Radiotherapy in the Management of Carcinoma of the Oral Cavity

Fig. 4.1

Patient in position with thermoplastic mask used for immobilization. Multiple lasers are used for verification of proper isocenter and patient alignment
Table 4.1

Glossary of commonly used terms in radiation oncology
Measurement and calculation of absorbed dose delivered during delivery of ionized radiation; also a professional field dedicated to the task of radiation planning
Interstitial brachytherapy
Treatment where radioactive sources, or catheters, which will serve as passageway for sources, are implanted directly into tumor and/or surrounding tissue – treatment is from within
Treatment from outside the body, a beam of radiation is directed at the target (a.k.a. external beam radiation)
Mobile head of a teletherapy unit, rotates into position prior to delivering radiation toward target
Linear accelerator
Modern teletherapy unit, uses large-voltage potential to create beam of electrons or x-rays
The process of modifying a beam of radiation to achieve a desired shape, generally conformal to the target
Unit of absorbed dose, with which radiation is typically prescribed. 1 Gy = 1 joule absorbed by 1 kg of matter
Low-dose rate (LDR)
Refers to brachytherapy in which the dose delivered does not exceed a rate of 2 cGy/min
High-dose rate (HDR)
Refers to brachytherapy in which the dose delivered exceeds a rate of 20 cGy/min
The process of splitting a dose of radiation into multiple smaller treatments, generally with the goal of allowing adequate healing time for irradiated normal tissue
Pretreatment procedure where the patient is aligned and positioned akin to treatment, so images and measurements can be obtained necessary for the planning process
Flat surface on which the patient lies, under the treatment unit. Capable of moving in all directions, brings patient into position under the treatment beam
Treatment room specifically engineered to contain the high-energy radiation used in modern radiation treatments. Often contains several feet of cement, lead, and other materials to achieve appropriate shielding
A tool placed in the gantry, in the beam path, meant to create an uneven beam to compensate for irregular thickness. The goal is to create a homogenous dose distribution within the patient
Multi-leaf collimator (MLC)
An apparatus within the gantry capable of producing customized beam shapes through the movement of multiple small “leaves”
Three-dimensional conformal radiation therapy
Type of planning using CT images obtained during simulation. Allows for delineation of targets and organs in three dimensions, leading to volume-based planning
Intensity-modulated radiotherapy
An advanced technique designed to minimize dose to normal structures surrounding the target. This is accomplished by modulating the position of the MLC leaves during treatment delivery, creating a nonuniform dose distribution
Point in patient around which the treatment gantry rotates. Generally corresponds to alignment marks placed on patient during simulation
Portal images
Images taken by treatment unit, used to verify patient’s position prior to radiation delivery
On-board Imaging (OBI)
Modern addition to linear accelerator, capable of producing high-quality images of patient on the treatment couch
Image-guided radiation therapy (IGRT)
Refers to the use of OBI to more precisely verify patient’s position on treatment couch, prior to complex treatment delivery
Radiation therapist
Medical professional with expertise in patient setup and delivery of daily radiation treatments prescribed by physician
Stereotactic body radiation therapy (SBRT)
Highly conformal radiation treatment given in no more than 1–5 fractions, referring to non-cranial targets
Altered fractionation
Radiation regimen that deviates from conventional/standard fractionation (i.e., 1.8–2.0 Gy per fraction, per day). Common examples include accelerated, hyper-, hypo-, and concomitant boost fractionation
A term used to denote additional dose beyond that already given, usually implying a smaller field as well
Intraoral devices are often used for treatment of certain head and neck malignancies, especially those of the oral cavity (Fig. 4.2). They can accomplish one of two goals with regard to enhancing normal tissue sparing. Shielding and positional devices serve to attenuate radiation and displace normal tissue from the field, respectively [4]. These are typically designed as a collaborative effort between the radiation oncologist and dentist. A common example of a positioning device is an intraoral stent used to depress the tongue and mandible. This is particularly useful for treatment of the hard palate, where the tongue and lower oral cavity is not meant to be targeted. Without said device, the thermoplastic mask would be created for the patient with a closed jaw, leaving the oral tongue in close juxtaposition with the hard palate. Shielding devices are made from photon-attenuating materials (e.g., Cerrobend), which will serve to shield normal tissues from high doses of radiation, if not desired to be included as target tissue.

Fig. 4.2

Examples of intraoral devices used for positioning, shielding, or immobilization of the oral cavity. Devices are made prior to simulation and remain in place during every fraction, ensuring reproducibility

4.2.4 Three-Dimensional Radiation Therapy and Intensity-Modulated Radiation Therapy

The ability to use tools to modulate the beam to better cover the tumor (e.g., wedges, blocking) allowed for patient- and plan-specific beam design. The mechanical feature that was perhaps the biggest leap forward in beam shaping was the multi-leaf collimator (MLC). This is a device that allowed automated, custom beam shaping. It consists of multiple leaves that travel parallel to one another and meet on a central perpendicular axis (Fig. 4.3). This obviated the need for creating custom blocks for the corners of fields, which was very time and labor intensive. A parallel development was that of three-dimensional radiation therapy (3DRT). This is a process of simulation, planning, and treatment based on 3D images (i.e., stacked CT slices). The ability to devise and create radiation plans on a 3D image set allowed for delineation of volumes and evaluation of dose to a volume. Combining the 3D planning and the aforementioned MLC leads to one of our modern standards, three-dimensional conformal radiation therapy, or 3DCRT. By prescribing dose to a volume, it is possible to ensure adequate coverage to the entire target volume (i.e., tumor), as opposed to calculating dose to a point within the center of the tumor, which was the norm with two-dimensional radiation therapy.

Fig. 4.3

Multi-leaf collimator. Multiple small leaves conform to desired shape, or move during treatment delivery to create a modulated field
With the above technique, a dose is prescribed to a volume, and the resulting radiation plan is evaluated in terms of target coverage, and dose to adjacent critical structures. This is known as forward planning. Since the advent of computer dosimetry in the 1960s, we have developed increasingly complex uses for computation in the treatment planning process. Intensity-modulated radiation therapy (IMRT) represents a dramatic advance. IMRT is a marriage of two distinct processes. The first is inverse planning. Contrary to forward planning, inverse planning specifies the desired dose for a treatment volume and identifies dose limits to adjacent critical structures. A computer-based optimization algorithm subsequently modulates the intensity of the delivered beams in an effort to achieve the prescribed dose constraints (both target and organ). The modulation is affected by dynamic action from the MLC. In other words, the conformation of the MLC during the delivery of radiation for a given field is not steady. This allows different areas of the same radiation field to receive more or less dose (i.e., dose modulation). The end result of these processes is the ability to create bends in the delivered dose distribution (Fig. 4.4).

Fig. 4.4

Left: dose distribution typical of 3DCRT plan. Note the posterior edge of the radiation field is roughly linear, correlating with the designed field blocking. The parotid tissue (outlined in green/blue) is receiving full dose. Right: dose distribution typical of IMRT plan. The dose is sculpted to conform to the target tissues, while sparing the parotid glands
IMRT has been widely adopted for treatment in head and neck cancers due to this ability to dose escalate while achieving improved normal tissue sparing. Using IMRT postoperatively for oral cavity squamous cell carcinoma (OCSCC), Gomez et al. reported 3-year estimates of 77 %, 85 %, 64 %, and 74 % for locoregional progression-free survival (PFS), distant metastasis-free survival (DMFS), disease-free survival (DFS), and overall survival (OS), respectively. Trismus and osteoradionecrosis (ORN) were noted in 17 % and 5 %, respectively [5]. Similarly, Chen et al. compared outcomes of 49 stage III and IV OCSCC patients treated with either postoperative IMRT or conventional radiotherapy. At 3 years, the OS was comparable, and acute toxicities did not differ. Late toxicity appeared to be significantly reduced by the use of IMRT, 36 % vs. 82 % for xerostomia and 21 % vs. 59 % for dysphagia [6]. Chen et al. published a second report looking at IMRT use in their postoperative oral cavity patients from 2005 to 2008 and reported increased 3-year locoregional control (76 % vs. 54 %) and disease-free survival rate (70 % vs. 48 %) for IMRT and conventional RT, respectively [7]. Daly et al. reported on 37 patients undergoing IMRT for OCSCC (30 postoperative, 7 definitive). They reported 3-year actuarial estimates of local control (67 %), locoregional control (53 %), freedom from distant metastasis (81 %), and OS (60 %) among postoperative patients. The authors highlighted the balance required between target delineation and organ sparing. Their cohort experienced a few marginal misses, which led them to emphasize the importance of target delineation and perhaps dose intensification [8].
A multicenter randomized phase III trial performed in the United Kingdom was published in 2011. This study included only patients with SCC of the pharynx, but was effective in showing xerostomia could be effectively reduced. At 24 months, grade 2 or worse xerostomia was seen in 83 % of patients receiving conventional radiation vs. 29 % in those receiving parotid-sparing IMRT. The authors concluded that the results were likely generalizable to all head and neck cancer sites [9]. Another multicenter prospective trial from Europe allowed multiple head and neck subsites, including 24 patients with oral cancer. Two-year locoregional control and overall survival were 86 % and 86.7 %, respectively. Reduced rates of xerostomia relative to historical controls were seen as well. The authors concluded that IMRT was capable of reducing late side effects without compromising local control or survival [10].
Studer et al. retrospectively analyzed the outcomes of 160 oral cavity patients treated with IMRT between 2002 and 2011. One hundred twenty-two were treated primarily with radiation, while 38 were referred for recurrence, at least 3 months after surgery alone. Seventy-two percent of patients received concomitant chemotherapy. Patients who received IMRT as primary treatment or postoperative IMRT with macroscopic residual disease had significantly poorer outcomes compared with those receiving IMRT after a R0–1 resection. Three-year local control rates and overall survival rates were 35–37 % vs. 80 % and 30–37 % vs. 80 %, respectively. Patients with T1 tumor status post resection exhibited 100 % 4-year locoregional control (LRC), and T2-T4 had LRC rates of 70–80 %. In stark contrast, all T-stages of patients treated with primary radiation had 4-year LRC rates of 30–40 % [11]. This suggests IMRT is not a substitute for resection.
In one of the largest pure OCSCC populations reported, Chan et al. published outcomes on postoperative patients who received IMRT with or without concurrent chemotherapy. Two-year OS and LRC were 65 % and 78 %, respectively. Thirty-eight patients experienced locoregional failures. Of these, 26 were in-field, 7 were marginal, and 5 were out of field. Locoregional failures occurred in six patients receiving ipsilateral neck irradiation, one patient receiving primary site irradiation only, and five patients receiving bilateral neck irradiation [12]. These results again emphasize the importance of careful target delineation and thorough consideration of chosen elective neck volumes. Having the power to spare normal tissue must be carefully weighed with the risk of marginal/out-of-field failures. Additional small series have demonstrated comparable rates of locoregional failure, further supporting routine use of IMRT in the postoperative setting [13].

4.2.5 Image-Guided Radiation Therapy

The ability to tailor dose delivery to irregularly shaped targets while achieving rapid dose falloff carries with it the responsibility of delivering the planned treatment accurately. Advances in dose delivery have paralleled advances in real-time imaging during radiation therapy.
A significant advance was made with the introduction of on-board imaging (Fig. 4.5). The acquired images can be compared side by side or overlaid with simulation planning images. The physician is capable of making real-time shifts of the patient’s position on the treatment table, immediately prior to the therapy being delivered (Fig. 4.6). This on-the-spot, physician-approved, verification process is known as image-guided radiation therapy (IGRT). More complex on-board imaging modalities are now available as well, including CT scans (Fig. 4.7), fluoroscopy, and fiducial-guided tumor/target tracking. These processes have become vital to the delivery of more complex, and higher dose-per-fraction treatments. A study looking at daily patient realignment data for head and neck treatment analyzed different IGRT protocols. When IGRT is used only 15–30 % of the time during treatment, errors of 3 mm or greater, and 5 mm or greater, are seen 50–60 % of the time and 26–31 % of the time, respectively [14]. While 3–5 mm may seem like a small and acceptable margin of error, these discrepancies are certainly of great clinical importance when high-dose regions are immediately adjacent to vital structures being spared (e.g., parotid glands, spinal cord) or targeted (e.g., tumors, elective nodal volumes). For this reason, it has become standard to use IGRT prior to treatment (with images verified by radiation therapists and intermittently approved by the treating physician), to allow planning margins to approach 3 mm. The delivery of complex treatments (e.g., IMRT) without accounting for daily setup errors has been suggested to have significant implications for accuracy [15].

Fig. 4.5

Modern linear accelerator with imaging arms extended (OBI). They are capable of obtaining X-rays vital for patient setup. By rotating 360°, the imaging arms are capable of producing a CT image set
Fig. 4.6

Left: digitally reconstructed radiograph generated from the simulation CT images. Right: X-ray film taken by the linear accelerator, with the patient in the treatment position. The two images are compared to ensure positional accuracy, and shifts are made in real time if necessary
Fig. 4.7

Functional comparison of CT scan acquired by linear accelerator and simulation-acquired CT scan. This process allows for three-dimensional shifts prior to treatment, a process known as IGRT

4.2.6 Stereotactic Body Radiation Therapy (SBRT)

With the ability to deliver radiation dose in an extremely conformal manner, and the capability to confidently verify patient positioning in real time, there has been interest in delivering larger doses per fraction, while reducing the total number of fractions. Much of this work has focused on tumor types that have suboptimal outcomes with fractionated therapy such as brain and lung cancers. Compared to brain and lung tumors, the outcomes of head and neck cancer treated by fractionated radiation therapy are quite high. Consequently, the head and neck SBRT literature is largely limited to patients with recurrent disease.
In a retrospective-matched cohort study, Heron et al. reported outcomes of 70 patients receiving SBRT for locally recurrent HNSCC (including nasopharynx, larynx, oral cavity, and oropharynx), with or without cetuximab. Patients received a median of 40 Gy in 5 fractions. Response rates were 63–77 %, and median duration of LC was 13–24 months. Local failure occurred in 50–60 % of cases. There were no grade 4–5 toxicities, and grade 3 toxicity was seen in only three patients [16]. A multi-intuitional, European phase II SBRT trial included inoperable recurrent HNSCC, or new primary HNSCC in a previously irradiated area. SBRT consisted of 36 Gy in 6 fractions, with concurrent cetuximab. Results demonstrated a 58 % response rate, 92 % disease control rate, and a 1-year OS rate of 48 %. One treatment-related death was attributed to hemorrhage and malnutrition [17].
As the technique thus far seems safe and relatively effective, its use as primary treatment has been attempted in certain populations. The largest series of this type comes from Kawaguchi et al., where 14 patients with HNSCC (5 oral cavity) were treated with SBRT. Dosing was 35–42 Gy, in 3 or 5 fractions. After a mean follow-up of 36 months, local control and overall survival rates were 71 % and 79 %, respectively [18]. Two smaller case series have reported similar results and also seem to suggest reasonable toxicity profiles [19, 20].

4.2.7 Experience Matters and Outcomes Are Improving

Evidence exists across all disciplines of medicine for improved patient outcomes in centers of excellence and for those who care for large volumes of patients. A matched pair analysis was performed seeking to determine if patients receiving adjuvant radiation therapy at an academic center fared better than their counterparts who received it in the community, all following curative resection at an academic center. The analysis revealed improved OS, DSS, and LRC for those who received their RT at the academic center. However, there were notable discrepancies between the groups. There was a higher percentage of never smokers in the group treated at academic centers, and those treated at non-academic centers received a lower total and fractional dose. On multivariate analysis accounting for these imbalances, the difference in OS remained significant [21]. Besides treatment location, prognoses have changed over time as well. A large retrospective study from seven international cancer centers revealed improved outcomes in OCSCC during the first decade of the new millennium, compared to the prior decade. Five-year OS improved from 59 to 70 %, despite the latter cohort having more advanced tumors, higher rate of distant metastases, and older age. This group also underwent selective neck dissection more often and, most notably, received adjuvant RT more often, reflecting the evolving treatment programs for OCSCC [22].

4.3 General Management Options with Radiotherapy in the Oral Cavity

4.3.1 Definitive Radiotherapy

A report from Sher et al. published in 2011 details the results of 42 patients treated with IMRT, either in the postoperative or definitive setting. Patients were treated between 2004 and 2009 and consisted of 12 % stage I, 24 % stage II, 33 % stage III, and 31 % stage IV. Thirty of 42 patients received surgery prior to radiotherapy. The remaining 12 received concurrent chemoradiotherapy (CRT), with or without induction chemotherapy. In this population, results from definitive RT were significantly inferior. Two-year OS was 85 % and 63 %, and LRC was 91 % and 64 %, for surgical vs. nonsurgical management, respectively [23]. A larger series assessing the impact of location of primary site within the oral cavity utilized definitive CRT alone. One hundred fifteen patients, staged IIIA, IVA, and IVB (6 %, 47 %, 47 %), received a median RT dose of 72 Gy. Response rate was 96.5 % (76.5 partial, 20 % complete). Overall, 3-year OS and PFS rates were 22 and 25 %. Interestingly, the 3-year PFS rates varied notably between subsites. Tumors of the buccal mucosa, FOM, and gingiva had a 3-year PFS of 51 %. Tumors of the retromolar trigone/hard palate and tongue/lip had significantly worse PFS, at 18 % and 6 %, respectively [24]. Cohen et al. retrospectively reviewed T4 OC tumors treated with definitive CRT on prospective protocols. Thirty-nine patients were reviewed and treated with a median 74 Gy. Results at 5 years of OS, PFS, and LC were 56 %, 51 %, and 75 %, respectively. The authors concluded that these were comparable results to historical controls and that primary CRT should be considered in this population [25]. Gore et al. retrospectively reported on 104 patients with advanced OCSCC treated with curative surgery or chemoradiation and found significantly improved survival in those treated with surgery [26].

4.3.2 Management of the Neck

Management of the elective nodal volumes in HNSCC is an important issue. Generally, structures of the oral cavity drain to bilateral lymphatics, with preferential involvement of certain levels [27]. There are exceptions, however, leading to instances in which unilateral neck radiation may be considered if the suspected contralateral failure rate is sufficiently low. This paradigm is well studied in the setting of the palatine tonsil [28, 29]. A small study assessing well-lateralized, early-stage OC tumors and tonsillar tumors following surgery revealed a 5 yr LRC of 100 % [30]. The best example of a well-lateralized structure within the oral cavity is the buccal mucosa. In a retrospective review of 145 patients receiving surgery and adjuvant RT, 83 % received unilateral neck RT. For all patients, the 5-year disease-specific survival (DSS) for stage I–IV was 87 %, 83 %, 61 %, and 60 %, respectively. There was no difference in LRC between patients who received unilateral vs. bilateral treatment (p = 0.95). The rate of failure within the contralateral neck was only 2.1 % [31]. Another retrospective review from Vergeer et al. assessed well-lateralized tumors of the oral cavity (oral tongue, FOM, alveolar process, buccal mucosa) and oropharynx. Sixty-one percent of those included had tumors of the gingiva or buccal mucosa. Eighty-three percent of patients had ipsilateral-only neck dissection. Contralateral neck failure occurred in 6 % of patients, and the only significant prognostic factor affecting contralateral neck failure was number of positive lymph nodes. Five-year rates of contralateral neck control were 99 %, 88 %, and 73 % in N0, N1 or N2a, and N2b cases, respectively. There was no significant difference in tumor subsite related to rate of contralateral neck failure [32].

4.3.3 Role of Altered Fractionation

Historically, radiotherapy has been fractionated in doses of 1.8–2.0 Gy/day, for a period of several weeks. This schema allowed dose escalation to the point of adequate tumor control, while taking advantage of normal tissue’s ability to self-repair in between fractions. This pattern of treatment is generally referred to as conventional fractionation. Various alternate regimens have been attempted.
The seminal American trial for altered fractionation in squamous cell carcinoma of the head and neck (HNSCC) was Radiation Therapy Oncology Group (RTOG) 90–03. This trial enrolled about 1100 locally advanced patients (stage II–IV) with tumors of the oral cavity, oropharynx, hypopharynx, and supraglottic larynx. OC patients represented just over 10 % of the enrollees. Patients were randomized to one of four arms: (1) standard fractionation at 2 Gy/fraction/day, 5 days/week, to 70 Gy over 7 weeks; (2) hyperfractionation at 1.2 Gy, twice daily, 5 days/week to 81.6 Gy over 7 weeks; (3) accelerated fractionation with split at 1.6 Gy/fraction, twice daily, 5 days/week to 67.2 Gy over 6 weeks, including a 2-week break after 38.4 Gy; or (4) accelerated fractionation with concomitant boost at 1.8 Gy/fraction/day, 5 days/week and 1.5 Gy/fraction/day to a boost field as a second daily treatment during the last 12 days to a total of 72 Gy over 6 weeks. The trial was initially reported in 2000 [33] and revealed improved locoregional control compared with standard fractionation. While there was a trend toward improved PFS in these groups, neither it nor OS was significantly improved. All three altered fractionation groups had significantly worse acute toxicity. Final results from the trial were published in 2014 and revealed that only hyperfractionation improved LRC (HR 0.79, p = 0.05) and OS (HR 0.81, p = 0.05) without increasing delayed toxicity [34]. Another large, phase III trial was conducted in multiple continents to compare accelerated fractionation to standard fractionation. Nine hundred patients with HNSCC of the larynx, pharynx, or oral cavity were enrolled (24 % oral cavity). Standard fractionation consisted of 66–70 Gy in 33–35 fractions, while accelerated fractionation was the same total dose, while receiving 6 fractions/week. Five-year LRC was 42 % vs. 30 %, favoring the accelerated group (p = 0.004) at the cost of significantly worse mucositis and skin reaction [35].
Regarding definitive management, concurrent chemotherapy and radiation have taken the forefront in advanced-stage disease of non-oral cavity subsites. Data suggests that modifying the fractionation style of radiation cannot compensate for the benefit that concurrent chemotherapy provides when it is required [36]. Currently, with chemotherapy, the usual radiotherapy fractionation is 5–6 fractions per week to a total dose between 66 and 72 Gy in 2–2.2 Gy daily fractions.
As surgery tends be the primary option for OCSCC, not definitive RT, altered fractionation is not as frequently discussed. There have been attempts to shorten the treatment time in the postoperative setting, however. The long-term results of small pilot study from Trotti et al. suggested that locoregional control could be improved with accelerated RT, consisting of 1.8 Gy per day in just over 5 weeks, using a concomitant boost approach. The total dose was 63 Gy, and patients received a second daily fraction once a week for the first 4 weeks, then on the final four treatment days. As expected, this approach did result in increased acute mucosal reactions, but did not affect rates of long-term toxicity [37]. Another small prospective study of accelerated RT following curative resection for HNSCC has been performed [38]. While thought provoking, these deviations from conventional fractionation have not garnered great support, and standard fractionation remains standard of care in the adjuvant setting.

4.3.4 Preoperative (Chemo)-Radiotherapy

RTOG 73–03 evaluated preoperative versus postoperative radiotherapy. It included 277 patients, and with 10-year median follow-up, LRC was significantly better in the postoperative population; however, there was no difference in survival [39]. This study established the postoperative treatment paradigm for HNSCC. A more modern series from Germany evaluated 151 patients specifically with OCSCC and N2 disease, who underwent either pre- or postoperative chemo-RT. They found an increased 5-year survival in those who received the therapy prior to surgery (46 % vs. 27 %, p = 0.035). When broken down by T-stage, the benefit was found to be confined to patients with T4 disease [40]. This series suggests a potential subgroup of patients who may benefit from neoadjuvant CRT, perhaps due to its ability to assist in curative resection with negative margins. This hypothesis is further supported by a retrospective study assessing pathologic response rate and effect on prognosis after neoadjuvant CRT. In this series of 154 patients, a clinical response rate of nearly 93 % and a pathologic complete response rate of 60 % were observed after a preoperative RT dose of only 40 Gy, together with platinum-based chemotherapy. After a complete clinical response, residual disease was found on dissection in only 8 % of cases, and only in levels IB-IIA. The authors suggest that neoadjuvant CRT might allow for a more tailored surgical intervention, perhaps avoiding multilevel selective neck dissection [41]. In a large literature-based meta-analysis of 2015 patients (predominantly stage III–IV), complete histopathological response was found in 48 %. After a number of analyses, the mean survival rates at 3 and 5 years were 73 and 57 % [42]. These are numbers that compare favorably to cohorts treated with postoperative therapy. It remains an attractive treatment approach; however, prospective randomized trials are required to firmly establish efficacy.

4.3.5 Induction Chemotherapy

Chemotherapy prior to definitive surgery for HNSCC (a.k.a. induction) has been studied for many years. Induction has also been studied extensively prior to definitive CRT in other cancers of the head and neck. This approach has many supporters and is backed by a wealth of hypothetical advantages. These facts aside, there is a lack of high-level evidence supporting the use of this modality. Large phase III trials have concluded the optimal regimen to be TPF (docetaxel, cisplatinum, 5-fluorouracil) [43, 44]. Recently, a phase III trial comparing induction chemotherapy followed by surgery to up-front surgery was reported in the OCSCC population. This trial randomized patients to two cycles of TPF followed by curative resection and postoperative RT vs. surgery and postoperative RT alone. Two hundred fifty-six patients were enrolled, and 222 completed the full course of treatment. Clinical response was 81 %. After a median of 30 months, there was no difference in OS or DFS. Again, clinical response was found to be predictive [45]. Induction chemotherapy prior to definitive surgery for OCSCC is not a recommendation from the National Comprehensive Cancer Network (NCCN) [46].

4.3.6 Repeat Irradiation

Locoregional recurrence represents a significant proportion of failures, and these are often in patients who have had prior radiation. Lee et al. have published their data on the subject, looking at 105 patients with recurrent HNSCC. Median RT dose was 59.4 Gy, and 2-year locoregional PFS and OS rates were 42 % and 37 %, respectively. The use of IMRT was found to be significant for decreasing LRF. Severe late complications were observed in 12 patients (11 %), which developed after a median of 6 months [47]. The RTOG conducted a prospective trial to assess the toxicity of re-irradiation with chemotherapy. There was a 7.6 % rate of grade 5 toxicity and an 18 % rate of grade 4 toxicity. Improved survival was seen in those who had an inter-treatment interval of greater than 1 year [48]. Comorbidity is also known to be a prognostic factor, as demonstrated by Tanvetyanon et al. who produced a nomogram, to predict probability of 24-month survival [49]. Despite the mentioned data, re-irradiation remains a high-risk venture, best left for clinical trials and experienced hands in high-volume centers.

4.4 Adjuvant Radiotherapy in the Oral Cavity

4.4.1 Paradigm Development and Indications for Adjuvant Treatment

Several studies have sought to define the tumor factors that portend high risk of recurrence and merit adjuvant radiation or chemoradiation therapy. In a prospective dose-finding trial from Peters et al., poor prognostic factors were identified in an attempt to tailor adjuvant RT dosing. Three hundred two patients with SCC of the oral cavity, oropharynx, hypopharynx, or larynx were enrolled, and 92 % had stage III–IV disease. Patients were stratified by risk group based on certain factors and randomized to one of three doses: 52.2 Gy, 63 Gy, or 68.4 Gy. Low risk could not receive the high dose and vice versa. Presumed risk factors for locoregional recurrence were drawn from prior reports and included site of disease, surgical margins, perineural invasion (PNI), number and location of involved lymph nodes, and presence of extracapsular extension (ECE). Patients receiving less than 54 Gy had higher primary failure rates. Only patients with ECE benefitted from a dose greater than 57.6 Gy, and ECE was a significant predictor of LRR. Other factors were found to confer increased risk when grouped in two or more. These included oral cavity primary, close/positive mucosal margins, PNI, 2 or more involved nodes, largest node greater than 3 cm, treatment delay greater than 3 weeks after surgery, and Eastern Cooperative Oncology Group (ECOG) performance status ≥2 [50]. A subsequent multi-institutional prospective trial that accrued between 1991 and 1995 enrolled 213 post-operative HNSCC patients. This trial aimed to validate the previously identified risk factors, while comparing conventional and accelerated RT in the adjuvant setting. Low-risk, intermediate-risk, and high-risk patients received no adjuvant treatment, 57.6 Gy and 63 Gy in either 5 or 7 weeks, respectively. Using the previously identified risk factors, patients were considered low risk if they had no adverse features, or intermediate risk if they had only one feature (excluding ECE). Anyone with ECE, or 2 or more other factors was considered high risk. Low- and intermediate-risk patients had a significantly improved LRC compared to high-risk patients, thereby validating the risk stratification. Notably, a decreased LRC rate was seen in high-risk patients experiencing a delay between surgery and the initiation of RT in the 7-week arm. Both LRC and OS were significantly worse in those who had RT initiated >6 weeks after the surgical date. Total treatment time of less than 11 weeks led to significantly improved outcomes [51].
The potential benefit of adding chemotherapy to further improve outcomes has also been studied. Two large phase III trials on this topic were accrued and published contemporaneously. EORTC (European Organization of Research and Treatment of Cancer) 22931 was a randomized trial that accrued 334 patients with SCC of the oral cavity, oropharynx, hypopharynx, or larynx. Eligible patients included those with T3–4 disease with negative margins, or early-stage disease with certain features (ECE, positive margins [defined as within 5 mm], PNI, lymphovascular invasion (LVI)). Oral cavity patients with nodal involvement of levels IV or V were included as well. Patients were randomized to RT with or without concomitant chemotherapy (cisplatin 100 mg/m2 every 21 days). At 5 years, LRC, PFS, and OS were all significantly improved with the addition of chemotherapy [52]. The second trial that ran in parallel was an American one, run by the RTOG. RTOG 95–01 randomized 416 patients with SCC of the oral cavity, oropharynx, larynx, or hypopharynx following gross total resection to RT alone, or RT with chemotherapy. Eligibility for this trial was slightly different and included patients with two or more lymph nodes, ECE, or positive surgical margins [defined at the inked margin]. The primary endpoint was LRC. At 2 years, LRC was significantly improved with chemotherapy (82 % vs. 72 %). DFS was also significantly improved; however, the improvement in OS did not reach statistical significance [53]. Given the substantial similarity between the two trials, a combined analysis was undertaken. This was published in 2005 and revealed that ECE and positive surgical margins were the only risk factors for which combined chemotherapy and RT provided benefit [54]. For this reason, these factors represent Category 1 indications from the NCCN (National Comprehensive Cancer Network) for the use of combined chemoradiotherapy [46]. The above data are summarized in Table 4.2.

Table 4.2

Important trials regarding adjuvant radiotherapy in HNSCC
# pts
% OC
Risk factors and inclusion
Tupchong et al. [39]
T2–4, any N
Preop RT
LRC 58 %
Helped establish postoperative RT as the treatment paradigm
Postop RT
LRC 70 % (SS)
Peters et al. [50]
Low: no risk factors
Int: 1 risk factor (non-ECE)
High: 2+ risk factors, or ECE
57.6 Gy
No dose response above 57.6 without ECE. With ECE, ≥63 Gy had improved response
Confirms proposed risk stratification
Factors include OC primary, close or positive margins, PNI, ≥2 LN, LN >3 cm, treatment delay >6 weeks, PS ≥ 2
63 Gy
68.4 Gy
Ang et al. [51]
Low risk
Significantly improved LRC in low and intermediate risk groups. Decreased LRC with treatment <11 weeks
Validates risk stratification. Highlights importance of total treatment package time following surgery
Intermediate risk
57.6 Gy
High risk
63 Gy/5 weeks
63 Gy/7 weeks
Bernier et al. [52]
Margins <5 mm, ECE, pT3-T4, LVI, PNI, OC/OP tumors with level IV/V LN
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Jun 24, 2017 | Posted by in Oral and Maxillofacial Surgery | Comments Off on Radiotherapy in the Management of Carcinoma of the Oral Cavity
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