Centro Oncologico

Tossicità epatica da farmaci antiblastici

Roma, 3 dicembre 2010

Michele BassoOncologia Medica

Liver toxicity in patients with HBV resolved infection(anti HBc+)

Liver damage and risk of liver failure in patientsreceiving neo-adjuvant chemotherapy for colorectal cancer liver metastases

Patients with cancer and chronic HBV infection have an high risk of viral reactivation on

chemotherapy, with two different outcomes:

Acute hepatitis:the spectrum of HBV reactivation ranges

from asymptomatic hepatitis to fatal liver failure.

Disruption in treatment protocols:may worsen the prognosis of cancer

because of delays or withdrawals of chemotherapeutic agents

BackgroundHBV in cancer patients

HBsAg+ Anti-HBc+

Europe China Europe China

Range 5.3-12.230-40%

40% 80%Taiwan

Italy 8.8%° 41.7%°

HBV reactivation 15-40% (Onc) 21-67% (Em) 12-50% (HSCT)

Mortality 20%

Linfomain portatori

0R 2.6 (Cina)-2.8 (USA) in B-NHL

Wang F et al, Cancer 2007; Ulcickas YM et al, Hepatology 2007

• °Marcucci et al ,Haematologica 2006

Prophylactic lamivudine in patients HBsAg+

Prophylactic lamivudine was shown to be effective in 13 studies (216 LAM+ vs. 443 LAM-:HBV reactivation 0-9% LAM+ vs. 25-85% LAM-)

Yeo, Hepatology 2006

Early lamivudine therapy is superior to the delayed one, in patients with HBV reactivation.

Lau, Gastroenterology 2003

(500 pts LAM+ vs.500 pts LAM-): Prophylactic lamivudine is effective in terms of HBV reactivation (9.6% LAM+ vs. 43.8% LAM-), liver-related deaths (0/500 LAM+ vs 20/500 LAM-), cancer therapy discontinuation or cancer-related deaths (39/500 LAM+ vs 47/500 LAM-).

Saab, Hepatology 2007

176 pts HBsAg-/anti-HBc+ :

seroreversion in 21 (12%)

Acute Hepatitis B:

4-30% during chemotherapy

14-50% during or after HSCT

Yeo W, Hepatology 2006

BackgroundRisk of HBV reactivation in patients with

HBsAg-/anti-HBc+ (anti-core)

Chemotherapeutic Agents That Have Been Associated with Development of HBV Reaction

Yeo & Johnson, Hepatology 2006; 43:209

Jan 2003-Dec 2006

All patients diagnosedwith DLBCL were testedfor anti HBc (anti HBS -)

Metastatic CRC

The Shift of the Paradigm

FromPalliation

ToCureto

The Aim is

TO CURE

Overall survival in advanced CRCin 2007: were might we be in 2017?

0 1 2 3 4

100

50

0

% s

urvi

ving

Years after diagnosis of colorectal metastases

2007 chemotherapy aloneMedian survival >24 months5-yr survival 9%

2007 overall with addition of surgeryMedian survival ~36 months5 year survival 20 %

20%

Poston GJ. EJSO 2005; 31: 325-30

9%1927 1997

3%

2007

?50%2017

Karoui, Nordlinger et al. Annals Surgery 2006

Postoperative morbidity was correlated with no. cyclesbut not with the type of chemotherapy

Extended chemotherapy

Resection rate of metastasesand tumour response

Studies with all patientswith metastatic CRC (solid line) R=0.74, P<0.001

Phase III studiesin metastatic CRC(dashed line)R=0.67, P=0.024

Studies with selected patientsLiver metastases only, no extra-hepatic diseaseR=0.96, P=0.002

Folprecth et al, Ann Oncol. 2005 Aug;16(8):1311-9.

Response rate,9,8,7,6,5,4,3

Res

ectio

n ra

te

,6 -

,5 -

,4 -

,3 -

,2 -

,1 -

0,0 -

Extended chemotherapy

Kishi et al; Ann Surg Oncol 2010

Resectable liver mtsCT vs Surg alone

CT + S (n=45) S alone (n=22) pSinusoidal dilation 22 (49%) 3 (14%) 0.05Steatosis

<20%20-50%>50%

25 (56%)6 (13%)9 (20%)

10 (22%)

14 (64%)6 (27%)5 (23%)3 (14%)

NS

FibrosisF0-F1F2

25 (56%)19 (42%)

15 (68%)7 (32%)

NS

Karoui, Nordlinger et al. Annals Surgery 2006

Postoperative morbidity was correlated with no. cyclesbut not with the type of chemotherapy

Appropriateness of medical treatments

BenefitsRisks

Primary ChemotherapyNeoadjuvant Chemoterapy

Adjuvant Chemotherapy

Appropriateness of medicaltreatments

DownsizingResectability

Survival

Pathologic damageSurgical risk

Late complications

Primary ChemotherapyNeoadjuvant Chemoterapy

Adjuvant Chemotherapy

A difficult balance

Risk Assessment Liver after CT

« congestive liver? » « blue liver? » « chemo’s liver? » « steatosis? » « cirrhosis? »

normal liver

Liver after chemotherapy

Risk assessment: Pathology

Vauthey et al. JCO 2006

Steatohepatitis (Irinotecan)

Sinusoidal distention and obstruction

(oxaliplatin)

Normal liver Liver after chemotherapy

Centrilobular vein

sinusoïds

Centrilobular vein

Centrilobularvein

sinusoïds

Similar to VOD, more appropriately named “Sinusoïdal Obstruction Syndrome (SOS)”

(De Leve et al. 2002)

Rubbia-Brandt L. et al Ann Oncol 2004

The integrity of the sinusoidal wall is interrupted

Liver after chemotherapyNormal liver

Type of Chemotherapy

No. Patients

Pathologic liver histology

n (%) No chemotherapy 66 0 (0)With chemotherapy 87 44 (51)5-FU 27 6 (22)5-FU / Irinotecan 17 4 (23)5-FU / Oxaliplatin 27 20 (74)5-FU / Oxali + Irinotecan 16 14 (88)

Rubbia-Brandt, Ann Oncol 2004

Risk assessment CT prior to resection

• 44/87 pts (51%) who received CT exhibited centrolobular lesions

Incidence of steatohepatitis with modern CT regimens

Treatment N Evidence of fatty changes

5-FU/FA 25 6 (24%)

Iri/5-FU/FA 25 12 (48%)Oxali/5-FU/FA 25 7 (28%)

Leonard et al ASCO 2005

Type of Chemotherapy

No.pts

Sinusoidaldilation

n=22

Steatosis>30%n=36

Steatohepatitis

n=34

No CT 158 3 (2%) 9% 4%5-FU 63 0 17% 5%

5-FU / IRI 94 4 (4%) 11% 20%

5-FU / Oxa 79 15 (19%) 4% 6%

90-day mortality 1% 1% 15%

Vauthey et al. JCO 2006

Hepatoxicity of preoperative CT

Relation between type of liver damage and clinical outcome

• Steatosis associated with higher infection rate (Kooby et al. 2003)

• Steatohepatitis associated with higher mortality rate due to liver failure after surgery (Vauthey et al.,2006)

• Vascular injury associated with higher rate of operative bleeding and transfusion requirement (Vauthey et al. 2006; Adam et al. 2005)

Difficult timing of duration of primary chemotherapy

«the Dream of the Oncologist is theNightmare of the Surgeon»

Complete response ofCRLM after chemotherapy doesn’t mean cure

CONCLUSION

Neadjuvant chemotherapy can increase the possibility of cure for patients withliver metastases of colorectal cancer

Response rate is strictly related with resection rate

Extended chemotherapy does not increase response but increase the risk ofmorbidity and mortality after surgery (risk of liver failure).

A multidisciplinary approach (oncologist, surgeon, pathologist) is warranted