Several systemic options exist for the treatment of advanced PNETs. Typically, treatment is initiated in patients with unresectable high-volume or progressive disease. At times, observation may be the optimal treatment in patients with advanced disease, particularly in those with low-volume disease. Currently, there is no evidence to suggest a role for adjuvant therapy after complete resection.
Somatostatin analogs currently approved for clinical use include octreotide (including long-acting octreotide) and lanreotide, which bind both SSTR2 and SSTR5. Functional imaging can predict response to somatostatin analogs, but it does not necessarily dictate therapy.
Three randomized studies have evaluated the role of somatostatin analogs in advanced NETs. The PROMID trial compared long-acting octreotide vs placebo in patients with midgut NETs, excluding PNETs. There was a significant improvement in median progression-free survival (PFS) (14.3 months vs 6 months; P = .000072) but no difference in OS. The CLARINET study compared lanreotide vs placebo in well-/moderately differentiated nonfunctioning NETs (including PNETs) and again showed an improvement in the PFS rate at 2 years (65.1% vs 33.1%; P < .0001) but no improvement in OS. A third phase III randomized trial evaluated the use of pasireotide, a somatostatin analog targeting SSTR5, in octreotide-resistant patients, but there was no difference in the response rate (RR) compared with long-acting octreotide. The trial was stopped prematurely.
The optimal timing for treatment of indolent, nonfunctional PNETs is unclear. Response to somatostatin analogs is diminished in patients with PNETs compared with patients who have small bowel NETs, moderate-grade tumors, extensive liver involvement, or markedly elevated CgA levels. In addition, NETs can potentially become resistant to octreotide therapy. Guidelines suggest somatostatin analog use in patients with advanced PNETs who have asymptomatic high-volume disease or slowly progressive disease.[33,65] Observation in patients with low-volume disease is supported by the fact that some patients initially regressed in the placebo arms of randomized trials.
Molecular targeted therapies are suitable for patients with well-differentiated PNETs whose disease progresses on best supportive care or a somatostatin analog, based on randomized studies that have shown an improvement in PFS but not OS. Currently, sunitinib and everolimus are approved for use in PNETs.
Sunitinib is a multi–tyrosine kinase inhibitor that targets the vascular endothelial growth factor receptor (subtypes 1, 2, and 3), among other receptors. Its efficacy in well-differentiated PNETs was demonstrated in a phase III randomized controlled trial that showed an improved median PFS in the sunitinib group compared with placebo (11.5 months vs 5.5 months; P < .001), with an overall response rate (ORR) of 9.3%. Final analysis showed a trend toward improved OS (38.6 months vs 29.1 months; P = .094). However, premature termination and a high crossover rate (69.3%) may have skewed the results.
Everolimus is an inhibitor of mammalian target of rapamycin (mTOR). In phase II trials (including RADIANT-2) in metastatic PNETs, everolimus showed an RR of 4% to 27% and a median PFS between 9.3 and 17.1 months.[67-69] The RADIANT-3 trial compared everolimus vs placebo in patients with progressive low-/intermediate-grade PNETs, and again showed an improved median PFS with everolimus (11 months vs 4.6 months; hazard ratio [HR], 0.35; 95% CI, 0.27–0.45) but no difference in median OS (44 months vs 37.7 months). These findings were further validated in the RADIANT-4 trial, which included patients with tumors in lung and at other gastrointestinal sites.
Combination regimens are currently being investigated. The Cancer and Leukemia Group B 80701/Alliance trial is a phase II randomized controlled trial comparing everolimus ± bevacizumab together with octreotide. Preliminary results show an improved RR in the combination arm (31% vs 12%; P = .005) and a trend toward improvement in median PFS (16.7 months vs 14 months; HR, 0.8; 95% CI, 0.55–1.17; P = .12), but not in median OS. The role of combination therapies is yet to be determined.
Recent interest in additional targets has led to the identification of mutations in MEN1, DAXX/ATRX, and mTOR genes in well-differentiated PNETs (Table 5). Initial studies suggest a prognostic role for these mutations; however, their clinical utility is still unknown. Currently, targeted therapy is not predicated on the presence or absence of mutations, and routine testing is not recommended. However, targeted therapies show promise and remain an active area of research in PNETs.
Cytotoxic chemotherapies are reserved for patients who are highly symptomatic from unresectable advanced disease; patients with rapid tumor growth; and those whose disease has progressed on other treatments, such as somatostatin analogs or targeted therapies. Historically, streptozotocin and dacarbazine were the chemotherapeutic agents of choice, with RRs of 30% to 70%; however, both agents are limited by toxicity.[73,74] Currently, the preferred cytotoxic regimens consist of temozolomide in combination with other chemotherapeutic agents (Table 6). Temozolomide-based regimens have ORRs of 24% to 45%.[75-77] PNETs are more likely than other gastrointestinal NETs to respond to temozolomide.
The role of capecitabine in combination with temozolomide (CAPTEM regimen) shows promise, with an RR between 17% and 70% and a partial RR of 65% to 97% for a median duration of 8 to 20 months. Preliminary data from a phase II nonrandomized clinical trial evaluating CAPTEM in PNETs (ClinicalTrials.gov identifier: NCT01824875) show an ORR of 45% in 30 patients, a stable disease rate of 54%, and an overall clinical benefit rate of 97%. CAPTEM is the current cytotoxic regimen of choice at our institution for the treatment of PNETs.
Cytotoxic chemotherapy is effective in high-grade, poorly differentiated NEC. Platinum-based chemotherapy—usually with etoposide—is the mainstay of treatment for both early- and advanced-stage NEC, given its tendency to metastasize. The best treatment for patients with grade-discordant, high-grade NETs is unclear. These patients do not typically respond as well to platinum-based chemotherapy and should be discussed in detail in a multidisciplinary setting to optimize treatment. Details of chemotherapy for NEC will not be discussed in this review.
Other Therapeutic Modalities
HAE is indicated in patients with high-volume, progressive, or symptomatic liver-predominant disease. HAE is often given sequentially or concurrently with hormonal or systemic treatment, although studies have yet to establish the optimal order of therapy. Bland embolization (gel foam), chemoembolization (gel foam in conjunction with doxorubicin, streptozotocin, cisplatin, or drug-eluting beads), and radioembolization (with yttrium-90 [90Y]) are effective because liver metastases derive their blood supply from the hepatic arterial system. All three techniques are usually well tolerated, with very few serious adverse events occurring. No comparison of these techniques has been completed, and such an assessment would be difficult. The preferred treatment modality is often institutionally dependent.
In a meta-analysis of 18 trials, ORRs among the various intra-arterial techniques ranged from 39% to 95% within 1 to 18 months of treatment. Symptomatic relief occurs in 80% to 90% of patients, whereas the radiologic RR ranges from 30% to 50% and median OS from 22 to 70 months. The range in survival likely reflects the variable timing of treatment, disparity in adjunctive therapies, and the heterogeneity of NETs.
Hepatic arterial therapies can be repeated as necessary. Extrahepatic disease does not always preclude the use of HAE, since a significant tumor burden or progression in the liver may lead to liver failure and death.
- Pancreatic neuroendocrine tumors are on the rise, likely due to an increase in detection resulting from better imaging modalities and specialized scans.
- Surgery is the mainstay of treatment for pancreatic neuroendocrine tumors, and includes surgical debulking of both the primary tumor and liver metastases, when possible.
- The future treatment of unresectable pancreatic neuroendocrine tumors appears promising, with peptide receptor radionuclide therapy a potential option and several newer drugs coming down the pipeline.
The role of HAE in conjunction with other treatment modalities is not well established. In addition, there has been no comparison with the standard of care—surgery. Our series suggests that radioembolization after liver resection is safe. HAE in the neoadjuvant setting may potentially convert borderline resectable disease into resectable disease; however, few data are available to support the safety of this approach. Future studies involving HAE should involve a multimodal approach.
Peptide receptor radionuclide therapy
Radiolabeled somatostatin analogs, currently available in the United States for compassionate use only, pending FDA approval, have shown promise in patients whose disease is refractory to other medical therapies. Peptide receptor radionuclide therapy (PRRT) has been used in Europe since the 1990s, based on retrospective data. The two most common radionuclides are 90Y and lutetium-177 (177Lu), which differ in their particle emission and depth of penetration.
90Y-DOTATOC has mainly been studied in the retrospective setting. The largest study to date included 1,109 patients treated with 1 to 10 cycles of 90Y-DOTATOC. Patients who had a response had a significantly longer median survival (44.7 months vs 18.3 months; P < .001), most pronounced in those with a morphologic response. Furthermore, uptake on octreotide-based imaging (including both 111In pentetreotide and 68Ga DOTATATE scanning) was predictive of survival (HR, 0.45; 95% CI, 0.29–0.69; P < .001).
The efficacy of 177Lu-DOTATATE is currently being evaluated in a phase III clinical trial (NETTER-1), which is comparing it vs octreotide for patients with midgut NETs. Interim analysis in 2016 showed promising results, with median PFS not reached in the 177Lu-DOTATATE group compared with 8.4 months in the octreotide group. RRs were 18.8% vs 3.0%, respectively, and preliminary analysis suggests an OS benefit (P < .019).
Data comparing 90Y and 177Lu are limited but may suggest superiority of 177Lu. One retrospective analysis compared 450 patients treated with 90Y alone (RR, 17%; median PFS, 27 months), 177Lu alone (RR, 54%; median PFS, 40 months), or 177Lu in combination with 90Y (RR, 29%; median PFS, 50 months). It is unclear at this time why one agent might outperform the other.
Multiple phase II clinical trials are currently evaluating 177Lu-DOTATATE in various settings, including in poorly differentiated NECs, in combination with chemotherapy (capecitabine + etoposide) for low- to intermediate-grade NETs (CONTROL NETS), in combination with sunitinib (OCCLURANDOM), and in the neoadjuvant setting prior to liver transplant (NEO-LEBE), among others. The role of PRRT in PNETs and its place in the current treatment paradigm is unknown. It is not yet known whether 177Lu will be approved for use in patients with PNETs. In addition, patients can become unresponsive to somatostatin analogs after prolonged treatment, and it is unclear whether this will alter the efficacy of PRRT. Overall, however, PRRT is a promising treatment modality for NETs.
The remarkable success of immunotherapy in melanoma and lung cancer has led to interest in using immunotherapeutic approaches in other malignancies. Although research on immunotherapy for NETs is in the earliest stages, there are some preliminary data to suggest an immune response in NETs.[87-90] Several phase I and phase II studies are actively being pursued. A trial involving PDR001, an anti–programmed death 1 inhibitor, in advanced or metastatic NETs (including PNETs), has recently opened for accrual (ClinicalTrials.gov identifier: NCT02955069). Clarification of the role of immunotherapeutics in NETs is highly anticipated.
PNETs—and NETs more broadly—are increasing in incidence. NETs encompass a heterogeneous group of tumors whose behavior and treatment often depend on grade. The majority of PNETs will metastasize to the liver, and treatment involves a multidisciplinary approach that includes surgery, even in some of the most advanced tumors. Beyond surgery, treatment consists of a combination of octreotide analogs, targeted therapies, systemic chemotherapy, and HAE. The future looks promising for treatment of PNETs, given the pending approval of PRRT and the potential role of immunotherapy in NETs.
Financial Disclosure: The authors have no significant financial interest in or other relationship with the manufacturer of any product or provider of any service mentioned in this article.
Acknowledgments: The writing of this article was supported by funds from the Leo and Anne Albert Trust. The authors wish to thank Indra M. Mahajan, PhD, for her assistance with proofreading and editing the manuscript.
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