© 2005 European Society for Medical Oncology
Articles |
New approaches to enhance chemotherapy in SCCHN
Institut Gustave Roussy, Villejuif 94805, France
* Correspondence to: Dr J. Bourhis, Institut Gustave Roussy, 39 Rue Camille Desmoulins, Villejuif 94805, France. Tel: +33 1 4211 4998; Fax: +33 1 4211 5281; E-mail: bourhis{at}igr.fr
 |
Abstract |
|---|
 Top Abstract IntroductionChemotherapy for...The benefits of chemotherapy...Targeted therapies in...ConclusionsDisclosureReferences |
|---|
Chemotherapy is the standard approach to the treatment of patients with recurrent and metastatic squamous cell carcinoma of the head and neck (SCCHN) and is also now a common component of treatment for patients with locoregionally advanced, non-metastatic disease. Cisplatin has for many years been the agent of choice, alone or in combination with other agents, particularly 5-FU. The advent of the taxanes, which demonstrate good non-clinical activity against SCCHN, spawned a series of investigations aimed at integrating these agents into treatment regimens. Molecular targeted agents, which do not demonstrate overlapping toxicities with commonly used chemotherapy agents for SCCHN, represent a promising avenue of investigation. The epidermal growth factor receptor (EGFR) is expressed both widely and at high levels in SCCHN and is associated with poor prognosis. The EGFR-directed monoclonal antibody (MAb) cetuximab (Erbitux®) in combination with chemotherapy has shown some activity in the treatment of recurrent/metastatic disease both as first-line therapy and following cisplatin failure, and preliminary results suggest single-agent activity in platinum-resistant disease. Promising activity has also been observed with a number of other EGFR inhibitors, both MAbs and tyrosine kinase inhibitors.
Key words: cetuximab, chemotherapy, EGFR, SCCHN
|
Introduction |
|---|
|
TopAbstractIntroductionChemotherapy for...The benefits of chemotherapy...Targeted therapies in...ConclusionsDisclosureReferences |
|---|
Cisplatin-based regimens are the standard approach to chemotherapy used in the post-operative setting for resectable disease, for locally advanced unresectable disease and by many also considered standard for the first-line treatment of recurrent/metastatic disease. In general, two-agent regimens are preferred, at least for unresectable and recurrent/metastatic disease, and 5-fluorouracil (5-FU) is often the combination agent of choice. This paper focuses on current and potential chemotherapy options for use in the management of locally advanced unresectable disease and recurrent/metastatic disease.
|
Chemotherapy for recurrent/metastatic disease |
|---|
|
TopAbstractIntroductionChemotherapy for...The benefits of chemotherapy...Targeted therapies in...ConclusionsDisclosureReferences |
|---|
Chemotherapy is the mainstay of treatment for patients with recurrent/metastatic squamous cell carcinoma of the head and neck (SCCHN). The benefits of cisplatin were shown nearly 20 years ago [1
] and it is probably the most important agent. Survival benefits of 10 weeks may be expected [1]. The dose-limiting toxicities associated with cisplatin are well documented and include haematological toxicity, neurotoxicity, nephrotoxicity and ototoxicity. Attempts to deliver higher-dose or dose-intensified cisplatin have largely been unsuccessful due to these toxicities. A randomized study by the European Organization for Research and Treatment of Cancer demonstrated that concurrent administration of amifostine reduced the risk of toxicity but did not enable cisplatin dose intensification [2]. Randomized trials have shown increased response rates but failed to show a survival benefit for cisplatin in combination with 5-FU or methotrexate over single-agent therapy [3–6]. Despite this, for patients who are able to tolerate more aggressive chemotherapy than standard methotrexate, combination chemotherapy with a cisplatin-based regimen is used by many as a standard approach for patients with recurrent/metastatic disease. With the advent of newer therapies over the last ten years, attempts to improve outcome to chemotherapy have continued. The taxanes are now an integral part of therapy for a number of different tumour types and are active in SCCHN. However, the results in the first-line setting are conflicting and on the whole disappointing. The Eastern Co-operative Oncology Group study conducted two randomized phase III studies with paclitaxel in combination with cisplatin. The first study involved the addition of high- or low-dose paclitaxel to cisplatin [7]. This study showed no survival advantage of high-dose paclitaxel, but an excess of haematological toxicity: 70% of those receiving high-dose paclitaxel and 78% receiving low-dose paclitaxel developed grade 3/4 neutropenia, despite the use of granulocyte-colony stimulating factor in those receiving high-dose paclitaxel. In the second study, the combination of cisplatin and paclitaxel was no more effective, in terms of response and survival, than cisplatin and 5-FU, but was less toxic in terms of both haematological and non-haematological toxicity [8]. A number of phase II trials have shown that combinations of docetaxel and cisplatin or paclitaxel and carboplatin show activity in metastatic disease, although prophylaxis to reduce haematological toxicity may be required [9, 10]. More recently, a phase II study suggested that a schedule of dose-dense weekly administration of reduced individual doses of paclitaxel in combination with carboplatin may be better tolerated [11]. The response rate of 60% achieved with this regimen suggests that it may be worth pursuing. Vinorelbine has also shown moderate activity as a single agent in the first-line treatment of recurrent/metastatic SCCHN [12]. An attempt to modulate the combination of cisplatin/5-FU with the biological response modifier interferon 
-2b failed to show any clinical benefits in a phase III trial [13].
The prognosis of patients with recurrent/metastatic SCCHN who progress on platinum-based chemotherapy is poor and these patients have only limited alternative therapeutic options. A retrospective analysis of 151 patients relapsing on platinum-based therapy who then received second-line chemotherapy, radiotherapy or best supportive care showed the median survival of this group to be only 3.5 months [14]. Of the 57 patients receiving second-line chemotherapy (including platinum, methotrexate, bleomycin or docetaxel, either alone or as part of a combination regimen) only 3% achieved a response [14]. The use of novel combinations of chemotherapy have been investigated in a number of small phase I/II studies (Table 1) [15–19]. The combination of vinorelbine with cisplatin, docetaxel or gemcitabine has shown some activity in patients with SCCHN, a proportion of whom had received previous chemotherapy [15–17]. A combination of capecitabine and cisplatin has also been shown to be feasible in a similar patient population [19]. However, improvements in survival appear limited and generally the outlook for patients failing on platinum therapy remains dismal.
|
|
The benefits of chemotherapy in loco-regional disease |
|---|
|
TopAbstractIntroductionChemotherapy for...The benefits of chemotherapy...Targeted therapies in...ConclusionsDisclosureReferences |
|---|
The benefit of adding chemotherapy to locoregional therapy for non-metastatic disease was confirmed by the results of a meta-analysis of 87 trials conducted by our group (meta-analysis of chemotherapy in head and neck cancer, MACH-NC collaborative group) [20
]. This analysis included more than 16 000 patients. Overall, there was a statistically significant survival benefit of 5% at 5 years for the use of chemotherapy (P < 0.0001). There was also a significant interaction between the timing of chemotherapy and survival (P < 0.0001). In 50 of the trials, chemotherapy was given concomitantly with radiotherapy and in these trials, the absolute benefit was 8% at 5 years (P < 0.0001). The type and timing of radiotherapy (conventional and altered fractionated radiotherapy, whether definitive or post-operative) used with chemotherapy did not influence the outcome. Also, there was no significant difference in survival between the use of monotherapy or combined chemotherapy. However, the greatest benefit was seen with platinum-based chemotherapy compared with other chemotherapy (P < 0.01). These results confirmed those of our previous, smaller analysis [21] and those of a review by Browman et al. [22]. In a pooled analysis of 18 randomized trials, involving 3,192 patients with locally advanced disease, Browman and colleagues reported an 11% reduction in the risk of death with the use of concomitant chemotherapy compared with radiotherapy alone (P < 0.00001). Platinum-based regimens were the most effective of the chemotherapy regimens used (P < 0.00001). The addition of chemotherapy concomitant with radiotherapy generally results in significant acute and late toxic effects [23]. Given the improved anti-tumour efficacy associated with the addition of chemotherapy, optimisation is needed to improve the tolerability of the combined treatment. With that in mind, intensity modulated radiotherapy could be a useful tool, decreasing the dose of radiotherapy delivered to normal tissues, while increasing the dose in the gross tumour volume. The use of new drugs, especially of targeted therapies that are associated with a relatively good tolerability profile, might also be of interest in terms of minimising side effects in combination with radiotherapy while maintaining antitumour efficacy [24].
The value of neoadjuvant therapy in SCCHN remains to be confirmed [25]. However, recent data with the taxanes is encouraging, and the addition of docetaxel or paclitaxel to cisplatin/5-FU appears to be a particularly promising approach [26, 27]. We recently reported an analysis comparing data from six phase II trials using the combination of docetaxel/cisplatin/5-FU (n = 195) as neoadjuvant therapy with data from five large randomized trials using platinum/5-FU (n = 585) (derived from the MACH-NC database) [28]. Patients received radiotherapy and/or surgery following chemotherapy. A patient selection standardisation method and Cox model were used to adjust for potential selection bias. The addition of docetaxel to treatment was associated with a significantly reduced risk of death: the relative risk of death was 1.85 in the platinum/5-FU arm in relation to the docetaxel/platinum/5-FU arm. This corresponded to a significant 2-year survival benefit of 20% (P < 0.0001). These results were confirmed by a randomized trial from the EORTC involving 358 patients with unresectable locally advanced SCCHN demonstrating a significant improvement in outcome with the addition of docetaxel to platinum/5-FU prior to radiotherapy. At a median follow-up of 32 months, the docetaxel group demonstrated significantly prolonged progression-free survival (P = 0.006) and overall survival (P = 0.016) and a higher response rate (68% vs. 54%, P = 0.007). The docetaxel regimen also appeared to be better tolerated and was associated with fewer toxic deaths (5% vs. 2%) [29].
|
Targeted therapies in combination with chemotherapy |
|---|
|
TopAbstractIntroductionChemotherapy for...The benefits of chemotherapy...Targeted therapies in...ConclusionsDisclosureReferences |
|---|
The combination of standard chemotherapy with molecular targeted therapy is an attractive proposition for improving response to treatment. Such agents offer a way of directly targeting the tumour without exacerbating the side effects associated with standard chemotherapy.
The epidermal growth factor receptor (EGFR) has been identified as an important target for cancer therapy. It is expressed at high levels in a number of tumour types and in most SCCHN [30], and is associated with an adverse impact on survival [31]. Inhibition of the EGFR, most commonly using monoclonal antibodies (MAbs) directed against the external ligand binding domain or small molecule tyrosine kinase inhibitors, has been the focus of much attention in recent years. Cetuximab is an IgG1 MAb that specifically targets the EGFR and inhibits signal transduction [32, 33]. Cetuximab is approved in Europe and the US for use in patients with EGFR-expressing metastatic colorectal cancer. Its use in head and neck cancers was a logical step in view of the expression of EGFR in a high proportion of SCCHN.
A series of studies have shown the activity of cetuximab in the treatment of recurrent/metastatic disease both as first-line therapy and following platinum failure.
In a randomized phase III trial in the first-line setting, 118 patients were randomized to receive cisplatin 100 mg/m2 q 28 days plus either cetuximab (400 mg/m2 on day 1 followed by subsequent weekly doses of 250 mg/m2) or placebo [34]. There was a significantly higher response rate among those patients receiving cetuximab (26% vs 10%, P = 0.048). Although there was no significant difference between the medians of progression-free survival (4.2 vs 3.4 months) and overall survival (9.3 vs 8.0 months) between the arms, there did appear to be a survival advantage for patients developing skin toxicity (P = 0.01). The most common grade 3/4 abnormalities were those expected with cisplatin chemotherapy. However, grade 3 rash, a characteristic side effect of EGFR inhibitors, was seen in 17% of patients receiving cetuximab but in none receiving placebo. Preliminary data from a phase I study in the first-line setting showed that the addition of cetuximab to a combination of cisplatin/carboplatin and 5-FU was well tolerated in the first-line setting and demonstrated encouraging activity [35].
The dismal prognosis of patients failing on first-line platinum-based therapy is well known. The combination of cetuximab and cisplatin or carboplatin in patients with SCCHN that had progressed on cisplatin-containing therapy was investigated in two phase II studies (Table 2) [36]. In a US study, a partial response rate of 12% was observed. A similar European study in 96 patients reported an overall response rate of 15%, with two complete and 12 partial responses [37]. A further 38 patients (40%) had stable disease or minor responses lasting for at least 6 weeks. The median survival was 5.9 months overall and 8.8 months in responding patients. The response rates (12% and 15%) observed in these two studies are encouraging in view of the 3% that has previously been reported for such patients.
|
Single-agent cetuximab has also shown significant activity in disease failing on platinum-based therapy. Preliminary findings with cetuximab monotherapy in 103 patients with documented progression of metastatic disease showed a response rate of 17% and clinical benefit (partial response + stable disease) in 53% of cases (Table 2) [38
]. The median time to progression was 85 days and the median survival 175 days. These findings are encouraging and in line with those reported for cetuximab in combination with cisplatin.
Anti-tumour activity has also been seen with a number of other EGFR inhibitors. The humanized MAb h-R3 [39, 40] and the rat MAb ICR-62 [41], which are both at an earlier stage of development than cetuximab, have shown activity against SCCHN cells and are currently being investigated in early clinical trials. The tyrosine kinase inhibitors erlotinib [42, 43] and gefitinib [44, 45] have also shown activity in phase II trials in SCCHN. Finally, given the complex nature of cellular signaling and the array of pathways involved, possible additional targets for novel SCCHN therapies include; DNA repair proteins, signal transduction pathways (farnesyl transferase inhibitors, PKC inhibitors), proteins involved in cell cycle regulation (cyclin-dependent kinases), proteosomes and angiogenesis.
|
Conclusions |
|---|
|
TopAbstractIntroductionChemotherapy for...The benefits of chemotherapy...Targeted therapies in...ConclusionsDisclosureReferences |
|---|
Chemotherapy remains an integral part of treatment for recurrent and metastatic SCCHN and has also been confirmed as a major component of therapy for many patients with locoregionally advanced disease. However, while chemotherapy is clearly a valuable tool, it is nearly 20 years since cisplatin was identified as the gold standard of treatment and optimum treatment regimens should be defined in the light of new agents and those with novel modes of action. The taxanes have emerged as some of the most active agents for SCCHN, that need further investigation. An additional promising approach is the use of molecular targeted agents, such as the EGFR inhibitor cetuximab, which generally do not have the dose-limiting side effects associated with standard chemotherapeutic agents. To date, clinical trials have shown the activity of cetuximab in combination with chemotherapy in the first-line treatment of recurrent/metastatic disease and in patients with platinum-resistant disease. Of particular interest are the preliminary results showing the activity of single-agent cetuximab in platinum-refractory SCCHN. It will be interesting to observe if these effects are confirmed in randomized phase III trials in the same patient category.
|
Disclosure |
|---|
|
TopAbstractIntroductionChemotherapy for...The benefits of chemotherapy...Targeted therapies in...ConclusionsDisclosureReferences |
|---|
The author does not have any financial relationships with companies whose products are mentioned in the text.
|
References |
|---|
|
TopAbstractIntroductionChemotherapy for...The benefits of chemotherapy...Targeted therapies in...ConclusionsDisclosureReferences |
|---|
1. Morton RP, Rugman F, Dorman EB et al. Cisplatinum and bleomycin for advanced or recurrent squamous cell carcinoma of the head and neck: a randomized factorial phase III controlled trial. Cancer Chemother Pharmacol 1985; 15: 283–289.[ISI][Medline]
2. Planting AS, Catimel G, de Mulder PH et al. Randomized study of a short course of weekly cisplatin with or without amifostine in advanced head and neck cancer. EORTC Head and Neck Cooperative Group. Ann Oncol 1999; 10: 693–700.
3. Forastiere AA, Metch B, Schuller DE et al. Randomized comparison of cisplatin plus fluorouracil and carboplatin plus fluorouracil versus methotrexate in advanced squamous-cell carcinoma of the head and neck: a Southwest Oncology Group study. J Clin Oncol 1992; 10: 1245–1251.
4. Jacobs C, Lyman G, Velez-Garcia E et al. A phase III randomized study comparing cisplatin and fluorouracil as single agents and in combination for advanced squamous cell carcinoma of the head and neck. J Clin Oncol 1992; 10: 257–263.
5. A phase III randomized trial of cisplatinum, methotrextate, cisplatinum + methotrexate and cisplatinum + 5-FU in end stage squamous carcinoma of the head and neck. Liverpool Head and Neck Oncology Group. Br J Cancer 1990; 61: 311–315.[ISI][Medline]
6. Clavel M, Vermorken JB, Cognetti F et al. Randomized comparison of cisplatin, methotrexate, bleomycin and vincristine (CABO) versus cisplatin and 5-fluorouracil (CF) versus cisplatin (C) in recurrent or metastatic squamous cell carcinoma of the head and neck. A phase III study of the EORTC Head and Neck Cancer Cooperative Group. Ann Oncol 1994; 5: 521–526.
7. Forastiere AA, Leong T, Rowinsky E et al. Phase III comparison of high-dose paclitaxel + cisplatin + granulocyte colony-stimulating factor versus low-dose paclitaxel + cisplatin in advanced head and neck cancer: Eastern Cooperative Oncology Group Study E1393. J Clin Oncol 2001; 19: 1088–1095.
8. Murphy B, Li Y, Cella D et al. Phase III study comparing cisplatin (C) and 5-fluorouracil (F) versus cisplatin & paclitaxel (T) in metastatic/recurrent head and neck cancer (MHNC). Proc Am Soc Clin Oncol 2001; 19: Abstr 894.
9. Clark JI, Hofmeister C, Choudhury A et al. Phase II evaluation of paclitaxel in combination with carboplatin in advanced head and neck carcinoma. Cancer 2001; 92: 2334–2340.[CrossRef][ISI][Medline]
10. Baur M, Kienzer HR, Schweiger J et al. Docetaxel/cisplatin as first-line chemotherapy in patients with head and neck carcinoma: a phase II trial. Cancer 2002; 94: 2953–2958.[CrossRef][ISI][Medline]
11. Hiller S, Mergenthaler H-G. Paclitaxel and carboplatin in patients with metastatic or recurrent squamous cell carcinoma of the head and neck. A phase II study. J Clin Oncol, ASCO Annual Meeting Proceedings (Post-Meeting Edition) 2004; 22 (No 14S): Abstr 5579.
12. Degardin M, Oliveira J, Geoffrois L et al. An EORTC-ECSG phase II study of vinorelbine in patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck. Ann Oncol 1998; 9: 1103–1107.
13. Schrijvers D, Johnson J, Jiminez U et al. Phase III trial of modulation of cisplatin/fluorouracil chemotherapy by interferon alfa-2b in patients with recurrent or metastatic head and neck cancer. Head and Neck Interferon Cooperative Study Group. J Clin Oncol 1998; 16: 1054–1059.[Abstract]
14. Leon X, Hitt R, Constenla M et al. A retrospective analysis of the outcome of patients (pts) with recurrent or metastatic squamous cell carcinoma of the head and neck (R&M SCCHN) who are progressing while on a platinum-based palliative chemotherapy. Proc Am Soc Clin Oncol 2003; 22: Abstr 2202.
15. Espinosa E, Zamora P, Milla A et al. A phase II trial of cisplatin and vinorelbine in patients with recurrent or metastatic squamous cell carcinoma of the head and neck. Head Neck 2002; 24: 1054–1059.[CrossRef][ISI][Medline]
16. Airoldi M, Cattel L, Cortesina G et al. Gemcitabine and vinorelbine in recurrent head and neck cancer: pharmacokinetic and clinical results. Anticancer Res 2003; 23: 2845–2852.[ISI][Medline]
17. Airoldi M, Cattel L, Marchionatti S et al. Docetaxel and vinorelbine in recurrent head and neck cancer: pharmacokinetic and clinical results. Am J Clin Oncol 2003; 26: 378–381.[CrossRef][ISI][Medline]
18. Pivot X, Raymond E, Laguerre B et al. Pemetrexed disodium in recurrent locally advanced or metastatic squamous cell carcinoma of the head and neck. Br J Cancer 2001; 85: 649–655.[CrossRef][ISI][Medline]
19. Pivot X, Chamorey E, Guardiola E et al. Phase I and pharmacokinetic study of the association of capecitabine-cisplatin in head and neck cancer patients. Ann Oncol 2003; 14: 1578–1586.
20. Bourhis J, Armand C, Pignon JP. Update of MACH-NC (Meta-Analysis of Chemotherapy in Head & Neck Cancer) database focused on concomitant chemoradiotherapy. J Clin Oncol, ASCO Annual Meeting Proceedings (Post-Meeting Edition) 2004; 22, No 14S: Abstr 5505.
21. 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.[ISI][Medline]
22. Browman GP, Hodson DI, Mackenzie RJ et al. Choosing a concomitant chemotherapy and radiotherapy regimen for squamous cell head and neck cancer: A systematic review of the published literature with subgroup analysis. Head Neck 2001; 23: 579–589.[CrossRef][ISI][Medline]
23. Denis F, Garaud P, Bardet E et al. Late toxicity results of the GORTEC 94–01 randomized trial comparing radiotherapy with concomitant radiochemotherapy for advanced-stage oropharynx carcinoma: comparison of LENT/SOMA, RTOG/EORTC, and NCI-CTC scoring systems. Int J Radiat Oncol Biol Phys 2003; 55: 93–98.[CrossRef][ISI][Medline]
24. Bonner JA, Giralt J, Harari P et al. Cetuximab prolongs survival in patients with locally advanced squamous cell carcinoma of head and neck: a phase III study of high dose radiation therapy with or without cetuximab. J Clin Oncol, ASCO Annual Meeting Proceedings (Post-Meeting Edition) 2004; 22 (No. 14S): Abstr 5507.
25. Licitra L, Vermorken JB. Is there still a role for neoadjuvant chemotherapy in head and neck cancer? Ann Oncol 2004; 15: 7–11.
26. Schrijvers D, Van Herpen C, Kerger J et al. Docetaxel, cisplatin and 5-fluorouracil in patients with locally advanced unresectable head and neck cancer: a phase I-II feasibility study. Ann Oncol 2004; 15: 638–645.
27. Hitt R, Paz-Ares L, Brandariz A et al. Induction chemotherapy with paclitaxel, cisplatin and 5-fluorouracil for squamous cell carcinoma of the head and neck: long-term results of a phase II trial. Ann Oncol 2002; 13: 1665–1673.
28. Pignon JP, Syz N, Posner M et al. Adjusting for patient selection suggests the addition of docetaxel to 5-fluorouracil-cisplatin induction therapy may offer survival benefit in squamous cell cancer of the head and neck. Anticancer Drugs 2004; 15: 331–340.[CrossRef][Medline]
29. Vermorken JB, Remenar E, Van Herpen C et al. Standard cisplatin/infusional 5-fluorouracil (PF) vs docetaxel (T) plus PF (TPF) as neoadjuvant chemotherapy for nonresectable locally advanced squamous cell carcinoma of the head and neck (LA-SCCHN): A phase III trial of the EORTC Head and Neck Cancer Group (EORTC #24971). J Clin Oncol, ASCO Annual Meeting Proceedings (Post-Meeting Edition) 2004; 22 (No 14S): Abstr 5508.
30. Grandis JR, Melhem MF, Barnes EL, Tweardy DJ. Quantitative immunohistochemical analysis of transforming growth factor-alpha and epidermal growth factor receptor in patients with squamous cell carcinoma of the head and neck. Cancer 1996; 78: 1284–1292.[CrossRef][ISI][Medline]
31. Ang KK, Berkey BA, Tu X 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.
32. Herbst RS, Shin DM. Monoclonal antibodies to target epidermal growth factor receptor- positive tumors: a new paradigm for cancer therapy. Cancer 2002; 94: 1593–1611.[CrossRef][ISI][Medline]
33. Goldstein NI, Prewett M, Zuklys K et al. Biological efficacy of a chimeric antibody to the epidermal growth factor receptor in a human tumor xenograft model. Clin Cancer Res 1995; 1: 1311–1318.[Abstract]
34. Burtness BA, Li Y, Flood W et al. Phase III randomized trial of cisplatin + placebo versus cisplatin + C225, a monoclonal antibody directed to the epidermal growth factor-receptor: an Eastern Cooperative Oncology Group trial. Clin Cancer Res 2003; 9: Abstr A77.
35. Humblet Y, Vega-Villegas E, Mesia R et al. Phase I study of cetuximab in combination with cisplatin or carboplatin and 5-fluorouracil (5-FU) in patients (pts) with recurrent and/or metastatic squamous cell carcinoma of the head and neck (SCCHN). J Clin Oncol, ASCO Annual Meeting Proceedings (Post-Meeting Edition) 2004; 22 (No 14S): Abstr 5513.
36. Kies MS, Arquette MA, Nabell L et al. Final report of the efficacy and safety of the anti-epidermal growth factor antibody Erbitux (IMC-C225), in combination with cisplatin in patients with recurrent squamous cell carcinoma of the head and neck (SCCHN) refractory to cisplatin containing chemotherapy. Proc Am Soc Clin Oncol 2002; 21: Abstr 925. Virtual Meeting at www.asco.org.
37. Baselga J, Trigo JM, Bourhis J et al. Cetuximab (C225) plus cisplatin/carboplatin is active in patients (pts) with recurrent/metastatic squamous cell carcinoma of the head and neck (SCCNH) progressing on a same dose and schedule platinum-based regimen. Proc Am Soc Clin Oncol 2002; 21: Abstr 900.
38. 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. Journal of Clinical Oncology, ASCO Annual Meeting Proceedings (Post-Meeting Edition) 2004; 22 (No 14S): Abstr 5502. Virtual meeting presentation: www.asco.org.
39. Crombet T, Torres L, Neninger E et al. Pharmacological evaluation of humanized anti-epidermal growth factor receptor, monoclonal antibody h-R3, in patients with advanced epithelial-derived cancer. J Immunother 2003; 26: 139–148.
40. Crombet-Ramos T, Rak J, Perez R, Viloria-Petit A. Antiproliferative, antiangiogenic and proapoptotic activity of h-R3: A humanized anti-EGFR antibody. Int J Cancer 2002; 101: 567–575.[CrossRef][ISI][Medline]
41. Hoffmann T, Hafner D, Ballo H et al. Antitumor activity of anti-epidermal growth factor receptor monoclonal antibodies and cisplatin in ten human head and neck squamous cell carcinoma lines. Anticancer Res 1997; 17: 4419–4425.[ISI][Medline]
42. Mauer AM, Cohen EE, Wong SJ et al. Phase I study of epidermal growth factor receptor (EGFR) inhibitor, erlotinib, and vascular endothelial growth factor monoclonal antibody, bevacizumab, in recurrent and/or metastatic squamous cell carcinoma of the head and neck (SCCHN). J Clin Oncol, ASCO Annual Meeting Proceedings (Post-Meeting Edition) 2004; 22 (No 14S): Abstr 5539.
43. 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.
44. 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.
45. Kane MA, Cohen EE, List M et al. Phase II study of 250 mg gefitinib in advanced squamous cell carcinoma of the head and neck (SCCHN). J Clin Oncol, ASCO Annual Meeting Proceedings (Post-Meeting Edition) 2004; 22 (No 14S): Abstr 5586.
CiteULike 
Connotea 
Del.icio.us What's this?
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||