Gemcitabine-Induced Cardiomyopathy: A Case Report

Abstract and Introduction

Abstract

Introduction: Newly developed antineoplastic drugs have resulted in improvements in morbidity and mortality from many forms of cancers. However, some of these new chemotherapeutic agents have potentially lethal side effects, which are now being exposed with their widespread use. Gemcitabine is a nucleoside analog, which is a commonly used agent for various solid organ malignancies. Phase 1 and 2 trials with gemcitabine did not show significant risk for cardiotoxicity; however, with its widespread clinical use over the last decade, a few cases of cardiotoxicity related to gemcitabine use have been reported. Cardiomyopathy after the use of gemcitabine monotherapy is extremely rare; and only one such case has been reported in detail previously.

Case presentation: We report a case of a 56-year-old African American man with pancreatic cancer who presented with signs and symptoms of congestive heart failure after being treated with gemcitabine for two cycles (six doses). A two-dimensional echocardiography showed left ventricular ejection fraction of 15 to 20 percent with global hypokinesia. With the absence of significant risk factors for coronary artery disease and a strong temporal relationship with the initiation of chemotherapy, it was concluded that our patient's cardiomyopathy was related to the use of gemcitabine. Gemcitabine was discontinued and our patient responded well to standard heart failure therapy. Two months later, a repeat echocardiogram showed significant improvements in left ventricular systolic function.

Conclusions: Gemcitabine should be considered as a potential cause of cardiomyopathy in patients receiving chemotherapy with this drug. We need further studies to look into potential mechanisms and treatments of gemcitabine-induced cardiac dysfunction.

Introduction

Anticancer therapy has emerged tremendously over the last few years. Newly available drugs and protocols have resulted in improvements in morbidity and mortality from many forms of cancers. However, these new antineoplastic drugs and protocols are not without potentially lethal side effects. It is therefore very important to recognize serious toxicities associated with some of these medications, so appropriate measures can be taken to avoid and manage such problems.

Gemcitabine is a nucleoside analog and a pyrimidine antimetabolite that inhibits deoxyribonucleic acid (DNA) synthesis by inhibition of DNA polymerase and ribonucleotide reductase.^[1] It is a commonly used antineoplastic for various solid organ malignancies including advanced pancreatic, ovarian, breast, bladder and non-small cell lung cancers.^[2–7] The Gastrointestinal Tumor Study Group Phase III trial has shown promising results and has led to the adoption of adjuvant chemoradiotherapy with gemcitabine as the standard of care for advanced pancreatic cancer.^[6]

Gemcitabine is generally well tolerated and is considered relatively safe as compared to many other chemotherapeutic agents. Its most common toxicities include myelosuppression, changes in gastrointestinal function (nausea, vomiting and diarrhea) and abnormalities in liver and renal function tests.^[8]

Phase 1 and 2 studies with gemcitabine did not show significant risk for cardiotoxicity, however, with its widespread clinical use over the last decade, a few cases of acute myocardial infarction (AMI) and arrhythmias associated with gemcitabine use have been reported. Here, we report a case of a 56-year-old man with pancreatic cancer who developed dilated cardiomyopathy after being treated with gemcitabine.

Table 1. Case reports of cardiotoxicity with gemcitabine monotherapy
Author	Demography	Dose of gemcitabine	Duration of treatment	Side effect	History of CAD	Timing	Outcome	Probability
Ozturk et al. ^[17]	59F with metastatic leiomyosarcoma	900mg/m2	8 days	Coronary vasospasm	Yes	30 minutes after infusion	Survived. Gemcitabine therapy stopped	Strong
Bdair et al . ^[18]	43F with metastatic NSCLC	1000mg/m2	7 weeks	NSTEMI VT	Yes	3 days after infusion	Survived. Gemcitabine therapy stopped	Weak
Kalapura et al . ^[19]	54M with metastatic pancreatic cancer	1900mg	5th cycle	NSTEMI	No CAD, no risk factors	6 hours after infusion	Survived. Recurrent symptoms with 7th cycle	Strong
Tayer-Shifman et al. ^[20]	67F with metastatic ductal carcinoma of breast	1000–1400mg/m2	3rd cycle	SVT/AVNRT	No CAD, no risk factors	Hours after infusion	Survived. Gemcitabine therapy stopped	Strong
Santini et al. ^[21]	78M with pancreatic adenocarcinoma	NK	1st cycle	AF	History of AF in the past	18–22 hours after the infusion	Survived 6 total episodes of AF 18–22 hours after the infusion	Strong
Ferrari et al. ^[22]	72F with metastatic lung adenocarcinoma	1200mg/m2	1st cycle	AF	No history of AF	18 hours after the infusion	Survived 3 total episodes of AF each after 18 hours of infusion	Strong
Ferrari et al. ^[22]	73F with NSCLC	1200mg/m2	3rd cycle	AF	No history of AF	12 hours after the infusion	Survived. Gemcitabine stopped	Strong
Tavil et al. ^[23]	65M with NSCLC	1200mg/m2	2nd cycle	AF	No history of AF	7 hours after the infusion	Gemcitabine stopped	Strong
Ciotti et al. ^[24]	70M with metastatic pancreatic adenocarcinoma	NK	1st cycle	AF	No history of AF	6 days after the infusion	AF recurred with further therapy	Strong
Yajima et al. ^[25]	82F with advanced pancreatic carcinoma	16, 800mg-total dose	Two years of treatment	HF	NK	2 years	Gemcitabine stopped	Weak
*Khan et al.* [present case]**	56M with pancreatic adenocarcinoma	1000mg/m2	Two cycles (2 months)	CMP/HF	No prior history of CHF/CAD	2 months	Gemcitabine stopped, partial recovery	Strong

Table 1. Case reports of cardiotoxicity with gemcitabine monotherapy

Author

Demography

Dose of gemcitabine

Duration of treatment

Side effect

History of CAD

Timing

Outcome

Probability

Ozturk et al. ^[17]

59F with metastatic leiomyosarcoma

900mg/m2

8 days

Coronary vasospasm

Yes

30 minutes after infusion

Survived. Gemcitabine therapy stopped

Strong

Bdair et al . ^[18]

43F with metastatic NSCLC

1000mg/m2

7 weeks

NSTEMI VT

Yes

3 days after infusion

Survived. Gemcitabine therapy stopped

Weak

Kalapura et al . ^[19]

54M with metastatic pancreatic cancer

1900mg

5th cycle

NSTEMI

No CAD, no risk factors

6 hours after infusion

Survived. Recurrent symptoms with 7th cycle

Strong

Tayer-Shifman et al. ^[20]

67F with metastatic ductal carcinoma of breast

1000–1400mg/m2

3rd cycle

SVT/AVNRT

No CAD, no risk factors

Hours after infusion

Survived. Gemcitabine therapy stopped

Strong

Santini et al. ^[21]

78M with pancreatic adenocarcinoma

1st cycle

History of AF in the past

18–22 hours after the infusion

Survived 6 total episodes of AF 18–22 hours after the infusion

Strong

Ferrari et al. ^[22]

72F with metastatic lung adenocarcinoma

1200mg/m2

1st cycle

No history of AF

18 hours after the infusion

Survived 3 total episodes of AF each after 18 hours of infusion

Strong

Ferrari et al. ^[22]

73F with NSCLC

1200mg/m2

3rd cycle

No history of AF

12 hours after the infusion

Survived. Gemcitabine stopped

Strong

Tavil et al. ^[23]

65M with NSCLC

1200mg/m2

2nd cycle

No history of AF

7 hours after the infusion

Gemcitabine stopped

Strong

Ciotti et al. ^[24]

70M with metastatic pancreatic adenocarcinoma

1st cycle

No history of AF

6 days after the infusion

AF recurred with further therapy

Strong

Yajima et al. ^[25]

82F with advanced pancreatic carcinoma

16, 800mg-total dose

Two years of treatment

2 years

Gemcitabine stopped

Weak

Khan et al. [present case]

56M with pancreatic adenocarcinoma

1000mg/m2

Two cycles (2 months)

CMP/HF

No prior history of CHF/CAD

2 months

Gemcitabine stopped, partial recovery

Strong

Gemcitabine-Induced Cardiomyopathy: A Case Report and Review of the Literature

Abstract and Introduction

Abstract

Introduction

Tables

References

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