1 Department of Medical Oncology and Head and Neck Surgery, Cliniques Universitaires Saint-Luc and Institut de Recherche Clinique et Expérimentale (Pole MIRO), Université Catholique de Louvain, Brussels, Belgium
2 Department of Medical Imaging and Radiology, Cliniques Universitaires Saint-Luc and Institut de Recherche Clinique et Expérimentale (Pole IMAG), Université Catholique de Louvain, Brussels, Belgium
3 Department of Nuclear Medicine, Cliniques Universitaires Saint-Luc, Université Catholique de Louvain, Brussels, Belgium
Background. Cetuximab, a monoclonal antibody targeting the Epidermal Growth Factor Receptor (EGFR), has demonstrated activity in various tumor types. Using dynamic contrast-enhanced computed tomography (DCE-CT), we investigated the early activity of cetuximab monotherapy in previously untreated patients with squamous cell carcinoma of the head and neck (SCCHN).
Methods. Treatment-naïve patients with SCCHN received cetuximab for 2 weeks before curative surgery. Treatment activity was evaluated by DCE-CT at baseline and before surgery. Tumor vascular and interstitial characteristics were evaluated using the Brix two-compartment kinetic model. Modifications of the perfusion parameters (blood flow Fp, extravascular space ve, vascular space vp, and transfer constant PS) were assessed between both time points. DCE data were compared to FDG-PET and histopathological examination obtained simultaneously. Plasmatic vascular markers were investigated at different time points.
Results. Fourteen patients had evaluable DCE-CT parameters at both time points. A significant increase in the extravascular extracellular space ve accessible to the tracer was observed but no significant differences were found for the other kinetic parameters (Fp, vp or PS). Significant correlations were found between DCE parameters and the other two modalities. Plasmatic VEGF, PDGF-BB and IL-8 decreased as early as 2 hours after cetuximab infusion.
Conclusions. Early activity of cetuximab on tumor interstitial characteristics was detected by DCE-CT. Modifications of plasmatic vascular markers are not sufficient to confirm anti-angiogenic cetuximab activity in vivo. Further investigation is warranted to determine to what extent DCE-CT parameters are modified and to evaluate whether they are able to predict treatment outcome.
1. Kalyankrishna S, Grandis JR. Epidermal growth factor receptor biology in head and neck cancer. J Clin Oncol 2006; 24: 2666-72.
2. Ang KK, Berkey BA, Tu X, Zhang HZ, Katz R, Hammond EH, et al. Impact of epidermal growth factor receptor expression on survival and pattern of relapse in patients with advanced head and neck carcinoma. Cancer Res 2002; 62: 7350-6.
3. Wheeler S, Siwak DR, Chai R, LaValle C, Seethala RR, Wang L, et al. Tumor epidermal growth factor receptor and EGFR PY1068 are independent prognostic indicators for head and neck squamous cell carcinoma. Clin Cancer Res 2012; 18: 2278-89.
4. Schmitz S, Machiels JP. Molecular biology of squamous cell carcinoma of the head and neck : relevance and therapeutic implications. Expert Rev Anticancer Ther 2010; 10: 1471-84.
5. Bonner JA, Harari PM, Giralt J, Azarnia N, Shin DM, Cohen RB, et al. Radiotherapy plus cetuximab for squamous-cell carcinoma of the head and neck. N Engl J Med 2006; 354: 567-78.
6. Bonner JA, Harari PM, Giralt J, Cohen RB, Jones CU, Sur RK, et al. Radiotherapy plus cetuximab for locoregionally advanced head and neck cancer: 5-year survival data from a phase 3 randomised trial, and relation between cetuximab-induced rash and survival. Lancet Oncol 2010; 11: 21-8.
7. Vermorken JB, Mesia R, Rivera F, Remenar E, Kawecki A, Rottey S, et al. Platinum-based chemotherapy plus cetuximab in head and neck cancer. N Engl J Med 2008; 359: 1116-27.
8. Vermorken JB, Trigo J, Hitt R, Koralewski P, Diaz-Rubio E, Rolland F, et al. Open-label, uncontrolled, multicenter phase II study to evaluate the efficacy and toxicity of cetuximab as a single agent in patients with recurrent and/ or metastatic squamous cell carcinoma of the head and neck who failed to respond to platinum-based therapy. J Clin Oncol 2007; 25: 2171-7.
9. Li S, Schmitz KR, Jeffrey PD, Wiltzius JJ, Kussie P, Ferguson KM. Structural basis for inhibition of the epidermal growth factor receptor by cetuximab.Cancer Cell 2005; 7: 301-11.
10. Lopez-Albaitero A, Lee SC, Morgan S, Grandis JR, Gooding WE, Ferrone S, et al. Role of polymorphic Fc gamma receptor IIIa and EGFR expression level in cetuximab mediated, NK cell dependent in vitro cytotoxicity of head and neck squamous cell carcinoma cells. Cancer Immunol Immunother 2009; 58: 1853-64.
11. Huang SM, Bock JM, Harari PM. Epidermal growth factor receptor blockade with C225 modulates proliferation, apoptosis, and radiosensitivity in squamous cell carcinomas of the head and neck. Cancer Res 1999; 59: 1935-40.
12. Chen DJ, Nirodi CS. The epidermal growth factor receptor: a role in repair of radiation-induced DNA damage. Clin Cancer Res 2007; 13: 6555-60.
13. De Luca A, Carotenuto A, Rachiglio A, Gallo M, Maiello MR, Aldinucci D et al. The role of the EGFR signaling in tumor microenvironment. J Cell Physiol 2008; 214: 559-67.
14. Viloria-Petit A, Crombet T, Jothy S, Hicklin D, Bohlen P, Schlaeppi JM, et al. Acquired resistance to the antitumor effect of epidermal growth factor receptor-blocking antibodies in vivo: a role for altered tumor angiogenesis. Cancer Res 2001; 61: 5090-101.
15. Cerniglia GJ, Pore N, Tsai JH, Schultz S, Mick R, Choe R, et al. Epidermal growth factor receptor inhibition modulates the microenvironment by vascular normalization to improve chemotherapy and radiotherapy efficacy. PLoS One 2009; 4: e6539.
16. Qayum N, Muschel RJ, Im JH, Balathasan L, Koch CJ, Patel S, et al. Tumor vascular changes mediated by inhibition of oncogenic signaling. Cancer Res 2009; 69: 6347-54.
17. Miles KA. Perfusion CT for the assessment of tumour vascularity: which protocol? Br J Radiol 2003; 76: S36-42.
18. Veit-Haibach P, Schmid D, Strobel K, Soyka JD, Schaefer NG, Haerle SK, et al. Combined PET/CT-perfusion in patients with head and neck cancers. Eur Radiol 2013; 23: 163-73.
19. Rumboldt Z, Al-Okaili R, Deveikis JP. Perfusion CT for head and neck tumors: pilot study. Am J Neuroradiol 2005; 26: 1178-85.
20. Gandhi D, Chepeha DB, Miller T, Carlos RC, Bradford CR, Karamchandani R, et al. Correlation between initial and early follow-up CT perfusion parameters with endoscopic tumor response in patients with advanced squamous cell carcinomas of the oropharynx treated with organ -preservation therapy. Am J Neuroradiol 2006; 27: 101-6.
21. Zima A, Carlos R, Gandhi D, Case I, Teknos T, Mukherji SK. Can pretreatment CT perfusion predict response of advanced squamous cell carcinoma of the upper aerodigestive tract treated with induction chemotherapy? Am J Neuroradiol 2007; 28: 328-34.
22. de Geus-Oei LF, van Krieken JH, Aliredjo RP, Krabbe PF, Frielink C, Verhagen AF, et al. Biological correlates of FDG uptake in non-small cell lung cancer. Lung Cancer 2007; 55: 79-87.
23. Hirasawa S, Tsushima Y, Takei H, Hirasawa H, Taketomi-Takahashi A, Takano A, et al. Inverse correlation between tumor perfusion and glucose uptake in human head and neck tumors. Acad Radiol 2007; 14: 312-8.
24. Tateishi U, Nishihara H, Tsukamoto E, Morikawa T, Tamaki N, Miyasaka K. Lung tumors evaluated with FDG-PET and dynamic CT: the relationship between vascular density and glucose metabolism. J Comput Assist Tomogr 2002; 26: 185-90.
25. Halligan S. Reproducibility, repeatability, correlation and measurement error. Br J Radiol 2002; 75: 193-5.
26. Ash L, Teknos TN, Gandhi D, Patel S, Mukherji SK. Head and neck squamous cell carcinoma: CT perfusion can help noninvasively predict intratumoral microvessel density. Radiology 2009; 251: 422-8.
27. Surlan-Popovic K, Bisdas S, Rumboldt Z, Koh TS, Strojan P. Changes in perfusion CT of advanced squamous cell carcinoma of the head and neck treated during the course of concomitant chemoradiotherapy. Am J Neuroradiol 2010; 31: 570-5.
28. Maia AC Jr, Malheiros SM, da Rocha AJ, da Silva CJ, Gabbai AA, Ferraz FA, et al. MR cerebral blood volume maps correlated with vascular endothelial growth factor expression and tumor grade in nonenhancing gliomas. Am J Neuroradiol 2005; 26: 777-83.
29. Kosaka N, Uematsu H, Kimura H, Ishimori Y, Kurokawa T, Matsuda T, et al. Assessment of the vascularity of uterine leiomyomas using double-echo dynamic perfusion-weighted MRI with the first-pass pharmacokinetic model: correlation with histopathology. Invest Radiol 2007; 42: 629-35.
30. Hermans R, Meijerink M, Van den Bogaert W, Rijnders A, Weltens C, Lambin P. Tumor perfusion rate determined noninvasively by dynamic computed tomography predicts outcome in head-and-neck cancer after radiotherapy. Int J Radiat Oncol Biol Phys 2003; 57: 1351-6.
31. Schmitz S, Hamoir M, Reychler H, Magremanne M, Weynand B, Lhommel R, et al. Tumour response and safety of cetuximab in a window pre-operative study in patients with squamous cell carcinoma of the head and neck. Ann Oncol 2013; 24: 2261-6.
32. Abramyuk A, Wolf G, Shakirin G, Haberland U, Tokalov S, Koch A, et al. Preliminary assessment of dynamic contrast-enhanced CT implementation in pretreatment FDG-PET/CT for outcome prediction in head and neck tumors. Acta Radiol 2010; 51: 793-9.
33. Donaldson SB, West CM, Davidson SE, Carrington BM, Hutchison G, Jones AP, et al. A comparison of tracer kinetic models for T1-weighted dynamic contrast-enhanced MRI: application in carcinoma of the cervix. Magn Reson Med 2010; 63: 691-700.
34. Coleman TF, Li Y. An interior, trust region approach for nonlinear minimization subject to bounds. SIAM J Optim 1996; 6: 418-45.
35. Young H, Baum R, Cremerius U, Herholz K, Hoekstra O, Lammertsma AA, et al. Measurement of clinical and subclinical tumour response using [18F]-fluorodeoxyglucose and positron emission tomography: review and 1999 EORTC recommendations. European Organization for Research and Treatment of Cancer (EORTC) PET Study Group. Eur J Cancer 1999; 35: 1773-82.
36. Thévenaz P, Ruttimann UE, Unser M. A pyramid approach to subpixel registration based on intensity. IEEE Trans Image Process 1998; 7: 27-41.
37. Luwor RB, Lu Y, Li X, Mendelsohn J, Fan Z et al. The antiepidermal growth factor receptor monoclonal antibody cetuximab/C225 reduces hypoxiainducible factor-1 alpha, leading to transcriptional inhibition of vascular endothelial growth factor expression. Oncogene 2005; 24: 4433-41.
38. Jouan-Hureaux V, Boura C, Merlin JL, Faivre B. Modulation of endothelial cell network formation in vitro by molecular signaling of head and neck squamous cell carcinoma (HNSCC) exposed to cetuximab. Microvasc Res 2012; 83: 131-7.
39. Lutgendorf SK, Cole S, Costanzo E, Bradley S, Coffin J, Jabbari S, et al. Stressrelated mediators stimulate vascular endothelial growth factor secretion by two ovarian cancer cell lines. Clin Cancer Res 2009; 9: 4514-21.
40. Fan F, Gray MJ, Dallas NA, Yang AD, Van Buren G 2nd, Camp ER, et al. Effect of chemotherapeutic stress on induction of vascular endothelial growth factor family members and receptors in human colorectal cancer cells. Mol Cancer Ther 2008; 7: 3064-70.