General principles of radiation therapy for head and neck cancer

INTRODUCTION — Radiation therapy (RT) is an important and potentially curative modality for head and neck cancers. For many primary sites within the head and neck, RT yields better functional outcomes than surgery and, thus, is often preferred for localized disease. For locoregionally advanced lesions, RT is often used in combination with chemotherapy as a definitive organ function-preserving approach, or after surgery as an adjuvant.

The general principles of RT for head and neck squamous cell carcinoma will be reviewed here. The approach to dose and schedule for definitive RT of head and neck cancer is discussed separately. (See "Definitive radiation therapy for head and neck cancer: Dose and fractionation considerations".)

GENERAL PRINCIPLES — Ionizing radiation produces its biologic effects by imparting energy to tissues. Free radicals are generated, which cause single-strand and double-strand DNA breaks and loss of cellular reproductive ability.

Some cells die relatively rapidly through apoptosis. However, most cells do not manifest evidence of damage until mitosis occurs, and several divisions may ensue before actual cell death (termed mitotic cell death). The cellular doubling time (typically three to five days for head and neck cancer) also influences the rapidity with which a tumor shrinks. For this reason, most tumors do not show immediate shrinkage after starting RT. While radioresponsive tumors start to shrink in a few days, most head and neck cancers may take weeks or longer to shrink. Some low-grade, slowly proliferating tumors histologically appear to be viable for prolonged periods after irradiation.

The radiation dose is measured in Gray (Gy), which is defined as the absorption of 1 joule of energy per kilogram of matter (water or human tissue). One Gy is equivalent to 100 centigray (cGy) or 100 rad (the formerly used unit of measure). As the radiation beam passes through tissue, its energy is absorbed; the higher the energy of the beam (expressed as megavoltage [MV]), the deeper it penetrates. The depth of tumor in the head and neck area is relatively shallow compared with many other visceral organs. Thus, the energy of the beam used for head and neck cancer treatment is usually lower compared with other visceral sites.

RT for head and neck cancers can be administered by an external beam source or, rarely, by brachytherapy using either interstitial implants or intracavitary techniques. The choice of technique depends upon the site of a tumor and the goal of therapy.

EXTERNAL BEAM RADIATION THERAPY — Most head and neck cancers are treated with external beam radiation therapy (EBRT). The most commonly used forms of ionizing radiation are high-energy photons (ie, x-rays) and electrons, both of which are produced by linear accelerators. The beam energy and choice of photons versus electrons are based upon the location of the tumor and its target volume. Electrons are most commonly used to treat skin cancers and other superficial malignancies. (See "Radiation therapy techniques in cancer treatment".)

Linear accelerators — Photons are usually generated by a linear accelerator, which uses high-frequency electromagnetic waves to accelerate electrons to high energy. The electron beam strikes a tungsten target in the machine. This collision produces the high-energy photon beam that is used to treat deep-seated tumors. Alternatively, by moving the tungsten target out of the beam path, the electron beam itself may be used to treat superficial tumors.

●Photons – Photons with energy in the megavoltage (MV) range exhibit important skin-sparing effects. With increasing energy, the maximum tissue dose occurs at a greater depth. In the head and neck region, where tumors are relatively shallow as compared with other areas, such as the chest or abdomen, photons with low energies (typically in the 4 to 6 MV range) are used. All photon beams in the MV range have "skin-sparing" effects, as the maximal dose is delivered to an area deeper in the tissue. To treat more superficial lesions, a material with similar density to tissue (called "bolus") can be placed directly on the skin surface. Commercial gel-like bolus materials in different thicknesses are available. Sometimes other materials, such as wet gauze, can also be used as bolus. The use of bolus, the thickness of which is calculated according to the depth of the targets, helps to bring the dose distribution closer to skin so that superficial tumor targets receive an adequate dose.

●Electrons – Electrons with energies between 5 and 22 MV are available on most linear accelerators. Electrons lose energy on their path in tissues more quickly than photons and can only reach a certain depth depending on their initial energy. Organs beyond their reach can be spared while the tumors within their reach get sufficient doses. This characteristic may be exploited when the treatment targets are superficial or there are critical structures deeper to the treatment targets.

As an example, electron beam therapy may be used to treat skin cancers where a concentrated superficial dose is desirable. Bolus (eg, tissue equivalent material) is often used to increase the skin dose by allowing for dose buildup prior to reaching the skin surface.

Imaging for treatment planning and setup — Image-based determination of the location of the tumor and its relationship to normal structures is critical for RT planning. Advances in imaging technology have facilitated advances in RT treatment techniques.

Advanced imaging technologies are required for three-dimensional conformal radiation therapy (3D-CRT) and intensity-modulated radiation therapy (IMRT) techniques.

●A treatment-planning computed tomography (CT) scan is performed prior to therapy with the patient immobilized in the same position as will be employed for actual treatment. Ideally, intravenous (IV) contrast enhancement should be performed with a planning CT scan in order to optimally delineate the size and location of all tumor target volumes. The planning scan accurately determines the tumor volume as well as the relationship of the tumor to normal anatomic structures in three dimensions. Typically, scan slice thickness should be 2 to 3 mm. A slice thickness of 1 mm is preferable for delineation of cranial nerves and at the skull base.

●Magnetic resonance imaging (MRI) is often useful as an adjunct to the planning CT to help delineate the relevant tumor and normal tissue anatomy. It is particularly crucial for nasopharyngeal and skull-based tumors to help determine tumor extent, cranial nerve involvement, cavernous sinus involvement, as well as extent of bone involvement. Fast imaging employing steady-state acquisition (FIESTA) or constructive interference steady state (CISS) T2 sequences can be helpful to visualize intracranial cranial nerves. Thin-cut (1 to 2 mm), fat-saturated, contrast-enhanced axial and coronal images, as well as thin-cut, non-fat-saturated T1 images (for bone involvement), are also critical to evaluating the skull base.

●Fluorodeoxyglucose (FDG) positron emission tomography (PET)/CT is commonly used to determine tumor extent and can be fused to the planning CT scan. In addition to its value in ruling out distant metastases, PET/CT has also increased the sensitivity of detecting involved lymph nodes that were apparently normal on CT alone. Many centers are using PET/CT or MRI/CT simulators for RT planning to obtain the imaging in treatment positioning and to decrease the error and distortion of image fusion. New PET tracers are being investigated that may be more particularly useful for head and neck tumors. (See "Overview of the diagnosis and staging of head and neck cancer", section on 'PET and integrated PET/CT'.)

During the actual treatment, patients are aligned by comparing bony structures on the CT scan with kilovoltage radiation (x-rays) taken on a linear accelerator. Kilovoltage radiation produces much sharper images and has replaced the MV radiation (portal films) formerly used.

Cone beam CT scanners have been incorporated into linear accelerators, which produce three-dimensional images of the treatment area, including not only bony structures, but also some soft tissue organs. This enables even more precise image-guided patient localization prior to each treatment. (See 'Image-guided RT' below.)

Three-dimensional conformal RT — The current minimum standard for delivery of RT to head and neck cancer is 3D-CRT.

With 3D-CRT, the anatomic relationship between the patient's tumor and normal anatomy is used to deliver a radiation dose that conforms to the target volume and minimizes exposure to other structures. 3D-CRT requires a precise definition of anatomy, a sophisticated treatment planning system that can calculate the dose in three dimensions, and a treatment device that can deliver the specified dose.

Intensity-modulated RT — IMRT, an advanced form of 3D-CRT, is indicated for the treatment of head and neck cancers. IMRT uses nonuniform radiation beam intensities to maximize the delivery of radiation to the planned target volume while minimizing irradiation of normal tissue outside the target. IMRT represents best practice in the United States and has supplanted older treatment techniques for head and neck cancer despite theoretical concerns about the dose inhomogeneity, the additional time required for planning computation and quality assurance verification, and the exposure of larger volumes of normal tissues to a lower dose [1].

Randomized studies demonstrate that IMRT can reduce side effects (particularly xerostomia) in comparison with older three-dimensional conformal techniques, even in the setting of concurrent chemotherapy. The benefit of IMRT in preventing xerostomia was demonstrated in the PARSPORT trial and others [2-4]. In addition, the improved ability to deliver more conformal RT while still sparing normal organs may also improve tumor-related outcomes in some head and neck cancer patients with tumors of the paranasal sinus or nasopharynx, although data are limited [5,6]. (See "Management and prevention of complications during initial treatment of head and neck cancer", section on 'Highly conformal RT technique'.)

Studies are evaluating ways to further refine IMRT techniques. Dysphagia-optimized IMRT (DO-IMRT) decreases the amount of radiation to the pharyngeal muscles. As an example, in a randomized trial in patients with oropharyngeal and hypopharyngeal cancers, DO-IMRT improved dysphagia relative to standard IMRT, according to a patient-administered questionnaire [7]. Although the improvement was less than the predefined threshold for clinical significance, the difference is still likely clinically meaningful based on prior studies and the UpToDate contributors' experience [8]. There was no difference in the time to recurrence in either group. Additional data, including long-term follow-up of clinical trials, are needed to determine the optimal method of administering DO-IMRT.

The delivery of each IMRT dose to the tumor has become much faster with the introduction of volumetric modulated arc therapy (VMAT), where the gantry moves around the patient as the beam is being modulated. Typically, IMRT plans require 20 to 25 minutes for delivery of the daily treatment, while a VMAT plan can now be delivered in approximately three to five minutes (approximately 1.5 minutes per gantry rotational arc), which is easier for patients. There are emerging data that demonstrate superior normal tissue avoidance with VMAT-based techniques compared with step-and-shoot IMRT techniques [9].

The development and use of new planning tools and software have made the planning process much faster and more efficient. Due to the fact that IMRT intentionally introduces dose inhomogeneity between target and normal tissues, an IMRT treatment plan needs to be carefully reviewed by treating clinicians, and a strict and vigorous quality assurance process is performed before treatment starts. Importantly, optimizing normal tissue sparing is tumor and anatomy dependent, and clinicians should try to achieve doses that are as low as possible on a case-by-case basis rather than rely on static dose constraint recommendations found in guidelines or protocols [10]. Subsequent studies have investigated the use of artificial intelligence to optimize dose constraints for IMRT planning [11]. (See "Radiation therapy techniques in cancer treatment", section on 'Intensity-modulated radiation therapy'.)

The importance of adequate experience with IMRT techniques was evidenced by a retrospective analysis that analyzed outcomes as a function of case volume at treatment centers. In a study from the Surveillance, Epidemiology, and End Results (SEER)-Medicare database, there was a significant decrease in all-cause mortality at high-volume compared with low-volume treatment centers (median overall survival 2.5 versus 2.8 years, hazard ratio [HR] 0.79, 95% CI 0.67-0.94 for every five additional patients treated per year) [12].

Image-guided RT — Image-guided radiation therapy (IGRT) is a technique that complements IMRT in that enhanced pretreatment imaging on a daily basis allows for reduction of the margins needed to ensure that the target is accurately treated despite daily tumor motion and setup error. In many cancer centers, IGRT is used routinely for head and neck cancer patients.

Daily patient positioning errors that range from 3 to 10 mm can occur during RT [13,14]. To compensate for these errors, a safety margin of 2 to 5 mm of normal tissue is included in the treatment volume so that the tumor will not be underdosed. A corollary to this increase in target volume is that more normal tissue is exposed to the high-dose region, which can significantly increase toxicity.

IGRT utilizes high-resolution on-board imaging to guide radiation delivery immediately prior to each radiation treatment, not just during the treatment-planning process. These techniques include onboard kilovoltage radiation imaging and cone beam CT scan. This allows smaller margins (2 to 5 mm) to account for day-to-day differences in positioning. Small changes in patient positioning can be adjusted from the treatment console. Most treatment couches can make small translational shifts, and some of the newer machines can also compensate for rotational shifts (6D couch).

Image-guided adaptive radiation therapy — Image-guided adaptive radiation therapy, a further refinement of IGRT, allows for adjustment of the radiation treatment plan according to tumor size changes or normal organ shift during the course of the six to seven weeks of treatment [15].

Adaptive replanning can be used to improve accuracy of treatment delivery when there has been significant anatomic change secondary to patient weight loss, tumor shrinkage, or normal tissue change [16-18]. Thus, the relative locations of the tumor and normal organs may change during treatment; as a consequence, more normal tissue may be treated with an excessive dose during the later course of the radiation treatment. For example, the salivary glands often shift medially during the course of treatment, and adapting the RT plan could potentially improve salivary sparing [19]. Treatment replanning may be particularly important for patients with dramatic tumor shrinkage or significant weight loss during their RT course [20]. Some studies also suggest a potential advantage in avoiding underdosing of tumor targets by adaptive replanning [21]. With improvements in online cone beam CT imaging quality and AI based replanning programs, daily adaptive replanning is a promising investigational strategy [22].

For patients receiving induction chemotherapy prior to RT, treatment simulation is often carried out prior to chemotherapy in order to determine the initial extent of disease. Simulation is carried out again after induction in the same treatment position. Both image sets are used in conjunction with a physical exam to delineate treatment volumes so that all areas of initial tumor extent can be targeted [20]. (See "Locally advanced squamous cell carcinoma of the head and neck: Approaches combining chemotherapy and radiation therapy".)

Stereotactic body radiation therapy — Large doses of RT given over one to five fractions to limited targets is called stereotactic body radiation therapy (SBRT) or stereotactic ablative body radiation therapy (SABR). This approach has yielded good local tumor control in a variety of tumor settings. (See "Radiation therapy techniques in cancer treatment", section on 'Stereotactic radiation therapy techniques'.)

Using SBRT, only the gross tumor is generally targeted without prophylactic nodal irradiation. The treatment is more effective for smaller tumors and is generally well tolerated because of the smaller treatment volume. The treatment can be delivered on most modern machines with IGRT capability but requires special quality assurance and machine calibration.

SBRT can be particularly useful for patients with recurrent head and neck tumors who have had prior RT, where further conventional RT is limited [23]. Also, the short one- to two-week course of treatment may be attractive for patients with an overall poor prognosis. The addition of a systemic agent such as cetuximab to these treatments may also improve local control rates [24]. A more recent multi-institutional study of SBRT demonstrated comparable efficacy to and superior safety over IMRT-based reirradiation in a subset of patients undergoing reirradiation [25].

Charged particle radiation — Heavy charged particles, such as protons or carbon ions, are being increasingly used for head and neck cancers, particularly those requiring high doses adjacent to critical organs at risk, such as the skull base, or in the reirradiation setting.

For well-defined and relatively small lesions, proton therapy provides better dosimetric sparing of normal organs or structures [26,27]. Whether this dosimetric advantage translates into clinical benefit for patients is currently unknown. There are also significant uncertainties about the biologic effectiveness of these particles as well as the accuracy of predicting dose deposition.

A randomized clinical trial comparing IMRT with intensity-modulated proton therapy (IMPT) for patients with oropharynx and oral cavity tumors has completed accrual and is awaiting results (NCT01893307). An analysis of a subset of patients in this trial demonstrated that IMPT was associated with improved work and productivity recovery trends compared with IMRT (78 versus 52 percent of patients back to work at two years posttreatment, respectively) [28]. Some studies suggest IMPT may be associated with an increase in late toxicity, although there is conflicting data on this question [29,30]. Additional long term research is needed to answer this question. (See "Radiation therapy techniques in cancer treatment", section on 'Particle therapy' and "Overview of the treatment of locoregionally advanced head and neck cancer: The oropharynx", section on 'Radiation schedule and technique'.)

Other particle beams, such as carbon ions, are being investigated in other indications (eg, for salivary gland tumors) [31].

Spatially fractionated radiation therapy — The principle of spatially fractionated radiation therapy (SFRT), also known as GRID therapy, is distinctive from standard radiation approaches. SFRT applies a nonuniform dose to the total tumor, effectively treating the tumor while remaining within normal tissue tolerance of the surrounding structures [32]. In the 3D era, physical blocks with many small circular apertures allowed for the grid or lattice type distribution of dose in tissue. With the advancement of modern linear accelerators and volumetric arc therapy (VMAT), multileaf collimators can be used to create GRID-equivalent dosimetry for either photon or proton beams. Studies have shown high rates of clinical response with minimal toxicities in large-volume primary or metastatic malignancies including head and neck cancers; further clinical trials are necessary to clarify its utility [33].

BRACHYTHERAPY — Brachytherapy utilizes a radioactive source placed within or next to the tumor using either an interstitial implant or an intracavitary device. For cancers in the head and neck region, temporary implants, rather than permanent implants, are used. Intracavitary brachytherapy places the radiation source in the lumen of cavitary structures, such as the nasopharynx or oral cavity. Brachytherapy can be used as a boost technique following external beam treatment or as the sole treatment in carefully selected, small oral cavity or oropharynx tumors [34-36].

Although brachytherapy can deliver high doses of radiation to the target and spare surrounding tissues, it requires special expertise; interstitial implants usually require placement in the operating room and are not used as commonly as other techniques. A pilot study of cesium brachytherapy for recurrent head and neck cancer demonstrated acceptable toxicity with a two-year disease-free survival of 49 percent at the site of treatment [37].

INTRAOPERATIVE RADIATION THERAPY — In some institutions, RT machines are available in the operating rooms, and a larger dose of RT can be delivered during the operation. Usually, orthovoltage or electron machines are used to deliver superficial treatments. This can be useful in recurrent head and neck tumors that have had prior RT, in which further RT as part of salvage treatment is limited. The advantage of intraoperative radiation therapy (IORT) is the ability to give the treatment directly to the surgical bed without having to deliver the dose through surrounding normal tissues. If the recurrence is amenable to surgical salvage, surgery with IORT is performed, followed by a lower dose of external beam radiation therapy (EBRT) [38].

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".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topics (see "Patient education: Radiation therapy (The Basics)")

SUMMARY

●External beam radiation therapy – Most head and neck cancers are treated with external beam radiation therapy (EBRT) using high-energy photons generated by a linear accelerator. Image-based determination of the location of the tumor and its relationship to normal structures is critical for radiation therapy (RT) planning and accurate treatment delivery. (See 'External beam radiation therapy' above.)

●Three-dimensional conformal radiation therapy – Three-dimensional conformal radiation therapy (3D-CRT), such as intensity-modulated radiation therapy (IMRT) and image-guided radiation therapy (IGRT), have become the standard of care in most radiation treatment centers. Further refinements in technique have led to the development and implementation of other techniques to spare normal tissue and minimize toxicity such as image-guided adaptive radiation therapy and dysphagia-optimized IMRT. (See 'Three-dimensional conformal RT' above.)

●Proton beam therapy – Use of proton beam therapy is increasing for head and neck cancer, although studies proving its superiority over IMRT are required in order to justify its increased cost. (See 'Charged particle radiation' above.)

●Dosing regimens and fractionation schedules – Dosing regimens and fractionation schedules are discussed separately. (See "Definitive radiation therapy for head and neck cancer: Dose and fractionation considerations".)

ACKNOWLEDGMENTS — The UpToDate editorial staff acknowledges Shiyu Song, MD, and Wendy Hara, MD, who contributed to earlier versions of this topic review.