Effects of Therapy with [¹⁷⁷Lu-DOTA⁰, Tyr³]Octreotate in Patients with Paraganglioma, Meningioma, Small Cell Lung Carcinoma, and Melanoma

Patients

We studied 12 patients with paragangliomas, 5 with meningiomas, 3 with SCLCs, and 2 with melanomas. All patients had tumor tissue uptake with [¹¹¹In-DTPA⁰]octreotide (DTPA is diethylenetriaminepentaacetic acid) (OctreoScan) scintigraphy that was equal to or higher than uptake in normal hepatic tissue on planar images. Patients had not been treated before with other radiolabeled somatostatin analogs. Prerequisites for treatment were hemoglobin ≥ 5.5 mmol/L (≥8.9 mg/dL), white blood cells ≥ 2 × 10⁹/L, platelets ≥ 80 × 10⁹/L, creatinine ≤ 150 μmol/L (≤1.70 mg/dL), creatinine clearance ≥ 40 mL/min, and Karnofsky performance status (KPS) ≥ 50. All patients gave written informed consent to participate in the study, which was approved by the medical ethical committee of the hospital.

Methods

[DOTA⁰,Tyr³]Octreotate was obtained from Mallinckrodt. ¹⁷⁷LuCl₃ was obtained from the Nuclear Research and Consultancy Group and the Missouri University Research Reactor and was distributed by IDB-Holland. ¹⁷⁷Lu-Octreotate was prepared locally as described previously (17).

Granisetron (3 mg) was injected intravenously. To reduce the radiation dose to the kidneys, an infusion of amino acids (2.5% arginine and 2.5% lysine) was started 30 min before the administration of the radiopharmaceutical and lasted 4 h. The radiopharmaceutical was coadministered via a second pump system. The dose administered in each cycle was 7.4 GBq, injected in 30 min. The interval between treatments was 6−10 wk. Patients were treated up to an intended cumulative dose of 22.2–29.6 GBq. If dosimetric calculations indicated that the radiation dose to the kidneys would exceed 23 Gy with a dose of 29.6 GBq, the cumulative dose was reduced to 22.2–27.8 GBq. To obtain this cumulative dose, the dose of the fourth cycle was 3.7 or 5.55 GBq, injected in 30 min as well.

Routine hematology, liver and kidney function tests, and hormone measurements were performed before each therapy as well as on follow-up visits. CT or MRI was performed within 3 mo before the first therapy, within 6–8 wk, 3 mo, and 6 mo after the last treatment, within every 6 mo thereafter.

Imaging

Planar spot images of the upper abdomen and other regions with somatostatin receptor–positive pathology were obtained 24 h after injection of the therapeutic dose of ¹⁷⁷Lu-octreotate. Upper abdominal images were also obtained on day 3 or day 4 and on day 7 or day 8 for kidney dosimetry. Counts from the 208-keV (20% window) γ-peak were collected. The acquisition time was 7.5 min per view. For dosimetry, counts from a standard with a known aliquot of the injected dose were collected over 3 min.

In Vivo Measurements

The tumors on CT or MRI were measured and scored according to the Southwest Oncology Group (SWOG) solid tumor response criteria (18).

The uptake during pretreatment [¹¹¹In-DTPA⁰]octreotide scintigraphy was scored visually on planar images using the following 4-point scale: lower than (grade 1), equal to (grade 2), or higher than (grade 3) normal liver tissue; or higher than normal spleen or kidney uptake (grade 4).

Estimation of the elimination rate (ER) of ¹⁷⁷Lu-octreotate from tumors was done as follows to evaluate the differences between SCLC and paraganglioma on one hand and GEP NETs on the other. Counts in 3 regions of interest (ROI) were measured on posttherapy scintigraphy on day 1, on day 3 or day 4, and on day 7. ROI 1 included the entire tumor, ROI 2 included the entire tumor and surrounding area for calculating counts in background, and ROI 3 included a standard with a known aliquot of the injected dose. The counts in these ROIs were used to calculate the percentage uptake in the tumor of the injected dose, using the same method as for kidney dosimetry. Because we were only interested in a difference in shape of the curve displaying the amount of radioactivity in time, no attenuation correction was done. To normalize the shape of the curve and make comparison possible between different patients and tumors, radioactivity at 24 h after injection was then set at 100 and expressed as a fraction of this on day 3 or day 4 and on day 7 according to the measured radioactivity. Radioactivity at 400 h after injection was assumed to be zero. These 4 values were plotted and the area under the curve was calculated to give an estimate of the ER. The ER in paraganglioma and SCLC (ER_nG) was compared with the ER in GEP NET (ER_G) with a resemblance in size, location, and grade of uptake on posttherapy scintigraphy.

Statistics

The Fisher exact test was used in testing for significant differences in treatment outcome between groups of different grade of uptake on ¹¹¹In-octreotide scintigraphy. To compare ER_G and ER_nG, we used the unpaired t test, as the Kolmogorov–Smirnov test indicated that both ER_G and ER_nG are normally distributed. P < 0.05 was considered to be statistically significant. Values of ER are given as mean ± SD.

Patient Characteristics, Side Effects, and Responses

Baseline characteristics of the patients are shown in Table 1. Twenty-two patients were included. Age ranged from 22 to 74 y (median, 46 y). The median KPS at entry was 85 (range, 60–100). Seven patients (32%) had nonmetastasized disease; the other patients had distant metastases. Three patients (14%) had grade 2 uptake on ¹¹¹In-octreotide scintigraphy, 15 patients (68%) had grade 3 uptake, and 4 patients (18%) had grade 4 uptake. Twelve patients (55%) had PD within 1 y before starting treatment with ¹⁷⁷Lu-octreotate. The other patients had SD or the baseline disease status was unknown. Three patients (14%) had not had therapies before ¹⁷⁷Lu-octreotate. Other patients had undergone surgery, chemotherapy, or radiotherapy or a combination of these.

World Health Organization (WHO) hematologic toxicity grade 4 occurred in 1 patient. WHO grade 3 toxicity was not noted in any patient. The onset or aggravation of nausea was present after 49% of administrations of ¹⁷⁷Lu-octreotate. This was mild, in general; however, vomiting occurred in 18% of administrations. Pain in the sites of tumor deposits developed or increased temporarily after 15% of administrations. Eleven patients (50%) reported hair loss, primarily during the first weeks after a cycle. This was mild and never resulted in complete alopecia.

Twelve patients had paraganglioma. Table 1 indicates the distribution of the primary tumors. Two patients had inoperable, nonmetastasized tumors. One patient had an operable tumor but refused surgery. One patient was treated on a compassionate basis despite severe anemia and thrombocytopenia requiring several blood transfusions. Because the thrombocytopenia was probably paraneoplastic, this was considered not to be an exclusion criterion. Nine patients received the intended dose of 22.2–29.6 GBq ¹⁷⁷Lu-octreotate. Treatment had to be stopped in 2 patients because of persistent thrombocytopenia and anemia. One patient died because of disease progression after a cumulative dose of 14.8 GBq ¹⁷⁷Lu-octreotate. One patient had a partial remission (PR). (Fig. 1) In this patient, plasma chromogranin A (CgA) decreased from 326 μg/L at baseline to 100 μg/L before the last cycle of ¹⁷⁷Lu-octreotate. Unfortunately, a myelodysplastic syndrome (MDS) developed in this patient. MDS was most probably a complication of prior chemotherapy (dacarbazine, adriamycin, ifosfamide), given the very short interval of 4 mo between the last dose of ¹⁷⁷Lu-octreotate and the development of MDS. The interval between the last cycle of chemotherapy and the development of MDS was 22 mo. One patient had a minor response ([MR] tumor diameter decrease, 25%–50%) (Fig. 1); however, progression of disease was noted after 11 mo. Figure 2 demonstrates the initial tumor reduction. Six patients, including 1 with initial PD, had SD, 3 patients had PD, and no data are available for 1 patient because of the absence of measurable disease on CT. Two years after the first cycle, liver function tests and CgA still have not changed. The median TTP in patients with paragangliomas cannot be determined yet. Follow-up ranged from 4 to 30 mo (median, 13 mo). The TTP was 11 and 15 mo in 2 patients. In 6 others, disease remained unchanged for the time of follow-up. Two patients died during follow-up: 1 patient 9 mo after starting ¹⁷⁷Lu-octreotate and the other patient after 24 mo. PD developed in both patients during treatment.

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FIGURE 1. 

Effects of therapy with ¹⁷⁷Lu-octreotate in groups of tumors in relation to disease status before treatment. PD = progressive disease; SD = stable disease; MR = minor response; PR = partial remission; CR = complete remission.

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FIGURE 2. 

MR image (T1 weighted) of cervicothoracic spine of patient with pheochromocytoma. (A) Baseline scan 3 mo before ¹⁷⁷Lu-octreotate therapy shows tumor extending into spinal canal (arrow, *spinal cord). (B) Scan 3 mo after fourth cycle of 7.4 GBq ¹⁷⁷Lu-octreotate shows reduction in tumor extension into spinal canal (arrow).

Five patients with meningioma were treated with ¹⁷⁷Lu-octreotate. Two patients had extremely large, exophytic, cranial tumors and 1 patient also had cervical metastases. One patient had a large, exophytic, cervical meningioma with rapid progression. These 3 patients had WHO grade III (malignant/anaplastic) meningiomas and all standard treatments had failed. Two patients had a cavernous sinus meningioma. The WHO grade was unknown, as no biopsy had been performed. One of these patients also had a neuroendocrine tumor (carcinoid) with somatostatin receptor–positive metastases in the bone and liver. Three patients received the intended dose of 29.6 GBq ¹⁷⁷Lu-octreotate. One patient decided to stop treatment after cumulative administration of 22.2 GBq. The patient with cervical meningioma received a cumulative dose of 14.8 GBq ¹⁷⁷Lu-octreotate and died shortly after the second cycle because of progression of the tumor. Two patients with exophytic, cranial meningioma still had PD (Fig. 3 depicts progression in one of these patients). Two patients, including one with PD at baseline, with cavernous sinus meningioma, had SD (Fig. 1) after therapy. In the patient with the double tumors (meningioma and carcinoid), the meningioma was stable both before and after therapy. The carcinoid tumor showed a MR. This patient died 18 mo after the start of therapy because of progression of the carcinoid tumor.

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FIGURE 3. 

Example of patient with large, cranial meningioma. Patient already had undergone surgery 4 times and had had external beam radiotherapy before ¹⁷⁷Lu-octreotate. (A) MR image 1 wk after first cycle of ¹⁷⁷Lu-octreotate shows meningioma (arrow, curved arrow) with some extracranial involvement. (B) MR image 1 mo after final dose of ¹⁷⁷Lu-octreotate. Intracranial part of meningioma has increased (arrows). Extracranial, exophytic parts have increased as well (arrowheads). (C) Photograph of patient 18 mo after last dose of ¹⁷⁷Lu-octreotate (view from right, posterooblique). Patient had undergone surgery and had had external beam radiotherapy again and had just finished 6 cycles of cisplatin without therapeutic effect. Arrow indicates very large, extracranial part of meningioma with ulcerated skin.

Three patients with a SCLC were studied. The KPS at baseline ranged from 60 to 90. One patient had an initial complete response (CR) after chemotherapy with carboplatin and etoposide, followed by external beam radiotherapy of the primary tumor. The CR lasted 16 mo. Then recurrence was noted and topotecan was started without response. ¹⁷⁷Lu-Octreotate was started 4 mo after the recurrence. The second patient had a CR after 5 cycles of cyclophosphamide, doxorubicin, and etoposide (CDE), followed by external beam radiotherapy of the primary tumor. Recurrence was noted after 10 mo and CDE was given again, resulting in tumor regression. One month later, treatment with ¹⁷⁷Lu-octreotate was started. During this therapy, plasma neuron-specific enolase (NSE) rose from 165 to 321 mg/L and plasma CgA increased from 45 to 116 μg/L. The patient had liver metastases and had progressive liver enzyme disturbances (Fig. 4; SCLC 2, third treatment could not be given.). The third patient had 8 cycles of carboplatin and etoposide, resulting in a PR followed by imatinib and gefitinib. Then 1 cycle of ¹⁷⁷Lu-octreotate was given. Because of occlusion of the superior vena cava (SVC), external beam radiotherapy and a cycle of adriamycin, vincristin, and cyclophosphamide were given. Then the second cycle of ¹⁷⁷Lu-octreotate was administered. Plasma NSE rose from 236 mg/L just before the first cycle to 905 mg/L before the second cycle and plasma CgA increased from 362 to 1,077 μg/L. This patient had liver metastases as well, and liver enzymes progressively deteriorated (Fig. 4; SCLC 1). The 2 patients discussed first had progression, despite the administration of ¹⁷⁷Lu-octreotate, and died before finishing all planned cycles of the treatment: 1 patient after administering 7.4 GBq and the other after administering 14.8 GBq. Figure 5 shows progression in the latter patient on posttherapy scintigraphy. The patient with occlusion of the SVC seemed to have tumor regression on the CT scan but died because of a pulmonary embolus after a cumulative dose of 14.8 GBq ¹⁷⁷Lu-octreotate. We have classified this as PD. (Fig. 1)

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FIGURE 4. 

γ-Glutamylpeptidase (γ-GT) in patients with SCLC or melanoma with hepatic metastases. *Third therapy could not be given.

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FIGURE 5. 

Scintigraphy performed 4 d after administration of 7.4 GBq ¹⁷⁷Lu-octreotate in patient with SCLC. (A) Scan (posterior chest) after first dose. Arrow indicates a cervical lesion. (B) Scan (posterior chest) after second and last dose 2 mo later. Several new lesions are visible (arrowheads). Uptake in lesions already present on first scan has increased (arrow).

Finally, 2 patients had melanoma of the eye with liver metastases. Both had rapidly PD at baseline. The KPS at baseline was 80 and 100. Both patients received a cumulative dose of 22.2 GBq ¹⁷⁷Lu-octreotate. In 1 patient, this was the intended dose. Both still had PD (Fig. 1) and both died: 1 patient 4 mo and the other 5 mo after the first dose. Plasma CgA increased in 1 patient from 93 to 191 μg/L and increased from 75 to 216 μg/L in the other. Liver function tests also progressively deteriorated. (Fig. 4)

In the whole group, including all tumor types, we analyzed whether a relation exists between treatment outcome and tumor uptake on ¹¹¹In-octreotide scintigraphy. All 3 patients (1 paraganglioma, 1 melanoma, 1 SCLC) with grade 2 uptake had PD. In 14 patients (6 paraganglioma, 5 meningioma, 2 SCLC, 1 melanoma) with grade 3 uptake, 50% had PD, 43% had SD, and 7% had tumor regression. In 4 patients (4 paraganglioma) with grade 4 uptake, these values were 25%, 50%, and 25%, respectively (Fig. 6). We tested for a significant difference in treatment outcome between groups of different uptake on ¹¹¹In-octreotide scintigraphy. Because of the small number of patients, grade 2 uptake and grade 3 uptake were both considered to belong to the low-uptake group, and grade 4 uptake was considered to belong to the high-uptake group. For treatment outcome, SD and tumor regression were combined into 1 non-PD group. No statistically significant difference was found in treatment outcome (non-PD vs. PD) between the patients with high uptake and those with low uptake (2-tailed Fisher exact test; P = 0.31).

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FIGURE 6. 

Relation between uptake of ¹¹¹In-octreotide on pretherapy somatostatin receptor scintigraphy and response to ¹⁷⁷Lu-octreotate therapy. PD = progressive disease; SD = stable disease; MR = minor response; PR = partial remission; CR = complete remission.

In 2 of 3 patients with SCLC, an estimation of the ER of ¹⁷⁷Lu-octreotate was determined. In 1 patient this was impossible because of a technical problem. In 3 of 12 patients with paraganglioma determining the ER was not possible. One patient had cranial tumors solely, and no matching GEP NET could be found in our database. In 2 patients, tumors were not visualized at all 3 time points. In 11 patients with SCLC (n = 2) or paraganglioma (n = 9), (non-GEP NETs), ER was measured (ER_nG) and compared with ER in 11 patients with GEP NETs (ER_G). The mean ER_nG was 129.7 ± 16.7 and mean ER_G was 127.6 ± 24.8. This difference was not significant (unpaired t test; P = 0.82).