Treatment of Head and Neck Paragangliomas

Kenneth Hu, MD; Mark S. Persky, MD

Disclosures

Cancer Control. 2016;23(3):228-241. 

In This Article

Radiotherapy

Traditionally, radiotherapy was offered to those with postoperative recurrence or for those patients who were not surgical candidates due to technical unresectability issues, patient refusal, age, or illness. Unlike surgery, concern exists with radiotherapy because lesions may remain dormant as they rarely regress completely after this treatment modality. Yet, evidence supports the long-term efficacy of moderate doses of radiation to prevent tumor progression while also preserving cranial nerve function.[1–3] Thus, radiotherapy has become a first-line treatment for these largely benign tumors, and it is commonly considered for skull-base tumors of a jugulotympanic origin as well as vagal tumors.[1–3] Given the demonstrable and favorable long-term outcomes, successful treatment is typically defined as lack of tumor progression on serial radiographic follow-up and includes stability of tumor size or partial regression.[1–3]

Primary radiotherapy may be delivered with conventional external beam radiotherapy (EBRT), stereotactic radiosurgery, or hypofractionated stereotactic radiotherapy — all of these approaches have excellent rates of local control and outcomes.[1–3] Typically, doses of 45 Gy in 5 weeks are given with conventional EBRT, 12 to 15 Gy with stereotactic radiosurgery, and 21 Gy for 3 fractions or 25 Gy for 5 fractions with hypofractionated stereotactic radiotherapy.[1–3] Patients whose intracranial tumors measure less than 3 cm are the best candidates for stereotactic approaches, whereas those whose tumors are larger or have a component of extracranial spread are best suited for EBRT.[1–3] The ablative nature of stereotactic radiosurgery can cause a small increase or exacerbation in the rate of cranial neuropathy, and, thus, a more fractionated approach with stereotactic radiotherapy or conventional EBRT may be considered in those whose baseline cranial nerve function is excellent.[1–3]

Histopathological Changes

Multiple reports have described the histopathological impact of radiation on paragangliomas.[35–37] Gardner et al[36] studied 6 irradiated tumor specimens resected 4 to 6 weeks following radiotherapy and found evidence of vascular endarteritis with mural thrombi as well as necrotic infarct and pyknotic cellular death. Fibrosis around nests of the pathognomonic chief cells has been reported at 6 months post-treatment with diminished vascularity.[35,38–40] Chief cells may show evidence of senescence such as nuclear pleomorphism, irregular nuclear outlines, and chromatin clumping.[36,37,40] Thus, radiation appears to create sclerosing endarteritis with subsequent fibrosis, which in turn prevents tumor growth and involution while also causing a loss of reproductive capacity of the chief cells.[22,35,41]

External Beam Radiotherapy

Ever since the first major review was published more than 50 years ago of 106 cases of paragangliomas that demonstrated similar rates of efficacy between radiotherapy and surgery, numerous retrospective studies have confirmed the effectiveness of radiation for managing head and neck paragangliomas.[35,42–68] Reflecting a wide variety of delivery techniques, beam energies, and dosing schedules, cumulative rates of local control average 90% (range, 65%–100%) and are based on more than 1,000 cases (median follow-up time, 10 years).[35,42–68]

Primary radiotherapy may be delivered with conventional fractionation, the results of which have the largest and longest experience. Typically, a dose of 45 Gy in 5 weeks is given with conventional fractionation (Fig 5).[3] The effectiveness of radiotherapy is not affected by site of origin, whether it be the jugulotemporal, carotid body, or vagal space.[43,48,62,69] Gilbo et al[63] reported on a 45-year experience with conventional fractionation and prescribed a dose of 45 Gy. A total of 131 patients were enrolled and 156 paragangliomas were studied. The 5- and 10-year rates of local control were 99% and 96%, respectively, at a median follow-up of 8.7 years.[63] Five tumors recurred between approximately 1 and 8 years following treatment.[63]

Figure 5.

Jugular paraganglioma treated with external beam radiotherapy. A man aged 27 years presented with diplopia and tinnitus and was found to have paraganglioma of the jugular area that extended extracranially and to the cavernous sinus. He was treated with definitive intensity-modulated radiotherapy (dose of 45 Gy in 25 fractions). Both symptoms resolved by the end of radiotherapy.

Compared With Surgery. The effectiveness of surgery compared with EBRT is difficult to ascertain because of the retrospective nature of data from authors at single institutions, who report small patient numbers confounded with selection bias and other conflicting outcomes.[66,70–73] To extract meaningful comparative outcomes based on a common staging system, an analysis of 5 studies was performed to report on the outcomes of temporal bone tumors using McCabe/Fletcher staging.[43,47,51,60,68] That analysis demonstrated that study patients treated with radiotherapy, surgery, or a combination of both had average rates of local control of 93%, 78%, and 85%, respectively, for a median follow-up period of 11 to 16 years.[43,47,51,60,68] Despite a larger number of advanced tumors in the radiotherapy group, the rate of local control was similar or better than those undergoing surgery alone or receiving combination treatment.[43,47,51,60,68] Others have shown debulking surgery does not improve outcomes when patients are treated with radiotherapy.[60]

In a systematic literature review, Suarez et al[10] reported on the role of surgery and EBRT in the treatment of carotid body paragangliomas. The mean follow-up times were 80.6 months for surgery (n = 2,175) and 99.9 months for those receiving EBRT (n = 127).[10] No difference was seen in local control in the surgery and EBRT arms (93.8% vs 94.5%, respectively).[10] Reduction in tumor size was reported in 25.2% of study patients treated with EBRT. All received conventional doses of radiotherapy (40–65 Gy); 44% received doses between 40 and 50 Gy.[10] Iatrogenic cranial neuropathy — primarily occurring in cranial nerves X and XII — occurred in 22.2% of patients treated with surgery vs 0% in those treating with EBRT (P = .004).[10] Iatrogenic Horner syndrome occurred in 2.5% of patients treated with surgery.[10] The carotid artery was resected in 12.5% because of injury or tumor encasement, 3% developed permanent stroke, and 1.3% died because of postoperative complications.[73] The rates of iatrogenic cranial neuropathy and vascular complications were 2.3% for Shamblin class 1/2 tumors and 35.7% for Shamblin class 3 tumors (P < .001).[74] With use of EBRT, a potential increased risk of ischemic stroke of approximately 12% has been observed with long-term follow-up of 15 years.[75,76]

Suarez et al[73] also studied patients with jugular or vagal paragangliomas treated with surgery (n = 1,310), EBRT (n = 461), or stereotactic radiosurgery (n = 261). The median follow-up times for surgery, EBRT, and stereotactic radiosurgery were 66 months, 113 months, and 41 months, respectively.[73] Among patients with jugular paragangliomas, better rates of local control were observed with radiotherapy compared with surgery (91.5% vs 78.1%; P = .002), and fewer major complications were seen with radiotherapy compared with surgery (11% vs 26%; P = .02) — in particular, lower iatrogenic cranial neuropathy (0.08 vs 1.0/per patient; P < .001).[73] Perioperative complications of major importance were, in order of decreasing incidence, cerebrospinal fluid leak, aspiration/pneumonia, wound infection, meningitis, and stroke.[73] A rate of perioperative mortality was reported to be 1.6%.[73] Severe complications from radiotherapy included, in order of decreasing incidence, deafness, osteonecrosis, death, and brain necrosis.[73] No significant difference was observed in rates of local control between EBRT and stereotactic radiosurgery.[73]

Impact on Neurological Function

In the majority of patients with jugulotympanic tumors who present with tinnitus, EBRT can be used to reduce or resolve it.[48,55] Cummings et al[55] demonstrated complete resolution of tinnitus in 79% and stable or partial relief in 21% of the cases they studied. With regard to sensorineural hearing loss, they found that 5% of patients reported a return to normal hearing, 30% reported some improvement, and 62% noted no change after radiotherapy.[55] Improvement of other cranial neuropathies after radiotherapy has been reported in approximately one-third of patients.[44,47,48,50,51,53,55,62,69] Complete restoration of cranial nerve function is less common, occurring in about 10% (range, 8%–20%).[44,47,48,50,51,53,55,62,69] The probability that cranial nerve function will improve following radiotherapy is most likely inversely related to the duration of cranial neuropathy.[48,73] Suarez et al[73] reported improvement of cranial nerve function in 8.8% of patients after stereotactic radiosurgery compared with 4.1% in those treated with EBRT. Hearing loss occurred in 6.5% patients treated with stereotactic radiosurgery.[73]

Radiation-induced cranial neuropathy following EBRT is rare and has been associated with doses above what are recommended.[48,53,62] Four such cases have been reported: 2 cases of cranial nerve VII palsy, 1 case of cranial nerve VIII dysfunction occurring after a high dose of radiotherapy (64–66 Gy), and 1 case of cranial nerve VI palsy that the authors stated had an "unclear etiology."[48,53,62]

Impact on Radiographic Tumor Regression

Results of the radiographic follow-up of patients after EBRT demonstrate stability in tumor size or modest tumor regression.[51,60,77] Mukherji et al[78] reported on 17 patients with 18 paragangliomas treated with definitive radiotherapy who underwent pre-treatment and post-treatment imaging using CT or MRI. A total of 61% showed a decrease in tumor size, with an average reduction of 23% (range, 8%–45%) at a median follow-up of 2.5 years. Postradiotherapy findings on MRI included reduction in flow voids, decreased heterogeneous enhancement, and a reduced T2 signal.[78] Other studies have demonstrated tumor regression in 57% to 73% of patients followed by CT.[47,49] Thus, paragangliomas will show modest radiographic change or stable tumor in the majority of cases.

van Hulsteijn et al[79] performed a meta-analysis of 15 studies involving 283 jugulotympanic paragangliomas in 276 patients to evaluate the proportion of patients whose tumors had regressed after stereotactic radiosurgery or conventional EBRT. All studies had to have a minimum of 12 months of follow-up with adequate radiologic evaluation.[79] The percentages of patients demonstrating some regression after stereotactic techniques and treated with definitive intent, combined modality, and salvage treatment were 21%, 33%, and 52%, respectively; for those receiving conventional EBRT, the corresponding outcomes were 4%, 0%, and 64%.[79] No differences in local control were noted between the 2 treatment techniques nor in those with tumor regression vs those without.[79]

Fractionated Radiotherapy

Rates of morbidity following radiotherapy vary according to the radiation technique and treatment site.[1–3] Common toxicities related to radiotherapy include mucositis, fatigue, otitis, dermatitis, nausea, xerostomia, epilation, skin dryness, fibrosis, and cerumen build up.[1–3] Severe complications after radiotherapy have been reported in 30 series and occur in approximately 6% of patients; the rate of treatment-related mortality has been observed to be 0.6%.[35,42–68] Severe morbidity primarily consists of osteoradionecrosis, chronic otitis, brain necrosis, radiation-related cranial neuropathy, radiation-induced sarcoma, external auditory canal stenosis, and trismus.[1]

Most of these severe complications are related to radiotherapy that exceed the current recommended dose, use outdated treatment techniques, or are due to toxicity from reirradiation.[1] For example, of the 4 reported cranial neuropathies related to radiotherapy, 3 occurred after receiving 64 to 66 Gy of radiation.[48] Cole et al[45] reported that all of the severe complications seen in their series occurred in patients treated with orthovoltage; none occurred in those treated with megavoltage. It is worth noting that the reported incidence of radiation-induced secondary malignancies was low (0.4%).[45] These included 2 fibrosarcomas occurring 15 and 25 years after treatment and 1 osteosarcoma occurring 5 years post-treatment.[45] In 2015, Gilbo et al[63] reported on 131 patients (156 benign paragangliomas) in a 45-year report. The patients were treated for paragangliomas of the jugular bulb, vagal area, temporal bone, and carotid body. At nearly 12 years of median follow-up, they observed no severe (grade 4/5) complications, and none of their study patients developed iatrogenic cranial neuropathy/malignancy.[63] Thus, with current recommended dosing guidelines and modern treatment techniques, definitive radiotherapy can be well tolerated in patients with paragangliomas.

Stereotactic Radiosurgery

Stereotactic radiosurgery is a successful first-line treatment for paragangliomas and as salvage therapy for treatment failure. Stereotactic radiosurgery uses a highly focused, single ablative dose of radiation to a small target with a steep dose gradient to spare as much surrounding normal tissue as possible. For most patients, the plan for treatment and the treatment itself are performed in a single session. Radiation is delivered using non-coplanar beams, rigid immobilization, and MRI-based treatment planning.

Multiple series have reported on the success of this approach to treat jugular paragangliomas and have observed generally high rates of local control.[77,80–84] A wide range of median doses has also been reported between 15 and 32 Gy, with 15 Gy being the most common.[77,80–84] Chen et al[85] reported on a 15-patient series and found that 13 Gy was associated with higher rates of failure than 15 Gy (P = .08). Treatments appeared to be well tolerated, with low incidence rates of transient facial neuropathy, hearing impairment, and vertigo.[85] Stereotactic radiosurgery does have limitations, which include the location of the intracranial tumor and tumor size.[80] Tumors are typically no larger than 3 cm to achieve tight dose conformality.

A population-based meta-analysis of 19 studies comprising 335 glomus jugulare cases treated with radiosurgery was reported by Guss et al.[86] For all of the 19 studies, the rate of tumor control was 97%; among 8 reports studied whose median follow-up times were longer than 36 months, the rate of control achieved was 95%.[86] No difference in outcome was reported by radiosurgical technique used.[86]

Compared With Surgery. Gottfried et al[87] performed a meta-analysis of 109 studies comprising 869 glomus jugulare cases treated either by gross total resection, subtotal resection, stereotactic radiosurgery alone, or subtotal resection combined with stereotactic radiosurgery. The median follow-up times for gross total resection, subtotal resection, subtotal resection in combination with stereotactic radiosurgery, and stereotactic radiosurgery were 88 months, 72 months, 96 months, and 71 months, respectively.[87] The rates of tumor control for gross total resection, subtotal resection, subtotal resection in combination with stereotactic radiosurgery, and stereotactic radiosurgery were 86%, 69%, 71%, and 95%, respectively.[87] The study patients undergoing stereotactic radiosurgery alone had the best tumor control rates (P < .001).[87] Those undergoing gross total resection had worse deficits in cranial nerves IX to XI compared with those assigned to stereotactic radiosurgery, although deficits in cranial nerve XII were comparable in the 2 groups.[87]

Gottfried et al[87] also performed a comprehensive literature review comparing stereotactic radiosurgery and conventional surgery for the treatment of jugular paragangliomas in 576 patients. They reviewed 8 radiosurgery series reporting outcomes on 142 patients and 7 conventional surgical series that detailed outcomes on 374 patients.[87] The mean age for patients undergoing surgery was 47 vs 57 years of age for those treated with stereotactic radiosurgery.[87] A total of 48% of patients underwent first-line radiosurgery and 52% underwent salvage or adjuvant radiosurgery.[87] Tumor shrinkage was reported in 36% of patients treated with radiosurgery while 61% remained unchanged.[87] With regard to neurological symptoms, 39% showed improvement, 58% showed no change, and 3% had worsening symptoms; moreover, most study patients experiencing neurological improvement did so within the first 12 months.[87] At a follow-up period of 49 and 39 months (range, 20.0–86.4 months) for the surgical and radiosurgical groups, respectively, the rates of local control in the surgical group were 92% and 98% for the radiosurgical group.[87] The neurological complication rate after stereotactic radiosurgery was 8.5% (6.4% transient, 2.1% permanent).[87] Transient complications included exacerbation of pre-existing cranial nerve deficits, tinnitus, or vertigo; permanent complications were reported as worsening facial nerve function (n = 3), worsening vertigo (n = 1), and progressive hearing loss to deafness (n = 1).[87] No patients experienced new deficits in the lower cranial nerves.[87] Meningitis, wound infection, pneumonia, ischemia, cerebrospinal fluid leak, and aspiration were the major surgical complications reported.[87] Iatrogenic cranial nerve deficits were reported in several surgical series and involved cranial nerves VII and IX to XII.[87] The rate of perioperative mortality was 1.3%.[87]

Hypofractionated Stereotactic Radiotherapy

Hypofractionated stereotactic radiotherapy combines the high precision of stereotactic planning, the function preservation advantages of fractionation, and the convenience of short-course treatment. Some authors have reported excellent outcomes with low rates of severe toxicity. For example, Wegner et al[88] reported an early experience of 18 glomus jugulare cases treated with linear accelerator–based stereotactic radiotherapy; 8 had persistent tumors after prior surgery, 1 had recurrence after EBRT, and 2 were treated with combined extracranial stereotactic radiotherapy with intracranial Gamma Knife (Elekta, Crawley, UK) radiotherapy.[88] The median radiation dose was 21 Gy delivered in 3 fractions (16–25 Gy in 1–5 fractions) to the 80% isodose line.[88] At a median follow-up of 22 months, the observed rate of local control was 100%. No cases of new or worsening pre-existing neurological deficits were observed.[88]

Chun et al[89] reported on 31 patients with jugular paragangliomas (n = 30) or carotid body tumors (n = 1) treated with CyberKnife (Accuray, Sunnyvale, California) fractionated stereotactic radiotherapy at a dose of 25 Gy in 5 fractions.[89] Mean tumor size was reported as 10.7 mL, which is twice the size of the typical volumes used in Gamma Knife series.[88,89] At a median follow up time of 24 months, the rate of local control was reported as 100%.[89] Tumor volume was reduced for the entire study population by 37%; at 2 years, that rate was 49%.[89] A total of 60% of patients reported improvement in tinnitus.[89] Grade 1/2 adverse events (primarily headache) were reported in 19% of the patients studied.[89]

Lieberson et al[90] reported on 36 patients (41 paragangliomas): 17 of whom were treated with fractionated stereotactic radiotherapy, and 19 were treated with surgery. They reported that, on average, smaller lesions (< 8 mL) were treated with 18 Gy in 1 fraction, moderately sized lesions (8–16 mL) were treated with 20 Gy in 2 fractions, and larger-sized lesions (≥ 16 mL) were treated with 22 Gy in 3 fractions (median lesion size = 1.64 mL).[90] One large lesion measuring 69 mL received 25 Gy in 5 fractions, and another measuring 42 mL received 24 Gy in 3 fractions.[90] Five of the 19 patients treated with single-dose radiation had worsening of their pretreatment deficit, 2 patients had transient worsening of cranial nerve deficits, and 7 patients had an improvement of their pretreatment deficit, including 4 treated with stereotactic radiosurgery and 3 treated with stereotactic radiotherapy.[90]

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