esmo preceptorship on advanced non resectable ... · • resume when bilirubin decreases to ≤3.0...
TRANSCRIPT
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
SOLID ORGAN TRANSPLANTATION
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
SOLID ORGAN TRANSPLANTATION
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
SOLID ORGAN TRANSPLANTATION
Increased risk of de-novo cancer development
Engels et al JAMA. 2011
SOLID ORGAN TRANSPLANTATION
Tailor Management
➢ Multidisciplinary Approach
➢ Tumour site/stage
➢ Organ reserves
➢ Type of immunosuppressant
➢ Type of oncological treatment
➢ PS
➢ Goal of Tx and Risks
interactions
SOLID ORGAN TRANSPLANTATION
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
SOLID ORGAN TRANSPLANTATION
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.
H Torres, & M. Davila Nat. Rev. Clin. Oncol. 2012
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
H Torres, & M. Davila Nat. Rev. Clin. Oncol. 2012
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