antonio m. alencar jr. oncologista clínico...s y m p to m s a n d p r o lo n g s u r v iv a l. i n...

Antonio M. Alencar Jr.Oncologista Clínico

Hospital São DomingosHospital Universitário UFMA

Apresentação

• O problema: prognóstico ruim da doençaavançada não passível de tratamento local curativo.

• Opções disponíveis de tratamento sistêmico: evidências e expectativa de resultado

• Perspectivas de novos tratamentos sistêmicos (dados reais de novas terapias alvo / estudos em andamento)

Doença refratária à quimioterapia neoadjuvante não operável

Open Journal of Urology, Vol. 1 No. 4, 2011

Indian J Nucl Med. 2012 Jul;27(3):189-91J Med Case Rep. 2016 Mar 9;10:53

Doença metastática à distância

T1-3N3,T4N0-3

• 688 pacientes.

• 1960 a 2006

• metástases àdistância ocorreramem 4%.

• Tardiamante apóstratamentolocorregional

Ornellas AA, Kinchin EW, Nóbrega BL, Wisnescky A, Koifman N, Quirino R. Surgical treatment of invasive squamous cell carcinoma of the penis: Brazilian National Cancer Institute long-term experience. J Surg Oncol. 2008 May 1;97(6):487-95.

• 392 pacientes

• 2004 a 2014

Coelho RWP, Pinho JD, Moreno JS, Garbis DVEO, do Nascimento AMT, Larges JS, Calixto JRR, Ramalho LNZ, da Silva AAM, NogueiraLR, de Moura Feitoza L, Silva GEB. Penile cancer in Maranhão, Northeast Brazil: the highest incidence globally? BMC Urol. 2018 May 29;18(1):50. doi: 10.1186/s12894-018-0365-0.

Leijte JA, Kirrander P, Antonini N, Windahl T, Horenblas S. Recurrence patterns of squamous cell carcinoma of the penis: recommendations for follow-up based on a two-centre analysis of 700 patients. Eur Urol. 2008 Jul;54(1):161-8. Epub 2008 Apr 15.

Penile Cancer

Recurrence Patterns of Squam ous Cell Carcinom a of the Pen is:

Recom m endations for Follow -Up Based on a Tw o-Centre

Analysis of 700 Patien ts

Joost A.P. Leijtea, Peter Kirrander b, Ninja Antonini c, Torgny Windahl b, Simon Horenblas a,*

aDepartment of Urology, The Netherlands Cancer Institute – Antoni van Leeuwenhoek Hospital, Amsterdam, The NetherlandsbDepartment of Urology, Orebro University Hospital, Orebro, SwedencDepartment of Biostatistics, The Netherlands Cancer Institute – Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands

e u r o pe a n u r o l o g y 5 4 ( 2 0 0 8 ) 1 6 1 –1 6 9

av ai l ab l e a t w w w .sc i en ced i r ec t .co m

j o u r n al h o m ep ag e: w w w .eu r o p ean u r o l o g y .c o m

Article in fo

Art icle history:

Accepted Apri l 7, 2008

Published online ahead of

print on Apri l 15, 2008

Keywords:

Follow -up recom m endat ions

Penile neoplasm s

Recurrence

Survival

Abstract

Background: Curren t fol low -up recom m endat ion s for pat ients w ith penile carcinom a

are based on sm al l num bers of pat ients.

Objectives: To give further insight in to the recur rence patterns of penile carcinom a in

different treatm ent sett ings and provide recom m endat ions for fol low up.

Designs, Sett ing, and Participants: In th is retrospect ive study, w e analysed 700 pat ients

from tw o refer ral centres for penile carcinom a for recurrences.

Measurements: Recurrences w ere categorized as local, regional, or distant. The rate of

local recurrences w as com pared betw een pat ien ts undergoing penile-preserving treat-

m ents and part ial/ t otal am putat ion. Regional recurrences w ere com pared betw een

pat ients surgically staged as pN0 or pN+ and clin ically node-negat ive (cN0) pat ien ts

subjected to a w ait-and-see policy. The total recurrence rate, type of recurrence, t im e to

recurrence, and survival w ere calculat ed.

Results and Limitat ions: 205 out of 700 pat ients (29.3%) had a recurrence, consist ing of

18.6% local, 9.3% regional, and 1.4% distant recurrences. Of the recurrences, 92.2%

occurred w ith in 5 yr after prim ary treatm ent. All regional and distant recurrences

occurred w ith in 50 and 16 m o, respect ively . The local recurrence rate w as 27.7% after

penile-preserving therapy and 5.3% after am putat ion. The regional recur rence rate w as

2.3% in pat ien ts staged as pN0, 19.1% in pat ients staged as pN+, and 9.1% in pat ien ts

undergoing a w ait-and-see policy. The 5-yr disease-specific survival w as 92% after a local

recurrence and 32.7% after a regional recurrence. All pat ients w ith a distan t recurrence

died w ith in 22 m o. Although the num ber of analysed pat ients is substant ial, the result s

do not necessari ly reflect those of other centres using different techniques for the

m anagem ent of penile carcinom a.

Conclusions: Pat ients undergoing penile-preserving therapy, pat ients surgical ly staged

as pN+, and those undergoing a w ait-and-see pol icy for the nodal status are at h igh risk

of developing a recurrence. Fol low -up recom m endat ions are provided based on the risk

and im pact on survival of a recurrence.

# 2008 European Associat ion of Urology. Published by Elsevier B.V. All r ights reserved.

* Correspond ing author . The Netherlands Cancer Inst i tute – Antoni van Leeuw enhoek

Hospital, Plesm anl aan 121, 1066 CX Am sterdam , The Netherl ands. Tel. +31 (0)20-5122559;

Fax: +31 (0)20-5122554.

E-m ail address: s.horenblas@nki .n l (S. Horenblas).

0302-2838/$ – see back m atter # 2008 European Associat ion of Urology. Published by Elsevier B.V. All r ights reserved. doi:10.1016/j.eururo.2008.04.016

92%

32,7%

9,3%

1,4%

1956 a 2007

Mortalidade câncer-específica de acordo com o padrão de recidiva

Rieken M, Djajadiningrat RS, Kluth LA, Favaretto RL, Xylinas E, Guimaraes GC, Soares FA, Kent M, Sjoberg DD, Horenblas S, Shariat SF . Predictors of cancer-specific mortality after disease recurrence in patients with squamous cell carcinoma of the penis. Eur Urol. 2014;66(5):811.

Apresentação




Pettaway CA, Pagliaro L, Theodore C, Haas G . Treatment of visceral, unresectable, or bulky/unresectable regional metastases of penile cancer. Urology. 2010;76(2 Suppl 1):S58.

Cisplatina + Irinotecan

• Fase II – excluir resposta < 30%

• Mai 2004 – jan 2006 – 6 centros na França

• 28 pacientes inoperáveis (13 M1)

Theodore C, Skoneczna I, Bodrogi I, Leahy M, Kerst JM, Collette L, Ven K, Marréaud S, Oliver RD, EORTC Genito-Urinary Tract CancerGroup . A phase II multicentre study of irinotecan (CPT 11) in combination with cisplatin (CDDP) in metastatic or locally advancedpenile carcinoma (EORTC PROTOCOL 30992). Ann Oncol. 2008;19(7):1304. Epub 2008 Apr 15.

Cisplatina + 5-FU

• Fase II - Jan 200 – jun 2011 – 4 centros na Itália

• 25 pacientes inoperáveis (15 doença locorregional e 10 à distância)

Di Lorenzo G, Buonerba C, Federico P, PerdonàS, Aieta M, Rescigno P, D'Aniello C, Puglia L, Petremolo A, Ferro M, Marinelli A, Palmieri G, Sonpavde G, Mirone V, De Placido S. Cisplatin and 5-fluorouracil in inoperable, stage IV squamous cell carcinoma of the penis. BJU Int. 2012;110(11 Pt B):E661. Epub 2012 Sep 10.

Nicholson S, Hall E, Harland SJ, Chester JD, Pickering L, Barber J, Elliott T, Thomson A, Burnett S, Cruickshank C, Carrington B, Waters R, Bahl A . Phase II trial of docetaxel, cisplatin and 5FU chemotherapy in locally advanced and metastatic penis cancer (CRUK/09/001). Br J Cancer. 2013 Nov;109(10):2554-9. Epub 2013 Oct 29.

2 pacientes com doença locorregional → cCR

• Fase II– resposta > 60% para recomendar futuras investigações

• Set 2009 – dez 2010 – NHS (Reino Unido)

TPF (Docetaxel + Cisplatina + 5-FU)Estudo britânico

TPF (Docetaxel + Cisplatina + 5-FU)Estudo chinês

Zhang S, Zhu Y, Ye D. Phase II study of docetaxel, cisplatin, and fluorouracil in patients with distantly metastatic penile cancer as first-line chemotherapy. Oncotarget. 2015 Oct 13;6(31):32212-9.

• Fase II– resposta > 38,5 % (15 de 39 pacientes) de para recomendar futurasinvestigações

• Nov 2009 – jul 2013 – 1 hospital em Shangai, China – 39 pacientes apenas com metástases à distância

Oncotarget32215www.impactjournals.com/oncotarget

Table 2: Response to regimen (N = 39)

No. of patients %

Confir

m

e d response

Complete response 0 0

Partial response 15 38.5

Confir

m

e d stabl e di sease 14 35.9

Progressive disease 10 25.6

Overall response rate 15 38.5

95% CI for ORR 23.4–55.4

Abbreviations: CI, confid

e

nce int erval . ORR, obj ect ive response rat e.

Figure 1: Kaplan-Meier survival Kaplan curves for progression-free survival A. and overall survival B. with 95% CI curves.

Seguimento mediano = 11 mesesPFS = 3 mesesOS= 7 meses

Oncotarget32216www.impactjournals.com/oncotarget

symptoms and prolong survival. In this study using similar

regimen to our trial, the authors reported considerable and

troublesome toxicity: more than 20% patients experienced

grade 3 or higher febrile neutropenia and diarrhea was

prevalent in the patients. However, in our trial, these

toxicities were moderate and manageable. Grade 3 or

higher febrile neutropenia and diarrhea were only 7.7%

and 5.2%, respectively. One reason for the difference

might be the requirement of prophylactic growth

factor support in our study. In addition, in the study by

Nicholsons et al [20], patients with ECOG performance

status 2 were also recruited. However, in our study, only

ECOG performance status 0 to 1 were allowed. So the

different general conditions of patients may also partially

account for different toxicity profile . More importantly, we

used lower dose of fluo r our aci l (500 mg/m2/d) compared

with that in Nicholson’s study. When fluo r our aci l 750

mg/m2/d in TPF regimen was used previously in other

cancer treatments, gastrointestinal toxicities were the most

common adverse events leading to dose reduction [15, 16].

And fluo r our aci l dose was most commonly reduced [16].

Because M1 stage penile cancer patients were more fragile

compared with the locally advanced head and neck cancer

patients for whom TPF was frequently given (the OS for

the latter can be over 2 years.), lower dose of fluo r our aci l

at 500 mg/m2 was given in our trial. This might be also a

reason for the better tolerability in our trial.

Previously, there were several other phase II

studies for advanced penile cancer treatments [3, 21]. The

southwestern oncology group study of single-agent cisplatin

was the largest phase II chemotherapy trial at that time, with

26 patients evaluable for response. All but 1 patient had stage

IV disease, and none had undergone previous chemotherapy.

An overall response rate of 15% was achieved. And the

median overall survival time was 4.7 months [22].

In the largest published prospective study on

advanced penile carcinoma, Haas et al. administered

the BMP regimen in 40 evaluable patients with locally

Table 3: Toxicities of patients (N = 39)

Toxicity Grade 1 or 2 Grade 3 or 4

No % No. %

Anemia 8 20.5 3 7.7

Neutropenia 24 61.5 13 33

Thrombocytopenia 7 18 3 7.7

Febrile neutropenia / / 3 7.7

Central vein catheter

related thrombosis1 2.6 1 2.6

Nausea/vomiting 14 36 7 18

Diarrhea 8 20.5 2 5.2

Infection 6 15.4 4 10.3

Fever 2 5.2 1 2.6

Mucositis 5 13 2 5.2

Deep vein thrombosis 1 2.6 1 2.6

Neuropathy sensor 9 23 6 15.4

Table 4: Results of the multivariable Cox proportional hazard model for overall survival

Hazard ratio (95% CI) p value

ECOG performance status

1 versus 02.58 (1.21–6.31) 0.0026

Visceral metastases 7.21 (2.33–24.24) 0.001

Hemoglobin, less than 100 g/L versus at

least 100 g/L0.63 (0.29–1.62) 0.29

Albumin 1.65 (0.53–4.84) 0.414

Abbreviation: ECOG, Eastern Cooperative Oncology Group.

TPF (Docetaxel + Cisplatina + 5-FU)Estudo chinês

• Fase II– resposta > 38,5 % (15 de 39 pacientes) de para recomendar futuras investigações

• Nov 2009 – jul 2013 – 1 hospital em Shangai, China – 39 pacientes apenas com metástases à distância

Zhang S, Zhu Y, Ye D. Phase II study of docetaxel, cisplatin, and fluorouracil in patients with distantly metastatic penile cancer as first-line chemotherapy. Oncotarget. 2015 Oct 13;6(31):32212-9.

Paclitaxel

• Fase II - 25 Pacientes metastáticos pré-tratados com esquemasbaseados em platina (neoadj, adj ou paliativo) – 5 centros italianos

• 175 mg/m2 q3w

Di Lorenzo G, Federico P, Buonerba C, Longo N, Cartenì G, Autorino R, Perdonà S, Ferro M, Rescigno P, D'Aniello C, Matano E, AltieriV, Palmieri G, Imbimbo C, De Placido S, Mirone V. Paclitaxel in pretreated metastatic penile cancer: final results of a phase 2 study. Eur Urol. 2011 Dec;60(6):1280-4.

Cabazitaxel

• Fase II - 9 Pcts localmente avançados ou metastáticos pré-tratados comesquemas baseados em platina (neoadj ou paliativo) – 4 centros britânicos– ORR > 25%

• 25 mg/m2 q3w

Challapalli A, Pearson S, Mitra AV, Coe M, Thomson A, Elliott T, Kirkbride P, Pickering L, Kirk H, Foulstone E, Evans H, Bravo A, BahlAK. A phase II trial of cabazitaxel as second line chemotherapy in relapsed locally advanced and/or metastatic carcinoma of the penis. J Int Med Res. 2019 Oct;47(10):4664-4672.

ORR 0

SD 2

PD 7

Resposta após 2 ciclos de QT

Apresentação




• HPV– 33% dos casos

– HPV 16 e 18 (rhHPV)

Alemany L, Cubilla A, Halec G, Kasamatsu E, Quiros B, Masferrer. E et al (2016) Role of human papillomavirus in penile carcinomasworldwide. Eur Urol 69(5):953–961

• Inflamação crônica– Cox-2 → Prostaglandinas E2 + Tromboxane→ proliferação, invasão,

angiogênese

• Alterações genéticas somáticas

Emmanuel A, Nettleton J, Watkin N, Berney DM. The molecular pathogenesis of penile carcinoma-current developments andunderstanding. Virchows Arch. 2019 Oct;475(4):397-405

Emmanuel A, Nettleton J, Watkin N, Berney DM. The molecular pathogenesis of penile carcinoma-current developments andunderstanding. Virchows Arch. 2019 Oct;475(4):397-405

www.inovio.com

Trimble, C.L.; Morrow, M.P.; Kraynyak, K.A.; Shen, X.; Dallas, M.; Yan, J.; Edwards, L.; Parker, R.L.; Denny, L.; Giffear, M.; et al. Safety, efficacy, and immunogenicity of VGX-3100, a therapeutic synthetic DNA vaccine targeting human papillomavirus 16 and 18 E6 and E7 proteins for cervical intraepithelial neoplasia 2/3: A randomised, double-blind, placebo-controlled phase 2b trial. Lancet 2015, 386, 2078–2088.

Stevanovic , S.; Draper, L.M.; Langhan, M.M.; Campbell, T.E.; Kwong, M.L.; Wunderlich, J.R.; Dudley, M.E.; Yang, J.C.; Sherry, R.M.; Kammula, U.S.; et al. Complete Regression of Metastatic Cervical Cancer After Treatment With Human Papillomavirus–Targeted Tumor-Infiltrating T Cells. J. Clin. Oncol. 2015, 33, 1543–1550.

EGFR

Chaux, A.; Munari, E.; Katz, B.; Sharma, R.; Lecksell, K.; Cubilla, A.L.; Burnett, A.L.; Netto, G.J. The epidermal growth factor receptor is frequently overexpressed in penile squamous cell carcinomas: A tissue microarray and digital image analysis study of 112 cases. Hum. Pathol. 2013, 44, 2690–2695.

Panitumumabe

• Fase II - 11 Pcts metastáticos ou irressecáveis pré-tratados com esquemasbaseados em platina (1 ou mais linhas).

Necchi A, Giannatempo P, Lo Vullo S, et al. Panitumumab treatment for advanced penile squamous cell carcinoma when surgery and chemotherapy have failed. Clin Genitourin Cancer 2016; 14: 231–236. 2015

Di Lorenzo, G.; Buonerba, C.; Ferro, M.; Calderoni, G.; Bozza, G.; Federico, P.; Tedesco, B.; Ruggieri, V.; Aieta, M. The epidermal growth factor receptors as biological targets in penile cancer. Expert Opin. Biol. Ther. 2015, 15, 473–476.

Dacomitinibe

• Inibidor pan-HER (EGFR/HER1, HER2 e HER4)

• Fase II – doença localmente avançada ou metastática – 1ª linha

Necchi A, Lo Vullo S, Perrone F, Raggi D, Giannatempo P, Calareso G, Nicolai N, Piva L, Biasoni D, Catanzaro M, Torelli T, Stagni S, Togliardi E, Colecchia M, Busico A, Gloghini A, Testi A, Mariani L, Salvioni R. First-line therapy with dacomitinib, an orally available pan-HER tyrosine kinase inhibitor, for locally advanced or metastatic penile squamous cell carcinoma: results of an open-label, single-arm, single-centre, phase 2 study. BJU Int. 2018 Mar;121(3):348-356.

1 CR

8 PR

OS 13,7 meses

PFS 4,1 meses

1

Results

Table 1.

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Angiogênese / VEGF

Zhu, Y.; Li, H.; Yao, X.D.; Zhang, S.L.; Zhang, H.L.; Shi, G.H.; Yang, L.F.; Yang, Z.Y.; Wang, C.F.; Ye, D.W. Feasibility and activity of sorafenib and sunitinib in advanced penile cancer: A preliminary report. Urol. Int. 2010, 85, 334–340.

• PD-L1 + (> 05%) em 62 % (23/37) das amostras de câncer de pênis

Boa correlação PD-L1 primário x metástese

Udager, A.M.; Liu, T.Y.; Skala, S.L.; Magers, M.J.; McDaniel, A.S.; Spratt, D.E.; Feng, F.Y.; Siddiqui, J.; Cao, X.; Fields, K.L.; et al. Frequent PD-L1 expression in primary and metastatic penile squamous cell carcinoma: Potential opportunities for immunotherapeutic approaches. Ann. Oncol. 2016, 27, 1706–1712.

34

LACOG 0218 HERCULESPhase II study of pembrolizumab with cisplatin base therapy as first-line systemic therapy in advanced penile cancer

Study Design

Estudos em andamento

Estudo Droga Linha de tto Fase Tumores Resultados

NCT03866382 Nivolumabe + Ipilimumabe + Cabozatininbe

1ª e 2ª II Pênis, bexiga, rim, testículo,

neuroendócrino

2023

NCT03774901 Avelumabe Manutençao pós-QT com platina

II Pênis 2022

NCT03686332 Avelumabe vsAvelumabe + RT

1ª II Pênis 2020 / 2022

NCT03391479 Avelumabe vs BSC 1ª e 2ª II Pênis 2021 / 2022

NCT03357757 Avelumabe + ácidovalpróico

1ª II Tumores relacionadosao HPV

2022

NCT03333616 Nivolumabe + Ipilimumabe

1ª II Tumores GU raros 2021/2025

NCT03074513 Atezolizumabe + Bevacizumabe

1ª II Tumores sólidos raros 2021

NCT02837042 Pembrolizumabe 2ª II Pênis 2019/2020

NCT02721732 Pembrolizumabe 1ª II Tumores rarosirressecáveis

2020

Estudos em andamento

Estudo Droga Linha de tto Fase Tumores Resultados

NCT02379520 Células-T específicascontra HPV +/-Fludarabina +

Ciclofosfamida + Nivolumabe

1ª I Tumores relacionadosao HPV

2019/2033

NCT03427411 M7824 1ª II Pênis 2020/2021

NCT03418480 HARE-40 (VancinaRNA anti-CD4 HPV)

1ª I / II CEC relacionado ao HPV 2019/2020

NCT02057913 Vinflunina 1ª II Pênis 2018

Conclusões

• Apesar de metástases à distância serem uma ocorrência raraem câncer de pênis, o prognóstico desses pacientes, assimcomo o de pacientes com doença locorregional inoperávelrefratária a QT neoadjuvante, é péssimo e a morbidade dadoença muito alta.

• Há uma escassez de evidências provenientes de estudosprospectivos e ausência de estudos de fase III queestabeleçam o melhor tratamento sistêmico.

Conclusões

• A quimioterapia citotóxica com esquemas baseados em platina(triplets ou doublets) permanece como padrão de escolha emprimeira linha até então.

• Terapias anti-EGFR e imunoterapia com inibidores de checkpoint,vacinas de DNA e células T específicas se mostram promissoras,mas necessitamos esperar os resultados de estudos prospectivos.

• Uma melhor compreensão da carcinogênse do câncer de pênispode sinalizar novos potenciais alvos terapêuticos. Portanto,investimento em pesquisa, especialmente em regiões de altaincidência dessa neoplasia é extremamente necessário.

antonio m. alencar jr. oncologista clínico...s y m p to m s a n d p r o lo n g s u r v iv a l. i n...

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