaining 31.2% the main indication was luminal disease. Fifteen patients (46.9%) received antibiotics at the initiation of UST, 8 (25%) combo therapy with thiopurines and 21 (65.6%) had setons. Patients received a 6mg/kg IV dose and 87.5% received 90mg/8 week SQ for maintenance. Dose intensification was needed in 20 patients (62.5%) at a median of 13 months (IQR 8.00-19.5). Fifteen patients (46,9%) achieved clinical response at week 16, while 18/30 (60%) had clinical response at 12 months (three of them were in clinical remission). Nineteen patients (59,4%) had an MRI performed pre and post-treatment at a median of 15 months (IQR 10-19). 10/19 patients (52.6%) achieved a radiological response although no patient had all fistulas healed. In the multivariate analysis the only factor associated with clinical response at 12 months was the presence of setons at UST initiation (OR 7.0; IC95% 1.3-37.9). There were no factors significantly associated with radiological response or clinical response at week 16. Four patients experienced adverse effects (three perianal abscesses and one transient skin rash). Conclusion Ustekinumab was effective in achieving clinical and radiological response in anti-TNF-refractory fistulising pCD patients, although clinical and radiological remission was rare. Most patients needed UST dose intensification in this highly refractory cohort. Adverse effects were infrequent, mainly perianal abscesses.