Originally published as JCO Early Release 10.1200/JCO.2004.05.205 on January 15 2004

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Mortality After Cure of Testicular Seminoma

From the departments of Radiation Oncology and Epidemiology, The University of Texas M.D. Anderson Cancer Center, Houston TX

Address reprint requests to Gunar K. Zagars, MD, Department of Radiation Oncology, Box 97, M.D. Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030; e-mail: gzagars{at}mdanderson.org

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... REFERENCES

 
PURPOSE: To determine the incidence of potentially treatment-related mortality in long-term survivors of testicular seminoma treated by orchiectomy and radiation therapy (XRT).

PATIENTS AND METHODS: From all 477 men with stage I or II testicular seminoma treated at The University of Texas M.D. Anderson Cancer Center (Houston, TX) with postorchiectomy megavoltage XRT between 1951 and 1999, 453 never sustained relapse of their disease. Long-term survival for these 453 men was evaluated with the person-years method to determine the standardized mortality ratio (SMR). SMRs were calculated for all causes of death, cardiac deaths, and cancer deaths using standard US data for males.

RESULTS: After a median follow-up of 13.3 years, the 10-, 20-, 30-, and 40-year actuarial survival rates were 93%, 79%, 59%, and 26%, respectively. The all-cause SMR over the entire observation interval was 1.59 (99% CI, 1.21 to 2.04). The SMR was not excessive for the first 15 years of follow-up: SMR, 1.30 (95% CI, 0.93 to 1.77); but beyond 15 years the SMR was 1.85 (99% CI, 1.30 to 2.55). The overall cardiac-specific SMR was 1.61 (95% CI, 1.21 to 2.24). The cardiac SMR was significantly elevated only beyond 15 years (P < .01). The overall cancer-specific SMR was 1.91 (99% CI, 1.14 to 2.98). The cancer SMR was also significant only after 15 years of follow-up (P < .01). An increased mortality was evident in patients treated with and without mediastinal XRT.

CONCLUSION: Long-term survivors of seminoma treated with postorchiectomy XRT are at significant excess risk of death as a result of cardiac disease or second cancer. Management strategies that minimize these risks but maintain the excellent hitherto observed cure rates need to be actively pursued.

	INTRODUCTION

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Testicular seminoma presents at a relatively early phase in its natural history, spreads systematically via lymphatics—only later hematogenously—and is exquisitely sensitive to radiation and chemotherapy. Thus, today almost all men (> 95%) with this disease are cured [1-3]. Since those afflicted with this disease are typically in their fourth decade of life, they have a long potential life expectancy with a corresponding risk for long-term morbidity and mortality attributable to treatment. When cure rates approach 100%, any significant treatment-related morbidity and mortality may compromise longevity, even posing a greater threat to life than the original disease itself. This does not negate the axiomatic importance of appropriately aggressive oncologic treatment—which achieved the excellent cure rate in the first place—but it highlights the significance of identifying potential treatment-related long-term morbidity and mortality with a view to the development of management strategies that minimize toxicity and maintain excellent cure rates.

Radiation therapy (XRT) was the first successful, and remains the most widely used, modality for the postorchiectomy treatment of seminoma. Historically, the traditionally recognized early and late organ toxicities potentially attributable to XRT, and the 5-, 10-, and even 15-year survival rates for men with testicular seminoma treated with XRT have been regarded as satisfactory [1-3]. However, several recent reports suggest a significant incidence of late morbidity. There is evidence that long-term survivors of seminoma are at increased risk for second malignancies [4-10] and for cardiac disease [4,11,12]. The magnitude of these risks remains uncertain as some reports suggest a real, but low risk [6,9], while others suggest a more substantial risk [5,10,12]. Moreover, the impact of this morbidity on longevity is poorly documented [4]. Finally, the risk of morbidity, particularly cardiac, relative to XRT volume and dose remains controversial. Some reports found that cardiac morbidity was related to prophylactic mediastinal irradiation [4,11] whereas others found no such correlation [12].

Because of the long-standing interest in this disease at our institution [1,13-18], a significant number of patients with testicular seminoma has been accumulated and followed over a prolonged time. This retrospective analysis of men, none of whom experienced relapse of their seminoma, was undertaken to determine mortality by cause and its potential relation to XRT parameters; nonfatal morbidity was not evaluated.

	PATIENTS AND METHODS

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All 502 men who received postorchiectomy XRT without chemotherapy for testicular seminoma at The University of Texas M.D. Anderson Cancer Center (Houston, TX) since the establishment of the Department of Radiation Oncology in 1948 to the end of 1999 were identified by a search of the prospective database maintained in our department. Patients with lymphatic metastases above the diaphragm (n = 5), with hematogenous metastases (n = 2), or treated with orthovoltage equipment (n = 18) were excluded. Thus, 477 men with stage I or II seminoma treated with postorchiectomy megavoltage XRT were identified. Twenty-four of these patients sustained relapse of their disease and were also excluded, leaving 453 men treated between 1951 and 1999 and ostensibly cured of their seminoma, as the subjects for this study. The distribution of patients by decade of treatment was: 21 patients for 1951 to 1960; 74 patients for 1961 to 1970; 99 patients for 1971 to 1980; 142 patients for 1981 to 1990; and 117 patients for 1991 to 1999. Half of the patients were treated after 1983.

The diagnosis of seminoma was confirmed by a review of pathologic material at our institution. Stage I was defined as disease confined to the testis or extending into the epididymis, tunica vaginalis, scrotum, or spermatic cord but without clinical-radiographic evidence of lymphatic or hematogenous spread. Stage II was disease involvement of subdiaphragmatic nodes. Assignment of stage was based on available staging procedures during the time period encompassed in this series. Before 1961, abdominal lymphatics were evaluated by clinical examination and intravenous urography; after 1961 bipedal lymphangiography was used, and after 1985, computed tomography became the standard. Further details on the evaluation of these patients can be found in earlier reports from our department [13-18]. Patients' median age at treatment was 34 years (range, 16 to 69 years).

Para-aortic XRT fields extended from the top of T10 to the bottom of L5 and measured 9 to 11 cm in width [15,16]. The recommended dose for microscopic disease was 25 Gy in 15 fractions over 3 weeks. A boost to approximately 30 Gy for the site of any gross disease was recommended. Actual para-aortic doses for stage I ranged from 11.75 to 41 Gy (median, 25 Gy), and only 39 men (10%) received a dose different to the nominal 25 Gy. For stage II, actual total dose to the nodal tumor mass ranged from 24.4 to 48.43 Gy (median, 30.62 Gy) with 18 men (23%) receiving doses outside the range 30 to 40 Gy. In the earlier years, preceding modern radiography, 31 men (7%) received whole abdominal XRT to doses ranging 11.15 to 33 Gy (median, 24.4 Gy). The ipsilateral pelvis was treated in 437 men (96%) to a nominal dose of 25 Gy. Treatment policies relative to supradiaphragmatic nodal treatment—prophylactic mediastinal irradiation (PMI)—which included the mediastinum and left supraclavicular fossa, changed significantly over the years. Before 1971, most patients, regardless of stage had PMI [13]; after 1971, PMI was used only for stage II disease [14,16]; between 1984 and 1991, inclusive, no supradiaphragmatic XRT was used regardless of stage [17]; and after 1991, patients with stage II disease had elective left supraclavicular XRT [18]. In all, 71 men had PMI (26 with stage I and 45 with stage II). Mediastinal dose ranged from 15 to 25.36 Gy (median, 25 Gy). Fifty-one (72%) had a nominal dose of 25 Gy, 16 had 20 Gy, and the rest had other doses within the range specified. No patient received chemotherapy for his index tumor. Additional details on treatment can be found in our earlier publications [15-18].

After treatment, patients were followed at 3 to 6 month intervals for the first few years and yearly thereafter. Additional follow-up information was obtained by contacting patients, relatives, or physicians. For patients who died, a cause of death was ascertained by contacting his physician or by obtaining a death certificate. Causes of death were classified as cardiac, cancer, other, or unknown. Cardiac deaths were those due to acute myocardial infarction, ischemic heart disease, congestive cardiac failure, or cardiac but not otherwise specified. Cancer deaths were those specified as due to a malignant neoplasm, including all primary sites and tumor types. Deaths as a result of all other causes, including cerebrovascular, atherosclerotic, pulmonary embolism, infection, and trauma were classified as other. In nine patients, a cause of death could not be ascertained.

Actuarial curves were constructed using the product-limit method, and tests of significance between actuarial curves were based on the log-rank statistic [19,20]. Times were calculated from the end of XRT. Ninety-five percent confidence intervals for actuarial proportions were calculated with the Rothman method [21]. Multivariate proportional hazards regression was done with standard techniques [19]. Expected survival curves were calculated by adjusting for each patient's age and race, using US National Vital Statistics data [22]. Since all US population life-tables are period life-tables, they do not reflect the life expectation of an actual cohort followed from birth through consecutive ages and calendar years; instead they give a survival expectation for individuals subjected to the force of mortality at some specified calendar year [23]. Although useful for a crude assessment, expected survival curves generated by using such data are only approximate to the true survival expectation because of the changing force of mortality in successive calendar years. Hence, we used the person-years approach to validly calculate mortality expectations.

The person-years method calculates the number of years that each individual at every successive age spends in each calendar year during his period of observation, enabling an estimate of the expected mortality, allowing for cohort ageing and changing age-specific mortality rates [24,25]. US male age-specific mortality rates are given in 10-year age intervals [22], and we used the following age intervals in our analysis: 15 to 24 years, 25 to 34 years, 35 to 44 years, 45 to 54 years, 55 to 64 years, 65 to 74 years, 75 to 84 years, and 85 years and older. All data were grouped into 5-year calendar time intervals. Likewise, US cause-specific mortality for the categories "heart disease" and "malignant neoplasms" was used to calculate expected cause-specific mortality for these categories. With these methods, the observed-to-expected mortality—the standardized mortality ratio (SMR)—was computed using computer software specific for this purpose [26]. Calculations were done for whites and blacks separately, and then combined to estimate the overall SMR. Confidence intervals for SMRs were calculated on the assumption that the deaths were distributed as a Poisson random variable [26]. SMRs are significantly elevated when the 95% CI does not include 1.00 (ie, P < .05); the statistical significance is higher (P < .01) when the 99% interval does not include 1.00.

	RESULTS

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At the time of analysis, 102 patients had died and 351 were alive. The duration of follow-up for the surviving patients ranged 1.4 to 42.8 years (median, 13.3 years; mean, 14.9 years). The survival rates at 10, 20, and 30 years were 93% (95% CI, 90 to 95), 79% (95% CI, 74 to 84), and 59% (95% CI, 50 to 67), respectively, and are illustrated in Figure 1, which also shows age- and race-adjusted period expected survival curves from US mortality data for 1975, 1985, and 1995. Only for times beyond 15 years did the observed survival curve fall significantly below those expected. Time to death for the 102 dead men ranged from 0.1 to 44.5 years after the end of XRT and age at death ranged 22 to 87 years (median, 60 years; mean, 61 years). Univariate analysis of factors that potentially might correlate with survival is summarized in Table 1. The only statistically significant factor was the use of PMI, and its effect is illustrated in Figure 2. There was no significant difference in age at treatment between those having PMI (median age, 36 years) and those not having PMI (median age, 34 years; Mann-Whitney P = .211). On multivariate analysis, no factor other than PMI was significant for mortality.

View larger version (18K): [in this window] [in a new window]   Fig 1. Survival of all 453 patients. Vertical bars are 95% CIs. The number of men at risk is shown above the abscissa. The individually age- and race-adjusted expected survival curves from life-tables for the male US population in 1975, 1985, and 1995 are also shown. These survival curves give the age- and race-adjusted expected survival rates for individuals subjected to the force of mortality in the US male population for that year.

View larger version (15K): [in this window] [in a new window]   Fig 2. Actuarial survival curves according to whether prophylactic mediastinal irradiation (PMI) was delivered. Vertical ticks are patients alive at last contact (censored observations) and vertical bars are 95% CIs.

Although there appeared to be differences in the mortality in different subgroups as shown in Table 3, we felt it prudent not to overanalyze or overinterpret these because of the relatively small number of patients and events in most of these categories. However, since it has been reported that cardiac death is potentially related to PMI and age at treatment [4,11], we generated the SMRs summarized in Table 4. None of these were significantly elevated, though for all men receiving PMI, cardiac deaths were excessive (Table 3) as were cardiac deaths in all those younger than 40 years (Table 3).

	DISCUSSION

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The increased mortality was not evident during the first 15 years of follow-up. This, as well as the rarity of the disease, likely accounts for the historic difficulty in observing this effect. Few reports on seminoma give follow-up beyond 5 or 10 years. A long latency for XRT-related cancers is well-documented after the treatment of many index malignancies, including seminoma [5,6,8,10], Hodgkin's disease [28], and others [29]. Likewise, a long latency has been observed for cardiac disease following XRT to the mediastinum [30-33]. This underscores the need for adequate long-term follow-up to fully assess the risk of such problems.

We will now consider the pathobiologic basis for this increased mortality, beginning with cardiac mortality. The most plausible explanation for excess cardiac events among patients treated with XRT is to postulate a direct adverse effect of treatment on the heart, and a variety of abnormalities have been convincingly linked to direct cardiac XRT including pericarditis, myocardial fibrosis, conduction defects, valvular defects, and coronary artery disease [31,34,35]. Significant cardiac events following cardiac XRT have been well-documented for Hodgkin's disease [30-32,36] and breast cancer [37,38]. These reports also show that such events become particularly evident only beyond approximately 15 years of follow-up [31,36,37]; short-term follow-up, even with sophisticated cardiac evaluation, is unlikely to disclose any significant abnormality [39]. These studies have also generally concluded that the direct adverse effect of XRT on the heart is dose and volume dependent and that doses less than approximately 30 Gy are unlikely to cause significant problems [31-33,36]. Published data on seminoma are not so straightforward. Whereas some have found that excess cardiac events are confined to those receiving PMI [4,11], one large study found no such correlation and excess cardiac events occurred in patients who received para-aortic XRT alone [12]. Our study revealed excess cardiac deaths among patients receiving PMI particularly beyond 15 years, but also among those not receiving PMI but followed beyond 15 years. We could not elicit any age effect for PMI such as some have observed [4,11], where the adverse effect of PMI was confined to men over 40 years old at the time of treatment, although the number of patients in that category was small in our series. It has been suggested that cardiac toxicity might be related to the small volume of heart included in extended para-aortic portals or to renal hypertension secondary to partial kidney irradiation by the para-aortic field [12,40]. However, no convincing evidence to support these propositions has been published and our finding that the small number of patients who received whole abdominal XRT did not appear to be at a particularly high risk for cardiac death argues against an indirect renal mechanism. It has been found that patients with known risks for coronary atherosclerosis are particularly susceptible to the adverse effects of cardiac irradiation [31,41]. We were unable to evaluate this issue in our retrospective review, but it still begs the mechanistic question. There remains the possibility that the excess risk for cardiac death among our patients reflected a correlate with testicular seminoma and not with its treatment. While possible, since we had no record of cardiovascular risk factors among our patients, one other study on this question used a group of testicular cancer patients placed on surveillance as the reference group and found a significant incidence of cardiac events among those receiving XRT, mostly without PMI [12]. It seems likely that, through a still unknown mechanism, postorchiectomy XRT is associated with a significant risk for cardiac events and cardiac mortality.

Regarding second malignancies, radiation is a known carcinogen [29] and second malignant neoplasms have been well-documented to follow XRT for a variety of tumors, including seminoma [4,7-9,28,29]. Our results show that this increased incidence of subsequent cancers translates to a significant survival decrement.

Given these substantial nonseminoma risks, how could the initial treatment of men with testicular seminoma be optimized? Potentially optimizing postorchiectomy management strategies for stage I disease include the use of radiation with smaller volumes and doses, the use of carboplatin chemotherapy, or surveillance. Although we could not demonstrate convincing XRT dose-volume relations for nonseminoma mortality, general principles suggest that the toxic effects of treatment are likely to diminish if dose and volume are decreased. There is good evidence that ipsilateral pelvic XRT is unnecessary for stage I disease [42]; moreover, the use of para-aortic fields extending to the top of T10 is highly questionable. We now recommend that if XRT is to be used for stage I, then the fields should extend from the top of T12 to the bottom of L5 [18]. Furthermore, we believe that our previously standard dose of 25 Gy in 15 fractions can be safely replaced with 20 Gy in 10 fractions [18,43,44]. Whether these modifications will reduce excess morbidity/mortality remains to be seen (though not for another 15–20 years). A second strategy would consist in administering carboplatin [45-48]. This approach, particularly if two cycles are given, is highly effective in terms of disease control [48]. Unfortunately, the long-term effects of such treatment have not been documented. There are some data that show cisplatin (and, perhaps by analogy, carboplatin) is associated with a significant cardiac risk, either by virtue of long-term platination of cardiac tissue or by affecting lipid metabolism [12,49], and the long-term safety of adjuvant platinum-based chemotherapy cannot be assumed. Perhaps then, it is shrewd to embrace surveillance for stage I disease. This represents a departure from our hitherto held opinion [50] which supported routine postorchiectomy XRT, largely on grounds of simplicity, efficacy, and lack of toxicity—the former reasons remain valid, but not the latter. The results of surveillance have proven to be excellent [51] and while treatment may sometimes be preferable, we believe that in light of this analysis, surveillance may be the most prudent approach to stage I seminoma.

The issues for stage II disease are somewhat more straightforward. These patients have demonstrable disease and for them surveillance is not an option. The choice of optimal therapy is still largely based on antitumor efficacy and little data exist to draw conclusions based on relative long-term toxicities, although general principles suggest that excessive multimodality treatment should be avoided. Our current recommendation is for XRT as previously described [18].

	Authors' Disclosures of Potential Conflicts of Interest

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The authors indicated no potential conflicts of interest.

	NOTES

 
This study was supported in part by grant CA 06.294 awarded by the National Cancer Institute, US Department of Health and Human Services.

Authors' disclosures of potential conflicts of interest are found at the end of this article.

	REFERENCES

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Submitted May 30, 2003; accepted October 8, 2003.

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