Jorma Heikkonen

Radiation related complications after ruthenium plaque radiotherapy of uveal melanoma.

AIMS/BACKGROUND: To analyse radiation related complications and secondary enucleation after irradiation of malignant uveal melanoma with ruthenium-106 plaques. METHODS: A series of 100 consecutive eyes irradiated in 1981-91 was analysed using the life table method and the Cox proportional hazards model. The median apical and scleral tumour dose was 100 Gy (range 15-200 Gy) and 1000 Gy (range 200-1200 Gy), respectively. The median follow up time was 2.8 and 2.0 years (range 1 month to 10 years) for anterior and posterior segment complications, respectively. RESULTS: The 3 and 5 year probabilities of being without radiation cataract were 73% and 63%, without neovascular glaucoma 91% and 81%, without vitreous haemorrhage 83% and 74%, without radiation maculopathy 85% and 70%, and without radiation optic neuropathy 90% and 88%, respectively. The risk of radiation cataract was highest with large tumour size (T1 + T2 v T3, p = 0.0027; height < or = 5 v > 5 mm, p = 0.029; largest basal diameter (LBD) < or = 15 v > 15 mm, p < 0.0001) and location of anterior tumour margin anterior v posterior to the equator (p = 0.0003); the risk of neovascular glaucoma with large size (T1 + T2 v T3, p = 0.039; LBD < or = 15 mm v 15 mm, p = 0.021); and the risk of maculopathy and optic neuropathy with proximity of the posterior tumour margin to the fovea and the optic disc (< or = 1.5 v > 1.5 mm; p = 0.030 and p = 0.0004, respectively). In Coxs multivariate analysis the strongest risk indicator for radiation cataract (RR 1.5, 95% CI 1.4-1.6) and vitreous haemorrhage (RR 1.6, 95% CI 1.4-1.8) was the height of the tumour; for neovascular glaucoma the TNM class (RR 6.2, 95% CI 2.7-13.8); for radiation maculopathy location of posterior tumour margin within 2 mm from the fovea (RR 3.4, 95% CI 2.0-6.0); and for radiation optic neuropathy location of tumour margin within 1 DD of the optic disc (RR 6.1, 95% CI 3.0-12.4). The 3 and 5 year probabilities of avoiding enucleation were 92% and 85%, respectively. Ten eyes were enucleated--six because of recurrent tumour growth, three because of treatment complications, and one because of mistakenly suspected extraocular growth. CONCLUSION: The results suggest that the frequency of radiation related complications after ruthenium brachytherapy of uveal melanoma is acceptable, in particular as regard irradiation of small and medium sized tumours for which ruthenium therapy generally is recommended.

Iodine brachytherapy as an alternative to enucleation for large uveal melanomas.

PURPOSE To evaluate the safety and efficacy of iodine 125 plaque brachytherapy (IBT) for large uveal melanomas. DESIGN Retrospective, nonrandomized comparative trial (historical control). PARTICIPANTS One hundred twenty-one consecutive patients with a large uveal melanoma according to the Collaborative Ocular Melanoma Study (COMS) criteria who attended a national ocular oncology service. METHODS Ninety-seven patients (80%) underwent primary IBT (mean dose to tumor apex, 87 Gy) with noncollimated 20- to 25-mm plaques. Assessment of metastatic disease at death and visual outcome followed COMS guidelines. Time to low vision (20/70 or worse) and blindness (loss of 20/400 vision) in the study eye were modeled by Cox proportional hazards regression, based on both single- and repeated-failure data sets. Person-years of retained vision were calculated. MAIN OUTCOME MEASURES All-cause and melanoma-specific survival, local and distant recurrence, and preservation of vision and cosmesis. RESULTS Median tumor height was 10.7 mm (range, 4.5-16.8 mm), and largest basal tumor diameter was 16.1 mm (range, 7.3-25.0 mm). The Kaplan-Meier estimate for all-cause and melanoma-specific survival was 62% (95% confidence interval [CI], 49%-72%) and 65% (95% CI, 52%-75%) at 5 years. The corresponding estimate for local tumor recurrence was 6% (95% CI, 2%-14%) and for major cosmetic abnormality was 38% (95% CI, 26%-52%). The median visual acuity in the study eye was 20/100 at baseline and 20/1600 at 2 years after treatment. The Kaplan-Meier estimate for avoiding low vision and blindness was 11% (95% CI, 4%-24%) and 26% (95% CI, 16%-37%) at 2 years, respectively. Tumor height and location entirely posterior to the ora serrata were the most robust predictors of visual loss. In this series, 49 person-years without low vision (median, 0.6 years; range, 0.04-8.2 years) and 111 person-years without blindness (median, 1.0 years; range, 0.03-8.6 years) in the treated eye were conserved. CONCLUSIONS Iodine 125 plaque brachytherapy seems to be a safe and effective alternative to enucleation with regard to survival and local tumor control. It provides a fair chance of preserving the eye with acceptable cosmesis and a reasonable chance of conserving useful vision for 1 to 2 years.

Low vs. High Radioiodine Activity to Ablate the Thyroid after Thyroidectomy for Cancer: A Randomized Study

Background Radioactive iodine is commonly administered following thyroidectomy for differentiated thyroid carcinoma to ablate the thyroid remnant. The optimal administered activity of radioiodine is unknown. Methodology/Principal Findings Adult subjects (n = 160) diagnosed with papillary or follicular thyroid carcinoma were randomly allocated to receive either 1100 MBq (30 mCi) or 3700 MBq (100 mCi) activity of radioiodine (131I) following thyroidectomy. The study participants were prepared for ablation using thyroid hormone withdrawal. Ablation was considered successful when serum thyroglobulin concentration was less than 1 ng/mL and no uptake was present in 131I scan. Ablation was successful following one administration of radioiodine in 42 (52%; 95% CI, 41% to 63%) of the 81 evaluable study participants who received 1100 MBq, and in 43 (56%, 45% to 67%) of the 77 subjects who received 3700 MBq activity (P = .61). There was no difference between the groups in the numbers of repeat radioiodine treatments needed to complete ablation (P = .27). The higher activity was associated with more nausea and taste disturbances, and a longer stay in a radioprotected isolation unit. None of the participants died from thyroid cancer during a median follow up of 51 months; three subjects in the 3700 MBq group and none in the 1100 MBq group were diagnosed with distant metastases during follow-up. In a meta-analysis of four randomized studies that compared the 1100 and 3700 MBq activities, the 1100 MBq activity tended to be associated with a higher risk of unsuccessful ablation (relative risk 1.148, 95% CI 0.974 to 1.353, P =  .10). Conclusions/Significance The results provide no conclusive evidence that 3700 MBq activity is more effective for ablation of the thyroid remnant than 1100 MBq activity. The 3700 MBq activity is associated with more adverse effects. Trial Registration ClinicalTrials.gov NCT00115895

Sebaceous carcinoma of the eyelid associated with retinoblastoma.

OBJECTIVE To analyze the association between retinoblastoma (Rb) and sebaceous carcinoma (SC) of the eyelid to improve surveillance of survivors of RB: DESIGN Case report and systematic literature review. METHODS Ten patients who had SC develop after Rb were identified by systematic literature review, and a child who died with lymph node, lung, and liver metastases 7 years after irradiation for Rb is described. The data were analyzed by univariate statistics, including cumulative frequency distribution plots and Kaplan-Meier analysis. RESULTS Of 11 children with SC of the eyelid who all had hereditary RB, 9 (82%; 95% confidence interval, 48-98) received a median of 46 Gy (range, 21-89) of radiotherapy at a median age of 16 months (range, 0.5-15 years) and had SC develop within the field of radiation. Their median age at diagnosis of SC was 14 years (range, 8-30 years), median diagnostic delay 12 months (range, 6 months-3 years), and median interval from irradiation 11 years (range, 5-26 years); 7 of them (78%; 95% confidence interval, 40-97) were diagnosed between 5 and 15 years after radiotherapy. SC also developed at the age of 32 and 54 years in two nonirradiated Rb patients. Five patients had regional lymph node metastases after a median time of 12 months (range, 1 month-24 years). The 5-year cumulative probability of survival was 87%. CONCLUSIONS SC of the eyelid may occur in patients with hereditary Rb regardless of primary treatment, especially within the field 5 to 15 years after radiotherapy.

Scintigraphy in prediction of the salivary gland function after gland-sparing intensity modulated radiation therapy for head and neck cancer

BACKGROUND AND PURPOSE To evaluate salivary gland scintigraphy in prediction of salivary flow following radiation therapy. PATIENTS AND METHODS Twenty patients diagnosed with head and neck cancer were treated with intensity modulated radiation therapy with an intention to spare the salivary gland function. The total quantitative saliva secretion was measured prior to and 6 and 12 months after therapy, and the function of the major salivary glands was monitored using Tc-99m-pertechnetate scintigraphy. Two models were designed for prediction of the post-treatment salivary flow: an average model, based on the average proportions of saliva produced by each of the four major glands in healthy subjects, and an individual model, based on saliva produced by each gland as measured by scintigraphy prior to therapy. These models were compared with volume-based (Lyman) normal tissue complication probability models using two published sets of model parameters. RESULTS The D(50) for the parotid and the submandibular gland function assessed at 6 and 12 months after radiotherapy was approximately 39Gy. The scintigraphy-based individual model predicted well the measured post-treatment saliva flow rates. The correlation coefficient between the predicted stimulated and the measured saliva flow rate was 0.77 (p<0.0001) at 6 months and 0.55 (p=0.034) at 12 months after completion of radiotherapy. The relative changes in unstimulated and stimulated salivary flow rates showed similar dependency on the cumulative radiation dose. CONCLUSIONS Salivary gland function assessed by scintigraphy prior to radiotherapy is useful in prediction of the residual salivary flow after radiotherapy.

Visual Outcome of Eyes With Malignant Melanoma of the Uvea After Ruthenium Plaque Radiotherapy

BACKGROUND AND OBJECTIVE To analyze the overall visual outcome in 100 consecutive eyes with malignant uveal melanoma irradiated with ruthenium-106 plaques between 1981 and 1991. PATIENTS AND METHODS The follow-up ranged from 4 months to 10.1 years (median 3.0 years). Scattergrams of equal follow-up periods, life-table survival analysis, and Coxs proportional hazards analysis were used to analyze visual outcome. RESULTS VA increased for some time in 14 eyes. By 3 years, VA of at least 20/70, 20/200, counting fingers, and light perception were retained in 27%, 41%, 67% and 82% of eyes, respectively. Macular pathology cause loss of reading vision; neovascular glaucoma or enucleation caused loss of light perception. In univariate analysis, large tumor size (height > 5 mm or TNM class T3) predicted visual loss of all VA levels. For the loss of light perception, the tumors largest basal diameter > 15 mm reached significance. In Coxs multivariate analysis tumor height > 5 mm was the only significant independent risk indicator for loss of VA levels 20/70 and 20/200. For the level CF, largest basal tumor diameter also reached significance, but location of the tumor within 1 disc diameter of the optic disc, either alone or in addition to the fovea, had the greatest risk ratio (6.3, 95% CI 4.1-9.8). For losing light perception, large TNM size (T3) was the strongest risk indicator (risk ratio 10.0; 95% CI 4.5-22.5), followed by proximity of the tumor to the optic disc (risk ratio 4.3, 95% CI 2.4-7.8). CONCLUSION Ruthenium brachytherapy may retain vision in an eye with a malignant melanoma of the uvea for a considerable period of time. The data presented are useful in patient counseling and allow comparison to subsequent series.

Radiotherapy of malignant melanoma of the uvea with I‐125 seeds

Abstract Nineteen patients with malignant uveal melanomas were treated with I‐125 applicators. There were 10 males and 9 females with a median age of 61 years (range 42–76). The tumour was located in the choroid in 12 eyes and in the choroid and ciliary body in 7 eyes. The size of the tumours was 7–18 mm in maximal basal diameter (median 12), 5–16 mm in minimal basal diameter (median 10), and 5.5–15 mm in thickness (median 8.5). The volume of the tumours was 123–1890 mm3 (median 540). All tumours were classified as large (T3). For the irradiation, a computer program, which calculates three‐dimensional dose distribution of I‐125 seeds in gold plaques, was developed. By modifying the seed positions, activity and the orientation, patients can be treated individually. Iodine‐125 emits low energy photons, ideal for intraocular tumour therapy and tissue. Extra‐ocular tissue located behind the applicator can be completely shielded by a 0.5 mm gold layer. The dose at the apex of the tumour ranged from 30 to 120 Gy (median 93). The treatment time ranged from 44 to 600 h (median 235). Preliminary results are good. After a median follow‐up of 6 months, the tumour growth has been arrested in all eyes and in 10 eyes the tumour has decreased in size.

Accuracy requirements for head and neck intensity-modulated radiation therapy based on observed dose response of the major salivary glands

BACKGROUND AND PURPOSE We estimated accuracy requirements for dose and position of the major salivary glands in head and neck intensity-modulated radiotherapy (IMRT) based on the dose response characteristics of the glands obtained by using the sigmoidal dose response model. MATERIALS AND METHODS Dose response of the parotid and submandibular salivary glands was determined for 25 head and neck cancer patients treated by IMRT. Individual salivary gland functions were assessed by scintigraphy before and 6months after radiotherapy. Accuracy requirements were estimated by using the maximal slope of the fitted dose response model and average value of the dose gradients within the glands. In addition, systematic and random set-up errors were estimated for each patient by at least weekly portal imaging. We investigated the changes in the salivary gland mean doses (D(mean)) that would have occurred without correction of patient positioning. This was done by shifting the planned isocenter according to the obtained systematic set-up error and by recalculating the dose distribution in treatment planning system (TPS). RESULTS The maximal slope and D(50) values of the dose response model were -0.0411/Gy and 30.4Gy, respectively. The results suggested that spared fraction of individual salivary gland function can be estimated with an accuracy of +/-10%, if actual D(mean) of the gland is within +/-2.4Gy with the planned value. On the average, this was achieved with maximal systematic positional 3D shift of 3.0mm for the parotid glands and 2.7mm for the submandibular glands. The magnitude of systematic 1D set-up errors was 1.7+/-1.3mm (mean+/-SD) while that of systematic 3D errors was 3.4+/-1.6mm. The SD of random set-up errors was 1.5mm. The magnitude of D(mean) shifts due to set-up errors was 1.5+/-1.4Gy. The steepness of dose gradients within the glands was 0.8+/-0.5Gy/mm in the most critical direction (toward the glands). CONCLUSIONS When substantial part of salivary gland function is intended to be spared in head and neck IMRT, narrow dosimetric and positional tolerances should be adopted for the major salivary glands due to steep dose response curve obtained for the glands.

Tumor Regression After Brachytherapy for Choroidal Melanoma: Reduction of Thickness and Cross-Sectional Area by Shape and Regression Pattern.

PURPOSE To model regression rate of thickness and cross-sectional area of choroidal melanomas after ruthenium and iodine brachytherapy by shape and regression pattern (RP). METHODS We enrolled 330 of 388 consecutive uveal melanomas from 2000 to 2008 and analyzed images from I3 System-ABD 10-MHz B-Scan at diagnosis and during a 3-year-long follow-up. We classified tumor shape by Collaborative Ocular Melanoma Study definitions and RP according to an earlier study. We plotted regression over time and compared thickness and cross-sectional area. RESULTS The observed RP by thickness was classified as decrease (D) in 43%, stable (S) in 5%, increase (I) in 1%, and other in 40% of eyes; main subpatterns were decrease-stable (DS) in 16% and zigzag in 10% of eyes. The corresponding percentages by area were 42%, 3%, 1%, 45%, 16%, and 14%. Regression pattern was discordant in 34% of eyes for thickness versus area. Area reduced faster than thickness when shape was oval to dome or mushroom and if RP was D. Pooled patterns D, DS, decrease-increase (DI), and zigzag corresponded with progressive but increasingly less pronounced regression for 3 years (56% by thickness and 69% by area), 2 years (50% and 52%), 6 months (29% and 33%), and 6 months (19% and 23%), respectively. First-order exponential decay function fitted thickness and area regression for every shape and for patterns D, DS, DI, and zigzag. CONCLUSIONS Heterogeneity in RP, variation in shape, and tumor cross-sectional area as an alternative measure must be considered when tumor regression rate is used in outcome analysis.

Management of choroidal melanomas less than 10 mm in largest basal diameter with a 10-mm ruthenium plaque.

Purpose: To assess tumor control, complications, and vision after brachytherapy for posterior choroidal melanoma <10 mm in largest basal diameter with the 10-mm ruthenium plaque. Methods: This was a retrospective cohort study of consecutive choroidal melanomas <10 mm by largest basal diameter in a national ocular oncology service in 1998 to 2010. The median dose was 116 Gy (range, 80–194 Gy) to the apex and 327 Gy (range, 201–824 Gy) to the sclera. The median tumor height and largest basal diameter were 1.9 mm (range, 0.4–5.2 mm) and 7.0 mm (range, 3.3–9.6 mm), respectively. The median distance to disk and foveola was 3.0 mm (range, 0–7.5 mm) and 2.0 mm (range, 0–8.5 mm), respectively. Results: Four recurrences occurred at a median of 1.4 years (range, 0.6–3.1 years) after irradiation. Five-year cumulative incidence of local recurrence was 9% (95% confidence interval [CI], 3–20). Six patients died at a median of 4.2 years (range, 0.28–8.6 years) after treatment, one with evidence of metastases. At 5 years, 57% (95% CI, 31–79), 72% (95% CI, 58–85), and 97% (95% CI, 88–100) of eyes were free of any maculopathy, radiation maculopathy, and optic neuropathy, respectively. Cumulative incidence of developing low vision and blindness were 17% (95% CI, 7–31) and 3% (95% CI, 2–12) at 5 years, respectively. Thickness >3.0 mm, largest basal diameter >7.0 mm, and location ⩽1.5 mm of foveola were associated with visual loss. Conclusion: Local tumor control and vision outcomes support the use of 10-mm ruthenium plaques in managing smallest choroidal melanomas.