Investigational New Drugs

, Volume 29, Issue 5, pp 1090–1093 | Cite as

Pneumatosis intestinalis associated with treatment of cancer patients with the vascular growth factor receptor tyrosine kinase inhibitors sorafenib and sunitinib

  • Romain Coriat
  • Stanislas Ropert
  • Olivier Mir
  • Bertrand Billemont
  • Stanislas Chaussade
  • Pierre-Philippe Massault
  • Benoit Blanchet
  • Olivier Vignaux
  • François Goldwasser
SHORT REPORT

Summary

Recently, pneumatosis intestinalis has been described in patients receiving bevacizumab, a monoclonal antibody to VEGF-A. Pneumatosis intestinalis is a condition characterized by subserosal and submucosal gas-filled cysts in the gastrointestinal tract. We report on pneumatosis intestinalis in patients receiving oral anti-VEGF agents. Patients shared the following characteristics: long-term (> 4 months) exposure to anti-VEGF agents, lack of other factors predisposing to pneumatosis intestinalis, and lack of recent surgical intervention. Taken together, these observations suggest that pneumatosis intestinalis is a probable class-effect of anti-VEGF agents.

Inhibitors of vascular endothelial growth factor (VEGF) signalling pathway can block angiogenesis and thereby reduce tumor growth. Multi-targeted tyrosine kinase inhibitor sorafenib (BAY-43-9006 Nexavar® ; Bayer Pharmaceuticals Corp. Wayne NJ and Onyx Pharmaceuticals Inc. Emeryville CA) block the Ras-Raf kinase pathway in cancer cells, as well as the VEGF and the platelet-derived growth factor (PDGF) receptors on endothelial cells [1]. Sunitinib malate (Sutent®; Pfizer, New York, NY), another tyrosine kinase inhibitor, targets various receptors including VEGF and PDGF receptors, and c-KIT [2].

Recently, pneumatosis intestinalis has been described in patients receiving bevacizumab (Avastin®; Genentech Inc, South San Francisco, CA), a monoclonal antibody to VEGF-A [3].

Pneumatosis intestinalis is a condition characterized by subserosal and submucosal gas-filled cysts in the gastrointestinal tract. The diagnosis is best made using computed tomography, on which its appearance is described as diffuse, microvesicular or cystic [4].

We report on three cases of pneumatosis intestinalis in patients receiving oral anti-VEGF agents. All patients had prospective monitoring of plasma drug levels in our center. We point out the role of treatment duration rather than excessive systemic exposure, and propose a pathophysiological mechanism for pneumatosis intestinalis occurring during anti-VEGF therapy.

Case reports

Patients’ characteristics are summarized in Table 1. Basically, they shared the following characteristics: long-term (> 4 months) exposure to anti-VEGF agents, lack of other factors predisposing to pneumatosis intestinalis, and lack of recent surgical intervention.
Table 1

Patients’ characteristics

 

Gender, age (years)

Primary tumour

Metastatic sites

Prior therapy

Time under anti-VEGF treatment

Overall survival (months)

1

F, 40

Fibrolamellar carcinoma

- Liver

- Liver surgery

5 months

+6 months

- Lung

2

F, 48

Papillary Thyroid Cancer

- Brain metastasis

- Iratherapy

23 months

1 monthsa

- Lymph nodes

- Bones

- Liver

3

M, 68

Renal Cell carcinoma

- Lymph nodes

- Nephrectomy

28 months

+16 months

- Irradiation

- Bone

- Temserolimus

aPatient died of disease progression; + patients alive at follow-up

Case 1

A 40-year-old woman had a medical history of invasive fibrolamellar carcinoma resected 2 years ago. During follow-up, multiple liver and lung metastases were discovered, and the patient was started on sorafenib 400 mg bid. Within the first two months, side effects were grade 1 diarrhea and hand-foot skin reaction, weight loss of 4 kg, and grade 3 hypertension managed with calcium channel blocker (felodipine). Five months after the beginning of sorafenib treatment, the patient presented with a 24-hour history of mild abdominal pain and temperature up to 39°C. On admission, her body temperature was 37°C, and she had a blood pressure of 131/92 mm Hg. Physical examination was otherwise unremarkable. Laboratory findings showed no anemia (haemoglobin: 13.6 g/dL), but a biological inflammation with thrombocytosis (690000 G/L), elevated C-reactive protein (36.6 mg/dL) and hyperleukocytosis (13580 G/L). An abdominal computed tomography (CT) revealed a moderate pneumoperitoneum and extensive small bowel pneumatosis. Neither bowel obstruction nor necroses were suspected on CT.

Case 2

Second case concerns a 48-year-old woman with a medical history including chronic lymphoid hemopathy associated with monoclonal gammopathy without treatment, pericarditis, and invasive papillary thyroid carcinoma treated with surgery and Radioactive Iodine I-131 therapy 10 years earlier. During follow-up, multiple lymph nodes and bones metastases were evidenced. Sorafenib was started at 400 mg bid and continued for 20 months until progressive disease (bone metastasis) was diagnosed. Sorafenib was switched to sunitinib at a dose of 37.5 mg/day (4 weeks out of 6). Within the first two months, side effects were exclusively grade 2 hand-foot skin reactions, and diarrhea. Five months after the introduction of sunitinib, the patient presented with a 24-hour history of diarrhea and mild abdominal pain, together with deterioration of general condition. Abdominal CT revealed an extensive small bowel pneumatosis with peritoneal effusion (Fig. 1). No bowel obstruction or necrosis was suspected on the CT.
Fig. 1

Computed tomography showing bubblelike pneumatosis (long arrow) in small bowel

Case 3

Third case concerns a 68-year old man with a medical history of pulmonary embolism and invasive renal carcinoma resected 6 years ago. During follow-up, bone metastases were discovered within the first 2 years post-surgery, justifying bone irradiation. Three years after the end of irradiation, the patient developed bone pain secondary to metastases. Sunitinib was then started at a dose of 50 mg/day (4 weeks out of 6), then 37.5 mg/day (4 weeks out of 6) for recurrent abdominal pain. Other side effects were grade 2 diarrhea. Twenty seven months after the initiation of sunitinib, the patient developed a cauda equina syndrome without digestive symptoms. Abdominal CT revealed an extensive small bowel pneumatosis and a peritoneal effusion. Since bowel necrosis was suspected on CT, the patient underwent surgical exploration that confirmed the pneumatosis intestinalis without necrosis.

Plasma exposure of tyrosine kinase inhibitors

Patients underwent a prospective monitoring of plasma concentrations of tyrosine kinase inhibitors (routinely assessed every 2 weeks in our institution). At the time of diagnosis of pneumatosis intestinalis, no overexposure was noticed. Hence, sorafenib Cmax was 6.0 mg/L in case 1, and sunitinib Cmax were 102.5 mg/l in case 2 and 30.9 mg/l in case 3. These values were within the range of concentrations observed in phase 1 studies of these drugs [5, 6].

Evolution of Pneumatosis intestinalis

Given the reassuring physical examination in all three cases, symptomatic treatment was implemented, which included fasting, parenteral nutrition, anti-emetics and close surveillance. Anti-VEGF therapy was stopped. The symptoms gradually tapered, and abdominal CT carried out 4 weeks later showed complete resolution of the intestinal pneumatosis and the pneumoperitoneum in all three patients. In the third case, anti-VEGF therapy was re-introduced seven months after complete recovery. No recurrences were diagnosed over the following 10 months (date of last follow-up: march 10).

Discussion

Sorafenib and sunitinib are oral multi-tyrosine kinase inhibitors with Food and Drug Administration approval for the treatment of advanced renal cell carcinoma (both drugs), hepatocellular carcinoma (sorafenib) and gastrointestinal stromal tumors (sunitinib). Both drugs block the VEGF and PDGF receptors on endothelial cells [1], and have a significant impact on the capillary beds of small intestinal villi. Such inhibition was found to significantly reduce capillary density within these intestinal villi. Hence, they may contribute to the development of micro-perforation within the intestinal wall secondary to reduced regenerative capacity of the intestinal mucosa, as a result of the decreased blood vessel density [7, 8, 9].

In this case series, sunitinib and sorafenib were introduced at least five months before the onset of pneumatosis intestinalis. Time exposure to the drug may induce chronic damage to the intestinal microvasculature due to VEGF pathway inhibition. This long drug exposure was constantly mentioned in previously reported cases.

Pneumatosis intestinalis is a pathologic condition defined as infiltration of gas into the wall of the gastrointestinal tract. Pneumatosis intestinalis is seen in other conditions than chemotherapy, including chronic obstructive pulmonary disease, connective tissue disorders, infectious enteritis, celiac disease, leukemia, amyloidosis, and acquired immunodeficiency syndrome; it is also found in association with organ transplantation, and steroid use [10, 11, 12]. Asthma, emphysema, and cystic fibrosis are the main benign causes for pneumatosis intestinalis. Those aetiologies are thought to induce chronic tissular hypoxia and particularly bowel hypoxia. VEGF inhibitors can block angiogenesis and reduce tumor growth vascularity, thereby inducing chronic tumor ischemia [13]. Similarly, one could hypothesize that chronic hypoxia induced by VEGF inhibition in healthy tissues might increase abdominal hypoxia, and thus favor the occurrence of pneumatosis intestinalis. Moreover, repeated cholesterol embolies might participate to bowel hypoxia. Indeed, antiangiogenic treatments favor the embolies from the atheroma [14]. Whereas other acute digestive side effects of anti-VEGF agents such as perforation have been described early after initiation of therapy [15], pneumatosis intestinalis should be considered as a unpredictable effect after a long exposure to drugs [16].

Pneumatosis intestinalis is usually diagnosed on abdominal CT scan. It may be associated with bowel ischemia, perforation, and a subsequent high mortality rate. As a result, many authorities advocate an aggressive surgical approach in patients with pneumatosis intestinalis.

Our patients diagnosed with pneumatosis intestinalis triggered by VEGF inhibitors didn’t developed bowel ischemia [3, 17]. All patients had a complete recovery within 4 weeks after anti-VEGF therapy was stopped. Little is known about the reversibility of abnormal digestive vascularity after treatment withdrawal. However, rebound in tumour growth and revascularization have been previously documented in mice and in humans after anti-VEGF treatment withdrawal [18, 19].

Although rare, pneumatosis intestinalis has already been reported in patients receiving sunitinib or bevacizumab [3, 17]. To the best of our knowledge, we presently report on the first case of pneumatosis intestinalis in a patient treated with sorafenib. Taken together, these observations suggest that according to the Naranjo scale pneumatosis intestinalis is a probable class-effect of anti-VEGF agents [20].

Conclusion

Our observations suggest that all VEGF inhibitors may be involved in the occurrence of pneumatosis intestinalis, a rare side effect potentially due to chronic bowel ischemia. This is the first report of pneumatosis intestinalis induced by sorafenib.

In this case series, pneumatosis intestinalis induced by VEGF inhibitors occurred after a long exposure to the causative drug, and may be poorly symptomatic.

Clinicians should keep in mind that in absence of perforation or necrosis, pneumatosis intestinalis can be managed by treatment interruption and symptomatic treatment.

Notes

Acknowledgments

Acknowledgments of research support for the study: none.

Competing interest

None.

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Copyright information

© Springer Science+Business Media, LLC 2010

Authors and Affiliations

  • Romain Coriat
    • 1
    • 2
    • 3
    • 7
  • Stanislas Ropert
    • 1
    • 2
  • Olivier Mir
    • 1
    • 2
  • Bertrand Billemont
    • 1
    • 2
  • Stanislas Chaussade
    • 1
    • 3
  • Pierre-Philippe Massault
    • 1
    • 4
  • Benoit Blanchet
    • 1
    • 5
  • Olivier Vignaux
    • 1
    • 6
  • François Goldwasser
    • 1
    • 2
  1. 1.Center for Research on Angiogenesis Inhibitors (CERIA)Université Paris Descartes, AP-HP, Teaching Hospital CochinParisFrance
  2. 2.Department of Medical OncologyTeaching Hospital CochinParisFrance
  3. 3.Department of GastroenterologyTeaching Hospital CochinParisFrance
  4. 4.Department of SurgeryTeaching Hospital CochinParisFrance
  5. 5.Laboratory of PharmacologyTeaching Hospital CochinParisFrance
  6. 6.Department of RadiologyTeaching Hospital CochinParisFrance
  7. 7.Center for Research on Angiogenesis Inhibitors (CERIA), Medical Oncology UnitUniversité Paris DescartesParisFrance

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