Stage III Oropharyngeal Cancer
The management of stage III carcinomas of the oropharynx is complex and requires multidisciplinary input to establish the optimal treatment.
Standard treatment options:
- A combination of surgery with postoperative radiation therapy (PORT) or postoperative chemoradiation for selected high-risk patients.[1-4][Level of evidence: 1iiA]
- Altered fractionation radiation therapy yields a higher control rate and survival rate than standard fractionated radiation therapy only for patients with stage III cancer of the oropharynx.[5-9][Level of evidence: 1iiA]
- Concomitant radiation therapy with targeted agents.[10,11][Level of evidence: 1iiA]
- Concomitant chemoradiation therapy.[12-15][Level of evidence: 1iiA]
New surgical techniques for resection and reconstruction developed in the last 7 to 10 years that provide access and functional preservation have extended the surgical options. PORT is indicated based on pathological risk factors. High-risk features, including positive margins and extracapsular nodal extension, show additional locoregional control and survival benefit with the addition of concomitant chemotherapy.[1-4][Level of evidence: 1iiA] All of these patients may be considered for entry into neoadjuvant chemotherapy trials.
Specific surgical procedures and their modifications are not designated here because of the wide variety of surgical approaches to the area, the variety of opinions about the role of modified neck dissections, and the multiple reconstructive techniques that may give the same results. This group of patients should be managed by head and neck surgeons who are skilled in the multiple procedures available and actively and frequently involved in the care of these patients.
Surgery Followed by PORT or Chemoradiation Therapy
Postoperative chemoradiation therapy for oropharyngeal squamous cell carcinoma demonstrates a locoregional control and survival benefit compared with radiation therapy alone in patients who have extracapsular extension (ECE) of a lymph node or positive margins.[1-4][Level of evidence: 1iiA]
For patients with T3 and T4 disease (or stage III and stage IV disease), perineural infiltration, vascular embolisms, and clinically enlarged level IV or level V lymph nodes secondary to tumors arising in the oral cavity or oropharynx; two or more histopathologically involved lymph nodes without ECE; and close margins less than 5 mm, the addition of cisplatin chemotherapy given concurrently with PORT is unclear. The addition of cetuximab with radiation therapy in the postoperative setting for these risk factors is being tested in a randomized trial (RTOG-0920 [NCT00956007]).
Radiation therapy alone with altered fractionation may be used for patients with locally advanced oropharyngeal cancer who are not candidates for chemotherapy. Altered fractionated radiation therapy yields a higher locoregional control rate than standard fractionated radiation therapy for patients with stage III and stage IV oropharyngeal cancer. The long-term analysis of randomized trial RTOG-9003 (NCT00771641) included the following four radiation therapy treatment arms:
- Standard fractionation (SFX) to 70 Gy in 35 daily fractions for 7 weeks.
- Hyperfractionation (HFX) to 81.6 Gy in 68 twice-daily fractions for 7 weeks.
- Accelerated fractionation (AFX-S) to 67.2 Gy in 42 fractions for 6 weeks with a 2-week rest after 38.4 Gy.
- Accelerated continuous fractionation (AFX-C) to 72 Gy in 42 fractions for 6 weeks.
The three experimental arms were to be compared with SFX. Only the HFX arm showed superior locoregional control and survival at 5 years compared with the SFX arm (hazard ratio [HR], 0.79; 95% confidence interval [CI], 0.62–1.00; P = .05). AFX-C was associated with increased late toxicity compared with SFX.[5-9,16][Level of evidence: 1iiA]
In a meta-analysis of 15 randomized trials with a total of 6,515 patients and a median follow-up of 6 years involving the assessment of HFX or AFX-S for patients with stage III and stage IV oropharyngeal cancer, there was a significant survival benefit with altered fractionated radiation therapy and a 3.4% absolute benefit at 5 years (HR, 0.92; 95% CI, 0.86–0.97; P = .003). Altered fractionated radiation therapy improves locoregional control, and the benefit is higher in younger patients. HFX demonstrated a greater survival benefit (8% at 5 years) than AFX-S (2% with accelerated fractionation without total dose-reduction and 1.7% with total dose-reduction at 5 years, P = .02).[Level of evidence: 1iiA]
Concomitant Radiation Therapy With Targeted Agents
In a randomized trial of locally advanced head and neck cancer patients, curative-intent radiation therapy alone (213 patients) was compared with radiation therapy plus weekly cetuximab (211 patients). The initial dose was 400 mg/m2 of body-surface area 1 week before starting radiation therapy followed by a weekly dose of 250 mg/m2 of body-surface area for the duration of radiation therapy. At a median follow up of 54 months, patients treated with cetuximab and radiation therapy demonstrated significantly higher progression-free survival (HR for disease progression or death, 0.70; P = .006). Patients in the cetuximab arm experienced higher rates of acneiform rash and infusion reactions, although the incidence of other grade 3 or higher toxicities, including mucositis, did not differ significantly between the two groups. This study allowed altered fractionation regimens to be used in both arms.[10,11][Level of evidence: 1iiA]
Concomitant Chemoradiation Therapy
Concomitant chemoradiation therapy is a standard treatment option for locally advanced (stage III and stage IV) oropharyngeal carcinoma. A meta-analysis of 93 randomized, prospective head and neck cancer trials published between 1965 and 2000 showed a 4.5% absolute survival advantage in the subset of patients receiving chemotherapy and radiation therapy.[Level of evidence: 2A] Patients receiving concomitant chemotherapy had a greater survival benefit than those receiving induction chemotherapy.
Treatment options under clinical evaluation:
- Neoadjuvant chemotherapy as given in clinical trials has been used to shrink tumors and render them more definitively treatable with either surgery or radiation. Chemotherapy is given before the other modalities; therefore, the designation neoadjuvant to distinguish it from standard adjuvant therapy, which is given after or during definitive therapy with radiation or after surgery. Many drug combinations have been used in neoadjuvant chemotherapy.[18-22]
- In a randomized study (PARADIGM [NCT00095875]) of docetaxel, cisplatin, and fluorouracil (TPF) neoadjuvant chemotherapy followed by concomitant chemoradiation, no survival advantage was demonstrated in the neoadjuvant chemotherapy group over standard chemoradiation. This study did not stratify for human papillomavirus status, and the role of neoadjuvant chemotherapy that is administered before concurrent chemoradiation remains unclear.
Current Clinical Trials
Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with stage III oropharyngeal cancer. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.
General information about clinical trials is also available from the NCI Web site.
- Bernier J, Cooper JS, Pajak TF, et al.: Defining risk levels in locally advanced head and neck cancers: a comparative analysis of concurrent postoperative radiation plus chemotherapy trials of the EORTC (#22931) and RTOG (# 9501). Head Neck 27 (10): 843-50, 2005. [PUBMED Abstract]
- Cooper JS, Zhang Q, Pajak TF, et al.: Long-term follow-up of the RTOG 9501/intergroup phase III trial: postoperative concurrent radiation therapy and chemotherapy in high-risk squamous cell carcinoma of the head and neck. Int J Radiat Oncol Biol Phys 84 (5): 1198-205, 2012. [PUBMED Abstract]
- 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 350 (19): 1937-44, 2004. [PUBMED Abstract]
- 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 350 (19): 1945-52, 2004. [PUBMED Abstract]
- 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 (4): 231-41, 1992. [PUBMED Abstract]
- Bourhis J, Lapeyre M, Tortochaux J, et al.: Phase III randomized trial of very accelerated radiation therapy compared with conventional radiation therapy in squamous cell head and neck cancer: a GORTEC trial. J Clin Oncol 24 (18): 2873-8, 2006. [PUBMED Abstract]
- 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 randomised controlled trial. Lancet 362 (9388): 933-40, 2003. [PUBMED Abstract]
- Overgaard J, Mohanti BK, Begum N, et al.: Five versus six fractions of radiotherapy per week for squamous-cell carcinoma of the head and neck (IAEA-ACC study): a randomised, multicentre trial. Lancet Oncol 11 (6): 553-60, 2010. [PUBMED Abstract]
- 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 (1): 7-16, 2000. [PUBMED Abstract]
- 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 (6): 567-78, 2006. [PUBMED Abstract]
- Curran D, Giralt J, Harari PM, et al.: Quality of life in head and neck cancer patients after treatment with high-dose radiotherapy alone or in combination with cetuximab. J Clin Oncol 25 (16): 2191-7, 2007. [PUBMED Abstract]
- 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 (1): 69-76, 2004. [PUBMED Abstract]
- Olmi P, Crispino S, Fallai C, et al.: Locoregionally advanced carcinoma of the oropharynx: conventional radiotherapy vs. accelerated hyperfractionated radiotherapy vs. concomitant radiotherapy and chemotherapy--a multicenter randomized trial. Int J Radiat Oncol Biol Phys 55 (1): 78-92, 2003. [PUBMED Abstract]
- Semrau R, Mueller RP, Stuetzer H, et al.: Efficacy of intensified hyperfractionated and accelerated radiotherapy and concurrent chemotherapy with carboplatin and 5-fluorouracil: updated results of a randomized multicentric trial in advanced head-and-neck cancer. Int J Radiat Oncol Biol Phys 64 (5): 1308-16, 2006. [PUBMED Abstract]
- Pignon JP, le Maître A, Maillard E, et al.: Meta-analysis of chemotherapy in head and neck cancer (MACH-NC): an update on 93 randomised trials and 17,346 patients. Radiother Oncol 92 (1): 4-14, 2009. [PUBMED Abstract]
- Beitler JJ, Zhang Q, Fu KK, et al.: Final results of local-regional control and late toxicity of RTOG 9003: a randomized trial of altered fractionation radiation for locally advanced head and neck cancer. Int J Radiat Oncol Biol Phys 89 (1): 13-20, 2014. [PUBMED Abstract]
- Baujat B, Bourhis J, Blanchard P, et al.: Hyperfractionated or accelerated radiotherapy for head and neck cancer. Cochrane Database Syst Rev (12): CD002026, 2010. [PUBMED Abstract]
- Al-Kourainy K, Kish J, Ensley J, et al.: Achievement of superior survival for histologically negative versus histologically positive clinically complete responders to cisplatin combination in patients with locally advanced head and neck cancer. Cancer 59 (2): 233-8, 1987. [PUBMED Abstract]
- Stupp R, Weichselbaum RR, Vokes EE: Combined modality therapy of head and neck cancer. Semin Oncol 21 (3): 349-58, 1994. [PUBMED Abstract]
- Ensley J, Crissman J, Kish J, et al.: The impact of conventional morphologic analysis on response rates and survival in patients with advanced head and neck cancers treated initially with cisplatin-containing combination chemotherapy. Cancer 57 (4): 711-7, 1986. [PUBMED Abstract]
- Pfister DG, Harrison LB, Strong EW, et al.: Organ-function preservation in advanced oropharynx cancer: results with induction chemotherapy and radiation. J Clin Oncol 13 (3): 671-80, 1995. [PUBMED Abstract]
- Dimery IW, Hong WK: Overview of combined modality therapies for head and neck cancer. J Natl Cancer Inst 85 (2): 95-111, 1993. [PUBMED Abstract]
- Haddad R, O'Neill A, Rabinowits G, et al.: Induction chemotherapy followed by concurrent chemoradiotherapy (sequential chemoradiotherapy) versus concurrent chemoradiotherapy alone in locally advanced head and neck cancer (PARADIGM): a randomised phase 3 trial. Lancet Oncol 14 (3): 257-64, 2013. [PUBMED Abstract]