esmo preceptorship on advanced non resectable ... · • resume when bilirubin decreases to ≤3.0...

ESMO PRECEPTORSHIP ON ADVANCED NON RESECTABLEHEPATOCELLULAR CARCINOMA,BILIARY AND PANCREATIC CANCER

Chemotherapy for difficult cases (jaundice, cirrhosis, lver

transplantation, HBV, HCV infection)

Konstantinos Kamposioras, FRCP, PhD

Department of Medical Oncology

The Christie NHS Foundation Trust

Manchester, UK

Paris, 06/12/2019

DISCLOSURES

No conflicts of interest

OVERVIEW

What to consider when you treat patients with

➢ Jaundice

➢ Liver dysfunction

➢ Sold Organ Transplantation

➢ HBV infection

➢ HCV infection

Fargo et al American Family Physician 2017

JAUNDICE

Differential Diagnosis

JAUNDICE

Differential Diagnosis

Fargo et al American Family Physician 2017

JAUNDICE

Challenges in Oncology

➢ Biliary obstruction vs. liver metastases vs. other factors

➢ Patients with jaundice (usually > 1.5 UNL) are excluded from clinical

trials

➢ Lack of RCTs

➢ Biliary obstruction is an emergency

Krens et al. Lancet Oncol 2019

JAUNDICE

Gong et al. J Gastrointest Oncol 2017

& Chemotherapy

JAUNDICE

& Chemotherapy

A

Lamarca et al. EJC 2015

B

(A) Estimated overall survival in patients with biliary tract obstruction-related jaundice (BTO) and liver metastases-related jaundice (LM). (B) Estimated overall survival in patients with BT) and LM-related jaundice (LM)) according to bilirubin level (<55 versus >=55 μmol/L)

HEPATIC DYSFUNCTION & CHEMOTHERAPY

❖ Be aware of liver toxicity from anti-cancer drugs and have good understanding of

pharmacokinetics (PKs)

❖ Hepatic metabolism and biliary elimination is even narrower in the case of HD

❖ Causes of HD need to be considered (liver metastases, paraneoplastic

hepatotoxicity, pre-existing liver infections, concurrent medication, and

complementary and illicit substances).

❖ The most appropriate measures in cases of HD include avoiding or discontinuing

hepatotoxic drugs and searching for potential clots or extrahepatic cholestasis.

Joerger and Beumer 2013 ESMO Handbbok of Cancer treatments in special clinical situations

HEPATIC DYSFUNCTION

Assessment

1 point 2 points 3 points

Total bilirubin (mg/dL) <2 2–3 >3

Albumin (g/dL) >3·5 2·8–3·5 <2·8

Prothrombin time (sec prolonged)

or INR

<4 or

<1·7

4–6 or

1·7–2·3

>6 or

>2·3

Ascites Absent Slight Moderate

Encephalopathy (grade)† None 1 or 2 3 or 4Grade 0: normal

consciousness,

personality,

neurological

examination, and

electroencephalogram.

Grade 1: restless, sleep

disturbed, irritable or agitated,

tremor, and impaired

handwriting, five cycles per s

(cps) waves.

Grade 2: lethargic, time-

disoriented, inappropriate,

asterixis, ataxia, slow triphasic

waves.

Grade 3: somnolent, stuporous,

place-disoriented, hyperactive

reflexes, rigidity, and slower

waves.

Grade 4: unarousable coma, no

personality or behaviour,

decerebrate, and slow 2–3 cps

delta activity

Child-Pugh score by clinical and lab criteria

Krens et al. Lancet Oncol 2019

Points ClassOne-yearsurvival

Two-yearsurvival

5–6 A 100% 85%

7–9 B 80% 60%

10–15 C 45% 35%

CHEMOTHERAPY DRUGS REQUIRING CAUTION IN LIVER DISEASEDrug PK summary Recommendations in hepatic impairment

Capecitabine • Capecitabine (prodrug) is enzymatically converted to 5-

fluorouracil (5-FU). 5-FU is converted intracellularly to inactive

metabolites by Dihydropyrimidine dehydrogenase (DPD).

• Capecitabine and its metabolites are predominantly excreted

renally (95·5%) and to a lesser extent hepatically 2·6%)

• Stop if bilirubin >3.0 × ULN or ALT/AST >2.5 × ULN

• Resume when bilirubin decreases to ≤3.0 × ULN or ALT/AST

decreases to ≤ 2.5 × ULN

• Drug-induced haemolysis can lead to a solitary rise in bilirubin that

does not require dose alteration/delay

Fluorouracil • A small part of fluourouracil is excreted unchanged in urine

(15%). The remainder is metabolised in the liver. Metabolites are

mainly excreted in urine

• 50% dose if bilirubin >3 × ULN or if ALT/AST >2.5 × ULN

Oxaliplatin • Oxaliplatin is not metabolised. It is highly protein bound (>90%).

Oxaliplatin is mainly excreted in urine (54%) and minimally in

feces (<3%).

• 50% dose if bilirubin >3 × ULN

Irinotecan and active

metabolites

• Irinotecan (prodrug) is converted in the liver to its active

metabolite SN-38. SN-38 is glucuronidated to the inactive

glucuronide metabolite SN-38G.

• Irinotecan and its metabolitesare excreted in urine (11-20%

unchanged) and in feces.

• 50% dose reduction if bilirubin 1.5–3.0 × ULN or ALP 5 × ULN

• Contraindicated if bilirubin >3 × ULN

Gemcitabine • Gemcitabine is converted intracellularly to active metabolites.

Gemcitabine is also metabolised by cytidine deaminase in the

liver, kidney, blood and other tissues.

• Gemcitabine and its metabolites are predominantly excreted in

urine (92-98%, 10% unchanged)

• 80% dose if bilirubin ≥1.5 × ULN

• Limited data on bilirubin >5 × ULN, but consider 50% dose reduction

and monitor closely

Modified by Krens et al. Lancet Oncol 2019 & courtesy slide from R Jones

HEPATIC DYSFUNCTION & CHEMOTHERAPY

❖ The FDA recommends an HD study if hepatic metabolism and/or excretion

accounts for a substantial proportion (>20% of the absorbed drug) of the

elimination of a parent drug or active metabolite.

❖ If the drug has a narrow therapeutic range or if the metabolism of the drug is

unknown, a study is also recommended.

❖ Even though there is a clear emphasis on PK measures to explain differences in

tolerability across HD categories, there may not always be such an HD–PK

correlation.

SOLID ORGAN TRANSPLANTATION

1. Increased risk of de-novo cancer development

2. Tailor Management


Increased risk of de-novo cancer development

10 656 new cases of cancer / 175 732 SOT recipients US

Incidence:1375 cancers per 100 000 person-years

Causes:

- Immunosuppression and activation of oncogenic infectious agents

- Immunosuppressants (e.g. ciclosporin) per se are carcinogenic

- Genetic predisposition

- Increasing age

- Pre-existing conditions e.g. smoking- related diseases and primary sclerosing

cholangitis


Cancer Site Standardized Incidence

Ratio (95% CI)

p

Lung 1.97 (1.86- 2.08) <0.0001

Prostate 0.92 (0.87- 0.98) 0.009

Kidney 4.65 (4.32 4.99) <0.0001

Colorectal 1.24 (1.15- 1.34) <0.0001

Breast 0.85 (0.77- 0.93) 0.0002

Melanoma 2.38 (2.14- 2.63) <0.0001

Thyroid 2.95 (2.58- 3.34) <0.0001

Urinary bladder 1.52 (1.33- 1.73) <0.0001

Skin (non-melanoma,

non-epithelial)

13.85 (11.92- 16.00) <0.0001

Pancreas 1.46 (1.24- 1.71) <0.0001

Intrahepatic bile

duct

5.76 (4.08- 7.91) <0.0001

Gallbladder 2.00 (1.25- 3.02) 0.005

Other biliary 2.45 (1.74- 3.35) <0.0001

Cancer Type Causative agent Standardized

Incidence

Ratio (95% CI)

p

HCC Hepatitis B,C 11.56 (10.83 - 12.33) <0.0001

Hodgkin’s Lymphoma Epstein-Barr virus

(EBV)

3.58 (2.86 - 4.43) <0.0001

Non-Hodgkins’

lymphoma

EBV 7.54 (7.17-7.93)

Kaposi’s sarcoma Human Herpes Virus 8 61.46 (50.95 - 73.49) <0.0001

Gastric Cancer Helicobacter pylori 1.67 (1.42 - 1.96) <0.0001

Nasopharyngeal

cancer

EBV 0.96 (0.42 - 1.90) 1.00

Oropharyngeal

carcinoma

(Human papilloma

virus) HPV

2.01 (1.64 - 2.43) <0.0001

Anal cancer HPV 5.84 (4.70 - 7.18) <0.0001

Vulvar cancer HPV 7.60 (5.77 - 9.83) <0.0001

Cervical cancer HPV 1.03 (0.75 - 1.38) 0.88

Vaginal cancer HPV 2.35 (0.94 - 4.84) 0.07

Penile cancer HPV 4.13 (2.59 - 6.26) <0.0001


Increased risk of de-novo cancer development

Engels et al JAMA. 2011


Tailor Management

➢ Multidisciplinary Approach

➢ Tumour site/stage

➢ Organ reserves

➢ Type of immunosuppressant

➢ Type of oncological treatment

➢ PS

➢ Goal of Tx and Risks

interactions


Immunosuppressant Interaction Outcome Cancer agent

Azathioprine Increased sensitivity to UVA

Increased skin toxicity Radiotherapy

Ciclosporin Inhibits CYP450 3A4 metabolism

Reduced metabolism – increased toxicity risk

Methotrexate, taxanes, platinum drugs, anthracyclines, etoposide, vinca alkaloids, mTOR inhibitors (e.g. tacrolimus, everolimus)

Inhibits P-glycoprotein efflux transporter

Reduced clearance – increased toxicity risk

Taxanes, topoisomerase II inhibitors (etoposide and tenoposide), anthracyclines, mitoxantrone, topoisomerase I inhibitors (topotecan and irinotecan), vinca alkaloids

Concomitant bone marrow suppression

Increased infection risk Most immunosuppressants and cytotoxins, especially tumour necrosis factor (TNF) blockers

Renal Increased nephrotoxicity risk

Cisplatin, melphalan, tacrolimus/ sirolimus

Peripheral nerves Increased neurotoxicity risk

Anthracycline

Methotrexate Lungs Increased pulmonary toxicity

Cisplatin

Liver Increased hepatic toxicity

Retinoic acid

Venugopal et al. 2013 ESMO Handbbok of Cancer treatments in special clinical situations

Tailor Management

Radiotherapy:

❖ Interaction with Immunosuppressnts

❖ Site of transplant organ/careful planning

❖ Toxicity: Dose modification

Chemotherapy:

❖ Primary prophylaxis with G-CSF ?

❖ Anti-infective Prophylactic Agents to be Considered

(acyclovir, co-trimoaxazole,fluconazole)

❖ Toxicity profile of agent used

❖ Dose modifications as indicated


Wong et al. 2019 Transplantation Proceedings

Tailor Management

Immunotherapy

❖ Limited evidence

❖ Risk of graft rejection

❖ Risk of organ failure

❖ Alter the immunossuppressant?

Table 1: Currently Published Case Reports of Patients With Post-Renal Transplant Malignancy Treated With Checkpoint Inhibitors BID, twice daily; DDRT, deceased-donor renal transplant; LDRT, living-donor renal transplant; LRRT, living-related donor renal transplant; LURT, living-unrelated donor renal transplant; NA, not available.

HBV INFECTION

❖ 1 in every 3 individuals worldwide may

have been exposed to hepatitis B virus

(HBV) infection

❖ 350 million people worldwide suffer from

chronic hepatitis B (CHB) infection

❖ 780000 HBV-related deaths/year

❖ HBV reactivation:

• Frequency: 14-72%

• Mortality: 5-52%

Loomba et al. Gastroenterology 2017; Schweitzer et al. Lancet. 2015

HBV REACTIVATION

Definition :

A sudden and rapid increase in HBV-DNA level by at least a 100-fold in patients with previously detectable HBV DNA

or

reappearance of HBV-DNA viremia in individuals who did not have viremia before the initiation of immune-suppressive

or biological modifier therapy or cancer chemotherapy

HBV reactivation: (HBsAg +) In patients who are positive for hepatitis B

surface antigen (HBsAg) in the serum with or without detectable HBV-DNA viremia in the blood

Reverse seroconversion: (HBsAg -)Reappearance of HBsAg and HBV DNA in individuals whoinitially are negative for HBsAg and HBV DNA in the serumbefore immunosuppression and then become positive afterexposure to immunosuppressive therapies

Loomba et al, Gastroenterology 2017

HBV REACTIVATION-

NATURAL HISTORY

H Torres, & M. Davila Nat. Rev. Clin. Oncol. 2012

HBV REACTIVATION-

NATURAL HISTORY

Loomba et al, Gastroenterology 2017

❖ 10% will become jaundiced❖ fatality rate in patients with

icteric hepatitis is up to 40%.

HBV REACTIVATION-RISK FACTORS

Viral factors

◼ HBsAg positivity

◼ HBeAg positivity

◼ High baseline HBV DNA levels (>105 copies/ml)

◼ HBV genotype (B genotype)

◼ Precore–core promoter HBV mutation

◼ Co-infection (HCV,HDV,HIV)

Host factors

◼ Male gender

◼ Young age

◼ High basal serum ALT levels

◼ Absence or decrease of anti-HBs titres during chemotherapy

◼ Type of malignancy (haematological malignancies: lymphoma)

Treatment factors

◼ Chemotherapeutic agents: anthracyclines, cyclophosphamide,

fludarabine, vinca alkaloids

◼ Steroid-containing regimens

◼ Monoclonal antibodies: rituximab, alemtuzumab

◼ Haematopoietic stem cell transplantation (HSCT)

Patient’s HBV profile and treatment are the main risk factor for HBV reactivation.


STEROIDS – REACTIVATION RISK

HBs Ag + HBsAg-/ anti HBc +

High dose(Prednisone>20mg/d), >4w

High Moderate

Medium dose (Prednisone 10-20mg/d), >4w

High Moderate

Low dose(Prednisone <10mg/d), >4w

Moderate Low

High risk: >10%Moderate risk: 1-10%Low risk: <1%

CHEMOTHERAPY – REACTIVATION RISK

HBs Ag + HBsAg-/anti HBc +

Anthracycline(doxorubin/epirubicin) High Moderate

Antimetabolites(Αza, MTX, 6-MP) Low Low

Systemic ChT(Taxanes, V. Alkaloids etc. ) Moderate Moderate

Platinum compounds(cisplatin) High Moderate

Immunotherapies(nivolumab, ipilimumab)

Low*(prophylaxis)

Low*(prophylaxis)

High risk: >10%Moderate risk: 1-10%Low risk: <1%

HBV PROPHYLAXIS

❖ Multidisciplinary approach

❖ Screen for HBsAg and anti-HBc (anti-HBs) before

initiation of therapy (geographic variation, high risk

groups)

❖ Universal HBV screening conducted per current

guidelines is not cost-effective in patients with solid

tumours

❖ HBV screening is cost effective for patients

receiving Rituximab/ lymphoma

•

Terrault et al, Hepatology 2018; EASL Journal of Hepatology 2017; Day, J ClinOncol 2011; Zurawska U, J. Clin. Oncol. 2012

HIGH RISK GROUP• Patients born in regions of intermediate and high

HBV endemicity (HBsAg prevalence >2%); Children of individuals who were born in regions of high endemicity (HBsAg prevalence >8%)South Asia, Africa, Middle East, South America

• IVDU• Haemodialysis• HIV-positive patients • STDs • Homosexual men.

HBV PROPHYLAXIS

❖ Prophylaxis should start 2-4 weeks before

initiation of immunosuppressive Tx.

❖ Prophylaxis should continue for at least 12

months (18 months for rituximab-based

regimens) and discontinued only if the

underlying disease is under remission.

• Liver function tests and HBV DNA should be

tested every 3 to 6 months during prophylaxis

and for at least 12 months after NA withdrawal.

NAs: Nucleoside/Nucleotide analogues: LAM, lamivudine, TBV; telbivudine; ETV, entecavir / TDF, tenofovir disoproxil fumarate; TAF, tenofoviralafenamide; ADF, Adefovir

HBV PROPHYLAXIS FOR HBS AG+ DISEASE


Huang et al JAMA 2014

HBV PROPHYLAXIS FOR HBS AG- / ANTI-HBC + DISEASE

❖ Treat the high risk group patients (esp. on rituximab)

❖ Medium/low risk group patients: pre-emptive therapy

- Monitor HBsAg and/or HBV DNA every 1– 3 months

during and after immunosuppression and starting ETV, TDF or TAF

treatment in case of detectable HBV DNA or HBsAg seroreversion.

❖ Prophylaxis should continue for at least 12 months (18 months for rituximab-

based regimens)

Modified by H Torres, & M. Davila Nat. Rev. Clin. Oncol. 2012

ETV, entecavir ; TDF, tenofovir disoproxil fumarate; TAF, tenofovir alafenamide;

HCV INFECTION

❖ 71 million people globally have chronic

hepatitis C infection

❖ 399000 deaths every year.

❖ Higher prevalence in haematological

cancers (NHL): 9–15% vs. 1.5–3% in the

general population

❖ 7–30% of lymphoma patients infected by

HCV seem to be at risk of experiencing

hepatotoxicity from chemotherapy

❖ Mortality in HCV-positive patients may be as

high as 20–45%, once hepatoxicity

develops

❖ No preventive treatment approved

Gower et al. J Hepatol. 2014

HCV INFECTION

Definition of reactivation: At least a threefold increase in serum ALT level in a patient in whom the tumour does not

affect the liver, who did not receive hepatotoxic drugs and had no other systemic infections besides HCV

Gower et al. J Hepatol. 2014

TAKE HOME MESSAGE

➢ Multidisciplinary management is of paramount importance.

➢ Understand causes of liver dysfunction and modify medication based on current

evidence and drug’s PKs.

➢ Management of cancer in SOT recipients presents a unique challenge to

oncologists.

➢ Increased risks of toxicities and the goals need to be clearly agreed upon.

➢ Treatment guidelines to improve clinical outcome for those SOT patients who

develop malignancies are needed.

TAKE HOME MESSAGE

➢ Reactivation of HBV or HCV can occur after immunosuppression in patients with

cancer who receive chemotherapy

➢ Periodic monitoring of ALT and HBV or HCV viral load levels should be

performed during chemotherapy and after treatment is withdrawn.

➢ In high-risk patients, HBV reactivation can be preventable with the use of NAs.

➢ Management of HCV reactivation is mainly supportive

esmo preceptorship on advanced non resectable ... · • resume when bilirubin decreases to ≤3.0...

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