Oral squamous cell carcinoma (OSCC) is a multidisciplinary disease, with surgery or radiation therapy used as a single modality for early disease (stage I and II) and combinations of surgery, radiation therapy, and chemotherapy used for stage III and IV disease. The exact role of chemotherapy is still being established, although its use is becoming more defined. Many chemotherapy trials have been flawed by not including a gold standard surgery arm or surgery plus radiation therapy arm and have compared different chemotherapeutic agents against each other; in addition, other variables are also frequently altered, such as the dose or fractionation method used for radiation therapy in each arm, thus making the results difficult to critically analyze. Moreover, because of the comparative rarity of OSCC, different head and neck sites have been lumped together in trials, which has made individual analysis for oral cavity cancer alone impossible. Despite these problems, we may consider the role of adjunctive chemotherapy with radiation therapy in three situations. First, it may be used as a definitive therapy in organ-sparing regimens. Second, it can be used for advanced locoregional or unresectable disease. Third, it can be used as combination adjuvant therapy after surgery in patients at high risk for failure.
In all three situations we must appreciate that the addition of chemotherapy will increase toxicity and therefore decrease the therapeutic index. Complications of therapy may prevent patients from completing adjuvant therapy of proven benefit, such as radiation therapy, so patient selection and experience in managing these aggressive protocols are essential to prevent excessive morbidity and mortality.
Historical Perspective
In the 1990s to 2000 a number of large meta-analyses of chemotherapy trials were published ( Table 55-1 ). The conclusions from these studies were that neoadjuvant (induction) chemotherapy and adjuvant chemotherapy had no significant survival advantages over locoregional treatment alone. However, concurrent chemoradiation therapy was seen to confer a significant survival benefit over radiation therapy alone. These meta-analyses also showed an increase in both short- and long-term toxicity and demonstrated that the benefit from concurrent chemoradiation therapy was improved locoregional control with no significant effect on distant metastases. Thus, at the present time, concurrent chemoradiation therapy is the standard of care for the treatment of head and neck cancer.
| AUTHOR | YEAR | NUMBER OF TRIALS |
|---|---|---|
| Stell | 1992 | 28 |
| Munro | 1995 | 54 |
| El Sayed and Nelson | 1996 | 42 |
| Pignon et al. | 2000 | 63 |
Diagnostic Studies
Positron emission tomography (PET) may be helpful in staging or restaging cancer and planning radiation therapy. This new imaging technique is useful for detecting recurrent disease, which computed tomography (CT) and magnetic resonance imaging have difficulty differentiating from scarring. In one series, treatment was changed in 38.7% of patients with recurrent head and neck cancer following PET/CT; 16.3% underwent major changes in therapy. However, false-positive results in the area of the tonsils, base of the tongue, and oral tongue are not uncommon. PET standard uptake values may also have prognostic value when they are very elevated. The use of PET in deciding whether to perform neck dissection after chemoradiation therapy is discussed later in the chapter.
Diagnostic Studies
Positron emission tomography (PET) may be helpful in staging or restaging cancer and planning radiation therapy. This new imaging technique is useful for detecting recurrent disease, which computed tomography (CT) and magnetic resonance imaging have difficulty differentiating from scarring. In one series, treatment was changed in 38.7% of patients with recurrent head and neck cancer following PET/CT; 16.3% underwent major changes in therapy. However, false-positive results in the area of the tonsils, base of the tongue, and oral tongue are not uncommon. PET standard uptake values may also have prognostic value when they are very elevated. The use of PET in deciding whether to perform neck dissection after chemoradiation therapy is discussed later in the chapter.
Treatment/Goals
In discussing organ-sparing protocols it should be remembered that functional organ preservation is the goal. Preserving a mandible that later fractures and requires resection for osteoradionecrosis or preserving a tongue that cannot move because of fibrosis is not better than surgical resection and good reconstruction. In the unresectable/advanced locoregional disease category, definitions are complex, and different types of patient are often included in this category. Involvement of the internal carotid artery, spine, or brachial plexus may make a lesion surgically unresectable, but patients with large lesions that could be excised but only with gross functional morbidity are also often included in this cohort. Patients with resectable OSCC may be inoperable because of medical co-morbid conditions, and medically fit patients with resectable locoregional disease may not be candidates for extensive surgery if they already have distant metastases. Finally, when concurrent adjuvant chemoradiation therapy is used following surgery, an attempt is made to select patients who will benefit the most and will tolerate the extra toxicity.
In conventional fractionated radiation therapy, one fraction is given per day for 5 to 7 weeks up to a total dose of 65 to 70 Gy. Altered fractionation schedules to improve results include hyperfractionation and accelerated fractionation. Accelerated fractionation delivers the same total dose over a shorter period, either by giving more fractions per week or by giving twice-daily treatments during the final 12 days (concomitant boost). Hyperfractionation involves a higher total dose, but lower individual fractions are given twice per day to reduce acute toxicity. Intensity-modulated radiation therapy (IMRT) creates a very exact target volume that conforms to the three-dimensional structure of the tumor so that the tumor receives a higher dose with sparing of adjacent normal structures.
Specific Treatment and Techniques
Organ-Sparing Definitive Primary Chemoradiation Therapy
Concurrent chemoradiation therapy protocols have been used as an alternative to surgery to spare important organs and preserve function. These protocols were initially used for laryngeal preservation, which is beyond the scope of this chapter. No trials have been specifically conducted for OSCC; however, this organ-sparing approach has been used for oropharyngeal primaries, especially base of the tongue and tonsil OSCC. Before data supporting the use of chemoradiation therapy, surgery and radiation were the mainstays of therapy. In a randomized phase III trial of 226 patients with stage III and IV oropharyngeal SCC in which 70-Gy radiation alone was compared with 70-Gy radiation plus three cycles of carboplatin and fluorouracil, there was no statistical difference in severe late morbidity. Overall survival, disease-free survival, and locoregional control rates at 5 years were 22% and 16%, 27% and 15%, and 48% and 25%, respectively, in favor of the chemoradiation arm. There was no change in the rate of distant metastases. The conclusions from this study were that chemoradiation therapy improves survival and locoregional control. Currently, the National Comprehensive Cancer Network (NCCN) guidelines for T3-T4a N0 or any N2 oropharyngeal SCC have chemoradiation therapy with a cisplatin-based regimen with or without planned neck dissection as their category 1 preferred treatment. Evidence of the need for neck dissection in patients with N2 and N3 disease is contradictory in the literature. However, recent papers indicate that dissection is not indicated in patients with N2 disease who have a complete response following chemoradiation therapy. In patients with residual nodes following chemoradiation therapy, published level I evidence supports PET scanning and observation of PET-negative necks while reserving neck dissection for PET-positive necks.
In addition, identification of human papillomavirus (HPV) as an etiologic factor in a cohort of patients with tonsillar cancer. The subsequent findings of improved response and survival following radiation or chemoradiation therapy in prospective studies of these head and neck cancer patients and in patients with OSCC associated with HPV raises the possibility of using less aggressive protocols in patients with HPV-positive cancers in the future.
Treatment of Unresectable/Advanced Locoregional Disease
The majority of patients with head and neck cancer already have advanced disease at initial evaluation, and in surgically unresectable patients, the 5-year survival rate with radiation therapy alone is less than 25%. Trials of altered fractionation resulted in improvement in locoregional control but no benefit in overall survival. The publication of two large meta-analyses finally resolved the question of whether survival can be improved by altered fractionation. The first, with 6515 patients, showed not only improvement in locoregional control but also an overall survival benefit of 3.4% at 5 years, with 8% for hyperfractionation and only 2% for accelerated fractionation. The second, with 10,225 patients, showed hyperfractionation to increase median survival by 14.2 months, which was highly significant. There was no benefit from accelerated radiotherapy. Also in this trial, the addition of chemotherapy to all radiation regimens significantly improved absolute survival benefit 13% to 15% at 2 years. Concurrent chemotherapy with altered fractionation radiotherapy gave the most benefit.
A meta-analysis by Pignon and colleagues involving 10,741 patients had previously shown that the greatest benefit from chemoradiation regimens was afforded by concurrent chemoradiation therapy, with an overall survival benefit of 8% at 5 years. An update of this meta-analysis in which further trials were incorporated and the patient pool was increased to 16,000 confirmed a significant 8% increase in absolute overall survival and a 19% reduction in the risk for death with concurrent chemoradiation therapy. Although this benefit is very similar to the results obtained with altered fractionation radiotherapy, concurrent chemoradiation therapy has become the standard of care in the United States. The current standard is the use of cisplatin (100 mg/m 2 ) on days 1, 22, and 43. Although this results in better locoregional control and overall survival than conventional radiotherapy alone does, it does increase the toxicity. Whether the use of multiagent chemotherapy instead of a single agent has any benefit to justify the increased toxicity is unknown. The largest updated meta-analysis failed to show any benefit with multiple agents over cisplatin alone.
Chemoradiation As Adjunctive Therapy after Surgery
The gold standard for treatment of advanced stage III and IV disease was surgery plus postoperative radiation therapy, although for patients with a single positive node without extracapsular spread (ECS), surgery alone without radiation therapy was considered sufficient. However, locoregional recurrence was frequently seen in patients with advanced disease, and it was questioned whether the addition of concurrent chemotherapy may improve the results. In view of the increased side effects and complications, there was a search to identify patients who may benefit the most, so-called targeted chemotherapy. In a paper examining rationales for postoperative radiation therapy, the argument for risk assessment by clusters was first proposed. In this analysis, two or more positive nodes, ECS, or both were significantly associated with failure. In addition, combinations of two or more risk factors—oral primary, close/positive margins, perineural invasion, two or more nodes, nodes larger than 3 cm, delay longer than 6 weeks after surgery, and decreased patient performance status—increased the chance for local failure. In a further extension of this approach, analysis of Radiation Therapy Oncology Group (RTOG) data was undertaken to identify which histologic findings best defined high-risk postsurgical patients who would benefit from chemoradiation therapy. As a result of this work, two major trials were established under the auspices of the European Organization for Research and Treatment of Cancer (EORTC) and the RTOG; the results, published in 2004, provided the first level I evidence for the benefit of chemoradiation therapy in postoperative high-risk patients.
Both these landmark trials compared radiotherapy alone with a concurrent chemoradiation arm in postoperative patients considered to be at high risk for treatment failure. Overall, 750 patients were randomly allocated in the two trials. The criteria for “high-risk” patients were slightly different in the two trials. Both EORCT 22931 and RTOG 9501 included microscopically positive margins and ECS. The RTOG trial included two or more positive nodes, whereas the EORTC trial included stage III and IV, positive level IV and V nodes, vascular embolisms, and perineural invasion. Their findings were remarkably similar in favor of the chemoradiation arm ( Table 55-2
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