Capecitabine and oxaliplatin induced Steven–Johnson syndrome following nivolumab in a patient of metastatic esophageal carcinoma

Abstract

Stevens–Johnson syndrome presents as mucocutaneous blistering and sloughing, which may follow a devastating clinical course. Although Stevens–Johnson syndrome has been reported following the administration of anticancer drugs, only a few cases induced by cytotoxic anticancer drugs, administered after immune checkpoint inhibitors, have been reported. The present report describes a case of Stevens–Johnson syndrome caused by capecitabine and oxaliplatin (CAPEOX) combination chemotherapy, in a patient with esophageal squamous cell carcinoma, who had been previously treated with nivolumab.

Introduction

Stevens–Johnson syndrome (SJS) is a type IV hypersensitivity reaction, mostly to drugs, that presents as mucocutaneous blistering and sloughing and which may follow a devastating clinical course. However, its incidence is around 1–2 cases per million/year with a mortality rate of approximately 1–5% [1].

Antibiotics are the most common cause of SJS, followed by analgesics, non-steroidal anti-inflammatory drugs, anticonvulsants, antigout, and anticancer drugs. Anticancer drugs such as chemotherapy, targeted therapy, and recent immunotherapy cause mild skin rash to life-threatening severe cutaneous adverse reactions (SCARs). Recently, with the advent of immune checkpoint inhibitors (ICIs), which elicit its effects by targeting programmed death-1 (PD-1), programmed death ligand-1 (PDL-1), and cytotoxic T-lymphocyte-associated antigen-4, combination chemotherapy drugs, and ICIs are being used simultaneously or sequentially for various cancers. Cytotoxic combination anticancer drugs have general side effects such as myelosuppression and digestive symptoms. In contrast, ICIs are known to cause immune-related adverse events (irAEs) such as skin disorders, interstitial pneumonia, endocrine disorders, liver disorders, and renal disorders due to immune overreaction. Against this background, ICIs have been reported to have long-lasting effects, and may additively or synergistically enhance not only clinical efficacy but also the side effects of cytotoxic anticancer drugs administered sequentially after ICIs [2]. Indeed, few cases of severe toxicities induced by cytotoxic anticancer drugs, administered after ICIs, have been reported [3]. This may be explained by the fact that ICIs reduce the threshold for the development of serious side effects of cytotoxic anticancer drugs in patients treated with cytotoxic anticancer drugs following ICI therapy. However, to date, information on the side effects in patients treated with cytotoxic agents following ICI therapy remains limited. Here, we report a case of SJS caused by capecitabine and oxaliplatin (CAPEOX) combination chemotherapy, in a patient with esophageal squamous cell carcinoma, who had been previously treated with nivolumab.

Case report

A 43 year-old male with a case of esophageal squamous cell carcinoma (cT3N0M0) post-video-assisted thoracic surgery (VATS) esophagectomy, presented with bilateral pleural effusion. The patient had no history of hypertension, diabetes mellitus, history skin diseases, autoimmune diseases, or drug allergies. He was administered 3 cycles of neoadjuvant chemotherapy with paclitaxel and carboplatin.

Pleural fluid was sent for cytological examination, which showed malignant cells. Hence, the patient was started on palliative immunotherapy with nivolumab every 2 weeks. After 8 cycles of palliative immunotherapy, CECT showed liver metastasis. As the patient had progressive disease, he was then started on chemotherapy with CAPEOX. One week following the 3rd cycle of CAPEOX chemotherapy, the patient complained of black patches and bleeding from the oral cavity. On examination, there were multiple hemorrhagic bullae, the largest measuring 2 × 1 cm on the right side in the buccal mucosa, which bled on touch. The platelet count, prothrombin time, activated partial thromboplastin time, and platelet aggregation test were all within normal range. However, after 3 days, the patient developed conjunctivitis associated with photophobia followed by eruptions of discrete purpuric typical and atypical target lesions with blisters distributed all over the body, mainly on the palms and soles. (Fig. 1). Nikolsky’s sign was positive. There were similar lesions on the lips with crusting (Fig. 1). A biopsy from the lip lesion showed predominantly necrotic tissue with entrapped necrotic keratinocytes along with inflammatory exudates consistent with Steven–Johnson syndrome (Fig. 2).

Fig. 1.

Photograph of the patient showing crusting over the lips and discrete purpuric skin lesions of palms

Fig. 2.

Skin biopsy showing detachment of epidermis with necrotic keratinocytes (H and E, 200×)

The patient was managed with intravenous steroids, oral antihistaminic, topical steroids, topical astringent, and antipruritic lotion along with supportive care. Conjunctivitis was managed with antibiotic eye drops, antibiotic ointment, and eye lubricant. The patient’s condition improved. Buccal mucosa lesions resolved after 10 days. Conjunctivitis improved in 1 week and resolved after 2 weeks. Scaling of skin lesions started after 2 weeks of initiation of treatment. The patient fully recovered after 3 weeks (Fig. 3).

Fig. 3.

Photograph of the patient 3 weeks after the start of treatment showing complete resolution of the lesion over the palms

Discussion

The present case describes an advanced esophageal squamous cell carcinoma patient developing SJS during chemotherapy with CAPEOX after nivolumab therapy. The patient was initiated with nivolumab monotherapy as the literature suggests nivolumab is associated with a significant improvement in overall survival and a favourable safety profile compared with chemotherapy in patients with advanced esophageal squamous cell carcinoma [4]. As the patient had progressive disease after 8 weeks of immunotherapy, he was started on chemotherapy with CAPEOX.

CAPEOX is a widely used drug for locally advanced and metastatic esophageal carcinoma. SJS, although already reported in several case reports, appears rarely in clinical practice [5]. The Food and Drug Administration (FDA) approved Nivolumab for patients with unresectable advanced, recurrent, or metastatic esophageal squamous cell carcinoma in 2020; however, it has irAEs. Since ICIs targeting PD-1 or its ligand PD-L1 have revealed favourable results in patients with esophageal carcinoma, anti-PD–PD-1 or anti-PD-L1 antibodies are being considered standard treatment for esophageal carcinomas. These antibodies disrupt suppressive signaling between cytotoxic T cells and tumours and thereby exhibit clinical benefits [6]. The development of irAEs has been reported to be related to preferred outcomes. On the other hand, a higher response rate was observed in patients with subsequent CAPEOX chemotherapy after nivolumab compared to previous reports of salvage-line chemotherapy without Nivolumab [7]. It has been suggested that the high efficacy of cytotoxic combination cancer drugs after ICI treatment is attributable to the following two mechanisms. The first mechanism is alteration of the tumour and/or microenvironment by ICI treatment resulting in increased sensitivity to cytotoxic agents. The other mechanism is the combination of cytotoxic agents resulting in an intensified ICI treatment [7, 8]. Previous ICI treatment may also enhance the risk for SJS due to chemotherapy. Conversely, chemotherapy may trigger SJS as a late‐onset irAE [8].

In some cases, a durable response to anti-PD-1 or anti-PD-L1 antibodies may occur even after discontinuation [8]. This phenomenon can be explained by the fact that ICIs may affect the immune response even at low concentrations. Even after nivolumab was no longer detectable in the blood (1.2 g/mL), PD-1 occupancy was 60–80% in a phase I evaluation of the drug [9]. In addition, a T-cell response can be triggered by nivolumab at concentrations as low as 1 g/mL, as per an in-vivo study [10]. The durable efficacy of nivolumab explains the occurrence of delayed irAEs. Although the half-life of a single dose of 3 mg/kg of nivolumab is known to be 13 days (± 7 days), it is yet unknown how long it takes for nivolumab's impact on the immune system to adequately reduce so that it won't interfere with subsequent treatment [11].

Anti-cancer drugs that cause SJS/TEN are known to be involved in the activation and proliferation of drug-specific and/or metabolite-specific T cells, which develop quickly after exposure to the causative agent [12]. In contrast, the onset of these reactions to ICIs such as nivolumab is delayed to week 8 or later, which is atypical of classic SJS or TEN [13]. Delayed SJS or toxic epidermal necrolysis (TEN)-like reactions to ICIs may involve disruption of peripheral tolerance and homeostasis [13]. In one study, while maculopapular rashes occurred relatively early after a mean of 1 month since initiation of an ICI, other morphologies of rashes were more delayed in their presentation like lichenoid rashes occurred after a mean of 6.2 months, psoriasiform after 5.7 months, immunobullous after 4.5 months, and eczematous after 5.8 months [14]. It may be difficult to pinpoint the mechanism underlying SJS in patients administered with a combination of anti-cancer drugs and ICIs. In the present case, considering nivolumab followed by CAPEOX was administered, suggests a complex interplay between immune checkpoint inhibitors and cytotoxic chemotherapy, particularly in the context of esophageal squamous cell carcinoma.

To prevent SJS associated with anti-cancer drugs and ICIs, it is crucial to carefully select patients based on their medical history and risk factors. In the present case, the patient had no significant risk factors, however, malignancy is a risk factor for SJS. A comprehensive baseline evaluation, including symptoms like fever, and skin rashes, and baseline laboratory tests including C-reactive protein, should be conducted [15]. Patient education is pivotal in informing individuals about potential skin reactions, emphasizing the prompt reporting of any symptoms. Continuous monitoring during treatment is essential for early detection of potential issues. If SJS is suspected, immediate discontinuation of the culprit drugs and seeking medical intervention are paramount [15]. Collaborative healthcare, involving open communication among oncologists, dermatologists, and specialists, ensures a holistic approach to patient care. Dose adjustments or temporary discontinuation may be considered based on the severity of symptoms [15].

Conclusion

The present case reports a patient of esophageal squamous cell carcinoma developing SJS during CAPEOX treatment following nivolumab therapy. Careful assessment is required before commencing CAPEOX treatment in patients previously treated with nivolumab. Further studies investigating the risk of SJS during combination chemotherapy following nivolumab pre-treatment are required to reach more definitive conclusions.

Declarations

Conflict of interest

All authors declared that there are no conflicts of interest.

Consent to participate

Informed written consent and permission were obtained from the patient for the use of the clinical material and photographs for study and publication. No identifiable information was included in this report.