INTRODUCTION — Patients with head and neck squamous cell carcinoma arising at certain sites (eg, larynx, oropharynx) can often be managed with surgical resection or with radiation therapy (RT) with or without chemotherapy, whereas other sites (eg, oral cavity, paranasal sinus) are traditionally treated surgically with or without adjuvant RT. Other treatment sites (nasopharyngeal cancer) are typically treated with a nonsurgical radiation-based approach. For patients with early stage disease (T1-2N0), radiation monotherapy is a standard alternative to surgery as a curative modality. In patients with locally advanced disease (T3-4, node positive), intensified RT or concurrent chemoradiotherapy is frequently used as a nonsurgical, organ-preserving alternative to resection.
In both earlier and more-advanced stages of disease, there are unique considerations regarding optimal radiation dosing, fractionation schedules, and timing of therapy for patients managed nonoperatively with definitive RT. These issues are reviewed here.
The principles of RT as applied to patients with head and neck cancer are presented separately. (See "General principles of radiation therapy for head and neck cancer".)
PATIENT SELECTION FOR DEFINITIVE RADIATION — Definitive radiation therapy (RT) alone remains a standard option for patients with stage I to II disease. A detailed presentation of selecting operative versus nonoperative therapy for early stage head and neck cancer is discussed elsewhere. (See "Treatment of early (stage I and II) head and neck cancer: The larynx" and "Treatment of early (stage I and II) head and neck cancer: The hypopharynx".)
In the locally advanced (stage III/IV) setting, single-modality definitive RT is also an appropriate option for selected patients. These include:
●Patients with a contraindication to platinum-based chemotherapy (eg, hearing loss, renal insufficiency, neuropathy, bone marrow disease). The use of RT plus cetuximab in this setting is discussed elsewhere. (See "Locally advanced squamous cell carcinoma of the head and neck: Approaches combining chemotherapy and radiation therapy", section on 'Cetuximab plus radiation therapy'.)
●Patients who refuse chemotherapy but still desire the locoregional control and possible survival benefits of RT.
●Patients who have a small absolute benefit from the addition of concurrent systemic therapy (eg, patients >70 years old or those with T1-2N1 disease, especially those that are p16+) or are at relatively higher risk of chemotherapy-related complications (eg, older age, poor social support, noncompliant).
Meta-analyses and large clinical trials have demonstrated the benefit of chemoradiotherapy compared with RT alone for patients with locally advanced but nonmetastatic (T3, T4, N2b, N2c, N3) squamous cell carcinoma of the head and neck. The data supporting chemoradiotherapy and its clinical usage are discussed separately. (See "Locally advanced squamous cell carcinoma of the head and neck: Approaches combining chemotherapy and radiation therapy".)
For patients with locally advanced human papillomavirus (HPV)-associated oropharyngeal tumors, treatment de-intensification, including reducing radiation dose, is an active area of investigation. This approach is not yet standard outside the context of a formal clinical trial. (See "Treatment of human papillomavirus associated oropharyngeal cancer", section on 'Is there a role for treatment deintensification?'.)
PARADIGMS OF DOSE AND FRACTIONATION MODIFICATION — Daily radiation therapy (RT) using a dose of 2 Gy to gross tumor on a five-days-per-week schedule to a total dose of 66 to 70 Gy in seven weeks is the standard treatment regimen for definitive treatment of head and neck cancer, but there is evidence that outcomes may be improved with alternative fractionation schedules in selected settings.
Alternative regimens are divided into three fundamental categories with distinct biologic objectives:
●Hypofractionation with or without dose modification – Hypofractionation implies using fewer fractions than conventional fractionation by increasing the daily radiation dose, typically leading to a lower total dose delivered. Increased daily doses can range from 2.2 Gy per fraction all the way up to 8.5 Gy per fraction in the case of stereotactic body radiation therapy (SBRT) of the head and neck. While SBRT is typically used in the reirradiation setting, studies are emerging that are evaluating its role in the upfront setting, either for early stage larynx cancer [1] or for patients who are too old or frail for a conventional protracted course of RT for more-advanced disease [2]. (See 'Hypofractionation' below and "Reirradiation for locally recurrent head and neck cancer", section on 'Stereotactic body radiation therapy'.)
Hypofractionation has most commonly been explored in earlier stage disease as a means of reducing the length of the treatment course and intensifying the biologic effectiveness of radiation. Although increasing the dose per fraction typically causes concern about an increased risk of late effects, the relatively smaller volumes of radiation in early stage disease and the lack of concurrent chemotherapy use have mitigated those concerns.
Finally, hypofractionation has also been used to deliver a boost after an initial course of conventional RT, with the goal of intensifying radiation and improving outcomes [3].
●Hyperfractionation with dose escalation – Hyperfractionation utilizes multiple daily treatments with smaller-than-conventional fraction sizes given over approximately the same treatment duration. Typical hyperfractionation schedules use 1.1 to 1.2 Gy per fraction, two fractions per day (with an interval of six hours or more between fractions), to total doses of 74 to 82 Gy. This regimen exploits the differential radiation sensitivity of tumors and late-reacting normal tissues, and allows for the delivery of a higher tumor dose without increasing the risk of severe long-term complications beyond those associated with standard fractionation. (See 'Hyperfractionation' below.)
●Accelerated fractionation with or without dose reduction – Accelerated fractionation administers the same or a slightly reduced total dose to tumor but over a shorter treatment course by giving multiple smaller doses (1.5 to 1.6 Gy) per day or giving additional standard-size doses (2 Gy) per week (eg, six or seven fractions versus five fractions per week). This approach attempts to reduce tumor repopulation during the course of RT, which is a known cause of RT failure. An older technique commonly used in the pre-intensity-modulated radiation therapy (IMRT) era was called "concomitant boost," in which 54 Gy was delivered in 30 fractions of 1.8 Gy once daily and a boost was given by a second RT plan directed to the gross disease only to a dose of 18 Gy in 12 fractions given as a second daily fraction. This technique is not commonly used in the IMRT era.
A more commonly used accelerated fractionation approach with IMRT is that of the Danish Head and Neck Cancer Group (DAHANCA), in which 70 Gy is delivered in 35 fractions, six fractions over five days per week over six weeks, using a single RT plan. A second plan in which a boost volume to sites of gross disease constitutes the sixth fraction can also be used. (See 'Accelerated fractionation RT' below.)
Early versus advanced stage disease — Hypofractionation has been studied primarily in early stage disease (eg, stage I to II) due to smaller treatment volumes and the lack of chemotherapy use. For patients with locally advanced disease (eg, stage III to IV), typical strategies of radiation intensification include hyperfractionation with dose escalation, and/or accelerated fractionation with or without dose modification. For locally advanced disease, the use of altered fractionation in the setting of RT alone significantly improves treatment outcomes; however, when RT is combined with chemotherapy, the survival benefit from altered fractionation is no longer present [4,5].
HYPOFRACTIONATION — Hypofractionation attempts to improve tumor control by increasing the biological effectiveness of the treatment by using higher daily doses of radiation. Because increasing the dose per fraction has been associated with increasing risks of late effects, this has primarily been used in earlier stage disease, where the treatment volume is relatively smaller and concurrent chemotherapy is not used.
Hypofractionation in early stage laryngeal cancer — Data supporting the use of hypofractionation comes from studies conducted in patients with early stage larynx cancer. The general treatment approach to these patients is discussed separately. (See "Treatment of early (stage I and II) head and neck cancer: The larynx".)
●A randomized Japanese trial compared the use of 2.25 Gy per fraction with the standard 2 Gy per fraction regimen in stage I glottis cancer [6]. Total dose was dependent on bulk; if less than or equal to two-thirds of a vocal cord was involved with cancer, then the standard dose of 60 Gy in 30 fractions was compared with 56.25 Gy in 25 fractions. Bulkier tumors were randomized between 66 Gy in 33 fractions and 63 Gy in 28 fractions. Overall, hypofractionation significantly improved local control rates compared with standard fractionation (92 versus 77 percent), without any impact on cause-specific survival. No significant differences were found in terms of rates of acute mucosal reaction, skin reactions, or chronic adverse reactions.
●A randomized Korean trial in 156 patients included both stage I and II patients and compared standard fractionation with hypofractionation plus dose escalation. Stage I patients were randomized between 60 Gy in 30 fractions (2 Gy per fraction) and 63 Gy in 28 fractions (2.25 Gy per fraction), while stage II patients were randomized between 66 Gy in 33 fractions (2 Gy per fraction) and 67.5 Gy in 30 fractions (2.25 Gy per fraction) [7]. The trial did not complete enrollment and was stopped early. Overall, there was no significant difference in the five-year larynx progression-free survival, which nominally favored the hypofractionation arms (77.8 versus 88.5 percent; p = 0.2). There was no increase in adverse effects, and the authors advocated the hypofractionated approach for its convenience and potential benefit.
This approach has become a standard for patients with early larynx cancer, with 63 Gy in 28 fractions commonly used for stage T1 cancers and 65.25 Gy in 29 fractions used for T2 cancers with mobile vocal cords [8]. The National Comprehensive Cancer Network (NCCN) guidelines recommend either conventionally fractionated RT (2 Gy per fraction to 66 to 70 Gy) or hypofractionated RT (2.25 Gy per fraction to 63 to 65.25 Gy) for early stage, node-negative (T1-2N0) glottic cancer.
A National Cancer Database (NCDB) study of over 10,000 patients with T1-2N0 larynx cancer treated with radiation therapy (RT) between 2004 and 2013 revealed that hypofractionated regimens were associated with improved overall survival (77 versus 74 percent). The survival difference is somewhat unexpected given the high rates of surgical salvage for these patients, and it may reflect unrecognized selection biases that cannot be further interrogated due to the lack of disease-specific outcomes data in the NCDB. Only 40 percent of patients were treated with hypofractionated regimens, but 60 percent were treated with hypofractionation in the final year of the study, indicating an increasing frequency of its use [9]. In another meta-analysis of 1762 patients with glottic carcinoma, hypofractionated RT was associated with reduced rates of local recurrence compared with conventional RT [10].
Observational data suggest that patients with less favorable subsets of stage II larynx cancer (ie, impaired cord mobility) may have high local failure rates with dose-escalated hypofractionated RT [11]. In select patients, concurrent chemotherapy may be an option to enhance larynx preservation, similar to those with T3 cancers [11]. We use this approach frequently in patients eligible for cisplatin-based chemotherapy. (See "Treatment of early (stage I and II) head and neck cancer: The larynx", section on 'Definitive chemoradiation'.)
Another commonly used hypofractionated regimen for radiation alone is 66 Gy in 30 fractions (2.2 Gy per fraction), which was tested in the Radiation Therapy Oncology Group (RTOG) 0022 trial in patients with T1-2N0-1 oropharyngeal cancer [12], which is commonly used for oropharyngeal cancer patients being treated with RT alone.
In patients with locally advanced head and neck cancer, hypofractionated RT has also been investigated in conjunction with concurrent cisplatin-based chemotherapy. One trial from Brazil of 20 patients treated with 55 Gy in 20 fractions with concurrent weekly cisplatin (35 mg/m2) has shown promising results with low rates of late effects [13]. Larger studies are needed with longer follow-up to validate these initial findings.
Stereotactic body radiation — Stereotactic body radiation therapy (SBRT) remains an investigational treatment approach in patients with early stage laryngeal cancer and older adults, irrespective of fractionation schedule.
SBRT has been studied in patients with early stage laryngeal cancer in several small early phase trials. As an example, one phase I clinical trial with 20 patients with Tis-T2N0 glottic cancer evaluated incrementally reduced fractions from 50 Gy in 15 fractions; to 45 Gy in 10 fractions; and finally, 42.5 Gy in five fractions [14]. The study showed favorable tumor control results (one-year local disease-free survival of 82 percent, overall) with a manageable toxicity profile. Similar outcomes were seen in a retrospective study of 12 older adults and medically frail patients with head and neck cancer receiving SBRT as primary treatment modality [2]. Longer follow-up is needed to verify the efficacy and safety of such an approach. Similarly, the risk of increased toxicity is underscored by the early termination of a phase I trial conducted in South Korean trial of SBRT in patients with T1-T2 laryngeal cancer. This trial demonstrated unacceptable rates of toxicity in their second dose cohort of 55 Gy in 11 fractions, including laryngeal ulceration and chondronecrosis requiring partial laryngectomy [15].
A hypofractionated SBRT boost after an initial course of conventionally fractionated RT has also been studied in patients with oropharyngeal tumors. This approach demonstrates good local tumor control but high toxicity rates, which will likely limit its use. As an example, in one retrospective study, 195 patients with T1 to low volume T3 oropharyngeal squamous cell carcinoma were treated with an SBRT boost of 16.5 Gy (5.5 Gy for three fractions) after an initial 46 Gy in 23 fractions [3]. In this study, at median follow-up of approximately four years, the five-year overall survival rate was 67 percent, which is lower than expected for conventionally fractionated regimens. The grade ≥3 late toxicity rate was 28 percent and included mucosal ulceration, dysphagia, and osteoradionecrosis as the most prominent late toxicities. This toxicity rate is relatively high for such patients who typically have human papillomavirus (HPV) associated disease and have a generally good prognosis. (See "Epidemiology, staging, and clinical presentation of human papillomavirus associated head and neck cancer", section on 'Oropharyngeal carcinoma'.)
HYPERFRACTIONATION — True hyperfractionation attempts to improve tumor control by using multiple smaller fractions per day to increase the total dose of radiation while maintaining a constant total treatment time and rate of late toxicity relative to conventional fractionation. Long-term toxicity to normal tissues depends in part upon the size of each treatment fraction, as well as the total radiation dose. Decreasing the size of each radiation fraction should permit higher total doses without increasing late morbidity compared with conventionally fractionated irradiation [16].
Clinical trial results — Hyperfractionation is now favored over concomitant boost as the intensified radiation therapy (RT) regimen of choice to exploit the tumor control benefits without significantly increasing late effects. This conclusion is supported by results from the largest trial (Radiation Therapy Oncology Group [RTOG] 9003) and the Meta-analysis of Radiotherapy in Carcinomas of the Head and Neck (MARCH).
RTOG 9003 — In the RTOG 9003 trial, 1076 patients with stage III/IV cancer of the head and neck were randomly assigned to one of four schedules of radiation without chemotherapy [16,17]:
●Standard fractionation (2 Gy per fraction per day, five days per week to 70 Gy)
●Hyperfractionation (1.2 Gy per fraction, twice daily, five days per week to 81.6 Gy)
●Split-course accelerated fractionation with a treatment break (AFX-S; twice daily fractions of 1.6 Gy, five days per week to 67.2 Gy in 42 fractions over six weeks, with a two-week break after 38.4 Gy)
●Concomitant-boost accelerated fractionation (AFX-C; 1.8 Gy/fraction per day, five days per week) without a treatment break but with a concurrent boost field (1.5 Gy per day) as a second daily treatment for the last 12 treatment days (total dose 72 Gy in 42 fractions over six weeks)
The primary endpoint of the trial was locoregional control of disease. An initial report at median follow-up of 23 months showed significant improvement in tumor control and a trend toward improvement in disease-free survival in the patients treated with hyperfractionation and AFX-C (groups 2 and 4) [16]. Final results of this trial were published in 2014 with a median follow-up of 14 years for surviving patients [17]. Locoregional failure occurred in 568 patients, 553 (97 percent) within the first five years. Overall, there were no significant differences in locoregional control or overall survival between the arms in long-term follow-up. There was a 19 percent reduction in locoregional failure for both the hyperfractionation and AFX-C arms relative to standard fractionation (hazard ratio [HR] 0.81, p = 0.08 for both), and the hyperfractionation arm had significantly improved locoregional control for those patients censored at five years (HR 0.79, p = 0.05). There was no statistically significant difference in the incidence of distant metastases or second malignancies.
Although hyperfractionation schedules result in improved locoregional disease control, this technique may be associated with an increase in late side effects. In the final report [17], the one-year feeding tube dependency rates for disease-free patients were significantly higher for all three experimental arms (hyperfractionation = 17.3 percent; AFX-S = 12 percent; AFX-C = 13.4 percent) compared with the standard fractionation arm (4.6 percent). However, there appeared to be continued recovery in these patients, leaving no statistically significant differences in these groups at five years post-therapy (standard fractionation = 8.3 percent; hyperfractionation = 4.8 percent; AFX-S = 4.8 percent; AFX-C = 13 percent). There were also no statistically significant differences in the incidence of grade 3 to 5 toxicity at five years between the arms; these data suggest that hyperfractionation may offer the best toxicity profile. (See 'Toxicity of hyperfractionated and accelerated RT' below.)
MARCH meta-analysis — The MARCH meta-analysis included individual patient data from 11,423 patients in 33 trials comparing altered fractionation with conventional fractionation, primarily in patients with stage III to IV disease treated without chemotherapy [18,19]. Altered fractionation was associated with a statistically significant improvement in overall survival, with an absolute benefit of 3.1 percent at five years (HR 0.94, 95% CI 0.90-0.98). The overall survival benefit associated with altered fractionation was limited to hyperfractionation (8.1 and 3.9 percent, respectively, at 5 and 10 years).
In subset analysis, the benefit from hyperfractionation decreased when age increased, but it was consistent across other subgroups. This age-related loss of benefit is also seen in meta-analysis data of the addition of concomitant chemotherapy to radiation, serving as a reminder that attempts to intensify treatment may be detrimental in the ill or older adult patient [20].
Optimal hyperfractionation: Dose and schedule — There are only limited data comparing different hyperfractionation schedules. Commonly used regimens, and what is used at our institution when indicated, are 79.2 Gy to 81.6 Gy without concurrent chemotherapy, and 74.4 Gy with concurrent chemotherapy [17,21,22]. We administer 1.2 Gy per fraction twice daily with a ≥6-hour interfraction interval.
The most extensive information comes from a trial (RTOG 8313) in which 479 patients with inoperable head and neck cancer were randomly assigned to different hyperfractionation doses, ranging from 67.2 to 81.6 Gy in twice-daily 1.2 Gy fractions, with intertreatment intervals of four to eight hours [23]. The majority of patients in this trial were treated for stage III or IV disease.
Local control at two years was higher for hyperfractionated doses of 72 to 81.6 Gy as compared with 67.2 Gy (43 to 45 versus 25 percent), but there was no difference in survival among the groups. There was no apparent dose-response relationship for late effects over the range of 67.2 to 81.6 Gy [24]. However, there was a difference when the interinterval duration was considered. Estimates of late toxicity were significantly higher for intervals of 4.5 hours or less (5.5, 9.8, and 15.4 percent at one, two, and three years, respectively versus 1.7 percent for all three periods with intervals longer than 4.5 hours). However, the applicability of these data to contemporary patients is limited, as these studies were conducted in the era prior to IMRT and included predominantly HPV negative patients.
Concurrent chemoradiotherapy using hyperfractionated RT — The administration of concurrent chemotherapy results in improved efficacy compared with hyperfractionated RT given without chemotherapy [25-28]. However, the benefit of dose-escalated hyperfractionated RT is unclear in the presence of cisplatin-based chemotherapy. As an example, in one trial, 116 patients with head and neck cancer were randomly assigned to hyperfractionated RT either alone or with fluorouracil and cisplatin [25]. The RT alone group received 1.25 Gy twice daily for a total of 75 Gy, while the chemoradiotherapy group received 1.25 Gy twice daily for a total of 70 Gy. At three years, chemoradiotherapy was associated with significantly higher rates of locoregional control (70 versus 44 percent), as well as a trend toward better relapse-free survival (61 versus 41 percent) and overall survival (55 versus 34 percent). The incidence of late toxicity was similar in both groups.
ACCELERATED FRACTIONATION RT — Accelerated fractionation attempts to reduce tumor repopulation as a prominent cause of radiation therapy (RT) failure by decreasing the total time over which the radiation is administered. This can be accomplished either by using the same or a slightly reduced fraction size and administering treatments more frequently while keeping the total dose the same or reducing it slightly, or by changing other parameters (eg, fraction size, interval between treatments).
Clinical trial results — The concept of accelerated RT has been evaluated in multiple randomized trials, which have used different dose-fractionation schedules.
In Radiation Therapy Oncology Group (RTOG) 9003, the concomitant-boost arm demonstrated superior locoregional control in initial reports, although this finding did not retain statistical significance on long-term follow-up [16,17]. Importantly, it also clarified that accelerated treatment using split courses of RT [29-33] or reduced total doses [30,34,35] does not improve locoregional tumor control or overall survival. (See 'RTOG 9003' above.)
Accelerated regimens that employ continuous rather than split-course schedules without decreasing the total dose of radiation do appear to improve local control [16,36,37]. The impact of this approach on overall survival is uncertain, with only one trial demonstrating a survival benefit:
●In the Danish Head and Neck Cancer Group (DAHANCA) 6 trial, 694 patients with glottic squamous cell carcinoma (86 percent with T1 and T2 tumors) were randomly assigned to RT using either a six-day-per-week or five-day-per-week schedule [38]. The cumulative incidence of locoregional failure was significantly reduced using accelerated fractionation compared with a five-day-per-week schedule (21.6 versus 29.3 percent). However, there were no statistically significant differences in overall survival, and acute toxicity was more pronounced in the accelerated RT group. There was a trend toward less-frequent laryngectomy in the six- versus five-day groups (hazard ratio [HR] 0.72, 95% CI 0.50-1.04).
●In a Polish trial of mostly 100 patients (82 percent with T3 and T4 tumors), patients were randomly assigned to continuous accelerated irradiation (seven days per week) or to conventional RT (five days per week), both to a total dose of 66 to 72 Gy [37]. The five-year local tumor control and overall survival rates were better with continuous accelerated irradiation (75 versus 33 and 62 versus 20 percent, respectively). That group subsequently randomized 345 patients to either the seven-day-per-week regimen or adding a second daily fraction twice weekly. They found both approaches to yield equivalent 5- and 10-year locoregional control (60 percent), overall survival, and severe late toxicity (6 percent) [39].
Concurrent chemoradiotherapy using accelerated RT — Chemoradiotherapy using accelerated RT does not appear to be superior to chemoradiotherapy using conventional fractionation of the RT [4,5]:
●In a French study [4], no significant differences were seen between the two arms, each containing carboplatin and fluorouracil, and the two radiation arms containing either standard-fractionation RT or accelerated RT with a concomitant boost.
●The RTOG 0129 trial compared standard-fractionation RT along with cisplatin 100 mg/m2 on days 1, 22, and 43 versus accelerated-fractionation RT with a concomitant boost and the same dose of cisplatin given concurrently on days 1 and 22. There was no difference in the eight-year rate of survival (48 percent with both regimens, HR 0.96, 95% CI 0.79-1.18); there were also no significant differences in progression-free survival, locoregional failure, or rate of distant metastases [40].
While more contemporary RTOG studies (eg, RTOG 1016) have incorporated accelerated RT (six fractions weekly based on the DAHANCA regimen discussed above) in the setting of concurrent chemotherapy, once-daily regimens are becoming the standard approach in upcoming NRG Oncology trials that incorporate systemic therapy [41].
TOXICITY OF HYPERFRACTIONATED AND ACCELERATED RT — There is a well-established tradeoff between the increased efficacy of altered radiation therapy (RT) fractionation and the associated increasing morbidity with such approaches. Virtually every randomized study has reported a statistically significant increase in grade 3 acute effects with altered fractionation.
●In Radiation Therapy Oncology Group (RTOG) 9003, both the hyperfractionated arm (54 percent) and concomitant boost arm (58 percent) had higher rates of grade 3 acute effects than the conventional arm (35 percent) [16].
●In the Polish randomized study, confluent mucositis was significantly more common (94 versus 53 percent), more severe, and more prolonged with the continuous schedule compared with five-day-per-week fractionation [37].
●In the Danish Head and Neck Cancer Group (DAHANCA) 6 and 7 randomized trials, delivering six fractions weekly for weeks 2 to 6 was associated with significant increases in the use of analgesics, dysphagia, and mucositis [42].
●A more recent, sophisticated analysis of toxicity that examined head and neck symptom clustering in patients treated on RTOG 0129 with either conventional or concomitant-boost RT (in conjunction with concurrent cisplatin) found that the concomitant-boost RT group had significantly higher rates of mucositis, pain, and nausea at three months after the initiation of RT than the conventional arm [43].
Despite the increases in acute effects with altered RT fractionation schemes, these effects typically resolve. Increased late effects are rarely reported as a consequence of altered RT fractionation. One notable exception is the concomitant-boost technique, which was associated with a significant increase in feeding tube use in patients disease free at five years in the RTOG 9003 update [17]. Additionally, in a phase III randomized trial (GORTEC 99-02), compared with conventionally fractionated RT with concurrent chemotherapy, very accelerated RT worsened progression-free and overall survival and had higher rates of both acute (70 versus 60 percent) and long-term feeding tube dependency at five years (25 versus 13 percent) [4]. Further details of this trial are discussed separately. (See "Locally advanced squamous cell carcinoma of the head and neck: Approaches combining chemotherapy and radiation therapy", section on 'Radiation therapy schedule' and "Management and prevention of complications during initial treatment of head and neck cancer", section on 'Highly conformal RT technique'.)
Importantly, all of these data derived from trials conducted before the routine use of intensity-modulated radiation therapy (IMRT), which has been shown in multiple studies to reduce acute and late morbidity in head and neck cancer patients [44]. The widespread use of IMRT may widen the therapeutic index of altered fractionation in this setting.
COST AND CONVENIENCE — There are substantial logistical and cost differences in these varied altered fractionation strategies, which should be taken into account. While the data from Radiation Therapy Oncology Group (RTOG) 9003 and the Meta-analysis of Radiotherapy in Carcinomas of the Head and Neck (MARCH) favor hyperfractionation as the approach of choice for intensified radiation therapy, hyperfractionation is certainly the most costly, resource- and time-intensive, and inconvenient regimen. As such, accelerated fractionation schemes such as six fractions weekly have gained favor in recent years as they are less costly and more convenient for patients. If hyperfractionation is not feasible for a particular patient, this accelerated fractionation regimen may be preferable to the concomitant-boost approach as the latter has been associated with increasing late effects.
SIMULTANEOUS INTEGRATED BOOST TECHNIQUE WITH IMRT — With the advent of intensity-modulated radiation therapy (IMRT) and its widespread adoption in the treatment of locally advanced head and neck cancer, the ability to focally increase the dose per fraction to the tumor itself while maintaining lower doses to elective areas of interest has gained in popularity as a means of radiation therapy (RT) intensification. This has been studied most closely in the nasopharyngeal cancer setting, where the Radiation Therapy Oncology Group (RTOG) 0225 and 0615 trials used a regimen of 70 Gy in 33 fractions using 2.12 Gy per fraction. More recent results of this approach reveal excellent locoregional control and favorable toxicity profiles [45].
Several institutions use this regimen as a standard, with or without chemotherapy. This slightly hypofractionated regimen has never been systematically compared with the hyperfractionated or accelerated strategies described above, nor has it been compared with other IMRT techniques such as sequential boost.
ELECTIVE DOSE CONSIDERATIONS — In addition to the high doses delivered to gross disease in conventionally fractionated radiation for head and neck cancer, two standard paradigms are used to target areas at risk of microscopic disease (eg, uninvolved nodal levels) in a simultaneous integrated fashion.
●The first paradigm includes all microscopic disease targets to a single dose, typically 56 Gy in 35 fractions (1.6 Gy per fraction).
●The second paradigm allows for a third, intermediate-dose level, typically 63 Gy in 35 fractions (1.8 Gy per fraction) to higher-risk areas that potentially harbor a higher burden of subclinical disease, albeit still radiographically occult (eg, the entire nodal level in which there are some macroscopically involved nodes).
While many head and neck cancer protocols allow for either approach, we favor avoiding the intermediate-dose level because it adds planning complexity and increased dose to organs at risk, without any evidence of improved disease control.
Deintensification of the total elective radiation dose for more favorable disease (eg, stage I human papillomavirus (HPV) associated oropharyngeal cancer) is being investigated [46]. (See "Treatment of human papillomavirus associated oropharyngeal cancer", section on 'Dose-reduced definitive radiation'.)
MANAGEMENT OF THE NECK AFTER RT — The management of the neck after completion of radiation therapy for patients who have an incomplete response or evidence of residual disease is an evolving area; this is discussed separately. (See "Management of the neck following definitive radiotherapy with or without chemoradiotherapy in head and neck squamous cell carcinoma".)
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Head and neck cancer".)
SUMMARY AND RECOMMENDATIONS
●Definitive radiation therapy (RT) is a standard treatment approach for appropriately selected early stage head and neck cancer.
•In patients with early larynx cancers, hypofractionated regimens (eg, using 2.2 to 2.25 Gy per fraction) have been shown to be safe and effective and appear to offer superior local control and enhanced convenience compared with conventionally (eg, 2 Gy per fraction) fractionated regimens. (See 'Hypofractionation' above and "Treatment of early (stage I and II) head and neck cancer: The larynx".)
•The use of SBRT is investigational for patients with early stage larynx cancer, as well as for definitive treatment in older adults and medically frail patients. (See 'Stereotactic body radiation' above.)
●In locally advanced (eg, stage III to IV) disease, radiation, usually administered with concurrent platinum-based chemotherapy, is the treatment of choice for patients with potentially resectable locoregionally advanced head and neck cancer who desire nonsurgical organ preservation and for those who have surgically unresectable disease. In the setting of concurrent chemotherapy, once-a-day fractionated RT is standard. (See "Locally advanced squamous cell carcinoma of the head and neck: Approaches combining chemotherapy and radiation therapy".)
●There are patients with stage III/IV disease who can be appropriately managed with RT alone. These include patients with a contraindication to platinum-based chemotherapy, those who refuse chemotherapy, and those who may have a small absolute benefit from the addition of concurrent systemic therapy (eg, patients >70 years old or those with T1-2N1-2a disease, especially those that are p16 positive) and may be at relatively higher risk of chemotherapy-related complications (eg, older age, poor social support, noncompliance). (See 'Patient selection for definitive radiation' above.)
●The relative benefits of hyperfractionation and accelerated fractionation need to be balanced against the increased cost and inconvenience with which these approaches are associated. For patients who are treated with RT alone, we suggest either a hyperfractionated schedule or an accelerated schedule (Grade 2B). These approaches improve locoregional control and overall survival compared with standard fractionation. The optimal hyperfractionated schedule is uncertain; our approach is to use a dose of 79.2 to 81.6 Gy with 1.2 Gy per fraction with an interval of six hours or more between fractions in the absence of chemotherapy, and 74.4 Gy in conjunction with chemotherapy. (See 'Hyperfractionation' above and 'Optimal hyperfractionation: Dose and schedule' above.)
•Patients for whom hyperfractionation is not logistically feasible appear to benefit from accelerated RT strategies, such as six fractions weekly, as an alternative method of intensifying RT efficacy without significantly increasing the risk of late toxicity. While the survival advantages seen in some trials may not be evident in the Meta-analysis of Radiotherapy in Carcinomas of the Head and Neck (MARCH) meta-analysis, improved locoregional control is an important endpoint in these patients that justifiably influences the choice of RT regimen. However, accelerated regimens using split courses of RT or reduced total doses do not improve locoregional tumor control or overall survival. (See 'Accelerated fractionation RT' above.)
•Hyperfractionation and standard-dose continuous-course accelerated RT increase the incidence of clinically significant acute effects, including mucositis, edema, and pain. While late effects can also be higher with these regimens, these differences may abate over time. (See 'Toxicity of hyperfractionated and accelerated RT' above.)
•A conventional treatment regimen using a total dose of 70 Gy over seven weeks, given as a single fraction (2 Gy) once daily, five days per week, with 50 to 60 Gy targeting of elective areas, is a reasonable alternative to hyperfractionation or an accelerated treatment approach. (See 'Paradigms of dose and fractionation modification' above.)
●Newer treatment technologies (intensity-modulated RT and image-guided RT) can improve sparing of normal tissues and, thus, potentially increase the daily tumor dose without an increase in normal tissue toxicity. Using these techniques, many RT centers have increased their daily dose range to 2.1 to 2.2 Gy per day. (See "General principles of radiation therapy for head and neck cancer".)
ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Shiyu Song, MD, and Wendy Hara, MD, who contributed to an earlier version of this topic review.
