Pazopanib is an oral small-molecule multi-kinase inhibitor(1). It can block vascular endothelial growth factor(VEGFR) -1 and − 2 to stop vasculogenesis and angiogenesis. It also effects VEGFR-3 of endothelial cells by blocking lymphagiogenesis, all of which lead to tumor necrosis. It can influence platelet endothelial growth factor receptor-α and -β expressed by tumor cells and stromal cells, causing blockage of autocrine stimulation, angiogenesis, and decreased tumor interstitial pressure, which are thought to be factors related to soft tissue tumor progression. In addition, pazopanib has an effect on the stem cell factor receptor C-kit, which inhibits tumor cell proliferation, survival, and decreased metastasis (Fig. 3)(2).
According to the results of a phase III clinical trial of pazopanib in patients with soft tissue sarcoma, adverse effects such as fatigue, diarrhea, nausea, weight loss, anorexia, hair hypopigmentation, vomiting, dysgeusia, mucositis, and hypertension were observed. Some uncommon adverse effects were described in the study, including venous thromboembolic events, pneumothorax, and cardiotoxicity(3). Bowel perforation was not noted. However, pazopanib is also used for renal cell carcinoma with metastasis. This indication of a phase III clinical trial has listed GI perforation or fistula as an adverse effect(4).
Bowel perforation is well known as an adverse effect of bevacizumab, which is also a VEGFR inhibitor. A meta-analysis revealed that the use of bevacizumab increased the risk of GI perforation with a relative risk of 2.14, 95% confidence interval (CI): 1.19–3.85, p = 0.011. The incidence of GI perforation ranged from 0–4.9%, and its incidence leading to death was 0.7%, 95% CI: 0.4–1.1%. The mortality associated with GI perforation was as high as 28.6% (range 15.0–47.6%)(5, 6) Although other VEGFR inhibitors, such as sorafenib, sunitinib, vandetanib, pazopanib, axitinib, regorafenib, tivozanib, cediranib, and cabozantinib, seemed to have a lower incidence of leading to bowel perforation, even close to the result with placebo, it was thought to be under evaluation owing to neglect of the risk associated with the medications(6). Pazopanib (Votrien) package inserts mention the risk of bowel perforation or fistula in their clinical trial. In a renal cell carcinoma trial, the incidence of GI perforation or fistula was 0.9% (5/586) with 0.3% (2/586) causing death(4). In a soft tissue sarcoma trial, the incidence of GI perforation or fistula was 1% (4/382) with 0.3% (1/382) causing death, which indicates a lack of sufficient published data in medical studies. A clinical trial of pazopanib was published in 2012; however, more details on GI tract complications have been reported since 2019 (Table 1). A study highlighted the complication in retroperitoneal leiomyosarcoma under pazopanib therapy which was thought to result in a tumor-bowel fistula. The median duration of treatment at the time of perforation or fistula formation was 7.4 months(7), which was consistent with the duration of 8 months for the initiation of pazopanib in our case for bowel perforation.
A 71-year-old man with a sizable recurrent malignant retroperitoneal tumor under pazopanib was reported in 2020(8). This case involved a colon perforation and he underwent an emergency left colectomy with end transverse colostomy. The author listed two major categories that influenced colon perforation risk while under pazopanib. One was the patient’s illness condition, including bowel obstruction, chemotherapy-induced colitis, diverticulitis, peptic ulcer, tumor or tumor necrosis, abdominal carcinomatosis, pancreatic primary cancer, ovarian primary cancer, tumor with rectosigmoid involvement, or bowel involvement on CT. The other was previous management with abdominal radiation, bowel surgery, receiving colonoscopy, non-steroidal anti-inflammatory drugs, or steroid use(8). However, in our case, there were no other risk factors except pazopanib use.
The question is whether Pazopanib leads to ulcer formation. It seems possible that pazopanib directly caused the ulcerative GI tract. A 61-year-old man with pulmonary metastasis of clear cell renal cell carcinoma who was treated with pazopanib presented duodenal ulcer perforation(9). There was no Helicobacter pylori infection or non-steroidal anti-inflammatory drug usage in that case. The association between penetrating ulcers and pazopanib was emphasized by the author.
As a member of the VEGFR inhibitor family, pazopanib remains a risk factor for vascular thrombus events(3, 10–12) and leads to the regression of intestinal vasculature(6, 13). These phenomena may lead to ischemic colitis or micro-perforation. Pazopanib-related ulcer formation has also been observed by other physicians(6, 9). With the use of VEGFR inhibitors, ulceration healing status is influenced; therefore, perforation may have developed(6, 14). Other colon illnesses, including diverticulosis, diverticulitis, radiation colitis, and bowel obstruction, will also aggravate owing to poor vascular supply under pazopanib use(8), which eventually results in colonic perforation. The other possible pathway is that the tumor involves the bowel and has a good response to pazopanib, leading to tumor necrosis and perforation. (Fig. 4)
Because the initial presentation was more like a thrombus event with lower chest pain instead of a typical peritonitis, no abdominal CT scan image was available, which could support our conjecture that ischemic changes result in ulcer formation. However, after ruling out other risk factors for bowel perforation, pazopanib therapy was the major suspect in relation to the event.