Abstract

Purpose

To evaluate outcomes of proton therapy and x-ray radiation treatments for head and neck paragangliomas.

Patients and Methods

Between 2004 and 2014, 13 patients with paragangliomas were treated with radiation using proton therapy (n = 7) or x-ray modalities (n = 6). Paragangliomas were jugular fossa, vagal, tympanic, and carotid body in 5, 4, 2, and 2 patients, respectively. Patients were treated definitively (n = 8), for recurrence or progression after prior surgery (n = 4), or for residual tumor after surgery (n = 1). The median age was 55 years (range, 35 to 77 years). The median dose of proton therapy was 35 Gy (RBE) in 15 fractions, and 50.4 Gy in 28 fractions for those treated with x-rays. Tumor volume was delineated at treatment planning and on follow-up images to assess volumetric changes over time. The median follow-up time after proton therapy was 52 months (range, 6 to 105 months) and 73 months (range, 37 to 91 months) after x-ray therapy.

Results

No acute grade 3 or greater toxicities occurred. After radiation therapy, tumor control was maintained and performance status was unchanged or improved in all patients. Of the patients, 10 had stable findings, 2 had improvement in preexisting cranial nerve deficits, and 1 had progression of previously intermittent vocal cord paresis to paralysis, compensated by vocal-fold injection. No secondary malignancies have been observed. Volumetric tumor response assessment found 1 patient with an increase in tumor volume of 0.4 cm3 at first postradiation assessment, followed by 6 years of stable tumor size. The remaining 12 patients had reduction in tumor volume over time with a median tumor volume reduction of 33% at the last follow-up. The median tumor regression slope for the proton cohort was −1.21 cm3/y compared with −0.27 cm3/y in the x-ray cohort (P = .02).

Conclusion

Both proton and x-ray radiation were effective in treating paraganglioma and had minimal acute side effects and few long-term complications.

Introduction

Paragangliomas of the head and neck are rare vascular neuroendocrine tumors of the autonomic ganglia derived from embryonic neural crest tissues [1]. The estimated occurrence is 2 to 5 patients per million per year, and they are more likely to occur in women [2]. Head and neck paragangliomas may arise along the glossopharyngeal or vagal nerves or branches thereof in the temporal bone (tympanicum), jugular foramen, vagal, or carotid body locations. Genetic predisposition has been found in around 30% of patients, and the most common mutations are in the succinate dehydrogenase genes on chromosome 11: SDHB, SDHC, and SDHD being common mutations [3]. Nearly all (90% to 95%) of these tumors are benign [4], and the natural history of untreated tumors is of slow growth at an estimated rate of 1 mm per year with a median tumor-doubling time of 4.2 years [5]. Despite a benign histology and slow growth rate, paragangliomas can result in significant toxicity because of involvement of lower cranial nerves. Surgical removal is curative but associated with some risk of iatrogenic injury [6].

Radiotherapy has a high rate of tumor control [7], but concerns persist regarding risk of secondary malignancy and other potential adverse effects of radiation therapy in patients with a long natural history [8, 9]. Proton therapy is a modality of radiation therapy that differs from x-ray based modalities by providing a finite range of dose deposition within tissue, delivering radiation to the depth of the target, and then terminating, with no exit dose radiation to normal tissue beyond the target [10]. Proton therapy is theorized to reduce the risk of secondary malignancy because of the reduced radiation exposure of nontarget tissues, and it may reduce other late toxicities of treatment [11]. To our knowledge, there are currently no published outcomes of proton therapy in management of head and neck paragangliomas. Thus, we review our experience in treating these tumors with x-ray modalities and proton therapy.

Materials and Methods

In an institutional review board–approved retrospective study, patients with head and neck paragangliomas treated at Indiana University Health University and Methodist hospitals (Indianapolis, Indiana) and at the now closed Indiana University Health Proton Therapy Center (Bloomington, Indiana) for head and neck paragangliomas between 2004 and 2014 were reviewed. The proton and x-ray treatment sites are geographically separated, and during the first half of this time period the proton therapy center was not programmatically integrated, so that utilization of radiation treatment modality was directed by different referral patterns rather than physician selection. Patients managed with x-ray therapy were treated in conventional fractionation at 1.8 Gy per fraction, while the physicians at the proton therapy center approached these patients with the hypofractionated treatment protocol used at the Princess Margaret Hospital [12], a distinction in approach that was maintained after programmatic integration of the two practice sites. Diagnosis of paraganglioma was made by imaging with computed tomography (CT) and/or magnetic resonance imaging (MRI) in 7 patients or by histology in 6 patients with prior surgery (n = 5) or biopsy (n = 1).

Patient characteristics collected included age, gender, location of tumor, Karnofsky Performance Status before treatment and in follow-up, prior surgical interventions, and deficits present before radiation. Treatment details included radiation modality, radiation dose, and dose per fraction.

Details of the proton beam delivery system have been previously published [13]. Proton treatment planning involved an alpha cradle and thermoplastic mask for immobilization and acquisition of a CT scan with 1 mm slice thickness. Diagnostic imaging with contrast-enhanced CT and/or MRI was coregistered to delineate the tumor. The clinical target volume was typically 0.5 cm around the tumor, and a 2 mm uniform expansion was added for a planning target volume. Orthogonal kilovoltage x-ray images were used for daily patient alignment before treatment of each field, using a robotic patient position with 6 degrees of freedom [14]. Proton dose is expressed in Gy (RBE) with a relative biologic effectiveness of 1.1 compared with megavoltage x-ray therapy.

Patients receiving x-ray therapy were treated with image-guided intensity-modulated radiation therapy (IMRT), 3-dimensional conformal radiation therapy, or fractionated stereotactic radiation therapy using similar methods of immobilization with a thermoplastic mask, target delineation, and image-guided delivery.

Months of follow-up time were calculated from the completion date of radiotherapy. Information on acute and late toxicity was retrospectively gathered from weekly treatment status notes, the treatment completion summary, follow-up notes, and correspondence from follow-up with other physicians. Acute toxicities were scored according to the Common Terminology Criteria for Adverse Events (version 4.03, National Cancer Institute, Bethesda, Maryland). Also recorded were change in baseline cranial nerve deficits and the development of any new deficits. Tumor surveillance and follow-up included annual imaging with MRI or CT. Follow-up imaging was coregistered to the treatment plan and the volume of tumor delineated on serial imaging by the senior author to assess volumetric change in tumor over time. The authors were not blinded to patient details, including treatment modality, in assessing volumetric response. The slope of a linear regression line fit to each patient's volumetric data over time was calculated, and the distribution of slopes between the x-ray and proton cohorts was compared using the Mann-Whitney U test. End points assessed included local tumor control, assessed by diagnostic radiology in evaluation of follow-up scans, and overall survival. Because of the small sample size, further statistical analysis was not undertaken.

Results

Thirteen patients were treated for head and neck paragangliomas. Patient and treatment characteristic are shown in Table 1. Seven patients with treated with image-guided proton therapy and 6 with x-ray therapy (fractionated stereotactic radiation therapy = 3, IMRT = 2, 3-dimensional conformal radiation therapy = 1). Eight patients were treated with primary radiation therapy, 4 for recurrence after prior surgery and 1 for residual disease after incomplete surgery. One patient who had had 2 prior surgeries for recurrent tumor was reirradiated with IMRT for recurrent disease after a remote history of prior irradiation using electron therapy. The SDHC mutation was confirmed in 1 patient.

Table 1.

Patient and treatment characteristics.

Patient and treatment characteristics.
Patient and treatment characteristics.

Of the 7 patients treated with proton therapy, 5 were treated using a hypofractionated course of 35 Gy (RBE) in 15 fractions [12]. One patient with a massive, highly atypical paraganglioma with features raising concerns about malignancy received 59.4 Gy (RBE) in 33 fractions. The remaining patient undergoing proton therapy patient received 54 Gy (RBE) in 30 fractions. Patients treated with x-ray therapy received between 45 and 54 Gy in fractions of 1.8 Gy.

The median follow-up for the entire cohort was 68 months (range, 6 to 105 months). The median follow-up time was 52 months (range, 6 to 105 months) after completion of proton therapy and 73 months (range, 37 to 91) after x-ray therapy. At the time of analysis, all patients are alive; no patients experienced tumor progression or secondary malignancies. Acute toxicities of therapy are summarized in Table 2. No acute grade 3 or greater toxicities occurred.

Table 2.

Acute toxicity of therapy.

Acute toxicity of therapy.
Acute toxicity of therapy.

After therapy, 10 patients had stable findings, 2 had improvement in preexisting cranial nerve deficits, and 1 had progression of previously intermittent vocal cord paresis to a vocal cord paralysis, compensated by vocal-fold injection. Karnofsky Performance Status at the time of last follow-up was unchanged or improved in all patients.

Volumetric tumor response assessment is shown in Figures 1 and 2. One patient had an increase in tumor volume of 0.4 cm3 at the first postradiation assessment (12% relative volume increase), followed by 6 years of stable tumor size. The remaining 12 patients had reduction in tumor volume over time with a median tumor volume reduction of 33% at the last follow-up. Comparing tumor regression by cohort, the median linear regression slope for the proton cohort was −1.21 cm3/y compared with −0.27 cm3/y in the x-ray cohort; distributions in the 2 groups differed significantly (Mann-Whitney U = 5.0, P = .02).

Figure 1.

Volumetric tumor response after x-ray radiation.

Figure 1.

Volumetric tumor response after x-ray radiation.

Figure 2.

Volumetric tumor response after proton radiation.

Figure 2.

Volumetric tumor response after proton radiation.

Discussion

In our experience, radiation therapy for head and neck paragangliomas resulted in excellent local control, and no treatment failures were observed in the proton or x-ray cohorts. Acute toxicities were minor in both radiation modality cohorts. With the small sample size; the low baseline observed toxicity; and the varied tumor locations, size, and geometry, no discernible difference in acute toxicity was noted by modality. Our findings are similar to the results reported in larger studies of radiotherapy outcomes [7, 12].

On serial imaging, tumor volume was reduced in 12 of 13 patients. Figure 3 shows an example of tumor shrinkage after proton therapy. A systematic review and meta-analysis of results of radiotherapy for jugulotympanic paragangliomas details varied radiographic criteria used to define regression and local tumor control and highlights the relative paucity of data on tumor regression [15]. Two prior small series using volumetric measurements reported tumor reduction in about one-third of patients [16, 17]. Volumetric imaging has been described and used in the evaluation of other slowly progressive tumors, such as meningiomas, and has the advantages of being tolerant of differences in head positioning between serial scans and being sensitive to changes in tumor extension in any direction [18, 19].

Figure 3.

Postcontrast magnetic resonance imaging sequences at T1 are shown in a patient irradiated for a recurrent vagal paraganglioma after prior surgery. On the left is the magnetic resonance image before radiation. On the right, tumor regression is noted 7 years after proton therapy to 35 Gy (RBE) in 15 fractions.

Figure 3.

Postcontrast magnetic resonance imaging sequences at T1 are shown in a patient irradiated for a recurrent vagal paraganglioma after prior surgery. On the left is the magnetic resonance image before radiation. On the right, tumor regression is noted 7 years after proton therapy to 35 Gy (RBE) in 15 fractions.

Comparing the percent change in tumor volume over time by treatment modality, there was, on average, a steeper slope for tumor regression over time in the proton cohort. This finding may be attributable to the difference in fractionation between the 2 cohorts, suggesting that the hypofractionated regimen most commonly used in the proton cohort may result in a greater rate or earlier observation of tumor regression, perhaps through increased or earlier microvascular fibrosis. However, the linear quadratic equation estimates that the biologically effective dose (BED) to late-responding tissues (alpha-beta ratio of 3) for 35 Gy in 15 fractions (BED = 62.2 Gy3) is lower than for 45 Gy in 25 fractions (BED = 72 Gy3) [20]. Another hypothetical explanation for the apparent difference is the slightly larger average tumor size in the proton therapy cohort. Discerning volumetric changes may be easier in larger tumors, or there may be an inverse relationship between the rate of tumor regression and tumor volume that may be based on potential varied proportions by size of more radiosensitive vascular elements to more radioresistant neural elements [21]. Although the apparent difference in the cohorts may be an artifact of a small sample size, further exploration of tumor response by fraction size, tumor volume, and other parameters in a larger cohort of patients would be of interest.

Our series is retrospective in nature, with all the incumbent selection biases inherent in retrospective analysis. Radiation dose prescription was variable within a range of benign doses over the 10-year period of this review. For conventional fractionation, 45 Gy in 25 fractions is widely regarded as the standard dose for benign paragangliomas [7]. In our patients undergoing proton therapy, we more consistently used the modestly hypofractionated dose published in the Princess Margaret Hospital experience of 35 Gy in 15 fractions, in which results appeared as effective as conventional fractionation [12]. The conformality of proton therapy has lent itself to application of hypofractionation in a number of tumor sites, and these shorter courses of treatment can address some of the cost differential between x-ray and proton treatment modalities [22].

Randomized controlled trials to study paragangliomas are unlikely given the rarity of the diagnosis and variations in treatment approach. Although the numbers are small, the encouraging treatment outcomes of proton therapy at a long median follow-up support prospective evaluation of proton therapy in this disease site. Figures 4 and 5 show an example of comparative treatment planning for paraganglioma that illustrates reduced radiation dose to nontarget tissues using proton therapy. A true or realistic estimate of risk of second tumors after radiotherapy for paraganglioma is unknown. A review of results of radiation therapy for paraganglioma based on 19 clinical series published between 1965 and 1988 identified a single case of a reported presumed radiation-induced secondary tumor among 356 treated patients and thereby estimated a crude risk of 0.28% [23]. A crude incidence estimate lacks statistical rigor and is additionally constrained by the limitations of the underlying data set, including adequacy of follow-up, underreporting, and publication bias. Although the risk may be small, concern for radiation-induced malignancy is a frequently cited issue regarding application of radiation therapy for paraganglioma [8, 24, 25].

Figure 4.

Comparative treatment plans are shown on a T1 postcontrast magnetic resonance image in a patient with a vagal paraganglioma. The plans evaluated included a wedged pair x-ray radiation therapy (XRT) plan with 6 MV photons, a volumetric modulated arc therapy plan with 6 MV photons, and a 2-field proton plan with uniform scanning. The tumor and target are encircled in red, and the parotid glands, oral cavity, and spinal cord are delineated. The proton treatment plan shows the absence of exit dose beyond the target and reduced volumes of nontarget tissues receiving low and intermediate dose.

Figure 4.

Comparative treatment plans are shown on a T1 postcontrast magnetic resonance image in a patient with a vagal paraganglioma. The plans evaluated included a wedged pair x-ray radiation therapy (XRT) plan with 6 MV photons, a volumetric modulated arc therapy plan with 6 MV photons, and a 2-field proton plan with uniform scanning. The tumor and target are encircled in red, and the parotid glands, oral cavity, and spinal cord are delineated. The proton treatment plan shows the absence of exit dose beyond the target and reduced volumes of nontarget tissues receiving low and intermediate dose.

Figure 5.

A dose volume histogram from the comparative treatment plans shown in Figure 4. X-ray radiation therapy (XRT) = a wedged pair x-ray plan, volumetrics-modulated arc therapy (VMAT) = volumetric modulated arc therapy. Nontarget normal tissue was defined as the outer body contour extending from 0.5 cm above to 0.5 cm below the planning target volume (PTV) minus the PTV. For this representative patient, the mean dose to nontarget tissues, as well as the area under the curve (AUC), for each comparative treatment modality is shown.

Figure 5.

A dose volume histogram from the comparative treatment plans shown in Figure 4. X-ray radiation therapy (XRT) = a wedged pair x-ray plan, volumetrics-modulated arc therapy (VMAT) = volumetric modulated arc therapy. Nontarget normal tissue was defined as the outer body contour extending from 0.5 cm above to 0.5 cm below the planning target volume (PTV) minus the PTV. For this representative patient, the mean dose to nontarget tissues, as well as the area under the curve (AUC), for each comparative treatment modality is shown.

Proton therapy is anticipated to reduce the risk of secondary malignancy compared with x-ray techniques, thereby addressing and potentially mitigating this concern regarding application of radiotherapy for paragangliomas. Although no data have been specific to paragangliomas, the potential risk reduction for secondary malignancy with proton therapy compared with x-ray therapy has been explored in radiobiologic modeling, predicting a lower risk of both in-field [26] and out-of-field [27] second malignancies using proton therapy. Some clinical data also suggest a reduction in the risk of secondary tumors after proton therapy compared with x-ray therapy, including a cohort analysis of primarily adult patients with varied tumor histologies [11] and a cohort analysis in pediatric patients with retinoblastoma [28].

In conclusion, our institutional experience with this rare tumor found that proton therapy resulted in excellent tumor control, comparable with results achieved with x-ray modalities. Both modalities tended to produce measurable reductions in tumor volume over time. Further research with longer follow-up is warranted to better define the role of proton radiation therapy in the treatment of paragangliomas.

ADDITIONAL INFORMATION AND DECLARATIONS

Conflicts of Interest: The authors have no conflicts of interest to disclose.

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