First Site Of Recurrence Research Articles

Abstract A074: Integrated clinical and single-cell profiling analysis reveals cellular states associated with metastatic organotropism and survival in patients with pancreatic ductal adenocarcinoma

Abstract Some patients with localized pancreatic ductal adenocarcinoma (PDAC) undergo resection with curative intent, but most experience disease recurrence and succumb to their disease. Through examination of 743 PDAC patients in a single center we found that the site of first recurrence is a major predictor for survival. Patients with liver-metastatic recurrence (LIV-MR) had significantly shorter disease free and overall survival compared to those with recurrence to the lung (LUN-MR). We performed single-nucleus RNA-seq (snRNA-seq) and whole-genome sequencing (WGS) of primary PDAC with either LIV-MR or LUN-MR and found that malignant cells adopt transcriptional programs that mimicked that of their ultimate metastatic target organ. We validated this observation in independent data sets of human adult and fetal liver and lung tissues, and two additional patient cohorts who underwent molecular profiling of their actual PDAC liver and lung metastatic lesions. We reconstructed two different trajectories of malignant transformation in PDAC and found that the LIV-MR and LUN-MR are associated with these, suggesting that subsequent metastatic organotropism may be imprinted early in tumorigenesis. Furthermore, primary PDAC tumors recurring with LIV-MR compared to LUN-MR were depleted of infiltrating T cells and enriched with M2-like macrophages, highlighting potential contributions to subsequent outcomes. Taken together, this work provides evidence for pre-existing cellular adaptations that may determine metastatic organotropism in the context of cancer recurrence. These insights may be useful for prognostication and development of therapeutic strategies at the time of diagnosis of resectable PDAC. Citation Format: Morteza Chalabi Hajkarim, Michael May, Amit Dipak Amin, Jacob Jamison, Somnath Tagore, Lindsay Caprio, Zachary Walsh, Parin Shah, Sinan Abuzaid, Alissa Michel, Sun Dajiang, Winston Wong, Neha Shaikh, Priyanka Ramaradj, Basil Bakir, Michael D Kluger, John Chabot, Hanina Hibshoosh, Anil K Rustgi, Alexander Raufi, Gulam A Manji, Benjamin Izar. Integrated clinical and single-cell profiling analysis reveals cellular states associated with metastatic organotropism and survival in patients with pancreatic ductal adenocarcinoma [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research; 2024 Sep 15-18; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl_2):Abstract nr A074.

Real-world outcomes of stage II and III colorectal cancers treated by postoperative adjuvant chemotherapy based on the mismatch repair status.

In Japan, immunohistochemistry for mismatch repair (MMR) proteins targeted at stage II and III colorectal cancers (CRCs) has been covered by national insurance since October, 2022. This study aimed to clarify the long-term outcomes of patients with stage II and III CRCs receiving postoperative adjuvant chemotherapy based on their MMR status. The outcomes of 640 patients who underwent radical surgery for stage II and III CRCs were analyzed retrospectively. Deficient MMR (dMMR) was diagnosed in 41 (13.3%) patients with stage II and 28 (9.1%) patients with stage III CRC. The overall survival and recurrence rates were not significantly different between the patients with stage II and those with stage III CRC. The risk factors for recurrence among those with stage II CRC were tumors on the left side, T4 disease, and the presence of BRAF wild type. The recurrence rates were lower in the stage II CRC patients with sporadic dMMR than in those with suspected Lynch syndrome (LS). The first site of recurrence was more frequently the peritoneum or distant lymph node in patients with dMMR. Stage IICRC patients with sporadic dMMR were found to have a very good prognosis. On the other hand, peritoneal dissemination or distant lymph node metastasis tended to develop in patients with dMMR.

765. PATTERNS, TIMING, AND SURVIVAL OF RECURRENCE FOLLOWING SURGERY FOR ESOPHAGEAL ADENOCARCINOMA IN THE EUROPEAN MULTICENTRE ENSURE STUDY

Abstract Background After surgery for esophageal cancer approximately half of patients will develop disease recurrence. A more accurate and detailed understanding of the pattern, timing, treatment and prognosis of initial recurrence sites can guide improvements in surveillance and therapy. Therefore, the aim of this study was to accurately describe the pattern and timing of esophageal cancer recurrence, and to assess the distinct survival patterns of these recurrence locations. Methods This study included all patients who underwent surgical resection for esophageal and junctional adenocarcinoma registered in the ENSURE study. ENSURE was an international multicenter study of consecutive patients undergoing surgery for esophageal and esophagogastric junction cancers between 2009 and 2015 across 20 centers in Europe and Canada (NCT03461341). The first recurrence site was recorded and recurrence-free survival (RFS) was estimated using Kaplan-Meier curves. Sites of first recurrence were stratified into different groups and survival outcomes post recurrence detection were estimated using Kaplan-Meier curves. Results Of 3397 eligible patients, 1310 patients had disease recurrence with comprehensive follow-up data available (median RFS of 12.1 months). First recurrence was detected at multiple distant sites (n=469; 37.3%) or at a single distant site (n=463; 33.7%), while isolated local recurrence occurred in 189 (14.4%) patients. Liver-only recurrence occurred significantly earlier (median 9.0 months), while lung-only (15.2 months) and local-only occurred later (17.8 months). Patients with multiple-sites and liver-only recurrence had significant worse median post recurrence survival (7.4 and 8.3 months, respectively) when compared with lung- or local-only recurrence (10.4 and 15.9 months, respectively). Conclusion This study demonstrates that specific recurrence locations of esophageal cancer possess distinct RFS curves. Furthermore, specific recurrence locations result in different post recurrence survival outcomes. This information can help guide improvements in surveillance after esophageal cancer surgery and decisions regarding treatment of esophageal cancer recurrence.

Patterns and Predictors of Recurrence After Curative Resection of Colorectal Liver Metastasis (CRLM).

Our study aims to determine the predictors and patterns of relapses after curative colorectal liver metastasis (CRLM) resection. A single-centre, retrospective study of CRLM patients operated between 2010 and 2022 was performed. The site of first recurrence was either hepatic (marginal (≤ 1cm) or extramarginal), extrahepatic, or both. Factors that predicted relapse patterns and overall survival were determined by multivariable Cox regression analysis with backward elimination of variables. The study consisted of 258 patients, with a similar proportion of synchronous (144; 56%) and metachronous(114; 43%) metastasis. At a 43-month median follow-up, 156 patients (60.4%) developed recurrences with 33 (21.1%) in the liver, 62(24.03%) extra-hepatic recurrences, and 58 (22.48%) having both. Isolated marginal liver relapses were seen in seven (9.89%) liver recurrence patients. The median overall and relapse-free survivals were 38months (30-54) and 13months (11-16), respectively. The 3-year liver-relapse-free survival was 54.4% (44.9-60.6). Size of liver metastases > 5cm (HR 2.06 (1.34-3.17), involved surgical margins (HR 2.16 (1.27-3.68)), and adjuvant chemotherapy (HR 1.89 (1.07-3.35)) were predictors of hepatic recurrences. Node positivity of primary (HR 1.61 (1.02-2.56)), presence of baseline extra-hepatic metastases (HR 0.30 (0.18-0.51)), size of liver metastases > 5cm (HR 2.02 (1.37-2.99)), poorly differentiated histology (HR 2.25 (1.28-3.49)), presence of LVI (HR 2.25 (1.28-3.94)), and adjuvant chemotherapy (HR 2.15 (1.28-3.61)) were predictors of extra-hepatic recurrences. The study found majority relapses occurred at extrahepatic sites whilst isolated marginal recurrences were few. The consistent predictors of recurrence were size and inability to deliver adjuvant therapy. A tailored adjuvant therapy might improve outcomes after liver metastasectomy in colorectal cancers.

Relationships between postoperative recurrences and standardized uptake value on 18F-fluorodeoxyglucose-positron emission tomography in patients with resectable and borderline resectable pancreatic ductal adenocarcinoma who underwent curative pancreatic resection after neoadjuvant chemoradiotherapy

BackgroundThis study aimed to examine postoperative recurrence after curative pancreatic resection following neoadjuvant chemoradiotherapy (NACRT) in patients with resectable (R-) and borderline resectable (BR-) pancreatic ductal adenocarcinoma (PDAC), focusing on its relationship with the standardized uptake value (SUV) on 18F-fluorodeoxyglucose-positron emission tomography (FDG-PET). MethodThe postoperative initial recurrence patterns were examined in patients with R- and BR-PDAC who underwent NACRT followed by curative pancreatic resection. Data collected from three prospective clinical trials were retrospectively analysed. ResultsAfter a median follow-up of 29 months, 91 (60 %) of 151 patients experienced postoperative recurrence. The median recurrence-free survival (RFS) for all patients was 18 months. The sites of first recurrence were lung-only in 24 (26 %) patients, liver-only in 23 (25 %), local-only in 11 (12 %), peritoneum-only in 10 (11 %), other single site in 5 (5 %), and multiple sites in 19 (21 %) patients. Multivariate analysis identified the maximum standardized uptake value (SUVmax) on FDG-PET at diagnoses ≥5.40 (hazard ratio [HR], 1.62; 95 % confidence interval [CI], 1.01–2.61; p = 0.045) and node-positive pathology (HR, 2.01; 95 % CI, 1.32–3.08; p = 0.001) as significant predictors of RFS. Furthermore, the SUVmax at initial diagnosis and after NACRT correlated with liver metastasis. ConclusionR- and BR-PDACs with high SUV on FDG-PET at diagnosis are risk factors for postoperative recurrence. Among patients who undergo surgery after NACRT, those with a high SUVmax at diagnosis or post-NACRT require careful attention for postoperative liver recurrence.

Intrahepatic cholangiocarcinoma: Recurrence patterns, genomics and survival.

570 Background: Recurrence is common after resection of intrahepatic cholangiocarcinoma (IHC) but how recurrence patterns impact survival remains unclear. This study investigated the clinicopathologic and genomic factors associated with site of first recurrence and their impact on outcome after curative intent resection. Methods: Patients who underwent curative intent hepatectomy for IHC at two medical centers (MSKCC and EMC) with complete follow up and tumor genomic data were included. Documented sites of first disease recurrence were classified as liver only (LO), extrahepatic (EH) only or simultaneous liver and extrahepatic (SIM). Time to recurrence (TTR) and recurrence-free (RFS) were calculated from time of resection while OS was calculated from time of recurrence. Primary tumors underwent targeted next generation sequencing. Clinical, histopathologic and genomic factors associated with site(s) of recurrence, RFS and OS were assessed. Results: A total of 318 patients (n=296 MSK, n=22 EMC) treated between 1993 and 2021 met inclusion criteria and were analyzed; 232 patients (73%) developed recurrence. TTR was 11 (9.8, 12) months; OS and RFS was 26 (20, 33) and 14 (13, 18) months, respectively, among patients that recurred. Sites of first recurrence were LO 93 (40%), EH 80 (34%) and SIM 59 (26%). Median OS was similar in the LO (33 [26,42] months) and EH groups (33 [23,46] months) but much lower in SIM (12 [9.8,18] months) (p < 0.001). Moderate/poor tumor differentiation (p = 0.004), LVI (p = 0.004), N1 disease (p = 0.003), and PNI (p = 0.012) were associated with SIM; only positive resection margin predicted LO (p = 0.007). No individual genomic or pathway alterations predicted site of initial recurrence; however, for all patients, TP53 mut (HR 2.01, 1.4-2.9; p < 0.001), CDKN2A del (HR 1.96, 1.29-2.98; p = 0.003), CDKN2B del (HR 3.2, 2.03-5.05; p < 0.001) and KRAS mut (HR 2.49, 1.56-3.96; p < 0.001) were associated with worse survival. On multivariable analysis, SIM (HR 2.23, 1.49-3.34; p < 0.001), clinical stage III (HR 1.94, 1.26-2.99; p = 0.011), and alterations in TP53 (HR 2.07, 1.4-3.07; p < 0.001), CDKN2B (HR 4.1, 2.53-6.63; p < 0.001) and KRAS (HR 2.72, 1.68-4.43; p < 0.001) were independent predictors of worse OS. Of note, 13 LO patients were treated with regional chemotherapy after recurrence, with an associated median OS of 49 (33, NR) months compared to 28 (20, 39) months in the 80 patients treated with systemic therapy alone. Conclusions: Recurrence after resection of IHC was common, and the liver was the single most common site (66%). Clinicopathologic and genomic variables had limited ability to predict site of first recurrence. While LO and EH were associated with similar OS, simultaneous recurrences were dramatically worse. The data support adjuvant strategies targeting liver recurrence to improve outcome after resection of IHC.

The Clinical Impact of the Pretreatment Albumin to Fibrinogen Ratio in Esophageal Cancer Patients Who Receive Curative Treatment.

The albumin to fibrinogen ratio (AFR) has been identified as a promising prognostic marker for some malignancies. The aim of the present study was to evaluate the clinical impact of AFR in esophageal cancer patients who received curative resection. The present study included 123 patients who underwent curative treatment for esophageal cancer between 2005 and 2020. The prognosis and clinicopathological parameters were compared between patients with high and low AFRs. The overall survival (OS) stratified by each clinical factor was compared using the log-rank test, and a significant difference was observed when using a pretreatment AFR of 1.23. When comparing the patient backgrounds between the high-AFR (AFR ≥12.3) and low-AFR (AFR<12.3) groups, significant differences were noted in the pathological T status. The high-AFR group had significantly higher OS rates at 3 years (70.8%) and 5 years (59.3%) after surgery in comparison to the low-AFR group (46.6% and 37.4%, respectively). Univariate and multivariate analyses for OS showed that the AFR was a significant prognostic factor. In addition, when comparing the site of first recurrence, a marginally significant difference was noted in hematological recurrence. The AFR is a significant risk factor in patients with esophageal cancer, holding promise as a valuable prognostic factor.

The Naples Prognostic Score Is an Independent Prognostic Factor for Gastric Cancer Patients Who Receive Curative Treatment.

This study aimed to evaluate the clinical impact of the Naples Prognostic Score (NPS) in patients with gastric cancer and to clarify the potential of the NPS as a nutritional and inflammation evaluation system. This study included 158 patients who underwent curative treatment for gastric cancer between 2005 and 2020. The prognosis and clinical pathological parameters of the high-NPS (NPS >2) and low-NPS (NPS=0, 1) groups were analyzed. The overall survival (OS) rates at 3 and 5 years were 86.7% and 77.7%, respectively, in the low-NPS group and 55.4% and 47.4%, respectively, in the high-NPS group. There were significant differences in OS between the two groups. Uni- and multivariate analyses demonstrated that the NPS was an independent prognostic factor for OS (HR=2.495, 95%CI=1.240-5.451). In addition, the 3- and 5-year recurrence-free survival (RFS) rates were 82.1% and 76.0%, respectively, in the NPS-low group, and 43.8% and 36.6% in the NPS-high group. Univariate and multivariate analyses demonstrated that the NPS was an independent prognostic factor for RFS (HR=2.739, 95%CI=1.509-4.972). When the first site of recurrence was compared between the low-NPS group and high-NPS group, there were significant differences in peritoneal recurrence (8.7% vs. 34.3%, p=0.001) and hematologic recurrence (5.6% vs. 21.9%, p=0.004). The NPS was a significant prognostic factor in patients with gastric cancer who received curative treatment. The NPS may be a promising biomarker for the treatment and management of gastric cancer.

Progression of Site-specific Recurrence of Pancreatic Cancer and Implications for Treatment.

To analyze postrecurrence progression in the context of recurrence sites and assess implications for postrecurrence treatment. Most patients with resected pancreatic ductal adenocarcinoma (PDAC) recur within 2 years. Different survival outcomes for location-specific patterns of recurrence are reported, highlighting their prognostic value. However, a lack of understanding of postrecurrence progression and survival remains. This retrospective analysis included surgically treated patients with PDAC at NYU Langone Health (2010-2021). Sites of recurrence were identified at the time of diagnosis and further follow-up. Kaplan-Meier curves, log-rank test, and Cox regression analyses were applied to assess survival outcomes. Recurrence occurred in 57.3% (196/342) patients with a median time to recurrence of 11.3 months (95% CI: 12.6-16.5). The first site of recurrence was local in 43.9% of patients, liver in 23.5%, peritoneal in 8.7%, lung in 3.6%, whereas 20.4% had multiple sites of recurrence. Progression to secondary sites was observed in 11.7%. Only lung involvement was associated with significantly longer survival after recurrence compared with other sites (16.9 vs 8.49 months, P = 0.003). In local recurrence, 21 (33.3%) patients were alive after 1 year without progression to secondary sites. This was associated with a CA19-9 of <100 U/mL at the time of primary diagnosis ( P = 0.039), nodal negative disease ( P = 0.023), and well-moderate differentiation ( P = 0.042) compared with patients with progression. Except for lung recurrence, postrecurrence survival after PDAC resection is associated with poor survival. A subset of patients with local-only recurrence do not quickly succumb to systemic spread. This is associated with markers for favorable tumor biology, making them candidates for potential curative re-resections when feasible.

Outcomes of Watch and Wait Following Total Neoadjuvant Therapy for Rectal Cancer

To evaluate the outcomes of patients with locally advanced rectal cancer who achieved a clinical complete response (cCR) after total neoadjuvant therapy and enrolled in a prospective watch and wait (WW) database. Consecutive patients with locally advanced rectal cancer who achieved cCR following total neoadjuvant therapy (long-course chemoradiotherapy plus systemic chemotherapy) and were enrolled in our institutional WW surveillance protocol from 2014 through 2022 with the intention of organ preservation. Patients with lack of follow up according to our institutional protocol were excluded. Primary outcomes included local tumor regrowth and distant metastatic disease recurrence. Thirty-three consecutive patients (48% male; median age 61 [33-77] years) with the diagnosis of locally advanced rectal adenocarcinoma were managed by a multidisciplinary team. All patients had Eastern Cooperative Oncology Group Performance Status score of 0 or 1 at time of rectal cancer diagnosis. Location of tumor included upper rectum (18%), middle rectum (40%), and lower rectum (42%). On initial staging magnetic resonance imaging, 4 (12%) patients had evidence of extramural venous invasion, 6 (18%) had a threatened mesorectal margin, and 4 (12%) had anal sphincter or levator ani tumor involvement. A majority (61%) received chemotherapy followed by long-course chemoradiotherapy. Only one patient had an unplanned break during radiotherapy. Local tumor regrowth was diagnosed in 4 (12%) patients and all underwent successful salvage surgery without additional local failures at a median follow-up of 19 [12-48] months. Two of these four patients remain disease-free at a median follow-up time of 12.5 months. Mean time to local tumor regrowth as first site of cancer recurrence was 33.5 [18-46] months. Distant metastatic disease as the first site of recurrence occurred two patients (6%). Mean time to distant metastatic disease as first site of recurrence was 27 months. Only one mortality occurred in the entire group at a median follow-up of 49 [8-102] months. Organ preservation after total neoadjuvant therapy for locally advanced rectal cancer yields excellent outcomes with low local and distant relapse rates. Structured surveillance protocols and multidisciplinary care are essential for success.

Patterns of Failure for Poor Response to Neoadjuvant Chemotherapy in Gastric Cancer

Peri-operative chemotherapy has emerged as the standard of care in the treatment of locally advanced gastric cancer. Improved treatment strategies are needed for patients with a poor response to neoadjuvant chemotherapy and postoperative chemoradiation has been proposed as a potential method of treatment intensification. We aimed to describe the patterns of failure for patients with no or partial response (NR, PR) to pre-operative chemotherapy. We retrospectively reviewed charts of patients with locally advanced gastric cancer treated at our institution from 2008 to 2022 with pre-operative chemotherapy followed by surgery with a D2 resection. We excluded patients who received pre-operative or post-operative radiation therapy, or patients who had a complete response (CR) following neoadjuvant chemotherapy. Cumulative incidence of locoregional failure (LRF) and distant metastases (DM) were calculated from the time of diagnosis with competing risk analysis with death as a competing risk and censored at the last follow up. Overall survival (OS) was analyzed using Kaplan-Meier. A total of 57 patients were identified and 60% are male. Median follow-up time was 31.3 months (range 6.9-181.5 months), and the median age at diagnosis was 68 years old (range 30-86). The most used pre-operative chemotherapy regimen was FLOT (38.6%), followed by FOLFOX (29.8%), and ECF/ECX/EOX (19.3%), and a majority of patients (57.9%) received adjuvant chemotherapy. The most common histology was adenocarcinoma (85.9%), and 61.4% of patients had poorly differentiated disease. Thirty-three (57.9%), and 9 patients (15.8%) were characterized as PR and NR to neoadjuvant therapy by pathology, respectively. The distribution of pathologic stages following neoadjuvant chemotherapy were as follows: 17 patients (29.8%) with Stage IA-B, 12 patients (21.1%) with Stage IIA-B, 15 patients (26.3%) with Stage IIIA, 9 patients (15.8%) with Stage IIIB, and 3 patients (5.3%) with Stage IIIC disease. Two patients had positive lymph nodes with a T0 primary tumor. Median OS was 51.4 months (95% confidence interval [CI] 39.8-68.4) for the entire cohort, and 92.1 months (95% CI 34.6-73.0) versus 42.8 months (95% CI 23.1-88.0) for patients with a PR, and NR, respectively (p = 0.14). The 2-year cumulative incidence of LRF and DM was 7.4% (95% CI 0.4-14.3) and 36.3% (95% CI 23.6-49.1), respectively. Of the five patients who experienced LRF, three of the patients also eventually or concurrently developed DM. 60% of these patients would have had their first site of recurrence covered by standard post-operative radiation treatment volumes. Patients with locally advanced gastric cancer who do have less than a CR to chemotherapy have poor outcomes due to high rates of DM. Adjuvant locoregional therapy such as radiation is unlikely to affect survival while DM is the predominant pattern of progression. Further studies are needed to identify adjuvant therapies to improve distant control.

Long-Term Outcomes in a Phase II Study of Hypofractionated IGRT 60Gy/ 20F in Patients with Isolated Lymph Node Recurrence after Surgery for Esophageal Carcinoma

In oligo metastases in lymph node recurrence after surgery for esophageal cancer, since SBRT (BED>100 Gy10) to mediastinal and abdominal lymph node lesions was not an option due to toxicities in the organs at risk (OAR) such as vessels and gastrointestinal tract, we performed a prospective cohort study of hypofractionated IGRT for isolated lesions. The primary end-points of this study are disease specific survival (DSS) and late treatment toxicities. From 2011 to 2021, 60 Gy/20F/4-4.5wks (78 Gy10) hypofractionated IGRT was performed in a total ITT population of 70 patients after radical surgery (67 cases) and ESD (3 cases), who were diagnosed by CT/PET-CT as having solitary lymph node recurrence (62 cases) or up to 2 adjacent nodes (8 cases). The mean time from surgery to recurrence was 17.9 months (SD 18.1) with a mean age of 67.5 years (SD 9.3), and male to female ratio was 62:8. Pathological results showed that 63 patients (90%) had squamous cell carcinoma. The mean maximum diameter of lesions was 2.5 cm (SD; 1.1 cm). And 51 cases (73%) were treated with CRT concurrently using 5FU plus CDDP (FP), and the rest were treated with RT alone. Lymph node location was lower neck or upper mediastinum in 42 cases, middle and lower mediastinum in 16 cases, and abdomen in 12 cases, respectively. Treatment planning was performed by taking 4DCT fusing PET or MRI images. The Kaplan-Meier method and the Cox proportional hazards regression model were used for overall survival (OS), DSS, and progression free survival (PFS). The mean observation period was 38 months. Primary efficacy was CR in 45 cases (64%), but CR was maintained only in 29 cases (41%). Twenty-two of the 70 patients were relapse-free. OS were 53% and 34% at 2 and 5 years, DSS were 56% and 38% at 2 and 5 years, and PFS were 40% and 39% at 2 and 5 years, respectively. The site of first recurrence was the same or adjacent lymph nodes in 33 cases (47%) and distant metastases in 9 cases (13%). Number of tumors (1 vs. 2), age, and CRT were not significant prognostic factors for OS, DSS, or PFS. In a multivariate analysis, the time from surgery to recurrence ≥12 months was the only significant prognostic factor for PFS (p = 0.018, HR0.50). The same multivariate analysis showed that the only significant prognostic factor for DSS was the location of the recurrent lymph node in the neck and upper mediastinal regions (p = 0.009, HR 0.59). The only late adverse events of Grade 2 or higher were Grade 2 pleural effusion (little and transient) in 6 cases and Grade 2 radiation pneumonitis in 1 case. No acute adverse events were observed other than hematologic toxicity due to FP administration. In locally advanced esophageal cancer, a relatively reliable regional lymph node dissection is often performed, so there is still a chance to aim for cure in cases of solitary recurrence. We found that if the lesion is solitary, localized RT of about 60 Gy/20F/4-4.5 weeks with IGRT can achieve a long-term survival in 40% of patients without any significant adverse events.

Patterns of Recurrence for Lymph Node Positive Cutaneous Melanoma in the Era of Immunotherapy

The management of patients with lymph node positive, nonmetastatic cutaneous melanoma has changed significantly with the adoption of anti-PD-1 immunotherapy. We compared clinical outcomes and patterns of recurrence of patients with lymph node positive, nonmetastatic cutaneous melanoma who received adjuvant immunotherapy with those who did not receive immunotherapy. Patients with lymph node or in-transit metastasis positive, nonmetastatic cutaneous melanoma diagnosed from 2013-2020 were identified from a prospectively-maintained, single-institution database. Baseline patient demographics and treatment details were recorded. Patients were stratified by receipt of adjuvant immunotherapy. Local and regional recurrence, distant metastasis, first site of recurrence, and overall survival (OS) were recorded, and rates of OS, progression-free survival (PFS), freedom from distant metastasis (ffDM), local recurrence (ffLR), and regional lymph node recurrence (ffRR) were estimated using the Kaplan-Meier method. Wilcoxon rank-sum test, Fisher's exact test, and chi-square test of independence were used to analyze variables between groups. Ninety-two patients were included with a median age of 67 years and a median follow-up of 2.9 years. Fifty-six (61%) patients received adjuvant immunotherapy for a median duration of 8.5 months. Fifty-three (58%) patients had a sentinel lymph node dissection alone while thirty-two (35%) had a complete regional lymph node dissection. A median of 3 lymph nodes were removed (range 0-83) with a median of 1 positive lymph node (range 1-15). Twenty-four (26%) patients had extranodal extension, thirty-nine (42%) had ulceration of the primary site, and twenty-eight (30%) had LVSI present. Median age of patients receiving immunotherapy versus those who did not was 63 years versus 72 years (p = 0.02). There were no differences in primary site, disease thickness, Clark stage, primary site ulceration, LVSI, extranodal extension, satellite metastasis, AJCC T- and N-stage, and completion lymph node dissection rates between the groups. Patients receiving immunotherapy had significantly improved OS (HR = 0.3, p = 0.001) with no difference in PFS (HR = 0.6, p = 0.08), ffDM (HR = 0.66, p = 0.28), ffLR (HR = 0.18, p = 0.1), and ffRR (HR = 2.5, p = 0.08). The initial site of recurrence was regional lymph nodes in thirteen (23%) patients receiving immunotherapy versus two (6%) patients who did not receive immunotherapy (p = 0.01). On UVA, male gender, number of positive lymph nodes, clinically positive lymph nodes, extranodal extension, in-transit metastasis, LVSI, and tumor thickness were significant predictors of regional lymph node recurrence. Patients with lymph node positive cutaneous melanoma receiving immunotherapy had a higher rate of initial disease progression in the regional lymph nodes compared with patients not receiving immunotherapy.

Patterns of Recurrence After Poor Response to Neoadjuvant Chemotherapy in Gastric Cancer and the Role for Adjuvant Radiation.

Improved treatment strategies are needed for patients with locally advanced gastric cancer with poor response to neoadjuvant chemotherapy. We aimed to describe patterns of failure for patients with no or partial response (NR, PR) to preoperative chemotherapy. We analyzed patients with locally advanced gastric cancer treated from 2008 to 2022 with preoperative chemotherapy followed by surgery with D2 resection. We excluded patients who received radiation. Cumulative incidence of locoregional failure (LRF) and distant metastases (DM) were calculated. For patients with recurrent abdominal disease, hypothetical radiation clinical treatment volumes (CTV) were contoured on postoperative scans and compared with patterns of recurrence. A total of 60 patients were identified. The most used preoperative chemotherapy was FLOT (38.6%), followed by FOLFOX (30%) and ECF/ECX/EOX (23.3%). Four (6.7%), 40 (66.7%), and 9 patients (15%) had a complete pathologic response (CR), PR, and NR to neoadjuvant therapy, respectively. Among patients without a CR, 3-year overall and progression-free survival rates were 62.3% (95% CI 48-76.6%) and 51.3% (95% CI 36.9-65.7%), respectively. Three-year cumulative incidence of LRF and DM were 8.4% (95% CI 0.4-16.4%) and 41.0% (95% CI 26.3-55.4%), respectively. Absolute rates of patients having the first site of recurrence encompassed by a postoperative radiation CTV was 2.0% for patients without a CR and 0% for patients with NR. Patients with locally advanced gastric cancer with less than a CR to chemotherapy have poor outcomes due to high rates of DM. Adjuvant locoregional therapy such as radiation is unlikely to affect survival.

Postoperative recurrence in locally advanced rectal cancer: how does neoadjuvant treatment affect recurrence pattern?

BackgroundThe treatment strategy for locally advanced rectal cancer (LARC) has recently expanded from total mesorectal excision to additional neoadjuvant chemoradiotherapy (nCRT) and/or systemic chemotherapy (NAC). Data on disease recurrence after each treatment strategy are limited.MethodsClinical stage II to III rectal cancer patients who underwent curative surgery between July 2005 and February 2021 were analyzed. The cumulative incidence and site of first recurrence were assessed. The median follow-up duration was 4.6 years.ResultsAmong the 332 patients, we performed nCRT and NAC in 15.4% (N=51) and 14.8% (N=49), respectively. The overall recurrence rate was 23.5% (N=78). Although several differences in tumor stage or location were observed, there was no significant difference in the rate among the surgery alone (N=54, 23.3%), nCRT (N=11, 21.6%), and NAC (N=13, 26.5%) groups. In this cohort, the local recurrence rate (18.4%) was higher than the rate of distant metastasis in the NAC group (14.3%). All patients with recurrence in the nCRT group had distant metastases (N=11: one patient had distant and local recurrences simultaneously). For pathological stage 0-I, the recurrence rate was higher in the nCRT and NAC groups than in the surgery-alone group (nCRT, 10.0%; NAC, 15.4%; and surgery-alone, 2.0%). Curative-intent resection of distant-only recurrences significantly improved patients’ overall survival (hazard ratio [95% confidence interval], 0.34 [0.14–0.84]), which was consistent even when stratified according to neoadjuvant treatment. Regardless of neoadjuvant treatment, >80% of recurrences occurred in the first 2.2 years, and 98.7% within 5 years after surgery.ConclusionRegardless of neoadjuvant treatment, detecting distant metastases with intensive surveillance, particularly in the first 2 years after surgery, is important. Also, even if neoadjuvant treatment can downstage LARC to pathological stage 0-I, careful follow-up is needed.

Feasibility and long-term outcomes of post-chemotherapy-based consolidation radiotherapy in extensive stage small-cell lung cancer

BackgroundThe target definition of consolidation radiotherapy (RT) for extensive stage small-cell lung cancer (ES-SCLC) has not been standardized. This study aimed to demonstrate the feasibility of post-chemotherapy based consolidation RT in ES-SCLC. MethodsAll ES-SCLC patients without initial brain metastases who completed ≥ 4 cycles of systemic therapy at Department of Radiation and Medical Oncology, Zhongnan Hospital of Wuhan University from 2012 to 2021 were included in this retrospective study. We correlated the site of first recurrence to the post-chemotherapy-based radiation volume (small-field). Relapse pattern, progression-free survival (PFS) and overall survival (OS) were compared between those received and did not receive consolidation RT. ResultsA total of 152 patients were followed up for a median of 31.7 months (interquartile range [IQR], 23.9–39.6 months). The median PFS and OS of the cohort were 8.3 months (IQR, 6.1–11.2 months) and 16.2 months (IQR, 9.9–24.9 months), respectively. Thoracic consolidation RT served not only as an independent prognostic factor for improved PFS in the entire cohort, but also significantly prolonged OS in the subgroup without synchronous liver metastases. Small-field consolidation RT markedly reduced in-field recurrences (hazard ratio [HR], 0.28 [95% CI, 0.12–0.38]; P < 0.001) without increasing out-of-field recurrences (HR, 0.40 [95% CI, 0.13–1.16]; P = 0.080). No relapse was observed at the margin of the targets. Treatment-related toxicities were moderate, with grade 3 acute radiation pneumonia, radiation esophagitis, and bone marrow suppression rates of 8.3%, 3.1%, and 12.5%, respectively. No grade 5 toxicity occurred. ConclusionSmall-field consolidation RT based on post-chemotherapy volume is safe and can significantly improve local control in ES-SCLC.

Radiotherapy-Dose Escalated for Large Volume Primary Tumors-And Cetuximab with or without Induction Chemotherapy for HPV Associated Squamous Cell Carcinoma of the Head and Neck-A Randomized Phase II Trial.

Eligible patients in this multicenter, randomized, controlled, phase 2 trial had p16-positive locoregionally advanced SCCHN. Patients were randomized in a 1:1 ratio to either RT with cetuximab (arm B) versus the same regimen preceded by two cycles of taxotere/cisplatin/5-FU (arm A). The RT dose was escalated to 74.8 Gy for large volume primary tumors. Eligibility criteria included patients of 18-75 years, an ECOG performance status 0-1, and adequate organ functions. From January 2011 to February 2016, 152 patients, all with oropharyngeal tumors were enrolled, 77 in arm A and 75 in arm B. Two patients, one in each group, withdrew their consent after randomization, leaving 150 patients for the ITT analysis. PFS at 2 years was 84.2% (95% CI 76.4-92.8) in arm A and 78.4% (95% CI 69.5-88.3) in arm B (HR 1.39, 95% CI 0.69-2.79, p = 0.40). At the time of analysis, there were 26 disease failures, 9 in arm A and 17 in arm B. In arm A, 3 patients had local, 2 regional, and 4 distant relapses as first sites of recurrence, and in arm B, 4, 4, and 9 relapses in corresponding sites. Eight out of 26 patients with disease progression had salvage therapy and 7 were alive NED (no evidence of disease), at 2 years. Locoregional control was 96% in arm A and 97.3% in arm B and OS 93% and 90.5%, respectively. Local failure as first site of recurrence was low, in 4.6% of patients and was similar for T1/T2 and T3/T4 tumors (n.s). Nevertheless, out of 7 patients with primary local failures, 4 were treated with the escalated RT dose. Toxicity was low and similar in the treatment arms. There was one fatal event in arm A where the combined effects of the drugs used in chemotherapy and cetuximab could not be ruled out. PFS, locoregional control and toxicity did not differ between the two arms, OS was high, and there were few local relapses. In arm B, more than twice as many patients had distant metastasis as the first site of relapse compared to arm A. The response to IC was found to define 29% of patients in arm A who did not have a tumor relapse during follow-up. An escalated dose of 74.8 Gy could mitigate the negative impact of large tumor volume but for some patients, even this intensified treatment was insufficient.

Abstract P1-11-17: The real-world outcome of human epidermal growth factor type-2 positive breast cancer patients receiving neoadjuvant therapy with or without pertuzumab

Abstract Background Standard treatment in early HER2 positive BC involves the use of neoadjuvant chemotherapy (NACT) with Trastuzumab (T) plus Pertuzumab (P). Dual blockade increases pathological complete response (pCR) and improves disease free survival (DFS). However, Chilean public health system does not include P use in the NACT schedule, while private insurers only provide partial coverage. Here, we aim to compare pCR, Distant DFS (DDFS) and site of recurrence in HER2 positive BC patients treated in the neoadjuvant setting with the use of T with or without P, in the largest BC Chilean registry. Methods We conducted a retrospective population-cohort study involving females with stage I-III HER2 positive BC treated with NACT in a public and academic private centre between 2012 to 2021. CT regimens for comparison included anthracyclines, taxanes, T and P. pCR was defined as the absence of residual invasive disease in the breast and in the axillary lymph nodes (ypT0/is N0) at the completion of the NACT. DDFS was measured from the time of diagnosis to the event or lost to follow-up. We performed Cox regression analysis to identify factors associated with prognosis and a logistic regression to identify factors related to the first metastasis site. Results 372 patients with HER2 positive BC were included. Median age was 51 years (24 – 79), 57.5% were classified as Hormone Receptor positive (HR), and 4.5% were stage I, 48.2% stage II and 47.3% stage III. 65.8% were treated in a Public Hospital (PH) and 34.2% in an Academic Private Centre (AC). 85.2% received both anthracyclines and taxanes, 10.0% only taxanes and 4.8% only anthracyclines-based CT. 55 patients (14.8%) received both T and P, while 3.3% did not receive any HER2 directed therapy as NA treatment. Median T doses before surgery were 6 (1 – 12). pCR rate was 46.5% which varied according to HR expression: 61.0% in HR-positive BC vs. 36.2% in HR-negative disease (p=0.0001). pCR according to treatment were as follows: no-T no-P 22.2%, only-T 49.4%, both T-P 60.0% (p=0.02). We found no difference in pCR rate between anthracycline and non-anthracycline based CT (49.1% vs. 45.9%, p=0.72). With a median follow-up of 36 months, DDFS at 3 and 5 years differed regarding pathological response: 94.8% vs. 77.1% and 86.3% vs. 69.1% (p=0.0006), for pCR and non-pCR group, respectively. In a multivariate analysis, stage III vs. I-II (HR 2.5, p=0.005), non-pCR vs. pCR (HR 2.6, p=0.01) and not receiving NA anti-HER2 treatment (HR 2.6, p=0.01) were associated with higher risk of distant metastasis. Regarding recurrence, 7 out of 198 non-pCR tumors and 6 out of 174 pCR tumors presented brain metastasis (BM) as the first site of distant recurrence(p=0.96). In contrast, visceral metastasis (VM) as the first site of recurrence, were more frequent in non-pCR (21/198) than pCR patients (3/174, p=0.001). In a multivariate analysis, the only factor associated with BM was stage III (HR 5.8 vs stage I-II, p=0.02) and with VM was not achieving pCR (HR 6.3, p=0.02) and not using T nor P (HR 5.1, p=0.008). Conclusion The use of anti-HER2 treatment in a NA scheme is critical in HER2 positive disease. Although P is associated with increased pCR, we found no survival benefit with its use. Retrospective analysis, few events, post-surgical treatment might have influenced these results. Achieving pCR is associated with better prognosis by reducing distant recurrence but not BM. New strategies are needed to prevent the occurrence of this event. Citation Format: FRANCISCO ACEVEDO, Benjamin Walbaum, Lidia Medina, Tomas Merino, Catherine Bauerle, Mauricio Camus, Augusto Leon, Manuel Manzor, Paulina Veglia, Raul Martinez, Constanza Guerra, Marisel Navarro, Francisco Dominguez, CÉSAR SÁNCHEZ. The real-world outcome of human epidermal growth factor type-2 positive breast cancer patients receiving neoadjuvant therapy with or without pertuzumab [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P1-11-17.

Tumor deposits are associated with a higher risk of peritoneal disease in non-metastatic colorectal cancer patients.

Tumor deposit (TD) is a poor prognostic factor in colorectal cancer (CRC) patients. This study aimed to determine whether TD carry the same risk of peritoneal recurrence as known high-risk (HR) features in CRC patients. A retrospective cohort-study of stage I-III CRC patients from 2010 to 2015 was conducted. TD group was defined by the presence of TD on histopathology whereas HR group was defined by the presence of obstruction, perforation, or T4-stage. A total of 151 patients with CRC were identified, of which 50 had TD and 101 had a HR feature. The overall risk of peritoneal recurrence was higher in the TD group versus HR group (36.0% vs. 19.8%, p = 0.03). The risk of peritoneum as the site of first recurrence was also higher in the TD group (22.0% vs. 12.9%, p = 0.03). Overall cancer recurrence at any site was also higher in the TD group (56.0% vs. 34.7%, p = 0.01). Median time to first recurrence was 1.2 (0.7-1.9) years in the TD group compared to 1.4 (0.8-2.1) years in the HR group (p = 0.31). In non-metastatic CRC patients, TD might have a higher risk of tumor recurrence versus their HRcounterparts. Alternative strategies for surveillance and treatment should be considered.

Adjuvant chemotherapy for resected intrahepatic cholangiocarcinoma confers no survival advantage.

560 Background: Randomized data suggest improved survival with adjuvant chemotherapy for biliary tract cancers, but subset analyses of intrahepatic cholangiocarcinoma (ICC) show limited survival benefit. This study uses a large bi-institutional cohort of resected ICC patients to evaluate the impact of adjuvant therapy on recurrence patterns and overall survival (OS) and compares these findings to data from a national cancer registry. Methods: Patients with resected ICC were identified within a bi-institutional cohort (Duke and Memorial Sloan Kettering, 1997-2020) and the National Cancer Database (NCDB, 2010-2018). Patients were stratified by treatment with adjuvant chemotherapy (adj). Site of first recurrence was categorized as local (liver only), regional (liver and perihepatic nodes), nodal (perihepatic nodes only), distant, or mixed (both liver and distant). OS was compared with Kaplan-Meier methods. Results: 367 patients underwent resection for ICC, and 163 (44%) patients received adjuvant therapy. Median follow-up was 33 vs. 44 months (adj vs observation (obs), p=0.15). 263 (72%) patients had recurrent disease, most commonly in the liver (72%). There was no difference in recurrence patterns stratified by treatment with adjuvant chemotherapy (% recurrence, adj vs obs; local: 42 vs 42; regional: 2 vs 2; nodal: 0 vs 3; distant only: 27 vs 26; mixed: 29 vs 27, p=0.5). OS was the same between groups (adj vs obs; 42 vs 49 months, p=0.3) and when stratified by recurrence site (p=0.5). Similarly, in an NCDB cohort of 1,159 ICC patients over the same time period, there was no association between adjuvant therapy and OS (adj vs obs; 49 vs 57 months, p=0.1). Conclusions: In this retrospective dual registry analysis, corroborated by national data, adjuvant chemotherapy was not associated with an improvement in OS in ICC patients subjected to curative intent resection. Further, adjuvant therapy had no impact on the high rate of hepatic recurrence, suggesting that alternative strategies, such as liver directed therapies, are needed to improve recurrence rates and OS.