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Clinical and dosimetric implications of intensity-modulated radiotherapy for early-stage glottic carcinoma
Medical Dosimetry ] (2015) ]]]–]]]
Medical Dosimetry journal homepage: www.meddos.org
Clinical and dosimetric implications of intensity-modulated radiotherapy for early-stage glottic carcinoma Matthew Christopher Ward, M.D., Yvonne D. Pham, M.D., Rupesh Kotecha, M.D., Sara J. Zakem, B.S., Eric Murray, C.M.D., and John F. Greskovich, M.D., M.B.A. Department of Radiation Oncology, Taussig Cancer Institute, Cleveland, OH
A R T I C L E I N F O
A B S T R A C T
Article history: Received 8 February 2015 Received in revised form 19 June 2015 Accepted 31 August 2015
Conventional parallel-opposed radiotherapy (PORT) is the established standard technique for early-stage glottic carcinoma. However, case reports have reported the utility of intensity-modulated radiotherapy (IMRT) and volumetric-modulated arc therapy (VMAT) with or without image guidance (image-guided radiotherapy, IGRT) in select patients. The proposed advantages of IMRT/VMAT include sparing of the carotid artery, thyroid gland, and the remaining functional larynx, although these benefits remain unclear. The following case study presents a patient with multiple vascular comorbidities treated with VMAT for early-stage glottic carcinoma. A detailed explanation of the corresponding treatment details, dose-volume histogram (DVH) analysis, and a review of the relevant literature are provided. Conventional PORT remains the standard of care for early-stage glottic carcinoma. IMRT or VMAT may be beneficial for select patients, although great care is necessary to avoid a geographical miss. Clinical data supporting the benefit of CRT are lacking. Therefore, these techniques should be used with caution and only in selected patients. & 2015 American Association of Medical Dosimetrists.
Keywords: IMRT Early-stage glottis cancer VMAT Carotid sparing
Introduction Early-stage glottic carcinoma is a highly curable cancer of the true vocal folds. Owing to the sensitive location on the vocal folds, patients typically develop progressive painless hoarseness early in the course of the disease and present with small (American Joint Committee on Cancer stage I-II) superficial lesions of the mucosa with minimal invasion. Therapies are intended to provide both excellent oncologic outcomes and voice preservation. For early lesions, microsurgery is possible with excellent voice outcomes, but for bulky, recurrent, or deeply invasive lesions, radiotherapy (RT) has been the accepted standard of care rather than total laryngectomy. RT is typically delivered via parallel-opposed beams to doses between 60 and 70 Gy. Recently highly conformal techniques such as step-and-shoot intensity-modulated radiotherapy (IMRT) or volumetric-modulated arc therapy (VMAT) have been described but carry a risk of geographical miss with unclear benefits. We present a case of early-stage glottic carcinoma
Reprint requests to Matthew Christopher Ward, M.D., Department of Radiation Oncology, Taussig Cancer Institute, 9500 Euclid Avenue, T28, Cleveland, Ohio 44195. E-mail: [email protected] http://dx.doi.org/10.1016/j.meddos.2015.08.004 0958-3947/Copyright Copyright Ó 2015 American Association of Medical Dosimetrists
followed by the rationale for IMRT/VMAT techniques and a review of the current literature addressing their use.
Case Description A 79-year-old man who is an avid singer with an 80 pack-year smoking history presented to his primary care physician with a 2month history of hoarseness. His medical history was significant for coronary artery disease, chronic obstructive pulmonary disease, sleep apnea, obesity, hyperlipidemia, and hypertension. He was otherwise well with an excellent performance status. Flexible laryngoscopy and subsequent biopsy (Fig. 1) showed a T1bN0M0 stage I squamous cell carcinoma of the true glottis. Clinical decision making On presentation to the radiation oncologist, treatment options were discussed, including surgery (total or partial laryngectomy, transoral laser microsurgery, and transoral robotic surgery) vs definitive RT. RT was recommended to a dose of 63 Gy in 28 fractions.1 Given the anterior location on the vocal fold and his known vascular comorbidities, a course of carotid-sparing IMRT was recommended.
2
M.C. Ward et al. / Medical Dosimetry ] (2015) ]]]–]]]
was also well within the constraints listed on modern head and neck trials. The time required to deliver treatment was extended with the VMAT plan compared with the 3D-CRT. The beam-on time to deliver the VMAT plan was 37 seconds and the predicted time for delivery of the parallel-opposed plan was estimated to be 38 seconds. In addition, the time to acquire the CBCT is on average 35 seconds, with alignment verification and shifts requiring approximately 3 to 5 minutes. The total difference in treatment time is therefore approximately 45 seconds for the 3D-CRT plan compared with 5 to 6 minutes for the image-guided VMAT plan. Clinical outcome Fig. 1. Initial flexible laryngoscopic evaluation demonstrating an exophytic mass arising from the left true vocal fold posterior to the anterior commissure and extending to the vocal process of the arytenoid. For orientation, the anterior commissure is shown at the bottom of the image with the patient's right on the image's left. The tracheal rings are seen below the vocal folds. (Color version of figure is available online.)
Treatment planning
The treatment was completed in 38 days without treatment breaks. Acute hoarseness was experienced with some fatigue as expected, but otherwise no significant acute toxicity was appreciated. At 1 year after treatment the patient's singing voice was improved when compared with the pretreatment baseline; all detectable acute toxicity had resolved, and flexible laryngoscopic stroboscopy showed a complete response to RT with an intact mucosal wave(Fig. 5).
A noncontrasted computed tomography (CT) simulation was performed using a 5-point aquaplast mask for immobilization with mild extension of the neck. Target volumes were contoured using a high-dose and a low-dose clinical target volume (CTV, Fig. 2). The known gross disease along the left and the anterior right vocal folds was included in the high-dose CTV63 (red contour in Fig. 2). The low-dose CTV51.8 (yellow contour in Fig. 2) included a 3-mm superior-inferior expansion on the CTV63 as well as elective treatment of the entire posterior right vocal fold and left arytenoid cartilage. A 2-mm planning target volume was uniformly added to each CTV as per our institution's standard when daily IGRT was applied. When counseling the patient, emphasis was placed on the importance of not swallowing. Organs at risk (OARs) included the bilateral carotid arteries, posterior pharyngeal wall (constrictor muscles), thyroid gland, esophagus, supraglottic larynx, and submandibular glands. A VMAT plan was generated using 2 partial arcs with gantry angles ranging between 921 and 2681 (with the patient facing 01) using 6-MV photons prescribed to the 96.5% isodose line. Daily image guidance with a 120-kV cone beam CT (CBCT) was used with primary alignment to the nearby vertebral bodies and secondary alignment to the target volumes of the soft tissues of the larynx. The plan was generated using Pinnacle treatment planning system version 9.6 (Philips Healthcare, Netherlands). The plan was delivered on the Novalis TX radiosurgery system (Brainlab, Feldkirchen, Germany) with 2.5-mm multileaf collimators at a dose rate of 400 monitor units per minute. Heterogeneity corrections were applied and the dose was calculated using the collapsed cone convolution method. To compare, a classic 3-dimensional conformal (3D-CRT) plan was also generated using equally weighted parallel-opposed beams with gantry angles of 901 and 2701 to a field size of 6.5 6 cm with a 301 wedge and no control points. Dosimetric parameters are listed in the Table with dose-volume histograms shown in Fig. 3. Comparative sideby-side treatment plans with representative isodose lines are shown in Fig. 4.
Early-stage larynx cancer presents special issues related to dosimetry and motion management. Targeting a superficial tumor at an air-tissue interface requires attention to the coverage within the dose buildup region of the beam.4 Although underdosage of the tumor is a potential issue, it is known that a degree of compensation exists for treatments with multiple beam angles when compared with a 2-field design and therefore is not likely a significant issue for low-energy beams.5-7 More importantly, swallowing motion requires special consideration. Larynx motion during swallowing covers an average distance of 1.6 cm and a maximum of 3.1 cm superiorly.8 This presents 2 problems: First, modern helical CT scanners used for simulation are fast enough to capture a larynx midswallow, potentially leading to incorrect isocenter placement and incorrect planning. Second, with the advent of rapid VMAT treatments, an improperly timed swallow could cause the vocal cords to be displaced throughout the fraction. Image-guided RT is a necessity in these cases, but consideration of the slower speed of CBCT when compared with helical CT simulation must be considered. Patients must be instructed not to swallow before simulation, CBCT, and treatment delivery, and failure to do so may result in a geographical miss.
Plan evaluation
Clinical experience to support IMRT use
Comparison between the 3D-CRT and VMAT plans showed excellent coverage of the target volumes with a reduced dose to nearly all measured structures in the VMAT plan with the exception of the spinal cord (Table). Doses to most of the critical organs were well less than conventional limits, including the esophagus, spinal cord, and submandibular glands. The cervical esophagus
The dosimetric benefits of IMRT for early-stage glottic cancer have been previously documented,9-16 but the clinical outcomes remain limited. Beyond case reports, a single institutional experience from Jansseen et al. forms most of the published clinical experience with IMRT for early-stage glottic cancer. Of the 77 patients included in the report, 21 were treated with definitive
Discussion Although the use of IMRT has markedly reduced the rates of acute and late treatment-related toxicities without compromising tumor control in other head and neck sites, the efficacy and safety of IMRT have not yet been evaluated in the setting of the mobile, small target volumes associated with early-stage glottic carcinoma.2,3 We weigh the potential benefits of IMRT against the risk of geographical miss. Will IMRT show similar rates of disease control to 3D-CRT?
M.C. Ward et al. / Medical Dosimetry ] (2015) ]]]–]]]
3
Fig. 2. Axial CT images at time of simulation (table position z ¼ 40.6 slice A through z ¼ 45.1 cm for slice I) showing target volumes and organs at risk (OARs). Target volumes include the CTV63 (red), which was expanded 3-mm superior-inferior to include the entire posterior right vocal fold and left arytenoid cartilage to create CTV51.8 (yellow). Normal structures include the bilateral common carotid arteries (pink), pharyngeal constrictors (brown), supraglottis (blue), thyroid gland (orange), submandibular glands (green), and esophagus (white). (Color version of figure is available online.)
carotid-sparing IMRT for T1-2N0 disease. In these patients, a mean dose of 29.4 Gy to the ipsilateral carotid was achieved.17 The local tumor control for the entire cohort was 77%, although the results
for T1-2N0 were not specifically reported. Certainly, additional experience is necessary if IMRT is to become a standard option for these patients.
M.C. Ward et al. / Medical Dosimetry ] (2015) ]]]–]]]
4
Table Dosimetric comparison between 3D-CRT and VMAT plans. V50 is the percentage of the structure receiving at least a 50-Gy dose. V50 was chosen as an arbitrary representation of the higher isodose lines 3D-CRT
VMAT
CTV63 (V63) Max point
99.9% 68.9 Gy
99.7% 65.5 Gy
5
CTV51.8 (V51.8)
100%
100%
0
Right carotid Mean Max V50
26.3 Gy 65.9 Gy 21.1%
13.7 Gy 28.8 Gy 0.0%
48 56 100
Left carotid Mean Max V50
27.9 Gy 67.7 Gy 22.6%
15.7 Gy 32.2 Gy 0.0%
44 52 100
Thyroid
25.2 Gy
11.7 Gy
54
Esophagus (max)
40.3 Gy
32.9 Gy
18
Pharyngeal constrictors Mean Max V50
24.2 Gy 69.1 Gy 27.7%
16.3 Gy 60.1 Gy 1.0%
33 13 96
Supraglottis (mean)
65.4 Gy
44.7 Gy
32
Left submandibular gland Mean Max
6.6 Gy 67.2 Gy
1.5 Gy 10.2 Gy
77 85
Right submandibular gland Mean Max
4.9 Gy 62.0 Gy
1.2 Gy 7.8 Gy
76 87
it is safe to say that the risk of dysphagia or vocal dysfunction alone may not be high enough to warrant the use of IMRT.
% Reduction
Cerebrovascular disease
Spinal cord Max
The most significant possible toxicity of early-stage glottic irradiation may be stroke associated with irradiation of the carotid artery. A recent Surveillance, Epidemiology, and End Results (SEER) report investigating the risk of fatal cerebrovascular accidents (CVA) after RT vs surgery for T1 glottic cancer showed that the 15-year risk of fatal CVA increased from 1.5% with surgery to 2.8% with RT (n ¼ 8721, hazard ratio ¼ 1.75, 95% CI: 1.04 to 2.96; p ¼ 0.0437).21 Another SEER analysis including a more broad definition of CVA showed that the 10-year risk increased with the use of RT, although the difference was not statistically significant (56.5% with RT vs 48.7% with surgery, p ¼ 0.27).22 Although these are the only data specific to early-stage glottic cancer, an additional SEER analysis compiling multiple head and neck sites showed that definitive RT increases the 10-year risk of cerebrovascular disease from 26% in those treated with surgery alone to 34% in those treated with definitive RT.23 Other series investigating carotid stenosis have agreed with these results and established a dose-response relationship.24,25 Perhaps IMRT/ VMAT techniques could reduce the rate of vascular complications after RT.
Hypothyroidism 2.5 Gy
19.8 Gy
792
What is the toxicity that needs improvement? Parallel-opposed 3D-CRT for early-stage glottic carcinoma is perhaps the least toxic definitive RT regimen for head and neck cancer. However, it is not without risks. The rates of severe (Common Terminology Criteria for Adverse Events grade 3 or higher) late toxicity for definitive treatment of early-stage glottic carcinoma are typically between 0% and 3% in most series.1,18-20 However, it is important to note that these series only investigated swallowing and voice outcomes. Based on this clinical experience,
Another OAR that may be substantially spared with IMRT is the thyroid gland. The risk of hypothyroidism after RT appears significant, perhaps as high as 48%.26-28 In a study investigating patients treated specifically for early-stage laryngeal cancer, the risk of hypothyroidism was 30% (subclinical and clinical combined), therefore showing that there is room for improvement.29 The literature evaluating the thyroid dosimetric benefit of IMRT for early-stage glottic cancer is limited, but a report on 15 patients showed a 32% reduction in the mean dose to the thyroid gland with a 93% reduction in V50.30 Although hypothyroidism is a relatively benign toxicity when considering RT for head and neck cancer, the potential cost savings by decreasing the need for lifetime thyroid-replacement medication is a valid end point to consider.
Fig. 3. Dose-volume histogram (DVH) showing comparison of the VMAT (solid line) vs parallel-opposed conventional radiotherapy (dashed line) plans. Target volumes shown include the CTV63 (red) and CTV51.8 (gray). OARs include left and right common carotid arteries (pink), supraglottis (blue), thyroid (orange), cervical esophagus (black), pharyngeal constrictors (brown), and submandibular glands (green). (Color version of figure is available online.)
M.C. Ward et al. / Medical Dosimetry ] (2015) ]]]–]]]
5
Fig. 4. Axial, sagittal, and coronal isodose lines comparing VMAT (left) vs opposed lateral (right) plans. The red isodose line represents the 63-Gy prescription line and the green represents the 51.8-Gy isodose line. The lowest isodose line shown represents the 20-Gy distributions (purple). (Color version of figure is available online.)
Voice and swallowing function The final OARs that may be spared are the supraglottic larynx and hypopharynx. The rates of severe (Common Terminology Criteria for Adverse Events grade 3 or higher) late dysphagia or voice toxicity for definitive treatment of early-stage glottic carcinoma are typically between 0% and 3% in most series.1,18-20 Previous reports have established the role of the supraglottic larynx and the hypopharynx in toxicity after head and neck RT.31-34 These reports, of course, are all in the setting of locoregionally advanced cancers. To date, there are no clinical reports of significant improvement with sparing of these structures using IMRT in early-stage glottic carcinoma, but our study shows that the mean doses are decreased. As differences may be small,
detailed prospective patient-reported voice and swallowing outcomes may be required to document any benefit.
Conclusion There remain nontrivial risks to standard parallel-opposed RT for early-stage glottic carcinoma, including cerebrovascular disease and hypothyroidism. Although these toxicities may improve with the use of IMRT/VMAT techniques, long-term clinical data are lacking, and there exists a significant chance of geographical miss due to setup error or swallowing motion. With caution, IMRT/ VMAT could be considered a reasonable option for compliant patients with vascular comorbidities.
6
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12. 13. 14.
15. 16.
17.
Fig. 5. Posttreatment office laryngoscopy showing an early complete response to radiotherapy at 1 month after completion. Orientation is similar to Fig. 1. Compare the exophytic white mass on the vocal fold that is now resolved to smooth mucosa. (Color version of figure is available online.)
18.
19. 20.
References 1. Yamazaki, H.; Nishiyama, K.; Tanaka, E.; et al. Radiotherapy for early glottic carcinoma (T1N0M0): Results of prospective randomized study of radiation fraction size and overall treatment time. Int. J. Radiat. Oncol. Biol. Phys. 64:77–82; 2006. 2. Gupta, T.; Agarwal, J.; Jain, S.; et al. Three-dimensional conformal radiotherapy (3D-CRT) versus intensity modulated radiation therapy (IMRT) in squamous cell carcinoma of the head and neck: A randomized controlled trial. Radiother. Oncol. 104:343–8; 2012. 3. Vergeer, M.R.; Doornaert, P.A.; Rietveld, D.H.; et al. Intensity-modulated radiotherapy reduces radiation-induced morbidity and improves health-related quality of life: Results of a nonrandomized prospective study using a standardized follow-up program. Int. J. Radiat. Oncol. Biol. Phys. 74:1–8; 2009. 4. Martens, C.; Reynaert, N.; De Wagter, C.; et al. Underdosage of the upper-airway mucosa for small fields as used in intensity-modulated radiation therapy: A comparison between radiochromic film measurements, Monte Carlo simulations, and collapsed cone convolution calculations. Med. Phys. 29:1528–35; 2002. 5. Capote, R.; Sanchez-Doblado, F.; Leal, A.; et al. An EGSnrc Monte Carlo study of the microionization chamber for reference dosimetry of narrow irregular IMRT beamlets. Med. Phys. 31:2416–22; 2004. 6. Panettieri, V.; Barsoum, P.; Westermark, M.; et al. AAA and PBC calculation accuracy in the surface build-up region in tangential beam treatments. Phantom and breast case study with the Monte Carlo code PENELOPE. Radiother. Oncol. 93:94–101; 2009. 7. Chow, J.C.; Jiang, R.; Leung, M.K. Dosimetry of oblique tangential photon beams calculated by superposition/convolution algorithms: A Monte Carlo evaluation. J. Appl. Clin. Med. Phys. 12:3424; 2011. 8. Bradley, J.A.; Paulson, E.S.; Ahunbay, E.; et al. Dynamic MRI analysis of tumor and organ motion during rest and deglutition and margin assessment for radiotherapy of head-and-neck cancer. Int. J. Radiat. Oncol. Biol. Phys. 81: e803–e812; 2011. 9. Chera, B.S.; Amdur, R.J.; Morris, C.G.; et al. Carotid-sparing intensity-modulated radiotherapy for early-stage squamous cell carcinoma of the true vocal cord. Int. J. Radiat. Oncol. Biol. Phys. 77:1380–5; 2010. 10. Rosenthal, D.I.; Fuller, C.D.; Barker Jr. J.L.; et al. Simple carotid-sparing intensitymodulated radiotherapy technique and preliminary experience for T1-2 glottic cancer. Int. J. Radiat. Oncol. Biol. Phys. 77:455–61; 2010. 11. Gomez, D.; Cahlon, O.; Mechalakos, J.; et al. An investigation of intensitymodulated radiation therapy versus conventional two-dimensional and 3D-
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Medical Dosimetry journal homepage: www.meddos.org
Clinical and dosimetric implications of intensity-modulated radiotherapy for early-stage glottic carcinoma Matthew Christopher Ward, M.D., Yvonne D. Pham, M.D., Rupesh Kotecha, M.D., Sara J. Zakem, B.S., Eric Murray, C.M.D., and John F. Greskovich, M.D., M.B.A. Department of Radiation Oncology, Taussig Cancer Institute, Cleveland, OH
A R T I C L E I N F O
A B S T R A C T
Article history: Received 8 February 2015 Received in revised form 19 June 2015 Accepted 31 August 2015
Conventional parallel-opposed radiotherapy (PORT) is the established standard technique for early-stage glottic carcinoma. However, case reports have reported the utility of intensity-modulated radiotherapy (IMRT) and volumetric-modulated arc therapy (VMAT) with or without image guidance (image-guided radiotherapy, IGRT) in select patients. The proposed advantages of IMRT/VMAT include sparing of the carotid artery, thyroid gland, and the remaining functional larynx, although these benefits remain unclear. The following case study presents a patient with multiple vascular comorbidities treated with VMAT for early-stage glottic carcinoma. A detailed explanation of the corresponding treatment details, dose-volume histogram (DVH) analysis, and a review of the relevant literature are provided. Conventional PORT remains the standard of care for early-stage glottic carcinoma. IMRT or VMAT may be beneficial for select patients, although great care is necessary to avoid a geographical miss. Clinical data supporting the benefit of CRT are lacking. Therefore, these techniques should be used with caution and only in selected patients. & 2015 American Association of Medical Dosimetrists.
Keywords: IMRT Early-stage glottis cancer VMAT Carotid sparing
Introduction Early-stage glottic carcinoma is a highly curable cancer of the true vocal folds. Owing to the sensitive location on the vocal folds, patients typically develop progressive painless hoarseness early in the course of the disease and present with small (American Joint Committee on Cancer stage I-II) superficial lesions of the mucosa with minimal invasion. Therapies are intended to provide both excellent oncologic outcomes and voice preservation. For early lesions, microsurgery is possible with excellent voice outcomes, but for bulky, recurrent, or deeply invasive lesions, radiotherapy (RT) has been the accepted standard of care rather than total laryngectomy. RT is typically delivered via parallel-opposed beams to doses between 60 and 70 Gy. Recently highly conformal techniques such as step-and-shoot intensity-modulated radiotherapy (IMRT) or volumetric-modulated arc therapy (VMAT) have been described but carry a risk of geographical miss with unclear benefits. We present a case of early-stage glottic carcinoma
Reprint requests to Matthew Christopher Ward, M.D., Department of Radiation Oncology, Taussig Cancer Institute, 9500 Euclid Avenue, T28, Cleveland, Ohio 44195. E-mail: [email protected] http://dx.doi.org/10.1016/j.meddos.2015.08.004 0958-3947/Copyright Copyright Ó 2015 American Association of Medical Dosimetrists
followed by the rationale for IMRT/VMAT techniques and a review of the current literature addressing their use.
Case Description A 79-year-old man who is an avid singer with an 80 pack-year smoking history presented to his primary care physician with a 2month history of hoarseness. His medical history was significant for coronary artery disease, chronic obstructive pulmonary disease, sleep apnea, obesity, hyperlipidemia, and hypertension. He was otherwise well with an excellent performance status. Flexible laryngoscopy and subsequent biopsy (Fig. 1) showed a T1bN0M0 stage I squamous cell carcinoma of the true glottis. Clinical decision making On presentation to the radiation oncologist, treatment options were discussed, including surgery (total or partial laryngectomy, transoral laser microsurgery, and transoral robotic surgery) vs definitive RT. RT was recommended to a dose of 63 Gy in 28 fractions.1 Given the anterior location on the vocal fold and his known vascular comorbidities, a course of carotid-sparing IMRT was recommended.
2
M.C. Ward et al. / Medical Dosimetry ] (2015) ]]]–]]]
was also well within the constraints listed on modern head and neck trials. The time required to deliver treatment was extended with the VMAT plan compared with the 3D-CRT. The beam-on time to deliver the VMAT plan was 37 seconds and the predicted time for delivery of the parallel-opposed plan was estimated to be 38 seconds. In addition, the time to acquire the CBCT is on average 35 seconds, with alignment verification and shifts requiring approximately 3 to 5 minutes. The total difference in treatment time is therefore approximately 45 seconds for the 3D-CRT plan compared with 5 to 6 minutes for the image-guided VMAT plan. Clinical outcome Fig. 1. Initial flexible laryngoscopic evaluation demonstrating an exophytic mass arising from the left true vocal fold posterior to the anterior commissure and extending to the vocal process of the arytenoid. For orientation, the anterior commissure is shown at the bottom of the image with the patient's right on the image's left. The tracheal rings are seen below the vocal folds. (Color version of figure is available online.)
Treatment planning
The treatment was completed in 38 days without treatment breaks. Acute hoarseness was experienced with some fatigue as expected, but otherwise no significant acute toxicity was appreciated. At 1 year after treatment the patient's singing voice was improved when compared with the pretreatment baseline; all detectable acute toxicity had resolved, and flexible laryngoscopic stroboscopy showed a complete response to RT with an intact mucosal wave(Fig. 5).
A noncontrasted computed tomography (CT) simulation was performed using a 5-point aquaplast mask for immobilization with mild extension of the neck. Target volumes were contoured using a high-dose and a low-dose clinical target volume (CTV, Fig. 2). The known gross disease along the left and the anterior right vocal folds was included in the high-dose CTV63 (red contour in Fig. 2). The low-dose CTV51.8 (yellow contour in Fig. 2) included a 3-mm superior-inferior expansion on the CTV63 as well as elective treatment of the entire posterior right vocal fold and left arytenoid cartilage. A 2-mm planning target volume was uniformly added to each CTV as per our institution's standard when daily IGRT was applied. When counseling the patient, emphasis was placed on the importance of not swallowing. Organs at risk (OARs) included the bilateral carotid arteries, posterior pharyngeal wall (constrictor muscles), thyroid gland, esophagus, supraglottic larynx, and submandibular glands. A VMAT plan was generated using 2 partial arcs with gantry angles ranging between 921 and 2681 (with the patient facing 01) using 6-MV photons prescribed to the 96.5% isodose line. Daily image guidance with a 120-kV cone beam CT (CBCT) was used with primary alignment to the nearby vertebral bodies and secondary alignment to the target volumes of the soft tissues of the larynx. The plan was generated using Pinnacle treatment planning system version 9.6 (Philips Healthcare, Netherlands). The plan was delivered on the Novalis TX radiosurgery system (Brainlab, Feldkirchen, Germany) with 2.5-mm multileaf collimators at a dose rate of 400 monitor units per minute. Heterogeneity corrections were applied and the dose was calculated using the collapsed cone convolution method. To compare, a classic 3-dimensional conformal (3D-CRT) plan was also generated using equally weighted parallel-opposed beams with gantry angles of 901 and 2701 to a field size of 6.5 6 cm with a 301 wedge and no control points. Dosimetric parameters are listed in the Table with dose-volume histograms shown in Fig. 3. Comparative sideby-side treatment plans with representative isodose lines are shown in Fig. 4.
Early-stage larynx cancer presents special issues related to dosimetry and motion management. Targeting a superficial tumor at an air-tissue interface requires attention to the coverage within the dose buildup region of the beam.4 Although underdosage of the tumor is a potential issue, it is known that a degree of compensation exists for treatments with multiple beam angles when compared with a 2-field design and therefore is not likely a significant issue for low-energy beams.5-7 More importantly, swallowing motion requires special consideration. Larynx motion during swallowing covers an average distance of 1.6 cm and a maximum of 3.1 cm superiorly.8 This presents 2 problems: First, modern helical CT scanners used for simulation are fast enough to capture a larynx midswallow, potentially leading to incorrect isocenter placement and incorrect planning. Second, with the advent of rapid VMAT treatments, an improperly timed swallow could cause the vocal cords to be displaced throughout the fraction. Image-guided RT is a necessity in these cases, but consideration of the slower speed of CBCT when compared with helical CT simulation must be considered. Patients must be instructed not to swallow before simulation, CBCT, and treatment delivery, and failure to do so may result in a geographical miss.
Plan evaluation
Clinical experience to support IMRT use
Comparison between the 3D-CRT and VMAT plans showed excellent coverage of the target volumes with a reduced dose to nearly all measured structures in the VMAT plan with the exception of the spinal cord (Table). Doses to most of the critical organs were well less than conventional limits, including the esophagus, spinal cord, and submandibular glands. The cervical esophagus
The dosimetric benefits of IMRT for early-stage glottic cancer have been previously documented,9-16 but the clinical outcomes remain limited. Beyond case reports, a single institutional experience from Jansseen et al. forms most of the published clinical experience with IMRT for early-stage glottic cancer. Of the 77 patients included in the report, 21 were treated with definitive
Discussion Although the use of IMRT has markedly reduced the rates of acute and late treatment-related toxicities without compromising tumor control in other head and neck sites, the efficacy and safety of IMRT have not yet been evaluated in the setting of the mobile, small target volumes associated with early-stage glottic carcinoma.2,3 We weigh the potential benefits of IMRT against the risk of geographical miss. Will IMRT show similar rates of disease control to 3D-CRT?
M.C. Ward et al. / Medical Dosimetry ] (2015) ]]]–]]]
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Fig. 2. Axial CT images at time of simulation (table position z ¼ 40.6 slice A through z ¼ 45.1 cm for slice I) showing target volumes and organs at risk (OARs). Target volumes include the CTV63 (red), which was expanded 3-mm superior-inferior to include the entire posterior right vocal fold and left arytenoid cartilage to create CTV51.8 (yellow). Normal structures include the bilateral common carotid arteries (pink), pharyngeal constrictors (brown), supraglottis (blue), thyroid gland (orange), submandibular glands (green), and esophagus (white). (Color version of figure is available online.)
carotid-sparing IMRT for T1-2N0 disease. In these patients, a mean dose of 29.4 Gy to the ipsilateral carotid was achieved.17 The local tumor control for the entire cohort was 77%, although the results
for T1-2N0 were not specifically reported. Certainly, additional experience is necessary if IMRT is to become a standard option for these patients.
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Table Dosimetric comparison between 3D-CRT and VMAT plans. V50 is the percentage of the structure receiving at least a 50-Gy dose. V50 was chosen as an arbitrary representation of the higher isodose lines 3D-CRT
VMAT
CTV63 (V63) Max point
99.9% 68.9 Gy
99.7% 65.5 Gy
5
CTV51.8 (V51.8)
100%
100%
0
Right carotid Mean Max V50
26.3 Gy 65.9 Gy 21.1%
13.7 Gy 28.8 Gy 0.0%
48 56 100
Left carotid Mean Max V50
27.9 Gy 67.7 Gy 22.6%
15.7 Gy 32.2 Gy 0.0%
44 52 100
Thyroid
25.2 Gy
11.7 Gy
54
Esophagus (max)
40.3 Gy
32.9 Gy
18
Pharyngeal constrictors Mean Max V50
24.2 Gy 69.1 Gy 27.7%
16.3 Gy 60.1 Gy 1.0%
33 13 96
Supraglottis (mean)
65.4 Gy
44.7 Gy
32
Left submandibular gland Mean Max
6.6 Gy 67.2 Gy
1.5 Gy 10.2 Gy
77 85
Right submandibular gland Mean Max
4.9 Gy 62.0 Gy
1.2 Gy 7.8 Gy
76 87
it is safe to say that the risk of dysphagia or vocal dysfunction alone may not be high enough to warrant the use of IMRT.
% Reduction
Cerebrovascular disease
Spinal cord Max
The most significant possible toxicity of early-stage glottic irradiation may be stroke associated with irradiation of the carotid artery. A recent Surveillance, Epidemiology, and End Results (SEER) report investigating the risk of fatal cerebrovascular accidents (CVA) after RT vs surgery for T1 glottic cancer showed that the 15-year risk of fatal CVA increased from 1.5% with surgery to 2.8% with RT (n ¼ 8721, hazard ratio ¼ 1.75, 95% CI: 1.04 to 2.96; p ¼ 0.0437).21 Another SEER analysis including a more broad definition of CVA showed that the 10-year risk increased with the use of RT, although the difference was not statistically significant (56.5% with RT vs 48.7% with surgery, p ¼ 0.27).22 Although these are the only data specific to early-stage glottic cancer, an additional SEER analysis compiling multiple head and neck sites showed that definitive RT increases the 10-year risk of cerebrovascular disease from 26% in those treated with surgery alone to 34% in those treated with definitive RT.23 Other series investigating carotid stenosis have agreed with these results and established a dose-response relationship.24,25 Perhaps IMRT/ VMAT techniques could reduce the rate of vascular complications after RT.
Hypothyroidism 2.5 Gy
19.8 Gy
792
What is the toxicity that needs improvement? Parallel-opposed 3D-CRT for early-stage glottic carcinoma is perhaps the least toxic definitive RT regimen for head and neck cancer. However, it is not without risks. The rates of severe (Common Terminology Criteria for Adverse Events grade 3 or higher) late toxicity for definitive treatment of early-stage glottic carcinoma are typically between 0% and 3% in most series.1,18-20 However, it is important to note that these series only investigated swallowing and voice outcomes. Based on this clinical experience,
Another OAR that may be substantially spared with IMRT is the thyroid gland. The risk of hypothyroidism after RT appears significant, perhaps as high as 48%.26-28 In a study investigating patients treated specifically for early-stage laryngeal cancer, the risk of hypothyroidism was 30% (subclinical and clinical combined), therefore showing that there is room for improvement.29 The literature evaluating the thyroid dosimetric benefit of IMRT for early-stage glottic cancer is limited, but a report on 15 patients showed a 32% reduction in the mean dose to the thyroid gland with a 93% reduction in V50.30 Although hypothyroidism is a relatively benign toxicity when considering RT for head and neck cancer, the potential cost savings by decreasing the need for lifetime thyroid-replacement medication is a valid end point to consider.
Fig. 3. Dose-volume histogram (DVH) showing comparison of the VMAT (solid line) vs parallel-opposed conventional radiotherapy (dashed line) plans. Target volumes shown include the CTV63 (red) and CTV51.8 (gray). OARs include left and right common carotid arteries (pink), supraglottis (blue), thyroid (orange), cervical esophagus (black), pharyngeal constrictors (brown), and submandibular glands (green). (Color version of figure is available online.)
M.C. Ward et al. / Medical Dosimetry ] (2015) ]]]–]]]
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Fig. 4. Axial, sagittal, and coronal isodose lines comparing VMAT (left) vs opposed lateral (right) plans. The red isodose line represents the 63-Gy prescription line and the green represents the 51.8-Gy isodose line. The lowest isodose line shown represents the 20-Gy distributions (purple). (Color version of figure is available online.)
Voice and swallowing function The final OARs that may be spared are the supraglottic larynx and hypopharynx. The rates of severe (Common Terminology Criteria for Adverse Events grade 3 or higher) late dysphagia or voice toxicity for definitive treatment of early-stage glottic carcinoma are typically between 0% and 3% in most series.1,18-20 Previous reports have established the role of the supraglottic larynx and the hypopharynx in toxicity after head and neck RT.31-34 These reports, of course, are all in the setting of locoregionally advanced cancers. To date, there are no clinical reports of significant improvement with sparing of these structures using IMRT in early-stage glottic carcinoma, but our study shows that the mean doses are decreased. As differences may be small,
detailed prospective patient-reported voice and swallowing outcomes may be required to document any benefit.
Conclusion There remain nontrivial risks to standard parallel-opposed RT for early-stage glottic carcinoma, including cerebrovascular disease and hypothyroidism. Although these toxicities may improve with the use of IMRT/VMAT techniques, long-term clinical data are lacking, and there exists a significant chance of geographical miss due to setup error or swallowing motion. With caution, IMRT/ VMAT could be considered a reasonable option for compliant patients with vascular comorbidities.
6
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12. 13. 14.
15. 16.
17.
Fig. 5. Posttreatment office laryngoscopy showing an early complete response to radiotherapy at 1 month after completion. Orientation is similar to Fig. 1. Compare the exophytic white mass on the vocal fold that is now resolved to smooth mucosa. (Color version of figure is available online.)
18.
19. 20.
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