1. Strosberg, Jonathan R. MD

Article Content

Beyond the progression-free survival (PFS) benefit already demonstrated in the NETTER-1 phase III study, 177Lu-Dotatate as compared with high-dose (60 mg) octreotide provides significant quality of life (QoL) benefits in patients with progressive midgut neuroendocrine tumors (NETs) (N Engl J Med 2017;376(2):125-135).

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Jonathan R. Strosber... - Click to enlarge in new windowJonathan R. Strosberg, MD. JONATHAN R. STROSBERG, MD, is Associate Professor at Moffitt Cancer Center, Tampa, Fla., and leads Moffitt's Neuroendocrine Tumor Division and Gastrointestinal Department Research Program.

Improvements with 177Lu-Dotatate in the QoL sub-analysis of NETTER-1 were observed across multiple clinically relevant categories, according to results published in Journal of Clinical Oncology (2018; doi:10.1200/JCO.2018.78.5865).


177Lu-Dotatate is a peptide receptor radionuclide therapy. The drug is made of a targeting molecule (dotatate) and the lutetium 177 radionuclide, which is both beta- and gamma-emitting, with a maximum particle range of 2 mm and a half-life of 160 hours.


NETs of the midgut (jejuno-ileum and proximal colon) are biologically diverse neoplasms that tend to secrete active hormones (e.g., serotonin). They are often associated with carcinoid syndrome, with symptoms of flushing, diarrhea, and bronchospasm. NETs often metastasize to the mesentery, peritoneum, and liver.


Metastatic disease 5-year survival rates are less than 50 percent (J Clin Oncol 2008;26:3063-3072; Cancer 2003;97(4):934-959). Typical front-line treatment to control tumor growth and to control or reduce hormonal symptoms is a somatostatin analog (e.g., octreotide, lanreotide). When progression occurs, as it does in most patients with metastatic disease, both tumor growth and hormone production lead to diminished QoL. Also, treatment-related toxicities can more than offset the benefits of the limited treatment options available.


According to the study authors, evaluation of health-related QoL (HRQoL) is a key criterion to be considered when new treatment options are assessed. This is especially important in the NET patient population, whose life expectancy is generally longer due to the indolent nature of the disease.


Preserving HRQoL

In many analyses of randomized clinical trials of experimental treatments, merely preserving HRQoL is considered favorable. In that light, it is notable that that time to deterioration (TTD) of HRQoL was significantly improved with 177Lu-Dotatate compared to octreotide LAR. The TTD endpoint, the authors also emphasize, is increasingly recognized as a valid method for analysis of longitudinal HRQoL data; TTD enables Kaplan-Meier methodology comparisons of study arms.


Strosberg, et al, cite prior research in both Sweden and the U.S. showing that NET patients to have impaired QoL compared with the general population. In the Swedish study, reduced QoL was reported in domains including role function, social function, fatigue, diarrhea, and global QoL (Health Qual Life Outcomes 2007;5:18). In the U.S. study of HRQoL, physical functioning and role functioning (including physical, general health, and vitality scores) were worse by at least one half of a standard deviation or more (Pancreas 2012;41(3):461-466). Impairment of HRQoL was greater in those with carcinoid syndrome than in those with nonfunctional tumors.


Primary analysis results of the multicenter, international NETTER-1 trial significantly favored 177Lu-Dotatate over controls at 20 months. Investigators randomly assigned 229 NET patients to 177Lu-Dotatate (7.4 GBq q8 weeks x 4 treatments) or to high-dose octreotide LAR 60 mg every 4 weeks. Estimated 20-month PFS was 65.2 percent (95% confidence interval [CI], 50.0 to 76.8) in the 177Lu-Dotatate group and 10.8 percent (95% CI, 3.5 to 23.0) in the control group. Response rates were 18 percent and 3 percent in the 177Lu-Dotatate and control groups, respectively (p<0.001). Interim overall survival also favored the 177Lu-Dotatate group (p=0.004).


Investigators in the Strosberg, et al, HRQoL study used the EORTC quality-of-life questionnaire (QLQ), including both its 30-question survey for all cancer patients (QLQ C-30) and the 21-question module (G.I.NET-21) addressing NET-related symptoms. Survey results are converted to a 100-point scale, allowing comparisons of longitudinal changes with baseline scores. Changes of 10 points or greater, the authors note, are often considered to be clinically meaningful. TTD, using Kaplan-Meier methodology, was assessed based on 10-point declines indicating a progressive event.


Single-arm study evaluations of HRQoL with 177Lu-Dotatate have demonstrated promising effects, including one with 265 NET patients showing significant EORTC QLQ C-30 improvements in global health status, emotional functioning, social functioning, insomnia, loss of appetite, and diarrhea (J Clin Oncol 2005;23(12):2754-2762). The phase III NETTER-1 study is the first prospective randomized trial of a radiolabeled somatostatin analog.


All included patients had pathologically confirmed low- or intermediate-grade midgut NETs with baseline radiographic progression and evidence of somatostatin receptor expression on all target lesions. Treatment continued until progression or intolerable adverse events. HRQoL assessed through EORTC QLQ-C 30 and G.I.NET 21 questionnaires was a major secondary endpoint of NETTER-1.


Patients completed the questionnaires at baseline and every 12 weeks thereafter until central radiologic confirmation of disease progression or a maximum of 72 weeks from randomization. Questionnaire compliance rates were >80 percent in both arms of the trial for all visits.


Impact of 177Lu-Dotatate

Strosberg, et al, reported that TTD in the 177Lu-Dotatate arm of NETTER-1 was significantly longer than in the high-dose octreotide arm in the following domains: global health, physical functioning, role functioning, diarrhea, pain, body image, disease-related worries, and fatigue (Table 1).

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The hazard ratio (HR) for global health with 177Lu-Dotatate was 0.41 (95% CI, 0.24 to 0.69; p< .001), with a 22.7-month difference in median TTD between both arms. The HR for physical functioning was 0.52 (95% CI, 0.30 to 0.89; p=.015), with a 13.7-month difference. HRs favoring 177Lu-Dotatate were 0.52 for physical functioning, 0.58 for role functioning, 0.47 for diarrhea, 0.57 for pain and disease-related worries, 0.43 for body image, and 0.62 for fatigue. TTD analysis did not reveal any domains with benefit for high-dose octreotide LAR.


The domain with the greatest clinical and statistically significant improvement for 177Lu-Dotatate was global health, a domain in which patients rate their overall health and QoL (Figure 1).

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Strosberg, et al, called the prolongation of TTD with 177Lu-Dotatate for this domain of 22.7 months compared with octreotide "striking." This finding, along with significant physical (activities of daily living) and role (advanced activities of daily living, such as employment and leisure) functioning improvements, indicate that on average patients receiving 177Lu-Dotatate are able to maintain stable levels of both physical and social activity longer than they would without this treatment.


Diarrhea is one of the hallmark symptoms of carcinoid syndrome. Strosberg, et al, point to the HR of 0.43 for diarrhea with 177Lu-Dotatate versus octreotide LAR in TTD as especially relevant for patients with midgut NET. The authors underscored benefits in pain and fatigue, as well.


For other symptoms of carcinoid syndrome, including flushing and sweats, no significant improvement was observed in TTD with 177Lu-Dotatate as compared with high-dose octreotide LAR. Addressed in the endocrine scale of the G.I.NET-21, score improvements occurred in a substantial proportion of patients in both the 177Lu-Dotatate and octreotide LAR arms, making it likely that both agents affect TTD positively.


Because of the significant differences between the treatment modalities of the two treatment arms in NETTER-1, patients were not blinded to their treatment allocation. Strosberg, et al, commented, however, that the HRQoL benefits were seen mostly in clinically relevant symptoms (pain, diarrhea, and fatigue), making it likely that perception bias effects on survey results were minimal.


Strosberg, et al, concluded: "Analysis of HRQoL from the phase III NETTER-1 study demonstrates that 177Lu-Dotatate provides a statistically significant and clinically robust quality-of-life benefit for patients with progressive midgut NETs compared with high-dose octreotide."


The benefits occur across multiple clinically relevant symptom categories and in functional HRQoL categories pertaining to activities of daily living. Significant and sustained improvements in global health are perhaps the most important benefits. Overall, the data validate the use of 177Lu-Dotatate in this patient population.


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