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

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). 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. 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. 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 diagnosticquality 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 RT and, subsequently, IMRT, 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, 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. 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, illustrating improved results as experience is gained. Kam et al 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. 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. was the observer-rated Radiotherapy and Oncology Group/European Organisation for Research and Treatment of Cancer (RTOG/ JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 25 NUMBER 31 NOVEMBER 1 2007