To the Editor
Established systemic treatment choices for metastatic neuroendocrine tumours (NETs) are somatostatin analogues and alpha interferons (IFN-alpha) both reducing the secretory activity of the tumour. IFN-alpha also has an anti-proliferative effect, inhibiting angiogenesis, blocking the cell cycle, and stimulating apoptosis Citation[1]. Chemotherapy has limited value, used in NETs with a high-proliferative index.
Angiogenesis has raised interest as a new target in NETs. This interest is fuelled by the fact that NETs are highly vascularised and vascular endothelial growth factor (VEGF) and its receptors are present Citation[2]. We performed a study with IFN-alpha, 5-fluorouracil (5-FU) and leucovorin in patients with metastatic NETs because of the suggested synergistic effects between 5-FU and IFN-alpha, and promising results of this combination obtained by others Citation[3]. In this feasibility study, approved by the Medical Ethical Committee, patients were treated with IFN-alpha-2b (2.5 million U/day subcutaneously), and after 2 weeks, intravenous 5-FU 750 mg/m2 (day 2) and oral leucovorin 180 mg/day (day 1 and 2) was added as a 2 weekly cycle.
The primary endpoint was toxicity, the secondary endpoints included radiological and biochemical response. In addition, serum was prospectively stored for serum VEGF level measurements.
This study was prematurely closed after nine patients because of side effects. After one cycle, three patients had to stop, because of grade 3 fatigue (n = 2) and heart failure (n = 1). Three additional patients discontinued after respectively two, three and four cycles because of arthritis and polyneuropathy (n = 1) and grade 3-4 diarrhoea and fatigue (n = 2). The remaining three patients completed 10, 19 and 20 cycles. Median survival was 22 months; two patients are still alive after 144 months. All three radiological evaluable patients experienced stable disease lasting 5–84 + months.
Serum VEGF levels (R&D Systems, Minneapolis, USA) decreased in seven of eight evaluable patients, from a median level of 352 pg/ml (range 41–1 276 pg/ml) to 219 pg/ml (range 18–938 pg/ml), a median reduction of 40% in 88 days (median) (range 34–462 days). This suggests an antiangiogenic effect of the combination IFN-alpha and 5-FU. One study showed that IFN-alpha alone did not reduce serum VEGF levels in patients with carcinoid tumours, although it did in another study (median reduction 33%) also decreasing VEGF mRNA expression in liver metastases Citation[1], Citation[4].
In the present study toxicity was considerable. Next to the synergistic effect of this regime, IFN-alpha also can potentiate the toxicity of 5-FU. Four different dosages of 5-FU and IFN-alpha were previously studied in patients with NETs, only the regimen in a study of Andreyev and colleagues was well tolerated in which 5-FU was given continuously Citation[3].
Bevacizumab, a monoclonal antibody against VEGF was found to prolong progression free survival compared to IFN-alpha in carcinoids while sunitinib, a tyrosine kinase inhibitor, induced stable disease in NETs Citation[5], Citation[6]. Recently Zhang et al. showed that bevacizumab inhibited tumour growth in carcinoid xenograft, but at the same time up regulation of VEGF transcription occurred as a possible resistance mechanism Citation[2]. During sunitinib therapy elevated baseline serum VEGF also increased, possibly due to resistance Citation[7].
We conclude that this combination of 5-FU and IFN-alpha is not feasible due to side effects. However taken our observation of decreased VEGF levels, less toxic modifications, e.g. 5-FU given continuously or IFN-alpha combined with capecitabine, an oral fluoropyrimidine prodrug, in combination with one of the new antiangiogenic drugs can be envisioned. Such a regime might potentiate the effect of angiogenesis inhibitors.
References
- Rosewicz S, Detjen K, Scholz A, von Marschall Z. Interferon-alpha: Regulatory effects on cell cycle and angiogenesis. Neuroendocrinology 2004; 80(Suppl 1)85–93
- Zhang J, Jia Z, Li Q, Wang L, Rashid A, Zhu Z, et al. Elevated expression of vascular endothelial growth factor correlates with increased angiogenesis and decreased progression-free survival among patients with low-grade neuroendocrine tumors. Cancer 2007; 109: 1478–86
- Andreyev HJ, Scott-Mackie P, Cunningham D, Nicolson V, Norman AR, Badve SS, et al. Phase II study of continuous infusion fluorouracil and interferon alfa-2b in the palliation of malignant neuroendocrine tumors. J Clin Oncol 1995; 13: 1486–92
- Nilsson A, Janson ET, Eriksson B, Larsson A. Levels of angiogenic peptides in sera from patients with carcinoid tumours during alpha-interferon treatment. Anticancer Res 2001; 21: 4087–90
- Yao, JC, Ng, C, Hoff, PM, Phan, AT, Hess, K, Chen, H, et al. Improved progression free survival (PFS), and rapid, sustained decrease in tumor perfusion among patients with advanced carcinoid treated with bevacizumab. J Clin Oncol 2005;23:16S, Abstract 4007.
- Kulke, MH, Lenz, HJ, Meropol, NJ, Posey, J, Ryan, P, Picus, J, et al. A phase 2 study to evaluate the efficacy of SU11248 in patients with unresectable neuroendocrine tumors. J Clin Oncol 2005;23:16S, Abstract 4008.
- Bello, CL, Deprimo, SE, Friece, C, Smeraglia, J, Sherman, L, Tye, L, et al. Analysis of circulating biomarkers of sunitinib malate in patients with unresectable neuroendocrine tumors (NET): VEGF, IL-8, and soluble VEGF receptors 2 and 3. J Clin Oncol 2006;24:18S, Abstract 4045.