COMMENTARY For reprint orders, please contact: [email protected]
Sorafenib in squamous cell carcinoma of the head and neck: molecular basis and potential role
“Use of targeted therapy, such as sorafenib, in patients who are most likely to benefit may help improve outcomes in squamous cell carcinoma of the head and neck.” Vijaya R Bhatt*1
Apar Kishor Ganti1,2
With a worldwide incidence of 263,900 cases and 128,000 deaths from oral cavity and lip cancer in 2008, squamous cell carcinoma of the head and neck (SCCHN) is one of the most common cancers and a major cause of cancer-related deaths [1]. SCCHN comprises a wide spectrum of neoplasms, such as cancers of the lip, oral cavity, larynx, pharynx and paranasal sinuses. National and international reports on cancer statistics on oral cavity and lip cancer, which often do not account for these other cancers, are therefore, likely to underestimate the magnitude of problems associated with SCCHN. Consistent with the high incidence of the disease, the economic consequence of managing SCCHN is also enormous; in the USA, the annual total direct and indirect cost of SCCHN is estimated to be approximately US$2 billion (2001 value) [2]. In the USA, cancer of the oral cavity and pharynx presents with localized disease in 32% cases, whereas it is 47 and 16% present with regional and distant metastasis, respectively. The corresponding 5-year survivals for localized,
regional and distant metastasis are 82, 57 and 35%, respectively. Although the 5-year survival has improved from 53% in 1975–1977 to 65% in 2002–2008 [3], this has mostly been observed in earlier disease stages. Outcomes in the setting of distant metastases are dismal, with a median survival of less than 1 year [4]. Hence there is still scope for significant improvement in the management of these cancers. In this article, we discuss the molecular biology of SCCHN and the potential role of sorafenib. Molecular biology of SCCHN Recent discoveries of genomic and molecular markers in SCCHN have improved our understanding about the complexity of the signal transduction pathways as well as their relevance in normal and head and neck cancer cells. SCCHN is associated with several alterations at the genomic and molecular levels, which include overexpression of growth factors and growth factor receptors, such as EGFR and VEGF; mutation or loss of tumor suppressor genes,
KEYWORDS
• biomarker • EGFR • neoadjuvant therapy • PDGF-β • sorafenib • squamous cell carcinoma of the head and neck • VEGF
“National and international reports on cancer statistics on oral cavity and lip cancer, which often do not account for these other cancers, are therefore, likely to underestimate the magnitude of problems associated with squamous cell carcinoma of the head and neck.”
Department of Internal Medicine, Division of Hematology & Oncology, University of Nebraska Medical Center, Omaha, NE, USA 2 Department of Internal Medicine, Division of Hematology & Oncology, VA Nebraska Western Iowa Health Care System, Omaha, NE, USA *Author for correspondence: Tel.: +1 402 559 5388; Fax: +1 402 559 6520; [email protected] 1
10.2217/FON.13.212 © 2014 Future Medicine Ltd
Future Oncol. (2014) 10(1), 17–20
part of
ISSN 1479-6694
17
Commentary Bhatt & Ganti
“Identifying patients who
would respond to sorafenib would help improve response rates and subsequent outcomes for patients with squamous cell carcinoma of the head and neck.”
such as TP53, p16 and FHIT; amplification of proto-oncogenes, such as CCND1; and overexpression of the activity of cellular enzymes, such as COX2 and matrix metalloproteinases. These multitudes of changes are involved in several steps of carcinogenesis, progression and metastasis of SCCHN [5]. Overexpression of growth factors and growth factor receptors in SCCHN is particularly important because they present attractive targets for therapy. EGFR in tumor cells and PDGFR-b and VEGFR in endothelial cells or pericytes are cell-surface receptor tyrosine kinases, which upon ligand binding, activate Raf–MEK–ERK pathways [6]. Ultimately, EGFR activation results in inhibition of apoptosis, cellular proliferation, angiogenesis and metastasis [5–7]. Similarly, VEGFR and PDGFR-b activation leads to inhibition of apoptosis and promotion of angiogenesis by differentiation, proliferation, migration and survival of endothelial cells [5,6]. Additionally, animal models have shown that PDGF overexpression leads to VEGF expression in newly formed vessels and attracts vessel-associated pericytes, thereby promoting tumorigenesis [8]. Dual inhibition of PDGFR and VEGFR results in apoptosis of endothelial cells and, thereby, results in decreased neovascularization [9]. EGFR overexpression has been identified in 30–80% of SCCHNs [5,10] and has been shown to correlate with a more aggressive tumor behavior, increased resistance to radiotherapy, and decreased disease-free and overall survival [5]. VEGF-A and VEGF-C are also overexpressed in SCCHN and the VEGF levels correlate with the presence of cervical lymph node metastasis in early-stage disease and overall survival in advanced cases [5]. These findings suggest that the activation of EGFR as well as VEGFR-2 and -3 (receptors for VEGF‑A and -C, respectively) and, therefore, Raf–MEK–ERK pathways play an important role in the development and growth of SCCHN. PDGFR is highly expressed in SCCHN as well as normal pharyngeal and laryngeal mucosa, but its role in carcinogenesis is not well established [11]. Blocking EGFR or ‘growth factor-based cellular signaling’ and VEGFR or ‘angiogenesis-related cellular signaling’ thus provides important targets for therapy [12]. Sorafenib in SCCHN Sorafenib is an oral multikinase inhibitor that targets the Raf kinase signaling pathway in cancer cells and VEGFR-1, -2 and -3, and PDGFR-b
18
Future Oncol. (2014) 10(1)
tyrosine kinases in blood vessels, thus blocking the Raf–MEK–ERK pathway [6,13,14]. Sorafenib has been approved for use in unresectable hepatocellular carcinoma and advanced renal cell carcinoma [13]. Since there is overexpression of EGFR, VEGF and PDGFR-b in SCCHN, sorafenib, which targets the Raf kinase pathway, offers an attractive option for targeted therapy in SCCHN [5,10,11]. Three Phase II clinical trials have been reported on the efficacy and safety of sorafenib in SCCHN (Table 1) [15–17]. In all the above trials, overall sorafenib was well tolerated. Grade 4 toxicity was noticed in only one patient who had an asymptomatic pulmonary embolus [17]. Grade 3 toxicities included: hand–foot syndrome; cytopenia(s); febrile neutropenia; fatigue; gastrointestinal symptoms, such as anorexia, mucositis, diarrhea, or elevated lipase or amylase; hyponatremia; neuropathy, hypoxia, somnolence; weight loss; skin rash; pain; and hypertension [15–17]. Single-agent sorafenib has at least modest efficacy on SCCHN with two trials showing median progression-free survival of 1.8 months (26 out of 27 patients had radiation; 19 out of 27 had systemic therapy with chemotherapy or targeted agents) [15] to 4 months (36 out of 41 had recurrent or metastatic disease) [17]. Although single-agent sorafenib has shown only modest activity [15,17], the results of a combination of sorafenib and cytotoxic agents (paclitaxel and carboplatin) are promising in advanced or metastatic SCCHN [16]. Further studies should assess the efficacy of sorafenib in combination with conventional chemotherapy. Future perspective Identifying patients who would respond to sorafenib would help improve response rates and subsequent outcomes for patients with SCCHN. Currently, there is a lack of biomarkers to predict the patient population that is likely to respond to such targeted agents. In one study, biomarker analysis pre- and post-treatment with sorafenib therapy in five patients demonstrated a decrease in pERK (100%) and Ki67 (80%) indicating disruption of ERK signaling. There was downregulation of Mcl-1 protein (80%) as well as evidence of antiangiogenic activity [15]. Further studies are required to confirm these findings. Additionally, neoadjuvant sorafenib therapy with pre- and on-treatment biopsies may help identify biological markers that predict response. This would also help in the determination of
future science group
Sorafenib in squamous cell carcinoma of the head & neck: molecular basis & potential role
Commentary
Table 1. Single-arm Phase II trials of sorafenib in squamous cell carcinoma of the head and neck. Study (year)
M/N
Median Treatment age (years)
Response
Median PFS/OS Common grade 3 toxicities (months)
Elser et al. (2007)†
17/27
53
S in a 28-day cycle
3.7% PR and 37% SD
1.8/4.2
Williamson et al. (2010)‡
34/41
63.5
S in a 28-day cycle
2% PR and 51% SD/PR
4/9
Paclitaxel/carboplatin (day 1); S (days 2–19) in a 3-week cycle
55% RR and 8.51/22.6 84% SD
Blumenschein 39/44 56 et al. (2012)
Lymphopenia (17%), fatigue (7%), hyponatremia, leucopenia and lipase elevation (3% each) Hand–foot syndrome (7%), anorexia, stomatitis/oral cavity pain and nausea (4% each) Hand–foot syndrome (22%), pain (13%), neutropenia (11%) and elevated lipase (9%)§
Ref. [15]
[17]
[16]
All the patients in these studies either had persistent, recurrent or metastatic squamous cell carcinoma of the head and neck. One prior line of chemotherapy or one prior induction, concomitant or adjuvant chemotherapy was allowed. The dose of S was 400 mg twice daily. † Dose reduction was required in 16 patients and there were dose delays in 14 patients. ‡ Grade 4 toxicities were noted only in this study: asymptomatic pulmonary embolism in one patient (2%) and cerebral ischemia in one ineligible patient (2%). § Other grade 3 toxicities included elevated amylase and anemia (6% each), thrombocytopenia, febrile neutropenia, fatigue, hypertension and neuropathy (4% each). M: Number of males; N: Total number of patients; OS: Overall survival; PFS: Progression-free survival; PR: Partial response; RR: Response rate; S: Sorafenib; SD: Stable disease.
the mechanism of action of sorafenib in vivo. Although neoadjuvant sorafenib has not been studied in SCCHN, there is some experience with neoadjuvant sorafenib therapy in renal cell carcinoma, with at least five retrospective and prospective studies showing no increase in any major surgical complications or mortality [18–22]. Use of targeted therapy, such as sorafenib, in patients who are most likely to benefit may help improve outcomes in SCCHN. References 1
2
3
4
5
6
Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics. CA Cancer J. Clin. 61(2), 69–90 (2011). Lee JM, Turini M, Botteman MF, Stephens JM, Pashos CL. Economic burden of head and neck cancer. A literature review. Eur. J. Health Econ. 5(1), 70–80 (2004). Siegel R, Naishadham D, Jemal A. Cancer statistics, 2013. CA Cancer J. Clin. 63(1), 11–30 (2013). Price KA, Cohen EE. Current treatment options for metastatic head and neck cancer. Curr. Treat. Options Oncol. 13(1), 35–46 (2012). Thomas GR, Nadiminti H, Regalado J. Molecular predictors of clinical outcome in patients with head and neck squamous cell carcinoma. Int. J. Exp. Pathol. 86(6), 347–363 (2005). Wilhelm SM, Adnane L, Newell P, Villanueva A, Llovet JM, Lynch M. Preclinical overview of sorafenib, a multikinase inhibitor that targets both Raf
future science group
Financial & competing interests disclosure AK Ganti reports serving as a consultant for Boehringer Ingelheim and Otsuka Pharmaceuticals. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript.
and VEGF and PDGF receptor tyrosine kinase signaling. Mol. Cancer Ther. 7(10), 3129–3140 (2008). 7
8
9
Alroy I, Yarden Y. The ErbB signaling network in embryogenesis and oncogenesis: signal diversification through combinatorial ligand-receptor interactions. FEBS Lett. 410(1), 83–86 (1997). Guo P, Hu B, Gu W et al. Platelet-derived growth factor-B enhances glioma angiogenesis by stimulating vascular endothelial growth factor expression in tumor endothelia and by promoting pericyte recruitment. Am. J. Pathol. 162(4), 1083–1093 (2003). Erber R, Thurnher A, Katsen AD et al. Combined inhibition of VEGF and PDGF signaling enforces tumor vessel regression by interfering with pericyte-mediated endothelial cell survival mechanisms. FASEB J. 18(2), 338–340 (2004).
10 Salomon DS, Brandt R, Ciardiello F,
Normanno N. Epidermal growth factorrelated peptides and their receptors in human malignancies. Crit. Rev. Oncol. Hematol. 19(3), 183–232 (1995).
11 Ongkeko WM, Altuna X, Weisman RA,
Wang-Rodriguez J. Expression of protein tyrosine kinases in head and neck squamous cell carcinomas. Am. J. Clin. Pathol. 124(1), 71–76 (2005). 12 Gold KA, Lee HY, Kim ES. Targeted
therapies in squamous cell carcinoma of the head and neck. Cancer 115(5), 922–935 (2009). 13 Iyer R, Fetterly G, Lugade A, Thanavala Y.
Sorafenib: a clinical and pharmacologic review. Expert Opin. Pharmacother. 11(11), 1943–1955 (2010). 14 Liu L, Cao Y, Chen C et al. Sorafenib blocks
the RAF/MEK/ERK pathway, inhibits tumor angiogenesis, and induces tumor cell apoptosis in hepatocellular carcinoma model PLC/PRF/5. Cancer Res. 66(24), 11851–11858 (2006). 15 Elser C, Siu LL, Winquist E et al. Phase II
trial of sorafenib in patients with recurrent or metastatic squamous cell carcinoma of the head and neck or nasopharyngeal carcinoma. J. Clin. Oncol. 25(24), 3766–3773 (2007).
www.futuremedicine.com
19
Commentary Bhatt & Ganti 16 Blumenschein GR, Glisson BS, Lu C et al.
Final results of a Phase II study of sorafenib in combination with carboplatin and paclitaxel in patients with metastatic or recurrent squamous cell cancer of the head and neck (SCCHN). ASCO Meeting Abstracts 30(15 Suppl.), Abstract 5592 (2012). 17 Williamson SK, Moon J, Huang CH et al.
Phase II evaluation of sorafenib in advanced and metastatic squamous cell carcinoma of the head and neck: Southwest Oncology Group Study S0420. J. Clin. Oncol. 28(20), 3330–3335 (2010).
20
18 Cowey CL, Amin C, Pruthi RS et al.
Neoadjuvant clinical trial with sorafenib for patients with stage II or higher renal cell carcinoma. J. Clin. Oncol. 28(9), 1502–1507 (2010). 19 Amin C, Wallen E, Pruthi RS, Calvo BF,
Godley PA, Rathmell WK. Preoperative tyrosine kinase inhibition as an adjunct to debulking nephrectomy. Urology 72(4), 864–868 (2008). 20 Kondo T, Hashimoto Y, Kobayashi H et al.
Presurgical targeted therapy with tyrosine kinase inhibitors for advanced renal cell carcinoma: clinical
Future Oncol. (2014) 10(1)
results and histopathological therapeutic effects. Jpn J. Clin. Oncol. 40(12), 1173–1179 (2010). 21 Margulis V, Matin SF, Tannir N et al.
Surgical morbidity associated with administration of targeted molecular therapies before cytoreductive nephrectomy or resection of locally recurrent renal cell carcinoma. J. Urol. 180(1), 94–98 (2008). 22 Thomas AA, Rini BI, Stephenson AJ et al.
Surgical resection of renal cell carcinoma after targeted therapy. J. Urol. 182(3), 881–886 (2009).
future science group
Sorafenib in squamous cell carcinoma of the head and neck: molecular basis and potential role
“Use of targeted therapy, such as sorafenib, in patients who are most likely to benefit may help improve outcomes in squamous cell carcinoma of the head and neck.” Vijaya R Bhatt*1
Apar Kishor Ganti1,2
With a worldwide incidence of 263,900 cases and 128,000 deaths from oral cavity and lip cancer in 2008, squamous cell carcinoma of the head and neck (SCCHN) is one of the most common cancers and a major cause of cancer-related deaths [1]. SCCHN comprises a wide spectrum of neoplasms, such as cancers of the lip, oral cavity, larynx, pharynx and paranasal sinuses. National and international reports on cancer statistics on oral cavity and lip cancer, which often do not account for these other cancers, are therefore, likely to underestimate the magnitude of problems associated with SCCHN. Consistent with the high incidence of the disease, the economic consequence of managing SCCHN is also enormous; in the USA, the annual total direct and indirect cost of SCCHN is estimated to be approximately US$2 billion (2001 value) [2]. In the USA, cancer of the oral cavity and pharynx presents with localized disease in 32% cases, whereas it is 47 and 16% present with regional and distant metastasis, respectively. The corresponding 5-year survivals for localized,
regional and distant metastasis are 82, 57 and 35%, respectively. Although the 5-year survival has improved from 53% in 1975–1977 to 65% in 2002–2008 [3], this has mostly been observed in earlier disease stages. Outcomes in the setting of distant metastases are dismal, with a median survival of less than 1 year [4]. Hence there is still scope for significant improvement in the management of these cancers. In this article, we discuss the molecular biology of SCCHN and the potential role of sorafenib. Molecular biology of SCCHN Recent discoveries of genomic and molecular markers in SCCHN have improved our understanding about the complexity of the signal transduction pathways as well as their relevance in normal and head and neck cancer cells. SCCHN is associated with several alterations at the genomic and molecular levels, which include overexpression of growth factors and growth factor receptors, such as EGFR and VEGF; mutation or loss of tumor suppressor genes,
KEYWORDS
• biomarker • EGFR • neoadjuvant therapy • PDGF-β • sorafenib • squamous cell carcinoma of the head and neck • VEGF
“National and international reports on cancer statistics on oral cavity and lip cancer, which often do not account for these other cancers, are therefore, likely to underestimate the magnitude of problems associated with squamous cell carcinoma of the head and neck.”
Department of Internal Medicine, Division of Hematology & Oncology, University of Nebraska Medical Center, Omaha, NE, USA 2 Department of Internal Medicine, Division of Hematology & Oncology, VA Nebraska Western Iowa Health Care System, Omaha, NE, USA *Author for correspondence: Tel.: +1 402 559 5388; Fax: +1 402 559 6520; [email protected] 1
10.2217/FON.13.212 © 2014 Future Medicine Ltd
Future Oncol. (2014) 10(1), 17–20
part of
ISSN 1479-6694
17
Commentary Bhatt & Ganti
“Identifying patients who
would respond to sorafenib would help improve response rates and subsequent outcomes for patients with squamous cell carcinoma of the head and neck.”
such as TP53, p16 and FHIT; amplification of proto-oncogenes, such as CCND1; and overexpression of the activity of cellular enzymes, such as COX2 and matrix metalloproteinases. These multitudes of changes are involved in several steps of carcinogenesis, progression and metastasis of SCCHN [5]. Overexpression of growth factors and growth factor receptors in SCCHN is particularly important because they present attractive targets for therapy. EGFR in tumor cells and PDGFR-b and VEGFR in endothelial cells or pericytes are cell-surface receptor tyrosine kinases, which upon ligand binding, activate Raf–MEK–ERK pathways [6]. Ultimately, EGFR activation results in inhibition of apoptosis, cellular proliferation, angiogenesis and metastasis [5–7]. Similarly, VEGFR and PDGFR-b activation leads to inhibition of apoptosis and promotion of angiogenesis by differentiation, proliferation, migration and survival of endothelial cells [5,6]. Additionally, animal models have shown that PDGF overexpression leads to VEGF expression in newly formed vessels and attracts vessel-associated pericytes, thereby promoting tumorigenesis [8]. Dual inhibition of PDGFR and VEGFR results in apoptosis of endothelial cells and, thereby, results in decreased neovascularization [9]. EGFR overexpression has been identified in 30–80% of SCCHNs [5,10] and has been shown to correlate with a more aggressive tumor behavior, increased resistance to radiotherapy, and decreased disease-free and overall survival [5]. VEGF-A and VEGF-C are also overexpressed in SCCHN and the VEGF levels correlate with the presence of cervical lymph node metastasis in early-stage disease and overall survival in advanced cases [5]. These findings suggest that the activation of EGFR as well as VEGFR-2 and -3 (receptors for VEGF‑A and -C, respectively) and, therefore, Raf–MEK–ERK pathways play an important role in the development and growth of SCCHN. PDGFR is highly expressed in SCCHN as well as normal pharyngeal and laryngeal mucosa, but its role in carcinogenesis is not well established [11]. Blocking EGFR or ‘growth factor-based cellular signaling’ and VEGFR or ‘angiogenesis-related cellular signaling’ thus provides important targets for therapy [12]. Sorafenib in SCCHN Sorafenib is an oral multikinase inhibitor that targets the Raf kinase signaling pathway in cancer cells and VEGFR-1, -2 and -3, and PDGFR-b
18
Future Oncol. (2014) 10(1)
tyrosine kinases in blood vessels, thus blocking the Raf–MEK–ERK pathway [6,13,14]. Sorafenib has been approved for use in unresectable hepatocellular carcinoma and advanced renal cell carcinoma [13]. Since there is overexpression of EGFR, VEGF and PDGFR-b in SCCHN, sorafenib, which targets the Raf kinase pathway, offers an attractive option for targeted therapy in SCCHN [5,10,11]. Three Phase II clinical trials have been reported on the efficacy and safety of sorafenib in SCCHN (Table 1) [15–17]. In all the above trials, overall sorafenib was well tolerated. Grade 4 toxicity was noticed in only one patient who had an asymptomatic pulmonary embolus [17]. Grade 3 toxicities included: hand–foot syndrome; cytopenia(s); febrile neutropenia; fatigue; gastrointestinal symptoms, such as anorexia, mucositis, diarrhea, or elevated lipase or amylase; hyponatremia; neuropathy, hypoxia, somnolence; weight loss; skin rash; pain; and hypertension [15–17]. Single-agent sorafenib has at least modest efficacy on SCCHN with two trials showing median progression-free survival of 1.8 months (26 out of 27 patients had radiation; 19 out of 27 had systemic therapy with chemotherapy or targeted agents) [15] to 4 months (36 out of 41 had recurrent or metastatic disease) [17]. Although single-agent sorafenib has shown only modest activity [15,17], the results of a combination of sorafenib and cytotoxic agents (paclitaxel and carboplatin) are promising in advanced or metastatic SCCHN [16]. Further studies should assess the efficacy of sorafenib in combination with conventional chemotherapy. Future perspective Identifying patients who would respond to sorafenib would help improve response rates and subsequent outcomes for patients with SCCHN. Currently, there is a lack of biomarkers to predict the patient population that is likely to respond to such targeted agents. In one study, biomarker analysis pre- and post-treatment with sorafenib therapy in five patients demonstrated a decrease in pERK (100%) and Ki67 (80%) indicating disruption of ERK signaling. There was downregulation of Mcl-1 protein (80%) as well as evidence of antiangiogenic activity [15]. Further studies are required to confirm these findings. Additionally, neoadjuvant sorafenib therapy with pre- and on-treatment biopsies may help identify biological markers that predict response. This would also help in the determination of
future science group
Sorafenib in squamous cell carcinoma of the head & neck: molecular basis & potential role
Commentary
Table 1. Single-arm Phase II trials of sorafenib in squamous cell carcinoma of the head and neck. Study (year)
M/N
Median Treatment age (years)
Response
Median PFS/OS Common grade 3 toxicities (months)
Elser et al. (2007)†
17/27
53
S in a 28-day cycle
3.7% PR and 37% SD
1.8/4.2
Williamson et al. (2010)‡
34/41
63.5
S in a 28-day cycle
2% PR and 51% SD/PR
4/9
Paclitaxel/carboplatin (day 1); S (days 2–19) in a 3-week cycle
55% RR and 8.51/22.6 84% SD
Blumenschein 39/44 56 et al. (2012)
Lymphopenia (17%), fatigue (7%), hyponatremia, leucopenia and lipase elevation (3% each) Hand–foot syndrome (7%), anorexia, stomatitis/oral cavity pain and nausea (4% each) Hand–foot syndrome (22%), pain (13%), neutropenia (11%) and elevated lipase (9%)§
Ref. [15]
[17]
[16]
All the patients in these studies either had persistent, recurrent or metastatic squamous cell carcinoma of the head and neck. One prior line of chemotherapy or one prior induction, concomitant or adjuvant chemotherapy was allowed. The dose of S was 400 mg twice daily. † Dose reduction was required in 16 patients and there were dose delays in 14 patients. ‡ Grade 4 toxicities were noted only in this study: asymptomatic pulmonary embolism in one patient (2%) and cerebral ischemia in one ineligible patient (2%). § Other grade 3 toxicities included elevated amylase and anemia (6% each), thrombocytopenia, febrile neutropenia, fatigue, hypertension and neuropathy (4% each). M: Number of males; N: Total number of patients; OS: Overall survival; PFS: Progression-free survival; PR: Partial response; RR: Response rate; S: Sorafenib; SD: Stable disease.
the mechanism of action of sorafenib in vivo. Although neoadjuvant sorafenib has not been studied in SCCHN, there is some experience with neoadjuvant sorafenib therapy in renal cell carcinoma, with at least five retrospective and prospective studies showing no increase in any major surgical complications or mortality [18–22]. Use of targeted therapy, such as sorafenib, in patients who are most likely to benefit may help improve outcomes in SCCHN. References 1
2
3
4
5
6
Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics. CA Cancer J. Clin. 61(2), 69–90 (2011). Lee JM, Turini M, Botteman MF, Stephens JM, Pashos CL. Economic burden of head and neck cancer. A literature review. Eur. J. Health Econ. 5(1), 70–80 (2004). Siegel R, Naishadham D, Jemal A. Cancer statistics, 2013. CA Cancer J. Clin. 63(1), 11–30 (2013). Price KA, Cohen EE. Current treatment options for metastatic head and neck cancer. Curr. Treat. Options Oncol. 13(1), 35–46 (2012). Thomas GR, Nadiminti H, Regalado J. Molecular predictors of clinical outcome in patients with head and neck squamous cell carcinoma. Int. J. Exp. Pathol. 86(6), 347–363 (2005). Wilhelm SM, Adnane L, Newell P, Villanueva A, Llovet JM, Lynch M. Preclinical overview of sorafenib, a multikinase inhibitor that targets both Raf
future science group
Financial & competing interests disclosure AK Ganti reports serving as a consultant for Boehringer Ingelheim and Otsuka Pharmaceuticals. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript.
and VEGF and PDGF receptor tyrosine kinase signaling. Mol. Cancer Ther. 7(10), 3129–3140 (2008). 7
8
9
Alroy I, Yarden Y. The ErbB signaling network in embryogenesis and oncogenesis: signal diversification through combinatorial ligand-receptor interactions. FEBS Lett. 410(1), 83–86 (1997). Guo P, Hu B, Gu W et al. Platelet-derived growth factor-B enhances glioma angiogenesis by stimulating vascular endothelial growth factor expression in tumor endothelia and by promoting pericyte recruitment. Am. J. Pathol. 162(4), 1083–1093 (2003). Erber R, Thurnher A, Katsen AD et al. Combined inhibition of VEGF and PDGF signaling enforces tumor vessel regression by interfering with pericyte-mediated endothelial cell survival mechanisms. FASEB J. 18(2), 338–340 (2004).
10 Salomon DS, Brandt R, Ciardiello F,
Normanno N. Epidermal growth factorrelated peptides and their receptors in human malignancies. Crit. Rev. Oncol. Hematol. 19(3), 183–232 (1995).
11 Ongkeko WM, Altuna X, Weisman RA,
Wang-Rodriguez J. Expression of protein tyrosine kinases in head and neck squamous cell carcinomas. Am. J. Clin. Pathol. 124(1), 71–76 (2005). 12 Gold KA, Lee HY, Kim ES. Targeted
therapies in squamous cell carcinoma of the head and neck. Cancer 115(5), 922–935 (2009). 13 Iyer R, Fetterly G, Lugade A, Thanavala Y.
Sorafenib: a clinical and pharmacologic review. Expert Opin. Pharmacother. 11(11), 1943–1955 (2010). 14 Liu L, Cao Y, Chen C et al. Sorafenib blocks
the RAF/MEK/ERK pathway, inhibits tumor angiogenesis, and induces tumor cell apoptosis in hepatocellular carcinoma model PLC/PRF/5. Cancer Res. 66(24), 11851–11858 (2006). 15 Elser C, Siu LL, Winquist E et al. Phase II
trial of sorafenib in patients with recurrent or metastatic squamous cell carcinoma of the head and neck or nasopharyngeal carcinoma. J. Clin. Oncol. 25(24), 3766–3773 (2007).
www.futuremedicine.com
19
Commentary Bhatt & Ganti 16 Blumenschein GR, Glisson BS, Lu C et al.
Final results of a Phase II study of sorafenib in combination with carboplatin and paclitaxel in patients with metastatic or recurrent squamous cell cancer of the head and neck (SCCHN). ASCO Meeting Abstracts 30(15 Suppl.), Abstract 5592 (2012). 17 Williamson SK, Moon J, Huang CH et al.
Phase II evaluation of sorafenib in advanced and metastatic squamous cell carcinoma of the head and neck: Southwest Oncology Group Study S0420. J. Clin. Oncol. 28(20), 3330–3335 (2010).
20
18 Cowey CL, Amin C, Pruthi RS et al.
Neoadjuvant clinical trial with sorafenib for patients with stage II or higher renal cell carcinoma. J. Clin. Oncol. 28(9), 1502–1507 (2010). 19 Amin C, Wallen E, Pruthi RS, Calvo BF,
Godley PA, Rathmell WK. Preoperative tyrosine kinase inhibition as an adjunct to debulking nephrectomy. Urology 72(4), 864–868 (2008). 20 Kondo T, Hashimoto Y, Kobayashi H et al.
Presurgical targeted therapy with tyrosine kinase inhibitors for advanced renal cell carcinoma: clinical
Future Oncol. (2014) 10(1)
results and histopathological therapeutic effects. Jpn J. Clin. Oncol. 40(12), 1173–1179 (2010). 21 Margulis V, Matin SF, Tannir N et al.
Surgical morbidity associated with administration of targeted molecular therapies before cytoreductive nephrectomy or resection of locally recurrent renal cell carcinoma. J. Urol. 180(1), 94–98 (2008). 22 Thomas AA, Rini BI, Stephenson AJ et al.
Surgical resection of renal cell carcinoma after targeted therapy. J. Urol. 182(3), 881–886 (2009).
future science group
