[ 131I]Iodometomidate for Targeted Radionuclide Therapy of Advanced Adrenocortical Carcinoma
Stefanie Hahner,* Michael C. Kreissl,* Martin Fassnacht, Heribert Haenscheid, Pascal Knoedler, Katharina Lang, Andreas K. Buck, Christoph Reiners, Bruno Allolio,* and Andreas Schirbel*
Endocrinology and Diabetes Unit (S.H., M.F., K.L., B.A.), Department of Internal Medicine I, University of Wuerzburg; Department of Nuclear Medicine (M.C.K., H.H., A.K.B., C.R., A.S.); and Department of Radiology (P.K.), University of Wuerzburg, D-97080 Wuerzburg, Germany
Context: In advanced adrenocortical carcinoma (ACC), many patients have progressive disease despite standard treatment, indicating a need for new treatment options. We have shown high and specific retention of [123I]metomidate ([123I]IMTO) in ACC lesions, suggesting that labeling of metomidate with 131I offers targeted radionuclide therapy for advanced ACC.
Objective: Safety and efficacy of radionuclide therapy with [13]]]IMTO in advanced ACC.
Design/Setting: This monocentric case series comprised 19 treatments in 11 patients with nonre- sectable ACC.
Patients and Intervention: Between 2007 and 2010, patients with advanced ACC not amenable to radical surgery and exhibiting high uptake of [123I]IMTO in their tumor lesions were offered treat- ment with [13]]]IMTO (1.6-20 GBq in one to three cycles of [131|]IMTO).
Main Outcome Measure: Tumor response was assessed according to response evaluation criteria in solid tumors (RECIST version 1.1) criteria, and side effects were assessed by Common Toxicity Criteria (version 4.0).
Results: Best response was classified as partial response in one case with a change in target lesions of -51% from baseline, as stable disease in five patients, and as progressive disease in four patients. One patient died 11 d after treatment with [13]]]IMTO unrelated to radionuclide therapy. In pa- tients responding to treatment, median progression-free survival was 14 months (range, 5-33) with ongoing disease stabilization in three patients at last follow-up. Treatment was well tolerated, but transient bone marrow depression was observed. Adrenal insufficiency developed in two patients.
Conclusions: Radionuclide therapy with [131I]IMTO is a promising treatment option for selected patients with ACC, deserving evaluation in prospective clinical trials. (J Clin Endocrinol Metab 97: 914-922, 2012)
P atients with European Network for the Study of Ad- renal Tumors (ENSAT, www.ensat.org) stage IV ad- renocortical carcinoma (ACC) have a median survival be- low 15 months (1, 2). The only specific drug currently approved for the treatment of ACC is mitotane, which prolongs recurrence-free survival in an adjuvant setting
(3). However, in advanced disease, it has an overall re- sponse rate of only 26% according to retrospective anal- yses (4). The combination of mitotane with etoposide, doxorubicin, and cisplatin (EDP) (5) or streptozotocin (6) are considered as current first-line therapies in metastatic ACC (7). However, response rates are low (25-50%) (8).
Copyright @ 2012 by The Endocrine Society
doi: 10.1210/jc.2011-2765 Received October 7, 2011. Accepted November 28, 2011. First Published Online December 14, 2011
* S.H., M.C.K., B.A., and A.S. equally contributed. Abbreviations: ACC, Adrenocortical carcinoma; CT, computed tomography; EDP, etopo- side, doxorubicin, and cisplatin; ENSAT, European Network for the Study of Adrenal Tumors; FDG, [18F]fluorodesoxyglucose; IMTO, iodometomidate; PET, positron emission tomography; SOD, sum of diameter of target lesions; SPECT, single-photon emission com- puted tomography; SUV, standardized uptake value.
Accordingly, in many patients, salvage therapies are needed. So far, studies investigating targeted therapies in this patient population have been rather disappointing (9- 11). Thus, new treatment options for patients with ad- vanced ACC are of great interest.
Radiolabeled metomidate has been shown to be highly suitable for molecular adrenocortical imaging (12- 15). We have recently developed [123I]iodometomidate ([123I]IMTO) for single-photon emission computed to- mography (SPECT) imaging of adrenocortical diseases (16). IMTO binds to both 11ß-hydroxylase and aldoste- rone synthase with high specificity and affinity, thus en- abling excellent visualization of tissue of adrenocortical origin. High tracer uptake was also observed in both pri- mary tumor and metastases in patients with ACC, sug- gesting that [131IJIMTO represents a suitable compound for targeted radionuclide therapy. External beam radio- therapy has historically been considered ineffective in the management of ACC. However, a recent review covering radiotherapy in a total of 129 patients has shown relevant radiosensitivity of ACC, comparable to that observed in other solid tumors (17).
Given the limited treatment options in patients with advanced ACC, the high specific uptake of [123IJIMTO and the radiosensitivity of ACC, our aim was to assess the therapeutic activity of [131IJIMTO in patients with ad- vanced ACC.
Patients and Methods
Radiopharmaceuticals
[123I]IMTO and [13] ]]IMTO were prepared as previously de- scribed (18). The radiosynthesis of [131IJIMTO followed a sim- ilar protocol using higher amounts of all substances. Briefly, to a lead-shielded vial containing up to 33.3 GBq [131 I]iodide in 1 ml 0.01 N NaOH (IBSSO; GE Healthcare, Braunschweig, Ger-
many), a solution of 10 mg 4-trimethylstannylmetomidate in 1 ml ethanol, 80 pl 3 N HCI, and a solution of 1.5 mg chloramine-T in 100 ul water were consecutively added by syringe. After a reaction time of 5 min at room temperature, 90 pl 3 N NaOH was added, and the solution was injected into a HPLC system equipped with a semipreparative RP-18 column (Nucleosil 100- 5C18, 250 × 8 mm; CS Chromatographie Service, Langerwehe, Germany). HPLC separation was performed using ethanol/PBS 50/50 as eluent with a flow of 2.0 ml/min. The [131I]IMTO- containing fraction was collected, passed through a sterile filter (0.22 um), and directly used for administration.
Patients and treatments
Forty-nine patients with nonresectable ACC were evaluated by [123IJIMTO SPECT regarding eligibility for [13] ]]IMTO ther- apy. Thirteen patients exhibited very high tracer uptake in all lesions detected by other imaging methods. Two patients rejected any further treatment or rapidly worsened in their clinical con- dition. Between May 2007 and November 2010, radionuclide therapy with [131IJIMTO was administered to 11 patients with advanced ACC. All patients fulfilled the following criteria: ad- vanced ACC not amenable to radical resection and histologically confirmed by a reference pathologist. All patients had measur- able target lesions as defined by response evaluation criteria in solid tumors (RECIST version 1.1). They were aged over 18 yr, in acceptable clinical condition (Eastern Cooperative Oncology Group stage of 0-2) including adequate hematological, renal, and hepatic function and desired further treatment. Patient char- acteristics before treatment are given in Table 1.
All patients underwent clinical, radiological [computed to- mography (CT) of chest and abdomen], and hormonal assess- ment (determination of glucocorticoid and mineralocorticoid production, estradiol, androgens, and androgen precursors). [123I]IMTO-SPECT/CT was performed after iv administration of 185 MBq [123IJIMTO to ensure sufficient tracer uptake. Im- aging was performed as described recently (16).
Eligible patients underwent dosimetry with [131IJIMTO be- fore treatment. Thirty minutes after thyroid blocking by 1000 mg sodium perchlorate by mouth, 40 MBq [131IJIMTO was in- jected iv. Whole-body planar images were acquired 5 min and 4, 24, 48, 72, and 96 h after injection. Imaging was performed without autocontour and with concurrent acquisition of a stan-
| TABLE 1. Characteristics of 11 patients with advanced ACC (ENSAT stage IV) | ||||||||
|---|---|---|---|---|---|---|---|---|
| Patient ID | Sex | Age (yr) | Hormone production | Sites of tumor manifestation | Time from diagnosis of nonsurgically curable ACC to start of IMTO (months) | Previous surgical treatments (n) | Previous systemic therapies | Other previous therapies |
| 1 | Female | 54 | C, A | LR, LI, LU, LN | 20 | 1 | EDP, M, P + 5FU | |
| 2 | Female | 43 | C | LR, LU, LN, ST | 28 | 6 | M | RT tumor bed |
| 3 | Male | 68 | C | LR, LI, LU, LN | 14 | 2 | Sz, EDP-M, BC | |
| 4 | Male | 80 | NF | LR, LN | 3 | 2 | ||
| 5 | Female | 25 | C, A | LR, LI, retroperitoneal spread | 16 | 1 | EDP-M, Sz-M, Su-M | |
| 6 | Female | 26 | C, A | LI, LN, ST | 8 | 1 | DP | |
| 7 | Female | 37 | Aldo | LU | 3 | 1 | ||
| 8 | Female | 75 | C, A | LR, LI, LU, LN, ip spread | 8 | 4 | M | |
| 9 | Female | 60 | A | LU, LN, B, myocardium | 12 | 2 | M | RT femoral bone |
| 10 | Female | 63 | C, A | LR, LI | 21 | 2 | M, EDP-M, Sz-M | metastases |
| 11 | Female | 76 | NF | LR, retroperitoneal spread | 3 | 5 | ||
A, Androgens; Aldo, aldosterone; B, bone; BC, bevacizumab plus capecitabine; C, cortisol; DP, doxorubicin and cisplatin; EDP, etoposide, doxorubicin, and cisplatin; EDP-M, etoposide, doxorubicin, and cisplatin plus mitotane; LI, liver; LU, lung; LN, lymph nodes; LR, local recurrence; M, mitotane; NF, nonfunctioning; P + 5FU, cisplatin and doxorubicin plus 5-fluorouracil; RT, radiotreatment; ST, soft tissue; Su-M, sunitinib plus mitotane; Sz, streptozotocin; Sz-M, streptozotocin + mitotane.
dard activity for quality control. In parallel, blood samples were taken to quantify the activity concentration in the peripheral blood. Activity time functions and residence times were deduced, and the specific radiation absorbed dose to the blood was de- termined as recommended (19). In absence of major specific 131I accumulation in nonadrenocortical tissue, blood was considered as a surrogate of the actual critical organ at risk, i.e. the bone marrow. The maximal tolerable activity was calculated aiming at a bone marrow dose of 2 Gy.
Before therapy, thyroidal uptake was blocked using both po- tassium iodide and perchlorate; also antiemetic drugs (dimen- hydrinate or ondansetrone) were administered. Up to 20 GBq [131IJIMTO, dissolved in 10-20 ml ethanol/PBS 50/50, was ad- ministered with the help of an infusion pump and an iv catheter. To prevent pain during injection, the tracer was diluted imme- diately before infusion with saline solution using a three-way valve attached to the indwelling cannula. Finally, the whole sys- tem was flushed with 100 ml saline containing 5% ethanol. Dur- ing inpatient treatment, an intratherapeutic dosimetry was per- formed to verify the results of pretherapeutic dosimetry. Therapeutic dosimetry was performed from whole-body reten- tion measurements with a survey meter at 2 m distance and mea- surements of activity concentrations in concomitantly drawn blood samples as described previously (19). Planar whole-body scans were acquired as soon as the radioactivity level of the pa- tient was below 1000 MBq 131I. Most patients also received a SPECT/CT before discharge.
[123I]IMTO imaging had been performed within a clinical trial that was approved by the local ethics committee of the Uni- versity of Wuerzburg (Permit 100/05), the German Federal In- stitute for Drugs and Medical Devices (BfArM) (Permit 4031230), and the German Federal Office for Radiation Protec- tion (BfS) (Permit Z5-22461/2-2006-024). [131IJIMTO dosim- etry and treatment were performed after individual decision on a compassionate-use basis. Ethical counseling for these individ- ual ACC cases was obtained by the ethical board of the Univer- sity Hospital of Wuerzburg, Wuerzburg, Germany.
Due to the experimental nature of the therapy, the treatment protocol, which is similar to the well-established protocol for high-dose therapy of patients with differentiated thyroid carci- noma (19), was not fully standardized. Especially in the first courses of treatment, the administered activity was kept far be- low the calculated maximal tolerable activity.
Evaluation of toxicity and tumor response
Baseline evaluation included standard documentation of pa- tient history, physical examination, and performance status. A complete blood cell count, serum chemistry profile, and imaging (chest and abdominal CT or magnetic resonance scans). Drug- related adverse events and toxicities were evaluated according to the Common Toxicity Criteria of the National Cancer Institute (version 4.0). For tumor evaluation, CT imaging and, because [18F]fluorodesoxyglucose (FDG)-positron emission tomogra- phy (PET) has shown high sensitivity in ACC, in some patients, additionally FDG-PET was performed (in 3- to 6-month inter- vals) as generally recommended (20-22). Tumor response was assessed using RECIST version 1.1 criteria (23).
Metabolic response to therapy was assessed by FDG-PET, assigning spherical volumes of interest (diameter of 1.5 cm) to the three metabolically most active tumor lesions for the calculation of the mean standardized uptake value (SUV). The volumes of
interest were then copied to the same anatomical locations on subsequent FDG studies. Metabolic response was evaluated on the basis of PERCIST (PET Response Criteria In Solid Tumors) version 1.0 (24).
Results
Eleven patients (nine females) underwent dosimetry and received [131IJIMTO treatment. In total, 19 [13]]]IMTO treatments were performed. Patient characteristics includ- ing hormonal activity and previous surgical, radiological, or medical therapies are given in Table 1. Median time from diagnosis of surgically not curable ACC to time of [13]]]IMTO treatment was 11 months (range, 3-21 months). All patients had significant tumor burden, and progressive disease was documented before initiation of [131I]IMTO therapy. Eight patients had also local recur- rence. Most patients had a history of several surgeries [me- dian two (range, one to six)]. Eight patients had been treated with systemic therapies with a median number of two drug regimens (range, one to five). One patient (pa- tient 5) received mitotane treatment during radionuclide therapy (mitotane plasma level at the time of treatment was 13.1 mg/liter), whereas seven of 11 patients had been treated with mitotane before [131IJIMTO therapy. Two patients (patients 9 and 10) had stopped mitotane shortly before radionuclide therapy but had mitotane levels of 10 mg/liter and 13 mg/liter, respectively. In all other patients who had received mitotane, treatment had been stopped for more than 6 months before [131IJIMTO. In these pa- tients, mitotane levels were not determined before starting [131IJIMTO therapy. Three patients (patients 4, 7, and 11) refused both mitotane and cytotoxic therapy and, there- fore, had no previous antineoplastic medical treatment: patient 4 rejected additional surgical or cytotoxic treat- ment due to his high age (80 yr), a second patient (patient 7) with an aldosterone-producing ACC had multiple non- resectable lung lesions. Mitotane and cytotoxic chemother- apy was offered as first-line treatment. However, the patient was afraid of the toxicity. Because it is known that mitotane is less capable to lyse glomerulosa cells (4) and because IMTO binds with high avidity to aldosterone synthase, the option of radionuclide treatment with [131IJIMTO was then discussed with this patient. The third patient (patient 11) refused mitotane and cytotoxic chemotherapy because she also was afraid of toxicity.
Biokinetics and dosimetry
IMTO is subject to fast metabolic degradation in vivo. At the time of the first dosimetric measurements at 1 to 2 h, 131I is almost entirely bound to metabolites, and 16 ± 5% of the activity is found in blood. The remaining activity is
A
B
C
D
HP-1200.T 8,000001)
HUD -1 200,T 0,000061)
homogeneously distributed in the remainder of the body, indicating that it is dissolved in the pool of exchangeable body water. No prominent specific uptake is observable in posttherapeutic scans except for tissues of adrenocortical origin. Minor accumulations in the thyroid or intestine occur in individual patients. The activity is excreted pre- dominantly via renal elimination.
Activities in total body and blood were well fitted by mono or biexponential decay functions with median res- idence times of 23.7 h (range, 11.0-56.9 h) and 2.4 h (range, 1.3-8.6 h), respectively. A median of 12% (range, 7-17%) of total body residence time was attributable to blood with a median specific blood absorbed dose of 0.10 mGy/MBq of 131I administered (range, 0.06-0.27 mGy/ MBq). The distribution pattern indicated that the blood absorbed dose can be used as a conservative estimate for the radiation absorbed dose to the red marrow.
Planar whole-body scintigraphic imaging initiated 2-4 d after therapy was used to assess the kinetics in tumor lesions and to estimate tumor absorbed doses. Effective half-lives typically ranged from 40-100 h, and most cal- culated dose values were between 0.5 and 4 Gy/GBq [131IJIMTO administered (Supplemental Fig. 1, published on The Endocrine Society’s Journals Online web site at http://jcem.endojournals.org).
Antitumor efficacy of [13]]]IMTO treatment
Follow-up imaging data were available from 10 of 11 patients. One patient (patient 5) with severe Cushing’s syndrome died 11 d after treatment from septic shock without follow-up imaging. No change in hematological
parameters due to [13]]]IMTO treatment was noted. Best response according to RECIST 1.1 criteria was classified as partial response in one case [patient 7 (Fig. 1), change in the sum of the largest diameter of target lesions, SOD, -20 mm (-51% from baseline)] and as stable disease in five of 10 evaluable cases [median change in SOD (sum of diameter of target lesions), 1 mm (range -35-18 mm), median increase from baseline 2.4% (-26-11%)], whereas progressive disease was noted in four cases [me- dian change in SOD of target lesions, 54 mm (-5-135); 24% (-5.8-55%) (Table 2 and Figs. 2 and 3]. Progressive patients with stable target lesions had developed new le- sions (n = 1, patient 2). In the six patients responding to treatment (defined as disease control), median duration of progression-free survival was 14 months (range, 5-33 months) with still ongoing disease stabilization in three patients at last follow-up (Table 2). Median survival after first treatment in the whole cohort was 13 months (range, 0.35-33 months) (Table 2).
FDG-PET data were available from seven patients (Table 2 and Fig. 3B). After the first cycle, a partial met- abolic response (reduction of mean SUV >30%) was ob- served in four cases. One patient who did not have a base- line FDG-PET was metabolically stable after the second cycle (patient 8). Of note, one patient (patient 3) with progressive disease in CT had a significant decrease in mean SUV in FDG-PET (Fig. 3B). Another patient was progressive despite a slightly decreasing SUV (patient 10), and one patient showed a metabolic progression after one cycle followed by a metabolic stabilization thereafter (pa-
| TABLE 2. Response to treatment | ||||||||||
|---|---|---|---|---|---|---|---|---|---|---|
| Patient ID | Follow-up after IMTO treatment (months) | Best response in CT | Response in CT at last follow-up | Mean SUV of target lesions before treatment in FDG-PET | Mean SUV of target lesions at first follow-up in FDG-PET | SOD (cm) before treatment | SOD (cm) at best response | Progression-free survival (months) | Survival after first treatment (months) | Other treatments after IMTO |
| 1 | 3 | PD | PD | NA | NA | 22.5 | 30.2 | 3 | 3ª | Sz |
| 2 | 21 | PD | PD | NA | NA | 9.1 | 8.6 | 2 | 21ª | EDP, Gem |
| 3 | 13 | PD | PD | 14.6 | 5.7 | 21.7 | 24.8 | 5 | 13ª | Thalid |
| 4 | 33 | SD | SD | 9.6 | 12.5 | 13.3 | 9.9 | 33 | 33 | |
| 5 | No follow-up | NA | NA | NA | NA | 30.2 | NA | 11 d | 11 dª | |
| 6 | 3 | PD | PD | NA | NA | 24.6 | 38.3 | 2 | 5ª | M |
| 7 | 31 | PR | PD | 6.4 | 3.5 | 3.8 | 1.8 | 26 | 31 | |
| 8 | 13 | SD | PD | 4.5b | 3.8 | 7.0 | 7.2 | 11 | 13ª | |
| 9 | 17 | SD | SD | 21.7 | 6.0 | 8.3 | 7.2 | 17 | 17 | |
| 10 | 8 | SD | PD | 8.1 | 6.2 | 15.9 | 17.7 | 5 | 8ª | M, tro, |
| pioglit, meb | ||||||||||
| 11 | 6 | SD | SD | 7.3 | 1.9 | 5.3 | 5.4 | 6 | 6 | |
EDP, Etoposide, doxorubicin, and cisplatin; Gem, gemcitabine; M, mitotane; meb, mebendazole; NA, not available; PD, progressive disease; pioglit, pioglitazone; PR, partial response; SD, stable disease; Sz, streptozotocin; thalid, thalidomide; tro, trofosfamide.
a Deceased.
b Before second treatment.
tient 4). After two cycles of radionuclide treatment, a com- plete metabolic response was observed in one patient (pa- tient 7) (Fig. 1).
Adverse effects of [131I]IMTO treatment
In general, treatment was very well tolerated. Median time of hospitalization was 7.5 d (range, 4-15 d). Acute side effects on the radionuclide therapy unit were observed in six patients. Patients 6 and 7 (at each of the three cycles) developed transient nausea (grade 1) during the first 2 d after the treatment. Patients 1 and 6 reported mild to mod- erate intraabdominal pain that did not require further in- tervention. Both patients had large intraabdominal tumor masses. In three patients (patients 2, 3, and 5), edema of the lower limbs developed, most likely related to severe ongoing hypercortisolism; in one case, loop diuretics were administered (Table 3).
Reversible bone marrow suppression that was most prominent around 5-7 wk after treatment was consis- tently observed (Table 1 and Supplemental Fig. 2). Mega- karyopoiesis was most severely impaired (common toxic- ity criteria grade 1, seven of 18; grade 2, six of 18; grade
change in target lesions (SOD) in %
80
60
56
40
34
20
14
11
3
1.8
0
-20
-3
-13
-40
-26
-60
-51
PID
6
1
3
10
8
11
2
9
4
7
3, two of 18; and grade 4, two of 18 treatment cycles), but also transient leukopenia (grade 1, 13 of 18; grade 2, three of 18) and anemia (grade 1, three of 18; grade 2, five of 18; grade 3, three of 18) were observed. One patient received granulocyte colony-stimulating factor (patient 2) after the second treatment, and one patient (patient 3) received a single platelet transfusion as a preventive measure after 1.25 Gy blood absorbed dose. Both patients who devel-
A
change of target lesions (SOD) % from baseline
200
180
PID 1
160
PID 2
140
PID 3
120
PID 4
100
4 PID 6
PID 7
80
PID 8
60
PID 9
PID 10
40
· PID 11
20
0
B
3
6
9
12
15
18
21
change of target lesions (SUV mean) % from baseline
time (months)
140
120
100
PID3
PID4
80
PID7
60
PID8
PID9
40
PID10
PID11
20
0
0
3
6
9
12
15
18
21
time (months)
| Result | |
|---|---|
| Acute adverse effects (during hospital stay for treatment) | |
| Edema of the lower limb (n) | 3 grade 1 |
| Nausea (n) | 4 grade 1 |
| Abdominal pain (n) | 1 grade 1, 1 grade 2 |
| Subacute adverse effects | |
| Leukocyte nadir (103/pl) | 2.45 (0.6-3) |
| Erythrocyte nadir (106/pl) | 3.33 (2.8-4.44) |
| Hemoglobin nadir (g/dl) | 9.85 (6.5-14.3) |
| Platelet nadir (103/pl) | 65 (15-196) |
| Time to leukocyte nadir (wk) | 7 (1-15) |
| Time to erythrocyte nadir (wk) | 7 (1-15) |
| Time to hemoglobin nadir (wk) | 7 (1-15) |
| Time to platelet nadir (wk) | 5 (3-15) |
| Chronic adverse effects | |
| Adrenal insufficiency (n) | 2 |
| Hypothyroidism (n)ª | 1 |
a Probably unrelated to [13][]IMTO treatment
oped thrombocytopenia common toxicity criteria grade 4 (patients 3 and 10) had received cytotoxic chemotherapy before [131I]IMTO. No case of hemorrhage was observed. Blood counts returned to pretreatment values also in pa- tients that received repeated radionuclide therapies.
No changes in aspartate aminotransferase or alanine aminotransferase levels were observed, and kidney func- tion as assessed by creatinine levels and modification of diet in renal disease also remained stable. Patients 7 and 9 who did not suffer from ACC-related cortisol excess grad- ually developed adrenal insufficiency after 12 and 3 months, respectively, requiring hydrocortisone replace- ment therapy.
One patient (patient 7) was diagnosed with primary hypothyroidism 13 months after first treatment. She had received 11 and 1 Gy radiation absorbed dose to the thy- roid from her treatments with [131IJIMTO; hence, an ef- fect of the [13]]]IMTO therapy is very unlikely.
Discussion
This is the first report on radionuclide therapy with the adrenal-specific radiopharmaceutical [131I]IMTO in pa- tients with advanced ACC. In this case series, we could demonstrate disease stabilization in more than half of the patients and, in a single patient, partial response to treat- ment with [131IJIMTO. This is a remarkable result taking into account the high tumor burden and the number of pretreatments in most patients. In addition, progression- free survival was extraordinarily long with a median of 14 months and ongoing disease stabilization in three patients at last follow-up.
Recent studies initiated for salvage therapy of advanced ACC using emerging new drugs were largely unsuccessful. The combination of the epidermal growth factor receptor inhibitor erlotinib with gemcitabine resulted in stable dis- ease in one patient and progressive disease in the remain- ing nine patients with advanced ACC (9). Similarly, no response to the epidermal growth factor receptor antag- onist gefitinib was seen in 19 patients with advanced ACC (25). A combination of the anti-vascular endothelial growth factor antibody bevacizumab plus capecitabine given as salvage treatment did not result in any response in 10 patients with advanced ACC (10). Imatinib mesylate, a selective inhibitor of the ABL, platelet-derived growth factor receptor, and stem cell ligand receptor (c-kit) ty- rosine kinases has been investigated in four ACC patients positive for c-kit or platelet-derived growth factor recep- tor. Disease progression was observed in three patients, and treatment was discontinued in one patient due to an adverse event (26). Combined treatment with gemcitabine and 5-fluorouracil has shown more promising results. In 28 patients with advanced ACC progressing after mito- tane plus one or two systemic chemotherapies, 15 patients (54%) had progressive disease after 4 months of treat- ment, whereas stable disease was noted in 11 patients and partial or complete response in one patient, respectively (27). ACC express high levels of IGF-II (28-30), stimu- lating tumor growth via the IGF-I receptor. Accordingly, blockade of the IGF-I receptor has been introduced as a treatment option for ACC in a phase I trial, demonstrating stable disease in five of 16 patients for more than 12 wk and partial response in one patient (31). Thus, inhibition of IGF-II signaling is considered promising, and further evaluation in clinical trials is ongoing. Taking these trial results into consideration, radionuclide therapy with [131I]IMTO compares favorably with other treatment op- tions and holds promise as an important therapeutic tool in the management of ACC.
Furthermore, in contrast to other cytotoxic treatments, only few adverse effects were observed, and treatment was well tolerated. The most important and consistent toxicity is transient bone marrow suppression, indicating that bone marrow is the critical dose-limiting tissue, as antic- ipated by dosimetry. It is well known from radioiodine therapy in thyroid cancer that administration of less than 2 Gy radiation absorbed dose to the blood is safe, making repeated radiotherapies feasible. The observed distribu- tion volume of the activity after injection of [131I]IMTO and the ratio of the activity concentrations in whole blood and plasma are similar to those of [131 I]iodide, indicating that this safety limit is also applicable for [131I]IMTO. However, medical intervention (transfusion of platelets or administration of growth factors) was initiated in two in-
stances after 1 Gy absorbed dose to the blood, revealing that previous treatments with cytotoxic agents might lower this safety limit. Follow-up is still limited, and long- term toxicity (e.g. myelodysplastic syndrome) cannot be excluded as has been described in few patients treated with high-dose [131I]metaiodobenzylguanidine for metastatic pheochromocytoma and paraganglioma (32). However, due to the poor prognosis of advanced ACC, this potential risk seems to be much lower than the potential benefit of [13]]]IMTO radionuclide therapy.
During follow-up, adrenal insufficiency with need of hydrocortisone replacement therapy was observed in two of the four patients, who did not exhibit cortisol hyper- secretion due to their ACC, indicating radioablation of normal adrenocortical tissue by radionuclide therapy with [131IJIMTO. Again it is conceivable that with longer fol- low-up, an even higher percentage of patients will develop adrenal failure requiring replacement therapy.
In a recent analysis of the German ACC registry, a sig- nificant reduction of local recurrences was found in pa- tients who had received postoperative tumor bed irradi- ation, indicating radiosensitivity of ACC. However, overall survival did not differ significantly due to the fre- quent occurrence of distant metastases (33). In contrast to local tumor bed irradiation, radionuclide therapy with [13]]]IMTO is a systemic therapy and may hold particular potential in the adjuvant treatment of ACC, allowing se- lective elimination of small tumor remnants throughout the body.
Our analysis has important limitations. First, [131]] IMTO treatment has been based on an individualized de- cision and was performed on a compassionate-use basis. Therefore, treatment and follow-up were not rigorously standardized. However, the available data concerning ad- verse events (e.g. bone marrow suppression) are highly consistent, and imaging was sufficiently frequent to draw firm conclusions concerning effectiveness of the treat- ment. Second, the patient group was highly heteroge- neous. Most patients had advanced ACC and had received several pretreatments as is exemplified by patient 5, who died 11 d after treatment. Including such patients clearly limits the capability to detect sufficient treatment effects. On the other hand we treated three patients who also had ENSAT stage IV ACC but refused other systemic treat- ments before IMTO radionuclide therapy. In these pa- tients, [131IJIMTO treatment was particularly successful, suggesting that this treatment option might be useful as first-line treatment in ACC. However, first-line treatment results are invariably superior to salvage therapies, poten- tially leading to overestimation of the therapeutic activity of [13]]]IMTO. Third, in our series, treatment doses dif- fered substantially (see Supplemental Table 2) ranging
from 1.6-20 GBq [131]]IMTO with 0.42-1.92 Gy radia- tion absorbed dose to the blood. Initially lower treatment dosages were chosen for safety reasons. Furthermore, ini- tially, a relatively large proportion of tracer adhered to the infusion system, a technical problem that subsequently was resolved. All these factors might have contributed to some lack of efficacy, especially in the treatment of the first pa- tients. Also, the number of treatments and the cumulative administered dose largely differed. Patients with progressive disease did not receive additional treatments, but also in pa- tients who responded to [13]]]IMTO treatment, treatment was stopped latest after the maximum of three treatment cycles, and only follow-up imaging was performed. Of note, in patient 7, time between the last [131I]IMTO treatment and diagnosis of progressive disease was 12 months without any further treatment. It is conceivable that a fourth treatment cycle might have prevented disease progression.
Characteristics of the ideal candidate for successful [131IJIMTO treatment remain to be further established by subsequent studies. Key for successful [131IJIMTO treat- ment is a high uptake of the radiotracer in all tumor le- sions, ensuring sufficient tumor doses, which is not the case in many ACC patients, limiting the number of pa- tients eligible for this therapeutic option. Furthermore, because radiotherapy needs some time to fully develop its antitumor effects, the disease should not be very rapidly progressing and the number of previous unsuccessful sys- temic treatments probably should be limited to two. Mi- totane is known to attenuate the uptake of metomidate in adrenocortical tissue (34, 35) and should, therefore, be interrupted before [131IJIMTO treatment. However, in our series, several patients under mitotane treatment still exhibited high tracer uptake.
In conclusion, the data derived from our case series suggests that [131I]IMTO radionuclide therapy is a prom- ising treatment option in selected cases of advanced ACC, combining relevant therapeutic efficacy with few side ef- fects and high patient acceptance. Clinical trials are now warranted to fully evaluate this new treatment strategy.
Acknowledgments
We thank all colleagues who provided us with detailed clinical and radiological data of their patients: Marcus Quinkler, Charite Berlin, Germany; Sylwia Szpak-Ulczok and Barbara Jarzab, both Gliwice, Poland; and Gert Mueller-Esch, Konstanz, Germany. We furthermore thank the whole team of the radionuclide ward and the clinics in the Department of Nuclear Medicine and the Endocrine Unit of the Department of Internal Medicine I of the University Hospital of Wuerzburg for their excellent coopera- tion. We also thank Martin Ries, Wuerzburg, for technical as- sistance and data collection.
Address all correspondence and requests for reprints to: Prof. Dr. Bruno Allolio, M.D., Endocrinology and Diabetes Unit, De- partment of Medicine I, University of Wuerzburg, Oberduerr- bacher Strasse 6, D-97080 Wuerzburg, Germany. E-mail: allolio_b@medizin.uni-wuerzburg.de
This work was supported by the Wilhelm Sander Foundation (Grant 2003.175.2) and the Interdisziplinäres Zentrum für Klinische Forschung Wuerzburg (Grant F-124 to S.H. and A.S.). S.H. is an awardee of the Else-Kröner-Fresenius Stiftung (Grant 2010-EKES.29).
Disclosure Summary: The authors have nothing to disclose.
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