Locoregional Disease Research Articles

Real world data on off-label use of consolidation durvalumab in newly diagnosed stage II and recurrent non-small cell lung cancer patients treated with definitive chemoradiotherapy.

e18857 Background: Consolidation durvalumab is approved for treatment of newly diagnosed, unresectable stage III non-small cell lung cancer (NSCLC) who have not progressed after definitive chemoradiotherapy (CRT) and the NCCN guidelines has since included stage II NSCLC who have not progressed after definitive CRT. Methods: A retrospective, observational real-world study was conducted to identify and describe the off-label use of consolidation durvalumab in NSCLC after completion of CRT between June 2018-June 2021. Data sources included claims data and electronic medical records submitted with prior authorization (PA) requests to OncoHealth, a digital health company that reviews PA requests for cancer treatment. With a data cut-off of 12/22/2022, real-world Time to Progression (rwTTP) and real-world Time to Next Treatment (rwTTNT) were evaluated. All endpoints were measured from the start of consolidation durvalumab treatment; rwTTP spanned until earliest date of clinician-reported progression and rwTTNT spanned until initiation of subsequent treatment. Results: Among 326 patients identified to have received durvalumab after definitive CRT, 45 (13.8%) received off-label treatment. The median age was 71 years (range: 53 to 88), 51% male, 53% former smokers, 29% Stage I, IIA or IIB, 71% locoregional recurrent disease; 58% squamous histology, 47% had undergone prior surgery +/- adjuvant chemo, 27% received prior radiation only and 98% received concomitant platinum-based chemotherapy prior to durvalumab. Median time to initiating durvalumab after CRT was 47 days. After a median follow up of 13.1 (range: 7.0-50.7) months, 33% (n = 15) had progression of disease. The median rwTTP was 14.0 (range: 4.2-32.9) months and median rwTTNT was 14.7 (range: 6.0-33.0) months. Conclusions: In the real world, off-label use of consolidation durvalumab was based on clinical justification and extrapolation of results from PACIFIC trial. The results of rwTTP and rwTTNT outcomes suggest patients with early stage or recurrent disease achieved clinically meaningful benefit from treatment approach used in the PACIFIC trial. With additional patients and longer follow up, real-world data could shed light on the appropriateness of expanding off-label use of durvalumab consolidation.

Personalized circulating tumor DNA (ctDNA) analysis in predicting residual disease after neoadjuvant chemoradiotherapy (nCRT) for esophageal squamous cell carcinoma (ESCC).

e16062 Background: For ESCC patients who receive nCRT, high pathological complete response (pCR) rates could be achieved. A “Watch and Wait” strategy has been proposed for patients with clinical complete response (cCR) after nCRT. However, clinical assessments would inevitably misclassify non-pCR as cCR. We previously showed that ctDNA analysis with tumor-naïve fixed panel could improve the prediction of cCR. This study further investigates the value of personalized ctDNA analysis in predicting tumor response and residual disease after nCRT in ESCC. Methods: This is a side study of the prospective, diagnostic preSINO trial (NCT03937362). After completion of nCRT, patients underwent one or two clinical response evaluations (CREs) before planned surgery. CRE‐1 was 4–6 weeks after nCRT. CRE‐2 was 10–12 weeks after nCRT for patients without histological evidence of residual tumor at CRE-1. Individual tumors and matched white blood cells at baseline (B0) were whole-exome sequenced and somatic mutations were identified. Serial plasma samples were analyzed by brPROPHET tracking up to 50 somatic mutations at three timepoints: B0, CRE-1, CRE-2. This assay was developed to detect residual disease with a limit of detection of 0.004% and sample-level specificity of greater than 99% in the analytical validation. Residual disease was also detected and quantified through TNFP in the same samples for a head-to-head comparison. We correlated post-nCRT ctDNA status with pCR and major locoregional residual disease (MLRD) (>10% residual cancer or any residual nodal disease). Results: At this interim analysis, 55 ESCC patients (stage III, 87%) who received per-protocol treatments had sufficient sample to test ctDNA. The pCR rate was 27 % (15/55). 98% (2918/2966) of variants selected for patient-specific panel design were private to a specific patient, only 3% (92/2966) of variants were included in the fixed panel. After nCRT, ctDNA was detected by brPROPHET prior to nCRT in 100% of samples (n=55), significantly higher than that by TNFP assay (73%, 40/55). ctDNA was detected in 55% (30/55) of patients at CRE-1, 43% (10/23) at CRE-2. Importantly, the brPROPHET achieved higher sensitivity than TNFP in predicting non-pCR and MLRD owing to its ability to detect extremely low ctDNA fractions (to 1.14 x 10-5). Moreover, combining brPROPHET with CREs could further improve the sensitivity. Conclusions: Personalized ctDNA analysis can supplement the clinical assessment to decrease the false negative rate in identifying patients with residual disease after nCRT, and might become useful in the “Watch and Wait” strategy for the management of ESCC. Clinical trial information: NCT03937362 . [Table: see text]

Carboplatin and paclitaxel chemoradiation for localized anal cancer in patients not eligible for mitomycin and 5-fluorouracil.

e15500 Background: Anal cancer (AC) is a relatively uncommon malignancy in the United States, however, this disease continues to increase in incidence, especially in individuals over 50 years old. Current standard of care for locoregional disease includes mitomycin and 5-fluorouracil (M/5FU) with radiation. This combination is associated with significant toxicity limiting its use in those patients who are elderly or have multiple comorbidities. Carboplatin and paclitaxel (C/P) is now the preferred standard of care treatment regimen for metastatic AC. Weekly C/P has become a standard of care option in combination with radiation for locally advanced esophageal cancer. Here we evaluate the efficacy of weekly C/P chemoradiation in treating a cohort of patients unable to receive standard M/5FU chemoradiation. Methods: Subjects were consented to an IRB approved AC registry at the University of Wisconsin Carbone Cancer Center. Patients (pts) were identified to have received weekly infusional C/P concurrent with standard-dose radiation for localized AC between January 1, 2016 and December 1, 2022. Clinical response was determined based on evidence of disease on imaging or anoscopy and toxicities were graded according to CTCAE v5. Results: 8 pts (7F/1M; median age 76 (54-87)) were found to meet eligibility criteria. 6 had perianal cancers and 2 had cancers within the anal canal. 6 had T2 disease and 2 had T3 tumors. 2 had node positive disease. Dosing ranged from C (AUC 1.5-2), P (30-50mg/m2) and radiation (50.4-58 Gy). Patients completed a median of 82.5% (40%-100%) of intended treatments. Most common toxicities included leukopenia, anemia, perianal pain, and fatigue. Grade 3 or higher toxicities included neutropenia (3) of which 2 resulted in febrile neutropenia, and anemia (3). All patients had a complete clinical response. With a median follow-up of 17 mos (3-40 mos), no patients have had recurrence and all patients are still alive. Conclusions: This study demonstrates promising tolerability and efficacy for weekly C/P chemoradiation for patients with anal cancer unable to receive M/5FU. This regimen merits further investigation in prospective clinical trials.

Prospective study of integrating post-radiotherapy [18F] fluorodeoxyglucose-positron emission tomography/computed tomography scan and plasma Epstein-Barr virus DNA in surveillance of locoregionally advanced nasopharyngeal carcinoma.

6072 Background: To evaluate the role of [18F] fluorodeoxyglucose-positron emission tomography/computed tomography (FDG-PET/CT) scan at 12-weeks after the end of Radiotherapy (RT) integrated with plasma EBV DNA in surveillance and standardized implementation of locoregionally advanced nasopharyngeal carcinoma (LA-NPC). Methods: This prospective study was conducted in patients with stage III-IVa LA-NPC. FDG-PET/CT examination and plasma Epstein-Barr virus (EBV) DNA measurements was performed pretreatment and at 12-weeks after the end RT. The primary study endpoint was the negative predictive value (NPV) and other supporting diagnostic test characteristics of 12-weeks FDG-PET/CT for the surveillance of residual locoregional disease and new distant metastasis. Results: From June 2018 to December 2019, 506 eligible patients were enrolled and entered follow-up (median,45 months). At 12 weeks after the end of RT, there were 22 (4.3%) patients have residual locoregional disease, 30 (5.9%) patients developed distant metastasis and 6 (1.2%) patients presented both residual locoregional disease and distant metastasis. The NPV of 12-weeks FDG-PET/CT for overall residual diseases and distant metastasis was 96.3% (95% confidence interval [CI], 94.0%-97.8%) with sensitivity of 72.4% (95%CI, 58.9%-83.0%), specificity of 93.3% (95%CI, 90.5%-95.4%), positive predictive value (PPV) of 58.3% (95%CI, 46.1%-69.6%) and accuracy of 90.9% (95%CI, 88.4%-93.4%). In EBV DNA-based risk subgroups, the NPV of 12-weeks PDG-PET/CT was 96.8% (95%CI, 94.5%-98.2%) in patients with undetectable 12-weeks plasma EBV DNA and 87.0% (95%CI, 65.3%-96.5%) in patients with detectable 12-weeks plasma EBV DNA. Conclusions: 12-weeks PDG-PET/CT was reliable in the surveillance of LA-NPC and could help optimize the follow-up strategy and provide implications for timely and effective therapeutic regimen, especially for patients in different EBV DNA-based risk groups. Clinical trial information: NCT03601390 .

Phase 2 study of bintrafusp alfa in recurrent/metastatic olfactory neuroblastoma.

TPS6116 Background: Olfactory neuroblastoma (ONB, esthesioneuroblastoma) is a rare malignant tumor of the nasal cavity, believed to arise from the basal cells of the olfactory neurosensory epithelium. ONB is often locally advanced at diagnosis with high rates of spread both locoregionally and systemically. Current therapy for locoregional disease is local resection with adjuvant (chemo-) radiotherapy. Actionable mutations are rare, and treatment options for recurrent or advanced, non-resectable, disease are limited and include off-label combination chemotherapy (most frequently platinum-containing) and somatostatin-directed therapies (ONB expresses somatostatin receptors). These are based on limited data, with response rates poorly characterized. Bintrafusp alfa is a first-in-class, bifunctional TGF-β “trap”/anti-PD-L1 fusion protein. Analysis of ONB has demonstrated both PD-1/PD-L1 (London et al, 2018) and TGF-β ligand expression (Romani et al, 2021). Pre-clinical and clinical data in advanced solid tumors demonstrate enhanced antitumor activity with combination PD-L1/TGF-β blockade, with responses observed independently of high PD-L1 levels (Strauss et al, 2020). Thus, combination PD-L1/TGF-β blockade in ONB is a rational approach in a setting of unmet clinical need. Methods: This study is a Phase 2 single-site, single-arm clinical trial of bintrafusp alfa (1200mg IV every 2 weeks for up to 26 doses) for patients with recurrent or metastatic ONB. Participants must co-enroll to the ONB Natural History study at the NCI (NCT4755205). Patients must not be candidates for local therapy, have received at least 1 line of systemic therapy (including a platinum salt), have RECIST 1.1 measurable disease and have adequate organ function. Prior checkpoint inhibitor therapy is permitted with patients cohorted according to checkpoint exposure; up to 21 checkpoint-naïve and 8 checkpoint-resistant patients will be enrolled. The primary objective is objective response rate by RECIST 1.1 with secondary endpoints including safety and tolerability, duration of response and overall survival; exploratory endpoints include pharmacokinetic analyses, PD-L1 and immune cell correlative analyses. The trial follows a Simon two-stage design, requiring ≥1 response in the first 12 patients. Tumor biopsy at enrollment is optional. Imaging for response assessment is planned for 8-week intervals and PET scan (preferably 68Ga-DOTATATE) will be obtained for all patients at baseline and first restaging, then on an individualized basis per radiology advice. This study is presently open at the NCI with 5 patients enrolled as of January 2023. Clinical trial registry:NCT05012098. Clinical trial information: NCT05012098 .

Phase II prospective trial of induction chemotherapy for advanced sinonasal squamous cell or poorly differentiated carcinoma.

6090 Background: The standard treatment for resectable advanced sinonasal carcinoma is surgery followed by adjuvant therapy. Despite aggressive therapy, disease control and survival have historically remained poor. The role of induction chemotherapy (IC) has not been fully assessed. The objective of this study is to prospectively evaluate IC for local disease control, organ preservation, and response-based local treatment selection. Methods: This is a phase II, open-label, single-center trial of patients with previously untreated, resectable and nonresectable, locally advanced squamous cell or poorly differentiated carcinoma of the nasal cavity or paranasal sinuses. Eligible patients were > 16 years of age, had an ECOG Performance Status of 0-1, and stage II-IV, M0 disease . Patients were treated with an IC regimen of docetaxel, cisplatin, and fluorouracil (TPF) for 2 cycles, then evaluated for response using clinical (symptoms and nasal endoscopy) and radiographic (RECIST 1.1 and PET) assessments. Those who achieved an objective response received a third cycle followed by chemoradiotherapy (CRT); non-responders underwent surgery with adjuvant radiotherapy. The primary endpoints were overall response rate (ORR) and 2-year local disease control. Secondary endpoints included disease-specific survival (DSS), overall survival (OS), disease-free survival (DFS), organ preservation, patterns of failure, and treatment toxicity. Results: 31 patients were enrolled between 2008 and 2020, of which 28 were evaluable for efficacy. Disease was T4a (57%) or T4b (21%), N+ (38%), and would have required maxillectomy (89%), craniotomy (54%), or orbital exenteration (29%). After IC, the ORR was 82.1% (7.1% complete response, 75.0% partial response), and the non-response rate was 17.9% (17.9% stable disease, 0% progressive disease). Patients then underwent CRT (79%) or surgery (21%). Following CRT, salvage surgery was performed for 41% of patients. Grade 3 or 4 adverse events occurred in 18% of patients. The 2-year local control rate was 53.6%. The 2-year DSS rate was 75% (median DSS not reached). For patients alive at 2 years, 63% had organ preservation (avoiding maxillectomy 38%, craniotomy 13%, orbital exenteration 38%). The median DFS and OS were 19.2 and 47.4 months, respectively. Factors associated with worse OS were nonwhite race ( P = .035), T4 category ( P = .037), overall stage IV ( P = .038), and paranasal sinus subsite ( P = .002). Surgery did not have significantly different OS than CRT ( P = .86). Conclusions: This phase II study demonstrates the validity of induction chemotherapy as a guide for local treatment selection in patients with advanced sinonasal carcinoma. A majority of patients achieved disease control and organ preservation. The median survival was 4 years in a cohort with very advanced locoregional disease, with no survival difference between CRT and surgery. NCT03493425. Clinical trial information: NCT00707473 .

Acute Toxicity of Hypofractionated and Conventionally Fractionated (Chemo)Radiotherapy Regimens for Bladder Cancer: An Exploratory Analysis from the RAIDER Trial

AimsAdding concurrent (chemo)therapy to radiotherapy improves outcomes for muscle-invasive bladder cancer patients. A recent meta-analysis showed superior invasive locoregional disease control for a hypofractionated 55 Gy in 20 fractions schedule compared with 64 Gy in 32 fractions. In the RAIDER clinical trial, patients undergoing 20 or 32 fractions of radical radiotherapy were randomised (1:1:2) to standard radiotherapy or to standard-dose or escalated-dose adaptive radiotherapy. Neoadjuvant chemotherapy and concomitant therapy were permitted. We report exploratory analyses of acute toxicity by concomitant therapy-fractionation schedule combination. Materials and methodsParticipants had unifocal bladder urothelial carcinoma staged T2-T4a N0 M0. Acute toxicity was assessed (Common Terminology Criteria for Adverse Events) weekly during radiotherapy and at 10 weeks after the start of treatment. Within each fractionation cohort, non-randomised comparisons of the proportion of patients reporting treatment emergent grade 2 or worse genitourinary, gastrointestinal or other adverse events at any point in the acute period were carried out using Fisher's exact tests. ResultsBetween September 2015 and April 2020, 345 (163 receiving 20 fractions; 182 receiving 32 fractions) patients were recruited from 46 centres. The median age was 73 years; 49% received neoadjuvant chemotherapy; 71% received concomitant therapy, with 5-fluorouracil/mitomycin C most commonly used: 44/114 (39%) receiving 20 fractions; 94/130 (72%) receiving 32 fractions. The acute grade 2+ gastrointestinal toxicity rate was higher in those receiving concomitant therapy compared with radiotherapy alone in the 20-fraction cohort [54/111 (49%) versus 7/49 (14%), P < 0.001] but not in the 32-fraction cohort (P = 0.355). Grade 2+ gastrointestinal toxicity was highest for gemcitabine, with evidence of significant differences across therapies in the 32-fraction cohort (P = 0.006), with a similar pattern but no significant differences in the 20-fraction cohort (P = 0.099). There was no evidence of differences in grade 2+ genitourinary toxicity between concomitant therapies in either the 20- or 32-fraction cohorts. ConclusionGrade 2+ acute adverse events are common. The toxicity profile varied by type of concomitant therapy; the gastrointestinal toxicity rate seemed to be higher in patients receiving gemcitabine.

AIUM Practice Parameter for the Performance and Interpretation of Diagnostic Ultrasound of the Thyroid and Extracranial Head and Neck.

AIUM Practice Parameter for the Performance and Interpretation of Diagnostic Ultrasound of the Thyroid and Extracranial Head and Neck.

D91. Effect of Pre-pectoral Versus Sub-pectoral Implant Placement in Breast Reconstruction on the Delivery of Post-mastectomy Radiation

PURPOSE: The placement of breast implants in a pre-pectoral compared to sub-pectoral plane has become increasingly popular in breast reconstruction, though data are limited on how this affects radiation delivery for locoregional disease control in women with breast cancer. This study aims to assess the dosimetric implications of implant location in women undergoing post-mastectomy radiation therapy (PMRT) after immediate breast reconstruction. METHODS: Patients with breast cancer treated with mastectomy, implant breast reconstruction, and PMRT between 2014-2022 at a single center were included. All patients received either intensity-modulated or 3-D conformal radiation therapy over an average of 5 weeks. Demographic, clinical and treatment data were collected through chart review. Patients were matched 1:1 on cancer sidedness, use of boost, fractionation and extent of radiation fields. Groups were compared using Mann-Whitney U or t-tests for continuous variables, and chi-square or Fisher’s Exact tests for categorical variables, as appropriate. RESULTS: Twenty-seven patients with pre-pectoral and 26 patients with sub-pectoral implants were included. Patients with pre-pectoral reconstruction had lower average implant volumes (452cc vs 503cc) prior to radiation. There was no difference in chest wall coverage (p=0.107), internal mammary node coverage (p=0.215), heart dose (p=0.627) or lung V20Gy (p=0.774). CONCLUSION: In this assessment of radiotherapeutic dosimetry in patients undergoing immediate breast reconstruction, we found no significant difference in target coverage or normal tissue dose based on pre- versus sub-pectoral implant location. This suggests that implant placement can be selected to optimize reconstructive outcomes, without concern for compromise to the oncologic quality of PMRT.

Abstract LB198: A first-in-human, open-label, multicenter study of intratumoral SAR441000 (mixture of cytokine encoding mRNAs), as monotherapy and in combination with cemiplimab in patients with advanced solid tumors

Abstract Background: SAR441000 is an intratumoral (IT) therapy consisting of a mixture of mRNAs encoding the cytokines IL-12, IFN-α 2b, GM-CSF, and IL-15sushi. SAR441000 is hypothesized to induce a local and systemic immune response with reduced toxicity, and potentially enhance anti-tumor response when combined with checkpoint inhibitors. Methods: We conducted a phase 1 dose escalation and expansion study (NCT03871348) in patients with advanced/metastatic solid tumors to investigate SAR441000 as monotherapy (QW) and in combination with cemiplimab (350mg Q3W). The recommended dose (RD) of SAR44100 in combination with cemiplimab was further investigated to confirm the anti-tumor activity in patients with metastatic melanoma who had previously exhausted all standard of care options and failed treatment with anti-PD-(L)1 therapies. Serum samples and tumor biopsies were collected at baseline and post-treatment to characterize the PK/PD profile, and immune cell tumor infiltration. Tumor assessment was performed per RECIST 1.1 and iRECIST, where ≥1 non-injected lesion was considered as target lesion. Analysis was triggered after the last treated patient underwent their 2nd tumor assessment. Results: 77 patients were treated, 36 in escalation phase (21 in monotherapy, 15 in combination therapy) across eight dose levels (8µg-4000µg) and 41 in expansion phase. No dose limiting toxicities were observed. During escalation phase, 1 patient (6%) achieved confirmed complete response (iCR), 1 (6%) partial response (iPR), and 3 (20%) stable disease (iSD) as per iRECIST in combination therapy. Paired biopsies from the iPR patient showed significant increases in CD3+ and CD8+ immune cells in both injected and non-injected lesions compared to baseline. Increase of peripheral PK and PD (IFN-γ and IP-10) cytokines were observed post-treatment but no clear dose response relationship was established. Based on the overall data, 4000µg was chosen as the RD. During expansion phase, 2 (5%) melanoma patients achieved confirmed iPR and 12 (29%) achieved iSD as best overall response. Although clinically meaningful responses of injected and/or non-injected lesions were observed in 13 (32 %) patients, responses were mostly limited to loco-regional disease and no significant distant non-injected lesion response was seen. Post-treatment biopsies showed increased CD3+ and CD8+ immune cells in approximately 50% and 40% of injected and non-injected tumors, respectively. Most frequent (&amp;gt;10%) related TEAEs observed in expansion phase included injection site pain (26.8%), fatigue, diarrhea, pruritus, and asthenia (each 12.2%). Conclusion: IT with SAR441000 in combination with cemiplimab was generally well tolerated and demonstrated anti-tumor activity and immune cell infiltration in both injected and non-injected tumors. Citation Format: Oliver Bechter, Carmen Loquai, Stephane Champiat, Jean Francois Baurain, Jean-Jacques Grob, Jochen Utikal, Sylvie Rottey, Alfonso Berrocal, Jessica Hassel, Ana Arance, Miguel F. Sanmamed, Marye Boers-Sonderen, Brian Gastman, Christoffer Gebhardt, Brant Delafontaine, Ugur Sahin, Özlem Türeci, Giovanni Abbadessa, Gianfranco Di Genova, Patrick Brueck, Rahul Marpadga, Helen Lee, Céleste Lebbe. A first-in-human, open-label, multicenter study of intratumoral SAR441000 (mixture of cytokine encoding mRNAs), as monotherapy and in combination with cemiplimab in patients with advanced solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB198.

The relation between hypoxia and proliferation biomarkers with radiosensitivity in locally advanced laryngeal cancer

PurposeTreatment decision-making in advanced-stage laryngeal squamous cell carcinoma (LSCC) is difficult due to the high recurrence rates and the desire to preserve laryngeal functions. New predictive markers for radiosensitivity are needed to facilitate treatment choices. In early stage glottic LSCC treated with primary radiotherapy, expression of hypoxia (HIF-1α and CA-IX) and proliferation (Ki-67) tumour markers showed prognostic value for local control. The objective of this study is to examine the prognostic value of tumour markers for hypoxia and proliferation on locoregional recurrent disease and disease-specific mortality in a well-defined cohort of patients with locally advanced LSCC treated with primary, curatively intended radiotherapy.MethodsIn pre-treatment biopsy tissues from a homogeneous cohort of 61 patients with advanced stage (T3–T4, M0) LSCC primarily treated with radiotherapy, expression of HIF-1α, CA-IX and Ki-67 was evaluated with immunohistochemistry. Demographic data (age and sex) and clinical data (T- and N-status) were retrospectively collected from the medical records. Cox regression analysis was performed to assess the relation between marker expression, demographic and clinical data, and locoregional recurrence and disease-specific mortality.ResultsPatients with high expression of HIF-1α developed significantly more often a locoregional recurrence (39%) compared to patients with a low expression (21%) (p = 0.002). The expression of CA-IX and Ki-67 showed no association with locoregional recurrent disease. HIF-1α, CA-IX and Ki-67 were not significantly related to disease-specific mortality. Clinical N-status was an independent predictor of recurrent disease (p < 0.001) and disease-specific mortality (p = 0.003). Age, sex and T-status were not related to locoregional recurrent disease or disease-specific mortality.ConclusionHIF-1α overexpression and the presence of regional lymph node metastases at diagnosis were independent predictors of locoregional recurrent disease after primary treatment with curatively intended radiotherapy in patients with locally advanced LSCC.

Low-grade malt lymphoma of the nasopharynx in young adults: Successful treatment of a rare diagnosis at a rare site by radiotherapy.

Mucosa Associated Lymphoid Tissue (MALT) lymphoma is the third most common subgroup of Non-Hodgkin's lymphoma and is the most common type of primary extranodal lymphoma. They are rarely found in the nasopharyngeal region and their mean age at presentation is the sixth decade of life. We present the clinical, pathological, treatment and 5-year follow-up data of 5 cases of nasopharyngeal MALT lymphoma treated with definitive radiotherapy at our hospital, between 2009 and 2011. The average age of diagnosis was 27 years which is more than a decade earlier than what has been reported previously. Clinical symptoms included nasal obstruction, tinnitus and hearing loss. All five patients had locoregional disease. They were treated by definitive radiotherapy to a dose between 30 to 40 Gy. At 5 years of follow-up, 4 patients were in complete remission while one had disease relapse. The younger age of presentation compared to older reports in this rare subsite was an interesting finding in our study. The authors speculate that rising levels of particulate air pollution may have played a part in the etiology in this younger population. Our series shows that despite the younger age, the disease displays an indolent course and responds well to radiotherapy alone as the primary treatment. Recurrence or disseminated disease is also highly treatable with systemic chemotherapy.

Abstract 3359: Sensitive detection of locoregional MRD after head and neck cancer surgery

Abstract Background: Plasma cell-free DNA (cfDNA) has low sensitivity to detect locoregional molecular residual disease (MRD) immediately after surgery for limited-stage head and neck cancer. To enhance locoregional MRD sensitivity, we utilize a novel biofluid proximal to the primary tumor: the serosanguinous fluid collected by surgical drains inserted into the wound bed following regional lymph node dissection. We demonstrate that cancer-associated cfDNA in the surgical drain fluid (SDF) is a sensitive biomarker of locoregional MRD detection, risk stratification, and prognostication. Methods: We extracted DNA from 168 SDFs, 48 paired plasmas, and 44 tumor specimens collected 24 hours after surgery from 90 patients: 74 HPV (+) oropharyngeal cancers (OPC), 8 HPV (-) oral cancers, 2 thyroid cancers, and 6 benign neck pathologies. SDFs were also collected at 0, 6, 12, and 24 hours after surgery from 11 HPV (+) patients. We applied TaqMan qPCR to our specimens to quantify cell-free HPV (cf-HPV), a proxy for cancer-associated cfDNA in HPV (+) malignancies. We then measured the association between cf-HPV and extranodal extension (ENE), AJCC 8 staging, and established clinical and pathological risk criteria from 4 HPV (+) OPC clinical trials. We validated our findings using HPV next-generation sequencing. We also compared the predictive value of high-risk pathology with cf-HPV MRD for HPV (+) OPC recurrences. Lastly, we developed a second assay for cell-free BRAF V600E (cf-V600E) in thyroid cancer SDF. Results: Serially collected SDF revealed cf-HPV decreased continuously from 0 to 24 hours postoperative, and that the 24-hour timepoint stratified detectable versus undetectable persistent residual disease. At 24 hours, SDF was significantly more enriched with cf-HPV compared to plasma (P &amp;lt; 0.0001). In a subset of 9 patients, HPV genotype and detection in SDF were 100% concordant between NGS and PCR. Strikingly, SDF cf-HPV was 11-fold higher in pN2 patients versus pN1/N0 (P = 0.02) and 15-fold higher in cases with ENE (P = 0.003), suggesting SDF reflects aggressive nodal pathology and captures locoregional MRD. When we classified our patients according to established clinical and pathological risk criteria, we found significantly higher SDF cf-HPV among high-risk patients (AUC = 0.77). Crucially, in HPV (+) patients treated with surgery alone, SDF MRD detected 100% of locoregional recurrences, while plasma MRD and high-risk pathology detected 0%. Lastly, as proof of concept, we demonstrated SDF cf-V600E detection in the context of high-risk thyroid cancer. Conclusions: Surgical drain fluid cancer-associated cfDNA is a novel minimally invasive biomarker. Our SDF assay was strongly associated with high-risk criteria and detected locoregional relapse with 100% sensitivity compared to 0% in plasma. Our data suggest that SDF liquid biopsy is ultra-sensitive and has the potential to inform postoperative molecular-based risk stratification. Citation Format: Noah Earland, Ricardo J. Ramirez, Sophie P. Gerndt, Peter K. Harris, Andrew I. Hearn, Matthew Inkman, Jeffrey J. Szymanski, Nick Semenkovich, Benjamin M. Wahle, Zhongping Xu, Kevin Chen, Jin Zhang, Jose P. Zevallos, Aadel A. Chaudhuri. Sensitive detection of locoregional MRD after head and neck cancer surgery [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3359.

Abstract 2098: Molecular based blood screening assay for metastatic adenoid cystic carcinoma

Abstract Adenoid cystic carcinoma (ACC) is a rare, yet highly lethal, tumor that originates in the excretory glands of the head and neck. It is a locally aggressive disease, with more than half of patients presenting with perineural invasion and/or bone erosion. The current standard of care consists of surgical excision followed by radiation. Many healthy patients are left with positive margins after surgery and receive systemic therapy in addition to adjuvant radiation without evidence showing added benefit for that approach. Despite extensive surgery, long-term survival rates remain low due to a high incidence of locoregional disease progression and metastatic disease to the lung, liver, brain, or bones, sometimes several years after definitive treatment. Extensive genome analysis of ACC has uncovered a high mutation rate of the proto-oncogene MYB, typically as a genomic translocation resulting in an MYB fusion event with one of the following gene loci: nuclear factor I/B (NFIB), transforming growth factor beta 3 (TGFBR3) or RAD51B. The translocation approximates an enhancer to the MYB regulatory element which can be transactivated by the MYB fusion product, thus leading to the overexpression of MYB via a positive feedback mechanism. Currently, detection of systemic disease relies on diagnostic imaging, which can be imprecise, costly and time-consuming. Years of routine imaging is very impractical, attrition rates are high, and patients often present years later with symptomatic metastatic disease. A rapid and sensitive molecular-based blood screening tool would allow for continuous monitoring and earlier detection of metastatic ACC, ideally improving survival outcomes for these patients. In this study, we hypothesized that the dysregulation in MYB, and the reliance of ACC cells on MYB for survival and progression could be harnessed to develop a molecular screening tool to monitor for metastatic disease of ACC. We developed a blood-based PCR screening probes for metastatic disease in patients with a history of ACC. By analyzing blood samples from four cohorts: healthy individuals (no history of cancer) (n=6), patients with a history of ACC but with no evidence of disease for longer than 3yrs (NED) (n=16), patients with newly diagnosed local disease (n=8), and patients with confirmed metastatic disease (n=7), we demonstrate that our assay was able to detect significantly elevated levels of aberrant MYB expression in all blood specimens from our metastatic disease cohort (p &amp;lt; 0.01). Additionally, our probes were able to detect aberrant levels of MYB in the blood of a patient 11 months before imaging techniques identified metastatic lung lesions. These findings indicate that we can harness a specific ACC genetic trait to develop a sensitive, rapid, and inexpensive molecular screening assay from blood to detect metastatic ACC. We continue to expand and validate these findings by screening existing and new ACC patients every 6 months. Citation Format: Acadia H. Moeyersoms, Ryan A. Gallo, Zoukaa B. Sargi, Jason M. Leibowitz, Andrew J. Rong, David T. Tse, Daniel Pelaez. Molecular based blood screening assay for metastatic adenoid cystic carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2098.

Referral and treatment patterns in pancreatic acinar cell carcinoma: A regional population-level analysis

BackgroundPancreatic acinar cell carcinoma (PACC) is a rare exocrine tumor of the pancreas. We evaluated the effect disease stage, surgical intervention, and institutional volume status plays in survival. MethodsWe queried the Oregon State Cancer Registry for patients with PACC from 1997 to 2018. Treatment and referral patterns were analyzed, and overall survival (OS) was evaluated with Kaplan-Meier and Cox-proportional hazard analysis. Results43 patients were identified. Median OS was 33.1 and 7.1 months in those with locoregional and metastatic disease respectively (p ​= ​0.008). Surgical intervention was associated with improved OS (hazard ratio 0.28, p ​< ​0.0001). High volume center (HVC) care trended towards improving OS. While the majority of cases were diagnosed at low volume centers (74%), referral to HVCs was rare (n ​= ​4) and limited to advanced (stage III/IV) disease. ConclusionStage and surgical resection influence survival outcomes in PACC, more data is needed to delineate the impact of institutional volume status.

MP49-07 THE UGANDAN BLADDER EXSTROPHY-EPISPADIAS COMPLEX INITIATIVE: A PROGRAM FOR TRANSFERENCE OF COMPLEX SURGICAL RECONSTRUCTIVE SKILLS

You have accessJournal of UrologyCME1 Apr 2023MP49-07 THE UGANDAN BLADDER EXSTROPHY-EPISPADIAS COMPLEX INITIATIVE: A PROGRAM FOR TRANSFERENCE OF COMPLEX SURGICAL RECONSTRUCTIVE SKILLS Anthony Schaeffer, Pamela Artigas, Amanya Colline, Marlo Eldridge, Janet Gibson, Emily Haddad, Martin Situma (Posthumous), Stephen Watya, and Ranjiv Mathews Anthony SchaefferAnthony Schaeffer More articles by this author , Pamela ArtigasPamela Artigas More articles by this author , Amanya CollineAmanya Colline More articles by this author , Marlo EldridgeMarlo Eldridge More articles by this author , Janet GibsonJanet Gibson More articles by this author , Emily HaddadEmily Haddad More articles by this author , Martin Situma (Posthumous)Martin Situma (Posthumous) More articles by this author , Stephen WatyaStephen Watya More articles by this author , and Ranjiv MathewsRanjiv Mathews More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000003297.07AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Patients with the bladder exstrophy-epispadias (BE) complex in resource limited countries lack access to readily available state-of-the-art BE care. We aim to describe a collaboration between US-based BE experts and Ugandan care providers to address this unmet need. METHODS: Described below. RESULTS: Need: Despite 43 million citizens, Uganda has only 5 pediatric surgeons and 1 pediatric urologist. Ugandans have sparse access to BE surgical care, and if unable to obtain adequate BE care have limited educational and/or employment prospects. Advanced training in state-of-the-art BE operative and perioperative care for healthcare providers is also limited. Response: As the largest BE patient/parent support group, the Association for the Bladder Exstrophy Community (A-BE-C) has partnered with US-based BE experts, a Ugandan hospital, and local healthcare providers to address this gap. The mission of this 5-year program is to provide hands-on BE skills training to Ugandan surgeons, nurses, and social workers and facilitate BE knowledge transfer through an intensive didactic symposium. This is accomplished using the same care team each year. The goal is to develop a self-sustaining program to provide optimal, cost effective BE care in local facilities. This program also benefits urologists, nurses, and social workers who are members of the College of Surgeons of East Central and Southern Africa. Outcomes: An initial planning visit occurred in 2018. The first of 5 yearly, 7 day long symposia commenced in October 2019 when 18 patients received care (1 delayed closure w/ osteotomy, 1 epispadias repair, 16 cystoscopies for treatment planning). 2 females attained urinary continence with new catheterization regimens. Social workers, assigned to each individual patient, are absolutely critical to ensure ongoing patient communication, assist with travel and supply delivery, and liaise with BE providers in Kampala and the US. 7 talks were given to symposia attendees from many East African countries. Challenges: Challenges identified include: the need for pediatric orthopedists with BE experience; selection of the most suitable urinary continence operation; medical supply access/payment/delivery; program cancellations due to global (2020, 2021) and locoregional disease outbreaks (2022). CONCLUSIONS: Partnering with nonprofit organizations and identifying a supportive local facility committed to providing short- and long-term management has been a crucial step in starting to advance BE care in Uganda. Source of Funding: Schaeffer: NIH K08DK119535 © 2023 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 209Issue Supplement 4April 2023Page: e680 Advertisement Copyright & Permissions© 2023 by American Urological Association Education and Research, Inc.MetricsAuthor Information Anthony Schaeffer More articles by this author Pamela Artigas More articles by this author Amanya Colline More articles by this author Marlo Eldridge More articles by this author Janet Gibson More articles by this author Emily Haddad More articles by this author Martin Situma (Posthumous) More articles by this author Stephen Watya More articles by this author Ranjiv Mathews More articles by this author Expand All Advertisement PDF downloadLoading ...

BRCA1 and BRCA2 carriers with breast, ovarian and prostate cancer demonstrate a different pattern of metastatic disease compared with non-carriers: results from a rapid autopsy programme.

To catalogue and compare the pattern of metastatic disease in germline BRCA1/2 pathogenic mutation carriers and non-carriers with breast, ovarian and prostate cancer from a rapid autopsy programme. The number of metastases in the major body systems and the proportion of participants with metastases were documented in 50 participants (19 germline mutation carriers). Analysis was conducted on the participants' pattern of disease for the different cancers and mutation subgroups. The four commonly affected organ systems were the digestive (liver only) (82%), respiratory (76%), gastrointestinal (65%) and reticuloendothelial (42%). There were significant differences in the pattern of metastatic breast cancer in BRCA1/2 germline carriers compared with non-carriers. Breast cancer carriers had significantly fewer organ systems involved (median n=3, range=1-3) compared with non-carriers (median n=9, range=1-7) (P=0.03). BRCA1/2 carriers with ovarian carcinomas had significantly more organ systems with metastatic carcinoma (median n=10, range=3-8) than non-carriers (median n=5, range=3-5) (P < 0.001). There were no significant differences in the number of involved systems in BRCA2 carriers compared with non-carriers with prostate cancer (P=1.0). There was an absence of locoregional disease (6.5%) compared with distant disease (93.5%) among the three cancer subtypes (P < 0.001). The majority of metastatic deposits (97%) collected during the autopsy were identified by recent diagnostic imaging. Even though a major limitation of this study is that our numbers are small, especially in the breast cancer carrier group, the metastatic patterns of breast and ovarian cancers may be impacted by BRCA1/2 carrier status, suggesting that tumours derived from patients with these mutations use different mechanisms of dissemination. The findings may focus clinical diagnostic imaging for monitoring metastases where whole-body imaging resources are scant.

Tolerability of concurrent external beam radiotherapy and [177Lu]Lu-PSMA-617 for node-positive prostate cancer in treatment naïve patients, phase I study (PROQURE-I trial)

BackgroundProstate cancer patients with locoregional lymph node disease at diagnosis (N1M0) still have a limited prognosis despite the improvements provided by aggressive curative intent multimodal locoregional external beam radiation therapy (EBRT) with systemic androgen deprivation therapy (ADT). Although some patients can be cured and the majority of patients have a long survival, the 5-year biochemical failure rate is currently 29–47%. [177Lu]Lu-PSMA-617 has shown impressive clinical and biochemical responses with low toxicity in salvage setting in metastatic castration-resistant prostate cancer. This study aims to explore the combination of standard EBRT and ADT complemented with a single administration of [177Lu]Lu-PSMA-617 in curative intent treatment for N1M0 prostate cancer. Hypothetically, this combined approach will enhance EBRT to better control macroscopic tumour localizations, and treat undetected microscopic disease locations inside and outside EBRT fields.MethodsThe PROQURE-I study is a multicenter prospective phase I study investigating standard of care treatment (7 weeks EBRT and 3 years ADT) complemented with one concurrent cycle (three, six, or nine GBq) of systemic [177Lu]Lu-PSMA-617 administered in week two of EBRT. A maximum of 18 patients with PSMA-positive N1M0 prostate cancer will be included. The tolerability of adding [177Lu]Lu-PSMA-617 will be evaluated using a Bayesian Optimal Interval (BOIN) dose-escalation design. The primary objective is to determine the maximum tolerated dose (MTD) of a single cycle [177Lu]Lu-PSMA-617 when given concurrent with EBRT + ADT, defined as the occurrence of Common Terminology Criteria for Adverse Events (CTCAE) v 5.0 grade three or higher acute toxicity. Secondary objectives include: late toxicity at 6 months, dosimetric assessment, preliminary biochemical efficacy at 6 months, quality of life questionnaires, and pharmacokinetic modelling of [177Lu]Lu-PSMA-617.DiscussionThis is the first prospective study to combine EBRT and ADT with [177Lu]Lu-PSMA-617 in treatment naïve men with N1M0 prostate cancer, and thereby explores the novel application of [177Lu]Lu-PSMA-617 in curative intent treatment. It is considered likely that this study will confirm tolerability as the combined toxicity of these treatments is expected to be limited. Increased efficacy is considered likely since both individual treatments have proven high anti-tumour effect as mono-treatments.Trial registrationClinicalTrials, NCT05162573. Registered 7 October 2021.

Small Bowel Carcinoma in the Setting of Inflammatory Bowel Disease.

Small bowel carcinomas are rare in the general population, but the incidence is increasing. Patients with inflammatory bowel diseases (IBDs) are at significantly higher risk of small bowel adenocarcinomas than their non-IBD counterparts, with Crohn's patients having at least a 12-fold increased risk and ulcerative colitis patients with a more controversial and modest 2-fold increased risk compared with the general population. IBD patients with small bowel carcinomas present with nonspecific symptoms that overlap with typical IBD symptoms, and this results in difficulty making a preoperative diagnosis. Cross-sectional imaging is rarely diagnostic, and most cancers are found incidentally at the time of surgery performed for an IBD indication. As such, most small bowel carcinomas are found at advanced stages and carry a poor prognosis. Oncologic surgical resection is the treatment of choice for patients with locoregional disease with little evidence available to guide adjuvant therapy. Patients with metastatic disease are treated with systemic chemotherapy, and surgery is reserved for palliation in this population. Prognosis is poor with few long-term survivors reported.

Care at high‐volume centers is associated with improved outcomes for patients with pancreatic neuroendocrine tumors: A population‐level analysis

Primary resection and debulking of liver metastases have been associated with improved survival in pancreatic neuroendocrine tumors (PNETs). The treatment patterns and outcomes differences between low-volume (LV) institutions and high-volume (HV) institutions remains unstudied. A statewide cancer registry was queried for patients with nonfunctional PNET from 1997 to 2018. LVinstitutions were defined as treating <5 newly diagnosed patients with PNET per year, while HV institutions treated ≥5. We identified 647 patients: 393 with locoregional (n = 236 HV care, n = 157 LV care) and 254 with metastatic disease (n = 116 HV care, n = 138 LV care). Patients with HV care had improved disease-specific survival(DSS) compared to patients with LV care for both locoregional (median 63 vs. 32 months, p < 0.001) and metastatic disease (median 25 vs. 12 months, p < 0.001). In patients with metastatic disease, primary resection (hazard ratio [HR]: 0.55, p = 0.003) and HV institution (HR: 0.63, p = 0.002) were independently associated with improved DSS. Furthermore, diagnosis at a HV center was independently associated with higher odds of receiving primary site surgery (odds ratio [OR]: 2.59, p = 0.01) and metastasectomy (OR: 2.51, p = 0.03). Care at HV centers is associated with improved DSS in PNET. We recommend referral of all patients with PNETs to HV centers.