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ORIGINAL REPORTS
May 09, 2011

Response, Survival, and Long-Term Toxicity After Therapy With the Radiolabeled Somatostatin Analogue [90Y-DOTA]-TOC in Metastasized Neuroendocrine Cancers

Publication: Journal of Clinical Oncology

Abstract

Purpose

To investigate response, survival, and safety profile of the somatostatin-based radiopeptide 90yttrium-labeled tetraazacyclododecane-tetraacetic acid modified Tyr-octreotide ([90Y-DOTA]-TOC) in neuroendocrine cancers.

Patients and Methods

In a clinical phase II single-center open-label trial, patients with neuroendocrine cancers were treated with repeated cycles of [90Y-DOTA]-TOC. Each cycle consisted of a single intravenous injection of 3.7GBq/m2 body-surface [90Y-DOTA]-TOC. Additional cycles were withheld in case of tumor progression and/or permanent toxicity.

Results

Overall, 1,109 patients received 2,472 cycles of [90Y-DOTA]-TOC (median, two; range, one to 10 cycles per patient). Of the 1,109 patients, 378 (34.1%) experienced morphologic response; 172 (15.5%), biochemical response; and 329 (29.7%), clinical response. During a median follow-up of 23 months, 491 patients (44.3%) died. Longer survival was correlated with each: morphologic (hazard ratio [HR], 0.46; 95% CI, 0.38 to 0.56; median survival, 44.7 v 18.3 months; P < .001), biochemical (HR, 0.75; 95% CI, 0.59 to 0.96; 35.3 v 25.7 months; P = .023), and clinical response (HR, 0.68; 95% CI, 0.56 to 0.82; 36.8 v 23.5 months; P < .001). Overall, 142 patients (12.8%) developed grade 3 to 4 transient hematologic toxicities, and 103 patients (9.2%) experienced grade 4 to 5 permanent renal toxicity. Multivariable regression revealed that tumoral uptake in the initial imaging study was predictive for overall survival (HR, 0.45; 95% CI, 0.29 to 0.69; P < .001), whereas the initial kidney uptake was predictive for severe renal toxicity (HR, 1.59; 95% CI, 1.17 to 2.17; P = .003).

Conclusion

This study documents the long-term outcome of [90Y-DOTA]-TOC treatment in a large cohort. Response to [90Y-DOTA]-TOC is associated with longer survival. Somatostatin receptor imaging is predictive for both survival after [90Y-DOTA]-TOC treatment and occurrence of renal toxicity.

Introduction

Differentiated neuroendocrine cancers frequently express subtypes of the somatostatin receptor family.1 This feature allows treatment with the somatostatin analog octreotide LAR,2,3 facilitates receptor imaging with radiolabeled somatostatins,4 and provides the rationale for somatostatin-based radiopeptide therapy.
Somatostatin-based radiopeptide therapy with 90yttrium-labeled tetraazacyclododecane-tetraacetic acid modified Tyr3-octreotide ([90Y-DOTA]-TOC) was developed and introduced into clinical practice by our department in 1997.5 The introduction of tyrosine into the third position of the octreotide sequence increases the hydrophilicity and receptor affinity of the peptide, and conjugation with the β emitter 90Y allows for irradiation of the tumor. [90Y-DOTA]-TOC is administered intravenously, binds to somatostatin receptors on the target cell, and exerts cytotoxic effects via β irradiation.
Initial reports showed that [90Y-DOTA]-TOC was able to induce morphologic responses (10 of 41 patients),6 biochemical responses (nine of 31 patients),7 and clinical responses (13 of 21 patients)8 in progressive metastasized neuroendocrine cancer. This report describes the long-term outcome of all 1,109 patients with metastasized neuroendocrine cancers treated with [90Y-DOTA]-TOC in our institution between October 1997 and February 2010.

Patients and Methods

This clinical phase II single-center open-label trial investigated response, survival, and safety profile of [90Y-DOTA]-TOC in metastasized neuroendocrine cancer.

Eligibility

We included patients with histologically confirmed neuroendocrine cancers, metastasized disease, disease progression within 12 months before study entry, and visible tumor uptake in the pretherapeutic somatostatin receptor scintigraphy. We excluded patients with concurrent antitumor treatment, urine incontinence, preexisting grade 3 to 4 hematologic toxicities, and severe concomitant illness as well as those who were pregnant or breastfeeding. Patients were recruited from referring centers in Europe, Asia, North America, and South America. 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 (Ethikkommission beider Basel Reference No. M120/97; www.ekbb.ch) and registered. Written informed consent was obtained from all participants or their legal representatives.

Treatment

DOTA-TOC was synthesized in a five-step synthetic procedure according to good laboratory practice.9 Radiolabeling was performed with 3.7GBq/m2 body surface of the β emitter 90Y for therapeutic purposes and 0.111GBq of the γ emitter 111Indium for intratherapeutic imaging.5,10 Quality control was performed using solid-phase extraction and high-performance liquid chromatography, with a minimum required labeling yield of more than 99.5%. An infusion of 1,000 mL physiologic NaCl solution containing 20.7 mg/mL of arginine and 20.0 mg/mL of lysine was started 30 minutes before and continued for 3 hours after [90Y-DOTA]-TOC injection to inhibit tubular reabsorption of the radiopeptide. Patients were hospitalized 3 days for each cycle, in accordance with the Swiss requirements for legal radiation protection.

Somatostatin Receptor Imaging

The intratherapeutic biodistribution of the radiopeptide was assessed using planar whole-body imaging.7 The maximum tracer accumulation in the tumor lesion with the highest uptake (tumor score) and the kidneys (kidney score) was visually scored by a panel of three board-certified nuclear medicine physicians using a four-point scale: score 0, no uptake; score 1, uptake lower than liver uptake; score 2, uptake similar to liver uptake; and score 3, uptake higher than liver uptake. The readers were blinded 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, vital signs were monitored before and for 72 hours after each [90Y-DOTA]-TOC administration. All toxicities were continuously recorded. After discharge, blood chemistry and hematologic parameters were measured in biweekly intervals for 10 weeks after each cycle or until normalization of marker levels. The first post-therapeutic morphologic imaging was planned 6 to 8 weeks after each cycle.
Additional treatment cycles were withheld if at least one of the following stop criteria was met: tumor progression under [90Y-DOTA]-TOC treatment or permanent toxicity. In these cases, study patients were observed for long-term toxicities until death. Follow-up data were obtained from the referring centers, with a minimum frequency of two follow-up visits per year, adapted to individual patient requirements. All follow-up data were centrally collected, and each case was reviewed and approved for completeness at the study center. Family physicians and patients were contacted directly 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 of the National Cancer Institute. Kidney function after [90Y-DOTA]-TOC was assessed using the Modification of Diet in Renal Disease formula11; renal toxicities were classified according to guidelines of the National Kidney Foundation (www.kidney.org).

Response

Initial staging and eligibility were determined based on imaging, laboratory, and clinical results from the respective international referring center. Follow-up assessments were performed with the identical modality at the same center.
Morphologic response was assessed by computed tomography, magnetic resonance imaging, or ultrasound. Response was defined as any measurable decrease in the sum of the longest diameters of all pretherapeutically detected tumor lesions. Complete response was defined as disappearance of all lesions, and mixed response was defined as concurrence of increasing and decreasing lesions. Stable disease was present if no changes occurred, whereas progress was defined as any measurable increase in the sum of the longest diameters of the pretherapeutically detected lesions.
Biochemical response was assessed using the following tumor markers: 5-hydroxyindole-3-acetic acid, angiotensin converting enzyme, adrenocorticotropic hormone, α-fetoprotein, CA-125, CA-19.9, parathormone, calcitonin, carcinoembryonic antigene, chromogranin A, dopamine, gastrin, glucagon, noradrenalin, neuron specific enolase, pancreatic polypeptide, proinsulin, serotonin, and vasointestinal peptide. Biochemical response was achieved if there was pretherapeutic tumor marker progression and any post-therapeutic decrease of the respective marker. Clinical response was achieved if there was reduced frequency of flushes or diarrhea, pain reduction, improvement in fatigue, and/or weight gain after involuntary weight loss.
Repeated [90Y-DOTA]-TOC cycles were performed in patients exhibiting clinical response, biochemical response, or morphologic disease control, defined as morphologic response or stable disease after [90Y-DOTA]-TOC. Additional cycles were withheld in cases of progression, permanent toxicity, loss of transferability, or denial of [90Y-DOTA]-TOC treatment.

Statistical Analyses

Main outcomes of interest were overall survival, severe renal toxicity (defined as grade 4 to 5 toxicity), and treatment response. The overall response rate was defined following intention-to-treat principles, whereas loss of follow-up was regarded as treatment failure. Survival was assessed from time of first [90Y-DOTA]-TOC treatment to death as a result any cause.
Predictors of survival were studied by multivariable Cox regression with the following prespecified candidate variables: sex, age, histology, duration of disease, previous surgery, previous chemotherapy, previous radiation, solitary versus multiple metastases, liver versus no liver metastases, bone versus no bone metastases, tumor uptake score, and response to [90Y-DOTA]-TOC. Effect estimates were expressed as hazard ratios (HRs) with 95% CIs.
To accurately investigate predictors of renal toxicity, the competing risk of death before renal toxicity was considered in all analyses. Cumulative incidence functions were used to display the proportion of patients with renal toxicity or the competing event of death as time progressed,12 and a Fine and Gray regression model for the subdistribution hazard13 was employed. The following prespecified variables were tested in the model: sex, age, baseline glomerular filtration rate, and kidney uptake score.
Survival analyses were repeated using the RECIST (Response Evaluation Criteria in Solid Tumors) response criteria.14 Spearman's rank correlation was used to analyze the correlation of morphologic, biochemical, and clinical response. The influence of all prespecified predictors on 1-, 2- and 5-year survival and the influence of year of treatment on survival were analyzed. Two-sided P values of less than .05 were considered indicative of statistical significance.

Results

Patients

Between October 1997 and February 2010, 2,041 patients were screened for eligibility; 130 patients (6.4%) were not eligible, and 802 patients (39.3%) were eligible but not treated (Fig 1). The remaining 1,109 patients (54.3%) received a total of 2,472 cycles of [90Y-DOTA]-TOC (median, two; range, one to 10 cycles per patient). The distribution of age, sex, and histology in eligible patients treated and not treated were similar.
Fig 1. CONSORT diagram. [90Y-DOTA]-TOC, 90yttrium-labeled tetraazacyclododecane-tetraacetic acid modified Tyr-octreotide.
Patients were recruited from more than 100 centers in 29 countries (Germany, 359 patients; Switzerland, 297; United States, 133; Israel, 89; Denmark, 74; France, 67; Hungary, 41; Italy and Spain, six patients each; Luxembourg and Turkey, four each; Austria and Brazil, three each; United Arab Emirates, Croatia, Ireland, Japan, the Netherlands, Portugal, and Ukraine, two each; Belgium, Latvia, Libya, Mexico, Pakistan, Slovakia, Slovenia, South Africa, and the United Kingdom, one each). Baseline characteristics are listed in Table 1.
Table 1. Baseline Characteristics and Spectrum of Outcomes in Different Types of Neuroendocrine Cancer (N = 1,109)
CharacteristicPatientsMorphologic ResponseBiochemical ResponseClinical ResponseMean Survival95% CI
No.%No.%No.%No.%
Sex          
    Female47743.0        
    Male63257.0        
Age, years          
    Median58.9        
    Range11.2-91.1        
Disease duration, years          
    Median1.9        
    Range0.1-37.8        
Pretreatment          
    Surgery60554.6        
    Chemotherapy32929.7        
    Radiation14312.9        
Extent of disease          
    Single metastasis1109.9        
    Liver metastases91282.2        
    Bone metastases21219.0        
Creatinine, μmol/L          
    Median70.0        
    Range22-434        
Tumor uptake score          
    1686.1        
    2686.1        
    397387.7        
Kidney uptake score          
    0565.0        
    113011.7        
    225923.3        
    365759.2        
Histology          
    Carcinoids47943.2        
        Thymus8 337.5225.0225.03719 to 56
        Bronchus84 2428.61113.13238.14031 to 50
        Esophagus1 000011004 
        Stomach6 116.7116.7233.3315 to 56
        Small bowel265 7126.84717.77327.55548 to 62
        Appendix4 125.0125.0125.0130 to 32
        Large bowel44 2147.749.11022.73325 to 42
        Unknown primary67 2334.369.02232.84937 to 60
    PNET34230.8        
        Gastrinoma25 520.01040.0312.03221 to 42
        Insulinoma8 337.5112.5337.5176 to 29
        Glucagonoma8 450.0112.5112.53920 to 57
        VIPoma4 375.0125.000405 to 76
        ACTHoma2 150.000005.3 
        Nonfunctioning295 14549.24013.68528.86050 to 69
    Rare NET1039.3        
        Medullary thyroid cancer29 26.9724.1724.13620 to 52
        Neuroblastoma4 125.000125.0110 to 25
        Pheochromocytoma11 436.4218.2545.53215 to 49
        Paraganglioma28 310.7414.3621.48256 to 109
        Small-cell lung cancer12 18.300433.3210 to 47
        Pituitary gland tumor3 0000133.3740 to 203
        Merkel cell cancer8 225.0112.5125.063 to 10
        Cervix uteri2 000000  
        Other locations*6 233.30000224 to 39
    Unknown primary18516.76334.13317.86836.84736 to 58
Abbreviations: ACTHoma, adrenocorticotropic hormone–producing tumor; NET, neuroendocrine tumor; PNET, pancreatic neuroendocrine tumor; VIPoma, vasoactive intestinal peptide–producing tumor.
*
Tumors of other location included one Klatskin tumor, one neuroendocrine tumor of the ovary, two neuroendocrine tumors of the prostate, and two hepatic neuroendocrine tumors.
Patients with 25 different neuroendocrine cancer subtypes qualified for [90Y-DOTA]-TOC treatment. Treatment was feasible in all entities. However, a wide spectrum of morphologic, biochemical, and clinical response rates was found among the different subtypes (Table 1).

Response

Morphologic response was found in 378 patients (34.1%), and stable disease was found in 58 patients (5.2%). Accordingly, disease control was achieved in 436 patients (39.3%). Mixed response was found in two patients. Complete remission occurred in seven patients (0.6%), specifically in three patients with gastrinomas, two with nonfunctioning pancreatic neuroendocrine tumors, one with a Merkel cell tumor, and one with a neuroendocrine tumor of unknown origin. All demonstrated higher tumoral [90Y-DOTA]-TOC uptake compared with liver uptake (tumor score, 3; Fig 2). Their median time to progression was 12.7 months (range, 2.1 to 24.7 months). Biochemical response was found in 172 patients (15.5%), with a median tumor marker decrease of 56.9% (interquartile range, 39.8% to 72.8%). Clinical response was found in 329 patients (29.7%).
Fig 2. Intratherapeutic [111Indium-labeled tetraazacyclododecane-tetraacetic acid modified Tyr-octreotide] whole-body scans. (A) 61-year-old man with solitary scapula metastasis of a bronchus carcinoid (predictor: tumor uptake score, 1). (B) 76-year-old man with mediastinal metastasized medullary thyroid cancer (predictor: tumor uptake score, 2). (C) 85-year-old woman with a malignant paraganglioma (predictor: tumor uptake score, 3). (D) 52-year-old man with multiple cutaneous and pleural metastases from Merkel cell cancer (predictor: multiple metastases). (E) 63-year-old man with extensive liver metastases from a neuroendocrine cancer of unknown primary (predictor: liver metastases). (F) 29-year-old woman with extensive bone metastases from neuroblastoma (predictor: bone metastases). HR, hazard ratio.
Overall, 671 patients (60.5%) showed clinical response, biochemical response, and/or morphologic disease control after [90Y-DOTA]-TOC and thereby qualified for repeated cycles. Of these, 206 patients (20.2%) showed more than one type of response; the correlation between types of response is displayed in Appendix Figure A1 (online only).

Survival

Overall, 491 patients (44.3%) died, 609 (54.9%) survived, and nine (0.8%) were not available for follow-up. The median survival from diagnosis was 94.6 months. Cox regression analyses revealed that longer survival was found with morphologic (HR, 0.46; 95% CI, 0.38 to 0.56; median survival, 44.7 v 18.3 months; P < .001), biochemical (HR, 0.75; 95% CI, 0.59 to 0.96, median survival, 35.3 v 25.7 months; P = .023), and clinical response (HR, 0.68; 95% CI, 0.56 to 0.82; median survival, 36.8 v 23.5 months; P < .001). Additional analyses revealed that patients qualifying for re-treatment because of clinical response, biochemical response, and/or morphologic disease control had longer survival from both time of initial diagnosis (HR, 0.41; 95% CI, 0.34 to 0.50; median survival, 102.2 v 81.6 months; P < .001) and time of first [90Y-DOTA]-TOC treatment (HR, 0.68; 95% CI, 0.57 to 0.82, 45.6 v 16.8 months; P < .001; Fig 3A).
Fig 3. Survival and kidney toxicity after 90yttrium-labeled tetraazacyclododecane-tetraacetic acid modified Tyr-octreotide ([90Y-DOTA]-TOC; n = 1,109). Covariate-adjusted estimates of overall survival are shown for disease control versus progression after [90Y-DOTA]-TOC, whereas disease control was defined as (A) response (n = 631) or stable disease (n = 40) and (B) different scores of tumoral DOTA-TOC uptake. Disease control and high tumoral [90Y-DOTA]-TOC uptake are associated with longer survival from time of first [90Y-DOTA]-TOC treatment. (C) Cumulative incidence functions display the proportion of patients with renal toxicity for different scores of renal [90Y-DOTA]-TOC accumulation and competing event of death.
High tumor uptake of the radiopeptide, indicated by a high tumor score, was significantly associated with longer survival after [90Y-DOTA]-TOC treatment (36.0 v 22.8 v 20.4 months for tumor scores of 3, 2, and 1, respectively; Fig 3B). The estimated survival effects for all tested variables are listed in Table 2.
Table 2. Hazard Ratios for Overall Survival and Severe Kidney Toxicities After [90Y-DOTA]-TOC (N = 1,109)
Candidate VariableHR*95% CI*P
Overall survival   
    Sex (male v female)0.920.76 to 1.11.37
    Age (per 10 years)1.091.01 to 1.18.03
    Duration of disease (per year)0.980.96 to 1.01.23
    Previous surgery (v no surgery)0.780.63 to 0.96.02
    Previous chemotherapy (v no chemotherapy)1.581.30 to 1.93< .001
    Previous radiation (v no radiation)0.970.74 to 1.27.81
    Single metastasis (v multiple metastases)0.930.67 to 1.30.69
    Liver metastases (v no liver metastases)1.551.11 to 2.16.009
    Bone metastases (v no bone metastases)1.541.22 to 1.94< .001
    Tumor uptake score 2 (v score 1)0.600.35 to 1.01.055
    Tumor uptake score 3 (v score 1)0.450.29 to 0.69< .001
    Response (v no response)0.410.34 to 0.50< .001
Severe kidney toxicity   
    Sex (male v female)0.840.55 to 1.28.42
    Age (per 10 years)1.281.05 to 1.57.02
    Baseline glomerular filtration rate (per 10 mL/min/1.73 m2)0.800.73 to 0.87< .001
    Kidney uptake score (per score)1.591.17 to 2.17.003
Abbreviations: HR, hazard ratio; [90Y-DOTA]-TOC, 90yttrium-labeled tetraazacyclododecane-tetraacetic acid modified Tyr-octreotide.
*
Estimates for each covariable have been adjusted for histology as a categoric covariable as well as for all other covariables listed.
Sensitivity analyses indicated a 4% average annual decrease of the mortality hazard. The HRs for the main predictors, response and score, did not significantly change over the enrollment period. The predictors for 1-, 2-, and 5-year survival are listed in Appendix Table A1 (online only).
Overall, 731 patients showed no morphologic response. RECIST criteria were applicable in 159 of all 378 morphologic responders. Of these, seven achieved complete responses and 72 achieved partial responses (reduction of sum of longest diameter > 30%), whereas 80 showed stable disease (reduction of sum of longest diameter < 30%). Generally, response according to RECIST was associated with significantly longer survival than disease progression (HR, 0.54; 95% CI, 0.37 to 0.78; median survival, 53.8 v 43.2 months; P = .001). This effect was more pronounced in cases of complete response (HR, 0.32; 95% CI, 0.08 to 1.34; median survival, 73.0 v 43.2 months; P = .12) than in cases of partial response (HR, 0.56; 95% CI, 0.38 to 0.82; median survival, 50.8 v 43.2 months; P = .003; Appendix Fig A2, online only).

Adverse Events

Overall, 142 patients (12.8%) developed severe transient grade 3 to 4 hematologic toxicities (leucopenia, 67 patients; anemia, 11; thrombocytopenia, 64). Two patients developed myeloproliferative diseases after [90Y-DOTA]-TOC treatment (one developed myelodysplastic syndrome after two cycles; one, acute myeloic leukemia after four cycles).
Two patients experienced tumor lyses syndrome directly after [90Y-DOTA]-TOC with acute reversible kidney failure, and 102 patients (9.2%) experienced severe permanent renal toxicity (grade 4, 67 patients; grade 5, 35). There was no difference in the survival of patients with and without post-therapeutic kidney toxicity (P = .76).
Fifteen patients had a baseline glomerular filtration rate below 30 mL/min/1.73 m2; the remaining 1,095 were included in analyses to identify predictors of kidney toxicity. These analyses suggested that older age, low baseline glomerular filtration rate, and high kidney uptake score were associated with the occurrence of severe nephrotoxicity (Table 2; Fig 3C).
Two patients (0.2%) died on the day of the first [90Y-DOTA]-TOC administration. Autopsy revealed a duodenal ulcer bleeding as cause of death in a 50-year-old woman, whereas cause of death could not be established conclusively in an 83-year-old woman.

Discussion

This phase II trial in 1,109 patients with a wide spectrum of neuroendocrine cancers showed that response to [90Y-DOTA]-TOC was associated with longer survival; however, this involved risk of severe permanent renal toxicities. The results of this study enable the refinement of the clinical use of [90Y-DOTA]-TOC.
The present study demonstrates that [90Y-DOTA]-TOC can be used for the entire spectrum of neuroendocrine tumors. The different efficacies among different subtypes potentially derive from their respective somatostatin receptor status and radiosensitivity. Gastrinomas, for instance, encompass high somatostatin receptor expression15 and radiosensitivity,16 and complete remissions after [90Y-DOTA]-TOC were found more frequently in cases of gastrinomas than in other subtypes. Conversely, small-cell lung cancers have low somatostatin receptor expression,17 and in these, [90Y-DOTA]-TOC was much less effective. Thus, [90Y-DOTA]-TOC should preferably be used in subtypes with high somatostatin receptor expression.
Consistent with previous reports,18 high tumor load with multiple metastases and metastatic patterns involving liver and bones were associated with shorter survival. In constrast, high tumoral uptake in pretherapeutic somatostatin receptor imaging was associated with extended survival. Consequently, [90Y-DOTA]-TOC therapy is most promising and should be preferably used in patients with high pretherapeutic tracer uptake.
Response to [90Y-DOTA]-TOC was also associated with extended survival. Consequently, re-treatment seems to be a valuable option in responders, whereas nonresponders should be transferred to alternative treatment modalities. These modalities include streptozotocin-, fluorouracil-, and doxorubicin-based chemotherapies, which, however, are more efficient in de-differentiated than in differentiated neuroendocrine cancers.19 The kinase inhibitors sunitinib20 and everolimus21 and the radiopeptide [177Lutetium-DOTA]-TOC22 have shown promising results in differentiated neuroendocrine cancers. Yet contrary to both kinase inhibitors, [90Y-DOTA]-TOC and [177Lutetium-DOTA]-TOC frequently induce clinical responses.8,23
The median survival from diagnosis in this study was 94.6 months. Acknowledging the inherent problems of interstudy comparisons, survival after [90Y-DOTA]-TOC was 2.9 times longer than the expected 33-month survival (95% CI, 31 to 35) in patients with differentiated metastasized neuroendocrine cancer receiving various treatments.18
Loss of renal function remained the dose-limiting toxicity of [90Y-DOTA]-TOC.24 Infusions of amino acid solutions were used to inhibit tubular reabsorption of the radiopeptide. Nevertheless, the incidence of kidney toxicity increased yearly during follow-up. Additional research is warranted to avoid nephrotoxicity after [90Y-DOTA]-TOC. The predictors identified in this study are low baseline glomerular filtration rate, older age, and high renal tracer uptake in the somatostatin receptor whole-body scan. These predictors will be useful in identifying high-risk patients in need of additional renal protective measures.
Somatostatin receptor imaging was initially introduced as a diagnostic tool to detect somatostatin receptor–expressing tumors.4 Subsequently, it was established as a prognostic test, with longer survival in somatostatin receptor–positive tumors.25 In the present study, high tumor uptake was associated with longer survival, and high kidney uptake was associated with nephrotoxicity after [90Y-DOTA]-TOC. These results are in contrast with findings from our previous studies,7,26 which had, however, only limited statistical power. Somatostatin receptor imaging might become a valuable predictive imaging tool that allows for early identification of patients likely to benefit from [90Y-DOTA]-TOC. Upcoming trials are warranted to assess the predictive value of positron emission tomography with 68Ga-labeled somatostatin analogs, which has already shown superior diagnostic accuracy compared with simple scintigraphy.27
Strengths of the present study include the comprehensive recruitment of more than 1,000 patients from more than 100 international referring centers in 29 countries, representing the entire range of neuroendocrine tumors. This allowed for powerful analyses and enhanced the external validity of our findings. The single-center design provided homogeneity of intervention among all patients. Nevertheless, in collaborating with numerous international centers, we also faced several challenges. Patients and radioisotopes were scheduled 2 months before treatment. Thus, initial staging tests had to be performed at the referring center. Patients were transferred to our hospital 1 day before treatment and discharged to their respective home countries 2 days thereafter. Subsequently, follow-up assessments were performed at the referring centers.
Considering the variety of imaging modalities and laboratory tests available worldwide, we decided to use simple criteria for re-treatment: any sign of response or disease stabilization qualified for repeated cycles. Because all patients had experienced progression before enrollment, the decision for repeated [90Y-DOTA]-TOC cycles was made based on the perception of treatment-induced changes to the natural course of disease. This concept of disease control has already proved useful in other targeted therapies, such as erlotinib in non–small-cell lung cancer28; sorafinib,29 sunitinib,30 and everolimus31 in renal cell cancer; and trastuzumab32 and lapatinib33 in human epidermal growth factor receptor 2–positive breast cancer.
The simplified response criteria were easily applicable worldwide, but they are less strict than WHO34 or RECIST35 criteria. However, the fact that all three response definitions led to statistically highly significant correlations with survival proves that our findings are biologically and clinically meaningful. Indeed, the application of RECIST in a subset of patients revealed similar effects on overall survival.
The clinical benefit of [90Y-DOTA]-TOC has previously been demonstrated.8 In the present study, however, this effect was not longitudinally measured with quality-of-life assessment tools. Thus, quantitative analyses of the duration of the clinical benefit of [90Y-DOTA]-TOC remain for study in future trials.
In conclusion, this study examined the long-term outcome of [90Y-DOTA]-TOC in a large patient cohort with a wide spectrum of neuroendocrine cancers. Response to [90Y-DOTA]-TOC was associated with longer survival, along with the risk of significant nephrotoxicity. The initial scan was predictive for both survival after [90Y-DOTA]-TOC and renal toxicity and may become a useful tool for risk stratification.

Acknowledgment

We thank all patients and referring centers for their participation. Furthermore, we are grateful to our nursing, laboratory, and technical staff for their support in patient care, preparation of radiopharmaceuticals, and acquisition of all scans.We thank Anat Ben-Shlomo,Heiner Bucher, Johannes Czernin, and Gordon Guyatt for their helpful comments on themanuscript. Finally, we acknowledge the support of the Swiss National Science Foundation.
Clinical trial information can be found for the following: NCT00978211.

Authors' Disclosures of Potential Conflicts of Interest

The author(s) indicated no potential conflicts of interest.

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Appendix

Table A1. Hazard Ratios for Overall Survival and Kidney Toxicities 1, 2, and 5 Years After [90Y-DOTA]-TOC (N = 1,109)
Covariate1-Year Survival2-Year Survival5-Year Survival
HR*95% CI*PHR*95% CI*PHR*95% CI*P
Sex (male v female)0.890.66 to 1.19.430.880.70 to 1.11.300.940.78 to 1.16.50
Age (per 10 years)1.000.99 to 1.02.271.011.00 to 1.02.021.011.00 to 1.02.01
Duration of disease (per year)0.960.92 to 1.01.140.960.93 to 1.00.0490.980.96 to 1.01.16
Previous surgery (v no surgery)0.840.60 to 1.18.320.790.61 to 1.02.070.800.64 to 0.98.04
Previous chemotherapy (v no chemotherapy)1.871.35 to 2.52< .0011.731.36 to 2.20< .0011.691.37 to 2.06< .001
Previous radiation (v no radiation)0.720.46 to 1.15.150.860.60 to 1.20.370.980.72 to 1.28.88
Solitary metastases (v multiple metastases)1.180.70 to 1.86.511.010.67 to 1.46.951.040.72 to 1.42.80
Liver metastases (v no liver metastases)1.931.15 to 3.26.011.701.14 to 2.53.0091.571.12 to 2.22.009
Bone metastases (v no bone metastases)1.571.13 to 2.29.011.631.23 to 2.16.0011.511.18 to 1.91.001
Tumor uptake score 2 (v score 1)0.630.31 to 1.32.210.700.39 to 1.26.240.580.35 to 1.02.048
Tumor uptake score 3 (v score 1)0.400.20 to 0.71.0040.460.28 to 0.77.0030.460.28 to 0.68.001
Morphologic response (v no morphologic response)0.260.18 to 0.39< .0010.390.30 to 0.50< .0010.450.33 to 0.50< .001
Biochemical response (v no biochemical response)0.510.31 to 0.86.0120.710.51 to 0.99.0460.730.36 to 0.56.025
Clinical response (v no clinical response)0.360.25 to 0.53< .0010.500.38 to 0.64< .0010.600.49 to 0.75< .001
Abbreviations: HR, hazard ratio; [90Y-DOTA]-TOC, 90yttrium-labeled tetraazacyclododecane-tetraacetic acid modified Tyr-octreotide.
*
Estimates for each covariate have been adjusted for histology as a categoric covariable as well as for all other covariates listed.
Fig A1. Overall, 671 patients achieved clinical response, biochemical response, and/or morphologic disease control. Of these, 40 patients showed stable disease, whereas 631 patients showed tumor response. Among these responders, 206 patients showed more than one type of response. Spearman's rank correlation revealed significant correlation between biochemical response and clinical and morphologic response.
Fig A2. Survival after 90yttrium-labeled tetraazacyclododecane-tetraacetic acid modified Tyr-octreotide ([90Y-DOTA]-TOC) using RECIST (Response Evaluation Criteria in Solid Tumors) criteria (n = 810). Covariate-adjusted estimates of overall survival are shown for disease progression versus complete remission versus partial remission after [90Y-DOTA]-TOC according to RECIST criteria. HR, hazard ratio.

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Journal of Clinical Oncology
Pages: 2416 - 2423
PubMed: 21555692

History

Published online: May 09, 2011
Published in print: June 10, 2011

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Anna Imhof
Anna Imhof, Philippe Brunner, Nicolas Marincek, Matthias Briel, Helmut Rasch, Helmut R. Mäcke, Christoph Rochlitz, Jan Müller-Brand, and Martin A. Walter, University Hospital Basel; Christian Schindler, University of Basel, Basel, Switzerland; Matthias Briel, McMaster University, Hamilton, Ontario, Canada; and Martin A. Walter, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA.
Philippe Brunner
Anna Imhof, Philippe Brunner, Nicolas Marincek, Matthias Briel, Helmut Rasch, Helmut R. Mäcke, Christoph Rochlitz, Jan Müller-Brand, and Martin A. Walter, University Hospital Basel; Christian Schindler, University of Basel, Basel, Switzerland; Matthias Briel, McMaster University, Hamilton, Ontario, Canada; and Martin A. Walter, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA.
Nicolas Marincek
Anna Imhof, Philippe Brunner, Nicolas Marincek, Matthias Briel, Helmut Rasch, Helmut R. Mäcke, Christoph Rochlitz, Jan Müller-Brand, and Martin A. Walter, University Hospital Basel; Christian Schindler, University of Basel, Basel, Switzerland; Matthias Briel, McMaster University, Hamilton, Ontario, Canada; and Martin A. Walter, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA.
Matthias Briel
Anna Imhof, Philippe Brunner, Nicolas Marincek, Matthias Briel, Helmut Rasch, Helmut R. Mäcke, Christoph Rochlitz, Jan Müller-Brand, and Martin A. Walter, University Hospital Basel; Christian Schindler, University of Basel, Basel, Switzerland; Matthias Briel, McMaster University, Hamilton, Ontario, Canada; and Martin A. Walter, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA.
Christian Schindler
Anna Imhof, Philippe Brunner, Nicolas Marincek, Matthias Briel, Helmut Rasch, Helmut R. Mäcke, Christoph Rochlitz, Jan Müller-Brand, and Martin A. Walter, University Hospital Basel; Christian Schindler, University of Basel, Basel, Switzerland; Matthias Briel, McMaster University, Hamilton, Ontario, Canada; and Martin A. Walter, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA.
Helmut Rasch
Anna Imhof, Philippe Brunner, Nicolas Marincek, Matthias Briel, Helmut Rasch, Helmut R. Mäcke, Christoph Rochlitz, Jan Müller-Brand, and Martin A. Walter, University Hospital Basel; Christian Schindler, University of Basel, Basel, Switzerland; Matthias Briel, McMaster University, Hamilton, Ontario, Canada; and Martin A. Walter, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA.
Helmut R. Mäcke
Anna Imhof, Philippe Brunner, Nicolas Marincek, Matthias Briel, Helmut Rasch, Helmut R. Mäcke, Christoph Rochlitz, Jan Müller-Brand, and Martin A. Walter, University Hospital Basel; Christian Schindler, University of Basel, Basel, Switzerland; Matthias Briel, McMaster University, Hamilton, Ontario, Canada; and Martin A. Walter, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA.
Christoph Rochlitz
Anna Imhof, Philippe Brunner, Nicolas Marincek, Matthias Briel, Helmut Rasch, Helmut R. Mäcke, Christoph Rochlitz, Jan Müller-Brand, and Martin A. Walter, University Hospital Basel; Christian Schindler, University of Basel, Basel, Switzerland; Matthias Briel, McMaster University, Hamilton, Ontario, Canada; and Martin A. Walter, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA.
Jan Müller-Brand
Anna Imhof, Philippe Brunner, Nicolas Marincek, Matthias Briel, Helmut Rasch, Helmut R. Mäcke, Christoph Rochlitz, Jan Müller-Brand, and Martin A. Walter, University Hospital Basel; Christian Schindler, University of Basel, Basel, Switzerland; Matthias Briel, McMaster University, Hamilton, Ontario, Canada; and Martin A. Walter, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA.
Martin A. Walter [email protected]
Anna Imhof, Philippe Brunner, Nicolas Marincek, Matthias Briel, Helmut Rasch, Helmut R. Mäcke, Christoph Rochlitz, Jan Müller-Brand, and Martin A. Walter, University Hospital Basel; Christian Schindler, University of Basel, Basel, Switzerland; Matthias Briel, McMaster University, Hamilton, Ontario, Canada; and Martin A. Walter, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA.

Notes

Corresponding author: Martin A. Walter, MD, Institute of Nuclear Medicine, University Hospital, Petersgraben 4, CH-4031 Basel, Switzerland; e-mail: [email protected].
A.I., P.B., and N.M. contributed equally to this article.

Author Contributions

Conception and design: Matthias Briel, Christian Schindler, Helmut R. Mäcke, Christoph Rochlitz, Jan Müller-Brand, Martin A. Walter
Administrative support: Anna Imhof, Philippe Brunner, Nicolas Marincek, Jan Müller-Brand, Martin A. Walter
Collection and assembly of data: Anna Imhof, Philippe Brunner, Nicolas Marincek, Jan Müller-Brand, Martin A. Walter
Data analysis and interpretation: Matthias Briel, Christian Schindler, Helmut Rasch, Christoph Rochlitz, Martin A. Walter
Manuscript writing: All authors
Final approval of manuscript: All authors

Disclosures

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

Funding Information

Supported by the Swiss National Science Foundation.

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Anna Imhof, Philippe Brunner, Nicolas Marincek, Matthias Briel, Christian Schindler, Helmut Rasch, Helmut R. Mäcke, Christoph Rochlitz, Jan Müller-Brand, Martin A. Walter
Journal of Clinical Oncology 2011 29:17, 2416-2423

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