ORIGINAL ARTICLE

Outcome and toxicity of salvage therapy with 177Lu-octreotatein patients with metastatic gastroenteropancreaticneuroendocrine tumours

Amir Sabet & Torjan Haslerud & Ulrich-Frank Pape &

Amin Sabet &Hojjat Ahmadzadehfar & FrankGrünwald &

Stefan Guhlke & Hans-Jürgen Biersack & Samer Ezziddin

Received: 15 April 2013 /Accepted: 14 August 2013 /Published online: 13 September 2013# Springer-Verlag Berlin Heidelberg 2013

AbstractPurpose We assessed the outcome and toxicity of salvage ther-apy (repeat treatment) with 177Lu-octreotate and high cumulativeactivities in patients with metastatic gastroenteropancreatic neu-roendocrine tumours (GEP-NET).Methods We retrospectively analysed a consecutive cohort of33 patients with metastatic GEP-NETwho underwent salvagepeptide receptor radionuclide therapy (PRRT) in our institu-tion. All patients had progressive NET prior to salvage treat-ment and had shown an initial response to PRRT. The meancumulative activity was 44.3 GBq (30.0–83.7 GBq). Radio-graphic response was assessed using CT and/or MRIaccording to modified SWOG criteria. Toxicity was evaluatedusing laboratory data, including complete blood counts andrenal function tests using CTCAE 3.0. Survival analysis wasperformed with the Kaplan-Meier curve method and a signif-icance level at p <0.05.Results Radiographic responses consisted of complete re-sponse in 1 patient (3.0 %), partial response in 6 patients(18.2 %), minor response in 1 patient (3.0 %), stable diseasein 14 patients (42.4 %), and progressive disease in 11 patients(33.3 %). Median progression-free survival (PFS) from the

start of salvage therapy was 13 months (95 % CI 9–18) andpatients with a history of a durable PFS after initial PRRTtended to have long-lasting PFS after salvage treatment(p =0.04). None of the patients developed severe nephrotox-icity (grade 3/4) or a myelodysplastic syndrome duringfollow-up. Relevant albeit reversible haematotoxicity (grade3/4) occurred in 7 patients (21.2 %). The cumulative admin-istered activity was not associated with an increased incidenceof haematotoxicity.Conclusion PRRTwith 177Lu-octreotate in the re-treatment set-ting is safe and effective in patients with metastatic GEP-NET.

Keywords PRRT . 177Lu-octreotate . NET . Salvage therapy

Introduction

Peptide receptor radionuclide therapy (PRRT) with radiolabelledsomatostatin analogues is a highly effective systemic treatment inpatients with metastatic gastroenteropancreatic neuroendocrinetumours (GEP-NET) with a low overall toxicity [1–10]. Never-theless, substantial numbers of patients will experience diseaseprogression after a period of remission or disease stabilization,and further PRRT especially with 90Y-labelled peptides mayincrease the risk of severe toxicity [11–13]. Due to the lowerenergy profile and the shorter tissue penetration of the emittedbeta particles, 177Lu-labelled peptides may be safer in this setting[14–16]. However, there is a lack of published data regarding thefeasibility of PRRT with 177Lu-octreotate as a salvage therapy[17]. We assessed the safety and efficacy of PRRT with 177Lu-octreotate in patients with relapse of progressive NET whoinitially benefited from this treatment. Special attention wasgiven to the impact of higher cumulative activities on the inci-dence of toxicity.

A. Sabet : T. Haslerud :A. Sabet :H. Ahmadzadehfar : S. Guhlke :H.<J. Biersack : S. Ezziddin (*)Department of Nuclear Medicine, University Hospital Bonn,Sigmund-Freud-Str. 25, 53105 Bonn, Germanye-mail: samer.ezziddin@ukb.uni-bonn.de

U.<F. PapeDepartment of Hepatology and Gastroenterology, Charité, CampusVirchow Clinic, University Medicine Berlin, Berlin, Germany

F. GrünwaldDepartment of Nuclear Medicine, University Hospital, Frankfurt,Germany

Eur J Nucl Med Mol Imaging (2014) 41:205–210DOI 10.1007/s00259-013-2547-z

Methods and materials

Initial and salvage PRRT were performed in accordance withthe principles of the Declaration of Helsinki and with nationalregulations. Treatment decisions were made on a multidisci-plinary basis and all subjects provided written informed con-sent. The local committee on ethics approved this retrospec-tive study.

Patients

Included into this retrospective analysis were 33 consecutivepatients (mean age 61 years, range, 43–76 years) who hadreceived salvage PRRTwith 177Lu-octreotate at our institutionbetween 2007 and 2012. All patients had initially respondedto the PRRT but showed tumour progression prior to salvagetherapy. All patients had well-differentiated (G1/G2), distantmetastatic GEP-NET (TNM stage IV). Of the 33 patients, 14had pancreatic NET, and 19 had nonpancreatic GEP-NET, ofwhich 3 were foregut GEP-NET, 6 were midgut GEP-NET, 3were hindgut GEP-NET, and 7 were other GEP-NETs includ-ing an unknown primary. Metastatic sites included the liver in30 patients, lymph nodes in 16, bone in 12 and other organs in7. Apart from PRRT with 177Lu-octreotate, previous treat-ments comprised surgery, biotherapy, chemotherapy andlocoregional treatment (Table 1).

PRRT

Inclusion criteria for salvage PRRT were sufficient traceruptake (equal to or greater than that of normal liver) onsomatostatin receptor images obtained less than 3 weeks be-fore the start of salvage PRRT, a glomerular filtration rate(GFR) of >30 mL/min/1.73 m2, haemoglobin of ≥8 g/dl, awhite blood cell count of ≥2×109/L, and platelets of ≥70×109/L. A mean activity of 7.4 GBq of 177Lu-octreotate per treat-ment cycle was administered at standard intervals of 3 months(10–14 weeks). The 177Lu (IDB Holland, Baarle-Nassau,Netherlands) had a specific activity in the approximate range100–160 GBq/μmol at the time of administration. The peptidewas labelled to provide an apparent specific activity of about

54 GBq/μmol (ratio of activity to the total amount of peptide).Nephroprotection was implemented with standard amino acidcoinfusion according to the Rotterdam protocol (2.5 % lysineand 2.5 % arginine in 1 L 0.9 % NaCl; infusion at 250 mL/h)[15, 18]. Short-acting somatostatin analogues were stopped1 day and long-acting analogues at least 6 weeks beforeadministration of 177Lu–octreotate.

Assessment of toxicity and treatment response

Haematological parameters were determined prior to each treat-ment course, at intervals of 2–4 weeks between the courses,8–12 weeks after the last course of PRRT, and at intervals of3 months in the further follow-up. GFR was measured prior toeach treatment course and at intervals of 6 months after the endof treatment using the 99mTc-DTPA clearancemethod. This wasperformed as a single injection technique with a two samplingpoints at 1 h and 3 h after injection according to the method ofRussell et al. [19]. Toxicity was recorded using the CommonTerminology Criteria for Adverse Events (CTCAE) v3.0.

Patients were restaged 3 months after the end of PRRT byCT or MRI. The results of somatostatin receptor imaging(111In-DTPA-octreotide, 68Ga-DOTA-TOC PET/CT) werenot included in the study response classification. Follow-upimaging was performed at intervals of 6 months after the firstrestaging. Overall tumour response was defined according tothe modified Southwest Oncology Group (SWOG) solid tu-mour response criteria [20, 21]; an additional response cate-gory, minor response, was defined as a 25–49 % remission ofthe sum of products of the perpendicular diameters of allmeasurable tumour lesions.

Statistical analysis

The relationship between treatment-induced toxicity with thecumulative administered activity was examined using non-parametric tests for independent samples. The correlationbetween time-to-progression after initial and after salvagePRRT was analysed using Pearson’s correlation coefficienttest. Progression-free survival (PFS) was censored at the timeof starting another significant treatment, such as chemothera-py but not somatostatin analogue medication. In patients whoreceived somatostatin analogue treatment for symptomaticcontrol (three patients), any alteration in the required dosesof somatostatin analogues was considered as a nonsignificantmodification of treatment and not a sign for response ordisease progression for PFS assessment. Survival analysiswas performed using the Kaplan-Meier curve method. Alltests were performed with a significance level of p <0.05.The statistical software package SPSS (version 20; SPSSInc., Chicago, IL) was used for the analysis.

Table 1 Previous treatments in the 33 patients who had received salvagePRRT

Previous therapy No. (%) of patients

PRRT 33 (100)

Surgery 13 (39.4)

Biotherapy 17 (51.6)

Chemotherapy 9 (27.3)

Locoregional treatment 6 (18.2)

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Results

A total of 79 courses of salvage PRRTwere administered to 33patients (median two treatment courses per patient). We aimedat a minimum of two cycles and further repeated cycles (up tofour in total) were dependent on the patient’s clinical condi-tion, tumour load and recorded toxicities, and patient request.Thus 22 patients received two treatment cycles, 3 patientsreceived three cycles and 5 patients received four cycles inthe salvage setting. The remaining 3 patients received onlyone cycle because of low tumour load. 177Lu-octreotate ad-ministrations were well tolerated without any serious acuteadverse events. The mean administered activity during sal-vage therapy was 17.7 GBq (8.0–33.2 GBq) and the cumula-tive activity was 44.3 GBq (30.0–83.7 GBq). The medianfollow-up period was 37±16 months from the start of initialPRRT and 23±7 months from the start of salvage PRRT.

At the start of salvage treatment, 24 patients had baselinereductions in at least one blood cell type (platelets, red bloodcells or white blood cells): anaemia in 18 patients (14 grade I,4 grade II), thrombocytopenia in 14 patients (13 grade I, 1grade II), and leucopenia in 12 patients (8 grade I, 3 grade II, 1grade III) according to CTCAE criteria. One patient receivedPRRT despite grade III leucopenia at baseline because of alack of treatment alternatives and progressive tumour disease.Relevant haematotoxicity (grade III/IV) was observed 3–10 weeks after 13 administrations (16.5 %) or, on a per-patient basis, after at least one of the administrations in sevenpatients (21.2 %). Significant leucopenia and thrombocytope-nia occurred after nine administrations (11.4 %) and anaemiaafter four administrations (5.1%; Table 2). Blood count valuesreturned to within normal ranges in all patients, and the meantime to complete bone marrow recovery was 14 months afterthe end of PRRT (range 3–24 months). Higher cumulativeactivity was not associated with a higher incidence or degreeof myelosuppression (Fig. 1).

The change in GFR varied widely among the patients.However, we observed no significant nephrotoxicity (grade3 or higher) during the follow-up period. The mean relativechange in GFR was −3±25.1 % per year (median −1.0 % peryear). An increase in GFR was seen in 15 patients (median11 %, mean of 14 % per year) after salvage PRRT. Patientswho received higher cumulative activities showed a trendtowards a more pronounced decline in GFR, but the correla-tion was not statistically significant (p =0.08, Fig. 2).

Table 2 PRRT-induced toxicities according to CTCAE v.3

Toxicity Per patient Per cycle

n % n %

Leucopenia 5 15.2 9 11.4

Grade 3 4 12.2 8 10.1

Grade 4 1 3.0 1 1.3

Thrombocytopenia 5 15.2 9 11.4

Grade 3 3 9.1 6 7.6

Grade 4 2 6.1 3 3.8

Anaemia 2 6.1 4 5.1

Grade 3 2 6.1 4 5.1

Grade 4 0 0.0 0 0.0

Total 7 21.2 13 16.5

Fig. 1 Relationship between cumulative administered activity and inci-dence of haematotoxicity after each treatment cycle (n=79).WBC whiteblood cells, Hb haemoglobin, PLT platelets, No/Yes means significanthematotoxicity yes/no (No significant (= 0–2° CTC) or significant(=3–4° CTC) hematotoxicty)

Fig. 2 Relationship between cumulative administered activity and rela-tive change in GFR (% per year)

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Before the initiation of salvage PRRT three patients werereceiving somatostatin analogue treatment because of func-tional symptoms. Two of these patients showed a partialresolution of symptoms after PRRT which resulted in reduc-tion of the required doses of somatostatin analogue treatment.

The observed treatment response consisted of a completeresponse in 1 patient (3.0 %), partial remission in 6 (18.2 %),minor response in 1 (3.0 %), stable disease in 14 (42.4 %), andprogressive disease in 11 (33.3%).Median PFSwas 13months(95%CI 9–18months) from the start of salvage treatment. PFSafter initial PRRT (median 22 months, 95 % CI 19–25 months)was correlated with PFS after salvage PRRT: patients with ahistory of a durable PFS after initial PRRT tended to have long-lasting PFS after salvage treatment as well (p =0.04, Fig. 3).The Kaplan-Meier plot for the patient cohort is shown in Fig. 4.

Discussion

This retrospective study in 33 patients showed that PRRTwith177Lu-octreotate may be an effective and safe salvage treat-ment for patients with GEP-NET who previously benefitedfrom PRRT. The observation of stabilization or remission ofthe disease in 22 patients (67 %) and a median PFS of13 months (95 % CI 9–18 months) is very remarkable andencourages the use of 177Lu-octreotate in patients with relapseof progressive disease. In our cohort, patients who experi-enced relapse in later stages after the initial PRRT alsoexhibited a longer time to progression after the salvage treat-ment. This observation suggests that PFS after the initialPRRT could be used as a prognostic factor before the start ofsalvage treatment. Consistent with previous reports [17], PFSafter initial PRRT (median 22 months) was correlated withPFS after salvage PRRT (median 13 months, p =0.008). Thisobservation suggests that the initially achieved PFS (after thefirst PRRT) could be used as a predictor of outcome aftersalvage PRRT.

Significant haematotoxicity following standard treatmentwith 177Lu-octreotate (cumulative activity <29.6 GBq) hasbeen reported in 3.6 % of administrations and in 9.5 % of504 patients with advanced GEP-NET [17, 22–28]. In ourretreatment study cohort, the rates were considerably higher:administration of high cumulative activities in the range 30.0–83.7 GBq led to relevant—albeit reversible—haematotoxicity(grade 3/4) after 16.5 % of administrations and in 21.2 % ofpatients. These results are in accordance with the results of theonly published study on haematotoxicity after treatment withcumulative activities >30 GBq 177Lu-octreotate and underlinethe acceptable toxicity profile of PRRT in the salvage treatment

Fig. 4 Kaplan-Meier curve forPFS after salvage PRRT (medianPFS 13 months, 95 % CI 9–18 months)

Fig. 3 Relationship between PFS after initial PRRTand PFS after salvagePRRT (p=0.008)

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setting and even after administration of high cumulative activ-ities of 177Lu-octreotate [17]. Myelodysplastic syndrome wasnot observed in our patients. This may have been due to therelative short follow-up period in our study as this delayed sideeffect may appear months to years after treatment [2, 15, 29].However, the poor prognosis in patients with advanced meta-static NETand the low risk of this late side effect should not bemajor arguments against performing salvage PRRT.

Renal toxicity (grade 3/4) after treatment with 177Lu-labelledsomatostatin analogues has been reported in less than 3 % ofpatients [14, 27, 30, 31]. In our study, no patient experiencedsignificant renal impairment during follow-up but a trend to-wards more pronounced reductions in GFR was seen afteradministration of higher activities (p =0.08). However, anyobservation regarding the renal safety after salvage PRRTshould be viewed with particular caution as renal functionimpairment may become clinically evident months after thetreatment [12, 32–35]. A mild to moderate posttreatment in-crease in GFR was observed in 15 patients (45.5 %) which wasmost probably due to the tumoricidal effects of treatment andthe improvement in general condition of the patients.

This study had several limitations. Themain limitations of thisstudy are the retrospective setting and the small patient cohort.Moreover, the relatively short and variable follow-up periodrestricts the strength of the conclusions, especially regarding therenal safety of salvage PRRTand the absence of myelodysplasticsyndrome in patients receiving high cumulative activities.

Conclusion

PRRT with 177Lu-octreotate is feasible, safe and effective inpatients with advanced inoperable GEP-NET relapsing afterprevious 177Lu-based PRRT. The initially achieved PFS mayserve as a predictor for estimating outcome after salvage PRRT.Future studies should eventually provide a potential cut-off forcumulative administered activities above which there is anincreased risk of serious adverse events.

Conflicts of interest None.

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