Practical Essentials of Intensity Modulated Radiation Therapy, 3 Ed.

4. Nodal Target Volume for Head and Neck Cancer and Normal Tissue Dose Constraints

Tony J. C. Wang • Cheng-Chia Wu • K. S. Clifford Chao

Neck Lymph Nodes – Highlights

Key Studies and Guidelines

New nodal station guidelines from New American Head and Neck Society (Arch Otolaryngol Head Neck Surg 2008) nodal station guidelines as updated by AJCC. (PMID 18490577)

Normal tissue constraints from RTOG protocols and QUANTEC reviews.

Apisarnthanarax et al. (IJROBP 2006) showed nodes that are at high risk for ECE but not grossly infiltrating musculature and demonstrated that the ECE was <5 mm from the capsule in 96% of the nodes. They recommended 1 cm clinical target volume margins around the nodal gross tumor volume to cover microscopic nodal extension in head and neck cancer.

Complete Nodal Delineation Guidelines

FIGURE 4-7. Differentiation of ECE (+) and ECE (−) necks in patients receiving postoperative IMRT. In the ECE (+) neck, soft tissues are more generously included, and the CTV1 and CTV2 should extend close to the skin surface, especially in the region or level of the ECE (−) node(s) specified by pathologic findings. ECE, extracapsular extension

1. INTRODUCTION

• Intensity-modulated radiation therapy (IMRT) provides greater dose conformality and is commonly used in the treatment for head and neck cancers.

• IMRT can protect critical normal tissue without compromising target coverage, but requires extensive knowledge of tumor spread and the ability to accurately delineate both the tumor target volumes and the cervical lymph nodes.

• Careful understanding of tumor spread ensures the delineation of the clinical target volume (CTV), which represents the region containing microscopic disease as defined in the International Commission on Radiation Units and Measurements Reports 50 and 62.1,2 In 2010 ICRU issued a new set of guidelines specifically for the use of IMRT, report number 83.3 This document should be read by all practicing radiation oncologists.

• Neither physical examination nor the radiologic imaging techniques used in clinical practice are sufficient in detecting microscopic disease. Sako et al.4 found that the submandibular nodes must measure at least 0.5 cm in size to be clinically detectable, while deep cervical nodes located adjacent to muscles must exceed 1 cm in diameter to be clinically palpable. Computed tomography (CT) is not sufficient to detect micrometastasis <1 cm in diameter.5

• The incidence of occult nodal metastasis ranged from 25% to 60% from the 1950s to the 1960s. Even with advances in morphology-based imaging techniques, such as helical CT or magnetic resonance imaging (MRI), determination of nodal metastasis on the basis of the size of the lymph node still underestimates between 12% and 60% of micrometastases. In addition, detection of micrometastasis by positron emission tomography (PET) has not demonstrated any further benefit, with sensitivities of 67% to 79% and specificities of 82% to 95%.6,7 Therefore, the current clinical practice to determine target volume for IMRT relies on historical information from surgical pathologic experiences.

• In 1948, Rouviere8 described the anatomic details of the cervical lymphatic network. On the basis of this description, the TNM atlas proposed a terminology that divides the head and neck lymph nodes into several groups according to their relationship with the adjacent muscles, vessels, and nerves.9

• In 1991, the American Head and Neck Society (AHNS) postulated a classification (Robbins’ classification) that divides the neck into six levels or eight nodal groups for those lymph nodes routinely removed during neck dissection.10 These recommendations were updated in 2002, with minor revisions of some boundaries by using radiologic landmarks and a better definition of sublevels of levels II and V (Table 4-1).11 More recently, the AHNS updated the guidelines on the classification and terminology of neck dissection (Table 4-2).12

• The boundaries of regional nodal levels have been described by the American Joint Committee on Cancer (see Edge et al. 2010).13 The cervical nodes are shown in Figure 4-1Figure 4-2 presents a graphical summary of the cranial nerves affected by head and neck cancer.

2. DETERMINATION OF CLINICAL TARGET VOLUMES

• Determination of CTVs is based on the data on incidence and location of metastatic neck nodes from various head and neck subsites, which come from the published literature and summarized in Table 4-3. The distribution of nodal metastasis to different lymph node levels in the head and neck region varies by primary tumor subsite. The number under each column represents the percentage of lymph node metastasis in patients with squamous cell carcinoma arising from various head and neck subsites. Because metastatic nodes may be manifest in more than one nodal level at presentation, the summation of percentage from all nodal levels (regions) may exceed 100%, especially in the N+ group.

• Other factors that influence the extent of CTV margins include tumor size, stage, differentiation, morphology, and whether other lymph node levels are involved.14,15

• Avoiding elective contralateral neck radiation is an area of great interest primarily to reduce significant morbidity without compromising clinical outcome. Earlier studies demonstrated that node-negative, well-lateralized tonsillar cancers had low contralateral neck failures.16,17 More recent prospective studies have shown that ipsilateral neck radiotherapy may have a role in the treatment of well-selected oral cavity and node-positive oropharyngeal cancer patients. Rusthoven et al. demonstrated that primary and ipsilateral neck radiation in node-positive, lateralized tonsillar cancer did not appear to increase the risk of contralateral nodal failure, although follow-up was short.18 Cerezo et al. showed that ipsilateral irradiation for well-lateralized oropharynx and oral cavity cancers spared salivary gland function without compromising locoregional control.19 While ipsilateral radiation is appropriate for selected cases, contralateral nodal regions should be included for tumors that tend to spread to the contralateral neck nodes or those that arise from or invade a midline structure, including the soft palate, base of tongue (BOT), posterior pharyngeal wall, or nasopharynx. For example, nodal metastasis exists in 85% to 90% of patients with nasopharyngeal carcinoma, and approximately 50% of them have bilateral disease; therefore, both sides of the neck should be treated for this particular disease. In addition, the risk of contralateral neck involvement is high in oral cavity cancers if tumor is above T3 classification, crosses the midline, or presents with ipsilateral node metastasis, which requires bilateral treatment of lymph nodes.20

FIGURE 4-1. Nodal anatomy. The neck or cervical nodes are regional nodes for the head and neck cancer sites. Any cluster can be a sentinel node that drains a specific site (A, B, C). These are assigned using the International Anatomical Terminology and are identified by numbers to denote the clusters of regional nodes that could be sentinel nodes. (A) Anterior view of deep jugular nodes. (B) Lateral view of deep nodes with the sternocleidomastoid muscle removed. Anterior deep jugular (A) and lateral (no sternocleidomastoid muscle) (B) lymph nodes: (1) retropharyngeal; (2) submandibular; (3) submental; (4) superior deep cervical; (5) jugulodigastric; (6) mid deep jugular; (7) prelaryngeal; (8) jugulo-omohyoid; (9) inferior deep cervical (jugular); (10) supraclavicular; (11) paratracheal; and (12) pretracheal. C: Lateral view of superficial nodes: (1’) preauricular; (2’) parotid; (3’) facial; (4’) mastoid; (5’) superficial cervical; (6’) external jugular; (7’) submandibular; (8’) submental; and (9’) spinal accessory. (D)AJCC nomenclature of seven levels of cervical lymph nodes. (E) Node-bearing region according to staging in Hodgkin’s lymphoma. (Taken from Rubin P, Hansen JT. TNM Staging Atlas with Oncoanatomy, 2nd ed. Philadelphia, PA: Lippincott Williams & Wilkins, 2012:11.)

FIGURE 4-2. Graphical representation of the cranial nerves. (Modified from Agur AMR, Dalley, AF, eds. Grant’s Atlas of Anatomy, 12th edition. Philadelphia; Lippincott Williams & Wilkins, 2009.)

• Table 4-4 shows that macroscopic or microscopic bilateral nodal metastases present with more than 30% of tumor residing in the BOT, pharyngeal wall, and pyriform sinus.

• The probability of contralateral nodal metastasis can be predicted with better accuracy if certain tumor characteristics are taken into account. Table 4-5 shows the tumor factors for oral cavity carcinoma that could influence the incidence of contralateral nodal metastasis.

• If a tumor arises from the buccal mucosa and retromolar trigone, which have a lower chance of contralateral neck node metastasis, especially when the primary tumor size is small and no involvement of the ipsilateral neck node is evident, the contralateral neck may not require treatment.

• We define three CTVs for target volume specification: CTV1, CTV2, and CTV3 (Table 4-6).

º CTVl for patients receiving definitive IMRT is defined as gross tumor volume (GTV) or nodal GTV with margins based on clinical and radiologic factors.

º CTVl for postoperative patients encompasses the preoperative GTV plus a 0.5 to 1.5 cm margin including the resection bed with soft tissue invasion by the tumor or extracapsular extension (ECE) by metastatic neck nodes. Preoperative imaging, surgical defects, or postsurgical changes seen on postoperative CT scan determine the surgical bed.

º CTV2 for patients receiving definitive IMRT encompasses the CTVl and the region adjacent to CTVl but with no direct tumor involvement based on clinical findings and CT or MRI imaging. Radiologically or clinically involved neck node is also included in CTV2 with 1-cm margins truncating air and bone.

º CTV2 for postoperative patients primarily includes the clinically/radiologically or pathologically uninvolved cervical lymph nodes, deemed as elective nodal regions, or the prophylactically treated neck.

º CTV3 for patients receiving definitive IMRT includes the clinically/radiologically or pathologically uninvolved cervical lymph nodes, deemed as elective nodal regions, or the prophylactically treated neck.

• Our approach to selective neck treatment was similar to that recommended by Gregoire et al.21 These target volume specifications were integrated with the published clinical data shown in Table 4-3. On the basis of these historical data, we proposed that treatment of the N0 neck is warranted if the probability of occult cervical metastasis is higher than 5% to 10%.

• The CTV (CTV1, CTV2, and CTV3) determination guidelines for various head and neck tumor subsites for postoperative and definitive IMRT are divided into separate recommendations for node negative and node positive neck, which are summarized in Tables 4-7 and 4-8, respectively.

• IMRT is applied to the upper neck for salivary sparing. The lower neck is treated with a conventional AP lower neck port if indicated. The standard superior border for the lower neck field is at the level of the thyroid notch. In patients with a tumor or metastatic lymph node extending below this level, the junction line is adjusted to avoid bisecting gross disease.

3. DELINEATION OF CLINICAL TARGET VOLUME

• Because the definition of neck node levels and the anatomic boundaries described in Robbins’ classification were designed on the basis of specific soft-tissue landmarks for surgical procedures and are not easily seen on CT and MRI slices, we implemented modified guidelines for the delineation of the various node levels in the neck. We supplemented Robbins’ classification with a retropharyngeal nodal group to provide the readers a better understanding of the nodal target volume determination and delineation for head and neck IMRT. Our recommendations for the radiologic boundaries of these nodal levels are summarized in Table 4-9.

º Level la: Submental; see figure 3 of Reference 15.

• Contains the submental nodes.

• Drains the skin of chin, mid-lower lip, tip of the tongue, and anterior floor of the mouth.

• Greatest risk of harboring metastases from the lower lip, floor of the mouth, anterior oral tongue, and anterior alveolar mandibular ridge.

º Level lb: Submandibular; see figure 3 of Reference 15.

• Contains the submandibular nodes.

• Drains the medial canthus, lower nasal cavity, hard and soft palate, maxillary and alveolar ridges, cheek, upper and lower lips, and most of the anterior tongue. It also receives efferent lymphatics from the submental nodes.

• Greatest risk of harboring metastases from the oral cavity, anterior nasal cavity, soft tissue structures of the mid-face, and submandibular gland.

º Level IIa: Ventral upper jugular group; see figures 2 through 6 in Reference 15.

• Contains upper one-third of jugular lymph nodes anterior to the jugular vein.

• Receives efferent lymphatics from the face; parotid gland; and submandibular, submental, and retropharyngeal lymph nodes. It also directly drains from the nasal cavity, pharynx, larynx, external auditory canal, middle ear, and sublingual and submandibular glands.

• Greatest risk of harboring metastases from the oral cavity, nasal cavity, nasopharynx, oropharynx, hypopharynx, larynx, and major salivary glands.

º Level IIb: Dorsal upper jugular group; see figure 4 of Reference 15.

• Contains upper one-third of jugular lymph nodes posterior to the jugular vein.

• Greatest risk of harboring metastases from the oropharynx and nasopharynx, and less likely from the oral cavity, larynx, and hypopharynx.

º Level III: Middle jugular group; see figures 3, 4, 6, and 7 of Reference 15.

• Contains middle jugular lymph nodes.

• Drains from the BOT, tonsils, larynx, hypopharynx, and thyroid gland. Receives efferent lymphatics from levels II and V, and some from the retropharyngeal, pretracheal, and recurrent laryngeal nodes.

• Greatest risk of harboring metastases from the oropharynx, nasopharynx, oral cavity, larynx, and hypopharynx.

º Level IV: Inferior jugular group; see figure 6 of Reference 15.

• Contains the inferior jugular lymph nodes.

• Receives efferent lymphatics from levels III and V, and some from the retropharyngeal, pretracheal, and recurrent laryngeal nodes.

• Greatest risk of harboring metastases from the larynx, hypopharynx, and cervical esophagus.

º Level V: Posterior triangle group; see figure 8 of Reference 15.

• Contains the posterior cervical (Level Va) and supraclavicular lymph nodes (Level Vb).

• Drains from the occipital scalp, postauricular and nuchal regions, skin of the lateral and posterior neck, nasopharynx, and oropharynx (tonsil and BOT).

• Greatest risk of harboring metastases from the nasopharynx, oropharynx, subglottic larynx, apex of pyriform sinus, cervical esophagus, and thyroid gland.

º Level VI: Anterior compartment; see figure 8 of Reference 15.

• Contains the lymph nodes of the anterior compartment from the hyoid bone superiorly to the suprasternal notch inferiorly. On each side, the lateral border is formed by the medial border of the carotid sheath.

• These include LN cervicales anteriores superficiales and LN cervicales anteriores profundi (LN infrahyoidales, LN prelaryngeales, LN pretracheales, LN paratracheales, and LN thyroidei).

º Retropharyngeal nodes:

• Contains the lymph nodes that lie within the retropharyngeal space.

• Retropharyngeal nodes are divided into lateral and medial groups. There is data to suggest that sparing medial retropharyngeal nodes is safe in node-negative oropharyngeal cancers.34

• Greatest risk of harboring metastases from the nasopharynx, oropharynx, soft palate, hypopharynx, and pharyngeal tumors with positive neck nodes in other levels.

• In addition to the LN regions classified by Robbins et al., there are other LN regions which include the parotid level (LN parotidei superficiales and profundi, which drain to level IIa), the retroauricular level (LN retroauriculares), the retropharyngeal level (LN retropharyngeales), the buccales level (LN facials, which drains to level Ib), and the external jugular level (LN cervicales laterals superficiales, which drain to level III). See figure 9 of Reference 15.

• Two summary figures from Reference 15 are reprinted here as Figures 4-3 and 4-4.

• In view of the differences observed between recent guidelines, a multidisciplinary working party including members of both groups was created to try to elaborate a unique set of recommendations for the delineation of the various levels in the node negative neck. Subsequently, the party was extended to include representatives of American and European cooperative groups.

• The general objectives that guided the activities of the panel were to translate as accurately as possible the surgical guidelines into a set of radiologic guidelines by using axial CT sections and to minimize differences in interpretation of the guidelines by defining less ambiguous boundaries than previously described.

• As a result of this consensus meeting, a complete atlas of contrast-enhanced CT sections depicting the various node levels from the base of the skull to the level of the sternoclavicular joint for the node negative neck has been created, which is posted on the website of the Danish Head and Neck Cancer Study Group, figure 4-3A,B (http://www.dshho.suite.dk/dahanca/guidelines.html).

• Figure 4-5 gives an atlas of CTV delineation for head and neck squamous cell carcinoma. Figure 4-6 illustrates an example of sequential steps in delineating the CTVs.

• One significant pathologic factor to take into consideration for target volume delineation is the presence of ECE. The probability of the tumor extending outside of the nodal capsule increases as a function of tumor size. When metastatic nodal disease expands and ruptures the capsule of cervical lymph nodes, the incidence of local recurrence increases.

• Huang et al.35 demonstrated a higher tumor recurrence in patients with ECE (+) neck, whereas postoperative radiation therapy improved local regional control. Peters et al.36 differentiated the resected neck into high- and low-risk groups, for which different radiation doses were recommended.

• Thus, when delineating target volume in the postoperative neck, inclusion of generous soft-tissue margins around the tumor bed is imperative. If the information regarding which lymph node levels contain ECE (+) nodes is not available pathologically, a preoperative imaging study (CT or MRI) can assist in determining which regions require a more generous soft-tissue margin for CTV1 and CTV2 delineation.

• Figure 4-7 differentiates ECE (+) and ECE (−) necks in patients receiving postoperative IMRT. In the ECE (+) neck, soft tissues are more generously included, and the CTV1 and CTV2 should extend close to the skin surface, especially in the region or level of the ECE (−) node(s) specified by the pathologic findings.

• When postoperative IMRT is required for the ECE (−) neck, the target volume should avoid skin surface to decrease acute dermal toxicity. In our experience, sparing 2 to 3 mm of dermal structures in target volume design (Fig. 4-7) clearly results in much better radiation tolerance, less treatment breaks, and no compromise in locoregional control.

FIGURE 4-3. Coronal DRR showing lymph node regions, bones, and veins. From top to bottom: ventral upper jugular lymph nodes (IIA), middle jugular lymph nodes (III), inferior jugular lymph nodes (IV), dorsal upper jugular lymph nodes (IIB), posterior cervical lymph nodes (VA), supraclavicular lymph nodes (VB), Level III axillary lymph nodes, Level II axillary lymph nodes, anterior mediastinal lymph nodes. (Reprinted from Vorwerk H, Hess CF. Guidelines for delineation of lymphatic clinical target volumes for high conformal radiotherapy: head and neck region. Radiat Oncol 2011;6:97. With permission from BioMed Central.)

• Although the lower neck was treated with conventional techniques in the majority of patients, similar principles as applied to the upper neck have been applied to depict CTV delineation in the lower neck region in Figures 4-64-7, and 4-8 for readers’ reference.

• Also, it should be emphasized that margins for organ motion or patient set-up error are not included in delineating the target volume because they are determined by the individual institutions implementing head and neck IMRT programs. Our experience indicated that with the use of a reinforced thermoplastic mask for immobilization, 3 mm margins were required for IMRT plan computation to account for patient set-up uncertainty.37,38

• The dilemma comes when definitive IMRT is used to treat an undissected neck, and no pathologic information is available to determine whether metastatic disease has extended outside the lymph node capsules. In this case, we seek surgical pathologic experience for guidance. Table 4-10 summarizes the incidence of ECE in various sizes of lymph nodes that contain metastatic disease. When nodal size is as small as 1 cm, 17% to 40% may have broken through the capsule. When the size of the metastatic node exceeds 3 cm, more than 75% have ECE. This information is pertinent to target volume design because additional soft tissue margins around the whole nodal level where grossly enlarged nodes reside should be included in CTV1, which usually provides margins around the gross disease truncating air and bone (Fig. 4-7). The CTVs that we used are, for the most part, generous and likely contributive to the high control rates. Because head and neck IMRT is still in its infancy, we elected to be generous in target volume delineation to avoid undesirable marginal failure.

FIGURE 4-4. Lymph node drainage, sagittal view. From top to bottom: preauricular lymph nodes, infra-/intraparotid lymph nodes, superficial parotid lymph nodes, facial lymph nodes, submental lymph nodes (IA), submandibular lymph nodes (IB), retroauricular lymph nodes, superficial lateral cervical lymph nodes, occipital lymph nodes, posterior cervical lymph nodes (VA), upper jugular lymph nodes (IIA), middle jugular lymph nodes (III), inferior jugular lymph nodes (IV), anterior cervical lymph nodes (VI). (Reprinted from Vorwerk H, Hess CF. Guidelines for delineation of lymphatic clinical target volumes for high conformal radiotherapy: head and neck region. Radiat Oncol 2011;6:97. With permission from BioMed Central.)

• To address this uncertainty of CTV margins, a retrospective pathologic–imaging correlation study was performed at M. D. Anderson Cancer Center.33 The ECE of 96 neck lymph node samples from the neck dissections of 48 patients with squamous head and neck cancer was measured and correlated with CT imaging. The median size of lymph nodes was 1.1 cm (0.4 to 4 cm), and the median ECE was 1.8 mm (0.4 to 9 mm). The results of the study by Apisarnthanarax et al.33 are shown in Figure 4-9; approximately 96% of the lymph nodes had an ECE of 5 mm or less. No lymph node had an ECE that extended beyond 1 cm from the lymph node capsule. Although preliminary, these data indicate that 5-mm and 10-mm margins beyond the GTV would be able to cover 90% and 100% of microscopic nodal extension, respectively. These recommendations will continue to be adjusted according to future prospective pathologic-imaging studies.

FIGURE 4-5. An atlas of the delineation of the clinical target volumes (CTVs) for head and neck squamous cell carcinoma with N0 neck in noncontrast axial computed tomography (CT) slices. (A) Levels I and II. (B) Levels III and IV.

• Sparing salivary gland function is important in preserving the quality of life of patients. An example of dose response of parotid gland function after radiation treatment is available in the literature.3942 We elected not to spare the deep lobe of the parotid gland to prevent marginal failure in the parapharyngeal space. Therefore, only the superficial lobes of parotid glands were demarcated.

4. DOSE PRESCRIPTION FOR HEAD AND NECK INTENSITY-MODULATED RADIATION THERAPY

• Conventional radiation techniques sequentially deliver various amounts of radiation dose to different target volumes on the basis of the rank of “risk.” Usually, several plans will be generated for a full course of treatment to first cover the whole region with a lower dose followed by a cone-down boost to the areas with higher risk of containing gross or microscopic disease.

• In contrast, IMRT delivers a single plan throughout the course of radiotherapy. Although we have the option to generate two or more IMRT plans simulating the conventional scheme, it may require more resources and manpower in contouring and data processing.

FIGURE 4-6. A–F: Steps to delineate the CTVs in a patient with a T1N1 base-of-tongue (BOT) cancer for definitive intensity-modulated radiation therapy—successive steps in the treatment planning process. (A) Diagnostic head and neck CT shows primary T1 BOT lesion (arrow) on right side. (B) A 1.5-cm enlarged left jugulodigastric lymph node (arrow). (C) Primary nodal target volume (outlined in green). (D) CTV1 (outlined in red). (E) CTV2 outlines (blue) adjacent lymph nodes, including level V nodes. (F) CTV3 outlines (yellow) elective contralateral nodes.

FIGURE 4-7. CTV delineation of pathologically extracapsular extension (ECE)± necks in BOT cancers receiving postoperative IMRT. Axial enhanced postoperative CT scans at the level of mandible (A, B), thyroid cartilage (C, D), and thyroid gland (E, F) in a patient with metastatic head and neck cancer. CTVs with the presence of ECE+ (A, C, E) are compared with ECE− volumes (B, D, F). CTV1 (red line); CTV2 (blue line); ECE+, presence of extracapsular extension; ECE−, absence of ECE; GTV, gross tumor volume (grossly enlarged lymph node). (Adapted from Chao KSC, Wippold FJ, Ozyigit G, et al. Determination and delineation of nodal target volumes for head-and-neck cancer based on patterns of failure in patients receiving definitive and postoperative IMRT. Int J Radiat Oncol Biol Phys 2002;53:1174–1184, with permission.)

FIGURE 4-8. CTV target delineation of clinically N+/N− necks in BOT cancers receiving definitive IMRT. Axial enhanced CT scans at the level of pterygoid plates (A), mandible (B), submandibular gland (C), hyoid bone (D), thyroid cartilage (E), and cricoid cartilage (F) in a patient with metastatic head and neck cancer. CTVs with the presence of metastatic lymphadenopathy are compared with those without radiologic evidence of metastatic neck node. The gross tumor was operatively demarcated to provide readers visual assistance in understanding the location of gross nodal disease and corresponding target volume. CTV1 (red line); CTV2 (blue line); lb, level lb node; II, level II node; III, level III node; V, level V node; N+, positive nodes; N−, negative nodes; NR, nodes of Rouvière; GTV, gross tumor volume (grossly enlarged lymph node). (Adapted from Chao KSC, Wippold FJ, Ozyigit G, et al. Determination and delineation of nodal target volumes for head-and-neck cancer based on patterns of failure in patients receiving definitive and postoperative IMRT. Int J Radiat Oncol Biol Phys 2002;53:1174–1184, with permission.)

• The options for dose prescription are:

1. Set the dose prescription to the low-dose target at 1.8 to 2 Gy and increase daily fraction size (reduce total dose) to the high-dose region.

2. Keep the daily fraction size at 2 Gy to the high-dose region and increase total dose to the low-dose region to compensate for lower daily fraction size (1.6 to 1.7 Gy). Currently, there are various examples of implementing IMRT dose prescription within these two categories (Table 4-11).

• Mohan and colleagues48 examined IMRT fractionation strategies based on radiobiologic considerations and defined the term “simultaneous integrated boost” to describe IMRT treatments designed to synchronously deliver different dose levels to different tissues of the head and neck region.

• Butler and colleagues49 used an inverse-planning IMRT-based accelerated fractionation schedule for the treatment of head and neck cancer and named it “Simultaneous Modulated Accelerated Radiation Therapy” (SMART).

• SMART used higher daily doses (2.4 Gy) to high-dose target to shorten the overall treatment time to 5 weeks without requiring multiple daily doses. Dose limits to critical structures were adjusted to compensate for the larger fraction size.

• This IMRT dose scheme tries to limit the high-dose volume and reduce the risk of late complications associated with larger fraction size. However, critical normal tissues such as muscle, mucosa, blood vessels, and nerves are still embedded within target volumes. The long-term quality-of-life data are not yet available for this approach.

FIGURE 4-9. Study of extracapsular extension (ECE) in 96 involved nodes from 48 patients. (A) Example of ECE from a patient with T4N2c hypopharyngeal primary tumor. Hematoxylin and eosin-stained cross-section at 5x (left) and 10x (right) magnification. Capsule outlines in white. Tumor (T) extension out of capsule (C) marked on 10x magnification; arrow points to point of capsule eruption. Picture below the two sections illustrates size of ECE.

FIGURE 4-9 (B) Summary of statistical data on ECE size distribution. (C) Nodal CTV delineation. CT imaging findings for a level III/IV 2.0-cm left neck node (white outline) from a patient with a T3N2a hypopharyngeal tumor. CTV (green outline) has 1 cm margin around CT-defined gross tumor volume. Inset shows hematoxylin and eosin–stained specimen at 10x magnification. LN, lymph node; C, capsule; T, tumor extension outside capsule. (Based on figures and data in Apisarnthanarax S, Elliott DD, El-Naggar AK, et al. Determining optimal clinical target volume margins in head-and-neck cancer based on microscopic extracapsular extension of metastatic neck nodes. Int J Radiat Oncol Biol Phys 2006;64(3):678–683, with permission.)

• The ongoing Radiation Therapy Oncology Group study H-0022 adopted a strategy to accommodate the fraction size differences and deliver a higher-than-standard fraction dose to the GTV of early stage oropharyngeal cancer (T1, T2, or N1) and standard fraction doses to the CTVs. The GTV received a total of 66 Gy in 30 fractions at 2.2 Gy per fraction. High-risk CTVs received 60 Gy, and low-risk CTVs received 54 Gy at 2 and 1.8 Gy per fraction, respectively. Thus, the GTV received a normalized total dose of 70 Gy in 2-Gy fractions within 6 weeks.

• This approach may be suitable for patients with early-stage head and neck cancer (smaller high-dose target volume) who are to receive definitive radiation without concurrent chemotherapy. The short- and long-term toxicity profiles are unknown.

• We presented therapeutic results and toxicity data by using the approach of maintaining daily fraction size at 2 Gy to the high-dose region and increasing the total dose to the low-dose region to compensate for the lower daily fraction.50

º The concern that lower fraction size to the prophylactically treated areas may result in a higher local failure rate was addressed because we have not observed an increase in tumor recurrence.

º Further, IMRT prescription is usually normalized to the 80%-to-90% isodose line, which will create hot spots within the high-dose target.

º In addition, the majority of patients receiving definitive IMRT in the current series were also treated with concurrent chemotherapy. To avoid unforeseen detrimental late complications, we elected to limit daily fraction size to the high-dose region at no more than 2 Gy per day. Grade 3 or above late complications with this approach were <2.5%.

• The observation that patients treated with <2 Gy per day to the high-dose target had inferior disease-free survival requires further confirmation.51 This could be associated with the learning curve of early implementations of the techniques.

• Daily fraction size to CTV has been found to be associated with locoregional control rate in our experience. Patients receiving 2-Gy fraction doses to the primary target volume (CTV1) showed better 2-year disease-free survival (94% vs. 78%, P = 0.05).51 Because we have not noticed any significant difference in treatment tolerance in patients treated with <2 Gy versus 2 Gy per fraction, the latter (2 Gy per fraction) is our preferred dose prescription scheme.

• Liauw and colleagues investigated the effects of intravenous contrast on IMRT dose calculations for head and neck radiotherapy treatment planning. The results of their study showed that dose differences between planning set of images using intravenous contrast and images without contrast were less than 0.2% for all relevant target volumes and critical structures. These results suggest that planning for head and neck IMRT from CT scans that contain intravenous contrast does not result in clinically important errors in dose delivery.52

• Table 4-12 summarizes the respective dose prescriptions for CTV1, CTV2, and CTV3. CTV1 is considered a higher-risk volume; a higher dose is given to this target volume.

5. CLINICAL RESULTS OF HEAD AND NECK INTENSITY-MODULATED RADIATION THERAPY AND IMAGE-GUIDED THERAPY

• One of the early IMRT studies by Chao et al. in 200355 analyzed 126 patients treated for head and neck cancers, with the majority having locally advanced disease. Fifty-two patients received definitive treatment, and 74 patients received postoperative IMRT. With a median follow-up of 26 months, nodal failure was observed in 6 of 52 patients (12%) receiving definitive IMRT, out of which four treatment failures were “in-field” to the CTVl and two were in the lower neck outside of the IMRT volume; nodal failure was observed in 7 of 74 patients (9%) receiving postoperative IMRT, out of which one treatment failure was “marginal” to the CTVl but “in-field” to the CTV2, two were marginal to the CTV2, two were in the lower neck and outside of the IMRT field, and two were in the CTVl. There was also lower neck failure, which was outside of the IMRT field, in one of the two treatment failures in the CTV1 mentioned last in the above list. The 3-year local control, locoregional control, and overall survival rates were 92%, 83%, and 85%, respectively.

• Predominant “in-field” failures denote the urgent requirement to discern the radioresistant tumor, such as hypoxic tumor, by functional imaging or molecular markers.

• Chen and co-workers56 recently demonstrated that the addition of daily image guidance to IMRT appeared to allow reduction of 5 mm PTV expansion margins to 3 mm without compromising oncologic outcomes.

• Table 4-13 summarizes recently reported therapeutic outcomes of published head and neck IMRT series.

6. NORMAL TISSUE CONSTRAINTS

• As the new ICRU guidelines (report 83)3 note, one of the singular advantages of IMRT is its high conformality. However, this brings some dangers as well—very steep dosage gradients and the need for image guidance to prevent unintended morbidity to normal tissues. ICRU explicitly denotes a “remaining volume at risk” (RVR), which basically includes all other tissues not otherwise included in the PTV or Organs-at-Risk (OAR). Dose constraints in the RVR are necessary to prevent the treatment planning algorithms from achieving optimization in the PTV while creating hot spots elsewhere.

• Table 4-14 presents a quick summary of the normal tissue constraints as gathered from four recent RTOG protocols and from the QUANTEC review papers published in 2010. Readers are strongly encouraged to consult the original papers for discussion and details.

• Head and neck disease presents a daunting problem of RT-associated morbidity due to direct involvement or very close proximity to critical structures, for example, the optic nerve and spinal cord.

• In a recent study by Pak et al.57 73 patients were treated for stage III or IV oropharyngeal cancer. Of these 21% reported Lhermitte sign (LS) following IMRT, and this was associated with larger mean V30 Gyand V40 Gy of the spinal cord as compared to non-LS patients (76.7% vs. 54.9% and 32.6% vs. 12.3%, respectively). Fortunately, the symptoms resolved spontaneously within a mean duration of 5.5 months. RTOG protocols (see below) allow a dose of no more than 48 Gy to a volume of 0.03 cm3. The authors reported a maximum dose in the LS patients of 43.1 ± 4.5 Gy, which on average seems within the RTOG guidelines.

• Truong et al.58 treated 114 advanced head and neck patients (89% stage III or IV) with IMRT specifically contouring the brachial plexus (BP) as an organ at risk. Dose was <60 Gy if nodal involvement was adjacent; this was lowered to 54 to 56 Gy for patients receiving elective nodal irradiation. The authors noted that constraints could not always be achieved since tumor coverage was the priority. Mean BP dose was 58.4 and 63.4 Gy for T0-3 and T4 disease, respectively; maximum dose of ≤70 Gy occurred in 90% of patients treated. However, at 24 months, no brachial plexopathy was reported.

• There are other not-so-seemingly-vital functions that have a tremendous impact on the patient’s quality of life, such as salivary gland output, speech, and swallowing. One of the early successes of IMRT was its ability to reduce morbidity in salivary function41 in patients treated with RT for head and neck cancer (see Dijkema et al. for a recent summary).59 Larynx preservation is discussed in Chapter 9.

• Another significant cause of morbidity was the effect of RT on the swallowing structures—pharyngeal constrictors (PCs) and glottic/supraglottic larynx (GSL). This can range from difficulty swallowing normally to being restricted to soft or liquid foods, or even to the requirement for a feeding tube. Aspiration of foreign matter into the lungs can also be present with the attendant risk of pneumonia.

• A 2009 MRI study by Popovtzer et al.60 showed that the likely causes for dysphagia problems were inflammation and edema caused by the intensified chemoradiation regimens employed to treat head and neck cancers.

• Earlier, Eisbruch et al. in 200461 had shown that IMRT plans specifically tailored to spare the pharyngeal constrictors and GSL could be constructed, which reduced the V50 Gy by about 20% from that in standard treatment. Since then a number of studies have demonstrated statistically significant correlations between radiation dose to the PC and/or GSL and dysphagia.

• A study from Li et al.62 on 39 patients with squamous cell cancer presented logistic regression data indicating that a V65 Gy of > 30%, a V60 Gy of >60%, and a mean dose of >62 Gy to the inferior pharyngeal constrictor were all predictive of extended feeding-tube dependence. Schwartz et al.63 examined 31 patients with stage IV oropharyngeal cancer and found that a V55 Gy of > 80% and a V65 Gy of >30% were predictive for swallowing dysfunction. Gokhale et al.64 retrospectively studied 80 patients treated for head and neck cancers. Their results from multivariate analysis indicated that V70 Gy of >30% and T-stage of III or IV were the factors most correlated with long-term feeding-tube requirement. Feng et al.65 conducted a prospective trial of 36 patients with stage III–IV oropharyngeal or nasopharyngeal cancer. Using videofluoroscopy to detect aspiration, they found that this morbidity was correlated with mean PC doses of >60 Gy or a PC V65 Gy of >50%, and also a GSL V50 Gy of >50%. Similarly, Peponi et al.66reported 1% grade 3 or 4 dysphagia in 82 stage III or IV diseases treated with SIB-IMRT with a PC mean dose of 59 Gy. In a contradictory report, Bhide et al.67 concluded from a retrospective study of 57 patients with head and neck squamous cell carcinoma that there was no statistically significant difference in dysphagia between patients receiving >60 Gy and those receiving less. It should be noted that in the low-dose cohort in this study, all received >50 Gy to the superior and inferior pharyngeal constrictors; so perhaps the “low dose” was not low enough so that the difference in radiation-induced toxicity could be seen.

• As an aside, a recent molecular genetic study by Werbrouck et al.68 showed that polymorphisms in DNA double-strand break repair genes were associated with severe IMRT-induced dysphagia. They created a risk analysis model which has a sensitivity of 76.8% and a specificity of 77.6%.

• However, there are other considerations: In a subsequent paper, Feng and co-workers69 studied the problem of the retropharyngeal lymph nodes (RPN), which are important metastatic sites and located close to the PC structures. They found that exclusion of medial RPNs from targeting, in order to spare the pharyngeal constrictors, had no significant impact on locoregional disease control while achieving important protection of swallowing function.

• RTOG has not included the pharyngeal constrictors as organs at risk (OAR) in its most recent protocols. However, the summary of the studies cited here indicates that the PC should be included in treatment plans as a specific OAR with planning goals such as no volume of >30% receives >60 Gy and the mean dose be limited to 50 to 60 Gy, the lower the better.

• Other tissues subject to severe radiation-induced toxicities are the skin and bone in the vicinity of the tumor being treated. For example, Terezakis et al.70 report on fistulas arising from postoperative treatment with IMRT. Osteoradionecrosis of bone is another severe morbidity; for a review covering the literature from 1990 to 2008 see Peterson et al.71 They showed that this toxicity occurred generally in bone receiving >60 Gy and that it was seen in about 3% to 7% of patients depending on the radiation method (the lowest was for IMRT). Notably the lowest RTOG protocol guideline recommended dose for mandible is <60 Gy (see Table 4-14).

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