1. May, Brandon

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A new study from Moffitt Cancer Center researchers in Tampa, Fla., shows that 177Lutetium-dotatate, a systemic radiolabeled somatostatin analog belonging in the peptide receptor family of radiotherapies, improves progression-free survival as well as overall quality of life in patients with progressive midgut neuroendocrine tumors (NETs). Additionally, the study found that treatment with 177Lutetium-dotatate provided these benefits to a significantly greater degree than treatment with high-dose octreotide (J Clin Oncol 2018; doi:10.1200/JCO.2018.78.5865).

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"177Lutetium-dotatate significantly delays time to deterioration in quality of life in patients with progressive midgut neuroendocrine tumors," lead study author Jonathan Strosberg, MD, of Moffitt Cancer Center, told Oncology Times. Strosberg leads Moffitt Cancer Center's Neuroendocrine Tumor Division and Gastrointestinal Department Research Program and is currently serving as chair of the Scientific Review Committee. "The drug is FDA-approved and an expanding number of treatment centers (including Moffitt Cancer Center) are providing this treatment."


Patients with NETs, described by Moffitt researchers as "biologically diverse neoplasms," often secrete serotonin, among other active hormones. Midgut NETs, which typically arise in the ileum, jejunum, and proximal colon, are relatively rare in the population (Int J Endocr Oncol 2016;3(2):175-189). Presentation is generally later in life and follows a prolonged history of vague and nonspecific symptoms (Radiographics 2014;34(2):413-426).


At presentation, the vast majority of midgut NETs are metastatic, with the liver representing the central metastasis site (J Clin Oncol 2008;26(18):3063-3072). The 5-year survival rate for midgut NETs is approximately 60 percent (Br J Surg 2012;99(11):1480-1486), yet mortality is high due to complications caused by the primary carcinoma.


Treatment for NETs that progress to other areas of the body are limited, and therapeutic options that are available can often introduce the risk for toxicity and lower quality of life. Investigators at Moffitt Cancer Center sought to determine the impact of 177Lutetium-dotatate on time to quality-of-life deterioration on treatment as well as the effect of treatment in PFS.


Aspects of the Trial

In the multicenter, randomized, phase III NETTER-1 trial, Moffitt researchers enrolled adult patients with clinically confirmed progressive low- or intermediate-grade midgut NETs. At baseline, patients presented with radiographic progression and somatostatin receptor expression evidence on 100 percent of targeted lesions.


Treatment allocation was performed in a randomized 1:1 manner, with patients receiving either 200 mCi 177Lu-dotatate every 8 weeks for a total of four treatments with subsequent 30 mg octreotide long-acting repeatable (n=117) or high-dose octreotide at 60 mg at 4-week intervals (n=114).


Researchers assessed the impact of treatment versus control on health-related quality of life by administering the European Organisation for Research and Treatment of Cancer quality-of-life questionnaires QLQ C-30 and G.I. NET-21 at baseline and every 12 weeks until tumor progression. The primary endpoint was time to quality-of-life deterioration (TTD), which was defined as the time from randomization to the first marker of quality-of-life deterioration >=10 points from baseline.


The primary endpoint was significantly longer for patients randomized to 177Lutetium-dotatate versus control, particularly for global health status (HR, 0.406; 95% CI 0.24-0.69; p<.001), physical functioning (HR, 0.518; 95% CI, 0.30 to 0.89; p=.015), role functioning (HR, 0.580; 95% CI 0.35-0.96; p=.030), fatigue (HR, 0.621; 95% CI 0.40-0.96; p=.030), pain (HR, 0.566; 95% CI 0.34-0.94; p=.025), diarrhea (HR, 0.473; 95% CI 0.26-0.85; p=.011), disease-related worries (HR, 0.572; 95% CI 0.36-0.91; p=.018), and body image (HR, 0.425; 95% CI 0.23-0.80; p=.006).


In terms of median TTD, there were significant differences between treatment and control for global health status (28.8 months vs. 6.1 months, respectively; HR, 0.41; 95% CI 0.24-0.69; p<.001) and physical functioning (25.2 months vs. 11.5 months, respectively; HR 0.52; 95% CI 0.30-0.89; p=.015).


"177Lu-Dotatate demonstrated a very substantial improvement in progression-free survival compared to high-dose octreotide, and also showed very encouraging preliminary results with respect to overall survival benefit," Strosberg commented. "Comparable outcomes have not been observed with other medications in this particular population of patients."


In regard to quality-of-life outcomes, the drug provided more advantages than just preserving quality of life overall. "In fact," Strosberg added, "it very significantly delayed decline in quality of life in clinically relevant domains such as global health, physical functioning, role functioning, diarrhea, fatigue, and pain."


A limitation of the analysis included the lack of treatment blinding among participants, precluding the ability of the researchers in making a fair judgement of whether treatment knowledge impacted health-related quality-of-life perception.


"The fact that clinically and statistically significant HRQoL benefits were observed predominantly in clinically relevant symptoms, such as pain, diarrhea, and fatigue," the researchers wrote, "suggests that effect of perception bias on HRQoL survey results was likely minimal."


"Moffitt Cancer Center offers a variety of treatment options for NET patients including an expanding number of systemic treatments and liver-directed therapies," Strosberg said. "Moffitt is one of the few locations in the Southeast to offer 177Lu-dotatate treatment for patients with progressive gastroenteropancreatic NETs. Our program also focuses on clinical research with multiple clinical trials evaluated new treatments."


Additional Research

Researchers from The University of Texas MD Anderson Cancer Center in Houston, recently wrote in an update article published in the International Journal of Endocrine Oncology that current antineoplastic therapies "have limited role given their slow-growing property and their role continues to be limited and SSA are the mainstay of tumor and hormone control." Over the next few years, the researchers argued, long-acting and/or radiolabeled somatostatin analogs like 177Lutetium-dotatate "are expected to play a central role in the management of these tumors," yet the approval of PRRT and mTOR inhibitors may contribute to expansion of midgut NET treatment (2016;3(2):175-189).


According to Strosberg, multiple and current studies are underway at Moffitt Cancer Center looking at similar patient populations, including "a trial which is evaluating another radiolabeled somatostatin analog versus everolimus in patients with progressive nonfunctioning NETs."


Additionally, another study at Moffitt includes an evaluation of a new bispecific antibody to the somatostatin receptor and T-cell receptor, and another research initiative that is examining a new anti-diarrheal treatment. "Also, we are currently researching cabozantinib, a multitargeted tyrosine kinase inhibitor, and a trial is underway comparing several liver embolization modalities," Strosberg added. "We are also conducting several preclinical studies including development of a CAR-T therapy for NETs.


"The NETTER-1 study was the first prospective phase III study of a radiolabeled somatostatin analog," Strosberg concluded. "We are looking forward to additional studies comparing radiolabeled SSAs to another standard treatment options to help answer questions regarding optimal treatment sequencing. Also, we are looking forward to long-term outcomes of the NETTER1 study to answer further questions regarding long-term risk and benefit, particular in the final overall survival outcomes."


Brandon May is a contributing writer.


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