ABSTRACT: The treatment of patients with locoregionally advanced or unresectable squamous cell carcinoma of the head and neck is complex and associated with significant toxicities. During the past 30 years, there has been an ongoing shift in what is perceived as the best treatment approach. Differing radiation techniques have been employed, and chemotherapy has been incorporated in both sequential and concomitant strategies. In this article, we will review the available data regarding many of the advances that have been achieved. We will also discuss the most relevant recent clinical trials, as well as ongoing trials that will hopefully answer some of the questions that remain as we attempt to best treat this patient population.
About 500,000 head and neck carcinomas are diagnosed worldwide annually. This accounts for approximately 8% of all newly diagnosed cases of cancer, ranking head and neck carcinoma the sixth most common. In the United States, 47,560 new head and neck carcinomas are expected to be diagnosed in 2008, and this disease accounts for 5% of all newly diagnosed cases of cancer. Approximately 90% to 95% are squamous cell carcinomas of the head and neck (SCCHNs). The majority (60%) of patients present with stage III/IV poor-prognosis disease. Historically, 50% to 60% of patients with locoregionally advanced head and neck cancer treated with radiation therapy (RT), surgery, or both have developed a locoregional recurrence in 2 years. In addition, 20% to 30% of those patients have developed distant metastases. For unresectable head and neck cancer, the 5-year survival rate with RT alone is less than 25%.
Significant advances have been made in the multimodality treatment of patients with locoregionally advanced or unresectable SCCHN over the past 2 decades, which will be the focus of this review. These advances have included the integration of chemotherapy with radiation therapy, the use of targeted agents, and surgery as salvage or completion neck dissection. Despite this progress, many challenges and questions remain. In the following sections, we will first review the radiotherapy techniques that have been investigated. We will then review the progressive advances achieved with the addition of chemotherapeutic strategies to RT in an attempt to achieve better outcomes.
Definition of Locoregional Advanced and Unresectable
The definition of locoregional advanced is generally related to an advanced T or N stage. Defining the term unresectable is difficult, as resectability has evolved over time due to advances in surgical and reconstruction techniques. Criteria for unresectability of the primary site or adenopathy include fixation to the spine or prevertebral muscles or involvement of skin, dura, base of skull, or brachial plexus. Some patients are also categorized as unresectable due to the expectation of poor functional outcomes following surgery. Also, patients may be considered unresectable due to significant medical comorbidities, rendering them unable to tolerate the extensive resections required for locally advanced disease.
RT and Recent Advances in Management of Unresectable Head and Neck Cancer
Radiation therapy is the primary treatment modality for unresectable head and neck cancer, administered alone or concurrent with chemotherapy. Treatments are traditionally delivered at daily fractions of 1.8 to 2 Gy, to approximately 70 Gy over 6 to 7 weeks, with local control rates of 50% to 70% for locoregionally advanced disease.
In an attempt to improve outcomes, altered-fractionation schemes have been investigated.[4-9] Among the altered-fractionation schema investigated were hyperfractionation regimens and accelerated regimens. Hyperfractionation regimens deliver lower doses of radiation, twice daily, with the intent of minimizing acute toxicity. In order to account for the smaller dose per fraction, higher total doses are delivered. Accelerated-fractionation schemes deliver a course of radiation using conventional doses of radiation delivered more than five times weekly, with the intent of shortening overall treatment time at the expense of higher acute toxicity. Accelerated fractionation has been achieved in various ways, such as treating six fractions per week or using a delayed concomitant boost scheme, during which the patient is treated in 6 weeks, with twice-daily treatments delivered during the final 12 days of treatment.
The Radiation Therapy Oncology Group (RTOG) conducted a landmark trial (RTOG 90-03) comparing the leading US altered fractionated regimens for multiple head and neck cancer sites, including oropharyngeal cancers (60%). Patients, the majority of whom had stage III/IV locally advanced SCHN, were randomized to one of four fractionation schemes.
In a preliminary analysis after a median of 23 months of follow-up, 2-year locoregional control was significantly better for patients treated via either a delayed concomitant boost or a hyperfractionation regimen compared with conventional fractionation (Table 1). The investigators noted a trend toward improved disease-free survival in both the delayed concomitant boost and hyperfractionation arms compared with conventional fractionation. However, overall survival was no different.
Hyperfractionation and delayed concomitant boost both increased acute grade 3/4 toxicity. Delayed concomitant boost increased chronic grade 3/4 toxicity at 3 months, but by 6 to 24 months, there was no difference in grade 3/4 toxicity There was no difference in chronic grade 3/4 toxicity in the hyperfractionation arm.
Horiot et al reported similar results from European Organisation for Research and Treatment of Cancer (EORTC) 22791, a randomized trial comparing hyperfractionation vs conventional fractionation. Hyperfractionation improved 5-year actuarial locoregional control compared with conventional fractionation (59% vs 40%, respectively; P = .02), with a trend toward improved survival.
The Danish Head and Neck Cancer Study (DAHANCA) 6 and 7 trials were multicenter phase III investigations of conventional fractionation vs accelerated fractionation using six weekly fractions of radiation with a hypoxic cell sensitizer (DAHANCA 6 examining glottic tumors, and DAHANCA 7 studying other head and neck sites). The accelerated regimen resulted in improved 5-year local control, locoregional control, and disease-specific survival, but no significant effect on overall survival was seen.
Several other randomized trials examining altered-fractionation schemes have been reported to date, most of which also demonstrate an improvement in local and locoregional control at the expense of increased acute toxicity, but without an impact on overall survival.[14-20] Thus, conventional fractionation and accelerated fractionation yield equivalent survival results, but accelerated fractionation yields higher local and locoregional control, at the expense of increased acute mucosal toxicity.
Meta-analyses of Fractionation Schemes and Concurrent Chemoradiation Regimens
Large randomized trials have been included in meta-analyses to achieve greater statistical significance to determine the efficacy of altered-fractionation RT. Budach et al reported a meta-analysis of hyperfractionation, accelerated fractionation, and chemoradiation regimens used to treat locally advanced SCCHN, which included 32 trials with 10,225 patients. Eligible trials included patients with squamous cell carcinoma of the oral cavity, oropharynx, hypopharynx, and larynx treated with definitive radiation or chemoradiation, with no surgery to the primary site (although a neck dissection was allowed). Accelerated radiation was defined as a course of treatment time shortened by 10% to 50% (with the total dose decreased by < 5%); or if the total dose was decreased by > 5%, the radiation dose could be decreased by > 50%. Hyperfractionation was defined as twice-daily radiation with < 1.25 Gy per fraction and > 5% increase in total dose.
The addition of simultaneous chemotherapy to all RT fractionations resulted in an overall survival benefit of 12 months (P < .0001), with an absolute survival gain of 13% to 15% at 2 years. In patients who did not receive chemotherapy, there was no significant gain in overall survival for accelerated fractionation compared to conventional fractionation, but hyperfractionation increased median survival by 14.2 months (P < .001). Thus, concurrent chemotherapy with hyperfractionation or accelerated fractionation yielded the greatest benefit.
Another meta-analysis, by Bourhis et al, compared conventional-fractionation, hyperfractionation, and accelerated-fractionation schedules utilized in 15 trials to treat 6,515 patients. Tumor sites were primarily the oropharynx and larynx; 74% of patients were diagnosed with stage III/IV disease. Altered fractionation—both accelerated fractionation and hyperfractionation—led to a significant overall survival benefit of 3.4% at 5 years. The benefit was significantly higher with hyperfractionation (8% at 5 years) than with accelerated fractionation (approximately 2% at 5 years). Moreover, altered-fractionation RT led to a significant decrease in locoregional failure, with a 23% reduction in risk and an absolute benefit of 8.5% at 5 years. These results are comparable to the benefits achieved by chemoradiotherapy reported in the Meta-Analysis of Chemotherapy in Head and Neck Cancer (MACH-NC), which is discussed later in this article, with a 5-year overall survival benefit of 6.5% in the altered-fractionation meta-analysis vs 8% in the MACH-NC.
In summary, based on the convincing data from the pivotal EORTC 22791 and RTOG 90-03 trials, there is a benefit to hyperfractionation therapy for unresectable head and neck cancers. However, radiation therapy alone is utilized only in select cases; the standard of care for unresectable SCCHN is concurrent chemoradiation. The Budach and Bourhis meta-analyses have shown that there is a benefit to accelerated-fractionation RT, which is similar to that observed for concurrent chemoradiation.[21,22]
There may be an added benefit to concurrent chemoradiation with altered-fractionation radiation; however, the role of concomitant chemotherapy in the setting of altered fractionation is unclear. RTOG 0129 may clarify the issue. In RTOG 0129, patients with locally advanced SCCHN treated with concurrent cisplatin were randomized to standard-fractionation RT or accelerated fractionation with concomitant boost (the same fractionation employed in the delayed concomitant boost arm of RTOG 90-03). The trial closed in 2005, and the data are presently maturing.