Case
A 56-year-old female patient presented with complaints of sinus
congestion, diplopia and right orbital pain associated with proptosis. A
magnetic resonance imaging (MRI) scan noted a 6.5 cm mass involving the
right maxillary and frontal sinuses. A biopsy demonstrated a poorly
differentiated neoplasm that stained positively for cytokeratin (CAM
5.2) and focally for epithelial membrane antigen (EMA), consistent with
sinonasal undifferentiated carcinoma (SNUC). She underwent transfacial
resection including right orbital exenteration with final staging as
pT4bNxM0. Due to a positive posterior margin, she underwent
postoperative radiation (5,940 cGy) concurrently with high-dose
cisplatin (100 mg/m2, 3 cycles).
One year after initial diagnosis, she presented with cervical
radiculopathy and was found to have T1 metastatic recurrence (4.5 x 2
cm) as well as extensive liver metastases (12 lesions, largest 11.5 x
5.2 x 9.5 cm). She received palliative radiation therapy to the T1
metastasis.
Next-generation sequencing of the liver biopsy (Foundation Medicine,
Cambridge, MA) revealed several genomic alterations, including equivocal
amplifications of CD274 (PD-L1) and PDCD1LG2 (PD-L2). PD-L1 22C3 assay
resulted in a tumor proportion score (TPS) of 0%. The liver biopsy was
also found to be positive for p16 and therefore potentially indicative
of a human papilloma virus (HPV) infection.
The patient completed 6 cycles of carboplatin (AUC 5)/etoposide 100
mg/m2 days 1-3 with peg-filgrastim support. Her best
response to therapy was a 65% reduction of the largest liver target
lesion. Due to mild progression after the 6th cycle of
chemotherapy, single-agent pembrolizumab 2 mg/kg every 3 weeks was
started with excellent clinical tolerance; however, a computed
tomography (CT) scan after four cycles demonstrated radiographic
progression of liver metastases along with elevation of lactate
dehydrogenase (LDH) to 1201 U/L (313-618 U/L), alkaline phosphatase
(ALP) to 251 U/L (38-126), AST to 74 U/L (14-36), and ALT to 80 U/L
(9-52).
Because of atypical clinical benefit, pembrolizumab was continued for a
fifth cycle, now in combination with celecoxib 200 mg/day in hopes of
suppressing constitutive expression of immunosuppressive molecule
indoleamine 2,3-dioxygenase (IDO1). During the time of progression,
repeat genomic testing was done on a lymph node biopsy, which revealed
the same alterations of CD274 and PDCD1LG2 though now classified as
variance of unknown significance (VUS).
Three weeks after starting celecoxib, LDH decreased to 675 U/L, ALP
improved to 158 U/L, and AST and ALT remained stable. Dual checkpoint
inhibition with pembrolizumab 200 mg and ipilimumab 1 mg/kg was started
every 3 weeks for the 6th and 7th cycles of treatment.
Three days after the last treatment she experienced grade II autoimmune
dermatologic toxicity manifesting as diffuse pruritic rash, which
responded to topical steroids. Six days after treatment she was admitted
to an outside hospital with polyneuropathy of her upper extremities,
generalized weakness, and anorexia. Additionally, she was found to have
a sodium of 122 mg/dL secondary to syndrome of inappropriate
antidiuretic hormone (SIADH) as well as mildly worsening liver function
tests (LFTs). Celecoxib was stopped. An MRI of the brain did not show
evidence of metastases but did show meningeal enhancement, concerning
for leptomeningeal spread. There was also no evidence of hypophysitis,
and adrenocorticotropic hormone (ACTH) and cortisol levels were normal.
A lumbar puncture was negative for malignancy or infection in
cerebrospinal fluid.
Due to the perceived poor prognosis and the patient’s declining
condition, the patient was recommended hospice care by the inpatient
team. The treating oncologist, however, requested a subsequent CT scan
of the liver to document true disease progression, but the imaging
demonstrated marked improvement of hepatic metastases. Because of this
significant improvement in target lesions, it was thought that her
decompensation was due to an immune-related adverse event (irAE) rather
than disease progression.
The patient was started on prednisone 1 mg/kg daily with marked
improvement of her performance status and eventually improved to
baseline while continuing a steroid taper over two months. 11 weeks
after the last immunotherapy, she returned to her oncologist with a CT
scan demonstrating continued improvement of liver metastases. LFTs were
within normal limits at this time. She did not continue immunotherapy;
however, she was advised to restart celecoxib 200mg/day. Two weeks
later, she developed the onset of autoimmune hepatitis manifesting as
fever: ALP 1445 IU/L, AST 190, ALT 203. She started back on prednisone 1
mg/kg and slowly tapered to 5 mg/day.
A CT scan 24 weeks after last immunotherapy showed continued ongoing
durable response with continued regression and/or stability of remaining
target liver lesions. LFTs were back to normal despite continuing
celecoxib and low-dose prednisone. She was then advised to stop
prednisone completely and, within two days, had recurrence of autoimmune
hepatitis: ALP 148 IU/L, AST 140 IU/L, ALT 178 IU/L. She was advised to
stop celecoxib and resume a prednisone taper, and liver enzymes remained
normal thereafter.
Although the patient had oligometastatic recurrences over the subsequent
years, she had good disease control and a relatively indolent course
managed with single-agent pembrolizumab plus stereotactic body radiation
therapy (SBRT). Unfortunately, the patient ultimately died four years
after she started immunotherapy due to COVID-19 complications.