Somatostatin Receptor–Targeted Radiopeptide Therapy with ⁹⁰Y-DOTATOC and ¹⁷⁷Lu-DOTATOC in Progressive Meningioma: Long-Term Results of a Phase II Clinical Trial

Patients

Eligibility was screened at the University Hospital Basel, Switzerland. Patients were eligible if they met the following criteria: histologically confirmed meningioma, disease progression within 12 mo before study entry, and visible tumor uptake on pretherapeutic octreotide scintigraphy. Patients were excluded if they met one of the following criteria: concurrent antitumor treatment other than somatostatin analogs, pregnancy, breastfeeding, urinary incontinence, preexisting grade 3 or 4 hematologic toxicity, or severe concomitant illness, including severe psychiatric disorders. Initial staging and eligibility were based on CT and MR imaging and clinical results from the referring centers.

All patients were prospectively recruited into this study, which was designed and performed in accordance with good clinical practice guidelines, Swiss drug laws, and the Declaration of Helsinki. The study was approved by the local ethics committee for human studies (EKBB reference number M120/97; www.ekbb.ch). Written informed consent was obtained from all participants or their legal representatives. The current results represent a post hoc analysis of the long-term data on safety and efficacy.

Test Drug

⁹⁰Y-DOTATOC was the standard treatment from 1997 to 2001 (3). Combined treatment with ⁹⁰Y-DOTATOC plus ¹⁷⁷Lu-DOTATOC became standard treatment after 2001; after 2001, patients with reduced baseline kidney function preferably received ¹⁷⁷Lu-DOTATOC alone (4,5).

DOTATOC was synthesized as previously described (6) or was purchased from Bachem AG. Radiolabeling was performed using lyophilized kits containing, for example, 220 μg of DOTATOC, 8 mg of gentisic acid, and sodium acetate buffer (0.4 M, pH 5.5 after reconstitution). A total of 7.4 GBq (200 mCi) of ⁹⁰Y (Perkin Elmer) and 111 MBq (3 mCi) of ¹¹¹In (Mallinckrodt) solution (both in 0.1 M HCl) were added to the lyophilized kit followed by heating to 95°C for 30 min. Alternatively, 7.4 GBq of ¹⁷⁷Lu (0.1 M HCl; IDB Holland bv) were added to the lyophilized kit followed by heating as described above.

Quality control was performed using reverse-phase high-performance liquid chromatography on a Phenomenex Jupiter C18 5 μm, 250 × 4.6 mm column (eluents, A = 0.1% trifluoroacetic acid and B = acetonitrile; flow, 0.75 mL/min; gradient, 0–25 min; 95%–50% A). Labeling yields were greater than 99.5%. Amino acid solutions containing lysine and arginine were administered before and after radiopeptide injection to inhibit tubular reabsorption (7–9).

Intervention

Patients were hospitalized 3 d for each cycle, in accordance with the Swiss requirements for legal radiation protection. Long-acting somatostatin analogs were withheld for at least 6 wk and short-acting somatostatin analogs for at least 3 d before radiopeptide therapy. On the basis of the results of our pilot study (10), repeated treatment cycles were performed with a minimum interval of 6 wk in cases of stabilization or decrease in the longest diameter of all pretherapeutically detected tumor lesions or any clinical improvement, such as pain relief or improvement of visual symptoms.

There was no a priori defined upper limit to the number of treatment cycles. Further cycles were withheld if there was progression, permanent toxicity, loss of the ability to travel to the treatment center, or refusal of further treatment.

Somatostatin Receptor Imaging

Tumor uptake and intratherapeutic biodistribution of the radiopeptide were assessed using planar whole-body imaging 24 h after injection of radiolabeled DOTATOC. The maximum tracer accumulation in the tumor was scored by a panel of 3 board-certified nuclear medicine physicians using a 4-point scale: no uptake (score 0), uptake lower than liver uptake (score 1), uptake similar to liver uptake (score 2), and uptake higher than liver uptake (score 3). The interpreters were masked to patient baseline data (including sex, age, histology, duration of disease, and pretreatment) and all follow-up results (including response, toxicity, and survival).

Follow-up

During hospitalization, clinical status and vital signs were monitored before and for 72 h after each therapeutic cycle. All toxicity was continuously recorded. After discharge, blood chemistry and hematologic parameters were measured at biweekly intervals for 10 wk after each cycle or until normalization of marker levels. Follow-up was performed to obtain information on survival and long-term toxicity until the patient’s death. Follow-up data were obtained from the referring centers, with a minimum frequency of 2 follow-up visits per year, adapted to the patient’s individual requirements.

All follow-up data were centrally collected, and each case was reviewed and approved for completeness at the study center. Family physicians and the patients were directly contacted if additional follow-up results were needed.

Acute and long-term adverse events were graded according to the Common Terminology Criteria for Adverse Events, version 3.0 (11), of the National Cancer Institute. Kidney function was assessed using the Modification of Diet in Renal Disease formula (12). Renal toxicity was classified according to the guidelines of the National Kidney Foundation (www.kidney.org), where grade 4 and 5 renal toxicity is defined as a glomerular filtration rate of less than 30 and less than 15 mL/min/1.73 m², respectively.

Outcomes and Statistical Analyses

The main outcomes of interest were survival, response, and toxicity. Survival was assessed from the time of diagnosis and the time of first radiopeptide treatment to death from any cause. Predictors of survival were studied by multivariable Cox regression with the following candidate variables: high tumor uptake (uptake score 3 vs. score 1 or 2), sex (male vs. female), age, and response (stable disease vs. disease progression). Disease progression was defined as an at least 20% increase in the sum of the longest diameters of target lesions or the appearance of one or more new lesions or unequivocal progression of existing nontarget lesions, according to the Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1. Effect estimates were expressed as hazard ratios with 95% confidence intervals. The overall response rate was defined following intention-to-treat principles, and loss of follow-up after treatment was regarded as treatment failure.

Sensitivity analyses were performed to compare overall survival, survival predictors, and toxicity in all patients and patients treated with ⁹⁰Y-DOTATOC alone. Further sensitivity analyses assessed the influence of WHO grade on survival after enrollment. Two-sided P values of less than 0.05 were considered to indicate statistical significance.