Computer planning of stereotactic iodine-125 seed brachytherapy for recurrent malignant gliomas

At St Thomas' Hospital, we have developed a computer program on a Titan graphics supercomputer to plan the stereotactic implantation of iodine-125 seeds for the palliative treatment of recurrent malignant gliomas. Use of the Gill-Thomas-Cosman relocatable frame allows planning and surgery to be carried out at different hospitals on different days. Stereotactic computed tomography (CT) and positron emission tomography (PET) scans are performed and the images transferred to the planning computer. The head, tumour and frame fiducials are outlined on the relevant images, and a three-dimensional model generated. Structures which could interfere with the surgery or radiotherapy, such as major vessels, shunt tubing etc., can also be outlined and included in the display. Catheter target and entry points are set using a three-dimensional cursor controlled by a set of dials attached to the computer. The program calculates and displays the radiation dose distribution within the target volume for various catheter and seed arrangements. The CT co-ordinates of the fiducial rods are used to convert catheter co-ordinates from CT space to frame space and to calculate the catheter insertion angles and depths. The surgically implanted catheters are after-loaded the next day and the seeds left in place for between 4 and 6 days, giving a nominal dose of 50 Gy to the edge of the target volume. 25 patients have been treated so far.

Biochemical control of prostate cancer with iodine-125 brachytherapy alone: experience from a single institution

Brachytherapy is an adequate option as monotherapy for localised prostate cancer. The objective of this study was to evaluate and compare biochemical failure free survival (BFFS) after low-dose-rate brachytherapy (LDRB) alone for patients with prostate cancer using ASTRO and Phoenix criteria, and detect prognostic factors. Data on 220 patients treated between 1998 and 2002 with LDRB were retrospectively analysed. Neoadjuvant hormone therapy was used in 74 (33.6%) patients. Median follow-up was 53.5 months (24-116). Five year BFFS was 83.0% and 83.7% using, respectively, the ASTRO and Phoenix criteria. Low -and intermediate-risk patients presented, respectively, 86.7% and 77.8% 5-year BFFS using the ASTRO definition (p=0.069), and 88.5% and 78.6% considering the Phoenix criteria (p=0.016). Bounce was observed in 66 (30%) patients. Multivariate analysis detected PSA at diagnosis < 10 ng/ml and less than 50% positive biopsy fragments as favourable prognostic factors, regarding BF using both criteria. For the Phoenix criteria, also Gleason score < 7 and low-risk group were identified as independent favourable prognostic factors. LDRB alone should be considered mostly for low-risk patients. PSA level was a strong independent prognostic factor. We support the use of the Phoenix criteria for detection of BF in patients submitted to LDRB alone.

Iodine Brachytherapy for Large Uveal Melanomas

Uveal melanoma is the most common primary intraocular malignancy in adults. Vision in the affected eye is threatened by both the tumor and side-effects from the treatments currently available. Poor prognosis for saving vision increases with tumor size and, consequently, enucleation has been the treatment of choice for large uveal melanomas in most centers. However, increasing evidence suggests that no survival benefit is gained (nor lost) by enucleation as compared to eye-conserving methods. The Helsinki University Eye Hospital has since 1990 offered episcleral iodine-125 plaque brachytherapy (IBT) for all patients unwilling to undergo enucleation for a large uveal melanoma. The primary aim of this study was to assess survival, local tumor recurrence and preservation of the eye and vision after IBT in a population-based series of 97 patients with uveal melanomas classified as large by the Collaborative Ocular Melanoma Study (COMS) criteria. Further aims included reporting the incidence of side-effects and assessing the role of intraocular dose distribution and clinical risk factors in their development. Finally, means to improve the current treatment were investigated by using computer models to compare existing plaques with collimating ones and by comparing the outcome of a subgroup of 54 IBT patients with very thick tumors with 33 patients with similarly-sized tumors managed with transscleral local resection (TSR) in Liverpool, United Kingdom. Kaplan-Meier estimates of all-cause and melanoma-specific survival at 5 years after IBT were 62% and 65%, respectively, and visually comparable with the survival experience of patients reported after enucleation by the COMS. Local recurrence developed in 6% of eyes and 84% of eyes were conserved at 5 years. Visual prognosis was guarded with 11% avoiding loss of 20/70 vision and 26% avoiding loss of 20/400 vision in the tumor eye at 2 years. Large tumor height and short distance from the posterior pole were independently associated with loss of vision. Using cumulative incidence analysis to account for competing risks, such as enucleation and metastatic death, the 5-year incidence of cataract after IBT was 79%, glaucoma 60%, optic neuropathy 46%, maculopathy 52%, persistent or recurring retinal detachment (RD) 25%, and vitreous hemorrhage 36%. In multivariate competing risks regression models, increasing tumor height was associated with cataract, iris neovascularization and RD. Maculopathy and optic neuropathy were associated with distance from the tumor to the respective structure. Median doses to the tumor apex, macula and optic disc were 81 Gy (range, 40-158), 79 Gy (range, 12-632), and 83 Gy (range, 10-377), respectively. Dose to the optic disc was independently associated with optic neuropathy, and both dose to the optic disc and dose to the macula predicted vision loss after IBT. Simulated treatment using collimating plaques resulted in clinically meaningful reduction in both optic disc (median reduction, 30 Gy) and macular (median reduction, 36 Gy) doses as compared to the actual treatment with standard plaques. In the subgroup of patients with uveal melanomas classified as large because of tumor height, cumulative incidence analysis revealed that while long-term preservation of 20/70 vision was rare after both IBT and TSR, preservation of 20/400 vision was better after TSR (32% vs. 5% at 5 years). In multivariate logistic regression models, TSR was independently associated with better preservation of 20/400 vision (OR 0.03 at 2 years, P=0.005) No cases of secondary glaucoma were observed after TSR and optic neuropathy was rare. However, local tumor recurrence was more common after TSR than it was after IBT (Cumulative incidence 41% vs. 7% at 5 years, respectively). In terms of survival, IBT seems to be a safe alternative to enucleation in managing large uveal melanomas. Local tumor control is no worse than with medium-sized tumors and the chances of avoiding secondary enucleation are good. Unfortunately, side-effects from radiotherapy are frequent, especially in thick tumors, and long-term prognosis of saving vision is consequently guarded. Some complications can be limited by using collimating plaques and by managing uveal melanomas that are large because of tumor height with TSR instead of IBT. However, the patient must be willing to accept a substantial risk of local tumor recurrence after TSR and it is best suited for cases in which the preservation of vision in the tumor eye is critical.

Braquiterapia com sementes de iodo-125: manufatura e tratamento

According to the National Institute of Cancer – INCA, 466.730 new cancer cases will occur in Brazil in 2009. Prostate and Lung cancer in man are the most incident types (in exception of the non-melanoma cancer). The brachytherapy with 125-iodine sources is an important method of prostate cancer treatment. The implant with iodine-125 seeds uses aproximately 100 seeds that are imported impossibilitating the treatment in large scale. For this reason, a multidisciplinary group was created at the Energetic and Nuclear Research Institute – Radiation Technology Center (IPEN –CTR / SP) to develop a national 125-iodine source and established a facility for local production. The seeds manufacture in Brazil will diminish the cost of treatment and prostate brachytherapy will be offered to more patients. This work aim is to observe and discuss the methods used in seeds manufacture there are being developed in Brazil and to present an prostate cancer case folloied in A.C. Camargo Hospital. The 125-iodine is adsorbed in an silver wire, then deposited at titanium coat. The weld is made by an process of plasm sealing. The seeds goes through several test to guarantee that there is no leakage. The result is an high quality and cheaper product. The implant tecnique is an fast and save procedure. The medical physicst preplan the case to stipulate the quantity of seeds there will be used. At the dat of the implant the medical physicst replan the procedure due to changes of volume in the organ. That assure the correct dose distribution in the target. Besides, the 125-iodine low energy is absorbed at the volume of interrest saving sourronding healthy tissues such as the rectum and the urethra

Estudo dos parâmetros dosimétricos de sementes de Iodo-125 desenvolvidas pelo IPEN-CNEN/SP utilizadas em braquiterapia por simulação computacional pelo método de Monte Carlo

As expectativas da Organização Mundial de Saúde para o ano de 2030 são que o número de mortes por câncer seja de aproximadamente 13,2 milhões, evidenciando a elevada parcela desta doença no problema de saúde mundial. Com relação ao câncer de próstata, de acordo com o Instituto Nacional do Câncer, o número de casos diagnosticados no mundo em 2012 foi de aproximadamente 1,1 milhão, enquanto que no Brasil os dados indicam a incidência de 68 mil novos casos. O tratamento deste tipo de neoplasia pode ser realizado com cirurgia (prostatectomia) ou radioterapia. Dentre a radioterapia, podemos destacar a técnica de braquiterapia, a qual consiste na introdução (implante) de pequenas fontes radioativas (sementes) no interior da próstata, onde será entregue um valor elevado de dose no volume de tratamento e baixa dose nos tecidos ao redor. No Brasil, a classe médica estima uma demanda de aproximadamente 8000 sementes/mês, sendo o custo unitário de cada semente de pelo menos U$ 26,00. A Associação Americana de Físicos na Medicina publicou alguns documentos descrevendo quais parâmetros e análises devem ser realizadas para avaliações da distribuição de dose, como por exemplo, os parâmetros Constante de taxa de dose, Função radial e Função de anisotropia. Estes parâmetros podem ser obtidos através de medidas experimentais da distribuição de dose ou por simulações computacionais. Neste trabalho foram determinados os parâmetros dosimétricos da semente OncoSeed-6711 da empresa Oncura-GEHealthcare e da semente desenvolvida pelo Grupo de Dosimetria de Fontes de Braquiterapia do Centro de Tecnologia das Radiações (CTR IPEN-CNEN/SP) por simulação computacional da distribuição de dose utilizando o código MCNP5, baseado no Método de Monte Carlo. A semente 6711 foi modelada, assim como um sistema dosimétrico constituído por um objeto simulador cúbico de 30x30x30 cm3 preenchido com água. Os valores obtidos da semente 6711 foram comparados com alguns apresentados na literatura, onde o parâmetro Constante de taxa de dose apresentou erro relativo em relação ao valor publicado no TG- 43 de 0,1%, sendo que os outros parâmetros analisados também apresentaram boa concordância com os valores publicados na literatura. Deste modo, pode-se considerar que os parâmetros utilizados nas simulações (espectro, modelagem geométrica e avaliação de resultados) estão compatíveis com outros estudos, sendo estes parâmetros também utilizados nas simulações da semente do IPEN. Considerando as análises de incerteza estatística, os valores obtidos da semente do IPEN são semelhantes aos valores da semente 6711.

Estudo dos parâmetros dosimétricos de sementes de Iodo-125 desenvolvidas pelo IPEN-CNEN/SP utilizadas em braquiterapia por simulação computacional pelo método de Monte Carlo

Dissertação (Mestrado em Tecnologia Nuclear)

Desenvolvimento e construção de sistema automatizados para controle de qualidade na produção de sementes de iodo-125

Tese (Doutorado em Tecnologia Nuclear)

Estramustine and its Derivatives in Potentiating Radiotherapy of Prostate Cancer

The purpose of this study was to deepen our knowledge of the combined use of estramustine and radiotherapy in the treatment of prostate cancer. Prostate cancer is a common disease, with a high variability between subjects in its malignant potential. In many cases, the disease is an incidental finding with little or no clinical significance. In other cases, however, prostate cancer may be an aggressive malignant disease, which, if the initial treatment fails, lacks an effective cure and may lead to severe symptoms, metastasis, and death despite all treatment. In many cases, the methods of treatment available at the moment provide cure or significant regression of symptoms, but often at the cost of considerable side effects. Estramustine, a cytostatic drug used for treating advanced cancer of the prostate, has been shown to inhibit prostate cancer progression and also to increase the sensitivity of cancer cells to radiotherapy. The goals of this study were, first, to find out whether it is possible to use either estramustine or an antibody against estramustine binding protein as carrier molecules for bringing therapeutic radioisotopes into prostate cancer cells, and, secondly, to gain more understanding of the mechanisms behind the known radiosensitising effect of estramustine. Estramustine and estramustine binding protein antibody were labelled with iodine-125 to study the biodistribution of these substances in mice. In the first experiment, both of the substances accumulated in the prostate, but radioiodinated estramustine also showed affinity to the liver and the lungs. Since the radiolabelled antibody was found out to accumulate more selectively to the prostate, we studied its biodistribution in nude mice with DU-145 human prostate cancer implants. In this experiment, the prostate and the tumour accumulated more radioactivity than other organs, but we concluded that the difference in the dose of radiation compared to other organs was not sufficient for the radioiodinated antibody to be advocated as a carrier molecule for treating prostate cancer. Mice with similar DU-145 prostate cancer implants were then treated with estramustine and external beam irradiation, with and without neoadjuvant estramustine treatment. The tumours responded to the treatment as expected, showing the radiation potentiating effect of estramustine. In the third experiment, this effect was found without an increase in the amount of apoptosis in the tumour cells, despite previous suggestions to the contrary. In the fourth experiment, we gave a similar treatment to the mice with DU-145 tumours. A reduction in proliferation was found in the groups treated with radiotherapy, and an increased amount of tumour hypoxia and tumour necrosis in the group treated with both neoadjuvant estramustine and radiation. This finding is contradictory to the suggestion that the radiation sensitising effect of estramustine could be attributed to its angiogenic activity.

Otimização de esquemas terapêuticos do carcinoma da próstata envolvendo braquiterapia de baixa taxa de dose e radioterapia externa : abordagens física e radiobiológica

RESUMO: Este trabalho teve como objetivo a determinação de esquemas de tratamento alternativos para o carcinoma da próstata com radioterapia externa (EBRT) e braquiterapia de baixa taxa de dose (LDRBT) com implantes permanentes de Iodo-125, biologicamente equivalentes aos convencionalmente usados na prática clínica, com recurso a modelos teóricos e a métodos de Monte Carlo (MC). Os conceitos de dose biológica efetiva (BED) e de dose uniforme equivalente (EUD) foram utilizados, com o modelo linear-quadrático (LQ), para a determinação de regimes de tratamento equivalentes. Numa primeira abordagem, utilizou-se a BED para determinar: 1) esquemas hipofracionados de EBRT mantendo as complicações retais tardias de regimes convencionais com doses totais de 75,6 Gy, 77,4 Gy, 79,2 Gy e 81,0 Gy; e 2) a relação entre as doses totais de EBRT e LDRBT de modo a manter a BED do regime convencional de 45 Gy de EBRT e 110 Gy de LDRBT. Numa segunda abordagem, recorreu-se ao código de MC MCNPX para a simulação de distribuições de dose de EBRT e LDRBT em dois fantomas de voxel segmentados a partir das imagens de tomografia computorizada de pacientes com carcinoma da próstata. Os resultados das simulações de EBRT e LDRBT foram somados e determinada uma EUD total de forma a obterem-se: 1) esquemas equivalentes ao tratamento convencional de 25 frações de 1,8 Gy de EBRT em combinação com 110 Gy de LDRBT; e 2) esquemas equivalentes a EUD na próstata de 67 Gy, 72 Gy, 80 Gy, 90 Gy, 100 Gy e 110 Gy. Em todos os resultados nota-se um ganho terapêutico teórico na utilização de esquemas hipofracionados de EBRT. Para uma BED no reto equivalente ao esquema convencional, tem-se um aumento de 2% na BED da próstata com menos 5 frações. Este incremento dá-se de forma cada vez mais visível à medida que se reduz o número de frações, sendo da ordem dos 10-11% com menos 20 frações e dos 35-45% com menos 40 frações. Considerando os resultados das simulações de EBRT, obteve-se uma EUD média de 107 Gy para a próstata e de 42 Gy para o reto, com o esquema convencional de 110 Gy de LDRBT, seguidos de 25 frações de 1,8 Gy de EBRT. Em termos de probabilidade de controlo tumoral (igual EUD), é equivalente a este tratamento a administração de EBRT em 66 frações de 1,8 Gy, 56 de 2 Gy, 40 de 2,5 Gy, 31 de 3 Gy, 20 de 4 Gy ou 13 de 5 Gy. Relativamente à administração de 66 frações de 1,8 Gy, a EUD generalizada no reto reduz em 6% com o recurso a frações de 2,5 Gy e em 10% com frações de 4 Gy. Determinou-se uma BED total de 162 Gy para a administração de 25 frações de 1,8 Gy de EBRT em combinação com 110 Gy de LDRBT. Variando-se a dose total de LDRBT (TDLDRBT) em função da dose total de EBRT (TDEBRT), de modo a garantir uma BED de 162 Gy, obteve-se a seguinte relação:.......... Os resultados das simulações mostram que a EUD no reto diminui com o aumento da dose total de LDRBT para dose por fração de EBRT (dEBRT) inferiores a 2, Gy e aumenta para dEBRT a partir dos 3 Gy. Para quantidades de TDLDRBT mais baixas (<50 Gy), o reto beneficia de frações maiores de EBRT. À medida que se aumenta a TDLDRBT, a EUD generalizada no reto torna-se menos dependente da dEBRT. Este trabalho mostra que é possível a utilização de diferentes regimes de tratamento para o carcinoma da próstata com radioterapia que possibilitem um ganho terapêutico, quer seja administrando uma maior dose biológica com efeitos tardios constantes, quer mantendo a dose no tumor e diminuindo a toxicidade retal. A utilização com precaução de esquemas hipofracionados de EBRT, para além do benefício terapêutico, pode trazer vantagens ao nível da conveniência para o paciente e economia de custos. Os resultados das simulações deste estudo e conversão para doses de efeito biológico para o tratamento do carcinoma da próstata apresentam linhas de orientação teórica de interesse para novos ensaios clínicos. --------------------------------------------------ABSTRACT: The purpose of this work was to determine alternative radiotherapy regimens for the treatment of prostate cancer using external beam radiotherapy (EBRT) and low dose-rate brachytherapy (LDRBT) with Iodine-125 permanent implants which are biologically equivalent to conventional clinical treatments, by the use of theoretical models and Monte Carlo techniques. The concepts of biological effective dose (BED) and equivalent uniform dose (EUD), together with the linear-quadratic model (LQ), were used for determining equivalent treatment regimens. In a first approach, the BED concept was used to determine: 1) hypofractionated schemes of EBRT maintaining late rectal complications as with the conventional regimens with total doses of 75.6 Gy, 77.4 Gy, 79.2 Gy and 81.0 Gy; and 2) the relationship between total doses of EBRT and LDRBT in order to keep the BED of the conventional treatment of 45 Gy of EBRT and 110 Gy of LDRBT. In a second approach, the MC code MCNPX was used for simulating dose distributions of EBRT and LDRBT in two voxel phantoms segmented from the computed tomography of patients with prostate cancer. The results of the simulations of EBRT and LDRBT were added up and given an overall EUD in order to obtain: 1) equivalent to conventional treatment regimens of 25 fraction of 1.8 Gy of EBRT in combination with 110Gy of LDRBT; and 2) equivalent schemes of EUD of 67 Gy, 72 Gy, 80 Gy, 90 Gy, 100 Gy, and 110Gy to the prostate. In all the results it is noted a therapeutic gain using hypofractionated EBRT schemes. For a rectal BED equivalent to the conventional regimen, an increment of 2% in the prostate BED was achieved with less 5 fractions. This increase is visibly higher as the number of fractions decrease, amounting 10-11% with less 20 fractions and 35-45% with less 20 fractions. Considering the results of the EBRT simulations an average EUD of 107 Gy was achieved for the prostate and of 42 Gy for the rectum with the conventional scheme of 110 Gy of LDRBT followed by 25 fractions of 1.8 Gy of EBRT. In terms of tumor control probability (same EUD) it is equivalent to this treatment, for example, delivering the EBRT in 66 fractions of 1.8 Gy, 56 fractions of 2 Gy, 40 fractions of 2.5 Gy, 31 fractions of 3 Gy, 20 fractions of 4 Gy or 13 fractions of 5 Gy. Regarding the use of 66 fractions of 1.8 Gy, the rectum EUD is reduced to 6% with 2.5 Gy per fraction and to 10% with 4 Gy. A total BED of 162 Gy was achieved for the delivery of 25 fractions of 1.8 Gy of EBRT in combination with 110 Gy of LDRBT. By varying the total dose of LDRBT (TDLDRBT) with the total dose of EBRT (TDEBRT) so as to ensure a BED of 162 Gy, the following relationship was obtained: ....... The simulation results show that the rectum EUD decreases with the increase of the TDLDRBT, for EBRT dose per fracion (dEBRT) less than 2.5 Gy and increases for dEBRT above 3 Gy. For lower amounts of TDLDRBT (< 50Gy), the rectum benefits of larger EBRT fractions. As the TDLDRBT increases, the rectum gEUD becomes less dependent on the dEBRT. The use of different regimens which enable a therapeutic gain, whether deivering a higher dose with the same late biological effects or maintaining the dose to the tumor and reducing rectal toxicity is possible. The use with precaution of hypofractionated regimens, in addition to the therapeutic benefit, can bring advantages in terms of convenience for the patient and cost savings. The simulation results of this study together with the biological dose conversion for the treatment of prostate cancer serve as guidelines of interest for new clinical trials.