{"entity":{"id":"metastasis-free-survival","kind":"term","name":"Metastasis-free survival (MFS)","aka":["MFS","metastasis free survival","time to first metastasis","distant metastasis-free survival","DMFS"],"tldr":"The time from joining a trial until a scan first shows the cancer has spread, or the man dies, whichever comes first. It is the endpoint that got three hormone drugs licensed for prostate cancer that had not yet spread, because waiting for deaths would have taken another decade.","summary":"Metastasis-free survival is a composite time-to-event endpoint: the interval from randomisation to the first radiographic evidence of distant metastasis or death from any cause, whichever occurs first. Its rise in prostate cancer solved a specific problem. In non-metastatic castration-resistant disease and in high-risk localised disease, overall survival takes ten to fifteen years to read out, by which time the control arm has received several treatments that did not exist when the trial opened. PCWG3 recommended time to first metastasis and time to progression as outcome measures for trials in the non-metastatic castration-resistant state for exactly this reason.\n\nThe surrogacy evidence is the ICECaP meta-analysis. Xie, Regan and colleagues collected individual patient data from 28 randomised trials in localised prostate cancer covering 28,905 patients, with metastasis-free survival evaluable in 12,712 patients from 19 trials after a median 10 years of follow-up. At the patient level Kendall's tau correlation with overall survival was 0.91; at the trial level, the correlation of treatment effects measured as log hazard ratios was R squared 0.92 (95 percent confidence interval 0.81 to 0.95), against 0.73 for disease-free survival. That is a strong surrogate by the two-stage meta-analytic standard, and it is the reason regulators accepted the endpoint.\n\nThe definition differs between trials, which is the part that matters when two numbers are compared. It is set by each protocol, not by a single standards body, and the three things that vary are the imaging used, who reads it and what counts as an event. SPARTAN defined metastasis-free survival as the time from randomisation to the first detection of distant metastasis on imaging or death, in men with non-metastatic castration-resistant disease and a prostate-specific antigen doubling time of 10 months or less, with conventional imaging (technetium bone scan and computed tomography) read by blinded independent central review; median metastasis-free survival was 40.5 months with apalutamide against 16.2 months with placebo (hazard ratio 0.28; 95 percent confidence interval 0.23 to 0.35). Conventional imaging is doing the work in all of these trials. PSMA PET finds metastatic disease that a bone scan cannot see, so a man classified as non-metastatic in 2018 would often be classified as metastatic in 2026, and the ninth edition of TNM now asks that such a finding be recorded as M1(PET). Metastasis-free survival figures measured on bone scan and on PSMA PET are not the same quantity and should not be pooled.","asOf":"2026-09-25","links":[{"label":"Xie et al., Journal of Clinical Oncology 2017 (ICECaP): metastasis-free survival is a strong surrogate of overall survival in localized prostate cancer","url":"https://doi.org/10.1200/jco.2017.73.9987"},{"label":"Smith et al., New England Journal of Medicine 2018 (SPARTAN): apalutamide treatment and metastasis-free survival in prostate cancer","url":"https://doi.org/10.1056/nejmoa1715546"},{"label":"Scher et al., Journal of Clinical Oncology 2016 (PCWG3): trial design and objectives for castration-resistant prostate cancer, updated recommendations","url":"https://doi.org/10.1200/jco.2015.64.2702"}],"tags":["gu","prostate-glossary"],"related":["radiographic-progression-free-survival","psa-doubling-time","prosper","aramis","embark","hazard-ratio"],"cancers":["prostate","prostate-high-risk","prostate-bcr","prostate-nmcrpc","prostate-mhspc"],"sections":["hormonal","imaging"],"technologies":["psma-pet","pet"],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":["radiographic-progression-free-survival","psa-doubling-time","hazard-ratio","castration-resistance","biochemical-recurrence","tnm-prostate-cancer"],"trials":[],"people":[],"bottlenecks":["b-trial-design","b-regulatory-fragmentation","b-early-detection"],"keyPapers":["paper-uspstf-prostate-screening-jama-2018"],"journals":[],"dependsOn":[],"notes":["Who defines it: the protocol, not a standards body. PCWG3 recommends time to first metastasis as an outcome measure in the non-metastatic castration-resistant state but does not impose a single operational definition, so each trial specifies its own imaging schedule, its own reader (investigator or blinded independent central review) and its own handling of death without metastasis. Reading two metastasis-free survival numbers side by side means reading two protocols.","Metastasis-free survival counts death from any cause as an event, which is what makes it a survival endpoint rather than a progression endpoint. In an elderly population with substantial other-cause mortality, a meaningful share of the events are deaths without metastasis, and a drug that delays metastasis without affecting mortality will show a smaller effect than the imaging alone would suggest.","Do not confuse it with radiographic progression-free survival. Metastasis-free survival is used where there is no measurable metastatic disease yet and asks when the first deposit appears. Radiographic progression-free survival is used where metastatic disease already exists and asks when it grows or spreads further."],"category":"Endpoints"},"route":"/terms/metastasis-free-survival/","neighbours":{"term":[{"id":"biochemical-recurrence","kind":"term","name":"Biochemical recurrence (BCR)","route":"/terms/biochemical-recurrence/"},{"id":"castration-resistance","kind":"term","name":"Castration-resistant prostate cancer (CRPC)","route":"/terms/castration-resistance/"},{"id":"hazard-ratio","kind":"term","name":"Hazard ratio (HR)","route":"/terms/hazard-ratio/"},{"id":"psa-doubling-time","kind":"term","name":"PSA doubling time","route":"/terms/psa-doubling-time/"},{"id":"radiographic-progression-free-survival","kind":"term","name":"Radiographic progression-free survival (rPFS)","route":"/terms/radiographic-progression-free-survival/"},{"id":"tnm-prostate-cancer","kind":"term","name":"TNM staging for prostate cancer, and what changed in the 9th edition","route":"/terms/tnm-prostate-cancer/"}],"trial":[{"id":"aramis","kind":"trial","name":"ARAMIS","route":"/trials/aramis/"},{"id":"embark","kind":"trial","name":"EMBARK","route":"/trials/embark/"},{"id":"prosper","kind":"trial","name":"PROSPER","route":"/trials/prosper/"}],"cancer":[{"id":"prostate-bcr","kind":"cancer","name":"Biochemical recurrence of prostate cancer","route":"/cancers/prostate-bcr/"},{"id":"prostate-high-risk","kind":"cancer","name":"Localised prostate cancer, high and very high risk","route":"/cancers/prostate-high-risk/"},{"id":"prostate-mhspc","kind":"cancer","name":"Metastatic hormone-sensitive prostate cancer","route":"/cancers/prostate-mhspc/"},{"id":"prostate-nmcrpc","kind":"cancer","name":"Non-metastatic castration-resistant prostate cancer","route":"/cancers/prostate-nmcrpc/"},{"id":"prostate","kind":"cancer","name":"Prostate cancer","route":"/cancers/prostate/"}],"section":[{"id":"hormonal","kind":"section","name":"Hormonal Therapy","route":"/fronts/hormonal/"},{"id":"imaging","kind":"section","name":"Imaging","route":"/fronts/imaging/"}],"technology":[{"id":"pet","kind":"technology","name":"PET (positron emission tomography)","route":"/technologies/pet/"},{"id":"psma-pet","kind":"technology","name":"PSMA PET","route":"/technologies/psma-pet/"}],"bottleneck":[{"id":"b-regulatory-fragmentation","kind":"bottleneck","name":"Regulatory divergence between regions","route":"/bottlenecks/b-regulatory-fragmentation/"},{"id":"b-early-detection","kind":"bottleneck","name":"The hardest cancers are found late","route":"/bottlenecks/b-early-detection/"},{"id":"b-trial-design","kind":"bottleneck","name":"Trial design, endpoints and cost","route":"/bottlenecks/b-trial-design/"}],"paper":[{"id":"paper-beer-prevail-enzalutamide-nejm-2014","kind":"paper","name":"PREVAIL: enzalutamide in metastatic prostate cancer before chemotherapy","route":"/key-papers/paper-beer-prevail-enzalutamide-nejm-2014/"},{"id":"paper-uspstf-prostate-screening-jama-2018","kind":"paper","name":"USPSTF 2018: screening for prostate cancer, recommendation statement (grade C at 55 to 69, grade D at 70 and over)","route":"/key-papers/paper-uspstf-prostate-screening-jama-2018/"}],"idea":[{"id":"idea-prostate-metastatic-presentation-as-the-screening-endpoint","kind":"idea","name":"Judge a prostate screening programme on metastatic presentation, not on incidence or mortality","route":"/ideas/idea-prostate-metastatic-presentation-as-the-screening-endpoint/"},{"id":"idea-prostate-randomise-the-sequence-not-only-the-drugs","kind":"idea","name":"Randomise the order of treatment, not only the drugs: a strategy platform for metastatic prostate cancer","route":"/ideas/idea-prostate-randomise-the-sequence-not-only-the-drugs/"}]}}