Word of Caution on Angiogenesis Inhibitor for Liver Cancer

A 66-year-old man presents to an emergency department in New York City with confusion and progressively worsening altered mental status. Two years previously he was diagnosed with stage 3b hepatocellular carcinoma (HCC), and his comorbidities include liver cirrhosis, chronic hepatitis C (Child-Turcotte-Pugh B), and hypothyroidism.

CT of the abdomen and pelvis reveals the tumor to be in the right lobe of the liver, 3 cm in size and located in segments V and VI.

Treatment (as part of a clinical trial) had initially included pembrolizumab (Keytruda) and lenvatinib (Lenvima), but when this regimen failed, his therapy was changed to ramucirumab (Cyramza), an approved second-line treatment for HCC.

At the time of his presentation to the emergency department, he had been taking ramucirumab for 4 months.

Vital signs at presentation include:

• Blood pressure 145/90 mm Hg

• Pulse 92 beats/min

• Respiratory rate 17 breaths/min

• Oxygen saturation 98% on room air

Physical examination shows no focal neurological deficits, widespread abdominal tenderness, and no bowel sounds.

Laboratory test results of note include:

• Hemoglobin 11.8 g/dL

• Leukocytes 14 × 10/μL

• Alanine aminotransferase (ALT) 17 U/L

• Aspartate aminotransferase (AST) 54 U/L

• Total bilirubin 2.0 mg/dL

• Direct bilirubin 1.0 mg/dL

• Ammonia 91 μmol/L

• Lactate 4.7 mmol/L

All other findings are within normal range.

One month previously, results of the patient's baseline liver function tests showed:

• ALT 15 U/L

• AST 50 U/L

• Total bilirubin 1.7 mg/dL

• International normalized ratio 1.6

• Albumin 2.8 g/L

CT of the head and chest show no evidence of significant acute pathology, but CT of the abdomen and pelvis with contrast material reveal pneumoperitoneum with multiple abdominal and pelvic collections.

Given the patient's leukocytosis, lactic acidosis, peritoneal signs on physical examination, and CT scan with multiple fluid collection areas, clinicians suspect gastric or duodenal perforation and start the patient on broad-spectrum antibiotics.

Exploratory laparotomy identifies a nodular shrunken liver with necrotic parenchyma in segments V and VI of the liver, which appears to be perforated. A microperforation is also noted in the proximal duodenum.

Clinicians remove necrotic tissue, the omentum is packed in the liver bed, and 6 L of ascitic fluid is drained.

The pathology sample reveals fragments of HCC with extensive necrosis. The peritoneal fluid analysis is consistent with secondary bacterial peritonitis (white blood cell count 6,200 cells/mm³ with 92% neutrophils), and cytology is negative for malignant cells.

Clinicians prescribe antibiotic therapy with piperacillin-tazobactam, however, the patient develops multiorgan dysfunction. A palliative therapy approach is implemented, and the patient is discharged to hospice care.

Discussion

Clinicians reporting this rare case of HCC and duodenal perforation in the setting of ramucirumab treatment note that these potentially severe effects have increasingly been reported with this antiangiogenic drug.

Liver cancer is the sixth most common cancer worldwide, and the fourth leading cause of cancer-related death globally. HCC develops in 85-95% of patients with cirrhosis of the liver, at a rate of 2-7% per year, the case authors note, adding that HCC has an incidence/mortality ratio of almost 1:1, showing that ultimately, few patients survive.

While spontaneous rupture of these tumors affects fewer than 3% of patients in western countries, the incidence reaches 12-14% in Asian countries, with an overall mortality rate of almost 50%.

Ramucirumab is a recombinant human immunoglobulin G1 monoclonal antibody that binds to the extracellular binding domain of vascular endothelial growth factor (VEGFR)-2 to prevent the binding of VEGFR ligands, the case authors explain. The drug thus inhibits the angiogenesis pathways involved in the development and progression of cancer.

However, the medication has been associated with hypertension and proteinuria, as well as hemorrhage and GI perforation, which may be severe or even fatal, the authors note.

They cite a 2016 meta-analysis of 11 studies in approximately 5,000 patients with a variety of solid tumors, showing overall incidences of 27.6% of all-grade and 2.3% high-grade hemorrhagic events. The relative risk of hemorrhagic events with ramucirumab compared with control patients was significantly increased for low-grade (RR 2.06, 95% CI 1.85-2.29, P < 0.001) but not high-grade (RR 1.19, 95% CI 0.80-1.76, P=0.39) hemorrhagic events, with the risk varying depending on tumor type and ramucirumab dosage.

Those researchers concluded that hemorrhagic events associated with ramucirumab are modest and manageable and that patients could continue to receive ramucirumab treatment to achieve maximum clinical benefits.

Another analysis of ramucirumab data, however, noted a 1.5% rate of all grades of GI perforation, with approximately 30% mortality. However, in a letter to the editor about the study, researchers with the drug's manufacturer, Eli Lilly, disputed the accuracy of the report, saying that data were missing and there were errors in calculation.

The case authors note that importantly, after carcinoma progression and liver failure, spontaneous rupture is the third leading cause of mortality in patients with HCC.

Factors known to be associated with an increased risk for spontaneous rupture include underlying diseases of hypertension, liver cirrhosis, tumor size over 5 cm, vascular thrombus, and extrahepatic invasion.

The mechanism of tumor rupture in HCC is poorly understood, the case authors observe, noting that the VEGF signaling pathway is involved in HCC angiogenesis and lymphangiogenesis and likely plays a crucial role in the pathogenesis of the disease.

The "vascular injury hypothesis" suggests that certain changes in the arterial walls supplying the tumor could lead to HCC rupture; these vascular changes may also include collagenase expansion, leading to degradation of type IV collagen and elastin proliferation, a process the case authors said they believe was accelerated in their patient although they caution that large-scale studies are still needed to explore this association.

Ramucirumab's antiangiogenic activity raises concern about serious adverse effects in addition to GI perforation, including impaired wound healing and hemorrhage.

Although a spontaneous rupture in a tumor smaller than 5 cm remains rare (in the case of this patient the size was 3 cm), "the gross specimen recovered from surgery in our patient showed necrotic liver tissue with clots, whereas the biopsy specimen showed HCC with extensive necrosis," the authors write. "Another important finding in our patient was the presence of a microperforation in the proximal duodenum leading to pneumoperitoneum."

The patient had no known risk factors for GI perforation -- i.e., no history of alcohol abuse, trauma, foreign body ingestion, peptic ulcer disease, primary or metastatic intestinal tumor, or use of nonsteroidal anti-inflammatory drugs.

The FDA recommends discontinuing ramucirumab permanently in patients who have perforation, and as with HCC rupture, antiangiogenesis is the likely mechanism for GI perforation.

In addition, the case authors write, there is no standard approach to treatment of a ruptured HCC tumor: the main goal is to correct hypovolemic shock, with subsequent treatment options based on an individual patient's tumor stage and feasibility of resection. Conservative management has been linked to a mortality rate of 85-100%.

In the acute phase, transarterial embolization effectively controls bleeding from the ruptured HCC. Important prognostic considerations include serum bilirubin levels, shock on hospital admission, and prerupture disease state.

The case authors advise that elective liver resection after achieving initial hemostasis via transarterial embolization is preferred over emergency liver resection, since tumor stage and liver function reserve are unclear in the latter.

Conclusions

In conclusion, the authors state, ramucirumab has shown efficacy in patients with advanced HCC, although there are still concerns about the risk of serious antiangiogenic adverse effects including not only GI perforation but also impaired wound healing and hemorrhage.

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