© 2005 European Society for Medical Oncology
Articles |
Current clinical outcomes demand new treatment options for SCCHN
Département de Cancérologie Cervico-Faciale, Centre Oscar Lambret, Lille, France
* Correspondence to: Dr J.-L. Lefebvre, Département de Cancérologie Cervico-Faciale, Centre Oscar Lambret, 3 rue Frédéric Combemale, B.P. 307, F-59020, Lille, France. Tel: +33 3 2029 5531; Fax: +33 3 2029 5961; E-mail: jl-lefebvre{at}o-lambret.fr
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Abstract |
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Head and neck cancer can be a devastating disease. The mainstays of treatment for early stage disease are either radiotherapy or surgery. However, although disease responds well at this stage, the risk of a second primary cancer is high, with a development rate of about 4% per year. Advanced diseases are treated either by surgery with postoperative radiotherapy or by definitive radiotherapy, with surgery in reserve for salvage if necessary. Over the past two decades major advances have been made in surgery (reconstructive surgery, non-mutilating surgery). Either definitive or postoperative, radiotherapy is an integral part of the treatment for the majority of non-metastatic stages of disease and ways of improving the effects of radiotherapy are constantly being explored. Good activity has been reported for the use of altered radiation fractionation regimens, which allow the delivery of intensified radiation doses. In addition, in recent years randomized trials and meta-analyses have confirmed the survival benefit of adding chemotherapy to radiotherapy in a number of different settings. Cisplatin-based regimens have been identified as the most active and are now standard treatment choices. The survival benefits of chemotherapy appear to be limited to concomitant administration and do not extend to neoadjuvant administration, although this has demonstrated clinical utility in preserving organ function. Platinum-based combination chemotherapy is by many clinicians considered the standard approach to the treatment of recurrent/metastatic disease for patients who are able to tolerate such regimens, but the prognosis for these patients remains poor; this is particularly true for those whose disease progresses on such therapy. This paper discusses current approaches and recent advances in the treatment of head and neck cancer, specifically squamous cell carcinoma, and suggests future management aims for the different disease stages.
Key words: chemoradiotherapy, chemotherapy, head and neck cancer, locally advanced, radiotherapy, recurrent/metastatic
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Introduction |
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Head and neck cancers (comprising cancers of the oral cavity, nasopharynx, pharynx and larynx), make up around 6% of all cancers worldwide (excluding non-melanoma skin cancers) [1
]. In most countries they are more common in men than in women. In Europe alone in 2002, the estimated incidence was around 143 000, with over 68 000 deaths [1]. Tobacco and alcohol are major contributors to the development of head and neck cancers. They also generate notable comorbidities, in terms of pulmonary, cardiovascular, hepatic or neurological disorders.
The main histological subtype within head and neck cancers is squamous cell carcinoma (SCCHN). Up to 40% of patients with SCCHN present with metastatic disease, and the main sites of metastases are the lung, mediastinal nodes, liver and bone. The survival of patients with head and neck cancers depends on a number of factors, the most important being disease stage and patient performance status. In a retrospective study of over 3000 mucosal cancers, utilising the fifth edition of the Tumour Node Metastasis (TNM) classification, 5-year survival rates were 91% for stage I disease, 77% for stage II, 61% for stage III, 32% for stage IVa, 25% for stage IVb and less than 4% for stage IVc disease. Survival rates are reduced in patients with comorbidities. Head and neck cancers are characterized by a relatively high risk of a secondary primary cancer, with a constant development rate of approximately 4% per year [3].
General treatment principles
For non-metastatic diseases, whatever the stage, radiotherapy plays an integral part of the treatment strategy plan in the vast majority of the cases. Improvements in delivery methods, such as the use of altered fractionation regimens, have been shown to increase locoregional control both in patients not undergoing resection [4] and in the post-surgical setting [5]. The benefits of chemotherapy are also being increasingly recognized in both resectable and unresectable disease, and the value of adding chemotherapy to radiotherapy in several settings has been confirmed in two meta-analyses [6, 7]. Bourhis et al. showed that among 87 trials, the use of chemotherapy was associated with a survival advantage of 5% at 5 years [7]. This benefit was confined mainly to the use of concurrent chemotherapy and radiotherapy (chemoradiotherapy), which was shown to give an 8% survival advantage at 5 years. The use of chemotherapy in the neoadjuvant setting did not confer a survival benefit [8].
Early stage (stage I and II) disease
Early stage disease is often treated with single modality therapy, namely open or endoscopic surgery, brachytherapy or external beam radiotherapy. In stage I disease, surgery and radiotherapy produce quite similar results. It is generally accepted that treatment of early stage disease should be individualized to the patient and should be based primarily on the disease and the patient's clinical characteristics, including tumour site and size, and the patient's age, performance score, cardiovascular and pulmonary functions and wishes. In addition, the patient's occupation and access to medical resources should also be taken into account. Importantly, the intention of treatment should be determined, i.e. initial cure, ultimate cure (salvage therapy, if any), or cosmetic and optimal functional outcome (quality of life).
In view of the high risk of development of a second primary tumour, which is particularly common in tobacco-exposed tissue, lifestyle changes, for example avoidance of alcohol and tobacco, are advised as a way of helping to reduce this risk, although the extent of any benefit is uncertain. Another way of potentially reducing the risk of second primaries is by the use of chemoprevention, which has been attempted in a number of malignancies, with notable success in some (for example the use of tamoxifen in breast cancer) [9]. In head and neck cancers, retinoids are some of the most extensively investigated compounds and high dose treatment may be effective against premalignant oral lesions. However, recent results from a phase III randomized study in patients with radically treated SCCHN failed to show a significant chemopreventive effect of 13-cis retinoic acid, with no differences between the treatment groups in overall or relapse-free survival [10]. Another large randomized study showed no significant activity of N-acetylcysteine and vitamin A, either alone or in combination, in preventing the development of second primary tumors, compared with no intervention [11]. Novel molecular targets, such as the epidermal growth factor receptor and cyclo-oxygenase-2, appear to be attractive options for chemoprevention and further investigation should help to define their role [9].
Non-metastatic locally advanced disease
For patients with resectable disease, treatment with surgery and post-operative radiotherapy is considered a standard approach. At this stage, as radical resection is the aim, surgery is often extensive. In our experience, the 5-year survival of patients treated in this way is between 35% and 65%. Wherever possible, however, organ preservation is also a desirable aim, and balancing these two goals is difficult. In terms of the success of resection, positive steps have been made with advances in surgical techniques and pre-surgical tumour mapping. However, limitations continue to exist in the form of technical obstacles, patient characteristics (predominantly performance status) and potential cosmetic and functional sequelae.
Despite the use of post-operative radiotherapy following resection, there is a relatively high risk of tumour recurrence (locoregionally or at distance). Combining chemotherapy with radiotherapy was postulated to reduce this risk and this was recently confirmed in two randomized trials, both using cisplatin chemotherapy. In a US trial, 459 patients who had undergone tumour resection were randomized to receive radiotherapy (60 to 66 Gy in 30–33 fractions over 6–6.6 weeks) either alone or in combination with cisplatin (100 mg/m2, days 1, 22, and 43) therapy [12]. After a median follow-up of nearly 46 months, the rate of local and regional control was significantly higher in patients receiving chemoradiotherapy than in those receiving radiotherapy alone (hazard ratio 0.61, P = 0.01). Disease-free survival was significantly longer with chemoradiotherapy than with radiotherapy alone (P = 0.04), but there was no significant difference in overall survival. The second trial, a European trial in 334 patients, was of a similar design [13]. After a median follow-up of 60 months, the incidence of local and regional relapse was significantly lower in the chemoradiotherapy group (P = 0.007) and the rate of progression-free survival was significantly higher (P = 0.04), with 5-year estimates of 47% and 36% for chemoradiotherapy and radiotherapy alone, respectively. In this study, the rate of overall survival was also significantly longer with chemoradiotherapy (P = 0.02), with 5-year estimates of 53% and 40% (Figure 1). Although the efficacy of chemoradiotherapy was clearly demonstrated by these trials, there are some toxicity concerns relating to this treatment approach. In both trials, there was a significant increase in the incidence of acute grade 3/4 adverse events. In the US trial, the incidence of acute grade 3/4 adverse events with chemoradiotherapy was 77% compared with 34% for radiotherapy alone (P < 0.001) [12]. In addition, there were four treatment-related deaths in the chemoradiotherapy arm. In the European trial, the corresponding figures for grade 3/4 adverse events were 41% and 21% (P = 0.001). However, there was no increase in the incidence of late adverse events which are in general more problematic with postoperative chemoradiotherapy [13].
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The value of neoadjuvant chemotherapy in the treatment of SCCHN has yet to be confirmed [14
]. Theoretically, in responders, this approach should decrease the tumour burden (improving the chances of cure following resection and/or organ preservation), reduce the likelihood of the formation of distant metastases, and, thereby, prolong survival. Despite indications that this approach may improve response rate, prolongation of survival has not been achieved. A randomized trial in 195 patients with resectable oral cavity squamous cell carcinoma, conducted over a 10-year period, showed no survival advantage of preoperative cisplatin/5-FU [15]. Strong evidence for the lack of survival efficacy of neoadjuvant therapy was provided by a meta-analysis on nearly 11 000 patients [8]. While the effects of neoadjuvant chemotherapy on survival need further investigation, an area in which this approach has been shown to be of value is in organ preservation [16, 17]. In an American randomized study of 332 patients with stage III/IV laryngeal carcinoma, comparing the use of chemotherapy followed by radiotherapy with conventional laryngectomy followed by radiotherapy, the former strategy enabled laryngeal preservation in 64% of patients in this group [16]. Importantly, organ preservation was achieved without an adverse effect on survival. After a median follow-up of 33 months, there was no difference in overall survival between the two groups. Interestingly, however, there was a significant increase in local recurrence with chemotherapy/radiotherapy but a significant reduction in the development of distant metastases compared with the surgery/radiotherapy group. In a European trial, 202 patients with hypopharyngeal SCC were included in a similar randomized comparison [17, 18]. With a 10-year follow-up, there was no deleterious impact on overall disease control and survival, and more than half of the survivors were able to retain a functional larynx [18]. The preservation of organ function can have an important impact on a patient's quality of life. A small study compared swallowing outcome (assessed using emotional and functional measures) in patients who received chemoradiotherapy or who underwent resection followed by post-surgical radiotherapy for stage III/IV oropharyngeal primaries, and who were disease-free after at least 12 months [19]. This study showed that patients receiving chemoradiotherapy had a significantly better swallowing outcome than those receiving surgery and subsequent radiotherapy. Interestingly, however, there were no significant differences between treatment groups for laryngeal and hypopharyngeal primary tumours. Finally, the Radiation Therapy Oncology Group (RTOG) published preliminary results of a 3-arm randomized trial for organ preservation in 547 patients with laryngeal SCC [20]. Patients were randomly assigned to receive either neoadjuvant chemotherapy (as in the American trial discussed previously), chemoradiotherapy (70 Gy with cisplatin 100 mg/m2 on days 1, 22 and 43) or irradiation alone. The preliminary results revealed a significantly improved larynx preservation rate in the chemoradiotherapy arm but with a significantly increased incidence of acute toxicity. There was no difference in survival between the three arms.
For unresectable disease, radiotherapy was for many years the treatment of choice. In our experience, this approach to therapy can be expected to be associated with a 5-year survival rate of 15–25%. The use of radiotherapy alone has now largely been superseded by chemoradiotherapy, whenever compatible with the patient's performance status. The benefits of chemoradiotherapy were shown in the meta-analyses reported by Browman [6] and Bourhis [7], and, more specifically, in a number of recently published studies in unresectable disease. In a French randomized study in 163 evaluable patients with unresectable oro- and hypo-pharyngeal carcinomas, the addition of 3 cycles of cisplatin (100 mg/m2) and 5-FU (750 mg/m2 for cycle 1 and 430 mg/m2 for cycles 2 and 3) to radiotherapy significantly improved the overall survival rate (48% vs 36%, P = 0.05) [21]. The benefits were generally confined to the 123 patients with oropharyngeal carcinoma: in these patients the median survival time was prolonged to 17 months compared with 10 months (P < 0.05). For the 40 patients with hypopharyngeal carcinoma, however, there was no significant difference between the two treatment arms. Maguire et al. reported that the use of hyperfractionated radiotherapy in combination with cisplatin and 5-FU gave a longer survival than that seen in a historical control group of patients receiving radiotherapy alone [22]. At a median follow-up of 23 months, the overall survival rates were 80% and 43% (P < 0.01), respectively. Although the efficacy was encouraging, grade 3 mucosal toxicity was universal and there was a relatively high incidence of grade 3/4 late toxicities. Following on from this, a German randomized study compared hyperfractionated accelerated radiotherapy (HART) alone and with chemotherapy (C-HART) in patients with inoperable SCCHN, mainly oro- (60%) and hypo-pharyngeal (32%) malignancies [23]. Adding a combination of 5-FU and mitomycin C to HART significantly improved locoregional control and progression-free and overall survival rates at 5 years. There was no significant difference between treatment arms in acute and late reactions. Another German study is now comparing C-HART using 5-FU in combination with either mitomycin C or cisplatin in patients with stage IV disease. A recently reported study highlighted the problem of chemoradiotherapy-associated dysphagia, which is common and can be life-threatening if mismanaged [24].
Although neoadjuvant chemotherapy has shown some benefit in resectable disease, albeit for organ preservation rather than survival, the use of this approach followed by radiotherapy alone or by surgery, should the primary tumour become resectable, has not shown any survival benefit in unresectable disease, and is not a recommended standard approach [25]. However, a recent randomized trial in unresectable disease showed that the addition of docetaxel to four cycles of cisplatin-5-FU significantly improved overall survival, suggesting that neoadjuvant chemotherapy should be revisited [26].
Metastatic and recurrent disease
In recurrent and metastatic disease, chemotherapy is the standard management option and is generally used with palliative intent. Chemotherapy using single-agent cisplatin has been shown to prolong survival compared with best supportive care [27], and a response rate of between 15 and 30% can be expected [28–30]. The combination of cisplatin with other active agents, such as 5-FU and methotrexate, has increased response rates to around 35% [28, 29], but this has not been accompanied by significant improvements in overall survival (median 6–9 months). Despite the absence of obvious survival benefit, many clinicians consider combination regimens as a standard treatment approach today and generally comprise cisplatin/carboplatin in combination with either 5-FU or a taxane.
Reirradiation has shown some success in recurrent disease or in patients presenting with a second primary [31, 32]. While this appears to be a feasible approach, at least for some patient subgroups, its utility needs to be confirmed in randomized trials.
Patients with advanced SCCHN have limited therapeutic options once they progress on platinum-based chemotherapy, and there is no standard treatment approach [33]. The median survival of such patients is only around four months. Those treated with commonly used salvage chemotherapy regimens generally have a poor response rate, in the region of 3%.
Conclusions and goals for future treatment strategies
Progress has been, and continues to be, made in the treatment of head and neck cancers. However, current outcomes particularly for the advanced stages of the disease are poor and necessitate new and innovative approaches to disease management. In mapping out the aims for future treatment plans, which are necessarily different at the various stages of the disease and which are dictated by our experience to date, it is important that we temper our idealism with realism (Figure 2). In early stage disease, progress in surgical and pre-surgical techniques (imaging) has enabled more accurate resection. The goal now is to maintain a favourable efficacy/toxicity ratio for treatment and to reduce the incidence of second primary tumours, the major cause of relapse. One of the milestones in treatment in recent years has been the confirmation, from randomized studies and meta-analyses, that the addition of chemotherapy to radiotherapy improves survival in patients with both resectable and non-resectable, advanced disease. Likewise, altered fractionation radiation schedules have enabled the delivery of intensified doses of radiotherapy with improved locoregional disease control. As expected, both of these approaches are generally associated with an increase in the incidence of acute grade 3/4 side effects. This toxicity limits the use of such intensified therapies in patients that present with co-morbidities. The immediate aim of treatment at this stage should be to increase survival, locoregional control and organ preservation and to reduce both the formation of distant metastases and the incidence of severe acute treatment-related toxicities, particularly mucositis. In addition, the use of neoadjuvant chemotherapy, which has so far failed to fulfil expectations, merits further investigation in well defined, controlled trials. The outlook for patients with recurrent/metastatic disease remains poor, particularly for those whose disease progresses on platinum-based therapies. For these patients, our goal is to improve response rates to chemotherapy and, wherever possible, to prolong survival without compromising quality of life.
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In the search for treatments to improve outcome in various cancers, molecular targeted therapies are at the forefront of investigational strategies. In head and neck cancers, much of the data generated with such therapies to date are with the EGFR inhibitors, particularly the IgG1 monoclonal antibody (MAb) cetuximab (Erbitux®) which enhances the effects of conventional chemotherapy and acts as a radiosensitiser. Clinical experience with cetuximab in combination with radiotherapy in locally advanced disease and chemotherapy in recurrent/metastatic disease is promising [34
, 35]. Particularly encouraging are the findings in cisplatin-resistant disease showing the activity of cetuximab both in combination with cisplatin [36, 37] and as a single agent. The ability of targeted therapies to increase the therapeutic index of current conventional therapies without increasing their toxicities means that these agents undoubtedly have a valuable role to play in clinical practice and one that must be evaluated further. |
Disclosure |
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The author is a member of advisory boards for Sanofi-Aventis, Merck Lipha Sante and Merck KGaA.
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1. GLOBOCAN 2002. http://www-dep.iarc.fr
2. Kowalski LP, Carvalho AL. Natural history of untreated head and neck cancer. Eur J Cancer 2000; 36: 1032–1037.[CrossRef][Web of Science][Medline]
3. Tepperman BS, Fitzpatrick PJ. Second respiratory and upper digestive tract cancers after oral cancer. Lancet 1981; 2: 547–549.[CrossRef][Web of Science][Medline]
4. Overgaard J, Hansen HS, Specht L et al. Five compared with six fractions per week of conventional radiotherapy of squamous-cell carcinoma of head and neck: DAHANCA 6 and 7 randomized controlled trial. Lancet 2003; 362: 933–940.[CrossRef][Web of Science][Medline]
5. Awwad HK, Lotayef M, Shouman T et al. Accelerated hyperfractionation (AHF) compared to conventional fractionation (CF) in the postoperative radiotherapy of locally advanced head and neck cancer: influence of proliferation. Br J Cancer 2002; 86: 517–523.[CrossRef][Web of Science][Medline]
6. 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][Web of Science][Medline]
7. 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 (14S): Abstr 5505.
8. 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.[Web of Science][Medline]
9. Rhee JC, Khuri FR, Shin DM. Advances in chemoprevention of head and neck cancer. Oncologist 2004; 9: 302–311.
10. Toma S, Bonelli L, Sartoris A et al. 13-cis retinoic acid in head and neck cancer chemoprevention: results of a randomized trial from the Italian Head and Neck Chemoprevention Study Group. Oncol Rep 2004; 11: 1297–1305.[Web of Science][Medline]
11. van Zandwijk N, Dalesio O, Pastorino U et al. EUROSCAN, a randomized trial of vitamin A and N-acetylcysteine in patients with head and neck cancer or lung cancer. For the EUropean Organization for Research and Treatment of Cancer Head and Neck and Lung Cancer Cooperative Groups. J Natl Cancer Inst 2000; 92: 977–986.
12. Cooper JS, Pajak TF, Forastiere AA et al. Postoperative concurrent radiotherapy and chemotherapy for high-risk squamous-cell carcinoma of the head and neck. N Engl J Med 2004; 350: 1937–1944.
13. Bernier J, Domenge C, Ozsahin M et al. Postoperative irradiation with or without concomitant chemotherapy for locally advanced head and neck cancer. N Engl J Med 2004; 350: 1945–1952.
14. Licitra L, Vermorken JB. Is there still a role for neoadjuvant chemotherapy in head and neck cancer? Ann Oncol 2004; 15: 7–11.
15. Licitra L, Grandi C, Guzzo M et al. Primary chemotherapy in resectable oral cavity squamous cell cancer: a randomized controlled trial. J Clin Oncol 2003; 21: 327–333.
16. Induction chemotherapy plus radiation compared with surgery plus radiation in patients with advanced laryngeal cancer. The Department of Veterans Affairs Laryngeal Cancer Study Group. N Engl J Med 1991; 324: 1685–1690.[Abstract]
17. Lefebvre JL, Chevalier D, Luboinski B et al. Larynx preservation in pyriform sinus cancer: preliminary results of a European Organization for Research and Treatment of Cancer phase III trial. EORTC Head and Neck Cancer Cooperative Group. J Natl Cancer Inst 1996; 88: 890–899.
18. Lefebvre JL, Chevalier D, Luboinski B et al. Is laryngeal preservation (LP) with induction chemotherapy (ICT) safe in the treatment of hypopharyngeal SCC? Final results of the phase III EORTC 24891 trial. J Clin Oncol, ASCO Annual Meeting Proceedings (Post-Meeting Edition) 2004; 22 (14S): Abstr 5531.
19. Gillespie MB, Brodsky MB, Day TA et al. Swallowing-related quality of life after head and neck cancer treatment. Laryngoscope 2004; 114: 1362–1367.[CrossRef][Web of Science][Medline]
20. Forastiere AA, Goepfert H, Maor M et al. Concurrent chemotherapy and radiotherapy for organ preservation in advanced laryngeal cancer. N Engl J Med 2003; 349: 2091–2098.
21. Bensadoun RJ, Dassonville O, Ramaioli A et al. Phase III multicenter randomized study of concurrent twice-a-day radiotherapy with and without cisplatin (BiCRF) in unresectable pharyngeal carcinoma. Results at 18 months (FNCLCC-GORTEC). J Clin Oncol, ASCO Annual Meeting Proceedings (Post-Meeting Edition) 2004; 22 (14S): Abstr 5504 and virtual presentation http://www.asco.org.
22. Maguire PD, Meyerson MB, Neal CR et al. Toxic cure: Hyperfractionated radiotherapy with concurrent cisplatin and fluorouracil for Stage III and IVA head-and-neck cancer in the community. Int J Radiat Oncol Biol Phys 2004; 58: 698–704.[CrossRef][Web of Science][Medline]
23. Budach VG, Stuschke M, Budach W et al. Accelerated hyperfractionated chemoradiation (C-HART) plus 5-FU/MMC is superior to HART for inoperable locally advanced head and neck cancer. Final results of the German ARO 95–06 multicentre trial. J Clin Oncol, ASCO Annual Meeting Proceedings (Post-Meeting Edition) 2004; 22 (14S): Abstract 5503 and virtual presentation http://www.asco.org.
24. Nguyen NP, Moltz CC, Frank C et al. Dysphagia following chemoradiation for locally advanced head and neck cancer. Ann Oncol 2004; 15: 383–388.
25. Pivot X. ESMO Minimum Clinical Recommendations for diagnosis, treatment and follow-up of squamous cell carcinoma of the head and neck. Ann Oncol 2003; 14: 1014–1015.
26. 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 (14S): Abstract 5508.
27. 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.[Web of Science][Medline]
28. 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.
29. 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.
30. Wittes RE, Cvitkovic E, Shah J et al. CIS-Dichlorodiammineplatinum(II) in the treatment of epidermoid carcinoma of the head and neck. Cancer Treat Rep 1977; 61: 359–366.[Web of Science][Medline]
31. Spencer SA, Harris J, Wheeler RH et al. RTOG 96–10: reirradiation with concurrent hydroxyurea and 5-fluorouracil in patients with squamous cell cancer of the head and neck. Int J Radiat Oncol Biol Phys 2001; 51: 1299–1304.[CrossRef][Web of Science][Medline]
32. Schaefer U, Micke O, Schueller P, Willich N. Recurrent head and neck cancer: retreatment of previously irradiated areas with combined chemotherapy and radiation therapy-results of a prospective study. Radiology 2000; 216: 371–376.
33. 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: Abstract 2202.
34. 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 (14S): Abstr 5507.
35. 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.
36. Baselga J, Trigo JM, Bourhis J et al. A phase II multicenter study of the anti-epidermal growth factor receptor (EGFR) 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 (SCCHN). J Clin Oncol 2005; in press.
37. 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 http://www.asco.org.
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