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Reducing Xerostomia by IMRT: What May, and May Not, Be Achieved

Department of Radiation Oncology, University of Michigan, Ann Arbor, MI

Permanent xerostomia is the most prevalent late consequence of irradiation (RT) of head and neck (HN) cancer and a major cause of reduced quality of life (QOL).¹ In addition to patient perception of dryness, diminished salivary output has other effects, including making mastication and deglutition difficult, which may contribute to nutritional deficiencies, predisposing the patient to mucosal fissures and ulcerations, and changing the composition of oral flora, promoting dental caries and contributing to osteoradionecrosis.² The prevalence of xerostomia after RT of HN cancer relates to the extreme radiosensitivity of the salivary glands, with salivary acinar cell apoptosis at low doses and necrosis at high doses.³

In traditional (2-dimensional [2D]) RT of head and neck cancer, the placement of the radiation fields and their shapes were based on the bony anatomy acquired by the simulator diagnostic-quality films. These fields typically encompass the large majority of all the salivary glands when advanced HN cancer is irradiated. During the early 1990s, 3-dimensional (3D) conformal RT became available, followed by intensity-modulated RT (IMRT). Using IMRT, the desired target doses can be delivered with a high conformity, and dose limits to critical noninvolved organs are achieved at a higher degree than was previously possible. In treating advanced HN cancer with highly conformal RT, an important goal has been the sparing of the parotid glands to reduce xerostomia. Such efforts, initially using 3D RT⁴ and, subsequently, IMRT,^5-7 demonstrated the ability to partly spare these glands while encompassing targets in the bilateral neck, including the gross tumor and the tissue at risk of subclinical disease like lymph node metastasis, by the prescribed radiation doses. The main questions associated with these efforts have been whether highly conformal radiotherapy increases the risk of locoregional tumor recurrence compared with 2D RT, whether there are benefits related to improved salivary flow regarding xerostomia symptoms, and what is the best way to assess these benefits. Over the last few years, a substantial number of phase II–like clinical studies of parotid-sparing RT have been conducted addressing these issues, and the randomized study of IMRT versus 2D RT for early-stage nasopharyngeal cancer, reported by Kam et al in this issue of the Journal,⁸ affirms our current knowledge.

Correct definition of the targets and their outlining on the planning CT is the most important task faced by the radiation oncologist treating HN cancer with IMRT. It requires adequate use of diagnostic imaging to define the extent of the gross disease, and knowledge of the patterns of anatomic local disease extension and lymph node metastasis. A very high rate of locoregional disease control was achieved by Kam et al in both IMRT and 2D RT patient groups, suggesting that the highly conformal dose distributions in the IMRT group did not increase the risk of "geographical misses." Similar high rates of locoregional tumor control in nasopharyngeal cancer treated with IMRT were reported by other groups, including series containing more advanced cancers.^9,10 In fact, the highly conformal dose distributions achieved by IMRT may improve tumor control rates in advanced cancers because they facilitate the delivery of high-doses to areas of the tumor adjacent to critical organs like the brainstem and optic nerves, without exceeding the normal tissue tolerance. However, it is likely that a learning curve exists and that the high tumor control rates reported by groups treating large numbers of patients may not be reproduced by radiation oncologists treating small numbers of HN patients with IMRT. For example, few recurrences at the margins of the target volume were noted in the initial failure analysis of patients treated at the University of Michigan with parotid sparing 3D RT or IMRT. After modifications in target delineation, no additional marginal recurrences were observed,¹¹ illustrating improved results as experience is gained.

Kam et al⁸ found that in the patients treated with IMRT, significantly lower parotid gland mean doses were achieved compared with patients treated with 2D RT, and the lower doses translated into higher stimulated salivary flow rates. Moreover, the salivary flows in the IMRT patients improved over time, compared with no improvement in the 2D RT patients. These findings corroborate what we have known: following 2D RT of HN cancer, the salivary output is meager and does not improve over time. By contrast, reducing the mean dose to the parotid gland using 3D RT or IMRT, salivary flow is partially preserved and increases over time through a compensatory response (the mechanism is not clear) by the part of the glands that received a low dose.¹² As the parotid salivary output is partially preserved and increasing over time, it has been predicted that parallel improvements in the symptoms of xerostomia would follow. However, this expected effect was found to be much more complex and uncertain. The uncertainties relate to the poor correlation between the measured parotid flow rates and symptoms of xerostomia, and also to questions about the best way to evaluate xerostomia.

The primary end point in the study of Kam et al.⁸ was the observer-rated Radiotherapy and Oncology Group/European Organisation for Research and Treatment of Cancer (RTOG/EORTC) late xerostomia scores, demonstrating significant difference favoring the IMRT arm compared with the 2D RT arm. This is consistent with observations in previous single-arm series of IMRT for nasopharyngeal cancer, which reported no, or very low, xerostomia after therapy according to RTOG/EORTC scores.⁹ Conversely, the differences between the arms in patient-reported xerostomia scores were not statistically significant. What was the reason for this difference in outcome, which seems to relate to the method of assessment? A study comparing the observer-rated RTOG/EORTC scoring to a validated patient-reported xerostomia questionnaire after IMRT for HN cancer found a modest agreement among the various observers in the RTOG/EORTC scores, low correlation with the salivary output, and an underestimation by the observers of the severity of xerostomia compared with that reported by patients.¹³ The lack of robust agreement and underestimation were likely due to the inherent difficulties faced by observers assessing the severity of another's symptoms. As xerostomia is primarily a QOL issue, patient-reported scores are expected to be more reliable than observer-rated ones.

How good is the correlation between patient-reported xerostomia and the measured salivary output? Several studies did not show significant correlations,¹⁴ while others did^10,13; however, the correlation coefficients in these studies were modest, meaning that a substantial variability in the scores could not be explained by the salivary flow rates alone. The results of Kam et al fit into this pattern: the salivary flow rates, but not patient-reported xerostomia scores, were significantly better following IMRT compared with 2D RT. A possible reason might be the failure of the questionnaire to adequately assess the degree of symptoms. A more likely explanation is that the sparing of the parotid glands alone was not sufficient. This was demonstrated by another recent study randomizing patients with early-stage nasopharyngeal cancer to IMRT or to 2D RT, in which significantly higher salivary flow rates were observed in the IMRT group, but the improvement in symptoms, assessed by a direct question ("rate dry mouth"), was quite modest.¹⁰ The failure of the preserved parotid saliva to impact greatly on patient-reported xerostomia relates to the composition of the parotid saliva, which is devoid of mucins. Mucins serve as mucosal lubricants and as a selective permeability barrier of the mucosa. They bind water and their presence on the mucous membrane surface helps maintain a hydrated state and contributes to a patient's subjective sense of hydration.¹⁵ Mucin-secreting glands like the minor salivary glands dispersed in the oral cavity produce less than 10% of the total volume of the saliva but contribute the majority of the total mucins.¹⁶ The submandibular glands are another source of mucins. The importance of the mucin-producing glands in determining the severity of xerostomia was demonstrated in studies that correlated RT doses to these glands, their salivary output, and patient-reported xerostomia,¹² and in studies that used surgical transfer of a submandibular gland to the nonirradiated submental space, resulting in a significant patient-reported benefit.¹⁷ When IMRT is used for treatment of the bilateral neck, sufficient reduction of the dose delivered to the contralateral submandibular gland is difficult to achieve, owing to its close proximity to the jugulodigastric nodes, which are the first echelon nodes in most HN cancers and require the full prescribed radiation dose to maximize regional tumor control.

In conclusion, the partial sparing of the parotid salivary glands using IMRT has achieved significant preservation of the parotid salivary flow rates, but only modest improvement in patient-reported xerostomia. The issue of the sparing of the mucin-producing salivary glands has not been solved. To further improve xerostomia, we may need to achieve a higher degree of RT dose conformity and to also incorporate effective radiation protectors or salivary stimulants.

AUTHOR'S DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

The author(s) indicated no potential conflicts of interest.

ACKNOWLEDGMENTS

Supported in part by National Institutes of Health Grant No. CA59827.

REFERENCES

1. 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[Medline]

2. Balogh JM, Sutherland SE: Osteoradionecrosis of the mandible: A review. J Otolaryngol 18 : 245 -250, 1989[Medline]

3. Stephens LC, Ang KK, Schultheiss TE, et al: Target cell and mode of radiation injury in rhesus salivary glands. Radiother Oncol 7 : 165 -174, 1986[Medline]

4. 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[CrossRef][Medline]

5. Vineberg KA, Eisbruch A, Coselmon MM, et al: Is uniform target dose possible in IMRT plans in the head and neck? Int J Radiat Oncol Biol Phys 52 : 1159 -1172, 2002[CrossRef][Medline]

6. Chao KSC, Low D, Perez CA, et al: Intensity-modulated radiation therapy in head and neck cancer: The Mallincrodt experience. Int J Cancer 90 : 92 -103, 2000[CrossRef][Medline]

7. Butler EB, The BS, Grant WS, 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[CrossRef][Medline]

8. Kam MMK, Leung SF, Zee B, et al: Impact of intensity modulated radiotherapy (IMRT) on salivary gland function in early stage nasopharyngeal carcinoma patients: A prospective randomized study. J Clin Oncol 25 : 4873 -4879, 2007[Abstract/Free Full Text]

9. Lee N, Xia P, Quivey JM, et al: Intensity modulated radiotherapy in the treatment of nasopharyngeal carcinoma: An update of the UCSF experience. Int J Radiat Oncol Biol Phys 53 : 12 -22, 2002[CrossRef][Medline]

10. Pow EHN, Kwong DLW, McMillan AS, et al: Xerostomia and quality of life after intensity modulated radiotherapy vs conventional radiotherapy for early-stage nasopharyngeal carcinoma: Initial report on a randomized controlled trial. Int J Radiat Oncol Biol Phys 66 : 981 -991, 2006[CrossRef][Medline]

11. Eisbruch A, Marsh LH, Dawson LA, et al: Recurrences near the base of the skull following IMRT of head and neck cancer: Implications for target delineation in the high neck, and for parotid sparing. Int J Radiat Oncol Biol Phys 59 : 28 -42, 2004[CrossRef][Medline]

12. Eisbruch A, Kim HM, Terrell JE, et al: Xerostomia and its predictors following parotid-sparing irradiation of head and neck cancer. Int J Radiat Oncol Biol Phys 50 : 695 -704, 2001[CrossRef][Medline]

13. Meirovitz A, Murdoch-Kinch CA, Schipper M, et al: Grading xerostomia by physicians or by patients after IMRT of head and neck cancer. Int J Radiat Oncol Biol Phys 66 : 445 -453, 2006[Medline]

14. Wang SL, Zhao ZT, Li J, et al: Investigation of the clinical value of total saliva flow rates. Arch Oral Biol 43 : 39 -43, 1998[CrossRef][Medline]

15. Tabak LA: In defense of the oral cavity: Structure, biosynthesis, and function of salivary mucins. Annual Rev Physiol 57 : 547 -564, 1995[CrossRef][Medline]

16. Milne RW, Dawes C: The relative contributions of different salivary glands to the blood group activity of whole saliva in humans. Vox Sang 25 : 298 -307, 1973[Medline]

17. Jha N, Seikaly H, Harris J, et al: Prevention of radiation induced xerostomia by surgical transfer of submandibular salivary gland into the submental space. Radiother Oncol 66 : 283 -289, 2003[CrossRef][Medline]

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