Visual Abstract
Abstract
We aim to evaluate the efficacy and safety of 124I-metaiodobenzylguanidine (MIBG) dosimetry-guided high-activity 131I-MIBG therapy of advanced pheochromocytoma or neuroblastoma. Methods: Fourteen patients with advanced pheochromocytoma or neuroblastoma, age 9–69 y, underwent 124I-MIBG PET scans and whole-body retention measurements to assess the whole-body dose as a surrogate of bone marrow toxicity and tumor (absorbed) dose per unit of administered activity. Dosimetry results together with individual patient characteristics were combined to guide a single therapeutic activity to achieve a high tumor dose without exceeding toxicity threshold. Toxicity was assessed for hematologic, hepatic, and renal function. Response was evaluated by RECIST, International Society of Pediatric Oncology Europe Neuroblastoma–like score, change in PET uptake, and quantitative PET parameters (SUVmax, SUVpeak, metabolic tumor volume, total lesion glycolysis), as well as visual decrease in number or in visual intensity of lesions on baseline to follow-up 124I-MIBG PET/CT. Results: The average therapeutic activity was 14 GBq. Eleven of 14 patients (79%) received each more than 10 GBq. One male patient was treated with a single activity of 50 GBq. Three patients were treated with lower activities between 3.5 and 7.0 GBq. Median overall survival was 85 mo (95% CI), and median progression-free survival was 25 mo (95% CI). Four (29%) and 5 (36%) patients demonstrated response (complete response or partial response) by RECIST and functional imaging, respectively. One patient exceeded whole-body dose of 2 Gy and demonstrated grade 3 hematologic toxicity, which resolved spontaneously within 12 mo after the therapy without the need for further treatment. Three patients (21%) demonstrated transient grade 1 renal toxicity. Conclusion: 124I-MIBG dosimetry-guided high-activity 131I-MIBG therapy in patients with advanced pheochromocytoma or neuroblastoma resulted in durable responses with a low rate of manageable adverse events. Efficacy of 124I-MIBG–guided activity escalation should further be assessed in a prospective setting.
Metaiodobenzylguanidine (MIBG), a guanethidine derivative, is a substrate for norepinephrine reuptake transporters, which are highly expressed on the cell surface of neuroendocrine tumors, such as pheochromocytoma or neuroblastoma (1). 123/131I-MIBG imaging is one of the most sensitive lesion detection modalities for pheochromocytoma and neuroblastoma. Although 123I-MIBG allows for quantification, 124I-MIBG offers the benefit of quantification at higher PET spatial resolution (2,3). Similar biodistribution compared with 123I-MIBG allows for translation of established systems of image interpretation and therapy monitoring (e.g., International Society of Pediatric Oncology Europe Neuroblastoma score [SIOPEN] or Curie score) (3–5). 124I-MIBG imaging and dosimetry is a companion tool for planning of high-activity 131I-MIBG therapy (6).
Patients with malignant unresectable, metastatic, or recurring pheochromocytoma have a poor prognosis with an average 5-y survival rate of 12%–20% (7,8), whereas in refractory or relapsing neuroblastoma, the 10-y survival probability is less than 15% (9). Efficacy of 131I-MIBG for the treatment of unresectable, locally advanced, and metastatic pheochromocytoma and paraganglioma using empiric activities led to recent US Food and Drug Administration approval (10). In the prospective trial, objective tumor response occurred in 15 patients (22%; 95% CI, 14%–33%). However, most patients did not demonstrate notable tumor shrinkage despite focal 131I-MIBG uptake in tumor lesions. Nonresponder patients under empiric activities might benefit from high-activity regimens. Pretherapeutic 124I-MIBG PET/CT-based dosimetry of the tumor and organs at risk enables planning of patient-specific activity escalation (11,12). However, feasibility, toxicity, and efficacy have, to the authors’ knowledge, not yet been assessed.
The aim of this study was to evaluate the efficacy and safety of 124I-MIBG dosimetry-guided high-activity 131I-MIBG therapy in patients with long follow-up after treatment of advanced pheochromocytoma or neuroblastoma.
MATERIALS AND METHODS
Study Design
This is a retrospective, single center study of the efficacy and safety of 124I-MIBG dosimetry-guided, activity-escalated 131I-MIBG therapy of unresectable neural crest tumors. The goal was to achieve a high tumor (absorbed) dose without exceeding the toxicity threshold. This retrospective analysis was approved by the ethics committee of the University Hospital Essen (reference no. 20–9656-BO). Long-term follow-up included survival, imaging, clinical information, and laboratory data. Primary endpoints in these patients were overall survival (OS) and progression-free survival (PFS) after 131I-MIBG therapy. Secondary endpoints included late hematologic/liver/renal toxicity in relation to the estimated whole-body dose evaluated up to 12 mo after therapy and the efficacy of 124I-MIBG-guided 1311-MIBG therapy as determined by response rate (partial response [PR] and complete response [CR]) within 12 mo after therapy in relation to achieved lesion tumor doses.
Patient Cohort
Patients who underwent 124I-MIBG PET/CT with subsequent 131I-MIBG therapy between August 2006 and July 2016 were included. Thirty patients with histologically proven unresectable neural crest tumors were considered for evaluation. Pretherapeutic imaging revealed no detectable tumor lesions by means of 124I-PET/CT in 16 patients. In total, 14 patients with at least 1 tumor lesion with measurable volume and uptake underwent tumor and whole-body dosimetry. All therapy patients demonstrated progressive disease at baseline, defined either by an endocrinologist/oncologist by worsening clinical symptoms or by radiology/nuclear medicine specialists, defined by RECIST, or both. All patients received a potassium iodide–saturated solution to prevent thyroid accumulation of free radioactive iodine starting 48 h before administration and continuing for 15 d after therapy according to European Association of Nuclear Medicine Practice Guidelines (13). The patients provided written informed consent before dosimetry and therapy and were admitted to our ward in accordance with radiation protection requirements. Both 124I- and 131I-MIBG were applied intravenously. Labeling and preparation of the carrier-added 124I-MIBG are described elsewhere (3).
Tumor and Whole-Body Dosimetry
Our 124I-MIBG dosimetry protocol involves determination of the estimated tumor dose per unit of administered 131I-MIBG activity for selected tumor deposits by serial PET and PET/CT examinations (14) and of determination of the maximum tolerable whole-body 131I-MIBG activity via whole-body retention measurements (11). The approach is similar to the pretherapy dosimetry protocol used in thyroid cancer patients (15–17). Both the tumor dose and maximum tolerable whole-body 131I-MIBG activity serve as primary input for the choice of the actual recommended therapeutic activity and other interventions, supplemented by clinical judgment based on patient and disease characteristics (age, previous myelotoxic therapies, current general and nutritional condition, comorbidities, notes from [pediatric] oncologists, availability of autologous stem cells) and biochemistry results (bone marrow and kidney and liver function).
For tumor dosimetry, serial PET data were acquired 4, 24, 48, and 96–120 h after 124I-MIBG administration (average activity of 46 MBq 124I-MIBG). The PET scans were performed on 2 PET systems: a dedicated ECAT EXACT HR+ PET scanner (Siemens) and a PET/CT Biograph Emotion Duo scanner (Siemens Medical Solutions). The interscanner variability was examined elsewhere (18), demonstrating good agreement between the 2 systems with individual deviations of less than 10%. PET and PET/CT emission data were acquired through whole-body scans performed from head to thigh using 5–8 bed positions (5 min each). PET image reconstruction was performed using an iterative attenuation-weighted ordered-subset expectation maximation algorithm (2 iterations and 8 subsets, 5-mm postreconstruction gaussian filter) (17). For the dedicated PET and PET/CT scanning, the rod source transmission data and CT data were used for PET attenuation correction, respectively. Recovery correction was performed as described by Jentzen et al. (14). The metastatic lesion volumes for recovery correction were estimated using anatomic information obtained by the CT component of PET/CT. If no lesion volume could be derived from anatomic information, a PET volumetric segmentation method was used (19,20). The predicted cumulative activity per unit of administered 131I-MIBG activity (tumor residence time) was obtained using the time–activity curves of the serial PET scans corrected with the measured recovery coefficient and corrected for the difference in the physical half-lives of 124I and 131I (14,21). Both the tumor volume (mass) and the respective residence time were used to predict the tumor dose using the sphere model of OLINDA/EXM.
For whole-body dosimetry, multiple whole-body retention measurements (2, 4, 24, 48, 72, and 96 h after 124I-MIBG administration) were performed placing the patient approximately 3 m in front of an uncollimated γ-camera (E.CAM Signature Series; Siemens). Anterior and posterior counts for calculation of a geometric mean were measured considering dead time effects. After correcting for the difference in the physical half-lives of 124I and 131I, the whole-body residence time was calculated using the whole-body retention curves. The predicted whole-body dose per unit administered activity was calculated using the whole-body-to-whole-body S values corrected for patient mass (11). The resulting whole-body dose per administered activity was used to calculate the maximum tolerable whole-body 131I-MIBG activity, a value that represents the maximum therapeutic activity that can be safely administered without exceeding the 2-Gy whole-body absorbed dose threshold (as a surrogate to estimate the myelotoxicity).
Analysis
At least 1 and up to 4 tumor lesions with measurable volume and uptake were taken into consideration per patient. Toxicity was graded with Common Terminology Criteria for Adverse Events version 3.0. Response was evaluated by baseline to follow-up changes in 124I-MIBG-PET/CT, defined by RECIST criteria (10), and by visual and quantitative (SUVmax, SUVpeak, metabolic tumor volume, total lesion glycolysis) PET analysis. For tumors in which exact size measurements were not available, such as osteoblastic bone metastases, a visual impression of nuclear medicine physicians was used. Visual 124I-MIBG PET evaluation was categorized as follows: CR was described as the disappearance of all lesions; PR was a decrease in the number or visual intensity of lesions; stable disease was no discernible change; and progressive disease was the appearance of new lesions (11). Furthermore, we defined a SIOPEN-like score for baseline to follow-up response assessment (not including the assessment of soft-tissue areas of tumor) as follows: the scan area was segmented into 8 body regions, excluding the 4 lower limb areas, which are not included in the usual PET/CT scan field of view performed in the clinical routine in our institution. Each region was assigned with 1–6 points, corresponding to established SIOPEN scoring (4), and then summarized. The baseline to follow-up change in this sum was then used as an additional mean to assess the response in accordance with the SIOPEN score.
Statistics and Software
Statistical analysis was performed using IBM SPSS Statistics, version 26 (IBM Corp.). Patient characteristics, toxicity, and response are presented as descriptive statistics. Assessment of statistically significant differences between groups was performed using a t test. Predictors for PFS and OS were assessed by univariate Cox regression analysis and log-rank test and plotted using Kaplan–Meier curves. PMOD 3.1 (PMOD Technologies Ltd.) was used to coregister and determine the volumes and activities shown. The absorbed tumor dose was calculated using OLINDA/EXM 1.1 software (Vanderbilt University).
RESULTS
Patient Characteristics
Patient characteristics are summarized in Table 1. The mean patient age (range) was 36 (9–69) y. Six of 14 (43%) patients were female, and 8 of 14 (57%) were male. Among the 14 patients, 4 (29%) had histologically confirmed neuroblastoma and 10 (71%) had malignant pheochromocytoma. An average time period of 1.2 ± 1.6 (SD) mo from pretherapeutic 124I-MIBG dosimetry to therapy and an average of 4.6 ± 2.4 (SD) mo for the interval between therapy and posttherapeutic follow-up PET/CT were documented. A single therapy activity ranged from 3.5 to 50 GBq (average, 13.7 GBq; ±11.3 SD). The average time from diagnosis to dosimetry-based 131I-MIBG therapy was 75 ± 55.8 (SD) mo (range, 1–189 mo). All eligible patients had received previous therapies, including surgery (93%), radiotherapy (43%), or chemotherapy (50%).
Survival
Figure 1 shows OS and PFS along with predictors of survival.
Median OS after therapy was 85 mo (hazard ratio 6.9; 95% CI [3.2–10.5]), and median PFS was 25 mo (hazard ratio 1.9; 95% CI [0.0–4.3]). Minimum follow-up time was 5 mo, and the average follow-up time (range) for the cohort was 76 ± 48.7 (SD) mo (range, 5–164 mo). Five of 14 (36%) patients died during the observation period. By log-rank analysis, significant predictors of OS and functional response were achieved with average tumor lesion dose higher than median (88 Gy; P < 0.004), the highest uptake lesion dose higher than median (109 Gy; P < 0.009), and the functional response by means of 124I-MIBG PET/CT defined as CR/PR, respectively (P < 0.001). Changes in SIOPEN-like score translated from conventional 123I-MIBG imaging did not show a significant correlation with OS (P < 0.205) or response (P < 0.059 for morphologic response and P < 0.017 for functional response).
Dosimetry and Toxicity
The dosimetry and toxicity data are shown in Tables 2 and 3. One patient received a single therapy activity of 50 GBq 131I-MIBG (in a curative intention and close cooperation with the pediatric oncologists, after autologous stem cells have been collected and cryopreserved), exceeded the estimated whole-body dose of 2 Gy (median in all patients, 1.4 Gy; range, 0.4–6 Gy), and demonstrated transient grade 3 hematologic toxicity (leukocytopenia and thrombocytopenia), which resolved spontaneously within 12 mo after therapy without the need for stem cell rescue. Additionally, 2 patients demonstrated grade 1 hematologic toxicity. Transitional grade 1 kidney function deterioration was noted in 3 patients (21%). One patient with pheochromocytoma showed a transitional grade 1 kidney function deterioration after receiving a cumulative activity of 21.6 GBq and was diagnosed with operable urothelial carcinoma (pTa, R0) 4 y after 131I-MIBG therapy.
Treatment Response
Treatment response is summarized in Table 4. Of the 14 evaluable patients, 4 (29%) and 5 (36%) demonstrated CR/PR by RECIST and functional imaging, respectively. Disease control, defined by CR, PR, or stable disease, was achieved in 71% of the patients according to morphologic imaging and in 79% by functional imaging. All 4 patients (3 with neuroblastoma and 1 with metastatic pheochromocytoma) demonstrating progressive disease by means of morphologic imaging were extensively pretreated during the long disease history.
The median tumor dose of the lesions with highest uptake was 109 Gy, ranging from 10.5 to 495 Gy. An overview of individual patient characteristics combined with individual tumor dose along with response is given in Table 5. Figure 2 shows an example of a patient with metastatic pheochromocytoma. Figure 3 shows an example of a patient with metastatic neuroblastoma.
DISCUSSION
131I-MIBG is an efficacious therapy for MIBG-positive unresectable, locally advanced/metastatic neural crest tumors. Prospective phase 2 data (10) recently led to the US Food and Drug Administration approval of 131I-MIBG for the treatment of unresectable, locally advanced, and metastatic pheochromocytoma and paraganglioma using empiric activities. High-activity 131I-MIBG therapy has been reported previously; however, the feasibility of the 124/131I-MIBG theranostic pair for dose escalation has not yet been assessed systematically. Here we demonstrate feasibility of dosimetry guided 124/131I-MIBG theranostic therapy, which resulted in durable responses in 57% and 50% of patients at 12 and 24 mo, respectively. Median OS after therapy was 85 mo, and median PFS was 25 mo, which compares favorably to previously published data (10,22,23). For instance, overall response (CR/PR) rate was 22%, and 8% of patients maintained stable disease for greater than 12 mo in the cohort described by Gonias et al. (22). In comparison, the median OS was 36.7 mo in a study by Pryma et al. (10). In the long-term follow-up, 1 grade 3 event was noted for 1 patient, and possible secondary malignancy was noted in 1 patient in our cohort. The much lower toxicity rates compared with previous data, reporting grade 3/4 neutropenia in 85%, low platelet count in 83%, and anemia in 8% of patients (22), additionally strengthen 124I-MIBG dosimetry to mitigate toxicity.
This study demonstrates the advantages of calculated treatment planning and targeted therapy in a heterogenous group of patients with neural crest tumors. Here we provide evidence for the feasibility of using the theranostic pair 124I/131I-MIBG to achieve a high tumor dose without exceeding toxicity thresholds, especially for the bone marrow (10,22). The superior diagnostic performance and improved possibilities of quantification of 124I-MIBG PET/CT over scintigraphy with 123I- or 131I-MIBG have been discussed and confirmed in the current literature (2,3,24). Previous studies conducted in a preclinical environment have shown similar potential (6,25). Furthermore, the use of the 124I/131I pair is well established for imaging and therapy of differentiated thyroid carcinoma (15,26–29).
A low adverse events rate in comparison with other activity-escalated concepts (22,23,30,31) additionally confirms the central role of 124I-MIBG PET/CT dosimetry in targeted therapy planning. Improved quantification possibilities using 124I-MIBG PET/CT and the knowledge of tumor doses can further help to assess the individual response probability and establish the threshold doses needed to achieve partial or complete response (absorbed doses in relation to associated response rates), similar to data published for differentiated thyroid carcinoma (26,32–34). Significant predictors of OS and functional response in our cohort were an achieved tumor dose in the highest uptake lesion higher than 109 Gy and the average achieved dose higher than 88 Gy, as well as the functional response defined as CR/PR. Disease control, defined by either CR, PR, or stable disease, was achieved in 71% of the patients by morphologic imaging and in 79% by functional imaging lesion count, respectively. Changes in SIOPEN-like score did not show a significant correlation with OS or response. An association between lesions dose and response/survival is noted. Therefore, dosimetry-guided high-activity therapy could be critical for favorable outcomes. In addition, through 124I-MIBG prescreening/dosimetry, patients most likely to benefit from 131I-MIBG therapy can be selected, and long-term outcomes can be predicted to guide subsequent management.
Strengths of our study include dosimetry guidance and long-term follow-up with mature survival data. Limitations of this study include a small sample size, the retrospective study design, and the heterogenous patient cohort concerning tumor entity and age. Prospective studies are needed to compare efficacy and safety of 124I-MIBG dosimetry-guided 131I-MIBG therapy versus conventional 131I-MIBG therapy using standard activities in larger patient cohorts.
CONCLUSION
124I-MIBG dosimetry-guided high-activity 131I-MIBG therapy is feasible and results in durable responses, long survival, and a low rate of manageable adverse events. 124I-MIBG PET-derived tumor dose and response assessment predict survival after 131I-MIBG therapy.
124/131I-MIBG theranostics offer individual treatment planning with a promising efficacy/safety tradeoff: 124I-MIBG–guided 131I-MIBG activity escalation should further be assessed in prospective trials.
DISCLOSURE
This work is a part of the doctoral thesis of Ines Maric. Andre Prochnow, Jochen Schmitz, Nicole Unger, Thorsten Poeppel, Christoph Rischpler and Andreas Bockisch have nothing to declare. Walter Jentzen received research funding from Siemens Healthineers. Manuel Weber reports fees from Boston Scientific, Terumo, Advanced Accelerator Applications, and Lilly, outside of the submitted work. Benedikt M. Schaarschmidt is supported by a research grant from PharmaCept, outside the submitted work. Ken Herrmann reports personal fees from Bayer SIRTEX, Adacap, Curium, Endocyte, IPSEN, Siemens Healthineers, GE Healthcare, Amgen, Novartis, and ymabs; personal fees and other from Sofie Biosciences; nonfinancial support from ABX; and grants and personal fees from BTG, outside the submitted work. Wolfgang Fendler reports fees from SOFIE Bioscience (research funding), Janssen (consultant, speaker), Calyx (consultant), Bayer (consultant, speaker, research funding), Parexel (image review), Novartis (speaker), and Telix (speaker), outside of the submitted work. No other potential conflict of interest relevant to this article was reported.
KEY POINTS
QUESTION: Is 124I-MIBG dosimetry-guided high-activity 131I-MIBG therapy of advanced pheochromocytoma or neuroblastoma effective and safe?
PERTINENT FINDINGS: 124I-MIBG dosimetry-guided high-activity 131I-MIBG therapy is feasible and results in durable responses, long survival, and a low rate of manageable adverse events. 124I-MIBG PET tumor uptake and tumor response assessment can further predict outcome after 131I-MIBG therapy.
IMPLICATIONS FOR PATIENT CARE: 124/131I-MIBG theranostics offer individual treatment planning with a promising efficacy/safety tradeoff: 124I-MIBG-guided 131I-MIBG activity escalation should further be assessed in prospective trials.
Footnotes
Published online Feb. 2, 2023.
- © 2023 by the Society of Nuclear Medicine and Molecular Imaging.
REFERENCES
- Received for publication August 15, 2022.
- Revision received January 30, 2023.