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Biological agents in head and neck cancer
Annals of Oncology 17 (Supplement 10): x45–x48, 2006 doi:10.1093/annonc/mdl235
Biological agents in head and neck cancer L. Licitra, L. Locati & P. Bossi Istituto Nazionale dei Tumori, Head and Neck Medical Oncology Unit, Milan, Italy
introduction
the epidermal growth factor receptor (EGFR) system The EGFR system represents the most widely-studied molecular target. EGFR is highly expressed in SCCHN, nasopharyngeal cancer, salivary gland malignant tumours and differentiated thyroid cancer. In SCCHN all the four major signalling EGFR controlled pathways have been described: the RAS-mitogen activated protein kinase (MAPK) system responsible for proliferation signals, the AKT, involved in survival and anti-apoptotic stimuli, the protein kinase C (PKC) activation which results in cell cycle progression and finally the signal transducer and activator of transcription (STAT) system, particularly STAT3, which is associated with gene transcription. In SCCHN, EGFR overexpression is due to overproduction of messenger RNA (mRNA) with an increased EGFR gene copy number in approximately 60% of cases. Similarly to other models the grade of EGFR overexpression does not seem to be correlated with treatment outcome [2]. Moreover, an interesting uncoupling of epidermal growth factor-dependent proliferation and invasion between tumour site and its nodal metastasis has been shown [3] suggesting a possible differential response to anti-EGFR of the same tumour depending on its site. ª 2006 European Society for Medical Oncology
EGFR and carcinogenesis In SCCHN, EGFR and its ligands are involved in the multistep carcinogenetic process characterised by the accumulation of genetic and epigenetic changes of the normal mucosa cell to the premalignant one and finally to the overt infiltrating carcinoma. Within this carcinogenetic model the presence of EGFR highly expressing morphological normal cells at the level of excised tumours is not surprising. Indeed a 30-fold increased mRNA EGFR expression in normal mucosa of HNC patients has been detected [5]. Within this framework there is a strong rationale for using anti-EGFR directed drugs in clinical research, for the inhibition of recurrences, second primary and field tumours [6]. An ongoing study combines it with other relevant biological markers inhibiting drugs, such as anti-COX2, which has been shown to crosstalk with EGFR in preclinical models, thus strengthening the rational for a combined use of such molecular target therapeutics [7]. Whether the effect of this approach will be dependent on smoking habits and specific host factors, as it has been suggested for chemoprevention with micronutrients such as beta-carotene, is left to be demonstrated [8].
EGFR as predictive and prognostic factor EGFR overexpression has shown to be related to more advanced tumour and nodal stage, as well as worse prognosis both in terms of locoregional control and survival [9, 10]. However, another study was not able to either correlate it with tumour stage or with tumour grading; but with tumour subsite and tumour angiogenesis [11]. Interestingly EGFR overexpression was differently correlated with locoregional control in presence of conventional versus altered fractionated radiotherapy, thus suggesting that it may represent a predictive factor rather than a prognostic one [11–13]. Recently a high
Downloaded from http://annonc.oxfordjournals.org/ at California Institute of Technology on July 16, 2015
Despite major advances in therapeutic strategies, including cell and molecular biology, the survival of head and neck cancer (HNC) patients has not improved over the last 30 years. Tumor recurrence and the development of second primaries in association with cure limiting co-morbidities represent the major causes of treatment failure. Aberrant expression of growth factor systems and dysregulation of signalling pathways have been reported in HNC [1]. The better understanding of such mechanisms and the identification of clinically relevant biological markers represent the mainstay of the modern research approach for head and neck cancer, since this is expected to lead to more effective targeting of old and new therapeutic strategies. In the following sections, the focus is on the epidermal growth factor receptor (EGFR) system in squamous head and neck cancer (SCCHN); on recent advances in immunotherapy for head and neck cancer; and in the biological treatment of thyroid cancer.
EGFR expression and activity are both dependent on some polymorphisms distributed in the gene and in the gene promoter region. The percentage of EGFR mutations is less than 10%, it typically occurs on exone 19 [4] and it might be even lower in non-Asian populations. To date there is no correlative study between mutation and tyrosine kinase inhibitors sensitivity and, in general, to what extent EGFR gene profile in SCCHN might contribute to treatment selection has yet to be defined.
Annals of Oncology
gene copy number has been reported to be correlated with a worse prognosis [14].
targeting EGFR Various drugs are available today to inhibit EGFR activity. Two major drug classes have already been extensively studied in HNC.
x46 | Licitra et al.
monoclonal antibodies locally advanced HNC. Cetuximab (Erbitux) has been studied in a phase III trial in combination with radiotherapy versus radiotherapy alone [30]. The results demonstrated that the association of cetuximab concomitantly with radiation produced a significantly better locoregional control (median duration 24.4 versus 14.9 months) and a significant better survival (49 versus 29.3%, with an HR for death of 0.74). Interestingly and unlike chemotherapy, the drug was not associated with enhanced radiation-related mucositis. These observations would lead to the conclusion that cetuximab has an optimal target modulation, apparently due to sufficient drug availability, additive effect at the tumour level in absence of synergistic effect on normal tissues. Taken together, the results would also lead to the conclusion that cetuximab plus radiotherapy represents the state-of-the-art treatment for locally advanced SCCHN. Nonetheless, the current knowledge would indicate that the concomitant use of chemotherapy and radiation therapy is still recognised as the reference treatment. This has also been confirmed by the recent updating of the MACH meta-analyis in 2000 [31, 32]. In this scenario the place of cetuximab concurrently with radiotherapy has to be further tested either in association with chemotherapy or at least for intermediate risk patients (e.g. stage III, oropharyngeal cancer, human papilloma virus (HPV)-positive patients) in comparison with concomitant standard chemoradiotherapy. recurrent and metastatic HNC. Cetuximab has been studied in phase II trials, both as first-line and as second-line in so-called platinum-refractory HNC patients, including nasopharyngeal cancer (NPC). It has been employed both as single agent or in combination with cisplatin [33–35]. Overall, response rate when used as single agent or in combination with cisplatin is similar (approximately 10–15%), thus indicating that cetuximab as single agent has anti-tumour activity regardless of pretreatment. Also in these studies severity of skin rash was associated with better outcome. These results lead to the
Volume 17 | Supplement 10 | September 2006
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small molecules tyrosine kinase inhibitors recurrent and metastatic HNC. The most studied drug has been gefitinib (Iressa). It has already undergone phase II and III trials in recurrent and metastatic SCCHN (RM-SCCHN). As single agent it has been studied in patients already pretreated with previous chemotherapy for their recurrent disease and in a cohort of untreated patients [15–17]. Gefitininb was studied at 250 mg or 500 mg daily. In general, drug toxicity was mild, characterised by skin rash and diarrhoea, probably higher with 500 mg. At full dose (e.g. 500 mg/day), response rate was higher compared to 250 mg, ranging between 10–15%, with 25–40% of disease stabilisation in previously untreated patients, indicating a dose-dependent relationship. A phase I study explored the combination with celecoxib. No dose limiting toxicity was observed. Four responses were observed among 18 treated patients [18]. In every patient skin rash was associated with better outcome. Gefitinib is currently studied within phase III trials: docetaxel with or without gefitininib (ECOG) and a trial in which gefitinib is compared at two different dosages versus methotrexate alone. The results of these trials will contribute to clarify the role of this drug in RM-SCCHN. A phase II study of gefitinib in advanced, progressive salivary malignancies was performed in 29 patients of whom 19 had adenoid cystic carcinoma (ACC). No major objective responses were observed; 10 of 19 (53%) had disease stabilization, which was for at least 16 weeks in five patients [19]. Erlotinib (Tarceva) has been used in a phase II study in more than 100 patients. Response rate was 4%, with a median overall survival (OS) of 6 months with a 20% 1-year survival, which is probably not different from conventional chemotherapy [20]. In this study, there was also a positive correlation between drug-related skin rash and treatment outcome. At 150 mg/day, erlotinib has been safely combined with cisplatin and docetaxel-based chemotherapy [21]. Erlotinib was also associated with bevacizumab in a phase I study which demonstrated no synergistic toxicity with interesting activity [22]. However, in this study vascular incidents happened questioning the role of anti-VEGF therapy at least in unselected RM-SCCHN. Other EGFR dual inhibitors are also under study either in early phase I or phase II. The most studied among them is lapatinib, which, although well tolerated, showed little activity in a phase II trial including 42 RM-SCCHN patients [23]. This drug was also used in recurrent or metastatic EGFR and/or ErbB2-positive salivary gland tumours. In this study no responses were observed, although disease stabilisations were seen [24].
locally advanced HNC. In the locally advanced setting, gefitinib was associated with neoadjuvant chemotherapy (carboplatin and paclitaxel), followed by twice-daily radiation with gefitinib, hydroxyurea, and fluorouracil and by a maintenance treatment for 2 years [25]. There was no increase of typical radiation therapy associated mucositis and dermatitis. Seventy percent of patients continued gefitinib in the maintenance phase; in 30% drug discontinuation was due to liver toxicity. The drug was safely associated with conventional radiotherapy at different dosages and maintenance for 2 years [26]. However, when it was given at 250 mg concurrently with radiation and weekly cisplatin, toxicity was prohibitive. Erlotinib and lapatinib were separately used in two different exploratory phase I studies in which they were combined with cisplatin (3-week schedule) and radiation, showing in both studies that the combination was feasible and well tolerated [27, 28]. Erlotinib has been also employed, with similar conclusions with weekly docetaxel and concomitant radiation [29].
Annals of Oncology
immunotherapy in HNC Immunotherapy is based on immunogeneity of human cancer and a multitude of tumour-related proteins that stimulate immunity in cancer patients. Effective anti-tumour response requires potent antigen–presenting cells, such as dendritic cells and cytotoxic T-cell and B-cells. On the other hand, there is mounting evidence of the ability of head and neck tumours to effectively escape immune response for example by inhibiting immune cells both at the local and systemic level by inducing apoptosis of circulating T-cells [39]. In the light of the above, there is the concern that unless vaccine strategies can be effectively protected from the tumour inhibiting effect, little activity will be seen. As such potentially effective vaccine programs should be studied in the adjuvant setting. NPC is an EBV-associated malignancy. NPC cells express two distinct EBV membrane proteins LMP-1 and LMP-2 and those antigens are exploited for immunotherapy. EBV-DNA is also quantifiable by means of polymerase chain reaction (PCR) in NPC patients and seems to be promising as prognostic marker and helpful for the monitoring of disease. The hypothesis which was evaluated in a phase I trial was that an ex-vivo expansion of EBV-specific cytotoxic T lymphocytes (CTLs) and its subsequent tranfer into the patient could be of benefit [40]. A total of 10 patients were treated, six had failed previous treatments while four were at high risk for relapse. The procedure was well tolerated, except for one patient where a facial swelling requiring tracheostomy was observed. Interestingly there was a fall in EBV viral load in six out of nine with detectable amount of EBV-DNA and from a clinical point of view there where three long-lasting responses among the six patients with evidence of disease. Similar results were observed in a second trial in 10 recurrent and metastatic NPC patients [41]. This successful approach indicates that treatment strategies for NPC will soon evolve. Ongoing research in this field is trying to increment the tumour-specific CTLs production and to deliver ‘protective’ cytokines with the aim of prolonging survival of vaccine induced immune cells.
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radioiodine-resistant thyroid cancer Several new biological agents are currently being tested in clinical studies that are logical to consider for advanced thyroid cancer based on its cancer cell biology, particularly because some of the early key oncogenic events are activating mutations of genes coding for tyrosine kinases (TKs). RET can be considered the ‘natural’ target in both medullary and papillary cancers. One of the compounds (ZD6474) with inhibitory RET kinase activity has been studied in a phase II trial including 16 patients with hereditary metastatic medullary carcinoma with two confirmed responses [42]. BRAF represents the most prevalent thyroid oncogene. Moreover a specific BRAF mutation is the most common genetic change in papillary thyroid cancer (PTC), so that BRAF represents an interesting target for treatment of PTC. Sorafenib is a potent Raf inhibitor, as well as vascular epidermal growth factor (VEGF) receptor inhibitor, and it has been used in a phase II trial that was recently updated with significant clinical and biological activity [43]. High level of VEGF expression has been demonstrated with immunohistochemistry in thyroid cancer and this is associated with the occurrence of metastases and probably with worse prognosis. Axitinib, a potent multitarget VEGF receptor inhibitor as well as KIT and PDGFR-beta, provided a partial response in three out of 32 patients, thus showing promising activity. Preliminary signs of activity with depsipeptide (DEP), an histone deacetylase inhibitor in restoring radioactive iodine avidity, has been also reported [44].
references 1. Kalyankrishna S, Grandis JR. Epidermal growth factor receptor biology in head and neck cancer. J Clin Oncol 2006; 24: 2666–2672. 2. Bonner JA, Harari PM, Giralt J et al. EGFR expression and clinical outcome in head and neck patients treated with radiotherapy with or without cetuximab. Proc Am Soc Clin Oncol 2006; 24: 282S. 3. Yeudall WA, Miyazaki H, Ensley JF et al. Uncoupling of epidermal growth factordependent proliferation and invasion in a model of squamous carcinoma progression. Oral Oncol 2005; 41: 698–708. 4. Lee JW, Soung YH, Kim SY et al. Somatic mutations of EGFR gene in squamous cell carcinoma of the head and neck. Clin Cancer Res 2005; 11: 2879–2882. 5. Grandis JR, Tweardy DJ. Elevated levels of transforming growth factor alpha and epidermal growth factor receptor messenger RNA are early markers of carcinogenesis in head and neck cancer. Cancer Res 1993; 53: 3579–3584. 6. Thiery-Vuillemin A, Nguyen T, Pivot et al. Molecularly targeted agents: their promise as cancer chemopreventive interventions. Eur J Cancer 2005; 41: 2003–2015. 7. Dannenberg AJ, Lippman SM, Mann JR et al. Cyclooxygenase-2 and epidermal growth factor receptor: pharmacologic targets for chemoprevention. J Clin Oncol 2005; 23: 254–266. 8. Mayne ST, Lippman SM. Cigarettes: a smoking gun in cancer chemoprevention. J Natl Cancer Inst 2005; 97: 1319–1321. 9. Dassonville O, Formento JL, Francoual M et al. Expression of epidermal growth factor receptor and survival in upper aerodigestive tract cancer. J Clin Oncol 1993; 11: 1873–1878. 10. Santini J, Formento JL, Francoual M et al. Characterization, quantification, and potential clinical value of the epidermal growth factor receptor in head and neck squamous cell carcinomas. Head Neck 1991; 13: 132–139. 11. Bentzen SM, Atasoy BM, Daley FM et al. Epidermal growth factor receptor expression in pretreatment biopsies from head and neck squamous cell
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conclusion that it represents an interesting drug in RM-SCCHN. In NPC treatment results in a platinum-refractory population were similar to those observed in non-NPC tumours [36], although treatment with platinum seems not the best choice since these patients might also benefit from non-platinum containing regimens after platinum failure in first-line. Cetuximab has also been evaluated in a randomised trial in combination with cisplatin versus placebo. Interestingly the response rate was superior for the combination (23% versus 9%), even though progression-free survival (PFS) was not significantly different [37]. Although the study was not powered enough to detect any PFS difference, these results are similar to those observed when comparing monochemotherapy to polychemotherapy in this setting. Cetuximab was also used as single agent in salivary gland tumours. There was no response although long lasting disease stabilisations occurred in some patients [38]. Other EGFR targeting antibodies such as martuzumab, h-R3 and panitumumab are under evaluation in HNC patients.
Annals of Oncology
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carcinoma of the head and neck (SCCHN). Proc Am Soc Clin Oncol 2006; 24: 293S. Savvides P, Agarwala SS, Greskovich J et al. Phase I study of the EGFR tyrosine kinase inhibitor erlotinib in combination with docetaxel and radiation in locally advanced squamous cell cancer of the head and neck (SCCHN). Proc Am Soc Clin Oncol 2006; 24: 291S. Bonner JA, Harari PM, Giralt J et al. Radiotherapy plus cetuximab for squamous-cell carcinoma of the head and neck. N Engl J Med 2006; 354: 567–578. Pignon JP, Bourhis J, Domenge C, Designe L. Chemotherapy added to locoregional treatment for head and neck squamous-cell carcinoma: three meta-analyses of updated individual data. MACH-NC Collaborative Group. Meta-Analysis of Chemotherapy on Head and Neck Cancer. Lancet 2000; 355: 949–955. Bourhis J, Amand C, Pignon JP et al. Update of MACH-NC (Meta-Analysis of Chemotherapy in Head & Neck Cancer) database focused on concomitant chemoradiotherapy. Proc Am Soc Clin Oncol 2004; 23: 488. Trigo J, Hitt R, Koralewski P et al. Cetuximab monotherapy is active in patients (pts) with platinum-refractory recurrent/metastatic squamous cell carcinoma of the head and neck (SCCHN): Results of a phase II study. Proc Am Soc Clin Oncol 2004; 23: 487. Herbst RS, Arquette M, Shin DM et al. Phase II multicenter study of the epidermal growth factor receptor antibody cetuximab and cisplatin for recurrent and refractory squamous cell carcinoma of the head and neck. J Clin Oncol 2005; 23: 5578–5587. Baselga J, Trigo JM, Bourhis J et al. Phase II multicenter study of the antiepidermal growth factor receptor monoclonal antibody cetuximab in combination with platinum-based chemotherapy in patients with platinum-refractory metastatic and/or recurrent squamous cell carcinoma of the head and neck. J Clin Oncol 2005; 23: 5568–5577. Chan AT, Hsu MM, Goh BC et al. Multicenter, phase II study of cetuximab in combination with carboplatin in patients with recurrent or metastatic nasopharyngeal carcinoma. J Clin Oncol 2005; 23: 3568–3576. Burtness B, Goldwasser MA, Flood W et al. Phase III randomized trial of cisplatin plus placebo compared with cisplatin plus cetuximab in metastatic/recurrent head and neck cancer: an Eastern Cooperative Oncology Group study. J Clin Oncol 2005; 23: 8646–8654. Licitra LF, Locati LD, Potepan P et al. Cetuximab (C225) in recurrent and/or metastatic salivary gland carcinomas (RMSGCs): A monoinstitutional phase II study. Proc Am Soc Clin Oncol 2006; 24: 291S. Whiteside TL. Immunobiology of head and neck cancer. Cancer Metastasis Rev 2005; 24: 95–105. Straathof KC, Bollard CM, Popat U et al. Treatment of nasopharyngeal carcinoma with Epstein-Barr virus–specific T lymphocytes. Blood 2005; 105: 1898–1904. Comoli P, Pedrazzoli P, Maccario R et al. Cell therapy of stage IV nasopharyngeal carcinoma with autologous Epstein-Barr virus-targeted cytotoxic T lymphocytes. J Clin Oncol 2005; 23: 8942–8949. Wells S, You YN, Lakhani V et al. A phase II trial of ZD6474 in patients with hereditary metastatic medullary thyroid cancer. Proc Am Soc Clin Oncol 2006; 24: 288S. Kloos R, Ringel M, Knopp M et al. Significant clinical and biologic activity of RAF/VEGF-R kinase inhibitor BAY 43–9006 in patients with metastatic papillary thyroid carcinoma (PTC): Updated results of a phase II study. Proc Am Soc Clin Oncol 2006; 24: 288S. Su YB, Tuttle RM, Fury M et al. A phase II study of single agent depsipeptide (DEP) in patients (pts) with radioactive iodine (RAI)-refractory, metastatic, thyroid carcinoma: Preliminary toxicity and efficacy experience. Proc Am Soc Clin Oncol 2006; 24: 293S.
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carcinoma as a predictive factor for a benefit from accelerated radiation therapy in a randomized controlled trial. J Clin Oncol 2005; 23: 5560–5567. Ang KK, Berkey BA, Tu·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: 7350–7356. Eriksen JG, Steiniche T, Askaa J et al. The prognostic value of epidermal growth factor receptor is related to tumor differentiation and the overall treatment time of radiotherapy in squamous cell carcinomas of the head and neck. Int J Radiat Oncol Biol Phys 2004; 58: 561–566. Chung CH, Ely K, Carter J et al. High gene copy number of epidermal growth factor receptor by fluorescence in situ hybridization is frequent in head and neck squamous cell carcinomas and associates with worse recurrence-free survival. Proc Am Soc Clin Oncol 2006; 24: 280S. Cohen EE, Rosen F, Stadler WM et al. Phase II trial of ZD1839 in recurrent or metastatic squamous cell carcinoma of the head and neck. J Clin Oncol 2003; 21: 1980–1987. Kane MA, Cohen E, List M et al. Phase II study of 250 mg gefitinib in advanced squamous cell carcinoma of the head and neck (SCCHN). Proc Am Soc Clin Oncol 2004; 23: 507. Wheeler RH, Johnes D, Sharma P et al. Clinical and molecular phase II study of gefitinib in patients (pts) with recurrent squamous cell cancer of the head and neck (H&N Ca). Proc Am Soc Clin Oncol 2005; 24: 507S. Wirth LJ, Haddad RI, Lindeman NI et al. Phase I study of gefitinib plus celecoxib in recurrent or metastatic squamous cell carcinoma of the head and neck. J Clin Oncol 2005; 23: 6976–6981. Glisson BS, Blumenschein G, Francisco M et al. Phase II trial of gefitinib in patients with incurable salivary gland cancer. Proc Am Soc Clin Oncol 2005; 24: 508S. Soulieres D, Senzer NN, Vokes EE et al. Multicenter phase II study of erlotinib, an oral epidermal growth factor receptor tyrosine kinase inhibitor, in patients with recurrent or metastatic squamous cell cancer of the head and neck. J Clin Oncol 2004; 22: 77–85. Kim ES, Kies M, Sabichi A et al. Phase II Study of Combination Cisplatin, Docetaxel and Erlotinib in Patients with Metastatic/Recurrent Head and Neck Squamous Cell Carcinoma (HNSCC). Proc Am Soc Clin Oncol 2005; 24: 511S. Vokes EE, Cohen EE, Mauer AM et al. A phase I study of erlotinib and bevacizumab for recurrent or metastatic squamous cell carcinoma of the head and neck (HNC). Proc Am Soc Clin Oncol 2005; 24: 501S. Abidoye OO, Cohen EE, Wong SJ et al. A phase II study of lapatinib (GW572016) in recurrent/metastatic (R/M) squamous cell carcinoma of the head and neck (SCCHN). Proc Am Soc Clin Oncol 2006; 24: 279S. Agulnik M, Cohen EE, Cohen RB et al. A phase II study of lapatinib in recurrent or metastatic EGFR and/or ErbB2 expressing adenoid cystic (ACC) and non-ACC malignant tumors of the salivary glands (MSGT). Proc Am Soc Clin Oncol 2006; 24: 296S. Cohen EE, Haraf DJ, Stenson KM et al. Integration of Gefitinib (G), into a Concurrent Chemoradiation (CRT) Regimen Followed by G Adjuvant Therapy in Patients with Locally Advanced Head and Neck Cancer (HNC) – a Phase II Trial. Proc Am Soc Clin Oncol 2005; 24: 501S. Raben D, Kane MA, Chen C et al. Update on the toxicity and response of a phase I trial of recurrent, daily gefitinib and radiation or chemo-radiation for patients with locally advanced squamous cell cancer of the head and neck (LASCCHN). Eur J Cancer 2004; 2 (Suppl): 196. Herchenhorn D, Dias FL, Ferreira CG et al. Phase I/II study of erlotinib combined with cisplatin and radiotherapy for locally advanced squamous cell carcinoma of the head and neck (SCCHN). Proc Am Soc Clin Oncol 2006; 24: 298S. Harrington KJ, Bourhis J, Nutting CM et al. A phase I, open-label study of lapatinib plus chemoradiation in patients with locally advanced squamous cell
Biological agents in head and neck cancer L. Licitra, L. Locati & P. Bossi Istituto Nazionale dei Tumori, Head and Neck Medical Oncology Unit, Milan, Italy
introduction
the epidermal growth factor receptor (EGFR) system The EGFR system represents the most widely-studied molecular target. EGFR is highly expressed in SCCHN, nasopharyngeal cancer, salivary gland malignant tumours and differentiated thyroid cancer. In SCCHN all the four major signalling EGFR controlled pathways have been described: the RAS-mitogen activated protein kinase (MAPK) system responsible for proliferation signals, the AKT, involved in survival and anti-apoptotic stimuli, the protein kinase C (PKC) activation which results in cell cycle progression and finally the signal transducer and activator of transcription (STAT) system, particularly STAT3, which is associated with gene transcription. In SCCHN, EGFR overexpression is due to overproduction of messenger RNA (mRNA) with an increased EGFR gene copy number in approximately 60% of cases. Similarly to other models the grade of EGFR overexpression does not seem to be correlated with treatment outcome [2]. Moreover, an interesting uncoupling of epidermal growth factor-dependent proliferation and invasion between tumour site and its nodal metastasis has been shown [3] suggesting a possible differential response to anti-EGFR of the same tumour depending on its site. ª 2006 European Society for Medical Oncology
EGFR and carcinogenesis In SCCHN, EGFR and its ligands are involved in the multistep carcinogenetic process characterised by the accumulation of genetic and epigenetic changes of the normal mucosa cell to the premalignant one and finally to the overt infiltrating carcinoma. Within this carcinogenetic model the presence of EGFR highly expressing morphological normal cells at the level of excised tumours is not surprising. Indeed a 30-fold increased mRNA EGFR expression in normal mucosa of HNC patients has been detected [5]. Within this framework there is a strong rationale for using anti-EGFR directed drugs in clinical research, for the inhibition of recurrences, second primary and field tumours [6]. An ongoing study combines it with other relevant biological markers inhibiting drugs, such as anti-COX2, which has been shown to crosstalk with EGFR in preclinical models, thus strengthening the rational for a combined use of such molecular target therapeutics [7]. Whether the effect of this approach will be dependent on smoking habits and specific host factors, as it has been suggested for chemoprevention with micronutrients such as beta-carotene, is left to be demonstrated [8].
EGFR as predictive and prognostic factor EGFR overexpression has shown to be related to more advanced tumour and nodal stage, as well as worse prognosis both in terms of locoregional control and survival [9, 10]. However, another study was not able to either correlate it with tumour stage or with tumour grading; but with tumour subsite and tumour angiogenesis [11]. Interestingly EGFR overexpression was differently correlated with locoregional control in presence of conventional versus altered fractionated radiotherapy, thus suggesting that it may represent a predictive factor rather than a prognostic one [11–13]. Recently a high
Downloaded from http://annonc.oxfordjournals.org/ at California Institute of Technology on July 16, 2015
Despite major advances in therapeutic strategies, including cell and molecular biology, the survival of head and neck cancer (HNC) patients has not improved over the last 30 years. Tumor recurrence and the development of second primaries in association with cure limiting co-morbidities represent the major causes of treatment failure. Aberrant expression of growth factor systems and dysregulation of signalling pathways have been reported in HNC [1]. The better understanding of such mechanisms and the identification of clinically relevant biological markers represent the mainstay of the modern research approach for head and neck cancer, since this is expected to lead to more effective targeting of old and new therapeutic strategies. In the following sections, the focus is on the epidermal growth factor receptor (EGFR) system in squamous head and neck cancer (SCCHN); on recent advances in immunotherapy for head and neck cancer; and in the biological treatment of thyroid cancer.
EGFR expression and activity are both dependent on some polymorphisms distributed in the gene and in the gene promoter region. The percentage of EGFR mutations is less than 10%, it typically occurs on exone 19 [4] and it might be even lower in non-Asian populations. To date there is no correlative study between mutation and tyrosine kinase inhibitors sensitivity and, in general, to what extent EGFR gene profile in SCCHN might contribute to treatment selection has yet to be defined.
Annals of Oncology
gene copy number has been reported to be correlated with a worse prognosis [14].
targeting EGFR Various drugs are available today to inhibit EGFR activity. Two major drug classes have already been extensively studied in HNC.
x46 | Licitra et al.
monoclonal antibodies locally advanced HNC. Cetuximab (Erbitux) has been studied in a phase III trial in combination with radiotherapy versus radiotherapy alone [30]. The results demonstrated that the association of cetuximab concomitantly with radiation produced a significantly better locoregional control (median duration 24.4 versus 14.9 months) and a significant better survival (49 versus 29.3%, with an HR for death of 0.74). Interestingly and unlike chemotherapy, the drug was not associated with enhanced radiation-related mucositis. These observations would lead to the conclusion that cetuximab has an optimal target modulation, apparently due to sufficient drug availability, additive effect at the tumour level in absence of synergistic effect on normal tissues. Taken together, the results would also lead to the conclusion that cetuximab plus radiotherapy represents the state-of-the-art treatment for locally advanced SCCHN. Nonetheless, the current knowledge would indicate that the concomitant use of chemotherapy and radiation therapy is still recognised as the reference treatment. This has also been confirmed by the recent updating of the MACH meta-analyis in 2000 [31, 32]. In this scenario the place of cetuximab concurrently with radiotherapy has to be further tested either in association with chemotherapy or at least for intermediate risk patients (e.g. stage III, oropharyngeal cancer, human papilloma virus (HPV)-positive patients) in comparison with concomitant standard chemoradiotherapy. recurrent and metastatic HNC. Cetuximab has been studied in phase II trials, both as first-line and as second-line in so-called platinum-refractory HNC patients, including nasopharyngeal cancer (NPC). It has been employed both as single agent or in combination with cisplatin [33–35]. Overall, response rate when used as single agent or in combination with cisplatin is similar (approximately 10–15%), thus indicating that cetuximab as single agent has anti-tumour activity regardless of pretreatment. Also in these studies severity of skin rash was associated with better outcome. These results lead to the
Volume 17 | Supplement 10 | September 2006
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small molecules tyrosine kinase inhibitors recurrent and metastatic HNC. The most studied drug has been gefitinib (Iressa). It has already undergone phase II and III trials in recurrent and metastatic SCCHN (RM-SCCHN). As single agent it has been studied in patients already pretreated with previous chemotherapy for their recurrent disease and in a cohort of untreated patients [15–17]. Gefitininb was studied at 250 mg or 500 mg daily. In general, drug toxicity was mild, characterised by skin rash and diarrhoea, probably higher with 500 mg. At full dose (e.g. 500 mg/day), response rate was higher compared to 250 mg, ranging between 10–15%, with 25–40% of disease stabilisation in previously untreated patients, indicating a dose-dependent relationship. A phase I study explored the combination with celecoxib. No dose limiting toxicity was observed. Four responses were observed among 18 treated patients [18]. In every patient skin rash was associated with better outcome. Gefitinib is currently studied within phase III trials: docetaxel with or without gefitininib (ECOG) and a trial in which gefitinib is compared at two different dosages versus methotrexate alone. The results of these trials will contribute to clarify the role of this drug in RM-SCCHN. A phase II study of gefitinib in advanced, progressive salivary malignancies was performed in 29 patients of whom 19 had adenoid cystic carcinoma (ACC). No major objective responses were observed; 10 of 19 (53%) had disease stabilization, which was for at least 16 weeks in five patients [19]. Erlotinib (Tarceva) has been used in a phase II study in more than 100 patients. Response rate was 4%, with a median overall survival (OS) of 6 months with a 20% 1-year survival, which is probably not different from conventional chemotherapy [20]. In this study, there was also a positive correlation between drug-related skin rash and treatment outcome. At 150 mg/day, erlotinib has been safely combined with cisplatin and docetaxel-based chemotherapy [21]. Erlotinib was also associated with bevacizumab in a phase I study which demonstrated no synergistic toxicity with interesting activity [22]. However, in this study vascular incidents happened questioning the role of anti-VEGF therapy at least in unselected RM-SCCHN. Other EGFR dual inhibitors are also under study either in early phase I or phase II. The most studied among them is lapatinib, which, although well tolerated, showed little activity in a phase II trial including 42 RM-SCCHN patients [23]. This drug was also used in recurrent or metastatic EGFR and/or ErbB2-positive salivary gland tumours. In this study no responses were observed, although disease stabilisations were seen [24].
locally advanced HNC. In the locally advanced setting, gefitinib was associated with neoadjuvant chemotherapy (carboplatin and paclitaxel), followed by twice-daily radiation with gefitinib, hydroxyurea, and fluorouracil and by a maintenance treatment for 2 years [25]. There was no increase of typical radiation therapy associated mucositis and dermatitis. Seventy percent of patients continued gefitinib in the maintenance phase; in 30% drug discontinuation was due to liver toxicity. The drug was safely associated with conventional radiotherapy at different dosages and maintenance for 2 years [26]. However, when it was given at 250 mg concurrently with radiation and weekly cisplatin, toxicity was prohibitive. Erlotinib and lapatinib were separately used in two different exploratory phase I studies in which they were combined with cisplatin (3-week schedule) and radiation, showing in both studies that the combination was feasible and well tolerated [27, 28]. Erlotinib has been also employed, with similar conclusions with weekly docetaxel and concomitant radiation [29].
Annals of Oncology
immunotherapy in HNC Immunotherapy is based on immunogeneity of human cancer and a multitude of tumour-related proteins that stimulate immunity in cancer patients. Effective anti-tumour response requires potent antigen–presenting cells, such as dendritic cells and cytotoxic T-cell and B-cells. On the other hand, there is mounting evidence of the ability of head and neck tumours to effectively escape immune response for example by inhibiting immune cells both at the local and systemic level by inducing apoptosis of circulating T-cells [39]. In the light of the above, there is the concern that unless vaccine strategies can be effectively protected from the tumour inhibiting effect, little activity will be seen. As such potentially effective vaccine programs should be studied in the adjuvant setting. NPC is an EBV-associated malignancy. NPC cells express two distinct EBV membrane proteins LMP-1 and LMP-2 and those antigens are exploited for immunotherapy. EBV-DNA is also quantifiable by means of polymerase chain reaction (PCR) in NPC patients and seems to be promising as prognostic marker and helpful for the monitoring of disease. The hypothesis which was evaluated in a phase I trial was that an ex-vivo expansion of EBV-specific cytotoxic T lymphocytes (CTLs) and its subsequent tranfer into the patient could be of benefit [40]. A total of 10 patients were treated, six had failed previous treatments while four were at high risk for relapse. The procedure was well tolerated, except for one patient where a facial swelling requiring tracheostomy was observed. Interestingly there was a fall in EBV viral load in six out of nine with detectable amount of EBV-DNA and from a clinical point of view there where three long-lasting responses among the six patients with evidence of disease. Similar results were observed in a second trial in 10 recurrent and metastatic NPC patients [41]. This successful approach indicates that treatment strategies for NPC will soon evolve. Ongoing research in this field is trying to increment the tumour-specific CTLs production and to deliver ‘protective’ cytokines with the aim of prolonging survival of vaccine induced immune cells.
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radioiodine-resistant thyroid cancer Several new biological agents are currently being tested in clinical studies that are logical to consider for advanced thyroid cancer based on its cancer cell biology, particularly because some of the early key oncogenic events are activating mutations of genes coding for tyrosine kinases (TKs). RET can be considered the ‘natural’ target in both medullary and papillary cancers. One of the compounds (ZD6474) with inhibitory RET kinase activity has been studied in a phase II trial including 16 patients with hereditary metastatic medullary carcinoma with two confirmed responses [42]. BRAF represents the most prevalent thyroid oncogene. Moreover a specific BRAF mutation is the most common genetic change in papillary thyroid cancer (PTC), so that BRAF represents an interesting target for treatment of PTC. Sorafenib is a potent Raf inhibitor, as well as vascular epidermal growth factor (VEGF) receptor inhibitor, and it has been used in a phase II trial that was recently updated with significant clinical and biological activity [43]. High level of VEGF expression has been demonstrated with immunohistochemistry in thyroid cancer and this is associated with the occurrence of metastases and probably with worse prognosis. Axitinib, a potent multitarget VEGF receptor inhibitor as well as KIT and PDGFR-beta, provided a partial response in three out of 32 patients, thus showing promising activity. Preliminary signs of activity with depsipeptide (DEP), an histone deacetylase inhibitor in restoring radioactive iodine avidity, has been also reported [44].
references 1. Kalyankrishna S, Grandis JR. Epidermal growth factor receptor biology in head and neck cancer. J Clin Oncol 2006; 24: 2666–2672. 2. Bonner JA, Harari PM, Giralt J et al. EGFR expression and clinical outcome in head and neck patients treated with radiotherapy with or without cetuximab. Proc Am Soc Clin Oncol 2006; 24: 282S. 3. Yeudall WA, Miyazaki H, Ensley JF et al. Uncoupling of epidermal growth factordependent proliferation and invasion in a model of squamous carcinoma progression. Oral Oncol 2005; 41: 698–708. 4. Lee JW, Soung YH, Kim SY et al. Somatic mutations of EGFR gene in squamous cell carcinoma of the head and neck. Clin Cancer Res 2005; 11: 2879–2882. 5. Grandis JR, Tweardy DJ. Elevated levels of transforming growth factor alpha and epidermal growth factor receptor messenger RNA are early markers of carcinogenesis in head and neck cancer. Cancer Res 1993; 53: 3579–3584. 6. Thiery-Vuillemin A, Nguyen T, Pivot et al. Molecularly targeted agents: their promise as cancer chemopreventive interventions. Eur J Cancer 2005; 41: 2003–2015. 7. Dannenberg AJ, Lippman SM, Mann JR et al. Cyclooxygenase-2 and epidermal growth factor receptor: pharmacologic targets for chemoprevention. J Clin Oncol 2005; 23: 254–266. 8. Mayne ST, Lippman SM. Cigarettes: a smoking gun in cancer chemoprevention. J Natl Cancer Inst 2005; 97: 1319–1321. 9. Dassonville O, Formento JL, Francoual M et al. Expression of epidermal growth factor receptor and survival in upper aerodigestive tract cancer. J Clin Oncol 1993; 11: 1873–1878. 10. Santini J, Formento JL, Francoual M et al. Characterization, quantification, and potential clinical value of the epidermal growth factor receptor in head and neck squamous cell carcinomas. Head Neck 1991; 13: 132–139. 11. Bentzen SM, Atasoy BM, Daley FM et al. Epidermal growth factor receptor expression in pretreatment biopsies from head and neck squamous cell
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conclusion that it represents an interesting drug in RM-SCCHN. In NPC treatment results in a platinum-refractory population were similar to those observed in non-NPC tumours [36], although treatment with platinum seems not the best choice since these patients might also benefit from non-platinum containing regimens after platinum failure in first-line. Cetuximab has also been evaluated in a randomised trial in combination with cisplatin versus placebo. Interestingly the response rate was superior for the combination (23% versus 9%), even though progression-free survival (PFS) was not significantly different [37]. Although the study was not powered enough to detect any PFS difference, these results are similar to those observed when comparing monochemotherapy to polychemotherapy in this setting. Cetuximab was also used as single agent in salivary gland tumours. There was no response although long lasting disease stabilisations occurred in some patients [38]. Other EGFR targeting antibodies such as martuzumab, h-R3 and panitumumab are under evaluation in HNC patients.
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