Locoregional Research Articles

Nature and management of melanoma recurrences following adjuvant anti-PD-1 based therapy

IntroductionApproximately 50 % of resected stage II-IV melanoma patients develop recurrent disease by 5 years despite adjuvant anti-PD-1 therapy. Data to define best management of recurrences is lacking. MethodsThis was a multicentre, international, retrospective cohort study. Patients with resected stage II-IV melanoma who commenced adjuvant anti-PD-1-based therapy before January 2022 and later recurred were identified. Data on demographics, disease characteristics, recurrence patterns, management and outcomes were collected. Results711 patients from 17 sites were included. Median age was 60 [range 16–92], 64 % were male, 2 % stage II, 91 % were stage III, 7 % stage IV. Median time to recurrence was 6.2 months (0–68.5) and median follow up time from recurrence was 19.8 months (range 0.2–73.1). 63 % recurred on anti-PD-1 therapy, 36 % off therapy [3 % < 6 months, 33 % > 6 months]. Initial recurrences were locoregional (LR) alone in 44 %, distant alone (DR) in 43 %, and 11 % in both sites. LR recurrences were managed with local therapy, alone (62 %) or with “second adjuvant” anti-PD-1 (14 %) or BRAF/MEK therapy (23 %); 12 m RFS2 was 25 %, 29 % and 69 % respectively (p = 0.0045). Definitive systemic therapy at first recurrence was given in 16 % LR and 86 % DR, with best outcomes for anti-CTLA4 + anti-PD-1 and trial combinations (24 m PFS 63 % and 69 %, respectively). The 24 m OS for the entire cohort was 65 %. ConclusionMost recurrences following adjuvant anti-PD-1 based therapy occur early and while still on drug. Outcomes are poor, regardless of site, timing of recurrence, and subsequent treatment.

Recent safety and efficacy findings from a phase 1b/2 open-label combination study of ASP-1929 photoimmunotherapy with anti-PD-1 therapy in EGFR-expressing advanced head and neck squamous cell carcinoma (HNSCC).

6083 Background: In the challenging landscape of advanced HNSCC, patients (pts) have overall low survival and high locoregional (LR) recurrence rates. While LR progression is a key contributor to morbidity and mortality, LR control remains low despite aggressive therapy including surgery, radiation, chemotherapy, and immunotherapy. ASP-1929 photoimmunotherapy (PIT) combines EGFR-targeting cetuximab, with a light-activatable dye, IRDye 700DX, and a laser light for localized drug activation. This novel approach has demonstrated rapid and selective tumor necrosis in preclinical studies, and a manageable safety profile in HNSCC early clinical trials. Phase I/II and preclinical data indicate a potential synergy in anti-tumor activity of PIT when combined with anti-PD-1 therapy. Here we present updated interim evaluation findings based on a recent data cut from this study initially presented at the 2023 American Head and Neck Society meeting. Methods: A phase 1b/2 open-label study of pts with recurrent locally advanced (rLA) and/or metastatic (m) HNSCC evaluating the safety and efficacy of ASP-1929 PIT in combination with anti-PD-1 (pembrolizumab) therapy (NCT04305795). Pts with measurable disease by modified RECIST 1.1, at least 1 lesion accessible to light illumination, combined positive score (CPS) ≥1, and who were not candidate for LR therapy could be eligible for the study. Treatment included ASP-1929 PIT (infusion day 8, target tumors illuminated 24±4 hours later) plus anti-PD-1 (days 1&amp;22) during a 6-week cycle for up to 24 months. Primary objectives: safety/tolerability; objective response rate (ORR). Secondary objectives: overall survival (OS); progression-free survival (PFS); duration of response (DOR). Planned sample size: 26 HNSCC pts. Results: Of the 19 r/m HNSCC pts enrolled, 18 pts received both study therapies (PIT-evaluable). Data cut-off was August 31, 2023 (previously reported data cut-off: October 4, 2022). Efficacy results updated for the 18 PIT-evaluable pts: ORR of 33.3% (95% CI 13.3-59.0), including 4 CRs (22.2%) and 2 PRs (11.1%). Median OS not reached; 24-month OS rate estimate was 52.4% (95%CI 25.9-73.4). No change in median PFS, 2.9 months (95%CI 1.4-14.6). Median DOR was not reached at data cut-off (range 2.8+ to 18.0+ months). Safety data remained consistent with the data previously presented. Most common serious adverse reactions were dysphagia (10.5%) and tongue edema (10.5%). There were two grade 4 events: laryngeal edema (PIT-related) and tumor hemorrhage due to advanced disease, and no fatal events. Conclusions: ASP-1929 PIT in combination with anti-PD-1 therapy was generally well tolerated. Initial data demonstrate promising overall survival and response rates with this combination therapy in pts with rLA and/or m HNSCC lacking LR treatment options. Clinical trial information: NCT04305795 .

Early radiologic and metabolic tumour response assessment during combined chemo-radiotherapy for locally advanced NSCLC

BackgroundThe role of early treatment response for patients with locally advanced non-small cell lung cancer (LA-NSCLC) treated with concurrent chemo-radiotherapy (cCRT) is unclear. The study aims to investigate the predictive value of response to induction chemotherapy (iCX) and the correlation with pattern of failure (PoF). Materials and methodsPatients with LA-NSCLC treated with cCRT were included for analyses (n = 276). Target delineations were registered from radiotherapy planning PET/CT to diagnostic PET/CT, in between which patients received iCX. Volume, sphericity, and SUVpeak were extracted from each scan. First site of failure was categorised as loco-regional (LR), distant (DM), or simultaneous LR+M (LR+M). Fine and Gray models for PoF were performed: a baseline model (including performance status (PS), stage, and histology), an image model for squamous cell carcinoma (SCC), and an image model for non-SCC. Parameters included PS, volume (VOL) of tumour, VOL of lymph nodes, ΔVOL, sphericity, SUVpeak, ΔSUVpeak, and oligometastatic disease. ResultsMedian follow-up was 7.6 years. SCC had higher sub-distribution hazard ratio (sHR) for LRF (sHR = 2.771 [1.577:4.87], p < 0.01) and decreased sHR for DM (sHR = 0.247 [0.125:0.485], p < 0.01). For both image models, high diagnostic SUVpeak increased risk of LRF (sHR = 1.059 [1.05:1.106], p < 0.01 for SCC, sHR = 1.12 [1.03:1.21], p < 0.01 for non-SCC). Patients with SCC and less decrease in VOL had higher sHR for DM (sHR = 1.025[1.001:1.048] pr. % increase, p = 0.038). ConclusionPoor response in disease volume was correlated with higher sHR of DM for SCC, no other clear correlation of response and PoF was observed. Histology significantly correlated with PoF with SCC prone to LRF and non-SCC prone to DM as first site of failure. High SUVpeak at diagnosis increased the risk of LRF for both histologies.

The implication of failure patterns after neoadjuvant chemoradiotherapy with small involved-field in esophageal squamous cell carcinoma.

376 Background: In this study, we aimed to analyze failure patterns, the clinical and biological prognostic factors for treatment outcomes, and evaluate the feasibility of involved-field irradiation (IFI) in patients with esophageal squamous cell carcinoma (ESCC) undergoing neoadjuvant chemoradiotherapy (CCRT). Methods: We retrospectively reviewed the medical records of 511 patients diagnosed with ESCC and underwent neoadjuvant CCRT and radical esophagectomy between January 2016 and February 2022 at Samsung Medical Center. For IFI, the clinical target volume (CTV) was defined as the primary gross tumor volume (GTV) plus a 2.0-3.0 cm longitudinal margin and a 0.5-1.0 cm circumferential margin, as well as the GTV of lymph nodes (LN) plus a 0.5-1.0 cm margin. For elective nodal irradiation (ENI), the CTV encompassed supraclavicular, mediastinal, or abdominal LN regions based on the primary tumor location. IFI was applied in most cases (98%). The failure patterns, loco-regional control (LRC), and survival outcome were analyzed. Regional lymph nodes (LNs) were defined and classified according to the AJCC 8th edition. Non-regional LNs were defined as metastatic LNs in neck, thorax, abdominal area except regional LNs. Results: With a median follow-up of 44.4 months, 213 (41.7%) patients experienced recurrence. The first recurrent sites were locoregional (LR) in 98 patients (19.2%), non-regional LN in 81 (15.9%), and distant organs in 152 (29.7%). Among the 98 patients with LR recurrence, RT in-field failure occurred in 53 (10.4%) patients, in &amp; out-field failure in 18 (3.5%), and out-field failure in 27 (5.3%). In 27 cases of out-field failure only, LR recurrent lesion could be included in the target volume in 7 (1.4%) cases if ENIs were applied. Among the 27 patients, 10 received salvage treatment and 2 did not experience further recurrence. The analysis for the detailed LN recurrence showed that the upper mediastinal and supraclavicular LNs were the most frequent area, regardless of the primary tumor location and other clinical factors. Among 213 recurrent cases, 54 (10.5%) recurred in upper paratracheal LN and 40 (7.8%) in supraclavicular LN. The 5-year LRC rates, disease-control rates, and overall survival (OS) rates were 77.5%, 53%, and 54.3%, respectively. Multivariate analysis revealed that gender, age, cStage, ypStage, and resection margin status were independent prognostic factors for OS. Conclusions: Neoadjuvant CCRT using IFI with a small margin showed favorable treatment outcomes and out-field recurrence that the traditional ENI field could cover accounted for a small portion; thus, it might be feasible in the neoadjuvant setting. However, we need to consider that the upper mediastinal and supraclavicular areas were the most frequent recurrence sites.

5-Year Results from a Prospective Phase II Trial of Ten-Fractions Hypofractionated Radiotherapy in Locally Advanced Breast Cancer

There is a growing interest for adjuvant loco-regional hypofractionated radiotherapy (Hypo-RT) regimens in patients (pts) undergoing surgery for locally advanced breast cancer (LABC). We report the 5-year results of a phase II study on Hypo-RT targeting the primary and regional lymph nodes in ten fractions (fxs). A schedule of 34 Gy/10 fxs/2 wks to the whole breast/chest wall and to the draining lymph nodes was used; an optional single fraction 8 Gy boost was administered with electrons to the tumor bed in patients who had undergone conservative surgery. Both acute (CTCAE 4.0) and late (LENT/SOMA) toxicities were collected. All pts but those who underwent mastectomy without reconstruction or with temporary expander were also asked to rate their cosmetic outcome according to the Harvard scale. Toxicity was assessed weekly during RT and then at each follow-up (fup) examination (1, 3, 6 months and then yearly). Late toxicity was assessed starting from 3 months after the end of Hypo-RT and loco-regional toxicity was prospectively collected. Cancer related endpoints in terms of loco-regional (LR) recurrence, distant metastasis, specific disease- free survival and overall survival (OS) were evaluated from the date of RT start to the diagnosis of local relapse/distant metastases or the last fup respectively. From February 2015 to March 2019, 59 women (median age 60 yrs, IQR: 48.3-68.8 yrs) with stage II to IIIA breast cancer who underwent axillary dissection and conservative surgery (83%) or mastectomy (17%) were accrued. One patient was lost to fup immediately after the end of RT. Of the 58 evaluable pts, 56 underwent neo-adjuvant (27.5%) or adjuvant (57%) chemotherapy and 15.5% exclusive hormone therapy as well. Trastuzumab was administered concomitant to RT in HER2 positive pts (25%). All pts completed treatment as planned. No grade 2+ acute toxicity was recorded. At the median fup of 63 months (range: 25-92 mths), the cumulative incidence of any grade locoregional late toxicity estimated with the Kaplan-Meier method is 43.4% (95% CI) (30.0% and 46.1% for patients undergone mastectomy and lumpectomy, respectively). Peak 2 events have been observed for fibrosis (1 pt, 1.7%), telangiectasia (1 pts, 1.7%) and lymphoedema (1 pt, 1.7%). One patient (1.7%) experienced grade 3 breast retraction. Of all eligible patients (N = 51), patient reported cosmetic outcome was excellent, good, fair and poor in 51.7%, 22.4%, 10.3% and 3.4%, respectively. No late lung toxicity was observed. The actuarial LR control rate at 5 years is 98%; for distant metastasis-free survival, specific disease-free survival and OS rates are 89.2%, 80.8% and 93.7% respectively. Our results support the activity of a 10-fxs Hypo-RT schedule targeting the primary site as well as the draining lymph node stations after surgery for LABC.

PET-Based Radiogenomics Supports KEAP1/NFE2L2 Pathway Targeting for Non-Small Cell Lung Cancer Treated with Curative Radiotherapy

Radiotherapy (RT) is one of the major treatment options for localized lung cancer. Either delivered in normo- or moderate/highly hypofractionated regimens, use of RT is increasing especially thanks to the development of stereotactic radiotherapy (SBRT). RT is associated with a higher risk of local relapse when compared with surgery but with a preferable toxicity profile. The KEAP1/NFE2L2 mutational status has been proven as significantly correlated with local relapse in patients treated with RT. Several (33) transcriptomic features were previously identified as dependent from the KEAP1/NFE2L2 mutational status. However, these genetic and transcriptomic tests are rarely performed because of their cost and lack of availability. Prediction of the KEAP1/NFE2L2 mutational status on non-invasive modalities such as imaging could help in further personalizing each therapeutic strategy. Due to the small size of patients with both mutation status (MutKEAP1-NFE2L2) and PET/CT, a first model (RNASeq) predicting the mutation status (MutRNASeq) using the 33 previously identified transcriptomic features was developed on patients from the TCGA-LUSC, TCGA-LUAD, CPTAC-LSCC and CPTAC-LUAD cohorts (770 patients) and externally validated on the NSCLC-Radiogenomics cohort (117 patients). Narrowing the patients to those with an available PET/CT, a second model (RNAPET) was then built and internally validated to predict the previously MutRNASeq probability using PET/CT-extracted radiomics features. The RNAPET model was then validated on an external cohort of 151 patients treated with curative radiotherapy for a localized non-small cell lung cancer (VMAT cohort). For each model, features were combined using a neural network approach (Multilayer Perceptron) within a statistical software modeler. Performances were evaluated based on the ROC-features as well as decision curve analysis. The RNASeq model resulted in a C-Index of 0.82, Sensitivity (Se) of 70.3% and Specificity (Sp) of 93.4% in the validation cohort. Regarding the PET/CT-based prediction on a training cohort of 101 patients, the retained RNAPET model resulted in an AUC of 0.90 (p < 0.001). With a probability threshold of 20% and applied to the testing cohort, the RNAPET model achieved a C-Index of 0.7 with respective Se/Sp of 60.0% and 80.9% for the prediction of the MutRNASeq. The same radiomics model was validated on the VMAT cohort as patients were significantly stratified based on their risk of locoregional (LR) relapse with a hazard ratio of 2.61 (p = 0.02). Our three-step approach enables the prediction of the MutKEAP1-NFE2L2 using PET/CT-extracted radiomics features and efficiently classified patient at risk of LR relapse in an external cohort treated with radiotherapy. This first evidence should be further evaluated on larger cohorts, and implemented in LR risk prediction models.

Evolution of Patterns of Care and Outcomes in the Real-Life Setting for Patients with Metastatic GIST Treated in Three French Expert Centers over Three Decades.

Gastrointestinal stromal tumors (GIST) are rare mesenchymal tumors characterized by KIT or PDGFRA mutations. Over three decades, significant changes in drug discovery and loco-regional (LR) procedures have impacted treatment strategies. We assessed the evolution of treatment strategies for metastatic GIST patients treated in the three national coordinating centers of NetSarc, the French network of sarcoma referral centers endorsed by the National Institute of Cancers, from 1990 to 2018. The primary objective was to describe the clinical and biological profiles as well as the treatment modalities of patients with metastatic GIST in a real-life setting, including access to clinical trials and LR procedures in the metastatic setting. Secondary objectives were to assess (1) patients' outcome in terms of time to next treatment (TNT) for each line of systemic treatment, (2) patients' overall survival (OS), (3) evolution of patients' treatment modalities and OS according to treatment access: <2002 (pre-imatinib approval), 2002-2006 (pre-sunitinib approval), 2006-2014 (pre-regorafenib approval), post 2014, and (4) the impact of clinical trials and LR procedures on TNT and OS in the metastatic setting. 1038 patients with a diagnosis of GIST made in one of the three participating centers between 1990 and 2018 were included in the national prospective database. Among them, 492 patients presented metastasis, either synchronous or metachronous. The median number of therapy lines in the metastatic setting was 3 (range 0-15). More than half of the patients (55%) participated in a clinical trial during the course of their metastatic disease and half (51%) underwent additional LR procedures on metastatic sites. The median OS in the metastatic setting was 83.4 months (95%CI [72.7; 97.9]). The median TNT was 26.7 months (95%CI [23.4; 32.3]) in first-line, 10.2 months (95%CI [8.6; 11.8]) in second line, 6.7 months (95%CI [5.3; 8.5]) in third line, and 5.5 months (95%CI [4.3; 6.7]) in fourth line, respectively. There was no statistical difference in OS in the metastatic setting between the four therapeutic periods (log rank, p = 0.18). In multivariate analysis, age, AFIP Miettinen classification, mutational status, surgery of the primary tumor, participation in a clinical trial in the first line and LR procedure to metastatic sites were associated with longer TNT in the first line, whereas age, mitotic index, mutational status, surgery of the primary tumor and LR procedure to metastatic sites were associated with longer OS. This real-life study advocates for early reference of metastatic GIST patients to expert centers to orchestrate the best access to future innovative clinical trials together with LR strategies and further improve GIST patients' survival.

Nature and management of melanoma recurrences following adjuvant anti-PD-1 (PD1) therapy.

9575 Background: Despite improved outcomes with the use of adjuvant PD1 therapy, approximately 50% of patients (pts) develop recurrent disease by 5 years. Data to define best management of recurrences is lacking, including whether retreatment with PD1 has benefit. Methods: This was a multicentre, international retrospective study of pts with resected stage II-IV melanoma who commenced adjuvant PD1 therapy before January 2022 and then recurred. Demographics, disease characteristics, treatment, toxicity, recurrence patterns, management and outcomes were collected. Results: 711 pts from 17 sites were included. Med age was 60 [range 16-92], 64% (N=451) were male. 641 (91%) pts were stage III (A 7%, B 24%, C 54%, D 3%), 18 (2%) stage II, 51 (7%) stage IV. 80% (N=536) underwent SLNB prior to PD1, of which 44% (N=236) went onto CLND. 635 pts (90%) received PD1, 74 (10%) PD1 + other. Med time to recurrence was 6.2 months (m) (0-68.5); 63% (N=444) recurred ON PD1, while 36% (N=257) recurred OFF. 338 pts (48%) recurred within 6m of starting adjuvant, 166 (23%) between 6-12m, 140 (20%) 12-24m and 59 (8%) after 24m. Initial recurrences were locoregional (LR) alone in 315 (44%), 307 (43%) distant alone, and 78 (11%) both. Patients with LR recurrences alone underwent definitive surgery, or surgery + radiation in 98 (31%) and 42 (13%) respectively. After initial LR management, 164 (52%) had a further local and 129 (41%) distant recurrence. Those with initial distant recurrences were managed with definitive surgery (21, 7%), surgery + radiation (8, 3%) and radiation alone (14, 5%). Further ‘second’ adjuvant therapy was given in 27% (N=86) of LR and 6% (N=25) of distant recurrences. Definitive systemic therapy at first recurrence was given in 77% (N=296) distant and 23% (N=73) LR recurrences (Table). Conclusions: Patients recurring after adjuvant PD1 therapy do so early, and often while on drug. Patients with resected recurrences often receive “second adjuvant” therapy, although whether adjuvant or definitive, outcomes are poor. Novel drug therapies and clinical trials are required for those who recur despite PD1 therapy. [Table: see text]

Estimating the impact of adjuvant atezolizumab in preventing recurrences and reducing costs in resectable early PD-L1 high non-small cell lung cancer in Europe.

e20501 Background: Recurrences of non-small cell lung cancer (NSCLC) after surgery remain common and are associated with significant morbidity and mortality. Loco-regional or metastatic disease recurrence can lead to a substantial health care resource use and economic burden. The aim of this study was to estimate the effect of treating patients with early-stage NSCLC with adjuvant atezolizumab (ATZ) on the number of recurrences and direct healthcare costs in Germany, Spain, France Italy and the UK, together referred to as EU5. Methods: Using an epidemiological model, we estimated the reduction in loco-regional (LR) recurrences or distant metastases (DM) after adjuvant ATZ treatment following chemotherapy in operable NSCLC patients with PDL-1 expression of ≥ 50% on tumor cells (PD-L1 high), stage II-IIIA (AJCC 7th edition staging), without EFGR or ALK alterations. We used data from cancer registries, published literature sources, and market research to obtain incidence rates, staging distribution, biomarker status data, and adjuvant treatment rates. Moreover, we used evidence on the disease-free survival (DFS) of patients on adjuvant ATZ from the IMpower010 (NCT02486718) clinical trial to calculate the projected reduction in the number of LR recurrences or DM over a 10-year period post-ATZ launch relative to best supportive care (BSC). The model considers the costs associated with treatment, management of adverse events, monitoring of the disease, and follow-up healthcare. Results: We project that between 2023 and 2033, 20,483 patients with resected PD-L1 high stage II-IIIA NSCLC would experience recurrence (LR, or DM, or both) in the EU5 if they were treated with BSC (adjuvant platinum-based chemotherapy) alone (Table 1). Assuming peak ATZ uptake of 75%, the model estimates that following adjuvant ATZ and chemotherapy, a total of 4,665 recurrences would be prevented in this patient population in the EU5 over 10 years, representing a 23% decrease in recurrence relative to BSC. These avoided recurrences in EU5 could translate into a considerable reduction in direct healthcare costs. Conclusions: Adjuvant ATZ following chemotherapy results in a considerable population-level reduction of loco-regional recurrence or distant metastasis in resected PD-L1 high stage II-IIIA NSCLC patients. This could translate into a substantial decrease in the economic and societal burden caused by the disease. [Table: see text]

Long term disease-free survival in locoregional, metastatic and/or recurrent UCNT.

e18023 Background: Undifferentiated Carcinoma of Nasopharyngeal Type (UCNT) is a rare and aggressive type of head and neck cancer related to the Epstein Barr virus (EBV), genetic (HLA B5 in Algeria) and environmental factors. It is the most frequent histological variant of ENT cancers. It has geographically selective epidemiologic features unrelated to external carcinogens, and is known to be radiosensitive and chemosensitive. Methods: Seventy-one patients with biopsy-proven UCNT presenting to a single oncology unit between 2015 and 2022 were assessed for their long-term response to treatment. The sex ratio of cases was 3M: 1F; thirty-one patients (43%) were under the age of 50; 11 (15%) under the age of 35; and among these, there were two 19 year old males. The initial median World Health Organization (WHO) performance status was 1.6. These patients with locoregional (LR), recurrent (REC) and/or metastatic (MTS) UCNT were treated with monthly cycles of platinum-based chemotherapy of cisplatin (CDDP) 75 mg/m2 IV or Carboplatine AUC-4 and Docetaxel 75 mg/m2 IV followed by fluorouracil (5FU) 1000 mg/m2/day continuous IV infusion days 1 to 4 (TPF) in locally advanced disease, and with cisplatin (CDDP) 75 mg/m2 day 1 or Carboplatine AUC-5; and fluorouracil (5FU) 1000 mg/m2/d continuous IV infusion days 1 to 4 (PF) in recurrent and/or metastatic cases. The choice of systemic therapy was individualized based on patient characteristics including performance status, goals of therapy. Results: Those LR or MTS patients who were still alive without evidence of disease after 36+ months were categorized as complete responders (CRs). A subgroup of CRs was identified who had failed prior chemotherapy. MTS patients with less than three distant osseous sites underwent additional radiation therapy. Conclusions: Encouraging results for this particular type of head and neck cancer confirm the chemosensitivity of UCNT, and the observation of long-term responders makes curability a real consideration.

Prognostic Image Biomarkers in the Treatment of Patients with Locally Advanced NSCLC

<h3>Purpose/Objective(s)</h3> Image biomarkers on planning PET/CT-scans are potential prognostic tools in patient-specific predisposition to first site of failure in the treatment of locally advanced NSCLC-patients (LA-NSCLC) with curative intended chemo-/radiotherapy (cCRT). <h3>Materials/Methods</h3> Patients treated with cCRT for LA-NSCLC at a single institution from 2012-2018 were retrospectively included (N=197). Planning PET/CT scans were analyzed (commercially available software) with respect to selected image biomarkers (volume and sphericity of GTV-T on CT and SUV_peak and percentage of GTV-T volume with PET-signal above 50% of SUV_peak on PET). Clinical baseline characteristics (gender, stage, histology, performance status (PS)) were collected. Progression was scored as either loco-regional (LR), distant metastasis (M), simultaneous loco-regional and distant (LR+M) or death with no evidence of disease (DNED). Data were analyzed with a Fine and Gray competing risk analysis and variables included are shown in table 1. For each failure mode, subdistributed hazard ratios (sHR) with 95%-confidence intervals are reported. <h3>Results</h3> Median follow-up-time was 24 months. Significant predictors of LR failure were histology (squamous cell carcinoma (SCC) vs. adenocarcinoma (AC), sHR=2.05 [1.02-4.13], p=0.045) and SUV_peak (sHR=1.079 pr. SUV-increase [1.01-1.16], p=0.03). Histology remained a significant predictor for M failure (sHR=0.195 [0.07-0.52], p<0.01). No significant predictive parameters for LR+M-failure or DNED were found. Comparing cumulative incidences between the four groups (divided by histology and SUV_peak above/below median) using Fine-Gray test showed significant differences between the four groups in terms of LR-failure (P<0.01), M-failure (p<0.01) and LR+M-failure (p<0.01). LR-failures 2 years after treatment were similar for SCC regardless of SUV_peak (37% vs. 32%). Meanwhile, AC with SUV_peak above median had a significantly higher risk of LR-failure after 2 years than AC with SUV_peak below median (27% vs. 8%). M-failure after 2-years varied with histology but not with SUV_peak (AC: 35% vs. 28%, SCC: 9% vs. 5%). <h3>Conclusion</h3> In a competing risk analysis of 197 LA-NSCLC patients treated with cCRT, histology and SUV_peak prior to cCRT were identified as significant predictors of LR-failure. Patients with AC displayed a lower risk of LR-failure if SUV_peak was below median, which separated this group from the remaining patients. In general, AC were significantly more prone to M-failure than SCC.

SBRT for Nodal Metastasis

<h3>Purpose/Objective(s)</h3> Lymph node metastases (NMs) are a common site of tumor spread that can occur at the time of diagnosis or during systemic therapy or during follow-up with variable incidence based on the primary tumor site, stage, histology, and grading. Stereotactic body Radiation Therapy (SBRT) can be a therapeutic option for NMs in the setting of oligometastatic disease (OMD). The oligometastatic disease is an area of research rapidly evolving in the definition, characterization and treatment. The first end point of this study is to evaluate the outcomes of lymph node metastases treated with SBRT in terms of Local Control (LC), Loco Regional Nodal Control (LRNC), Distant Nodal Control (DNC), Distant Metastasis Free Survival (DMFS), Progression Free Survival (PFS) and Overall Survival (OS). The secondary end point is to identify predictive factors of response and to assess the toxicities. <h3>Materials/Methods</h3> In this study we included patients with a maximum of 5 metastasis and various primary tumors (31% lung, 22% prostate, 13% colon rectal, 10% gynecological, 7% breast, 6% upper GI, 5% genito urinary, 2% H&N, 4% others). Concomitant treatments were allowed. From November 2007 to September 2021, 228 NMs were treated in 174 patients with SBRT (<8 fractions). At time of treatment 49% of patients were classified as oligorecurrent, 41% oligoprogressive, 3% oligometastatic and 7% oligopersistent. The single fraction and multiple fractions were administered respectively in the 22% and 78% of cases. Most represented schedule was 30 Gy in 5 fractions, the medium BED (10) of SBRT was 74,7 Gy (range: 33,6- 120 Gy). <h3>Results</h3> The median follow-up was 22 months (range 0-148 months). Rates of LC at 1, 2 and 3 years were 93%, 89% and 86%. Rates of LRNC at 1, 2 and 3 years were 88%, 81% and 82%. Rates of DNC were at 1, 2 and 3 years 90%, 86%, and 83%. Rates of DMFS were at 1, 2 and 3 years 58%, 49%, and 42%. Rates of PFS were at 1, 2 and 3 years 41%, 28% and 22%. Rates of OS were at 1, 2 and 3 years 73%, 56% and 43%. At univariate analysis, the total number of metastases were associated with worse DMFS (P< 0,0001) and PFS (P = 0,0004). The genitor-urinary and gynecological tumors showed a statistically significant correlation with worse results in terms of DMFS (P = 0,0003), PFS (P = 0,0460) and OS (P = 0,0023). Treatment was well tolerated. The acute toxicities were 9 (4%) cases Grade 1, in the form of pain, fatigue, nausea, vomiting and cough, one case (0.44%) of anemia G2 and one case (0.44%) of death caused by esophageal bleeding, G5. The late toxicity was a case G2 (0.44%) in the form of dyspnea. <h3>Conclusion</h3> In conclusion, our analysis confirmed the efficacy and safety of SBRT in the treatment of NMs. Despite the marked heterogeneity of the included cases and the retrospective nature of the analysis, the results of this study are encouraging. Prospective studies are required to further confirm the benefit of this treatment.

Mediastinal and Hilar Lymphadenopathy Treated by SABR

<h3>Purpose/Objective(s)</h3> Mediastinal and hilar lymphadenopathy (MHL) is a frequent pattern of cancer spread, most frequent in lung cancer, but also in others primary disease. Traditionally, the local treatments included surgical resection or conventional RT, with or without systemic treatments. Recently, there is a considerable interest in the application of stereotactic ablative radiotherapy (SABR) for MHL. Safety and efficacy of SABR for mediastinal and hilar lymphadenopathy (MHL) have not yet been established. SABR treatment on ultra-central localizations has been found to be associated with higher rates of severe toxicity. Aim of this study is to evaluate the safety, clinical outcomes of survival and predictive factors of response of SABR on MHL. <h3>Materials/Methods</h3> One hundred and thirteen MHL were treated in 97 patients with SABR, from 2007 to 2021. Patients were more commonly affected by lung tumor (47%). The median age of patients was 67 (range 43-90). The schedule most represented was 30 Gy in 5 fractions (range 23-60 Gy in 1-8 fractions). The medium BED (10) was 81 Gy (range 37.5-120Gy). Twenty-six (23%) cases received a single fraction, 87 (77%) cases received multiple fractions. The patients were classified as oligorecurrent (52%), oligoprogressive (35%), oligometastatic (4%) and oligopersistent (9%). <h3>Results</h3> The median follow-up was 20 months (range 0-130 months). Acute toxicities were: five cases (4%) Grade 1 (in form of pain, fatigue, nausea, vomiting and cough), one case (0.9%) with anemia G2, one case (0.9%) died 3 days after treatment on mediastinal lymph node by esophageal bleeding, G5. One case (0.9%) presented late toxicity with dyspnea Grade 2. The rates of Local Control at 1 and 3 years were 90% and 84%, respectively. The rates of Loco Regional Nodal Control at 1 and 3 years were 84% and 75% respectively. The rates of Distant Nodal Control at 1 and 3 years were 93% and 84%, respectively. The rates of Distant Metastasis Free Survival at 1 and 3 years were 57% and 47%, respectively. The rates of Progression Free Survival at 1 and 3 years were 36% and 20%, respectively. The rates of Overall Survival at 1 and 3 years were 69% and 41%, respectively. Univariate analysis showed that the state of disease was statistically significant correlated with OS with better results for oligometastatic patients (p= 0,044). The number of metastases was statistically significant correlated with OS (p= 0,0046) and with DMFS (p= 0,0121). The DMFS was also correlated with number of previous systemic therapy. Patients receiving more than one line (range: 2-4 lines) of systemic therapy prior to SABR presented the worst results (p=0,0065). <h3>Conclusion</h3> In conclusion, our study showed that SABR on MHL is able to achieve excellent results in terms of local control with acceptable toxicity. More prospective studies are needed to confirm these results.

675P Patterns of radiological responses to anti-PD1 in patients (pts) with recurrent or metastatic head and neck squamous cell carcinoma (R/M HNSCC) in TOPNIVO (T) study

Nivolumab (N) is the standard of care in pts with platinum refractory R/M HNSCC. Novel patterns of response and progression to immunotherapy (hyperprogression (HP), pseudoprogression (PSPD), dissociated responses (DR)) have been described that are not observed with conventional cytotoxic or targeted anticancer drugs. No prospective data have been reported for pts with R/M HNSCC. T was a single-arm, phase II trial that included, from 08/2017 to 11/2018, 343 pts with platinum refractory R/M HNSCC treated with N (3 mg/kg, Q2W) (Even et al Ann Oncol 2020). Timing of studied CT scans for this study was: pre-baseline, baseline before N, 1st evaluation (E1) at week 8, 2nd evaluation (E2) at week 16. Tumor response was evaluated by RECIST 1.1. HP was evaluated using the 3 first CT by 2 different methods (Champiat et al Clin Cancer Res 2017 (C), Ferrara et al JAMA Oncol 2018 (F)). PSPD was defined as progression at E1 and stabilization of tumor growth or response at E2. DR was studied at E1 and defined as objective response (OR) in loco-regional (LR) site and no OR in metastatic (M) site or no OR in LR site and OR in M site. Of the 115 pts evaluable with C method and the 118 with F method, 15 (13%, 95% confidence interval (CI) 7-21) and 9 (8%, 95%CI 4-14) respectively experienced HP. Of the 128 pts evaluable for PSPD, 4 (3%, 95%CI 1-8) met the criteria. 208 pts had CT at baseline and at E1: -144 pts had HN disease, OR in HN sites was observed in 9 pts (6%, 95%CI 3-12) -122 pts had M disease, OR in M sites was observed in 16 pts (13%, 95%CI 8-20) DR was evaluated in 58 pts who had disease in both LR and M sites: -No OR in LR site and OR in M site: 8 (14%) pts -OR in LR site and no OR in M site: 2 (3%) pts -No OR in LR and M sites: 48 (83%) pts -OR in LR and M sites: 0 (0%) pt Overall, the DR rate was 17% (95%CI 9-29). The rate of DR was 22% (10 pts) (95%CI 11-36) in the 46 pts who previously received HN radiotherapy (RT), and 0% (95%CI 0-26) in the 12 pts without prior HN RT. In this prospective study, we estimated the rate of R/M HNSCC pts with HP under N between 4 and 21%. The rate of PSPD is very low, which should be considered in our clinical practice. 17% (95%CI 9-29) of the pts presented DR, mainly by absence of OR in LR site while OR occurred in M site.

Axillary nodal metastasis and resection margins as predictors of Loco Regional Recurrence in Breast Cancer Patients.

Surgical resection margins (RM), axillary nodal involvement and lymph node ratio (LNR) determine loco-regional control (LRC) in breast cancer management. Late presentation precludes breast conservation therefore surgical option is usually mastectomy and adjuvant chemoradiation minimize loco-regional recurrence (LRR). We investigated the prognostic role of lymph nodes positive for malignancy (pN), LNR and RM on LRR of breast cancer in a tertiary hospital in Ibadan, Nigeria. Longitudinal cohort study of 225 females with breast carcinoma managed and followed up for 5-years with end point of LRR or not. Chi-square test and logistic regression analysis were used to evaluate the interaction of resection margin and proportion of metastatic lymph nodes with LRR. The receiver-operator curve was plotted to determine the proportion of metastatic lymph nodes which predicted LRR. Ninety-nine percent had modified radical mastectomy and 163 (72.4%) had negative resection margins. A mean of 11 axillary lymph nodes were harvested at surgery. The age, positive resection margin and number of harvested nodes with malignant cells are associated with LRR. The overall 5-year LRR rate was 16%. LRR is dependent on lymph node involvement as well as and tumor aggressiveness.

Mapping of Recurrence Sites Following Adjuvant or Salvage Radiotherapy for Prostate Cancer Patients.

IntroductionAlthough salvage and adjuvant radiotherapy (RT) are effective in prostate cancer (PC) patients, 30%–40% of men will have disease progression. The objective was to describe the pattern of recurrence in PC patients with biochemical failure (BF) following postoperative RT.MethodsWe retrospectively analyzed 935 PC patients treated from 2009 to 2019 with adjuvant or salvage RT at the Institut de Cancérologie de l’Ouest. Of these, 205 (22%) developed BF of whom 166 underwent imaging. Patients with identified radiologic failure prior any specific treatment were included to determine the site of relapse categorized as local (L)-only, locoregional (LR), or metastatic (M) recurrence. Main disease characteristics and RT fields were examined in relation to sites of recurrence.ResultsOne hundred forty-one patients were identified with 244 sites of failure on imaging. Of these, 108 patients had received RT to the PB alone and 33 RT to the PB and pelvic lymph nodes (PB+PLN). Androgen-deprivation therapy was used concomitantly in 50 patients (35%). The median PSA at imaging was 1.6 ng/ml (range, 0–86.7). In all, 74 patients (52%) had M disease (44% in the PB group and 79% in the PB+PLN group), 61 (43%) had LR failure (52% in the PB alone group and 15% in the PB+PLN group), and six (4%) had L-only failure, at a median of 26.7 months (range, 5–110.3) from RT. Metastases were in extra-pelvic LN (37 (15%)), bones (66 (27%)), and visceral organs (eight (3%)). Fifty-three (48%) of the pelvic LN failures in the PB group would have been encompassed by standard PLN RT volume.ConclusionWe found that most patients evaluated for BF after postoperative RT recurred outside the RT field. Isolated pelvic nodal failure was rare in those receiving RT to the PB+PLN but accounted for half of failures in those receiving PB alone RT. Imaging directed salvage treatment could be helpful to personalize radiation therapy plan.

Impact of Post-Mastectomy Radiation Therapy in Women With T1-2N1M0 Breast Cancer With Sentinel Lymph Node Biopsy Alone

To report outcomes for women with pT1-2N1M0 breast cancer undergoing mastectomy and sentinel lymph node biopsy (SLNB) without completion axillary dissection, and to investigate the effect of post-mastectomy radiation therapy (PMRT).Data from 5 North American institutions were pooled to include women with pT1-2N1M0 breast cancer from 1997-2015 who underwent mastectomy with a positive SLNB and ≤ 5 lymph nodes (LNs) resected. All patients were clinically N0 and none received neoadjuvant chemotherapy. Competing-risks regression was performed to identify factors associated with overall recurrence (OR), inclusive of locoregional (LR) and distant recurrence (DM).Among 871 patients included, median age at diagnosis was 57 years, 92% were ER/PR-positive, 85% HER2-negative, and 60% received adjuvant chemotherapy. The 500 (57%) patients who received PMRT were significantly younger, had larger tumors, more positive LN, lymphovascular invasion (LVI), extracapsular extension (ECE), HER2-positive disease, and more frequently received adjuvant chemotherapy (all P < 0.05) compared to those not receiving PMRT. Median number of lymph nodes sampled in each group was 3 (range: 1-5). At a median follow up of 5.2 years, the 5-year cumulative incidence rates of LR, DM, OR, and breast cancer mortality (BCM) were 2%, 4%, 5%, and 3%, respectively. The 5-year rates of disease-free survival (DFS) and overall survival (OS) were 87% and 91%. LR was the only endpoint with a statistically significant difference between those receiving PMRT (0.4%) as compared to those without PMRT (3.9%), P < 0.001. On univariable competing risks regression, tumor size, nodal ratio, grade, LVI, and ER/PR status were significantly associated with OR and were included in multivariable analysis. On multivariable competing risks regression, larger tumor size (HR 1.47, 95% CI 1.19-1.81, P < 0.001), grade III (HR 1.81, 95% CI 1.07-3.05, P = 0.03), higher nodal ratio (HR 2.86, 95% CI 1.01-7.69, P = 0.049), and LVI (HR 2.04, 95% CI 1.27-3.28, P = 0.003) were significantly associated with increased risk of OR. PMRT was associated with decreased risk of OR (HR 0.60, 95% CI 0.26-1.00, P = 0.05), though this effect did not reach statistical significance.In selected patients undergoing mastectomy and SLNB without completion axillary dissection for pT1-2N1 breast cancer, larger tumor size, higher grade, increased nodal ratio and the presence of LVI are associated with increased risk of overall recurrence. Further studies are needed to identify which subset of patients may benefit most from PMRT.

Ten Fraction Adjuvant Hypofractionated Radiotherapy in Node Positive Breast Cancer: 3 Year-Follow-Up of a Phase II Toxicity Study

Post-operative loco-regional (LR) hypofractionated radiotherapy (Hypo-RT) is an attractive approach in locally advanced breast cancer (LABC). The aim of this study is to report the preliminary results of a 10 fraction hypofractionated schedule in patients (pts) with resected LABC.The present is a single arm phase II study assessing toxicity outcomes after 34 Gy/10 fxs/2 wks to the whole breast/chest wall and to the draining lymph nodes; an optional single fraction 8 Gy boost was administered with electrons to the tumor bed in patients who had undergone conservative surgery. Both acute (CTCAE v4.0) and late (LENT/SOMA) toxicities were collected. All pts but those who underwent mastectomy without reconstruction or with temporary expander were also asked to rate their cosmetic outcome according to the Harvard scale. Toxicity was assessed weekly during RT and then at each follow-up examination (1, 3, 6 months and then yearly).From February 2015 to March 2019, 59 women (median age 60 yrs, IQR: 48.3-68.8 yrs) with stage II to IIIA breast cancer who underwent axillary dissection and conservative surgery (83%) or mastectomy (17%) entered the study. One patient refused follow up immediately after the end of RT. Of the 58 evaluable pts, 56 underwent neo-adjuvant (41%) or adjuvant (59%) chemotherapy. Trastuzumab was administered concomitant with RT in all HER2 positive pts (25%). RT was delivered initially with a conformal 3D-CRT (32.8%) and then with an optimized IMRT (67.2%) technique to improve the dose distribution. A deep inspiration breath hold technique was used in compliant left-sided LABC pts (48.4%). All ptscompleted treatment as planned. At a median follow up of 42.3 months (IQR 31.4-57.2 mths), no locoregional failures have been observed. Peak acute toxicity was as follows: grade 0, 30 pts (51.7%); grade 1, 25 pts (43.1%); grade 2, 3 pts (5.2%); no grade > 2 toxicity was recorded. Regarding late toxicity, peak 2 events were found for fibrosis (1 pt, 1.7%), telangiectasia (1 pts, 1.7%); lymphedema (1 pt, 1.7%). One patient (1.7%) experienced grade 3 breast retraction. No other grade 2+ events were reported. Of eligible patients (N = 51) patient-reported cosmetic outcome was excellent, good, fair and poor in 59%, 23.5%, 11.7% and 5.8%, respectively.These preliminary data support the feasibility and tolerability of our 10-fraction fractionation schedule targeting the primary site as well as the draining lymph node stations after surgery for LABC.

Adjuvant Radiation Does Not Affect Locoregional Control Following Resection of Melanoma Satellitosis or In-Transit Disease.

This study evaluates the association of adjuvant radiation therapy (RT) with improved locoregional (LR) recurrence for resected melanoma satellitosis and in-transit disease (ITD). Data were collected retrospectively for resected melanoma satellitosis/ITD from 1996 to 2017. 99 patients were identified. 20 patients (20.2%) received adjuvant RT while 79 (79.8%) did not. Mean follow-up in the RT group was 4.3years and 4.7years in the non-RT group. 80% of patients who underwent RT suffered a complication, most commonly dermatitis. Locoregional recurrence occurred in 9 patients (45%) treated with adjuvant RT and 30 patients (38%) in the non-RT group (P = 0.805). Median LR-DFS was 5.8years in the RT group and 9.5years in the non-RT group (P = 0.604). On multivariable analysis, having a close or positive margin was the only independent predictor of LR-DFS (HR 3.8 95% CI 1.7-8.7). In-transit disease was associated with improved overall survival when compared to satellitosis (HR 0.260, 95% CI 0.08-0.82). The use of adjuvant RT is not associated with improved locoregional control in resected melanoma satellitosis or ITD. Close or positive margin was the only treatment-related factor associated with decreased LR-DFS after surgical resection of satellitosis/ITD.

Surgical Resection or Ablation for Recurrent Pancreatic Ductal Adenocarcinoma: An Analysis of Oncologic Outcomes According to the Recurrence Type.

To evaluate the survival benefits of curative-intent treatment (CIT, including surgery or ablation) for recurrent pancreatic ductal adenocarcinoma (PDAC) depending on the recurrence type and compared the survival outcomes with other treatment modalities. The treatment for recurrent PDAC is mostly chemotherapy or best supportive care (BSC). Still, the role of CIT for recurrent PDAC is not well established. PDAC patients who underwent pancreatectomy between 2004 and 2019 were included. Recurrences were categorized as locoregional (LR), distant, or disseminated. Recurrent PDAC management was classified as CIT, chemotherapy ± radiation therapy (CTX ± RTX), or BSC. The survival after recurrence (SAR) rate was measured from the first day of recurrence to the date of death or last follow-up. Two hundred eighteen patients had recurrent PDAC and were analyzed (27 CIT, 128 CTX ± RTX, 63 BSC). The 1-, 3-, and 5-year SAR rates were 65.4%, 11.5%, and 11.5% for CIT, 42.1%, 4.0%, and 0% for CTX ± RTX, and 15.9%, 1.6%, and 0% for BSC, respectively. Subgroup analysis indicated the SAR rate was significantly better in the CIT group than in the CTX ± RTX and BSC groups in LR type (P = 0.027) and distant type (P < 0.001). In multivariate analysis, the albumin level at recurrence (hazard ratio, 2.14; 95% confidence interval, 1.15-18.3, P = 0.038) and operation time of the second operation (hazard ratio, 0.98; 95% confidence interval, 0.97-0.99, P = 0.021) were associated with a favorable prognosis of SAR in the CIT group. CIT should be considered in recurrent PDAC for LR and distant metastases in selected patients.