The incidence of sunitinib or sorafenib related GI perforation is unknown, since only few cases were reported in trials [
6‐
13] and case reports [
14‐
20]. Because of the potential serious outcome, it would be extremely helpful if we could predict patients at-risk on basis of risk factors and underlying biological mechanisms. In addition, more insight in these underlying mechanisms is important to develop potential novel agents with an improved toxicity profile.
Since the first observations of GI perforation during bevacizumab treatment, the risk factors of primary tumor in situ and recent history of endoscopy or abdominal radiotherapy [
5,
21‐
26] were described. Pathological findings, frequently associated with observed perforations, include perforation at the tumor or anastomotic site, abdominal carcinomatosis, diverticulitis, GI obstruction and intra-abdominal abcess [
5,
22‐
24]. Different biological mechanisms of bevacizumab related perforations have been theorized, which we have outlined in the next part. Whether the same risk factors and mechanisms may be involved in TKI related perforation is unknown, but seems very likely, because both type of agents inhibit VEGF signaling. We have summarized in Table
1 that for both type of agents, gastrointestinal perforations were reported in diverse parts of the gastrointestinal tract. In the reported cases for sunitinib and sorafenib, tumor cells at the site of perforation and previous radiation treatment were frequently mentioned similar to bevacizumab reports [
6,
13‐
17].
Table 1
An overview of the percentages and localisations of all reported gastrointestinal perforations for treatment with sunitinib and sorafenib and of a few larger studies and meta-analyses regarding bevacizumab treatment
Sunitinib | Phase I | Various | 7.1% (2/28) | Rectum (fistula) | |
Phase II | RCC | 1.1% (1/88) | Colon | |
Phase II | PAC | 2% | Gastrointestinal | |
Case report | GIST | 1 pt | Transverse colon | |
Retrospective | GIST | 7.1% (3/42) | Bowel | |
Retrospective (sunitinib or imatinib) | GIST | 4 pts | Intestinal | |
Case report | RCC | 2 pts | Ascending colon | |
Case report | RCC | 1 pt | Peri-anal (fistulas) | Walraven et al. |
Sorafenib | Phase II | Sarcomas | 0.7% (1/144) | Bowel | |
Phase II | Melanoma | 2.7% (1/37) | Intestinal | |
Phase II | GIST | 3.8% (1/26) | Not mentioned | |
Phase II | Galbladder canc./cholangiocarc. | 2.7% (1/36) | Gastrointestinal | |
Phase I (plus chemo) | NSCLC | 7.7% (1/13) | Small bowel | |
Case report | RCC | 1 pt | Left colon | |
Case report | RCC | 1 pt | Transv. and sigm. colon (multiple perforations) | |
Case report | Melanoma | 1 pt | Ascending colon (multiple perforations) | |
Case report | RCC | 1 pt | Colon | Walraven et al. |
Bevacizumab | Phase III (plus chemo) | CRC | 1.5% (6/393) | Gastrointestinal | |
Phase III (plus chemo) | CRC | 1.9% (37/1914) | Gastrointestinal | |
BRITE registry (plus chemo) | CRC | 1.7% (34/1968) | Gastrointestinal | |
Literat. search (single agent/plus chemo/plus erlotinib) | Gynaecologic tumors | 5.4% (16/298) | Bowel | |
Retrospective (single agent/plus chemo) | Various | 1.7% (24/1442) | Gastroesophageal, -jejunostomy, duodeno-pancreatic, small bowel, appendix, colorectal | |
Meta-analysis (plus IFN/chemotherapy/erlotinib) | Various | 0.9% (of >6000 pts) | Gastrointestinal | |
Case report (plus chemo) | CRC | 1 pt | Rectal and anal | Walraven et al. |
Case report (plus antiangiogenic TKI) | Ovarian cancer | 1 pt | Colon | Walraven et al. |
Possible mechanisms of GI perforations due to angiogenesis inhibition
Tol et al. [
27] suggested a relationship between bevacizumab treatment and ulcer development, which may eventually cause a GI perforation. In a phase III study with 755 patients receiving chemotherapy with bevacizumab plus or minus cetuximab, twelve GI perforations were observed of which four were located in an ulcer. The high incidence of ulcers in this study (1.3 vs. 0.1% in the general population), the occurrence of perforations early in treatment, the established role of VEGF in ulcer healing [
28‐
30] and the inhibitory effect of bevacizumab on wound healing support their hypothesis. Since the majority of perforations were located at the primary tumor site, pre-existent mucosal lesions were expected as preferential localizations.
In another report it was speculated that bevacizumab induced VEGF inhibition might result in the cholesterol emboli syndrome (CES), which may consequently give rise to GI perforations due to mesenteric ischemia [
31]. Hypertension in combination with eosinophilia is a feature of CES. All three out of twenty-two prospectively observed patients who developed hypertension during bevacizumab treatment had atherosclerotic risk factors, an increased heart rate and eosinophilia at onset of hypertension. In this report it was hypothesized that CES might cause all acute bevacizumab related complications in atherosclerotic patients, including GI perforations as a consequence of mesenteric ischemia.
Alternatively, Saif et al. [
22] postulated that GI perforation is caused directly by regression of normal blood vessels in the GI tract, induced by excessive VEGF inhibition. The authors extrapolated data from animal models in which VEGF inhibition has shown to reduce vascular density in the small intestinal villi as well as in other organs [
32].
In a recent editorial on the risk of bevacizumab associated GI perforation in ovarian cancer it was speculated that bevacizumab induces necrosis of malignant ovarian cells that invade the bowel serosa resulting in GI perforation [
4]. In addition, in this editorial it was suggested that increased pressure due to abdominal carcinomatosis or adhesions from prior surgeries might lead to micro-perforations in vulnerable areas of the bowel, with subsequent delayed healing due to bevacizumab. Finally, loss of nitric oxide (NO) release due to VEGF inhibition, leading to decreased blood flow to the splanchnic vasculature, was proposed to result in bowel infarction and perforation at areas with marginal blood supply.
On account of early closure of the ORBIT trial, evaluating bevacizumab treatment in platinum resistant ovarian cancer, tumor involvement of the bowel was suggested [
33]. Five out of 44 patients developed GI perforation and showed radiographic evidence of bowel involvement at study entry. A significant association of GI perforations with increased number of prior chemotherapy regimens (respectively three) and a non-significant relation with bowel wall thickening/obstruction were found. In contrast, in another study with twenty-five heavily pretreated (median of five prior chemotherapy regimens) patients with advanced ovarian cancer, treatment with bevacizumab did not cause any GI perforations [
34].
We recently discussed the role of platelets in antiangiogenic treatment related toxicity [
35,
36]. Platelets contain VEGF in their α-granules which they secrete upon activation and on the other hand VEGF activation of the endothelium results in platelet binding and subsequent activation [
37‐
39]. In addition, we found that bevacizumab is taken up by platelets, leading to VEGF neutralization [
35]. Since VEGF is an endothelial cell survival factor [
2,
40,
41], we postulated that the subsequent disturbed platelet-endothelial cell interaction might be involved in GI perforation, disturbed wound healing and bleeding complications [
36]. The platelet–endothelial cell homeostasis may be disturbed by antiangiogenic treatment. Therefore an increased leakiness and extravasation of inflammatory cells may cause submucosal inflammation and subsequent ulcer formation.
It is of clinical importance to study underlying biological mechanisms of bevacizumab related GI perforation. In addition, it is expected that these underlying mechanisms and risk factors might account for antiangiogenic TKI treatment as well. Risk factors of tumors at the primary site and recent history of endoscopy or abdominal radiotherapy should be taken into account before treatment initiation with angiogenesis inhibitors. In ovarian cancer patients it is recommended to consider the number of prior chemotherapy regimens and abdominal surgeries and to exclude tumor involvement of the bowel by physical examination and CT-scan upon start of treatment with angiogenesis inhibitors. Endoscopic evaluation is advised in patients with symptoms possibly related to GI ulcer during treatment [
27]. In addition, based on this report, rubber band ligation should be prevented until bevacizumab or TKI treatment is interrupted or terminated. The third case of GI perforation during combined bevacizumab and TKI treatment emphasizes a possible increased perforation risk related to combination treatment with antiangiogenic agents with different biological mechanisms. Although most of the current preclinical and clinical knowledge on potential underlying mechanisms of angiogenesis inhibitor induced gastrointestinal perforations is on bevacizumab, based on preclinical and clinical studies potential underlying mechanisms as described may hold true for TKI-induced perforations as well.
In conclusion, we would like to advocate to include GI perforation in the differential diagnoses, when patients complain of (vague) abdominal pain during treatment with TKIs as well as with bevacizumab.