Treatment with radiotherapy in carotidal paraganglioma: experience of the General Hospital of Mexico

Abstract

Background

Paragangliomas are highly vascularized tumours that have benign histology, with malignant dissemination being infrequent (< 5%). Surgery is the only option offering complete resection; however, there is significant morbidity. Treatment with radiotherapy (RT) offers good results in controlling the disease.

Materials and methods

Retrospective, observational and descriptive study from the RT Service of the General Hospital of Mexico conducted from January 1, 2016 to January 1, 2021 that included patients with carotid paraganglioma in whom RT response was evaluated by determining clinical and image size at the beginning of the study and end of follow-up. Correlation of response to treatment, and toxicity related to RT, were analysed.

Results

55 patients were included, 92.7% were female, the mean age was 58.7 years, and the mean follow-up time was 28.87 months. The mean initial clinical size was 4.75 cm. Initial imaging study mean size was 4.76 cm. A total of 92.7% received intensity-modulated radiotherapy (IMRT) and conformal RT (7.3%), mean prescribed dose was 51.90 Gy (50–54), with a median of 50.4 Gy/25 fractions. The mean final clinical size was 3 cm. The final imaging study mean size was 3.48 cm. At the end of the study, 96.4% showed a response to treatment and 3.6% progressed. Analysis showed no significance between treatment response and RT dose (p < 0.5) or between RT response and the % dose to the planned treatment volume (PTV) (p = 0.91). Acute toxicity was found in 55 patients, with grade 1 radiodermatitis, and chronic toxicity in 44 patients, with atrophy grade 1.

Conclusion

RT represents a therapeutic option in the management of patients with carotid paraganglioma because it offers a high probability of local control, without toxicity.

Introduction

Paragangliomas are highly vascularized tumours associated with blood vessels and neural structures, and they are histologically benign. Distinguishing between benign and malignant tumours is not easy; the only true criterion for malignancy is distant dissemination, which probably occurs in less than 5% of cases [1, 2].

In the majority of cases paraganglioma presents clinically as a neck tumour and can be accompanied by a murmur or thrill; when the tumour is large, it can have a compressive effect [3]. The diagnosis is established by the clinic and supported by angiography, angiotomography, magnetic resonance, computed tomography-positron emission tomography (CT-PET) and functional tumour studies with radioisotopes such as metaiodobenzylguanidine (MIBG) [4, 5]. Surgical treatment is the only therapeutic option that can offer immediate and complete resection due to the compromise of critical vascular and neural structures; total resection is associated with significant morbidity, so other options, such as radiotherapy (RT), can be considered [6].

RT has been used as a primary treatment for patients who cannot undergo surgery due to advanced age, comorbidity or unresectable tumours. The objective of RT is to control the disease or inhibit growth. According to Powell et al., the tumour control rate with external RT is 90% at 10 years but 73% at 25 years [7].

Materials and methods

This is a retrospective, observational and descriptive study conducted in the RT unit of the Oncology Service of the General Hospital of Mexico “Dr. Eduardo Liceaga” from January 1, 2016, to January 1, 2021. Records and digital files containing data on the treatment of patients with carotid paraganglioma treated in the RT unit were reviewed. The inclusion criteria were age > 18 years, a diagnosis of carotid paraganglioma made by imaging study, complete clinical records and digital archive (from the ECLIPSE V.13.5 planning system), nonsurgical status due to unresectability or comorbid diseases, and follow-up time greater than 6 months. The exclusion criteria were incomplete clinical and digital records, previous surgery, incomplete RT treatment, and follow-up < 6 months.

The clinical records and those of the digital file of the Eclipse planning system V.13.5 were analysed to collect information on the study variables and generate the database in the statistical program SPSS V.25, based on the inclusion and exclusion criteria described. In the digital file, the planning parameters and the dose-volume histogram were reviewed to collect the dose to the target volume and organs at risk. Patients were evaluated at the initial appointment to determine the radiation technique and prescription dose, with informed consent obtained beforehand. Virtual simulation was performed with a General Electric CT simulator from 2016 until October 2018 and December 2018 to January 2021 with a Phillips 16-slice CT simulator. Treatment volumes were delineated according to the ICRU 50. RT treatment was performed with Linear Accelerator Varian equipment.

Treatment response was evaluated by comparing the initial size of the tumour clinically and by imaging with the size at the end of follow-up. Disease control was defined as tumour regression or no evidence of progression during the entire follow-up period, and toxicity was recorded according to the RTOG criteria. The follow-up data were obtained from the clinical record from the first consultation to the last control appointment. The statistical analysis was performed by evaluating central tendency measures and dispersion of quantitative variables, and descriptive and contingency tables of qualitative variables were constructed. The correlation of treatment response, as well as toxicity related to RT, was analysed with the chi-squared test in SPSS V.25.

Results

A total of 60 records of patients diagnosed with carotid paraganglioma treated with RT were reviewed; 5 patients were excluded for not meeting the inclusion criteria. Of the 55 patients analysed, 51 were female (92.7%), and 4 were male. The mean age was 56.87 years (range 29–85), and the mean follow-up time was 28.87 months (8–60). The 55 patients had a place of residence at high altitude (> 1,500 m above sea level). Based on the Shamblim classification, 65.5% (36 patients) were grade III, 34.5% (19 patients) were grade II, 36 were on the left side, and 19 were on the right side. The mean initial clinical size was 4.75 cm (range 2–11), with a median of 5 cm and a standard deviation of 1.74. Regarding dimensions on the initial imaging study, the mean size was 4.76 cm (2.1–11.5), with a median of 4.3 cm and a standard deviation of 1.7. Regarding treatments, 51 patients (92.7%) received intensity-modulated radiotherapy (IMRT), and the remaining patients (7.3%) received conformal RT. The mean prescribed dose was 51.90 Gy (50–54), with a median of 50.4 Gy and a standard deviation of 1.94. The patients and treatment characteristics are shown in Table 1.

Table 1.

Characteristics of patients

		N	%
Patients	Total	55	100
Sex	Female	51	92.7
	Male	4	7.3
Age (years)	Mean	56.87
	Median	57
	Range	29–85
Glomus localization	Right	19	34.5
	Left	36	65.5
Shamblin	Ii	19	34.5
	Iii	36	65.5
Initial clinical size [cm]	Mean	4.75	Range (2–11)
	Median	5
	Standard deviation	1.74
Initial radiological size	Mean	4.76	Range (2.1–11.5)
	Median	4.3
	Standard deviation	1.7
Technique	Imrt	51	92.7%
	3D-CRT	4	7.3%
Dose [Gy]	Mean	51.9	Range (50–54)
	Median	50.4
	Standard deviation	1.94

The mean tumour volume was 93.17 cc (16–416 cc). The mean dose percentage to the planned treatment volume (PTV) was 97.3% (92–99), and the mean dose to the PTV was 53.5 Gy (42–57). The doses to the organs at risk were as follows: mean dose to the contralateral parotid 3.9 Gy (1–8.9), ipsilateral parotid 16.2 Gy (6–32), mandible 1 cc, and mean 53.3 Gy (31–58). Example of an IMRT treatment plan is shown in Figure 1AB.

Figure 1.

AB. Intensity-modulated radiotherapy (IMRT) treatment plan

Acute toxicity occurred in 55 patients, with radiodermatitis grade 1 predominating, and chronic toxicity occurred in 44 patients, with atrophy grade 1 predominating; the rest of the toxicity data is shown in Tables 2 and 3.

Table 2.

Acute toxicity

	Not present	Grade 1 [N (%)]	Grade 2 [N (%)]	Total [N (%)]
Radiation dermatitis	0	43 (78.2)	12 (21.8)	55 (100%)
Xerostomia	0	45 (81.8)	10 (18.2)	55 (100%)
Dysgeusia	2 (3.6)	51 (92.7)	2 (3.6)	55 (100%)
Mucositis	38 (69.1)	9 (16.4)	8 (14.5)	55 (100%)

Table 3.

Chronic toxicity

	N (%)
Atrophia (grade 1)	38 (69.1)
Fibrosis (grade 1)	6 (10.9)
Total	44 (80)
Not present	11 (20)
Total	55 (100)

The mean final clinical size was 3 cm (range 1.2–7.1), median 3 cm; the dimensions on the final imaging study were as follows: mean size of 3.48 cm of the major axis (1–7.9), median of 3.1 cm and standard deviation of 1.3. Data is shown in Table 4. The difference between the mean of the initial size of the paraganglioma and at the size at the end of the study was 1.3 cm, which is a reduction of 30% in the initial volume. At the end of the study, 96.4% (53 patients) showed a treatment response with tumour volume reduction, and 3.6% (2 patients) progressed. In the Pearson’s chi-squared test, there was no significant association between treatment response and RT dose (p < 0.5) or between RT response and the % dose to the PTV (p = 0.91); additionally, the relationship between tumour size at the end of the study and RT dose was not significant (p = 0.27). The mean parotid dose in acute toxicity had a significant correlation with tumour volume (cc) (p < 0.006) but not with the total RT dose (p = 0.3) or RT technique (p = 0.4). The dose to the mandible was related to the volume (p < 0.02) but not to the total RT dose (p = 0.1). In relation to chronic toxicity with the total RT dose (p = 0.58), tumour volume (cc) (p = 0.52) approached significance. However, there was no correlation between chronic toxicity and the % dose to the PTV (p = 0.74) or RT technique (p =0.79).

Table 4.

Final size of the paraganglioma (cm)

	Radiologic	Clinical
Mean	3.48	3
Median	3.10	3
Minimum	1.0	1.2
Maximum	7.9	7.1
Standard deviation	1.3	1.2

Discussion

The first report of paraganglioma was presented by Von Haller (1743), who studied the carotid body. In 1862, Von Luschka published the first report on carotid body tumours, and Kohn coined the term paraganglion. In 1975, Mascorro and Yates named the group of chromaffin cells derived from the neuroectoderm paraganglionic system, which are located in extra-adrenal sites [13].

Glenner and Grimley classified paragangliomas into adrenal and extra-adrenal; 85% of the extra-adrenal paragangliomas are located in the abdomen, 12% are in the thorax, and 3% are in the head and neck [14]. Carotid body tumours are rare, with an incidence of 1 in 100,000. In some series, these tumours occur mostly in women and are more often in the carotid and vagal bodies [15]. Conditions that lead to chronic hypoxemia, such as living at high altitudes, smoking, chronic obstructive pulmonary disease, and other conditions that cause hypoxia, can be sporadic causes of carotid body hyperplasia [16].

Three percent of paragangliomas are associated with hereditary syndromes: multiple endocrine neoplasia syndromes; neurofibromatosis type 1 (NF1), which includes part of the Carney triad (sarcoma of the gastric stroma, pulmonary chondroma, and paraganglioma); and von Hippel–Lindau disease (pheochromocytoma, spinal haemangioblastoma, and paraganglioma). These patients develop synchronous or metachronous paragangliomas (17–85%), and 1–2% of these patients develop sporadic ones [17, 18].

The Shamblim classification was developed in 1971 based on the size of the tumour and the invasion of the carotid artery, allowing us to evaluate the possibilities of resection, as follows: in Group I, the tumour is well localized, does not invade adjacent major vessels, and is small and easily resectable; in Group II, the tumour adheres to and partially surrounds the vessels, compresses the internal carotid artery and the external carotid artery, and can be resected with careful subadventitial dissection; and in Group III, the tumour is large in size and extensively involves the carotids and adjacent structures, so it is considered unresectable due to the high possibility of haemorrhage [19].

Postoperative neurological deficits are reported in 41–46%, including paresis and/or cranial nerve palsy and Claude Bernard–Horner syndrome. Neurological defects due to infiltration or tumour compression of the cranial nerves are usually irreversible. Thromboembolic events have resulted in transient ischaemic attacks in 7% and even mortality in 4% of cases. [22] The organs at risk in head and neck paragangliomas are mainly the parotid, mandible and larynx; with modern techniques, it is possible to significantly reduce the doses to these organs [23].

Paragangliomas predominate in women, as demonstrated by the study and the literature. The effectiveness of resection of carotid paragangliomas is clearly established; it is the treatment of choice, as long as resection is possible. Treatment with RT is preferred in the presence of high surgical risk or contraindication of the procedure.

Since 1950, patients have been treated with RT as an alternative to surgery, with local control rates of 95%. In a retrospective study of benign pathology treated with RT, paragangliomas were the second most frequently treated pathology. RT stopped the progression of symptomatic disease, and recurrences occurred up to 18 years later. Carotid and yugulotympanic tumours both showed 100% response and control at 45 months [24].

Conventional external RT, at doses of 45 to 50.4 Gy/25 fractions, is usually sufficient to control most paragangliomas; it allows the disease to remain stable and not progress. Current publications support the notion that the objective of conventional external RT, at doses of 45 to 50.4 Gy in 25 fractions, is usually sufficient to control most carotid paragangliomas. There are series that include patients with carotid paragangliomas treated with radical RT. A total of 461 patients were treated with conventional RT in the 20 series submitted for evaluation; most patients received a total dose of 45–50 Gy. Disease control during the entire follow-up period was obtained in 89.1% of cases, and a reduction in tumour size was not documented. However, in 50 patients, tumour growth was observed [26, 27].

The new treatment techniques with RT developed over the last 20 years, such as 3D conformal radiotherapy, IMRT and volumetric modulated arc therapy (VMAT), have brought advantages regarding the treatment of carotid paragangliomas. These techniques allow high doses to be administered to the tumour or target volume, as well as protection of organs at risk, and reduction in acute and chronic toxicity. Such as mandibular osteonecrosis, carotid fibrosis and laryngeal lesions. The availability of 3D planning systems has improved the ability to use this treatment technique for large tumours [28, 29].

The dose used in this study ranged from 50 to 54 Gy/25 fractions, based on the regimens used in these retrospective series that favour a treatment response. IMRT technique was preferred over 3D conformal RT for the majority of patients as well, regarding the administration of higher doses to the target volume with better toxicity outcomes and protection of organs at risk.

Stereotaxic radiosurgery and hypofractionated radiotherapy, another RT options, seem to offer similar rates of local control, with a lower incidence of adverse effects, but there are fewer publications in this regard [30]. In the present review, they were not used as a radiation modality.

In this study, the acute toxicity documented was most frequently radiodermatitis grade 1, which was acceptable and medically treatable, and a low incidence of chronic toxicity was also observed. This makes RT treatment a favourable choice for such patients who have contraindications for surgical treatment. Different series have documented that treatment with RT allows carotid paragangliomas to remain stable and not progress; however, a benefit regarding size reduction has not been documented. In our study, we found that the majority of patients had a treatment response (92.7%). In terms of initial and final size reduction, we found that the difference between the mean initial size of the carotid paraganglioma and the final size at the end of the study was 1.3 cm, with a reduction of 30% in the initial volume.

Conclusion

RT is an important therapeutic option in the management of patients with carotid paraganglioma. It is an excellent non-invasive alternative because it offers a high probability of local control, evidenced by its high response rate and decrease in tumour size, without producing neurological sequelae or vascular damage.