Treatment of Advanced Head and Neck Cancer: Past, Present, and Future

OncologyONCOLOGY Vol 22 No 10
Volume 22
Issue 10

Bruce Culliney and colleagues have provided a thorough and well written summary of the literature regarding multimodality treatment of patients with locoregionally advanced or unresectable head and neck malignancies. In particular, they offer a detailed outline of recent insights into radiation dosing and fractionation and their optimal use in the combined-modality setting.

Bruce Culliney and colleagues have provided a thorough and well written summary of the literature regarding multimodality treatment of patients with locoregionally advanced or unresectable head and neck malignancies. In particular, they offer a detailed outline of recent insights into radiation dosing and fractionation and their optimal use in the combined-modality setting.

Therapeutic Evolution

Surgery and/or radiation were historically standard of care in locally advanced head and neck malignancies. During the 1980s, various radiation schedules were studied. Chemotherapy was eventually added to radiotherapy, first sequentially, as induction chemotherapy, then concurrently, recognizing the primary need of improved locoregional control over that of distant disease control. Simultaneously, the optimization of radiation as single-modality therapy was pursued. The authors review multiple randomized trials and meta-analyses evaluating altered fractionation radiation schedules and conclude that altered fractionation improves local and local regional control compared to conventional fractionated radiation.[1-12]

The Budach and Bourhis meta-analyses have demonstrated local and regional control using altered fractionated radiation equivalent to that seen with concurrent chemoradiotherapy however, only the Bourhis meta-analysis reported an improvement in overall survival of 2% with accelerated fractionation and 8 % with hyperfractionation. This 8% improvement in overall survival with hyperfractionation is similar to the benefit in survival demonstrated with concurrent chemoradiation. In addition, the Budach meta-analysis reported that concurrent chemoradiotherapy with any radiation fractionation schedules resulted in a statistically significant survival benefit of 12 months and an absolute survival gain of 13% to 15% at 2 years.[11] Reevaluation of the overall survival at 5 years confirmed 8% improvement. Additionally, when compared to conventional radiation fractionation, an increase in acute mucosal toxicity is noted with altered-fractionation schedules.

Therefore, while radiation alone should only be used in select cases, some data suggest that the use of altered fractionation may be most beneficial in these cases. Due to these study trends toward improved survival with altered-fractionation radiotherapy, at the University of Chicago we include hyperfractionated radiation schedules with concurrent chemotherapy for high-risk patients with locoregionally advanced head and neck cancer.

Intensity-modulated radiotherapy (IMRT) with concurrent chemotherapy is becoming routinely used in the treatment of head and neck malignancies. The advantages of this type of radiation include tight target coverage and associated sparing of normal tissue. In addition, multiple targets may be treated simultaneously with different doses of radiation, but a learning curve is involved with this modality. IMRT has never been compared in a prospective manner with standard three-dimensional conformal radiation therapy. Hence, it is unclear exactly how efficacy and toxicity following IMRT differ from those achieved with conformal radiation.

Role of Chemotherapy

When added to radiation, chemotherapy improves locoregional control and overall survival while allowing for organ preservation. Toxicities are increased compared to the use of radiation alone. These toxicities are primarily those of enhanced radiation but also related to the concurrent chemoradiotherapy regimen used. The benefit of chemoradiotherapy has also been established by several randomized published trials and subsequent meta-analyses. However, few studies have directly compared one regimen to another. Often the differing regimens are evaluated in phase II studies or meta-analyses where the chemotherapeutic agents and radiation schedules were highly variable.[15-21] Trials demonstrate fairly consistent improvements in locoregional control and survival with chemoradiotherapy.

As the standard, many institutions accept cisplatin at 100 mg/m2 given on days 1, 22, and 43 with radiation. However, whether to use multiagent regimens or single-agent platinum regimens with radiation remains debatable. The Meta-Analysis of Chemotherapy in Head and Neck Cancer (MACH-NC) initially reported a significant survival benefit for multiagent regimens compared to single-agent regimens.[22] Updated analysis did not demonstrate the same benefit.[2] This is confounded by the use of different radiation schedules and the shortcomings of meta-analyses, which never directly compare the agents in the same patient populations.

Currently, chemoradiotherapy is the standard of care, but the particular regimen given at various institutions varies markedly. At the University of Chicago, we continue to attempt to improve on our TFHX platform (paclitaxel, infusional fluorouracil [5-FU], hydroxyurea, and twice-daily radiation therapy administered every other week), with 3-year progression-free survival of 80% and 3-year overall survival of 70% in locally advanced head and neck malignancies.[23]

Addition of Cetuximab

The epidermal growth factor receptor (EGFR) is overexpressed and abnormally activated in squamous cell cancers of the head and neck.[24,25] The use of the monoclonal antibody cetuximab (Erbitux), directed against EGFR, has been evaluated with radiation. It appears to have activity both as a radiosensitizing agent and as an antineoplastic drug.[26] Cetuximab has produced improvement in locoregional control and overall survival compared to radiation alone. Of note, these benefits with cetuximab were most pronounced with altered-­fractionation radiation.

Cetuximab and radiation is not currently considered a standard of care for most patients with locoregionally advanced head and neck cancer, as cetuximab with radiation has not yet been compared to more conventional chemoradiotherapy or an induction chemotherapy approach. However, in light of the low rate of severe added toxicities to radiation by cetuximab and apparent benefits, this combination may be considered in medically unfit patients and those with poor performance status, where the risks of added chemotherapy outweigh the benefits. Currently, studies are underway evaluating the use of chemoradiotherapy with added cetuximab.

Induction Chemotherapy

Historically, locoregional recurrence was the problem associated with head and neck malignancies. With all of the advances in altered-fractionation radiation schedules and more aggressive chemoradiotherapy regimens, locoregional control has improved, but distant metastasis has become a more prevalent site of first failure. This forces us to readdress the issue of induction chemotherapy incorporated into the chemoradiotherapy approach.[27-29]

Recently, randomized trials of induction chemotherapy have demonstrated that taxanes added to platinum and 5-FU regimens produce improved response rate and survival compared to platinum and 5-FU alone.[27-29] However, no recent randomized studies have shown induction to be superior to chemoradiotherapy alone or vice versa.[30-32] In the setting of optimized altered-fractionation radiation delivered with chemotherapy, the role of induction chemotherapy is unclear. Ongoing trials are aimed at determining the role of induction chemotherapy in the setting of highly active chemoradiotherapy in patients with high-risk head and neck squamous cell carcinomas. (ie, the Paradigm, Decide, and Italian trials)

Present and Future Perspectives

The advances of the past 20 years demonstrate that chemoradiotherapy is superior to standard fractionated radiation alone in the treatment of locoregionally advanced head and neck malignancies. Acute toxicities are increased with chemoradiotherapy, but patients have improved locoregional control and overall survival. Additionally, patients often enjoy improved organ preservation and avoid cosmetically detrimental surgeries. Similarly, induction chemotherapy can now be considered a standard treatment choice.

Ongoing trials continue to define optimum chemotherapeutic regimens, radiation delivery techniques, and schedules. Targeted agents will likely be integrated with induction or concomitant approaches, with the goal of further overcoming radioresistance without increasing toxicities. The results of ongoing induction chemotherapy trials will determine whether initial induction therapy improves survival over chemoradiotherapy alone. Research directed at serum markers, tumor tissue analysis, genomics, proteomics, and pharmacogenomics may help select patients for the most appropriate treatment to obtain maximum benefit with minimal side effects.

The most effective approach to our limited patient population will be with cooperative trials conducting studies that establish the best regimens in controlled, randomized phase III trials.

-Victoria M. Villaflor, MD
-Everett Vokes, MD


Financial Disclosure: The authors have no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.


1. Culliney B, Birhan A, Young A, et al: Management of locally advanced or unresectable head and neck cancer. Oncology (Williston Park) 22:1152-1161, 2008.
2. Bourhis J, Overgaard J, Audry H, et al: Meta-analysis of radiotherapy, in Update of MACH-NC (Meta-Analysis of Chemotherapy in Head and Neck Cancer) database focused on concomitant chemoradiotherapy (abstract 5505). Proc Am Soc Clin Oncol 23:488, 2004.
3. Mendenhall WM, Amdur RJ, Stringer SP, et al: Radiation therapy for squamous cell carcinoma of the tonsillar region: A preferred alternative to surgery? J Clin Oncol 18:2219-2225, 2000.
4. Gwozdz JT, Morrison WH, Garden AS, et al: Concomitant boost radiotherapy for squamous carcinoma of the tonsillar fossa. Int J Radiat Oncol Biol Phys 39:127-135, 1997.
5. Ang KK: Altered fractionation trials in head and neck cancer. Semin Radiat Oncol 8:230-236, 1998.
6. Ang KK, Peters LJ, Weber RS, et al: Concomitant boost radiotherapy schedules in the treatment of carcinoma of the oropharynx and nasopharynx. Int J Radiat Oncol Biol Phys 19:1339-1345, 1990.
7. Wang CC: Local control of oropharyngeal carcinoma after two accelerated hyperfractionation radiation therapy schemes. Int J Radiat Oncol Biol Phys 14:1143-1146, 1988.
8. Million RR, Parsons JT, Cassisi NJ: Twice-a-day irradiation technique for squamous cell carcinomas of the head and neck. Cancer 55(9 suppl):2096-2099, 1985.
9. Fu KK, Pajak TF, Trotti A, et al: A Radiation Therapy Oncology Group (RTOG) phase III randomized study to compare hyperfractionation and two variants of accelerated fractionation to standard fractionation radiotherapy for head and neck squamous cell carcinomas: First report of RTOG 9003. Int J Radiat Oncol Biol Phys 48:7-16, 2000.
10. Horiot JC, Le Fur R, N’Guyen T, et al: Hyperfractionation versus conventional fractionation in oropharyngeal carcinoma: Final analysis of a randomized trial of the EORTC cooperative group of radiotherapy. Radiother Oncol 25:231-241, 1992.
11. Budach W, Hehr T, Budach V, et al: A meta-analysis of hyperfractionated and accelerated radiotherapy and combined chemotherapy and radiotherapy regimens in unresected locally advanced squamous cell carcinoma of the head and neck. BMC Cancer 6:28, 2006.
12. Bourhis J, Audry H, Ang KK, et al: Meta-Analysis of Radiotherapy in Carcinomas of Head and neck (MARCH) Collaborative Group. Hyperfractionated or accelerated radiotherapy in head and neck cancer: A meta-analysis. Lancet 368:843-854, 2006.
13. Posner MR: Paradigm shift in the treatment of head and neck cancer the role of neoadjuvant chemotherapy. Oncologist 10(suppl 3):11-19, 2005.
14. Argiris A, Jayaram P, Pichardo D: Revisiting induction chemotherapy for head and neck cancer. References and reviews. Oncology (Williston Park) 19:932-945, 2005.
15. Adelstein DJ, Li Y, Adams GL, et al: An intergroup phase III comparison of standard radiation therapy and two schedules of concurrent chemoradiotherapy in patients with unresectable squamous cell head and neck cancer. J Clin Oncol 21:92-98, 2003.
16. Brizel DM, Albers ME, Fisher SR, et al: Hyperfractionated irradiation with or without concurrent chemotherapy for locally advanced head and neck cancer. N Engl J Med 338:1798-1804, 1998.
17. Denis F, Garaud P, Bardet E, et al: Final results of the 94-01 French Head and Neck Oncology and Radiotherapy Group randomized trial comparing radiotherapy alone with concomitant radiochemotherapy in advanced-stage oropharynx carcinoma. J Clin Oncol 22:69-76, 2004.
18. Calais G, Alfonsi M, Bardet E, et al: Randomized trial of radiation therapy versus concomitant chemotherapy and radiation therapy for advanced stage oropharynx carcinoma. J Natl Cancer Inst 91:2081-2086, 1999.
19. Adelstein DJ, Saxton JP, Rybicki LA, et al: Multiagent concurrent chemoradiotherapy for locoregionally advanced squamous cell head and neck cancer: mature results from a single institution. J Clin Oncol 24:1064-1071, 2006.
20. Staar S, Rudat V, Stuetzer H, et al: Intensified hyperfractionated accelerated radiotherapy limits the additional benefit of simultanteous chemotherapy-results of a multicentric randomized German trial in advanced head-and-neck cancer. Int J Radiat Oncol Biol Phys 50:1161-1171, 2001.
21. Budach B, Stuschke M, Budach W, et al: Hyperfractionated accelerated chemoradiation with concurrent fluorouracil-mitomycin is more effective than dose-escalated hyperfractionated accelerated radiation therapy alone in locally advanced head and neck cancer: Final results of the the radiotherapy cooperative clinical trials group of the German Cancer Society 95-06 Prospective Randomized Trial. J Clin Oncol 23:1125-1135, 2005.
22. Pignon JP, Bourhis J, Domenge C, et al: 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 355:949-955, 2000.
23. Vokes EE, Stenson KM, Rosen FR, et al: Weekly carboplatin and paclitaxel followed by concomitant paclitaxel, fluorouracil, and hydroxyrea chemoradiotherapy: Curative and organ-preserving therapy for advanced head and neck cancer. J Clin Oncol 21:320-326, 2003.
24. Mendelsohn J, Baselga J: Status of epidermal growth factor receptor antagonists in the biology and treatment of cancer. J Clin Oncol 21:2787-2799, 2003.
25. Hynes NE, Lane HA: ERBB receptors and cancer: The complexity of targeted inhibitors. Nat Rev Cancer 5:341-354, 2005.
26. Bonner JA, Harari PM, Giralt J, et al: Radiotherapy plus cetuximab for squamous-cell carcinoma of the head and neck. N Engl J Med 354:567-578, 2006.
27. Vermorken JB, Remenar E, van Herpen C, et al: Cisplatin, fluorouracil, and docetaxel in unresectable head and neck cancer. N Engl J Med 357:1695-1704, 2007.
28. Hitt R, López-Pausa A, Martínez-Trufero J, et al: Phase III study comparing cisplatin plus fluorouracil to paclitaxel, cisplatin, and fluorouracil induction chemotherapy followed by chemoradiotherapy in locally advanced head and neck cancer. J Clin Oncol 23:8636-8645, 2005.
29. Posner MR, Hershock DM, Blajman CR, et al: Cisplatin and fluorouracil alone or with docetaxel in head and neck cancer. N Engl J Med 357:1705-1715, 2007.
30. Forastiere AA, Goepfert H, Maor M, et al: Concurrent chemotherapy and radiotherapy for organ preservation in advanced laryngeal cancer. N Engl J Med 349:2091-2099, 2003.
31. Forastiere AA, Maor M, Weber RS, et al: Long-term results of intergroup RTOG 91-11: A phase III trial to preserve the larynx-induction cisplatin/5FU and radiation therapy versus concurrent cisplatin and radiation therapy versus radiation therapy (abstract 5517). J Clin Oncol 24(18S):284s, 2006.
32. Taylor SG 4th, Murthy AK, Vannetzel JM, et al: Randomized comparison of neoadjuvent cisplatin and fluorouracil infusion followed by radiation versus concomitant treatment in advanced head and neck cancer. J Clin Oncol 12:385-395, 1994.

Related Videos
Treatment with toripalimab does not yield the same vascular toxicity seen with pembrolizumab in patients with advanced or metastatic nasopharyngeal carcinoma, according to Barbara Burtness, MD.
Overall survival also appears to improve with toripalimab compared with chemotherapy among patients with metastatic or advanced nasopharyngeal carcinoma.
head and neck cancer
head and neck cancer
head and neck cancer
Related Content