General Management

Surgery, radiation, and chemotherapy, either singly or in combination, are classical treatment options for patients with oral cavity cancer. Treatment recommendations depend on tumor stage and specific anatomic location, as well as relevant patient factors, including performance status, comorbid illness, and motivation for organ preservation. Broadly speaking, single-modality treatment (i.e., surgery or radiation) is generally preferred for early-stage lesions The control rates are similar for T1-T2 lesions with either modality delivered as monotherapy (Hintz et al. 1979). For more advanced lesions a combined-modality treatment approach is generally preferred to maximize locoregional tumor control. Several other treatment approaches, including definitive radiotherapy with or without chemotherapy, and neoadjuvant chemotherapy followed by surgery with or without radiotherapy, are areas of active clinical investigation. These approaches remain primarily investigational and are beyond the scope of the current summary.

The timing of radiation, before or after surgery, has been the subject of some debate. Notable disadvantages of preoperative radiation therapy include limitations on the dose of radiation that can be delivered due to the risk of postoperative wound complications, and the compromise of precise pathologic data, particularly as it pertains to occult nodal disease. Postoperative radiation treatment has the advantage of less relative dose limitation, no delay in definitive surgical resection, and preservation of complete pathologic tumor staging. However, it is recognized that postoperative wound complications may delay adjuvant radiation and that, compared with normal oxygenation, regional hypoxia following surgery may diminish the effectiveness of radiation. A single randomized trial including 59 oral cavity cancers in a population of 320 evaluable patients, identified no significant survival, locoregional control, or toxicity difference between preoperative and postoperative radiation (Snow et al. 1981). However, the preponderance of data as well as global practice patterns suggest that postoperative radiation is commonly preferred. Further, emerging data for selected patients with high-risk pathologic features indicate that the addition of concurrent chemotherapy during the postoperative radiation treatment course may further augment tumor control rates (Bernier et al. 2004; Cooper et al. 2004; Day et al. 2003). High-risk features commonly include advanced T stage, multiple positive nodes, extracapsular tumor spread, positive resection margins, and perineural invasion (Bernier et al. 2004; Cooper et al. 2004).

Combined-Modality Therapy

Disease control outcomes for advanced lesions of the oral cavity (T3, T4) are less than satisfactory with surgery or radiation alone, thereby prompting the common implementation of combined-modality therapy (Fu et al. 1976; Shah and Lydiatt 1995; Vikram et al. 1980). With steadily improving reconstruction techniques, surgery has emerged as the preferred initial treatment approach for the majority of patients with tumors of the oral cavity, with adjuvant radiation (or, in selected cases, chemoradiation) employed to enhance the likelihood of locoregional tumor control.

Adjuvant Radiation Technique

Carcinoma of the oral cavity has traditionally been treated with opposed lateral fields, using either two-dimensional or three-dimensional CT-based techniques. During simulation and treatment, patients are typically immobilized with a thermoplastic mask. Patients are placed in the supine position with a bite block (for oral tongue and floor of mouth cases) to depress the tongue away from the palate. The oral cavity tumor bed with a 1.5–2.0-cm margin and upper cervical lymph nodes constitute the initial lateral fields. The inferior border of the field resides at approximately the thyroid notch (or aryepiglottic folds when using CT-based planning), just above the true vocal cords. The posterior border is set at the mid-vertebral body level if level V nodal coverage is not required. For patients with more advanced neck disease or positive level V lymph nodes, the initial fields should be set behind the C1 vertebral body spinous process to facilitate coverage of the posterior triangle. The lateral fields are reduced at 40–45 Gy, depending upon patient anatomy, to spare the spinal cord from doses in excess of tolerance. Treatment of the low neck generally consists of a single half-beam-blocked anteroposterior field matched to the inferior border of the opposed lateral fields. An anterior larynx block is used, which functions to protect the central larynx from unnecessary radiation dose and to protect against spinal cord overdose due to field overlap. Beam energies between 4 and 6 MV are most suitable for treatment of cancers involving the oral cavity. Bolus material may be necessary to bring dose to the surface as required for tumors that extend to the skin, particularly in patients with large volume nodal disease or extracapsular extension (ECE) where adequate dosing of superficial tissues is crucial to the success of the treatment. All fields should be treated daily, with at least five scheduled treatment days per week.

In recent years, intensity-modulated radiation therapy (IMRT) has increasingly been used for the treatment of head and neck tumors (Fig. 6.1), with the goal of preserving treatment outcome while diminishing normal tissue toxicities, including damage to major salivary glands and mandible, which result in xerostomia or osteoradionecrosis, respectively (Yao et al. 2005; Studer et al. 2006; Daly et al. 2006). Dosimetric analysis of radiation dose to the parotid glands with evaluation of resultant salivary function suggests that limiting the mean parotid dose to <26 Gy may result in improved post-radiation salivary function (Eisbruch et al. 2003). In light of the steep dose gradients that often accompany IMRT plans, successful delivery is highly dependent on accurate and reproducible localization and immobilization. At several centers, an optically guided localization system is used to enhance daily treatment precision for IMRT delivery. Tomotherapy, which involves the helical delivery of intensity-modulated radiation, enables a high degree of target conformality coupled with the capacity for megavoltage CT scanning, thereby allowing image guidance for precise daily set-up verification (Fig. 6.2) (Sheng et al. 2006; Fiorino et al. 2006; Harari et al. 2004). Other treatment platforms have developed similar integrated CT-based imaging capabilities.

Fig. 6.1
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Treatment volume delineation for a patient with stage IVA (T3 N2b M0) cancer of the right retromolar trigone receiving definitive IMRT. The gross tumor volume (GTV, yellow), high-risk clinical target volume (CTV1, red), low-risk clinical target volume (CTV2, blue), and oral cavity (OC, magenta) are shown. (From Chao KS, Ozygit G, (eds) Intensity modulated radiation therapy for head & neck cancer. Philadelphia: Lippincott, 2003, with permission)

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Fig. 6.2
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Radiation dose distribution for an IMRT treatment plan delivered via helical tomotherapy to a patient with stage IVA (T2 N2b M0) squamous cell carcinoma of the left lateral oral tongue; status, postsurgical resection of the primary tumor. The high-risk clinical target volume (CTV1, red) and low-risk clinical target volume (CTV2, orange) are shown, with radiation dose distribution demonstrated by the 63 Gy (blue), 54 Gy (green), and 45 Gy (magenta) isodose lines. Critical normal structures, which have been contoured in this view, are the left parotid gland (light blue), right parotid gland (dark blue), and spinal cord (yellow)

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Dose and Fractionation

When postoperative radiation is used for oral cavity cancer, the most common dose fractionation in the United States is 1.8–2.0 Gy per day. The postoperative tumor bed should generally receive a total dose of 60 Gy. However, for close or positive microscopic margins, or extracapsular nodal extension, a 4- to 6-Gy localized boost should be considered. Peters and colleagues conducted a prospective randomized trial of radiation dose escalation in the postoperative setting. They concluded that a minimum dose of 57.6 Gy was necessary to achieve satisfactory tumor control and that doses in excess of 63 Gy were indicated in the setting of nodal ECE (Peters et al. 1993). If there is gross residual disease, either further surgical resection or focal boosting up to 70 Gy is advisable. Regions of somewhat lesser risk (i.e., clinically or pathologically uninvolved necks) should receive 50–54 Gy. As IMRT techniques are increasingly employed, simultaneous in-field boosts (Miller et al. 2005) are used to deliver these different doses in a comprehensive treatment plan composed of differential doses per fraction to the areas of high, intermediate, and low risk.

Altered Fractionation

It is well understood that head and neck squamous cell carcinomas (HNSCCs) are rapidly proliferating. There has been significant interest in the use of intensified radiation fractionation schedules to counter rapid tumor cell repopulation and potentially improve outcome in HNSCC treated with radiation. Altered fractionation regimens such as hyperfractionation or accelerated fractionation have been demonstrated to improve the likelihood of locoregional tumor control when used as definitive therapy (Peters et al. 1988). These altered fractionation regimens were associated with a higher incidence of grade 3 or worse acute mucosal toxicity, but no significant difference in overall toxicity at 2 years after completion of treatment. However, oral cavity carcinoma constituted a minority of cases enrolled in these studies (Fu et al. 2000), and data addressing the use of hyperfractionated radiation in the postoperative setting is sparse and heterogeneous in the conclusions reached (Ang et al. 2001; Awwad et al. 1992; Niewald et al. 1996), with some reports of excess morbidity in the form of osteoradionecrosis using this approach (Niewald et al. 1996). A single randomized study comparing conventional vs. accelerated fractionation in the postoperative setting showed no advantage to accelerated fractionation except in patients whose treatment initiation was delayed by postoperative complications (Sanguineti et al. 2005).

Brachytherapy

Historically, brachytherapy has played a key role in the treatment for oral cavity carcinoma, primarily as a boost to the primary site in the oral cavity before or after external beam radiation. Traditionally, radiation has been delivered using low dose rates of 0.4–0.6 Gy/h to the target volume (Mohanti et al. 2001; Strnad 2004). Treatments can be delivered using either rigid cesium needles or with 192Ir sources afterloaded into angiocatheters (Fig. 6.3). The most common technique is after loading with 192Ir (Wang et al. 1976). Guide needles can be inserted either free-hand or with the aid of a custom template to help maintain optimal source spacing.

Fig. 6.3
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(a) Stage II (T2 N0 M0) squamous cell carcinoma of the left lateral oral tongue. (b) Submental view of interstitial implantation catheters containing 192Ir sources for delivery of a 25 Gy tumor boost after previous external beam radiation to a dose of 50 Gy. (c) Implantation bed mucositis conforming to the tumor distribution 7 days after 25 Gy implant boost. (From Halperin EC, Perez CA, Brady LW, eds., Principles and practice of radiation oncology, fifth edition. Philadelphia: Lippincott Williams & Wilkins, 2008, with permission)

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Gradual improvements in both radiation and reconstructive surgery techniques have diminished the use of brachytherapy in the treatment of oral cavity carcinoma. Single-institution studies have evaluated brachytherapy techniques in the context of adjuvant therapy for locally advanced disease but have typically demonstrated unsatisfactory results in node-positive patients (Lapeyre et al. 2004). Further, the evolution of highly conformal external beam techniques such as IMRT has contributed to less frequent practice of brachytherapy in head and neck cancer overall.

Outcomes with Adjuvant Radiotherapy

Several randomized trials have evaluated surgery alone or in combination with radiotherapy. Robertson and colleagues conducted a phase III study in the United Kingdom of 350 patients with T2-4 N0-2 oral cavity or oropharyngeal cancers comparing surgery and postoperative radiation vs. radiation alone. Because a difference in survival was identified, the study was closed early. The authors found that after 23 months, overall survival, cause-specific survival, and local control were all improved on the surgery plus radiation arm (Robertson et al. 1998). Mishra et al. conducted a prospective randomized trial of surgery with or without adjuvant radiation 6 weeks after surgery in patients with carcinoma of the buccal mucosa (Mishra et al. 1996). They reported a 30% absolute improvement in disease-free survival, although there was no difference in overall survival with the use of adjuvant radiation therapy. Indications for postoperative radiation therapy include multiple cervical lymph node metastases, positive or close surgical margins, extracapsular nodal extension, perineural invasion, advanced T stage, and suspicion of mandibular cortical involvement.

Much of the outcome data for postoperative radiotherapy in regionally metastatic oral cavity cancer is gleaned from single-institution retrospective reports, which generally assess a specific subsite of the oral cavity (e.g., oral tongue, floor of mouth, buccal mucosa), and frequently include postoperative patients as only a small subset of the total cohort (Byers et al. 1981; Shibuya et al. 1984; Zelefsky et al. 1990; Rodgers et al. 1993; Hicks et al. 1997). These studies are all concordant with the limited randomized data in showing a locoregional control advantage to postoperative radiotherapy, providing additional clinical support for the use of combined-modality treatment.

Chemotherapy and Radiation

The role of chemotherapy in head and neck cancer has evolved considerably in recent years and is currently an important component of treatment in the definitive setting. Several studies demonstrate the benefit of radiation with concurrent chemotherapy administration in this setting (Adelstein et al. 2003; Brizel et al. 1998; Calais et al. 1999; Denis et al. 2004; Merlano et al. 1996; Staar et al. 2001; Wendt et al. 1998). Although these trials vary with respect to radiation dose, fractionation schedule, and chemotherapy regimen employed, they are all randomized comparisons between radiotherapy alone and radiotherapy plus chemotherapy. The advantage of concurrent chemotherapy with radiation has been further evaluated in several meta-analyses (Browman et al. 2001; El-Sayed and Nelson 1996; Munro 1995; Pignon et al. 2000). These meta-analyses generally identify a small overall survival benefit (1–8%) for the use of chemotherapy (Harari et al. 2003). Summary analyses suggest no significant survival benefit for the use of neoadjuvant and adjuvant chemotherapy but do suggest a clear benefit for the use of concurrent chemoradiation (Pignon et al. 2007). However, in many of the randomized studies comparing radiation alone to chemoradiation, oral cavity cancer patients are once again either excluded or make up only a small fraction of the study population.

The use of concurrent chemoradiation in the postoperative setting initially demonstrated encouraging locoregional control outcomes but failed to demonstrate an improvement in overall survival (Marcial et al. 1990; Al-Sarraf et al. 1997). These findings prompted several institutions to analyze both retrospective and prospective patient databases in an attempt to identify a population at high risk of local recurrence, with the hypothesis that treatment of appropriately selected high-risk patients with chemoradiation may confer an overall survival benefit. The findings of several of these studies are relatively homogeneous in nature, identifying positive surgical margins, ECE, and presence of two or more involved lymph nodes as being most strongly predictive of local recurrence (Ang et al. 2001; Cooper et al. 1998; Rosenthal et al. 2002; Langendijk et al. 2003). These findings provided impetus for two randomized multicenter trials to study the outcome in high-risk patients treated with postoperative chemoradiation.

Cooper et al. reported the results of a randomized study in North America comparing radiation alone (60–66 Gy) with chemoradiation (same radiation dose plus three cycles of 100 mg/m2 cisplatin) in patients with head and neck carcinoma demonstrating high-risk features after gross total resection (Cooper et al. 2004). High-risk disease was defined as any or all of the following: two or more involved lymph nodes, ECE of nodal disease, and microscopically involved resection margins. This study demonstrated a benefit in locoregional control and disease-free survival at 2 years, favoring the chemoradiation arm, but no overall survival benefit was appreciated (Fig. 6.4a). A recent update of this trial with extended follow-up failed to show a difference between treatment arms in 5-year locoregional control and disease-free survival, although an unplanned subgroup analysis suggested a benefit in patients with positive margins or ECE (Cooper et al. 2006).

Fig. 6.4
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Kaplan-Meier estimates for overall survival from EORTC 22931 (a), and RTOG 95-01 (b). (c) Comparative analysis of hazard ratio values for overall survival using pooled data from the European Organization for Research and Treatment of Cancer (EORTC) and RTOG trials in patients eligible for both trials or one trial only. Patients eligible for both trials included those with positive surgical margins and extracapsular nodal extension (ECE). (From 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. 2004 May 6; 350(19):1945–1952, 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. 2004 May 6; 350(19):1937–1944, with permission; and 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, 2005 Oct; 27(10):843–850, © 2005, J. Bernier, reprinted with permission of John Wiley & Sons, Inc.)

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A parallel study in Europe by Bernier et al. randomized patients to essentially equivalent treatment arms following head and neck cancer surgery (Bernier et al. 2004). Eligibility criteria included patients with pathologic T3 or T4 disease (except T3 N0), or patients with any T stage disease with two or more involved lymph nodes, or patients with T1/T2 and N0/N1 disease with unfavorable pathologic findings (extranodal spread, positive margins, perineural involvement, or vascular embolism). Local control, progression-free survival, and overall survival were superior for patients on the chemoradiation arm (Fig. 6.4b). Both of these randomized trials demonstrate a significant increase in treatment-related toxicity in the chemoradiation arms, reinforcing the concept that the outcome benefit observed is a consequence of more aggressive treatment, with no appreciable change to the existing therapeutic ratio. A pooled data analysis of these two trials demonstrates a small but statistically significant improvement in locoregional control, disease-free survival, and overall survival in the chemoradiation arm for all enrolled patients but confirms that patients with positive surgical margins and/or ECE derived the majority of the outcome benefit (Fig. 6.4c) (Bernier et al. 2005). It should be noted that the pooled analysis does not incorporate updated outcome data from either trial, thereby limiting the evidence-based recommendation for postoperative chemoradiation to patients with positive margins and/or ECE.

Targeted Agents Combined with Radiation

In recent years, there has been a substantial increase in the exploration of targeted agents in an effort to improve the therapeutic ratio by alleviating some of the treatment-related toxicities commonly associated with cytotoxic chemotherapy. One such agent, cetuximab, was shown in initial laboratory studies to be an effective radiosensitizing agent in head and neck cancer cell lines (Huang et al. 1999; Milas et al. 2000). A randomized clinical trial comparing radiation alone or in combination with cetuximab as definitive treatment for head and neck cancer demonstrated an absolute survival benefit of 10% at 3 years with the use of cetuximab, with little substantial additive toxicity over radiation alone (Bonner et al. 2006). This led to the subsequent US Food and Drug Administration (FDA)-approval for this agent in the treatment of head and neck cancer.

A phase II randomized clinical trial recently conducted by the Radiation Therapy Oncology Group (RTOG) evaluated two cetuximab-based postoperative chemoradiation regimens in the patient population defined as high-risk by the Cooper study discussed previously (positive margins, two or more involved lymph nodes or ECE). Initial feasibility and toxicity reports show that the cetuximab-containing regimens are tolerable, with an incidence of grade 4–5 toxicity (9.2–10.1%) that compares favorably to the 15% estimate for radiation plus cisplatin from RTOG 95-01 (Harari et al. 2007).

Although the efficacy data from this trial are still maturing, it is hoped that this and other trials of targeted agents in combination with radiation will continue to suggest a widening of the therapeutic ratio, with preservation or improvement of outcomes and minimal additive toxicity for patients with high-risk disease.