Indications of a Survival Benefit from Primary Tumor Treatment in Uveal Melanoma: Association Between initial AJCC Stage and Metastatic Survival

Indications of a Survival Benefit from Primary Tumor Treatment in Uveal Melanoma: Association Between initial AJCC Stage and Metastatic Survival | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article Indications of a Survival Benefit from Primary Tumor Treatment in Uveal Melanoma: Association Between initial AJCC Stage and Metastatic Survival Serdar Yavuzyigitoglu, Shiva Sabazade, Viktor Gill, Erwin Brosens, and 2 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4521528/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract In theory, a more advanced American Joint Committee on Cancer (AJCC) stage at the time of primary tumor diagnosis could correlate with shorter survival in metastatic uveal melanoma. However, this association has only been evaluated in relatively small cohorts. To address this, we investigated the prognostic relationship between AJCC stage and survival in a large cohort of patients who died from metastatic uveal melanoma. Among 1491 real-world patients, a higher AJCC stage at the time of primary tumor diagnosis was significantly associated with shorter survival. This association persisted even when the analysis was restricted to 350 patients already at stage IV, where a higher AJCC stage at primary tumor diagnosis continued to correlate with shorter survival (Log-rank test for trend, P < 0.001 for both comparisons). The relationship remained significant in multivariate Cox regression models, which included patient age as a covariate and the number of hepatic metastases upon detection of metastatic disease as a time-varying covariate, as well as in a Markov multi-state model. These findings suggest that primary tumor treatment, by preventing the tumor from advancing to a higher AJCC stage, may confer a survival benefit by potentially reducing the aggressiveness and growth rate of subsequent metastases. Biological sciences/Cancer/Eye cancer Health sciences/Oncology/Surgical oncology Health sciences/Oncology Health sciences/Oncology/Cancer Health sciences/Oncology/Cancer/Skin cancer/Melanoma Uveal melanoma Choroidal melanoma Stage Survival Metastasis Prognosis Figures Figure 1 Figure 2 INTRODUCTION Uveal melanoma is the most common primary intraocular malignancy in adults, characterized by its high propensity for developing fatal metastases. 1 The long-term incidence of metastatic death approaches 50%, with fewer improvements in prognosis compared to cutaneous melanoma. 2,3 Primary tumor size and anatomic extent are critical factors in the American Joint Committee on Cancer (AJCC) staging system, which strongly predicts the time to metastatic disease. 4,5 In 2014, Damato and colleagues demonstrated that among those who succumb to their disease, the median survival time from primary tumor treatment to death was 4.6 years for patients in stage I, compared to only 2.7 years for patients in stage III. 6 Thus, a shorter metastasis-free interval is associated with poorer overall survival outcomes. 7-10 However, it is challenging to determine from these observations whether treatment that prevents a primary tumor from progressing to a higher stage has a beneficial effect on patient survival. The shorter time to metastasis and death in patients with more advanced stages might simply reflect lead-time bias, with larger tumors having had more time to grow and metastasize. 11 In this scenario, the treatment of large and small tumors might occur at different points on the same timeline, potentially resulting in similar dates of death despite different initial tumor sizes. To address this issue, we propose evaluating the survival time from the detection of metastases to death. If this interval is shorter for patients whose primary tumors were larger at the time of treatment, it would suggest that the growth rate of metastases is influenced by the size of the primary tumor. This would imply a survival benefit of treating the primary tumor at an earlier stage, when its metastases are relatively slow-growing. In turn, this would clarify the potential benefit of treating uveal melanoma as soon as possible after diagnosis. Some previous studies have found that primary tumor diameter at the time of initial diagnosis is associated with an increased risk or hazard ratio for death if metastases develop, whereas others have not. 7,8,12,13 The largest study to date, which did not include time-to-event survival analyses, included 330 patients with metastatic choroidal and ciliary body melanomas. 12 This study confirmed the association between a shorter metastasis-free interval and shorter overall survival, but found no difference in the distribution of AJCC stage between patients with different overall survival times. In this study, we evaluate the prognostic significance of the AJCC stage of uveal melanoma at the time of primary tumor diagnosis across two distinct cohorts. The first cohort comprises 1,491 patients who were monitored from the diagnosis of the primary tumor until death due to metastatic disease. The second cohort includes 350 patients, where the analysis focuses on survival time following the detection of metastases, while also incorporating data on the interval from primary tumor diagnosis. By analyzing these cohorts, we aim to clarify whether the stage of the primary tumor at diagnosis has an impact not only on the time to metastasis but also on survival following the onset of metastatic disease. RESULTS Descriptive statistics Of 1491 patients who died from metastatic uveal melanoma (Primary Diagnosis to Metastatic Death Cohort [PDMD]), 688 (46%) were female. The mean age at the time of diagnosis of the primary uveal melanoma was 63 years (SD 13 years). The mean largest basal diameter (LBD) of the tumor was 14.5 mm (SD 3.9 mm), mean tumor thickness was 7.2 mm (SD 3.4 mm), and mean tumor volume was 828 mm³ (SD 1305 mm³). Of the 350 patients with metastatic disease (Metastasis Detection to Death Cohort [MDD]), 179 (51%) were female. The mean age at the time of diagnosis of the primary tumor was 61 years (SD 12 years). The mean largest basal diameter (LBD) of the tumor was 13.0 mm (SD 3.6 mm), mean tumor thickness was 6.5 mm (SD 2.9 mm), and mean tumor volume was 588 mm³ (SD 494 mm³). Further details on the included patients and tumors are provided in Table 1 . Visual inspection showed that the log-minus-log survival curves were parallel and did not cross, suggesting that the proportional hazards assumption was adequately met for the AJCC stage covariate in both cohorts ( Supplementary Figure 1 ). Prognostic implication of AJCC stage at initial diagnosis for those who die of uveal melanoma In the cohort of 1491 PDMD patients, the AJCC stage at the time of primary tumor diagnosis, which incorporates both tumor size and anatomic extent, was significantly associated with overall survival. The 5-year survival rates by AJCC stage were as follows: 58% (95% confidence interval [CI], 51–67) for stage I, 38% (95% CI, 34–44) for stage IIA, 36% (95% CI, 31–41) for stage IIB, 21% (95% CI, 17–26) for stage IIIA, 17% (95% CI, 13–23) for stage IIIB, and 2% (95% CI, 0.3–18) for stage IIIC (log-rank test for trend, P <0.001; Figure 1A ). When stratified by AJCC T-category, which considers only tumor size, the 5-year survival rates were: 53% (95% CI, 45–61) for T-category 1, 35% (95% CI, 31–39) for T-category 2, 28% (95% CI, 24–32) for T-category 3, and 12% (95% CI, 8–16) for T-category 4 (log-rank test for trend, P <0.001; Figure 1B ). Multivariate Cox regression analysis, adjusting for patient age, confirmed that AJCC stage at primary tumor diagnosis was an independent predictor of mortality among PDMD patients ( Table 2 ). Prognostic implication of AJCC stage at initial diagnosis for patients with metastases Among the 350 MDD patients, AJCC stage at the time of primary tumor diagnosis was significantly associated with survival after the detection of metastases. The median Kaplan-Meier survival estimate after first radiological detection of metastases was 2.2 years (95% CI, 1.9–2.6) for the entire cohort, 4.5 years (95% CI, 3.4–6.5) for stage I, 3.0 years (95% CI, 2.3–3.6) for stage IIA, 1.7 years (95% CI, 1.3–230) for stage IIB, 0.8 years (95% CI, 0.4–2.0) for stage IIIA, 0.7 years (95% CI, 0.4–1.0) for stage IIIB, and 0.3 years for stage IIIC (95% CI not determinable. The 1-year survival rates were: 83% (95% CI, 74–94) for stage I, 81% (95% CI, 74–88) for stage IIA, 69% (95% CI, 61–78) for stage IIB, 48% (95% CI, 36–64) for stage IIIA, and 40% (95% CI, 19–85) for stage IIIB. Both patients who had been in stage IIIC at the time of primary tumor diagnosis died within a year from detection of metastases (log-rank test for trend, P <0.001; Figure 2A ). When categorized by AJCC T-category, the 1-year survival rates were: 83% (95% CI, 73–93) for T-category 1, 74% (95% CI, 66–82) for T-category 2, 63% (95% CI, 55–71) for T-category 3, and 67% (95% CI, 49–85) for T-category 4 (log-rank test for trend, P < 0.001; Figure 2B ). Multivariate Cox regression analysis, with age at diagnosis included as a covariate, confirmed that AJCC stage at primary tumor diagnosis independently predicted mortality following the detection of metastases ( Table 3 ). Furthermore, we created a Cox model for the entire period from primary tumor diagnosis to death or last follow-up, with the number of hepatic metastases detected after the metastasis-free interval as a time-varying covariate. The results indicated that the number of hepatic metastases was significantly associated with an increased hazard of death, with a hazard ratio (HR) of 2.63 (95% CI, 2.35–2.96, P <0.001). AJCC stage and patient age at primary tumor diagnosis were also significantly associated with survival, with an HR of 1.26 (95% CI, 1.06–1.49, P =0.001) and 1.02 (95% CI 1.00–1.04, P =0.02), respectively. The overall model fit was good, with a concordance index of 0.95 and significant likelihood ratio, Wald, and score tests ( P <0.001, Table 4 ). Lastly, a Markov multi-state model was developed to examine transition dynamics from diagnosis of the primary tumor to metastasis detection and subsequent death. As expected, AJCC stage at primary tumor diagnosis significantly influenced the transition from non-metastatic to metastatic status. Each unit increase in AJCC stage was associated with a 34% increase in the hazard of developing metastases (HR, 1.34; 95% CI, 1.15–1.55; P <0.001). In examining the transition from metastatic disease diagnosis to death, the inclusion of both AJCC stage and the number of hepatic metastases as covariates revealed that both factors significantly contributed to the hazard of death. A unit increase in AJCC stage at primary tumor diagnosis resulted in a 20% increase in the hazard of death following metastasis detection (HR,1.03; 95% CI, 1.01–1.43; P =0.03), even after adjusting for the number of hepatic metastases, which itself was a significant predictor ( Table 5 ). DISCUSSION Here, we demonstrate that among patients who die from metastatic uveal melanoma, a higher AJCC stage at the time of primary tumor diagnosis is associated with shorter survival among patients who die from metastatic uveal melanoma. This association remains significant even in a cohort of patients already at stage IV, where a higher AJCC stage at primary tumor diagnosis continues to correlate with shorter survival, even after adjusting for the number of hepatic metastases visible upon detection of metastatic disease. These findings are crucial for understanding the impact of primary tumor treatment on survival. Tumor cells are believed to begin disseminating from the eye at an early stage, as indicated by the detection of circulating tumor cells and micrometastases in multiple organs of patients who have died from other causes. 14-16 At the same time, interventions such as enucleation or sterilization with plaque brachytherapy prevent tumors from advancing to higher AJCC stages than they would have reached without treatment. It is also well-established that tumors at lower stages are associated with lower mortality than tumors at higher stages. 4,17 Additionally, if a patient does develop metastases, the time needed for these metastases to become radiologically or clinically apparent is likely to be longer if the tumor was smaller at the time of treatment. A reasonable interpretation is that a patient's risk of metastasis is largely determined when the tumor is very small; however, by detecting and treating the tumor early, we can prevent the additional risk associated with further tumor growth. We acknowledge the validity of theories suggesting that a patient's lifespan from diagnosis to death from metastases could be determined by micrometastases and genetic traits established when the primary tumor is very small. 15,18,19 The longer interval between primary tumor diagnosis and metastatic death for smaller tumors might occur because these tumors are detected earlier in their progression. In contrast, larger tumors may have been growing undetected for a longer period, which could explain the shorter time from diagnosis to death for patients with larger tumors, as well as the observation of a greater number of metastases upon the initial detection of metastatic disease (even though patients were examined with identical intervals regardless of primary tumor stage). 20 However, this reasoning does not fully account for why patients with metastatic disease die sooner if they were initially diagnosed with a more advanced primary tumor, even when controlling for the number of metastases at that point. A more plausible explanation is that metastases originating from larger, more advanced primary tumors tend to grow more rapidly and are more immediately life-threatening than an equal number of metastases from smaller, less advanced primary tumors. Therefore, our findings suggest that the beneficial survival effect of primary tumor treatment lies in its ability to prevent the tumor from advancing to a higher AJCC stage, thereby reducing the aggressiveness and growth rate of metastases. As indicated by our Cox regression analysis and Markov multi-state model, each increase in AJCC stage at primary tumor diagnosis is associated with an increased rate of death by approximately 20% to 26% among these metastatic patients. In other words, when considering the time from primary tumor diagnosis to death, a higher AJCC stage is clearly associated with more advanced disease and a shorter time to death, even when solely including patients who die from metastatic disease. This is not surprising. However, when focusing on the time from metastasis detection to death, our findings indicate that patients with more advanced primary tumors at diagnosis, before any radiologically detectable metastases were present, tend to die sooner. This suggests that once metastases from larger, more advanced tumors become visible, they may grow faster and be more lethal. Still, the survival difference might also result from patients with larger primary tumors simply having more, not faster-growing, metastases at the time of detection, despite all patients being examined at six-month intervals. Therefore, adjusting for these factors in our analysis was crucial to accurately assess the impact of primary tumor stage on survival. These findings underscore the potential survival benefits of timely primary tumor treatment in uveal melanoma. 21,22 While it is evident that treatment cannot be initiated for tumors that have not yet been detected, and that some observation for growth is necessary to differentiate between benign and malignant choroidal melanocytic lesions, once a diagnosis of melanoma is established, delaying treatment may be detrimental. Treatment should be administered as soon as practically possible after diagnosis to minimize the risk of tumor progression to a more advanced AJCC stage. It is also important to note that small tumors that grow slowly will naturally take longer to progress to a higher AJCC stage, implying that delaying treatment for these lesions may have minimal or no impact on prognosis compared to rapidly growing tumors. 23 Conversely, while larger tumors are generally associated with more aggressive behavior, some small tumors may possess aggressive genetic mutations, and some larger tumors may have characteristics associated with a more favorable prognosis. 24 This variability highlights the need for a nuanced approach to treatment decisions, considering both tumor size and its biological behavior. Many institutions tailor their radiological surveillance programs based on perceived metastatic risk, determined by factors such as AJCC stage, chromosome 3 status, gene expression profiling, or other prognostic markers. 25 While it may seem logical to recommend more frequent examinations for patients with markers of aggressive disease, and less frequent or no examinations for those with markers of lower metastatic risk (e.g., AJCC stage I, disomy 3, or EIF1AX mutation), it is important to note that, to date, there is no evidence that surveillance improves survival in uveal melanoma. The next few years may be pivotal in this regard, as new treatments for metastatic disease could potentially improve survival rates, thereby increasing the value of early detection of metastatic lesions. The potential survival benefit of early treatment versus observation of small uveal melanomas has been debated within the field. 26 Most previous studies have not found a significant association between the stage or size of the primary tumor at initial diagnosis and survival in patients with metastatic disease. 7,8,12,13 For instance, in 2000, Eskelin and colleagues found no significant relationship between primary tumor diameter, thickness, or volume and the estimated doubling time of metastases in a cohort of 37 stage IV patients, suggesting caution in interpreting such associations. 27 In contrast, we include two distinct cohorts: a large sample of 1491 patients followed from the time of initial diagnosis until death due to metastatic uveal melanoma, and a second cohort of 350 patients monitored from the time of metastasis detection until death. This dual-cohort design captures the entire disease course and allows for an evaluation of how early intervention and primary tumor characteristics may influence survival across different stages of disease progression. Limitations This study has several limitations beyond those already discussed. Firstly, the results are derived from retrospective observational cohorts, which inherently limits the ability to draw definitive conclusions about causality. To definitively determine whether primary tumor treatment confers a survival benefit in uveal melanoma, a large randomized clinical trial would be necessary, comparing outcomes between a treated group and an untreated group. However, such a trial would raise serious ethical concerns and is unlikely to ever be conducted. Additionally, the validity of our findings relies on the accuracy of the underlying data, which was obtained from medical charts, treatment records, and cause of death registries. Although efforts were made to cross-verify information from cause of death registries with medical records, the possibility of misclassification remains. Such errors could have influenced the survival outcomes reported in this study. Secondly, our analysis included 350 stage IV patients selected from a non-random subset of all patients with metastatic melanoma during the study period. These patients were pooled from two different institutions, introducing potential heterogeneity. Additionally, the evaluated patients may not be fully representative of all individuals with metastatic melanoma, especially those who did not undergo metastatic surveillance or attend follow-up visits. Thirdly, the assessment of the dimensions and anatomical extent of primary tumors and metastases varies due to different measurement methods. For primary tumors, methods include fundus photography, ultrasonography, and gross pathological examination, while for metastases, ultrasound, MRI, CT, and PET/CT are used. Gross pathological examination, commonly performed on enucleated eyes, involves various techniques that may affect measurement consistency. Some pathologists measure the linear (chord length) of the tumor’s transillumination shadow using a caliper, while others use a flexible ruler to measure arc dimensions, which may differ, especially in larger tumors (>10 mm). Measurements can also vary after the globe is opened, depending on sectioning and whether taken fresh or after formalin fixation, which causes tissue shrinkage—affecting thickness more than basal diameters. Due to these variabilities, it is uncertain how well pathological measurements reflect the true tumor dimensions compared to clinical measurements obtained with current methods. Fourth, patient age was included as a covariate in regression analyses, despite ongoing debate about its association with prognosis, especially when considering competing risks and other prognostic factors in multivariate analyses. 2,28 However, age-related factors, such as comorbidities and overall health status, may affect both disease progression and a patient's ability to tolerate aggressive treatments for metastases. Additionally, age has been linked to aggressive genetic traits, such as BAP1 mutation and aggressive gene expression profiles. 29 Older patients may present with more advanced disease within the same stage category due to a longer potential duration of tumor growth, supporting our decision to include age as a covariate. Fifth, we lacked data on the genetic or cytogenetic characteristics of both primary tumors and metastases. Additionally, data on the number of metastases were available for only 144 patients, and the size of these lesions was not documented. Additionally, information regarding the involvement of organs other than the liver at the time of detection of the first metastases was not included. The size, and distribution, of metastatic lesions is an important prognostic factor in metastatic disease, and including this data in regression analyses could have potentially altered the results. However, the number of hepatic metastases, which is associated with the presence of miliary metastases, also has substantial prognostic value. 7,20,30 Thus, we believe that the absence of data on the size of the largest metastatic lesion, and the potential involvement of other organs, likely had a limited impact on our findings. Finally, the statistical analyses used, including Kaplan-Meier and Cox proportional hazards regression, do not account for competing risks. However, given that only patients who died from metastatic uveal melanoma, and those who had been diagnosed with metastatic disease, were included, it is unlikely that competing risks would have significantly influenced survival estimates. Conclusions A higher AJCC stage at the time of primary tumor diagnosis is associated with shorter survival in uveal melanoma patients who develop metastases. This relationship remains significant even when survival is assessed from the time of metastasis detection and after adjusting for the number of hepatic metastases present at that time. These findings indicate that primary tumor treatment, by preventing the tumor from progressing to a more advanced AJCC stage, may provide a survival benefit by potentially reducing the aggressiveness and growth rate of subsequent metastases. METHODS Aim of the study The aim of this study was to examine the prognostic implication of uveal melanoma stage at the time of primary tumor diagnosis for patients who die from metastatic disease. Patients and study design Primary Diagnosis to Metastatic Death Cohort (PDMD) We re-analyzed anonymized and openly available data from a previously published study that included consecutive patients from three international institutions. 24 Inclusion criteria: 1. Clinically or histopathologically confirmed diagnosis of choroidal and/or ciliary body melanoma. 2. Availability of complete clinical information, including patient age and sex, largest basal diameter (LBD) of the tumor, tumor thickness, ciliary body involvement (CBI), extraocular extension (EXE ≤5 mm or >5 mm), length of follow-up, and vital status at the last follow-up. Exclusion criteria: 1. Iris melanoma (patients with melanomas believed to have originated in the choroid or ciliary body with secondary infiltration into the iris were included. The primary site of the tumor was determined by the geometric center, assessed using B-scan ultrasonography, ultrasound biomicroscopy, wide-field retinal imaging, slit-lamp biomicroscopy, or a combination of these methods. These patients were excluded by design in the original publication). 2. Metastatic disease present at the time of primary tumor diagnosis (these patients were excluded by design in the original publication). 3. Patient alive, or death attributed to causes other than metastatic uveal melanoma ( n =5037), as verified through cause of death registries or medical records. Tumor size and anatomical extent data at the time of primary tumor diagnosis were used to assign an AJCC stage to each of the remaining 1491 patients. 31 Metastasis Detection to Death Cohort (MDD) We also collected data on all patients who developed metastatic disease after being diagnosed with primary uveal melanoma at either the Erasmus University Medical Center and the Rotterdam Eye Hospital, Rotterdam, The Netherlands, between 1993 and 2021, or the Ocular Oncology Service, St. Erik Eye Hospital, Stockholm, Sweden, between 1980 and 2021. A total of 643 patients met the following inclusion criteria: Inclusion criteria: 1. Data available in treatment registries at the respective institution. 2. Clinically or histopathologically confirmed diagnosis of choroidal and/or ciliary body melanoma at the time of primary tumor diagnosis. 3. Enrollment in a surveillance program with periodic liver examinations for a minimum of 5 years after primary tumor diagnosis (using contrast-enhanced ultrasound, computed tomography [CT], or magnetic resonance imaging [MRI]). 4. Radiologically detected metastases in the liver and/or other organs. 5. Availability of CT or MRI images. Exclusion criteria: 1. Iris melanoma ( n =0). 2. Lack of recorded primary tumor thickness or LBD at the time of primary tumor diagnosis ( n =29). 3. Unknown anatomical extent, specifically CBI or EXE, at the time of primary tumor diagnosis ( n =0). 4. Unrecorded location of metastases ( n =51). 5. Uncertain exact date of radiological detection of metastases, including cases where dates were not specified in referrals, medical notes, or radiological image files, or where the diagnosis was indeterminable due to unclear findings in one exam followed by an established diagnosis in a subsequent exam ( n =213). After applying these criteria, 350 patients remained in the final cohort, of which 129 were from Rotterdam and 221 from Stockholm. The date of the first radiological detection of metastases was used as the date of metastasis. Data on the number of patients who underwent biopsy for histopathological confirmation of metastases were not available. Of the 129 patients from Rotterdam, 123 were included in a previous study, with metastases to the liver being observed in 96% of cases. 20 For the 123 patients in the Rotterdam sample, and for 21 of the patients in the Stockholm samle, data were available on the number of metastases present at the initial CT or MRI scan when the first metastases were observed. The study was approved by the Swedish Ethical Review Authority (reference 2023-07537-02) and adhered to the tenets of the Declaration of Helsinki. Informed consent was waived by the Swedish Ethical Review Authority because the study relied on retrospective, pre-collected data. No sensitive information was shared between the institutions, and no new collection of identifiable information was conducted, including patients' names, identification numbers, addresses, contact details, or photographs. No interventions, testing, or examinations were performed, and no analyses of biological tissues were conducted. Statistical analyses Statistical significance was defined as P <0.05, and all P values were two-sided. Holm-Bonferroni corrections were applied to all reported P values. Kaplan-Meier survival curves were generated, and multivariate and time-varying Cox regression analyses were performed using the survival and survminer packages in R (version 4.4.1, The R Foundation for Statistical Computing, Vienna, Austria). Survival distributions across AJCC stages at primary tumor diagnosis were compared using the log-rank test for trend. To examine the transition dynamics from primary tumor diagnosis to metastasis detection and subsequent death, a Markov multi-state model was constructed using the mstate and survival packages in R. The proportional hazards assumption was assessed by inspecting log-minus-log survival curves; the assumption was considered satisfied if the curves were parallel and did not cross. Tumor volume was estimated using a formula consistent with previously described methods, where LBD represents the largest basal tumor diameter: 32,33 Declarations Funding Support for this study was provided to Gustav Stålhammar from: Region Stockholm (RS-2019-1138) The Swedish Cancer Society (20 0798 Fk) The Crown Princess Margareta Foundation for the Visually Impaired (2022-017) Karolinska Institutet (2022-01671) The Swedish Eye Foundation (2022-05-09) The sponsors or funding organizations had no role in the design or conduct of this study. Author contributions Serdar Yavuzyigitoglu : Conceptualization, Methodology, Data curation, Investigation, Resources, Writing – Reviewing and Editing. Shiva Sabazade : Writing- Reviewing and Editing, Validation. Viktor Gill : Writing- Reviewing and Editing, Validation. Erwin Brosens : Supervision, Writing – Reviewing and Editing. Emine Kiliç :Methodology, Data curation, Project Administration. Gustav Stålhammar : Conceptualization, Methodology, Formal analysis, Investigation, Writing -Original Draft, Visualization, Supervision. Data availability statement The data for the PDMD cohort is based on information that can be inferred from a previously published, openly accessible article (https://doi.org/10.1016/j.ophtha.2023.10.026). No new data was collected for this study. The data for the MDD cohort, including the Rotterdam and Stockholm samples, is available upon reasonable request from the corresponding author, subject to approval from the Swedish Ethical Review Authority. 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Ophthalmology 130 , 1290-1303 (2023). https://doi.org:10.1016/j.ophtha.2023.07.025 Gill, V. T. et al. Multiorgan Involvement of Dormant Uveal Melanoma Micrometastases in Postmortem Tissue From Patients Without Coexisting Macrometastases. Am J Clin Pathol 160 , 160-174 (2023). https://doi.org:10.1093/ajcp/aqad029 Eide, N. et al. The Results of Stricter Inclusion Criteria in an Immunomagnetic Detection Study of Micrometastatic Cells in Bone Marrow of Uveal Melanoma Patients - Relevance for Dormancy. Pathol Oncol Res 25 , 255-262 (2019). https://doi.org:10.1007/s12253-017-0355-7 Shields, C. L. et al. American Joint Committee on Cancer Classification of Uveal Melanoma (Anatomic Stage) Predicts Prognosis in 7,731 Patients: The 2013 Zimmerman Lecture. Ophthalmology 122 , 1180-1186 (2015). https://doi.org:10.1016/j.ophtha.2015.01.026 Field, M. G. et al. Punctuated evolution of canonical genomic aberrations in uveal melanoma. Nat Commun 9 , 116 (2018). https://doi.org:10.1038/s41467-017-02428-w Stalhammar, G. & Gill, V. T. Digital morphometry and cluster analysis identifies four types of melanocyte during uveal melanoma progression. Commun Med (Lond) 3 , 60 (2023). https://doi.org:10.1038/s43856-023-00291-z Yavuzyigitoglu, S. et al. Radiological Patterns of Uveal Melanoma Liver Metastases in Correlation to Genetic Status. Cancers (Basel) 13 (2021). https://doi.org:10.3390/cancers13215316 Stalhammar, G. Delays between Uveal Melanoma Diagnosis and Treatment Increase the Risk of Metastatic Death. Ophthalmology 131 , 1094-1104 (2023). https://doi.org:10.1016/j.ophtha.2023.11.021 Stalhammar, G. & Gill, V. T. The long-term prognosis of patients with untreated primary uveal melanoma: A systematic review and meta-analysis. Crit Rev Oncol Hematol 172 , 103652 (2022). https://doi.org:10.1016/j.critrevonc.2022.103652 Damato, B. et al. Deferral of Treatment for Small Choroidal Melanoma and the Risk of Metastasis: An Investigation Using the Liverpool Uveal Melanoma Prognosticator Online (LUMPO). Cancers (Basel) 16 (2024). https://doi.org:10.3390/cancers16081607 Stalhammar, G. et al. Improved Staging of Ciliary Body and Choroidal Melanomas Based on Estimation of Tumor Volume and Competing Risk Analyses. Ophthalmology 131 , 478-491 (2023). https://doi.org:10.1016/j.ophtha.2023.10.026 Hagström, A., Witzenhausen, H. & Stålhammar, G. Tailoring Surveillance Imaging in Uveal Melanoma Based on Individual Metastatic Risk. Canadian Journal of Ophthalmology/Journal canadien d'ophtalmologie (2024). https://doi.org:https://doi.org/10.1016/j.jcjo.2024.07.014 Damato, B. Does ocular treatment of uveal melanoma influence survival? British Journal of Cancer 103 , 285 (2010). https://doi.org:10.1038/sj.bjc.6605765 Eskelin, S., Pyrhönen, S., Summanen, P., Hahka-Kemppinen, M. & Kivelä, T. Tumor doubling times in metastatic malignant melanoma of the uvea: tumor progression before and after treatment. Ophthalmology 107 , 1443-1449 (2000). https://doi.org:10.1016/s0161-6420(00)00182-2 Kujala, E., Mäkitie, T. & Kivelä, T. Very long-term prognosis of patients with malignant uveal melanoma. Invest Ophthalmol Vis Sci 44 , 4651-4659 (2003). Decatur, C. L. et al. Driver Mutations in Uveal Melanoma: Associations With Gene Expression Profile and Patient Outcomes. JAMA Ophthalmol 134 , 728-733 (2016). https://doi.org:10.1001/jamaophthalmol.2016.0903 Mariani, P. et al. Surgical management of liver metastases from uveal melanoma: 16 years' experience at the Institut Curie. Eur J Surg Oncol 35 , 1192-1197 (2009). https://doi.org:10.1016/j.ejso.2009.02.016 Kivelä, T. et al. in AJCC Cancer Staging Manual Ch. 67, 805-817 (Springer, 2017). Richtig, E., Langmann, G., Mullner, K., Richtig, G. & Smolle, J. Calculated tumour volume as a prognostic parameter for survival in choroidal melanomas. Eye (Lond) 18 , 619-623 (2004). https://doi.org:10.1038/sj.eye.6700720 Uner, O. E., See, T. R. O., Szalai, E., Grossniklaus, H. E. & Stalhammar, G. Estimation of the timing of BAP1 mutation in uveal melanoma progression. Sci Rep 11 , 8923 (2021). https://doi.org:10.1038/s41598-021-88390-6 Tables Table 1: Characteristics of Included Patients and Tumors at the Time of Primary Tumor Diagnosis PDMD, n =1491 MDD, n =350 Potential Prognostic Variable Category of Variable Number of Cases (%) Number of Cases (%) Sex Female 688 46 179 51 Male 803 54 171 49 AJCC T-category* T1a 141 9 54 15 T1b 13 1 0 0 T1c 1 <1 0 0 T1d 3 <1 0 0 T2a 360 24 126 36 T2b 49 3 12 3 T2c 14 1 1 <1 T2d 8 1 3 1 T3a 325 22 95 27 T3b 205 14 18 5 T3c 22 2 6 2 T3d 48 3 5 1 T4a 86 6 23 7 T4b 158 11 5 1 T4c 20 1 0 0 T4d 33 2 1 <1 T4e 5 <1 1 <1 AJCC Stage* I 141 9 54 15 IIA 377 25 126 36 IIB 374 25 107 31 IIIA 335 23 51 15 IIIB 226 15 10 3 IIIC 38 3 2 1 *At the time of primary tumor diagnosis. AJCC, American Joint Committee on Cancer. MDD, Metastasis Detection to Death Cohort. PDMD, Primary Diagnosis to Metastatic Death Cohort. Table 2: Multivariate Cox Regression Analysis of Hazard Ratios for Death Among 1491 Patients Who Died from Metastatic Uveal Melanoma Variable ß S.E.ß Wald Test Statistic P † exp(ß) 95% CI of exp(ß) Age a 0.02 <0.001 72.3 <0.001 1.02 Lower: 1.01, Upper: 1.02 AJCC stage b 0.22 0.02 107.4 <0.001 1.25 Lower: 1.19, Upper: 1.30 AJCC, American Joint Committee on Cancer. ß, beta coefficient computed by the Cox Proportional Hazards analysis. CI, Confidence interval. exp(ß), Exponentiated beta coefficient, representing the hazard ratio. S.E.ß, standard error of the beta coefficient. a Per increasing year at the time of primary tumor diagnosis. b At the time of primary tumor diagnosis, per increasing step from stage I to IIA, from stage IIA to IIB, from IIB to IIIA, etc. † Holm-Bonferroni-corrected value. Table 3: Multivariate Cox Regression Analyses of Hazard Ratios for Death in 350 Patients with Metastatic Uveal Melanoma Variable ß S.E.ß Wald Test Statistic P † exp(ß) 95% CI of exp(ß) Age a 0.01 0.01 3.4 0.06 1.01 Lower: 1.00, Upper: 1.02 AJCC stage b 0.50 0.06 75.5 <0.001 1.66 Lower: 1.48, Upper: 1.86 AJCC, American Joint Committee on Cancer. ß, beta coefficient computed by the Cox Proportional Hazards analysis. CI, Confidence interval. exp(ß), Exponentiated beta coefficient, representing the hazard ratio. S.E.ß, standard error of the beta coefficient. a Per increasing year at the time of primary tumor diagnosis. b At the time of primary tumor diagnosis, per increasing step from stage I to IIA, from stage IIA to IIB, from IIB to IIIA, etc. † Holm-Bonferroni-corrected value. Table 4: Multivariate Cox Regression Analyses of Hazard Ratios for Death in 144 Patients with Metastatic Uveal Melanoma, with the number of metastatic lesions at the time of detection of metastatic disease included as a time-varying covariate. Variable ß S.E.ß z P † exp(ß) 95% CI of exp(ß) Age a 0.02 0.01 2.4 0.02 1.02 Lower: 1.00, Upper: 1.04 AJCC stage b 0.23 0.09 2.6 0.001 1.26 Lower: 1.06, Upper: 1.49 Number of hepatic metastases c 0.97 0.06 16.5 <0.001 2.63 Lower: 2.35, Upper: 2.96 AJCC, American Joint Committee on Cancer. ß, beta coefficient computed by the Cox Proportional Hazards analysis. CI, Confidence interval. exp(ß), Exponentiated beta coefficient, representing the hazard ratio. S.E.ß, standard error of the beta coefficient. z, Z-statistic, which is the test statistic for the null hypothesis that the corresponding coefficient is zero in the Cox proportional hazards model. a Per increasing year at the time of primary tumor diagnosis. b At the time of primary tumor diagnosis, per increasing step from stage I to IIA, from stage IIA to IIB, from IIB to IIIA, etc. c At the time of radiological detection of metastatic disease, per increasing step from a solitary metastasis to two to five, from two to five to six to ten, and from six to ten to >10 (time-varying covariate). † Holm-Bonferroni-corrected value. Table 5: Markov Multi-state Model hazard Ratios for Transition Dynamics in Uveal Melanoma Transition Covariate HR 95% CI of HR P † Concordance ‡ Non-metastatic to metastatic disease AJCC stage a 1.34 Lower: 1.15, Upper: 1.55 <0.001 0.55 Metastatic disease to death AJCC stage a 1.20 Lower: 1.01, Upper: 1.43 0.03 0.64 Number of hepatic metastases 1.36 Lower: 1.14, Upper: 1.60 <0.001 AJCC, American Joint Committee on Cancer. CI, Confidence Interval. HR, Hazard ratio. a At the time of primary tumor diagnosis, per increasing step from stage I to IIA, from stage IIA to IIB, from IIB to IIIA, etc. b At the time of radiological detection of metastatic disease, per increasing step from a solitary metastasis to two to five, from two to five to six to ten, and from six to ten to >10. † Holm-Bonferroni-corrected value. ‡ C-index, a measure of model performance; higher values indicate better predictive accuracy. Additional Declarations No competing interests reported. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-4521528","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":410676888,"identity":"545b831f-d865-425d-8adb-7bc354b97522","order_by":0,"name":"Serdar Yavuzyigitoglu","email":"","orcid":"","institution":"Erasmus MC","correspondingAuthor":false,"prefix":"","firstName":"Serdar","middleName":"","lastName":"Yavuzyigitoglu","suffix":""},{"id":410676889,"identity":"49d7b137-0f80-49d8-baba-6f9c8edecb4b","order_by":1,"name":"Shiva Sabazade","email":"","orcid":"","institution":"Karolinska Institutet","correspondingAuthor":false,"prefix":"","firstName":"Shiva","middleName":"","lastName":"Sabazade","suffix":""},{"id":410676890,"identity":"794cae13-1793-479b-bfaf-5dd14091a658","order_by":2,"name":"Viktor Gill","email":"","orcid":"","institution":"Karolinska Institutet","correspondingAuthor":false,"prefix":"","firstName":"Viktor","middleName":"","lastName":"Gill","suffix":""},{"id":410676891,"identity":"c264e2c7-265a-4f37-90e7-5297bda4d786","order_by":3,"name":"Erwin Brosens","email":"","orcid":"","institution":"Erasmus MC","correspondingAuthor":false,"prefix":"","firstName":"Erwin","middleName":"","lastName":"Brosens","suffix":""},{"id":410676892,"identity":"7a6135de-b0ec-4c08-81d5-a3afa9e40d94","order_by":4,"name":"Emine Kiliç","email":"","orcid":"","institution":"Erasmus MC","correspondingAuthor":false,"prefix":"","firstName":"Emine","middleName":"","lastName":"Kiliç","suffix":""},{"id":410676893,"identity":"ed9a9be6-c009-4252-8940-900603b7a3ca","order_by":5,"name":"Gustav Stålhammar","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAABB0lEQVRIie2PsUoEMRCGJwi3TcQ2yyr3ChcsbE7zGpYbFnabfYArcwhzzR62EX2O1BFhbe4BDtLsNtqccJYHK7p6VkJW7CzyFROYmY9/AhAI/G8OcP9GCPaXVaI+KwXyrdD6zwrLh/fHl8Vzs0MQIrrHZlea8dnNk7TQTb0KX5d8vkSQFZULvjSO37ncWoL+KK5LougKUgoS2aFxRCeFskQ9DChFO+9WIOhRi/GbcULHj6o/7N3/F5byKzoDUjGJSZ8iNRtZCyPrVSZ0w2+PZ0xW6xaTE+MyTfPUSsz8KYuied1MpiK6zur4xbhzHdWn22134U/ZH8B+tFOv0KeogWEgEAgEvvgAWFpZlVxPzcIAAAAASUVORK5CYII=","orcid":"","institution":"Karolinska Institutet","correspondingAuthor":true,"prefix":"","firstName":"Gustav","middleName":"","lastName":"Stålhammar","suffix":""}],"badges":[],"createdAt":"2024-06-03 11:31:13","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4521528/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4521528/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":75502899,"identity":"2eda4068-65b8-42b1-88ae-c2369dc65937","added_by":"auto","created_at":"2025-02-05 09:18:50","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":4519200,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eSurvival Curves for Patients Who Died from Metastatic Uveal Melanoma (Primary Diagnosis to Metastatic Death Cohort (PDMD)). \u003c/strong\u003eSurvival curves for 1491 patients categorized by their status at the time of primary tumor diagnosis. A) Curves by AJCC stage, which is based on both primary tumor size and anatomic extent. Patients diagnosed with less advanced AJCC stages demonstrated significantly longer survival (log-rank test for trend, \u003cem\u003eP\u003c/em\u003e\u0026lt; 0.001). B) Curves by AJCC T-category, which is based solely on primary tumor size. Patients with smaller tumors (lower T-categories) had significantly longer survival (log-rank test for trend, \u003cem\u003eP\u003c/em\u003e\u0026lt; 0.001). \u003cem\u003eP \u003c/em\u003evalues are Holm-Bonferroni-corrected. AJCC, American Joint Committee on Cancer.\u003c/p\u003e","description":"","filename":"Figure1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4521528/v1/67fb56f155f964d792ff9c78.jpg"},{"id":75502512,"identity":"93f0619f-d806-4f89-8ca4-693889b3e9e8","added_by":"auto","created_at":"2025-02-05 09:10:50","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":4106596,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eSurvival Curves for Patients with Metastatic Uveal Melanoma (Metastasis Detection to Death Cohort (MDD). \u003c/strong\u003eSurvival curves for 350 patients with metastatic uveal melanoma, categorized by AJCC stage and T-category at the time of primary tumor diagnosis. A) Curves by AJCC stage at the time of primary tumor diagnosis. Patients diagnosed with less advanced AJCC stages had significantly longer survival after metastasis detection (log-rank test for trend, \u003cem\u003eP\u0026lt;\u003c/em\u003e0.001). B) Curves by AJCC T-category at the time of primary tumor diagnosis. Patients with smaller primary tumors (lower T-categories) demonstrated significantly longer survival after metastasis detection (log-rank test for trend, \u003cem\u003eP\u003c/em\u003e\u0026lt;0.001). \u003cem\u003eP\u003c/em\u003e values are Holm-Bonferroni-corrected. AJCC, American Joint Committee on Cancer.\u003c/p\u003e","description":"","filename":"Figure2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4521528/v1/2f03bcc7e4a5cfa262ad1a1f.jpg"},{"id":75504526,"identity":"90e390a2-597f-4539-b0ad-1148ba690358","added_by":"auto","created_at":"2025-02-05 09:26:53","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":9838265,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4521528/v1/77fd5616-2f7e-44b3-a484-b7dbab4c4da0.pdf"},{"id":75502510,"identity":"90f474fb-15ef-406c-a38a-73e29e560795","added_by":"auto","created_at":"2025-02-05 09:10:50","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":102361,"visible":true,"origin":"","legend":"","description":"","filename":"SupplementaryFigure.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4521528/v1/8e231a6b746b7ccb4eba2999.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Indications of a Survival Benefit from Primary Tumor Treatment in Uveal Melanoma: Association Between initial AJCC Stage and Metastatic Survival","fulltext":[{"header":"INTRODUCTION","content":"\u003cp\u003eUveal melanoma is the most common primary intraocular malignancy in adults, characterized by its high propensity for developing fatal metastases.\u003csup\u003e1\u003c/sup\u003e The long-term incidence of metastatic death approaches 50%, with fewer improvements in prognosis compared to cutaneous melanoma.\u003csup\u003e2,3\u003c/sup\u003e\u003c/p\u003e\n\u003cp\u003ePrimary tumor size and anatomic extent are critical factors in the American Joint Committee on Cancer (AJCC) staging system, which strongly predicts the time to metastatic disease.\u003csup\u003e4,5\u003c/sup\u003e In 2014, Damato and colleagues demonstrated that among those who succumb to their disease, the median survival time from primary tumor treatment to death was 4.6 years for patients in stage I, compared to only 2.7 years for patients in stage III.\u003csup\u003e6\u003c/sup\u003e Thus, a shorter metastasis-free interval is associated with poorer overall survival outcomes.\u003csup\u003e7-10\u003c/sup\u003e\u003c/p\u003e\n\u003cp\u003eHowever, it is challenging to determine from these observations whether treatment that prevents a primary tumor from progressing to a higher stage has a beneficial effect on patient survival. The shorter time to metastasis and death in patients with more advanced stages might simply reflect lead-time bias, with larger tumors having had more time to grow and metastasize.\u003csup\u003e11\u003c/sup\u003e In this scenario, the treatment of large and small tumors might occur at different points on the same timeline, potentially resulting in similar dates of death despite different initial tumor sizes.\u003c/p\u003e\n\u003cp\u003eTo address this issue, we propose evaluating the survival time from the detection of metastases to death. If this interval is shorter for patients whose primary tumors were larger at the time of treatment, it would suggest that the growth rate of metastases is influenced by the size of the primary tumor. This would imply a survival benefit of treating the primary tumor at an earlier stage, when its metastases are relatively slow-growing. In turn, this would clarify the potential benefit of treating uveal melanoma as soon as possible after diagnosis.\u003c/p\u003e\n\u003cp\u003eSome previous studies have found that primary tumor diameter at the time of initial diagnosis is associated with an increased risk or hazard ratio for death if metastases develop, whereas others have not.\u003csup\u003e7,8,12,13\u003c/sup\u003e The largest study to date, which did not include time-to-event survival analyses, included 330 patients with metastatic choroidal and ciliary body melanomas.\u003csup\u003e12\u003c/sup\u003e This study confirmed the association between a shorter metastasis-free interval and shorter overall survival, but found no difference in the distribution of AJCC stage between patients with different overall survival times.\u003c/p\u003e\n\u003cp\u003eIn this study, we evaluate the prognostic significance of the AJCC stage of uveal melanoma at the time of primary tumor diagnosis across two distinct cohorts. The first cohort comprises 1,491 patients who were monitored from the diagnosis of the primary tumor until death due to metastatic disease. The second cohort includes 350 patients, where the analysis focuses on survival time following the detection of metastases, while also incorporating data on the interval from primary tumor diagnosis. By analyzing these cohorts, we aim to clarify whether the stage of the primary tumor at diagnosis has an impact not only on the time to metastasis but also on survival following the onset of metastatic disease.\u003c/p\u003e"},{"header":"RESULTS","content":"\u003cp\u003e\u003cstrong\u003eDescriptive statistics\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eOf 1491 patients who died from metastatic uveal melanoma (Primary Diagnosis to Metastatic Death Cohort [PDMD]), 688 (46%) were female. The mean age at the time of diagnosis of the primary uveal melanoma was 63 years (SD 13 years). The mean largest basal diameter (LBD) of the tumor was 14.5 mm (SD 3.9 mm), mean tumor thickness was 7.2 mm (SD 3.4 mm), and mean tumor volume was 828 mm³ (SD 1305 mm³).\u003c/p\u003e\n\u003cp\u003eOf the 350 patients with metastatic disease (Metastasis Detection to Death Cohort [MDD]), 179 (51%) were female. The mean age at the time of diagnosis of the primary tumor was 61 years (SD 12 years). The mean largest basal diameter (LBD) of the tumor was 13.0 mm (SD 3.6 mm), mean tumor thickness was 6.5 mm (SD 2.9 mm), and mean tumor volume was 588 mm³ (SD 494 mm³). Further details on the included patients and tumors are provided in \u003cstrong\u003eTable 1\u003c/strong\u003e.\u003c/p\u003e\n\u003cp\u003eVisual inspection showed that the log-minus-log survival curves were parallel and did not cross, suggesting that the proportional hazards assumption was adequately met for the AJCC stage covariate in both cohorts (\u003cstrong\u003eSupplementary Figure 1\u003c/strong\u003e).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePrognostic implication of AJCC stage at initial diagnosis for those who die of uveal melanoma \u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eIn the cohort of 1491 PDMD patients, the AJCC stage at the time of primary tumor diagnosis, which incorporates both tumor size and anatomic extent, was significantly associated with overall survival. The 5-year survival rates by AJCC stage were as follows: 58% (95% confidence interval [CI], 51–67) for stage I, 38% (95% CI, 34–44) for stage IIA, 36% (95% CI, 31–41) for stage IIB, 21% (95% CI, 17–26) for stage IIIA, 17% (95% CI, 13–23) for stage IIIB, and 2% (95% CI, 0.3–18) for stage IIIC (log-rank test for trend, \u003cem\u003eP\u003c/em\u003e\u0026lt;0.001; \u003cstrong\u003eFigure 1A\u003c/strong\u003e).\u003c/p\u003e\n\u003cp\u003eWhen stratified by AJCC T-category, which considers only tumor size, the 5-year survival rates were: 53% (95% CI, 45–61) for T-category 1, 35% (95% CI, 31–39) for T-category 2, 28% (95% CI, 24–32) for T-category 3, and 12% (95% CI, 8–16) for T-category 4 (log-rank test for trend, \u003cem\u003eP\u003c/em\u003e\u0026lt;0.001; \u003cstrong\u003eFigure 1B\u003c/strong\u003e).\u003c/p\u003e\n\u003cp\u003eMultivariate Cox regression analysis, adjusting for patient age, confirmed that AJCC stage at primary tumor diagnosis was an independent predictor of mortality among PDMD patients (\u003cstrong\u003eTable 2\u003c/strong\u003e).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePrognostic implication of AJCC stage at initial diagnosis for patients with metastases\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAmong the 350 MDD patients, AJCC stage at the time of primary tumor diagnosis was significantly associated with survival after the detection of metastases. The median Kaplan-Meier survival estimate after first radiological detection of metastases was 2.2 years (95% CI, 1.9–2.6) for the entire cohort, 4.5 years (95% CI, 3.4–6.5) for stage I, 3.0 years (95% CI, 2.3–3.6) for stage IIA, 1.7 years (95% CI, 1.3–230) for stage IIB, 0.8 years (95% CI, 0.4–2.0) for stage IIIA, 0.7 years (95% CI, 0.4–1.0) for stage IIIB, and 0.3 years for stage IIIC (95% CI not determinable. The 1-year survival rates were: 83% (95% CI, 74–94) for stage I, 81% (95% CI, 74–88) for stage IIA, 69% (95% CI, 61–78) for stage IIB, 48% (95% CI, 36–64) for stage IIIA, and 40% (95% CI, 19–85) for stage IIIB. Both patients who had been in stage IIIC at the time of primary tumor diagnosis died within a year from detection of metastases (log-rank test for trend, \u003cem\u003eP\u003c/em\u003e\u0026lt;0.001; \u003cstrong\u003eFigure 2A\u003c/strong\u003e).\u003c/p\u003e\n\u003cp\u003eWhen categorized by AJCC T-category, the 1-year survival rates were: 83% (95% CI, 73–93) for T-category 1, 74% (95% CI, 66–82) for T-category 2, 63% (95% CI, 55–71) for T-category 3, and 67% (95% CI, 49–85) for T-category 4 (log-rank test for trend, \u003cem\u003eP\u003c/em\u003e\u0026lt; 0.001; \u003cstrong\u003eFigure 2B\u003c/strong\u003e).\u003c/p\u003e\n\u003cp\u003eMultivariate Cox regression analysis, with age at diagnosis included as a covariate, confirmed that AJCC stage at primary tumor diagnosis independently predicted mortality following the detection of metastases (\u003cstrong\u003eTable 3\u003c/strong\u003e).\u003c/p\u003e\n\u003cp\u003eFurthermore, we created a Cox model for the entire period from primary tumor diagnosis to death or last follow-up, with the number of hepatic metastases detected after the metastasis-free interval as a time-varying covariate. The results indicated that the number of hepatic metastases was significantly associated with an increased hazard of death, with a hazard ratio (HR) of 2.63 (95% CI, 2.35–2.96, \u003cem\u003eP\u003c/em\u003e\u0026lt;0.001). AJCC stage and patient age at primary tumor diagnosis were also significantly associated with survival, with an HR of 1.26 (95% CI, 1.06–1.49, \u003cem\u003eP\u003c/em\u003e=0.001) and 1.02 (95% CI 1.00–1.04,\u003cem\u003eP\u003c/em\u003e=0.02), respectively. The overall model fit was good, with a concordance index of 0.95 and significant likelihood ratio, Wald, and score tests (\u003cem\u003eP\u003c/em\u003e\u0026lt;0.001, \u003cstrong\u003eTable 4\u003c/strong\u003e).\u003c/p\u003e\n\u003cp\u003eLastly, a Markov multi-state model was developed to examine transition dynamics from diagnosis of the primary tumor to metastasis detection and subsequent death. As expected, AJCC stage at primary tumor diagnosis significantly influenced the transition from non-metastatic to metastatic status. Each unit increase in AJCC stage was associated with a 34% increase in the hazard of developing metastases (HR, 1.34; 95% CI, 1.15–1.55; \u003cem\u003eP\u003c/em\u003e\u0026lt;0.001). In examining the transition from metastatic disease diagnosis to death, the inclusion of both AJCC stage and the number of hepatic metastases as covariates revealed that both factors significantly contributed to the hazard of death. A unit increase in AJCC stage at primary tumor diagnosis resulted in a 20% increase in the hazard of death following metastasis detection (HR,1.03; 95% CI, 1.01–1.43; \u003cem\u003eP\u003c/em\u003e=0.03), even after adjusting for the number of hepatic metastases, which itself was a significant predictor (\u003cstrong\u003eTable 5\u003c/strong\u003e).\u003c/p\u003e"},{"header":"DISCUSSION","content":"\u003cp\u003eHere, we demonstrate that among patients who die from metastatic uveal melanoma, a higher AJCC stage at the time of primary tumor diagnosis is associated with shorter survival among patients who die from metastatic uveal melanoma. This association remains significant even in a cohort of patients already at stage IV, where a higher AJCC stage at primary tumor diagnosis continues to correlate with shorter survival, even after adjusting for the number of hepatic metastases visible upon detection of metastatic disease.\u003c/p\u003e\n\u003cp\u003eThese findings are crucial for understanding the impact of primary tumor treatment on survival. Tumor cells are believed to begin disseminating from the eye at an early stage, as indicated by the detection of circulating tumor cells and micrometastases in multiple organs of patients who have died from other causes.\u003csup\u003e14-16\u003c/sup\u003e At the same time, interventions such as enucleation or sterilization with plaque brachytherapy prevent tumors from advancing to higher AJCC stages than they would have reached without treatment. It is also well-established that tumors at lower stages are associated with lower mortality than tumors at higher stages.\u003csup\u003e4,17\u003c/sup\u003e Additionally, if a patient does develop metastases, the time needed for these metastases to become radiologically or clinically apparent is likely to be longer if the tumor was smaller at the time of treatment. A reasonable interpretation is that a patient's risk of metastasis is largely determined when the tumor is very small; however, by detecting and treating the tumor early, we can prevent the additional risk associated with further tumor growth.\u003c/p\u003e\n\u003cp\u003eWe acknowledge the validity of theories suggesting that a patient's lifespan from diagnosis to death from metastases could be determined by micrometastases and genetic traits established when the primary tumor is very small.\u003csup\u003e15,18,19\u003c/sup\u003e The longer interval between primary tumor diagnosis and metastatic death for smaller tumors might occur because these tumors are detected earlier in their progression. In contrast, larger tumors may have been growing undetected for a longer period, which could explain the shorter time from diagnosis to death for patients with larger tumors, as well as the observation of a greater number of metastases upon the initial detection of metastatic disease (even though patients were examined with identical intervals regardless of primary tumor stage).\u003csup\u003e20\u003c/sup\u003e However, this reasoning does not fully account for why patients with metastatic disease die sooner if they were initially diagnosed with a more advanced primary tumor, even when controlling for the number of metastases at that point. A more plausible explanation is that metastases originating from larger, more advanced primary tumors tend to grow more rapidly and are more immediately life-threatening than an equal number of metastases from smaller, less advanced primary tumors. Therefore, our findings suggest that the beneficial survival effect of primary tumor treatment lies in its ability to prevent the tumor from advancing to a higher AJCC stage, thereby reducing the aggressiveness and growth rate of metastases. As indicated by our Cox regression analysis and Markov multi-state model, each increase in AJCC stage at primary tumor diagnosis is associated with an increased rate of death by approximately 20% to 26% among these metastatic patients.\u003c/p\u003e\n\u003cp\u003eIn other words, when considering the time from primary tumor diagnosis to death, a higher AJCC stage is clearly associated with more advanced disease and a shorter time to death, even when solely including patients who die from metastatic disease. This is not surprising. However, when focusing on the time from metastasis detection to death, our findings indicate that patients with more advanced primary tumors at diagnosis, before any radiologically detectable metastases were present, tend to die sooner. This suggests that once metastases from larger, more advanced tumors become visible, they may grow faster and be more lethal. Still, the survival difference might also result from patients with larger primary tumors simply having more, not faster-growing, metastases at the time of detection, despite all patients being examined at six-month intervals. Therefore, adjusting for these factors in our analysis was crucial to accurately assess the impact of primary tumor stage on survival.\u003c/p\u003e\n\u003cp\u003eThese findings underscore the potential survival benefits of timely primary tumor treatment in uveal melanoma.\u003csup\u003e21,22\u003c/sup\u003e While it is evident that treatment cannot be initiated for tumors that have not yet been detected, and that some observation for growth is necessary to differentiate between benign and malignant choroidal melanocytic lesions, once a diagnosis of melanoma is established, delaying treatment may be detrimental. Treatment should be administered as soon as practically possible after diagnosis to minimize the risk of tumor progression to a more advanced AJCC stage. It is also important to note that small tumors that grow slowly will naturally take longer to progress to a higher AJCC stage, implying that delaying treatment for these lesions may have minimal or no impact on prognosis compared to rapidly growing tumors.\u003csup\u003e23\u003c/sup\u003e Conversely, while larger tumors are generally associated with more aggressive behavior, some small tumors may possess aggressive genetic mutations, and some larger tumors may have characteristics associated with a more favorable prognosis.\u003csup\u003e24\u003c/sup\u003e This variability highlights the need for a nuanced approach to treatment decisions, considering both tumor size and its biological behavior. Many institutions tailor their radiological surveillance programs based on perceived metastatic risk, determined by factors such as AJCC stage, chromosome 3 status, gene expression profiling, or other prognostic markers.\u003csup\u003e25\u003c/sup\u003e While it may seem logical to recommend more frequent examinations for patients with markers of aggressive disease, and less frequent or no examinations for those with markers of lower metastatic risk (e.g., AJCC stage I, disomy 3, or \u003cem\u003eEIF1AX\u003c/em\u003e mutation), it is important to note that, to date, there is no evidence that surveillance improves survival in uveal melanoma. The next few years may be pivotal in this regard, as new treatments for metastatic disease could potentially improve survival rates, thereby increasing the value of early detection of metastatic lesions.\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;The potential survival benefit of early treatment versus observation of small uveal melanomas has been debated within the field.\u003csup\u003e26\u003c/sup\u003e Most previous studies have not found a significant association between the stage or size of the primary tumor at initial diagnosis and survival in patients with metastatic disease.\u003csup\u003e7,8,12,13\u003c/sup\u003e For instance, in 2000, Eskelin and colleagues found no significant relationship between primary tumor diameter, thickness, or volume and the estimated doubling time of metastases in a cohort of 37 stage IV patients, suggesting caution in interpreting such associations.\u003csup\u003e27\u003c/sup\u003e In contrast, we include two distinct cohorts: a large sample of 1491 patients followed from the time of initial diagnosis until death due to metastatic uveal melanoma, and a second cohort of 350 patients monitored from the time of metastasis detection until death. This dual-cohort design captures the entire disease course and allows for an evaluation of how early intervention and primary tumor characteristics may influence survival across different stages of disease progression.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eLimitations\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study has several limitations beyond those already discussed. Firstly, the results are derived from retrospective observational cohorts, which inherently limits the ability to draw definitive conclusions about causality. To definitively determine whether primary tumor treatment confers a survival benefit in uveal melanoma, a large randomized clinical trial would be necessary, comparing outcomes between a treated group and an untreated group. However, such a trial would raise serious ethical concerns and is unlikely to ever be conducted. Additionally, the validity of our findings relies on the accuracy of the underlying data, which was obtained from medical charts, treatment records, and cause of death registries. Although efforts were made to cross-verify information from cause of death registries with medical records, the possibility of misclassification remains. Such errors could have influenced the survival outcomes reported in this study.\u003c/p\u003e\n\u003cp\u003eSecondly, our analysis included 350 stage IV patients selected from a non-random subset of all patients with metastatic melanoma during the study period. These patients were pooled from two different institutions, introducing potential heterogeneity. Additionally, the evaluated patients may not be fully representative of all individuals with metastatic melanoma, especially those who did not undergo metastatic surveillance or attend follow-up visits.\u003c/p\u003e\n\u003cp\u003eThirdly, the assessment of the dimensions and anatomical extent of primary tumors and metastases varies due to different measurement methods. For primary tumors, methods include fundus photography, ultrasonography, and gross pathological examination, while for metastases, ultrasound, MRI, CT, and PET/CT are used. Gross pathological examination, commonly performed on enucleated eyes, involves various techniques that may affect measurement consistency. Some pathologists measure the linear (chord length) of the tumor’s transillumination shadow using a caliper, while others use a flexible ruler to measure arc dimensions, which may differ, especially in larger tumors (\u0026gt;10 mm). Measurements can also vary after the globe is opened, depending on sectioning and whether taken fresh or after formalin fixation, which causes tissue shrinkage—affecting thickness more than basal diameters. Due to these variabilities, it is uncertain how well pathological measurements reflect the true tumor dimensions compared to clinical measurements obtained with current methods.\u003c/p\u003e\n\u003cp\u003eFourth, patient age was included as a covariate in regression analyses, despite ongoing debate about its association with prognosis, especially when considering competing risks and other prognostic factors in multivariate analyses.\u003csup\u003e2,28\u003c/sup\u003e However, age-related factors, such as comorbidities and overall health status, may affect both disease progression and a patient's ability to tolerate aggressive treatments for metastases. Additionally, age has been linked to aggressive genetic traits, such as \u003cem\u003eBAP1\u003c/em\u003e mutation and aggressive gene expression profiles.\u003csup\u003e29\u003c/sup\u003e Older patients may present with more advanced disease within the same stage category due to a longer potential duration of tumor growth, supporting our decision to include age as a covariate.\u003c/p\u003e\n\u003cp\u003eFifth, we lacked data on the genetic or cytogenetic characteristics of both primary tumors and metastases. Additionally, data on the number of metastases were available for only 144 patients, and the size of these lesions was not documented. Additionally, information regarding the involvement of organs other than the liver at the time of detection of the first metastases was not included. The size, and distribution, of metastatic lesions is an important prognostic factor in metastatic disease, and including this data in regression analyses could have potentially altered the results. However, the number of hepatic metastases, which is associated with the presence of miliary metastases, also has substantial prognostic value.\u003csup\u003e7,20,30\u003c/sup\u003e Thus, we believe that the absence of data on the size of the largest metastatic lesion, and the potential involvement of other organs, likely had a limited impact on our findings.\u003c/p\u003e\n\u003cp\u003eFinally, the statistical analyses used, including Kaplan-Meier and Cox proportional hazards regression, do not account for competing risks. However, given that only patients who died from metastatic uveal melanoma, and those who had been diagnosed with metastatic disease, were included, it is unlikely that competing risks would have significantly influenced survival estimates.\u003c/p\u003e"},{"header":"Conclusions","content":"\u003cp\u003eA higher AJCC stage at the time of primary tumor diagnosis is associated with shorter survival in uveal melanoma patients who develop metastases. This relationship remains significant even when survival is assessed from the time of metastasis detection and after adjusting for the number of hepatic metastases present at that time. These findings indicate that primary tumor treatment, by preventing the tumor from progressing to a more advanced AJCC stage, may provide a survival benefit by potentially reducing the aggressiveness and growth rate of subsequent metastases.\u003c/p\u003e"},{"header":"METHODS","content":"\u003cp\u003e\u003cstrong\u003eAim of the study\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe aim of this study was to examine the prognostic implication of uveal melanoma stage at the time of primary tumor diagnosis for patients who die from metastatic disease.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePatients and study design\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePrimary Diagnosis to Metastatic Death Cohort (PDMD)\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe re-analyzed anonymized and openly available data from a previously published study that included consecutive patients from three international institutions.\u003csup\u003e24\u003c/sup\u003e\u003c/p\u003e\n\u003cp\u003eInclusion criteria:\u003c/p\u003e\n\u003cp\u003e1.\u0026nbsp; \u0026nbsp;Clinically or histopathologically confirmed diagnosis of choroidal and/or ciliary body melanoma.\u003c/p\u003e\n\u003cp\u003e2.\u0026nbsp; \u0026nbsp;Availability of complete clinical information, including patient age and sex, largest basal diameter (LBD) of the tumor, tumor thickness, ciliary body involvement (CBI), extraocular extension (EXE \u0026le;5 mm or \u0026gt;5 mm), length of follow-up, and vital status at the last follow-up.\u003c/p\u003e\n\u003cp\u003eExclusion criteria:\u003c/p\u003e\n\u003cp\u003e1.\u0026nbsp; \u0026nbsp;Iris melanoma (patients with melanomas believed to have originated in the choroid or ciliary body with secondary infiltration into the iris were included. The primary site of the tumor was determined by the geometric center, assessed using B-scan ultrasonography, ultrasound biomicroscopy, wide-field retinal imaging, slit-lamp biomicroscopy, or a combination of these methods. These patients were excluded by design in the original publication).\u003c/p\u003e\n\u003cp\u003e2.\u0026nbsp; \u0026nbsp;Metastatic disease present at the time of primary tumor diagnosis (these patients were excluded by design in the original publication).\u003c/p\u003e\n\u003cp\u003e3.\u0026nbsp; \u0026nbsp;Patient alive, or death attributed to causes other than metastatic uveal melanoma (\u003cem\u003en\u003c/em\u003e=5037), as verified through cause of death registries or medical records.\u003c/p\u003e\n\u003cp\u003eTumor size and anatomical extent data at the time of primary tumor diagnosis were used to assign an AJCC stage to each of the remaining 1491 patients.\u003csup\u003e31\u003c/sup\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMetastasis Detection to Death Cohort (MDD)\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe also collected data on all patients who developed metastatic disease after being diagnosed with primary uveal melanoma at either the Erasmus University Medical Center and the Rotterdam Eye Hospital, Rotterdam, The Netherlands, between 1993 and 2021, or the Ocular Oncology Service, St. Erik Eye Hospital, Stockholm, Sweden, between 1980 and 2021. A total of 643 patients met the following inclusion criteria:\u003c/p\u003e\n\u003cp\u003eInclusion criteria:\u003c/p\u003e\n\u003cp\u003e1.\u0026nbsp; \u0026nbsp;Data available in treatment registries at the respective institution.\u003c/p\u003e\n\u003cp\u003e2.\u0026nbsp; \u0026nbsp;Clinically or histopathologically confirmed diagnosis of choroidal and/or ciliary body melanoma at the time of primary tumor diagnosis.\u003c/p\u003e\n\u003cp\u003e3.\u0026nbsp; \u0026nbsp;Enrollment in a surveillance program with periodic liver examinations for a minimum of 5 years after primary tumor diagnosis (using contrast-enhanced ultrasound, computed tomography [CT], or magnetic resonance imaging [MRI]).\u003c/p\u003e\n\u003cp\u003e4.\u0026nbsp; \u0026nbsp;Radiologically detected metastases in the liver and/or other organs.\u003c/p\u003e\n\u003cp\u003e5.\u0026nbsp; \u0026nbsp;Availability of CT or MRI images.\u003c/p\u003e\n\u003cp\u003eExclusion criteria:\u003c/p\u003e\n\u003cp\u003e1.\u0026nbsp; \u0026nbsp;Iris melanoma (\u003cem\u003en\u003c/em\u003e=0).\u003c/p\u003e\n\u003cp\u003e2.\u0026nbsp; \u0026nbsp;Lack of recorded primary tumor thickness or LBD at the time of primary tumor diagnosis (\u003cem\u003en\u003c/em\u003e=29).\u003c/p\u003e\n\u003cp\u003e3.\u0026nbsp; \u0026nbsp;Unknown anatomical extent, specifically CBI or EXE, at the time of primary tumor diagnosis (\u003cem\u003en\u003c/em\u003e=0).\u003c/p\u003e\n\u003cp\u003e4.\u0026nbsp; \u0026nbsp;Unrecorded location of metastases (\u003cem\u003en\u003c/em\u003e=51).\u003c/p\u003e\n\u003cp\u003e5.\u0026nbsp; \u0026nbsp;Uncertain exact date of radiological detection of metastases, including cases where dates were not specified in referrals, medical notes, or radiological image files, or where the diagnosis was indeterminable due to unclear findings in one exam followed by an established diagnosis in a subsequent exam (\u003cem\u003en\u003c/em\u003e=213).\u003c/p\u003e\n\u003cp\u003eAfter applying these criteria, 350 patients remained in the final cohort, of which 129 were from Rotterdam and 221 from Stockholm. The date of the first radiological detection of metastases was used as the date of metastasis. Data on the number of patients who underwent biopsy for histopathological confirmation of metastases were not available. Of the 129 patients from Rotterdam, 123 were included in a previous study, with metastases to the liver being observed in 96% of cases.\u003csup\u003e20\u003c/sup\u003e For the 123 patients in the Rotterdam sample, and for 21 of the patients in the Stockholm samle, data were available on the number of metastases present at the initial CT or MRI scan when the first metastases were observed.\u003c/p\u003e\n\u003cp\u003eThe study was approved by the Swedish Ethical Review Authority (reference 2023-07537-02) and adhered to the tenets of the Declaration of Helsinki. Informed consent was waived by the Swedish Ethical Review Authority because the study relied on retrospective, pre-collected data. No sensitive information was shared between the institutions, and no new collection of identifiable information was conducted, including patients\u0026apos; names, identification numbers, addresses, contact details, or photographs. No interventions, testing, or examinations were performed, and no analyses of biological tissues were conducted.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStatistical analyses\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eStatistical significance was defined as \u003cem\u003eP\u003c/em\u003e\u0026lt;0.05, and all \u003cem\u003eP\u003c/em\u003e values were two-sided. Holm-Bonferroni corrections were applied to all reported \u003cem\u003eP\u003c/em\u003e values. Kaplan-Meier survival curves were generated, and multivariate and time-varying Cox regression analyses were performed using the survival and survminer packages in R (version 4.4.1, The R Foundation for Statistical Computing, Vienna, Austria). Survival distributions across AJCC stages at primary tumor diagnosis were compared using the log-rank test for trend. To examine the transition dynamics from primary tumor diagnosis to metastasis detection and subsequent death, a Markov multi-state model was constructed using the mstate and survival packages in R. The proportional hazards assumption was assessed by inspecting log-minus-log survival curves; the assumption was considered satisfied if the curves were parallel and did not cross. Tumor volume was estimated using a formula consistent with previously described methods, where LBD represents the largest basal tumor diameter:\u003csup\u003e32,33\u003c/sup\u003e\u003c/p\u003e\n\u003cp\u003e\u003csup\u003e\u003cimg src=\"data:image/png;base64,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\"\u003e\u003c/sup\u003e\u003cbr\u003e\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eSupport for this study was provided to Gustav St\u0026aring;lhammar from:\u003c/p\u003e\n\u003cul\u003e\n \u003cli\u003eRegion Stockholm (RS-2019-1138)\u003c/li\u003e\n \u003cli\u003eThe Swedish Cancer Society (20 0798 Fk)\u003c/li\u003e\n \u003cli\u003eThe Crown Princess Margareta Foundation for the Visually Impaired (2022-017)\u003c/li\u003e\n \u003cli\u003eKarolinska Institutet (2022-01671)\u003c/li\u003e\n \u003cli\u003eThe Swedish Eye Foundation (2022-05-09)\u003c/li\u003e\n\u003c/ul\u003e\n\u003cp\u003eThe sponsors or funding organizations had no role in the design or conduct of this study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSerdar Yavuzyigitoglu\u003c/strong\u003e: Conceptualization, Methodology, Data curation, Investigation, Resources, Writing \u0026ndash; Reviewing and Editing. \u003cstrong\u003eShiva Sabazade\u003c/strong\u003e: Writing- Reviewing and Editing, Validation. \u003cstrong\u003eViktor Gill\u003c/strong\u003e: Writing- Reviewing and Editing, Validation. \u003cstrong\u003eErwin Brosens\u003c/strong\u003e: Supervision, Writing \u0026ndash; Reviewing and Editing. \u003cstrong\u003eEmine Kili\u0026ccedil;\u003c/strong\u003e:Methodology, Data curation, Project Administration.\u003cstrong\u003e\u0026nbsp;Gustav St\u0026aring;lhammar\u003c/strong\u003e: Conceptualization, Methodology, Formal analysis, Investigation, Writing -Original Draft, Visualization, Supervision.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData availability statement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe data for the PDMD cohort is based on information that can be inferred from a previously published, openly accessible article (https://doi.org/10.1016/j.ophtha.2023.10.026). No new data was collected for this study. The data for the MDD cohort, including the Rotterdam and Stockholm samples, is available upon reasonable request from the corresponding author, subject to approval from the Swedish Ethical Review Authority.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAdditional information, competing interests statement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNo conflicting relationship exists for any author.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n \u003cli\u003eLane, A. M., Kim, I. K. \u0026amp; Gragoudas, E. S. Survival Rates in Patients After Treatment for Metastasis From Uveal Melanoma. \u003cem\u003eJAMA ophthalmology\u003c/em\u003e \u003cstrong\u003e136\u003c/strong\u003e, 981 (2018). https://doi.org:10.1001/jamaophthalmol.2018.2466\u003c/li\u003e\n \u003cli\u003eStalhammar, G. 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Age, survival predictors, and metastatic death in patients with choroidal melanoma: tentative evidence of a therapeutic effect on survival. \u003cem\u003eJAMA Ophthalmol\u003c/em\u003e \u003cstrong\u003e132\u003c/strong\u003e, 605-613 (2014). https://doi.org:10.1001/jamaophthalmol.2014.77\u003c/li\u003e\n \u003cli\u003eMariani, P.\u003cem\u003e\u0026nbsp;et al.\u003c/em\u003e Development of a Prognostic Nomogram for Liver Metastasis of Uveal Melanoma Patients Selected by Liver MRI. \u003cem\u003eCancers (Basel)\u003c/em\u003e \u003cstrong\u003e11\u003c/strong\u003e (2019). https://doi.org:10.3390/cancers11060863\u003c/li\u003e\n \u003cli\u003eValpione, S.\u003cem\u003e\u0026nbsp;et al.\u003c/em\u003e Development and external validation of a prognostic nomogram for metastatic uveal melanoma. \u003cem\u003ePLoS One\u003c/em\u003e \u003cstrong\u003e10\u003c/strong\u003e, e0120181 (2015). https://doi.org:10.1371/journal.pone.0120181\u003c/li\u003e\n \u003cli\u003eEskelin, S., Pyrhonen, S., Hahka-Kemppinen, M., Tuomaala, S. \u0026amp; Kivela, T. A prognostic model and staging for metastatic uveal melanoma. \u003cem\u003eCancer\u003c/em\u003e \u003cstrong\u003e97\u003c/strong\u003e, 465-475 (2003). https://doi.org:10.1002/cncr.11113\u003c/li\u003e\n \u003cli\u003eRietschel, P.\u003cem\u003e\u0026nbsp;et al.\u003c/em\u003e Variates of survival in metastatic uveal melanoma. \u003cem\u003eJ Clin Oncol\u003c/em\u003e \u003cstrong\u003e23\u003c/strong\u003e, 8076-8080 (2005). https://doi.org:10.1200/JCO.2005.02.6534\u003c/li\u003e\n \u003cli\u003eDamato, B. \u0026amp; Coupland, S. E. A reappraisal of the significance of largest basal diameter of posterior uveal melanoma. \u003cem\u003eEye (Lond)\u003c/em\u003e \u003cstrong\u003e23\u003c/strong\u003e, 2152-2160; quiz 2161-2152 (2009). https://doi.org:10.1038/eye.2009.235-cme/eye.2009.235\u003c/li\u003e\n \u003cli\u003eRantala, E. S.\u003cem\u003e\u0026nbsp;et al.\u003c/em\u003e Determinants of Long-Term Survival in Metastatic Choroidal and Ciliary Body Melanoma. \u003cem\u003eAm J Ophthalmol\u003c/em\u003e \u003cstrong\u003e246\u003c/strong\u003e, 258-272 (2023). https://doi.org:10.1016/j.ajo.2022.10.017\u003c/li\u003e\n \u003cli\u003eKodjikian, L.\u003cem\u003e\u0026nbsp;et al.\u003c/em\u003e Prognostic factors of liver metastases from uveal melanoma. \u003cem\u003eGraefes Arch Clin Exp Ophthalmol\u003c/em\u003e \u003cstrong\u003e243\u003c/strong\u003e, 985-993 (2005). https://doi.org:10.1007/s00417-005-1188-8\u003c/li\u003e\n \u003cli\u003eGrisanti, S.\u003cem\u003e\u0026nbsp;et al.\u003c/em\u003e Detection of Circulating Tumor Cells in Patients with Small Choroidal Melanocytic Lesions. \u003cem\u003eOphthalmology\u003c/em\u003e \u003cstrong\u003e130\u003c/strong\u003e, 1290-1303 (2023). https://doi.org:10.1016/j.ophtha.2023.07.025\u003c/li\u003e\n \u003cli\u003eGill, V. T.\u003cem\u003e\u0026nbsp;et al.\u003c/em\u003e Multiorgan Involvement of Dormant Uveal Melanoma Micrometastases in Postmortem Tissue From Patients Without Coexisting Macrometastases. \u003cem\u003eAm J Clin Pathol\u003c/em\u003e \u003cstrong\u003e160\u003c/strong\u003e, 160-174 (2023). https://doi.org:10.1093/ajcp/aqad029\u003c/li\u003e\n \u003cli\u003eEide, N.\u003cem\u003e\u0026nbsp;et al.\u003c/em\u003e The Results of Stricter Inclusion Criteria in an Immunomagnetic Detection Study of Micrometastatic Cells in Bone Marrow of Uveal Melanoma Patients - Relevance for Dormancy. \u003cem\u003ePathol Oncol Res\u003c/em\u003e \u003cstrong\u003e25\u003c/strong\u003e, 255-262 (2019). https://doi.org:10.1007/s12253-017-0355-7\u003c/li\u003e\n \u003cli\u003eShields, C. L.\u003cem\u003e\u0026nbsp;et al.\u003c/em\u003e American Joint Committee on Cancer Classification of Uveal Melanoma (Anatomic Stage) Predicts Prognosis in 7,731 Patients: The 2013 Zimmerman Lecture. \u003cem\u003eOphthalmology\u003c/em\u003e \u003cstrong\u003e122\u003c/strong\u003e, 1180-1186 (2015). https://doi.org:10.1016/j.ophtha.2015.01.026\u003c/li\u003e\n \u003cli\u003eField, M. G.\u003cem\u003e\u0026nbsp;et al.\u003c/em\u003e Punctuated evolution of canonical genomic aberrations in uveal melanoma. \u003cem\u003eNat Commun\u003c/em\u003e \u003cstrong\u003e9\u003c/strong\u003e, 116 (2018). https://doi.org:10.1038/s41467-017-02428-w\u003c/li\u003e\n \u003cli\u003eStalhammar, G. \u0026amp; Gill, V. T. Digital morphometry and cluster analysis identifies four types of melanocyte during uveal melanoma progression. \u003cem\u003eCommun Med (Lond)\u003c/em\u003e \u003cstrong\u003e3\u003c/strong\u003e, 60 (2023). https://doi.org:10.1038/s43856-023-00291-z\u003c/li\u003e\n \u003cli\u003eYavuzyigitoglu, S.\u003cem\u003e\u0026nbsp;et al.\u003c/em\u003e Radiological Patterns of Uveal Melanoma Liver Metastases in Correlation to Genetic Status. \u003cem\u003eCancers (Basel)\u003c/em\u003e \u003cstrong\u003e13\u003c/strong\u003e (2021). https://doi.org:10.3390/cancers13215316\u003c/li\u003e\n \u003cli\u003eStalhammar, G. Delays between Uveal Melanoma Diagnosis and Treatment Increase the Risk of Metastatic Death. \u003cem\u003eOphthalmology\u003c/em\u003e \u003cstrong\u003e131\u003c/strong\u003e, 1094-1104 (2023). https://doi.org:10.1016/j.ophtha.2023.11.021\u003c/li\u003e\n \u003cli\u003eStalhammar, G. \u0026amp; Gill, V. T. The long-term prognosis of patients with untreated primary uveal melanoma: A systematic review and meta-analysis. \u003cem\u003eCrit Rev Oncol Hematol\u003c/em\u003e \u003cstrong\u003e172\u003c/strong\u003e, 103652 (2022). https://doi.org:10.1016/j.critrevonc.2022.103652\u003c/li\u003e\n \u003cli\u003eDamato, B.\u003cem\u003e\u0026nbsp;et al.\u003c/em\u003e Deferral of Treatment for Small Choroidal Melanoma and the Risk of Metastasis: An Investigation Using the Liverpool Uveal Melanoma Prognosticator Online (LUMPO). \u003cem\u003eCancers (Basel)\u003c/em\u003e \u003cstrong\u003e16\u003c/strong\u003e (2024). https://doi.org:10.3390/cancers16081607\u003c/li\u003e\n \u003cli\u003eStalhammar, G.\u003cem\u003e\u0026nbsp;et al.\u003c/em\u003e Improved Staging of Ciliary Body and Choroidal Melanomas Based on Estimation of Tumor Volume and Competing Risk Analyses. \u003cem\u003eOphthalmology\u003c/em\u003e \u003cstrong\u003e131\u003c/strong\u003e, 478-491 (2023). https://doi.org:10.1016/j.ophtha.2023.10.026\u003c/li\u003e\n \u003cli\u003eHagstr\u0026ouml;m, A., Witzenhausen, H. \u0026amp; St\u0026aring;lhammar, G. Tailoring Surveillance Imaging in Uveal Melanoma Based on Individual Metastatic Risk. \u003cem\u003eCanadian Journal of Ophthalmology/Journal canadien d\u0026apos;ophtalmologie\u003c/em\u003e (2024). https://doi.org:https://doi.org/10.1016/j.jcjo.2024.07.014\u003c/li\u003e\n \u003cli\u003eDamato, B. Does ocular treatment of uveal melanoma influence survival? \u003cem\u003eBritish Journal of Cancer\u003c/em\u003e \u003cstrong\u003e103\u003c/strong\u003e, 285 (2010). https://doi.org:10.1038/sj.bjc.6605765\u003c/li\u003e\n \u003cli\u003eEskelin, S., Pyrh\u0026ouml;nen, S., Summanen, P., Hahka-Kemppinen, M. \u0026amp; Kivel\u0026auml;, T. Tumor doubling times in metastatic malignant melanoma of the uvea: tumor progression before and after treatment. \u003cem\u003eOphthalmology\u003c/em\u003e \u003cstrong\u003e107\u003c/strong\u003e, 1443-1449 (2000). https://doi.org:10.1016/s0161-6420(00)00182-2\u003c/li\u003e\n \u003cli\u003eKujala, E., M\u0026auml;kitie, T. \u0026amp; Kivel\u0026auml;, T. Very long-term prognosis of patients with malignant uveal melanoma. \u003cem\u003eInvest Ophthalmol Vis Sci\u003c/em\u003e \u003cstrong\u003e44\u003c/strong\u003e, 4651-4659 (2003).\u003c/li\u003e\n \u003cli\u003eDecatur, C. L.\u003cem\u003e\u0026nbsp;et al.\u003c/em\u003e Driver Mutations in Uveal Melanoma: Associations With Gene Expression Profile and Patient Outcomes. \u003cem\u003eJAMA Ophthalmol\u003c/em\u003e \u003cstrong\u003e134\u003c/strong\u003e, 728-733 (2016). https://doi.org:10.1001/jamaophthalmol.2016.0903\u003c/li\u003e\n \u003cli\u003eMariani, P.\u003cem\u003e\u0026nbsp;et al.\u003c/em\u003e Surgical management of liver metastases from uveal melanoma: 16 years\u0026apos; experience at the Institut Curie. \u003cem\u003eEur J Surg Oncol\u003c/em\u003e \u003cstrong\u003e35\u003c/strong\u003e, 1192-1197 (2009). https://doi.org:10.1016/j.ejso.2009.02.016\u003c/li\u003e\n \u003cli\u003eKivel\u0026auml;, T.\u003cem\u003e\u0026nbsp;et al.\u003c/em\u003e in \u003cem\u003eAJCC Cancer Staging Manual\u003c/em\u003e Ch. 67, 805-817 (Springer, 2017).\u003c/li\u003e\n \u003cli\u003eRichtig, E., Langmann, G., Mullner, K., Richtig, G. \u0026amp; Smolle, J. Calculated tumour volume as a prognostic parameter for survival in choroidal melanomas. \u003cem\u003eEye (Lond)\u003c/em\u003e \u003cstrong\u003e18\u003c/strong\u003e, 619-623 (2004). https://doi.org:10.1038/sj.eye.6700720\u003c/li\u003e\n \u003cli\u003eUner, O. E., See, T. R. O., Szalai, E., Grossniklaus, H. E. \u0026amp; Stalhammar, G. Estimation of the timing of BAP1 mutation in uveal melanoma progression. \u003cem\u003eSci Rep\u003c/em\u003e \u003cstrong\u003e11\u003c/strong\u003e, 8923 (2021). https://doi.org:10.1038/s41598-021-88390-6\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003e\u003cstrong\u003eTable 1:\u0026nbsp;\u003c/strong\u003eCharacteristics of Included Patients and Tumors at the Time of Primary Tumor Diagnosis\u0026nbsp;\u003c/p\u003e\n\u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\" width=\"520\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 87px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd style=\"width: 87px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 173px;\"\u003e\n \u003cp\u003e\u003cstrong\u003ePDMD, \u003cem\u003en\u003c/em\u003e=1491\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 173px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eMDD, \u003cem\u003en\u003c/em\u003e=350\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 87px;\"\u003e\n \u003cp\u003e\u003cstrong\u003ePotential Prognostic Variable\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 87px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eCategory of Variable\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 87px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eNumber of Cases\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 87px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e(%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 87px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eNumber of Cases\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 87px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e(%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 87px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eSex\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 87px;\"\u003e\n \u003cp\u003eFemale\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 87px;\"\u003e\n \u003cp\u003e688\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 87px;\"\u003e\n \u003cp\u003e46\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 87px;\"\u003e\n \u003cp\u003e179\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 87px;\"\u003e\n \u003cp\u003e51\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 87px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd style=\"width: 87px;\"\u003e\n \u003cp\u003eMale\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 87px;\"\u003e\n \u003cp\u003e803\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 87px;\"\u003e\n \u003cp\u003e54\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 87px;\"\u003e\n \u003cp\u003e171\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 87px;\"\u003e\n \u003cp\u003e49\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 87px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eAJCC T-category*\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 87px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd style=\"width: 87px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd style=\"width: 87px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd style=\"width: 87px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd style=\"width: 87px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 87px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd style=\"width: 87px;\"\u003e\n \u003cp\u003eT1a\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 87px;\"\u003e\n \u003cp\u003e141\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 87px;\"\u003e\n \u003cp\u003e9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 87px;\"\u003e\n \u003cp\u003e54\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 87px;\"\u003e\n \u003cp\u003e15\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 87px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd style=\"width: 87px;\"\u003e\n \u003cp\u003eT1b\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 87px;\"\u003e\n \u003cp\u003e13\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 87px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 87px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 87px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 87px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd style=\"width: 87px;\"\u003e\n \u003cp\u003eT1c\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 87px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 87px;\"\u003e\n \u003cp\u003e\u0026lt;1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 87px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 87px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 87px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd style=\"width: 87px;\"\u003e\n \u003cp\u003eT1d\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 87px;\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 87px;\"\u003e\n \u003cp\u003e\u0026lt;1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 87px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 87px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 87px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd style=\"width: 87px;\"\u003e\n \u003cp\u003eT2a\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 87px;\"\u003e\n \u003cp\u003e360\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 87px;\"\u003e\n \u003cp\u003e24\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 87px;\"\u003e\n \u003cp\u003e126\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 87px;\"\u003e\n \u003cp\u003e36\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 87px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd style=\"width: 87px;\"\u003e\n \u003cp\u003eT2b\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 87px;\"\u003e\n \u003cp\u003e49\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 87px;\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 87px;\"\u003e\n \u003cp\u003e12\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 87px;\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 87px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd style=\"width: 87px;\"\u003e\n \u003cp\u003eT2c\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 87px;\"\u003e\n \u003cp\u003e14\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 87px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 87px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 87px;\"\u003e\n \u003cp\u003e\u0026lt;1\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 87px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd style=\"width: 87px;\"\u003e\n \u003cp\u003eT2d\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 87px;\"\u003e\n \u003cp\u003e8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 87px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 87px;\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 87px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 87px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd style=\"width: 87px;\"\u003e\n \u003cp\u003eT3a\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 87px;\"\u003e\n \u003cp\u003e325\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 87px;\"\u003e\n \u003cp\u003e22\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 87px;\"\u003e\n \u003cp\u003e95\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 87px;\"\u003e\n \u003cp\u003e27\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 87px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd style=\"width: 87px;\"\u003e\n \u003cp\u003eT3b\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 87px;\"\u003e\n \u003cp\u003e205\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 87px;\"\u003e\n \u003cp\u003e14\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 87px;\"\u003e\n \u003cp\u003e18\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 87px;\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 87px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd style=\"width: 87px;\"\u003e\n \u003cp\u003eT3c\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 87px;\"\u003e\n \u003cp\u003e22\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 87px;\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 87px;\"\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 87px;\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 87px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd style=\"width: 87px;\"\u003e\n \u003cp\u003eT3d\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 87px;\"\u003e\n \u003cp\u003e48\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 87px;\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 87px;\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 87px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 87px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd style=\"width: 87px;\"\u003e\n \u003cp\u003eT4a\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 87px;\"\u003e\n \u003cp\u003e86\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 87px;\"\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 87px;\"\u003e\n \u003cp\u003e23\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 87px;\"\u003e\n \u003cp\u003e7\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 87px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd style=\"width: 87px;\"\u003e\n \u003cp\u003eT4b\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 87px;\"\u003e\n \u003cp\u003e158\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 87px;\"\u003e\n \u003cp\u003e11\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 87px;\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 87px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 87px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd style=\"width: 87px;\"\u003e\n \u003cp\u003eT4c\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 87px;\"\u003e\n \u003cp\u003e20\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 87px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 87px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 87px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 87px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd style=\"width: 87px;\"\u003e\n \u003cp\u003eT4d\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 87px;\"\u003e\n \u003cp\u003e33\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 87px;\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 87px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 87px;\"\u003e\n \u003cp\u003e\u0026lt;1\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 87px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd style=\"width: 87px;\"\u003e\n \u003cp\u003eT4e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 87px;\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 87px;\"\u003e\n \u003cp\u003e\u0026lt;1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 87px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 87px;\"\u003e\n \u003cp\u003e\u0026lt;1\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 87px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eAJCC Stage*\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 87px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd style=\"width: 87px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd style=\"width: 87px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd style=\"width: 87px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd style=\"width: 87px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 87px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd style=\"width: 87px;\"\u003e\n \u003cp\u003eI\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 87px;\"\u003e\n \u003cp\u003e141\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 87px;\"\u003e\n \u003cp\u003e9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 87px;\"\u003e\n \u003cp\u003e54\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 87px;\"\u003e\n \u003cp\u003e15\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 87px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd style=\"width: 87px;\"\u003e\n \u003cp\u003eIIA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 87px;\"\u003e\n \u003cp\u003e377\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 87px;\"\u003e\n \u003cp\u003e25\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 87px;\"\u003e\n \u003cp\u003e126\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 87px;\"\u003e\n \u003cp\u003e36\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 87px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd style=\"width: 87px;\"\u003e\n \u003cp\u003eIIB\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 87px;\"\u003e\n \u003cp\u003e374\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 87px;\"\u003e\n \u003cp\u003e25\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 87px;\"\u003e\n \u003cp\u003e107\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 87px;\"\u003e\n \u003cp\u003e31\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 87px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd style=\"width: 87px;\"\u003e\n \u003cp\u003eIIIA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 87px;\"\u003e\n \u003cp\u003e335\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 87px;\"\u003e\n \u003cp\u003e23\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 87px;\"\u003e\n \u003cp\u003e51\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 87px;\"\u003e\n \u003cp\u003e15\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 87px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd style=\"width: 87px;\"\u003e\n \u003cp\u003eIIIB\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 87px;\"\u003e\n \u003cp\u003e226\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 87px;\"\u003e\n \u003cp\u003e15\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 87px;\"\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 87px;\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 87px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd style=\"width: 87px;\"\u003e\n \u003cp\u003eIIIC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 87px;\"\u003e\n \u003cp\u003e38\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 87px;\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 87px;\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 87px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e*At the time of primary tumor diagnosis. AJCC, American Joint Committee on Cancer. MDD, Metastasis Detection to Death Cohort. PDMD, Primary Diagnosis to Metastatic Death Cohort.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cstrong\u003eTable 2:\u0026nbsp;\u003c/strong\u003eMultivariate Cox Regression Analysis of Hazard Ratios for Death Among 1491 Patients Who Died from Metastatic Uveal Melanoma\u003c/strong\u003e\u003c/p\u003e\n\u003ctable border=\"0\" cellspacing=\"3\" cellpadding=\"0\" width=\"652\"\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 110px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eVariable\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 64px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026szlig;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 55px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eS.E.\u0026szlig;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 142px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eWald Test Statistic\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 62px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003eP\u003c/em\u003e\u003c/strong\u003e\u003cstrong\u003e\u003csup\u003e\u0026dagger;\u003c/sup\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 64px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eexp(\u0026szlig;)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 139px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e95% CI of exp(\u0026szlig;)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 110px;\"\u003e\n \u003cp\u003eAge\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 64px;\"\u003e\n \u003cp\u003e0.02\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 55px;\"\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 142px;\"\u003e\n \u003cp\u003e72.3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 62px;\"\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 64px;\"\u003e\n \u003cp\u003e1.02\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 139px;\"\u003e\n \u003cp\u003eLower: 1.01, Upper: 1.02\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 110px;\"\u003e\n \u003cp\u003eAJCC stage\u003csup\u003eb\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 64px;\"\u003e\n \u003cp\u003e0.22\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 55px;\"\u003e\n \u003cp\u003e0.02\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 142px;\"\u003e\n \u003cp\u003e107.4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 62px;\"\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 64px;\"\u003e\n \u003cp\u003e1.25\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 139px;\"\u003e\n \u003cp\u003eLower: 1.19, Upper: 1.30\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eAJCC, American Joint Committee on Cancer.\u003cstrong\u003e\u003csup\u003e\u0026nbsp;\u003c/sup\u003e\u003c/strong\u003e\u0026szlig;, beta coefficient computed by the Cox Proportional Hazards analysis. CI, Confidence interval. exp(\u0026szlig;), Exponentiated beta coefficient, representing the hazard ratio. S.E.\u0026szlig;, standard error of the beta coefficient. \u003csup\u003ea\u003c/sup\u003e Per increasing year at the time of primary tumor diagnosis.\u003csup\u003eb\u003c/sup\u003e At the time of primary tumor diagnosis, per increasing step from stage I to IIA, from stage IIA to IIB, from IIB to IIIA, etc. \u003cstrong\u003e\u003csup\u003e\u0026dagger;\u003c/sup\u003e\u003c/strong\u003eHolm-Bonferroni-corrected value.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 3:\u0026nbsp;\u003c/strong\u003eMultivariate Cox Regression Analyses of Hazard Ratios for Death in 350 Patients with Metastatic Uveal Melanoma\u003c/p\u003e\n\u003ctable border=\"0\" cellspacing=\"3\" cellpadding=\"0\"\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003eVariable\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026szlig;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003eS.E.\u0026szlig;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003eWald Test Statistic\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003eP\u003c/em\u003e\u003c/strong\u003e\u003cstrong\u003e\u003csup\u003e\u0026dagger;\u003c/sup\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003eexp(\u0026szlig;)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003e95% CI of exp(\u0026szlig;)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eAge\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.01\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.01\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e3.4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.06\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e1.01\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eLower: 1.00, Upper: 1.02\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eAJCC stage\u003csup\u003eb\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.50\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.06\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e75.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e1.66\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eLower: 1.48, Upper: 1.86\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eAJCC, American Joint Committee on Cancer.\u003cstrong\u003e\u003csup\u003e\u0026nbsp;\u003c/sup\u003e\u003c/strong\u003e\u0026szlig;, beta coefficient computed by the Cox Proportional Hazards analysis. CI, Confidence interval. exp(\u0026szlig;), Exponentiated beta coefficient, representing the hazard ratio. S.E.\u0026szlig;, standard error of the beta coefficient. \u003csup\u003ea\u003c/sup\u003e Per increasing year at the time of primary tumor diagnosis.\u003csup\u003eb\u003c/sup\u003e At the time of primary tumor diagnosis, per increasing step from stage I to IIA, from stage IIA to IIB, from IIB to IIIA, etc. \u003cstrong\u003e\u003csup\u003e\u0026dagger;\u003c/sup\u003e\u003c/strong\u003eHolm-Bonferroni-corrected value.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 4:\u003c/strong\u003e Multivariate Cox Regression Analyses of Hazard Ratios for Death in 144 Patients with Metastatic Uveal Melanoma, with the number of metastatic lesions at the time of detection of metastatic disease included as a time-varying covariate.\u003c/p\u003e\n\u003ctable border=\"0\" cellspacing=\"3\" cellpadding=\"0\" width=\"614\"\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 186px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eVariable\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 36px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026szlig;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 45px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eS.E.\u0026szlig;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 55px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003ez\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 64px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003eP\u003c/em\u003e\u003c/strong\u003e\u003cstrong\u003e\u003csup\u003e\u0026dagger;\u003c/sup\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 64px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eexp(\u0026szlig;)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 148px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e95% CI of exp(\u0026szlig;)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 186px;\"\u003e\n \u003cp\u003eAge\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 36px;\"\u003e\n \u003cp\u003e0.02\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 45px;\"\u003e\n \u003cp\u003e0.01\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 55px;\"\u003e\n \u003cp\u003e2.4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 64px;\"\u003e\n \u003cp\u003e0.02\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 64px;\"\u003e\n \u003cp\u003e1.02\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 148px;\"\u003e\n \u003cp\u003eLower: 1.00, Upper: 1.04\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 186px;\"\u003e\n \u003cp\u003eAJCC stage\u003csup\u003eb\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 36px;\"\u003e\n \u003cp\u003e0.23\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 45px;\"\u003e\n \u003cp\u003e0.09\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 55px;\"\u003e\n \u003cp\u003e2.6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 64px;\"\u003e\n \u003cp\u003e0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 64px;\"\u003e\n \u003cp\u003e1.26\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 148px;\"\u003e\n \u003cp\u003eLower: 1.06, Upper: 1.49\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 186px;\"\u003e\n \u003cp\u003eNumber of hepatic metastases\u003csup\u003ec\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 36px;\"\u003e\n \u003cp\u003e0.97\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 45px;\"\u003e\n \u003cp\u003e0.06\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 55px;\"\u003e\n \u003cp\u003e16.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 64px;\"\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 64px;\"\u003e\n \u003cp\u003e2.63\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 148px;\"\u003e\n \u003cp\u003eLower: 2.35, Upper: 2.96\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eAJCC, American Joint Committee on Cancer.\u003cem\u003e\u003csup\u003e\u0026nbsp;\u003c/sup\u003e\u003c/em\u003e\u0026szlig;, beta coefficient computed by the Cox Proportional Hazards analysis. CI, Confidence interval. exp(\u0026szlig;), Exponentiated beta coefficient, representing the hazard ratio. S.E.\u0026szlig;, standard error of the beta coefficient. z, Z-statistic, which is the test statistic for the null hypothesis that the corresponding coefficient is zero in the Cox proportional hazards model. \u003csup\u003ea\u003c/sup\u003e Per increasing year at the time of primary tumor diagnosis.\u003csup\u003eb\u003c/sup\u003e At the time of primary tumor diagnosis, per increasing step from stage I to IIA, from stage IIA to IIB, from IIB to IIIA, etc. \u003csup\u003ec\u003c/sup\u003e At the time of radiological detection of metastatic disease, per increasing step from a solitary metastasis to two to five, from two to five to six to ten, and from six to ten to \u0026gt;10 (time-varying covariate). \u003csup\u003e\u0026dagger;\u003c/sup\u003eHolm-Bonferroni-corrected value.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 5:\u003c/strong\u003e Markov Multi-state Model hazard Ratios for Transition Dynamics in Uveal Melanoma\u003c/p\u003e\n\u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 198px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eTransition\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 217px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eCovariate\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eHR\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 180px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e95% CI of HR\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003eP\u003c/em\u003e\u003c/strong\u003e\u003cstrong\u003e\u003csup\u003e\u0026dagger;\u003c/sup\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 118px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eConcordance\u003csup\u003e\u0026Dagger;\u003c/sup\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 198px;\"\u003e\n \u003cp\u003eNon-metastatic to metastatic disease\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 217px;\"\u003e\n \u003cp\u003eAJCC stage\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e1.34\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 180px;\"\u003e\n \u003cp\u003eLower: 1.15, Upper: 1.55\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 118px;\"\u003e\n \u003cp\u003e0.55\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"2\" style=\"width: 198px;\"\u003e\n \u003cp\u003eMetastatic disease to death\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 217px;\"\u003e\n \u003cp\u003eAJCC stage\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e1.20\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 180px;\"\u003e\n \u003cp\u003eLower: 1.01, Upper: 1.43\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003e0.03\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" style=\"width: 118px;\"\u003e\n \u003cp\u003e0.64\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 217px;\"\u003e\n \u003cp\u003eNumber of hepatic metastases\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e1.36\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 180px;\"\u003e\n \u003cp\u003eLower: 1.14, Upper: 1.60\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eAJCC, American Joint Committee on Cancer.\u003cstrong\u003e\u003cem\u003e\u003csup\u003e\u0026nbsp;\u003c/sup\u003e\u003c/em\u003e\u003c/strong\u003eCI, Confidence Interval. HR, Hazard ratio. \u003csup\u003ea\u003c/sup\u003e At the time of primary tumor diagnosis, per increasing step from stage I to IIA, from stage IIA to IIB, from IIB to IIIA, etc.\u003csup\u003eb\u003c/sup\u003e At the time of radiological detection of metastatic disease, per increasing step from a solitary metastasis to two to five, from two to five to six to ten, and from six to ten to \u0026gt;10. \u003cstrong\u003e\u003csup\u003e\u0026dagger;\u003c/sup\u003e\u003c/strong\u003eHolm-Bonferroni-corrected value. \u003csup\u003e\u0026Dagger;\u003c/sup\u003eC-index, a measure of model performance; higher values indicate better predictive accuracy.\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Uveal melanoma, Choroidal melanoma, Stage, Survival, Metastasis, Prognosis","lastPublishedDoi":"10.21203/rs.3.rs-4521528/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4521528/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eIn theory, a more advanced American Joint Committee on Cancer (AJCC) stage at the time of primary tumor diagnosis could correlate with shorter survival in metastatic uveal melanoma. However, this association has only been evaluated in relatively small cohorts. To address this, we investigated the prognostic relationship between AJCC stage and survival in a large cohort of patients who died from metastatic uveal melanoma. Among 1491 real-world patients, a higher AJCC stage at the time of primary tumor diagnosis was significantly associated with shorter survival. This association persisted even when the analysis was restricted to 350 patients already at stage IV, where a higher AJCC stage at primary tumor diagnosis continued to correlate with shorter survival (Log-rank test for trend, \u003cem\u003eP\u003c/em\u003e\u0026lt; 0.001 for both comparisons). The relationship remained significant in multivariate Cox regression models, which included patient age as a covariate and the number of hepatic metastases upon detection of metastatic disease as a time-varying covariate, as well as in a Markov multi-state model. These findings suggest that primary tumor treatment, by preventing the tumor from advancing to a higher AJCC stage, may confer a survival benefit by potentially reducing the aggressiveness and growth rate of subsequent metastases.\u003c/p\u003e","manuscriptTitle":"Indications of a Survival Benefit from Primary Tumor Treatment in Uveal Melanoma: Association Between initial AJCC Stage and Metastatic Survival","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-02-05 09:10:45","doi":"10.21203/rs.3.rs-4521528/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"121b5ccb-7fea-4375-ae0e-afc2d9755572","owner":[],"postedDate":"February 5th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":43784886,"name":"Biological sciences/Cancer/Eye cancer"},{"id":43784887,"name":"Health sciences/Oncology/Surgical oncology"},{"id":43784888,"name":"Health sciences/Oncology"},{"id":43784889,"name":"Health sciences/Oncology/Cancer"},{"id":43784890,"name":"Health sciences/Oncology/Cancer/Skin cancer/Melanoma"}],"tags":[],"updatedAt":"2025-02-05T09:10:45+00:00","versionOfRecord":[],"versionCreatedAt":"2025-02-05 09:10:45","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-4521528","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4521528","identity":"rs-4521528","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}