Jethwa, Krishan R.

Objectives: Cervical esophageal cancer (CEC) is an uncommon malignancy accounting for <5% of all esophageal carcinomas. Treatment of CEC varies and is adapted from established regimens used for squamous cell carcinoma (SCC) or the lower esophageal and head and neck. The present systematic review and guidelines are intended to assist treatment decision making for patients with CEC based on the available evidence. Methods: Using the Population, Intervention, Comparator, Outcome, Timing, and Study Design (PICOTS) framework, the evidence regarding treatment outcomes was assessed using Cochrane and PRISMA 2020 methodology. Eligible studies included prospective Phase II to III trials and retrospective analyses published between January 1, 2013 and February 23, 2024 in the Ovid Medline database. These references were assessed through the American Radium Society (ARS) Appropriate Use Criteria (AUC) methodology. A systematic review PRISMA 2020 checklist confirmed the completion of essential elements. RAND-UCLA consensus methodology was used by the expert panel to rate the appropriateness of the treatment options. Results: ARS AUC recommendations include (1) larynx preservation using endoscopic resection (EMR or ESD) alone for the typical case with pT1a cN0 cM0 CEC, (2) definitive CRT for the typical case with cT1bN0M0 in patients who cannot undergo endoscopic resection, (3) larynx-preserving using definitive CRT (with or without induction chemotherapy) for the typical case with nonmetastatic locally advanced CEC (advanced T-stage tumors or involved lymph nodes), with surgery reserved for those patients with incomplete response or locoregional recurrence. Conclusions: This ARS AUC summary provides guidelines for the management of SCC of the cervical esophagus provides based on available evidence. Topics that warrant further investigation include optimization of (1) patient selection; (2) multimodality therapies including chemotherapy, immunotherapy, and targeted agents; (3) radiation dose, schedule, and treatment volume; and (4) supportive care for patients with CEC. Ongoing trials continue to improve outcomes for patients with CEC.

AbstractBackgroundExternal‐beam radiation (EBRT) is a noninvasive therapeutic alternative to transarterial chemoembolization (TACE) for hepatocellular carcinoma (HCC). The objective of this study was to conduct a systematic review and meta‐analysis of prospective randomized clinical trials to assess the clinical efficacy of EBRT versus TACE for HCC as either a definitive monotherapy or as a bridge to transplantation/surgery.MethodsA systematic review and meta‐analysis were performed to include prospective randomized trials comparing EBRT versus TACE. Data was analyzed with random and fixed‐effects models. The inconsistency index (I2) was chosen to assess heterogeneity. Three publications were included with a total of 142 patients. Outcomes included local control (LC), overall survival (OS), progression‐free survival (PFS), and occurrences of grade ≥3 toxicity. Comparisons are reported as hazard ratios (HRs) or risk ratios (RRs) with 95% confidence intervals (CIs).ResultsThere were three randomized trials that met inclusion criteria. The EBRT was delivered in three to 15 fractions with a total dose between 30 and 75 gray(Gy). EBRT was associated with significantly improved LC (HR, 0.16; 95% CI, 0.08–0.34; I2 = 0%) and PFS (HR, 0.37; 95% CI, 0.23–0.60; I2, 0%) compared with TACE. There was no significant difference between EBRT and TACE in OS (RR, 0.79; 95% CI, 0.51–1.22; I2 = 0%) or grade ≥3 toxicity (RR, 0.86; 95% CI, 0.31–2.37; I2 = 57%). None of the analyses had statistically significant heterogeneity.ConclusionsCompared with TACE, EBRT yields superior LC and PFS without providing a survival benefit in early and intermediate stage HCC. Additional larger prospective randomized controlled trials should be conducted to further investigate differences in clinical outcomes amongst patients with more advanced disease.

5 Background: Metastatic anal squamous cell carcinoma is rare and associated with a poor prognosis. There is limited evidence on the impact of local interventions on survival outcomes in patients with metastatic disease. We aimed to evaluate the survival of patients with liver-only metastatic anal cancer following definitive local management of liver lesions. Methods: This is a single-institution retrospective cohort study of patients with liver-limited metastatic anal cancer who underwent curative-intent local therapy. Clinical characteristics were collected and analyzed. The Kaplan-Meier method was used to calculate disease-free survival (DFS) and overall survival (OS). Prognostic factors associated with DFS and OS were assessed using Cox-proportional hazards models. Results: Twenty-five patients were included, median age was 59 years, and 92% were female. None of the patients had known HIV infection, 92% had HPV-positive disease and 76% had metachronous liver metastases following locoregional disease. All patients received chemoradiation for the primary lesion Unilobar hepatic involvement was present in 76% of the patients, with 56% having a single metastatic lesion. Pre-intervention systemic therapy was provided to 52% of the patients, including 8 who received carboplatin and paclitaxel, with a median duration of 3 months and ORR of 69%. Definitive treatment of metastatic disease included surgical resection (60%), non-surgical interventions (20%), and multimodal therapy (20%). All patients had viable tumor in the pathological specimen. With a median follow-up of 22 months, median DFS was 7.3 months, and median OS was 51.3 months. An ECOG performance status of 2, poorly differentiated histology, and extrahepatic recurrence were identified as significant prognostic factors in the univariate analysis, but not in the multivariate analysis. Conclusions: Our results demonstrate potential for long-term survival in liver-limited metastatic anal squamous cell carcinoma amenable to local therapeutic intervention combined with systemic therapy. These findings warrant further prospective study of local therapy in oligometastatic anal cancer. Characteristics N=25 (%) Median number of liver metastases (range), lesions- 1- 2-3- >3 1 (1-20)14 (56)8 (32)3 (12) Median maximal diameter of liver metastases (range), cm 3 (0.9-11.9) Best response of liver metastases to chemotherapy (N=13)- Complete response- Partial response- Stable disease- Progressive disease 2 (15)7 (54)3 (23)1 (8) Surgical procedure (N=20)- Right/left hemi-hepatectomy- Segmentectomy- Wedge resection 4 (20)14 (70)2 (10) Non-surgical procedure (N=10)- Local ablation- Radiotherapy- Other 5 (50)3 (30)2 (20) Hepatic surgical margins (N=20)- Positive margins- Close margins (<1mm)- Negative margins 02 (10)18 (90) Recurrent disease- Yeso Intrahepatico Extrahepatic- No 20 (80)14 (70)6 (30)5 (20)

Abstract Background Anal squamous cell carcinoma is a rare cancer with increased occurrence of multiple cancers before and after the anal squamous cell carcinoma diagnosis. However, there are limited data on this aspect. This multi-institutional analysis aimed to define the occurrence of malignancies before and after anal squamous cell carcinoma, time trends, and impact on survival and to identify prognostic factors. Methods Initial primary malignancy was defined as a malignancy occurring before the anal squamous cell carcinoma. Second primary malignancy was defined as a distinct primary cancer that developed after anal squamous cell carcinoma diagnosis. Retrospective multi-institutional chart review was done. Progression-free survival (PFS), overall survival, and prognostic factors were evaluated. Results A total of 647 patients with anal squamous cell carcinoma treated with curative intent were analyzed. Median age was 61.2 years with 72% as females. Of these, 150 (23.3%) patients had multiple malignancies with initial primary malignancy in 16% and second primary malignancy in 8%. Patients without prior cancer had better 5-year PFS (81.2% vs 67.2%, P = .011) and overall survival (81% vs 69%, P = .008) compared with those with prior cancer. Second primary malignancies had a statistically significant adverse impact on PFS (hazard ratio [HR] = 4.22) and overall survival (HR = 3.56). Females had better 5-year PFS (82% vs 70%, P = .016) as compared with males. The median time interval for developing anal squamous cell carcinoma (as second primary malignancy) after initial primary malignancy was 9.32 years. Conclusions Anal squamous cell carcinoma patients have an increased risk of multiple malignancies. These patients who have prior cancers have inferior outcomes. Second primary malignancy is a poor prognostic factor in patients with anal cancer. Second primary malignancy can develop years after treatment of primary anal squamous cell carcinoma.

Abstract Insulin-producing pancreatic tumors are a common subtype of neuroendocrine tumor. Standard of care includes surgical resection of the pancreatic tumor and medical management with somatostatin analogs. For patients with metastatic disease, tumor control and hypoglycemic symptom relief can be achieved through surgical resection of the tumor, hepatic artery embolization, radiofrequency ablation, or radioembolization using radioactive isotopes as well as with systemic therapy such as somatostatin analogs and everolimus. We present the case of a 74-year-old male with metastatic insulin-producing pancreatic carcinoma. After a long history of successfully controlling his hypoglycemic episodes post-liver wedge resection, bland embolizations subsequently failed to maintain control of the frequency and severity of his hypoglycemic symptoms. Stereotactic body radiotherapy (SBRT) with protons was used to achieve symptomatic control and led to partial radiographic response with complete resolution of his hypoglycemic episodes. This case demonstrates the potential utility of proton SBRT in metastatic insulinomas.

84 Background: Local therapies potentially offer a curative approach for patients with oligometastatic colorectal cancer (CRC). The effectiveness of systemic chemotherapy following definitive local treatment in this setting is not well-defined. Tumor-informed circulating tumor DNA (ctDNA) might guide management strategies after curative-intent local treatment. Methods: This is a single institution retrospective study of patients with CRC who underwent curative-intent local therapy to an isolated site of metastatic disease and had post-intervention tumor-informed ctDNA (Signatera) testing. The study was approved by the institutional review board. Clinical characteristics, including ctDNA results, were collected and evaluated. Kaplan-Meier method and log-rank test were used to calculate and compare disease-free survival (DFS). Factors associated with DFS were analyzed using multivariate Cox proportional hazards model. Results: 45 patients were included with median age of 59 years, 62% being male, 91% white, and 53% with stage IV disease at diagnosis. 37% of the patients had RAS mutations, no patient had BRAF mutation, and 2.2% patient had mismatch repair deficient disease. Isolated liver metastases were present in 80% of patients, lung metastases in 11% and other sites in 9%. 44 patients received chemotherapy prior to definitive treatment, with a median treatment duration of 16 weeks. ctDNA tests were done prior to local therapy in 23 patients, with 14 cases (61%) testing positive. Definitive treatment included resection (58%), ablation (13%), radiotherapy (4%), and multimodality (25%). Post-definitive treatment chemotherapy was administered to 24 (53%) patients. ctDNA positivity following definitive therapy was observed in 10 patients (22%), which was associated with a poorer prognosis, with a median DFS of 5.3 months compared to 21.3 months for the ctDNA-negative group (p<0.001). These findings were confirmed on multivariate analysis. In patients who had negative ctDNA after definitive local treatment, median DFS was 14.9 months for those who received post-intervention chemotherapy versus 21.3 months for those without post-intervention chemotherapy (p=0.835). Conclusions: Patients with negative ctDNA results following definitive local therapy for isolated metastatic CRC have better prognosis. Post-intervention chemotherapy in this group of patients was not associated with improved DFS. ctDNA guided omission of post-intervention chemotherapy following curative-intent local treatment of oligometastatic CRC warrants further study. [Table: see text]

(1) Background: Local therapies offer a potentially curative approach for patients with oligometastatic colorectal cancer (CRC). An evidence-based consensus recommendation for systemic therapy following definitive locoregional therapy is lacking. Tumor-informed circulating tumor DNA (ctDNA) might provide information to help guide management in this setting. (2) Methods: A multi-institutional retrospective study was conducted, including patients with CRC that underwent curative-intent locoregional therapy to an isolated site of metastatic disease, followed by tumor-informed ctDNA assessment. The Kaplan–Meier method and log-rank tests were used to compare disease-free survival based on ctDNA results. ctDNA test performance was compared to carcinoembryonic antigen (CEA) test results using McNemar’s test. (3) Results: Our study cohort consisted of 87 patients treated with locoregional interventions who underwent ctDNA testing. The initial ctDNA test post-intervention was positive in 28 patients and negative in 59 patients. The median follow-up time was 14.0 months. Detectable ctDNA post-intervention was significantly associated with early disease recurrence, with a median disease-free survival (DFS) of 6.63 months compared to 21.30 months in ctDNA-negative patients (p < 0.001). ctDNA detected a numerically higher proportion of recurrences than CEA (p < 0.097). Post-intervention systemic therapy was not associated with improved DFS (p = 0.745). (4) Conclusions: ctDNA results are prognostically important in oligometastatic CRC, and further prospective studies are urgently needed to define its role in guiding clinical decisions.

PURPOSE Recurrence after curative-intent treatment occurs in 20%-50% of patients with stage II-IV colorectal cancer (CRC), underscoring the need for early detection of minimal residual disease (MRD) using circulating tumor DNA (ctDNA). Here, we examined the pattern of use of a tumor-informed ctDNA assay in CRC MRD monitoring in routine clinical practice at Mayo Clinic, Rochester. METHODS We conducted a retrospective analysis of health records of patients with CRC who had at least one tumor-informed ctDNA assay from May 2019 through July 1, 2022. Recurrence was defined as radiographic evidence of disease. Descriptive characteristics of the cohort, ctDNA results, and subsequent interventions were recorded. RESULTS Of the 120 patients included, the median age at diagnosis was 67 years, 46% were female, and 94% were White. At diagnosis, 10 patients had stage I, 23 stage II, 60 stage III, and 25 stage IV disease. Of 476 ctDNA assays performed, 70% were performed in patients who had recurrent disease most commonly to monitor the effectiveness of therapeutic interventions and 16% resulted in a change in clinical decision making. There were 110 recurrences identified in 62 patients, as some patients experienced more than one recurrence over time. Compared with serum carcinoembryonic antigen levels, ctDNA results correlated better with radiologic imaging. CONCLUSION Routine ctDNA monitoring for MRD detection has been adopted in clinical practice; however, 84% of ctDNA assays performed did not result in a change in clinical management. This suggests the need for further clinical research data to guide routine clinical use of ctDNA MRD testing in CRC.

For patients with locoregionally confined pancreatic ductal adenocarcinoma (PDAC), margin-negative surgical resection is the only known curative treatment; however, the majority of patients are not operable candidates at initial diagnosis. Among patients with resectable disease who undergo surgery alone, the 5-year survival remains poor. Adjuvant therapies, including systemic therapy or chemoradiation, are utilized as they improve locoregional control and overall survival. There has been increasing interest in the use of neoadjuvant therapy to obtain early control of occult metastatic disease, allow local tumor response to facilitate margin-negative resection, and provide a test of time and biology to assist with the selection of candidates most likely to benefit from radical surgical resection. However, limited guidance exists regarding the relative effectiveness of treatment options. In this systematic review, the American Radium Society multidisciplinary gastrointestinal expert panel convened to develop Appropriate Use Criteria evaluating the evidence regarding neoadjuvant treatment for patients with PDAC, including surgery, systemic therapy, and radiotherapy, in terms of oncologic outcomes and quality of life. The evidence was assessed using the Population, Intervention, Comparator, Outcome, and Study (PICOS) design framework and “Preferred Reporting Items for Systematic Reviews and Meta-analyses” 2020 methodology. Eligible studies included phases 2 to 3 trials, meta-analyses, and retrospective analyses published between January 1, 2012 and December 30, 2022 in the Ovid Medline database. A summary of recommendations based on the available literature is outlined to guide practitioners in the management of patients with PDAC.

AbstractThe liver is a common site of cancer metastases. Systemic therapy is widely accepted as the standard treatment for liver metastases (LM), although select patients with liver oligometastases may be candidates for potentially curative liver resection. Recent data support the role of nonsurgical local therapies such as ablation, external beam radiotherapy, embolization, and hepatic artery infusion therapy for management of LM. Additionally, for patients with advanced, symptomatic LM, local therapies may provide palliative benefit. The American Radium Society gastrointestinal expert panel, including members representing radiation oncology, interventional radiology, surgical oncology, and medical oncology, performed a systemic review and developed Appropriate Use Criteria for the use of nonsurgical local therapies for LM. Preferred Reporting Items for Systematic reviews and Meta‐Analyses methodology was used. These studies were used to inform the expert panel, which then rated the appropriateness of various treatments in seven representative clinical scenarios through a well‐established consensus methodology (modified Delphi). A summary of recommendations is outlined to guide practitioners on the use of nonsurgical local therapies for patients with LM.