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]).Altered Fractionation
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.
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.References
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