PEMETREXED-CISPLATIN INDUCED SKIN TOXICITY IN A

PATIENT WITH LUNG CANCER

Dini Daniaty1, Hanif Sri Utami2, Andira Hardjodipuro3*, Endi Novianto4
Departemen Dermatologi and Venereology, FK Universitas Indonesia
RSUPN dr. Cipto Mangunkusumo, Jakarta
*
Hp: 081358111121, Email: dr.dinidaniaty1987@gmail.com

Abstract
Pemetrexed is a multitargeted antifolate drug approved as a single agent or in combination with
cisplatin for the treatment of a small number of malignancies including advanced and metastatic
non-squamous non-small cell lung cancer (NSCLC). The side profile includes fatigue,
haematological and gastrointestinal toxicity, an increase in hepatic enzymes, and cutaneous
toxicity. This case report is to highlight pemetrexed-cisplatin induced skin toxicity in a patient
with lung cancer. One week after the first cycle of pemetrexed and cisplatin, erythematous rash
occurred at back and spread to chest. A diffuse erythematous patch was also noticed at face,
both arms, and thighs. He was treated with adequate hydration, urine alkalinization, vitamin B,
and folic acid. The symptoms worsened within 9 days. The patient’s condition was deteriorating
due to neutropenic sepsis. Although severe skin reactions are rarely found, dermatologic
reactions after pemetrexed-cisplatin administration are common. Therefore, it is pivotal for
dermatovenereologists to be familiar with skin manifestations associated with pemetrexed-
cisplatin. Multidisciplinary approach is essential in the management of pemetrexed-cisplatin
induced skin toxicity.
Keywords: pemetrexed, cisplatin, skin toxicity, non-squamous non-small cell lung cancer

Abstrak
Pemetrexed adalah obat antifolat multitarget yang dipakai sebagai agen tunggal atau kombinasi
bersama dengan cisplatin sebagai modalitas terapi pada keganasan termasuk keganasan paru
non squamous non-small. Efek samping yang dapat terjadi adalah lemas, toksisitas hematologi
dan gastrointestinal, peningkatan enzim hati dan toksisitas kulit. Laporan kasus ini memaparkan
toksisitas kulit setelah pemberian pemetrexed-cisplatin pada pasien dengan keganasan paru.
Setelah satu minggu pemberian kemoterapi pemetrexed-cisplatin, timbul bercak kemerahan
pada punggung yang meluas ke area dada. Bercak terlihat juga pada wajah, kedua lengan, dan
kedua paha. Pasien diberikan hidrasi cairan, alkanisasi urin, vitamin B, dan asam folat. Pasien
mengalami perburukan ketika 9 hari perawatan. Pasien meninggal akibat sepsis neutropenik.
Walaupun reaksi kulit yang berat jarang terjadi, toksisitas kulit akibat pemberian pemetrexed-
cisplatin cukup lazim ditemukan. Oleh karena itu, penting bagi dokter spesialis dermatologi dan
venereologi untuk dapat mengenali kelainan kulit yang berkaitan dengan pemberian
pemetrexed-cisplatin. Pendekatan multidisiplin berperan penting dalam penanganan kulit akibat
toksisitas pemetrexed-cisplatin
Keywords: pemetrexed, cisplatin, toksisitas kulit, kanker paru non squamous non-small

Introduction
Pemetrexed is an effective chemotherapeutic drug used for treatment of a broad range of
malignancies. In combination with cisplatin, they show good efficacy as first line treatment for
patients with non-squamous non-small cell lung cancer (NSCLC). 1 Side effects commonly
reported associated with pemetrexed-cisplatin include fatigue, nausea, vomiting, skin rash, and
liver function abnormalities.2 Cutaneous adverse events are very rare, especially a rash (70-90%
of patients who have not received corticosteroids, compared to in 14-50% of patients who have
received corticosteroids).3 We present the case of a male patient with lung cancer who
experienced skin toxicity after pemetrexed-cisplatin administration. In this report, we will
discuss the management of the skin toxicity for the patient.

Case
A 36-year-old man was diagnosed with lung adenocarcinoma stage IV. He was treated with
combination of two chemotherapy drugs, pemetrexed and cisplatin. He was admitted with
fatigue, diarrhoea, and erythematous patch on his back one week after completion of the first
cycle. Physical examination revealed diffuse erythematous patch on his back. The erythematous
patch spread to face, chest, both arms, and thighs. The erythematous patch was non-blanchable
on diascopy. There was oral ulcer involving inner aspect of both lips. Blood examination
revealed the haemoglobin level was 8,7 g/dl, the platelet counts 21000 µL, and the white blood
cell count 950 µL. Further laboratory tests revealed C-reactive protein (CRP) of 335,8 mg/dl
and procalcitonin of 16,49 ng/mL. The patient was treated with intravenous fluids, urine
alkalinization, granulocyte colony-stimulating factor, antibiotics, vitamin B12, and folic acid.
He was already on a premedication regimen consisting of dexamethasone and folic acid to
prevent possible side effects one day before chemotherapy. After 9 days of observation, his skin
condition showed slight improvement marked by skin desquamation on some areas.
Unfortunately, the patient’s consciousness was deteriorating due to neutropenic sepsis.

A B C
Figure 1. Erythematous patches on his face and upper arms (A), trunk (B), and back (C)

Discussion
Drug-induced cutaneous eruptions vary widely from common rashes to rare life-threatening
diseases. Those reactions may be limited to the skin or part of severe systemic reaction.
Identifying reaction pattern is important to make precise diagnosis. Certain drugs are associated
with certain types of reactions. Recognizing the pattern could be a hint to estimate the causes of
the cutaneous eruptions.4

In this case, the patient received pemetrexed and cisplatin for the treatment of NSCLC.
Pemetrexed is an antifolate chemotherapeutic agent that approved in combination with cisplatin
as the first-line treatment and as a single-agent second-line treatment for NSCLC. 3 Several
studies showed that treatments with pemetrexed may be followed by dermatological toxicities,
varied from diffuse inflammatory rashes, hyperpigmented plaques, to even life-threatening toxic
epidermal necrolysis.2,5–7
Our patient complained erythematous patches on his face, trunk, back, upper arms, and thighs
with mild pruritus. The patches appeared after he received pemetrexed-cisplatin for one week.
Similar study reported erythematous papules-plaques with minimal erosions, localized on
extensor aspect of arms and hands, chest, and back that appeared ten days after a patient
received the first dose of pemetrexed and cisplatin. 7 The pathogenesis of skin rashes that occurs
after pemetrexed administration is estimated due to the cytotoxic effect on keratinocytes and
endothelial cells.8 On the other hand, cisplatin is widely known for inducing skin pigmentation
with unclear mechanism. Cisplatin may be attributed to an effect to melanocyte. 9 This case is
reported for its rarity as erythematous patches over patient’s face, trunk, back, and extremities
due to pemetrexed and cisplatin. The oral folic acid and vitamin B12 supplementation has been
found to significantly decrease the incidence of these toxicities. Daily administration of steroid
for 3 days preceding and the day following pemetrexed administration is thought to prevent
certain adverse reactions to pemetrexed.8

Conclusion
Pemetrexed-cisplatin induced skin toxicity should be managed appropriately according to the
current guidelines. Patient should be informed the possibility of this cutaneous toxicity and its
symptoms should be identified as early as possible. Preventive measures including folic acid,
vitamin B supplementation, and high-dose dexamethasone administration likely reduce severity
of skin toxicity. Multidisciplinary approach is required in the management of skin toxicity
associated with pemetrexed-cisplatin.

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