Treatment Option Overview
An optimal therapeutic approach to the oropharynx is not easily defined because no single therapeutic regimen offers a clear-cut, superior-survival advantage over other regimens. The literature is filled with reports highlighting various therapeutic options but does not contain reports presenting any valid comparative studies of therapeutic options. The ultimate therapeutic choice depends on a careful review of each case, attention to the staging of the neoplasm, the general physical condition of the patient, the emotional status of the patient, the experience of the treating team, and the available treatment facilities.
Traditionally, surgery and radiation therapy have been the standards for treatment of oropharyngeal cancers. No randomized data are available to compare surgery, radiation therapy, or combined treatment.
A pooled analysis of 6,400 patients from 51 reported series who were treated for base-of-tongue oropharyngeal carcinoma between 1970 and 2000 demonstrated local control rates of 79% (surgery ± radiation) and 76% (radiation), (P = .087); locoregional control was 60% versus 69% (P = .009); 5-year survival was 49% for surgery with or without radiation therapy versus 52% (P = .2) for radiation therapy with or without neck dissection. Severe complications were 32% for the surgery group versus 3.8% for the radiation therapy group (P < .001); fatal complications were 3.5% for the surgery group versus 0.4% for the radiation therapy group (P < .001). Similar findings showed equivalent overall and cause-specific survival between surgery versus radiation for tonsil carcinoma; however, 23% overall and cause-specific survival for severe complications in the surgery group versus 6% overall and cause-specific survival in the radiation therapy group (P < .001).
For patients with early-stage disease, single-modality treatment, usually radiation therapy alone, is preferred; however, emerging surgical techniques, including transoral surgery and transoral robotic surgery, are currently evolving. Nonrandomized comparisons suggest superior quality of life with minimally invasive surgical techniques. Historically, more invasive surgical techniques were associated with inferior quality of life and greater morbidity.
Historically, the post-therapy performance status of patients with base-of-tongue primary tumors appeared to be better after radiation therapy than after surgery. Local control and survival is similar in both treatment options.[3,4] Prospective multicenter trials, including RTOG-1221 (NCT01953952) and ECOG-3311 (NCT01898494), are currently underway comparing transoral surgery approaches with definitive radiation or chemoradiation.
Definitive Radiation Therapy
A review of published, clinical results of radical radiation therapy for head and neck cancer suggests a significant loss of local control when the administration of radiation therapy was prolonged; therefore, the lengthening of standard treatment schedules is not beneficial.[5,6] Patients who smoke during treatment with radiation therapy appear to have lower response rates and shorter survival durations than those who do not; therefore, counseling patients to stop smoking before beginning radiation therapy is beneficial.
Intensity-modulated radiation therapy (IMRT) has evolved over the past decade to become a standard technique for head and neck radiation therapy. IMRT allows a dose-painting technique also known as a simultaneous-integrated-boost (SIB) technique with a dose per fraction slightly higher than 2 Gy, which allows slight shortening of overall treatment time and increases the biologically equivalent dose to the tumor.
IMRT was studied in a phase II trial (RTOG-0022 [NCT00006360]) of 69 patients with stage T1–2, N0–1, M0 oropharyngeal carcinoma who were treated with primary radiation therapy without chemotherapy. The median follow-up was 2.8 years. Prescribed planning target volume (PTV)-doses to the primary tumor and involved nodes was 66 Gy at 2.2 Gy per fraction over 6 weeks. Subclinical PTVs received simultaneously 54 to 60 Gy at 1.8 to 2.0 Gy per fraction using an SIB technique. The 2-year estimated local-regional failure rate was 9%. Two of four patients (50%), who had major underdose deviations, had locoregional failure compared with 3 of 49 patients (6%) without such deviations (P = .04). Maximal late toxicities with a grade of 2 or greater were skin (12%), mucosa (24%), salivary (67%), esophagus (19%), and osteoradionecrosis (6%).
Longer follow-up revealed reduced late toxicity in all categories. Xerostomia grade 2 or greater was observed in 55% of patients at 6 months but was reduced to 25% of patients at 12 months and 16% of patients at 24 months. The RTOG-0022 study showed high control rates and the feasibility of IMRT at a multi-institutional level; the study also showed high tumor control rates and reduced salivary toxicity compared with previous RTOG studies. However, major target underdose deviations were associated with a higher locoregional failure rate. Similar nonrandomized multicenter studies using fractionally escalated doses, which ranged from 2.3 to 2.5 Gy with IMRT, have been safe when given without concurrent chemotherapy for pharyngolaryngeal T2N0, T2N1, or laryngeal T3N0 squamous cell carcinoma. No toxicity difference was observed between the different dose-escalated groups.[9-13]
In a randomized trial (PARSPORT [NCT00081029]) conducted in the United Kingdom that compared conventional 3-dimensional conformal radiation therapy with IMRT, xerostomia rates were significantly lower in the IMRT group compared with the conventional group.[Level of evidence: 1iiA] Fatigue was more prevalent in the IMRT group. At 24 months, there were no significant differences seen in nonxerostomia late toxicities, locoregional control, or overall survival (OS).
For patients with well-lateralized oropharyngeal cancer, such as a T1 or T2 tonsil primary tumor with limited extension into the palate or tongue base, consideration of elective treatment to the ipsilateral lymph nodes results in only minimal risk of failure to the contralateral neck. For T3 and T4 tumors that are midline or approach the midline, bilateral nodal treatment is a consideration. Retropharyngeal lymph nodes can also be encompassed in the elective nodal treatment in addition to the cervical lymph node chain.
Other late effects from radiation therapy include hypothyroidism in 30% to 40% of patients who have received external-beam radiation therapy to the entire thyroid gland. Thyroid function testing of patients should be considered before therapy and as part of posttreatment follow-up.[16,17]
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 per square meter of body-surface area 1 week before starting radiation therapy followed by 250 mg per square meter weekly for the duration of the radiation therapy. At a median follow up of 54 months, patients treated with cetuximab and radiation therapy demonstrated significantly higher progression-free survival (hazard ratio 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.[21,22][Level of evidence: 1iiA]
Postoperative Radiation Therapy (PORT) With or Without Chemotherapy
Depending on pathological findings after primary surgery, PORT or postoperative chemoradiation is used in the adjuvant setting for the following histological findings including:
- T4 disease.
- Perineural invasion.
- Lymphovascular invasion.
- Positive margins or margins less than 5 mm.
- Extracapsular extension of a lymph node.
- Two or more involved lymph nodes.
The benefit for OS has been demonstrated with postoperative chemoradiation therapy using cisplatin; an OS benefit has also been found for positive margins and extracapsular extension.[23-26][Level of evidence: 1iiA] The addition of chemotherapy to radiation therapy for other pathological risk factors is unclear. A postoperative randomized trial (RTOG-0920 [NCT00956007]) is evaluating the use of cetuximab with adjuvant radiation therapy in the postoperative setting.[23-26][Level of evidence: 1iiA]
- Parsons JT, Mendenhall WM, Stringer SP, et al.: Squamous cell carcinoma of the oropharynx: surgery, radiation therapy, or both. Cancer 94 (11): 2967-80, 2002. [PUBMED Abstract]
- Chen AM, Daly ME, Luu Q, et al.: Comparison of functional outcomes and quality of life between transoral surgery and definitive chemoradiotherapy for oropharyngeal cancer. Head Neck 37 (3): 381-5, 2015. [PUBMED Abstract]
- Harrison LB, Zelefsky MJ, Armstrong JG, et al.: Performance status after treatment for squamous cell cancer of the base of tongue--a comparison of primary radiation therapy versus primary surgery. Int J Radiat Oncol Biol Phys 30 (4): 953-7, 1994. [PUBMED Abstract]
- Mendenhall WM, Morris CG, Amdur RJ, et al.: Definitive radiotherapy for squamous cell carcinoma of the base of tongue. Am J Clin Oncol 29 (1): 32-9, 2006. [PUBMED Abstract]
- Fowler JF, Lindstrom MJ: Loss of local control with prolongation in radiotherapy. Int J Radiat Oncol Biol Phys 23 (2): 457-67, 1992. [PUBMED Abstract]
- Allal AS, de Pree C, Dulguerov P, et al.: Avoidance of treatment interruption: an unrecognized benefit of accelerated radiotherapy in oropharyngeal carcinomas? Int J Radiat Oncol Biol Phys 45 (1): 41-5, 1999. [PUBMED Abstract]
- Browman GP, Wong G, Hodson I, et al.: Influence of cigarette smoking on the efficacy of radiation therapy in head and neck cancer. N Engl J Med 328 (3): 159-63, 1993. [PUBMED Abstract]
- Eisbruch A, Harris J, Garden AS, et al.: Multi-institutional trial of accelerated hypofractionated intensity-modulated radiation therapy for early-stage oropharyngeal cancer (RTOG 00-22). Int J Radiat Oncol Biol Phys 76 (5): 1333-8, 2010. [PUBMED Abstract]
- Leclerc M, Maingon P, Hamoir M, et al.: A dose escalation study with intensity modulated radiation therapy (IMRT) in T2N0, T2N1, T3N0 squamous cell carcinomas (SCC) of the oropharynx, larynx and hypopharynx using a simultaneous integrated boost (SIB) approach. Radiother Oncol 106 (3): 333-40, 2013. [PUBMED Abstract]
- Buettner F, Miah AB, Gulliford SL, et al.: Novel approaches to improve the therapeutic index of head and neck radiotherapy: an analysis of data from the PARSPORT randomised phase III trial. Radiother Oncol 103 (1): 82-7, 2012. [PUBMED Abstract]
- Gulliford SL, Miah AB, Brennan S, et al.: Dosimetric explanations of fatigue in head and neck radiotherapy: an analysis from the PARSPORT Phase III trial. Radiother Oncol 104 (2): 205-12, 2012. [PUBMED Abstract]
- Kohler RE, Sheets NC, Wheeler SB, et al.: Two-year and lifetime cost-effectiveness of intensity modulated radiation therapy versus 3-dimensional conformal radiation therapy for head-and-neck cancer. Int J Radiat Oncol Biol Phys 87 (4): 683-9, 2013. [PUBMED Abstract]
- Gupta T, Agarwal J, Jain S, et al.: Three-dimensional conformal radiotherapy (3D-CRT) versus intensity modulated radiation therapy (IMRT) in squamous cell carcinoma of the head and neck: a randomized controlled trial. Radiother Oncol 104 (3): 343-8, 2012. [PUBMED Abstract]
- Nutting CM, Morden JP, Harrington KJ, et al.: Parotid-sparing intensity modulated versus conventional radiotherapy in head and neck cancer (PARSPORT): a phase 3 multicentre randomised controlled trial. Lancet Oncol 12 (2): 127-36, 2011. [PUBMED Abstract]
- O'Sullivan B, Warde P, Grice B, et al.: The benefits and pitfalls of ipsilateral radiotherapy in carcinoma of the tonsillar region. Int J Radiat Oncol Biol Phys 51 (2): 332-43, 2001. [PUBMED Abstract]
- Turner SL, Tiver KW, Boyages SC: Thyroid dysfunction following radiotherapy for head and neck cancer. Int J Radiat Oncol Biol Phys 31 (2): 279-83, 1995. [PUBMED Abstract]
- Constine LS: What else don't we know about the late effects of radiation in patients treated for head and neck cancer? Int J Radiat Oncol Biol Phys 31 (2): 427-9, 1995. [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]
- Mendenhall WM, Werning JW, Pfister DG: Treatment of head and neck cancer. In: DeVita VT Jr, Lawrence TS, Rosenberg SA: Cancer: Principles and Practice of Oncology. 9th ed. Philadelphia, Pa: Lippincott Williams & Wilkins, 2011, pp 729-80.
- Adelstein DJ: Oropharyngeal cancer: the role of chemotherapy. Curr Treat Options Oncol 4 (1): 3-13, 2003. [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]
- 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]