Abstract
Background/Aim: To quantify the prognostic impact of age on relapse and mortality in patients with metastatic testicular germ cell tumors (TGCT). Patients and Methods: Electronical medical records of 1,225 TGCT patients who were treated at a single academic center between 1994 and 2015 were reviewed. Results: Higher age did not predict for worse progression-free survival (PFS) or for higher progression risk. The corresponding 5-year PFS estimates were 85% in patients younger than 40 years and 83% in the elderly population. Although not statistically significant, higher age was numerically associated with worse overall survival (OS) (univariate HR per five years increase in age=1.18, 95%CI=0.99-1.41). This was explained in regression analysis where age predicted for significantly higher risk of treatment-related death (p=0.022). Conclusion: Elderly patients with metastatic TGCT can achieve high cure rates similar to younger patients if they tolerate risk-adapted chemotherapy.
Testicular germ cell tumors (TGCT) are the most common cancers in men aged 20 to 40 years (1, 2). However, approximately a quarter of patients are aged above 40 when they are diagnosed with TGCT and there is evidence of a shift towards higher age in recent years (3, 4). It is speculated that men with metastatic germ cell cancer who are above 40 years old have adverse outcome (3, 5-7). However, it is unclear if this association relies on a more aggressive tumor biology in the elderly patients, on reduced sensitivity to treatment or on treatment modifications due to comorbidities (8, 9). Miller et al. have analyzed 603 men with metastatic TGCT and have shown that men older than 40 years have a higher risk of relapse and a higher risk of death (5). They have also demonstrated that there was a significant difference in treatment patterns between the two age groups. After restriction of analysis to men who received risk-appropriate treatment the association between age and outcome became even stronger. These data suggest that the association between age and outcome may be confounded by a weaker tolerance of treatment by the elderly patients, due to comorbidities and worse performance status. Surprisingly, they have also found a higher risk for relapse when the analysis was restricted to patients who received risk-appropriate treatment. We, therefore, performed an analysis in our single-center institution to investigate age as a predictor for treatment outcome and closely examined treatment differences and dose modifications in the two age groups.
Patients and Methods
Study design. Electronical medical records of all consecutive TGCT patients (n=1225) who presented to the Division of Oncology at the Medical University of Graz between January 1994 and December 2015, were retrospectively reviewed. All patients with metastatic TGCT (n=353, clinical stage 1 disease at diagnosis with subsequent relapse or metastatic disease at diagnosis) were included in the final analysis. Patients were initially staged using computed tomographic (CT) scans of the abdomen and chest and tumor markers α-fetoprotein (AFP), human chorionic gonadotropin (HCG) and lactate dehydrogenase (LDH). Patients were risk-classified according to the International Germ Cell Cancer Collaborative Group (IGCCCG) classification. Treatment modalities were documented including dose modifications. Follow-up data were retrieved until January 2019. The study was approved by the Institutional Review Board of the Medical University of Graz (No. 26-196 ex 13/1).
Statistical methods. All statistical analyses were performed with Stata (Windows version 15.0, Stata Corp., Houston, TX, USA). Continuous variables were reported as medians [25th-75th percentile], whereas categorical data were summarized as absolute frequencies (%). The associations of continuous and categorical variables were quantified with chi-squared tests, Fisher's exact tests, and rank-sum tests, as appropriate. Age was treated as both a continuous variable as well as a binary variable with a cut-off at 40 years of age as previously reported by Miller et al. (5). Progression-free and overall survival (PFS and OS) were estimated with Kaplan–Meier estimators, whereas risks of progression were computed with competing risk cumulative incidence estimators treating death-from-any-cause as the competing event of interest. Modelling of event rates were estimated with uni- and multivariable Cox proportional hazards regression models (PFS, OS) and Fine & Gray proportional subdistribution hazards regression models (progression risk). Subsequent time-dependent risks of death were estimated with flexible parametric models with restricted cubic splines for the baseline hazard function (10).
Results
Overall, 353 patients were included in the final analysis (Table I). Median age was 36 years (IQR=28-42 years), half of the cohort had nonseminomatous germ cell tumours (NSGCT, n=188, 54%) and more than two thirds had IGCCCG good risk disease (n=277, 78%). As compared to patients <40 years (n=235, 67%), patients ≥40 years (n=118, 33%) had a higher body mass index (BMI) and were more likely to have seminomatous germ cell tumors (SGCT) and less likely to have de novo metastatic disease. Moreover, treatment with radiotherapy was more common in patients ≥40 years as well as Cisplatin/Etoposide (PE) chemotherapy (Table I). Otherwise the distribution of IGCCCG risk classes and Karnofsky indices were similar between the two age groups. Information about treatment regimens with respect to IGCCCG risk classification is given in Table II. Before 2001, the standard chemotherapy regimen for metastatic TGCT was four cycles of Bleomycin/Etoposide/Cisplatin (BEP) chemotherapy. In 2001, this was modified to 3cycles of BEP for patients with good prognosis and four cycles for patients with intermediate and poor prognosis.
Patients were followed-up for a median interval of 8.1 years, with 75% and 25% having follow-up times of at least 4.4. and 10.9 years, respectively. During this interval, 50 patients suffered from disease progression and 32 patients died. Deaths were adjudicated as related to disease progression (n=20, 63%), treatment complications (n=9, 28%) and other causes (n=3, 9%). Overall, this corresponded to 5-year PFS, progression risk, and OS estimates of 84% (95%CI=80-88), 14% (95%CI=10-18), and 91% (95%CI=88-94), respectively.
In univariate time-to-event analysis, higher age did not predict for worse PFS, higher progression risk, or worse OS. In detail, 5-year PFS estimates were 85% in patients <40 years and 83% in patients ≥40 years (log rank test p=0.934, Figure 1a). Corresponding estimates were 15% and 12% for progression risk (Grays test p=0.356, Figure 1b), and 93% and 87% for OS (log rank test p=0.143, Figure 1c). Within IGCCCG risk groups, patients <40 and ≥40 years had 5-year OS estimates of 98% and 91% in the good-risk group, 88% and 81% in the intermediate-risk group, and 72% and 51% in the poor-risk group, respectively.
Although not statistically significant at the five percent level, higher age was numerically and also borderline statistically significantly associated with worse OS (univariable HR per five years increase in age=1.18, 95%CI=0.99-1.41). In detail, a weak age-dependency of this observation was observed (p for interaction of age with linear follow-up time=0.124), with patients aged 40 or older having slightly worse short-term OS outcomes. This was confirmed in flexible parametric modelling of OS rates that indicated that patients in the elder group experienced higher rates of early mortality which, however, fell below the mortality of the younger age group after approximately 3 years of treatment initiation (Figure 2).
Analysis of causes of death suggested that deaths in the elderly group were primarily related to treatment complications and other causes (lung cancer, suicide, unknown), whereas deaths in the younger group were mainly related to disease progression (p=0.043).
In the elder group, one patient died from neutropenic sepsis, one patient developed acute leukaemia during salvage chemotherapy and three patients died from cardiovascular complications which were considered treatment-related. Two of those fatal events happened during first-line chemotherapy and one event occurred during salvage chemotherapy. In the younger group, one patient died from pulmonary embolism and two patients developed acute leukaemia while receiving further chemotherapy for subsequent relapses. This observation was confirmed in regression analysis where age ≥40 was related to a significantly higher risk of treatment-related death and death from other causes (HR=4.07, 95%CI=1.22-13.53, p=0.022), but not for death due to disease progression (HR=0.96, 95%CI=0.37-2.49, p=0.929) (Figure 3).
Importantly, a weak interaction between age, IGCCCG classification and PFS (p for interaction 0.076) was observed. In detail, 5-year PFS was worse in elder patients with good risk disease than in younger patients (HR per 5 years increase=1.20, 95%CI=1.02-1.42, p=0.028) whereas this association was not observed in patients with intermediate/poor risk disease (HR per 5 years increase=0.94, 95%CI=0.76-1.17 p=0.591). However, when patients with good risk who received radiotherapy were excluded, the adverse association between age and PFS became weaker (HR per 5 years increase 1.18, 95%CI=0.97-1.44, p=0.097).
Baseline characteristics – Overall distribution and by age group.
Other predictors of worse PFS were Karnofsky index<100%, residual mass, intermediate/poor IGCCCG risk and treatment adaption (Table III).
Discussion
In contrast to other studies, our retrospective cohort study could not confirm that age is a predictor for a higher risk of relapse after first line chemotherapy in TGCT patients (3, 5, 9). However, older patients showed a worse short-term OS that was explained by treatment-related compli-cations.
Treatment regimens by age group and IGCCCG risk classification.
Uni- and multivariate predictors of progression free survival – Cox regression.
Different factors like adjuvant treatment modalities, chemotherapy regimens and dose modifications during curative treatment influence prognosis of recurrent disease and, therefore, need to be taken into account (11-15). A very large registry of nearly 28,000 TGCT patients showed an increased mortality in men aged above 40 regardless of histology. As mentioned in that study, detailed information about treatment and risk distribution according to IGCCCG criteria was missing in this population (3). In a second study by Miller, including 603 patients with metastatic disease, the increased mortality for men aged ≥40 did not reach statistical significance in the subgroup of patients with metastatic seminoma. Interestingly, 46% of patients in our study population had SGCT compared to 25% of patients in Miller's study. When looking back at the adjuvant treatment modalities of SGCT patients, 87% of men in our cohort where managed with active surveillance compared to 65% of patients in Miller's cohort. This explains the higher percentage of SGCT patients with relapsed disease in our study population (16-20). Miller et al. have pointed out that there was a significant difference in treatment modalities between the two age groups. Men in the elderly group were more likely to receive a ‘not appropriate’ first-line chemotherapy. The authors also noted that the study lacked detailed information about exact chemotherapy dosing as many patients had first-line therapy at other institutions. Another retrospective analysis by Thomson et al. has confirmed the reduced cancer specific survival in TGCT patients aged ≥40 years treated with BEP chemotherapy. The association between age and progression-free survival was borderline significant (p=0.06). There were no differences in the administered doses of cisplatin and etoposide between the age groups but a decreased number of bleomycin doses was administered in the older patients (9). The inclusion of bleomycin in chemotherapy regimens has not significantly improved OS in previous studies but three cycles of BEP consistently showed a numerically superior outcome compared to four cycles of EP (12, 13). In our study, detailed information about treatment modifications during first line chemotherapy was obtained and no significant differences in treatment adaption between the two age groups was found. Although 96% of our patients received full doses of chemotherapy, we were able to show that treatment adaption was associated with a higher risk of progression. Similarly, in a smaller study by Inci et al. with 93 TGCT patients who were older than 40 years no correlation between age and survival could be found after adjusting for tumor stage (21).
Progression-free survival, progression risk and overall survival by age group.
Interestingly, when restricting our analysis to the IGCCCG good risk population, an age dependent outcome was found. Looking closer, the IGCCCG good risk population allows more flexibility in treatment options (1). Patients with stage IIA SGCT can be offered curative radiotherapy instead of chemotherapy. Furthermore, patients can be treated with either 3 cycles BEP or four cycles PE. Treatment with radiotherapy was more common in patients ≥40 years as well as PE chemotherapy. When restricting the analysis to patients who received curative chemotherapy, no age dependent outcome was found. Our findings are in accordance with the results of the Swedish Norwegian testicular cancer study group who showed a significantly higher relapse rate for CS IIA SGCT patients who were treated with curative radiotherapy compared to patients who received curative chemotherapy (22).
In IGCCCG intermediate risk patients, treatment did not differ between the age groups in our study population. In the poor risk group, more patients from the older group received etoposide/ifosfamide/cisplatin (VIP) chemotherapy instead of BEP chemotherapy. No significant difference in treatment adaption was noted. However, there were six treatment-related deaths in the elderly patient group compared to three treatment-related deaths in the younger patients. Cardiovascular complications were the main reasons in patients older than 40 years whereas two patients from the younger population suffered from acute leukaemia.
Our study results give the impression that elderly TGCT patients have adverse outcome due to less tolerance to risk-adapted treatment. This is supported by the fact that patients in the elder group experienced higher early mortality which reflects treatment-related complications. One patient in the younger group experienced a fatal event while three patients in the elder group died during first line chemotherapy.
Our cohort is not as big as the cohort of Miller, but the advantage of this single institution report is that detailed information about treatment modifications was available. Several factors like risk classification, adjuvant treatment modalities and dose modifications need to be considered to solve the question about an association between age as a predictor for metastatic TGCT patients. A definitive answer can only be given in a prospective study.
Six-month risk of death after treatment initiation.
Death due to disease progression or due to treatment-related complications/other causes by age group.
In conclusion, our study results suggest that patients aged 40 years old or higher can achieve the same outcome as younger patients if they tolerate risk-adapted treatment. However, comorbidities and prior therapies need to be taken into account as fatal treatment-related complications occur more often in the elderly patients.
Footnotes
Authors' Contributions
A.T. collected the data, conceived and designed the analysis, wrote the manuscript; F.P. performed the analysis and wrote the manuscript; T.B. supervised the work and commented on the manuscript; M.P. supervised the work and commented on the manuscript; H.P. collected the data and commented on the manuscript; J.S. collected the data and commented on the manuscript; J.R. collected the data and commented on the manuscript; G.C.H. supervised the work and commented on the manuscript; K.P. supervised the work and commented on the manuscript; R.P. collected the data and commented on the manuscript; K.S.K. supervised the work and commented on the manuscript; H.S. supervised the work and commented on the manuscript; M.S. collected the data, supervised the work and commented on the manuscript; A.G. supervised the work and commented on the manuscript.
Conflicts of Interest
The Authors of this manuscript have no financial disclosures or conflicts of interest to report.
- Received August 14, 2019.
- Revision received August 30, 2019.
- Accepted September 3, 2019.
- Copyright© 2019, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved
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