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Targeted Therapy in Squamous Cell Cancers of the Head and Neck

Targeted Therapy in Squamous Cell Cancers of the Head and Neck

The 5-year survival of patients with locally advanced squamous cell cancers of the head and neck is still less than 30%. Treatment of these cancers involves significant functional impairment, diminished quality of life, and considerable time and expense. Local recurrence and distant metastases are still fairly common, and the development of second primary cancers has a significant impact on survival in patients with initial early-stage disease. Despite the success of combination chemoradiation in locally advanced head and neck cancers, these facts stress the need for improved treatment of this disease.

Investigation of the molecular biology of squamous cell cancer of the head and neck has resulted in the identification of several molecular characteristics associated with the clinical course of the disease. Definition of molecular pathways of carcinogenesis and cancer progression provides a biologic rationale for the use of molecular characteristics, or markers, to define prognosis, predict response to current therapy, and develop novel targets for therapy. The rational clinical development of targeted agents for head and neck cancer comprises a significant portion of the clinical trial portfolio of the Cancer Therapy Evaluation Program (CTEP) of the National Cancer Institute (NCI).

Epidermal Growth Factor Receptor

Most head and neck squamous cell cancers overexpress the epidermal growth factor receptor (EGFR).[1] The EGFR is one of a family of receptor tyrosine kinases that, when bound to one of several possible ligands, dimerizes and initiates phosphorylation-driven signaling cascades that result in cell proliferation, decreased apoptosis, angiogenesis, and other mechanisms associated with tumor progression and metastasis.[2] Several retrospective studies have correlated increased EGFR expression with decreased likelihood of survival in head and neck cancers[1,3-5] independently of other known prognostic factors, such as stage.

While such studies are not definitive, in aggregate they suggest that EGFR is a promising target for study in this disease. Additional studies reporting synergism between EGFR signal blockade and the effects of chemotherapy and radiation[6,7] make combination studies a reasonable development goal. The NCI is developing two orally administered EGFR tyrosine kinase inhibitors, OSI-774 and ZD1839, for the treatment of head and neck cancer. These agents will be used in combination with chemotherapy (taxanes and platinums) and radiation therapy.

Antiangiogenesis Agents

Angiogenesis is necessary for tumors to grow beyond a limited size and for metastasis. It is known that angiogenesis is induced by hypoxia,[8] a condition prevalent in cancers of the head and neck.[9] Vascular endothelial growth factor (VEGF) stimulates proliferation of vascular endothelial cells and can be induced by radiation therapy.[10] Preclinical studies of angiostatin with radiation resulted in increased tumor control.[11]

Studies attempting to correlate a measure of angiogenesis with outcome in squamous cell cancers of the head and neck have reported disparate results.[12-20] Nevertheless, because of the association of hypoxia and radiation with angiogenesis, trials of antiangiogenesis agents in squamous cell cancers of the head and neck should be attempted. The NCI is supporting trials of antiangiogenesis agents for head and neck cancer, including bevacizumab (rhuMab VEGF) and interferon-alpha.

Cell-Cycle Control Abnormalities

In most cancers, abnormalities of cell-cycle control exist. Up to 90% of squamous cell cancers of the head and neck may have abnormalities in the cyclin D1/Rb/p16 pathway. Whereas abnormalities in cyclin D1 and p16 correlated with survival in two large studies, smaller studies have reported various results.[21,22] Currently, the NCI is evaluating various drugs that have an impact on cell-cycle control abnormalities in head and neck cancer clinical trials, including Ad5CMV-p53 (virally mediated transduction of the p53 gene), flavopiridol (a cyclin-dependent kinase inhibitor), and the proteasome inhibitor PS-341 (inhibits degradation of signaling or modulatory molecules, such as p53, p27, and I kappaB). Several other agents are also being evaluated in phase I trials, singly or in combination.

Measuring Drug’s Effect

In early clinical trials of signal transduction agents, especially single agents, it is not certain that activity will be manifested by either tumor shrinkage or toxicity. In order to be sure the target has been engaged by the experimental drug, early trials have attempted to measure the effect of the drug on the target, and consequent impact on downstream signaling. Therefore, studies of epidermal growth factor inhibitors may include tumor biopsies and evaluations of EGFR, phosphorylated EGFR, as well as downstream signaling molecules and their phosphorylated forms (Akt, Erk, etc). Some studies include measures of proliferation, such as Ki67 immunohistochemical staining, and imaging of tumor metabolic activity with positron-emission tomography.

Studies of antiangiogenic agents often include measurements of VEGF and its receptor KDR, magnetic resonance imaging of vessels, or assessment of histologic microvessel density. Studies of inhibitors of cell- cycle molecules may include assessment of proliferation, apoptosis, and specific effector molecules. Comprehensive analysis of the expression of many genes simultaneously using gene expression arrays or proteomic methods are increasingly common.

Phase II

Title: Phase II Study of Surgery and Ad5CMV-p53 Gene Followed by Cisplatin and Radiotherapy in Patients With Newly Diagnosed Resectable Stage III or IV Squamous Cell Carcinoma of the Oral Cavity or Oropharynx
Protocol Number:
SWOG-S0011
Participating Institutions: Southwest Oncology Group
Contact: Marj Godfrey, (210) 677-8808
Latest Information: http://www.cancer.gov/clinical_trials/

Title: Phase II Study of Flavopiridol in Patients With Recurrent or Metastatic Squamous Cell Carcinoma of the Head and Neck
Protocol Number: MB-401, NCI-00-C-0128, NCI-T99-0066
Participating Institutions: National Cancer Institute Medicine Branch
Contact: Edward A. Sausville, MD, PhD, (301) 496-8720
Latest Information: http://www.cancer.gov/clinical_trials/

Phase I/II

Title: Phase I/II Study of Erlotinib and Cisplatin in Patients With Recurrent or Metastatic Squamous Cell Cancer of the Head and Neck
Protocol Number: NCI-5380, PMH-PHL-002
Participating Institutions: Princess Margaret Hospital, Phase II Consortium
Contact: Lillian L. Siu, MD, FRCPC, (416) 946-2911
Latest Information: http://www.cancer.gov/clinical_trials/

Title: A Phase I/ II Study of the Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor, OSI-774, in Combination With Docetaxel and Radiation in Locally Advanced Squamous Cell Cancer of the Head and Neck
Protocol Number: NCI-5389
Participating Institutions: Case Western Reserve University
Contact: Vinit K. Makkar, MD, (216) 844-4735

Title: A Phase I and Phase II Study of OSI-774 in Combination With Docetaxel in Squamous Cell Carcinoma of the Head and Neck
Protocol Number: NCI-5393
Participating Institutions: Ohio State University Hospital
Contact: Chris A. Rhoades, MD, business: (614) 293-8729; patient contact: (614) 293-7531

Title: A Phase I/II Study of Bevacizumab (rhuMab VEGF) in Combination With OSI-744 for Patients With Recurrent or Metastatic Cancer of the Head and Neck
Protocol Number: NCI-5701
Participating Institutions: University of Chicago
Contact: Everett E. Vokes, MD, (773) 834-3093

Phase I

Title: Phase I Study of Bevacizumab, Fluorouracil, and Hydroxyurea With Concurrent Radiotherapy in Patients With Advanced Head and Neck Cancer
Protocol Number: NCI-2630, UCCRC-11033
Participating Institutions: University of Chicago
Contact: Everett E. Vokes, MD, (773) 834-3093; for a complete listing of study contacts, click here
Latest Information: http://www.cancer.gov/clinical_trials/

Title: Phase I Study of ZD 1839 and Radiotherapy With or Without Cisplatin in Patients With Locally Advanced Squamous Cell Carcinoma of the Head and Neck
Protocol Number: NCI-4551, UCHSC-01460
Participating Institutions: University of Colorado
Contact: David Raben, MD, (720) 848-0116
Latest Information: http://www.cancer.gov/clinical_trials/

Title: A Phase I Study of OSI-774 in Combination With Standard Fractionation Radiation Therapy in Patients With Oral Cavity or Oropharyngeal Cancer Stage II or III and in Combination With Standard Fractionation Radiation Therapy and Low Dose Daily Cisplatin in Patients With Oral Cavity or Oropharyngeal Cancer Stage III and IV
Protocol Number: NCI-5375
Participating Institutions: Johns Hopkins University
Contact: Maura L. Gillison, MD, PhD, (410) 955-8890

Title: Phase I Study of PS-341 and Radiotherapy in Patients With Recurrent or Metastatic Squamous Cell Carcinoma of the Head and Neck
Protocol Number: NCI-01-C-0104, NCI-751
Participating Institutions: National Cancer Institute Medicine Branch
Contact: Edward A. Sausville, MD, PhD, (301) 496-8720
Latest Information: http://www.cancer.gov/clinical_trials/

References

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2. Arteaga CL:The epidermal growth factor receptor: From mutant oncogene in nonhuman cancers to therapeutic target in human neoplasia. J Clin Oncol 19(18s):32s-40s, 2001.

3. Magne N, Pivot X, Bensadoun R-J, et al: The relationship of epidermal growth factor receptor levels to the prognosis of unresectable pharyngeal cancer patients treated by chemo-radiotherapy. Eur J Cancer 37:2169-2177, 2001.

4. Kiyota A, Shintani S, Mihara M, et al: Expression of a truncated epidermal growth factor receptor in oral squamous cell carcinomas. Cancer Lett 161:9-15, 2000.

5. Grandis JR, Melhem MF, Gooding WE, et al: Levels of TGF-alpha and EGFR protein in head and neck squamous cell carcinoma and patient survival. J Natl Cancer Inst 90:824-832, 1998.

6. Harari PM, Huang S-M: Head and neck cancer as a clinical model for molecular targeting of therapy: Combining EGFR blockade with radiation. Int J Radiat Oncol Biol Phys 49:427-433, 2001.

7. Ciardello F, Tortora G: A novel approach in the treatment of cancer: Targeting the epidermal growth factor receptor. Clin Cancer Res 7:2958-2970, 2001.

8. Laderoute KR, Alarcon RM, Brody MD, et al: Opposing effects of hypoxia on expression of the angiogenic inhibitor thrombospondin-1 and the angiogenic inducer vascular endothelial growth factor. Clin Cancer Res 6:2941-2950, 2000.

9. Vanselow B, Eble MJ, Rudat V, et al: Oxygenation of advanced head and neck cancer: Prognostic marker for the response to primary radiochemotherapy. Otolaryngol Head Neck Surg 122:856-862, 2000.

10. Gorski DH, Beckett MA, Jaskowiak NT, et al: Blockade of the vascular endothelial growth factor stress response increases the antitumor effects of ionizing radiation. Cancer Res 59:3374-3378, 1999.

11. Gorski DH, Mauceri HJ, Salloum RM, et al: Potentiation of the antitumor effect of ionizing radiation by brief concomitant exposures to angiostatin. Cancer Res 58:5686-5689, 1998.

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13. Sauter ER, Nesbit M, Watson JC, et al: Vascular endothelial growth factor is a marker of tumor invasion and metastasis in squamous cell carcinomas of the head and neck. Clin Cancer Res 5:775-782, 1999.

14. Mineta H, Miura K, Ogino T, et al: Prognostic value of vascular endothelial growth factor (VEGF) in head and neck squamous cell carcinomas. Br J Cancer 83:775-781, 2000.

15. Giatromanolaki A, Koukourakis MI, Sivridis E, et al: Tumor specific activation of the VEGF/KDR angiogenic pathway in a subset of locally advanced squamous cell head and neck carcinomas. Clin Exp Metastasis 18:313-319, 2000.

16. Salven P, Heikkila P, Anttonen A, et al: Vascular endothelial growth factor in squamous cell head and neck carcinoma: Expression and prognostic significance. Mod Pathol 10:1128-1132, 1997.

17. Alcalde RE, Shintani S, Yoshihama Y, et al: Cell proliferation and tumor angiogenesis in oral squamous cell carcinoma. Anticancer Res 15:1417-1422, 1995.

18. Giatromanolaki A, Koukourakis MI, Georgoulias V, et al: Angiogenesis vs response after combined chemoradiotherapy of squamous cell head and neck cancer. Int J Cancer 80:810-817, 1999.

19. Koukourakis MI, Giatromanolaki A, Fountzilas G, et al: Angiogenesis, thymidine phosphorylase, and resistance of squamous cell head and neck cancer to cytotoxic and radiation therapy. Clin Cancer Res 6:381-389, 2000.

20. Pignataro L, Carboni N, Midolo V, et al: Clinical relevance of microvessel density in laryngeal squamous cell carcinomas. Int J Cancer 92:666-670, 2001.

21. Bova RJ, Quinn DI, Nankervis JS, et al: Cyclin D1 and p16INK4A expression predict reduced survival in carcinoma of the anterior tongue. Clin Cancer Res 5:2810-2819, 1999.

22. Mineta H, Mirua K, Takebayashi S, et al: Cyclin D1 overexpression correlates with poor prognosis in patients with tongue squamous cell carcinoma. Oral Oncol 36:194-198, 2000.

 
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