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Evaluating the Clinical Effectiveness of ⁹⁰Y-SMT 487 in Patients with Neuroendocrine Tumors

¹ Iowa City Veterans Administration Hospital, Diagnostic Imaging and Radioisotope Therapy Service, Iowa City, Iowa
² Department of Radiology, Division of Nuclear Medicine, University of Iowa Roy J. and Lucille A. Carver College of Medicine, Iowa City, Iowa
³ Department of Internal Medicine, Division of Endocrinology, University of Iowa Roy J. and Lucille A. Carver College of Medicine, Iowa City, Iowa
⁴ Department of Internal Medicine, Division of Oncology, University of Iowa Roy J. and Lucille A. Carver College of Medicine, Iowa City, Iowa
⁵ Novartis Pharmaceuticals, East Hanover, New Jersey

	ABSTRACT

TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION CONCLUSION REFERENCES

 
Because of the presence of cell membrane somatostatin receptors (SSTRs), many neuroendocrine tumors will bind analogs of somatostatin. ⁹⁰Y-Dodecanetetraacetic acid-Phe1-Tyr3-octreotide (SMT 487) is an SSTR radiopharmaceutical currently under investigation as a therapeutic option for neuroendocrine tumors. Although there are a variety of methods for evaluating response to a given cancer therapy, an important indicator of success is the impact on the clinical status of the patient. The purpose of this work was to develop a semiquantitative method and assess the clinical effectiveness of ⁹⁰Y-SMT 487 therapy in patients with neuroendocrine tumors. Methods: A scoring system was developed to evaluate clinical response that included the following parameters: weight, health status score (determined by the patient), Karnofsky score, and tumor-related symptoms. Results: We applied this scoring system to 21 patients who had completed 3 cycles of therapy with ⁹⁰Y-SMT 487. Fourteen of the 21 showed a favorable clinical response, whereas 5 were clinically stable after treatment and 2 showed evidence of clinical progression. There was also a significant reduction in the amount of octreotide being used after completion of ⁹⁰Y-SMT 487 therapy in the 20 patients who were on this medication. Conclusion: Using this scoring method, ⁹⁰Y-SMT 487 appears effective in improving the clinical status of patients with ¹¹¹In-pentetreotide-positive neuroendocrine tumors.

Key Words: targeted radiotherapy • ⁹⁰Y • somatostatin • peptide

	INTRODUCTION

TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION CONCLUSION REFERENCES

 
Neuroendocrine tumors share a common tissue of origin and typically synthesize and secrete a variety of bioactive monoamines and peptides, which can cause debilitating symptoms. Therapy of metastatic neuroendocrine tumors was enhanced dramatically with the introduction of the somatostatin analog octreotide (Sandostatin; Novartis). Although having only a modest ability to control tumor growth, this agent nevertheless has a dramatic impact on the elaboration of the bioactive substances responsible for many of the symptoms (1). Unfortunately, nearly all such tumors will eventually become resistant to the effects of octreotide (1).

Because of the presence of somatostatin receptors (SSTRs), especially subtype 2, on the cell surface membrane, many types of neuroendocrine tumors will bind analogs of somatostatin. ⁹⁰Y-Dodecanetetraacetic acid-Phe1-Tyr3-octreotide (SMT 487 [OctreoTher; Novartis]) is an SSTR radiopharmaceutical currently under investigation as a therapeutic agent for patients with SSTR-positive neuroendocrine tumors. It differs from the imaging agent ¹¹¹In-pentetreotide (OctreoScan; Mallinckrodt Medical) by substituting tyrosine for phenylalanine at the 3 position and by replacing the chelator diethylenetriaminepentaacetic acid with dodecanetetraacetic acid. In addition, and critical for therapeutic application, the ß-emitter ⁹⁰Y takes the place of ¹¹¹In on this molecule. Early clinical studies have produced encouraging results for targeted radiotherapy of SSTR-positive tumors with this agent (2,3).

CT measurement of tumor size is a well-accepted method for assessing response to therapy. However, CT examination is not without limitations when one is attempting to determine the effectiveness of a particular cancer treatment (4). Ultimately, the most important indicator of treatment response is the impact on clinical status. Improvement in survival is easiest to measure and clearly vital, but an extended time may be required to complete the analysis. Assessment of the treatment impact on morbidity is more difficult but of great importance. The purpose of this work was to develop a clinical response scoring system and use it to assess the initial clinical effectiveness of ⁹⁰Y-SMT 487 therapy.

	MATERIALS AND METHODS

TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION CONCLUSION REFERENCES

 
The study group represented a subset of patients with neuroendocrine tumors who were enrolled as part of a phase II trial of the efficacy and safety of ⁹⁰Y-SMT 487 in patients with SSTR-positive metastatic tumors, as determined by SPECT or planar 24-h ¹¹¹In-pentetreotide imaging. The eligibility criterion was greater ¹¹¹In-pentetreotide uptake in at least 1 measurable tumor site than in normal liver. Patients were required to discontinue octreotide before imaging with ¹¹¹In-pentetreotide or therapy with ⁹⁰Y-SMT 487, and they signed an institutional review board-approved consent document before participation.

The trial design called for 3 treatment cycles of 4,400 MBq (120 mCi) each of ⁹⁰Y-SMT 487 every 6–9 wk. With each treatment cycle, 2 L of an amino acid solution containing arginine and lysine (Aminosyn II 7%; Abbott Laboratories) was infused over 4 h to reduce renal uptake of ⁹⁰Y-SMT 487. ⁹⁰Y-SMT 487 was administered intravenously over approximately 15–20 min, concurrent with the amino acid infusion through a separate intravenous line.

A scoring system was developed that included the following parameters evaluated at baseline and 6 wk after the third cycle of therapy: weight, health status score, Karnofsky score, and tumor-related symptoms. Tumor-related symptoms and Karnofsky score were determined by either the study nurse or the physician. Symptoms that were evaluated included fatigue, abdominal pain, diarrhea, nausea/vomiting, and flushing. These were assessed without knowledge of biochemical or CT follow-up results. The health status score was determined by the individual patients, who were asked to rate the state of their health on a scale of 1–100 by marking a point along a 100-mm line.

Table 1 summarizes the scoring system used to determine each patient’s clinical response status. An overall clinical response score was obtained for each patient by summing the individual scores described in Table 1. Consequently, the maximum clinical response score was +4 and the minimum was -4. A patient was considered to have a favorable clinical response to therapy if the clinical response score was +2 or greater; was considered stable if the score was -1, 0, or +1; and was considered to have clinical progression if the score was -2 or less.

	RESULTS

TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION CONCLUSION REFERENCES

 
The baseline and posttherapy assessments were completed for 21 patients with metastatic neuroendocrine tumors (20 of which were known to be enteropancreatic in origin) who successfully completed all 3 cycles of ⁹⁰Y-SMT 487 therapy. Seventeen individuals had carcinoid tumors, 2 had nonfunctional islet cell tumors of the pancreas, 1 had a glucagonoma, and 1 had metastases from a neuroendocrine tumor of unknown origin. There were 9 women and 12 men, ranging in age from 41 to 76 y. One other patient with a neuroendocrine tumor was excluded from the analysis because of inadequate clinical follow-up. We excluded 3 other individuals because of their different tumor types (small cell lung cancer, meningioma, and cranial hemangiopericytoma). Three additional patients were excluded because they did not complete the full 3 cycles of therapy.

Baseline and posttherapy body weights, health state scores, and Karnofsky scores and the response status of each clinical symptom for each patient are summarized in Table 2. On the basis of our scoring system, 14 patients (67%; 95% confidence interval, 43%–85%) showed a favorable clinical response, 5 patients (24%) were clinically stable, and 2 patients (10%) showed clinical progression.

View larger version (94K): [in this window] [in a new window]   FIGURE 1. Pretherapy (A) and posttherapy (B) CT images of liver of patient 7 show that multiple large, hypodense lesions seen at baseline were significantly smaller on posttherapy CT.

View larger version (89K): [in this window] [in a new window]   FIGURE 2. Pretherapy (A) and posttherapy (B) CT images of liver of patient 10 show that multiple large, hypodense lesions seen at baseline did not change significantly after therapy.

	DISCUSSION

TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION CONCLUSION REFERENCES

More recent reports have included limited data on the clinical effectiveness of this treatment. Waldherr et al. published results from a phase II study finding similar efficacy to the aforementioned studies in a larger group of patients with neuroendocrine tumors (5). Patients in this study received a total of 7.4 GBq (200 mCi)/m² administered over 4 therapy cycles. In addition, these authors assessed clinical effectiveness using a patient-scored questionnaire given before and after treatment to 21 of their patients. They found that, overall, 63% of these individuals reported improvement in at least 1 of 4 symptom categories, which included diarrhea, flushing, wheezing, or pellagra. Valkema et al. reported symptomatic improvement in 18 of 38 patients with neuroendocrine tumors, including 2 individuals with insulinomas (6). The administered activity of ⁹⁰Y-SMT 487 in this study was based on renal dosimetry estimates, with patients limited to a total of 27 Gy to the kidneys over multiple therapy cycles with ⁹⁰Y-SMT 487. Consequently, our finding of a 67% favorable clinical response is very consistent with what has been reported to date.

Because our study was not masked or placebo-controlled, there was, of course, the potential for bias in assessing symptom response. It may be beneficial if future applications of this methodology use WHO grading criteria for evaluation of the 4 symptoms listed in Table 1. Our scoring system did include an important objective measure (weight change) as well as the subjective assessments described. Additionally, we required a +2 overall score for classification as a favorable response to enhance the certainty of correctly identifying individuals who did in fact benefit from this therapy.

	CONCLUSION

TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION CONCLUSION REFERENCES

 
On the basis of the results from our clinical response scoring system and the finding of reduced medication requirements, therapy with ⁹⁰Y-SMT 487 appears to improve the clinical status of a substantial fraction of patients withSSTR-positive neuroendocrine tumors. Further data are needed to determine, among other things, the duration of clinical benefit and possible impact on survival. This multicenter phase II trial is ongoing, and the final results may change as additional data are received and analyzed from the other institutions.

	ACKNOWLEDGMENTS

 
We thank the personnel of the University of Iowa Clinical Research Center for their assistance with this project. We also thank John Bricker, Wayne Walkner, and James Ponto for their important contributions to this work. Funding for this work was provided by Novartis.

	FOOTNOTES

 
Received Jan. 21, 2003; revision accepted Jun. 13, 2003.

For correspondence or reprints contact: David Bushnell, MD, Diagnostic Imaging and Radioisotope Therapy Service, Iowa City Veterans Administration Hospital, Highway 6 West, Iowa City, IA 52240.

E-mail: david-bushnell{at}uiowa.edu

	REFERENCES

TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION CONCLUSION REFERENCES

 

1. Arnold R, Simon B, Wied M. Treatment of neuroendocrine GEP tumors with somatostatin analogues. Digestion. 2000;62(suppl): 84–91.
2. Otte A, Hermann R, Heppeler A, et al. ⁹⁰Y DOTATOC: first clinical results. Eur J Nucl Med. 1999;26:1439–1447.[Medline]
3. Paganelli G, Zoboli S, Cremonesi M, et al. Receptor-mediated radionuclide therapy with ⁹⁰Y-DOTA-D-Phe¹-Tyr³-octreotide: preliminary report in cancer patients. Cancer Biother Radiopharm. 1999;14:477–483.[Medline]
4. Jerusalem G, Beguin Y, Fassotte MF, et al. Whole body positron emission computed tomography using ¹⁸F-fluorodeoxyglucose for post treatment evaluation in Hodgkin’s and non-Hodgkin’s lymphoma has higher diagnostic and prognostic value than classical computed tomography scan imaging. Blood. 1999;94:429–433.[Abstract/Free Full Text]
5. Waldherr C, Pless M, Maecke H, et al. Tumor response and clinical benefit in neuroendocrine tumors after 7.4 GBq ⁹⁰Y-DOTATOC. J Nucl Med. 2002;43:610–616.[Abstract/Free Full Text]
6. Valkema R, Kvols L, Jamar F, et al. Phase 1 study of therapy with ⁹⁰Y-SMT487 (OctreoTher) in patients with somatostatin receptor (SS-R) positive tumors [abstract]. J Nucl Med. 2002;43(suppl):33P.

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