ORIGINAL
ARTICLE
E n d o c r i n e
C a r e
Changes in Bone Mineral Density in Newly Diagnosed Testicular Cancer Patients After Anticancer Treatment P. M. Willemse, N. A. T. Hamdy, M. L. de Kam, J. Burggraaf, and S. Osanto Departments of Clinical Oncology (P.M.W., S.O.) and Endocrinology and Metabolic Diseases (N.A.T.H.), Leiden University Medical Center, 2333 ZA Leiden, The Netherlands, and Centre for Human Drug Research (M.L.d.K., J.B.), 2333 CL Leiden, The Netherlands
Context: Patients with germ cell tumors (GCTs) have an excellent prognosis but are at risk for silent fractures. Data on bone mineral density (BMD) after anticancer treatment are scarce. Objective: The objective of the study was BMD monitoring in GCT patients treated with or without chemotherapy. Design: We prospectively studied 63 newly diagnosed GCT patients with a median age of 33 years (range 16 –70 y) within 3 months of unilateral orchidectomy. Twenty-seven patients (42.9%) had no metastases. Thirty-six patients (57.1%) with metastatic disease received combination chemotherapy. Setting: This study was conducted at the outpatient clinic of a single academic institution. Interventions: We performed dual-energy X-ray absorptiometry scans and collected blood samples on a yearly basis, before and up to 5 years after anticancer treatment. Main Outcome Measures: Changes in total hip and lumbar spine BMD, serum concentrations of gonadal hormones, and bone turnover markers were measured. Results: BMD remained normal in stage I patients. In patients with metastatic disease, a significant decrease in lumbar spine BMD (⫺1.52%; P ⫽ .004) and total hip BMD (⫺2.05%; P ⬍ .0001) was observed 1 year after chemotherapy and remained stable thereafter for up to 5 years. There was no significant relationship between the observed decrease in BMD and gonadal status, vitamin D status, or cumulative dose of cisplatin or (antiemetic) corticosteroids. Conclusions: Metastatic GCT survivors demonstrate significant bone loss within the first year after curative combination chemotherapy, with no recovery up to 5 years after anticancer treatment. Whether this bone loss is associated with increased fracture risk and whether this could be prevented by bone modifying treatment remains to be established. (J Clin Endocrinol Metab 99: 4101– 4108, 2014)
esticular germ cell tumors (GCTs) are the most common form of cancer in young male adults. The introduction of cisplatin-based combination chemotherapy has led to significant improvement in prognosis, with cure achieved in the vast majority of patients (1). This translates into an increasing number of long-term survivors of this malignancy who would have undergone unilateral orchidectomy with or without chemotherapy at a relatively young age. Long-term detrimental effects of cancer treat-
T
ments on the skeleton may be associated with significant skeletal morbidity, so that it is of clinical relevance to evaluate the presence of these skeletal complications in GCT survivors to allow timely intervention to decrease or prevent associated increased fracture risk. GCT patients may experience accelerated bone loss through the potentially deleterious effects of chemotherapy on the skeleton (2). A high prevalence of osteopenia and osteoporosis has been reported in a large cohort of
ISSN Print 0021-972X ISSN Online 1945-7197 Printed in U.S.A. Copyright © 2014 by the Endocrine Society Received March 12, 2014. Accepted August 6, 2014. First Published Online April 13, 2014
Abbreviations: BMD, bone mineral density; -CTX, -carboxyl-terminal cross-linking telopeptide of type I collagen; DXA, dual-energy X-ray absorptiometry; GCT, germ cell tumor.
doi: 10.1210/jc.2014-1722
J Clin Endocrinol Metab, November 2014, 99(11):4101– 4108
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823 GCT survivors with unilateral testicular cancer, a median 89 months after orchidectomy and anticancer treatment (3). In contrast, another study reported no deleterious effects of chemotherapy on skeletal health in longterm survivors of GCT or lymphoma (4). However, we have previously shown an increased prevalence of vertebral fragility fractures in cured long-term survivors of GCTs. The high prevalence of largely asymptomatic vertebral fractures we observed in these patients was independent of tumor stage, chemotherapy, or bone mineral density (BMD) (5). Chemotherapy may be causally related to decreases in BMD because of potential negative effects of treatment on bone remodeling. The widely used high doses of corticosteroids as part of antiemetic regimen concomitantly prescribed with chemotherapy may contribute to bone loss (6) as well as to osteonecrosis of the femoral head (7). Cytotoxic chemotherapy is associated with significant gonadal damage, with germ cells being more sensitive to the deleterious effects of treatment than Leydig cells, resulting in infertility being a more commonly encountered adverse effect than hypogonadism. Whether bone quantity and quality are directly affected by chemotherapy, or indirectly so by chemotherapy-mediated partial or complete hypogonadism is not clear. Various studies reported hypogonadism in chemotherapy-treated GCT survivors as evidenced by increased serum LH and low-normal serum T, up to 60 months after chemotherapy (8 –10). However, the diurnal pulsatile pattern of T secretion and the different parameters used to define hypogonadism preclude comparison between various studies. Interestingly, partial hypogonadism may be already present before orchidectomy in up to one third of GCT patients (11). Although the vast majority of patients remains or becomes eugonadal in time (10), the sometimes severe bone loss associated with iatrogenic hypogonadism may not be fully reversible. The aim of our study was to evaluate longitudinal changes in BMD in newly diagnosed and recently orchiectomized GCT patients 1, 2, and up to 5 years after anticancer treatment.
Patients and Methods All patients who were referred to the Department of Clinical Oncology of the Leiden University Medical Center between 2007 and 2009 after unilateral orchidectomy but before potential anticancer treatment were invited to participate in the study. The study was approved by the Medical Ethical Committee of the Leiden University Medical Center, and informed consent was obtained from all patients. The primary tumor was staged on the basis of tumor histology, computed tomography scan, and serum concentrations of the tumor markers, -human chorionic gonadotropins, ␣-fetoprotein and lactate dehydrogenase, as measured at the time of
J Clin Endocrinol Metab, November 2014, 99(11):4101– 4108
diagnosis. Patients were divided into 2 groups based on tumor stage and anticancer treatment. The first group consisted of patients with nonmetastatic disease (stage 1) who are treated with only a unilateral orchidectomy for nonseminomas or with unilateral orchidectomy in addition to a single dose of adjuvant carboplatin AUC7 for pure seminomas. In our experience and that of others, carboplatin does not appear to be associated with chemotherapy-related complications (5), so we decided to include these patients in the nonmetastatic group of patients. The second group consisted of patients with metastatic GCTs who received multiple courses of cisplatin-based combination chemotherapy. Baseline evaluation included medical history, prior and current medication, prior use of corticosteroids, smoking habits, and alcohol use. All patients underwent a full clinical examination including body height, weight, waist and hip circumference, pulse rate, and blood pressure. Information about fracture history was obtained by means of a brief questionnaire.
Laboratory investigations Blood samples were collected after an overnight fast and before 10:00 AM at baseline after orchidectomy and at 1, 2, and up to 5 years thereafter. Serum was routinely measured for creatinine, calcium (corrected for albumin), phosphate, and alkaline phosphatase concentrations using semiautomated techniques. Serum was also measured for the marker of bone resorption, -carboxyl-terminal cross-linking telopeptide of type I collagen (-CTX). Serum intact PTH, 25-hydroxyvitamin D, and 1,25dihydroxyvitamin D3 were measured using standard RIAs. Gonadal status was evaluated by measuring serum LH, FSH, total T, estradiol, and SHBG using standard RIAs. Free T was calculated using a standard formula (12, 13). Hypogonadism was defined as a serum total T concentration of less than 10.4 nmol/L (14). Vitamin D deficiency was defined as a 1,25-dihydroxyvitamin D3 concentrations of less than 50 nmol/L (15, 16). Renal function was calculated using the Cockcroft formula. Serum concentrations of -human chorionic gonadotropins, ␣-fetoprotein and lactate dehydrogenate were used for staging of the disease at time of diagnosis.
BMD measurements BMD was measured at the lumbar spine (L1-L4) and total hip using dual-energy X-ray absorptiometry (DXA; Hologic QDR 4500). The coefficient of variation of BMD measurements was 1%, and the machine was calibrated at regular intervals. The DXA scan used in this study was equipped with reference values based on the National Health and Nutrition Examination Surveys III for European men (17), which are compatible with those of a Dutch control population. World Health Organization criteria were used to define osteopenia (T-score between ⫺1 and ⫺2.5) and osteoporosis (T-score ⬍ ⫺2.5) (18). Lumbar BMD was assessed from L1 to L4 in posteroanterior incidence. Total hip BMD was reported as the mean of left and right total hip BMD measurements. Because of the relatively young age of the population studied, results were also expressed as Z-scores, indicating the number of SDs below the mean of age- and sexmatched controls (19).
Statistical analysis The SPSS for Windows software package and SAS for windows version 9.1.3 (SAS Institute, Inc) were used for statistical analysis. Results are expressed as mean ⫾ SD or as median
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(minimum-maximum). A two-tailed paired sample Student’s t test was used to compare single, normally distributed measurements between study groups. The Wilcoxon signed-rank test was used to compare unevenly distributed measurements between study groups. The comparability of the study groups at baseline was assessed as appropriate by one-way ANOVA. The serial measurements of the biochemical markers and BMD were analyzed with a repeated-measures model ANOVA, with an autoregressive first-order covariance structure. The estimated least square means) and their P values for the difference from zero test are used to establish whether the patients are deviant from their peers. Univariate linear regression analysis was used to determine a relationship between possible confounders.
Results Patient and disease characteristics Sixty-three consecutive newly diagnosed GCT patients aged 16 –70 years (median 33 y) were included in the study. Demographic and anthropometric characteristics of these patients are summarized in Table 1. Most GCT patients studied were asymptomatic, were leading an active life, and were in good clinical condition. Twentyseven patients (42.9%) had stage I disease (no metastases) and thirty-six patients (57.1%) had metastatic disease Table 1.
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(Table 1). Of the patients with metastatic disease, one (1.6%) had stage IS (elevated tumor markers but negative computed tomography scan indicating micrometastases), 23 (36.5%) had stage II disease (metastases in one or more locoregional paraaortic lymph nodes), and 12 (19%) had distant metastases, mostly in the lungs (Table 1). Patients with metastatic disease received first-line cisplatin-based combination chemotherapy consisting of three (n ⫽ 22) or four (n ⫽ 14) cycles of bleomycin, etoposide, and cisplatinum or four cycles of etoposide and cisplatinum. Each cycle consisted of iv-administered etoposide (100 mg/m2 over 1 h, d 1–5) and cisplatin (20 mg/m2 over 4 h, d 1–5), with or without bleomycin (30 IUSP over 30 min) at days 2, 8, and 15. As part of the antiemetic regimen, all 36 patients received iv-administered high doses of corticosteroids [10 mg dexamethasone iv daily during d 1–5 of their 3 weekly chemotherapy courses, with rapidly tapering of oral dexamethasone thereafter: twice daily 3 mg (d 6 –7) and twice daily 1.5 mg (d 8 –9)]. Two patients received two extra cycles of vinblastine, ifosfamide, and cisplatinum consolidation chemotherapy and consequently higher administered doses of corticosteroids. Only eight patients had comorbidities in
Baseline Clinical Characteristics of GCT Patients With or Without Metastatic Disease
Demographics (median, minimum-maximum) Age, y ␦Time, y Characteristics (mean ⫾ SD) Weight, kg BMI, kg/m2 Waist circumference, cm Systolic blood pressure, mm Hg Renal function, Cockroft clearance mL/min Lifestyle, n , % Smoking Alcohol use, ⬎20 U/wk Histology, n, % Seminoma Nonseminoma Combined tumor TNM tumor staging, n, %b Stage I (no metastasis) Stage IS (elevated serum tumor markers) Stage II (paraaortic lymph node metastasis) Stage III (distant metastasis) Treatment, n, % No adjuvant treatment Single-dose carboplatin Combination chemotherapy
All Patients (n ⴝ 63)
Stage I (n ⴝ 27)
Disseminated (n ⴝ 36)
P Valuea
33 (16 –70) 0.1 (0.0 – 6.2)
35 (22–70) 0.2 (0.0 – 0.8)
34 (16 –59) 0.1 (0.0 – 6.2)
NS NS
83 ⫾ 12 24.7 ⫾ 3.3 92 ⫾ 10 128 ⫾ 15 135 ⫾ 30
82 ⫾ 12 24.3 ⫾ 2.7 94 ⫾ 12 126 ⫾ 16 126 ⫾ 25
83 ⫾ 11 25.1 ⫾ 3.7 90 ⫾ 8 130 ⫾ 15 141 ⫾ 32
NS NS NS NS NS
24 (38.1) 16 (25.4)
7 (25.9) 7 (25.9)
17 (47.2) 9 (25.0)
NS NS NS
27 (42.9) 22 (34.9) 14 (22.2)
15 (55.6) 7 (25.9) 5 (18.5)
12 (33.3) 15 (41.7) 9 (25.0)
27 (42.9) 1 (1.6) 23 (36.5) 12 (19.0)
27 (100.0) 0 (0.0) 0 (0.0) 0 (0.0)
0 (0.0) 1 (2.8) 23 (63.9) 12 (33.3)
12 (19.1) 15 (23.8) 36 (57.1)
12 (44.4) 15 (55.6) 0 (0.0)
0 (0.0) 0 (0.0) 36 (100.0)
⬃
⬃
Abbreviations: BMI, body mass index; NS, nonsignificant, ␦Time, time between orchidectomy and first measurement (years); TNM, tumor node metastasis; ⬃, not calculated. a
P value for comparison between values of patients treated with and without chemotherapy (independent samples Student’s t test, independent samples Mann-Whitney test, or 2 test where appropriate). b
Patients with stage IS, stage II, and stage III are all classified as metastatic GCTs.
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Table 2. Gonadal Hormones Expressed as Mean ⫾ SD and Median (Minimum-Maximum) Before and After Anticancer Treatment Parameters
Baseline
Year 1
Year 2
Year 3
Year 4
Year 5
Stage I GCT S. total T
n ⫽ 27 17.4 ⫾ 7.5 15.3 (0.2–33.9) 69 ⫾ 20 75 (28 –98) 7.5 ⫾ 4.9 6.3 (2.9 –25.6) 12.4 ⫾ 7.7 10.2 (4.6 –32.1) 30.5 ⫾ 18.3 24.9 (3.0 –90.0) n ⫽ 36 17.4 ⫾ 5.6 17.4 (4.7–30.2) 104 ⫾ 56 91 (31–240) 5.9 ⫾ 5.8 4.8 (0.1–24.8) 10.4 ⫾ 11.1 7.4 (0.1– 44.5) 31.2 ⫾ 12.0 31.9 (6.8 – 64.0)
n ⫽ 27 15.6 ⫾ 4.9 17.1 (9.2–27.4) 66 ⫾ 22 63 (28 –109) 8.0 ⫾ 6.6 5.4 (2.5–31.3) 16.1 ⫾ 12.5 12.3 (3.9 –54.1) 29.2 ⫾ 9.1 26.3 (15.7– 48.4) n ⫽ 35 16.2 ⫾ 4.4 15.3 (9.1–26.5) 91 ⫾ 33 88 (25–181) 9.3 ⫾ 4.4 8.1 (3.4 –18.7) 24.0 ⫾ 12.3 21.6 (5.5– 46.0) 31.2 ⫾ 10.8 30.2 (13.3–52.7)
n ⫽ 19 16.3 ⫾ 4.5 15.8 (9.9 –25.8) 72 ⫾ 19 73 (42–118) 9.0 ⫾ 8.6 6.8 (2.5–36.0) 16.6 ⫾ 14.2 12.5 (3.9 –50.8) 32.4 ⫾ 15.0 26.3 (16.1– 85.4) n ⫽ 23 16.3 ⫾ 5.4 14.9 (10.0 –30.0) 76 ⫾ 25 78 (20 –123) 8.7 ⫾ 4.0 8.1 (2.7–16.4) 18.1 ⫾ 10.8 14.2 (5.0 –39.7) 26.4 ⫾ 9.8 23.9 (11.0 – 46.6)
n ⫽ 14 18.1 ⫾ 6.6 16.1 (11.4 –37.9) 60 ⫾ 23 59 (26 –113) 6.6 ⫾ 3.3 5.8 (2.6 –13.8) 12.6 ⫾ 9.6 10.8 (4.0 – 40.4) 28.9 ⫾ 6.4 27.4 (16.1– 44.8) n ⫽ 26 15.6 ⫾ 5.2 14.2 (5.4 –25.2) 84 ⫾ 32 74 (36 –160) 7.7 ⫾ 3.7 6.9 (2.6 –14.5) 16.8 ⫾ 10.2 14.2 (5.0 –39.7) 29.5 ⫾ 10.2 30.5 (14.0 – 48.4)
n ⫽ 12 16.0 ⫾ 5.0 15.6 (9.1–23.4) 63 ⫾ 10 60 (50 –77) 8.1 ⫾ 5.9 5.9 (3.3–19.0) 16.9 ⫾ 16.5 11.5 (4.9 – 49.1) 33.6 ⫾ 6.1 34.3 (23.2– 42.4) n ⫽ 20 17.2 ⫾ 5.7 17.6 (6.4 –25.1) 75 ⫾ 23 81 (21–108) 7.1 ⫾ 3.3 6.4 (2.9 –14.3) 13.3 ⫾ 4.6 10.8 (3.6 –29.1) 26.4 ⫾ 6.8 28.9 (14.3–35.3)
n ⫽ 14 16.1 ⫾ 7.2 16.0 (0.7–29.2) 66 ⫾ 20 61 (38 –99) 6.6 ⫾ 4.6 5.0 (3.1–20.1) 11.7 ⫾ 11.1 10.2 (4.5– 48.5) 33.1 ⫾ 10.1 32.6 (12.5– 49.9) n ⫽ 21 16.2 ⫾ 5.8 15.8 (7.0 –29.5) 82 ⫾ 21 82 (35–118) 6.7 ⫾ 3.2 6.1 (2.1–13.5) 12.8 ⫾ 8.0 10.3 (2.9 –29.1) 32.8 ⫾ 13.9 33.0 (11.7–59.3)
S. estradiol S. LH S. FSH S. SHBG Metastatic GCT S. total T S. estradiol S. LH S. FSH S. SHBG
Reference Range
8.0 –35.0 nmol/L 70 –200 pmol/L 2.0 –10.0 U/L 2.0 –10.0 U/L 20 –55 nmol/L
8.0 –35.0 nmol/L 70 –200 pmol/L 2.0 –10.0 U/L 2.0 –10.0 U/L 20 –55 nmol/L
Abbreviation: S, serum.
the form of diabetes mellitus (n ⫽ 3), hypertension (n ⫽ 2), chronic obstructive pulmonary disease (n ⫽ 1), ulcerative colitis (n ⫽ 1), or epilepsy (n ⫽ 1), unrelated to their malignancy or to the treatment received, and these comorbidities were equally distributed between patients with or without metastatic disease. Two patients aged 53 and 35 years developed avascular necrosis of the hip, respectively, 1 and 4 years after chemotherapy. They were treated with bisphosphonates and were excluded from further analysis. One patient, aged 21 years, diagnosed with osteoporosis of the lumbar spine 1 year after chemotherapy, who was treated with calcium and vitamin D supplements, was also excluded from further analysis. Fourteen patients (22.2%) had sustained a fracture after appropriate trauma at a median age of 18.5 years (range 4 –35 y), all before initial diagnosis and treatment of GCT. One of these patients had osteopenia and one osteoporosis, both at the lumbar spine site. BMD data were not available in all patients over the full follow-up period mainly because DXA scans could not be performed, particularly in the long term for different logistic reasons including loss to follow-up (n ⫽ 8), failure to attend for the test (n ⫽ 36), withdrawal of consent (n ⫽ 12), and death (n ⫽ 1). Laboratory measurements Median serum concentration of all measured biochemical parameters were normal at baseline, remained normal thereafter, and did not significantly differ at any time point between patient groups. Vitamin D deficiency was documented at baseline in 23 patients (36.5%), was equally distributed between the two patient groups, and did not change significantly thereafter.
At baseline, -CTX concentration was increased above the normal laboratory reference range in 17 of the 63 patients (27.0%): in 10 of the stage I patients (37.0%), and in seven of the patients with metastatic disease (19.4%). There was no change in -CTX concentration during follow-up. Gonadal hormone measurements, before, after 1 and 2 years, and up to 5 years after treatment, are shown in Table 2. At baseline, four of the 63 patients (6.3%) had plasma T concentrations less than 10.4 nmol/L. Independently of T levels, elevated LH and FSH levels were observed in, respectively, 11 (17.5%) and 28 (44.4%) patients. Serum estradiol was decreased in 23 patients (36.5%). There was no significant difference in mean levels of serum T, LH, and FSH between the 2 treatment groups (Figure 1, A–C). Patients with metastatic disease had significantly higher median serum estradiol concentrations before chemotherapy compared with patients with stage I disease (91 pmol/L, 31–240 vs 75 pmol/L, 28 –98; P ⫽ .007) (Table 2 and Figure 1D). Patients with disseminated disease had significantly higher median serum FSH (21.6 U/L, 5.5– 46.0 vs 12.3 U/L, 3.9 –54.1; P ⬍ .001) and higher median LH (8.1 U/L, 3.4 – 18.7 vs 5.4 U/L, 2.5–31.3; P ⫽ .008) concentrations in the absence of a decrease in serum total T and estradiol concentrations 1 year after anticancer treatment (Table 2 and Figure 1). Gonadal hormone concentrations did not fluctuate significantly during follow-up in stage I patients (Figure 1). No significant change was observed in free T over time. BMD measurements at baseline Femoral and lumbar spine BMD did not significantly differ at baseline between patients with stage I nonseminoma, patients with stage I seminoma scheduled to un-
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Figure 1. Time profile graph of serum LH, FSH, total T, and estradiol expressed as means with SD as error bars for patients with stage I GCT and patients with disseminated disease, obtained at baseline and up to five years after anticancer treatment.
dergo adjuvant single-dose carboplatin, or patients with disseminated disease (Figure 2). BMD measurements after anticancer treatment There was no significant change in BMD in stage I patients 1 year after orchidectomy or thereafter (Figure 2). There was no significant difference in BMD changes in patients who did or did not receive a single dose of carboplatin. BMD significantly decreased at the lumbar spine (⫺1.52% ⫾ 1.04%; P ⫽ .004) and at the hip (⫺2.05% ⫾ 0.98%; P ⬍ .0001) compared with pretreatment values in patients with metastatic disease who were treated with multiple chemotherapy courses (Figure 2). There was no recovery of BMD in patients with metastatic disease up to 5 years after treatment with combination chemotherapy (Figure 2).
Two patients with metastatic disease, aged 16 and 18 years, in whom peak bone mass may not have been reached at the time of diagnosis and treatment of their testis tumor, received cisplatin-based chemotherapy. The youngest patient had normal hip BMD but osteopenia at the lumbar spine, which improved at 1 year after anticancer treatment and continued to improve thereafter. The 18-yearold patient had normal BMD, which did not change over time. Prevalence of low bone mass at baseline Two of the 63 patients (3.2%) had osteoporosis of the lumbar spine but none at the hip at baseline. Eighteen patients (28.6%) had osteopenia: six patients (9.5%) at the lumbar spine and hip, nine (14.3%) only at the lumbar
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only at the lumbar spine, and one patient (1.6%) had osteopenia at the left hip. There was no significant difference in the prevalence of osteopenia and osteoporosis between patients with stage I GCT (33.3%) and those with disseminated disease (41.7%). Three of the 63 patients (4.8%) had Z-scores less than ⫺2 SD. Seventeen patients (27.0%) had Z-scores between ⫺1 and ⫺2 SD at the lumbar spine, hip, or both. Estimated BMD least square means remained low during follow-up in patients treated with chemotherapy (Figure 2). In the patients included in our longitudinal study, none developed clinical fractures of the lower lumbar vertebrae L1-L4, and none were reported to have significant degenerative changes on conventional radiographs of the lumbar spine, which would have precluded the accurate interpretation of lumbar spine BMD, by actually underestimating an actual BMD decline.
Figure 2. Time profile graph of lumbar spine BMD (grams per square centimeter, panel A) and total hip BMD (grams per square centimeter, panel B), shown as least square means difference from baseline measurements with SD as error bars for patients with stage I GCT and patients with disseminated disease.
spine, and three (4.8%) only at the total hip. There was no significant difference in the prevalence of osteopenia and osteoporosis between patients with stage I GCT (29.6%) or those with disseminated disease (33.4%). Four of the 63 patients (6.3%) had Z-scores less than ⫺2 SD. Twelve patients (19.0%) had Z-scores between ⫺1 and ⫺2 SD at the lumbar spine, total hip, or both sites. Prevalence of low bone mass after anticancer treatment One year after anticancer treatment, osteoporosis was still prevalent at the lumbar spine in one of the two patients in whom it was observed at baseline, but none of the patients studied had osteoporosis at the total hip. Twentytwo patients (34.9%) had osteopenia: eight patients (12.7%) at both the lumbar spine and hip, 13 (20.6%)
Potential risk factors for bone loss in GCTs At baseline, total hip BMD was related only to age ( ⫽ ⫺.31, P ⫽ .01) and weight ( ⫽ .43, P ⫽ .001). One year after anticancer treatment, there was no significant relationship between changes in BMD and the number of chemotherapy cycles, cumulative dose of individual chemotherapeutic agents, or cumulative dose of corticosteroids administered as antiemetic drugs during chemotherapy treatment. Bone loss was significant in patients with metastatic disease treated with chemotherapy, also after correction for age, weight, and androgen levels. There was no relationship between BMD and smoking or alcohol use. BMD changes were also independent of gonadal status, as expressed by serum T and estradiol levels, vitamin D status, or serum concentrations of -CTX. Decrease in lumbar spine and total hip BMD a year after anticancer treatment was not related to the number of chemotherapy cycles, dosage of individual chemotherapeutic agents, or the total dose of corticosteroids given as part of the antiemetic regimen. In patients with vitamin D deficiency (34.9%), lumbar spine and total hip BMD were not significantly lower compared with BMD in patients with normal serum vitamin D concentrations. There was no relationship between either -CTX or any biochemical parameters including gonadal hormones and BMD in patients receiving chemotherapy. We compared the clinical characteristics (see Table 1), bone turnover markers, lumbar and femoral BMD, and gonadal status of the patients with 5-year follow-up vs those without 5-year follow-up to assess the impact of loss to follow-up and could not elicit any statistically significant difference between these 2 groups. The direction of these associations indicated that those who were lost to follow-up were on the balance similar. The estimated between-group differences of baseline BMD and initial
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1-year BMD change comparing those treated with and without chemotherapy were similar when restricted from all patients to those with 5-year follow-up.
Discussion To our knowledge this is the first study addressing the longterm effects of chemotherapy on skeletal health in GCT survivors. We have previously established, in a cross-sectional study design, that vertebral fractures are prevalent in longterm survivors of GCTs (5), although it was not possible to determine at which stage before or after anticancer treatment these fractures were sustained. Our findings from this current study show that a relatively high percentage of newly diagnosed GCT patients already have evidence for some degree of bone loss, suggesting that skeletal fragility may predate anticancer treatment. Our data also suggest that patients with metastatic GCT experience bone loss at the lumbar spine and total hip within the first year after chemotherapy with spontaneous recovery of BMD at the lumbar spine but not at the total hip up to 5 years after anticancer treatment. Bone loss at 1 year was independent of gonadal status (serum concentrations of both T and estradiol), 25-hydroxyvitamin D concentrations, smoking habits, or changes in bone resorption markers. Whether the observed modest but persistent decrease in BMD from baseline may contribute to increased fracture risk in GCT patients treated with chemotherapy remains unclear. In patients with nonmetastatic GCTs who underwent unilateral orchidectomy but who required no systemic anticancer treatment, there was no observed bone loss at either the lumbar spine or total hip. BMD also remained unchanged in patients who received one course of adjuvant carboplatin after orchidectomy. Vitamin D levels were low in 23% of patients and, despite remaining uncorrected, were not related to any observed loss in BMD. We did not observe any effect of a single dose of carboplatin (AUC 7) on the skeleton, so it was deemed appropriate to include the 15 patients concerned in the group of patients with nonmetastatic GCTs who did not require chemotherapy. The decrease in BMD at both the total hip and lumbar spine in patients with metastatic GCTs treated with chemotherapy is most likely to represent an early direct effect of chemotherapy and/or concomitant corticosteroid treatment on bone remodeling cells or to be the result of an indirect effect of iatrogenically induced impaired gonadal function on the skeleton. Our study design did not allow the assessment of the additional contribution of the transient chemotherapy-induced hypogonadism, which occurs immediately after the start of treatment (8, 10, 20) but which may have partly recovered a year after treatment.
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Consistent with the known detrimental effects of chemotherapy on the germinal epithelium, which may be accompanied by an increase in FSH levels and/or reduced sperm counts (21, 22), FSH and LH concentrations significantly increased in GCT patients with metastatic disease 1 year after anticancer treatment. Serum estradiol and T concentrations also decreased, albeit not significantly, at 1 year after chemotherapy compared with baseline. Little is known about the gonadal status in patients with GCTs before the tumor is diagnosed, although there is some evidence that patients with the testicular dysgenesis syndrome develop partial hypogonadism long before the diagnosis of GCT is established (23). This could explain why a relatively large percentage of these patients already have abnormal BMD at the time of diagnosis of their GCT. These hypotheses may be substantiated by the observation of potential correction of bone loss in the long term by adequate correction of gonadal and vitamin D status. Corticosteroids exert their deleterious effects on the skeleton by significantly suppressing the number and function of osteoblasts as well as osteoclasts (24, 25), which is associated with a state of low bone turnover as demonstrated in animal models (26). Use of these agents may have contributed to the observed decline in BMD in survivors who underwent curative combination chemotherapy, although the cumulative dose of corticosteroids was not large, treatment was intermittent, was of short duration, and was given for only 9 –12 weeks to prevent emesis associated with chemotherapy. Four other cross-sectional studies have reported BMD data in long-term survivors of GCTs treated with and without chemotherapy. Brown et al (4) found no difference in BMD in GCT patients treated with or without chemotherapy in a cross-sectional study in 165 testicular cancer and 51 lymphoma survivors. Consistent with these data, two smaller studies in, respectively, 30 and 39 GCT survivors could also not demonstrate deleterious effects of chemotherapy or radiotherapy on bone mass in long-term GCT survivors (27, 28). In contrast, Ondrusova et al (3) reported a high prevalence of osteopenia and osteoporosis in a large cohort of 823 GCT survivors, a median of 89 months after orchidectomy and anticancer treatment. These last data are in keeping with our previously published data in 199 GCT survivors, in which we demonstrate a high prevalence of osteopenia and osteoporosis of 41.7% and 5.5%, respectively, a mean of 7.4 years after diagnosis and treatment (5). Our study has some strengths as well as limitations. A strength of our study is that we measured BMD in GCT patients with and without distant metastases, providing us the opportunity to evaluate the potential deleterious effect of intense 9 –12 weeks of combination chemotherapy on the skeleton. We also evaluated gonadal and vitamin D
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status 1 year after treatment, allowing us to assess the potential contribution of these important modulators of bone remodeling at the time point associated with maximum changes in BMD. The main limitations of our study are the relatively small size of the cohort studied and the loss to follow-up. Although it is possible that those with incomplete follow-up were in worse health, assessment of the characteristics of those lost to follow-up and sensitivity analysis do not suggest an obvious source of bias. In conclusion, our data suggest a hitherto unsuspected decline in BMD in metastatic GCT survivors a year after chemotherapy, which fails to recover in the long term. This may potentially translate in increased morbidity due to increased fracture risk, particularly considering their prolonged survival time. In addition to chemotherapy-induced bone loss, short-term high-dose corticosteroids and transient partial hypogonadism may also contribute to the decline in BMD observed after curative chemotherapy. Preexisting testicular dysgenesis syndrome may also contribute to disturbed bone quality and increased skeletal fragility in GCT patients. Whether the modest but persistent chemotherapy-induced changes in BMD may be associated with increased fracture risk and whether this potentially increased fracture risk may be decreased or prevented with the use of bone-modifying treatment remain to be established.
Acknowledgments We gratefully acknowledge the help provided by Mrs A. Q. M. J. van Steijn-van Tol, research nurse at the Department of Clinical Oncology, in the conduct of the study. We also acknowledge the help of J. Molenaar, head of the Department of Oncological Documentation, and the technical assistance of the Department of Nuclear Medicine for bone densitometry measurements. Address all correspondence and requests for reprints to: S. Osanto, MD, PhD, Department of Clinical Oncology, Leiden University Medical Center, Albinusdreef 2, 2333 ZA Leiden, The Netherlands. E-mail: [email protected]. Disclosure Summary: The authors have nothing to declare.
References 1. Einhorn LH, Donohue J. Cis-diamminedichloroplatinum, vinblastine, and bleomycin combination chemotherapy in disseminated testicular cancer. Ann Intern Med. 1977;87:293–298. 2. Pfeilschifter J, Diel IJ. Osteoporosis due to cancer treatment: pathogenesis and management. J Clin Oncol. 2000;18:1570 –1593. 3. Ondrusova M, Ondrus D, Dusek L, Spanikova B. Damage of hormonal function and bone metabolism in long-term survivors of testicular cancer. Neoplasma. 2009;56:473– 479. 4. Brown JE, Ellis SP, Silcocks P, et al. Effect of chemotherapy on skeletal health in male survivors from testicular cancer and lymphoma. Clin Cancer Res. 2006;12:6480 – 6486.
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5. Willemse PM, Hamdy NA, van Wulften L, van Steijn-van Tol A, Putter H, Osanto S. Prevalence of vertebral fractures independent of BMD and anticancer treatment in patients with testicular germ cell tumors. J Clin Endocrinol Metab. 2010;95:4933– 4942. 6. Baylink DJ. Glucocorticoid-induced osteoporosis. N Engl J Med. 1983;309:306 –308. 7. Fisher DE, Bickel WH. Corticosteroid-induced avascular necrosis. A clinical study of seventy-seven patients. J Bone Joint Surg Am. 1971; 53:859 – 873. 8. Brennemann W, Stoffel-Wagner B, Helmers A, Mezger J, Jager N, Klingmuller D. Gonadal function of patients treated with cisplatin based chemotherapy for germ cell cancer. J Urol. 1997;158:844 – 850. 9. Petersen PM, Skakkebaek NE, Rorth M, Giwercman A. Semen quality and reproductive hormones before and after orchiectomy in men with testicular cancer. J Urol. 1999;161:822– 826. 10. Nord C, Bjoro T, Ellingsen D, et al. Gonadal hormones in long-term survivors 10 years after treatment for unilateral testicular cancer. Eur Urol. 2003;44:322–328. 11. Bandak M, Aksglaede L, Juul A, Rorth M, Daugaard G. The pituitary-Leydig cell axis before and after orchiectomy in patients with stage I testicular cancer. Eur J Cancer. 2011;47:2585–2591. 12. Morley JE, Patrick P, Perry HM III. Evaluation of assays available to measure free testosterone. Metabolism. 2002;51:554 –559. 13. Vermeulen A, Verdonck L, Kaufman JM. A critical evaluation of simple methods for the estimation of free testosterone in serum. J Clin Endocrinol Metab. 1999;84:3666 –3672. 14. Lackner JE, Mark I, Schatzl G, Marberger M, Kratzik C. Hypogonadism and androgen deficiency symptoms in testicular cancer survivors. Urology. 2007;69:754 –758. 15. Holick MF. Vitamin D deficiency. N Engl J Med. 2007;357:266 –281. 16. Roux C, Bischoff-Ferrari HA, Papapoulos SE, de Papp AE, West JA, Bouillon R. New insights into the role of vitamin D and calcium in osteoporosis management: an expert roundtable discussion. Curr Med Res Opin. 2008;24:1363–1370. 17. Looker AC, Wahner HW, Dunn WL, et al. Proximal femur bone mineral levels of US adults. Osteoporos Int. 1995;5:389 – 409. 18. World Health Organization. Assessment of fracture risk and its application to screening for postmenopausal osteoporosis. WHO Technical Report Series 843. Geneva: World Health Organization; 1994. 19. Petak S, Barbu CG, Yu EW, et al. The official positions of the International Society for Clinical Densitometry: body composition analysis reporting. J Clin Densitom. 2013;16:508 –519. 20. Petersen PM, Giwercman A, Skakkebaek NE, Rorth M. Gonadal function in men with testicular cancer. Semin Oncol. 1998;25:224 –233. 21. Petersen PM, Skakkebaek NE, Vistisen K, Rorth M, Giwercman A. Semen quality and reproductive hormones before orchiectomy in men with testicular cancer. J Clin Oncol. 1999;17:941–947. 22. Huddart RA, Norman A, Moynihan C, et al. Fertility, gonadal and sexual function in survivors of testicular cancer. Br J Cancer. 2005; 93:200 –207. 23. Skakkebaek NE, Rajpert-De Meyts E, Main KM. Testicular dysgenesis syndrome: an increasingly common developmental disorder with environmental aspects. Hum Reprod. 2001;16:972–978. 24. Canalis E, Mazziotti G, Giustina A, Bilezikian JP. Glucocorticoidinduced osteoporosis: pathophysiology and therapy. Osteoporos Int. 2007;18:1319 –1328. 25. Weinstein RS. Glucocorticoid-induced osteoporosis. Rev Endocr Metab Disord. 2001;2:65–73. 26. Tobias J, Chambers TJ. Glucocorticoids impair bone resorptive activity and viability of osteoclasts disaggregated from neonatal rat long bones. Endocrinology. 1989;125:1290 –1295. 27. Stutz JA, Barry BP, Maslanka W, Sokal M, Green DJ, Pearson D. Bone density: is it affected by orchidectomy and radiotherapy given for stage I seminoma of the testis? Clin Oncol (R Coll Radiol). 1998;10:44 – 49. 28. Murugaesu N, Powles T, Bestwick J, Oliver RT, Shamash J. Longterm follow-up of testicular cancer patients shows no predisposition to osteoporosis. Osteoporos Int. 2009;20:1627–1630.
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ARTICLE
E n d o c r i n e
C a r e
Changes in Bone Mineral Density in Newly Diagnosed Testicular Cancer Patients After Anticancer Treatment P. M. Willemse, N. A. T. Hamdy, M. L. de Kam, J. Burggraaf, and S. Osanto Departments of Clinical Oncology (P.M.W., S.O.) and Endocrinology and Metabolic Diseases (N.A.T.H.), Leiden University Medical Center, 2333 ZA Leiden, The Netherlands, and Centre for Human Drug Research (M.L.d.K., J.B.), 2333 CL Leiden, The Netherlands
Context: Patients with germ cell tumors (GCTs) have an excellent prognosis but are at risk for silent fractures. Data on bone mineral density (BMD) after anticancer treatment are scarce. Objective: The objective of the study was BMD monitoring in GCT patients treated with or without chemotherapy. Design: We prospectively studied 63 newly diagnosed GCT patients with a median age of 33 years (range 16 –70 y) within 3 months of unilateral orchidectomy. Twenty-seven patients (42.9%) had no metastases. Thirty-six patients (57.1%) with metastatic disease received combination chemotherapy. Setting: This study was conducted at the outpatient clinic of a single academic institution. Interventions: We performed dual-energy X-ray absorptiometry scans and collected blood samples on a yearly basis, before and up to 5 years after anticancer treatment. Main Outcome Measures: Changes in total hip and lumbar spine BMD, serum concentrations of gonadal hormones, and bone turnover markers were measured. Results: BMD remained normal in stage I patients. In patients with metastatic disease, a significant decrease in lumbar spine BMD (⫺1.52%; P ⫽ .004) and total hip BMD (⫺2.05%; P ⬍ .0001) was observed 1 year after chemotherapy and remained stable thereafter for up to 5 years. There was no significant relationship between the observed decrease in BMD and gonadal status, vitamin D status, or cumulative dose of cisplatin or (antiemetic) corticosteroids. Conclusions: Metastatic GCT survivors demonstrate significant bone loss within the first year after curative combination chemotherapy, with no recovery up to 5 years after anticancer treatment. Whether this bone loss is associated with increased fracture risk and whether this could be prevented by bone modifying treatment remains to be established. (J Clin Endocrinol Metab 99: 4101– 4108, 2014)
esticular germ cell tumors (GCTs) are the most common form of cancer in young male adults. The introduction of cisplatin-based combination chemotherapy has led to significant improvement in prognosis, with cure achieved in the vast majority of patients (1). This translates into an increasing number of long-term survivors of this malignancy who would have undergone unilateral orchidectomy with or without chemotherapy at a relatively young age. Long-term detrimental effects of cancer treat-
T
ments on the skeleton may be associated with significant skeletal morbidity, so that it is of clinical relevance to evaluate the presence of these skeletal complications in GCT survivors to allow timely intervention to decrease or prevent associated increased fracture risk. GCT patients may experience accelerated bone loss through the potentially deleterious effects of chemotherapy on the skeleton (2). A high prevalence of osteopenia and osteoporosis has been reported in a large cohort of
ISSN Print 0021-972X ISSN Online 1945-7197 Printed in U.S.A. Copyright © 2014 by the Endocrine Society Received March 12, 2014. Accepted August 6, 2014. First Published Online April 13, 2014
Abbreviations: BMD, bone mineral density; -CTX, -carboxyl-terminal cross-linking telopeptide of type I collagen; DXA, dual-energy X-ray absorptiometry; GCT, germ cell tumor.
doi: 10.1210/jc.2014-1722
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823 GCT survivors with unilateral testicular cancer, a median 89 months after orchidectomy and anticancer treatment (3). In contrast, another study reported no deleterious effects of chemotherapy on skeletal health in longterm survivors of GCT or lymphoma (4). However, we have previously shown an increased prevalence of vertebral fragility fractures in cured long-term survivors of GCTs. The high prevalence of largely asymptomatic vertebral fractures we observed in these patients was independent of tumor stage, chemotherapy, or bone mineral density (BMD) (5). Chemotherapy may be causally related to decreases in BMD because of potential negative effects of treatment on bone remodeling. The widely used high doses of corticosteroids as part of antiemetic regimen concomitantly prescribed with chemotherapy may contribute to bone loss (6) as well as to osteonecrosis of the femoral head (7). Cytotoxic chemotherapy is associated with significant gonadal damage, with germ cells being more sensitive to the deleterious effects of treatment than Leydig cells, resulting in infertility being a more commonly encountered adverse effect than hypogonadism. Whether bone quantity and quality are directly affected by chemotherapy, or indirectly so by chemotherapy-mediated partial or complete hypogonadism is not clear. Various studies reported hypogonadism in chemotherapy-treated GCT survivors as evidenced by increased serum LH and low-normal serum T, up to 60 months after chemotherapy (8 –10). However, the diurnal pulsatile pattern of T secretion and the different parameters used to define hypogonadism preclude comparison between various studies. Interestingly, partial hypogonadism may be already present before orchidectomy in up to one third of GCT patients (11). Although the vast majority of patients remains or becomes eugonadal in time (10), the sometimes severe bone loss associated with iatrogenic hypogonadism may not be fully reversible. The aim of our study was to evaluate longitudinal changes in BMD in newly diagnosed and recently orchiectomized GCT patients 1, 2, and up to 5 years after anticancer treatment.
Patients and Methods All patients who were referred to the Department of Clinical Oncology of the Leiden University Medical Center between 2007 and 2009 after unilateral orchidectomy but before potential anticancer treatment were invited to participate in the study. The study was approved by the Medical Ethical Committee of the Leiden University Medical Center, and informed consent was obtained from all patients. The primary tumor was staged on the basis of tumor histology, computed tomography scan, and serum concentrations of the tumor markers, -human chorionic gonadotropins, ␣-fetoprotein and lactate dehydrogenase, as measured at the time of
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diagnosis. Patients were divided into 2 groups based on tumor stage and anticancer treatment. The first group consisted of patients with nonmetastatic disease (stage 1) who are treated with only a unilateral orchidectomy for nonseminomas or with unilateral orchidectomy in addition to a single dose of adjuvant carboplatin AUC7 for pure seminomas. In our experience and that of others, carboplatin does not appear to be associated with chemotherapy-related complications (5), so we decided to include these patients in the nonmetastatic group of patients. The second group consisted of patients with metastatic GCTs who received multiple courses of cisplatin-based combination chemotherapy. Baseline evaluation included medical history, prior and current medication, prior use of corticosteroids, smoking habits, and alcohol use. All patients underwent a full clinical examination including body height, weight, waist and hip circumference, pulse rate, and blood pressure. Information about fracture history was obtained by means of a brief questionnaire.
Laboratory investigations Blood samples were collected after an overnight fast and before 10:00 AM at baseline after orchidectomy and at 1, 2, and up to 5 years thereafter. Serum was routinely measured for creatinine, calcium (corrected for albumin), phosphate, and alkaline phosphatase concentrations using semiautomated techniques. Serum was also measured for the marker of bone resorption, -carboxyl-terminal cross-linking telopeptide of type I collagen (-CTX). Serum intact PTH, 25-hydroxyvitamin D, and 1,25dihydroxyvitamin D3 were measured using standard RIAs. Gonadal status was evaluated by measuring serum LH, FSH, total T, estradiol, and SHBG using standard RIAs. Free T was calculated using a standard formula (12, 13). Hypogonadism was defined as a serum total T concentration of less than 10.4 nmol/L (14). Vitamin D deficiency was defined as a 1,25-dihydroxyvitamin D3 concentrations of less than 50 nmol/L (15, 16). Renal function was calculated using the Cockcroft formula. Serum concentrations of -human chorionic gonadotropins, ␣-fetoprotein and lactate dehydrogenate were used for staging of the disease at time of diagnosis.
BMD measurements BMD was measured at the lumbar spine (L1-L4) and total hip using dual-energy X-ray absorptiometry (DXA; Hologic QDR 4500). The coefficient of variation of BMD measurements was 1%, and the machine was calibrated at regular intervals. The DXA scan used in this study was equipped with reference values based on the National Health and Nutrition Examination Surveys III for European men (17), which are compatible with those of a Dutch control population. World Health Organization criteria were used to define osteopenia (T-score between ⫺1 and ⫺2.5) and osteoporosis (T-score ⬍ ⫺2.5) (18). Lumbar BMD was assessed from L1 to L4 in posteroanterior incidence. Total hip BMD was reported as the mean of left and right total hip BMD measurements. Because of the relatively young age of the population studied, results were also expressed as Z-scores, indicating the number of SDs below the mean of age- and sexmatched controls (19).
Statistical analysis The SPSS for Windows software package and SAS for windows version 9.1.3 (SAS Institute, Inc) were used for statistical analysis. Results are expressed as mean ⫾ SD or as median
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(minimum-maximum). A two-tailed paired sample Student’s t test was used to compare single, normally distributed measurements between study groups. The Wilcoxon signed-rank test was used to compare unevenly distributed measurements between study groups. The comparability of the study groups at baseline was assessed as appropriate by one-way ANOVA. The serial measurements of the biochemical markers and BMD were analyzed with a repeated-measures model ANOVA, with an autoregressive first-order covariance structure. The estimated least square means) and their P values for the difference from zero test are used to establish whether the patients are deviant from their peers. Univariate linear regression analysis was used to determine a relationship between possible confounders.
Results Patient and disease characteristics Sixty-three consecutive newly diagnosed GCT patients aged 16 –70 years (median 33 y) were included in the study. Demographic and anthropometric characteristics of these patients are summarized in Table 1. Most GCT patients studied were asymptomatic, were leading an active life, and were in good clinical condition. Twentyseven patients (42.9%) had stage I disease (no metastases) and thirty-six patients (57.1%) had metastatic disease Table 1.
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(Table 1). Of the patients with metastatic disease, one (1.6%) had stage IS (elevated tumor markers but negative computed tomography scan indicating micrometastases), 23 (36.5%) had stage II disease (metastases in one or more locoregional paraaortic lymph nodes), and 12 (19%) had distant metastases, mostly in the lungs (Table 1). Patients with metastatic disease received first-line cisplatin-based combination chemotherapy consisting of three (n ⫽ 22) or four (n ⫽ 14) cycles of bleomycin, etoposide, and cisplatinum or four cycles of etoposide and cisplatinum. Each cycle consisted of iv-administered etoposide (100 mg/m2 over 1 h, d 1–5) and cisplatin (20 mg/m2 over 4 h, d 1–5), with or without bleomycin (30 IUSP over 30 min) at days 2, 8, and 15. As part of the antiemetic regimen, all 36 patients received iv-administered high doses of corticosteroids [10 mg dexamethasone iv daily during d 1–5 of their 3 weekly chemotherapy courses, with rapidly tapering of oral dexamethasone thereafter: twice daily 3 mg (d 6 –7) and twice daily 1.5 mg (d 8 –9)]. Two patients received two extra cycles of vinblastine, ifosfamide, and cisplatinum consolidation chemotherapy and consequently higher administered doses of corticosteroids. Only eight patients had comorbidities in
Baseline Clinical Characteristics of GCT Patients With or Without Metastatic Disease
Demographics (median, minimum-maximum) Age, y ␦Time, y Characteristics (mean ⫾ SD) Weight, kg BMI, kg/m2 Waist circumference, cm Systolic blood pressure, mm Hg Renal function, Cockroft clearance mL/min Lifestyle, n , % Smoking Alcohol use, ⬎20 U/wk Histology, n, % Seminoma Nonseminoma Combined tumor TNM tumor staging, n, %b Stage I (no metastasis) Stage IS (elevated serum tumor markers) Stage II (paraaortic lymph node metastasis) Stage III (distant metastasis) Treatment, n, % No adjuvant treatment Single-dose carboplatin Combination chemotherapy
All Patients (n ⴝ 63)
Stage I (n ⴝ 27)
Disseminated (n ⴝ 36)
P Valuea
33 (16 –70) 0.1 (0.0 – 6.2)
35 (22–70) 0.2 (0.0 – 0.8)
34 (16 –59) 0.1 (0.0 – 6.2)
NS NS
83 ⫾ 12 24.7 ⫾ 3.3 92 ⫾ 10 128 ⫾ 15 135 ⫾ 30
82 ⫾ 12 24.3 ⫾ 2.7 94 ⫾ 12 126 ⫾ 16 126 ⫾ 25
83 ⫾ 11 25.1 ⫾ 3.7 90 ⫾ 8 130 ⫾ 15 141 ⫾ 32
NS NS NS NS NS
24 (38.1) 16 (25.4)
7 (25.9) 7 (25.9)
17 (47.2) 9 (25.0)
NS NS NS
27 (42.9) 22 (34.9) 14 (22.2)
15 (55.6) 7 (25.9) 5 (18.5)
12 (33.3) 15 (41.7) 9 (25.0)
27 (42.9) 1 (1.6) 23 (36.5) 12 (19.0)
27 (100.0) 0 (0.0) 0 (0.0) 0 (0.0)
0 (0.0) 1 (2.8) 23 (63.9) 12 (33.3)
12 (19.1) 15 (23.8) 36 (57.1)
12 (44.4) 15 (55.6) 0 (0.0)
0 (0.0) 0 (0.0) 36 (100.0)
⬃
⬃
Abbreviations: BMI, body mass index; NS, nonsignificant, ␦Time, time between orchidectomy and first measurement (years); TNM, tumor node metastasis; ⬃, not calculated. a
P value for comparison between values of patients treated with and without chemotherapy (independent samples Student’s t test, independent samples Mann-Whitney test, or 2 test where appropriate). b
Patients with stage IS, stage II, and stage III are all classified as metastatic GCTs.
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Table 2. Gonadal Hormones Expressed as Mean ⫾ SD and Median (Minimum-Maximum) Before and After Anticancer Treatment Parameters
Baseline
Year 1
Year 2
Year 3
Year 4
Year 5
Stage I GCT S. total T
n ⫽ 27 17.4 ⫾ 7.5 15.3 (0.2–33.9) 69 ⫾ 20 75 (28 –98) 7.5 ⫾ 4.9 6.3 (2.9 –25.6) 12.4 ⫾ 7.7 10.2 (4.6 –32.1) 30.5 ⫾ 18.3 24.9 (3.0 –90.0) n ⫽ 36 17.4 ⫾ 5.6 17.4 (4.7–30.2) 104 ⫾ 56 91 (31–240) 5.9 ⫾ 5.8 4.8 (0.1–24.8) 10.4 ⫾ 11.1 7.4 (0.1– 44.5) 31.2 ⫾ 12.0 31.9 (6.8 – 64.0)
n ⫽ 27 15.6 ⫾ 4.9 17.1 (9.2–27.4) 66 ⫾ 22 63 (28 –109) 8.0 ⫾ 6.6 5.4 (2.5–31.3) 16.1 ⫾ 12.5 12.3 (3.9 –54.1) 29.2 ⫾ 9.1 26.3 (15.7– 48.4) n ⫽ 35 16.2 ⫾ 4.4 15.3 (9.1–26.5) 91 ⫾ 33 88 (25–181) 9.3 ⫾ 4.4 8.1 (3.4 –18.7) 24.0 ⫾ 12.3 21.6 (5.5– 46.0) 31.2 ⫾ 10.8 30.2 (13.3–52.7)
n ⫽ 19 16.3 ⫾ 4.5 15.8 (9.9 –25.8) 72 ⫾ 19 73 (42–118) 9.0 ⫾ 8.6 6.8 (2.5–36.0) 16.6 ⫾ 14.2 12.5 (3.9 –50.8) 32.4 ⫾ 15.0 26.3 (16.1– 85.4) n ⫽ 23 16.3 ⫾ 5.4 14.9 (10.0 –30.0) 76 ⫾ 25 78 (20 –123) 8.7 ⫾ 4.0 8.1 (2.7–16.4) 18.1 ⫾ 10.8 14.2 (5.0 –39.7) 26.4 ⫾ 9.8 23.9 (11.0 – 46.6)
n ⫽ 14 18.1 ⫾ 6.6 16.1 (11.4 –37.9) 60 ⫾ 23 59 (26 –113) 6.6 ⫾ 3.3 5.8 (2.6 –13.8) 12.6 ⫾ 9.6 10.8 (4.0 – 40.4) 28.9 ⫾ 6.4 27.4 (16.1– 44.8) n ⫽ 26 15.6 ⫾ 5.2 14.2 (5.4 –25.2) 84 ⫾ 32 74 (36 –160) 7.7 ⫾ 3.7 6.9 (2.6 –14.5) 16.8 ⫾ 10.2 14.2 (5.0 –39.7) 29.5 ⫾ 10.2 30.5 (14.0 – 48.4)
n ⫽ 12 16.0 ⫾ 5.0 15.6 (9.1–23.4) 63 ⫾ 10 60 (50 –77) 8.1 ⫾ 5.9 5.9 (3.3–19.0) 16.9 ⫾ 16.5 11.5 (4.9 – 49.1) 33.6 ⫾ 6.1 34.3 (23.2– 42.4) n ⫽ 20 17.2 ⫾ 5.7 17.6 (6.4 –25.1) 75 ⫾ 23 81 (21–108) 7.1 ⫾ 3.3 6.4 (2.9 –14.3) 13.3 ⫾ 4.6 10.8 (3.6 –29.1) 26.4 ⫾ 6.8 28.9 (14.3–35.3)
n ⫽ 14 16.1 ⫾ 7.2 16.0 (0.7–29.2) 66 ⫾ 20 61 (38 –99) 6.6 ⫾ 4.6 5.0 (3.1–20.1) 11.7 ⫾ 11.1 10.2 (4.5– 48.5) 33.1 ⫾ 10.1 32.6 (12.5– 49.9) n ⫽ 21 16.2 ⫾ 5.8 15.8 (7.0 –29.5) 82 ⫾ 21 82 (35–118) 6.7 ⫾ 3.2 6.1 (2.1–13.5) 12.8 ⫾ 8.0 10.3 (2.9 –29.1) 32.8 ⫾ 13.9 33.0 (11.7–59.3)
S. estradiol S. LH S. FSH S. SHBG Metastatic GCT S. total T S. estradiol S. LH S. FSH S. SHBG
Reference Range
8.0 –35.0 nmol/L 70 –200 pmol/L 2.0 –10.0 U/L 2.0 –10.0 U/L 20 –55 nmol/L
8.0 –35.0 nmol/L 70 –200 pmol/L 2.0 –10.0 U/L 2.0 –10.0 U/L 20 –55 nmol/L
Abbreviation: S, serum.
the form of diabetes mellitus (n ⫽ 3), hypertension (n ⫽ 2), chronic obstructive pulmonary disease (n ⫽ 1), ulcerative colitis (n ⫽ 1), or epilepsy (n ⫽ 1), unrelated to their malignancy or to the treatment received, and these comorbidities were equally distributed between patients with or without metastatic disease. Two patients aged 53 and 35 years developed avascular necrosis of the hip, respectively, 1 and 4 years after chemotherapy. They were treated with bisphosphonates and were excluded from further analysis. One patient, aged 21 years, diagnosed with osteoporosis of the lumbar spine 1 year after chemotherapy, who was treated with calcium and vitamin D supplements, was also excluded from further analysis. Fourteen patients (22.2%) had sustained a fracture after appropriate trauma at a median age of 18.5 years (range 4 –35 y), all before initial diagnosis and treatment of GCT. One of these patients had osteopenia and one osteoporosis, both at the lumbar spine site. BMD data were not available in all patients over the full follow-up period mainly because DXA scans could not be performed, particularly in the long term for different logistic reasons including loss to follow-up (n ⫽ 8), failure to attend for the test (n ⫽ 36), withdrawal of consent (n ⫽ 12), and death (n ⫽ 1). Laboratory measurements Median serum concentration of all measured biochemical parameters were normal at baseline, remained normal thereafter, and did not significantly differ at any time point between patient groups. Vitamin D deficiency was documented at baseline in 23 patients (36.5%), was equally distributed between the two patient groups, and did not change significantly thereafter.
At baseline, -CTX concentration was increased above the normal laboratory reference range in 17 of the 63 patients (27.0%): in 10 of the stage I patients (37.0%), and in seven of the patients with metastatic disease (19.4%). There was no change in -CTX concentration during follow-up. Gonadal hormone measurements, before, after 1 and 2 years, and up to 5 years after treatment, are shown in Table 2. At baseline, four of the 63 patients (6.3%) had plasma T concentrations less than 10.4 nmol/L. Independently of T levels, elevated LH and FSH levels were observed in, respectively, 11 (17.5%) and 28 (44.4%) patients. Serum estradiol was decreased in 23 patients (36.5%). There was no significant difference in mean levels of serum T, LH, and FSH between the 2 treatment groups (Figure 1, A–C). Patients with metastatic disease had significantly higher median serum estradiol concentrations before chemotherapy compared with patients with stage I disease (91 pmol/L, 31–240 vs 75 pmol/L, 28 –98; P ⫽ .007) (Table 2 and Figure 1D). Patients with disseminated disease had significantly higher median serum FSH (21.6 U/L, 5.5– 46.0 vs 12.3 U/L, 3.9 –54.1; P ⬍ .001) and higher median LH (8.1 U/L, 3.4 – 18.7 vs 5.4 U/L, 2.5–31.3; P ⫽ .008) concentrations in the absence of a decrease in serum total T and estradiol concentrations 1 year after anticancer treatment (Table 2 and Figure 1). Gonadal hormone concentrations did not fluctuate significantly during follow-up in stage I patients (Figure 1). No significant change was observed in free T over time. BMD measurements at baseline Femoral and lumbar spine BMD did not significantly differ at baseline between patients with stage I nonseminoma, patients with stage I seminoma scheduled to un-
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Figure 1. Time profile graph of serum LH, FSH, total T, and estradiol expressed as means with SD as error bars for patients with stage I GCT and patients with disseminated disease, obtained at baseline and up to five years after anticancer treatment.
dergo adjuvant single-dose carboplatin, or patients with disseminated disease (Figure 2). BMD measurements after anticancer treatment There was no significant change in BMD in stage I patients 1 year after orchidectomy or thereafter (Figure 2). There was no significant difference in BMD changes in patients who did or did not receive a single dose of carboplatin. BMD significantly decreased at the lumbar spine (⫺1.52% ⫾ 1.04%; P ⫽ .004) and at the hip (⫺2.05% ⫾ 0.98%; P ⬍ .0001) compared with pretreatment values in patients with metastatic disease who were treated with multiple chemotherapy courses (Figure 2). There was no recovery of BMD in patients with metastatic disease up to 5 years after treatment with combination chemotherapy (Figure 2).
Two patients with metastatic disease, aged 16 and 18 years, in whom peak bone mass may not have been reached at the time of diagnosis and treatment of their testis tumor, received cisplatin-based chemotherapy. The youngest patient had normal hip BMD but osteopenia at the lumbar spine, which improved at 1 year after anticancer treatment and continued to improve thereafter. The 18-yearold patient had normal BMD, which did not change over time. Prevalence of low bone mass at baseline Two of the 63 patients (3.2%) had osteoporosis of the lumbar spine but none at the hip at baseline. Eighteen patients (28.6%) had osteopenia: six patients (9.5%) at the lumbar spine and hip, nine (14.3%) only at the lumbar
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only at the lumbar spine, and one patient (1.6%) had osteopenia at the left hip. There was no significant difference in the prevalence of osteopenia and osteoporosis between patients with stage I GCT (33.3%) and those with disseminated disease (41.7%). Three of the 63 patients (4.8%) had Z-scores less than ⫺2 SD. Seventeen patients (27.0%) had Z-scores between ⫺1 and ⫺2 SD at the lumbar spine, hip, or both. Estimated BMD least square means remained low during follow-up in patients treated with chemotherapy (Figure 2). In the patients included in our longitudinal study, none developed clinical fractures of the lower lumbar vertebrae L1-L4, and none were reported to have significant degenerative changes on conventional radiographs of the lumbar spine, which would have precluded the accurate interpretation of lumbar spine BMD, by actually underestimating an actual BMD decline.
Figure 2. Time profile graph of lumbar spine BMD (grams per square centimeter, panel A) and total hip BMD (grams per square centimeter, panel B), shown as least square means difference from baseline measurements with SD as error bars for patients with stage I GCT and patients with disseminated disease.
spine, and three (4.8%) only at the total hip. There was no significant difference in the prevalence of osteopenia and osteoporosis between patients with stage I GCT (29.6%) or those with disseminated disease (33.4%). Four of the 63 patients (6.3%) had Z-scores less than ⫺2 SD. Twelve patients (19.0%) had Z-scores between ⫺1 and ⫺2 SD at the lumbar spine, total hip, or both sites. Prevalence of low bone mass after anticancer treatment One year after anticancer treatment, osteoporosis was still prevalent at the lumbar spine in one of the two patients in whom it was observed at baseline, but none of the patients studied had osteoporosis at the total hip. Twentytwo patients (34.9%) had osteopenia: eight patients (12.7%) at both the lumbar spine and hip, 13 (20.6%)
Potential risk factors for bone loss in GCTs At baseline, total hip BMD was related only to age ( ⫽ ⫺.31, P ⫽ .01) and weight ( ⫽ .43, P ⫽ .001). One year after anticancer treatment, there was no significant relationship between changes in BMD and the number of chemotherapy cycles, cumulative dose of individual chemotherapeutic agents, or cumulative dose of corticosteroids administered as antiemetic drugs during chemotherapy treatment. Bone loss was significant in patients with metastatic disease treated with chemotherapy, also after correction for age, weight, and androgen levels. There was no relationship between BMD and smoking or alcohol use. BMD changes were also independent of gonadal status, as expressed by serum T and estradiol levels, vitamin D status, or serum concentrations of -CTX. Decrease in lumbar spine and total hip BMD a year after anticancer treatment was not related to the number of chemotherapy cycles, dosage of individual chemotherapeutic agents, or the total dose of corticosteroids given as part of the antiemetic regimen. In patients with vitamin D deficiency (34.9%), lumbar spine and total hip BMD were not significantly lower compared with BMD in patients with normal serum vitamin D concentrations. There was no relationship between either -CTX or any biochemical parameters including gonadal hormones and BMD in patients receiving chemotherapy. We compared the clinical characteristics (see Table 1), bone turnover markers, lumbar and femoral BMD, and gonadal status of the patients with 5-year follow-up vs those without 5-year follow-up to assess the impact of loss to follow-up and could not elicit any statistically significant difference between these 2 groups. The direction of these associations indicated that those who were lost to follow-up were on the balance similar. The estimated between-group differences of baseline BMD and initial
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doi: 10.1210/jc.2014-1722
1-year BMD change comparing those treated with and without chemotherapy were similar when restricted from all patients to those with 5-year follow-up.
Discussion To our knowledge this is the first study addressing the longterm effects of chemotherapy on skeletal health in GCT survivors. We have previously established, in a cross-sectional study design, that vertebral fractures are prevalent in longterm survivors of GCTs (5), although it was not possible to determine at which stage before or after anticancer treatment these fractures were sustained. Our findings from this current study show that a relatively high percentage of newly diagnosed GCT patients already have evidence for some degree of bone loss, suggesting that skeletal fragility may predate anticancer treatment. Our data also suggest that patients with metastatic GCT experience bone loss at the lumbar spine and total hip within the first year after chemotherapy with spontaneous recovery of BMD at the lumbar spine but not at the total hip up to 5 years after anticancer treatment. Bone loss at 1 year was independent of gonadal status (serum concentrations of both T and estradiol), 25-hydroxyvitamin D concentrations, smoking habits, or changes in bone resorption markers. Whether the observed modest but persistent decrease in BMD from baseline may contribute to increased fracture risk in GCT patients treated with chemotherapy remains unclear. In patients with nonmetastatic GCTs who underwent unilateral orchidectomy but who required no systemic anticancer treatment, there was no observed bone loss at either the lumbar spine or total hip. BMD also remained unchanged in patients who received one course of adjuvant carboplatin after orchidectomy. Vitamin D levels were low in 23% of patients and, despite remaining uncorrected, were not related to any observed loss in BMD. We did not observe any effect of a single dose of carboplatin (AUC 7) on the skeleton, so it was deemed appropriate to include the 15 patients concerned in the group of patients with nonmetastatic GCTs who did not require chemotherapy. The decrease in BMD at both the total hip and lumbar spine in patients with metastatic GCTs treated with chemotherapy is most likely to represent an early direct effect of chemotherapy and/or concomitant corticosteroid treatment on bone remodeling cells or to be the result of an indirect effect of iatrogenically induced impaired gonadal function on the skeleton. Our study design did not allow the assessment of the additional contribution of the transient chemotherapy-induced hypogonadism, which occurs immediately after the start of treatment (8, 10, 20) but which may have partly recovered a year after treatment.
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Consistent with the known detrimental effects of chemotherapy on the germinal epithelium, which may be accompanied by an increase in FSH levels and/or reduced sperm counts (21, 22), FSH and LH concentrations significantly increased in GCT patients with metastatic disease 1 year after anticancer treatment. Serum estradiol and T concentrations also decreased, albeit not significantly, at 1 year after chemotherapy compared with baseline. Little is known about the gonadal status in patients with GCTs before the tumor is diagnosed, although there is some evidence that patients with the testicular dysgenesis syndrome develop partial hypogonadism long before the diagnosis of GCT is established (23). This could explain why a relatively large percentage of these patients already have abnormal BMD at the time of diagnosis of their GCT. These hypotheses may be substantiated by the observation of potential correction of bone loss in the long term by adequate correction of gonadal and vitamin D status. Corticosteroids exert their deleterious effects on the skeleton by significantly suppressing the number and function of osteoblasts as well as osteoclasts (24, 25), which is associated with a state of low bone turnover as demonstrated in animal models (26). Use of these agents may have contributed to the observed decline in BMD in survivors who underwent curative combination chemotherapy, although the cumulative dose of corticosteroids was not large, treatment was intermittent, was of short duration, and was given for only 9 –12 weeks to prevent emesis associated with chemotherapy. Four other cross-sectional studies have reported BMD data in long-term survivors of GCTs treated with and without chemotherapy. Brown et al (4) found no difference in BMD in GCT patients treated with or without chemotherapy in a cross-sectional study in 165 testicular cancer and 51 lymphoma survivors. Consistent with these data, two smaller studies in, respectively, 30 and 39 GCT survivors could also not demonstrate deleterious effects of chemotherapy or radiotherapy on bone mass in long-term GCT survivors (27, 28). In contrast, Ondrusova et al (3) reported a high prevalence of osteopenia and osteoporosis in a large cohort of 823 GCT survivors, a median of 89 months after orchidectomy and anticancer treatment. These last data are in keeping with our previously published data in 199 GCT survivors, in which we demonstrate a high prevalence of osteopenia and osteoporosis of 41.7% and 5.5%, respectively, a mean of 7.4 years after diagnosis and treatment (5). Our study has some strengths as well as limitations. A strength of our study is that we measured BMD in GCT patients with and without distant metastases, providing us the opportunity to evaluate the potential deleterious effect of intense 9 –12 weeks of combination chemotherapy on the skeleton. We also evaluated gonadal and vitamin D
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status 1 year after treatment, allowing us to assess the potential contribution of these important modulators of bone remodeling at the time point associated with maximum changes in BMD. The main limitations of our study are the relatively small size of the cohort studied and the loss to follow-up. Although it is possible that those with incomplete follow-up were in worse health, assessment of the characteristics of those lost to follow-up and sensitivity analysis do not suggest an obvious source of bias. In conclusion, our data suggest a hitherto unsuspected decline in BMD in metastatic GCT survivors a year after chemotherapy, which fails to recover in the long term. This may potentially translate in increased morbidity due to increased fracture risk, particularly considering their prolonged survival time. In addition to chemotherapy-induced bone loss, short-term high-dose corticosteroids and transient partial hypogonadism may also contribute to the decline in BMD observed after curative chemotherapy. Preexisting testicular dysgenesis syndrome may also contribute to disturbed bone quality and increased skeletal fragility in GCT patients. Whether the modest but persistent chemotherapy-induced changes in BMD may be associated with increased fracture risk and whether this potentially increased fracture risk may be decreased or prevented with the use of bone-modifying treatment remain to be established.
Acknowledgments We gratefully acknowledge the help provided by Mrs A. Q. M. J. van Steijn-van Tol, research nurse at the Department of Clinical Oncology, in the conduct of the study. We also acknowledge the help of J. Molenaar, head of the Department of Oncological Documentation, and the technical assistance of the Department of Nuclear Medicine for bone densitometry measurements. Address all correspondence and requests for reprints to: S. Osanto, MD, PhD, Department of Clinical Oncology, Leiden University Medical Center, Albinusdreef 2, 2333 ZA Leiden, The Netherlands. E-mail: [email protected]. Disclosure Summary: The authors have nothing to declare.
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