Nov 15, 2007 - Fax: 41-61-265-4897; E-mail: m.a.[email protected]. F2007 American Association for Cancer Research. doi:10.1158/1078-0432.CCR-07-0935.
Cancer Therapy: Clinical
Response to [90Yttrium-DOTA]-TOC Treatment is Associated with Long-term Survival Benefit in Metastasized Medullary Thyroid Cancer: A Phase II Clinical Trial Fabienne Iten,1,2 Beat Mu«ller,2 Christian Schindler,6 Christoph Rochlitz,3 Daniel Oertli,4 Helmut R. Ma«cke,5 Jan Mu«ller-Brand,1 and Martin A.Walter1,2
Abstract
Purpose: We aimed to explore the efficacy of 90Yttrium ^ 1,4,7,10-tetra-azacyclododecane N,N¶,N00,N--tetraacetic acid (90Y-DOTA)^ Tyr3-octreotide (TOC) therapy in advanced medullary thyroid cancer. Experimental Design: In a phase II trial, we investigated the response, survival, and long-term safety profile of systemic [90Y-DOTA]-TOC treatment in metastasized medullary thyroid cancer. Adverse events were assessed according to the criteria of the National Cancer Institute. Survival analyses were done using multiple regression models. Results: Thirty-one patients were enrolled. A median cumulative activity of 12.6 GBq (range, 1.7-29.6 GBq) of [90Y-DOTA]-TOC was administered. Response was found in nine patients (29.0%). Four patients (12.9%) developed hematologic toxicities and seven patients (22.6%) developed renal toxicities. Response to treatment was associated with longer survival from time of diagnosis (hazard ratio, 0.20; 95% confidenceinterval, 0.05-0.81; P = 0.02) and from time offirst [90Y-DOTA]-TOC therapy (hazard ratio, 0.16; 95% confidence interval, 0.04-0.63; P = 0.009).The visual grade of scintigraphic tumor uptake was not associated with treatment response or survival. Conclusions: Response to [90Y-DOTA]-TOC therapy in metastasized medullary thyroid cancer is associated with a long-term survival benefit. Treatment should be considered independently from the result of the pretherapeutic scintigraphy.
No
systemic therapy has been established for metastasized medullary thyroid cancer (1). Treatment with Adriamycin, cyclophosphamide, vincristine, dacarbazine, 5-fluorouracil, or combined regimes have shown only minor responses with considerable hematologic, nephrologic, cardiologic, or gastrointestinal toxicities (2, 3). On the other hand, preliminary studies revealed encouraging results with radiolabeled anti – carcinoembryonic antigen antibodies (4) and metaiodobenzylguanidine (5). Systemic treatment with the 90Yttrium (90Y)-labeled, 1,4,7,10tetra-azacyclododecane N,N¶,N00,N--tetraacetic acid (DOTA) – modified somatostatin analogue Tyr3-octreotide (TOC) was introduced in 1998 (6). [90Y-DOTA]-TOC is administered i.v. and binds to the somatostatin receptor subtype 2, located on the surface of the tumor cell, and exerts its cytotoxic effects by
Authors’ Affiliations: 1Institute of Nuclear Medicine, 2Division of Endocrinology, Diabetology, and Clinical Nutrition, Departments of 3Oncology and 4Surgery, 5 Division of Radiological Chemistry, University Hospital Basel, and 6Institute of Social and Preventive Medicine, University of Basel, Switzerland Received 4/19/07; revised 7/24/07; accepted 8/16/07. Grant support: Swiss National Science Foundation. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. Requests for reprints: Martin A.Walter, Institute of Nuclear Medicine, University Hospital, Petersgraben 4, CH-4031 Basel, Switzerland. Phone: 41-61-265-5684; Fax: 41-61-265-4897; E-mail: m.a.walter@ gmx.net. F 2007 American Association for Cancer Research. doi:10.1158/1078-0432.CCR-07-0935
Clin Cancer Res 2007;13(22) November 15, 2007
h-irradiation. The treatment has moderate acute hematologic and nephrologic toxicity and has developed into a promising therapeutic tool for tumors expressing its target receptor (7–9). Among other neuroendocrine tumors, medullary thyroid carcinomas express the somatostatin receptor subtype 2, which was initially used for tumor imaging (10). Pilot studies have provided proof of principle that [90Y-DOTA]-TOC treatment could achieve remissions in progressive medullary thyroid cancer (11, 12). Herein, we investigated the long-term efficacy and toxicity of [90Y-DOTA]-TOC treatment in medullary thyroid cancer.
Materials and Methods Trial design. In a clinical phase II, single-center, open-label trial, we investigated the response, survival, and safety profile of [90Y-DOTA]TOC treatment in progressive metastasized medullary thyroid cancer. Adverse events were assessed according to the criteria of the National Cancer Institute. Predictors for survival were examined among the participant’s baseline characteristics and the intensity of treatment. The study was designed and carried out 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 (The Ethics Committee of Basel, reference no. M120/97)7 and written informed consent was obtained from all participants.
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http://www.ekbb.ch
www.aacrjournals.org
DOTA-TOC in MedullaryThyroid Cancer
Fig. 1. Trial profile.
Trial cohort. We consecutively included patients with (a) histologically confirmed medullary thyroid cancer, (b) stage IVc disease by definition of the American Joint Committee on Cancer, i.e., occurrence of distant metastases, (c) disease progression within 12 months before
study entry as defined by increasing calcitonin levels, and (d) visible tumor uptake in the pretherapeutic somatostatin receptor subtype 2 scintigraphy (111In-Octreoscan). We excluded patients in case of (a) age younger than 18 years, (b) concurrent antitumor treatment, (c) secondary malignancies, (d) pregnancy, (e) breast-feeding, (f) incontinence, (g) severe concomitant illness including severe psychiatric disorders, or (h) reduced kidney function, assessed by creatinine clearance according to Cockcroft and Gault (13). Pretherapeutic somatostatin receptor subtype 2 scintigraphy. The severity of tumor uptake in the pretherapeutic 111In-Octreoscan was visually graded by a panel of two board-certified nuclear medicine physicians blinded to the patients characteristics using a fourpoint scale: (0) no uptake present, (1) uptake present but lower than liver uptake, (2) similar to liver uptake, and (3) higher than liver uptake. Therapeutic radiopeptide. DOTA-TOC was synthesized in a five-step synthetic procedure according to Good Laboratory Practices as previously described (6 – 8). For radiolabeling, kits containing 220 Ag of DOTATOC, 18.3 mg of ascorbic acid, and 160 mg of sodium ascorbate were labeled with 3.7 GBq/m2 body surface 90Y (h-emission for therapeutic purposes; Perkin-Elmer Life Sciences) and 0.111 GBq of 111 Indium chloride (g-emission for intratherapeutic imaging; Mallinckrodt Medical). The solution was heated at 95jC for 25 min and quality control was done using solid phase extraction (Sep-Pak C18 cartridge, Waters Associates, Inc.) and high-performance liquid chromatography, with a minimum required labeling yield of >99.5%. Radiopeptide treatment. A fractionated treatment protocol was done with i.v. injections of 3.7 GBq/m2 body surface [90Y-DOTA]-TOC per cycle as previously described (6 – 8). For each cycle, patients were hospitalized for 3 days in accordance with the local Swiss requirements for legal radiation protection. An infusion of 2,000 mL of HartmannHepa 8% amino acid solution (Ringer Lactate Hartmann, Proteinsteril Hepa 8%, Mg 5-Sulfat) was started 30 min before and continued until 3 h after the injection of the radiopeptide to inhibit the tubular
Table 1. Patients’ characteristics Characteristic Gender
Finding
Females Males Age (y) Median (range) Height (cm) Median (range) Weight (kg) Median (range) 2 Body surface (m ) Median (range) Cases of MEN syndromec MEN I MEN IIa MEN IIb Duration of disease (y)b Median (range) Pretreatment Radioiodine Radiation Embolization Chemotherapy Calcitonin (pg/mL) Median (range) Creatinine (Amol/L) Median (range) Creatinine clearance (mL/min/1.73 m2) Median (range) 9 Median (range) Leukocytes (10 /L) Platelets (109/L) Median (range) Hemoglobin (g/dL) Median (range) Scintigraphic uptake 0 1 2 3 Cumulative activity (GBq) Median (range)
All patients (N = 31) Responders (n = 9) Nonresponders (n = 22) P * 10 (32%) 21 (68%) 56.7 (24.0-76.9) 172 (155-193) 70 (46-88) 1.8 (1.4-2.2) 1 (3.2%) 2 (6.5%) 0 4.0 (0.1-30.8) 3 10 3 8 7,553 (39-61,467) 69 (27-115) 96.3 (45.1-171.0) 6.8 (3.5-13.3) 274 (121-863) 11.5 (6.9-17.2) 0 18 (54.8%) 5 (16.1%) 8 (25.8%) 12.6 (1.7-29.6)
2 7 50.2 175 69 1.8
(22%) (78%) (41.4-76.0) (160-186) (60-82) (1.6-2.0) 0 0 0 1.9 (0.3-13.4) 2 3 1 2 19,700 (141-61,467) 73 (60-94) 94.4 (53.9-132.7) 6.7 (4.5-12.8) 313 (223-450) 11.5 (8.8-17.2) 0 5 (55.5%) 2 (22.2%) 2 (22.2%) 14.8 (3.4-15.7)
8 14 57.5 170 74 1.8 1 2 4.5
4,471 64 99.1 6.8 260 11.5 13 3 6 12.2
(36%) (64%) (24.0-76.9) (155-193) (46-88) (1.4-2.2) (4.5%) (9.1%) 0 (0.1-30.8) 1 7 2 6 (39-40,000) (27-115) (45.1-171.0) (3.5-13.3) (121-863) (6.9-15.2) 0 (54.5%) (13.6%) (27.3%) (1.2-13.3)
0.68 0.51 0.38 0.66 0.98 1.0 1.0 1.0 0.51 0.19 1.0 1.0 1.0 0.16 0.19 0.48 0.98 0.06 0.56 0.83
0.12
NOTE: The respective reference ranges are: calcitonin,
