Conditional Survival Estimates Research Articles

Contemporary conditional cancer-specific survival rates in surgically treated nonmetastatic primary urethral carcinoma.

We examined the effect of disease-free interval (DFI) duration on cancer-specific mortality (CSM)-free survival, otherwise known as the effect of conditional survival, in radical urethrectomy nonmetastatic primary urethral carcinoma (PUC) patients. Using the Surveillance, Epidemiology, and End Results (SEER) database 2000-2020, patient (age, sex, race/ethnicity, and marital status) and tumor (stage and histology) characteristics, as well as systemic therapy exposure status of nonmetastatic PUC patients were tabulated. Conditional survival estimates at 5-year were assessed based on DFI duration and according to stage at presentation (T1 -2N0 vs. T3-4N0-2). Of all 512 radical urethrectomy PUC patients, 278 (54%) harbored T1-2N0 stage versus 234 (46%) harbored T3-4N0-2 stage. In 512 PUC patients, 5-year CSM-free survival at initial diagnosis was 61.8%. Provided a DFI duration of 36 months, 5-year CSM-free survival was 85.6%. In 278 T1-2N0 PUC patients, 5-year CSM-free survival at initial diagnosis was 68.4%. Provided a DFI duration of 36 months, 5-year CSM-free survival was 86.9%. In 234 T3-4N0-2 PUC patients, 5-year CSM-free survival at initial diagnosis was 53.8%. Provided a DFI duration of 36 months, 5-year CSM-free survival was 83.6%. Although intuitively, clinicians and patients are well aware of the concept that increasing DFI duration improves survival probability, only a few clinicians can accurately estimate the magnitude of survival improvement, as was done within the current study. Such information is crucial to survivors, especially in those diagnosed with rare malignancies, where the survival estimation according to DFI duration is even more challenging.

Statistical Challenges from Trials of Potentially Curative Treatments: Validation of Cure Assumptions When Analyzing Zuma-7 Follow-up Data of Axi-Cel and Standard of Care Therapy

Introduction: ZUMA-7 is the largest randomized controlled trial (RCT) for chimeric antigen receptor (CAR) T-cell therapy which compared axicabtagene ciloleucel (Axi-cel) to standard of care (SoC) including autologous stem cell transplant (ASCT) for the treatment of relapsed or refractory DLBCL. Both arms of ZUMA-7 contained potentially curative treatments; however, differences in the treatment completion rate (94% received axi-cel and 36% received ASCT) and timing to receive definitive treatment led to differences in the extent and timing of cure. Furthermore, 57% of the SoC arm received potentially curative CAR-T therapies in subsequent lines of therapy leading to a delayed cure in that fraction of the population. The resulting event-free survival (EFS) and overall survival (OS) curves can pose challenges in interpretation and extrapolation for the purpose of simulations of long-term treatment effects and cost-effectiveness. Mixture cure modeling (MCM) has been suggested as a superior method to evaluate treatments of a curative nature to allow for part of the population to achieve long-term remission. This method has been shown to be useful both in designing and powering clinical studies of curative therapies but also for extrapolation of long-term outcomes in simulation studies. However previous iterations of this method did not account for differences in timing of curative therapies. ZUMA-7 had two pivotal analyses separated by nearly 2-years of follow-up: a primary EFS (datacut 1) and a primary OS analyses (data cut 2). The aim of this study was to use the two data cuts of ZUMA-7 to validate MCM in 2L LBCL and describe differences that may have arisen due to treatment specific timing and extent of cure. Methods: Overall survival individual patient-level data from the ZUMA-7 trial for axi-cel and SoC from both data cut 1 (median follow-up: 24.9 months) and data cut 2 (median follow-up: 47.2 months) were used in this analysis. Three different parametric modeling approaches were applied and compared in both data cuts: standard parametric model, spline-based model, and MCMs. Modeling approaches were evaluated for plausibility across a range of metrics, across the two data cuts, including visual fit, plausibility of long-term estimates, statistical goodness of fit, inspection of hazard plots, point-estimate accuracy, and conditional survival estimates. Additionality, the ability of the early data cut extrapolation to predict the actual data was assessed by comparing the model predictions with the latest KM estimator in both trial arms. Differences between trial arms were evaluated. Results: Cure-based and spline models provided the best fit based on the percentage inaccuracy of extrapolations fitted with data cut 1 in comparison to 5-year OS Kaplan-Meier estimates confirmed by data cut 2. In the axi-cel treatment arm, the percentage inaccuracy range between 2% and 27% (Figure 1). Based on data cut 1, cure fractions ranged considerably across the MCM extrapolation forms considered for both treatment arms (range: 24-54% [Figure 2] and 35-49% for axi-cel and SoC, respectively). Notably, the range of cure fractions narrowed considerably based on extrapolations performed on the more mature data cut 2 (range: 50-54% [Figure 2] and 41-50% for axi-cel and SoC, respectively). Overall, the uncertainty in the estimate of cure fractions based on MCMs was reduced from data cut 1 to data cut 2 for axi-cel vs. SoC, suggesting clinical input is needed to validate early extrapolations using less mature data cuts. Conclusion: Our analysis suggests that MCMs are helpful in making accurate predictions of survival based on immature data when a plateau in the survival curve is clinically plausible. However, this analysis also highlights the importance of considering clinical plausibility to guide specific curve selection in the presence of immature survival data, as there was a high degree of variability in the early extrapolations which was reduced with the longer-term follow-up. The ability to reliably extrapolate from early data may improve clinical decision making and reduce delays in patient access to potentially lifesaving treatments as more mature follow-up data are being collected.

Conditional Survival Estimates for Malignant Glioma Patients by RPA Class: Secondary Analysis of RTOG 9006

The RTOG recursive partitioning analysis (RPA) for malignant glioma patients is a key prognostic factor correlated with survival for patients with a malignant glioma, which was established using data from RTOG 9006. While such data is useful when counseling patients on survival outcomes at the time of diagnosis, the utility of such data diminishes over time. Conditional survival (CS) is a way to provide 'real-time' estimates of how survival changes over time. The primary objective of this secondary analysis is to report conditional survival estimates for patients with malignant gliomas enrolled on RTOG 9006 stratified by RPA class. RTOG 9006 was a phase III trial of patients diagnosed with malignant gliomas randomized to BCNU and hyper-fractionated radiation therapy (RT) vs. BCNU and conventionally fractionated RT that showed no significant differences in toxicities or oncologic outcomes. We performed a post-hoc analysis of RTOG 9006 using data obtained from the NCI NCTN Data Archive to evaluate conditional survival estimates for different RPA subgroups. Eligible patients included those with a known RPA class who were enrolled on RTOG 9006 (n = 632). Conditional survival estimates from the time of diagnosis and following 1-, 3-, and 5-y of survival were calculated using the Kaplan-Meier method. Cox proportional hazards modeling was performed to evaluate the prognostic significance of treatment arm, histology, extent of surgical resection, and RPA class following 1-, 3-, and 5-y of survival. For RPA Group I (n = 68), OS at 1-y from diagnosis was 95.58%. At 1- (n = 65), 3- (49) and 5-y (42) of survivorship, the chances of surviving an additional 1-y were 84.62, 91.84, 98.62% respectively (See Table 1). RPA class continued to be significantly correlated with survival following 1- and 3-y of survival irrespective of treatment arm. Treatment arm was not significantly correlated with conditional survival at any time point following treatment completion, and there was no interaction between treatment arm and RPA subgroups. Histology was significant at all time points. Conditional risk of death for patients treated for malignant gliomas in RPA Group I remains low at levels similar to those at initial diagnosis. Conditional risk continuously improves for RPA Groups IV-V as patients live longer. In most groups, the lowest survival odds were found in patients who have already survived 1 year.

Conditional Prostate Cancer-Specific Survival Probabilities in Recurrent Prostate Cancer Patients Receiving Radiation ± Antiandrogen Therapy: Secondary Analysis of a Randomized Clinical Trial

Salvage radiation therapy (SRT) and androgen-deprivation therapy (ADT) are routinely used in patients with elevated prostate-specific antigen (PSA) levels after radical prostatectomy (RP) for prostate cancer (PCa). Although prostate cancer-specific survival (PCSS) following SRT is useful when counseling patients at the time of treatment, the utility of this data from time of diagnosis diminishes over time. Conditional survival (CS) can provide more relevant estimates, especially given long-term PCa survivorship. The primary aim of this study was to analyze CS estimates for recurrent PCa patients undergoing SRT ± ADT. The secondary objective was to determine if factors prognostic of PCSS at diagnosis remain relevant in survivorship. We analyzed data from 760 post-RP patients enrolled in NRG/RTOG 9601 (1998-2003). Eligible patients included men who had undergone prior RP and had pT2/T3 disease without nodal involvement and detectable PSA levels of 0.2-4.0 ng/mL. Patients were randomly assigned to undergo SRT and receive either 24 mo of ADT or placebo. OS was calculated (Kaplan-Meier), cumulative incidence was used to estimate PCSS rates, and prognostic factors associated with PCSS were analyzed by multivariable Cox proportional hazards modeling (MVA). Patients were followed for a median of 13 y. The 5- and 10-y PCSS estimates from diagnosis were 98.52% and 92.7%, respectively. At 1- (n = 755), 3- (n = 727), 5- (n = 680), and 8-y (n = 602) survivorship, chances of PCSS at an additional 5-y were 97.41%, 95.29%, 93.76%, and 91.04%, respectively. On MVA at diagnosis, omission of ADT (HR 2.156, P = 0.0003), increasing age (HR 1.833, P = 0.03), Gleason score (GS) 7 (HR 2.356, P = 0.0057), and GS 8-10 (HR 4.841, P < 0.0001) were associated with PCa-specific mortality. For those who achieved survivorship at 1-, 3-, 5-, and 8-y, all variables remained prognostic of PCa-specific mortality on MVA. Conditional risk of death from PCa for patients treated with SRT increases over time. The initial risk of dying from PCa over a given period, however, is higher than if already having survived a portion of that period. ADT, younger age, and lower GS continue to confer a reduced risk of PCa-specific mortality for long-term survivors. This data can be used to inform survivorship care planning, giving patients more relevant prognostic information during continued surveillance after completion of treatment.

Conditional survival of patients with low-risk prostate cancer: Temporal changes in active surveillance permanence over time.

To determine risk categories for patients with prostate cancer (PCa) in active surveillance (AS) and to test the conditional survival (CS) that examined the effect of event-free survival since AS-entrance. From January 2012 to December 2020 we analyzed 606 patients with PCa enrolled in our AS program. Kaplan-Meier (KM) plots depicted AS-exit rate. Multivariable Cox regression models (MCRMs) tested for AS-exit rate independent predictors to determine risk categories. CS estimates were used to calculate overall AS-exit rate after event-free survival intervals of 1, 2, 3, and 5 years, and after stratification according to risk categories. At MCRMs PSAd ≥ 0.15 (HR: 1.43; P-value 0.04), PI-RADS 4-5 (HR: 2.56; P-value <0.001) and number of biopsy positive cores ≥ 2 (HR: 1.75; P-value <0.001) were independent predictors of AS-exit. These variables were used to determine risk categories: low-, intermediate- and high-risk. Overall, according to CS-analyses, 5-year AS-exit free rate increased from 59.7% at baseline, to 67.3%, 74.7%, and 89.4% in patients who remained in AS respectively ≥1, ≥2, ≥3 and ≥5 years. After stratification according to risk categories, in those patients who remained in AS ≥ 5 years, 5-year AS-exit free rates increased from 76.3% to 100% in patients with a low-risk, from 62.7% to 83.7% in patients with an intermediate-risk and from 42.3% to 87.5% in patients with a high-risk. CS models showed a direct relationship between event-free survival duration and subsequent AS permanence in overall PCa patients and after stratification according to risk categories.

Conditional Survival in Lung Transplantation: An Organ Procurement and Transplantation Network Database Analysis.

Lung transplantation survival estimates are traditionally reported as fixed 1-, 5-, and 10-year mortality rates. Alternatively, this study aims to demonstrate how conditional survival models can provide useful prognostic information tailored to the time a recipient has already survived from the date of transplantation. Recipient data was obtained from the Organ Procurement and Transplantation Network database. Data from 24,820 adult recipients over age 18 who received a lung transplant between 2002 and 2017 were included in the study. Five-year observed conditional survival estimates were calculated by recipient age, sex, race, transplant indication, transplant type ( i.e. , single or double), and renal function at the time of transplantation. Significant variability exists in conditional survival following lung transplantation. Each specific recipient characteristic significantly impacted conditional survival during at least one time point in the first 5 years. Younger age and double lung transplantation were the two most positive predictors of improved conditional survival consistently throughout the 5-year study period. Conditional survival in lung transplantation recipients changes over time and across recipient characteristics. Hazards of mortality are not fixed and need to be dynamically evaluated as a function of time. Conditional survival calculations can provide more accurate prognostic predictions than unconditional survival estimates.

Conditional survival in multiple myeloma and impact of prognostic factors over time

Overall survival estimates from diagnosis are valuable for guiding treatment, but do not consider the years already survived. Conditional survival (CS) provides dynamic survival predictions over time. This study was conducted to estimate CS at 1–8 years from diagnosis and the impact of baseline prognostic factors on CS in multiple myeloma (MM) patients. This is a retrospective study including 2556 MM patients diagnosed between 2004 and 2019. CS (t | s) was defined as the probability of surviving t years given survival of s years. Median age was 64 years. Median follow-up was 6.2 years and median overall survival from diagnosis was 7.5 years. The 5-year CS estimates at s = 0, 1, 2, 3, and 5 years were 0.64, 0.61, 0.61, 0.61, and 0.58, respectively. On multivariate analysis, age ≥ 65 and proteasome inhibitor+immunomodulatory-based induction were associated with decreased survival and increased survival, respectively, retained at 5 years. The adverse impact of 1q gain/amplification, high-risk IgH translocation, and ISS-3 was significant at 1 and 3 years but not 5 years. Chromosome 17 abnormality was associated with decreased survival only at 1 year. Among MM patients, 5-year CS was stable at 1–5 years from diagnosis. The prognostic impact of high-risk cytogenetic factors decreased with additional years survived.

Prediction of conditional survival in esophageal cancer in a Population-based cohort study.

We aimed to produce a prediction model for survival at any given date after surgery for esophageal cancer (conditional survival), which has not been done previously. Using joint density functions, we developed and validated a prediction model for all-cause and disease-specific mortality after surgery with esophagectomy, for esophageal cancer, conditional on post-surgery survival time. The model performance was assessed by the area under the receiver operating characteristic curve (AUC) and risk calibration, with internal cross-validation. The derivation cohort was a nationwide Swedish population-based cohort of 1027 patients treated in 1987-2010, with follow-up throughout 2016. This validation cohort was another Swedish population-based cohort of 558 patients treated in 2011-2013, with follow-up throughout 2018. The model predictors were age, sex, education, tumor histology, chemo(radio)therapy, tumor stage, resection margin status, and reoperation. The medians of AUC after internal cross-validation in the derivation cohort were 0.74 (95% confidence interval [95%CI] 0.69-0.78) for 3-year all-cause mortality, 0.76 (95%CI 0.72-0.79) for 5-year all-cause mortality, 0.74 (95%CI 0.70-0.78) for 3-year disease-specific mortality, and 0.75 (95%CI 0.72-0.79) for 5-year disease-specific mortality. The corresponding AUC values in the validation cohort ranged from 0.71 to 0.73. The model showed good agreement between observed and predicted risks. Complete results for conditional survival any given date between 1 and 5 years of surgery are available from an interactive web-tool: https://sites.google.com/view/pcsec/home. This novel prediction model provided accurate estimates of conditional survival any time after esophageal cancer surgery. The web-tool may help guide post-operative treatment and follow-up.

Conditional survival for non-metastatic muscle-invasive adenocarcinoma of the urinary bladder after radical cystectomy

PurposeTo test the effect of conditional survival on 36-months’ cancer-specific mortality (CSM)-free survival in non-metastatic muscle-invasive adenocarcinoma of the bladder (ACB). Materials and methodsWithin the Surveillance, Epidemiology, and End Results database (2000–2018), ACB patients treated with radical cystectomy (RC) were identified. Multivariable competing risks regression (CRR) analyses assessed the independent predictor status of organ-confined (OC, T2N0M0) vs non-organ-confined stage (NOC, T3-4N0M0 or TanyN1-3M0) on CSM. Conditional 36-months’ CSM-free survival estimates were computed based on event-free intervals of 12, 24, 36, 48 and 60 months after RC, according to stage. ResultsOf 475 ACB patients, 132 (28%) harbored OC vs 343 (72%) harbored NOC stage. In multivariable CRR models, NOC vs OC stage independently predicted lower CSM (hazard ratio 3.55; 95% CI 2.66, 5.83; p < 0.001). Conversely, neither chemotherapy nor radiotherapy were independently associated with CSM. In OC stage, 36-months’ CSM-free survival rate was 84% at baseline. Provided event-free intervals of 12, 24, 36, 48 and 60 months, conditional 36-months’ CSM-free survival estimates were 84, 87, 87, 89 and 89%. In NOC stage, 36-months’ CSM-free survival rate was 47% at baseline. Provided event-free intervals of 12, 24, 36, 48 and 60 months, conditional 36-months’ CSM-free survival estimates were 51, 62, 69, 78 and 85%. ConclusionsConditional survival estimates provide better insight into survival of patients with longer event-free follow-up. In consequence, conditional survival estimates might be highly valuable for individual patient counselling.

Conditional survival in patients treated for gastric cancer with a curative intent.

Conditional survival (CS) provides the probability that a patient who has already survived a certain number of years after treatment will survive an additional number of years. We aim to study the CS of patients with gastric cancer. Patients who underwent curative intent treatment for gastric cancer in a single institution between 2007 and 2018 were included in the analysis. The probability (CS) that a patient who has already survived x years will survive an additional y year, was calculated as CS (y/x) = S(x + y)/S(x). The probability of surviving an additional 3 years if a patient had already survived 1, 2, 3, 4, and 5 years after treatment were 64.2%, 74.5%, 81.6%, 83.2%, and 88.2%, respectively whereas the 4-, 5-, 6-, 7-, and 8-year actuarial OS were only 47.2%, 43.2%, 41%, 39.4%, and 38.2%, respectively. The independent prognostic factors associated with poor survival were age >60 years, T stage ≥T3, N stage ≥N2, proximal tumor location, and lymph node ratio > 0.18. Patients with these high-risk features showed the greatest increase in CS3 over time. CS estimates provided a more dynamic prognostic information over time for patients treated for gastric cancer with curative intent.

Conditional survival after surgery for metastatic tumors of the spine: does prognosis change over time?

Conditional survival (CS) provides a dynamic prediction of patient survival by incorporating the time an individual has already survived given their disease specific characteristics. The objective of the current study was to estimate CS among patients after surgery for spinal cord compression or spinal instability, as well as stratify CS according to relevant patient- and disease-related characteristics. The clinical outcomes of 361 patients undergoing surgical management of metastatic spinal tumors were retrospectively analyzed. Stratification of this cohort according to disease and surgery-specific characteristics allowed for univariate and multivariate statistical analyses of our study population. Observed overall and conditional survival estimates were calculated by the Kaplan-Meier method. 12-month conditional survival in patients undergoing surgical management of metastatic spine tumors increased from 57% at baseline to 70% at 24months following spine surgery. Overall survival (OS) was influenced by CCI grade, Katagiri tumor type, presence of lung metastasis, type of spine surgery, presence of postoperative systemic therapy and ambulatory status at follow-up. Analyses of OS and CS by prognostic strata were similar with exception of stratification by surgery type. Differences in survival between strata tend to converge over time. Unfavorable factors for OS appear to be less relevant after a period of 24months following spine surgery. Patients after surgery for metastatic tumors of the spine can expect a positive trend in conditional survival as survivorship increases. Even patients with a more severe disease can be encouraged with gains in conditional survival over time. Level IV (retrospective cohort study).

Contemporary conditional cancer-specific survival rates in surgically treated adrenocortical carcinoma patients: A stage-specific analysis.

We examined the effect of disease-free interval (DFI) duration on cancer-specific mortality (CSM)-free survival, otherwise known as the effect of conditional survival, in surgically treated adrenocortical carcinoma (ACC) patients. Within the Surveillance, Epidemiology, and End Results database (2004-2018), 867 ACC patients treated with adrenalectomy were identified. Conditional survival estimates at 5-years were assessed based on DFI duration and according to stage at presentation. Separate Cox regression models were fitted at baseline and according to DFI. Overall, 406 (47%), 285 (33%), and 176 (20%) patients were stage I-II, III and IV, respectively. In conditional survival analysis, providing a DFI of 24 months, 5-year CSM-free survival at initial diagnosis increased from 66% to 80% in stage I-II, from 35% to 66% in stage III, and from 14% to 36% in stage IV. In multivariable Cox regression models, stage III (hazard ratio [HR]: 2.38;p < 0.001) and IV (HR: 4.67;p < 0.001) independently predicted higher CSM, relative to stage I-II. The magnitude of this effect decreased over time, providing increasing DFI duration. In surgically treated ACC, survival probabilities increase with longer DFI duration. This improvement is more pronounced in stage III, followed by stages IV and I-II patients, in that order. Survival estimates accounting for DFI may prove valuable in patients counseling.

Time to Complete Response within 24 Months As a Good Surrogate Marker of 8 Year-Progression Free Survival in Extranodal Marginal Zone Lymphoma

Background: Extranodal marginal zone lymphoma (EMZL) represents the most common marginal zone lymphoma (MZL) subtype and it generally has a very indolent course, thus requiring long and costly trials to provide evidence on novel therapies. The IELSG-19 open-label phase 3 trial was conducted at 78 centers in six countries and showed the advantage of double therapy (rituximab-chlorambucil) over single therapy (rituximab or chlorambucil). Based on this trial, we assessed whether time to complete response within 24 months (TTCR24) could be a surrogate marker of progression-free survival (PFS) in EMZL. Methods: We used a recently developed method which derives conditional survival estimates under a landmark Cox proportional hazards model. This method allows us 1) to estimate surrogacy via the proportion of treatment effect explained by surrogate information and 2) to decompose this proportion between information gathered on the true outcome and the incremental value of the surrogate outcome alone. True outcome was 8 year-PFS and candidate surrogate marker was TTCR24. For both outcomes, treatment effect was defined using restricted mean survival time difference (RMST) between the two study arms: the difference in mean progression-free survival time restricted at 8 years and the difference in mean time to CR. Results: Among 401 patients (median follow-up: 7.4 years), 8y-PFS was not achieved in the combined therapy arm vs 8.35 years in the single therapy arm. At 2 years, TTCR24 was 83% vs 65%, while 2y-PFS was 87% vs 75%, respectively. In terms of RMST, patients under double therapy had a shorter TTCR24 by 3.8 months and a longer PFS by 11 months, compared to patients under single therapy. The estimated proportion of treatment effect on 8y-PFS explained by TTCR24 was 95% (95% CI: 0.27,1.87). When decomposed, the proportion of treatment effect on 8y-PFS was explained by PFS24 was 75% (95% CI: 0.31, 1.27) and the incremental value of TTCR24 was 20% (95% CI: -0.23,0.86). Conclusion: We found that TTCR24 predicted 95% of the treatment effect on 8y-PFS and, when used as surrogate marker, it could reduce the needed follow-up time of a phase 3 trial by four. From this, one could conclude that a new therapy in EMZL would be effective if it offers a significantly shorter TTCR than the one obtained by rituximab-chlorambucil (5.5 months). Although this single-trial approach suffers of the lack of a trial-level evidence, there are, to date, too few MZL phase 3 trials to undertake a meta-analysis. The very strong surrogacy offered by TTCR24 could make it the most relevant surrogate marker in EMZL in the coming years.

Conditional Survival Probabilities in Recurrent Prostate Cancer (PCa) Patients Receiving Radiation ± Antiandrogen Therapy: Secondary Analysis of a Randomized Clinical Trial

<h3>Purpose/Objective(s)</h3> Salvage radiation therapy (SRT) and androgen-deprivation therapy (ADT) are routinely used in patients with elevated prostate-specific antigen (PSA) levels after radical prostatectomy (RP). Although overall survival (OS) and biochemical-failure (BF) following SRT are useful when counseling patients at the time of treatment, the utility of survival data from time of diagnosis diminishes over time. Conditional survival (CS) can provide more relevant estimates, especially given long-term PCa survivorship. The primary aim of this study was to analyze CS estimates for recurrent PCa patients undergoing SRT ± ADT. The secondary objective was to determine if factors prognostic of OS and BF at diagnosis remain relevant in survivorship. <h3>Materials/Methods</h3> We analyzed data from 760 post-RP patients enrolled in NRG/RTOG 9601 (1998–2003). Eligible patients included men who had undergone prior RP and had pT2/T3 disease without nodal involvement and detectable PSA levels of 0.2–4.0 ng/mL. Patients were randomly assigned to undergo SRT and receive either 24 mo of ADT or placebo. OS was calculated (Kaplan–Meier), cumulative incidence was used to estimate BF rates, and prognostic factors associated with OS and BF were analyzed by multivariable Cox proportional hazards modeling (MVA). <h3>Results</h3> Patients were followed for a median of 13 y. The 5- and 10-y OS estimates from diagnosis were 93% and 80%, respectively. At 1- (<i>n</i> = 755), 3- (<i>n</i> = 727), 5- (<i>n</i> = 680), 8- (<i>n</i> = 602), and 10-y (<i>n</i> = 543) survivorship, chances of surviving an additional 5 y were 92%, 89%, 86%, 80%, and 72%, respectively. On MVA at diagnosis, omission of ADT (HR 1.308, <i>P</i> = 0.0403), increasing age (HR 2.761, <i>P</i> < 0.0001), and Gleason score (GS) 8−10 (HR 1.054, <i>P</i> =0.01), were associated with all-cause mortality. For those who achieved survivorship at 5 y, only age (HR 2.973, <i>P</i> < 0.0001) and GS 8–10 (HR 1.801, <i>P</i> = 0.0063) were prognostic of mortality on MVA. The 5- and 10-y rates of BF from diagnosis were 36% and 52%, respectively. For patients who survived 1 (<i>n</i> = 725), 3 (<i>n</i> = 560), 5 (<i>n</i> = 435), 8 (<i>n</i> = 320), and 10 (<i>n</i> = 268) y without BF, chances of BF at an additional 5 y were 39%, 33%, 26%, 20%, and 20%, respectively. On MVA at time of SRT, omission of ADT (HR 2.139, <i>P</i> < 0.0001), GS 7 (HR 1.376, <i>P</i> = 0.0062), GS 8–10 (HR 1.717, <i>P</i> = 0.0005), and higher pretreatment PSA (HR 1.442, <i>P</i> = 0.0215), were associated with BF. For those who survived 5 y after treatment without failure, only omission of ADT (HR 1.407, <i>P</i> < 0.0384) was prognostic of BF. <h3>Conclusion</h3> Conditional risk of BF for patients treated with SRT remains elevated at levels similar to those at initial treatment for up to 3 y after SRT, after which BF rates decrease. ADT continues to confer a reduced risk for BF for long-term survivors. This data can be used to inform survivorship care planning and highlights the need for continued PSA surveillance after completion of treatment.

A Dynamic Clinical Calculator for Estimating Conditional Recurrence-Free Survival After Total Neoadjuvant Therapy for Rectal Cancer and Either Surgery or Watch-and-Wait Management

The risk of recurrence in patients with locally advanced rectal cancer has historically been determined after surgery, relying on pathologic variables. A growing number of patients are being treated without surgery, and their risk of recurrence needs to be calculated differently. To develop a dynamic calculator for estimating the probability of recurrence-free survival (RFS) in patients with rectal cancer who undergo total neoadjuvant therapy (TNT) (induction systemic chemotherapy and chemoradiotherapy) and either surgery or watch-and-wait management. This cohort study included patients who presented with stage II or III rectal cancer between June 1, 2009, and March 1, 2015, at a comprehensive cancer center. Conditional modeling was incorporated into a previously validated clinical calculator to allow the probability of RFS to be updated based on whether the patient remained in watch-and-wait management or underwent delayed surgery. Data were analyzed from November 2021 to March 2022. TNT followed by immediate surgery or watch-and-wait management with the possibility of delayed surgery. RFS, concordance index, calibration curves. Of the 302 patients in the cohort, 204 (68%) underwent surgery within 3 months from TNT completion (median [range] age, 51 [22-82] years; 78 [38%] women), 54 (18%) underwent surgery more than 3 months from TNT completion (ie, delayed surgery; median [range] age, 62 [31-87] years; 30 [56%] female), and 44 (14%) remained in watch-and-wait management as of April 21, 2021 (median [range] age, 58 [32-89] years; 16 [36%] women). Among patients who initially opted for watch-and-wait management, migration to surgery due to regrowth or patient choice occurred mostly within the first year following completion of TNT, and RFS did not differ significantly whether surgery was performed 3.0 to 5.9 months (73%; 95% CI, 52%-92%) vs 6.0 to 11.9 months (71%; 95% CI, 51%-99%) vs more than 12.0 months (70%; 95% CI, 49%-100%) from TNT completion (P = .70). RFS for patients in the watch-and-wait cohort at 12 months from completion of TNT more closely resembled patients who had undergone surgery and had a pathologic complete response than the watch-and-wait cohort at 3 months from completion of TNT. Accordingly, model performance improved over time, and the concordance index increased from 0.62 (95% CI, 0.53-0.71) at 3 months after TNT to 0.66 (95% CI, 0-0.75) at 12 months. In this cohort study of patients with rectal cancer, the clinical calculator reliably estimated the likelihood of RFS for patients who underwent surgery immediately after TNT, patients who underwent delayed surgery after entering watch-and-wait management, and patients who remained in watch-and-wait management. Delayed surgery following attempted watch-and-wait did not appear to compromise oncologic outcomes. The risk calculator provided conditional survival estimates at any time during surveillance and could help physicians counsel patients with rectal cancer about the consequences of alternative treatment pathways and thereby support informed decisions that incorporate patients' preferences.

Causes of death and conditional survival estimates of long-term lung cancer survivors.

IntroductionLung cancer ranks the leading cause of cancer-related death worldwide. This retrospective cohort study was designed to determine time-dependent death hazards of diverse causes and conditional survival of lung cancer.MethodsWe collected 816,436 lung cancer cases during 2000-2015 in the SEER database, after exclusion, 612,100 cases were enrolled for data analyses. Cancer-specific survival, overall survival and dynamic death hazard were assessed in this study. Additionally, based on the FDA approval time of Nivolumab in 2015, we evaluated the effect of immunotherapy on metastatic patients’ survival by comparing cases in 2016-2018 (immunotherapy era, n=7135) and those in 2013-2016 (non-immunotherapy era, n=42061).ResultsOf the 612,100 patients, 285,705 were women, the mean (SD) age was 68.3 (11.0) years old. 252,558 patients were characterized as lung adenocarcinoma, 133,302 cases were lung squamous cell carcinoma, and only 78,700 cases were small cell lung carcinomas. TNM stage was I in 140,518 cases, II in 38,225 cases, III in 159,095 cases, and IV in 274,262 patients. 164,394 cases underwent surgical intervention. The 5-y overall survival and cancer-specific survival were 54.2% and 73.8%, respectively. The 5-y conditional survival rate of cancer-specific survival is improved in a time-dependent pattern, while conditional overall survival tends to be steady after 5-y follow-up. Except from age, hazard disparities of other risk factors (such as stage and surgery) diminished over time according to the conditional survival curves. After 8 years since diagnosis, mortality hazard from other causes became higher than that from lung cancer. This critical time point was earlier in elder patients while was postponed in patients with advanced stages. Moreover, both cancer-specific survival and overall survival of metastatic patients in immunotherapy era were significantly better than those in non-immunotherapy era (P<0.001), indicating that immunotherapeutic intervention indeed bring remarkable benefits to advanced lung cancer patients.ConclusionsOur findings expand on previous studies by demonstrating that non-lung-cancer related death risk becomes more and more predominant over the course of follow-up, and we establish a personalized web-based calculator to determine this critical time point for long-term survivors. We also confirmed the survival benefit of advanced lung cancer patients in immunotherapy era.

639P Conditional survival in MM and impact of prognostic factors over time

Overall Survival (OS) estimates from diagnosis are important for predicting prognosis and guiding treatment selection in newly diagnosed patients, but do not consider the number of years already survived. Conditional survival (CS) estimates provide updated survival predictions over the disease course. Previous studies suggest that improvement in CS is less pronounced in multiple myeloma (MM) compared to other malignancies. It is unclear whether high-risk (HR) factors in MM retain their prognostic impact over time. This study was conducted to estimate CS at 1 to 5 years from diagnosis and evaluate the impact of baseline prognostic factors on CS over time in newly diagnosed MM patients. This is a retrospective study including 2556 MM patients diagnosed between 2004-2019. CS (t|s), defined as the probability of surviving additional t years given survival of s years, was estimated at 1 to 5 years from diagnosis using the conditional Kaplan-Meier method. The impact of baseline characteristics on CS was estimated using conditional Cox proportional hazards model. The median age was 64 years and 62% were male; >90% received novel-agent based induction; 46% had transplant within 1 year of diagnosis. The median follow-up was 6.2 years, and median OS was 7.5 years. The 5-year CS estimates at s=0, 1, 2, 3, and 5 years were 0.64, 0.61, 0.61, 0.61, and 0.58, respectively. On multivariate analysis, age ≥ 65 and proteasome inhibitor (PI)+Immunomodulatory (IMiD)-based induction retained prognostic significance at 5 years from diagnosis. The adverse impact of HR IgH translocations, 1q gain and ISS 3 was not significant at 5 years. Chromosome 17 abnormality predicted worse CS at 1 year, but not at 3 or 5 years from diagnosis (table).Table: 639PMultivariate CSVariableDiagnosisyear 1year 3year 5HRPHRPHRPHRPAge≥651.60<0.011.57<0.011.48<0.011.95<0.01Calcium ≥111.59<0.011.63<0.011.05NS1.05NSISS III1.74<0.011.75<0.011.80<0.011.52NSEarly transplant0.57<0.010.64<0.010.61<0.010.69NSPI+IMiD induction0.59<0.010.630.010.660.040.530.04LDH > 2221.29NS1.15NS1.13NS0.89NSCh17 abnormality1.53<0.011.430.021.32NS1.16NSHR IgH translocation1.90<0.011.97<0.011.550.041.51NSMonosomy 131.13NS1.09NS1.05NS0.86NS1q gain1.34<0.011.310.031.500.011.38NSSignificant P values are bolded. NS: not significant. Open table in a new tab Significant P values are bolded. NS: not significant. In a large cohort of MM patients treated with novel agents, CS was stable at 1 to 5 years from diagnosis. The adverse prognostic impact of HR cytogenetic factors and advanced ISS stage decreased over time.

Treatment Response and Conditional Survival in Advanced Pancreatic Cancer Patients Treated with FOLFIRINOX: A Multicenter Cohort Study.

Background FOLFIRINOX chemotherapy is the current Dutch standard of care for locally advanced (LAPC) and metastatic pancreatic cancer (PDAC) patients with good performance status. The objective of this study was to evaluate real-world response rates and survival in advanced PDAC and to assess conditional survival after FOLFIRINOX. Methods A multicenter, retrospective cohort study was conducted in four hospitals in the Netherlands. Consecutive patients with LAPC or metastatic PDAC, treated with FOLFIRINOX, were included. Results Between 2012 and 2018, 284 patients were included: n = 136 with LAPC and n = 148 with metastatic PDAC. Objective response rates were similar in both the groups: 14.0% in LAPC and 18.2% in metastatic patients. The disease control rate was higher in LAPC patients (77.2%) compared to metastatic PDAC (51.4%, P < 0.001). Median overall survival (OS) in LAPC patients was 12.7 months (95% CI 11.4–14.1 months). Their 2-year survival probability increased from 14% to 26% one year after the completion of FOLFIRINOX. Median OS in metastatic PDAC patients was 8.1 months (95% CI 6.5–9.6 months); 2-year survival probability increased from 10% to 29% after one year. Discussion. Our study provides real-world estimates of response rates, survival, and conditional survival in patients with advanced PDAC treated with FOLFIRINOX. These results are useful for patient counseling and clinical decision making.

Conditional estimates for uterine serous cancer: Tools for survivorship counseling and planning

ObjectivesDevelop conditional survival and risk-assessment estimates for uterine serous carcinoma (USC) overall and stratified by stage as tools for annual survivorship counseling and care planning. MethodsPatients in the National Cancer Data Base diagnosed between 2004 and 2014 with stage I-IV USC were eligible. Individuals missing stage or survival data or with multiple malignancies were excluded. Five-year conditional survival was estimated using the stage-stratified Kaplan-Meier method annually during follow-up. A standardized mortality ratio (SMR) estimated the proportion of observed to expected deaths in the U.S. adjusted for year, age, and race. The relationships between prognostic factors and survival were studied using multivariate Cox modeling at diagnosis and conditioned on surviving 5-years. ResultsThere were 14,575 participants, including 43% with stage I, 8% with stage II, 29% with stage III, and 20% with stage IV USC. Five-year survival at diagnosis vs. after surviving 5-years was 52% vs. 75% overall, 77% vs. 81% for stage I, 57% vs. 72% for stage II, 40% vs. 66% for stage III, and 17% vs. 60% for stage IV USC, respectively (P < 0.0001). Incremental improvements in 5-year conditional survival and reductions in SMR tracked with annual follow-up and higher stage. The adjusted risk of death at diagnosis vs. after surviving 5-years was 1.15 vs. 1.40 per 5-year increase of age, 1.26 vs. 1.68 for Medicaid insurance, 3.92 vs. 2.48 for stage III disease, and 6.65 vs. 2.79 for stage IV disease, respectively (P < 0.0001). ConclusionIn USC, the evolution of conditional survival permits annual reassessments of prognosis to tailor survivorship counseling and care planning.

Conditional survival and long-term efficacy with nivolumab plus ipilimumab versus sunitinib in patients with advanced renal cell carcinoma.

BackgroundConditional survival estimates provide critical prognostic information for patients with advanced renal cell carcinoma (aRCC). Efficacy, safety, and conditional survival outcomes were assessed in CheckMate 214 (ClinicalTrials.gov identifier NCT02231749) with a minimum follow‐up of 5 years.MethodsPatients with untreated aRCC were randomized to receive nivolumab (NIVO) (3 mg/kg) plus ipilimumab (IPI) (1 mg/kg) every 3 weeks for 4 cycles, then either NIVO monotherapy or sunitinib (SUN) (50 mg) daily (four 6‐week cycles). Efficacy was assessed in intent‐to‐treat, International Metastatic Renal Cell Carcinoma Database Consortium intermediate‐risk/poor‐risk, and favorable‐risk populations. Conditional survival outcomes (the probability of remaining alive, progression free, or in response 2 years beyond a specified landmark) were analyzed.ResultsThe median follow‐up was 67.7 months; overall survival (median, 55.7 vs 38.4 months; hazard ratio, 0.72), progression‐free survival (median, 12.3 vs 12.3 months; hazard ratio, 0.86), and objective response (39.3% vs 32.4%) benefits were maintained with NIVO+IPI versus SUN, respectively, in intent‐to‐treat patients (N = 550 vs 546). Point estimates for 2‐year conditional overall survival beyond the 3‐year landmark were higher with NIVO+IPI versus SUN (intent‐to‐treat patients, 81% vs 72%; intermediate‐risk/poor‐risk patients, 79% vs 72%; favorable‐risk patients, 85% vs 72%). Conditional progression‐free survival and response point estimates were also higher beyond 3 years with NIVO+IPI. Point estimates for conditional overall survival were higher or remained steady at each subsequent year of survival with NIVO+IPI in patients stratified by tumor programmed death ligand 1 expression, grade ≥3 immune‐mediated adverse event experience, body mass index, and age.ConclusionsDurable clinical benefits were observed with NIVO+IPI versus SUN at 5 years, the longest phase 3 follow‐up for a first‐line checkpoint inhibitor‐based combination in patients with aRCC. Conditional estimates indicate that most patients who remained alive or in response with NIVO+IPI at 3 years remained so at 5 years.