Bone mineral density, growth, and thyroid function in long-term survivors of pediatric Hodgkin's lymphoma treated with chemotherapy only.

BACKGROUND: The aim of this study was to investigate the long-term side effects of treatment for childhood Hodgkin's lymphoma with chemotherapy only on growth, bone mineral density (BMD), body composition, and thyroid function. PROCEDURE: A total of 88 patients (56 male, 32 female; 17.6-42.6 yr), treated for childhood Hodgkin's lymphoma from 1974-1998 with combination chemotherapy adriamycin (doxorubicin), bleomycin, vinblastine, and dacarbazine or epirubicin, bleomycin, vinblastine, dacarbazine with or without mechlorethamine, oncovin (vincristine), procarbazine, and prednisone (MOPP) with the intention to avoid radiotherapy, participated in this study. Median follow-up was 15.5 yr (range 5.6-30.2). BMD of lumbar spine and total body (BMD-TB), and body composition were measured using dual-energy x-ray absorptiometry. Bone mineral apparent density of the lumbar spine was calculated to correct for bone size. Free T4 and TSH were measured. RESULTS: Men treated with MOPP had a significantly reduced height with normal body proportions. Women treated with MOPP had decreased BMD-TB and bone mineral apparent density of the lumbar spine as compared with healthy controls. Percent body fat was significantly increased in female patients treated without MOPP. Body mass index was significantly increased in male patients treated without MOPP, whereas lean body mass was normal in all patients. All patients, except one, treated with chemotherapy only had normal thyroid function. However, five patients who received additional radiation to the thyroid either had abnormal levels of TSH or free T4, or used thyroid hormones. CONCLUSIONS: Lean body mass was normal in all patients; thyroid function was normal in all but one patient. The use of MOPP leads to decreased height and increased body mass index in men and decreased BMD-TB in women.

Effect of childhood cancer treatment on fertility markers in adult male long-term survivors.

BACKGROUND: Although it is accepted that pediatric cancer treatment harbors a risk of gonadal damage, large cohort studies using up-to-date fertility markers are lacking. PROCEDURE: The aim of our study was to evaluate the gonadal toxicity of childhood cancer treatment using fertility markers. We included 248 adult male long-term survivors of childhood cancer. Median age at diagnosis: 5 years, median age at follow-up: 24 years, median follow-up time 18 years. We evaluated patient characteristics, treatment modalities, testicular size, and endocrinological parameters including Inhibin B, luteinizing hormone (LH), follicle-stimulating hormone (FSH), and testosterone. RESULTS: The median value of Inhibin B in the cancer survivor group was 126 ng/L versus 177 ng/L in the control group (P < 0.001). In the survivors, 67% had Inhibin B levels below the normal reference value of 150 ng/L compared with 26% in the control group (P < 0.05). Inhibin B was the most sensitive discriminator between survivors and controls. Significantly decreased Inhibin B levels and increased FSH levels were found in men treated for Hodgkin and non-Hodgkin lymphoma, acute-myeloid leukemia, neuroblastoma, and sarcoma as compared to other malignancies. Cumulative dosages of procarbazine and cyclophosphamide were the only independent chemotherapy-related predictors for decrease of Inhibin B levels and increase of FSH. Age at time of treatment did not influence post-treatment Inhibin B or FSH levels. CONCLUSIONS: Severe gonadal impairment is a risk in a considerable subgroup of childhood cancer survivors based on current fertility markers like Inhibin B. Males receiving gonadotoxic treatment before puberty are not protected from post treatment gonadal dysfunction.

Inhibin B is superior to FSH as a serum marker for spermatogenesis in men treated for Hodgkin's lymphoma with chemotherapy during childhood.

BACKGROUND: The aim of this study was to evaluate the long-term gonadal sequelae after treatment for childhood Hodgkin's lymphoma with combination chemotherapy, using up to date fertility parameters and andrological evaluation, including for the first time inhibin B. METHODS: There were 56 male patients treated from 1974-1998 for childhood Hodgkin's lymphoma with combination chemotherapy ABVD or EBVD (adriamycin/epirubicin, bleomycin, vinblastine, dacarbazine) with or without MOPP (mechlorethamine, vincristin, prednisone, procarbazine) with the intention to avoid radiotherapy. These men were studied 15.5 years (range 5.6-30.2 years) after cessation of therapy. Serum follicle stimulating hormone (FSH), luteinizing hormone (LH), inhibin B, testosterone, sex hormone-binding globulin (SHBG), sperm concentration and sperm DNA integrity were determined. RESULTS: In men treated with MOPP, median FSH and LH were significantly increased (P < 0.001) and inhibin B (17.5 versus 143 ng/l; P < 0.001) and sperm concentration (1.05 versus 49.5 x 10(6)/ml; P < 0.05) were significantly decreased compared with patients treated without MOPP. The number of MOPP courses was significantly correlated with FSH and inhibin B levels. Only inhibin B showed an independent correlation with sperm concentration (r = 0.86; P < 0.001). CONCLUSIONS: The use of MOPP chemotherapy causes permanent gonadal damage in the far majority of male survivors of childhood Hodgkin's lymphoma and inhibin B is the most valuable serum marker for gonadal function.

Anti-Mullerian hormone is a sensitive serum marker for gonadal function in women treated for Hodgkin's lymphoma during childhood.

PURPOSE: The aim of this study was to evaluate the long-term effects of combination chemotherapy treatment for girls with Hodgkin's lymphoma (HL) on gonadal function using anti-Müllerian hormone (AMH) and inhibin B as ovarian reserve parameters. PATIENTS AND METHODS: LH, FSH, inhibin B, and AMH were measured in 32 women treated from 1974 to 1998 for pediatric HL with chemotherapy, with the intention to avoid radiotherapy. All patients [median age 25.0 yr (range 19.2-40.4 yr)] were in complete remission with a median follow-up time of 14.0 yr (range 5.7-24.5 yr) after therapy. All patients were treated with combination chemotherapy doxorubicin, bleomycin, vinblastine and dacarbazine (ABVD) or EBVD with or without mechlorethamine, vincristine, procarbazine, and prednisone (MOPP). Because of incomplete remission or relapse, involved field radiotherapy was needed in seven of 32 women. Results were compared with a healthy control group. RESULTS: Patients treated with six or more cycles of MOPP combination chemotherapy had significantly higher levels of FSH and lower serum levels of inhibin B and AMH, compared with healthy women [FSH, 17.0 vs. 6.0 U/liter (P < 0.05); inhibin B, 23.0 vs. 112.5 ng/liter (P < 0.01); AMH, 0.39 vs. 2.10 microg/liter (P < 0.01)]. AMH was also significantly lower, compared with women treated without MOPP (median 0.39 vs. 1.40 microg/liter; P = 0.01). CONCLUSIONS: Women treated during childhood for HL with MOPP seem to have a distinctly lower ovarian reserve as measured by lower AMH values at early adulthood, compared with healthy women. Moreover, AMH seems to be the only predictor that is sufficiently sensitive to detect this decrease in ovarian reserve.

Study of the factors associated with recurrence in children with sacrococcygeal teratoma.

PURPOSE: The aim of this study was to explore effects of (1) histological involvement of resection margins with microscopic residue, (2) incomplete removal of coccyx, and (3) tumor spillage on recurrence and on survival in children operated upon for sacrococcygeal teratoma (SCT). METHODS: Retrospective review of 70 patients treated between 1960 and 2003. RESULTS: Fifty-four girls and 16 boys presented with SCT diagnosed prenatally (12), at birth (37), or later (21). Thirty-six percent of tumors were Altman type I, 27% type II, 18% type III, and 18% type IV. Histologically, mature teratoma was observed in 48 patients, immature teratoma in 11, yolk sac tumor (YST) in 9, embryonal carcinoma in one, and mixed tumor in one. Eighty-four percent of patients solely underwent surgical extirpation. Six (8.5%) patients died. However, mortality for the group of 42 patients treated during the past 15 years was as low as 2.5%. Tumor recurrence was observed in 5 patients, 2 of whom died. Of 3 patients with initially mature teratoma, 1 showed local immature recurrence and 2 malignant recurrences. One of the latter died. Of 2 patients with initially immature teratoma grade I, one relapsed with a benign lesion and one with YST leading to death. Possible eliciting factors had been demonstrated in 3 patients. Histological analysis of resection margins showed tumoral involvement in 11 patients (and also in one patient after resection of a recurrent tumor). Only one of those with YST focus in the resection margin showed recurrence. Intraoperative tumor spillage presented in 2 patients, who both died of metastatic disease. Spillage of tumoral cyst fluid occurred in 6, none developed recurrence. One of 5 patients whose coccyx had not been removed died of metastatic disease. One with immature teratoma developed a benign recurrent tumor. The other 3 showed no recurrence. CONCLUSIONS: Microscopic involvement of the resection margins of mature or immature SCT is rarely associated with recurrence, provided there are no YST foci in the resection margins. A conservative attitude then appears to be justified. Spillage of cyst fluid was never associated with recurrence, unlike spillage of tumor and absence of removal of coccyx.

No difference between prednisolone and dexamethasone treatment in bone mineral density and growth in long term survivors of childhood acute lymphoblastic leukemia.

BACKGROUND: Dexamethasone is known to have both more potent leukemic activity and is associated with a higher incidence of side effects than prednisolone. In this study, we compared the long-term effects of dexamethasone and prednisolone on bone mineral density (BMD), body composition and growth in long-term survivors of ALL in first complete remission. PROCEDURE: Ninety patients (51 male, 49 female; 8.6-38.5 year), treated with either a prednisolone containing protocol (n = 47; n = 19 also with CNS-irradiation) or a dexamethasone containing protocol (n = 43; no cranial irradiation) participated in this cross-sectional single center study. Mean follow-up was 12.7 years (2.0-29.7 years). BMD of lumbar spine and total body, and body composition were expressed as standard deviation scores (SDS) using dual energy X-ray absorptiometry. Bone mineral apparent density of the lumbar spine (BMAD) was calculated to correct for bone size. RESULTS: There was no difference in height, height corrected for target height, BMD, or lean body mass between prednisolone and dexamethasone treated patients. Prednisolone treated patients had an increased percentage body fat (SDS +0.46; P < 0.05) and increased body mass index (SDS 0.88; P < 0.01) compared to normal. Dexamethasone treated patients had only an increased body mass index (SDS 0.52; P < 0.05). Height, total body BMD, and lean body mass were lower in patients treated with cranial irradiation as compared to non-irradiated patients, but differences in the latter two disappeared when corrected for height. BMAD was normal after CNS-irradiation. CONCLUSIONS: Long term survivors of ALL treated with prednisolone or dexamethasone containing regimens do not differ in height, BMD, or body composition.

Ovarian germ cell tumors in children: a clinical study of 66 patients.

BACKGROUND: Ovarian germ cell tumors are rare in childhood. The aim of this study is to review clinical presentation, management, and outcome in a two-center series of girls with ovarian germ cell tumor. PROCEDURE: The records of 66 patients (median age 9 years) with histologically proven ovarian germ cell tumor (either benign or malignant), treated over a 44-year-span, were reviewed. RESULTS: Pain and an abdominal mass were the most frequent symptoms. The tumors were right-sided in 35, left-sided in 28, and bilateral in 3. Most patients (52) were stage I, 4 were stage II, 6 stage III, and 1, with liver metastases, stage IV. Sixteen patients had an emergency operation for tumor torsion. Unilateral salpingo-oophorectomy was the most frequently performed procedure (n = 46), and ovarian-sparing tumorectomy was performed in 9 patients (one bilaterally). Histologically, teratomas were found most frequently (mature: 45, immature: 9), followed by mixed tumors (n = 7), yolk sac tumors (n = 3), dysgerminoma (n = 2), gonadoblastoma (n = 2), and embryonal carcinoma (n = 1). Surgical removal of the tumor with or without the ovary and/or adnex was the sole treatment in 55 patients, chemotherapy was administered in 10 and radiotherapy + chemotherapy in one. Intra-operative spillage of tumoral fluid occurred in six; this did not influence outcome in five. Recurrence was observed in three patients. Two patients, with malignant disease, died. The 64 survivors are now between 8 months and 44 years after treatment. CONCLUSIONS: With a recurrence rate of 4.5% and a mortality rate of 3%, this series confirms the excellent prognosis for girls with ovarian germ cell tumor (GCT).

Treatment of pediatric Hodgkin disease avoiding radiotherapy: excellent outcome with the Rotterdam-HD-84-protocol.

BACKGROUND: To reduce radiotherapy (XRT) induced toxicity of treatment of children with Hodgkin disease (HD) while maintaining a high cure rate, we introduced a risk-adapted protocol consisting of chemotherapy (CT) alone in 1984. PROCEDURE: The outcome of 46 children treated for HD from 1984 until 2000 according to the Rotterdam-HD-84-protocol was determined. Children with stage I-IIA disease (n = 23), were treated with six courses of epirubicin, bleomycin, vinblastine, and dacarbazine (EBVD). Children with stage IIB-IV disease (n = 23), were treated with three to five alternating cycles of EBVD and mechlorethamine, vincristine, procarbazine, and prednisone (MOPP). RESULTS: At a median follow-up time of 8.6 years (range 2.6-18.3 years), the 10-year overall survival (OS) is 95% and the event-free survival (EFS) 91%. In 5/46 patients XRT was administered because of residual mediastinal mass. Four children relapsed, two of them died. Up until now only one patient developed hypothyroidism; no symptomatic cardiac or pulmonary dysfunction, no second malignancy has been diagnosed. CONCLUSIONS: Risk-adapted treatment consisting of CT alone is highly efficacious for children with HD and toxicity is low. XRT was administered in only a small minority of children with HD. CT should be the first choice for HD in children and XRT should preferably be used for those with refractory or histologically proven residual disease or relapse.