Survival and Response After Peptide Receptor Radionuclide Therapy With [90Y-DOTA0,Tyr3]Octreotide in Patients With Advanced Gastroenteropancreatic Neuroendocrine Tumors

doi:10.1053/j.semnuclmed.2006.01.001

Seminars in Nuclear Medicine

Volume 36, Issue 2, April 2006, Pages 147-156

https://doi.org/10.1053/j.semnuclmed.2006.01.001 Get rights and content

Because the role of chemotherapy, interferon, or somatostatin analogs as antiproliferative agents is uncertain, currently few treatment options exist for patients with metastatic or inoperable gastroenteropancreatic neuroendocrine tumors (GEP-NET). Fifty-eight patients with somatostatin receptor-positive GEP-NET were treated in a phase I dose-escalating study with cumulative doses of 47 mCi to 886 mCi of the radiolabeled somatostatin analog [⁹⁰Y-DOTA⁰,Tyr³]-octreotide. At baseline, 47 patients had progressive disease, and 36 were symptomatic. The extent of disease was: 4 patients without liver metastases and 52 patients with liver metastases, including 16 patients with very advanced disease, qualified as “end-stage,” and 2 end-stage patients without liver metastases. The objective responses were 5 partial response (PR), 7 minor response (MR), 29 stable disease (SD), and 17 PD. Overall, 33 patients (57%) experienced some improvement in their disease status, including conversion from PD into SD and improvement from SD into MR. Accordingly, 21 of 36 patients (58%) had improvement in Karnofsky performance score or symptoms. The median overall survival (OS) was 36.7 months (95% confidence interval [CI] 19.4-54.1 months). The median progression-free survival in 41 patients who had at least stable disease at the end of the treatment period was 29.3 months (95% CI 19.3-39.3 months). Patients who had SD at baseline had a significantly better OS than patients who had PD at baseline. The extent of disease at baseline also was a significant predictive factor for OS. The OS after therapy with [⁹⁰Y-DOTA⁰,Tyr³]-octreotide was significantly better than in a historic control group of 32 comparable patients with GEP-NET who had been treated with another radiolabeled somatostatin analog, [¹¹¹In-DTPA⁰]-octreotide (median OS 12.0 months, 95% CI 6.2-17.8 months). The difference in OS for both therapies remained highly significant in a multivariate Cox proportional hazard model including progression status and extent of disease at baseline as covariates. Although the objective response after therapy with [⁹⁰Y-DOTA⁰,Tyr³]-octreotide by standard criteria seems modest, the significantly longer OS compared with historic controls is most encouraging.

Section snippets

PRRT with [⁹⁰Y-DOTA⁰,Tyr³]octreotide

The patients were all veterans of a multicenter phase-I, uncontrolled, open-label vertical (per cycle) and horizontal (number of cycles) dose-escalating study.18, 19 The primary goals were to establish the 1-cycle and 4-cycle maximum tolerated doses of [⁹⁰Y-DOTA⁰,Tyr³]octreotide (⁹⁰Y-SMT487, ⁹⁰Y-edotreotide) and to evaluate the immediate, 6 month, and long-term (18 month) safety profiles. All patients gave written informed consent. The study was approved by the local ethical committees of the 3

Results

In 34 patients, 4 equal cycles of [⁹⁰Y-DOTA⁰,Tyr³]octreotide were planned. Administered activities per cycle ranged from 19.7 mCi/m² to 103 mCi/m², and cumulative activities ranged from 222 mCi/m² to 403 mCi/m². In 24 patients, single-dose escalation from 97.3 mCi/m² per cycle to 251 mCi/m² per cycle was performed. Their cumulative activities ranged 19.5 mCi/m² to 349 mCi/m². The treatments were given between January 1998 and August 2002.

Two patients died during the first cycle (1 from

Discussion

At first sight, the results of our analysis of response and survival in patients with GEP-NET after PRRT with [⁹⁰Y-DOTA⁰,Tyr³]octreotide may seem contradictory. As assessed by standard SWOG response criteria, only 5 of 58 patients (9%) reached PR, and none reached CR. For most tumors, these disappointingly low figures would indicate that the therapy was hardly effective. In contrast, a median OS of 3 years after the start of PRRT and a median PFS of 2.5 years (in the 41/58 patients who were at

Conclusions

The objective response rate according standard SWOG criteria after PRRT with escalating doses in a phase 1 setting [⁹⁰Y-DOTA⁰,Tyr³]octreotide was low with PR in 5 of 58 patients (9%). With slowly growing tumors, however, any improvement in response parameters, including conversion from PD into SD or attaining MR, may reflect an important gain for the patient (Fig. 6). Therefore, in our opinion 33 of 58 patients (57%) have had a response (Table 2). The median OS of 36.7 months and median PFS of

Acknowledgments

We are grateful for the support from the nursing staff in the participating centers, in particular Joelle de Camps, Jane Hadley, and Jolande Kip. The phase 1 study with [⁹⁰Y-DOTA⁰,Tyr³]octreotide was sponsored by Novartis Pharmaceuticals. Principle investigators were Stanislas Pauwels, Larry K. Kvols, and Eric P. Krenning.

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Survival and Response After Peptide Receptor Radionuclide Therapy With [90Y-DOTA0,Tyr3]Octreotide in Patients With Advanced Gastroenteropancreatic Neuroendocrine Tumors

Section snippets

PRRT with [90Y-DOTA0,Tyr3]octreotide

Results

Discussion

Conclusions

Acknowledgments

Ann Oncol

Semin Nucl Med

Semin Nucl Med

Bioorg Med Chem Lett

Ann Oncol

Best Pract Res Clin Gastroenterol

Best Pract Res Clin Gastroenterol

Ann Oncol

Clin Gastroenterol Hepatol

A 5-decade analysis of 13,715 carcinoid tumors

Cancer

Natural history of digestive endocrine tumors

Treatment of neuroendocrine GEP tumours with somatostatin analoguesa review

Digestion

Prospective, randomized, multicenter trial on the antiproliferative effect of lanreotide, interferon alfa, and their combination for therapy of metastatic neuroendocrine gastroenteropancreatic tumors—the International Lanreotide and Interferon Alfa Study Group

J Clin Oncol

Combination chemotherapy trials in metastatic carcinoid tumor and the malignant carcinoid syndrome

Cancer Clin Trials

Streptozocin alone compared with streptozocin plus fluorouracil in the treatment of advanced islet-cell carcinoma

N Engl J Med

Streptozocin-doxorubicin, streptozocin-fluorouracil or chlorozotocin in the treatment of advanced islet-cell carcinoma

N Engl J Med

Failure to confirm major objective antitumor activity for streptozocin and doxorubicin in the treatment of patients with advanced islet cell carcinoma

Cancer

Failure to confirm major objective antitumor activity for streptozocin and doxorubicin in the treatment of patients with advanced islet cell carcinoma

Cancer

Treatment of neuroendocrine carcinomas with combined etoposide and cisplatin. Evidence of major therapeutic activity in the anaplastic variants of these neoplasms

Cancer

Radiotherapy with a radiolabeled somatostatin analogue, [111In-DTPA-D- Phe1]-octreotide. A case history

Ann N Y Acad Sci

Survival and Response After Peptide Receptor Radionuclide Therapy With [⁹⁰Y-DOTA⁰,Tyr³]Octreotide in Patients With Advanced Gastroenteropancreatic Neuroendocrine Tumors

PRRT with [⁹⁰Y-DOTA⁰,Tyr³]octreotide