High dose rate and low dose rate ruthenium brachytherapy for uveal melanoma. No association with ocular outcome.

BACKGROUND: Episcleral brachytherapy is the most common eye-preserving option for treating uveal melanoma, with ruthenium-106 widely used in Europe. Case series have reported on ocular outcome, but there are very little data on the impact of dose rate. Therefore, we studied the association of dose rate with secondary enucleation. METHODS: Data for all patients in Sweden managed with brachytherapy from 1979 to 2012 were retrieved (962 patients) and divided in quartiles based on dose rates at the tumour apex and at the scleral surface. Kaplan-Meier curves for secondary enucleation were generated independent of dose rate and for each dose rate quartile. Cox regression univariate and multivariate modelling included clinical parameters and dose rates at the tumour apex and the scleral surface. RESULTS: Baseline clinical characteristics were not significantly different across the quartiles except that thinner tumours had higher dose rates at the tumour apex. Dose rates ranged widely, with a near normal distribution at the scleral surface but skewed at the tumour apex. For all quartiles, secondary enucleation was more often caused by tumour progression than by ocular side effects. Univariate and multivariate modelling including clinical parameters showed no association between dose rate and secondary enucleation. CONCLUSIONS: Although dose rates ranged widely, there was no apparent association with secondary enucleation, suggesting that based on ocular survival, current practice of annual replacement of applicators is acceptable, irrespective of the significant reduction in each applicator's dose rate. Nevertheless, patients treated with higher dose rates have shorter plaque exposure and presumably less ocular irritation.

Predictors of outcome in patients with papillary thyroid carcinoma.

AIM OF THE STUDY: To evaluate prognostic factors with respect to the outcome in a consecutive series of patients with papillary thyroid carcinoma (PTC) treated at the same institution during a 20-year-period, and to evaluate further the predictive ability of outcome of the pTNM, AMES and MACIS prognostic systems in these patients. MATERIALS AND METHODS: Two hundred and twenty consecutive patients operated on for primary PTC at the Karolinska Hospital between 1980 and 1999 were examined retrospectively. Patient and tumour characteristics at the time of surgery were compared to the patients' outcomes. Univariate and multiple logistic regression analyses were used to identify independently significant prognostic factors with respect to the outcome. In addition, the classification of the patients according to the pTNM, AMES and MACIS prognostic systems were compared to the outcomes. RESULTS: At the end of the follow-up period 201 patients were still alive without disease, 6.5% had died from PTC and 2.5% were alive with persisting disease. In 16 patients, radical surgery could not be performed due to extensive tumour growth and/or distant metastases. Recurrences were detected in 14% of the patients considered as radically operated. The strongest independent predictors for local or distant recurrences and poor clinical outcome were the lack of radical surgery and increasing tumour size. In this investigation MACIS appeared to be the better system, regarding efficacy in predicting the outcome of PTC. CONCLUSION: Removal of all tumour tissue appears most important to a favorable outcome and in our patients MACIS appears the most useful prognostic system taking completeness of resection into account.

Anaplastic giant cell thyroid carcinoma.

Anaplastic (giant cell) thyroid carcinoma (ATC), is one of the most aggressive malignancies in humans with a median survival time after diagnosis of 3-6 months. Death from ATC was earlier seen because of local growth and suffocation. ATC is uncommon, accounting for less than 5 % of all thyroid carcinomas. The diagnosis can be established by means of multiple fine needle aspiration biopsies, which are neither harmful nor troublesome for the patient. The cytological diagnosis of this high-grade malignant tumour is usually not difficult for a well trained cytologist. The intention to treat patients with ATC is cure, although only few of them survive. The majority of the patients are older than 60 years and treatment must be influenced by their high age. We have by using a combined modality regimen succeeded in achieving local control in most patients. Every effort should be made to control the primary tumour and thereby improve the quality of remaining life and it is important for patients, relatives and the personnel to know that cure is not impossible. Different treatment combinations have been used since 30 years including radiotherapy, cytostatic drugs and surgery, when feasible. In our latest combined regimen, 22 patients were treated with hyper fractionated radiotherapy 1.6Gy x 2 to a total target dose of 46 Gy given preoperatively, 20 mg doxorubicin was administered intravenously once weekly and surgery was carried out 2-3 weeks after the radiotherapy. 17 of these 22 patients were operated upon and none of these 17 patients got a local recurrence. In the future we are awaiting the development of new therapeutic approaches to this aggressive type of carcinoma. Inhibitors of angiogenesis might be useful. Combretastatin has displayed cytotoxicity against ATC cell lines and has had a positive effect on ATC in a patient. Sodium iodide symporter (NIS) genetherapy is also being currently considered for dedifferentiated thyroid carcinomas with the ultimate aim of making radio-iodine therapy possible.

Anaplastic thyroid carcinoma: three protocols combining doxorubicin, hyperfractionated radiotherapy and surgery.

Patients with anaplastic thyroid carcinoma can rarely be cured, but every effort should be made to prevent death due to suffocation. Between 1984 and 1999, 55 consecutive patients with anaplastic thyroid carcinoma were prospectively treated according to a combined regimen consisting of hyperfractionated radiotherapy, doxorubicin, and when feasible surgery. Radiotherapy was carried out for 5 days a week. The daily fraction until 1988 was 1.0 Gyx2 (A) and 1989-92 1.3 Gyx2 (B). Thereafter 1.6 Gyx2 (C) was administered. Radiotherapy was administered to a total target dose of 46 Gy; of which 30 Gy was administered preoperatively in the first two protocols (A and B), while the whole dose was given preoperatively in the third protocol (C). The therapy was otherwise identical. Twenty mg doxorubicin was administered intravenously weekly. Surgery was possible in 40 patients. No patient failed to complete the protocol due to toxicity. In only 13 cases (24%) was death attributed to local failure. Five patients (9%) 'had a survival' exceeding 2 years. No signs of local recurrence were seen in 33 patients (60%); 5 out of 16 patients in Protocol A, 11 out of 17 patients in Protocol B, 17 out of 22 patients in Protocol C (P=0.017). In the 40 patients undergoing additional surgery, no signs of local recurrence were seen in 5 out of 9 patients, 11 out of 14 patients and 17 out of 17 patients, respectively (P=0.005).

Severe oral mucositis after therapeutic administration of [131I]MIBG in a child with neuroblastoma.

OBJECTIVE: The purpose of this report is to document a newly encountered oral side effect of targeted radiotherapy with iodine 131-metaiodobenzylguanidine ([(131)I]MIBG) in the treatment of neuroblastoma. STUDY DESIGN: A 14-month-old girl was diagnosed with stage 4 neuroblastoma. After completion of chemotherapy, the tumor showed no signs of regression; treatment with 3700 MBq [(131)I]MIBG was therefore decided on, 8 months after diagnosis. RESULTS: Fourteen days after infusion of MIBG, severe oral mucositis was diagnosed, with a generalized erythema involving the mucous membranes of the hard and soft palate, buccal mucosa, and upper and lower lips. The gingiva exhibited a general linear erythema. CONCLUSIONS: Visualization of the salivary glands on [(123)I]MIBG images suggests that accumulation of radiolabeled MIBG in the salivary glands may be related to sympathetic innervation.

Surgical treatment of hyperthyroidism: a ten-year experience.

Hyperthyroidism is treated either by antithyroid drugs, radioiodine (I131) or surgery. In Sweden, surgery is often performed in patients with large goiter or severe hyperthyroidism with infiltrative endocrine ophthalmopathy. To evaluate indications and results of surgical treatment, data from 380 patients operated on for hyperthyroidism at our department during 1986-1995 were analyzed. Twenty-six percent were referred for surgery because of failure of treatment with antithyroid drugs or I131. Ninety-one percent were subjected to subtotal thyroidectomy with a median remnant weight of less than 2 g. In the remaining patients, total thyroidectomy was performed. Transient vocal cord affection occurred in 2.6%, none of which was permanent. Prolonged postoperative hypocalcemia occurred in 3.1%, and permanent hypoparathyroidism in 1%. There was no difference in complication rate between subtotal or total thyroidectomy. In patients with Graves' disease, 5% worsened with regard to ophthalmopathy initially after surgery but later improved. Recurrent disease occurred in 2% of the patients, all of whom had undergone subtotal thyroidectomy. Surgery is not first-line therapy in all patients with hyperthyroidism. However, in experienced hands, surgery is a good therapeutic alternative that can be carried out with no mortality, few complications, and, provided that a minimal remnant is left, very few recurrences.

Six-year recurrence free survival after intraluminal iridium-192 therapy of human bilobar biliary papillomatosis. A case report.

BACKGROUND: Biliary papillomatosis is rare and often fatal. Liver resection or transplantation is recommended but may be impossible due to tumor or patient factors; furthermore, it appears to the authors of this study that no follow-up results after transplantation have been reported in previous studies. METHODS: Bilobar but limited biliary papillomatosis in a man age 54 years was mapped by cholangiopancreatography, cholecystectomy, and operative cholangioscopy. After cholangioscopic electrocoagulation, iridium-192 wires were temporarily inserted into the affected bile ducts, giving a dose of 60 grays at a 3-mm distance. Another percutaneous cholangioscopic electrocoagulation was performed 3 weeks later. RESULTS: The patient has been free of tumor and in good health for 80 months, but he has a long term stenting of a nonneoplastic stricture at the confluence of the bile ducts. CONCLUSIONS: Mechanical tumor reduction and intraluminal brachytherapy could possibly replace transplantation (which up to now has been suggested but not reported) when this life-threatening disease is bilobar, and also possibly replace liver resection for limited tumors in patients who are too frail for surgery.

Prognostic impact of complete remission after preoperative irradiation of tonsillar carcinoma: a retrospective analysis of the radiumhemmet data, 1980-1995.

PURPOSE: This retrospective study was done to determine the outcome of patients with tonsillar carcinoma treated at Radiumhemmet, Karolinska Hospital, between January 1980 and December 1995 with radiotherapy alone or in combination with surgery. In addition the importance of tumor remission for patient survival was analyzed. METHODS AND MATERIALS: The analysis is based on 167 previously untreated patients with biopsy-proven, invasive tonsillar squamous cell carcinoma of the tonsillar region. All patients were consecutively admitted to the Department of General Oncology, Radiumhemmet, and treated with curative intent. The median follow-up time was 20 months. The median target dose was 64 Gy, delivered in fractions of 2 Gy 5 times weekly. Twenty-eight percent of the patients underwent surgery of the primary site and/or neck dissection after radiotherapy (RT). RESULTS: The overall local control rate for the whole patient group after radiotherapy was 79%. Probability of survival after 5 years for patients responding with complete remission (CR) was 43% and for patients with incomplete response (non-CR) 9%, (p<0.0001). The survival in the non-CR group treated with combination therapy was 20 months longer than in patients receiving radiotherapy alone (p<0.0001). There was no statistically significant difference in prediction of long-term survival when the patient population was stratified according to tumor differentiation grade, age, sex, nodal status, or treatment time. CONCLUSION: The strongest clinical predictor of survival was the degree of tumor remission after RT. For the non-CR group receiving combination treatment including surgery there was a survival benefit as compared to patients treated with RT alone (p<0.0001) although there were few long-term survivors in this patient group.

Malignant human renin producing paraganglionoma-localization with 123I-MIBG and treatment with 131I-MIBG.

A 22-year-old woman presenting severe hypertension and hypokalaemia is described. Initial evaluation showed a large tumour localized at the position of the left adrenal gland. Subsequent surgery temporarily relieved all signs and symptoms caused by the tumour. The symptoms relapsed after a 2-year disease-free interval. At re-evaluation, the tumour was shown to produce an uncontrolled secretion of renin, thus triggering aldosterone-dependent hypertension. This report describes the diagnosis, treatment and clinical course of this unique patient with a malignant paraganglionoma of adrenal origin.

Quality of life aspects and costs in treatment of Graves' hyperthyroidism with antithyroid drugs, surgery, or radioiodine: results from a prospective, randomized study.

The patients' views and costs of three different forms of treatment for Graves' hyperthyroidism were investigated. The study comprises 174 patients with Graves' hyperthyroidism who were stratified into two age groups: 20 to 34 years and 35 to 55 years. The younger group was randomly assigned to treatment with antithyroid drug plus thyroxine for 18 months or subtotal thyroidectomy, and in the older group iodine-131 was added as a third alternative. The patients' views of their therapy were based on a questionnaire formulated to identify possible differences between the three treatment forms. The costs were assessed by analyzing the official hospital reimbursement system for both outpatient and inpatient costs for a period of 2 years from the day of randomization. The results show that no significant differences in opinion were found between the five treatment groups with regard to any of the questions. Furthermore, only 10% of the patients expressed slight and 3% major hesitation to recommend the treatment form received to a friend with similar disease. Twenty percent of the patients with endocrine ophthalmopathy reported the eye problems to be much more troublesome and 14% somewhat more troublesome than the thyroid problems. The cost proportion between the medical and surgical treatment in the young group was 1:2.5 (1 = 1126 United States dollars [USD]) before and 1:1.3 (1 = 2284 USD) after inclusion of the relapse costs. The proportion between the medical, surgical, and iodine-131 treatment in the older group was 1:2.5:1.6 (1 = 1164 USD) before and 1:1.6:1.4 (1 = 1972 USD) after inclusion of the relapse costs.

Anaplastic giant cell carcinoma of the thyroid gland: treatment and survival over a 25-year period.

Anaplastic giant cell carcinoma of the thyroid is a rare but highly malignant tumor. At the Karolinska Hospital in Stockholm, surgery, chemotherapy, and radiotherapy have been used separately or in various combinations in 81 patients admitted with this diagnosis during 1971-1997. In this study, we present the various multimodality treatment regimens and their changes over the years and the subsequent differences in survival and local tumor control. Overall, eight patients (10%) survived more than 2 years. All survivors were treated with combinations of chemotherapy, radiotherapy, and surgery. Among the patients who died, local tumor control was achieved by the therapy given in many cases. The results suggest that our current strategy with a combination of preoperative hyperfractionated accelerated radiotherapy, doxorubicin pre- and postoperatively, and debulking surgery whenever possible results in better local tumor control and an increased chance of survival.

Hypothyroidism after external radiotherapy for head and neck cancer.

PURPOSE: To study the development of thyroid hypofunction in patients with head and neck cancers admitted for external radiotherapy. METHODS AND MATERIALS: Between November 1990 and July 1996, thyroid function was measured in 264 consecutive patients, where the entire thyroid gland or part of it was included in the target volume. The time to development of hypothyroidism (HT) was calculated from the start of the radiotherapy. RESULTS: The median follow-up period was 19 months. Seventeen patients (6%) developed elevated serum thyroid-stimulating hormone levels with depressed (free) thyroxine levels (i.e., clinical HT). Elevated serum thyroid-stimulating hormone level with normal (free) thyroxine levels (i.e., chemical HT) developed in 57 (22%). The median time to clinical HT was 15 months (range: 7 to 32). The median time to chemical HT was also 15 months (range: 2 to 28). The actuarial risk of developing clinical or chemical HT 3 years after treatment was 15 and 40%, respectively. The incidence of chemical HT was significantly higher (p = 0.041) when the whole thyroid was included in the target volume compared to patients where only part of the thyroid was irradiated. The same trend was seen as regards clinical HT (p = 0.063). For those 20 patients who underwent laryngectomy, there was an increased risk of both chemical and clinical HT (p = 0.011 and 0.019, respectively). Increasing age was associated with an increased risk of chemical HT (p = 0.001), but not of clinical HT (p = 0.553). Sex, tumor site, radiation dose, and combination of radiotherapy and chemotherapy were not significant factors for thyroid hypofunction. CONCLUSION: Depressed thyroid function is common after external radiotherapy for cancers of the head and neck. Routine testing for possible thyroid hypofunction should be included in the follow-up procedures, even many years after end of radiotherapy.

Tumour cell proliferation after failed ruthenium plaque radiotherapy for posterior uveal melanoma.

Enucleation following ruthenium plaque radiotherapy for posterior uveal melanoma indicates failure of treatment. This study focused on the histopathological findings and remaining tumour cell growth fraction in 42 of 46 patients with failed ruthenium plaque treatment (of 266 patients treated) for melanoma of the choroid or ciliary body. The cause for enucleation was clinically detected tumour regrowth in 27 (64%) patients, treatment-related ocular side effects in 12 (29%) cases and the patient's personal preference in three (7%) cases. The median time elapsing from plaque radiotherapy to enucleation was not significantly different for patients with recurrent tumour growth (23 months) compared to those enucleated without clinical signs of regrowth (19 months). While all tumours showed some regressive features by histopathological examination, only five melanomas were completely necrotic and viable-appearing tumours cells were present in all of the remaining 37 (88%) irradiated tumours. Microwave processed PC-10 immunostainings increased the sensitivity to detect cycling cells compared to the sole use of mitotic cell counts. By the former technique, proliferating tumour cells were detected in 17 of 23 (74%) studied melanomas of eyes enucleated for tumour regrowth following brachytherapy. Also, the number of cycling melanoma cells was similar to that of non-irradiated controls managed solely by enucleation. In contrast, the proliferative compartments of irradiated, but non-recurrent, posterior uveal melanomas were significantly reduced compared to those of matched controls. Still, cycling tumour cells were present in four of 13 (31%) irradiated melanomas, clinically assumed to be successfully treated.

Radioiodine treatment, ablation, and ophthalmopathy: a balanced perspective.

In some patients with Graves' disease, ophthalmopathy develops or deteriorates after initiation of therapy for hyperthyroidism. The possible relationship between the management of hyperthyroidism and the course of ophthalmopathy has been addressed in several studies but with conflicting results. The overall impression, when comparing these studies, is that there is no definite difference between the three forms of therapy for hyperthyroidism with regard to the course of ophthalmopathy, although there are more studies suggesting that 131I carries a higher risk for aggravating the eye disease. However, many of these studies are retrospective, contain few patients, have a short follow-up time, and include patients who have received more than one type of treatment. We performed a prospective study in which patients were randomized to either antithyroid drugs, subtotal thyroidectomy, or 131I. We found that 33% of the patients treated with 131i deteriorated compared with 10% and 16% of patients treated with antithyroid drugs and surgery, respectively (p = 0.02). The risk was greater when patients had very high pretreatment thyroid hormone levels. On the other hand, patients treated with 131I were given thyroxine later than the other patients, although this fact did not appear to be of importance for the results. In another retrospective study, we showed that early administration with thyroxine can reduce the risk for ophthalmopathy, and we now are undertaking a prospective study in which treatment with antithyroid drugs is compared with 131I treatment and early thyroxine. Our guidelines for ablative therapy in patients with progressive ophthalmopathy are presented.

Results following episcleral ruthenium plaque radiotherapy for posterior uveal melanoma. The Swedish experience.

The Swedish experience of ruthenium 106 plaque radiotherapy for posterior uveal melanoma includes 266 patients treated between 1979 and 1995. The median dose delivered at the tumour apex was 100 Gy and the median follow-up after radiotherapy was 3.6 years (range = 0.5 to 12.5 years) with no patient being lost to follow-up. Visual acuity deteriorated moderately following treatment but appeared to stabilize after 5 to 6 years. Treatment failure defined as enucleation following plaque treatment occurred in 46 of the 266 (17%) studied patients. The cumulative 5-year probability of retaining the eye after radiotherapy was 82% and by univariate analysis tumour height, tumour diameter and tumour stage each predicted subsequent treatment failure, whereas in multivariate analysis no single covariate retained a predictive value. Forty-five of the 266 patients died of any cause during follow-up; 27 of these deaths were melanoma-related. The cumulative 5-year survival proportion (based on melanoma-related deaths only) was 86%. Death in metastatic disease appeared to be more common among patients that failed ruthenium plaque radiotherapy, however these patients also tended to have large tumours.

Graves' hyperthyroidism: treatment with antithyroid drugs, surgery, or radioiodine--a prospective, randomized study. Thyroid Study Group.

To analyze the benefits and risks of three common treatments, we randomly assigned 179 patients with Graves' hyperthyroidism as follows: 60 patients, 20-34 yr of age (young adults), received antithyroid drugs for 18 months (medical) or subtotal thyroidectomy (surgical), and 119 patients, 35-55 yr of age (old adults), received medical, surgical, or radioiodine (iodine-131) treatment. The follow-up time was at least 48 months. Antithyroid drugs, surgery, or iodine-131 treatment normalized the mean serum hormone levels within 6 weeks. The risk of relapse was highest in the medically treated young and old adults (42% vs. 34%), followed by that in those treated with iodine-131 (21%) and that in the surgically treated young and old adults (3% vs 8%), respectively. Elevated TSH receptor antibodies at the end of medical therapy or increasing TSH receptor antibodies values after medical or surgical treatment increased the probability of relapse. Development or worsening of ophthalmopathy was not associated with relapse per se. Ninety percent of the subjects in all groups were satisfied with the treatment they received. No significant difference in sick-leave due to Graves' or other diseases was seen during the first 2 yr after initiation of therapy. The increased risk of ophthalmopathy in patients with high serum T3 levels, especially when treated with iodine-131, and the relatively high frequency of relapse after treatment with antithyroid drugs are important factors to consider when selecting therapy for Graves' disease.

Allelotyping of follicular thyroid tumors.

To elucidate further the genetic mechanisms for follicular thyroid tumor development and progression, we allelotyped follicular thyroid tumors and other thyroid lesions from 92 patients. In general, a low frequency of loss of heterozygosity (LOH) was found, the highest being for chromosomes 3q, 10q, 11p, 11q, 13q, and 22q (10%-15%). However, detailed study of LOH of these chromosome arms with regard to the different histopathological diagnoses indicates that a locus on chromosome 10q may be involved in follicular thyroid tumor progression. In addition, the majority of Hürthle cell adenomas showed LOH on either chromosome 3q or 18q, in contrast to the other tumor types. This discrepancy in genetic alterations may contribute to the divergent clinical features occurring in these tumors.

Different dose regimens of 5-fluorouracil and interferon-alpha in patients with metastatic colorectal carcinoma.

Three different 5-fluorouracil (5-FU)-interferon-alpha-2b (IFN)-containing regimens were designed for treatment of patients with advanced colorectal cancer. 87 patients with a Karnofsky index > or = 70 were included in three sequential non-randomised phase II trials. Regimen A consisted of 5-FU (750 mg/m2/day) given as a continuous infusion on days 1-5 followed by weekly 1-h intravenous infusions until week 8. IFN (5 MU) was given subcutaneously on days 1, 3 and 5 followed by injections (9 MU) every second day until week 8. The cycle was then repeated. Regimen B consisted of 5-FU (750 mg/m2/day) given as a continuous infusion on days 1-5 followed by 5-min intravenous injections on days 12 and 19. IFN (3 MU) was given subcutaneously on days 1-5 followed by injections (5 MU) on days 11-13 and 18-20. The cycle was repeated every fourth week. Regimen C consisted of 5-FU (750 mg/m2/day) given as a continuous infusion on days 1-5. IFN (3 MU) was given subcutaneously on days 1-5. The cycle was repeated every third week. The objective response rates (complete response (CR) and partial response (PR)) after approximately 4 months of therapy or longer were as follows: regimen A (n = 27) 22% (2 CR, 4 PR), regimen B (n = 33) 42% (4 CR, 10 PR) and regimen C (n = 27) 22% (1 CR, 5 PR). The corresponding response figures for previously untreated patients were regimen A 50%, regimen B 64% and regimen C 38%. Response durations varied from a few weeks up to 142 + weeks. Toxicities were generally mild and reversible, and the treatments were convenient for the patients and cost effective since the 5-day infusions could be given by a portable pump without hospitalisation. Our results are in agreement with those of others showing that 5-FU/IFN combinations can be highly effective in advanced colorectal cancer, and that a number of factors such as doses, dose intensities, infusion rates and timing of the two drugs may be crucial for the anti-tumour activity of this drug combination.