UROLOGICAL ONCOLOGY Survival Differences in High-Risk Prostate Cancer by Age Clara García-Fuentes1*, Ana Guijarro1, Virginia Hernández1, Álvaro Gonzalo-Balbás1, Estíbaliz Jiménez-Alcaide1, Enrique de la Peña1, Elia Pérez-Fernández2, Carlos Llorente1 Purpose: Age is an established determining factor in survival in low-risk prostate cancer (PC), being this evidence weaker in high-risk tumors. Our aim is to evaluate the survival of patients with high-risk PC treated with curative intent and to identify differences across ages at diagnosis. Methods: We did a retrospective analysis of patients with high-risk PC treated with surgery (RP) or radiotherapy (RDT) excluding N+ patients. We divided patients by age groups: < 60, 60-70, and > 70 years. We performed a comparative survival analysis. A multivariate analysis adjusted for clinically relevant variables and initial treat- ment received was performed. Results: Of a total of 2383 patients, 378 met the selection criteria with a median follow-up of 8.9 years: 38 (10.1%) < 60 years, 175 (46.3%) between 60-70 years, and 165 (43.6%) >70 years. Initial treatment with surgery was predominant in the younger group (RP:63.2%, RDT:36.8%), and with radiotherapy in the older group (RP:17%, RDT:83%) (p = 0.001). In the survival analysis, significant differences were observed in overall survival, with better results for the younger group. However, these results were reversed in biochemical recurrence-free survival, with patients < 60 years presenting a higher rate of biochemical recurrence at 10 years. In the multivariate analysis, age behaved as an independent risk variable only for overall survival, with a HR of 2.8 in the group >70 years (95%CI: 1.22-6.5; p = 0.015). Conclusion: In our series, age appeared to be an independent prognostic factor for overall survival, with no differ- ences in the rest of the survival rates. Keywords: high-risk prostate cancer; age groups; survival differences 1Department of Urology, Hospital Universitario Fundación Alcorcón, Madrid, Spain. 2Research Unit, Hospital Universitario Fundación Alcorcón, Madrid, Spain. *Correspondence: Department of Urology, Hospital Universitario Fundación Alcorcón. Avda. Budapest 1, 28922 Alcorcón, Madrid, Spain. Tel: +34 618271570, Fax number: 916219404. Email: cgarciaf@salud.madrid.org and garciafuentes.clara@gmail.com. Received July 2022 & Accepted December 2022 INTRODUCTION Prostate cancer (PC) is the most commonly diag-nosed solid organ neoplasm in men in Europe and its incidence increases with age, with 60% of cases be- ing detected in men over 65 years of age.(1) The incidence of high-risk tumors is 15-20% according to American studies. In the Swedish registry, out of a total of 57187 patients with PC, 24% were classified as high risk.(2,3) In Spain, according to data from the 2010 National Prostate Cancer Registry, 89.4% of patients had localized disease, and of these, 28.8% had high-risk tumors according to the D'Amico classification.(4) While there is evidence that in low-risk tumors age is a determinant of survival(5), there are not many studies that identify the impact of age on survival in high-risk tumors. Our aim is to evaluate the survival of patients with high- risk PC treated with curative intent and to identify pos- sible differences according to age at diagnosis. MATERIAL AND METHODS We performed a retrospective analysis of all patients with prostate cancer, prospectively included in our hos- pital database from 1998 to 2016, to reach a minimum follow-up of 5 years. Review and approval by our hospital's ethics commit- tee did not apply to this study due to the retrospective nature of the study. We selected those patients who met the D'Amico criteria for high-risk disease (stage T2, PSA > 20 ng/mL or Gleason ≥ 8) and who had been treated with curative intent by radical prostatectomy and pelvic lymphadenectomy (RP + LFDN) or radio- therapy with neo and adjuvant hormone therapy for 2 years (RDT + HT). N+ patients were excluded. All radical prostatectomies from 2004 onward were performed laparoscopically. The approach was extra- peritoneal until 2009, and from that moment on the pro- cedure was performed transperitoneally with an extend- ed lymph node dissection. Until 2013, radiotherapy treatment was administered with radical intent with classic fractionation using IMRT (54.6 Gy on lymph node chains, 62.4 Gy on sem- inal vesicles and 78 Gy on the prostate) and IGRT daily. From 2013 onwards, treatment was administered with moderate hypofractionation (50.4 Gy on lymph node chains, 56 Gy on seminal vesicles and 70 Gy on the prostate that corresponds to EQD2 81Gy). We divided the subjects according to age into three groups: under 60, between 60 and 70, and over 70 years of age. We performed a descriptive analysis of the demograph- Urology Journal/Vol 20 No. 4/ July-August 2023/ pp. 215-221. [DOI:10.22037/uj.v20i.7393] ic characteristics of the patients including age and co- morbidity measured according to the Charlson index, as well as the characteristics referring to prostate cancer: PSA, T stage, Gleason at diagnosis and type of treat- ment received (RP + LFDN vs RDT + HT). The analysis of the surgical specimen was analyzed by the uropathologists of our center using TNM staging system according to European recommendations and Gleason according to the 2005 classification. Samples from patients prior to that date were reclassified accord- ing to these criteria. The rates of biochemical recurrence and disease pro- gression to metastasis recorded in each group (defined according to the criteria of the European guidelines) were analyzed, and the differences in survival were analyzed in terms of overall survival, cancer-specific survival, survival free of biochemical recurrence and survival free of progression to metastasis. A multivar- iate analysis adjusted for clinically relevant variables (age and D'Amico high-risk criteria) as well as initial treatment received was performed. Statistical analysis The distribution of quantitative data is presented by mean and standard deviation or median and interquar- tile range, according to data distribution. Univariate analysis was performed to compare the distribution of clinical variables according to age groups: the chi- square test or Fisher's exact test in case of small sample size for qualitative variables, and the one-way ANOVA F test or the nonparametric Kruskal–Wallis test to com- pare quantitative variables, depending on the distribu- tion data. Overall survival time is defined as the time from the date of treatment to the date of death from any cause or to the date of end of follow-up in the case of censored data. Reason for censoring is loss of follow-up. In the case of recurrence-free survival and progression-free survival, the recurrence event was considered to be biochemical recurrence (defined according to EAU guidelines criteria) after treatment with curative intent, and the progression event was considered to be the de- velopment of metastases during follow-up. Reason for censoring includes loss of follow-up and death without previous event. The Kaplan-Meier method was used to estimate the survival curves and the log-rank test was calculated to compare groups according to age: under 60, between 60 and 70, and over 70 years of age. Cox proportional hazards regression models were used to estimate hazard ratios (HR) according to age groups without adjustment and adjusting for other clinical var- iables of interest (D’Amico criteria and initial treatment received). Cox proportional hazard (PH) assumption and was evaluated testing linear nonzero slope of the residuals and linearity for age was assessed with a link test for model specification. The variables that no com- pliance PH assumption were including in the models with time-varying coefficients. All tests were considered bilateral and p-values less than 0.05 were considered statistically significant. Statistical analysis was performed using SPSS 17 and STATA 14 data analysis packages. RESULTS Of the 2383 patients included in our institutional pros- tate cancer database, 378 met the selection criteria. Of these, 38 patients (10.1%) were younger than 60 years, Prostate cancer survival by age-Garcia-Fuentes et al. Age: N (%) < 60 years (N = 38) 60-70 years (N = 175) > 70 years (N = 165) p Events recorded during the follow-up Biochemical recurrence 20 (52.6%) 69 (39.4%) 44 (26.7%) 0.003 Progression to metastasis 9 (23.7%) 18 (16%) 21 (12.7%) 0.227 Death from any cause 7 (18.4%) 28 (16%) 53 (32.1%) 0.002 Cancer-specific death 3 (7.9%) 5 (2.9%) 11 (6.7%) 0.191 Estimated survival at 10 years Overall Survival 85% (95% CI: 16.3 – 21.0) 88% (95% CI: 16.7 – 18.7) 71% (95% CI: 11.7 – 14.1) < 0.001 Cancer-specific survival 93% (95% CI: 18.9 – 22.3) 97% (95% CI: 19.6 – 20.7) 95% (95% CI: 16.3 – 18.7) 0.049 Biochemical recurrence-free survival 44% (95% CI: 7.9 – 13.6) 59% (95% CI: 11.6 – 14.3) 62% (95% CI: 11.4 – 13.8) 0.019 Metastasis progression-free survival 74% (95% CI: 14.6 – 20.0) 86% (95% CI: 16.6 – 18.7) 84% (95% CI: 15.7 – 17.9) 0.583 Table 2. Events recorded during the follow-up period and results of survival at 10 years Age: N (%) < 60 years(N = 38) 60-70 years (N = 175) > 70 years (N = 165) p PSA (ng/mL) a 24.49 24.58 22.73 0.036 Grade Group (ISUP) 1 6 (15.8%) 21 (12%) 14 (8.5%) 0.287 2 8 (21.1%) 22 (12.6%) 18 (10.9%) 3 2 (5.3%) 14 (8%) 15 (9.1%) 4 11 (28.9%) 84 (48%) 77 (46.7%) 5 11 (28.9%) 33 (18.9%) 41 (24.8%) T stage T1-T2b 28 (73.7%) 127 (72.6%) 114 (69.1%) 0.810 T2c 3 (7.9%) 8 (4.6%) 11 (6.7%) T3-T4 7 (18.4%) 40 (22.9%) 40 (24.2%) Treatment at diagnosis PR + LFDN 24 (63.2%) 85 (48.6%) 28 (17%) 0.001 RDT + HT 14 (36.8%) 90 (51.4%) 137 (83%) Table 1. Clinical characteristics and treatment received at diagnosis by age group a Variable expressed as mean (SD) Urological Oncology 216 175 (46.3%) were between 60 and 70 years, and 165 (43.6%) were older than 70 years. The mean age of each group was 55.8 (SD: 2.9), 65.7 (SD: 2.6) and 74.3 years (SD: 3.1) respectively. The median follow-up of the series was 8.9 years (IQR: 5.5-13.2). In those patients who were < 60 years-old and between 60 and 70 years it reached 10 years (10.6 and 10.4 respectively), however, in the group > 70 years-old it was slightly lower (7.5 years), being the difference statistically significant (p < 0.001). Patients > 70 years had higher Charlson Index scores than the other two groups. Specifically, 48 patients (29.1%) > 70 years had a score > 2, while in the 60-70 years group there were 29 (16.6%) and in the younger group only 5 (13.2%) (p = 0.03). The characteristics of the disease at diagnosis by age group are shown in Table 1. In patients who underwent surgery, we found no differ- ences between age groups in the pathologic findings of the prostatectomy specimen. The patients who associat- ed LFDN were: 20 (83.4%), 68 (80%) and 19 (67.9%) respectively, with no differences in the rate of positive nodes. The mean overall survival of the total series is 16.8 years (95% CI: 15.8 - 17.7). The events recorded dur- ing the follow-up, defined as biochemical recurrence, Figure 2. ROC curve analysis of all ADC values including b values for 400, 800, and 1400 to discriminate variant associated pathology. Table 3. The results of multivariate regression Cox models. Overall survival Coefficient HR CI 95% p Age at diagnosis (/10 years) 0.09 1.09 0.50 2.38 0.820 High risk Gleason 0.23 1.26 0.77 2.06 0.367 High risk PSA 0.08 1.08 0.69 1.71 0.730 High risk T stage 0.35 1.43 0.87 2.33 0.155 Treatment at diagnosis: RP + LNFD 1 RDT 0.04 1.04 0.60 1.82 0.878 Time varying coefficients Age at diagnosis (/10 years) 0.10 1.10 1.01 1.20 0.035 Recurrence-free survival Coefficient HR CI 95% p Age at diagnosis (/10 years) -0.21 0.81 0.61 1.08 0.143 High risk Gleason 0.65 1.92 1.24 2.97 0.003 High risk PSA 0.51 1.66 1.13 2.44 0.010 High risk T stage 0.71 2.02 1.31 3.14 0.002 Treatment at diagnosis: RP + LNFD 1 RDT -1.83 0.16 0.08 0.30 < 0.001 Time varying coefficients RDT 0.19 1.21 1.07 1.37 0.002 Progression-free survival Coefficient HR CI 95% p Age at diagnosis (/10 years) -0.39 0.68 0.43 1.06 0.088 High risk Gleason 0.92 2.50 1.29 4.84 0.007 High risk PSA 0.07 1.07 0.60 1.89 0.820 High risk T stage .05 2.86 1.52 5.36 0.001 Treatment at diagnosis RP + LNFD 1 RDT -0.29 0.75 0.39 1.43 0.384 Prostate cancer survival by age-Garcia-Fuentes et al. Vol 20 No 4 July-August 2023 217 Urological Oncology 218 progression to metastasis and death, and the estimated 10-year survival by age group is shown are presented in Table 2. Kaplan-Meier overall, cancer-specific, biochemical re- currence-free and metastasis progression-free survival curves are presented in Figure 1. The multivariate Cox PH regression model for overall survival showed that age has a time-dependent effect, with a statistically significant estimated time-varying coefficient and an estimated time-dependent HR of 1.1 (95% CI: 1.01-1.2, p = 0.035), whereby the HR is not constant over time increasing a 10% for each year dur- ing follow-up, therefore the HR is 1.2 in the first year of follow-up raising to 2.8 in the tenth year. However, in biochemical recurrence-free survival, age was no longer a risk factor, being the treatment re- ceived the one that had a significant impact, with effects change over time. The time varying coefficient estimat- ed is statistically significant with HR of 1.2 (95% CI: 1.1-1.4) so RDT had a protect effect in first year with HR= 0.2, but this protect effect decrease over time, with null effect in tenth year of follow up. Tumor-dependent variables (PSA, Gleason and T) were also significantly related to biochemical recurrence-free survival. Finally, in metastasis progression-free survival, neither age nor initial treatment at diagnosis had an impact on survival. Tumor-dependent variables Gleason and T stage were significantly associated. DISCUSSION There are no studies comparing survival outcomes in high-risk prostate cancer by age group, which is the main objective of our study. We found some studies about active treatment in PC according to the recommendations of the NCCN and EAU guidelines most of them in young patients, with- out a good representation of older ones.(6) However, it has been confirmed that elderly patients with localized prostate cancer are eligible for radical treatment with curative intent with good oncologic outcomes.(7) Due the aging population, several studies have empha- Figure 1. Kaplan-Meier overall, cancer-specific, biochemical recurrence-free and metastasis progression-free survival curves. Prostate cancer survival by age-Garcia-Fuentes et al. sized the need to change the approach of the disease by prioritizing tumour stage and biology over age, as they appear to have a greater impact on oncological out- comes.(8,9) All patients included in our series were treated accord- ing to the standard of care indicated in the guidelines. We believe that our findings may be interesting because we do not describe only the results in elderly patients, but we compare them with the rest of the patients in- cluded in our institutional database and perform a mul- tivariate analysis to find out if age actually influences in the results obtained or if it is a confounding factor. In general terms, our data on the survival of high-risk PC patients treated with curative intent are similar to those described in the literature.(10) The results obtained in overall survival were more favorable for the young- er group, without finding relevant differences in can- cer-specific survival between groups. However, as de- scribed in the results, there were significant differences in the treatment of the different age groups and because of this, we must take into account that the groups are not completely comparable and the results should be inter- preted with some caution. According to data from the National Registry, RP is the most frequent treatment for PC in our country, followed by RDT.(11) In our study, which only includes high-risk patients, we found a higher percentage of patients treat- ed with radiotherapy than with surgery, since it was not until 2009 that we started to perform RP associated with lymphadenectomy in high-risk patients. Although there is no age threshold that limits or con- traindicates surgery, it seems that patients with a life expectancy > 10 years benefit more from this therapeu- tic modality than those with a shorter life expectancy. (12) It has been shown that the greater number of comor- bidities, the greater likelihood of mortality from other causes unrelated to prostate cancer.(13,14) Based on this, and as we have seen in our results and as described in numerous studies, the patient's characteristics are the main variables to be taken into account when deciding the most appropriate type of treatment in each case. These findings are closely related to the retrospective review by Park et al. investigating the efficacy of the age-adjusted Charlson Comorbidity Index as a prognos- tic factor after RP in patients with very high-risk pros- tate cancer, confirming this hypothesis.(15) Post et al. also discussed this topic, confirming in their study that comorbidity was the most important prognostic factor in localized prostate cancer, especially for those under 70 years.(16) To this date, several meta-analyses comparing RP and RDT treatments have been published. Specifically, Wallis et al., Petrelli et al. and Roach et al. report bet- ter overall survival outcomes in patients treated with surgery than in those receiving RDT. The first one de- scribes a higher risk of overall mortality (HR = 1.63, p < 0.001) in the case of RDT, even in the analysis by risk subgroups and radiation regimen (SRT, IMRT, BT). The last two authors attribute this advantage to the dif- ferent baseline characteristics of the patients, assuming that those undergoing PR present a lower rate of comor- bidities.(17,18,19) In our series, we found no differences in overall sur- vival according to the treatment received in the mul- tivariate analysis. However, age does seem to be a de- termining factor in the evolution of the patients since, as mentioned above, advanced age is associated with a greater number of comorbidities and, consequently, with a greater probability of all-cause mortality. Therefore, older patients (> 70 years) have a reduced overall survival. However, these results are not repro- duced in cancer-specific survival, with the 3 age groups presenting similar survival rates. In relation to the aforementioned, Hamstra et al. studied the impact of age on overall survival, cancer-specific survival and 10-year metastasis-free survival in patients with high-risk PC. Broadly speaking, they agree on the relationship between age and patient survival, with the older age group (≤ 70 vs >70 years) showing a poorer overall survival (55% vs 41% respectively; p < 0.001), although better results in cancer-specific survival (18% vs 14%; p < 0.001) and metastasis-free survival (27% vs 20%; p < 0.001).(20) These results contrast with those described by Lin et al. who carried out a cohort study to analyze the possible relationship between age at diagnosis, tumor character- istics and survival in patients with prostate cancer. In their case they divided the patients by age group into 35-44, 45-54, 55-64 and 64-75 years, with the young- est group showing worse results than the rest, both in overall survival and cancer-specific survival, in high- risk tumors.(5) Our series also reports worse cancer-specific survival results in the younger group. We think that the type of treatment received may act as a confounding factor in the results obtained. As noted in the study by Briganti et al., in high-risk prostate cancer, long-term cancer-spe- cific mortality after radical prostatectomy is the lead- ing cause of death in young and presumably healthy patients. In contrast, older patients (with more associ- ated comorbidities and multiple risk factors) are more at risk of dying from other causes and therefore their cancer-specific mortality is lower although their overall survival will also be poorer.(21) When we focus on biochemical recurrence-free surviv- al, we assume the premise given by the study of D'Am- ico et al., who demonstrated that 29% of high-risk pa- tients treated with radical prostatectomy remained free of disease at 10 years.(22) In our study these figures are relatively higher, 44% in younger patients, 59% in patients between 60 and 70 years of age and 62% in older patients, although we must take into account that our series includes patients treated with adjuvant RDT+ HT, and that the median follow-up for the older group does not reach 10 years, which could partly justify these results. In addition, it is important to note that, although in the univariate analysis the younger age group is the one that shows the worst results in biochemical recurrence-free survival, in the multivariate analysis it is no longer significant, observing that the variables that are inde- pendently related to recurrence-free survival are the treatment received and the characteristics of the tumor. These data contrast with those described by Smith et al., who demonstrate a 10-year biochemical recurrence-free survival close to 60% in patients aged < 60 years. In fact, in younger patients (< 50 years), the results are even better with 10-year survivals around 90% (p = 0.010). After multivariate analysis adjusted for race, clinical and pathologic stage and pretreatment PSA, age remained a significant prognostic factor (p = 0.033).(23) Prostate cancer survival by age-Garcia-Fuentes et al. Vol 20 No 4 July-August 2023 219 Urological Oncology 220 It should be noted that this study only includes patients treated with RP and not RDT as in our case. In relation to the previous discussion and according to the results obtained in our series regarding to the pos- sible influence of the treatment received on survival free of biochemical recurrence, we must note that the criteria for biochemical recurrence after prostatectomy and after RDT are different and, therefore, these results must be interpreted with certain caution. Our study is not free of the limitations inherent to an ob- servational, retrospective, single-center study. In addi- tion, the sample size is somewhat limited, and some of the age groups have a small number of patients. In spite of this, our series has a long follow-up and a non-neg- ligible number of patients. Admiteddly, strong conclu- sions cannot be drawn but our hypothesis deserves fur- ther specifically designed studies. CONCLUSIONS In our series, survival of patients with high-risk PC treated with curative intent is similar to that described in the literature. Age only influences in overall survival, with no impact on cancer-specific survival, free of bio- chemical recurrence or progression to metastasis. ACKNOWLEDGEMENTS This study was developed in the Department of Urol- ogy, Hospital Universitario Fundación Alcorcón, as a research project. Special thanks to all the authors for their contribution to this manuscript, especially to Dr. Guijarro and Dr. Llorente for their support in the prepa- ration and revision of the manuscript. CONFLICT OF INTEREST The authors report no conflict of interest. REFERENCES 1. Sung H, Ferlay J, Siegel RL, Laversanne M, 1. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2019. CA Cancer J Clin. 2019; 69:7-34. 2. Cooperberg MR, Broering JM, Carroll PR. Time trends and local variation in primary treatment of localized prostate cancer. J Clin Oncol. 2010; 28:1117-23. 3. 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