XXII WORKSHOP UROLOGIA ONCOLÓGICA

Apresentação em tema: "XXII WORKSHOP UROLOGIA ONCOLÓGICA"— Transcrição da apresentação:

1 XXII WORKSHOP UROLOGIA ONCOLÓGICA
Hotel Solverde ESPINHO 10-11 Março 2017

2 Carcinoma da Próstata Radium 223 10 março 2017 Gracinda Costa
Medicina Nuclear. CHUC

3 Radium-223 Tratamento de doentes com carcinoma da próstata resistente à castração, com metástases ósseas sintomáticas e sem metástases viscerais conhecidas. Indicação Radiofármaco Aprovado pela FDA em 2013 INFARMED - utilização em 2ª linha em doentes que receberam previamente docetaxel

4 CRPC com Metástases Ósseas
> 90% dos doentes com mCRPC têm metástases ósseas, maior causa de morte, incapacidade, redução da QoL e aumento dos custos SRE Cost per event Pathologic bone fracture 9 512 € Spinal cord compression € External beam radiation 1 618 € Surgical Intervention 1. Tannock IF, et al. N Engl J Med. 2004;351:1502– Roodman GD. N Engl J Med. 2004;350:1655– Lange P and Vesella R. Cancer Metastases Rev. 1999;17:331– Lipton A. Semin Oncol. 2010;37:S15–S Adami S. Cancer ;80:1674– Silberstein EB. Semin Radiat Oncol. 2000;10:240– Fizazi K, et al. J Clin Oncol. 2009;27:1564– Fizazi K, et al. Lancet. 2011;377:813– Finlay IG, et al. Lancet Oncol. 2005;6:392– Lewington VJ. J Nucl Med. 2005;46(suppl):38S–47S. 11. Sartor O. Asian J Androl. 2011;13:366– Sartor O and Bruland O. Clin Genitourin Cancer. 2011;9:1– Sartor O, et al. Asian J Androl. 2011;13:783–84.

5 Prostate Cancer: Average Number of Deaths per Year and Age-Specific Mortality Rates per 100,000 Population, UK A mortalidade do carcinoma da próstata está fortemente relacionada com a idade “… the highest mortality rates being in older males. In the UK in , on average each year almost 6 in 10 (57%) deaths were in males aged 80 and over. Age-specific mortality rates rise sharply from around age 55-59, with the highest rates in the 90+ age group…” More than half of prostate cancer related deaths occurred in men older than 80 years old. Because of that is important that the last years of those patients are free of importante side efectes that compromise the QoL. Report remarkable tolerability of radium-223 in a population that had a baseline risk of progressive complications from underlying disease Source: cruk.org/cancerstats You are welcome to reuse this Cancer Research UK statistics content for your own work. Credit us as authors by referencing Cancer Research UK as the primary source. Suggested style: Cancer Research UK, full URL of the page, Accessed [month] [year].

6 Ra Radium Rádio – elemento químico N.º atómico 88 (n.º de protões)
N.º variável de neutrões 135 no caso do Ra-223 N

7 Radium Na natureza encontram-se quantidades vestigiais
minérios de uranio e tório 0,14gr/tonelada de uraninite 33 isótopos conhecidos todos radioativos Análogo do Cálcio Não faz parte da constituição dos organismos vivos uma dose de Ra-223 < 3ng de “princípio ativo”

8 Marie Curie e Radi(um)atividade
Marie Curie ( ) descobriu dois novos elementos químicos Radium Polonium 1911 Prémio Nobel da Química 1898 1903 Prémio Nobel da Física

9 História do Radium Saúde e bem estar
Radium and radon health spas took off in the 20s and 30s

10 História do Radium Tratamento da impotência
…. before the days of Viagra and Cialis, treatment for impotence took the form of radioactive “bougies” – wax rods inserted into the urethra – and even athletic supporters containing a layer of radium-impregnated fabric. A popular alternate treatment called the Radioendocrinator was a booklet that contained a number of cards coated in radium, which were worn inside the undergarments at night (the Radioendocrinator’s inventor died of bladder cancer in ) Radioendocrinator

11 Decaimento Radioativo: Ra-223
88  Terapêutica Pb 207 82 estável Rádio-223 emite (sobretudo) partículas α t½ = 11,43 dias Energia emitida 95.3%  3.6%  1.1% γ ou Rx

12 Partículas Alfa Dois protões e dois neutrões (núcleo de hélio) Velocidade = Km/sec Elevada Energia Alcance muito curto (100µm)

13 Ra-223: Mecanismo de Ação (I)
Ra-223 é um análogo do Ca Incorporado no osso – componente mineral (Ca5[PO4]3OH) em áreas de elevada remodelação óssea Metástase Óssea do Ca. P - modelo “perfeito” elevado metabolismo ósseo as células neoplásicas estão muito próximo da componente mineral Because Ra223 mimics calcium, it is incorporated in the mineral part of the bone. Prostate cancer bone metastases hall mark is an increase in new bone formation. We can use that biologic phenomenum to attract bone seeking radiopharmaceutical, like those used for bone functional imaging (scintigraphy or PET) or in bone therapy. In therapy, is important that Ra223 is as close as possible to the tumour cells (they do nor enter inside the cancer cells)

14 Ra-223: Mecanismo de Ação (II)
Partículas alfa provocam quebra da dupla cadeia do DNA hydroxyapatite Ra 223 Ca2+ Partícula Alfa mPCC

15 Curto alcance da partícula Alfa reduz a exposição da Medula Óssea ao efeito da radiação
Range of alpha-particle Bone surface Beta emitters were the 1st agents that were used. No survival benefit only in bone pain palliation. Haematologic toxicity. Ra-223 Henriksen G, et al. Cancer Res. 2002;62:3120–3125. Brechbiel MW. Dalton Trans. 2007;43:4918–4928.

16 Patofisiologia da Metástase Óssea do Ca. da Próstata
Ciclo Vicioso de destruição e formação óssea The cyclic feedback loop between prostate cancer cells, osteoblasts and osteoclasts Células Alvo Tumorais Osteoblastos Osteoclastos Cél. Inflamatórias? Outras? Efeito Bystander? Target cells Nature Reviews Urology (2015). doi: /nrurol

17 Radium-223: Protocolo de Administração
Pronto a usar1 Fácil de manusear – por pessoal devidamente autorizado Não necessita de equipamento ou material complexo 1 administração a cada 4 semanas1 6 IV administrações (55 kBq/Kg) Ambulatório Medidas de radioprotecção simples para a maior parte dos doentes BLAZEJ: I think the numbering is wrong here. See red numbers on left as guide Half-life is 11.4 days,1 which allows for sufficient time for preparation, distribution (including long-distance shipment), and administration2 Product is isotonic with physiological pH and is supplied as single-dose glass vials with radioactivity concentration of 1,000 kBq/mL (0.3 mCi/mL) at the reference date3 Requires no additional specialized detection equipment Phase III dose: 50 kBq/kg × 6 injections at 4-week intervals4 The ultra-short penetration of alpha particles is easily blocked (even by paper), allowing radium-223 to be simply handled without the requirement for complex shielding during shipping and administration5 Radium-223 that is not rapidly taken up in bone is rapidly excreted into the small bowel6,7 Virtually no restrictions on patients after they leave the clinic5 References 1. McDevitt MR, et al. Eur J Nucl Med. 1998;25(9): 2. Nilsson S, et al. Clin Cancer Res. 2005;11(12): 3. Data on file. Algeta ASA. 4. Parker C, et al. J Clin Oncol. 2012;30(suppl). Abstract LBA4512. 5. Biggin C. Eur J Nucl Med Mol Imag. 2007;34:S391. Abstract P646. 6. Lewington V, et al. Presented at ASCO GU Poster 216. 7. Morris MJ, et al. Presented at ASCO GU Poster 211. 1. Xofigo® (radium Ra 223 dichloride) solution for injection Summary of Product Characteristics (SmPC). Berlin, Germany: Bayer Pharma AG; Nilsson S, et al. Int J Radiat Oncol Biol Phys. 2010;78(3 suppl):S375-S376.

18 Seleção de Doentes Ra-223: Sim Ra-223: Não
mCRPC com várias metástases ósseas Visíveis nas cintigrafia óssea ou na PET óssea com NaF-18 ± Doença óssea muito extensa (superscan) Metástases sintomáticas – início dos sintomas Adenopatias ≤ 3cm Ra-223: Não Presença de metástases viscerais (pulmão, fígado, SNC, doença ganglionar difusa) DII em fase ativa Expectativa de vida < 3 meses The Journal of OncoPathology, Volume 3, Number 1, February 2015, pp. 1-25

19 Radium-223: Contraindicações e Precauções
Contraindicações – não existem Mielo-supressão Trombocitopenia e neutropenia Administração concomitante de QT – não recomendada Controlo hematológico deve ser realizado antes de cada dose de Ra-223 Baseline Before Subsequent Dose ANC ≥ 1.5x109/L Platelet count ≥ 100x109/L Hemoglobin ≥ 10 g/dL ANC ≥ 109/L Platelet count ≥ 50x109/L

20 Radium-223: Farmacocinética
< 25% do radiofármaco permanece no sangue 15 minutos após a injeção 4 horas após a administração 40-60% in osso 40-50% intestino ≈ 4% in sangue Distribuição Rapidamente clarificado do sangue e distribuído para o osso ou eliminação pelo intestino Metabolismo Ra-223 não é metabolizado Eliminação Fecal – 13% Urinária – 2% No dose adjustment is considered necessary in patients with hepatic or renal impairment Não é necessário ajuste de dose em doentes com insuf. hepática ou renal

21 Eficácia e Segurança

22 ALpharadin in SYMptomatic Prostate Cancer (ALSYMPCA)
PATIENTS (N=921) - Confirmed symptomatic CRPC - ≥2 bone metastases - No known visceral metastases - Post-docetaxel, unfit for docetaxel, or refused docetaxela STRATIFICATION -Total ALP: < 220U/L vs ≥220U/L - Bisphosphonate use: Yes vs No - Prior docetaxel: Yes vs No R Radium-223 - 50 kBq/kg* IV - 6 injections at 4-week intervals + best standard of careb Placebo - Saline - 6 injections at 4-week intervals+ best standard of careb Study Design 2 1 Patients were randomly assigned, in a 2:1 manner, to receive an infusion of radium-223 or saline 136 centers in 19 countries Planned follow-up is 3 years ALSYMPCA was halted early after the positive efficacy results reported from a planned interim analysis of 809 patients with 314 deaths occurred. An updated analysis of efficacy and safety was performed from all 921 enrolled patients when 528 deaths had occurred. ALP, alkaline phosphatase; *Value is based on data assessed by previously used NIST standard. Updated nominal value of Xofigo is 55 kBq/kg body weight and not 50 kBq/kg body weight. Please see: a. Unfit for docetaxel includes patients who were ineligible for docetaxel, refused docetaxel, or lived where docetaxel was unavailable. b. Best standard of care defined as a routine standard of care at each center, e.g., local external beam radiation therapy, corticosteroids, antiandrogens, estrogens (e.g., stilbestrol), estramustine, or ketoconazole. SOURCE: Parker C, et al. N Engl J Med. 2013;369(3):213–223.

23 ALSYMPCA: Patient Demographics and Baseline Characteristics (ITT Population)
RADIUM-223 (n=614) PLACEBO (n=307) Age, years, Median (range) >75 years, n (%) 71 (49-90) 171 (28) 71 (44-94) 90 (29) Caucasian race, n (%) 575 (94) 290 (94) Total ALP, n (%) <220 U/L ≥220 U/L 348 (57) 266 (43) 169 (55) 138 (45) Current use of bisphosphonates, n (%) Yes No 250 (41) 364 (59) 124 (40) 183 (60) Any prior use of docetaxel, n (%) 352 (57) 262 (43) 174 (57) 133 (43) ECOG PS, n (%) 0 1 ≥2 165 (27) 371 (60) 77 (13) 78 (25) 187 (61) 41 (13) ALP, alkaline phosphatase; ECOG PS, Eastern Cooperative Oncology Group Performance Status; ITT, intention-to-treat. SOURCE: Parker C, et al. N Engl J Med. 2013;369(3):213–223.

24 ALSYMPCA: Patient Demographics and Baseline Characteristics (ITT Population)
RADIUM-223 (n=614) PLACEBO (n=307) WHO ladder for cancer pain, n (%) 1 2 3 257 (42) 151 (25) 194 (32) 137 (45) 78 (25) 90 (29) Extent of disease, n (%) <6 metastases 6-20 metastases >20 metastases Superscan 100 (16) 262 (43) 195 (32) 54 (9) 38 (12) 147 (48) 91 (30) 30 (10) EBRT within 12 weeks of screening, n (%) Yes No 99 (16) 515 (84) 48 (16) 259 (84) Hemoglobin (g/dL), Median (range) [normal range: g/dL] 12.2 ( ) 12.1 ( ) Albumin (g/L), Median (range) [normal range: g/L] 40 (24-53) 40 (23-50) Total ALP (U/L), Median (range) [normal range: U/L] 211 ( ) 223 ( ) LDH (U/L), Median (range) [normal range: U/L] 315 ( ) 336 ( ) PSA (μg/L), Median (range) [normal range: μg/L] 146 ( ) 173 ( ) ITT, intention-to-treat; WHO, World Health Organization. SOURCE: Parker C, et al. N Engl J Med. 2013;369(3):213–223.

25 ALSYMPCA - Endpoints Overall survival PRIMARY ENDPOINT
Time to total ALP progressiona Total ALP responsea Time to occurrence of first SSE Total ALP normalizationa,b Time to PSA progressiona,c Other secondary efficacy endpointsa Safety Quality of life SECONDARY ENDPOINTS

26 Eficácia - Resultados

27 ALSYMPCA*: Ra-223 Significantly Improved Overall Survival
PRIMARY ENDPOINT The updated analysis confirmed the 30% reduction in risk of death (HR=0.70) for patients in the radium-223 group compared with placebo Increase OS ∆=3.6 mos MEDIAN OS (months) ━ Ra-223: ━ Placebo: 11.3 HR (95% CI): 0.70 (0.58–0.83) P <0.001 20 40 60 80 100 Survival, % Months Since Randomization 9 15 24 30 39 36 33 27 21 18 12 6 3 Time to total ALP progressiona Total ALP responsea Time to occurrence of first SSE Total ALP normalizationa,b Time to PSA progressiona,c Other secondary efficacy endpointsa Safety Quality of life SECONDARY ENDPOINTS Whereas other trials included asymptomatic fractures—detected by means of periodic radiologic review—as skeletal events, ALSYMPCA had no radiographic review and so only symptomatic pathologic bone fractures were captured. Thus “symptomatic skeletal event” (SSE) was deemed a more clinically relevant term for this measurement ━ Radium-223 614 578 504 369 274 178 105 60 41 18 7 1 ━ Placebo 307 288 228 157 103 67 39 24 14 4 2 ALP, alkaline phosphatase; PSA, prostate-specific antigen; SSE, symptomatic skeletal event. a. See slides (“Other Secondary Efficacy Endpoints”) for more details. b. Defined as return of total ALP to within normal range at 12 weeks [confirmed by two consecutive measurements ≥2 weeks apart] in patients with total ALP values above upper limit of normal (ULN) at baseline. c. Defined as ≥25% increase from baseline and an absolute value increase ≥2 ng/mL at ≥12 weeks [in patients with no PSA decline from baseline] or ≥25% increase and an absolute value increase ≥2 ng/mL above nadir confirmed ≥3 weeks later, in patients with an initial decrease from baseline. SOURCE: Parker C, et al. N Engl J Med. 2013;369(3):213–223. *Updated Analysis. CI, confidence interval; HR, hazard ratio; OS, overall survival.

28 ALSYMPCA*: Ra-223 Improved OS Across all Patient Subgroups
In respect to whether or not the patient had higher or lower ALP, whether or not receive or had received bisphosphonates or docetaxel, the survival benefit was preserved. This means that the results of the trial were replicable to the general of metastatic castration resistance prostate cancer population without visceral metastases ALSYMPCA*: Ra-223 Improved OS Across all Patient Subgroups *Updated Analysis ALP, alkaline phosphatase; CI, confidence interval; ECOG PS, Eastern Cooperative Oncology Group Performance Status; HR, hazard ratio. a. Includes patients with a score of 2 or 3 on the World Health Organization (WHO) ladder for cancer pain. b. Includes patients without pain or opioid use at baseline and patients with a score of 1 on the WHO ladder for cancer pain. SOURCE: Parker C, et al. N Engl J Med. 2013;369(3):213–223.

29 ALSYMPCA*: Ra-223 Significantly Improved All Secondary Efficacy Endpoints
The significant improvement in all main secondary efficacy endpoints provided support for the benefit of Ra-223 (+ BSoC) over placebo (+ BSoC). SECONDARY EFFICACY ENDPOINTS RADIUM-223 (n=614) PLACEBO (n=307) HAZARD RATIO (95% CI) P VALUE Median time to first SSE (months) 15.6 9.8 0.66 ( ) <0.001 Median time to total ALP progression (months) 7.4 3.8 0.17 ( ) Median time to PSA progression (months) 3.6 3.4 0.64 ( ) Total ALP response (≥30% reduction), n (%)a 233/497 (47) 7/211 (3) — Total ALP normalization, n (%)a,b 109/321 (34) 2/140 (1) In summary … *Updated Analysis ALP, alkaline phosphatase; BSoC, best standard of care; CI, confidence interval; ITT, intention-to-treat; PSA prostate-specific antigen; SSE, symptomatic skeletal event. a. Number of patients without missing values. b. In patients who had elevated total ALP at baseline. SOURCE: Parker C, et al. N Engl J Med. 2013;369(3):213–223.

30 Months Since Randomization
ALSYMPCA*: Ra-223 Significantly Improved Time to SSE (symptomatic skeletal event) 20 40 60 80 100 Patients Without SSE, % Increase TTSSE ∆=5.8 mos MEDIAN TIME TO SSE (months) ━ Radium-223: ━ Placebo: 9.8 HR (95% CI): 0.66 (0.52–0.83) P <0.001 Very important as well, and besides improving OS, Ra223 delay, in almost 6 months, the time of symptomatic skeletal event. We should not forget that those patients are in the last years or so of their lives, and 6 month delay in the appearance of bone fracture, spine cord compression, the EBRT is very significative in this group of patients Months Since Randomization 9 15 24 30 27 21 18 12 6 3 ━ Radium-223 614 496 342 199 129 63 31 8 1 ━ Placebo 307 211 117 56 36 20 9 7 4 *Updated Analysis BSoC, Best standard of care; CI, confidence interval; HR, hazard ratio; SSE, symptomatic skeletal event. SOURCE: Parker C, et al. N Engl J Med. 2013;369(3):213–223.

31 Radium-223 Reduced the Risk of Each Individual SSE Component
Radium-223 is currently the only agent in advanced CRPC shown to significantly decrease the risk of spinal cord compression in a phase 3 trial. RADIUM-223 (N=614) PLACEBO (N=307) INDIVIDUAL SSE COMPONENTS na (%) MEDIAN,b MONTHS HR (95% CI) P VALUEc External beam radiation therapy 186 (30) 17.1 105 (34) 17.5E 0.67 ( ) Symptomatic pathologic bone fracture 32 (5) NE 20 (7) 0.62 ( ) 0.10 Spinal cord compression 25 (4) 21 (7) 0.52 ( ) 0.03 Tumor-related orthopedic surgical intervention 12 (2) 7 (2) 0.72 ( ) 0.48 Favors Radium-223 Placebo 2 1 CI, confidence interval. CRPC, castration-resistant prostate cancer. NE, not estimable. a. Number of patients. b. Median time to first event. c. P values are for descriptive purpose only and not adjusted for multiplicity; the hazard ratio is the best interpretation of radium-223 effect. SOURCE: Sartor O, et al. Lancet Oncol. 2014;15(7):738–746.

32 ALSYMPCA*: Improvement in QoL with Radium-223
A significantly higher percentage of patients treated with radium-223, versus placebo, experienced a meaningful improvement in quality of life. **Updated Analysis FACT-P, Functional Assessment of Cancer Therapy–Prostate. SOURCE: Parker C, et al. N Engl J Med. 2013;369(3):213–223.

33 Segurança - Resultados

34 ALSYMPCA*: Safety Profiles Were Similar Between the Radium-223 and Placebo Arms
There were few grade 3 AEs and grade AEs were very low, also comparable to placebo. aSafety population comprised patients who received at least 1 dose; 1 patient in the placebo group received 1 injection of radium-223 (week 0) and is included in the radium-223 safety analysis. Parker C, et al. N Engl J Med. 2013;369: *Updated Analysis

35 ALSYMPCA Updated Analysis: Safety Profiles Were Similar Between the Radium-223 and Placebo Arms
There were few grade 3 AEs and grade 4 AEs were very low, also comparable to placebo NUMBER OF PATIENTS WITH AEs OCCURRING IN ≥5% OF PATIENTS IN EITHER TREATMENT GROUP EVENT  RADIUM-223 (n=600) PLACEBO (n=301) ALL GRADES, n (%) GRADE 3, n (%) GRADE 4, n (%) GRADE 5,a n (%) ALL GRADES, n (%) GRADE 3, n (%) GRADE 4, n (%) GRADE 5,a Hematologic AEs Anemia 187 (31) 65 (11) 11(2) 92 (31) 37 (12) 2 (1) 1 (<1) Thrombocytopenia 69 (12) 20 (3) 18 (3) 17 (6) 5 (2) Neutropenia 30 (5) 9 (2) 4 (1) 3 (1) Nonhematologic AEs  Constipation 108 (18) 6 (1) 64 (21) Diarrhea 151 (25) 45 (15) Nausea 213 (36) 10 (2) 104 (35) Vomiting 111 (19) 41 (14) 7 (2) Asthenia 35 (6) 5 (1) 18 (6) Fatigue 154 (26) 21 (4) 77 (26) 16 (5) General physical health deterioration 27 (5) 2 (<1) 21 (7) 8 (3) Peripheral edema 76 (13) 30 (10) Pyrexia 38 (6) 19 (6) Pneumonia Some haematological toxicity but similar to the placebo arm. Remember this patient develop bone marrow suppression as the disease progressed. Only thrombocytopenia were more common in radio and is slightly more serious in the radium arm, because have more grade 3 and 4 toxicity. Diarrhoea and vomiting is more common in radio arm, probably related to the fact that the Ra is excreted to the GI tract. However they were quite similar in grade 3 and 4. AE, adverse event. a. Only 1 grade 5 hematologic AE was considered possibly related to study drug: thrombocytopenia in 1 patient in the radium-223 group. SOURCE: Parker C, et al. N Engl J Med. 2013;369(3):213–223.

36 Chemotherapy Following Radium-223 Dichloride Treatment in ALSYMPCA
SARTOR O, ET AL. PROSTATE. 2016;76(10):905-16

37 Ra-223: Conclusões Simplicidade
“simples” elemento químico natural, análogo do cálcio mecanismo de ação “simples” baseado na sua captação preferencial em metástases ósseas com elevada atividade osteoblástica e na emissão de partículas alfa com efeito citotóxico potente Elevada transferência de E num trajeto muito curto Atividade Osteoblástica muito intensa muito próxima das células tumorais Atua independentemente da fase do ciclo celular, da expressão de marcadores celulares ou de recetores de membrana Deposita elevadas doses de radiação diretamente nas células tumorais, limitando a exposição dos tecidos vizinhos (células da medula óssea) O Ca. P é um modelo “ideal” – metastização preferencial para o osso e com uma capacidade notável de aumentar a atividade osteoblástica. Prolonga a sobrevida (aumento da sobrevida global em 3.6 meses) e o aparecimento de eventos ósseos sintomáticos (atraso em 5.8 meses)

38 Futuro Avaliar o benefício Ra-223 na doença óssea hormonossensível
Outros protocolos de administração Ciclos adicionais. Atividades mais elevadas. Re-tratamento. Associar outras modalidades terapêuticas Abiraterona, Enzalutamida, etc Ra-223 na doença óssea hormonossensível Maior radiossensibilidade Because the Low toxicity profile, the combination with other therapies is possible. We know from the EBRT, that combination of castration therapy with hormone agents in can enhance the effect of radiation. In many ways, the proposed Ra-223 studies in hormone-sensitive disease (and the administration of Ra-223 in combination with agents such as abiraterone/prednisone or enzalutamide) are extensions of this concept

39 Marie Curie was the first …
… woman of the degree in Physics … woman to graduate in France … woman to obtain a Nobel Prize … woman to obtain a chair at the Sorbonne … scientist to obtain two Nobel Prizes The only person to win a Nobel Prize in two different sciences