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Combination therapy with bevacizumab and temsirolimus in squamous cell carcinoma of the head and neck
Oral Oncology 49 (2013) e25
Contents lists available at SciVerse ScienceDirect
Oral Oncology journal homepage: www.elsevier.com/locate/oraloncology
Letter to the editor Combination therapy with bevacizumab and temsirolimus in squamous cell carcinoma of the head and neck
Bauman et al.1 report the result of a phase II study of temsirolimus and erlotinib in recurrent or metastatic platinum-refractory squamous cell carcinoma of the head and neck (SCCHN), which was prematurely closed because of poor tolerance. In their study, eighty-two percent (9/11) of patients had loss of the phosphatase and tensin homolog (PTEN) and 8% (1/12) had mutations in the phosphotidylinositol-3-kinase (PIK3CA). There was no correlation between loss of PTEN and patient outcome. Interestingly, higher baseline vascular endothelial growth factor (VEGF) (p = 0.07) and interferon-V levels (p = 0.09) marginally correlated to lack of response.1 Although the lack of statistical significance does not allow definite conclusion regarding VEGF level and the response rate, the study was not adequately powered to detect such a difference. Prior studies have shown that VEGF-A and VEGF-C are overexpressed in SCCHN and correlate with OS.2 In a meta-analysis of 12 studies (n = 1002) in patients with SCCHN, VEGF overexpression was associated with an estimated 2-year mortality risk ratio of 1.88 (95% confidence interval, 1.43–2.45; p < 0,001).3 These results indicate a potential role of VEGF pathway activation in tumor proliferation in SCCHN. Bauman’s study1 also suggests that either loss of PTEN does not correlate with the sensitivity to mammalian target of rapamycin (mTOR) inhibitors or blockade of PI3K/AKT/mTOR pathway alone is not effective in SCCHN. In another recent study by Holsinger et al. only patients treated with temsirolimus and bevacizumab (n = 3), as opposed to temsirolimus monotherapy (n = 2), had tumor regression.4 Patients included had either PTEN loss or PI3KCA mutation, however, VEGF level was not reported.4 Taken all these results together, this indicates a possible synergistic effect of combination therapy of temsirolimus and bevacizumab in SCCHN. Preclinical evidence suggests a possible synergism between temsirolimus and bevacizumab in SCCHN. In a head and neck cancer xenograft model, temsirolimus demonstrated synergistic antiproliferative effects when added to the combination of radiation therapy, cetuximab and bevacizumab. The use of combination therapy was associated with lower Ki67 staining (reduced tumor proliferation) and lower Bcl2 expression (greater apoptosis) in the tumor.5 In a more recent study, the combination of temsirolimus and bevacizumab showed synergistic inhibition of SCC in xenograft model. This combination also resulted in partial response in two patients with multiply relapsed SCCHN.6 In the Holsinger study,4 only combination therapy with temsirolimus and bevacizumab resulted in tumor regression. Although temsirolimus
1368-8375/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.oraloncology.2013.04.001
monotherapy is not effective and combination therapy with temsirolimus and erlotinib was poorly tolerated, dual inhibition of VEGF pathway and PI3/AKT/mTOR pathway, both of which are activated in SCCHN,2,7 may be of benefit in SCCHN. Trials focused on combination therapy with bevacizumab and temsirolimus should be conducted to explore their utility. References 1. Bauman JE, Arias-Pulido H, Lee SJ, et al. A phase II study of temsirolimus and erlotinib in patients with recurrent and/or metastatic, platinum-refractory head and neck squamous cell carcinoma. Oral Oncol. 2. Thomas GR, Nadiminti H, Regalado J. Molecular predictors of clinical outcome in patients with head and neck squamous cell carcinoma. Int J Exp Pathol 2005;86:347–63. 3. Kyzas PA, Cunha IW, Ioannidis JP. Prognostic significance of vascular endothelial growth factor immunohistochemical expression in head and neck squamous cell carcinoma: a meta-analysis. Clin Cancer Res 2005;11:1434–40. 4. Holsinger FC, Piha-Paul SA, Janku F, et al. Biomarker-directed therapy of squamous carcinomas of the head and neck: targeting PI3K/PTEN/mTOR pathway. J Clin Oncol 2013;31:e137–40. 5. Bozec A, Etienne-Grimaldi MC, Fischel JL, et al. The mTOR-targeting drug temsirolimus enhances the growth-inhibiting effects of the cetuximabbevacizumab-irradiation combination on head and neck cancer xenografts. Oral Oncol 2011;47:340–4. 6. Trafalis DT, Alifieris C, Dalezis P, Geromichalos G, Sitaras NM. Indications for an alternative effective treatment of head and neck squamous cell carcinoma with temsirolimus plus bevacizumab: from bench to bedside? Anticancer Drugs 2012;23:874–82. 7. Molinolo AA, Hewitt SM, Amornphimoltham P, et al. Dissecting the Akt/ mammalian target of rapamycin signaling network: emerging results from the head and neck cancer tissue array initiative. Clin Cancer Res 2007;13:4964–73.
Vijaya Raj Bhatt University of Nebraska Medical Center, Omaha, NE, United States Address: University of Nebraska Medical Center, Department of Internal Medicine, Division of Hematology–Oncology, 987680 Nebraska Medical Center, Omaha, NE 68198-7680, United States. Tel.: +1 402 559 5388; fax: +1 402 559 6520. E-mail address: [email protected] Apar Kishor Ganti VA Nebraska Western Iowa Health Care System, Omaha, NE, United States University of Nebraska Medical Center, Omaha, NE, United States Available online 28 April 2013
Contents lists available at SciVerse ScienceDirect
Oral Oncology journal homepage: www.elsevier.com/locate/oraloncology
Letter to the editor Combination therapy with bevacizumab and temsirolimus in squamous cell carcinoma of the head and neck
Bauman et al.1 report the result of a phase II study of temsirolimus and erlotinib in recurrent or metastatic platinum-refractory squamous cell carcinoma of the head and neck (SCCHN), which was prematurely closed because of poor tolerance. In their study, eighty-two percent (9/11) of patients had loss of the phosphatase and tensin homolog (PTEN) and 8% (1/12) had mutations in the phosphotidylinositol-3-kinase (PIK3CA). There was no correlation between loss of PTEN and patient outcome. Interestingly, higher baseline vascular endothelial growth factor (VEGF) (p = 0.07) and interferon-V levels (p = 0.09) marginally correlated to lack of response.1 Although the lack of statistical significance does not allow definite conclusion regarding VEGF level and the response rate, the study was not adequately powered to detect such a difference. Prior studies have shown that VEGF-A and VEGF-C are overexpressed in SCCHN and correlate with OS.2 In a meta-analysis of 12 studies (n = 1002) in patients with SCCHN, VEGF overexpression was associated with an estimated 2-year mortality risk ratio of 1.88 (95% confidence interval, 1.43–2.45; p < 0,001).3 These results indicate a potential role of VEGF pathway activation in tumor proliferation in SCCHN. Bauman’s study1 also suggests that either loss of PTEN does not correlate with the sensitivity to mammalian target of rapamycin (mTOR) inhibitors or blockade of PI3K/AKT/mTOR pathway alone is not effective in SCCHN. In another recent study by Holsinger et al. only patients treated with temsirolimus and bevacizumab (n = 3), as opposed to temsirolimus monotherapy (n = 2), had tumor regression.4 Patients included had either PTEN loss or PI3KCA mutation, however, VEGF level was not reported.4 Taken all these results together, this indicates a possible synergistic effect of combination therapy of temsirolimus and bevacizumab in SCCHN. Preclinical evidence suggests a possible synergism between temsirolimus and bevacizumab in SCCHN. In a head and neck cancer xenograft model, temsirolimus demonstrated synergistic antiproliferative effects when added to the combination of radiation therapy, cetuximab and bevacizumab. The use of combination therapy was associated with lower Ki67 staining (reduced tumor proliferation) and lower Bcl2 expression (greater apoptosis) in the tumor.5 In a more recent study, the combination of temsirolimus and bevacizumab showed synergistic inhibition of SCC in xenograft model. This combination also resulted in partial response in two patients with multiply relapsed SCCHN.6 In the Holsinger study,4 only combination therapy with temsirolimus and bevacizumab resulted in tumor regression. Although temsirolimus
1368-8375/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.oraloncology.2013.04.001
monotherapy is not effective and combination therapy with temsirolimus and erlotinib was poorly tolerated, dual inhibition of VEGF pathway and PI3/AKT/mTOR pathway, both of which are activated in SCCHN,2,7 may be of benefit in SCCHN. Trials focused on combination therapy with bevacizumab and temsirolimus should be conducted to explore their utility. References 1. Bauman JE, Arias-Pulido H, Lee SJ, et al. A phase II study of temsirolimus and erlotinib in patients with recurrent and/or metastatic, platinum-refractory head and neck squamous cell carcinoma. Oral Oncol. 2. Thomas GR, Nadiminti H, Regalado J. Molecular predictors of clinical outcome in patients with head and neck squamous cell carcinoma. Int J Exp Pathol 2005;86:347–63. 3. Kyzas PA, Cunha IW, Ioannidis JP. Prognostic significance of vascular endothelial growth factor immunohistochemical expression in head and neck squamous cell carcinoma: a meta-analysis. Clin Cancer Res 2005;11:1434–40. 4. Holsinger FC, Piha-Paul SA, Janku F, et al. Biomarker-directed therapy of squamous carcinomas of the head and neck: targeting PI3K/PTEN/mTOR pathway. J Clin Oncol 2013;31:e137–40. 5. Bozec A, Etienne-Grimaldi MC, Fischel JL, et al. The mTOR-targeting drug temsirolimus enhances the growth-inhibiting effects of the cetuximabbevacizumab-irradiation combination on head and neck cancer xenografts. Oral Oncol 2011;47:340–4. 6. Trafalis DT, Alifieris C, Dalezis P, Geromichalos G, Sitaras NM. Indications for an alternative effective treatment of head and neck squamous cell carcinoma with temsirolimus plus bevacizumab: from bench to bedside? Anticancer Drugs 2012;23:874–82. 7. Molinolo AA, Hewitt SM, Amornphimoltham P, et al. Dissecting the Akt/ mammalian target of rapamycin signaling network: emerging results from the head and neck cancer tissue array initiative. Clin Cancer Res 2007;13:4964–73.
Vijaya Raj Bhatt University of Nebraska Medical Center, Omaha, NE, United States Address: University of Nebraska Medical Center, Department of Internal Medicine, Division of Hematology–Oncology, 987680 Nebraska Medical Center, Omaha, NE 68198-7680, United States. Tel.: +1 402 559 5388; fax: +1 402 559 6520. E-mail address: [email protected] Apar Kishor Ganti VA Nebraska Western Iowa Health Care System, Omaha, NE, United States University of Nebraska Medical Center, Omaha, NE, United States Available online 28 April 2013