Oligometastatic Colorectal Cancer Research Articles

The utilization of circulating tumor DNA to predict the risk and location of relapse after curative-intent local therapy in oligometastatic colorectal cancer

The utilization of circulating tumor DNA to predict the risk and location of relapse after curative-intent local therapy in oligometastatic colorectal cancer

Abstract B004: PISCA-box: A user-friendly interface for Phylogenetic Inference using Somatic Chromosomal Alterations (PISCA)

Abstract PISCA, originally introduced by Martinez et al. in 2018, represents a pivotal Bayesian phylogenetics tool for the modeling of tumor evolution using multi-region somatic chromosomal alteration (SCA) data. PISCA takes allele-specific copy number data, typically obtained from deep genome sequencing or SNP arrays, or absolute copy number data from low-pass genome sequencing methodologies. It extends the classic BEAST1 framework and inherits a rich repertoire of evolutionary models. Importantly, PISCA leverages longitudinal sampling to estimate SCA mutational clock rates, either employing strict clock models, where mutation rates remain constant throughout the evolutionary tree, or relaxed clocks, which allow each branch or subtree to possess its distinct mutation rate. This nuanced approach empowers PISCA to account for the heterogeneous rates of mutations, a pivotal consideration in understanding tumor evolution dynamics. However, PISCA has historically posed a formidable entry barrier for wider community adoption due to platform and Java dependencies for installation, as well as the need for manual or custom-scripted XML file generation. Here we showcase PISCA-box, a user-friendly interface designed to streamline the generation and testing of XML files. Our PISCA-box Docker image works on any desktop machine to create a locally hosted webpage, where users can input SCA data, sampling dates, select clock and demographic models, and set priors for key parameters - similar to the BEAST XML generator, BEAUTi. The Docker or Singularity installation can then be used for longer analyses using high-performance computing resources. To demonstrate its practical utility, we present novel colorectal cancer data. First, we examine data from a patient with a long-standing history of inflammatory bowel disorder (IBD), a known high-risk factor for colorectal cancer. This patient had undergone surveillance colonoscopies for many years, which provided 38 samples, and subsequently an additional 118 samples were collected from a total colectomy. All were analyzed with low-coverage whole genome sequencing. We find some samples from surveillance and colectomy form lineages with overlapping copy number events, that we used to construct a phylogeny, finding a cancer-adjacent clade that appears to evolve rapidly. A second dataset of multi-region samples from a cohort of exceptional survivors of oligometastatic colorectal cancer who lived >60 months from metastatic diagnosis with biopsies/resections across 3-10 time points is examined and temporal models are used to estimate the ages of metastatic clades. PISCA therefore harnesses the power of longitudinal SCA data to enable a comprehensive study of SCA dynamics. We are currently expanding this framework to include fluctuating methylation clocks which PISCA-box will soon include. By providing this accessible tool, we enable researchers to readily apply Bayesian phylogenetics to real-world clinical datasets to better understand tumor evolution. Citation Format: Heather E. Grant, Rachel Alcraft, Pablo Bousquets-Muñoz, Calum Gabbutt, Alison Berner, Mehmet Yalchin, Carlo C. Maley, Trevor A. Graham, Diego Mallo. PISCA-box: A user-friendly interface for Phylogenetic Inference using Somatic Chromosomal Alterations (PISCA) [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Translating Cancer Evolution and Data Science: The Next Frontier; 2023 Dec 3-6; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(3 Suppl_2):Abstract nr B004.

Alliance A022101: A pragmatic randomized phase III trial evaluating total ablative therapy for patients with limited metastatic colorectal cancer—Evaluating radiation, ablation, and surgery (ERASur).

TPS236 Background: For patients with oligometastatic colorectal cancer (CRC), aggressive local therapy of isolated metastases, particularly in the liver, has been associated with long-term progression-free survival and overall survival (OS) primarily based on retrospective evidence. However, in patients with limited metastatic CRC that is deemed inoperable or those with additional disease outside of the liver or lungs, the role of local ablative therapies, including microwave ablation (MWA) and stereotactic body radiation therapy (SBRT), to render patients disease free is less clear. Further, despite the long history of treating oligometastatic CRC with local therapy, which is provider biased and not evidence based, questions remain regarding the benefit of extending the paradigm of metastatic directed therapy to patients with more extensive disease. This trial seeks to use a pragmatic multimodality approach that mirrors the current clinical dilemma. This study is designed to evaluate the safety and efficacy of adding total ablative therapy (TAT) of all sites of disease to standard of care systemic treatment in those with limited metastatic CRC. Methods: A022101 is a National Clinical Trials Network randomized phase III study planned to enroll 364 patients with newly diagnosed metastatic CRC (BRAF wild-type, microsatellite stable) with ≤4 sites of metastatic disease on baseline imaging. Liver-only metastatic disease is not permitted, and lesions must be amenable to any combination of surgical resection, MWA, and/or SBRT with SBRT required for at least one lesion. Patients receive first-line systemic therapy for 4-6 months and are then randomized 1:1, stratified by number of metastatic organ sites (1-2 vs. 3-4), timing of metastatic disease diagnosis (de novo vs. secondary), and presence of metastatic disease outside the liver and lungs in at least one site. Patients in Arm 1 will receive TAT which consists of treatment of all metastatic sites with SBRT ± MWA ± surgical resection followed by standard of care systemic therapy. Patients in Arm 2 will continue with standard of care systemic therapy alone. The primary endpoint is OS. Secondary endpoints include event-free survival, treatment-related toxicities, and local recurrence with exploratory biomarker analyses. The study needs 346 evaluable patients combined in the 2 arms to demonstrate an improvement in OS with a hazard ratio of 0.7 to provide 80% power with a one-sided alpha of 5%. The trial utilizes a group sequential design with two interim analyses (25% and 50% of events) for futility. The trial activated in January 2023 and recruitment is ongoing. Support: U10CA180821, U10CA180882; https://acknowledgments.alliancefound.org. U10CA180820 (ECOG-ACRIN); U10CA180868 (NRG); U10CA180888 (SWOG). Clinical trial information: NCT05673148 .

Use of tumor-informed ctDNA across gastrointestinal cancers.

758 Background: In colorectal cancer (CRC), the use of ctDNA for the purpose of early recurrence detection and prognostication is established, and multiple studies are testing its utility for guiding adjuvant therapy decisions. Tumor informed testing can be performed in clinical situations where adequate tissue is available for next-generation sequencing (NGS). Increasingly, ctDNA testing is being used clinically for colorectal cancer patients and other gastrointestinal (GI) cancers when there is an appropriate clinical scenario and adequate tumor tissue is available for sequencing. Methods: We identified GI cancer patients treated at our institution where Signatera (Natera) testing was ordered and performed between 2020 – 2023. We included all patients for whom testing was ordered. Then, among patients with any result further analyzed results by disease type, stage, and results. We examined clinical rationale for testing and whether results informed subsequent decisions. Results: A total of 99 GI cancer patients for whom ctDNA testing was ordered were identified. 80 patients had at least 1 ctDNA result including 68 colorectal patients and 12 other GI cancers (anal, bile duct, esophagogastric, pancreatic, and small bowel). Among patients with measurable ctDNA, at the most recent testing timepoint 16 had levels that met criteria for positive detection, while 64 were undetectable. Most commonly, testing was ordered in stage II/III CRC patients for post-operative surveillance. Other clinical use scenarios included 1) surveillance/treatment monitoring in oligometastatic CRC, 2) surveillance in non-metastatic esophagogastric cancer, 3) treatment monitoring in MSI-H/immunotherapy sensitive GI cancers. For at least 18 patients, results were a factor in shared clinical decision making between patients and providers. Conclusions: We found ctDNA monitoring is most commonly used in the adjuvant setting for CRC patients which is best supported by existing studies. Our data demonstrates that tumor informed testing can be successful in other GI cancers for both surveillance and therapy monitoring. Given the broad and rapid adoption of this technology, there needs to be continued efforts for both prospective validation studies and retrospective real world studies to guide clinical practice.

Optimizing Treatment Strategy for Oligometastases/Oligo-Recurrence of Colorectal Cancer.

Colorectal cancer (CRC) is the third most common cancer, and nearly half of CRC patients experience metastases. Oligometastatic CRC represents a distinct clinical state characterized by limited metastatic involvement, demonstrating a less aggressive nature and potentially improved survival with multidisciplinary treatment. However, the varied clinical scenarios giving rise to oligometastases necessitate a precise definition, considering primary tumor status and oncological factors, to optimize treatment strategies. This review delineates the concepts of oligometastatic CRC, encompassing oligo-recurrence, where the primary tumor is under control, resulting in a more favorable prognosis. A comprehensive examination of multidisciplinary treatment with local treatments and systemic therapy is provided. The overarching objective in managing oligometastatic CRC is the complete eradication of metastases, offering prospects of a cure. Essential to this management approach are local treatments, with surgical resection serving as the standard of care. Percutaneous ablation and stereotactic body radiotherapy present less invasive alternatives for lesions unsuitable for surgery, demonstrating efficacy in select cases. Perioperative systemic therapy, aiming to control micrometastatic disease and enhance local treatment effectiveness, has shown improvements in progression-free survival through clinical trials. However, the extension of overall survival remains variable. The review emphasizes the need for further prospective trials to establish a cohesive definition and an optimized treatment strategy for oligometastatic CRC.

Outcomes of Cytoreductive Stereotactic Body Radiotherapy (SBRT) in Patients with Oligometastatic or Oligoprogressive Dominant Lung Metastases from Colorectal Primary

Oxaliplatin based systemic therapy regimens have improved the prognosis of patients with colorectal cancer (CRC) and with this, there has been increased interest in the integration of local therapies to oligometastatic and oligoprogressive sites. There is a vast body of literature exploring the benefits of cytoreduction with surgery and stereotactic body radiation therapy (SBRT) approaches. We report our rates of local control (LC) and overall survival (OS) for patients with oligometastatic/progressive CRC with lung metastases treated with SBRT. Single institution retrospective review of patients diagnosed with oligometastatic or oligoprogressive CRC with dominant metastases to the lungs who were treated with SBRT between September 2009 and December 2022. Oligometastatic disease was defined as newly diagnosed, untreated CRC with up to 5 metastases, up to 3 in one organ. Oligoprogressive disease was defined as CRC with 1 - 2 distant sites that continued to progress on active treatment while the primary site was controlled. Survival was estimated using Kaplan-Meier. Association between local control and patient factors was analyzed using log-rank test. A total of 84 patients with oligometastatic or oligoprogressive CRC were treated with SBRT to 124 lung lesions. Colon cancer was the primary site for 54 patients with a median age at time of SBRT of 66 years (IQR 57 - 73) and a median tumor diameter of 1.20 cm (IQR 0.93 - 1.90). Rectal cancer was the primary site for 30 patients, median age was 60 years (IQR 49 - 70) and median tumor diameter was 1.10 cm (IQR 0.80 - 1.48). Median dose for the entire cohort was 6000 cGy (range 5000 - 6000) with median number of fractions 5 (range 3 - 5). Median follow-up after SBRT was 24 months. Overall, there were 9 local failures at last follow-up. Almost half (n = 42) of the patients experienced distant recurrence. Median local control (LC) for the entire cohort was not reached, 2-yr LC and 5-yr LC were 94.6% and 85.7% respectively. There were no differences in LC between colon and rectal cancer (p = 0.29). Actuarial median overall survival was 71 months (95% CI 44.3 - 97.7) and 5-yr OS was 50.2%. Due to the small number of events, we were unable to identify patient factors associated with local failure on univariate or multivariate analysis. Cytoreductive SBRT is an effective treatment option for patients with oligometastatic or oligoprogressive CRC with dominant lung metastases offering excellent rates of LC. Most patients failed distantly highlighting the importance of additional systemic therapies.

Alliance A022101: A Pragmatic Randomized Phase III Trial Evaluating Total Ablative Therapy for Patients with Limited Metastatic Colorectal Cancer – Evaluating Radiation, Ablation and Surgery (ERASur)

For patients with oligometastatic colorectal cancer (CRC), aggressive local therapy of isolated metastases, particularly in the liver, has been associated with long-term progression-free survival and overall survival (OS) primarily based on retrospective evidence. However, in patients with limited metastatic CRC that is deemed inoperable or those with additional disease outside of the liver or lungs, the role of local ablative therapies, including microwave ablation (MWA) and stereotactic body radiation therapy (SBRT), to render patients disease free is less clear. Further, despite the long history of treating oligometastatic CRC with local therapy, which is provider biased and not evidence based, questions remain regarding the benefit of extending the paradigm of metastatic directed therapy to patients with more extensive disease. This trial seeks to use a pragmatic multimodality approach that mirrors the current clinical dilemma. This study is designed to evaluate the safety and efficacy of adding total ablative therapy (TAT) of all sites of disease to standard of care systemic treatment in those with limited metastatic CRC. A022101 is a National Clinical Trials Network randomized phase III study planned to enroll 364 patients with newly diagnosed metastatic CRC (BRAF wild-type, microsatellite stable) with 4 or fewer sites of metastatic disease on baseline imaging. Liver-only metastatic disease is not permitted, and lesions must be amenable to any combination of surgical resection, MWA, and/or SBRT with SBRT required for at least one lesion. Patients receive first-line systemic therapy for 4-6 months and are then randomized 1:1, stratified by number of metastatic organ sites (1-2 vs. 3-4), timing of metastatic disease diagnosis (de novo vs. secondary), and presence of metastatic disease outside the liver and lungs in at least one site. Patients in Arm 1 will receive TAT which consists of treatment of all metastatic sites with SBRT ± MWA ± surgical resection followed by standard of care systemic therapy. Patients in Arm 2 will continue with standard of care systemic therapy alone. The primary endpoint is OS. Secondary endpoints include event-free survival, treatment-related toxicities, and local recurrence with exploratory biomarker analyses. The study needs 346 evaluable patients combined in the 2 arms to demonstrate an improvement in OS with a hazard ratio of 0.7 to provide 80% power with a one-sided alpha of 5%. The trial utilizes a group sequential design with two interim analyses (25% and 50% of events) for futility. The trial activated in January 2023. Recruitment is ongoing.

SIRPα blockade improves the antitumor immunity of radiotherapy in colorectal cancer

High-dose hypofractionated radiotherapy (HRT) is an important anticancer treatment modality that activates antitumor host immune responses. However, HRT for oligometastases of colorectal cancer (CRC) has shown frustrating results in the clinic. As part of immune evasion, myeloid cells express signal regulatory protein α (SIRPα) to inhibit phagocytosis by phagocytes in the tumor microenvironment (TME). We postulated that SIRPα blockade enhances HRT by alleviating the inhibitory action of SIRPα on phagocytes. We demonstrated that SIRPα on myeloid cells was upregulated in the TME after HRT. When SIRPα blockade was administered with HRT, we observed superior antitumor responses compared with anti-SIRPα or HRT alone. When anti-SIRPα was administered to local HRT, the TME could become a tumoricidal niche that was heavily infiltrated by activated CD8+ T cells, but with limited myeloid-derived suppressor cells and tumor-associated macrophages. While CD8+ T cells were required for the effectiveness of the anti-SIRPα + HRT combination. The triple therapy with anti-SIRPα + HRT + anti-PD-1 had superior antitumor responses compared with the combination of any two therapies and established a strong and long-lasting adaptive immunological memory. Collectively, SIRPα blockade provides a novel way to overcome HRT resistance in oligometastatic CRC patients. Our results herein provide a valuable cancer treatment strategy that has the potential to be translated into clinical practice.

Differential Perspectives by Specialty on Oligometastatic Colorectal Cancer: A Korean Oligometastasis Working Group's Comparative Survey Study.

Despite numerous studies on the optimal treatments for oligometastatic disease (OMD), there is no established interdisciplinary consensus on its diagnosis or classification. This survey-based study aimed to analyze the differential opinions of colorectal surgeons and radiation oncologists regarding the definition and treatment of OMD from the colorectal primary. A total of 141 participants were included in this study, consisting of 63 radiation oncologists (44.7%) and 78 colorectal surgeons (55.3%). The survey consisted of 19 questions related to OMD, and the responses were analyzed using the chi-square test to determine statistical differences between the specialties. The radiation oncologists chose "bone" more frequently compared to the colorectal surgeons (19.2% vs. 36.5%, p=0.022), while colorectal surgeons favored "peritoneal seeding" (26.9% vs. 9.5%, p=0.009). Regarding the number of metastatic tumors, 48.3% of colorectal surgeons responded that "irrelevant, if all metastatic lesions are amendable to local therapy", while only 21.8% of radiation oncologist chose same answer. When asked about molecular diagnosis, most surgeons (74.8%) said it was important, but only 35.8% of radiation oncologists agreed. This study demonstrates that although radiation oncologists and colorectal surgeons agreed on a majority of aspects such as diagnostic imaging, biomarker, systemic therapy, and optimal timing of OMD, they also had quite different perspectives on several aspects of OMD. Understanding these differences is crucial to achieving multidisciplinary consensus on the definition and optimal management of OMD.

Alliance A022101: A pragmatic, randomized phase III trial evaluating total ablative therapy for patients with limited metastatic colorectal cancer: Evaluating Radiation, Ablation, and Surgery (ERASur).

TPS3629 Background: For patients with oligometastatic colorectal cancer (CRC), aggressive local therapy of isolated metastases, particularly in the liver, has been associated with long-term progression-free survival and overall survival (OS) primarily based on retrospective evidence. However, in patients with limited metastatic CRC that is deemed inoperable or those with additional disease outside of the liver or lungs, the role of local ablative therapies, including microwave ablation (MWA) and stereotactic body radiation therapy (SBRT), to render patients disease free is less clear. Further, despite the long history of treating oligometastatic CRC with local therapy, which is provider biased and not evidence based, questions remain regarding the benefit of extending the paradigm of metastatic directed therapy to patients with more extensive disease. This trial seeks to use a pragmatic multimodality approach that mirrors the current clinical dilemma. This study is designed to evaluate the safety and efficacy of adding total ablative therapy (TAT) of all sites of disease to standard of care systemic treatment in those with limited metastatic CRC. Methods: A022101 is a National Clinical Trials Network randomized phase III study planned to enroll 364 patients with newly diagnosed metastatic CRC (BRAF wild-type, microsatellite stable) with ≤4 sites of metastatic disease on baseline imaging. Liver-only metastatic disease is not permitted, and lesions must be amenable to any combination of surgical resection, MWA, and/or SBRT with SBRT required for at least one lesion. Patients receive first-line systemic therapy for 4-6 months and are then randomized 1:1, stratified by number of metastatic organ sites (1-2 vs. 3-4), timing of metastatic disease diagnosis (de novo vs. secondary), and presence of metastatic disease outside the liver and lungs in at least one site. Patients in Arm 1 will receive TAT which consists of treatment of all metastatic sites with SBRT ± MWA ± surgical resection followed by standard of care systemic therapy. Patients in Arm 2 will continue with standard of care systemic therapy alone. The primary endpoint is OS. Secondary endpoints include event-free survival, treatment-related toxicities, and local recurrence with exploratory biomarker analyses. The study needs 346 evaluable patients combined in the 2 arms to demonstrate an improvement in OS with a hazard ratio of 0.7 to provide 80% power with a one-sided alpha of 5%. The trial utilizes a group sequential design with two interim analyses (25% and 50% of events) for futility. The trial activated in January 2023 and recruitment is ongoing. Support: U10CA180821, U10CA180882; https://acknowledgments.alliancefound.org. U10CA180820 (ECOG-ACRIN); U10CA180868 (NRG); U10CA180888 (SWOG); Clinicaltrials.gov identifier: NCT05673148 Clinical trial information: NCT05673148 .

Abstract 4647: Potential of TIMP3 regulating the versican status in the colorectal cancer tumor microenvironment

Abstract Background: In colorectal cancer (CRC), versican (VCAN) accumulation has been found to negatively correlate with CD8+ tumor infiltrating lymphocyte (TIL) abundance and its proteolysis into versikine (Vkine) positively correlates with TIL abundance. TIMP3 has demonstrated the ability to inhibit several ADAMTS proteases able to cleave VCAN to Vkine. Here we investigate the correlation of TIMP3 accumulation in CRCs with the VCAN status and CD8+ T cell infiltration. Methods: Matched primary and metastatic CRC samples from 156 patients who had resected oligometastatic CRC were stained for VCAN, Vkine, TIMP3, and CD8+ TILs. VCAN, Vkine, and TIMP3 were scored using an intensity binning system ranging from 0-3+ and T cells in the epithelium were reported per high power field (HPF). Tumors were designated as high (2 or 3+) or low (0 or 1) for both VCAN and Vkine and positive (+; 1-3) or negative (0) for TIMP3. Tumors designated VCAN low and Vkine high are considered VCAN proteolytic predominant (VPP) and all other combinations are considered VCAN proteolytic weak (VPW). Results: Across the whole dataset, 52% of cancers were VCAN high and 24% were VPP. TIMP3 was detected in 33% of cancers. The frequency of TIMP3 was similar between primary and metastatic tumors (39% and 29%, respectively). Of the VCAN high cancers, 42% were TIMP3+ whereas 61% of the TIMP3+ samples are VCAN high. Of the Vkine high cancers, 44% were TIMP3+ and 36% of VPP cancers were TIMP3+. The prevalence of the VPP phenotype was similar between the TIMP3+ and negative cancers. Additionally, among the TIMP3+ samples 68% were Vkine high versus 46% in TIMP3 negative cancers (p=0.001). VCAN proteolysis correlates with higher CD8+ TIL abundance, thus we assessed the number of CD8+ TILs in TIMP3+ and negative tumors. The TIMP3+ cancers had a median of 2 CD8+ TILs/HPF and the TIMP3 negative cancers has a median of 3 CD8+ TILs/HPF. For VPP cancers, those that were also TIMP3+ had a median of 3 CD8+ TILs/HPF compared to TIMP3 negative cancers which had a median of 6 CD8+ TILs/HPF (p=0.2). Conclusions: TIMP3 correlates with higher levels of VCAN accumulation but does not correlate with lower levels of proteolysis. Future studies are needed to better clarify the impact of TIMP3 and other mediators in regulating VCAN accumulation and proteolysis in the tumor microenvironment. Citation Format: Anna Field, Sean Kraus, Kristina Matkowskyj, Dustin Deming, Cheri A. Pasch, Wei Zhang. Potential of TIMP3 regulating the versican status in the colorectal cancer tumor microenvironment. [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 4647.

18F-FDG PET/CT in therapy response assessment: oligometastatic colorectal cancer

BackgroundColorectal cancer (CRC) is one of the most widespread cancers worldwide, leading to roughly half a million deaths yearly. The European Society for Medical Oncology defined oligometastatic CRC as a disease with few metastases affecting a small number of sites (5 or occasionally more metastases involving up to 3 sites). In addition to colonoscopy, magnetic resonance imaging (MRI), and digital rectal examination in patients with rectal cancer, response monitoring of CRC is commonly carried out by CT imaging. The use of PET for response monitoring has not been adapted into colorectal cancer guidelines until 2021. However, 18F-Fluorodeoxyglucose Positron Emission Tomography Computed Tomography (18F-FDG PET/CT) offers a higher efficiency for assessing treatment outcomes than traditional imaging. This study aims to explore the utility of 18F-FDG PET/CT imaging in the assessment of therapy response in patients with oligometastatic colorectal cancer (OMCRC).ResultsThe study comprised 79 OMCRC patients (35 and 44 patients with synchronous and metachronous metastasis respectively). In synchronous disease patients 18F-FDG PET/CT scan showed significant reduction of mean size and standardized uptake value (SUV) of the primary site lesions and the mean SUV of lymph nodes (LNs) and lung metastases (P = 0.00, 0.00,0.00, and 0.002, respectively) while, metachronous disease patients had significant reduction in the mean size and SUV of LNs (1.8 ± 0.7 & 4.7 ± 1.3 versus 1.1 ± 1.0 & 2.9 ± 3.0, P = 0.001 & 0.00 respectively) and the mean SUV of peritoneal metastases (8.7 ± 4.7 versus 6.8 ± 2.4 P = 0.00). Partial metabolic response (PMR) and stable metabolic disease (SMD) were found in more than half of the patients (58.2%). Complete metabolic response (CMR) and Progressive metabolic disease (PMD), on the other hand, were achieved in 41.8% of patients [17 (21.5%) and 16 (20.3%) patients, respectively] with substantially higher CMR rate in metachronous disease than synchronous disease [14.0 (31.8%) versus 3.0 (8.5%) patients, P = 0.015)].Conclusions18F-FDG PET/CT can be added as a valuable imaging method for identifying responders and non-responders among OMCRC patients, as it optimizes the selection of patients with CRC for local therapy and has a significant impact on directing their therapy course. Oligometastatic colorectal cancer seems to be a controllable disease with hopeful therapy outcomes, particularly for those with metachronous metastases.

Oligometastatic Colorectal Cancer: A Review of Definitions and Patient Selection for Local Therapies.

Nearly one-third of patients diagnosed with colorectal cancer (CRC) will ultimately develop metastatic disease. While a small percentage of patients can be considered for curative resection, more patients have limited disease that can beconsidered for local therapy. Challenges remain in defining oligometastatic CRC as well as developing treatment strategies guided by high level evidence. In this review, we present the challenges in defining oligometastatic CRC and summarize the current literature on treatment and outcomes of local therapy in patients with metastatic CRC. For patients with liver- and/or lung-confined CRC metastases, surgical resection is the standard of care given the potential for long-term progression-free and overall survival. For patients with liver- or lung-confined disease not amenableto surgical resection, non-surgical local therapies, such as thermal ablation, hepatic arterial infusion pump (HAIP), or stereotactic body radiation therapy (SBRT), should be considered. For patients with more advanced disease, such aslymph node or bony metastases, the role of metastasis-directed therapy is controversial. Emerging data suggests that SBRT to ablate all metastases can improve progression-free and overall survival. Multidisciplinary management is critical for patients with metastatic CRC due to the complexity of their cases and the nuanced patient, tumor, biological, and anatomical factors that must be weighed when considering local therapy. High-qualityprospective randomized data in CRC are needed to further clarify the role of local ablative therapy in patients with unresectable oligometastatic CRC with ongoing studies including the RESOLUTE trial (ACTRN12621001198819)and the upcoming NCTN ERASur trial (NCT05673148).

A predictive model of polymetastatic disease from a multicenter large retrospectIve database on colorectal lung metastases treated with stereotactic ablative radiotherapy: The RED LaIT-SABR study

AimStereotactic ablative radiotherapy (SABR) showed increasing survival in oligometastatic patients. Few studies actually depicted oligometastatic disease (OMD) evolution and which patient will remain disease-free and which will rapidly develop a polymetastatic disease (PMD) after SABR. Therefore, apart from the number of active metastases, there are no clues on which proven factor should be considered for prescribing local treatment in OMD. The study aims to identify predictive factors of polymetastatic evolution in lung oligometastatic colorectal cancer patients. MethodsThis international Ethical Committee approved trial (Prot. Negrar 2019-ZT) involved 23 Centers and 450 lung oligometastatic patients. Primary end-point was time to the polymetastatic conversion (tPMC). Additionally, oligometastases number and cumulative gross tumor volume (cumGTV) were used as combined predictive factors of tPMC. Oligometastases number was stratified as 1, 2–3, and 4–5; cumGTV was dichotomized to the value of 10 cc. ResultsThe median tPMC in the overall population was 26 months. Population was classified in the following tPMC risk classes: low-risk (1–3 oligometastases and cumGTV ≤ 10 cc) with median tPMC of 35.1 months; intermediate-risk (1–3 oligometastases and cumGTV > 10 cc), with median tPMC of 13.9 months, and high-risk (4–5 oligometastases, any cumGTV) with median tPMC of 9.4 months (p = 0.000). ConclusionThe present study identified predictive factors of polymetastatic evolution after SABR in lung oligometastatic colorectal cancer. The results demonstrated that the sole metastases number is not sufficient to define the OMD since patients defined oligometastatic from a numerical point of view might rapidly progress to PMD when the cumulative tumor volume is high. A tailored approach in SABR prescription should be pursued considering the expected disease evolution after SABR, with the aim to avoid unnecessary treatment and toxicity in those at high risk of polymetastatic spread, and maximize local treatment in those with a favorable disease evolution.

HPB P43 Stereotactic ablative radiotherapy is a safe and feasible option for non-surgical candidates with colorectal liver metastases

Abstract Background Stereotactic ablative radiotherapy (SABR) has been associated with an improvement in over-all survival in patients with oligometastatic colorectal cancer with a controlled primary tumour and one to five oligometastatic lesions. We report our centre's experience of SABR as an alternative local therapy for non-surgical candidates with colorectal liver metastases. Methods All patients were identified who received SABR irradiation for colorectal liver metastases in a tertiary HPB centre between June 2016 and February 2022. SABR criteria included patients with 1–3 liver metastasis with maximum tumour diameter < 6 cm, liver confined disease and a suitable performance status with pre-treatment Child-Pugh status A. A retrospective review of the patient's scans, letters and MDT outcomes was performed to analyse the pathology, indications and outcomes. Results 18 patients with oligometastatic colorectal cancer received SABR to metastases in the liver over the study period. Five were female and 13 were male. Median age was 71. Performance status was 1 in the majority of cases (10/18). Only 2 patients had synchronous disease. 4 patients had concomitant metastatic disease to the lung and all 4 had had a lung resection. Half of the patients had a previous liver resection with 2 of these having two previous liver resections and 1 having 3 liver resections. 4/18 patients underwent SABR because they were deemed unfit for surgery, 6/18 were for anatomical indications with risk of an R1 resection and one was down to patient choice. Metastases were of median size 30 mm (9–87 mm). 89% (16/18) patients had a single metastasis, 1 patient had 2 metastases and 1 patient had 3 metastases. Overall survival was 19 months (4–60 months). 3 patients achieved complete resolution of disease and 4 patients had partial resolution. 6 patients were deemed to have stable disease and 4 patients had disease progression. Outcome data was not available in 1 patient. Only 2/18 pa Conclusions We observed that SABR is feasible, well tolerated and effective in this cohort of patients. Longer-term follow up data is required to assess a survival benefit.

Prognostic differences between oligometastatic and polymetastatic disease after resection in patients with colorectal cancer and hepatic or lung metastases: Retrospective analysis of a large cohort at a single institution

BackgroundLong-term survival data are lacking, and prognostic factors are not well-defined for patients with colorectal cancer and hepatic or lung metastases. This study evaluated the outcomes after resection of oligometastatic hepatic or lung metastases from colorectal cancer and sought to identify prognostic factors. MethodsWe retrospectively investigated 1,123 patients with colorectal cancer and hepatic or pulmonary metastases who underwent curative surgery between January 1991 and December 2016. ResultsOf the 1,123 patients, 719 had hepatic metastases, 287 had pulmonary metastases, and 117 had both. The 5-year overall survival rate was 52.3% in the hepatic metastases group, 70.4% in the pulmonary metastases group, and 71.4% in the hepatic and pulmonary metastases group (P < .001). In total, 1,045 patients had oligometastases (1–5 metastatic lesions in 1 or 2 organs) and 78 had polymetastases (≥6 metastases in 1 or 2 organs). Prognosis was significantly better in patients with oligometastases than in those with polymetastases. The 5-year overall survival rate was 59.0% in the oligometastases group and 35.3% in the polymetastases group (P < .001); the respective 5-year relapse-free survival rates were 37.5% and 11.6% (P < .001). Multivariable analysis identified predictors of both poor overall survival and relapse-free survival to be a high carcinoembryonic antigen level before the first metastasectomy, largest metastasis measuring ≥2 cm, polymetastases, and synchronous metastases. ConclusionPrognosis after curative resection was better in patients with oligometastatic colorectal cancer in the liver or lung than in those with polymetastases. Multidisciplinary decision-making strategies, including about surgery, should be based on number of metastases rather than their site.

Recursive Partitioning Model to Identify Early Progression in Patients with Extracranial Oligometastatic Colorectal Cancer Treated with Stereotactic Body Radiotherapy

<h3>Purpose/Objective(s)</h3> Metastases directed therapy of oligometastatic colorectal cancer (CRC) may confer long-term disease advantages. However, there is a paucity of data to predict optimal patient selection. Our hypothesis is that pretreatment factors can identify patients at higher risk of early progression after SBRT for CRC oligometastases. <h3>Materials/Methods</h3> An institutional cohort was reviewed to identify patients with extracranial oligometastatic (≤ 5 metastases) colorectal cancer who received SBRT to all metastases. Outcomes of interest were local failure (LF), overall survival (OS) and progression-free survival (PFS). Recursive partitioning analysis (RPA) was performed to identify "early progression", defined as those having a PFS event within 6 months of SBRT, from a training set consisting of 70% of the cohort. The remaining 30% were used in the validation analysis of the model. <h3>Results</h3> From January 2008 to May 2021, 254 patients were identified with 408 lesions irradiated. Median age was 75 years (IQR: 62-82), median follow-up was 30.5 months (IQR: 17.7-48.8), and median time from diagnosis of cancer to metastatic disease was 12.0 months (IQR: 0.2-26.1). The majority of patients had a single metastasis (n=167, 65.8%). The 12-, 24- and 36-month cumulative incidence of LF was 10.3%, 22.8% and 27.5%, respectively. On multivariable analysis (MVA), liver metastasis (vs. non-liver, HR 1.99, 95%CI: 1.32-3.00, p<0.01) and lower mean PTV dose BED₁₀ (HR: 1.01, 95%CI: 1.01-1.02, p<0.01) predicted for higher LF. Median OS was 51.1 months (95%CI: 46.2-56.3) and 12-, 24- and 36-month OS was 94.0%, 79.5% and 64.9%, respectively. On MVA, higher pre-SBRT CEA (HR: 1.21, 95%CI: 1.01-1.45, p=0.04) and larger PTV volume (HR: 1.61, 95%CI: 1.31-1.97, p<0.01) were significant predictors of worse OS. Median PFS was 11.8 months (95%CI: 9.9-13.7) and 6-, 12- and 24-month PFS was 73.2%, 49.2% and 30.4%, respectively. Of the 254 patients included, 68 (26.8%) had "early progression". The RPA model ranked the following variables in order of importance: presence or history of any liver metastases, pre-SBRT CEA and number of lesions treated at time of SBRT. Four terminal nodes (i.e., groups) were generated, classifying the probability of "early progression" with a training and validation receiver operating characteristic curve (AUC) of 0.72 and 0.71, respectively. The two groups at highest risk of early progression were: 1) history or presence of any liver metastases and with ≥2 lesions treated; and 2) history or presence of any liver metastases with 1 lesion treated at the time of SBRT, and pre-SBRT CEA ≥8 ng/mL. <h3>Conclusion</h3> History or presence of liver metastases, higher number of lesions, and higher CEA levels can aid in the identification of oligometastatic patients who progress soon after SBRT. Such patients can be considered for alternative treatment strategies.

The Treatment Outcomes of Oligometastatic Colorectal Cancer Patients Treated with Stereotactic Body Radiation Therapy: A Multi-Institutional Analysis TROD 02-008

<h3>Purpose/Objective(s)</h3> Stereotactic body radiotherapy (SBRT) is increasingly being used to treat oligometastatic cancers, but high-level evidence to support policy decisions is lacking in patients with colorectal carcinoma (CRC). The purpose of this study was to determine the prognostic factors for survival in oligometastatic colorectal cancer patients treated with SBRT in a multicentric setting. <h3>Materials/Methods</h3> The clinical data of 437 oligometastatic CRC patients who received metastasis directed treatment (MDT) via SBRT at 18 institutions between February 2007 and February 2021 were reviewed retrospectively. Patients either had de novo oligometastasis (≤5 metastases) at the time of diagnosis or had oligometastatic recurrences during follow-up. All patients were treated with the goal of curing their metastasis, and 839 lesions were irradiated. <h3>Results</h3> The average age was 61 years (range; 27-92 years). The majority of patients (58.8%) had colon carcinoma with a single organ metastasis (88.8 %). The average number of metastatic lesions was 2 (range, 1-5). There were 103 patients with liver metastasis, 222 patients with lung metastasis, 58 patients with lymph node metastasis, 60 patients with bone metastasis, 32 patients with brain metastasis, and 6 patients with other organ metastasis. Before RT, the median CEA and Ca-19-9 levels were 5.16 ng/mL (range: 0-8181.1 ng/mL) and 19.4 (range: 0.60 - 3693), respectively. After RT, the median CEA and Ca-19-9 were 5.00 ng/mL (range, 0.4-5693v ng/mL) and 18 (range, 0 - 6577), respectively. The average period of follow-up was 15.2 months (range, 0.3-91.5 months). The rates of OS and PFS after two years were 76.3 % and 28.1 %, respectively. Age (p<0.001), pre-RT CEA (p=0.006), pre-RT Ca19-9 (p=0.02), post-RT CEA (p=0.01), and post-RT Ca19-9 (p=0.02) were all significant prognostic factors for OS in univariate analysis. Age (HR=1.03, 95 % CI, 1.01-1.04, p=0.004) and pre-RT CEA (HR=1.01, 95 % CI, 1.00-1.02, p=0.04) were independent predictors of OS in multivariate analysis, while post-RT CEA (HR=1.93, 95 % CI, 1.28-2.90, p=0.002) was an independent predictor of PFS. <h3>Conclusion</h3> SBRT to oligometastatic lesions was found to be a safe and effective treatment modality for patients with colorectal cancer. Survival was predicted by age, baseline CEA, and the Ca19-9 response to MDT. Additional prospective studies with larger cohorts are necessary to validate our findings.

Characterization of KRAS Mutational Regression in Oligometastatic Patients.

BackgroundWe previously reported rare regressive genetic trajectories of KRAS pathogenic mutations as a specific hallmark of the genuine oligometastatic status in colorectal cancer (CRC).MethodsSurvival and prognostic impact of disease extent in 140 metastatic CRC patients were evaluated through the Kaplan–Meyer curves and the Log-Rank test. KRAS mutations were assessed through the Illumina NovaSeq 6000 platform and TruSight™ Oncology 500 kit. HLA typing was carried out by PCR with sequence-specific oligonucleotides. Lymphocyte densities in tumors were expressed as cells per square millimeter. NKs isolated and CD8+ from NK-depleted PBMCs were characterized through flow cytometry. CD107a externalization was evaluated as NKs/CD8 cytotoxicity toward human colon cancer cells HT29, SW620, HCT116, and LS174T carrying different KRAS mutations.ResultsThe oligometastatic status was a strong and independent variable for survival (HR: 0.08 vs. polymetastatic disease; 95% CI: 0.02–0.26; p < 0.001). Eighteen oligometastatic patients were selected. Twelve were alive at the last follow-up, and 9 were characterized. Genetic regression of KRAS was observed in 3 patients: patient (PAT)2, PAT5, and PAT8. PAT2 and PAT5 presented the highest levels of GrzB+ lymphocytes in the tumor cores of the metastases (120 ± 11.2 and 132 ± 12.2 cells/mm2, respectively). Six out of 9 patients (67%), including PAT2 and PAT5, expressed HLA-C7. Twopatients (PAT2 and PAT5) presented high CD3+/CD8+-dependent cytotoxicity against HLA-C7+ SW620 cells (p.G12V-mutated cells), which was consistent with their observed mutational regression (p.G12V/p.G13D in primary→p.G13D in metastatic tumor).ConclusionsWe provide evidence that CD3+/CD8+ lymphocytes from oligometastatic CRC patients display differential cytotoxicity against human colon cancer cells carrying KRAS mutations. This could provide an interesting basis for monitoring oligometastatic disease and developing future adoptive immunotherapies.

P-174 OPTIMISE: Optimization of treatment selection and follow-up in oligometastatic colorectal cancer – a ctDNA-guided phase II randomized approach with a run-in feasibility part

Patients with detectable circulating tumor DNA (ctDNA) after surgery for colorectal cancer are considered to have microscopic residual disease and consequently a high risk of recurrence. The same applies to patients after local ablative treatment (LAT) for metastatic colorectal cancer (mCRC). We observed a temporal clearance of ctDNA during adjuvant chemotherapy, but ctDNA recurrence after therapy termination. This indicate that patients with ctDNA positive status may need more intensified adjuvant chemotherapy than standard of care (SOC). In OPTIMISE we investigate the use of ctDNA for treatment decisions on adjuvant chemotherapy after LAT for mCRC. We hypothesis that recurrence can be prevented with intensified adjuvant chemotherapy in patients with ctDNA positive blood samples post ablations, and that patients without detectable ctDNA have undergone successful radical treatment and will not need adjuvant chemotherapy. OPTIMISE is an open label 1:1 randomized multicentre, phase II study, comparing ctDNA guided adjuvant chemotherapy against standard of care (SOC) approach, with a run-in phase investigating feasibility measures. Eligibility criteria comprise, Radical intended treatment for metastatic spread from CRC (resection, radiofrequency ablation, stereotactic body radiation therapy, or other experimental local treatment), No evidence of further disease according to SOC, Age ≥ 18 years, ECOG performance status 0-2, Clinically eligible for adjuvant triple chemotherapy at investigators decision, Adequate bone marrow function allowing systemic chemotherapy, Anticonception for fertile women and for the male patients with a fertile partner, Written and verbally informed consent. Exclusion criteria are, Neuropathy CTCAE grade > 1, Other malignant tumour within 5 year except non-melanoma skin cancer or carcinoma in situ cervicis uteri, Pregnant or breastfeeding women, Intolerance or allergy to 5-FU, leucovorin, oxaliplatin, irinotecan or capecitabin Before randomization participants undergo a PET-CT scan to exclude metabolically detectable lesions. In ARM A patients are treated according to SOC, and blood samples collected for later retrospective ctDNA analysis. In ARM B, patients follow a ctDNA-guided strategy; ctDNA positivity lead to escalation strategy with 4 months of FOLFOXIRI followed by 2 months of 5-FU, ctDNA negative status to de-escalation strategy by shared decision-making. Endpoints Primary endpoint; fraction of patients alive without recurrence 2 years after inclusion. Secondary endpoints; CTCAE grade 3-5 toxicity, ctDNA negativity (6 months + 1 year), Time to molecular -biological and radiological recurrence, Rate of local and distant relapse, Overall survival, QoL and Cost-effectiveness. Laboratory methods. Blood samples are collected in streck-tubes and analysed for tumor specific mutations and methylations by multiplex ddPCRs in two Danish laboratories (with tumor-agnostic approach). Sample size is 350 but will be revised based on findings in the run-in phase. Feasibility measures for the run-in phase are: Inclusion of 30 patients over 12 months in two Danish Hospitals, Compliance with randomization > 80%, Rate of unexpected PET-CT positive cases 20%, Eligibility for triple chemotherapy > 80%. The study is including. NCT04680260. Sponsors.