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Using technology to decrease xerostomia for head and neck cancer patients treated with radiation therapy
Using Technology to Decrease Xerostomia for Head and Neck Cancer Patients Treated With Radiation Therapy Chad M. Amosson, Bin S. Teh, Wei-Yuan Mai, Shiao Y. Woo, J. Kam Chiu, Donald T. Donovan, Robert Parke, L. Steven Carpenter, Hsin H. Lu, Walter H. Grant III, and E. Brian Butler The treatment of head and neck cancer has evolved from conventional fields encompassing large volumes of normal tissue to focused treatment aimed at conforming the dose around the target while avoiding normal tissue. Intensity modulated radiation therapy has changed the way radiation oncologists think about head and neck cancer. Using the concepts of conformal treatment and avoidance, the therapeutic ratio can be improved and technology exploited to the patients’ advantage. This is particularly evident with head and neck irradiation, where a common side effect is xerostomia. By decreasing xerostomia through conformal avoidance of the parotid glands, we can improve patient satisfaction and quality of life. In this study, xerostomia is assessed through a subjective salivary gland function questionnaire. This article examines the use of intensity modulated radiation therapy in the treatment of head and neck cancer to decrease xerostomia. The purpose of this article is to evaluate the significance of parotid gland dosimetry in relation to subjective salivary gland function. Semin Oncol 29 (suppl 19):71-79. Copyright 2002, Elsevier Science (USA). All rights reserved.
A
NEW PARADIGM in radiation oncology entered the clinic in March 1994. This paradigm is intensity modulated radiation therapy (IMRT) using a process called “inverse planning.” To understand the clinical significance of IMRT one must understand the process of how radiation was previously deposited into tumors. Historically, the radiation oncologist used a trial and error method to create dose deposition patterns. Radiation portals were designed using multiple portals in an arrangement around the tumor and dose deposition was determined to be adequate or inadequate based on the coverage of the target and doses to normal structures. If the plan was determined to be inadequate, changes to the radiation portals were made, and the dose patterns were re-evaluated. It was a trial and error process of portal placement and dose deposition pattern evaluation. Intensity modulated radiation therapy changed the thought process for the radiation oncologist. With the introduction of IMRT, the radiation oncologist defined the dose deposition pattern. Just as importantly, normal tissue was defined to avoid dose deposition (avoidance patterns). No
Seminars in Oncology, Vol 29, No 6, Suppl 19 (December), 2002: pp 71-79
longer did the radiation oncologist select the best portals to create dose patterns. Radiation portals were selected by a computer for optimal geometric location based on the prescribed dose. The radiation oncologist would define target or tumor (deposition areas) and normal structures (avoidance areas). Limitations were placed on the amount of dose that could enter an avoidance area (eg, spinal cord, parotid glands). The computer uses an algorithm called simulated annealing to create these dose deposition and avoidance patterns. Large radiation portals 10 cm ⫻ 12 cm in size are broken into small fields called beamlets. In a system like the Peacock system (NOMOS Corp, Sewickley, PA) there are 40 small fields 2 cm ⫻ 1 cm in size. These fields rotate around the patient and can be turned on or off every 5 degrees of rotation for increments of 10% creating a potential of 2 ⫻ 107 fields (much more than with conventional fields). This number of beamlets rotating around the patient allows the radiation oncologist to create very specific dose deposition patterns (Fig 1). Intensity modulated radiation therapy may have its greatest advantage in the treatment of head and neck cancer where xerostomia can be a lifelong problem after radiation therapy. Figure 2 is a demonstration of IMRT’s ability to create dose deposition and avoidance patterns. The dose avoidance patterns are shown in the areas of the spinal cord and parotid glands. One of the major challenges in radiation oncology is to determine what dose the parotid glands can sustain without developing xerostomia. Limitation of dose deposition in the parotid glands is now possible using IMRT, which
From the Department of Radiology, Section of Radiation Oncology, and the Department of Otolaryngology, Baylor College of Medicine and The Methodist Hospital, Houston, TX. Dr Butler receives funding for data management support from NOMOS Corp. Address reprint requests to E. Brian Butler MD, Department of Radiation Oncology, The Methodist Hospital, 6565 Fannin, MS 121-B, Houston, TX 77030. Copyright 2002, Elsevier Science (USA). All rights reserved. 0093-7754/02/2906-1906$35.00/0 doi:10.1053/sonc.2002.37353 71
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Table 1. Dose to Parotid Glands Using Intensity Modulated Radiation Therapy Treatment Plan
Fig 1. Smiley face demonstrating dose deposition and avoidance patterns made possible with IMRT.
can improve xerostomia compared with conventional radiation.1-5 Table 1 shows the potential for parotid sparing in four different scenarios: (1) the patient with the oropharyngeal cancer that is expected to develop a great deal of xerostomia because the primary target is close to the parotids; (2) the patient with a hypopharyngeal/laryngeal carcinoma where the lymphatics lie near the parotids; (3) an adenoid cystic carcinoma patient where the perineural pathway of disease spread must be treated; and (4) a nasopharyngeal cancer patient.
Oropharyngeal cancer (right side) Right parotid Left parotid Laryngeal/hypopharyngeal cancer Right parotid Left parotid Hard palate adenoid cystic carcinoma Right parotid Left parotid Nasopharyngeal carcinoma Right parotid Left parotid
⬍ 20 Gy
⬍ 25 Gy
⬍ 30 Gy
39% 72%
67% 82%
82% 89%
74% 67%
85% 82%
94% 90%
83% 100%
95% 100%
99% 100%
56% 43%
77% 69%
87% 84%
The purpose of this article is to evaluate the relationship of dosimetric parameters to subjective salivary gland function for head and neck cancer patients treated with IMRT. MATERIALS AND METHODS Between January 1996 and June 2000, 30 evaluable patients with at least 6 months of follow-up were treated with the simultaneous modulated accelerated radiation therapy (SMART) boost technique with IMRT via the NOMOS Peacock system at The Methodist Hospital in Houston, TX, and evaluated with a subjective salivary gland function questionnaire.6 Patient characteristics are listed in Table 2. Gross disease was treated at 2.4 Gy/day to a total dose of 60 Gy over 5 weeks. Secondary targets, which are sites of possible microscopic disease including lymphatics, perineural routes of spread, and spaces at risk for spread of disease, were treated with conventional fractionation at 2 Gy/day to a total dose of 50 Gy. Disease characteristics are listed in Table 3. The 1997 American Joint Committee on Cancer staging was used.7
Step 1: Immobilization
Fig 2. Film dosimetry with primary target and lymphatics coverage with avoidance patterns around the parotid glands and spinal cord (darker: more radiation dose [for tumor/target]; lighter: less radiation dose [for avoidance structures, eg, spinal cord and parotids]). CP, contralateral parotid; IP, ipsilateral parotid; PT, primary tumor; SC, spinal cord.
When performing conformal therapy, immobilization, reproducibility, and quality assurance are critical. Previously used margins in large fields for set-up error must be minimized to spare normal tissue. Special consideration must be made to limit positional variability and organ movement. Initially, patients were immobilized by placement of intracranial screws secured to the Talon fixation device (NOMOS Corp, Sewickley, PA). The neurosurgeon would drill two screws into the inner table of the skull. Prophylactic antibiotics and screw-site care minimize the risk of infection. Target motion can be limited to 1 to 2 mm. Later, the reinforced aquaplast face mask replaced the Talon device for immobilization as a less invasive immobilization device. It does not require a
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Step 4: Defining Normal Tissue Table 2. Patient Characteristics Age (years) Mean Median Range Sex Male Female Follow-up (mos) Mean Median Range
60.5 63.0 43 to 73 24 (80.0%) 6 (20.0%) 39.9 38.5 16.6 to 71.4
neurosurgical procedure, anesthesia, prophylactic antibiotics, or wound care. The reinforced face mask can limit patient movement to 2 to 3 mm. Figure 3 demonstrates the Talon fixation device and reinforced aquaplast face mask. Intraoral stents or bite-blocks are used in selected patients for normal tissue avoidance and organ immobilization. Table position is important for reproducibility. The Target Box overlies the treatment area and is locked in place. Laser alignment is confirmed on the Target Box before every treatment. The Crane is attached to the couch and accurately locates the correct position. The micrometer located on the Crane provides exact measurements for arc field matching as the table is indexed.
Step 2: Imaging Once the patient is immobilized, computed tomography (CT) is performed for treatment planning purposes. Axial images at 3-mm intervals with 3 mm thickness are obtained. The images are transferred to the treatment-planning computer.
Step 3: Defining Target Volume Head and neck cancer is not encapsulated like prostate cancer; the borders are ill defined. Contiguous, perineural, and lymphatic spread are frequent and represent the invasive nature of this cancer. These pathways of spread are unique to each disease site. Head and neck anatomy consists of multiple spaces that may or may not contain lymph nodes. Understanding the lymphatic spaces and both barriers and pathways of spread for each disease site is necessary with conformal therapy. We use the SMART Charts (labeled axial images created by ear, nose, and throat surgeons and diagnostic radiologists at Baylor College of Medicine [Houston, TX] to delineate anatomic sites in the head and neck area) in the delineation of head and neck spaces (Fig 4).8 The gross tumor is outlined with margin and labeled as target 1. This includes radiographic, visible, and palpable disease. Target 2 includes areas at risk for microscopic disease. This includes subclinical disease, pathways of spread, lymphatic spaces, and nerves (in the case of perineural involvement with adenoid cystic carcinoma), as well as added margin around the primary tumor. This is illustrated in Fig 5.
Normal tissue can be spared with IMRT. Normal tissues were outlined on the CT slices and designated as avoidance structures. Dose limitations were set based on their tolerance. Differential weighting of the normal tissue versus tumor is necessary and poses the question: “What is more important, normal tissue or tumor?” The tumor is generally weighted more than avoidance structures to improve control. However, when the tumor is located near a serial structure (structure where damage to part of the structure has a profound effect on function) such as the optic chiasm, weighting is shifted to prevent the treatment-related complication of blindness. The axial CT images were reviewed in the treatment-planning computer. Normal structures were delineated using the SMART Charts. These structures were outlined on each axial slice. Adequate coverage of the primary target is given priority over parotid anatomy. Therefore, the dosimetric parameters represent the volume of parotid glands not included as target. The target doses and normal tissue threshold limits were then prescribed. Threshold limits for the ipsilateral and contralateral parotid glands were set at 35 Gy and 25 Gy, respectively, with adjustments made because of the preference of the treating physician, location of disease, and treatment plan outcome. No attempts were made to avoid the submandibular glands because
Table 3. Disease Characteristics Number (%) Tumor site Oropharynx Nasopharynx Oral cavity Larynx Hypopharynx Paranasal sinus Unknown primary Tumor stage T1 T2 T3 T4 Recurrent Unknown primary N stage N0 N1 N2 N3 Unknown Stage 1 2 3 4 Recurrent Unknown primary
16 (53.3) 4 (13.3) 2 (6.7) 4 (13.3) 1 (3.3) 2 (6.7) 1 (3.3) 7 (23.3) 12 (40.0) 5 (16.7) 4 (13.3) 1 (3.3) 1 (3.3) 11 (36.7) 9 (30.0) 6 (20.0) 3 (10.0) 1 (3.3) 3 (10.0) 7 (23.3) 9 (30.0) 9 (30.0) 1 (3.3) 1 (3.3)
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Fig 3.
(A) Talon fixation device and (B) reinforced aquaplast face mask used for immobilization.
submandibular lymph nodes were commonly included as target. The structures were weighted, with target usually being given priority over normal structures.
Step 5: Plan Evaluation Intensity modulated radiation therapy via Peacock tomotherapy is routinely treated to the 85% isodose line to ensure the majority of the target receives the prescribed dose and to minimize underdosing. The importance of inhomogeneity is still uncertain, as is the best method of evaluation. Detailed analysis of the plan is performed on all axial CT slices. Isodose lines are evaluated based on their proximity to avoidance structures and target volumes. It is uncertain which factor is the best predictor of treatment efficacy. Coverage and avoidance are reviewed on all CT slices. Mean, minimum, and maximum target doses are evaluated in reference to the prescribed dose. Target volume receiving dose below goal is also evaluated. This can be extrapolated from the
dose–volume histograms. The exact location of target volumes receiving doses below goal must also be evaluated, particularly when normal structures lie in close proximity to the target. Because side effects are dose and volume related, the dose and volume of normal structures above goal must be considered.
Step 6: Treatment Delivery A conventional megavoltage linear accelerator delivers 10-MV photons for IMRT treatment. Treatment is delivered through the multivane intensity modulating collimator as the gantry rotates up to 270 degrees around the patient. The multivane intensity modulating collimator consists of 40 vanes, which are 8-cm thick tungsten blocks and project to a 1 ⫻ 1 cm2 or 2 ⫻ 1 cm2 field at isocenter. Because there are two rows of 20 vanes each, arcs can be treated with a 2-cm or 4-cm width. The vanes are individually opened and closed as the gantry rotates around the patient. The treatment couch is arced using a micrometer for accuracy. Treatment generally consists of three to six treatment arcs. A single AP field using 6-MV photons is used to treat the supraclavicular fossa bilaterally.
Xerostomia Assessment
Fig 4. SMART Chart axial slice demonstrating head and neck anatomy. (Reprinted with permission.8)
A subjective salivary gland function questionnaire was designed to provide an adequate assessment of xerostomia. The questions were derived from multiple sources including the Radiation Therapy Oncology Group late salivary gland toxicity, visual analog scale, and quality-of-life studies.3,9-11 To assess long-term xerostomia, the questionnaire was administered at the most recent follow-up. Median time from completion of treatment to questionnaire administration was 38.5 months (mean, 39.9 months). The results of the questionnaire were statistically correlated to the dosimetric parameters of the parotid glands. The questions were: 1. What is the overall comfort of your mouth? 2. Does your mouth feel dry when eating? 3. Do you have difficulty swallowing any foods? 4. Do you need to sip liquids to swallow dry food? 5. Do you feel thirsty all the time? 6. Do you feel the amount of saliva in your mouth is too little, too much, or adequate?
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Fig 5. Axial slice treating the primary tumor and lymphatics in a patient with soft palate cancer with isodose lines indicating dosage received.
7. Do you have problems with speech because of dry mouth? 8. Does dry mouth interfere with your ability to sleep all the time? 9. Has your taste changed because of salivary gland function? 10. Do you need to carry water daily?
RESULTS
Dosimetric Parameters of the Parotid Glands Mean dose and maximum dose, as well as volume and percent of parotid glands above threshold doses were evaluated. The average mean doses to the ipsilateral and contralateral parotid glands were 24.2 Gy and 19.1 Gy, respectively. The average maximum doses were 56.1 Gy and 47.4 Gy, respectively. The ipsilateral gland volume above threshold was 10.6 cc (30.4%). The contralateral parotid volume above the threshold dose was 8.22 cc (23.4%). Because of the treatment planning system, these dosimetric parameters represent the parotid anatomy not included in the target volume.
Subjective Xerostomia The questionnaire was administered to 30 patients at the time of follow-up. Radiation Therapy Oncology Group/European Organization for Research and Treatment of Cancer assessment of late salivary gland toxicity was the first question.9 What is the overall comfort of your mouth? Thirty percent of patients felt that their mouth was very comfortable, 36.7% complained of grade 1 xerostomia (slight dryness), while 20% had grade 2 xerostomia (moderate dryness). Grade 3 xerostomia (severe dryness) was noted in four patients (13.3%). The contralateral mean and maximum doses correlated significantly with these results. Question 2 asked, “Does your mouth feel dry when eating?” This question correlated significantly with the maximum dose to the contralateral parotid gland. Question 3 asked, “Do you have difficulty swallowing any foods?” while question 4 asked, “Do you need to sip liquids to swallow dry food?” These questions correlated with the mean
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Table 4. P Values for Statistical Correlation of the Dosimetric Parameters of the Ipsilateral and Contralateral Parotid Glands With the Salivary Gland Function Questionnaire
Ipsilateral parotid Question 3 Question 4 Question 9 Contralateral parotid Question 1 Question 2 Question 3 Question 4 Question 6 Question 9
Mean Dose
Maximum Dose
Volume
Volume Over Prescribed Threshold
Percentage Over Prescribed Threshold
0.016 0.003 0.004
0.013 0.002 NS
NS NS NS
NS NS 0.014
NS 0.026 NS
0.008 NS 0.017 0.005 0.021 0.000
0.038 0.031 0.003 0.007 0.005 0.014
NS NS NS NS NS NS
NS NS NS NS 0.017 0.001
NS NS NS NS NS 0.001
Abbreviation: NS, not significant.
and maximum doses to both ipsilateral and contralateral parotid glands. Question 5 was “Do you feel thirsty all the time?” This did not correlate with the dosimetric parameters of the parotid glands. The mean and maximum doses to the contralateral parotid glands correlated with question 6, “Do you feel the amount of saliva in your mouth is too little, too much, or adequate?” Questions 7, “Do you have problems with speech because of dry mouth?” and 8, “Does dry mouth interfere with your ability to sleep all the time?” did not correlate significantly with the dosimetric parameters. Question 9, “Has your taste changed because of salivary gland function?” correlated with both ipsilateral parotid mean dose and volume above threshold. The contralateral mean, maximum, and volume above threshold also correlated well with abnormal taste. Question 10, “Do you need to carry water daily?” did not correlate with the dosimetric parameters of the parotid glands. Table 4 shows the P values for statistically significant correlation seen with the questionnaire. Evaluation of the statistically significant results show a clustering of doses, which could be clinically significant. The ipsilateral parotid mean doses correlated significantly with questions 3, 4, and 9. These questions evaluate difficulty swallowing, need to sip liquids when eating, and taste. Patients who responded negatively (ie, complained of xerostomia) to these questions had a range of mean ipsilateral parotid doses of 26.2 Gy
to 28.3 Gy. Patients who did not have these problems had mean doses ranging from 17.8 Gy to 21.1 Gy. A similar result was seen when examining the average contralateral mean doses for questions 1, 3, 4, 6, and 9 (ie, questions yielding statistical significance for contralateral mean dose). Patients responding negatively had average mean doses ranging from 21.3 Gy to 24.5 Gy compared with patients responding favorably who had average mean doses ranging from 12.6 Gy to 16.2 Gy. The ipsilateral and contralateral parotid mean doses for questions 3, 4, and 9 are seen in Table 5. Ipsilateral maximum dose was correlated significantly with questions 3 and 4. Patients who had swallowing difficulties related to xerostomia had
Table 5. Average Mean Doses for the Ipsilateral and Contralateral Parotid Glands Correlated With Questions 3, 4, and 9 Ipsilateral Parotid Mean Dose (Gy)
Contralateral Parotid Mean Dose (Gy)
3 4 9
26.5 26.2 28.3
21.5 21.3 24.5
3 4 9
20.3 17.8 21.1
14.7 12.6 15.1
Answer to the questions Yes Question Question Question No Question Question Question
DECREASED XEROSTOMIA IN HEAD & NECK IMRT
average maximum doses of 59.5 Gy and 59.1 Gy (questions 3 and 4, respectively) while patients who did not have swallowing problems had average maximum doses of 50.2 Gy and 46.4 Gy. The contralateral parotid maximum doses correlated with questions regarding overall mouth comfort, problems with eating, difficulty swallowing dry food, quantity of saliva, and abnormal taste (questions 1, 2, 3, 4, 6, and 9). Patients who responded favorably had average maximum doses to the contralateral parotid glands ranging from 35.5 Gy to 41.2 Gy, while patients who responded unfavorably had average maximum doses ranging from 51.8 Gy to 57.5 Gy. DISCUSSION
Radiation therapy to the head and neck region results in multiple side effects that affect quality of life.12-15 The use of IMRT in the treatment of head and neck cancer offers the radiation oncologist versatility and possibility. The dose limitations to the parotid glands can be overcome by IMRT using conformal avoidance.16-18 By limiting the parotid dose, we can improve xerostomia, outcome, and quality of life.2 Defining the primary target is difficult and extensive training is needed. Knowledge of contiguous spread is important when conformal therapy is considered. Where is the pterygopalatine fossa if it is a pathway of spread for maxillary sinus tumors? The pathways and barriers of spread for maxillary sinus tumors must be considered when outlining the primary tumor volume. Pathways of least resistance include superior invasion into the orbit, inferior invasion to the oral cavity, and anterior extension to the skin of the cheek. Once tumor has invaded the pterygopalatine fossa, it can spread in several directions. The pterygoid canal is adjacent to the foramen lacerum, which leads to the middle cranial fossa. Tumors can also invade the middle cranial fossa through the foramen rotundum. Invasion of the infratemporal fossa can occur through the pterygopalatine fissure. Orbital invasion occurs through the inferior orbital fissure. The sphenopalatine foramen leads to the nasopharynx. For each disease site, there are multiple pathways of spread, each with unique symptoms that must be understood. Perineural spread is commonly seen with adenoid cystic carcinoma, but is uncommon with squamous cell carcinoma. The risk of perineural
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spread must be assessed to determine if coverage is necessary. The nerves can be defined as secondary targets. Detailed knowledge of nerve pathways is necessary to provide adequate conformal treatment. Lymphatic involvement in head and neck cancer is complex. The incidence and location of lymph node involvement for each disease site is important. For example, the glottic larynx has a paucity of lymphatics whereas the supraglottic larynx has a rich lymphatic supply. It is important to know which lymph node levels are commonly involved. What is the incidence of ipsilateral, contralateral, and bilateral lymph node involvement? A detailed knowledge of the spaces that lymph nodes occupy is necessary in target delineation. Understanding head and neck spaces and pathways of disease spread allows the radiation oncologist to define target with consistency. By treating only where the disease is, the radiation oncologist can maximize normal tissue avoidance. Also, a systematic method of target delineation can be developed for each disease site. Our subjective salivary gland function questionnaire was derived from multiple sources, some of which validated their results with objective measurements of salivary flow rate.3,9-11 Prior attempts in our department to cannulate Stenson’s duct and measure salivary flow rates have been cumbersome and ineffective. Objective salivary function data are important information and validate patient perception. However, the most important criteria for evaluation of xerostomia are patient comfort and quality of life. The clustering of mean ipsilateral and contralateral doses may have clinical implications. The range of average mean doses to the ipsilateral parotid gland was 26.2 Gy to 28.3 Gy for patients who responded negatively to questions 3, 4, and 9 (ie, questions with a statistically significant relationship to ipsilateral mean dose). Patients who responded positively had a range of ipsilateral mean doses of 17.8 Gy to 21.2 Gy. A similar clustering of mean doses was seen when evaluating questions 1, 3, 4, 6, and 9, which corresponded to the contralateral parotid gland. The range for patients who responded negatively was 21.3 Gy to 24.5 Gy, while patients who responded positively had a range from 12.6 Gy to 16.2 Gy. Similar clustering of maximum doses was seen, but this parameter is highly variable and likely to be correlated with mean dose anyway. The clustering of
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mean doses may have clinical relevance in treatment plan evaluation. It appears from these data that the ipsilateral parotid mean dose should be limited to somewhere between 21 Gy and 26 Gy, while the contralateral parotid gland should be limited to somewhere between 16 Gy and 21 Gy. The need to differentiate between ipsilateral and contralateral parotid glands is also unknown. The exact threshold for parotid dose remains uncertain, and more patients are needed to clarify the data. University of Michigan data have indicated that the mean dose of the parotid glands should be limited to 26 Gy.19 Partial volume data are also available from the same source. Ultimately, it is likely that lower mean doses to the parotid glands will result in less xerostomia. Chao et al4 from Washington University have data to suggest that stimulated salivary flow decreases approximately 4% per Gy of mean parotid dose. Unfortunately, the location of lymphatics and the primary tumor combined with the current state of technology limit the minimum dose that can be delivered to the parotid glands. Of note, the fraction size may also play an important role. The ipsilateral parotid mean dose was 24.2 Gy delivered over 25 fractions. The dose per fraction was very small at 0.97 Gy per day, which is half the size of conventional fractionation. More patients treated with conformal technology are needed. Radiation therapy affects salivary gland function by damage to both the submandibular and parotid glands. These two glands produce different kinds of saliva at different times. The submandibular glands are responsible for baseline saliva. These glands lie in close proximity to the submandibular lymph nodes and are typically included in the irradiated area. Conformal avoidance of the submandibular glands is only possible in a subset of patients where the submandibular lymph nodes are not at risk. The parotid gland is responsible for stimulated flow of saliva. Damage to the parotid gland leads to preferential damage of serous saliva. Therefore, parotid gland damage leads to thick, mucinous saliva, which is frequently seen in patients under treatment. The use of conformal radiation therapy to decrease xerostomia can have a profound effect on quality of life. Intensity modulated radiation therapy can be exploited by conformal avoidance of the parotids. Even with rapidly evolving technol-
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ogy, it is difficult to completely eliminate xerostomia. Other methods to reduce xerostomia by exploiting biology, including amifostine and pilocarpine, have been successful.20-24 Future strategies to minimize the toxicity of head and neck radiation could include combining the advantages of technology and biology. By evaluating the treatment plan, we can anticipate which patients will experience xerostomia. Those patients may benefit from administration of amifostine during radiation. The combination of IMRT and amifostine could have a profound effect on both acute and late toxicity, leading to improvements in number of splits required, treatment time, and late xerostomia. This combination could dramatically change the concept that head and neck cancer treatment with radiation is traumatic and difficult to tolerate. Intensity modulated radiation therapy also makes it possible to deliver altered fractionation schedules. The SMART boost was developed at the Baylor College of Medicine in 1996.9 We treated the primary target at 2.4 Gy per day to a total dose of 60 Gy (mean dose, 63.8 Gy), while areas at risk for microscopic disease were treated at conventional fraction sizes of 2.0 Gy per day to a total dose of 50 Gy (mean dose, 54.8 Gy). The fraction size received by the tumor is approximately 2.55 Gy per day, while normal tissue is treated at small fraction sizes. Based on the results of RTOG 9003, altered fractionation in the form of concomitant boost or hyperfractionation provides an advantage over conventional treatment.25 With IMRT, any fractionation scheme can be delivered with conformal avoidance of normal tissue. This gives the radiation oncologist the flexibility to be aggressive, while still decreasing normal tissue dose. CONCLUSIONS
The use of IMRT in the treatment of head and neck cancer can have a profound effect on xerostomia and quality of life. We are still attempting to determine exactly what dose and volume of parotid gland irradiation leads to subjective xerostomia. A larger number of patients treated with IMRT for head and neck cancer is needed to better define these parameters.
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REFERENCES 1. Chao KSC, Majhail N, Huang CJ, et al: Intensity-modulated radiation therapy reduces late salivary toxicity without compromising tumor control in patients with oropharyngeal carcinoma: A comparison with conventional techniques. Radiother Oncol 61:275-280, 2001 2. Reddy SP, Leman CR, Marks JE, et al: Parotid-sparing irradiation for cancer of the oral cavity: Maintenance of oral nutrition and body weight by preserving parotid function. Am J Clin Oncol 24:341-346, 2001 3. Eisbruch A, Ship JA, Martel MK, et al: Parotid gland sparing in patients undergoing bilateral head and neck irradiation techniques and early results. Int J Radiat Oncol Biol Phys 36:469-480, 1996 4. Chao KSC, Deasy JO, Markman J, et al: A prospective study of salivary function sparing in patients with head-andneck cancers receiving intensity-modulated or three-dimensional radiation therapy: Initial results. Int J Radiat Oncol Biol Phys 49:907-916, 2001 5. Eisbruch A, Kim HM, Terrell JE, et al: Xerostomia and its predictors following parotid-sparing irradiation of head-andneck cancer. Int J Radiat Oncol Biol Phys 50:695-704, 2001 6. Butler EB, Teh BS, Grant WH, et al: SMART (simultaneous modulated accelerated radiation therapy) boost: A new accelerated fractionation schedule for the treatment of head and neck cancer with intensity modulated radiotherapy. Int J Radiat Oncol Biol Phys 45:21-32, 1999 7. Strong EW, Batsakis JG, Cassisi NJ, et al: Head and neck sites, in Fleming ID, Cooper JS, Henson DE, et al (eds): AJCC Cancer Staging Manual (5th ed). Philadelphia, PA, Lippincott-Raven, 1997, pp 21-58 8. Hayman LA, Taber KH, Diaz-Marchan PJ, et al: “SMART CHARTS.” Houston, TX, Baylor College of Medicine, and Richmond, VA, MCV Hospital, Virginia Commonwealth University. 9. Cox JD, Stetz J, Pajak TF: Toxicity criteria of the Radiation Therapy Oncology Group (RTOG) and the European Organization for Research and Treatment of Cancer (EORTC). Int J Radiat Oncol Biol Phys 31:1341-1346, 1995 10. Fox PC, Busch KA, Baum BJ: Subjective reports of xerostomia and objective measures of salivary gland performance. J Am Dent Assoc 115:581-584, 1987 11. Zimmerman RP, Marks RJ, Tran LM, et al: Concomitant pilocarpine during head and neck irradiation is associated with decreased post-treatment xerostomia. Int J Radiat Oncol Biol Phys 37:571-575, 1997 12. Bjordal K, Kaasa S, Mastekaasa A: Quality of life in patients treated for head and neck cancer: A follow-up study 7 to 11 years after radiotherapy. Int J Radiat Oncol Biol Phys 28:847-856, 1994 13. Cooper JS, Fu K, Marks J, et al: Late effects of radiation
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therapy in the head and neck region. Int J Radiat Oncol Biol Phys 31:1141-1164, 1995 14. Jensen AB, Hanse O, Jorgensen K, et al: Influence of late side effects upon daily life after radiotherapy for laryngeal and pharyngeal cancer. Acta Oncol 33:487-491, 1994 15. Harrison LB, Zelefsky MJ, Pfister DG, et al: Detailed quality of life assessment in patients treated with primary radiotherapy for squamous cell cancer of the base of the tongue. Head Neck 19:169-175, 1997 16. Marsh L, Eisbruch A, Watson B, et al: Treatment planning for parotid sparing in the patient requiring bilateral neck irradiation. Med Dosim 21:7-13, 1996 17. Nishioka T, Shirato H, Arimoto T, et al: Reduction of radiation-induced xerostomia in nasopharyngeal carcinoma using CT simulation with laser patient marking and three-field irradiation technique. Int J Radiat Oncol Biol Phys 38:705-712, 1997 18. Wu Q, Mannin M, Schmidt-Ullrich R, et al: The potential for sparing of parotids and escalation of biologically effective dose with intensity-modulated radiation treatments of head and neck cancers: A treatment design study. Int J Radiat Oncol Biol Phys 46:195-205, 2000 19. Eisbruch A, Ten Haken RK, Kim HM, et al: Dose, volume, and function relationships in parotid salivary glands following conformal and intensity-modulated irradiation of head and neck cancer. Int J Radiat Oncol Biol Phys 45:577587, 1999 20. Rieke JW, Hafermann MD, Johnson JT, et al: Oral pilocarpine for radiation-induced xerostomia: Integrated efficacy and safety results from two prospective randomized clinical trials. Int J Radiat Oncol Biol Phys 31:661-669, 1995 21. Johnson JT, Ferretti GA, Nethery WJ, et al: Oral pilocarpine for post-irradiation xerostomia in patients with head and neck cancer. N Engl J Med 329:390-395, 1993 22. LeVeque FG, Montgomery M, Potter D, et al: A multicenter, randomized, double-blind, placebo-controlled, dose-titration study of oral pilocarpine for treatment of radiationinduced xerostomia in head and neck cancer patients. J Clin Oncol 11:1124-1131, 1993 23. Brizel DM, Wasserman TH, Henke M, et al: Phase III randomized trial of amifostine as a radioprotector in head and neck cancer. J Clin Oncol 18:3339-3345, 2000 24. Koukourakis MI, Kyrias G, Kakolyris S, et al: Subcutaneous administration of amifostine during fractionated radiotherapy: A randomized phase II study. J Clin Oncol 18:22262233, 2000 25. Fu KK, Pajak TF, Trotti A, et al: A Radiation Therapy Oncology Group (RTOG) phase III randomized study to compare hyperfractionation and two variants of accelerated fractionation to standard fractionation radiotherapy for head and neck squamous cell carcinomas: First report of RTOG 9003. Int J Radiat Oncol Biol Phys 48:7-16, 2000
A
NEW PARADIGM in radiation oncology entered the clinic in March 1994. This paradigm is intensity modulated radiation therapy (IMRT) using a process called “inverse planning.” To understand the clinical significance of IMRT one must understand the process of how radiation was previously deposited into tumors. Historically, the radiation oncologist used a trial and error method to create dose deposition patterns. Radiation portals were designed using multiple portals in an arrangement around the tumor and dose deposition was determined to be adequate or inadequate based on the coverage of the target and doses to normal structures. If the plan was determined to be inadequate, changes to the radiation portals were made, and the dose patterns were re-evaluated. It was a trial and error process of portal placement and dose deposition pattern evaluation. Intensity modulated radiation therapy changed the thought process for the radiation oncologist. With the introduction of IMRT, the radiation oncologist defined the dose deposition pattern. Just as importantly, normal tissue was defined to avoid dose deposition (avoidance patterns). No
Seminars in Oncology, Vol 29, No 6, Suppl 19 (December), 2002: pp 71-79
longer did the radiation oncologist select the best portals to create dose patterns. Radiation portals were selected by a computer for optimal geometric location based on the prescribed dose. The radiation oncologist would define target or tumor (deposition areas) and normal structures (avoidance areas). Limitations were placed on the amount of dose that could enter an avoidance area (eg, spinal cord, parotid glands). The computer uses an algorithm called simulated annealing to create these dose deposition and avoidance patterns. Large radiation portals 10 cm ⫻ 12 cm in size are broken into small fields called beamlets. In a system like the Peacock system (NOMOS Corp, Sewickley, PA) there are 40 small fields 2 cm ⫻ 1 cm in size. These fields rotate around the patient and can be turned on or off every 5 degrees of rotation for increments of 10% creating a potential of 2 ⫻ 107 fields (much more than with conventional fields). This number of beamlets rotating around the patient allows the radiation oncologist to create very specific dose deposition patterns (Fig 1). Intensity modulated radiation therapy may have its greatest advantage in the treatment of head and neck cancer where xerostomia can be a lifelong problem after radiation therapy. Figure 2 is a demonstration of IMRT’s ability to create dose deposition and avoidance patterns. The dose avoidance patterns are shown in the areas of the spinal cord and parotid glands. One of the major challenges in radiation oncology is to determine what dose the parotid glands can sustain without developing xerostomia. Limitation of dose deposition in the parotid glands is now possible using IMRT, which
From the Department of Radiology, Section of Radiation Oncology, and the Department of Otolaryngology, Baylor College of Medicine and The Methodist Hospital, Houston, TX. Dr Butler receives funding for data management support from NOMOS Corp. Address reprint requests to E. Brian Butler MD, Department of Radiation Oncology, The Methodist Hospital, 6565 Fannin, MS 121-B, Houston, TX 77030. Copyright 2002, Elsevier Science (USA). All rights reserved. 0093-7754/02/2906-1906$35.00/0 doi:10.1053/sonc.2002.37353 71
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Table 1. Dose to Parotid Glands Using Intensity Modulated Radiation Therapy Treatment Plan
Fig 1. Smiley face demonstrating dose deposition and avoidance patterns made possible with IMRT.
can improve xerostomia compared with conventional radiation.1-5 Table 1 shows the potential for parotid sparing in four different scenarios: (1) the patient with the oropharyngeal cancer that is expected to develop a great deal of xerostomia because the primary target is close to the parotids; (2) the patient with a hypopharyngeal/laryngeal carcinoma where the lymphatics lie near the parotids; (3) an adenoid cystic carcinoma patient where the perineural pathway of disease spread must be treated; and (4) a nasopharyngeal cancer patient.
Oropharyngeal cancer (right side) Right parotid Left parotid Laryngeal/hypopharyngeal cancer Right parotid Left parotid Hard palate adenoid cystic carcinoma Right parotid Left parotid Nasopharyngeal carcinoma Right parotid Left parotid
⬍ 20 Gy
⬍ 25 Gy
⬍ 30 Gy
39% 72%
67% 82%
82% 89%
74% 67%
85% 82%
94% 90%
83% 100%
95% 100%
99% 100%
56% 43%
77% 69%
87% 84%
The purpose of this article is to evaluate the relationship of dosimetric parameters to subjective salivary gland function for head and neck cancer patients treated with IMRT. MATERIALS AND METHODS Between January 1996 and June 2000, 30 evaluable patients with at least 6 months of follow-up were treated with the simultaneous modulated accelerated radiation therapy (SMART) boost technique with IMRT via the NOMOS Peacock system at The Methodist Hospital in Houston, TX, and evaluated with a subjective salivary gland function questionnaire.6 Patient characteristics are listed in Table 2. Gross disease was treated at 2.4 Gy/day to a total dose of 60 Gy over 5 weeks. Secondary targets, which are sites of possible microscopic disease including lymphatics, perineural routes of spread, and spaces at risk for spread of disease, were treated with conventional fractionation at 2 Gy/day to a total dose of 50 Gy. Disease characteristics are listed in Table 3. The 1997 American Joint Committee on Cancer staging was used.7
Step 1: Immobilization
Fig 2. Film dosimetry with primary target and lymphatics coverage with avoidance patterns around the parotid glands and spinal cord (darker: more radiation dose [for tumor/target]; lighter: less radiation dose [for avoidance structures, eg, spinal cord and parotids]). CP, contralateral parotid; IP, ipsilateral parotid; PT, primary tumor; SC, spinal cord.
When performing conformal therapy, immobilization, reproducibility, and quality assurance are critical. Previously used margins in large fields for set-up error must be minimized to spare normal tissue. Special consideration must be made to limit positional variability and organ movement. Initially, patients were immobilized by placement of intracranial screws secured to the Talon fixation device (NOMOS Corp, Sewickley, PA). The neurosurgeon would drill two screws into the inner table of the skull. Prophylactic antibiotics and screw-site care minimize the risk of infection. Target motion can be limited to 1 to 2 mm. Later, the reinforced aquaplast face mask replaced the Talon device for immobilization as a less invasive immobilization device. It does not require a
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Step 4: Defining Normal Tissue Table 2. Patient Characteristics Age (years) Mean Median Range Sex Male Female Follow-up (mos) Mean Median Range
60.5 63.0 43 to 73 24 (80.0%) 6 (20.0%) 39.9 38.5 16.6 to 71.4
neurosurgical procedure, anesthesia, prophylactic antibiotics, or wound care. The reinforced face mask can limit patient movement to 2 to 3 mm. Figure 3 demonstrates the Talon fixation device and reinforced aquaplast face mask. Intraoral stents or bite-blocks are used in selected patients for normal tissue avoidance and organ immobilization. Table position is important for reproducibility. The Target Box overlies the treatment area and is locked in place. Laser alignment is confirmed on the Target Box before every treatment. The Crane is attached to the couch and accurately locates the correct position. The micrometer located on the Crane provides exact measurements for arc field matching as the table is indexed.
Step 2: Imaging Once the patient is immobilized, computed tomography (CT) is performed for treatment planning purposes. Axial images at 3-mm intervals with 3 mm thickness are obtained. The images are transferred to the treatment-planning computer.
Step 3: Defining Target Volume Head and neck cancer is not encapsulated like prostate cancer; the borders are ill defined. Contiguous, perineural, and lymphatic spread are frequent and represent the invasive nature of this cancer. These pathways of spread are unique to each disease site. Head and neck anatomy consists of multiple spaces that may or may not contain lymph nodes. Understanding the lymphatic spaces and both barriers and pathways of spread for each disease site is necessary with conformal therapy. We use the SMART Charts (labeled axial images created by ear, nose, and throat surgeons and diagnostic radiologists at Baylor College of Medicine [Houston, TX] to delineate anatomic sites in the head and neck area) in the delineation of head and neck spaces (Fig 4).8 The gross tumor is outlined with margin and labeled as target 1. This includes radiographic, visible, and palpable disease. Target 2 includes areas at risk for microscopic disease. This includes subclinical disease, pathways of spread, lymphatic spaces, and nerves (in the case of perineural involvement with adenoid cystic carcinoma), as well as added margin around the primary tumor. This is illustrated in Fig 5.
Normal tissue can be spared with IMRT. Normal tissues were outlined on the CT slices and designated as avoidance structures. Dose limitations were set based on their tolerance. Differential weighting of the normal tissue versus tumor is necessary and poses the question: “What is more important, normal tissue or tumor?” The tumor is generally weighted more than avoidance structures to improve control. However, when the tumor is located near a serial structure (structure where damage to part of the structure has a profound effect on function) such as the optic chiasm, weighting is shifted to prevent the treatment-related complication of blindness. The axial CT images were reviewed in the treatment-planning computer. Normal structures were delineated using the SMART Charts. These structures were outlined on each axial slice. Adequate coverage of the primary target is given priority over parotid anatomy. Therefore, the dosimetric parameters represent the volume of parotid glands not included as target. The target doses and normal tissue threshold limits were then prescribed. Threshold limits for the ipsilateral and contralateral parotid glands were set at 35 Gy and 25 Gy, respectively, with adjustments made because of the preference of the treating physician, location of disease, and treatment plan outcome. No attempts were made to avoid the submandibular glands because
Table 3. Disease Characteristics Number (%) Tumor site Oropharynx Nasopharynx Oral cavity Larynx Hypopharynx Paranasal sinus Unknown primary Tumor stage T1 T2 T3 T4 Recurrent Unknown primary N stage N0 N1 N2 N3 Unknown Stage 1 2 3 4 Recurrent Unknown primary
16 (53.3) 4 (13.3) 2 (6.7) 4 (13.3) 1 (3.3) 2 (6.7) 1 (3.3) 7 (23.3) 12 (40.0) 5 (16.7) 4 (13.3) 1 (3.3) 1 (3.3) 11 (36.7) 9 (30.0) 6 (20.0) 3 (10.0) 1 (3.3) 3 (10.0) 7 (23.3) 9 (30.0) 9 (30.0) 1 (3.3) 1 (3.3)
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Fig 3.
(A) Talon fixation device and (B) reinforced aquaplast face mask used for immobilization.
submandibular lymph nodes were commonly included as target. The structures were weighted, with target usually being given priority over normal structures.
Step 5: Plan Evaluation Intensity modulated radiation therapy via Peacock tomotherapy is routinely treated to the 85% isodose line to ensure the majority of the target receives the prescribed dose and to minimize underdosing. The importance of inhomogeneity is still uncertain, as is the best method of evaluation. Detailed analysis of the plan is performed on all axial CT slices. Isodose lines are evaluated based on their proximity to avoidance structures and target volumes. It is uncertain which factor is the best predictor of treatment efficacy. Coverage and avoidance are reviewed on all CT slices. Mean, minimum, and maximum target doses are evaluated in reference to the prescribed dose. Target volume receiving dose below goal is also evaluated. This can be extrapolated from the
dose–volume histograms. The exact location of target volumes receiving doses below goal must also be evaluated, particularly when normal structures lie in close proximity to the target. Because side effects are dose and volume related, the dose and volume of normal structures above goal must be considered.
Step 6: Treatment Delivery A conventional megavoltage linear accelerator delivers 10-MV photons for IMRT treatment. Treatment is delivered through the multivane intensity modulating collimator as the gantry rotates up to 270 degrees around the patient. The multivane intensity modulating collimator consists of 40 vanes, which are 8-cm thick tungsten blocks and project to a 1 ⫻ 1 cm2 or 2 ⫻ 1 cm2 field at isocenter. Because there are two rows of 20 vanes each, arcs can be treated with a 2-cm or 4-cm width. The vanes are individually opened and closed as the gantry rotates around the patient. The treatment couch is arced using a micrometer for accuracy. Treatment generally consists of three to six treatment arcs. A single AP field using 6-MV photons is used to treat the supraclavicular fossa bilaterally.
Xerostomia Assessment
Fig 4. SMART Chart axial slice demonstrating head and neck anatomy. (Reprinted with permission.8)
A subjective salivary gland function questionnaire was designed to provide an adequate assessment of xerostomia. The questions were derived from multiple sources including the Radiation Therapy Oncology Group late salivary gland toxicity, visual analog scale, and quality-of-life studies.3,9-11 To assess long-term xerostomia, the questionnaire was administered at the most recent follow-up. Median time from completion of treatment to questionnaire administration was 38.5 months (mean, 39.9 months). The results of the questionnaire were statistically correlated to the dosimetric parameters of the parotid glands. The questions were: 1. What is the overall comfort of your mouth? 2. Does your mouth feel dry when eating? 3. Do you have difficulty swallowing any foods? 4. Do you need to sip liquids to swallow dry food? 5. Do you feel thirsty all the time? 6. Do you feel the amount of saliva in your mouth is too little, too much, or adequate?
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Fig 5. Axial slice treating the primary tumor and lymphatics in a patient with soft palate cancer with isodose lines indicating dosage received.
7. Do you have problems with speech because of dry mouth? 8. Does dry mouth interfere with your ability to sleep all the time? 9. Has your taste changed because of salivary gland function? 10. Do you need to carry water daily?
RESULTS
Dosimetric Parameters of the Parotid Glands Mean dose and maximum dose, as well as volume and percent of parotid glands above threshold doses were evaluated. The average mean doses to the ipsilateral and contralateral parotid glands were 24.2 Gy and 19.1 Gy, respectively. The average maximum doses were 56.1 Gy and 47.4 Gy, respectively. The ipsilateral gland volume above threshold was 10.6 cc (30.4%). The contralateral parotid volume above the threshold dose was 8.22 cc (23.4%). Because of the treatment planning system, these dosimetric parameters represent the parotid anatomy not included in the target volume.
Subjective Xerostomia The questionnaire was administered to 30 patients at the time of follow-up. Radiation Therapy Oncology Group/European Organization for Research and Treatment of Cancer assessment of late salivary gland toxicity was the first question.9 What is the overall comfort of your mouth? Thirty percent of patients felt that their mouth was very comfortable, 36.7% complained of grade 1 xerostomia (slight dryness), while 20% had grade 2 xerostomia (moderate dryness). Grade 3 xerostomia (severe dryness) was noted in four patients (13.3%). The contralateral mean and maximum doses correlated significantly with these results. Question 2 asked, “Does your mouth feel dry when eating?” This question correlated significantly with the maximum dose to the contralateral parotid gland. Question 3 asked, “Do you have difficulty swallowing any foods?” while question 4 asked, “Do you need to sip liquids to swallow dry food?” These questions correlated with the mean
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Table 4. P Values for Statistical Correlation of the Dosimetric Parameters of the Ipsilateral and Contralateral Parotid Glands With the Salivary Gland Function Questionnaire
Ipsilateral parotid Question 3 Question 4 Question 9 Contralateral parotid Question 1 Question 2 Question 3 Question 4 Question 6 Question 9
Mean Dose
Maximum Dose
Volume
Volume Over Prescribed Threshold
Percentage Over Prescribed Threshold
0.016 0.003 0.004
0.013 0.002 NS
NS NS NS
NS NS 0.014
NS 0.026 NS
0.008 NS 0.017 0.005 0.021 0.000
0.038 0.031 0.003 0.007 0.005 0.014
NS NS NS NS NS NS
NS NS NS NS 0.017 0.001
NS NS NS NS NS 0.001
Abbreviation: NS, not significant.
and maximum doses to both ipsilateral and contralateral parotid glands. Question 5 was “Do you feel thirsty all the time?” This did not correlate with the dosimetric parameters of the parotid glands. The mean and maximum doses to the contralateral parotid glands correlated with question 6, “Do you feel the amount of saliva in your mouth is too little, too much, or adequate?” Questions 7, “Do you have problems with speech because of dry mouth?” and 8, “Does dry mouth interfere with your ability to sleep all the time?” did not correlate significantly with the dosimetric parameters. Question 9, “Has your taste changed because of salivary gland function?” correlated with both ipsilateral parotid mean dose and volume above threshold. The contralateral mean, maximum, and volume above threshold also correlated well with abnormal taste. Question 10, “Do you need to carry water daily?” did not correlate with the dosimetric parameters of the parotid glands. Table 4 shows the P values for statistically significant correlation seen with the questionnaire. Evaluation of the statistically significant results show a clustering of doses, which could be clinically significant. The ipsilateral parotid mean doses correlated significantly with questions 3, 4, and 9. These questions evaluate difficulty swallowing, need to sip liquids when eating, and taste. Patients who responded negatively (ie, complained of xerostomia) to these questions had a range of mean ipsilateral parotid doses of 26.2 Gy
to 28.3 Gy. Patients who did not have these problems had mean doses ranging from 17.8 Gy to 21.1 Gy. A similar result was seen when examining the average contralateral mean doses for questions 1, 3, 4, 6, and 9 (ie, questions yielding statistical significance for contralateral mean dose). Patients responding negatively had average mean doses ranging from 21.3 Gy to 24.5 Gy compared with patients responding favorably who had average mean doses ranging from 12.6 Gy to 16.2 Gy. The ipsilateral and contralateral parotid mean doses for questions 3, 4, and 9 are seen in Table 5. Ipsilateral maximum dose was correlated significantly with questions 3 and 4. Patients who had swallowing difficulties related to xerostomia had
Table 5. Average Mean Doses for the Ipsilateral and Contralateral Parotid Glands Correlated With Questions 3, 4, and 9 Ipsilateral Parotid Mean Dose (Gy)
Contralateral Parotid Mean Dose (Gy)
3 4 9
26.5 26.2 28.3
21.5 21.3 24.5
3 4 9
20.3 17.8 21.1
14.7 12.6 15.1
Answer to the questions Yes Question Question Question No Question Question Question
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average maximum doses of 59.5 Gy and 59.1 Gy (questions 3 and 4, respectively) while patients who did not have swallowing problems had average maximum doses of 50.2 Gy and 46.4 Gy. The contralateral parotid maximum doses correlated with questions regarding overall mouth comfort, problems with eating, difficulty swallowing dry food, quantity of saliva, and abnormal taste (questions 1, 2, 3, 4, 6, and 9). Patients who responded favorably had average maximum doses to the contralateral parotid glands ranging from 35.5 Gy to 41.2 Gy, while patients who responded unfavorably had average maximum doses ranging from 51.8 Gy to 57.5 Gy. DISCUSSION
Radiation therapy to the head and neck region results in multiple side effects that affect quality of life.12-15 The use of IMRT in the treatment of head and neck cancer offers the radiation oncologist versatility and possibility. The dose limitations to the parotid glands can be overcome by IMRT using conformal avoidance.16-18 By limiting the parotid dose, we can improve xerostomia, outcome, and quality of life.2 Defining the primary target is difficult and extensive training is needed. Knowledge of contiguous spread is important when conformal therapy is considered. Where is the pterygopalatine fossa if it is a pathway of spread for maxillary sinus tumors? The pathways and barriers of spread for maxillary sinus tumors must be considered when outlining the primary tumor volume. Pathways of least resistance include superior invasion into the orbit, inferior invasion to the oral cavity, and anterior extension to the skin of the cheek. Once tumor has invaded the pterygopalatine fossa, it can spread in several directions. The pterygoid canal is adjacent to the foramen lacerum, which leads to the middle cranial fossa. Tumors can also invade the middle cranial fossa through the foramen rotundum. Invasion of the infratemporal fossa can occur through the pterygopalatine fissure. Orbital invasion occurs through the inferior orbital fissure. The sphenopalatine foramen leads to the nasopharynx. For each disease site, there are multiple pathways of spread, each with unique symptoms that must be understood. Perineural spread is commonly seen with adenoid cystic carcinoma, but is uncommon with squamous cell carcinoma. The risk of perineural
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spread must be assessed to determine if coverage is necessary. The nerves can be defined as secondary targets. Detailed knowledge of nerve pathways is necessary to provide adequate conformal treatment. Lymphatic involvement in head and neck cancer is complex. The incidence and location of lymph node involvement for each disease site is important. For example, the glottic larynx has a paucity of lymphatics whereas the supraglottic larynx has a rich lymphatic supply. It is important to know which lymph node levels are commonly involved. What is the incidence of ipsilateral, contralateral, and bilateral lymph node involvement? A detailed knowledge of the spaces that lymph nodes occupy is necessary in target delineation. Understanding head and neck spaces and pathways of disease spread allows the radiation oncologist to define target with consistency. By treating only where the disease is, the radiation oncologist can maximize normal tissue avoidance. Also, a systematic method of target delineation can be developed for each disease site. Our subjective salivary gland function questionnaire was derived from multiple sources, some of which validated their results with objective measurements of salivary flow rate.3,9-11 Prior attempts in our department to cannulate Stenson’s duct and measure salivary flow rates have been cumbersome and ineffective. Objective salivary function data are important information and validate patient perception. However, the most important criteria for evaluation of xerostomia are patient comfort and quality of life. The clustering of mean ipsilateral and contralateral doses may have clinical implications. The range of average mean doses to the ipsilateral parotid gland was 26.2 Gy to 28.3 Gy for patients who responded negatively to questions 3, 4, and 9 (ie, questions with a statistically significant relationship to ipsilateral mean dose). Patients who responded positively had a range of ipsilateral mean doses of 17.8 Gy to 21.2 Gy. A similar clustering of mean doses was seen when evaluating questions 1, 3, 4, 6, and 9, which corresponded to the contralateral parotid gland. The range for patients who responded negatively was 21.3 Gy to 24.5 Gy, while patients who responded positively had a range from 12.6 Gy to 16.2 Gy. Similar clustering of maximum doses was seen, but this parameter is highly variable and likely to be correlated with mean dose anyway. The clustering of
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mean doses may have clinical relevance in treatment plan evaluation. It appears from these data that the ipsilateral parotid mean dose should be limited to somewhere between 21 Gy and 26 Gy, while the contralateral parotid gland should be limited to somewhere between 16 Gy and 21 Gy. The need to differentiate between ipsilateral and contralateral parotid glands is also unknown. The exact threshold for parotid dose remains uncertain, and more patients are needed to clarify the data. University of Michigan data have indicated that the mean dose of the parotid glands should be limited to 26 Gy.19 Partial volume data are also available from the same source. Ultimately, it is likely that lower mean doses to the parotid glands will result in less xerostomia. Chao et al4 from Washington University have data to suggest that stimulated salivary flow decreases approximately 4% per Gy of mean parotid dose. Unfortunately, the location of lymphatics and the primary tumor combined with the current state of technology limit the minimum dose that can be delivered to the parotid glands. Of note, the fraction size may also play an important role. The ipsilateral parotid mean dose was 24.2 Gy delivered over 25 fractions. The dose per fraction was very small at 0.97 Gy per day, which is half the size of conventional fractionation. More patients treated with conformal technology are needed. Radiation therapy affects salivary gland function by damage to both the submandibular and parotid glands. These two glands produce different kinds of saliva at different times. The submandibular glands are responsible for baseline saliva. These glands lie in close proximity to the submandibular lymph nodes and are typically included in the irradiated area. Conformal avoidance of the submandibular glands is only possible in a subset of patients where the submandibular lymph nodes are not at risk. The parotid gland is responsible for stimulated flow of saliva. Damage to the parotid gland leads to preferential damage of serous saliva. Therefore, parotid gland damage leads to thick, mucinous saliva, which is frequently seen in patients under treatment. The use of conformal radiation therapy to decrease xerostomia can have a profound effect on quality of life. Intensity modulated radiation therapy can be exploited by conformal avoidance of the parotids. Even with rapidly evolving technol-
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ogy, it is difficult to completely eliminate xerostomia. Other methods to reduce xerostomia by exploiting biology, including amifostine and pilocarpine, have been successful.20-24 Future strategies to minimize the toxicity of head and neck radiation could include combining the advantages of technology and biology. By evaluating the treatment plan, we can anticipate which patients will experience xerostomia. Those patients may benefit from administration of amifostine during radiation. The combination of IMRT and amifostine could have a profound effect on both acute and late toxicity, leading to improvements in number of splits required, treatment time, and late xerostomia. This combination could dramatically change the concept that head and neck cancer treatment with radiation is traumatic and difficult to tolerate. Intensity modulated radiation therapy also makes it possible to deliver altered fractionation schedules. The SMART boost was developed at the Baylor College of Medicine in 1996.9 We treated the primary target at 2.4 Gy per day to a total dose of 60 Gy (mean dose, 63.8 Gy), while areas at risk for microscopic disease were treated at conventional fraction sizes of 2.0 Gy per day to a total dose of 50 Gy (mean dose, 54.8 Gy). The fraction size received by the tumor is approximately 2.55 Gy per day, while normal tissue is treated at small fraction sizes. Based on the results of RTOG 9003, altered fractionation in the form of concomitant boost or hyperfractionation provides an advantage over conventional treatment.25 With IMRT, any fractionation scheme can be delivered with conformal avoidance of normal tissue. This gives the radiation oncologist the flexibility to be aggressive, while still decreasing normal tissue dose. CONCLUSIONS
The use of IMRT in the treatment of head and neck cancer can have a profound effect on xerostomia and quality of life. We are still attempting to determine exactly what dose and volume of parotid gland irradiation leads to subjective xerostomia. A larger number of patients treated with IMRT for head and neck cancer is needed to better define these parameters.
DECREASED XEROSTOMIA IN HEAD & NECK IMRT
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