The Oncologist, Vol. 12, No. 5, 565-568, May 2007; doi:10.1634/theoncologist.12-5-565
© 2007 AlphaMed Press
Commentary: IMRT for Head and Neck Cancer: Many Chapters Left to Write
Aaron M. Allen,
Roy B. Tishler
Department of Radiation Oncology, Dana-Farber/Brigham and Women's Cancer Center, Boston, Massachusetts, USA
Correspondence: Aaron M. Allen, M.D., Dana-Farber Cancer Institute, Department of Radiation Oncology, 44 Binney Street, Boston Massachusetts 02215, USA. Telephone: 617-632-3591; Fax: 617-632-4247; e-mail: AALLEN{at}LROC.HARVARD.EDU
Received March 9, 2007;
accepted for publication March 23, 2007.
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ABSTRACT
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Disclosure of potential conflicts of interest is found at the end of this article.
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INTRODUCTION
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Intensity modulated radiotherapy (IMRT) is a major improvement in radiotherapy delivery for head and neck cancer [1]. The question remains whether or not it represents a major improvement in the treatment of head and neck cancer. Grégoire et al. [2] have nicely reviewed the salient data that currently exist for the theoretical and actual benefits of IMRT in this issue of The Oncologist. However, many questions remain unanswered. These questions fall into two basic categories: (a) How do we use IMRT in concert with other important established advances in head and neck cancer treatment, such as altered fractionation, chemotherapy, and novel agents? (b) Does IMRT in its current formulation produce the risk–benefit improvements it purports to achieve, that is, salivary sparing/less xerostomia, and better targeting/local control? And what is the cost required to achieve these gains? Finally, are there any potential long-term effects of changing the method of delivery of head and neck radiotherapy, such as a greater societal cost and the potential risk for second malignancies [3].
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IMPROVED TARGETING—LOCAL CONTROL?
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One of the most important questions for IMRT is: "Does the technique improve local control or overall outcome?" The authors cite important papers on the subject of IMRT dose distributions as compared with traditional three-dimensional (3D)-conformal radiotherapy plans in nasopharyngeal cancer, sinus tumors, and base of skull lesions. In these studies, IMRT applies superior target coverage compared with traditional techniques [4, 5]. In terms of clinical results, reports from the University of California at San Francisco and the Memorial Sloan-Kettering Cancer Center (MSKCC) show excellent results, with local control >90% [6, 7] even in advanced lesions. However, what may limit the true gain from the use of IMRT is that, at the same time as IMRT has been developed, we have also progressed in the use of better imaging, including magnetic resonance imaging (MRI) and positron emission tomography (PET) scans to help delineate volumes. It is possible that the apparent benefit of IMRT is derived primarily from identifying the target better, rather than in the novel method of dose delivery. An earlier study by Wolden et al. [8] showed that patients with nasopharyngeal cancer who were treated with conventional techniques and a 3D boost, as opposed to IMRT, had a local control rate of only 77%. However, the authors state in their discussion that one of the possible reasons for the greater local failure rate was the fact that MRI and computed tomography fusion was not available at the time the patients were treated to assist in accurately delineating the targets. However, regardless of the reason, it does appears that in base of skull tumors, sinus tumors, and nasopharyngeal cancer, IMRT does produce better results.
Where IMRT has been less well tested is in tumors of the oropharynx, hypopharynx, and larynx. In these sites, the target is more easily defined and therefore the claim of better targeting has less weight. Many times these tumors do require elective treatment of high level II nodes at the base of the skull, because recurrence can occur in the retropharyngeal nodes [8]. In these cases, standard two-dimensional techniques may miss these nodes, as pointed out in an important paper by Sanguineti et al. [10] However, putting these exceptions aside, the data on these sites remain limited for disease control and must be balanced with the needs of altered fractionation, as explained below.
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ALTERED FRACTIONATION
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Early in the treatment of head and neck cancer, radiation oncologists recognized the advantage of giving multiple daily fractions of radiotherapy to improve disease control [11] or limit late effects of therapy [12]. The Radiation Therapy Oncology Group (RTOG) has shown, in a large phase III randomized trial, that accelerated or hyperfractionated radiotherapy improves local control in head and neck cancer by 8% over standard once-daily treatment [13]. This important evidence has served as the backbone for many clinical trials aimed at improving the outcome in patients with head and neck cancer. In many centers, it has become the de facto standard for treating aggressive disease. With the introduction of IMRT, which offers its own benefits, as outlined by Grégoire et al. [2], however, has come a dramatic reduction in the use of altered fractionation. IMRT is time-consuming to plan and deliver and thus makes the possibility of delivering altered fractionated radiation plus IMRT a logistical nightmare. Thus, many investigators and institutions have made one of two choices, either to omit altered fractionation in favor of IMRT or to develop a new technique called simultaneous integrated boost (SIB) [14]. SIB, as the name indicates, delivers a higher dose per fraction to areas at higher risk, while at the same time delivering a lower dose per fraction to areas of subclinical risk. This approach, while appealing and perhaps efficacious, is untested. It also ignores decades of radiobiology research regarding fraction size and late effects and many randomized trials that proved the benefit of altered fractionation [15–17]. While there are no fewer than 10 publications in the past 18 months on IMRT and planning algorithms of SIB, there are no data comparing the efficacy of standard altered fractionation schedules with SIB, nor studies examining efficient ways to combine IMRT and altered fractionation. Those data are sorely needed.
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INTEGRATION WITH CHEMOTHERAPY
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Recent improvements in overall survival and decreased distant metastasis are a result, in large part, of the integration of systemic therapy with radiotherapy. Large randomized trials have now confirmed the benefit of chemoradiotherapy in all disease sites in the head and neck [18–21]. However, with these improvements in outcome also comes more local toxicity, especially mucosal toxicity and dysphagia. Limited data exist on the combination of concurrent chemotherapy with IMRT. In one study from MSKCC, patients with oropharynx cancer who were treated with chemoradiotherapy and IMRT showed no greater incidence of mucosal toxicity or strictures as compared with historical series of chemoradiotherapy [22]. However, in that study, chemotherapy was primarily bolus cisplatin, and the question of whether or not any additional toxicity will occur with multiagent chemotherapy and/or induction chemotherapy remains to be seen. One important effort, as mentioned by the authors, is the work of Eisbruch et al. [23], who hypothesized that dysphagia could be reduced by sparing muscles and structures critical to swallowing. That study, and others like it, will be critical in the integration of new aggressive systemic therapies with IMRT.
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SALIVARY SPARING/XEROSTOMIA?
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Of all the potential benefits of IMRT in head and neck cancer, salivary sparing is the most well established. Several investigators, most prominently the authors of this paper, have shown the importance of IMRT in salivary sparing [24–26]. The data on a mean dose of 26 Gy as the critical metric are gaining acceptance. However, as the authors accurately point out, the data correlating patient-reported xerostomia with salivary flow are not as robust as one would like. In fact, a recently reported randomized trial from Hong Kong showed a clear benefit to IMRT in improving salivary flow and RTOG physician-reported xerostomia scores (82% versus 39% at 1 year) but no significant difference in patient-reported quality of life scores [27]. This confirms results as presented in the article in this issue of The Oncologist and begs a critical question. Despite clear benefits in salivary flow and physician-reported xerostomia, if patients continue to feel dry does the IMRT truly help them? The definitive answer, I believe is "yes." There are considerable benefits to dental hygiene and oral healing from increased salivary flow. In addition, it may be difficult for patients who undergo an initial period of dryness during treatment to accurately score their xerostomia-related quality of life up to a year after treatment when the highest benefit is seen. Nevertheless, as the authors point out, there is room for improvement in this area. One of the main directions that may be pursued is the combination of pharmacological salivary protection with IMRT. There is one investigation reported on this combination [28, 29] but no long-term results as of yet. Future results will be very important to improvements in the field.
An additional concern that has been raised is whether or not the use of IMRT poses a greater risk for radiation-induced cancers. It has long been accepted that there is a small but real risk of "second malignancies" following radiotherapy. These have most often been seen in survivors of childhood malignancies and lymphomas that occur at a young age and are often cured [30, 31]. With new technology, including IMRT, some have raised a theoretical risk that with more low-dose radiation, which is a consequence of IMRT, the second malignancy risk may be increased [3, 32]. While this hypothesis needs to be tested in the coming years, it is unlikely that this will dissuade anyone's use of IMRT for head and neck cancer.
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FUTURE DIRECTIONS
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Jonas Salk is quoted as saying, "this is perhaps the most beautiful time in human history; it is really pregnant with all kinds of creative possibilities made possible by science and technology which now constitute the slave of man—if man is not enslaved by it." This is certainly true about the state of head and neck radiation therapy today. IMRT represents the potential for a quantum leap forward in the treatment of head and neck cancer, for improvements in targeting and sparing of toxicity. However, there are more chapters left to write in this saga and more questions left to be answered. The authors of the paper represent the leaders in this field and have summarized some significant contributions that they have made to the field. We have tried to raise some questions for further study, such as integration of chemotherapy, altered fractionation, and radioprotectors. In addition, new agents such as cetuximab have now shown benefit in head and neck cancer [33]. How do we integrate these data with IMRT? Further studies are clearly needed. At the Dana-Farber Cancer Institute, current efforts include testing the use of concomitant boost IMRT, a phase I trial of panitumumab (a fully humanized monoclonal epidermal growth factor receptor antibody, Amgen Inc., Thousand Oaks, CA) with concurrent chemotherapy and IMRT, and detailed analysis of the effect of dose on swallowing function following chemoradiotherapy with IMRT.
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DISCLOSURE OF POTENTIAL CONFLICTS OF INTEREST
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The authors indicate no potential conflicts of interest.
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REFERENCES
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Abstract
Introduction
