Affiliations of authors: Department of Clinical Cancer Research, Norwegian Radium Hospital and University of Oslo, Norway (SDF); Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Department of Health and Human Services, Bethesda, MD (JC, SJS, KAM, MLM, MHG, LBT)
Correspondence to: Sophie D. Fosså, MD, Department of Clinical Cancer Research, The Norwegian Radium Hospital, Montebello, N-0310 Oslo, Norway (e-mail: s.d.fossa{at}radiumhospitalet.no).
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ABSTRACT |
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INTRODUCTION |
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The primary aim of this study was to evaluate the risk of developing metachronous contralateral testicular cancer in a large, population-based cohort of testicular cancer patients with respect to age at initial diagnosis, histologic type, and treatment and to examine the prevalence of synchronous contralateral testicular cancer in the same cohort. We also estimated long-term overall survival in patients diagnosed with unilateral testicular cancer and contralateral testicular cancer.
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PATIENTS AND METHODS |
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This study includes all patients who were diagnosed with testicular germ cell cancer as their first malignancy and whose diagnosis was reported from January 1, 1973, through December 31, 2001, to the following population-based cancer registries that participate in the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) Program (year of registry entry into the SEER Program): Connecticut (1973), Hawaii (1973), Iowa (1973), New Mexico (1973), Utah (1973), San FranciscoOakland (1973), Detroit (1973), SeattlePuget Sound (1974), Atlanta (1975), San JoseMonterey (1988), Los Angeles (1988), rural Georgia (1978), greater California (excluding San Francisco, San JoseMonterey, and Los Angeles; 1988), Kentucky (1995), Louisiana (1995), and New Jersey (1979). Men who had either an extragonadal germ cell tumor or a spermatocytic seminoma were excluded from this study. In addition, because testicular germ cell tumors are typically diagnosed in young and middle-aged men, and because misclassification of testicular lymphoma in older patients (20) cannot be excluded in a registry-based series of patients, we limited our study population to patients who were younger than 55 years at the initial diagnosis of testicular cancer.
The registries recorded the following information for each patient: month and year of birth; month and year of last observation; vital status at last observation; and month and year of testicular cancer and contralateral testicular cancer diagnoses.
Laterality
Men whose first testicular cancer was coded as "bilateral" at initial diagnosis or whose second testicular cancer was diagnosed within 2 months of the first diagnosis were considered to have synchronous contralateral testicular cancer. Men who were diagnosed with a contralateral testicular cancer more than 2 months after the first testicular cancer diagnosis were considered to have metachronous contralateral testicular cancer. Thus, we assessed the risk of developing metachronous contralateral testicular cancer only among patients who were diagnosed with contralateral testicular cancer more than 2 months after being diagnosed with unilateral testicular cancer. We evaluated the prevalence of synchronous contralateral testicular cancer among all eligible patients.
Histology
In the SEER Program registries, testicular cancer morphology is coded according to the International Classification of Diseases for Oncology (ICD-0) (21). We grouped the diagnoses into seminomas (codes 90609062 and 9064) or nonseminomas (codes 90709073, 90809085, and 91009102).
Extent of Disease
For any solid malignancy, the SEER Program registries record the extent of disease at initial diagnosis as "localized," "regional," "distant metastases," or "unknown," and these categorizations were used in this study. Since 1988, the SEER Program has also collected information on the size (in millimeters) of the testicular tumor as described in the pathology report of the orchiectomy specimen. For men with synchronous contralateral testicular cancer and who had a valid measurement for at least one tumor, and for men with metachronous contralateral testicular cancer in whom the size of the second tumor was evaluable, we calculated the proportion of men who presented with a contralateral testicular cancer of less than 20 mm because such men can be considered for testis-saving surgery (22,23).
Treatment
Unilateral orchiectomy was done in all patients diagnosed with unilateral testicular cancer. Patients who presented with a synchronous contralateral testicular cancer underwent bilateral orchiectomy. Thereafter, patients who were diagnosed with early-stage seminoma (localized at limited regional metastases) had radiotherapy alone (24)usually with testicular lead block shielding (25)or were managed by surveillance (26). Advanced metastatic seminoma was treated by chemotherapy, which was occasionally followed by radiotherapy or surgical removal of residual masses (27). Patients who were diagnosed with early-stage nonseminoma underwent primary retroperitoneal lymph node dissection after orchiectomy (28) or were included in a surveillance strategy (29). Adjuvant chemotherapy was given to patients with histologically confirmed metastatic disease; an alternative was abdominopelvic radiotherapy (30). Treatment of metastatic nonseminoma consisted of initial chemotherapy followed by surgery and/or (although rarely) radiotherapy (27). In the early 1970s, chemotherapy for testicular cancer consisted mainly of cyclophosphamide, chlorambucil, methotrexate, and actinomycin D; subsequently, this regimen was replaced by combinations of bleomycin, vinblastine, and doxorubicin (24,28). After 1975, cisplatin-based combination therapies were increasingly used. These therapies commonly included cisplatin, vinblastine, and bleomycin (31) or cisplatin, etoposide, and bleomycin (32).
SEER Program registries collected information only for the initial course of treatment applied after a diagnosis of testicular cancer or metachronous contralateral testicular cancer. No details were available about the type or doses of chemotherapy or radiotherapy received or about the use of salvage treatment. Initial postorchiectomy treatment, regardless of any concomitant surgery or hormonal therapy, was classified according to the following categories: 1) surgery alone; 2) radiotherapy alone; 3) chemotherapy alone; 4) radiotherapy and chemotherapy; and 5) other/not specified. We further stratified patients according to whether they received treatment with chemotherapy: no chemotherapy (initial treatment categories 1 and 2); any chemotherapy (initial treatment categories 3 and 4); and other/not specified (initial treatment category 5).
Statistical Analysis
We used SPSS software (version 12.0; SPSS, Chicago, IL) to calculate medians and ranges and to conduct KruskalWallis and Wilcoxon tests for comparisons. Categorical variables were compared by using the chi-square test. Latency was defined as the interval between the date of the first diagnosis of testicular cancer and the date of the diagnosis of metachronous contralateral testicular cancer.
To calculate the risk of metachronous contralateral testicular cancer, person-years at risk were assembled by age at diagnosis and by calendar year periods beginning 2 months after the diagnosis of unilateral testicular cancer to the date of diagnosis of metachronous contralateral testicular cancer, age 55 years, date of death, or end of the study (December 31, 2001), whichever occurred first. Of the 28 045 men who had more than 2 months of observation time, 43 men reached the age of 55 years within 3 months of their initial diagnosis and therefore did not contribute person-years to the analysis. Thus, estimates of metachronous contralateral testicular cancer risk were based on the remaining 28 002 (99.8%) patients. We estimated the expected number of testicular cancers by using SEER Program data to calculate testicular cancer incidence rates by 5-year age groups and by 5-year calendar year intervals; these rates were then multiplied by the number of accumulated person-years. We then added the total number of observed metachronous contralateral testicular cancers and the total number of expected testicular cancers, and the relative risk for each interval was defined as the ratio of the number of observed cases to the number of expected cases (O/E). We used the KaplanMeier method (33) to estimate the overall cumulative probability of developing a metachronous contralateral testicular cancer over time and the log-rank test (34) to test for differences in cumulative risks. For the analysis of cumulative risk, the observation time started 2 months after the date of diagnosis of the first testicular cancer and ended on the date the patient reached age 55 years, died, or was lost to follow-up or diagnosed with metachronous contralateral testicular cancer, whichever occurred first. Two patients who developed a metachronous contralateral nongerm cell cancer were censored at the date of the second diagnosis of testicular cancer.
To evaluate associations between features of the primary testicular cancer and the risk of metachronous contralateral testicular cancer, we performed Cox proportional hazards analysis to obtain hazard ratios (HRs) and 95% confidence intervals (CIs). The proportional hazards assumption was assessed using the method of Grambsch and Therneau (35) and was found to hold for all the fitted models. We used the Wald statistic to assess the statistical significance of the associations. We used logistic regression to examine which features of the primary testicular cancer were associated with the histology of the metachronous contralateral testicular cancer (seminoma versus nonseminoma). All statistical tests were two-sided, and P<.05 was considered statistically significant. We used Splus statistical software to perform Cox regression analysis and the logistic regression (Mathsoft, Seattle, WA).
We used the KaplanMeier method (33) to assess overall survival among patients with synchronous contralateral testicular cancer and among patients initially diagnosed with unilateral testicular cancer, stratifying by extent of disease in the latter group. The observation time started with the date of diagnosis of the first testicular cancer and ended with the date of the patient's death, the date the patient was lost to follow-up, or December 31, 2001, whichever occurred first. The log-rank test (34) was used to evaluate differences between the survival curves. In a separate analysis, we estimated overall survival in patients with metachronous contralateral testicular cancer from the date of metachronous contralateral testicular cancer diagnosis to the date of the patient's death, the date the patient was lost to follow-up, or December 31, 2001, whichever occurred first. Using the age-specific death rates in 2001 for the white male U.S. population (36), we also estimated the expected survival in the white U.S. population. Comparisons between the patients with unilateral testicular cancer and those with synchronous contralateral testicular cancer concentrated on 10-year survival because of the limited information on survival beyond 10 years for men with synchronous contralateral testicular cancer.
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RESULTS |
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After a median latency of 63 months (range = 3223 months), metachronous contralateral testicular cancer was diagnosed in 173 of the 15 640 men who were previously diagnosed with a seminoma and in 114 of the 12 230 men who were previously diagnosed with a nonseminoma (Table 3). Of these second tumors, 191 were seminomas and 96 were nonseminomas (Table 3). Only one (1%) of the 173 men with a seminoma at first diagnosis had received chemotherapy as initial treatment, compared with 38 (33%) of 114 men with a nonseminoma at first diagnosis. In all 39 of the patients, the metachronous contralateral testicular cancer developed after completion of the initial chemotherapy. Of the 244 patients with metachronous contralateral testicular cancer for whom extent of disease was known, 207 (85%) had localized disease. Only 27 patients (9%) with metachronous contralateral testicular cancer received chemotherapy. Of the 190 metachronous contralateral testicular cancers of known size, 69 (36%) were less than 20 mm in diameter.
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Overall Survival
The 10-year overall survival rates for all initially unilateral testicular cancer patients with localized disease, regional disease, and distant metastases were 95% (95% CI = 94.5% to 95.4%), 90% (95% CI = 88.8% to 91.0%), and 65% (95% CI = 63.0% to 67.1%), respectively (Fig. 3). The 10-year overall survival rate for all patients with synchronous contralateral testicular cancer was 85% (95% CI = 78% to 90%).
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DISCUSSION |
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The development of bilateral testicular cancer finds some etiologic explanation in the most frequently accepted hypothesis about germ cell carcinogenesis. The malignant process is believed to start during the 7th through 9th weeks of embryonal life (37). Environmental factors are believed to cause changes in the male embryo's primordial cells, from which the testes later develop. These prenatal influences are thought to be related to the initiation of carcinoma in situ and the subsequent development of invasive testicular cancer (37). Whether carcinogenesis occurs in one or both testes depends on the distribution of cells that were exposed to these prenatal influences. Cancer development is believed to start earlier and have a higher growth rate in men with nonseminoma (38) than in men with seminoma, which explains the younger age of nonseminoma patients at first presentation. In some men, the development of testicular cancer is also genetically determined, as indicated by the occurrence of familial testicular cancer (39,40).
This hypothesis provides a partial explanation for the occurrence of bilateral testicular cancer we observed in patients diagnosed with testicular cancer. In 2%5% of patients with testicular cancer, the germinative epithelium in both testes seems to contain cell clones with pre-malignant changes. Importantly, our finding that observed-to-expected ratios for metachronous contralateral testicular cancer started declining by 5 years after diagnosis, even among patients who received radiotherapy as initial treatment, indicates that the elevated risk of metachronous contralateral testicular cancer was unrelated to radiotherapy. These results contrast with the increased risks of the development of nongerm cell cancers among men treated for testicular cancer (41). Prenatal predisposition to bilateral germ cell malignancy also provides a reasonable explanation for our observations, and those of others (11,15,17), that young adult age at first testicular cancer diagnosis is a risk factor for developing a metachronous contralateral testicular cancer. The fact that the nonseminoma patients have a younger median age at diagnosis than seminoma patients supports the hypothesis that the carcinogenic process associated with the development of nonseminomas is faster and/or more intense than that associated with the development of seminomas.
The overall observed-to-expected ratio (12.4) and 15-year cumulative incidence risk (1.9%) of metachronous contralateral testicular cancer estimated in this study are lower than the estimates reported by most European studies with comparable information (13,16,17). The observed-to-expected ratio we report is, however, in line with the 11- to 12-fold increased risk of metachronous contralateral testicular tumors that has been reported among Swedish patients (18). There are several possible explanations for the discrepant results with the other European studies. First, European analyses of subsequent testicular cell cancer after a first germ cell cancer diagnosis often include patients with extragonadal germ cell cancer who have a particularly high incidence of metachronous testicular cancer (17,42). Second, in some studies, the reported incidence estimates included patients with synchronous contralateral testicular cancer and patients with metachronous contralateral testicular cancer (10,11,15,17). Third, as discussed by Tabernero et al. (43), the risk of developing a metachronous contralateral testicular cancer may reflect unexplained variations in testicular cancer rates between countries. For example, in SEER Program registries, the incidence of testicular cancer among white men was 5.6 per 100 000 from 1993 through 1997 (44). This rate is lower than published rates for Norway (8.2 per 100 000) and Denmark (9.9 per 100 000) but comparable to the Swedish rate (5.0 per 100 000) (44). Fourth, and probably most important, most published studies included many patients who were treated before cisplatin-based chemotherapy was introduced in the 1970s, whereas most patients with metastases reported to the SEER Program from 1973 through 2001 probably received cisplatin-based chemotherapy as standard therapy. Because cisplatin-based chemotherapy has been associated with decreased risk and delayed development of a metachronous contralateral testicular cancer (13,45), overall risk estimates will differ according to the use of this treatment regimen. In addition, the use of cisplatin-based chemotherapy series by patients in our study may have decreased the risk of metachronous contralateral cancer among nonseminoma patients. For example, studies that included patients diagnosed before the cisplatin era (16,17) have reported that patients initially diagnosed with nonseminoma had increased risks of metachronous contralateral testicular cancer compared with patients initially diagnosed with seminoma. In general, nonseminoma patients are more likely to receive cisplatin than are the seminoma patients. The use of chemotherapy was, for example, approximately five times higher in our patients with an initial nonseminoma than in those with seminoma.
Our findings on incidence are in agreement with those reported by Theodore et al. for patients treated between 1979 and 2001 (15). These authors reported crude incidence rates of metachronous contralateral testicular cancer of 3.2% and 1.4% for men with seminoma and with nonseminoma, respectively. It should be noted that differences in risk estimates of metachronous contralateral tumors between the two main treatment categories for our study subjects (no chemotherapy versus any chemotherapy) are likely larger than shown because of possible misclassification introduced by the fact that our records include data on only the initial course of therapy. Chemotherapy is known to be underreported in the SEER Program (46); thus, some patients whose initial treatment was designated as "surgery only" or "radiotherapy only" likely also received chemotherapy. Moreover, the SEER Program registries do not collect data on salvage treatment. For example, nonseminoma patients whose initial treatment was designated as surgery only may have later received chemotherapy as adjuvant or salvage treatment. Bearing in mind this potential misclassification, our finding that these patients had a reduced risk of developing a metachronous testicular cancer after chemotherapy, although statistically significant only in the univariate analysis, supports more limited observations that suggest that modern chemotherapy is associated with a decrease in the occurrence of metachronous contralateral testicular cancer (45). The fact that 39 patients in our study developed metachronous contralateral testicular cancer after completing chemotherapy also confirms published observations that cisplatin-based chemotherapy does not completely eliminate this risk (4749). A potential doseresponse relationship between cisplatin and eradication of germ cell carcinoma in situ should be investigated in future clinical studies.
The need to perform a routine biopsy of the contralateral testis in patients with newly diagnosed unilateral testicular cancer is a matter of ongoing discussion. On the basis of a 5.4% prevalence of carcinoma in situ in the contralateral testis (50) and a 5%6% overall cumulative risk of metachronous contralateral testicular cancer in Danish testicular cancer patients (51), some European investigators advise that all testicular cancer patients have a biopsy of the contralateral testis, followed by treatment of any carcinoma in situ (5153). Heidenreich and Moul (54) recommend this approach only for high-risk patients. Some American investigators have not been in favor of routine biopsy of the contralateral testis (55), a view that likely reflects the published low crude percentages of contralateral testicular cancer patients in U.S. studies (Appendix Table 1).
Our results suggest that, given current treatment practices in the United States, patients with unilateral testicular cancer are at increased risk of developing metachronous contralateral testicular cancer. Patients with seminomatous tumors had a statistically significantly higher probability of developing metachronous contralateral testicular cancer than patients with a nonseminoma, although the risk in both groups decreased with increasing age at first testicular cancer diagnosis. We therefore believe that clinicians should encourage all unilateral testicular cancer patients, especially those not receiving chemotherapy, to perform regular self-examination and, possibly, undergo regular testicular ultrasonography (56). The aim of this approach is to detect a nonmetastatic metachronous contralateral testicular cancer while the primary tumor is still small enough to perform testis-sparing surgery and thus avoid problems associated with androgen substitution after bilateral orchiectomy (57). Our observations on tumor size in the contralateral testis indicate that testis-sparing surgery might have been possible in at least one-third of SEER Program patients diagnosed with contralateral testicular cancer. This fraction can probably be increased with improved surveillance of men with unilateral testicular cancer, particularly the high-risk patients. Finally, a testicular biopsy followed by individual counseling and/or treatment of carcinoma in situ may be justified for high-risk patients, especially those with a history of testicular maldescent, infertility, or testicular atrophy or a family history of testicular cancer (58). Clinicians and patients should, however, be aware that the overall risk of developing a metachronous contralateral testicular cancer is low, given that the overall 15-year cumulative incidence in our population was less than 2%.
Many investigators have emphasized the good prognosis of patients with metachronous contralateral testicular cancer (11,12,15), but the published reports are based on small numbers and usually lack confirmatory statistical analyses. For example, Géczi et al. (14) reported a 93% 5-year survival rate for 53 patients after diagnosis with metachronous contralateral testicular cancer. This rate is comparable to the 10-year overall survival rate of 93% we report for all 287 patients with metachronous contralateral testicular cancer in our study. Our results should be viewed within the context of the limited initial use of radiotherapy or chemotherapy after the diagnosis of metachronous contralateral testicular cancer, given that most patients presented with localized disease. Furthermore, our observations indicate that a diagnosis of metachronous contralateral testicular cancer did not compromise 10-year overall survival compared with that of patients diagnosed with unilateral testicular cancer. However, the statistically significant association between regional metastases and mortality underscores the importance of early diagnosis of metachronous contralateral testicular cancer.
The major strength of this population-based study was its large size, which enabled us to perform statistical analyses of substantial numbers of synchronous contralateral testicular cancer and metachronous contralateral testicular cancer cases. Furthermore, the current study population was not subject to selection bias that may affect populations derived from referral centers. In addition, the likelihood of misclassification based on incorrect histology was greatly reduced because we restricted our analysis to patients who were younger than 55 years at testicular cancer diagnosis.
Limitations of our study include the lack of detailed information about any treatment received after initial treatment, incomplete information on adjuvant chemotherapy, and the lack of data on salvage treatment. Another limitation was the lack of information regarding additional clinical risk factors for developing a metachronous contralateral testicular cancer, such as history of testicular maldescent, infertility, or testicular atrophy. In addition, underreporting of metachronous contralateral testicular cancers, particularly those diagnosed in the youngest men who may migrate from registry catchment areas, may be a problem in the SEER Program registries.
In conclusion, our findingsthat U.S. patients with unilateral testicular cancer have a modest 15-year cumulative risk (1.9%) of metachronous contralateral testicular cancer and their high long-term survivalprovide support for continuing the usual clinical practice of not subjecting the contralateral testis to routine biopsy. Our results also provide indirect evidence that cisplatin-based chemotherapy may reduce, but not eliminate, the risk of developing a metachronous contralateral testicular cancer.
Appendix Table 1. Literature review of selected studies*
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* Studies with at least 1000 patients published in 1990 or later. Syn-CTC = synchronous contralateral testicular cancer; met-CTC = metachronous contralateral testicular cancer; O/E = observed-to-expected ratio; CI = confidence interval; sem = seminoma; nonsem = nonseminoma; NA = not available.
Numbers in parentheses represent crude percentages.
Incidence figures per 100 000 persons (29).
For whites only, based on data in the Surveillance, Epidemiology, and End Results (SEER) Program (59).
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NOTES |
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Manuscript received November 4, 2004; revised May 11, 2005; accepted May 19, 2005.
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