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Acute Fatal Liver Toxicity under Erlotinib

June 2010
Case Reports in Oncology 3(2):182-188

June 2010
3(2):182-188

DOI:10.1159/000315366

Source
PubMed

License
CC BY-NC 4.0

Authors:

Sabina Schacher

Kantonsspital Winterthur

Miklos Pless

Kantonsspital Winterthur

We describe the case of a never-smoker who received second-line erlotinib as a treatment for his non-small cell lung cancer. Within one month, acute hepatic failure developed as well as a thrombotic-thrombocytopenic microangiopathy, with fatal outcome. In patients with non-small cell lung cancer, hepatic toxicity of erlotinib is a rare but severe complication; so far three fatal cases have been reported. Patients' liver function should be assessed before starting erlotinib and special care is recommended if pretreatment bilirubin is elevated.

. Summary of published cases of erlotinib-induced acute liver toxicity

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a 4 days before the initiation of therapy. b 24th day of erlotinib treatment.

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Evolution of laboratory parameters.

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Available via license: CC BY-NC 4.0

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Case Rep Oncol 2010;3:182–188

DOI: 10.1159/000315366

ISSN 1662–6575

www.karger.com/cro

Sabina Schacher-Kaufmann Medical Oncology, Cantonal Hospital, Brauerstrasse 15

CH–8401 Winterthur (Switzerland)

Tel. +41 52 266 25 52, Fax +41 52 266 45 20, E-Mail sabina.schacher @ ksw.ch

182

Acute Fatal Liver Toxicity under

Erlotinib

Sabina Schacher-Kaufmann Miklos Pless

Division of Medical Oncology, Department of Internal Medicine, Winterthur,

Switzerland

Key Words

Erlotinib · Non-small cell lung cancer · NSCLC · Liver toxicity · Hepatopathy

Abstract

We describe the case of a never-smoker who received second-line erlotinib as a

treatment for his non-small cell lung cancer. Within one month, acute hepatic failure

developed as well as a thrombotic-thrombocytopenic microangiopathy, with fatal

outcome. In patients with non-small cell lung cancer, hepatic toxicity of erlotinib is a rare

but severe complication; so far three fatal cases have been reported. Patients’ liver

function should be assessed before starting erlotinib and special care is recommended if

pretreatment bilirubin is elevated.

Erlotinib (Tarceva쏐) is an oral, reversible epidermal growth factor receptor (EGFR)

tyrosine-kinase inhibitor. The drug was approved by the FDA in 2004 for treatment of

patients with locally advanced or metastasized non-small cell lung cancer (NSCLC) and in

2005, in combination with gemcitabine, for treatment of patients with pancreatic cancer,

both on the basis of randomized phase III studies [1, 2]. In a clinical phase I study, a daily

dose of 150 mg proved to be the maximum tolerated dose, the dose-limiting toxicities

being diarrhea, skin reactions und fatigue [3]. Serious liver dysfunction was rarely found

in phase III studies [1, 2, 4]. However, in the last two years there have been a number of

case reports on acute, severe liver toxicity with erlotinib [5, 6], a few with a fatal outcome

[7, 8]. We are describing the case of a patient with metastasized NSCLC, who developed

acute liver failure with a fatal coagulation complication under erlotinib treatment.

Case Report

A 53-year-old never-smoker was diagnosed with a deep leg vein thrombosis and one month later

with an adenocarcinoma of the lung (negative for EGFR mutation and EML4-ALK translocation), stage

IVB with a malignant pleural effusion. A nonproductive cough had been the only symptom.

Anticoagulation with low molecular weight heparin (LMWH) was started, overlapping with

phenprocoumon. A palliative chemotherapy with 4 cycles of cisplatin/vinorelbine was given, which

Case Rep Oncol 2010;3:182–188

DOI: 10.1159/000315366

ISSN 1662–6575

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183

resulted in a partial remission. Ten weeks later, the patient complained of a deterioration of his

performance status, and pulmonary and pleural tumor progression as well as the suspicion of a new

liver metastasis were diagnosed (fig. 1a). Laboratory results showed an anemia of 115 g/l, otherwise

normal hematology; ASAT/ALAT, alkaline phosphatase and creatinine were within the normal range,

bilirubin 19 μmol/l (<17), LDH 587 U/l (<450). A second-line therapy with a daily dose of 150 mg

erlotinib was started.

On the ninth day of therapy, the patient was bedridden, complained of lack of appetite and reported

being unable to walk. Clinically, he was in a bad general condition with a performance status 3. A

discrete folliculitis of the thoracic aperture and a relapse of the leg vein thrombosis were found, but

there was no evidence of neurological pathologies. Phenprocoumon was stopped and LMWH was

resumed in a therapeutic dose. The laboratory results showed constant anemia, discrete signs of

cholestasis, further elevated lactate dehydrogenase (LDH) and minor renal insufficiency. The

transaminases were not measured. We interpreted the general condition to be a consequence of the

tumor and the recurring deep vein thrombosis. Erlotinib was continued.

On the 17th day of therapy, the patient was hospitalized due to further deterioration of his general

condition, with a fever of 39.6°C, vomiting and upper abdominal pain. A slight anemia of 110 g/l was

found, Lc were 11.7 × 109/l, Tc 291 × 109/l, INR 4.55, bilirubin 20 μmol/l, alkaline phosphatase 475 U/l,

LDH 1,856 U/l, ASAT 1,011 U/l, ALAT 2,050 U/l, creatinine 120 μmol/l, CRP 132 mg/l (fig. 2). Blood

cultures and serologies for hepatitis A, B and C were negative.

The abdominal ultrasound showed a severely inhomogeneous liver, as well as progression of the liver

metastasis in segment II and thickening of the gall bladder. The differential diagnosis at this point was

acute hepatitis or cholangitis and an antibiotic therapy with ciprofloxacin und metronidazole was

initiated. Erlotinib was stopped since drug-induced hepatitis could not be excluded.

On day 24 after starting erlotinib, the patient complained of excruciating pain in his right upper

abdomen. Another rise in temperature was documented. The lab results showed an anemia of Hb 118

g/l, Lc 21.9 × 109/l, Tc 134 × 109/l, some fragmentocytes, INR 1.68, fibrinogen 1.7 g/l (2–4), factor II 49%

(70–120), factor V 64% (70–140), bilirubin 80 μmol/l, alkaline phosphatase 814 U/l, LDH 5,841 U/l,

ASAT 3,511 U/l, ALAT 884 U/l, creatinine 100 μmol/l, CRP 149mg/l (fig. 2). A CT scan revealed a

pulmonary and pleural tumor progression, edema of the gallbladder and also fresh hypodense areas in

the liver and hypodensities of the kidney and the upper pole of the spleen, which were interpreted as

necrosis (fig. 1b). Sonographically, the portal vein was dilated. The patient was put on hydration, and

allopurinol and vitamin K were given; LMWH was continued.

On day 30, acral necrosis of the toes was found. All peripheral pulses were palpable. The lab results

showed constant anemia with elevated reticuloytes 276 × 109/l (35–105), a further drop in factor V,

antithrombin III 23% (75–120), haptoglobin 0.2 g/l (0.6–3.6), a negative result in the PF4 antibody and

the direct Coombs test, an increase in bilirubin with unchanged alkaline phosphatase and declining

transaminases (fig. 2). The diagnosis of thrombotic microangiopathy with compensated hemolysis was

made and an antithrombin III substitution with fresh frozen plasma was started.

A heparin-induced thrombocytopenia was ruled out because of the lack of PF4 antibodies. After

unstoppable deterioration of his general condition, the patient died three days later.

Consent

The patient has unfortunately passed away and could not give his informed consent. There is no

immediate family to be contacted. All patient data are completely anonymized.

Discussion

This unfortunate patient died of acute liver failure, most likely due to erlotinib. First,

there was a rapidly progressive hepatopathy, which led to hospitalization 17 days after

initiating erlotinib. The patient presented a clinical picture of acute hepatitis. A second

row of events began on the seventh day of hospitalization with massive liver necrosis and

signs of a blood coagulation disorder.

Case Rep Oncol 2010;3:182–188

DOI: 10.1159/000315366

ISSN 1662–6575

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We attribute the acute hepatitis to the medication with erlotinib. The drug is

metabolized hepatically through the enzymes CYP3A4 und CYP1A2 of cytochrome P450.

Drug interaction can therefore affect the metabolism of erlotinib and possibly increase the

toxicity. During the first week of therapy, the only other comedication the patient took

was phenprocoumon. Phenprocoumon is partially inactivated by CYP3A4. When giving

erlotinib and coumarines simultaneously, an increase in INR but not in erlotinib

clearance has been described [12]. Consequently, we do not think that the combination

was the cause of the described toxicity.

The time course of the liver toxicity correlates with other documented case reports

(table 1). Presently it is unclear why exclusively cases with lung cancer took a fatal course.

Perhaps this is merely a quantitative problem; erlotinib is used in many more patients

with NSCLC than in patients with other cancers. Alternatively, the dose of erlotinib might

be relevant. In patients with pancreatic cancer, erlotinib was dosed mostly at 100 mg/day

in combination with gemcitabine [2]. In this study, the grade 3/4 liver toxicities were

comparable between gemcitabine alone and the combination of erlotinib and gemcitabine

(grade 3 elevation of ASAT/ALAT 18 vs. 23%, of bilirubin 10% in both groups), and were

likely to be tumor-related. In phase III studies in NSCLC patients, no [4] or just moderate

liver enzyme increases (4% grade 2 vs. 0% [1]) were found. However, only patients

without [1], or with liver enzyme increase grade ≤1 [4] were included in these trials. This

is also the case for the phase I study [3], in which a therapy-associated bilirubinemia grade

1 is described in 8/40 patients, but transaminases did not increase. More recent

pharmacokinetic data of patients with preexisting liver function problems are not

conclusive [9, 10]. The most significant factor to impair drug clearance seems to be

increased bilirubin [9]. Miller et al. [10] come to the conclusion that patients with

pretherapeutic liver dysfunction should be started on a reduced dose of erlotinib of 75

mg/day.

It is not known why a few patients react to erlotinib with such massive toxicity.

Pharmacogenomical studies have shown polymorphisms on the CYP3A4- as well as on

the CYP3A5-gene and have investigated their effect on the pharmacokinetics of erlotinib

[11]. No clear correlation was found, not even on commonly observed toxicities such as

exanthema or diarrhea. Further pharmacogenetic research is warranted.

Recently published cases of acute liver toxicity under erlotinib have caused OSI

Pharmaceuticals and Genentech to inform the physicians of this data in a ‘Dear Doctor’

letter in September 2008 and to amend the drug information accordingly. References to

‘hepatotoxicity’ and ‘patients with hepatic impairment’ now appear in the chapter

‘warnings’ [12]. Special caution is indicated in patients with pretreatment elevations of

bilirubin, but no dose reduction of erlotinib is suggested.

This patient’s course was complicated by a blood coagulation disorder. On the seventh

day in the hospital, at the time of the massive liver necrosis, first symptoms of a

microangiopathic and disseminated coagulopathy occurred: fragmentocytes,

thrombocytopenia, diminished fibrogen as well as factor V. It can be assumed that the

cause of the coagulation disorder was multifactorial, the extensive liver cell necrosis being

an important contributing factor. Considering the patient’s history with a deep vein

thrombosis as the first symptom of his malignancy, there was probably a tumor-

associated coagulopathy involved as well, which is a common paraneoplastic symptom,

frequently seen in adenocarcinomas of the lung [13, 14]. A direct link between erlotinib

monotherapy and coagulopathy seems less likely; there are no reports in the literature to

support such a hypothesis. Two cases of patients with pancreatic cancer and treatment

with erlotinib and gemcitabine who developed microangiopathic hemolytic anemia with

Case Rep Oncol 2010;3:182–188

DOI: 10.1159/000315366

ISSN 1662–6575

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185

thrombocytopenia have been described; this complication was, however, most likely

caused by gemcitabine [15]. Thus, we believe that the coagulopathy was not a direct

consequence of erlotinib but rather an indirect effect of erlotinib-induced acute hepatitis.

We are describing the third case of a fatal liver toxicity in a patient with

adenocarcinoma of the lung under treatment with erlotinib. It is estimated that each year

more than 100’000 patients receive erlotinib. Therefore, fortunately, this seems to be a

very rare complication [16]. However, because of its severity, we think it is important that

prescribing physicians know about this potential danger. We suggest monitoring liver

function tests after initiating erlotinib, and stopping treatment if there is a suspicion of

drug-induced hepatitis. Patients with preexisting elevations of bilirubin should be

monitored with special care and in these patients reducing the dose of erlotinib could be

considered [9, 10].

Table 1. Summary of published cases of erlotinib-induced acute liver toxicity

Diagnosis Age/

sex

Dose of

erlotinib

Concomitant

drug

Known liver

function

abnormality

Time to first

elevation

LFT

Outcome Time to

recover

LFT

Liu et al., 2007

[7]

lung cancer 67/F 150

100 by

reinduction

none none day 14

day 10 after

reinduction

fatal

Ramanarayanan

and Scarpace,

2007 [5]

pancreatic

cancer

70/M 100 gemcitabine none day 14 recovered 6 weeks

Saif, 2008 [6] pancreatic

cancer

52/M 100 gemcitabine none week 7 recovered 8 weeks

Pellegrinotti et al.,

2009 [8]

lung cancer 77/M 100 oral antidiabetic

omeprazole

prednisone

furosemide

none day 12 fatal

Present case lung cancer 53/M 150 phenpro-

coumon

liver

metastasis

day 10 fatal

LFT = Liver function tests.

Case Rep Oncol 2010;3:182–188

DOI: 10.1159/000315366

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Fig. 1. a 4 days before the initiation of therapy. b 24th day of erlotinib treatment.

Case Rep Oncol 2010;3:182–188

DOI: 10.1159/000315366

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Fig. 2. Evolution of laboratory parameters.

Case Rep Oncol 2010;3:182–188

DOI: 10.1159/000315366

ISSN 1662–6575

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References

1 Shepherd FA, Rodrigues Pereira J, Ciuleanu T, et al: Erlotinib in previously

treated non-small lung cancer. N Engl J Med 2005;353:123–132.

2 Moore MJ, Goldstein D, Hamm J, et al: Erlotinib plus gemcitabine compared with

gemcitabine alone in patients with advanced pancreatic cancer: a phase III trial of

the National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol

2007;25:1960–1966.

3 Hidalgo M, Siu LL, Nemunaitis J, Rizzo J, Hammond LA, Takimoto C, et al: Phase

I and pharmacologic study of OSI-774, an epidermal growth factor receptor

tyrosine kinase inhibitor, in patients with advanced solid malignancies. J Clin

Oncol 2001;s19:3267–3279.

4 Herbst RS, Prager D, Hermann R, Fehrenbacher L, Johnson BE, Sandler A, et al:

TRIBUTE: a phase III trial of erlotinib hydrochlorid (OSI-774) combined with

carboplatin and paclitaxel chemotherapy in advanced non-small-cell lung cancer.

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5 Ramanarayanan J, Scarpace SL: Acute drug induced hepatitis due to erlotinib. J

Pancreas 2007;8:39–43.

6 Saif MW: Erlotinib-induced acute hepatitis in a patient with pancreatic cancer.

Clin Adv Hematol Oncol 2008;6:191–199.

7 Liu W, Markauer FL, Qamar AA, Jänne PA, Odze RD: Fulminant hepatic failure

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8 Pellegrinotti M, Fimognari FL, Franco A, Repetto L, Pastorelli R: Erlotinib-

induced hepatitis complicated by fatal lactic acidosis in an elderly man with lung

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9 Lu JF, Eppler SM, Wolf J, Hamilton M, Rakhit A, Bruno R, Lum BL: Clinical

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10 Miller A, Murry D, Owzar K, Hollis D, Lewis L, Kindler H, Marshall J, et al: Phase

I and pharmacokinetic study of erlotinib for solid tumors in patients with hepatic

or renal dysfunction: CALGB 60101. J Clin Oncol 2007;25:3055–3060.

11 Rudin Ch, Liu W, Desai A, Karrison T, Jiang X, et al: Pharmacogenomic and

pharmacokinetic determinants of erlotinib toxicity. J Clin Oncol 2007;26:1119–

1127.

12 Genentech, Inc (2008)

http://www.gene.com/gene/products/information/pdf/tarceva-pr (accessed 1

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13 Tagalakis V, Levi D, Agulnik JS, Cohen V, Kasymjanova G, Small D: High risk of

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14 Blom JW, Osanto S, Rosendaal FR: The risk of a venous thrombotic event in lung

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15 Izzedine H, Isnard-Bagnis C, Launay-Vacher V, Mercadal L, Tostivint I, et al:

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16 Roche Pharmaceuticals, annual report 2008;39.

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Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) remain the frontline standard of care for patients with EGFR-mutant non-small cell lung cancer. An updated toxicity profile of EGFR-TKIs proves valuable in guiding clinical decision making. This study comprehensively assessed the risk of EGFR-TKI-related adverse events (AEs) involving different systems/organs. We systematically searched PubMed, Embase, Web of Science, and Cochrane library for phase III randomized controlled trials comparing EGFR-TKI monotherapy with placebo or chemotherapy in patients with non-small cell lung cancer. The odds ratio (OR) of all-grade and high-grade adverse events (AEs) including dermatologic, gastrointestinal, hematologic, hepatic, and respiratory events was pooled for a meta-analysis. Subgroup analyses based on the control arm (placebo or chemotherapy) and individual EGFR-TKIs (erlotinib, gefitinib, afatinib, dacomitinib, and osimertinib) were conducted. Thirty-four randomized controlled trials comprising 15,887 patients were included. The pooled OR showed EGFR-TKIs were associated with a significantly increased risk of all-grade dermatologic AEs including paronychia, pruritus, rash, skin exfoliation, and skin fissures, gastrointestinal AEs including abdominal pain, diarrhea, dyspepsia, mouth ulceration, and stomatitis, hepatic AEs including elevated alanine aminotransferase and aspartate aminotransferase, and respiratory AEs including epistaxis, interstitial lung disease and rhinorrhea. Furthermore, a significantly increased risk of high-grade rash (OR 7.83, 95% confidence interval [CI] 5.11, 12.00), diarrhea (OR 2.10, 95% CI 1.44, 3.05), elevated alanine aminotransferase (OR 3.93, 95% CI 1.71, 9.03), elevated aspartate aminotransferase (OR 3.22, 95% CI 1.05, 9.92) and interstitial lung disease (OR 2.35, 95% CI 1.38, 4.01) was observed in patients receiving EGFR-TKIs. When stratified by individual EGFR-TKIs, gefitinib showed a significant association with all-grade and high-grade hepatotoxicity and interstitial lung disease. Epidermal growth factor receptor tyrosine kinase inhibitors were associated with a significantly increased risk of various types of AEs. Clinicians should be vigilant about the risks of these EGFR-TKI-related AEs, particularly for severe hepatotoxicity and interstitial lung disease, to facilitate early detection and proper management.

Safety analysis of antineoplastic drugs for lung cancer: a retrospective analysis based on Shaanxi Province in Western China

Article

Mar 2023
EXPERT OPIN DRUG SAF

Background: China has the highest proportion of lung cancer-related deaths. Drug therapy is the main tool of comprehensive anticancer treatment. However, most studies to date have focused on certain types of targets or immunotherapeutic modalities for drug safety; few studies have addressed the factors that influence ADRs for each type of drug in patients with lung cancer, and even fewer studies have explored the risk factors for certain types of ADRs. Based on it, we comprehensively evaluate the drug safety of patients and provide a clinical reference with a focus on lung cancer. Research design and methods: We examined 767 reports of adverse drug reactions (ADRs) in patients with lung cancer and conducted a logistic regression analysis on the risk factors that may cause different types of organ system damage and serious ADRs. Results: The logistic regression identified various independent risk factors for system organ damage, and ADRs involving erythrocyte abnormalities (P < 0.001), respiratory system damage (P < 0.001), and leukocyte and reticuloendothelial system abnormalities (P < 0.001) were more likely to be severe. Conclusions: Rare adverse reactions and different Clinical medication guidelines for molecular-targeted drugs were identified. These findings had certain practical significance in clinical safe drug use.

Hepatotoxicity of Small Molecule Protein Kinase Inhibitors for Cancer

Article

Full-text available

Mar 2023

Simple Summary This review reports the risk and management of the hepatotoxicity of all the approved protein kinase inhibitors (PKIs) for cancer. Hepatotoxicity is one of the major safety concerns of these drugs, as reflected by the discontinuation of the development of some of them due to liver injury, or by the significant number of warnings for hepatotoxicity reported in drug labeling. Although these side effects are usually reversible by dose adjustment or therapy suspension, or by switching to an alternative PKI, and fatality is uncommon, all patients undergoing these drugs should be carefully pre-evaluated and monitored during treatment. Abstract Small molecule protein kinase inhibitors (PKIs) have become an effective strategy for cancer patients. However, hepatotoxicity is a major safety concern of these drugs, since the majority are reported to increase transaminases, and few of them (Idelalisib, Lapatinib, Pazopanib, Pexidartinib, Ponatinib, Regorafenib, Sunitinib) have a boxed label warning. The exact rate of PKI-induced hepatoxicity is not well defined due to the fact that the majority of data arise from pre-registration or registration trials on fairly selected patients, and the post-marketing data are often based only on the most severe described cases, whereas most real practice studies do not include drug-related hepatotoxicity as an end point. Although these side effects are usually reversible by dose adjustment or therapy suspension, or by switching to an alternative PKI, and fatality is uncommon, all patients undergoing PKIs should be carefully pre-evaluated and monitored. The management of this complication requires an individually tailored reappraisal of the risk/benefit ratio, especially in patients who are responding to therapy. This review reports the currently available data on the risk and management of hepatotoxicity of all the approved PKIs.

Synthesis and biological evaluation of novel [ , , ]triazolo-pyrrolo[1,2-a]pyrido[4,3-d]pyrimidines as EGFR targeting anticancer agents

Article

Full-text available

Oct 2022
J MOL STRUCT

Herein, we synthesized some new fused [1,2,3]triazolo-pyrrolo[1,2-a]pyrido[4,3-d]pyrimidines via click chemistry followed by carbon-carbon bond coupling as key approach and then characterized their structures by IR, NMR, mass and CHN analysis techniques. The structural parameters of compound 5n were also derived from geometry optimization. Molecular electrostatic potential (MEP), HOMO–LUMO energy gap, and Mulliken atomic charges were calculated. Later, the anticancer activity of the synthesized compounds was screened in vitro against different human cancer cell lines like MCF-7, NCI-H460, and A-549 and the results were compared with standard drug erlotinib. Most of the investigated compounds like 5c, 5e, 5f, 5j, 5m and 5n were found to be active against MCF-7. Specifically, compounds 5c and 5n had superior activity against MCF-7 and remarkable activity against A-549. The results of the inhibitory assay of most active compounds 5c and 5n against the wild type tyrosine kinase EGFR (PBS Bioscience, catalog # 40321), which is one of the enzymes expressed in the MCF-7 and A-549 cell lines revealed that both compounds had greater potency in inhibiting tyrosine kinase EGFR than the standard drug erlotinib. The in silico studies of six active compounds 5c, 5e, 5f, 5j, 5m, 5n and erlotinib were also carried out on EGFR receptor and observed that all the six compounds had appreciable binding energies and inhibition constants than the standard drug erlotinib. Finally, the in silico pharmacokinetic profile was predicted for potent compounds 5c, 5e, 5f, 5j, 5m and 5n using SWISS/ADME and pkCSM, where, all the compounds followed Lipinski, Lipinski, Veber, Egan and Muegge rules without any deviation.

Gemcitabine-induced thrombotic microangiopathy: A systematic review

Article

Full-text available

Dec 2006

Erlotinib in previously treated non-small cell lung cancer

Article

Jan 2005

TRIBUTE: A phase III trial of erlotinib HCl (OSI-774) combined with carboplatin and paclitaxel (CP) chemotherapy in advanced non-small cell lung cancer

Article

Jan 2005

Erlotinib-Induced Hepatitis Complicated by Fatal Lactic Acidosis in an Elderly Man With Lung Cancer

Article

Apr 2009
ANN PHARMACOTHER

To report a case of erlotinib-induced hepatitis complicated by fatal lactic acidosis in an elderly patient with lung adenocarcinoma and diabetes mellitus. A 77-year-old man with stage IIIB lung adenocarcinoma was treated with erlotinib 100 mg/day, an epidermal growth factor receptor inhibitor, after failure of chemotherapy and radiotherapy. The patient also had type 2 diabetes mellitus; metformin therapy had been initiated 5 years before presentation. Twelve days after the start of erlotinib therapy, he developed drug-related acute hepatitis complicated by renal deterioration (aspartate aminotransferase 1400 U/L, alanine aminotransferase 1299 U/L, creatinine 4.4 mg/dL, urea nitrogen 55 mg/dL). Viral causes of hepatitis were excluded and a recent computed tomography scan had ruled out liver metastases. According to the Roussel-Uclaf causality assessment method, the erlotinib-related hepatitis was classified as probable. The patient's condition was soon complicated by the onset of lactic acidosis, which caused death 2 hours after admission. In this patient, lactic acidosis was promoted by erlotinib-related hepatitis with initial liver failure (decreased lactate clearance), concomitant metformin treatment (increased lactate production), and acute renal deterioration (metformin accumulation). This is the second case of fatal erlotinib-induced liver toxicity in a patient with lung cancer. In the previous case, death occurred after about 11 days and was entirely due to fulminant hepatitis, whereas in our patient, the liver injury only initiated a drug-disease interaction that caused fatal lactic acidosis within a few hours. Liver function should be carefully monitored during erlotinib treatment, particularly in elderly and frail patients on multiple medications. Further studies are therefore needed for better testing the safety of erlotinib in such people, commonly encountered in the real world, but often excluded from participation in randomized trials of cancer treatment.

Phase I and Pharmacologic Study of OSI-774, an Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor, in Patients With Advanced Solid Malignancies

Article

Aug 2001

To assess the feasibility of administering OSI-774, to recommend a dose on a protracted, continuous daily schedule, to characterize its pharmacokinetic behavior, and to acquire preliminary evidence of anticancer activity. Patients with advanced solid malignancies were treated with escalating doses of OSI-774 in three study parts (A to C) to evaluate progressively longer treatment intervals. Part A patients received OSI-774 25 to 100 mg once daily, for 3 days each week, for 3 weeks every 4 weeks. Part B patients received OSI-774 doses ranging from 50 to 200 mg given once daily for 3 weeks every 4 weeks to establish the maximum tolerated dose (MTD). In part C, patients received this MTD on a continuous, uninterrupted schedule. The pharmacokinetics of OSI-774 and its O-demethylated metabolite, OSI-420, were characterized. Forty patients received a total of 123 28-day courses of OSI-774. No severe toxicities precluded dose escalation of OSI-774 from 25 to 100 mg/d in part A. In part B, the incidence of severe diarrhea and/or cutaneous toxicity was unacceptably high at OSI-774 doses exceeding 150 mg/d. Uninterrupted, daily administration of OSI-774 150 mg/d represented the MTD on a protracted daily schedule. The pharmacokinetics of OSI-774 were dose independent; repetitive daily treatment did not result in drug accumulation (at 150 mg/d [average]: minimum steady-state plasma concentration, 1.20 +/- 0.62 microg/mL; clearance rate, 6.33 +/- 6.41 L/h; elimination half-life, 24.4 +/- 14.6 hours; volume of distribution, 136. 4 +/- 93.1 L; area under the plasma concentration-time curve for OSI-420 relative to OSI-774, 0.12 +/- 0.12 microg/h/mL). The recommended dose for disease-directed studies of OSI-774 administered orally on a daily, continuous, uninterrupted schedule is 150 mg/d. OSI-774 was well tolerated, and several patients with epidermoid malignancies demonstrated either antitumor activity or relatively long periods of stable disease. The precise contribution of OSI-774 to these effects is not known.

The risk of a venous thrombotic event in lung cancer patients: Higher risk for adenocarcinoma than squamous cell carcinoma

Article

Nov 2004

Only limited data on the incidence of venous thrombosis in different types of malignancy are available. Patients with adenocarcinoma are believed to have the highest risk of developing venous thrombosis. To study the incidence of thrombosis in patients with lung cancer, with an emphasis on the comparison between adenocarcinoma and squamous cell carcinoma, we have performed a cohort study of patients with non-small-cell lung cancer. In addition the risk associated with treatment and extent of disease was assessed. A total of 537 patients with a first diagnosis of lung carcinoma were included. Patient and tumor characteristics as well as venous thrombotic events were recorded from the medical records and from the Anticoagulation Clinic. Thrombotic risk in lung cancer patients was 20-fold higher than in the general population (standardized morbidity ratio (SMR): 20.0 (14.6-27.4). In the group of patients with squamous cell cancer we found 10 (10/258) cases (incidence: 21.2 per 1000 years) of venous thrombosis whereas in the group of patients with adenocarcinoma 14 (14/133) cases (incidence: 66.7 per 1000 years) occurred. The crude adjusted hazard ratio was 3.1 (95% CI: 1.4-6.9). The risk increased during chemotherapy and radiotherapy and in the presence of metastases. The risk of venous thrombosis in lung cancer patients is increased 20-fold compared to the general population. Patients with adenocarcinoma have a higher risk than patients squamous cell carcinoma. During chemotherapy or radiotherapy and in the presence of metastases the risk is even higher.

Clinical pharmacokinetics of erlotinib in patients with solid tumors and exposure-safety relationship in patients with non-small cell lung cancer

Article

Sep 2006

Our objective was to assess the pharmacokinetics of erlotinib in a large patient population with solid tumors, identify covariates, and explore relationships between exposure and safety outcomes (rash and diarrhea) in patients with non-small cell lung cancer receiving single-agent erlotinib. The population pharmacokinetic analysis was performed by use of NONMEM based on 4068 concentration samples from 1047 patients receiving erlotinib as a single agent or in combination with chemotherapy. By use of a 1-compartment model with first-order absorption, the influence of demographic and clinical characteristics on clearance and volume was examined. Spearman rank correlation analyses were performed to test for correlations between maximum grades of rash and diarrhea and erlotinib exposure in non-small cell lung cancer patients treated with single-agent erlotinib. On the basis of the final model developed from patients treated with erlotinib as a single agent, the oral clearance was 3.95 L/h, the oral volume of distribution was 233 L, and the absorption rate was 0.95 h(-1). The median erlotinib half-life based on this patient population was 36.2 hours. Total bilirubin, alpha1-acid glycoprotein, and smoking status were the most important factors affecting clearance. The clearance in current smokers was 24% faster than that in former smokers or those who never smoked. There was a statistically significant correlation between drug exposure and rash (P < .05). However, there was significant overlap in the range of values for patients who had no rash (grade = 0) and those who had any grade of rash. No significant correlation was found between exposure and diarrhea. The long half-life of erlotinib supports the current once-daily dosing regimen at 150 mg/d. Effects of covariates on erlotinib clearance and correlations with adverse event severity were provided to aid in the detection of a treatment-emergent effect.

Acute Drug Induced Hepatitis Due to Erlotinib

Article

Feb 2007
J Pancreas

Acute drug induced hepatitis has not been commonly associated with epidermal growth factor receptor (EGFR) inhibitors. Hepatotoxicity seen with erlotinib, a small molecule tyrosine kinase inhibitor to EGFR, is usually transient with mild elevation of transaminases. We report a case of acute severe hepatitis resulting from erlotinib monotherapy in a patient with locally advanced pancreatic cancer. Hepatotoxicity resolved once erlotinib was discontinued and serum transaminases returned to baseline normal values. Acute severe hepatitis though rare is occasionally observed with EGFR inhibitors gefitinib or erlotinib. As EGFR inhibitors are now incorporated with chemotherapy in advanced pancreatic cancers, clinicians should be aware of this potential complication.

Fulminant Hepatic Failure Secondary to Erlotinib

Article

Sep 2007

Erlotinib is a tyrosine kinase inhibitor recently approved by the Food and Drug Administration for the treatment of non-small-cell lung cancer and pancreatic cancer. We report a case of a patient with stage IV non-small-cell lung cancer who died of fulminant hepatic failure as a result of treatment with erlotinib.

Phase I and Pharmacokinetic Study of Erlotinib for Solid Tumors in Patients With Hepatic or Renal Dysfunction: CALGB 60101

Article

Aug 2007
J CLIN ONCOL

We investigated dose and pharmacokinetics of erlotinib in patients with hepatic dysfunction or renal dysfunction. Patients were assigned to one of three cohorts: cohort 1, AST > or = 3x upper limit of normal; cohort 2, direct bilirubin of 1 to 7 mg/dL; and cohort 3, creatinine of 1.6 to 5.0 mg/dL. Cohort 1a was amended for albumin less than 2.5 g/dL. Erlotinib was administered orally daily to groups of at least three assessable patients in escalating doses of 50, 75, 100, and 150 mg, starting with 50 mg in hepatic dysfunction patients and 75 mg in renal dysfunction patients. Between December 2001 and May 2005, 55 patients were accrued. The distribution of assessable patients was: two of three in cohort 1, three of three in cohort 1a, 16 of 30 in cohort 2, and 18 of 18 in cohort 3. Dose-limiting toxicity (DLT) consisted of elevation of both total and direct bilirubin 1.5x baseline in three patients (cohort 1: one of five patients at 50 mg; cohort 2: two of six patients at 100 mg). In cohort 2, one of seven patients had DLT at 75 mg. No DLT was encountered in cohort 3 with 12 patients at 150 mg. Apparent oral clearance (mean +/- standard deviation) was cohort dependent as follows: 1.9 +/- 0.2 L/h in cohort 1; 3.7 +/- 4.7 L/h in cohort 1a; 2.4 +/- 1.1 L/h in cohort 2; and 4.5 +/- 2.7 L/h in cohort 3 (Kruskal-Wallis, P < .017). Patients with renal dysfunction tolerate 150 mg of erlotinib daily and seem to have an erlotinib clearance similar to patients without organ dysfunction. Patients with hepatic dysfunction should be treated at a reduced dose (ie, 75 mg daily) consistent with their reduced clearance.

Acute Fatal Liver Toxicity under Erlotinib

Abstract and Figures

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