Efficacy of peptide receptor radionuclide therapy with ¹⁷⁷Lu-octreotate in metastatic pulmonary neuroendocrine tumors: a dual-centre analysis

Abstract

There is lack of data on the specific benefit of peptide receptor radionuclide therapy (PRRT) in neuroendocrine tumors (NET) of pulmonary origin. This dual- centre study aimed to assess outcome and toxicity of standardized PRRT with ¹⁷⁷Lu-octreotate in a patient population of advanced pulmonary NET of grade 1-2. We retrospectively assessed 22 consecutively patients treated with 4 intended cycles at 3 monthly intervals (mean activity per cycle 7.8±0.68 GBq). In a median follow-up period of 54 months, no significant nephrotoxicity (≥ grade 3) was observed. Reversible hematotoxicity (grade 3) occurred in 3 patients (13.6%). Treatment response consisted of partial response in 6 (27.3%), stable disease in 9 (40.9%), and progressive disease in 7 (31.8%) patients. Median progression-free survival (PFS) and overall survival (OS) was 27 (95% CI, 9-45) and 42 months (95% CI, 25-59), respectively. High hepatic tumor load (> 50%) and high plasma chromogranin A (> 600 ng/mL) were negative baseline predictors for PFS and OS on univariate analysis, CgA remained significant on multivariate analysis (PFS, P=0.011; OS, P=0.026). Disease progression despite PRRT was associated with shorter survival (median OS 15 vs 53 mo, P<0.001). Despite a higher incidence of treatment failure compared to NET of other origins, the observed substantial and sustained disease stabilization (median PFS of 27 mo, disease control rate of > 2/3 of pts) indicates considerable efficacy of ¹⁷⁷Lu-octreotate in pulmonary NET.

Introduction

Well-differentiated neuroendocrine tumors (NET) of the respiratory tract, i.e. pulmonary NET, are rare malignancies with a serotonin-secreting potential comprising typical (low grade) and atypical (intermediate grade) forms [1]. Patients with metastatic pulmonary NET have generally worse prognosis compared to patients with metastatic NETs of other origins [2]. Furthermore, serotonin-related hypersecretion syndrome with intractable flushing may impact the quality of life in advanced metastatic stages. Treatment with somatostatin analogs is the recommended first-line therapy for unresectable disease with significant anti-secretory and suggested anti-proliferative, but very little cytoreductive capacities. Effective treatment options for somatostatin analog-refractory patients with uncontrolled functional symptoms or progressive metastatic disease are limited [3,4]. Various cytotoxic chemotherapy regimens and novel targeted treatments have shown only minor survival benefit with significant toxicity in a considerable portion of patients [5,6].

Peptide receptor radionuclide therapy (PRRT) with radiolabeled somatostatin analogs is a highly effective treatment for metastatic NET with outstanding treatment tolerance and low toxicity [7-9]. However, data regarding the outcome of pulmonary NET after PRRT have been mainly driven form subgroup analyses of ⁹⁰Y-based treatment in NET of different origins [10-15]. The only available report restricted to patients with pulmonary NET has described the outcome in a heterogeneous cohort treated with different compounds (¹⁷⁷Lu-octreotate, ⁹⁰Y-DOTATOC, or the combination) [16]. Although the inter-individual diversity of the treatment schemes hampered accurate comparative analyses, ¹⁷⁷Lu-octreotate seemed superior to ⁹⁰Y-DOTATOC [16]. In this dual-centre evaluation we aimed to assess the outcome and toxicity of PRRT with ¹⁷⁷Lu-octreotate in a well-characterized patient population with metastatic well-differentiated pulmonary NET (G1/2) and to explore potential predictors for impaired survival.

Material and methods

We retrospectively analyzed a consecutive cohort of 22 patients (16 men, 6 women; mean age 63 y; range, 42-74) with distant metastatic, unresectable pulmonary NET (stage IV), who underwent PRRT with ¹⁷⁷Lu-octreotate [17]. Other inclusion criteria for PRRT were sufficient tumor uptake, i.e. ≥ liver uptake on baseline receptor imaging, a glomerular filtration rate of > 30 ml/min/1.73 m², a WBC count ≥2000/mm³, haemoglobin ≥8 g/dl and platelets ≥75000/mm³. Treatment decisions were made on a multi-disciplinary basis. 17 patients (77.3%) had documented morphological tumor progression within 12 months before initiation of PRRT. The remaining 5 patients (22.7%) showed uncontrolled functional symptoms despite biotherapy with somatostatin analog medication. 10 patients (45.5%) had functioning tumors with serotonin hypersecretion-related symptoms. 8 patients (36.4%) had extensive hepatic tumor burden, i.e. metastatic replacement of > 50% of total liver volume according to pretreatment CT/MRI. Metastatic sites included the liver in 19 (86.4%), lymph nodes in 10 (45.5%), bone in 15 (68.2%) and other organs in 6 (27.3%) patients. Previous treatments were comprised of biotherapy (n=16, 72.7%), surgery (n=14, 63.6%), chemotherapy (n=7, 31.8 %), and locoregional treatment (n=1, 4.6%). The study was performed in accordance with the Declaration of Helsinki and with national regulations. The local committee on ethics approved this retrospective study, and all patients signed written informed consent.

PRRT

PRRT was performed by standard protocol with administration of a mean activity of 7.8±0.68 GBq (211±18 mCi) ¹⁷⁷Lu-octreotate per treatment cycle, aimed at four courses and standard intervals of 3 months (10-14 weeks). The ¹⁷⁷Lu (IDB Holland, Baarle-Nassau, Netherlands) had a specific activity of approximately 100-160 GBq/μmol at the time of administration. The peptide labeling was performed to obtain an apparent specific activity of about 54 GBq/μmol (ratio of activity to the total amount of peptide) [18,19]. Nephroprotection was implemented with standard amino acid co-infusion according to the Rotterdam protocol (lysine 2.5% and arginine 2.5% in 1 L 0.9% NaCl; infusion of 250 ml/h). As described in previous reports, tumor uptake was classified according to the ¹⁷⁷Lu-octreotate therapy scan of the first PRRT cycle (grade 3, > kidney/spleen; grade 2, > liver; grade 1 ~liver) [20,21]. This was done to standardize the uptake score for the entire cohort, since some patients underwent somatostatin receptor scintigraphy (eg. Octreoscan) at baseline whereas others received PET imaging with ⁶⁸Ga labeled somatostatin analogs.

Response and toxicity assessment

Hematological parameters were determined prior to each treatment course, in 2-4 weeks intervals between the courses, 8-12 weeks after the last course of PRRT and in 3 monthly intervals in the further follow-up. Toxicity was recorded using the Common Terminology Criteria for Adverse Events v3.0 (CTCAE). Symptomatic response in functioning tumors (n=10) was assessed according to the change in the intensity and frequency of tumor-specific symptoms and was categorized into complete resolution, partial resolution (≥50% reduction), no significant change, and progression of functional symptoms. Restaging was performed 3 months after termination of PRRT. Imaging consisted of CT and/or MRI according to the baseline imaging modality. Follow-up imaging was performed in 6-month intervals after the first restaging. In order to facilitate comparison with other studies, tumor response was classified according to Response Evaluation Criteria in Solid Tumors (RECIST) 1.1.

Survival assessment and statistical analysis

Survival analysis was performed using the Kaplan-Meier curve method. Progression free survival (PFS) was censored at the start of another anti-proliferative treatment. Univariate analysis using the log-rank test was performed for each baseline factor. Multivariate analysis (Cox proportional-hazards model) was performed with those variables showing significance on univariate analysis (log-rank test). All tests were performed with a significance level of P<0.05. The statistical software package SPSS (version 20; SPSS Inc., Chicago/ IL, USA) was used to analyze the data.

Results

22 patients underwent PRRT with ¹⁷⁷Lu-octreotate. The mean cumulative activity per patient was 27.2±5.9 GBq. ¹⁷⁷Lu-octreotate administrations were well tolerated without any serious acute adverse events. In 4 patients (18.1%), treatment was stopped after 1 (n=1) or 2 (n=3) cycles because of a documented disease progression. Relevant hematotoxicity (grade 3) was observed 3-10 weeks after at least one of the administrations in 3 patients (13.6%). Blood count values returned to the normal range in all patients, the mean time to complete bone marrow recovery was 19 months after termination of PRRT (range 9-22 months). No significant nephrotoxicity (≥ grade 3) was observed during the follow-up and the mean relative change of GFR was -1% per year. No other relevant toxicities or treatment related deaths were observed. 3 of 10 patients (30%) with functional symptoms had complete and 7 patients (70%) partial resolution of symptoms after treatment. The observed treatment response according to RECIST 1.1 criteria consisted of partial response (PR) in 6 (27.3%), stable disease (SD) in 9 (40.9%), and progressive disease (PD) in 7 (31.8%) patients. An example of a patient with partial response to PRRT is illustrated in Figure 1. Disease control rate (DCR) was 68.1% and patients with high hepatic tumor load (> 50%), neuron-specific enolase (NSE) plasma levels > 15 ng/ml and chromogranin A (CgA) plasma levels > 600 ng/ml tended to fail treatment (i.e. progress despite PRRT). The baseline characteristics of the study population and the associated DCR are given in Table 1.

Figure 1.

Partial remission illustrated by ⁶⁸Ga-DOTATOC PET/CT before (A) and 3 months after (B) PRRT in a patient with metastatic pulmonary NET. From left to right: Maximum-intensity-projection PET images (coronal view), fused PET-CT and unfused CT images.

Table 1.

Patient characteristics and disease control rate (DCR) according to RECIST 1.1 (SD and PR)

Variable	N	DCR (%)	P
Total	22	15 (68.2)
Age
≤ 65 y	14	10 (71.4)	0.512
> 65 y	8	5 (62.5)
Ki-67 index
≤ 2%	9	8 (88.9)	0.101
3-20%	13	7 (46.7)
Hepatic tumor burden
≤ 50%	14	12 (85.7)	0.052
> 50%	8	3 (35.7)
Tracer uptake
≤ grade 2	10	6 (60)	0.652
> grade 2	12	9 (75)
Progression at baseline
No	5	4 (80)	1.0
Yes	17	11 (64.7)
Presence of BMs
No	7	5 (71.4)	1.0
Yes	15	10 (66.7)
Functionality
Non-functional	12	8 (66.7)	1.0
Functional	10	7 (70.0)
CgA
≤ 600 ng/ml	7	7 (100)	0.051
> 600 ng/ml	15	8 (53.3)
NSE
≤ 15 ng/ml	9	9 (100)	0.017
> 15 ng/ml	13	6 (46.2)
Typical/Atypical
Typical	5	4 (80)	1.0
Atypical	17	11 (64.7)

CgA, chromogranin A; NSE, neuron-specific enolase; BMs, bone metastases.

Median PFS of the entire cohort was 27 months (95% CI, 9-45; Figure 2A). The baseline variables associated with shorter PFS in the univariate analysis were CgA > 600 ng/ml (P=0.006) and hepatic tumor load > 50% (P=0.008). As shown in Table 2 high CgA levels remained a significant predictor of earlier progression on multivariate analysis with cox proportional-hazards model: HR 4.4 (95%-CI, 1.4-13.6), P=0.011. The median follow-up period was 54 months (range 5-75) and 9 patients were still alive at the time of analysis. The median OS of the entire cohort was 42 months (95% CI, 25-59; Figure 2B). Treatment failure, i.e. disease progression despite PRRT, was associated with shorter survival: median OS of 15 mo (95% CI, 12-18) vs. 53 mo (95% CI, N/A), P<0.001 (Figure 3). The analysis of various baseline factors for potential contribution to OS is shown in Table 3. High hepatic tumor load (P=0.009) and high CgA levels (P=0.006) again were the only risk factors for impaired survival on univariate analysis; CgA > 600 ng/ml remained the only independent predictor of shorter OS on multivariate analysis: (HR 10.4 (95%-CI, 1.3-72.8), P=0.026). Kaplan-Meier curves (PFS and OS) of patients stratified by CgA and hepatic tumor burden are shown in Figure 4. Survival outcome of patients with typical and atypical tumors were similar (P=0.323). Patients with documented pretreatment morphologic tumor progression had comparable outcome to that of the remaining patients (P=0.570).

Figure 2.

Progression-free (A) and overall (B) survival of the entire patient cohort. The median PFS and OS were 27 months (95% CI, 9-45) and 42 months (95% CI, 25-59), respectively.

Table 2.

Uni- and multivariate analyses for potential factors associated with progression-free survival after PRRT

Variable	PFS (95% CI)	Univariate analyses	Multivariate analysis
		p	HR (95% CI)	p
Total	27 (9-45)
Age
≤ 65 y	23 (5-41)	0.171
> 65 y	20 (1-72)
Ki-67 index
≤ 2%	29 (22-36)	0.276
> 2%	14 (1-44)
Hepatic tumor burden
≤ 50%	8 (5-11)	0.008	1.9 (0.7-5.7)	0.224
> 50%	32 (29-35)
Tracer uptake
≤ grade 2	23 (1-50)	0.703
> grade 2	26 (1-51)
Presence of BMs
No	26 (1-52)	0.446
Yes	31 (12-50)
Functionality
No	31 (6-56)	0.268
Yes	23 (7-38)
CgA
≤ 600 ng/ml	42 (27-56)	0.006	4.4 (1.4-13.6)	0.011
> 600 ng/ml	16 (6-26)
NSE
≤ 15 ng/ml	35 (29-40)	0.088
> 15 ng/ml	9 (1-17)
Typical/atypical histology
Typical	29 (9-49)	0.758
Atypical	26 (6-47)

CgA, chromogranin A; NSE, neuron-specific enolase; BMs, bone metastases.

Figure 3.

Kaplan-Meier curves illustrating impaired survival of patients failing treatment, i.e. having progressive disease despite PRRT. The median OS of these patients was 15 mo (95% CI, 12-18) vs. 53 mo (95% CI, N/A) in the remaining patients (P<0.001).

Table 3.

Overall survival according to various baseline factors

Variable	OS (95% CI)	Univariate analyses	Multivariate analysis
		p	HR (95% CI)	P
Total	42 (24-60)
Age
≤ 65 y	42 (29-60)	0.883
> 65 y	33 (N/A)
Ki-67 index
≤ 2%	53 (N/A)	0.082
> 2%	33 (11-55)
Hepatic tumor burden
≤ 50%	NR	0.009	2.3 (0.7-8.1)	0.183
> 50%	27 (9-45)
Tracer uptake
≤ grade 2	33 (17-49)	0.569
> grade 2	47 (34-60)
Progression at baseline*
Yes	NR	0.570
No	42 (26-58)
Bone metastases
Yes	33 (27-39)	0.710
No	53 (16-90)
Functionality
Non-functional	NR	0.306
Functional	33 (14-52)
CgA
≤ 600 ng/ml	NR	0.006	10.4 (1.3-72.8)	0.026
> 600 ng/ml	33 (23-43)
NSE
≤ 15 ng/ml	47 (34-60)	0.266
> 15 ng/ml	33 (11-55)
Histology
Typical	42 (24-60)	0.323
Atypical	35 (N/A)

^*Documented pretreatment morphologic tumor progression within 12 months before initiation of PRRT;

NR, not reached.

Figure 4.

Progression-free survival (above) and overall survival (below) stratified by pre-treatment plasma levels of chromogranin A (CgA, cut-off 600 ng/ml; left) and hepatic tumor burden (liver volume replacement, cut-off 50%; right).

Discussion

This retrospective dual-centre analysis provides efficacy results including explicit progression-free survival and overall survival of PRRT in a patient cohort with advanced well-differentiated pulmonary NET after failing standard treatment with somatostatin analogs. Despite the small patient number (n=22) these findings seem important as they convey the idea on the persistent anti-proliferative activity of ¹⁷⁷Lu-octreotate in this specific NET entity at an advanced stage. Achievement of disease-control in more than 2/3 of the patient cohort and long-term stabilization with a median PFS of 27 months is very promising in the context of lacking established treatment alternatives.

Effective treatment options for patients with uncontrolled functionality (carcinoid syndrome) or tumor progression in metastatic pulmonary NET of well-differentiated histology are very limited. Previous investigations with various chemotherapy agents, either as mono- or combined-therapy, were generally discouraging. Best results have been observed after treatment of 13 patients (10 typical and 3 atypical carcinoids) with oral temozolomide achieving PR in 4 (31%) patients and disease stabilization in 8 (62%) patients [22]. Novel targeted treatments with tyrosine-kinase inhibitors such as sunitinib or inhibitor of mammalian target of rapamycin everolimus were also associated with limited efficacy in patients with non-pancreatic NET [23-26]. In a recent trial on patients with non-functional neuroendocrine tumors of lung or gastrointestinal origin (RADIANT4), everolimus could prolong the PFS in 203 patients including 63 patients with pulmonary NET to less than 15 months [27]. Particular efficacy in pulmonary NET, however, has only been reported in an earlier study on 33 patients and showed a statistically insignificant trend towards longer PFS (13.6 mo) under everolimus compared to 11 patients who received placebo (5.6 mo) [6].

Data supporting the efficacy of PRRT with radiolabelled somatostatin analogs in metastatic NET is accumulating [20,21,28-33] (Table 4). However, the particular benefit in patients with pulmonary NET, especially after ¹⁷⁷Lu-based PRRT, is unclear. In a large study on more than 1000 patients with NET of different origins treated with ⁹⁰Y-DOTATOC, 84 patients with pulmonary NET had a median OS of 40 months (95% CI, 31-50) with no PFS data available [10]. In a retrospective study on 59 patients with advanced NET, 13 patients with pulmonary NET were treated with ⁹⁰Y-DOTATOC and/or ¹⁷⁷Lu-DOTATOC. The reported objective response rate was 62% according to somatostatin receptor imaging; no further information regarding the characteristics and survival outcome of this subgroup was reported [34]. In a study on 16 patients with metastatic forgut NET (n=9 pulmonary, 5 gastric, and 2 of thymic origin) treated with¹⁷⁷Lu-octreotate 8 patients with pulmonary NET showed at least disease stabilization with a median time to progression of 31 months. Similar to our observations treatment outcome did not differ between atypical and typical pulmonary NETs [12].

Table 4.

Overview of published PRRT results in pulmonary NET

Author	Year/Type	Radioligand	n	ORR (%)	DCR (%)	PFS (mo)	OS (mo)
van Essen	2007/RS	177Lu-DOTATATE	9	55	89	31	NA
Pfeifer	2011/RS	90Y-DOTATOC/177Lu-DOTATOC	6	17	67	NA	NA
Imhof	2011/RS	90Y-DOTATOC	84	29	NA	NA	40
Filice	2012/RS	90Y-DOTATOC/177Lu-DOTATATE	13	62	85	NA	NA
Mariniello	2016/RS	90Y-DOTATOC/177Lu-DOTATATE	114	13	67	28	59*
Sabet	2017/RS	177Lu-DOTATATE	22	27	68	27	42

RS, retrospective study; ORR, objective response rate; DCR, disease control rate; PFS, progression-free survival; OS, overall survival; NA, not available;

^*Estimated overall survival. Note the lacking survival data from larger reports on primarily mixed NET cohorts.

The only available study restricted to patients with pulmonary NET has described the outcome in a heterogeneous cohort treated with ¹⁷⁷Lu-octreotate, ⁹⁰Y-DOTATOC, or the combination of both compounds over more than a decade [16]. Less favorable histological characteristics of the patients treated with ⁹⁰Y-DOTATOC and inter-individual diversity of the treatment schemes hampered an accurate comparative analysis of the therapeutic compounds. However, ¹⁷⁷Lu-octreotate seemed superior to ⁹⁰Y-DOTATOC. DCR of 75% was observed in patients treated with ¹⁷⁷Lu-octreotate administered at various therapeutic dosages [16]. Similarly encouraging DCR of 68.2% was seen in our cohort. The objective response rate of 27% also corresponds to the results of the largest published study on PRRT with ¹⁷⁷Lu-octreotate in GEP NET (n=310) by Kwekkeboom et al., reporting an overall response rate of 23% in patients with carcinoid tumors of different origins (n=188) [35]. Consistent with previous reports [36-38] a high level of plasma chromogranin A (> 600 ng/mL) was associated with worsened outcome in our cohort and remained the only independent risk factor for impaired PFS and OS (Tables 2, 3).

Small population size and the retrospective nature inevitably impact on the strength of our conclusions; especially comparisons with historical data should be interpreted with particular caution. We tried to characterize the study population in very detailed manner including all the important variables of potential influence on outcome in order to make comparative considerations possible. Therefore, the potency of therapeutic benefit for the patients seems to be perceptible from the large discrepancy between our findings and the reported data from other modalities.

Disclosure of conflict of interest

None.