Risk Factors for Loss to Follow-up During Active Surveillance of Patients with Stage I Seminoma

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1 Jpn J Clin Oncol 2014;44(4) doi: /jjco/hyu001 Advance Access Publication 20 February 2014 Risk Factors for Loss to Follow-up During Active Surveillance of Patients with Stage I Seminoma Tsuyoshi Endo 1, Koji Kawai 2, Tomomi Kamba 3, Hiromu Inai 1, Kazunori Uchida 1, Jun Miyazaki 2, Toshiyuki Kamoto 4, Osamu Ogawa 3 and Hiroyuki Nishiyama 2,* 1 Department of Urology, International University of Health and Welfare Hospital, Nasushiobara, Tochigi, 2 Department of Urology, Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki, 3 Department of Urology, Kyoto University Graduate School of Medicine, Sakyo-ku, Kyoto and 4 Department of Urology, Faculty of Medicine, University of Miyazaki, Kiyotake, Miyazaki, Japan *For reprints and all correspondence: Hiroyuki Nishiyama, Department of Urology, Faculty of Medicine, University of Tsukuba, Tennodai, Tsukuba, Ibaraki , Japan. nishiuro@md.tsukuba.ac.jp Received August 15, 2013; accepted December 27, 2013 Objective: To elucidate the patterns and risk factors for loss to follow-up during active surveillance for Stage I seminoma. Methods: A total of 425 cases with Stage I seminoma underwent radical orchiectomy from 1985 to 2006 at 25 Japanese institutions, including 22 community hospitals and 3 university hospitals. The post-orchiectomy management selected was active surveillance for 186 patients, adjuvant radiotherapy for 182 patients and chemotherapy for 57 patients. The Kaplan Meier method was used to estimate the recurrence-free survival and loss to follow-up rate. The risk factors for loss to follow-up were examined using Cox s proportional hazards model with multiple variables. Results: The 2-, 5- and 10-year loss to follow-up rates in the active surveillance group were 14.2, 37.8 and 71.3%, respectively, which were not significantly different in comparison with those in the active surveillance and adjuvant radiotherapy or chemotherapy groups. With regard to the active surveillance group, the multivariate analysis demonstrated that patients younger than 36 years at diagnosis, patients diagnosed since 2000 and patients treated at hospitals that enrolled more than 10 cases had a significant risk for loss to follow-up. No significant correlation between the loss to follow-up rate and pathological risk factors such as tumor size (4 versus.4 cm) and rete testis invasion (presence versus absence) was shown. Conclusions: The loss to follow-up rates beyond 5 years were unsatisfactorily high during active surveillance. Further approaches to improve the quality of active surveillance are needed, especially for high-risk patients such as those of younger age. Key words: testicular cancer seminoma active surveillance loss to follow-up younger age INTRODUCTION Recently, several investigations showed that early stage testicular seminoma is increasing. Powles et al. (1) reported that over half of testicular tumors diagnosed from 1996 to 2002 were Stage I seminoma. Three post-operative management options can be used for Stage I seminoma: active surveillance (AS), adjuvant radiotherapy (RT) and adjuvant chemotherapy (CT) with carboplatin. A large randomized clinical trial confirmed an equivalent oncological outcome of the latter two options (2), but RT is known to be associated with an increased risk of a second malignancy (3). In addition, concerns about the long-term toxicity of carboplatin remain. When managed with AS, 15 20% of patients with Stage I seminoma will experience a relapse (4), but nearly all the # The Author Published by Oxford University Press. All rights reserved. For Permissions, please journals.permissions@oup.com

2 356 Loss to follow-up during AS for Stage I seminoma relapsed patients can be cured with either subsequent RT or CT if they are under adequate AS. The advantage of AS is that patients can avoid unnecessary exposure to radiation or anticancer drugs without deterioration of overall survival (OS) rates (4). Therefore, recent clinical guidelines recommend AS as one of the preferred options (5,6) ( nccn.org/). Population-based investigations also have shown an increase in the use of AS in Stage I seminoma patients (7,8). However, several disadvantages of AS have been discussed. Frequent hospital visits, repeat blood testing and computed tomography scans, and anxiety about recurrence can compromise patients quality of life (4). Among them, the late relapse, usually defined as relapse after at least 2 years, is the possibly life-threatening disadvantage of AS. The majority of Stage I seminoma patients will relapse within the first 2 years, but a later relapse can also occur. A comprehensive review of surveillance studies reported that 23 of 2060 (2%) patients suffered from a late relapse (4). However, the exact frequency is unclear because follow-up periods differed greatly among studies, being from 30 to 120 months. Therefore, most clinical guidelines recommend a minimum follow-up of 10 years (5,6) ( Practically, this is not easy because young patients often move to different locations and may have difficulties with employment and paying for medical expenses. Previously, we reported the clinical outcomes of 425 Stage I seminoma patients who underwent orchiectomy at 25 hospitals in Japan (9). Three university hospitals and 22 community hospitals participated in that investigation. A total of 186 patients (44%) were managed by AS. This study clearly showed the increasing tendency of AS in the management of Stage I seminoma. Before 1999, only 29% of patients were managed with AS, whereas 60% of patients have been managed with AS since Since 2000, AS has become the first choice management for Stage I seminoma in the study. The clinical outcome was excellent: 10-year progression-free survival (PFS) and OS rates were 79 and 100%, respectively. However, 47% of the patients were lost to follow-up (LTFU), with a median follow-up of 4.5 years. The LTFU rate was higher than expected. Unfortunately, previous study did not analyze what factors were associated with LTFU. To address the question, we conducted the present post hoc analysis using a database of the previous outcome study of Stage I seminoma patients. the medical records. The LTFU was defined as discontinuation of follow-up on medical records. Since we did not plan to include the reasons for discontinuing follow-up, we cannot analyze definitive causes for LTFU in the present study. Other clinical variables available from this database include age at orchiectomy, year of diagnosis and pathological information such as tumor size and rete testis invasion. STATISTICAL ANALYSES The recurrence-free survival (RFS) and LTFU rates were assessed by Kaplan Meier plots. The RFS was calculated from the date of orchiectomy to the date of relapse or the date the patient was last known to be alive and relapse-free. The LTFU rates were calculated from the date of orchiectomy to the date of the last known follow-up visit, regardless of the presence or absence of relapse. The Kaplan Meier plots of RFS and LTFU rates were compared using a log-rank test. The relative effect of different factors on LTFU survival was estimated using Cox s proportional hazards model with multiple variables. We performed a purposeful selection of variables in the analysis, used a P value of,0.05 and excluded variables that were not statistically significant. Statistical analyses were performed using the JMP software (v. 10; SAS Institute, Inc., Cary, NC, USA). In all tests, P values were two-sided and significance was set at P, RESULTS In total, 240 of 425 patients (56.5%) with Stage I seminoma were LTFU, and 30 of 425 patients (7.1%) experienced a relapse of the disease, but no cancer death was observed during the observation period. As shown in Fig. 1, LTFU rates at 2 years were almost the same as the 14.1% of the AS group, 15.1% of the adjuvant RT group and 10.8% of the adjuvant CT group. The LTFU rates obviously increased during subsequent observation. In the AS group, the 5- and 10-year LTFU rates increased to 37.8 and 71.3%, respectively. Again, there PATIENTS AND METHODS PATIENTS A total of 425 cases with Stage I seminoma underwent radical orchiectomy from 1985 to 2006 at 25 Japanese institutions, including 22 community hospitals and 3 university hospitals. The post-orchiectomy management selected was AS for 186 patients, adjuvant RT for 182 patients and CT for 57 patients (9). In the present study, we focused on the 186 patients who were managed by AS. The follow-up data were collected from Figure 1. The Kaplan Meier curve for loss to follow-up (LTFU) in patients managed by active surveillance (AS), adjuvant radiotherapy (RT) and adjuvant chemotherapy (CT). No significant difference was observed among the three groups.

3 Jpn J Clin Oncol 2014;44(4) 357 were no differences in the 5- and 10-year LTFU rates between the AS and adjuvant RT or CT groups. In the AS group, the median age of patients at orchiectomy was 36 years (range 19 84). The median observation period was 44.9 months (range 0 219). The 5-year LTFU rate significantly differed among treatment institutions, ranging from 0 to 64.4%. Four hospitals followed all patients for 5 years. The 10-year LTFU rate of patients treated at these hospitals was 40.7%. We conducted univariate analysis to determine the risk factors of patients LTFU. Figure 2 represents the Kaplan Meier plots according to patient age at orchiectomy, time of orchiectomy, hospital size based on number of patients enrolled and two known histological risk factors for relapse (tumor size and presence or absence of rete testis invasion). The LTFU rate of patients younger than 36 years old tended to be higher than that of older patients, but the difference was not significant (Fig. 2a). Although statistically not significant, similar trends showing higher LTFU rates at a younger age Figure 2. Kaplan Meier curves comparing patients LTFU: (a) younger than 36 years old versus 36 years or older (P ¼ 0.10); (b) treated since 2000 versus treated until 1999 (P, 0.05); (c) treated at hospitals enrolling 10 patients or more versus treated at hospitals enrolling fewer than 10 patients (P ¼ 0.06); (d) based on tumor size (.4 versus 4 cm, P ¼ 0.84) and (e) based on rete testis invasion (presence versus absence, P ¼ 0.25).

4 358 Loss to follow-up during AS for Stage I seminoma were observed when the cut-off levels were 40 years old or 30 years old (data not shown). Unexpectedly, the LTFU rate was significantly higher in patients treated since 2000 compared with patients treated until 1999 (Fig. 2b; P ¼ 0.04). The cut-off point of treatment year (i.e. 2000) was selected because AS became the first choice management after 2000 in the present study. As shown in Fig. 2c,theLTFUrateof patients treated at hospitals that enrolled more than 10 cases tended to be higher compared with that of patients treated at hospitals with a smaller number of cases, but no significant difference was observed (P ¼ 0.06). No significant correlation between the LTFU rate and pathological risk factors such as tumor size (4 versus.4 cm) and rete testis invasion (presence versus absence) was shown (Fig. 2d and e). Based on the results of univariate analysis, we performed multivariate analysis using three covariates including patient age, treatment year and number of cases enrolled at the treating hospital. As shown in Table 1, multivariate analysis demonstrated that patients younger than 36 years old at diagnosis and patients diagnosed since 2000 had a significant risk forbeingltfuwithhazardratio(hr)of1.73[95%confidence interval (CI) ] and 1.97 (95% CI ), respectively. In addition, patients treated at hospitals that enrolled more than 10 cases had a higher independent risk for LTFU (HR 1.77: 95% CI ). DISCUSSION The present investigation clearly demonstrated that the LTFU rate increased beyond 2 years in patients managed by AS: the 5- and 10-year LTFU rates were 37.8 and 71.3%, respectively. The multivariate analysis revealed three significant risk factors for LTFU: younger patient age, treatment year and treatment institution. The LTFU rate in the present community-based study seems higher than that of previous reports. Daugaard et al. (10) reported that 23 of 695 patients (3.3%) with Stage I Table 1. Multivariate analyses of potential risk factors for loss to follow-up Variable/category Hazard ratio (95% CI) P value Age at orchiectomy (year) ( ) Year at orchiectomy ( ) Hospital size based on number of patients enrolled ( ) CI, confidence interval. testicular cancer including non-seminoma were LTFU before 5 years. In a longer-term observation, Choo et al. (11) identified only three (3.4%) patients LTFU among 88 Stage I seminoma patients with a median follow-up of 12 years. However, it is noted that the reported high compliance is based on data from a prospective study or single-center experience. When compared with clinical study setting, little has been known about compliance to surveillance protocol in a community rather than academic setting. Recently, Yu et al. (12) evaluated the quality of AS within a community setting using a private insurance claims database of 279 patients managed with AS. The authors reported nearly 30% of all surveillance patients received no imaging or tumor marker tests within the first year. A similar discrepancy in adherence to surveillance between community and academic settings was noted in an AS program in early prostate cancer (13). Because the success of AS largely depends on rigorous performance of regular imaging and laboratory testing, the present LTFU rates beyond 2 years cannot be ignored. Warde et al. (14) reported that the 5- and 10-year PFS rates of 638 patients were 82.3 and 78.7%, respectively. Chung et al. (15) reported that the actuarial risk of relapse between 5 and 10 years was 4%. Their results showed that Stage I seminoma patients have a small but clinically significant risk of relapse more than 5 years after orchiectomy. Therefore, multiple approaches should be undertaken to improve the long-term compliance. First, we found that patients younger than 36 years old, patients diagnosed since 2000 and patients treated at hospitals that enrolled more than 10 cases had a significant risk for LTFU. The latter two results were unexpected and inexplicable in the present study, but it is alarming that LTFU is an ongoing problem even when patients are managed in experienced hospitals. It is widely accepted that patients with testicular tumors should be treated and followed in experienced hospitals because patient number of testicular tumor is limited. But, the number of patients is relatively small even in experienced hospitals compared with that of hospitals in western countries. Efforts toward more centralization of patient care may be needed to improve the quality of AS. On the other hand, several possible explanations can be made for high risk for LTFU in younger patients. They are more likely to move to different locations, have employment difficulties, and feel healthier and no longer require close followup. Although the age cut-off level cannot be specified, younger age might be one factor related to the decision for adjuvant treatment. Secondly, there is a possibility that less experienced physicians are less familiar with current follow-up recommendations. To test this hypothesis, we and collaborators are conducting a questionnaire study concerning management of Stage I testicular cancer of 39 hospitals including 11 university hospitals. Although results are awaited, this might give a clue to improvement of long-term compliance. Besides a physician s perception of surveillance guidelines, limited resources for long-term observation in community hospitals might be responsible for the high LTFU rates.

5 Jpn J Clin Oncol 2014;44(4) 359 Thirdly,asshowninFig.2d and e, there were no differences in LTFU rates between patients having pathological risk factors and patients not having risk factors. Although these risk factors have not been prospectively validated, Warde et al. reported that patients with both factors represent a high-risk population, with a 5-year recurrence rate as high as 32%. Therefore, physician patient communication should be improved with discussions of the need for longterm follow-up. As part of a larger discussion of treatment options, risk factors for recurrence and the adverse effects of each option, the physician should inform the patient of the need for a minimum follow-up of 10 years when a patient selects AS. Our study has several limitations. In the present retrospective study, the LTFU rates were calculated from the date of the orchiectomy to the date of the last known follow-up visit. Therefore, it was possible that some patients who transferred to another hospital during AS might be counted as LTFU. This may result in overestimation of the LTFU rate. This database does not include detailed information on the surveillance protocol at each institution. Additionally, detailed compliance data on aspects such as missing a clinical visit, tumor marker test and chest or abdominal imaging study are lacking. Finally, the impact of low compliance on the spread of disease and the severity of recurrent disease, especially that of LTFU is unable to be evaluated. Despite these limitations, to our knowledge, this is the largest study on compliance in AS for Stage I seminoma in Japan. In conclusion, the LTFU rates during AS for Stage I seminoma were unsatisfactorily high beyond 5 years. Further approaches to improve the quality of AS are needed, especially for high-risk patients, such as younger ones. Conflict of interest statement None declared. References 1. Powles TB, Bhardwa J, Shamash J, et al. The changing presentation of germ cell tumours of the testis between 1983 and BJU Int 2005;95: Oliver RT, Mead GM, Rustin GJ, et al. Randomized trial of carboplatin versus radiotherapy for stage I seminoma: mature results on relapse and contralateral testis cancer rates in MRC TE19/EORTC study (ISRCTN ). J Clin Oncol 2011;29: Lewinshtein D, Gulati R, Nelson PS, et al. Incidence of second malignancies after external beam radiotherapy for clinical stage I testicular seminoma. BJU Int 2012;109: Groll RJ, Warde P, Jewett MA. A comprehensive systematic review of testicular germ cell tumor surveillance. Crit Rev Oncol Hematol 2007;64: Krege S, Beyer J, Souchon R, et al. European consensus conference on diagnosis and treatment of germ cell cancer: a report of the second meeting of the European Germ Cell Cancer Consensus Group (EGCCCG): Part II. Eur Urol 2008;53: Warde P, Huddart R, Bolton D, et al. Management of localized seminoma, stage I-II: SIU/ICUD Consensus Meeting on Germ Cell Tumors (GCT), Shanghai Urology 2011;78:S Steele GS, Richie JP, Stewart AK, et al. The National Cancer Data Base report on patterns of care for testicular carcinoma, Cancer 1999;86: Kollmannsberger C, Tyldesley S, Moore C, et al. Evolution in management of testicular seminoma: population-based outcomes with selective utilization of active therapies. Ann Oncol 2011;22: Kamba T, Kamoto T, Okubo K, et al. Outcome of different post-orchiectomy management for stage I seminoma: Japanese multi-institutional study including 425 patients. Int J Urol 2010;17: Daugaard G, Petersen PM, Rørth M. Surveillance in stage I testicular cancer. APMIS 2003;111: Choo R, Thomas G, Woo T, et al. Long-term outcome of postorchiectomy surveillance for stage I testicular seminoma. Int J Radiat Oncol Biol Phys 2005;61: Yu HY, Madison RA, Setodji CM, et al. Quality of surveillance for stage I testis cancer in the community. J Clin Oncol 2009;27: Ritchey J, Gay EG, Spencer BA, et al. Assessment of the quality of medical care among patients with early stage prostate cancer undergoing expectant management in the United States. JUrol2012;188: Warde P, Specht L, Horwich A, et al. Prognostic factors for relapse in stage I seminoma managed by surveillance: a pooled analysis. JClin Oncol 2002;20: Chung P, Parker C, Panzarella T, et al. Surveillance in stage I testicular seminoma risk of late relapse. Can J Urol 2002;9:

PROGNOSTIC FACTORS FOR RELAPSE IN STAGE I SEMINOMA: A NEW NOMOGRAM DERIVED FROM THREE CONSECUTIVE, RISK-ADAPTED STUDIES FROM THE SPANISH

Annals of Oncology Advance Access published September 10, 2014 PROGNOSTIC FACTORS FOR RELAPSE IN STAGE I SEMINOMA: A NEW NOMOGRAM 1 DERIVED FROM THREE CONSECUTIVE, RISK-ADAPTED STUDIES FROM THE SPANISH