This prospective phase II study shows that high-dose [131I]MIBG produced objective responses in patients with metastatic PHEO/PGL; 22% of patients attained CR/PR, 35% of patients attained an objective MR, and 8% of patients maintained SD for greater than 12 months. The 5-year OS was 64% (SE, ± 9%), which compares favorably to historical data.
Several studies have reported lower-dose [131
I]MIBG treatment for patients with malignant PHEO/PGL. Loh et al8
reported a retrospective meta-analysis of 116 patients with metastatic PHEO/PGL who were treated with [131
I]MIBG (mean dose, 158 mCi; mean cumulative dose, 490 mCi). The rate of progressive disease was 45% after a median interval of 19 months. The tumor response rate was 30% and the hormonal response rate was 45%.8
However, the criteria for responses were not presented. The results presented here show a comparable objective tumor response rate by strict criteria. In addition, 66% of patients in this study achieved a hormone response (CR, PR, or MR), which is markedly improved relative to the meta-analysis.
In this study, we assessed biochemical responses by using six different tumor markers: chromogranin A, catecholamines (ie, epinephrine, norepinephrine, dopamine) and metanephrines (ie, metanephrine, normetanephrine). Several patients achieved CR/PR by several tumor markers, but not by all six; as such, the MR category was necessary to distinguish the many patients who responded by several tumor markers from those who failed to respond at all.
Safford et al3
reported that hormone response was a significant predictor of survival in a retrospective review of 33 patients with malignant PHEO/PGL treated with a mean dose of 388 mCi of [131
I]MIBG. In their study, tumor volume declined more than 50% in 38% of patients, and hormone levels declined more than 50% in 60% of patients. The 5-year survival rate for patients was 45% after treatment. In their report, a hormone response predicted improved survival, whereas a reduction in tumor volume did not.3
In contrast, the data presented here show that hormone response was not predictive of OS but that a CR/PR by MIBG scans or CT/MRI imaging was predictive of OS. Safford et al3
also identified a survival benefit in patients who received greater than 500 mCi as their initial [131
I]MIBG doses, which supports the use of higher doses.3
The 5-year OS in our study, in which 98% of patients were treated with greater than 500 mCi, was 64%.
Chemotherapy is an option for patients with metastatic PHEO/PGL, but large clinical trials are lacking. One study reported a combination chemotherapy regimen that included cyclophosphamide, vincristine, and dacarbazine (CVD).2,9
In 14 patients with metastatic pheochromocytoma, this therapy produced CR/PR in 57%.9
More recently, results from a 22-year follow-up of 18 patients treated with CVD chemotherapy showed a CR rate of 11% and a PR rate of 44%, but 5-year survival of patients was less than 50%.10
Although CVD chemotherapy response rates may compare favorably with those for [131
I]MIBG therapy, estimated 5-year OS is substantially less than the 64% achieved in this study of high-dose [131
I]MIBG. In addition, antiangiogenic therapy with sunitinib may prove useful in the treatment of malignant PHEO/PGL.11
Although Safford et al3
showed an increased survival in patients who received additional chemotherapy after MIBG therapy, the data presented here show that prior chemotherapy portends poor survival. Tumors that are resistant to chemotherapy and radiation may be more aggressive and resistant to multiple therapeutic approaches, including [131
I]MIBG, as seen in this study.
SDHB mutations are autosomal dominant and are characterized by the development of paragangliomas with significant metastatic potential.12
In this study, patients with known SDHB mutations were significantly more likely to achieve CR/PR. SDHB status was not, however, predictive of OS or EFS, though only 50% of patients had known SDHB status. Patients with an SDHB mutation may have an improved response to [131
I]MIBG but may have a more aggressive natural history of their disease, which may explain the discrepancies between response analysis and hazards ratios for OS and EFS.
Two patients developed BOOP after [131
I]MIBG. A previous study reported that BOOP occurred 4 months after high-dose [131
I]MIBG in a child with neuroblastoma.13
BOOP may have occurred as a delayed pulmonary reaction to radiation exposure from [131
I]MIBG. BOOP has also been reported in patients after thoracic radiation therapy.14
Two patients developed ARDS after [131
I]MIBG. Although ARDS has not been reported previously after previously MIBG therapy, it has occurred spontaneously in patients with PHEO without prior [131
Because two of the four patients with pulmonary toxicity had nephrotic syndrome, it is possible that delayed clearance of MIBG may have contributed to this toxicity; however, neither patient had an elevated creatinine at the time of treatment. Nevertheless, we now restrict patients with nephrotic syndrome from receiving high-dose [131
I]MIBG. In addition, because three of four patients with pulmonary toxicity in this study received greater than 1,000 mCi per dose, we suggest that doses of [131
I]MIBG should not exceed 800 mCi.
MDS/leukemia was a fatal complication experienced by two patients at 2 and 6 years, respectively, after high-dose [131
I]MIBG. Radiation is a known risk factor for secondary malignancy, and the large cumulative doses received by these two patients likely placed them at increased risk. The observed cytogenetic abnormalities (ie, loss of chromosomes 5 and 7) have been reported in secondary leukemia after treatment with alkylating agents and radiation. MDS was previously reported in three of 95 children treated at UCSF with [131
I]MIBG for neuroblastoma, and a literature review revealed an additional three patients.18
In summary, high-dose [131
I]MIBG produced objective responses in patients with metastatic PHEO/PGL. Myelosuppression was common but well tolerated. Four patients developed pulmonary complications, and two developed MDS/leukemia after high-dose [131
I]MIBG. Nevertheless, the estimated 5-year OS was 64%, an improvement over the historical 5-year survival of 44% without such therapy.19
I]MIBG at doses of approximately 12 mCi/kg, with total doses that range from 500 to 800 mCi, may provide the maximum therapeutic benefit while minimizing risk of pulmonary toxicity. We conclude that high-dose [131
I]MIBG is an effective therapy for selected patients with metastatic PHEO/PGL.