On 5 November 2019, a 64-year-old Chinese male patient was admitted to Peking Union Medical College Hospital, because of discovering liver tumor by ultrasound in physical examination and manifested no positive symptoms. The patient had a history of hepatitis B virus infection for 29 years. Magnetic resonance imaging (MRI) showed a 6 cm tumor in the right liver. The liver function test was normal. The serum tumor marker showed that cancer antigen199 (CA199) was 103.9 U/ml (normal range was < 34 U/ml), carcinoembryonic antigen (CEA) was 7.1 ng/ml (normal range was < 5 ng/ml), and alpha-fetoprotein (AFP) was 12.5 ng/ml (normal range was < 20 ng/ml). The patient was not a candidate for surgical intervention, because PET-CT showed bilobar disease with innumerable liver lesions and metastatic lymph nodes. After a biopsy of the tumor, pathological diagnosis confirmed poorly differentiated adenocarcinoma, with immunohistochemical staining of CK7(+), CK19(partly+), Her-2 (3+). (Figure 1) Next-generation sequencing verified the amplification of the Her-2 gene. As the result, the patient was diagnosed as poorly differentiated ICC with multiple lymph nodes metastases (hilar, posterior pancreatic head, paraaortic, and diaphragmatic angle of right heart lymph nodes) harboring Her-2 amplification (cT2N1M0, stage IIIb).
Platinum-based chemotherapy was recommended. Because the patient was worried about adverse events of chemotherapy, he received the pyrotinib (administered orally each day at a dose of 400 mg per day) and tegafur (administered orally each day at a dose of 40 mg per day). But after six months of treatment, PET-CT showed enlargement of primary lesions and metastatic lymph nodes, with appearing of bone metastasis in the lumbar spine and pubis, the disease was evaluated progressed. (Figure 2). The progress free time of first-line treatment was 6 months. The patient developed grade 3 adverse reactions including skin rash, hypertension, and increased bilirubin concentration, but no grade 4 or 5 adverse reactions were observed.
After discussion with the patient and his families, second-line pyrotinib (administered orally each day at a dose of 80 mg per day) and lenvatinib (administered orally each day at a dose of 12 mg per day) coexisting with pembrolizumab (administered 2 mg/kg as an intravenous infusion over 30 minutes every 3 weeks) were applied. After two months, the lesions in the liver were found to have increased by MRI, but tumor markers decreased. We reevaluated the efficacy of treatment with a multi-disciplinary team including surgery, internal medicine oncology, and radiology department. Pseudo-progression was suspected based on the performance improvement and decrease in tumor markers, so the patients continued the treatment.
Four months later, the PET-CT showed that the primary lesions had shrunk, accompanied by CA 199 and CEA response (CA 199 level decreased from 185 U/ml to 57.3 U/mL, CEA level decreased from 8.1ng/mL to 2.6 ng/mL). This evaluation of efficacy was a partial response. In June 2020, lenvatinib was reduced to 8 mg per day because of increased bilirubin. The recent response evaluation by PET-CT in May 2021, was a complete response. The progress free time of second-line treatment is 26 months up to now. The patient developed grade 3 adverse reactions after using three drugs including fatigue, irregular bowel movement, skin rash, hypertension, and increased bilirubin concentration, but no grade 4 or 5 adverse reactions were observed. Written informed consent to publish the case details was obtained from the patient.