The major benefits of modern radiation therapy (eg, intensity-modulated [x-ray] radiation therapy [IMRT]) for oropharyngeal cancer are reduced xerostomia and better quality of life. Intensity-modulated proton therapy may provide additional advantages over IMRT by reducing radiation beam–path toxicities. Several acute and late treatment-related toxicities and symptom constellations must be kept in mind when designing and comparing future treatment strategies, particularly because currently most patients with oropharyngeal carcinoma present with human papillomavirus–positive disease and are expected to have a high probability of long-term survival after treatment.
| EGFR | Epidermal growth factor receptor |
| GORTEC | Groupe d’Oncologie Radiothérapie Tête et Cou |
| HNC | Head and neck cancer |
| HPV | Human papillomavirus |
| IMPT | Intensity-modulated proton therapy |
| IMRT | Intensity-modulated radiation therapy |
| LRC | Locoregional control |
| OPC | Oropharyngeal carcinoma |
| OS | Overall survival |
| RFS | Recurrence-free survival |
| RT | Radiation therapy |
Key points
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Altered-fractionation radiation therapy improves locoregional control and survival over that obtained with conventionally fractionated radiation therapy when either is used as single-modality treatment.
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Radiation therapy alone can achieve excellent locoregional control of early T-category oropharyngeal carcinoma.
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Advances in radiation therapy techniques such as intensity-modulated radiation therapy (IMRT) have improved patient functional and quality of life outcomes through parotid sparing with resultant reduction in xerostomia.
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Protons have unique physical properties compared with x-rays or photons owing to the Bragg peak.
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Intensity-modulated proton therapy may offer additional advantages over IMRT by reducing the toxicity associated with multiple beams passing through critical structures and by improving quality of life during and after treatment.
Radiation therapy (RT) has long been a standard approach for the definitive treatment of oropharyngeal carcinoma (OPC), with the dual treatment goals of cure and functional organ preservation. Current RT standards for patients with head and neck cancer (HNC) were defined through the sequential execution of several large randomized phase III clinical trials conducted over the past 2 to 3 decades, which led to improved disease control rates and improved survival. These important trials, along with data from meta-analyses, helped established the optimal radiation fractionation schedules and the benefit of concurrent radiosensitizing systemic therapy (chemoradiation).
Over the past decade, advances in RT planning and delivery techniques (eg, intensity-modulated RT [IMRT]) led to improved dose distributions compared with previous methods. These dosimetric gains, most notably the reduction of unnecessary irradiation of the parotid glands, translated into improved functional outcomes and quality of life for patients. More recently, advances in proton therapy planning and delivery are providing new opportunities to investigate whether proton therapy can further improve outcomes over those obtained with modern-day IMRT, specifically with regard to reducing treatment-related toxicity and symptoms and improving quality of life.
The goals of this article are to (1) highlight some key trials that established the current standards of care; (2) discuss some major studies that helped to guide current practice; (3) review some of the specific advantages and limitations of IMRT, the current standard of care for OPC, and (4) briefly describe features of proton therapy and its potential to further improve patient outcomes.
RT fractionation
Two aspects of the RT schedule generally regarded as important for tumor control and acute normal tissue reactions are the total radiation dose and overall treatment time; late normal tissue reactions depend more on other variables, such as radiation fraction size. Attempts to modify or alter fractionation schedules have been made in an effort to improve locoregional control rates over those that can be achieved with conventionally fractionated RT, through either decreasing the overall treatment time, increasing the total dose, or often both. Altered fractionation schedules typically involve the delivery of multiple smaller daily fractions as a component of the treatment schedule.
Landmark Fractionation Studies
Several institutions have developed and refined various altered fractionation schedules for locally advanced HNC during the past few decades. One landmark cooperative group trial, the Radiation Therapy Oncology Group (RTOG) trial 9003, compared 3 altered fractionation schedules against conventionally fractionated RT (70 Gy in 35 fractions over 7 weeks) for HNC. Most of the 1000 patients in this randomized trial had OPC. Fu and colleagues reported an absolute improvement in locoregional tumor control at 2 years of approximately 8% from continuous altered fractionation schedules compared with conventional fractionation, with a trend toward improved disease-specific survival. Acute reactions were noted to be worse in the groups given altered fractionation, but without an increase in long-term late radiation effects. These results led the RTOG to adopt altered fractionation as their standard schedule for RT in subsequent trials.
Likewise, Overgaard and colleagues, in the Danish Head and Neck Cancer Study Group trials, showed a similar magnitude of benefit in locoregional control for accelerated RT compared with conventionally fractionated RT. Importantly, a recent meta-analysis of 15 trials that included the aforementioned fractionation studies demonstrated that altered fractionation produced an overall survival advantage in HNC. For example, hyperfractionated RT conveyed an absolute overall survival advantage of 8% at 5 years compared with conventional fractionation, further establishing the advantage of altered fractionation schedules over conventionally fractionated RT when RT is given as monotherapy.
RT fractionation
Two aspects of the RT schedule generally regarded as important for tumor control and acute normal tissue reactions are the total radiation dose and overall treatment time; late normal tissue reactions depend more on other variables, such as radiation fraction size. Attempts to modify or alter fractionation schedules have been made in an effort to improve locoregional control rates over those that can be achieved with conventionally fractionated RT, through either decreasing the overall treatment time, increasing the total dose, or often both. Altered fractionation schedules typically involve the delivery of multiple smaller daily fractions as a component of the treatment schedule.
Landmark Fractionation Studies
Several institutions have developed and refined various altered fractionation schedules for locally advanced HNC during the past few decades. One landmark cooperative group trial, the Radiation Therapy Oncology Group (RTOG) trial 9003, compared 3 altered fractionation schedules against conventionally fractionated RT (70 Gy in 35 fractions over 7 weeks) for HNC. Most of the 1000 patients in this randomized trial had OPC. Fu and colleagues reported an absolute improvement in locoregional tumor control at 2 years of approximately 8% from continuous altered fractionation schedules compared with conventional fractionation, with a trend toward improved disease-specific survival. Acute reactions were noted to be worse in the groups given altered fractionation, but without an increase in long-term late radiation effects. These results led the RTOG to adopt altered fractionation as their standard schedule for RT in subsequent trials.
Likewise, Overgaard and colleagues, in the Danish Head and Neck Cancer Study Group trials, showed a similar magnitude of benefit in locoregional control for accelerated RT compared with conventionally fractionated RT. Importantly, a recent meta-analysis of 15 trials that included the aforementioned fractionation studies demonstrated that altered fractionation produced an overall survival advantage in HNC. For example, hyperfractionated RT conveyed an absolute overall survival advantage of 8% at 5 years compared with conventional fractionation, further establishing the advantage of altered fractionation schedules over conventionally fractionated RT when RT is given as monotherapy.
Chemoradiation
Historically, the predominant pattern of disease relapse after RT for locally advanced HNC has been locoregional recurrence, which has been attributed to the “radioresistance” of tumor-cell clonogens that persist after therapy. One approach taken to improve locoregional control was to add concurrent chemotherapy to RT with the intent of sensitizing malignant cells to the damaging effects of ionizing radiation. Although recent studies have refined induction chemotherapy regimens, this discussion of chemotherapy and RT will focus on concurrent chemoradiation, the current standard of care that is supported by the largest body of evidence.
Landmark Chemoradiation Studies
Calais and colleagues in the Groupe d’Oncologie Radiothérapie Tête et Cou (GORTEC) conducted an important trial in the late 1990s comparing chemoradiation with concurrent 5-flourouracil and carboplatin versus RT alone for locally advanced OPC. Increased rates of acute reactions were seen in the combined-modality arm; for example, high-grade mucositis was experienced by 71% of patients in the chemoradiation group versus 39% in the RT-only group. The rate of late reactions was substantial, occurring in 56% of patients receiving chemoradiation, and in a similar proportion of the RT-only group. Long-term follow-up revealed a benefit from chemoradiation in terms of both locoregional control rates at 5 years (48% vs 25%; P = .002) and long-term survival (22% vs 16%; P = .05).
Pignon and colleagues reported updated results from their meta-analysis of more than 16,000 patients participating in trials that incorporated chemotherapy and locoregional treatment. Overall, the addition of chemotherapy improved survival (5% absolute benefit at 5 years), with the greatest benefit seen among patients receiving concurrent chemotherapy (6.5% absolute benefit at 5 years). Another recent analysis from this same group showed that patients with primary OPC obtained the greatest magnitude of survival benefit from the addition of concurrent chemotherapy relative to those with HNC at other primary sites.
Epidermal growth factor receptor inhibition and RT
On the basis of important preclinical work and retrospective validation with pathology tumor specimens demonstrating the importance of tumor-cell expression of epidermal growth factor receptor (EGFR) in HNC, Bonner and colleagues performed a phase III randomized clinical trial comparing RT alone and RT plus concurrent cetuximab, a monoclonal antibody inhibitor of EGFR, in patients with locally advanced HNC. Assessments of toxicity revealed that those patients who received cetuximab experienced a greater number of high-grade acute reactions, such as infusion reaction and acneiform-like rash. However, the addition of cetuximab did not increase the reported rates of high-grade mucosal reactions or dysphagia and did not negatively affect patient quality of life compared with RT alone. Overall, the addition of cetuximab to RT improved locoregional control and overall survival rates (the latter being 45.6% vs 36.4% for RT only at 5 years; P = .018), and extended the median overall survival time from 29 to 49 months. This trial established RT and concurrent cetuximab as a standard treatment option for patients with locally advanced HNC.
RT as monotherapy for early T-category oropharyngeal cancer
Most of the patients who participated in the randomized trials that established the survival advantage for chemoradiation had higher T-category tumors; patients with T1 primary tumors were often excluded from these trials. For example, more than 80% of the patients in the GORTEC study had T3 or T4 disease. Although RT with concurrent systemic therapy remains the standard of care for patients with locally advanced disease, excellent locoregional control rates can be achieved with RT used as a single modality (ie, without systemic therapy), and this strategy may minimize the severity of treatment-related reactions.
For example, as part of a large single-institution series, Garden and colleagues reported excellent locoregional control rates for patients with T1 or T2 primary OPC tumors but with stage III through IVA disease (ie, patients who had smaller primary tumors but higher stage grouping because of nodal disease) treated with RT alone, and no benefit to the addition of concurrent chemotherapy for this early T-category group was seen ( Fig. 1 ). The authors’ current approach is to consider both the local and regional extent of disease when considering therapeutic strategies for individual patients; in terms of local therapy, they typically select concurrent chemoradiation as a component of treatment for advanced T-category tumors, but often treat early T-category OPC with RT alone.
Unilateral RT for Tonsillar Carcinoma
In carefully selected cases of lateralized tonsillar carcinoma, the RT treatment volume can often be restricted to treatment of the primary site and ipsilateral cervical and retropharyngeal lymph nodes; this treatment can result in excellent locoregional control, low contralateral cervical lymph node failure rates, and less toxicity than that expected from bilateral neck treatment. Compared with bilateral neck irradiation, this approach substantially reduces the dose to contralateral major salivary glands, nontarget upper aerodigestive tract mucosa, and important swallowing structures.
Chronowski and colleagues recently reported findings from 102 patients treated with this unilateral approach at The University of Texas MD Anderson Cancer Center. The ideal patients for this approach had T2 or lower primary site disease, no more than minimal soft palate invasion, and no base of tongue invasion. Only 5 of the patients in this series received systemic therapy as a component of treatment, and most received IMRT. Locoregional control rates for both the primary site and ipsilateral neck were 100% at 5 years. At a median follow-up interval of 39 months, only 2 patients had developed a contralateral recurrence. With regard to toxicity, only 9 patients required placement of a feeding tube during therapy, and no patient experienced long-term dependence on a feeding tube. A representative case of this unilateral approach is shown in Fig. 2 .
