Year
Author
n
Stage
Mean dose (Gy) constraint
End point assessments
Objective
Subjective
2013
31
I–IV
<25.8
SGS
NS
2010
Eisbruch et al. [11]
69
I–II
<26
SF
XQ
2007
Scrimger et al. [12]
47
I–IV
≤26
SF
XQ
2005
Saarilahti et al. [13]
17
II–IV
≤25.5
SF
NS
2004
Parliament et al. [14]
23
I–IV
≤26
SF
XQ
2004
Münter et al. [15]
18
I–IV
≤26
SGS
NS
2001
Eisbruch et al. [16]
84
I–IV
≤26
SF
XQ
2001
Chao et al. [17]
41
II–IV
≤32
SF
XQ
A number of prospective clinical trials have demonstrated that parotid-sparing IMRT reduces long-term xerostomia without jeopardizing local-regional control for nasopharyngeal cancer (NPC) compared with conventional RT [18–20] and preserved salivary flow in oropharyngeal cancer [10, 21].
Practice guidelines on parotid-sparing IMRT for HNC have been formulated with use of data on locoregional failure after IMRT. Based on the location of tumor, the parotid glands can be safely spared. For N0 at least one, but usually both, parotid glands; for N1 and 2 a, b disease, sparing of the contralateral parotid gland does not result in increased marginal failures [22, 23], and lower priority is given to the ipsilateral parotid if lymph nodes at level II are involved [5, 24, 25].
In addition, detailed delineation have been given about the cranial border of level II, as it has clear pertinence with the possibility of sparing the parotid [26]. For N0 disease, the upper boundary of level II is placed at the caudal edge of the lateral process of the first vertebra [27]. For N+, level II on the involved neck side is extended to the skull base and includes the retrostyloid space [28].
11.2.1.1 Dose Response
The prevalence and extent of dry mouth can be greatly reduced over time by reducing the mean dose to at least one parotid gland as salivary function can be partially preserved which improves gradually over time.
Among the variety of salivary endpoints, subjective xerostomia and objective stimulated/unstimulated salivary flow most commonly used have been correlated with the dosimetric dose–volume parameters. The mean parotid gland dose [12, 29–31] in particular has been correlated with whole mouth or individual gland salivary production.
Definition of dose–volume–response relationships for the parotid glands has been well established from the data regarding correlation of residual salivary function with radiation dose. Table 11.2 summarizes the reported dose–volume predictors for salivary flow and salivary function recovery. Minimal gland function reduction occurs at <10–15 Gy mean dose. Gland function reduction gradually increases at radiation doses of 20–40 Gy, with a strong reduction (usually by >75 %) at >40 Gy [12, 17].
Table 11.2
Dose–volume predictors for salivary flow
Author (year) | N | Tumor dose (Gy) | Follow-up (months) | End point stimulated | Dose–volume parameters (mean) |
|---|---|---|---|---|---|
Little et al. (2012) [32] | 78 | 50–25 | 24 | Saliva flow | 25.4 Gy |
Li et al. (2007) [30] | 142 | 60–25 | 24 | Saliva flow | <25–30 Gy |
Blanco et al. (2005) [10] | 55 | 50–21 | 12 | SOMA | <25.8 Gy# |
Eisbruch (1999) [33] | 88 | 58–22 | 12 | Saliva Flow | ≤25–26 Gy* |
Eisbruch et al. [33] studied the dose–volume effect relationships for the parotid glands, and they analyzed the correlations between fractional gland volumes receiving various doses and the mean doses and concluded that they were highly correlated; therefore, they concluded that mean dose was an adequate metric. Also a medial shift of the parotid glands during therapy in some patients may increase their mean doses compared with the treatment plans [31, 34].
11.2.1.2 Dose Recommendation
Definition of dose–volume–response relationships for the parotid glands has been well established from the data regarding correlation of residual salivary function with radiation dose. The consensus has been reached that xerostomia can be substantially reduced by limiting the mean parotid gland dose to <26–30 Gy as a planning criterion [35]. Xerostomia risk is reduced with sparing of at least one parotid gland or even one submandibular gland [13]. Severe xerostomia (long-term salivary function <25 % of baseline) can usually be avoided if at least one parotid gland has been spared to a mean dose of <20 Gy or if both glands have been spared to a mean dose of < 25 Gy [36]. At present, the mean noninvolved parotid mean dose is set to be ≤ 26 Gy in the Department of Radiation Oncology, University of Michigan.
11.2.2 Submandibular/Sublingual Glands
These glands lie anterior to the level II lymph node targets in the neck. In many advanced HNC treating bilateral neck disease, it is harder to spare a substantial amount of these glands, especially in cases of bilateral lymphadenopathy, resulting in no measurable salivary output from the majority of these glands after radiation.
Direct comparisons of parotid vs. submandibular gland (SMG) radiation sensitivity studies show a lesser sensitivity of the SMGs compared with the parotid glands [37–41]. Also, lower sensitivity of mucinous compared with serous cells is reported [42, 43]. These findings are confirmed further with the common symptoms of thick and sticky saliva during and shortly after the completion of RT, related to the faster decline in the watery content of the saliva produced by the serous parotid glands, compared with the decline of the mucinous component produced predominantly by the SMGs and the minor salivary glands
11.2.2.1 Dose–Volume Effects
While sparing SMGs, care must be taken so that it does not spare the tumor as it lies in close proximity to the base of tongue, tonsil, and level IIa lymph nodes, which require the full-prescribed radiation dose if gross and/or microscopic disease is in the abovementioned area. At present, available evidence has emerged regarding the efficacy and safety of SMGs-sparing IMRT.
Various studies support a lesser sensitivity of the SMGs compared with the parotid glands, and lower sensitivity of mucinous compared with serous cells is also reported [36, 39–43]. The common symptom of thick and sticky saliva was reported during and shortly after the completion of RT, which was related to the faster decline in the watery content of the saliva produced by the serous parotid glands, compared with the decline of the mucinous component produced predominantly by the SMGs and the minor salivary glands. A study of dose–effect relationships for the submandibular glands showed that their salivary output increased as mean dose was reduced from 40 to 30 Gy and then plateaued. No output was observed in glands receiving mean >40 Gy [44]. The treatment policy at the University of Michigan is to try and reduce the mean dose to 30 Gy depending on the need to treat level II (esp. the jugulodigastric nodes) which lay immediately posterior to the SMG.
11.2.3 Minor Salivary Glands
The minor salivary glands are dispersed throughout the oral cavity. It is well documented that they produce up to 70 % of the total mucins secreted by the salivary glands [45]. Hence, if the dose to the oral cavity is minimized, it might contribute to patient-reported xerostomia and also additional benefits like preventing mucositis and loss of taste [46]. Oral cavity should be contoured and delineated as an OAR and dose constraint given in designing IMRT plan whenever possible. In the Department of Radiation Oncology, University of Michigan, the mean dose for the noninvolved oral cavity is set to be ≤30 Gy with very low priority.
11.2.4 Salivary Glands Dose Recommendations [34]
The improvement in objective parotid function as measured by salivary flow is not always accompanied with improved patient-reported xerostomia [28, 31, 36]. Kam et al. indicated that the observer-based grades underestimated the severity of xerostomia compared with the patient self-reported scores [20]. Hence, not only the objective parotid function but also patient’s subjective scores should be the main end points in evaluating xerostomia. As xerostomia is mainly an issue of QOL, patient-reported symptoms are more suggestive of its true severity.
One of the strategies to eliminate xerostomia is to spare at least one parotid gland and to spare at least one submandibular gland to reduce xerostomia risk and increase stimulated and unstimulated salivary function. For complex partial volume RT patterns (IMRT), the mean dose to each parotid gland should be kept as low as possible, consistent with the desired clinical target volume coverage. Severe xerostomia (long-term salivary function <25 % of baseline) can usually be avoided if at least one parotid gland has been spared to a mean dose of less than 20 Gy or if both glands have been spared to a mean dose of less than 25 Gy. A lower mean dose to the parotid gland usually results in better function, even for relatively low mean doses (<10 Gy). Similarly, the mean dose to the parotid gland should still be minimized, consistent with adequate target coverage, even if one or both cannot be kept to a threshold of <20 or <25 Gy. Published variations in response among different patient cohorts were probably related to the lack of an accurate model that correctly includes the effects of multiple salivary glands and intra-gland sensitivity variations. When it can be deemed oncologically safe, submandibular gland sparing to modest mean doses (<35 Gy) might reduce xerostomia symptoms.
11.3 Dysphagia
Radiotherapy for HNC inevitably results in significant dose delivery to some of the critical structures necessary for normal deglutition (such as the tongue, soft palate, pharyngeal and laryngeal muscles) which leads to unavoidable mucositis and swallowing difficulty (dysphagia) [47–49]. These difficulties have become major issues after the wide adoption of concurrent chemotherapy–radiotherapy in the past decade.
IMRT use in head and neck malignancies increased from 1.3 to 46.1 % between 2000 and 2005 [50]. The rationale of using IMRT technique as a strategy to avoid dysphagia is based on the established relationship between functional status of the swallowing-related structures and irradiation dose distribution in these structures and on the ability of the IMRT to shape the high-dose volume in accord with the 3-dimensional outline of the target(s) [3].
Swallowing and mastication involve several nerves, muscles, and connective tissue structures. The inferior, middle, and superior constrictors, innervated by the vagal nerve are the three most important muscles [50, 51]. The mastication structures involved are the pterygoid, masseter, and temporalis muscles, and the mandibular condyle [45, 51–56]. Restricted and/or painful mouth opening affect normal chewing and eating and impair speech and oral hygiene [57, 58].
Normal tissue changes like edema, neuropathy, and fibrosis may impair the swallowing function. Acute toxicities like mucositis and edema commonly disrupt normal swallowing during treatment, but improve substantially in the months following radiotherapy or chemoradiotherapy in a majority of patients. However, neuropathy and fibrosis of the oral, laryngeal, and pharyngeal musculature may develop or persist long after the completion of treatment. These late effects ultimately impair the range of motion of key swallowing structures and have been implicated as the primary mechanisms of long-term dysphagia in HNC survivors [1]. Dysphagia may lead to (silent) aspiration, laryngeal penetration, and excess residue after the swallow and/or reflux [44]. Residue after the swallow is a common source of post-swallow aspiration.
Eisbruch et al. [59] were the first to report that radiation damage to the pharyngeal constrictors and the glottic/supraglottic larynx were implicated in post-RT dysphagia. They suggested that reducing the dose to DARS may lead to improved outcomes. Studies have found significant correlation with dysphagia/aspiration and various dose–volume parameters for the pharyngeal constrictor muscles (superior, medial, and inferior group), esophageal inlet, and glottic and supraglottic larynx [45, 60–62] (Table 11.3).
Table 11.3
Studies assessing correlation of dose and DARS
Author | Year | Dosimetric structure correlated |
|---|---|---|
Eisbruch et al. [59] | 2004 | PCMs (V50) and the glottic and supraglottic larynx (V50) |
Feng et al. [63] | 2007 | PCMs (mean dose, V50, V60, V65) and larynx (mean dose, V50) |
Levendag et al. [54] | 2007 | Superior and middle PCMs (mean dose) |
Jensen et al. [64] | 2007 | Supraglottic larynx (mean dose, median dose, V60, V65) |
Caglar et al. [47] | 2008 | Inferior PCMs and Larynx (both mean dose, V50, D60) |
Caudell et al. [48] | 2009 | Inferior PCMs (V60, V65) and larynx (mean dose, V55, V60, V65, V70) |
Dirix et al. [49] | 2009 | Middle PCMs (mean dose, V50) and supraglottic larynx (mean dose) |
11.3.1 Assessment
Dysphagia has been evaluated by both objective and subjective methods. Many researchers in clinical trials have analyzed the relationship between irradiated structures and dysphagia; the findings of published studies are nearly consistent regarding the crucial structures associated with swallowing dysfunctions. Few of them are mentioned briefly here.
Roe et al. [53] had done a systematic review of the literature on swallowing outcomes after IMRT (1998–2009), identifying 16 papers regarding methodologic quality and method of swallowing assessment. They conclude that if radiation dose to certain structures is limited, a favorable swallowing outcome may be possible. It is evident that it is impossible to compare results across studies due to heterogeneity in the patient population, use of a range of outcome measures that have not been shown to correlate with each other, and limited use of instrumental assessment (i.e., fiberoptic endoscopic evaluation of swallowing [FEES] and VFS). Also, the methods used to delineate and reduce dose to swallowing organs at risk varied.
Eisbruch et al. [59] recognized that muscular components of the swallowing apparatus, critical to the development of dysphagia in irradiated patients, can be spared by IMRT.
A series of trials have been done to establish whether dose reduction to DARS can improve swallowing outcomes for HNC treated by IMRT. The consistent finding that increased radiation dose to a larger volume of the pharyngeal constrictors resulted in higher levels of dysphagia was seen.
Studies that focused on radiation dose reduction and/or structure avoidance, unfortunately, cannot easily be compared, because of their heterogeneity in tumor sites, treatment protocols, and their overall retrospective nature [51, 64]. It is found that there is significant correlation with dysphagia/aspiration and various dose–volume parameters for the pharyngeal constrictor muscles (superior, medial, and inferior group), esophageal inlet, and glottic and supraglottic larynx [60–62, 65].
At the University of Michigan, Feng et al. [66] demonstrated in a group of 73 patients with oropharyngeal cancer that sparing these structures using IMRT is feasible with high LRC rates and very low treatment-related dysphagia. During delineation of the neck nodes, including only the lateral (lying medial to the carotid arteries) retropharyngeal (RP) nodes which are at risk in HNC, Feng et al. [66] could spare the parts of the pharyngeal constrictors medial to the RP nodes, resulting in mild or no dysphagia in almost all patients.
11.3.2 Dose Effect
The use of high-intensity treatments, especially chemoirradiation, has resulted in considerable rates of swallowing dysfunction, both acute (15–23 %) and long term (3–21 %) [65, 67–72].
The dose delivered to the pharyngeal constrictor muscles plays a crucial role in the development of severe late dysphagia/aspiration [45, 47–49, 55–58, 61–73]. With the technical ability of IMRT, this knowledge provides us with both the rationale and the means to reduce the dose to these structures. To obtain this, we can include these structures in the IMRT optimization process; however, the central location of the swallowing structures and the close proximity between tumor and crucial structures make this often an arduous task with only limited dosimetric gain. Multivariate analysis has identified that the bilateral lymph node irradiation was an important independent predictor for swallowing dysfunction 6 months after treatment [74]. The necessity of elective lymph node irradiation in the eradication of subclinical disease has long been established in HNC [75].
Snadra et al. [60] in their analysis demonstrated that dose de-escalation to the elective lymph nodes significantly reduces the volume of the swallowing apparatus irradiated up to a high dose without compromising target coverage and dose homogeneity. This clinically resulted into significantly less grade 3 dysphagia in the de-escalated arm 3 months after treatment with similar LRC and DFS rates. A combination of mucosal swelling and fibrosis of the swallowing muscles causes late dysphagia after radiation [76].
Various authors have confirmed the steep dose–response relationships between dose to different parts of swallowing apparatus and dysphagia in the short to medium term.
Levendag et al. [54] found a 19 % increase in the probability of late dysphagia grade 3/4 (>3 months after completion of the therapy) with every additional 10 Gy after a dose of 55 Gy in superior constrictor muscles
Eisbruch et al. [59] correlated doses with various outcome measures (objective and subjective outcomes) and noted varying correlation of the doses with each outcome measure. It is likely that mean pharyngeal constrictor doses above 45–60 Gy are associated with worse dysphagia.
Caudell et al. [48] have reported a 7–11 % increase in risk for gastrostomy dependence or aspiration with every 1-Gy increase in a mean dose to the larynx or inferior constrictor.
Van der Laan et al. [77] compared in their planning study 30 standard IMRT treatment plans with swallowing-sparing IMRT plans that aimed to reduce the dose to organs at risk for swallowing dysfunction in the same patients. The dose characteristics of the target volumes and normal structures were comparable. After adequate coverage of target volumes and dose to critical structures within acceptable limits were achieved, the mean doses to the various swallowing-related structures were reduced, depending on N classification and primary tumor location. In addition, the observed dose reductions were reflected in reduced estimates of the NTCP (normal tissue complication probability) values for both physician-rated [RTOG grade 3/4, for 9 %] and patient-rated measures for swallowing dysfunction (moderate to severe complaints: for solid food 7.9 %, for soft food 2.4 %, for liquid food 1.4 %, for choking when swallowing 0.9 %).
Lisette van der Molen et al. [78] reported dose–effect relationships between the radiation doses to the critical swallowing and mastication structures and dysphagia and trismus end points. They summarized that objective dysphagia (PAS) correlated significantly to the inferior constrictor (IC) and subjective patient-reported problems with swallowing solids at 10 weeks posttreatment correlated with the radiation dose to the IC and masseter muscle and at 1-year posttreatment to the masseter muscle. Significant associations were found with the radiation doses to the masseter and pterygoid muscles at 10 weeks for trismus. The radiation doses to the masseter, pterygoid, and temporalis muscles and the mandibular condyle at 1 year significantly correlated between patient-perceived limited mouth opening and at 10 weeks posttreatment with only masseter muscle. He concluded that both objective and subjective measurements are valuable for finding dose relationships.
In Feng’s study, significant correlations were observed between aspirations and the mean doses to the PC and GSL, as well as the partial volumes of these structures receiving 50–65 Gy [45]. Both the mean dose to the pharyngeal constrictor muscles and the larynx and the volume of structures receiving 50–60 Gy have been shown to remarkably correlate with the prevalence of dysphagia [33, 49, 55, 60, 66, 68, 73, 76, 78]. These findings imply that limiting the dose to the crucial swallowing structures might decrease both the incidence and severity of radiation-induced dysphagia.
At present, the routine IMRT practice for HNC at the University of Michigan is to keep the mean dose to the noninvolved PC and GSL ≤50 Gy. However, avoiding underdosing to the targets in the vicinity remains the highest priority. In cases of oropharyngeal cancer, the lower neck is either treated with split-field technique in which the glottis larynx and upper esophagus are shielded. Alternatively, whole-neck IMRT is performed while reducing mean doses to the larynx, inferior constrictors, and upper esophagus toward 20 Gy, a dose that is similar to that achieved with split-field IMRT using laryngeal block.
11.4 Hearing Loss
Hearing loss is a common but frequently ignored late complication after RT for HNC. In general, radiation-induced hearing loss includes conductive hearing loss due to damage to the outer and middle ear and sensorineural hearing loss (SNHL) caused by damage to the cochlea and/or the auditory nerve [79], which may result in long-lasting compromise of the quality of life [80]. Good hearing plays an important role in maintaining relationships. The frequent request of others to repeat what has been said might lead to misunderstanding and disruption of relationships and social isolation. It is known that hearing loss may result in serious depression, vertigo, cognitive impairment, and reduction in functional status [79].
Current data from the literature have shown that total radiation dose, cisplatin-based chemotherapy, age, male sex, and hearing deficit before RT are associated with the risk of hearing loss [79].
Patients treated with head and neck IMRT based on audiometric evaluation studies have reported about 0–63 % [79] of hearing loss. Chemoirradiation with cisplatin-based chemotherapy may increase the degree of hearing loss. By decreasing the dose to the cochlea, the incidence of hearing loss may significantly improve.
Cochlea is small in size and lies adjacent to the inner ear; hence, a small deviation of contouring will have a profound effect on hearing loss and defeat the purpose of IMRT. Pacholke et al. [81] established the first guidelines for contouring the middle ear and the two major components of the inner ear (the vestibular apparatus and cochlea). These guidelines have been of practical help to radiation oncologists in the process of radiotherapy planning.
Several studies have attempted to relate mean or median cochlear dose to persistent hearing loss [63, 82, 83] (Table 11.4).
Table 11.4
Studies related to radiation doses and hearing loss
Author | Year | N | Rx | Threshold dose (Gy) | Clinically cochlear damage studied |
|---|---|---|---|---|---|
Grau et al. [84] | 1991 | 22 | RT | 50 | SNHL at high frequencies (2–4 kHz) |
Anteunis et al. [85] | 1994 | 18 | RT | 50 | Conductive and/or SNHL |
Chen et al. [86] | 1999 | 21 | RT | 60 | SNHL |
Honore et al. [87] | 2002 | 20 | RT | 15 | Hearing impairment 0.3 dB/Gy and 15 % risk of SNHL with 15 Gy |
Johannesen et al. [88] | 2002 | 33 | RT or CRT | 54 | >4,000 Hz |
Oh et al. [74] | 2004 | 24 | CRT | 63.4 ± 9.1 | High frequency |
Merchant et al. [75] | 2004 | 72 | RT or CRT | 32 | Low and intermediate frequency (<32 Gy, shunt only); high frequency (>32 Gy, with or without shunt) |
Pan et al. [89] | 2005 | 31 | RT | 45 | ≥2,000 Hz |
Herrmann et al. [90] | 2006 | 32 | RT | 20–25 | ED50 was in range of 20–25 Gy |
Hitchcock et al. [91] | 2009 | 62 | RT | 40 for RT | SNHL |
CRT | 10 for CRT | High-frequency SNHL |
Oh et al. [74] observed a reduction in the radiation dose to the inner ear from 69.6 ± 11.8 to 63.4 ± 9.1 Gy and its resultant reduction in the incidence of SNHL from 68.2 % (15/22) to 0 % (0/8), even though no attempt was made to limit the radiation dose to the inner ear structure on the radiation planning.
Pan et al. [89] did a prospective study to determine the relationship between the RT dose to the inner ear and long-term hearing loss in HNC patients treated with RT. In each patient, hearing in the side that received a high dose to the cochlea was compared longitudinally with hearing on the contralateral side which received substantially lesser dose. This unique analysis potentially reduced bias and effects of aging and systemic therapy on the dose–response relationships. They reported that an increase in the mean dose to the inner ear was associated with increased hearing loss at high frequency (>2,000 Hz) and also clinically apparent hearing loss started at a threshold dose of 45 Gy.
Honore et al. [87] retrospectively estimated mean cochlear doses in 20 patients with HNC (1.8–2.3 Gy/fraction) and observed ∆BCT 7–79 months post-RT. A dose–response relationship was observed only for 4 kHz where BCT > 15 dB.
Chen et al. [86] retrospectively studied 22 patients treated with RT for NPC (1.6–2.3 Gy/fraction and concurrent/adjuvant chemotherapy) and studied ∆BCT 12–79 months post-RT. A significant increase in hearing loss (BCT of 20 dB at one frequency or 10 dB at two consecutive frequencies) was observed for all frequencies (0.5–2 kHz) when the mean dose received by the cochlea was >48 Gy.
Van de Putten [92] retrospectively evaluated ∆BCT 2–7 years after RT in 21 patients with unilateral parotid tumors (fraction sizes 1.8–2.0 Gy). Using the contralateral ear as a control, SNlll (BCT >15 dB difference in three frequencies between 0.25 and 22 kHz) was seen when mean doses received by the cochlea were >50 Gy.
Grau et al. [84] demonstrated that the probability and severity of the loss were correlated with dose and the sound frequency when cochlea received doses of 50–70 Gy leads to hearing loss within 18 months. Also in ¾ of the patients of NPC cases analyzed retrospectively showed that the cochleae lie within the PTV and that their position greatly affects the dose they receive.
At MSKCC, the dose limit to the cochlea for NPC patients is 60 Gy wherever possible given the target constraints with an additional constraint requiring ≥99 % of the GTV to receive ≥70 Gy is used to prevent underdosing the tumor. By IMRT dose painting and the simultaneous boost technique, lower cochlear maximum doses of 30 Gy without compromising target coverage can be achieved.
In a retrospective study of 26 patients with medulloblastoma treated by either conventional RT or IMRT, IMRT delivered 68 % of the radiation dose to the auditory apparatus (mean dose: 36.7 vs. 54.2 Gy), without compromising the target dose [82]. Grade 3 or 4 hearing loss was also reduced at 13 % vs. 64 % (p < 0.014) [93]. Similarly, hearing loss in NPC treated with IMRT is relatively uncommon and less severe.
Sultanem et al. [83] studied IMRT with concurrent and adjuvant cisplatin-based chemotherapy in 32 NPC. From dose–volume histograms (DVHs) analyzed, the average dose to 50 % of the right and left ear volume was 52.0 Gy (range 34.0–71.7 Gy) and 52.2 Gy (range 34.6–64.2 Gy), respectively. At a median follow-up of 21.8 months, only 5 cases developed Grade 3 hearing loss.
Wolden et al. [94] studied IMRT using accelerated fractionation along with concurrent and adjuvant platinum-based chemotherapy in 74 NPC patients (69/74 received CT). No patient had Grade 4 hearing loss at the end of 6 months, and only 15 % had Grade 3 SNHL based on audiograms. The average mean dose received to cochlea was 55.6 Gy.
Due to the large variance in literature reported incidence of hearing loss, future toxicity studies are still needed, such as multi-institutional or larger single prospective trials utilizing both pre- and posttreatment hearing tests, in order to determine absolute hearing loss as a function of frequency and the absolute radiation dose received by each cochlea. Moreover, due to the wide use of combined chemoradiotherapy, the response of SNHL to chemoradiation also needs to be established in prospective trials as a function of both cisplatin and radiation doses, as well as chemoregimen (neoadjuvant, concurrent, or adjuvant).
At the University of Michigan, the dose constraint for cochlea is 40 Gy if the target is close to the cochlea, as may be the case in advanced nasopharyngeal cancer. If the target is not close, we prefer to reduce the dose as much as possible to <30 Gy.
11.5 Larynx
The primary goals of larynx preservation are to assure speech and swallowing function. Radiotherapy may cause progressive edema, lymphatic disruption, and associated fibrosis, which can lead to long-term problems with phonation and swallowing [95].
Locally advanced laryngeal cancer frequently causes voice and swallowing dysfunction, including aspiration that might not improve even if the cancer has been eradicated. These are the main reasons patients presenting with marked laryngeal dysfunction are advised to undergo laryngectomy rather than a trial of chemo-RT. The addition of concurrent chemotherapy to high-dose, extensive-field RT worsens substantially the risk of laryngeal edema and dysfunction. RT without chemotherapy, delivered to small fields for stage T1 glottic larynx cancer, usually results in excellent voice quality [96].
Vocal function is assessed objectively using instruments like videostroboscopy for direct visualization to assess supraglottic activity, vocal fold edge, amplitude, mucosal wave, phase symmetry, and glottis closure [97], aerodynamic measurements of phonation time [98], or human observation [99] as subjective assessments can be made with validated patient-focused questionnaires to assess various combinations of voice, eating, speech, and social function.
Flexible fiberoptic examination is used to assess edema. As per RTOG scale [100], Grade 1 edema would correspond to “minimal” thickening of the epiglottis, aryepiglottic folds, arytenoids, and false cords. Grade 2 is a more diffuse and evident edema, although still without significant or symptomatic airway obstruction.
Due to the small size and close proximity of these vocal structures, high-resolution, contrast-enhanced computed tomography facilitates accurate substructure definition. The identification of the most important anatomic sites, whose dose–volume parameters would primarily affect vocal function, is of paramount importance. Various authors suggest different structures for planning purposes; Sanguineti et al. [99] considered the larynx from the tip of the epiglottis superiorly to the bottom of the cricoid inferiorly; the external cartilage framework was excluded from the laryngeal volume. Dornfeld et al. [100] considered the dose points in various structures (e.g., base of tongue, epiglottis, lateral pharyngeal walls, pre-epiglottic space, aryepiglottic folds, false vocal cords, and upper esophageal sphincter) to be related to vocal injury.
The exact correlation between voice abnormalities and the degree of laryngeal edema has not been assessed. Pre-RT voice abnormalities have not been considered in most studies and hence might have overestimated the degree of RT-related damage. Many studies have shown a good voice outcome after RT for Stage T1 laryngeal cancer (typically 60–66 Gy without chemotherapy). In the locally advanced setting, less information is available regarding voice quality after treatment.
Dornfeld et al. [100] found a strong correlation between speech and doses delivered to the aryepiglottic folds, pre-epiglottic space, false vocal cords, and lateral pharyngeal walls at the level of the false vocal cords. In particular, they noted a steep decrease in function after 66 Gy to these structures. Their study was limited by not having full three-dimensional dose metrics.
Fung et al. [96] evaluated the subjective and objective parameters of vocal function. Changes in voice were related to doses to the larynx and pharynx and oral cavity. They suggest that saliva, pharyngeal lubrication, and soft tissue/structural changes within the surrounding musculature play an important role in voice function.
Sanguineti et al. [99] found that neck stage, nodal diameter, mean laryngeal dose, and percentage of laryngeal volume receiving ≥30–70 Gy were all significantly associated with edema Grade 2 or greater on univariate analysis. On multivariate analysis, the mean laryngeal dose or percentage of volume receiving ≥50 Gy and neck stage were the only independent predictors.
Rancati et al. [101] studied two normal tissue complication probability models (the Lyman–Kutcher–Burman model and the logit model) with the dose–volume histogram reduced to the equivalent uniform dose (EUD). A significant volume effect was found for edema, consistent with a prevalent parallel architecture of the larynx for this endpoint. These findings suggested an EUD of <30–35 Gy to reduce the risk of Grade 2–3 edema.
Longitudinal studies consisting of objective scoring of laryngeal edema, voice quality, and patient-reported measures are necessary to assess the intercorrelations among these measures. Such studies should include pretherapy assessments to account for tumor-related voice abnormalities and should concentrate on patients receiving concurrent chemo-RT who are at the greatest risk of laryngeal toxicity.
The surrounding tissues might be indirectly affected by a reduction in salivary function or directly by effects on the intrinsic musculature and soft tissue. From the published data, it seems reasonable to suggest limiting the mean noninvolved larynx dose to 40–45 Gy and limiting the maximal dose to <63–66 Gy, if possible, according to the tumor extent. To minimize the risks of laryngeal edema, it is recommended that the percentage of larynx volume receiving ≥50 Gy be < 27 % and the mean laryngeal dose ≤ 44 Gy [102].
At the University of Michigan, 91 patients with stage III/IV oropharyngeal cancer were treated on two consecutive prospective studies of definitive chemoradiation using whole-field IMRT from 2003 to 2011. Patient-reported voice and speech quality were longitudinally assessed from pretreatment through 24 months using the Communication Domain of the Head and Neck Quality of Life (HNQOL-C) instrument and the speech question of the University of Washington QOL (UWQOL-S) instrument, respectively. Factors associated with patient-reported voice quality worsening from baseline and speech impairment were assessed. The results demonstrated that patient-reported voice quality decreased maximally at 1 month, with 68 and 41 % of patients reporting worse HNQOL-C and UWQOL-S scores compared to pretreatment, and improved thereafter, recovering to baseline by 12–18 months on average. In contrast, observer-rated larynx toxicity was rare (7 % at 3 months; 5 % at 6 months). Among patients with mean glottic larynx (GL) dose ≤20 Gy, >20–20 Gy, >30–20 Gy, >40–20 Gy, and >50 Gy, 10, 32, 25, 30, and 63 % reported worse voice quality at 12 months compared to pretreatment (p = 0.011). Results for speech impairment were similar. GL dose, N-stage, neck dissection, oral cavity dose, and time since chemo-IMRT were univariately associated with either voice worsening or speech impairment. On multivariate analysis, mean GL dose remained independently predictive for both voice quality worsening (8.1 % per Gy) and speech impairment (4.3 % per Gy). We concluded that voice quality worsening and speech impairment after chemo-IMRT were frequently reported by patients, under-recognized by clinicians, and independently associated with GL dose. These findings support limiting mean GL dose to <20 Gy during whole-neck IMRT when the larynx is not a target [103].
11.6 Neural Structures
11.6.1 Spinal Cord
The Spinal cord extends from the base of the skull through the top of the lumbar spine; individual nerves continue down to the spinal canal to the level of the pelvis. The spinal cord consists of gray and white matter similar to the brain. However, the gray matter is internalized with a butterfly arrangement in transverse section consisting of dorsal and anterior columns. The white matter is the external coat composed of nerve fibers, an inconspicuous vasculature, and glial cells. The concentric myelin sheath that surrounds the axon is formed by the cytoplasmic processes of oligodendrocytes. The reflex motor actions following stimulus enter via the afferent posterior sensory arc and leave delivered by the efferent anterior synapse or arc. The blood supply is via the anterior spinal artery and two posterior spinal arteries, with the longest branches occurring in the thoracic cord. Unique to the spinal cord is interruption or transection of any segment defunctionalizes the caudal extension. One of the most dreaded radiation injuries is a transverse myelopathy that leads to paraparesis or paralysis of the limbs with loss of bladder and rectal sphincter control.
Portions of the spinal cord are often included in radiotherapy (RT) fields for treatment of malignancies involving the neck. RT-induced spinal cord injury (i.e., myelopathy) can be severe, resulting in pain, paresthesias, sensory deficits, paralysis, Brown-Sequard syndrome, and bowel/bladder incontinence [104].
Radiation-induced transverse myelitis is an irreversible process with no effective treatment [105]. The damage that occurs after excessive doses of radiation does not manifest itself until late, 6–24 months after treatment, because the tissues that are damaged are slowly proliferating [105, 106]. Symptoms, usually paresthesias, appear from 6 months to 2 years after completion of radiation therapy and may progress to total paralysis [107].
Lhermitte’s sign (LS) is an electric shock-like sensation in the spine and extremities exacerbated by neck flexion. It is caused by reversible demyelination of ascending sensory neurons due to inhibition of oligodendrocyte proliferation after radiotherapy (RT) of the cervical or thoracic spine [108–110]. The denuded axons become sensitive to irritation from neck flexion, causing the characteristic shock sensations. Once oligodendrocytes recover and myelin synthesis is resumed, symptoms subside. Although LS is not usually associated with a progression to chronic progressive irreversible myelitis, delayed radiation myelopathy causing paralysis may be preceded by LS [111].
There are four clinical syndromes of radiation myelopathy as described by Reagan et al. [105]. The first is acute transient radiation myelopathy, distinguished by the presence of Lhermitte’s sign. It is the most common myelopathy and is associated with no other abnormalities on neurologic examination. The second syndrome is an acutely developing paraplegia or quadriplegia, presumably secondary to an infarction of the spinal cord because of radiation damage to the blood vessels. The third syndrome is manifested by signs of lower motor-neuron disease in the upper or lower extremities, presumably the result of selective anterior horn-cell damage. These latter two syndromes are exceedingly rare; the final syndrome is chronic progressive radiation myelopathy, the only syndrome for which pathologic findings have been described. This is the syndrome that most concerns radiation oncologists, for it is progressive and permanent and often leads to the development of a fatal complication such as infection or pulmonary embolus [104].
The incidence of permanent injury to the spinal cord as a complication of radiation therapy generally correlates positively with total radiation dosage. The pathogenesis of radiation injury is believed to be primarily from vascular/endothelial damage, glial cell injury, or both [112, 113]. The clinical endpoint in most studies is paralysis, with the spinal cord showing nonspecific white matter necrosis. Several animal study reports suggest regional differences in radiosensitivity across the spinal cord [112, 114].
Phillips and Buschke [113] concluded that the number of fractions was the most important factor in the development of late radiation damage to the spinal cord. They reported on the incidence of myelitis after treatment to portions of the cervical or thoracic spine correlating dosages with number of fractions. They found that a line connecting 6,000 cGy in 35 fractions in 7 weeks (171.5 cGy per fraction) or 5,000 cGy in 25 fractions in 5 weeks (200 cGy per fraction) excluded all their myelitis cases. Van der Kogel [114] also concluded that the spinal cord tolerance depended more on the number of fractions and less on overall treatment time.
Abbatucci [115] concluded that 5,000 cGy in 25 fractions could be tolerated safely if not more than 3–5 vertebral segments were involved. Kim and Fayos [116] also concluded that short lengths of spinal cord could safely tolerate 6,000 cGy in fractions of 180–200 cGy. They also suggested that fraction size was one of the most important factors in determining myelopathy.
McCunniff and Liang [117] observed that when doses higher than 6,000 cGy to the cervical spinal cord with fractions ranging from 133 to 180 cGy, only 1 developed spinal cord damage. They concluded that radiation injuries correlated not only with the total dose but also with fraction size.
Marcus and Million [118] reported that the risk of myelitis was 0/124 for a dose range 3,000–3,999 cGy, 0/442 for 4,000–4,499 cGy, 2/471 for 4,500–4,999, and 0/ 75 for 5,000 cGy or greater. They concluded that a risk of less than 0.5 % is often worth taking if it is necessary to treat a tumor near the spinal cord to a dose near 5,000 cGy and that a total dose of 5,500 given in fractions of less than 200 cGy was associated with a very low risk of permanent neurologic damage.
With conventional fractionation of 2 Gy per day, a total dose of 50 Gy, 60 Gy, and 69 Gy is associated with a 0.2, 6, and 50 % rate of myelopathy [119] (Table 11.5).
Table 11.5
Studies related to myelopathy
Author | Total dose | Fraction | 2 Gy dose equivalenta | n | Myelopathy | Myelopathy probabilityb |
|---|---|---|---|---|---|---|
Marcus and Million [118]
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