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Tratamento adjuvante em Câncer do Trato Biliar

Lucas V. dos Santos

Oncologista Clínico

BP – A Beneficência Portuguesa de São Paulo

Declaração de Conflito de Interesses

Eu declaro não possuir conflito de interesses em relação a esta apresentação.

Tratamento adjuvante em Câncer do Trato Biliar

• O Câncer do trato biliar (CTB) é relativamente incomum, e se associa a prognóstico reservado [1]

• Sobrevida em 1 ano de 22%

• Sobrevida em 5 anos de 9%

• O tratamento cirúrgico pode curar alguns pacientes, com sobrevida em 1 ano atingindo 15% dos casos [2]

• Porém apenas 20% dos casos pode ser operados

• Há controvérsias se o tratamento adjuvante pode ser útil na melhora dos resultados dos pacientes com CTB operados[3]

1. Khan SA, et al. J Hepatol. 2012;56:848-854. 2. Office for National

Statistics. 1999. https://www.springer.com/gp/book/9780116210319. 3.

Primrose JN , et al. ASCO 2017. Abstract 4006.

Tratamento adjuvante em Câncer do Trato Biliar

Nakeeb A, Pitt HA, Sohn TA, et al. Ann Surg. 1996;224(4):463; Fong Y, Blumgart LH, Lin E, et al. Br J Surg.

1996;83(12):1712. DeOliveira ML, Cunningham SC, Cameron JL, et al Ann Surg. 2007;245(5):755. Nakayama F, Miyazaki

K, Nagafuchi K. World J Surg. 1988;12(1):60; Bortolasi L, Burgart LJ, Tsiotos GG, et al. Dig Surg. 2000;17(1):36;

Murakami Y, Uemura K, Hayashidani Y, et al. World J Surg. 2007;31(2):337; Yoshida T, Matsumoto T, Sasaki A, et al.

Arch Surg. 2002;137(1):69; Lieser MJ, Barry MK, Rowland C,et al. J Hepatobiliary Pancreat Surg. 1998;5(1):41; Valverde

A, Bonhomme N, Farges O, et al. J Hepatobiliary Pancreat Surg. 1999;6(2):122. Cameron JL, Pitt HA, Zinner MJ et al.

Am J Surg. 1990;159(1):91; , Fortner JG, Vitelli CE, Maclean BJ Arch Surg. 1989;124(11):1275

Sobrevida em 5 anos

Intra-hepático Extra-hepático

Hilar

LN(-) e/ou R0 44-63% 20-50% 30-62%

LN(+) e/ou R1 11-20% <20% <20%**Contaminação por câncer peri-ampular, de melhor prognóstico

Tratamento adjuvante em Câncer do Trato Biliar

Horgan AM et al. J Clin Oncol. 2012 Jun 1;30(16):1934-40

20 estudos, 6712 pacientes

Tratamento adjuvante em Câncer do Trato Biliar

Horgan AM et al. J Clin Oncol. 2012 Jun 1;30(16):1934-40

20 estudos, 6712 pacientes

Primrose JN , et al. ASCO 2017. Abstract 4006.

BILCAP: Study Design• Open-label, randomized, controlled phase III trial

Primrose JN , et al. ASCO 2017. Abstract 4006.

Primary endpoint: OS

Secondary endpoints: RFS, toxicity, QoL, health economics

Capecitabine 1250 mg/m2 BID

Days 1-14 of 21-day cycle for 8 cycles

(n = 223)

Observation

(n = 224)

Histologically confirmed

biliary tract cancer*; radical

and macroscopically

complete surgery; ECOG

PS ≤ 2; no previous

chemotherapy or

radiotherapy for biliary

tract cancer

(N = 447)

Primary

analysis after

minimum 2-yr

follow-up

Resection

*Included: intrahepatic CC, hilar CC, muscle-invasive gallbladder cancer, and lower common bile duct CC

Excluded: pancreatic, ampullary, mucosal (T1a) gallbladder cancers; incomplete recovery from prior surgery

Stratified by surgical center,

R0 vs R1 resection, ECOG PS

BILCAP: Sample Size Calculation

Primrose JN , et al. ASCO 2017. Abstract 4006.

BILCAP: Flowchart

Primrose JN , et al. ASCO 2017. Abstract 4006.

BILCAP: Baseline CharacteristicsCharacteristic, % Capecitabine Arm

(n = 223)Observation Arm

(n = 224)

Male 50 50

Median age, yrs (IQR) 62 (55-68) 64 (55-69)

Tumor site Intrahepatic CC Hilar CC Muscle-invasive gall bladder carcinoma Lower common bile duct CC

19291734

18281836

Resection status, R0/R1 62/38 63/38

ECOG PS, 0/1/2 45/52/3 45/52/3

Tumor size, mm (IQR) 25 (19-45) 25 (20-44)

Lymph node status, N0/N1/not evaluable 45/48/7 48/46/6

Primrose JN , et al. ASCO 2017. Abstract 4006.

BILCAP: Treatment Compliance• Median capecitabine dose: 1250 mg/m2 BID (IQR: 1061-1250 mg/m2)

01 50 100 150 200 223

2

4

6

8

Cycle

s o

f C

ap

ecit

ab

ine

(n

)

Pts (n)

122 (55%) pts in the capecitabine

arm received 8 cycles

10 (< 5%) pts

received 0 cycles

Primrose JN , et al. ASCO 2017. Abstract 4006.

BILCAP: OSITT Population

Treatment Median OS, Mos (95% CI)

HR (95% CI)

Capecitabine 51.1 (34.6-59.1) 0.81 (0.63-1.04)P = .097Observation 36.4 (29.7-44.5)

Sensitivity analyses adjusting for further prognostic factors (gender, nodal status, disease grade) HR 0.70 (95% CI: 0.55-0.91; P = .007)

Treatment Median OS, Mos (95% CI)

HR (95% CI)

Capecitabine 52.7 (40.3-NR) 0.75 (0.58-0.97)P = .028Observation 36.1 (29.6-44.2)

Per Protocol Population

> 80% pts followed-up for 36 mos

0

25

50

75

100

Pts

Ali

ve (

%)

0 12 24 36 48 60Mos Since Randomization

0

25

50

75

100

Pts

Ali

ve (

%)

0 12 24 36 48 60Mos Since Randomization

Primrose JN , et al. ASCO 2017. Abstract 4006.

Primrose JN , et al. ASCO 2017. Abstract 4006.

Primrose JN , et al. ASCO 2017. Abstract 4006.

BILCAP: OS Subgroup Analysis

Primrose JN , et al. ASCO 2017. Abstract 4006.

Primrose JN , et al. ASCO 2017. Abstract 4006.

BILCAP: Relapse-Free Survival

Treatment Median RFS, Mos (95% CI)

HR (95% CI)

Capecitabine 24.6 (18.9-36.7) 0.76 (0.58-0.99)P = .039Observation 17.6 (12.8-27.6)

Treatment Median RFS, Mos (95% CI)

HR (95% CI)

Capecitabine 25.9 (19.8-46.3) 0.71 (0.54-0.92)P = .011Observation 17.6 (12.0-23.8)

0

25

50

75

100

Pts

Recu

rren

ce F

ree (

%)

0 12 24 36 48 60Mos Since Randomization

0

25

50

75

100

0 12 24 36 48 60

ITT Population Per Protocol Population

Pts

Recu

rren

ce F

ree (

%)

Mos Since Randomization

Primrose JN , et al. ASCO 2017. Abstract 4006.

BILCAP: Safety and QoL• Safety population included 213 patients who received capecitabine Adverse Event, n (%) All Grades Grades

1/2Grades

3/4

Fatigue 175 (82) 159 (75) 16 (8)

Plantar-palmar erythema 174 (82) 130 (61) 44 (21)

Diarrhea 137 (64) 121 (57) 16 (8)

Nausea 108 (51) 106 (50) 2 (1)

Mucositis/stomatitis 96 (45) 94 (44) 2 (1)

Vomiting 50 (24) 49 (23) 1 (0.5)

Neutropenia 49 (23) 45 (21) 4 (2)

Hyperbilirubinemia 45 (21) 42 (20) 3 (1)

Thrombocytopenia 26 (12) 25 (12) 1 (0.5)

Alopecia 20 (9) 20 (9) 0 (0)

SAE n (%)

All 93 (44)

Pts with ≥ 1 SAE 69 (32)

SAEs by treatment arm n

Capecitabine arm SAE

47 (64 events)30 (33 events)

Observation arm SAE resulting in death

22 (29 events)3

QoL was not reduced in

capecitabine arm compared with

placebo

Primrose JN , et al. ASCO 2017. Abstract 4006.

BILCAP: QoL

Primrose JN , et al. ASCO 2017. Abstract 4006.

BILCAP: Author’s Conclusions

• Adjuvant capecitabine associated with improved OS in pts with resected biliary tract cancer

• Authors suggest capecitabine should become standard of care in this setting

• Capecitabine treatment produced modest toxicity

• QoL in capecitabine arm comparable to observation arm

• Authors recommend using capecitabine control arm in future adjuvant trials in biliary tract cancer

Primrose JN , et al. ASCO 2017. Abstract 4006.

BILCAP: Minhas Conclusões

• Adjuvant capecitabine associated with does not improved OS in pts with resected biliary tract cancer

• I suggest capecitabine should NOT become standard of care in this setting

• Capecitabine treatment produced IMPORTANT toxicity

• QoL in capecitabine arm comparable to observation arm

• Authors recommend using capecitabine control arm in future adjuvant trials in biliary tract cancer

Primrose JN , et al. ASCO 2017. Abstract 4006.

"There are three kinds of lies: lies, damned lies, and statistics."

Benjamin Disraeli, 1804-1881