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Platinum Priority – Testis Cancer
Editorial by XXX on pp. x–y of this issue

Conditional Risk of Relapse in Surveillance for Clinical Stage I Testicular Cancer

By: Madhur Nayana, Michael A.S. Jewetta, Ali Hosnib, Lynn Anson-Cartwrighta, Philippe L. Bedardc, Malcolm Moored, Aaron R. Hansenc, Peter Chungb, Padraig Wardeb, Joan Sweete, Martin O’Malleyf, Eshetu G. Atenafug and Robert J. Hamiltona

European Urology, Volume 71 Issue 1, January 2017, Pages 120-127

Published online: 01 January 2017

Keywords: Germ cell tumor, Testicular neoplasm, Treatment outcome

Abstract Full Text Full Text PDF (2,1 MB)

Abstract

Background

Patients on surveillance for clinical stage I (CSI) testicular cancer are counseled regarding their baseline risk of relapse. The conditional risk of relapse (cRR), which provides prognostic information on patients who have survived for a period of time without relapse, have not been determined for CSI testicular cancer.

Objective

To determine cRR in CSI testicular cancer.

Design, setting, and participants

We reviewed 1239 patients with CSI testicular cancer managed with surveillance at a tertiary academic centre between 1980 and 2014.

Outcome measurements and statistical analysis

cRR estimates were calculated using the Kaplan-Meier method. We stratified patients according to validated risk factors for relapse. We used linear regression to determine cRR trends over time.

Results and limitations

At orchiectomy, the risk of relapse within 5 yr was 42.4%, 17.3%, 20.3%, and 12.2% among patients with high-risk nonseminomatous germ cell tumor (NSGCT), low-risk NSGCT, seminoma with tumor size ≥3 cm, and seminoma with tumor size <3 cm, respectively. However, for patients without relapse within the first 2 yr of follow-up, the corresponding risk of relapse within the next 5 yr in the groups was 0.0%, 1.0% (95% confidence interval [CI] 0.3–1.7%), 5.6% (95% CI 3.1–8.2%), and 3.9% (95% CI 1.4–6.4%). Over time, cRR decreased (p ≤ 0.021) in all models. Limitations include changes to surveillance protocols over time and few late relapses.

Conclusions

After 2 yr, the risk of relapse on surveillance for CSI testicular cancer is very low. Consideration should be given to adapting surveillance protocols to individualized risk of relapse based on cRR as opposed to static protocols based on baseline factors. This strategy could reduce the intensity of follow-up for the majority of patients.

Patient summary

Our study is the first to provide data on the future risk of relapse during surveillance for clinical stage I testicular cancer, given a patient has been without relapse for a specified period of time.

Take Home Message

Surveillance protocols in clinical stage I testicular cancer should be based on individualized estimates of the conditional risk of relapse. This may reduce clinic visits, exposure to radiation, and the cost of follow-up for the majority of patients.

Keywords: Germ cell tumor, Testicular neoplasm, Treatment outcome.

1. Introduction

Following orchiectomy, the 5-yr relapse rate for patients with clinical stage I (CSI) nonseminomatous germ cell tumor (NSGCT) is approximately 30%, while the relapse rate for CSI seminoma is approximately 15% [1] and [2]. Given the relatively low risk of relapse in CSI disease, many guidelines recommend surveillance as the preferred initial treatment for all CSI seminomas and low-risk NSGCTs [3], [4], and [5]. Surveillance has also been adopted by many centers for high-risk CSI NSGCT, as many patients do not require further therapy and those that do experience relapse can be treated with salvage therapy with high success [2], [6], and [7].

At the time of diagnosis, patients are informed of their relapse risk on surveillance. However, this baseline relapse risk does not reflect how prognosis changes over time, and can be considered a “static” prediction [8]. Patients and physicians would be more interested in the probability of future relapse, given that a patient has survived a period of time without relapse. This “dynamic”, more clinically meaningful risk is a concept referred to as conditional survival. Conditional survival has been reported for various malignancies, including testicular cancer [9], [10], [11], [12], [13], [14], [15], [16], [17], [18], and [19], but not specifically for surveillance in testicular cancer. We therefore evaluated the conditional risk of relapse (cRR) in our large institutional cohort stratified according to validated risk factors for relapse.

2. Patients and methods

2.1. Data source and cohort definition

Approval was obtained from our institutional Research Ethics Board. A total of 1355 patients with CSI disease managed with surveillance at Princess Margaret Cancer Centre were identified from our institutional database. Of these, 464 patients underwent orchiectomy for NSGCT between 1980 and 2011, and 893 patients underwent orchiectomy for seminoma between 1985 and 2014. Data were complete for all patients with NSGCT and for 775 (87%) of those with seminoma.

Our surveillance follow-up protocols have previously been reported [20] and [21]. For NSGCT cases, patients are usually followed for 5 yr before transition back to primary care. Although the protocol has evolved over the years, our current protocol includes measurement of tumor markers every 2 mo in the first 2 yr, then every 4 mo in year 3, every 6 mo in year 4, and yearly in year 5; low-dose computed tomography (CT) of the chest, abdomen, and pelvis every 4 mo in the first year, and then at the end of years 2 and 5. Patients with seminoma are usually followed for 9 yr before transition back to primary care. The protocol has also evolved over time but currently describes abdominal/pelvic CT every 6 mo for the first 3 yr, then abdominal CT only at year 4, 5, 7 and 9.

Disease relapse was defined as imaging or physical examination evidence of metastases and/or elevated tumor markers. Any relapses occurring after discharge to primary care were referred back to our centre for subsequent management. Outside pathology specimens for NSGCT were reviewed by Princess Margaret genitourinary pathologists in 90% of cases. When available, pathology review from Princess Margaret was used in the analysis.

2.2. Statistical analysis

The Kaplan-Meier product limit method was used to evaluate relapse-free survival. Relapse-free survival was measured from the date of orchiectomy to date of relapse or date of last follow-up. Patients were censored at their last follow-up if they did not experience relapse.

The 2-yr and 5-yr cRR estimates were calculated using Kaplan-Meier survival estimates at time points corresponding to visits in our surveillance protocol [22]. The 95% confidence intervals were calculated using a modified Greenwood formula [14].

Variables included in the model were chosen a priori based on validated risk factors for relapse on surveillance and included overall stage at presentation (stage IB vs IA) [23] and pure embryonal carcinoma (EC) in orchiectomy pathology for NSGCT [2] and [6], and primary tumor size for seminoma [24], [25], and [26]. To avoid collinearity, lymphovascular invasion was not included in the models for NSGCT as this information is captured in the overall stage at presentation. To allow for stratified cRR estimates based on tumor size in seminoma, tumor size was dichotomized to ≥3 cm versus <3 cm on the basis of results from our previous report [26].

To evaluate whether changes in the surveillance protocol over time may have influenced the timing of detected relapses, we evaluated whether including year of orchiectomy was predictive of outcome in both the NSGCT and seminoma models.

We used linear regression to evaluate whether cRR improved over time. All statistical analyses were performed using SAS (version 9.4; SAS Institute, Cary, NC, USA). A two-sided value of p < 0.05 was considered statistically significant.

3. Results

3.1. NSGCT

The baseline cohort characteristics are presented in Table 1. Of the 464 patients managed with surveillance for CSI NSGCT, 74 (15.9%) had pure EC on orchiectomy pathology, and 121 (26.1%) had CSIB disease. There were 126 patients with disease relapse. Median follow-up among those without relapse was 60.6 mo (interquartile range 34.1–99.1).

Table 1

Cohort characteristics for 1239 patients managed with surveillance for clinical stage I testicular cancer

Nonseminoma ( n =464)
Year of orchiectomy, n (%)
 1980–1989110 (24)
 1990–1999142 (30)
 2000–2011212 (46)
Mean age at orchiectomy, yr (SD)30.3 (8.6)
Left-sided orchiectomy, n (%)207 (45)
pT stage, n (%)
 pT1343 (73.9)
 pT2115 (24.8)
 pT34 (0.9)
 pT42 (0.4)
Mean tumor size, cm (SD)3.73 (2.68) a
Rete testis invasion, n (%)
 Yes173 (37.3)
 No113 (24.3)
 Unknown178 (38.4)
Pure embryonal carcinoma on orchiectomy pathology, n (%)74 (16)
Lymphovascular invasion on orchiectomy pathology, n (%)
 Yes115 (25)
 No316 (68)
 Unknown33 (7)
Overall clinical stage at presentation, n (%)
 IA343 (74)
 IB121 (26)
Seminoma ( n =775)
Year of orchiectomy, n (%)
 1985–1994192 (25)
 1995–2004243 (31)
 2005–2014240 (44)
Mean age at orchiectomy, yr (SD)37.00 (9.71)
Left-sided orchiectomy, n (%)361 (47.01)
pT stage, n (%)
 pT1489 (85.94)
 pT252 (9.14)
 pT37 (1.23)
 pT421 (3.69)
 Missing206
Mean tumor size, cm (SD)3.80 (2.17)

a Data missing for 44 men (9.5%).

SD=standard deviation.

Year of orchiectomy was not significantly predictive of relapse in NSGCT (p = 0.12), and therefore the final model consisted of overall stage at presentation and presence of pure EC on orchiectomy pathology.

Stratified cumulative risk of relapse curves are shown in Figure 1. The 2-yr and 5-yr cRR estimates stratified by clinical stage at presentation and pure EC on orchiectomy pathology are shown in Figure 2. Over time, cRR decreased significantly (p ≤ 0.015) in all models.

gr1

Fig. 1

Stratified cumulative risk of relapse among patients on surveillance for clinical stage I nonseminoma germ cell tumors. CS = clinical stage; EC = embryonal carcinoma; w/ = with; w/o = without.

gr2

Fig. 2

(A) The 2-yr conditional risk of relapse among patients on surveillance for CSI nonseminoma germ cell tumors. As an example, if a patient with CSIA w/o Pure EC disease is without relapse at 24 mo, the probability that he will have a relapse in the next 2 yr is 1.0%. Similarly, if the same patient is without relapse at 60 mo, the probability that he will have a relapse in the next 2 yr is 0.0%. (B) The 5-yr conditional risk of relapse among patients on surveillance for CSI nonseminoma germ cell tumors. CS = clinical stage; EC = embryonal carcinoma; w/ = with; w/o = without. Error bars represent 95% confidence intervals.

3.2. Seminoma

The baseline cohort characteristics are presented in Table 1. There were 135 patients with disease relapse. Median follow-up among those without relapse was 88.4 mo (interquartile range 52.1–122.1).

Year of orchiectomy was not significantly predictive of relapse in NSGCT (p = 0.38), and therefore the final model consisted of tumor size only.

Stratified cumulative risk of relapse curves are shown in Figure 3. The 2-yr and 5-yr adjusted cRR estimates stratified by tumor size on orchiectomy pathology are shown in Figure 4. Over time, cRR decreased significantly (p ≤ 0.021) in all models.

gr3

Fig. 3

Stratified cumulative risk of relapse among patients on surveillance for clinical stage I seminoma.

gr4

Fig. 4

(A) The 2-yr and (B) 5-yr conditional risk of relapse among patients on surveillance for clinical stage I seminoma. Error bars represent 95% confidence intervals.

4. Discussion

The present study is the first to provide cRR estimates for CSI testicular cancer patients on surveillance, and revealed a significant improvement over time in cRR in all risk factor subgroups in NSGCT and seminoma. These results have several implications for patients, physicians, and clinical guidelines: given that a diagnosis of testicular cancer can be associated with significant anxiety [27] and [28], cRR estimates may help to reassure patients, provide necessary information to obtain life insurance, and aid in planning for the future. Furthermore, these data could allow tailoring of surveillance follow-up protocols to estimated cRR over time in each risk factor subgroup.

The changes in cRR over time we observed are similar to those in studies evaluating conditional survival in other malignancies [10], [11], [12], [14], and [15]. Previous studies evaluating conditional overall survival across multiple cancers sites have included some testicular cancer patients [16], [17], and [19]. A Canadian population-based study found that 5-yr conditional overall survival for all testicular cancer patients at diagnosis was 95% and increased to 99% at 3 yr [16]. Another European study found that conditional overall survival estimates in testicular cancer patients were comparable across age groups, and became similar to that for the general population after the first year of diagnosis [17]. The former two studies did not differentiate disease histology; however, a more recent European study found that at 1 yr, the 5-yr conditional survival was 94% in seminoma and 88% in NSGCT [19]. While none of these studies distinguished between disease stage, a recent study of 942 patients with metastatic germ-cell tumors found no significant difference in conditional overall survival or relapse-free survival between seminoma and NSGCT [18]. Importantly, none of the above-mentioned studies have direct applicability to CSI testicular cancer, which comprises the majority of newly diagnosed patients.

Our results are consistent with a population-based study by Daugaard et al [2] evaluating outcomes of CSI surveillance in NSGCT. Their study revealed that the baseline risk of relapse depends on the number of risk factors present, the majority of relapses occur early, and that there are few relapses after 2 yr. However, our study provides further insight into the biology of testicular cancer and the timing of relapses within CSI testicular cancer subgroups. For example, in CSIB NSGCT, patients with pure EC disease have an approximately 40% risk of relapse at baseline. All of the relapses in this group occurred early, with the majority occurring before 4–6 mo. Thus, cRR improved rapidly over time. By comparison, patients without risk factors (CSIA and no pure EC) have a low relapse risk at baseline of 15%; cRR improved with time, but more slowly. Consequently, NSGCT patients who were relapse-free at 16 mo with risk factors for relapse had better 5-yr cRR than those without risk factors. Our data suggest that patients deemed at high risk tend to have early relapses; however, they can be considered to have a negligible risk of future relapse at an earlier time than those deemed to have low risk at baseline, who tend to have both early and late relapses. Taken together, the baseline “static” risk of relapse does not reflect the “dynamic” risk of relapse.

These differences in risks of relapse within CSI GCT subgroups may have important implications for clinical guidelines. The current European Association of Urology (EAU) guidelines recommend minimum follow-up schedules in both NSGCT and seminoma [4], but do not provide specific follow-up schedules based on the presence of risk factors. Our results suggest that guideline recommendations in surveillance for CSI testicular cancer should be based on the presence of risk factors, as not only is the baseline risk of relapse different, but the timing of relapses also differs. These cRR estimates may be particularly useful in tailoring follow-up imaging on surveillance. The current EAU guidelines recommend at least an abdominal/pelvic CT scan at 3, 12, 24, and 36 mo in NSGCT, and once a year for the first 5 yr in seminoma [4]. However, every CT scan adds to the cumulative lifetime exposure to ionizing radiation and the lifetime attributable risk for secondary malignancy [29]. If confirmed in other series, our results suggest that the frequency of CT imaging may be reduced, particularly in CSIB NSGCT patients with pure EC and CSIA NSGCT patients without pure EC, all of whom have a negligible risk of relapse after 3 yr. Conversely, CSIB NSGCT patients without pure EC and CSIA NSGCT patients with pure EC may warrant imaging beyond 3 yr. Similar implications for follow-up protocols are applicable to guidelines from other organizations.

Details regarding the timing, location, and method of detection of relapses in our cohort have previously been reported [6], [20], [21], and [30]. Our group has subsequently adjusted surveillance protocols on the basis of these reports, such as including a CT scan at 5 yr in NSGCT, and reducing the frequency of chest X-rays in seminoma. After validation in other surveillance cohorts, we anticipate that cRR estimates will be used to further specify surveillance protocols at our institution based on the presence of risk factors within disease histology, such as reducing the frequency and intensity of follow-up beyond 60 mo among seminoma patients with tumor size <3 cm.

Just as there are differences between centers in follow-up intensity, there are differences in follow-up length on surveillance [7], [31], and [32]. At Princess Margaret, we discharge NSGCT patients after 5 years of surveillance. Our data support this policy for CSIA without pure EC and, surprisingly, in CSIB with pure EC, for whom the 2-yr and 5-yr cRR is <1% at 5 yr. For CSIA with pure EC and CSIB without pure EC, it may be appropriate to prolong surveillance given the 5–8% chance of relapse in the next 5 yr despite having attained 5 yr of relapse-free survival. However, this should also be validated in other surveillance cohorts before implementing such a change. If centers trim their follow-up intensity and duration in keeping with cRR, this would minimize unnecessary physician visits and reduce the global financial burden of surveillance in testicular cancer.

At Princess Margaret we continue to preferentially offer non–risk-adapted surveillance for all CSI seminoma and NSGCT. A criticism of utilizing surveillance for those at high risk of relapse is the issue of noncompliance with follow-up. Those who do not support the use of surveillance quote smaller studies, in which noncompliance can be as high as 20% [33]. However, most large centers report a range of 3–5% [2], [6], and [34]. Data presented in the current study may help to alleviate concerns regarding compliance. For example, if patients at high risk (CSIB, pure EC) can be retained in a surveillance program even for just 8 mo, their 5-yr relapse risk will have decreased to 5%, which is similar to the relapse risk after a primary retroperitoneal lymph node dissection.

There are several limitations to this study. First, there were a limited number of relapses on surveillance. Second, data were missing for approximately 13% of seminoma patients. However, the majority of these patients were diagnosed at peripheral institutions or before the year 2000, after which data collection has improved. While it is possible that patients diagnosed outside our institution may differ, we previously demonstrated that the risk of progression on surveillance does not differ for orchiectomy performed outside of the Princess Margaret Cancer Centre [35]. Third, Daugaard et al [2] suggested that rete testis invasion is a prognostic marker of relapse in NSGCT; however, information on rete testis invasion was missing for one-third of our NSGCT subgroup. To date, only the Daugaard study demonstrated rete testis invasion as an independent prognostic factor in NSGCT and used imputation to assign values for patients with missing data for this factor, which comprised approximately 40% of their cohort [2]. When their analysis was restricted to patients with complete data, rete testis invasion was no longer significant [2]. Thus, the prognostic role of rete testis invasion in NSGCT remains unclear. While there is debate regarding risk factors associated with progression on surveillance, the results of this study should be used to tailor surveillance protocols based on individualized risk of relapse, with more intense follow-up reserved for patients deemed at higher risk, rather than based broadly on disease histology. Fourth, the accuracy of CT staging has improved over time and therefore it is possible that patients diagnosed in earlier years were misclassified as CSI, biasing towards earlier relapse. Indeed, we previously demonstrated a higher rate of relapse in earlier years, probably explained by stage migration because of better diagnostic evaluation [6]. Furthermore, changes in the surveillance protocol over time may have influenced the timing of detected relapses. However, year of orchiectomy was not predictive of relapse in either analysis, suggesting against a strong effect of this bias. Despite these limitations, our study capitalizes on a large cohort with extended follow-up and is the first to provide cRR estimates for testicular cancer during surveillance.

5. Conclusions

The conditional risk of relapse decreases over time in patients managed with surveillance for CSI testicular cancer. Providing patients with a personalized, more clinically meaningful estimate of their future risk of relapse during surveillance can aid in counseling and decrease anxiety for the patient and treating physician. Furthermore, consideration should be given to adapting surveillance protocols to individualized estimates of the conditional risk of relapse, which are likely to reduce the intensity of follow-up for the majority of patients.


Author contributions: Madhur Nayan had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: Nayan, Hamilton.

Acquisition of data: Nayan, Jewett, Hosni, Anson-Cartwright, Bedard, Moore, Hansen, Chung, Warde, Sweet, O’Malley, Atenafu, Hamilton.

Analysis and interpretation of data: Nayan, Jewett, Hosni, Anson-Cartwright, Bedard, Moore, Hansen, Chung, Warde, Sweet, O’Malley, Atenafu, Hamilton.

Drafting of the manuscript: Nayan.

Critical revision of the manuscript for important intellectual content: Jewett, Hosni, Anson-Cartwright, Bedard, Moore, Hansen, Chung, Warde, Sweet, O’Malley, Atenafu, Hamilton.

Statistical analysis: Nayan, Atenafu.

Obtaining funding: None.

Administrative, technical, or material support: Hamilton.

Supervision: Hamilton.

Other: None.

Financial disclosures: Madhur Nayan certifies that all conflicts of interest, including specific financial interests and relationships and affiliations relevant to the subject matter or materials discussed in the manuscript (eg, employment/affiliation, grants or funding, consultancies, honoraria, stock ownership or options, expert testimony, royalties, or patents filed, received, or pending), are the following: None.

Funding/Support and role of the sponsor: None.

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Footnotes

a Division of Urology, Departments of Surgery and Surgical Oncology, Princess Margaret Cancer Centre, University Health Network and the University of Toronto, Toronto, Canada

b Department of Radiation Oncology, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada

c Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre, University Health Network, Department of Medicine, University of Toronto, Toronto, Ontario, Canada

d British Columbia Cancer Agency, Vancouver, Canada

e Department of Pathology, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada

f Department of Medical Imaging, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada

g Department of Biostatistics, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada

Corresponding author. Division of Urology, Department of Surgery, Princess Margaret Cancer Centre, University Health Network, 610 University Avenue, Toronto, Ontario M5G 2M9, Canada. Tel. +1 416 9462909; Fax: +1 416 9466590.

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