High rate of local control and cure at 10 years after treatment of prostate cancer with external beam radiotherapy and high-dose-rate brachytherapy: a single centre experience.

BACKGROUND AND PURPOSE: To analyse the cumulative incidence of any failure (AF), prostate cancer-specific failure (PCSF), any death (AD), prostate cancer-specific death (PCSD), and local control in 2387 men with prostate cancer (PC), consecutively treated with combined high-dose-rate brachytherapy (HDRBT) and external beam radiotherapy (EBRT) from 1998 to 2010. MATERIAL AND METHODS: A retrospective, single-institution study of men with localised PC. The mean age was 66 years and 54.7% had high-risk PC according to the Cambridge prognostic group (CPG) classification. The treatment was delivered as EBRT (2 Gy × 25) and HDRBT (10 Gy × 2) with combined androgen blockade (CAB). The median follow-up was 10.2 years. RESULTS: The cumulative incidence of PCSD at 10 years was 5% [CI 95% 0.04-0.06]. The 10 years PCSD per risk group were: low (L) 0.4%, intermediate favourable (IF) 1%, intermediate unfavourable (IU) 4.3%, high-risk favourable (HF) 5.8%, and high-risk unfavourable (HU) 13.9%. The PCSF rate at 10 years was 16.5% [CI 95% 0.15-0.18]. The PCSF per risk group at 10 years were: L 2.5%, IF 5.5%, IU 15.9%, HF 15.6%, and HU 38.99%. PCSF occurred in 399 men, of whom 15% were found to have local failure. The estimated frequency of local failure in the entire cohort was 1.2%. CONCLUSIONS: HDRBT combined with EBRT is an effective treatment with long-term overall survival and excellent local control for patients with PC. The low rate of local recurrence among men with relapse suggests that these patients were micro metastasised at time of treatment, which calls for improved methods to detect disseminated disease.

Thyroid-associated ophthalmopathy; quality of life follow-up of patients randomized to treatment with antithyroid drugs or radioiodine.

OBJECTIVE: The objective of this study was to investigate quality of life (QoL) in patients with Graves' disease treated with radioiodine or antithyroid drugs. DESIGN AND METHODS: The design of the study consists of an open, prospective, randomized multicenter trial between radioiodine and medical treatment. A total of 308 patients were included in the study group: 145 patients in the medical group and 163 patients in the radioiodine group. QoL was measured with a 36-item Short Form Health Status Survey questionnaire (SF-36) at six time points during the 48-month study period. RESULTS: Patient who developed or got worse of thyroid-associated ophthalmopathy (TAO) at any time point during the 4-year study period (TAO group) had lower QoL when no respect was paid to the mode of treatment. TAO occurred in 75 patients who had radioiodine treatment at some time point during the study period as compared with TAO in 40 medically treated patients (P<0.0009). Comparisons between the group of patients who have had TAO versus the group without TAO, in relation to treatments and time, showed significantly decreased QoL scores for the TAO groups at several time points during the study. In patients without TAO, there were no differences in QoL related to mode of treatment. CONCLUSIONS: The QoL in patients with Graves' ophthalmopathy was similar in radioiodine and medically treated patients, but patients who developed or had worsening of TAO had decreased QoL independent of mode of treatment. Furthermore, patients with TAO recovered physically within 1 year but it took twice as long for them to recover mentally.

Thyroid-associated ophthalmopathy after treatment for Graves' hyperthyroidism with antithyroid drugs or iodine-131.

CONTEXT: Previous randomized trials have suggested an association between radioiodine treatment for Graves' hyperthyroidism and thyroid-associated ophthalmopathy (TAO). OBJECTIVES: The aim of the study was to compare the occurrence of worsening or development of TAO in patients who were treated with radioiodine or antithyroid drugs. DESIGN: We conducted a randomized trial (TT 96) with a follow-up of 4 yr. PATIENTS, SETTING, AND INTERVENTION: Patients with a recent diagnosis of Graves' hyperthyroidism were randomized to treatment with iodine-131 (163 patients) or 18 months of medical treatment (150 patients). Early substitution with T(4) was given in both groups. MAIN OUTCOME MEASURE: Worsening or development of TAO was significantly more common in the iodine-131 treatment group (63 patients; 38.7%) compared with the medical treatment group (32 patients; 21.3%) (P < 0.001). RESULTS: The risk for de novo development of TAO was greater in patients treated with iodine-131 (53 patients) than with medical treatment (23 patients). However, worsening of TAO in the 41 patients who had ophthalmopathy already before the start of treatment was not more common in the radioiodine group (10 patients) than in the medical group (nine patients). Smoking was shown to influence the risk of worsening or development of TAO, and smokers treated with radioiodine had the overall highest risk for TAO. However, in the group of smokers, worsening or development of TAO was not significantly associated with the choice of treatment for hyperthyroidism. CONCLUSIONS: Radioiodine treatment is a significant risk factor for development of TAO in Graves' hyperthyroidism. Smokers run the highest risk for worsening or development of TAO irrespective of treatment modality.

Incidence of hyperthyroidism in Stockholm, Sweden, 2003-2005.

OBJECTIVES: To investigate the incidence of hyperthyroidism in Stockholm County, in those patients who were diagnosed with hyperthyroidism for the first time during the years 2003-2005. DESIGN: All new cases of hyperthyroidism > or = 18 years of age were prospectively registered to calculate the total incidence of hyperthyroidism, as well as the incidence of the subgroups: Graves' disease (GD), toxic multinodular goitre and solitary toxic adenoma (STA). Eight specialized units/hospitals in Stockholm County participated in the registration. The participating physicians were all specialists in medical endocrinology, oncology, nuclear medicine or surgery. RESULTS: During a 3-year period, 1431 new patients of hyperthyroidism were diagnosed in a well-defined adult population (> 18 years of age) of in average 1,457,036 inhabitants. This corresponds to a mean annual incidence of hyperthyroidism of 32.7/100,000. The incidence of GD was 24.5/100,000 per year, toxic nodular goitre was 3.3/100,000 per year and STA was 4.9/100,000 per year. CONCLUSIONS: The total incidence of hyperthyroidism in Stockholm County was found to be 32.7/100,000 per year, of which 75% had GD. There were a higher percentage of smokers among the patients with hyperthyroidism compared with the overall population in Stockholm, but no difference in the frequency of smoking between patients with GD and toxic nodular goitre.

TSH-receptor autoimmunity in Graves' disease after therapy with anti-thyroid drugs, surgery, or radioiodine: a 5-year prospective randomized study.

INTRODUCTION: Autoimmunity against the TSH receptor is a key pathogenic element in Graves' disease. The autoimmune aberration may be modified by therapy of the hyperthyroidism. OBJECTIVE: To compare the effects of the common types of therapy for Graves' hyperthyroidism on TSH-receptor autoimmunity. METHODS: Patients with newly diagnosed Graves' hyperthyroidism aged 20-55 years were randomized to medical therapy, thyroid surgery, or radioiodine therapy (radioiodine was only given to patients > or = 35 years of age). L-thyroxine (L-T4) was added to therapy as appropriate to keep patients euthyroid. Anti-thyroid drugs were withdrawn after 18 months of therapy. TSH-receptor antibodies (TRAb) in serum were measured before and for 5 years after the initiation of therapy. RESULTS: Medical therapy (n=48) and surgery (n=47) were followed by a gradual decrease in TRAb in serum, with the disappearance of TRAb in 70-80% of the patients after 18 months. Radioiodine therapy (n=36) led to a 1-year long worsening of autoimmunity against the TSH receptor, and the number of patients entering remission of TSH-receptor autoimmunity with the disappearance of TRAb from serum during the following years was considerably lower than with the other types of therapy. CONCLUSION: The majority of patients with Graves' disease gradually enter remission of TSH-receptor autoimmunity during medical or after surgical therapy, with no difference between the types of therapy. Remission of TSH-receptor autoimmunity after radioiodine therapy is less common.

Monitoring of kindreds with hereditary predisposition for cutaneous melanoma and dysplastic nevus syndrome: results of a Swedish preventive program.

PURPOSE: To evaluate a program initiated in 1987 by the Swedish Melanoma Study Group aiming to provide preventive surveillance to kindreds with hereditary cutaneous melanoma and dysplastic nevus syndrome. PATIENTS AND METHODS: Overall, 2,080 individuals belonging to 280 melanoma families were followed for 14 years between 1987 and 2001 at 12 participating centers. Data were registered in a central database. RESULTS: Among 1,912 skin lesions excised during follow-up, 41 melanomas were removed in 32 individuals. Of these, 15 (37%) were in situ melanomas and 26 (63%) invasive melanomas. The median tumor thickness of invasive melanomas was 0.5 mm. Ulceration was absent in 24 of 26 invasive melanomas (92%) and 12 (46%) lacked vertical growth phase. Compared with melanomas in the general Swedish population, the melanomas identified in these kindreds during follow-up had better prognostic characteristics. All melanomas except one were diagnosed in families with two or more first-degree relatives with melanoma. Diagnosis of melanoma occurred in three of eight kindreds with germline CDKN2A mutations, supporting that families with such mutations are at increased risk for melanoma development. Of the 32 individuals who developed melanoma during follow-up, 21 (66%) had had at least one previously diagnosed melanoma. CONCLUSION: This study shows that a coordinated program aimed at detecting and offering skin surveillance in kindreds with hereditary cutaneous melanoma results in a low incidence of melanomas during the follow-up period and that the tumors that do arise have favorable prognostic characteristics.

Thyroid hormone state and quality of life at long-term follow-up after randomized treatment of Graves' disease.

OBJECTIVE: In a 14-21 year follow-up of health-related quality of life (HRQL) outcome of 179 patients after randomized treatment of Graves' disease (GD) with surgical, medical or radioiodine, we found no differences. The HRQL for Graves' patients, however, was lower compared with a large age- and sex-matched Swedish reference population. We have now studied whether the reported HRQL-scores by Medical Outcome Study 36-item Short-Form Health Status Survey (SF36) and quality of life 2004 (QoL2004) answers were related to the thyroid hormone state of the patient. METHODS: This report comprises 91 of the original patients in which both the results of SF36 and QoL2004 questionnaire as well as serum thyroid hormones and current use of l-thyroxine treatment were available. RESULTS: A large number of the patients had low or undetectable serum TSH concentrations. SF36 scores and answers to QoL2004 questionnaires were not correlated to TSH levels or associated with suppressed TSH. A low free triiodothyronine was weakly associated with a low GH score (P < 0.02) and elevated thyrotropin receptor antibody with a low physical component summary (P < 0.02). CONCLUSION: HRQL do not seem to be influenced by the thyroid hormone state of the patient including subclinical thyrotoxicosis. It is possible that the personality of GD patients as such may have resulted both in the development of GD and lower HQRL scores later on in life. Alternatively, the generic SF36 may not be a proper instrument to detect relevant differences in HRQL related to the thyroid state.

Graves' disease: a long-term quality-of-life follow up of patients randomized to treatment with antithyroid drugs, radioiodine, or surgery.

The effects of treatment modality for Graves' disease (GD) were studied with respect to long-term quality of life and present health status. A total of 179 patients with GD were randomized during the period 1983-1990 for treatment with antithyroid drugs, radioiodine, or surgery. A 36-item Short Form Health Status Survey questionnaire and specific questions for GD were sent to patients 14-21 years after randomization. Present medical records, and clinical and laboratory status were recorded. No major significant differences in quality of life among the three treatments were observed. Compared to a large Swedish reference group, all treatment groups had significantly lower scores for vitality (p < 0.05). The Mental Component Summary was lower for both the young medical, young surgical, and the older medical group (p < 0.05). Radioiodine-treated patients had a lower General Health score. Young medical patients (<35 years) had lower Mental Health scores (p < 0.05). There was also a strong trend, which barely met statistically significance, for older surgical and radioiodine groups for lower Mental Component Summary. GD patients have, compared with a large Swedish reference population, diminished vital and mental quality of life aspects even many years after treatment. The quality-of-life scores were not different among the three treatment modalities.

Extracranial stereotactic radiotherapy for primary and metastatic renal cell carcinoma.

BACKGROUND AND PURPOSE: We investigated the results of using stereotactic radiotherapy (SRT) for 58 patients with renal cell carcinomas (RCC) who were evaluated restrospectively for response rates, local control rates and side effects. PATIENTS AND METHODS: From October 1997 to January 2003, 50 patients suffering from metastatic RCC and eight patients with inoperable primary RCC received high-dose fraction SRT while placed in a stereotactic body-frame. The most common dose/fractionation schedules used were 8 Gyx4, 10 Gyx4 and 15 Gyx3 during approximately 1 week. RESULTS: SRT-treated tumor lesions regressed totally in 30% of the patients at 3-36 months, whereas 60% of the patients had a partial volume reduction or no change after a median follow-up of 37 months (SD 17.4) for censored and 13 months (SD 12.9) for uncensored patients. Side effects were generally mild. Of 162 treated tumors, only three recurred, yielding a local control rate of 90-98%, considering the 8% non-evaluable sites as defined here. For patients with one to three metastases, the time to new spread was 9 months. CONCLUSIONS: Our use of SRT for patients with primary and metastatic RCC yielded a high local control rate with low toxicity. Patients with one to three metastases, local recurrences after nephrectomy or inoperable primary tumors benefited the most, i.e. had fewer distant recurrences (13/23) and longer survival times compared to patients with >3 metastases (24/27 recurrences).

Ruthenium brachytherapy for uveal melanoma, 1979-2003: survival and functional outcomes in the Swedish population.

PURPOSE: To evaluate observed and relative survival rates, enucleation rates, and visual outcome after ruthenium 106 brachytherapy for uveal melanoma. DESIGN: Retrospective cases series from the Swedish national referral center. PARTICIPANTS: Five hundred seventy-nine patients (579 eyes) with choroidal or ciliary body melanomas, including 55 tumors more than 7 mm in height, treated with ruthenium episcleral plaques from January, 1979, through April, 2003. METHODS: Clinical and radiotherapy data were extracted from a dedicated database, and survival status was determined through population registries. Tumor size was classified according to the Collaborative Ocular Melanoma Study criteria. The 5- and 10-year relative survival rates were estimated, and univariate and multivariate regression models were constructed for predictive factors on observed survival, enucleation, and visual deterioration. MAIN OUTCOME MEASURES: Observed and relative survival rate, proportion of secondary enucleation, deterioration of visual acuity to less than 0.5, respectively, to 0.1 or worse. RESULTS: Tumors were classified as small in 10.5%, medium in 78.4%, and large in 9.2% of patients. The 5- and 10-year observed overall survival rates were 83.3% and 71.5%, respectively, and the corresponding relative rates were 95.5% and 94%, respectively. Factors predicting survival were tumor diameter, patient age, and secondary enucleation. One hundred six patients (18%) underwent enucleation up to 14 years after plaque treatment. The only predictive factor for enucleation was tumor size. At 5 years, 31% of the patients retained 0.5 visual acuity or better, and 49% retained better than 0.1 visual acuity. Predictive factors for visual deterioration were visual acuity and distance from posterior tumor border to the foveola. CONCLUSIONS: After ruthenium brachytherapy for uveal melanoma, the survival rates and visual outcomes in this population-based investigation were similar to previously published results. The eye was retained in 81.7% of patients. Careful patient selection (presently we only treat melanomas 7 mm or smaller in height) and life-long monitoring for recurrences is warranted.

Long-term incidence of hypothyroidism after radiotherapy in patients with head-and-neck cancer.

PURPOSE: To determine the long-term incidence of postirradiation hypothyroidism (HT) in patients with head-and-neck cancer. METHODS AND MATERIALS: The incidence of overt HT was assessed prospectively in 391 patients with nonthyroid head-and-neck cancer admitted for radiotherapy (RT) consecutively between 1990 and 1996. Eighty-three patients were excluded from the analysis because of known thyroid disease before treatment (n = 27), no RT was given (n = 15), or inadequate follow-up (n = 41). Overt HT was defined as increased thyroid-stimulating hormone (TSH) in combination with decreased fT4/T4 or in combination with initiation of thyroxine replacement therapy. RESULTS: With a median follow-up of 4.2 years (range, 3 months to 10.9 years) for 308 evaluable patients, the 5- and 10-year Kaplan-Meier actuarial risks of HT were 20% and 27%, respectively. The median time until development of HT was 1.8 years (3 months to 8.1 years). Multivariate analysis showed that patients with bilateral RT to the neck had a higher risk of HT in comparison with unilateral neck RT (relative hazard, 0.37; p = 0.02). The addition of surgery to RT increased the overall risk of HT (p < 0.001); and if surgery involved the thyroid gland, the relative hazard was 4.74 (p < 0.001). For an elevated pre-RT TSH value, the relative hazard was 1.58 (p < 0.001). CONCLUSION: The incidence of overt HT after locoregional RT for nonthyroid head-and-neck cancer continues to increase with time, even after long-term follow-up. We recommend life-long TSH testing in these patients.

Incidence of retinoblastoma from 1958 to 1998 in Northern Europe: advantages of birth cohort analysis.

PURPOSE: To assess change in incidence of retinoblastoma in Northern Europe and to compare commonly used methods for calculating its incidence against birth cohort analysis. DESIGN: Retrospective cohort study. PARTICIPANTS: Individual and pooled data of 291 Swedish and 174 Finnish children diagnosed with retinoblastoma between 1958 and 1998. MAIN OUTCOME MEASURES: Incidence per 1 million children younger than 5 years of age (37 812 035 person- years at risk) and per 100 000 live births (7 152 265 live-born children at risk). METHODS: Data were from Swedish and Finnish Cancer Registries and corresponding national referral centers for retinoblastoma. Incidence was calculated both by standard analysis per children younger than 5 years of age and per live births, and by birth cohort analysis. Curves were smoothed with robust, locally weighted regression. Linear regression was used to fit pooled data. RESULTS: The number of new retinoblastoma cases per year ranged from 0 to 13 (1-13 per birth cohort) in Sweden and from 0 to 10 in Finland (1-9 per birth cohort). The mean incidence was 11.8 (95% confidence interval [CI], 10.5-13.1) and 11.2 (95% CI, 9.4-13.0) per 1 million children younger than 5 years of age in Sweden and Finland, respectively, and 6.7 (95% CI, 5.9-7.5) and 6.2 (95% CI, 5.3-7.2) per 100 000 live births, respectively. Analysis based on year of diagnosis suggested moderate increase in incidence since 1990, but by birth cohort analysis, incidence rates were stable for both countries. The pooled incidence by birth cohort was 6.0 (95% CI, 5.4-6.6) per 100 000 live births, corresponding to 1 in 16 642 (95% CI, 15 105-18 528) live births. CONCLUSIONS: The data suggest that the incidence of retinoblastoma is stable in Northern Europe. Analysis based on birth cohort is recommended for future epidemiologic studies, because it minimizes the effect of variable age at diagnosis of this developmental cancer and results in less variable incidence rates than standard analysis based on year of diagnosis.

Uveal melanoma survival in Sweden from 1960 to 1998.

PURPOSE: To investigate the crude and relative survival rates in patients with uveal melanoma in Sweden during the period from 1960 to 1998. METHODS: A population-based national survey revealed 2997 cases of uveal melanoma in the Swedish Cancer Registry. The survival rates were calculated by the Hakulinen life-table method, using relative survival as an estimate for deaths due to uveal melanoma. The excess mortality rates were calculated with confidence intervals for the first 15 years after diagnosis. Multivariate regression analysis was undertaken to evaluate the influence of gender, age, and calendar period on relative survival the first 5 years after diagnosis. The underlying causes of deaths in the patients with uveal melanoma, as found in the Cause of Death Registry were also investigated. RESULTS: Up to December 31, 1998, 2003 patients had died. The 5-year crude survival rate was 60.3% and the relative survival 70.1%. After 10 years, the rates were 42.5% and 59.4%, respectively. Significant excess mortality existed up to 5.5 years after diagnosis. In the multivariate model, younger age (P < 0.001) and later calendar period (P = 0.002), but not gender (P = 0.117), were associated with better relative survival. Deaths due to uveal melanoma were misclassified in the Cause of Death Registry in more than half of the cases. CONCLUSIONS: This study, covering more than 95% of the uveal melanoma cases in the Swedish population revealed an improvement in relative survival rates for patients with uveal melanoma over time and a significant excess mortality up to 5.5 years after diagnosis.

Thyroid cancer risk after thyroid examination with 131I: a population-based cohort study in Sweden.

Ionizing radiation is the only established cause of thyroid cancer, though the effect of diagnostic administration of (131)I on thyroid cancer risk appears minimal. The annual number of thyroid examinations using radioiodine is currently 5 per 1,000 individuals worldwide, so this issue is of public health importance. Our objective was to evaluate the excess risk of thyroid cancer following a range of known doses of (131)I administered for diagnostic purposes. We conducted a nationwide, population-based cohort study in Sweden including all 36,792 individuals who received (131)I for diagnostic purposes during 1952-1969 and were alive and free of thyroid cancer 2 years after exposure. Accrual of person-time at risk commenced 2 years after the first (131)I administration. Follow-up for cancer was to the end of 1998. Standardized incidence ratios (SIRs) were calculated as the ratio between the observed and expected numbers of thyroid cancers. Estimates were stratified by previous exposure to external radiation therapy to the neck, reason for thyroid examination, (131)I dose, sex, age at exposure and time since exposure. Thyroid cancers (n = 129) were diagnosed during 886,618 person-years at risk. Excess thyroid cancers were observed only among the 1,767 patients who reported previous external radiation therapy to the neck [SIR = 9.8, 95% confidence interval (CI) 6.3-14.6] and among those originally referred due to suspicion of a thyroid tumor (SIR = 3.5, 95% CI 2.7-4.4 for 11,015 patients without previous external radiation therapy). The 24,010 patients without previous exposure to external radiation therapy to the neck who were referred for a reason other than suspicion of a thyroid tumor received an estimated dose to the thyroid of 0.94 Gy. Among these patients, 36 thyroid cancers were observed compared to 39.5 expected (SIR = 0.91, 95% CI 0.64-1.26). We found no evidence that administration of (131)I for diagnostic purposes increases risk of thyroid cancer. However, our study included few patients under age 20, so the results apply primarily to exposure among adults. Our data suggest that protraction of dose may result in a lower risk than brief X-ray exposure of the same total dose.

Incidence of uveal melanoma in Sweden from 1960 to 1998.

PURPOSE: To investigate the incidence of uveal melanoma in Sweden during the period from 1960 to 1998, with respect to age distribution, gender, and changes in incidence over time. METHODS: The Swedish Cancer Registry was searched for patients with uveal melanoma and cross-checked against hospital files over patients where an eye-sparing treatment had been applied, to ensure inclusion in the Registry even when no histologic specimen was available. The crude and age-standardized incidence was estimated separately for each gender. The Swedish population of 1970 to 1974 was used as a standard, and the annual change in incidence was calculated by using a regression model with logarithmic incidence numbers. RESULTS: In total, 2997 patients met the criteria, of whom 1542 were males and 1455 females. During the 39-year period, the age-standardized incidence of uveal melanoma declined significantly in the male population, from 11.7 cases/million to 8.4 cases/million (P = 0.002). The trend toward reduced incidence in females, from 10.3 to 8.7 cases/million did not reach statistical significance (P = 0.108). The annual relative change in incidence was 1% (95% CI, 0.8%-1.2%) in males and 0.7% (95% CI, 0%-1.3%) in females. The age-specific incidence revealed a significantly higher incidence among men older than 45 years (23.5 cases/million) compared with the incidence in women of the same age group (19.2 cases/million; P < 0.001). CONCLUSIONS: A Swedish national survey performed to establish the incidence of uveal melanoma during the period from 1960 to 1998 revealed a decreasing incidence in the male and a stable incidence in the female population.