Treatment of inoperable or metastatic paragangliomas and pheochromocytomas with peptide receptor radionuclide therapy using 177Lu-DOTATATE

in European Journal of Endocrinology

Correspondence should be addressed to W T Zandee; Email: w.zandee@erasmusmc.nl

Objectives

Inoperable or metastatic paragangliomas (PGLs) and malignant pheochromocytomas (PCCs) are rare tumours with limited options for systemic treatment. Aim of this study was to assess the safety and efficacy of the radiolabelled somatostatin analogue (177LutetiumDOTA0-Tyr3)octreotate (177Lu-DOTATATE) for the treatment of PGLs and PCCs.

Methods

Patients with histologically proven inoperable or malignant PGLs and PCCs treated with 177Lu-DOTATATE at our centre were retrospectively analysed. Patients were treated with up to four cycles of 177Lu-DOTATATE with an intended dose of 7.4 Gb per cycle. Response was assessed with use of RECIST 1.1.

Results

Thirty patients were included: 17 with parasympathetic, 10 with sympathetic PGLs and 3 with PCCs. Grade 3/4 subacute haematotoxicity occurred in 6 (20%) of patients. A reversible subacute adverse event due to cardiac failure following possible catecholamine release occurred in two patients. Best tumour response was partial response in 7 (23%) and stable disease in 20 (67%), whereas 3 (10%) patients had progressive disease. In 20 patients with baseline disease progression, tumour control was observed in 17 (85%); the median progression-free survival was 91 months in patients with parasympathetic PGLs, 13 months in patients with sympathetic PGLs and 10 months in patients with metastatic PCCs.

Conclusion

This study suggests that PRRT with 177Lu-DOTATATE is a safe and effective treatment option for patients with inoperable or malignant PGL and PCC.

Abstract

Objectives

Inoperable or metastatic paragangliomas (PGLs) and malignant pheochromocytomas (PCCs) are rare tumours with limited options for systemic treatment. Aim of this study was to assess the safety and efficacy of the radiolabelled somatostatin analogue (177LutetiumDOTA0-Tyr3)octreotate (177Lu-DOTATATE) for the treatment of PGLs and PCCs.

Methods

Patients with histologically proven inoperable or malignant PGLs and PCCs treated with 177Lu-DOTATATE at our centre were retrospectively analysed. Patients were treated with up to four cycles of 177Lu-DOTATATE with an intended dose of 7.4 Gb per cycle. Response was assessed with use of RECIST 1.1.

Results

Thirty patients were included: 17 with parasympathetic, 10 with sympathetic PGLs and 3 with PCCs. Grade 3/4 subacute haematotoxicity occurred in 6 (20%) of patients. A reversible subacute adverse event due to cardiac failure following possible catecholamine release occurred in two patients. Best tumour response was partial response in 7 (23%) and stable disease in 20 (67%), whereas 3 (10%) patients had progressive disease. In 20 patients with baseline disease progression, tumour control was observed in 17 (85%); the median progression-free survival was 91 months in patients with parasympathetic PGLs, 13 months in patients with sympathetic PGLs and 10 months in patients with metastatic PCCs.

Conclusion

This study suggests that PRRT with 177Lu-DOTATATE is a safe and effective treatment option for patients with inoperable or malignant PGL and PCC.

Introduction

Paragangliomas (PGLs) are rare tumours that arise from the chromaffin cells of the neural crest-derived sympathetic and parasympathetic paraganglia. Sympathetic paraganglia are located from the superior cervical ganglion down to the pelvis and are predominantly found in the abdomen (1). Lesions originating specifically from the adrenal medulla are called pheochromocytomas (PCCs). Parasympathetic PGLs are found in the head and neck region, by originating from the carotid bodies and the jugulotympanic and vagal paraganglia. In recent years, an increasing numbers of genetic mutations have been identified that predispose for PGLs and PCCs, in particular in the genes encoding succinate dehydrogenase (SDH) (2, 3). The subtype B (SDHB) mutation is primarily associated with sympathetic PGLs and carries a high risk of malignancy, whereas the subtype D (SDHD) mutation is mostly associated with multiple parasympathetic head and neck PGLs (4).

Predominantly sympathetic but also parasympathetic PGLs can present with clinical symptoms due to catecholamine hypersecretion (5). In case of secretory PGLs and PCCs, treatment can be complicated by excess (nor)epinephrine/(nor)adrenaline release during interventions. Therefore, patients should be carefully monitored and receive adequate (pre-)treatment with alpha-adrenergic receptor blockade (6). Independent of hormonal status, PGLs and PCCs are considered malignant if there are regional or distant metastases (6). Sympathetic PGLs are more likely to be hormonally active and often show distant metastatic spread, whereas parasympathetic PGLs often present with local swelling and neurological signs due to local extent of disease (5, 7). For localised disease, surgery is the treatment of first choice. In metastatic disease, treatment options are limited and prognosis is usually poor; the reported 5-year survival rate of metastatic PGLs is between 34 and 60% (8).

PGLs and PCCs are known to express high levels of somatostatin receptor (SSTR) subtypes, in particular subtype 2, on their cell surface, similar to other neuroendocrine tumours (NETs) (9, 10). These receptors can be targeted for imaging and treatment of the tumours using radiolabelled somatostatin analogues (SSAs). This technique has been established as a successful treatment for gastroenteropancreatic NETs, but can be more widely applied for other tumours expressing high affinity SSTRs (11, 12, 13). The efficacy of peptide receptor radionuclide therapy (PRRT) with (177Lutetium-DOTA0-Tyr3)octreotate (177Lu-DOTATATE) is dependent on adequate SSTR subtype 2 expression, which is usually assessed by planar scintigraphy with single photon emission computed tomography (SPECT) or positron emission tomography (PET) using radiolabelled SSAs (14, 15). In clinical practice, many patients with PGLs have been treated with surgery, chemotherapy and/or 131iodine-metaiodobenzylguanidine (131I-MIBG) at the time of assessment for PRRT. Patients with metastatic PCCs usually undergo resection of the primary tumour and subsequent therapy with 131I-MIBG for the metastases (16). In these settings, but perhaps also at an earlier stage, PRRT may be considered as a (salvage) treatment. There is limited experience with PRRT in PGLs and metastatic PCCs, but recent evidence suggests a favourable effect of PRRT at limited toxicity advocating consideration of radiolabelled SSAs in the treatment algorithm for these tumours (17). This paper reports on the single-institution experience with the treatment of PGLs and metastatic PCCs using 177Lu-DOTATATE.

Methods

Patients

This is a retrospective case series of patients with PGLs and PCCs treated with PRRT at the department of Radiology and Nuclear Medicine at the Erasmus University Medical Centre Rotterdam, the Netherlands, starting from January 2000. The study was approved by Medical Ethical Review Board of the Erasmus Medical Center and written informed consent was obtained from all participants. Inclusion criteria for this cohort were adequate tumour SSTR expression (uptake equal to (grade 2) or greater than normal liver tissue (grade 3) or greater than kidneys/spleen (grade 4)) as evaluated on planar scintigraphy with 111In-DPTA-octreotide SPECT, haemoglobin ≥5.5 mmol/L, white blood cell count ≥2 × 109/L, platelet count ≥75 × 109/L, creatinine clearance ≥40 mL/min (assessed in 2 × 24-h urine collection) and Karnofsky performance status ≥50. From this cohort, all patients with histologically proven inoperable or metastatic PGLs and patients with metastatic PCCs were considered, if treated with at least one cycle of PRRT with 177Lu-DOTATATE. Patients were treated for indications as radiological progression, symptomology or high tumour burden. For inclusion a follow-up of more than 1 year after the last therapy cycle was required. Foreign patients and patients without at least one response evaluation were excluded. Baseline radiological progression was defined as tumour growth or new lesions on radiological imaging (CT/MRI) or new lesions on nuclear imaging (MIBG/SSTR-imaging).

Treatment

177Lu-DOTATATE was prepared and administered as described earlier (13, 18). Standard treatment consisted of four cycles of PRRT with a dose of 7.4 GBq per cycle, up to an intended cumulative dose of 29.6 GBq with intervals of 6–12 weeks between cycles. Patients with elevated catecholamine production were pre-treated with alpha- and, if indicated, beta-adrenergic receptor blockers.

Outcome measurements and analysis

Routine haematology, liver and kidney function tests and quality of life measurement were performed at baseline, 4–6 weeks after every treatment and at follow-up visits. Follow-up imaging was performed at 3 and 6 months after the last treatment, and every 6 months thereafter. Toxicity was graded based on the Common Terminology Criteria for Adverse Events version 3.0, radiographic tumour assessment was performed according to the response evaluation criteria in solid tumours (RECIST) 1.1 (19). Primary events are defined as progressive disease (PD) according to RECIST, start of another treatment or death. Progression-free survival (PFS) was defined as time from the start of PRRT until primary event or last radiographic outcome measurement. Overall survival (OS) was defined as time from the start of PRRT until death or the last clinical follow-up. Kaplan–Meier survival analysis was used to express survival corrected for differences in follow-up. All statistics were performed with SPSS, version 23.0 (IBM Corp). A P value of smaller than 0.05 was considered statistically significant.

Results

Thirty patients were included of which 17 patients with parasympathetic PGLs, 10 with sympathetic PGLs and 3 patients with metastatic PCCs. At baseline 17 (57%) patients had metastatic disease and 13 (43%) patients has localised disease of which 9 (69%) patients had a PGL with multiple localisations. SDHB mutations were confirmed in five out of ten patients (50%) with sympathetic PGLs and SDHD mutations were confirmed in 11 (65%) patients with parasympathetic PGL. Previous therapies included surgery (63%) and external beam radiotherapy (20%). Eight patients (27%) were treated earlier with systemic therapy including chemotherapy (n = 5), MIBG (n = 3) and somatostatin analogues (n = 2).

Baseline characteristics are shown in Table 1; seven patients had been previously reported (11). Twenty (67%) patients had radiological PD at baseline. The remaining ten patients had radiological stable disease and were treated for symptom control.

Table 1

Baseline characteristics.

CharacteristicsAllPS-PLGS-PLGPCC
n3017103
Female, n (%)20 (66.7)14 (82.4)4 (40.0)2 (66.7)
Age (median (range))47 (29–74)44 (29–74)49 (30–74)47 (38–63)
Localisation, n (%)
 Solitary4 (13.3)2 (11.7)2 (20.0)0
 Multiple9 (30.0)9 (52.3)00
 Metastatic17 (56.7)6 (35.2)8 (80.0)3 (100)
  Lymph nodes10 (33.3)5 (29.4)3 (30.0)2 (66.7)
  Liver7 (23.3)3 (17.6)3 (30.0)1 (33.3)
  Lungs6 (20.0)3 (17.6)03 (100)
  Bones13 (43.3)3 (17.6)9 (90.0)1 (33.3)
Genetics, n (%)
 SDHB5 (16.7)05 (50.0)0
 SDHD11 (36.7)11 (64.7)00
 ‘Familial’2 (6.7)1 (5.9)01 (33.3)
 Sporadic (No SDHx)5 (16.7)1 (5.9)4 (40.0)0
 Unknown7 (23.3)4 (23.5)1 (10.0)2 (66.7)
(Nor)metanephrine, n (%)
 Elevated12 (40.0)2 (11.7)7 (70.0)3 (100)
 Normal18 (60.0)15 (88.2)3 (30.0)0
Baseline disease status, n (%)
 Progressive disease20 (66.7)10 (58.8)7 (70.0)3 (100)
 Stable disease7 (23.3)5 (29.4)2 (20.0)0
 Unknown3 (10.0)2 (11.7)1 (10.0)0
Previous treatments, n (%)
 Surgery19 (63.3)9 (52.3)7 (70.0)3 (100)
 Radiotherapy6 (20.0)3 (17.6)2 (20.0)1 (33.3)
 Chemotherapy5 (16.7)1 (5.9)3 (30.0)1 (33.3)
 Somatostatin analogue2 (6.7)01 (10.0)1 (33.3)
131I-MIBG3 (10.0)03 (30.0)0
Number of previous treatments, n (%)
 010 (33.3)8 (47.1)2 (20.0)0
 110 (33.3)6 (35.2)3 (30.0)1 (33.3)
 25 (16.7)2 (11.7)2 (20.0)1 (33.3)
 35 (16.7)1 (5.9)3 (30.0)1 (33.3)
Uptake on 111In-DPTA-octreotide scan (range: 1–4), n (%)
 Grade 211 (36.7)7 (41.2)4 (40.0)0
 Grade 313 (43.3)6 (35.2)5 (50.0)2 (66.7)
 Grade 46 (20.0)4 (23.5)1 (10.0)1 (33.3)
Cumulative dose (GBq), n (%)
 14.82 (6.7)1 (5.9)1 (10.0)0
 22.26 (20.0)2 (11.7)3 (30.0)1 (33.3)
 25.92 (6.7)2 (11.7)00
 29.620 (66.7)14 (82.4)6 (60.0)2 (66.7)

PCC, pheochromocytoma; PS-PLG, parasympathetic paraganglioma; S-PLG, sympathetic paraganglioma.

Treatment administration

Twenty-two patients received four cycles of 7.4 GBq 177Lu-DOTATATE. Due to recurring thrombocytopaenia, PRRT with 177Lu-DOTATATE was limited to three cycles in two patients and to two cycles in one patient. Furthermore, treatment was limited because of disease progression in three patients and because of previous treatment with 131I-MIBG (5.6 GBq) in one patient. One patient received two cycles of PRRT, after which response evaluation showed stable disease and elective embolisation of the primary tumours was performed.

Safety and toxicity

A total of 110 therapies of 177Lu-DOTATATE were administered. Acute toxicity in the form of nausea, vomiting and abdominal pain was generally mild and well controlled with anti-emetic and analgesic medication (Table 2). Nausea occurred after 37 (34%), vomiting after 14 (13%), and mild abdominal pain after 25 (23%) of the administrations. Grade 3/4 subacute haematotoxicity was observed in 6 (20%) patients (Table 2). One patient developed myelodysplastic syndrome after six cycles of 177Lu-DOTATATE (including retreatment, cumulative dose 44.4 GBq), diagnosed 45 months after the first administration. The patient was not previously treated with chemotherapy or 131I-MIBG and did not have bone marrow infiltration of the PGL. He was referred to a local hospital for best supportive care and died of complications of MDS 4.5 years after the first administration op PRRT.

Table 2

Toxicity data. Data are presented as (n (%)).

Toxicityn (%)
Acute toxicity (per treatment)
 Nausea37 (33.6)
 Vomiting14 (12.7)
 Pain25 (22.7)
Subacute toxicity (per patient)
 Anaemia
  Grade 32 (6.7)
  Grade 40 (0.0)
 Thrombopaenia
  Grade 34 (13.3)
  Grade 41 (3.3)
 Leukopaenia
  Grade 33 (10)
  Grade 40 (0.0)
 Catecholamine crisis2 (6.7)
Late toxicity
 Myelodysplastic syndrome1 (3.3)

Elevated plasma and/or urinary normetanephrines were found in 2 (12%) patients with parasympathetic and 10 (77%) patients with sympathetic PGLs. A possible adverse event due to post-therapy catecholamine release occurred in two patients after their first cycle. The first patient had a sporadic metastatic carotid body PGL with lung and bone metastases. The 24-h urinary excretion of normetanephrines at baseline was two times elevated. This patient was not pre-treated with alpha-adrenergic receptor blockers. After the first PRRT cycle, patient had symptoms of increased flushing and sweating and developed cardiac failure. A diminished ejection fraction was measured with echocardiography, possibly caused by chronic catecholamine release. Administration of diuretics and octreotide resulted in a full clinical recovery. The second patient was treated for a sporadic metastatic PCC with alpha- and beta-adrenergic receptor blockade. The 24-h urinary excretion of normetanephrines was approximately 25 times the upper limit of normal with normal metanephrine excretion. This patient developed pleural effusion and a delirium after the first cycle, possibly caused by heart failure or catecholamine release which was successfully treated with haloperidol and standard supportive care. After discharge an echocardiography reported normal ejection fraction. In both patients, further cycles were uneventful with pre-cycle preventive pre-treatment. There were no incidences of hypertensive crises or clinical deterioration of local nerve compression after PRRT.

Efficacy

In all 30 patients, the best response according to RECIST 1.1 was partial response (PR) in seven patients (23%) and stable disease (SD) in 20 patients (67%), whereas three patients (10%) had PD. In 20 patients with baseline radiological PD, disease control (PR + SD) was observed in 17 patients (85%). In patients with a localised PGL the disease control rate was 100% and in patients with a metastatic GL or PCC treatment with PRRT resulted in disease control in 79% of patients. Response stratified for baseline PD is shown in Fig. 1.

Figure 1
Figure 1

Treatment outcome stratified for tumour type and baseline disease status. PCC, pheochromocytomas; PD, progressive disease; PR, partial response; PS-PGL, parasympathetic paragangliomas; SD, stable disease; S-PGL, sympathetic paragangliomas.

Citation: European Journal of Endocrinology 181, 1; 10.1530/EJE-18-0901

Survival was assessed in 20 patients with PD at baseline (Table 3). In these patients, the median follow-up was 52.5 (range 7–155) months. During follow-up, 14 patients had a registered primary event (PD in seven patients and start of a new treatment in seven patients) and nine patients had died. In the ten patients with parasympathetic PGLs, the median PFS was 91 months. In the seven patients with sympathetic PGLs this was 13 months. The PFS in the three patients with PCCs was respectively 8, 10 and 14 months. The median OS was not reached in the parasympathetic PGL patients and this was 59 months in the sympathetic PGLs patients. OS in the three patients with PCC was respectively 9, 17 and 21 months. Figures 2 and 3 show the Kaplan–Meier curves for PFS and OS in these patients. In patients with a localised PGL, the median PFS was not reached while patients with a metastatic (N1 and/or M1) PGL or PCC had a median PFS of 13 months after treatment with PRRT.

Figure 2
Figure 2

Progression-free survival in patients with parasympathetic (PS-PGL)/sympathetic paragangliomas (S-PGL) and malignant phaechromocytomas (PCC) who showed progressive disease before the start of the treatment.

Citation: European Journal of Endocrinology 181, 1; 10.1530/EJE-18-0901

Figure 3
Figure 3

Overall survival in patients with parasympathetic and sympathetic paragangliomas who showed progressive disease before the start of the treatment.

Citation: European Journal of Endocrinology 181, 1; 10.1530/EJE-18-0901

Table 3

Treatment outcomes.

All (n=30)TypeTNM stage
PS-PGL (n=17)S-PGL (n=10)PCC (n=3)Localised (n=13)Metastatic (n=17)
Best response, n (%)
 Partial response7 (23.3)2 (11.8)4 (40.0)1 (33.3)1 (7.7)6 (35.3)
 Stable disease20 (66.7)14 (82.3)5 (50.0)1 (33.3)12 (92.3)8 (47.1)
 Progressive disease3 (10.0)1 (5.9)1 (10.0)1 (33.3)03 (17.6)
Disease control rate, n (%)*17 (85.0)9 (90.0)6 (85.7)2 (66.7)6 (100)11 (78.6)
Survival, months*201073614
Median follow-up, months52.57642.517 8744
Primary events 14473113
Median PFS (months)30911810n.r.13
Deaths924309
Median OS (months)n.r.n.r.5917n.r.23

*In patients with baseline disease progression; Localised, TxN0M0; Metastatic, N1 and/or M1.

n.r., not reached; OS, overall survival; PCC, pheochromocytoma; PFS, progression-free survival; PS-PLG, parasympathetic paraganglioma; S-PLG, sympathetic paraganglioma.

Clinical response and quality of life

In ten patients, objective PD at baseline was not determined or could not be determined. The indication for treatment in six out of seven patients with parasympathetic PGLs was (progressive) symptoms relating to local nerve compression, such as muscle weakness, hearing loss and tinnitus. These symptoms were ameliorated in two and remained stable in the other four. Out of the three patients with sympathetic PGLs without PD at baseline, two had symptoms related to catecholamine hypersecretion. After treatment, symptoms and catecholamine levels were stable. The third patient was treated because of high tumour volume which did not respond to cisplatin/etoposide chemotherapy. After PRRT, SD was achieved and this was maintained for over 13 years.

Out of 12 patients with elevated catecholamine secretion, baseline and follow-up measurements were available in six. In two patients, normalisation of urinary normetanephrine excretion was observed and in one a decrease in normetanephrine levels of more than 50% was observed. Three other patients showed no response and in one patient with a PCC urinary normetanephrine excretion increased from 53 times upper limit of normal (ULN) to 73× ULN.

European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionneaires-C30 version 3.0 were used to assess the quality of life (20). In 17 patients, baseline and at least one follow-up assessment (at 4–6 weeks or 3 months after the last treatment) were available. Using the paired sample t-test, there were no statistically significant differences between the pre- and posttreatment assessments in any of the five functional or seven symptom scales or in global health status (data not shown).

Discussion

This analysis of 30 patients treated with PRRT with 177Lu-DOTATATE for inoperable or malignant PGLs or PCCs demonstrates encouraging results with induction of tumour stabilisation in the majority of patients including those with PD at baseline. PRRT is well tolerated in this patient group, even in patients with elevated catecholamine levels or local nerve compression. However, a subacute adverse event due to possible post-therapeutic catecholamine release occurred in two patients out of 12 (17%) with elevated normetanephrines. This catecholamine-related complication occurred after the first cycle, underscoring the need for accurate assessment, careful monitoring and (pre-)treatment of patients with hormonally active tumours, mainly before the first cycle (21). An echocardiography can be considered in the pre-treatment evaluation to assess the risk of cardiac failure, given the high prevalence of myocardial dysfunction in this patient subset (22). After an uneventful first therapy, no crises were observed after the following cycles with 177Lu-DOTATATE.

In the patients with objective PD at baseline, disease control was observed in 85% of patients and the median PFS was 91 and 13 months in patients with parasympathetic and sympathetic PGLs, respectively. Limitations of our analysis are the heterogeneity of this relatively small patient cohort and the retrospective design of the study. Also, the absence of a control group limits the interpretation of PFS. Furthermore, not all patients showed radiographic PD before treatment, as some patients were treated because of progressive symptoms or to decrease the risk of onset or progression of symptoms in inoperable tumours. In line with the radiological outcomes, the most frequent clinical outcome was stabilisation of symptoms.

For the treatment of metastatic PGLs there are no uniform guidelines. Surgery is the first line of treatment for benign PGLs and, even with distant metastases, surgery may improve survival and reduce symptoms (23, 24). If inoperable, systemic treatment options mainly include radionuclide therapy and cytotoxic chemotherapy; Table 4 also shows the response rates for these different treatment modalities. Traditionally, a chemotherapeutic regimen with cyclophosphamide, vincristine and dacarbazine is used (25). More recently, treatments with temozolomide, sunitinib or interferon-alpha have been explored, but the evidence for the beneficial effects of these therapies is still very limited (26, 27, 28, 29). External radiotherapy can be used for the treatment of head and neck PGLs and of bone metastases (30). Another radionuclide therapy than PRRT is performed using 131I-MIBG and was used in three of our patients prior to PRRT. Recent, meta-analysis showed objective response in at least 30% of patients (31). However, it must be noted that not all PGL subtypes show sufficient MIBG uptake and thus, as with PRRT, reported results are from a selected population (6). There is however, growing evidence in the literature for the efficacy and safety of PRRT with radiolabelled SSAs for the treatment of inoperable or metastatic PGLs or malignant PCCs (Table 4). In four case series, the results of PRRT were retrospectively analysed, showing disease control rates of 71–80% in patients with baseline PD (17, 32, 33, 34). In addition to these case series, Imhof et al. reported on PRRT in 11 patients with PCCs and 28 patients with PGLs, which showed morphological response in 36 and 11% of patients, respectively (35). Our current study reports the highest response rate in patients with radiological progression and mainly in patients with sympathetic PGL or PCC. Therefore, these patients seem to be the best candidate for treatment with 177Lu-DOTATATE (Fig. 4). In patients treated for indications other than PD, no radiological PR was noted. Specifically in patients with parasympathetic PGL treated for local nerve compression no radiological response was noted. However, PRRT resulted in a symptomatic response of 33% and PRRT with 177Lu-DOTATATE can therefore still be considered for these patients if localised therapy like surgery is not feasible. Haematotoxicity does however seem to be higher than for patients treated for gastroentreopacreatic NETs. Subacute haematotoxicity occurred in 20% of patients similar to the incidence reported by Kong et al. (17). Whether this adverse effect is caused by previous treatment regimens, a higher incidence of bone metastases or other causes remains unclear.

Figure 4
Figure 4

Response of liver metastasis in a patient with a metastatic sympathetic paraganglioma. A1/2: Planar anterior and posterior total body scintigraphs after the first cycle with 177Lu-DOTATATE. A3: CT scan of liver before first cycle. B: CT-scan of liver 6 months after the last cycle. Note the shrinkage of the liver metastasis in segment 8.

Citation: European Journal of Endocrinology 181, 1; 10.1530/EJE-18-0901

Table 4

Therapeutic outcomes in case series on inoperable or metastatic paragangliomas or malignant pheochromocytomas.

First author (Reference)YearnTypeTreatmentBsln PD (%)CR (%)PR (%)SD* (%)PD (%)Criteria
Kong (17)201714mPGL, PCC177Lu-DOTATATE300295714RECIST 1.1
Pinato (32)20165mPGL177Lu-DOTATATE1000206020n.a.
Puranik (33)20159i/m PSP, PGL90Y- or 90Y/177Lu-DOTATATEn.a.001000RECIST 1.1
Forrer (34)200828i/mPGL, PCC90Y-octreotide or 177Lu-DOTATATE100076429WHO
Imhof (35)2011mPGL, PCC90Y-octreotide100018n.a.n.a.n.a.
Hadoux (26)201411mPGL, PCCTemozolomide100036559RECIST 1.1
Ayala-R. (27)201214SP mPGL, PCCSunitinib1000213643RECIST 1.1
Hadoux (28)201714mPGL, PCCInterferon-alpha860216414RECIST 1.1/PERCIST 1.0
Hulsteijn** (31)2014243mPGL, PCC131I-MIBGn.a.3275218***variable
Huang (38)200818mPGL, PCCCVDn.a.1144440variable
Tanabe (39)201317mPGL, PCCCVDn.a.0244729RECIST 1.1

*Including all reported cases with minimal/minor response; **meta-analysis; ***calculated by author.

Bsln PD, baseline progressive disease; CR, complete response; CVD, cyclophosphamide, vincristine, dacarbazine; i, inoperable; m, metastatic; n.a., not available; PCC, pheochromocytoma; PGL, paraganglioma; PR, partial response; PSP, parasympathetic; RECIST, response evaluation criteria in solid tumours; SD, stable disease; SP, sympathetic.

Conclusion

In light of limited treatment options, this study supports the practice of screening every patient with inoperable or metastatic PGL and PCC with SSA-labelled functional imaging to assess the possibility of off-label usage of PRRT with 177Lu-DOTATATE (36, 37). Our analysis shows that PRRT using 177Lu-DOTATATE can be a safe and an effective therapeutic option. However, to determine the optimal sequence of PRRT and other available treatments further, preferably prospective, studies are required.

Declaration of interest

J Hofland has received travel fee from Advanced Accelerator Applications. W W de Herder has joined advisory boards for Ipsen and Novartis. The other authors have nothing to disclose.

Funding

This research did not receive any specific grant from any funding agency in the public, commercial or not-for-profit sector.

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    • Export Citation
  • 8

    PacakKEisenhoferGAhlmanHBornsteinSRGimenez-RoqueploAPGrossmanABKimuraNMannelliMMcNicolAMTischlerAS et al. Pheochromocytoma: recommendations for clinical practice from the first International Symposium. October 2005. Nature Clinical Practice: Endocrinology and Metabolism 2007 3 . (https://doi.org/10.1038/ncpendmet0396)

    • Search Google Scholar
    • Export Citation
  • 9

    ReubiJCWaserBSchaerJCLaissueJA. Somatostatin receptor sst1-sst5 expression in normal and neoplastic human tissues using receptor autoradiography with subtype-selective ligands. European Journal of Nuclear Medicine 2001 28 . (https://doi.org/10.1007/s002590100541)

    • Search Google Scholar
    • Export Citation
  • 10

    van der HarstEde HerderWWBruiningHABonjerHJde KrijgerRRLambertsSWvan de MeirackerAHBoomsmaFStijnenTKrenningEP et al. [(123)I]Metaiodobenzylguanidine and [(111)In]octreotide uptake in begnign and malignant pheochromocytomas. Journal of Clinical Endocrinology and Metabolism 2001 86 . (https://doi.org/10.1210/jcem.86.2.7238)

    • Search Google Scholar
    • Export Citation
  • 11

    van EssenMKrenningEPKooijPPBakkerWHFeeldersRAde HerderWWWolbersJGKwekkeboomDJ. Effects of therapy with [177Lu-DOTA0, Tyr3]octreotate in patients with paraganglioma, meningioma, small cell lung carcinoma, and melanoma. Journal of Nuclear Medicine 2006 47 .

    • Search Google Scholar
    • Export Citation
  • 12

    BrabanderTTeunissenJJVan EijckCHFranssenGJFeeldersRAde HerderWWKwekkeboomDJ. Peptide receptor radionuclide therapy of neuroendocrine tumours. Best Practice and Research: Clinical Endocrinology and Metabolism 2016 30 . (https://doi.org/10.1016/j.beem.2015.10.005)

    • Search Google Scholar
    • Export Citation
  • 13

    BrabanderTvan der ZwanWATeunissenJJMKamBLRFeeldersRAde HerderWWvan EijckCHJFranssenGJHKrenningEPKwekkeboomDJ. Long-term efficacy, survival, and safety of [(177)Lu-DOTA(0),Tyr(3)]octreotate in patients with gastroenteropancreatic and bronchial neuroendocrine tumors. Clinical Cancer Research 2017 23 . (https://doi.org/10.1158/1078-0432.CCR-16-2743)

    • Search Google Scholar
    • Export Citation
  • 14

    KwekkeboomDJKrenningEP. Somatostatin receptor imaging. Seminars in Nuclear Medicine 2002 32 . (https://doi.org/10.1053/snuc.2002.31022)

  • 15

    JanssenIChenCCMilloCMLingATaiebDLinFIAdamsKTWolfKIHerscovitchPFojoAT et al. PET/CT comparing (68)Ga-DOTATATE and other radiopharmaceuticals and in comparison with CT/MRI for the localization of sporadic metastatic pheochromocytoma and paraganglioma. European Journal of Nuclear Medicine and Molecular Imaging 2016 43 . (https://doi.org/10.1007/s00259-016-3357-x)

    • Search Google Scholar
    • Export Citation
  • 16

    BaudinEHabraMADeschampsFCoteGDumontFCabanillasMArfi-RoufeJBerdelouAMoonBAl GhuzlanA et al. Therapy of endocrine disease: treatment of malignant pheochromocytoma and paraganglioma. European Journal of Endocrinology 2014 171 R111R122. (https://doi.org/10.1530/EJE-14-0113)

    • Search Google Scholar
    • Export Citation
  • 17

    KongGGrozinsky-GlasbergSHofmanMSCallahanJMeirovitzAMaimonOPattisonDAGrossDJHicksRJ. Efficacy of peptide receptor radionuclide therapy for functional metastatic paraganglioma and pheochromocytoma. Journal of Clinical Endocrinology and Metabolism 2017 102 . (https://doi.org/10.1210/jc.2017-00816)

    • Search Google Scholar
    • Export Citation
  • 18

    KwekkeboomDJBakkerWHKooijPPKonijnenbergMWSrinivasanAErionJLSchmidtMABugajJLde JongMKrenningEP. [177Lu-DOTAOTyr3]octreotate: comparison with [111In-DTPAo]octreotide in patients. European Journal of Nuclear Medicine 2001 28 . (https://doi.org/10.1007/s002590100574)

    • Search Google Scholar
    • Export Citation
  • 19

    EisenhauerEATherassePBogaertsJSchwartzLHSargentDFordRDanceyJArbuckSGwytherSMooneyM et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). European Journal of Cancer 2009 45 . (https://doi.org/10.1016/j.ejca.2008.10.026)

    • Search Google Scholar
    • Export Citation
  • 20

    AaronsonNKAhmedzaiSBergmanBBullingerMCullADuezNJFilibertiAFlechtnerHFleishmanSBde HaesJC. The European organization for research and treatment of cancer QLQ-C30: a quality-of-life instrument for use in international clinical trials in oncology. Journal of the National Cancer Institute 1993 85 . (https://doi.org/10.1093/jnci/85.5.365)

    • Search Google Scholar
    • Export Citation
  • 21

    MakisWMcCannKMcEwanAJ. The challenges of treating paraganglioma patients with (177)Lu-DOTATATE PRRT: catecholamine crises, tumor lysis syndrome and the need for modification of treatment protocols. Nuclear Medicine and Molecular Imaging 2015 49 . (https://doi.org/10.1007/s13139-015-0332-6)

    • Search Google Scholar
    • Export Citation
  • 22

    FerreiraVMMarcelinoMPiechnikSKMariniCKaramitsosTDNtusiNABFrancisJMRobsonMDArnoldJRMihaiR et al. Pheochromocytoma is characterized by catecholamine-mediated myocarditis, focal and diffuse myocardial fibrosis, and myocardial dysfunction. Journal of the American College of Cardiology 2016 67 . (https://doi.org/10.1016/j.jacc.2016.03.543)

    • Search Google Scholar
    • Export Citation
  • 23

    ZografosGNVasiliadisGFarfarasANAggeliCDigalakisM. Laparoscopic surgery for malignant adrenal tumors. Journal of the Society of Laparoendoscopic Surgeons 2009 13 .

    • Search Google Scholar
    • Export Citation
  • 24

    HanssenWEKuhryECasseresYAde HerderWWSteyerbergEWBonjerHJ. Safety and efficacy of endoscopic retroperitoneal adrenalectomy. British Journal of Surgery 2006 93 . (https://doi.org/10.1002/bjs.5337)

    • Search Google Scholar
    • Export Citation
  • 25

    NiemeijerNDAlblasGvan HulsteijnLTDekkersOMCorssmitEP. Chemotherapy with cyclophosphamide, vincristine and dacarbazine for malignant paraganglioma and pheochromocytoma: systematic review and meta-analysis. Clinical Endocrinology 2014 81 . (https://doi.org/10.1111/cen.12542)

    • Search Google Scholar
    • Export Citation
  • 26

    HadouxJFavierJScoazecJYLeboulleuxSAl GhuzlanACaramellaCDeandreisDBorgetILoriotCChougnetC et al. SDHB mutations are associated with response to temozolomide in patients with metastatic pheochromocytoma or paraganglioma. International Journal of Cancer 2014 135 . (https://doi.org/10.1002/ijc.28913)

    • Search Google Scholar
    • Export Citation
  • 27

    Ayala-RamirezMChougnetCNHabraMAPalmerJLLeboulleuxSCabanillasMECaramellaCAndersonPAl GhuzlanAWaguespackSG et al. Treatment with sunitinib for patients with progressive metastatic pheochromocytomas and sympathetic paragangliomas. Journal of Clinical Endocrinology and Metabolism 2012 97 . (https://doi.org/10.1210/jc.2012-2356)

    • Search Google Scholar
    • Export Citation
  • 28

    HadouxJTerroirMLeboulleuxSDeschampsFAl GhuzlanAHescotSTselikasLBorgetICaramellaCDéandréisD et al. Interferon-alpha treatment for disease control in metastatic pheochromocytoma/paraganglioma patients. Hormones and Cancer 2017 8 . (https://doi.org/10.1007/s12672-017-0303-8)

    • Search Google Scholar
    • Export Citation
  • 29

    TenaIGuptaGTajahuerceMBenaventMCifrianMFalconAFonfriaMDel OlmoMRebollRCondeA et al. Successful second-line metronomic temozolomide in metastatic paraganglioma: case reports and review of the literature. Clinical Medicine Insights: Oncology 2018 12 1179554918763367. (https://doi.org/10.1177/1179554918763367)

    • Search Google Scholar
    • Export Citation
  • 30

    GravelGLeboulleuxSTselikasLFassioFBerrafMBerdelouABaBHescotSHadouxJSchlumbergerM et al. Prevention of serious skeletal-related events by interventional radiology techniques in patients with malignant paraganglioma and pheochromocytoma. Endocrine 2018 59 . (https://doi.org/10.1007/s12020-017-1515-y)

    • Search Google Scholar
    • Export Citation
  • 31

    van HulsteijnLTNiemeijerNDDekkersOMCorssmitEP. 131I-MIBG therapy for malignant paraganglioma and phaeochromocytoma: systematic review and meta-analysis. Clinical Endocrinology 2014 80 . (https://doi.org/10.1111/cen.12341)

    • Search Google Scholar
    • Export Citation
  • 32

    PinatoDJBlackJRRamaswamiRTanTMAdjogatseDSharmaR. Peptide receptor radionuclide therapy for metastatic paragangliomas. Medical Oncology 2016 33 47. (https://doi.org/10.1007/s12032-016-0737-9)

    • Search Google Scholar
    • Export Citation
  • 33

    PuranikADKulkarniHRSinghABaumRP. Peptide receptor radionuclide therapy with (90)Y/(177)Lu-labelled peptides for inoperable head and neck paragangliomas (glomus tumours). European Journal of Nuclear Medicine and Molecular Imaging 2015 42 . (https://doi.org/10.1007/s00259-015-3029-2)

    • Search Google Scholar
    • Export Citation
  • 34

    ForrerFRiedwegIMaeckeHRMueller-BrandJ. Radiolabeled DOTATOC in patients with advanced paraganglioma and pheochromocytoma. Quarterly Journal of Nuclear Medicine and Molecular Imaging 2008 52 .

    • Search Google Scholar
    • Export Citation
  • 35

    ImhofABrunnerPMarincekNBrielMSchindlerCRaschHMackeHRRochlitzCMuller-BrandJWalterMA. Response, survival, and long-term toxicity after therapy with the radiolabeled somatostatin analogue [90Y-DOTA]-TOC in metastasized neuroendocrine cancers. Journal of Clinical Oncology 2011 29 . (https://doi.org/10.1200/JCO.2010.33.7873)

    • Search Google Scholar
    • Export Citation
  • 36

    TaiebDPacakK. Molecular imaging and theranostic approaches in pheochromocytoma and paraganglioma. Cell and Tissue Research 2018 372 . (https://doi.org/10.1007/s00441-018-2791-4)

    • Search Google Scholar
    • Export Citation
  • 37

    TaiebDTimmersHJHindieEGuilletBANeumannHPWalzMKOpocherGde HerderWWBoedekerCCde KrijgerRR et al. EANM 2012 guidelines for radionuclide imaging of phaeochromocytoma and paraganglioma. European Journal of Nuclear Medicine and Molecular Imaging 2012 39 . (https://doi.org/10.1007/s00259-012-2215-8)

    • Search Google Scholar
    • Export Citation
  • 38

    HuangHAbrahamJHungEAverbuchSMerinoMSteinbergSMPacakK & FojoT. Treatment of malignant heochromocytoma/paraganglioma with cyclophosphamide, vincristine, and dacarbazine: recommendation from a 22-year follow-up of 18 patients. Cancer 2008 113 .

    • Search Google Scholar
  • 39

    TanabeANaruseMNomuraKTsuikiMTsumagariA & IchiharaA. Combination chemotherapy with cyclophosphamide, vincristine, and dacarbazine in patients with malignant pheochromocytoma and paraganglioma. Hormones & Cancer 2013 4.

    • Search Google Scholar

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     European Society of Endocrinology

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  • View in gallery

    Treatment outcome stratified for tumour type and baseline disease status. PCC, pheochromocytomas; PD, progressive disease; PR, partial response; PS-PGL, parasympathetic paragangliomas; SD, stable disease; S-PGL, sympathetic paragangliomas.

  • View in gallery

    Progression-free survival in patients with parasympathetic (PS-PGL)/sympathetic paragangliomas (S-PGL) and malignant phaechromocytomas (PCC) who showed progressive disease before the start of the treatment.

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    Overall survival in patients with parasympathetic and sympathetic paragangliomas who showed progressive disease before the start of the treatment.

  • View in gallery

    Response of liver metastasis in a patient with a metastatic sympathetic paraganglioma. A1/2: Planar anterior and posterior total body scintigraphs after the first cycle with 177Lu-DOTATATE. A3: CT scan of liver before first cycle. B: CT-scan of liver 6 months after the last cycle. Note the shrinkage of the liver metastasis in segment 8.

  • 1

    LloydRVOsamuraRYKlöppelGRosaiJ. WHO Classification of Tumours of Endocrine Organs. 2018.

  • 2

    CronaJTaiebDPacakK. New perspectives on pheochromocytoma and paraganglioma: toward a molecular classification. Endocrine Reviews 2017 38 . (https://doi.org/10.1210/er.2017-00062)

    • Search Google Scholar
    • Export Citation
  • 3

    ToledoRABurnichonNCasconABennDEBayleyJPWelanderJPTopsCMFirthHDwightT et al. Consensus statement on next-generation-sequencing-based diagnostic testing of hereditary phaeochromocytomas and paragangliomas. Nature Reviews: Endocrinology 2017 13 . (https://doi.org/10.1038/nrendo.2016.185)

    • Search Google Scholar
    • Export Citation
  • 4

    JanssenIChenCCZhuangZMilloCMWolfKILingALinFIAdamsKTHerscovitchPFeeldersRA et al. Functional imaging signature of patients presenting with polycythemia/paraganglioma syndromes. Journal of Nuclear Medicine 2017 58 . (https://doi.org/10.2967/jnumed.116.187690)

    • Search Google Scholar
    • Export Citation
  • 5

    EricksonDKudvaYCEbersoldMJThompsonGBGrantCSvan HeerdenJAYoungWFJr. Benign paragangliomas: clinical presentation and treatment outcomes in 236 patients. Journal of Clinical Endocrinology and Metabolism 2001 86 . (https://doi.org/10.1210/jcem.86.11.8034)

    • Search Google Scholar
    • Export Citation
  • 6

    LendersJWDuhQYEisenhoferGGimenez-RoqueploAPGrebeSKMuradMHNaruseMPacakKYoungWFJr & Endocrine Society. Pheochromocytoma and paraganglioma: an Endocrine Society Clinical Practice guideline. Journal of Clinical Endocrinology and Metabolism 2014 99 . (https://doi.org/10.1210/jc.2014-1498)

    • Search Google Scholar
    • Export Citation
  • 7

    CorssmitEPRomijnJA. Clinical management of paragangliomas. European Journal of Endocrinology 2014 171 R231R243. (https://doi.org/10.1530/EJE-14-0396)

    • Search Google Scholar
    • Export Citation
  • 8

    PacakKEisenhoferGAhlmanHBornsteinSRGimenez-RoqueploAPGrossmanABKimuraNMannelliMMcNicolAMTischlerAS et al. Pheochromocytoma: recommendations for clinical practice from the first International Symposium. October 2005. Nature Clinical Practice: Endocrinology and Metabolism 2007 3 . (https://doi.org/10.1038/ncpendmet0396)

    • Search Google Scholar
    • Export Citation
  • 9

    ReubiJCWaserBSchaerJCLaissueJA. Somatostatin receptor sst1-sst5 expression in normal and neoplastic human tissues using receptor autoradiography with subtype-selective ligands. European Journal of Nuclear Medicine 2001 28 . (https://doi.org/10.1007/s002590100541)

    • Search Google Scholar
    • Export Citation
  • 10

    van der HarstEde HerderWWBruiningHABonjerHJde KrijgerRRLambertsSWvan de MeirackerAHBoomsmaFStijnenTKrenningEP et al. [(123)I]Metaiodobenzylguanidine and [(111)In]octreotide uptake in begnign and malignant pheochromocytomas. Journal of Clinical Endocrinology and Metabolism 2001 86 . (https://doi.org/10.1210/jcem.86.2.7238)

    • Search Google Scholar
    • Export Citation
  • 11

    van EssenMKrenningEPKooijPPBakkerWHFeeldersRAde HerderWWWolbersJGKwekkeboomDJ. Effects of therapy with [177Lu-DOTA0, Tyr3]octreotate in patients with paraganglioma, meningioma, small cell lung carcinoma, and melanoma. Journal of Nuclear Medicine 2006 47 .

    • Search Google Scholar
    • Export Citation
  • 12

    BrabanderTTeunissenJJVan EijckCHFranssenGJFeeldersRAde HerderWWKwekkeboomDJ. Peptide receptor radionuclide therapy of neuroendocrine tumours. Best Practice and Research: Clinical Endocrinology and Metabolism 2016 30 . (https://doi.org/10.1016/j.beem.2015.10.005)

    • Search Google Scholar
    • Export Citation
  • 13

    BrabanderTvan der ZwanWATeunissenJJMKamBLRFeeldersRAde HerderWWvan EijckCHJFranssenGJHKrenningEPKwekkeboomDJ. Long-term efficacy, survival, and safety of [(177)Lu-DOTA(0),Tyr(3)]octreotate in patients with gastroenteropancreatic and bronchial neuroendocrine tumors. Clinical Cancer Research 2017 23 . (https://doi.org/10.1158/1078-0432.CCR-16-2743)

    • Search Google Scholar
    • Export Citation
  • 14

    KwekkeboomDJKrenningEP. Somatostatin receptor imaging. Seminars in Nuclear Medicine 2002 32 . (https://doi.org/10.1053/snuc.2002.31022)

  • 15

    JanssenIChenCCMilloCMLingATaiebDLinFIAdamsKTWolfKIHerscovitchPFojoAT et al. PET/CT comparing (68)Ga-DOTATATE and other radiopharmaceuticals and in comparison with CT/MRI for the localization of sporadic metastatic pheochromocytoma and paraganglioma. European Journal of Nuclear Medicine and Molecular Imaging 2016 43 . (https://doi.org/10.1007/s00259-016-3357-x)

    • Search Google Scholar
    • Export Citation
  • 16

    BaudinEHabraMADeschampsFCoteGDumontFCabanillasMArfi-RoufeJBerdelouAMoonBAl GhuzlanA et al. Therapy of endocrine disease: treatment of malignant pheochromocytoma and paraganglioma. European Journal of Endocrinology 2014 171 R111R122. (https://doi.org/10.1530/EJE-14-0113)

    • Search Google Scholar
    • Export Citation
  • 17

    KongGGrozinsky-GlasbergSHofmanMSCallahanJMeirovitzAMaimonOPattisonDAGrossDJHicksRJ. Efficacy of peptide receptor radionuclide therapy for functional metastatic paraganglioma and pheochromocytoma. Journal of Clinical Endocrinology and Metabolism 2017 102 . (https://doi.org/10.1210/jc.2017-00816)

    • Search Google Scholar
    • Export Citation
  • 18

    KwekkeboomDJBakkerWHKooijPPKonijnenbergMWSrinivasanAErionJLSchmidtMABugajJLde JongMKrenningEP. [177Lu-DOTAOTyr3]octreotate: comparison with [111In-DTPAo]octreotide in patients. European Journal of Nuclear Medicine 2001 28 . (https://doi.org/10.1007/s002590100574)

    • Search Google Scholar
    • Export Citation
  • 19

    EisenhauerEATherassePBogaertsJSchwartzLHSargentDFordRDanceyJArbuckSGwytherSMooneyM et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). European Journal of Cancer 2009 45 . (https://doi.org/10.1016/j.ejca.2008.10.026)

    • Search Google Scholar
    • Export Citation
  • 20

    AaronsonNKAhmedzaiSBergmanBBullingerMCullADuezNJFilibertiAFlechtnerHFleishmanSBde HaesJC. The European organization for research and treatment of cancer QLQ-C30: a quality-of-life instrument for use in international clinical trials in oncology. Journal of the National Cancer Institute 1993 85 . (https://doi.org/10.1093/jnci/85.5.365)

    • Search Google Scholar
    • Export Citation
  • 21

    MakisWMcCannKMcEwanAJ. The challenges of treating paraganglioma patients with (177)Lu-DOTATATE PRRT: catecholamine crises, tumor lysis syndrome and the need for modification of treatment protocols. Nuclear Medicine and Molecular Imaging 2015 49 . (https://doi.org/10.1007/s13139-015-0332-6)

    • Search Google Scholar
    • Export Citation
  • 22

    FerreiraVMMarcelinoMPiechnikSKMariniCKaramitsosTDNtusiNABFrancisJMRobsonMDArnoldJRMihaiR et al. Pheochromocytoma is characterized by catecholamine-mediated myocarditis, focal and diffuse myocardial fibrosis, and myocardial dysfunction. Journal of the American College of Cardiology 2016 67 . (https://doi.org/10.1016/j.jacc.2016.03.543)

    • Search Google Scholar
    • Export Citation
  • 23

    ZografosGNVasiliadisGFarfarasANAggeliCDigalakisM. Laparoscopic surgery for malignant adrenal tumors. Journal of the Society of Laparoendoscopic Surgeons 2009 13 .

    • Search Google Scholar
    • Export Citation
  • 24

    HanssenWEKuhryECasseresYAde HerderWWSteyerbergEWBonjerHJ. Safety and efficacy of endoscopic retroperitoneal adrenalectomy. British Journal of Surgery 2006 93 . (https://doi.org/10.1002/bjs.5337)

    • Search Google Scholar
    • Export Citation
  • 25

    NiemeijerNDAlblasGvan HulsteijnLTDekkersOMCorssmitEP. Chemotherapy with cyclophosphamide, vincristine and dacarbazine for malignant paraganglioma and pheochromocytoma: systematic review and meta-analysis. Clinical Endocrinology 2014 81 . (https://doi.org/10.1111/cen.12542)

    • Search Google Scholar
    • Export Citation
  • 26

    HadouxJFavierJScoazecJYLeboulleuxSAl GhuzlanACaramellaCDeandreisDBorgetILoriotCChougnetC et al. SDHB mutations are associated with response to temozolomide in patients with metastatic pheochromocytoma or paraganglioma. International Journal of Cancer 2014 135 . (https://doi.org/10.1002/ijc.28913)

    • Search Google Scholar
    • Export Citation
  • 27

    Ayala-RamirezMChougnetCNHabraMAPalmerJLLeboulleuxSCabanillasMECaramellaCAndersonPAl GhuzlanAWaguespackSG et al. Treatment with sunitinib for patients with progressive metastatic pheochromocytomas and sympathetic paragangliomas. Journal of Clinical Endocrinology and Metabolism 2012 97 . (https://doi.org/10.1210/jc.2012-2356)

    • Search Google Scholar
    • Export Citation
  • 28

    HadouxJTerroirMLeboulleuxSDeschampsFAl GhuzlanAHescotSTselikasLBorgetICaramellaCDéandréisD et al. Interferon-alpha treatment for disease control in metastatic pheochromocytoma/paraganglioma patients. Hormones and Cancer 2017 8 . (https://doi.org/10.1007/s12672-017-0303-8)

    • Search Google Scholar
    • Export Citation
  • 29

    TenaIGuptaGTajahuerceMBenaventMCifrianMFalconAFonfriaMDel OlmoMRebollRCondeA et al. Successful second-line metronomic temozolomide in metastatic paraganglioma: case reports and review of the literature. Clinical Medicine Insights: Oncology 2018 12 1179554918763367. (https://doi.org/10.1177/1179554918763367)

    • Search Google Scholar
    • Export Citation
  • 30

    GravelGLeboulleuxSTselikasLFassioFBerrafMBerdelouABaBHescotSHadouxJSchlumbergerM et al. Prevention of serious skeletal-related events by interventional radiology techniques in patients with malignant paraganglioma and pheochromocytoma. Endocrine 2018 59 . (https://doi.org/10.1007/s12020-017-1515-y)

    • Search Google Scholar
    • Export Citation
  • 31

    van HulsteijnLTNiemeijerNDDekkersOMCorssmitEP. 131I-MIBG therapy for malignant paraganglioma and phaeochromocytoma: systematic review and meta-analysis. Clinical Endocrinology 2014 80 . (https://doi.org/10.1111/cen.12341)

    • Search Google Scholar
    • Export Citation
  • 32

    PinatoDJBlackJRRamaswamiRTanTMAdjogatseDSharmaR. Peptide receptor radionuclide therapy for metastatic paragangliomas. Medical Oncology 2016 33 47. (https://doi.org/10.1007/s12032-016-0737-9)

    • Search Google Scholar
    • Export Citation
  • 33

    PuranikADKulkarniHRSinghABaumRP. Peptide receptor radionuclide therapy with (90)Y/(177)Lu-labelled peptides for inoperable head and neck paragangliomas (glomus tumours). European Journal of Nuclear Medicine and Molecular Imaging 2015 42 . (https://doi.org/10.1007/s00259-015-3029-2)

    • Search Google Scholar
    • Export Citation
  • 34

    ForrerFRiedwegIMaeckeHRMueller-BrandJ. Radiolabeled DOTATOC in patients with advanced paraganglioma and pheochromocytoma. Quarterly Journal of Nuclear Medicine and Molecular Imaging 2008 52 .

    • Search Google Scholar
    • Export Citation
  • 35

    ImhofABrunnerPMarincekNBrielMSchindlerCRaschHMackeHRRochlitzCMuller-BrandJWalterMA. Response, survival, and long-term toxicity after therapy with the radiolabeled somatostatin analogue [90Y-DOTA]-TOC in metastasized neuroendocrine cancers. Journal of Clinical Oncology 2011 29 . (https://doi.org/10.1200/JCO.2010.33.7873)

    • Search Google Scholar
    • Export Citation
  • 36

    TaiebDPacakK. Molecular imaging and theranostic approaches in pheochromocytoma and paraganglioma. Cell and Tissue Research 2018 372 . (https://doi.org/10.1007/s00441-018-2791-4)

    • Search Google Scholar
    • Export Citation
  • 37

    TaiebDTimmersHJHindieEGuilletBANeumannHPWalzMKOpocherGde HerderWWBoedekerCCde KrijgerRR et al. EANM 2012 guidelines for radionuclide imaging of phaeochromocytoma and paraganglioma. European Journal of Nuclear Medicine and Molecular Imaging 2012 39 . (https://doi.org/10.1007/s00259-012-2215-8)

    • Search Google Scholar
    • Export Citation
  • 38

    HuangHAbrahamJHungEAverbuchSMerinoMSteinbergSMPacakK & FojoT. Treatment of malignant heochromocytoma/paraganglioma with cyclophosphamide, vincristine, and dacarbazine: recommendation from a 22-year follow-up of 18 patients. Cancer 2008 113 .

    • Search Google Scholar
  • 39

    TanabeANaruseMNomuraKTsuikiMTsumagariA & IchiharaA. Combination chemotherapy with cyclophosphamide, vincristine, and dacarbazine in patients with malignant pheochromocytoma and paraganglioma. Hormones & Cancer 2013 4.

    • Search Google Scholar