Proceedings From a Live Symposium
June 2, 2018 • Chicago, Illinois
Translating Landmark Trial-Based Evidence to the Front Lines of Care for Pancreatic Cancer: The Evolving Trial-Based and Guideline-Supported Role for Nanoliposomal Topoisomerase Inhibitors in Metastatic Pancreatic Adenocarcinoma
Caio Max S. Rocha Lima, MD
Frontline Options in Pancreatic Cancer
The prognosis for patients with pancreatic cancer remains poor, and advances in therapeutic approaches have been incremental and gradual. In 1997, a small, randomized phase 3 trial of treatment-naive patients with unresectable, locally advanced, or metastatic pancreatic cancer showed an improvement in clinical benefit and overall survival with gemcitabine compared with 5-fluorouracil (5-FU).1 Clinical benefit response was defined as a composite measurement of pain (analgesic use and pain intensity), performance status, and weight.1 More patients in the gemcitabine arm experienced clinical benefit vs the 5-FU arm (23.8% vs 4.8%; P=.0022).1 The median overall survival was also improved in the gemcitabine arm (5.7 vs 4.4 months; P=.0025).1 These results established gemcitabine as the therapeutic backbone for frontline treatment of pancreatic adenocarcinoma.
In a randomized phase 3 trial of 569 patients with advanced pancreatic cancer, the addition of erlotinib to gemcitabine was associated with a modest but significant improvement in median overall survival vs gemcitabine alone (6.24 vs 5.91 months; P=.038).2 The 1-year survival and the median progression-free survival (PFS) were also longer in the erlotinib group, but the overall response rate (ORR) was not significantly different.2 The US Food and Drug Administration (FDA) approved erlotinib in combination with gemcitabine. The clinical use of erlotinib remains low, however, based on the modest improvement in overall survival.
In a randomized phase 2 trial in patients with metastatic pancreatic cancer, a regimen of folinic acid, 5-FU, irinotecan, and oxaliplatin (FOLFIRINOX) improved median overall survival vs single-agent gemcitabine (11.1 vs 6.8 months; P<.001).3 In a phase 3 trial, the addition of nab-paclitaxel to gemcitabine improved median overall survival vs gemcitabine alone (8.5 vs 6.7 months; P<.001).4 These results established 2 frontline standards of care: FOLFIRINOX and nab-paclitaxel plus gemcitabine.
Second-Line Options in Advanced Pancreatic Cancer
The phase 3 CONKO-003 trial (A Phase 3 Second Line Trial in Advanced Pancreatic Cancer) was a randomized, open-label trial enrolling gemcitabine-refractory patients.5 The primary analysis included 160 patients. At a median follow-up of 54.1 months, the addition of oxaliplatin to folinic acid and 5-FU improved median overall survival vs folinic acid plus 5-FU alone (5.9 vs 3.3 months; P=.010).5 Time to progression was significantly longer in the oxaliplatin group. Rates of adverse events were similar. However, in a randomized phase 3 trial of patients previously treated with gemcitabine, the addition of oxaliplatin to 5-FU plus leucovorin was associated with an inferior median overall survival (6.1 vs 9.9 months; P=.024).6 A toxicity profile resulting in frequent discontinuations of therapy in the oxaliplatin group could explain the inferior results.
Several trials have assessed irinotecan in the second-line setting for pancreatic cancer. 7-11 The median overall survival was approximately 6 to 7 months, suggesting some benefit to the incorporation of irinotecan in the second-line setting.
Nanoliposomal Irinotecan
A formulation in which irinotecan is encased within a nanoliposome was designed to improve drug delivery to the tumor. Nanoliposomal irinotecan is taken up by tumor-associated macrophages.12 After macrophage uptake, the nanoliposome dissolves, and irinotecan is metabolized to its active form, SN-38, by carboxylesterase.12 SN-38 is delivered to the tumor, creating a large deposit of irinotecan within it.12 This nanoliposomal formulation of irinotecan allows longer drug exposure to plasma and the tumor at lower doses.12,13
Clinical Trials of Nanoliposomal Irinotecan
The randomized, phase 3 NAPOLI-1 trial (Nanoliposomal Irinotecan) compared the safety and efficacy of 3 treatment regimens: nanoliposomal irinotecan plus 5-FU/leucovorin, nanoliposomal irinotecan alone, and 5-FU/leucovorin alone.14 Patients had progressive disease after frontline gemcitabine-based treatment. The combination of nanoliposomal irinotecan plus 5-FU/leucovorin improved median overall survival compared with 5-FU/leucovorin alone (6.1 vs 4.2 months; P=.012; Figure 1).14 The addition of nanoliposomal irinotecan also improved median PFS (3.1 vs 1.5 months; P=.0001) and the ORR (16% vs 1%; P<.0001) compared with 5-FU/leucovorin alone. Single-agent nanoliposomal irinotecan was not superior to 5-FU/leucovorin, suggesting that this agent does not have a role as monotherapy.
Subgroup analyses suggested that most patients benefited from the addition of nanoliposomal irinotecan to 5-FU/leucovorin.14 In an expanded per-protocol analysis, median overall survival was 8.9 months with the addition of nanoliposomal irinotecan to 5-FU/leucovorin vs 5.1 months with 5-FU/leucovorin alone (P=.0018).15 In comparison, the median overall survival was 6.1 months with nanoliposomal irinotecan in the intention-to-treat population, suggesting that patients who follow the protocol could experience a greater clinical benefit.
The safety profile was generally manageable. In the nanoliposomal irinotecan arms, the most frequent grade 3/4 adverse events were neutropenia (27%), fatigue (14%), diarrhea (13%), and vomiting (11%).14 The protocol for NAPOLI-1 did not mandate the use of antiemetics, which can decrease the rate of grade 3/4 vomiting, or loperamide, which could reduce diarrhea. Similarly, growth factor support was not routinely used in the trial to treat neutropenia (which manifested predominantly as myelosuppression), another approach that could be applied in clinical practice to better manage toxicities.
NAPOLI-1 was not a second-line trial; patients could have received 2 or more prior lines of therapy. Approximately one-third of patients received treatment as third-line or even fourth-line therapy.14 Additionally, although nab-paclitaxel plus gemcitabine is the standard of care in the United States, in this international trial, only approximately 20% of patients had received this regimen as a prior therapy.14 Nanoliposomal irinotecan with 5-FU/leucovorin is now recommended by the National Comprehensive Cancer Network (NCCN) for second-line treatment of pancreatic cancer.16
Disclosure
Dr Rocha Lima is on the speakers bureaus of Celgene and Ipsen.
References
1. Burris HA III, Moore MJ, Andersen J, et al. Improvements in survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced pancreas cancer: a randomized trial. J Clin Oncol. 1997;15(6):2403-2413.
2. Moore MJ, Goldstein D, Hamm J, et al; National Cancer Institute of Canada Clinical Trials Group. Erlotinib plus gemcitabine compared with gemcitabine alone in patients with advanced pancreatic cancer: a phase III trial of the National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol. 2007;25(15):1960-1966.
3. Conroy T, Desseigne F, Ychou M, et al; Groupe Tumeurs Digestives of Unicancer; PRODIGE Intergroup. FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. N Engl J Med. 2011;364(19):1817-1825.
4. Von Hoff DD, Ervin T, Arena FP, et al. Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine. N Engl J Med. 2013;369(18):1691-1703.
5. Oettle H, Riess H, Stieler JM, et al. Second-line oxaliplatin, folinic acid, and fluorouracil versus folinic acid and fluorouracil alone for gemcitabine-refractory pancreatic cancer: outcomes from the CONKO-003 trial. J Clin Oncol. 2014;32(23):2423-2429.
6. Gill S, Ko YJ, Cripps C, et al. PANCREOX: a randomized phase III study of fluorouracil/leucovorin with or without oxaliplatin for second-line advanced pancreatic cancer in patients who have received gemcitabine-based chemotherapy. J Clin Oncol. 2016;34(32):3914-3920.
7. Ulrich-Pur H, Raderer M, Verena Kornek G, et al. Irinotecan plus raltitrexed vs raltitrexed alone in patients with gemcitabine-pretreated advanced pancreatic adenocarcinoma. Br J Cancer. 2003;88(8):1180-1184.
8. Yi SY, Park YS, Kim HS, et al. Irinotecan monotherapy as second-line treatment in advanced pancreatic cancer. Cancer Chemother Pharmacol. 2009;63(6):1141-1145.
9. Yoo C, Hwang JY, Kim JE, et al. A randomised phase II study of modified FOLFIRI3 vs modified FOLFOX as second-line therapy in patients with gemcitabine-refractory advanced pancreatic cancer. Br J Cancer. 2009;101(10):1658-1663.
10. Zaniboni A, Aitini E, Barni S, et al. FOLFIRI as second-line chemotherapy for advanced pancreatic cancer: a GISCAD multicenter phase II study. Cancer Chemother Pharmacol. 2012;69(6):1641-1645.
11. Ioka T, Komatsu Y, Mizuno N, et al. Randomised phase II trial of irinotecan plus S-1 in patients with gemcitabine-refractory pancreatic cancer. Br J Cancer. 2017;116(4):464-471.
12. Drummond DC, Noble CO, Guo Z, Hong K, Park JW, Kirpotin DB. Development of a highly active nanoliposomal irinotecan using a novel intraliposomal stabilization strategy. Cancer Res. 2006;66(6):3271-3277.
13. Kalra AV, Kim J, Klinz SG, et al. Preclinical activity of nanoliposomal irinotecan is governed by tumor deposition and intratumor prodrug conversion. Cancer Res. 2014;74(23):7003-7013.
14. Wang-Gillam A, Li CP, Bodoky G, et al; NAPOLI-1 Study Group. Nanoliposomal irinotecan with fluorouracil and folinic acid in metastatic pancreatic cancer after previous gemcitabine-based therapy (NAPOLI-1): a global, randomised, open-label, phase 3 trial. Lancet. 2016;387(10018):545-557.
15. Chen LT, Von Hoff DD, Li CP, et al. Expanded analyses of NAPOLI-1: phase 3 study of MM-398 (nal-IRI), with or without 5-fluorouracil and leucovorin, versus 5-fluorouracil and leucovorin, in metastatic pancreatic cancer (mPAC) previously treated with gemcitabine-based therapy [ASCO GI abstract 234]. J Clin Oncol. 2015;33(suppl 3).
16. NCCN Clinical Practice Guidelines in Oncology. Pancreatic adenocarcinoma. Version 2.2018. https://www.nccn.org/professionals/physician_gls/pdf/pancreatic. pdf. Updated July 10, 2018. Accessed July 11, 2018.
A Treatment Landscape in Evolution: New Strategies, Guidelines, and Therapeutic Advances for Metastatic Pancreatic Adenocarcinoma
Tanios Bekaii-Saab, MD
Pancreatic cancer is the third-leading cause of cancer-related death in the United States.1 Within the next decade, it is expected to become the leading cause (Figure 2).1 The prognosis for pancreatic cancer remains poor, with the lowest survival of any malignancy, stage for stage.2 Additionally, 80% to 85% of patients have advanced-stage disease at the time of diagnosis, and patients diagnosed with early-stage disease have a 70% to 80% chance of relapsing following curative surgery.2-4 The cure rate for metastatic disease remains at 1% to 2%, and the 5-year relative survival rate across stages is 8.5% (95% CI, 8.0-9.0).5 The incidence of pancreatic cancer varies geographically, with a high exceeding 6.3 new cases per 100,000 people per year in developed countries.6
Patients with resectable disease have improved out-comes, likely based on the negative margins achieved during surgery plus the neoadjuvant and adjuvant therapy used after the procedure. Patients with borderline res-ectable disease are likely to have positive tumors after surgery, and therefore should receive neoadjuvant therapy postsurgery. Patients with unresectable disease should never undergo tumor resection. Some palliative surgical procedures, such as combined biliary and duodenal bypass, are possible options for patients with locally advanced disease and unresectable tumors,7 although these approaches have not been assessed in randomized clinical trials.
Anatomy of the Pancreas and Development of Pancreatic Cancer
The pancreas is located in close proximity to blood vessels and nerve bundles, and therefore surgery is limited to less than 20% of cases.8,9 At diagnosis, surgery is not an option for more than 80% of patients, who will present with disease that advanced locally or became metastatic during the asymptomatic phase.8,9 Structurally, the pancreas consists of 4 sections. The head is the rightmost section of the pancreas; it is surrounded by the duodenum and delivers pancreatic enzymes directly to the intestines. To the left of the pancreatic head is the neck, then the body, and then the leftmost section of the tail. Disease-related symptoms are diverse and affected by the location of the tumors. The extent of symptoms does not necessarily correlate with the tumor burden.10 Tumors that arise in the pancreatic head often wrap around the bile ducts, resulting in jaundice.11 Tumors that develop in the pancreatic tail frequently drop into the abdominal cavity and cause symptoms of epigastric pain.9
Treatment of Pancreatic Cancer
In the frontline setting, chemotherapy usually consists of FOLFIRINOX or gemcitabine with nab-paclitaxel. After frontline FOLFIRINOX, second-line therapy will vary according to the patient’s performance status, with gemcitabine plus nab-paclitaxel for those with a performance status of 0 to 1 and either gemcitabine monotherapy or best supportive care for patients with a performance status of 2 or worse. Guidelines do not indicate third-line therapy for patients who received frontline FOLFIRINOX.9,12 For patients who received frontline gemcitabine-based therapy (gemcitabine alone or with nab-paclitaxel or erlotinib), second-line therapy consists of nanoliposomal irinotecan with 5-FU for those with a performance status of 0 or 1 and fluoropyrimidine monotherapy or best supportive care for those with a performance status of 2. For patients with a performance status of 0 or 1, third-line treatment consists of platinum-based chemotherapy if they had not received it earlier.9,12
The many types of treatment-emergent toxicities include deep vein thrombosis, anemia, sepsis, infusion-related reactions, and severe diarrhea.9 Management of treatment-emergent toxicity, along with disease symptoms, presents a challenge.
Treatment of Subgroups in Pancreatic Cancer
Clinical trials have examined the role of inhibitors of poly-adenosine 5’-diphosphate (ADP)-ribose polymerase (PARP) in pancreatic cancer patients harboring mutations in the breast cancer 1 or 2 (BRCA1/2) gene. In a study of 23 patients with BRCA-mutated pancreatic cancer and a mean of 2 prior lines of therapy, the response rate to the PARP inhibitor olaparib was 22%, and the rate of stable disease was 35%.13 In a study of 16 patients with BRCA-mutated pancreatic cancer and a mean of 2 prior lines of therapy, the PARP inhibitor veliparib was associated with a response rate of 0%, and a stable disease rate of 25%.14 Among 19 patients with BRCA-mutated pancreatic cancer who had received a mean of 1 to 2 prior lines of therapy, the PARP inhibitor rucaparib was associated with an ORR of 15%, and a stable disease rate of 21%.15
Approximately 1% of patients with pancreatic cancer are mismatch repair deficient (MMR-D) or have high microsatellite instability (MSI-H). Under these conditions, tumors can be susceptible to treatment with an immune checkpoint inhibitor.16 The immune checkpoint inhibitor pembrolizumab is now approved for MMR-D or MSI-H tumors, regardless of tumor type, and can be used to treat this small subset of patients with pancreatic cancer.17
Disclosure
Dr Bekaii-Saab is an advisor or consultant for Amgen, ARMO, Bristol-Myers Squibb, Celgene, Exelixis, Genentech, Glenmark, Ipsen, Merck & Co, Merrimack, Roche, and SillaJen.
References
1. Rahib L, Smith BD, Aizenberg R, Rosenzweig AB, Fleshman JM, Matrisian LM. Projecting cancer incidence and deaths to 2030: the unexpected burden of thyroid, liver, and pancreas cancers in the United States. Cancer Res. 2014;74(11):
2913-2921.
2. Philip PA, Mooney M, Jaffe D, et al. Consensus report of the National Cancer Institute clinical trials planning meeting on pancreas cancer treatment. J Clin Oncol. 2009;27(33):5660-5669.
3. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2018. CA Cancer J Clin. 2018;68(1):7-30.
4. Regine WF, Winter KA, Abrams R, et al. Fluorouracil-based chemoradiation with either gemcitabine or fluorouracil chemotherapy after resection of pancreatic adenocarcinoma: 5-year analysis of the U.S. Intergroup/RTOG 9704 phase III trial. Ann Surg Oncol. 2011;18:1319-1326.
5. Jemal A, Ward EM, Johnson CJ, et al. Annual report to the nation on the status of cancer, 1975-2014, featuring survival. J Natl Cancer Inst. 2017;109(9).
6. GLOBOCAN 2012: estimated cancer incidence, mortality, and prevalence worldwide in 2012. International Agency for Research on Cancer. World Health Organization. http://globocan.iarc.fr/Pages/Map.aspx. Accessed July 10, 2018.
7. Karapanos K, Nomikos IN. Current surgical aspects of palliative treatment for unresectable pancreatic cancer. Cancers (Basel). 2011;3(1):636-651.
8. Lopez NE, Prendergast C, Lowy AM. Borderline resectable pancreatic cancer: definitions and management. World J Gastroenterol. 2014;20(31):10740-10751.
9. Ducreux M, Cuhna AS, Caramella C, et al; ESMO Guidelines Committee. Cancer of the pancreas: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2015;26(suppl 5):v56-v68.
10. Saif MW. Palliative care of pancreatic cancer. Highlights from the “2011 ASCO Annual Meeting”. Chicago, IL, USA; June 3-7, 2011. JOP. 2011;12(4):355-357.
11. Ryan DP, Hong TS, Bardeesy N. Pancreatic adenocarcinoma. N Engl J Med. 2014;371(11):1039-1049.
12. NCCN Clinical Practice Guidelines in Oncology. Pancreatic adenocarcinoma. Version 2.2018. https://www.nccn.org/professionals/physician_gls/pdf/pancreatic.pdf. Updated July 10, 2018. Accessed July 11, 2018.
13. Kaufman B, Shapira-Frommer R, Schmutzler RK, et al. Olaparib monotherapy in patients with advanced cancer and a germline BRCA1/2 mutation. J Clin Oncol. 2015;33(3):244-250.
14. Lowery MA, Kelsen DP, Capanu M, et al. Phase II trial of veliparib in patients with previously treated BRCA-mutated pancreas ductal adenocarcinoma. Eur J Cancer. 2018;89:19-26.
15. Domchek SM, Hendifar AE, McWilliams RR, et al. RUCAPANC: an open-label, phase 2 trial of the PARP inhibitor rucaparib in patients (pts) with pancreatic cancer (PC) and a known deleterious germline or somatic BRCA mutation [ASCO abstract 4110]. J Clin Oncol. 2017;35(suppl 15).
16. Hu ZI, Shia J, Stadler ZK, et al. Evaluating mismatch repair deficiency in pancreatic adenocarcinoma: challenges and recommendations. Clin Cancer Res. 2018;24(6):1326-1336.
17. Le DT, Durham JN, Smith KN, et al. Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade. Science. 2017;357(6349):409-413.
New Guideline-Sanctioned and Emerging Interventions for Pancreatic Cancer
Tanios Bekaii-Saab, MD
Pancreatic adenocarcinoma accounts for approximately 90% of all cases of pancreatic cancer, and more than half of these cases are metastatic.1,2 Guidelines from the NCCN for the management of metastatic pancreatic cancer recommend placement of a self-expanding metal stent if jaundice is present, and suggest consideration of testing for microsatellite instability and mismatch repair deficiency.3 Subsequent treatment depends on the patient’s performance status.3 Patients with a poor performance status should receive palliative radiotherapy or palliative best supportive care, with consideration of single-agent chemotherapy.3 The NCCN guidelines recommend that patients with a good performance status enroll in a clinical trial or receive chemotherapy.3
First-Line Therapy in Pancreatic Cancer
Historically, gemcitabine has been the standard of care in the first-line setting, as it improved clinical benefit and overall survival compared with 5-FU in patients with advanced disease.4 A randomized phase 3 trial compared gemcitabine vs 5-FU in 126 patients with advanced symptomatic pancreatic cancer.4 Clinical benefit—a composite measurement of pain, performance status, and weight—was reported in 23.8% of patients in the gemcitabine arm vs 4.8% of patients in the 5-FU arm (P=.0022).4 The median overall survival was 5.7 months vs 4.4 months, respectively (P=.0025). This trial established gemcitabine as the backbone of frontline therapy.4
Subsequent trials that combined other chemotherapeutic agents with gemcitabine established additional
treatment options.5 Phase 3 trials also evaluated gemcitabine in combination with a targeted therapy, but the results were generally not encouraging.6 For example, an early-stage trial of a farnesyltransferase inhibitor plus gemcitabine showed clinical efficacy compared with gemcitabine alone, but no improvement was seen in a phase 3 trial.6
In a phase 2/3 trial, median overall survival was 11.1 months with FOLFIRINOX vs 6.8 months with gemcitabine (hazard ratio [HR] for death, 0.57; 95% CI, 0.45-0.73; P<.001).7 A phase 3 trial comparing nab-paclitaxel with gemcitabine vs single-agent gemcitabine showed a median overall survival of 8.5 months vs 6.7 months, respectively (HR for death, 0.72; 95% CI, 0.62-0.83; P<.001).8 The results from these trials cannot be compared because they occurred in different regions and enrolled different patient populations.7,8 No clinical trials have directly compared FOLFIRINOX with the combination of nab-paclitaxel and gemcitabine.
A real-world, retrospective analysis compared outcomes with first-line nab-paclitaxel plus gemcitabine, gemcitabine alone, or FOLFIRINOX in patients with metastatic pancreatic adenocarcinoma treated in the community setting in the United States. Time to treatment discontinuation and database persistence were lowest among patients treated with gemcitabine alone. There were no significant differences in surrogate endpoints between nab-paclitaxel plus gemcitabine vs FOLFIRINOX (Figure 3).9 Results were not impacted by the patients’ age.9 Additionally, surrogate endpoints remained similar regardless of whether nab-paclitaxel plus gemcitabine or FOLFIRINOX was used first, and the other regimen initiated after disease progression.9
The phase 3 MPACT trial (Metastatic Pancreatic Adenocarcinoma Clinical Trial) compared gemcitabine alone or with the addition of nab-paclitaxel as frontline therapy in patients with metastatic pancreatic cancer.10 Both drugs were administered in a dose-modified schedule.10 In the nab-paclitaxel arm, dose reduction and delay improved median overall survival. In contrast, dose reduction, but not dose delay, improved median overall survival in the single-agent gemcitabine arm. The study indicates that dose reductions and delays can help manage toxicities and avoid discontinuation of therapy.
A retrospective analysis showed that gemcitabine and nab-paclitaxel administered biweekly instead of weekly improved clinical efficacy, decreased cost of treatment, and improved toxicity compared with the historical control.11 Cost savings on this regimen reflected reductions in the costs of the treatment drugs and in the management of toxicities.11
Second-Line Therapy in Metastatic Pancreatic Cancer
The phase 3 NAPOLI-1 trial compared the addition of nanoliposomal irinotecan to 5-FU and leucovorin vs 5-FU/leucovorin in metastatic pancreatic cancer previously treated with a gemcitabine-based regimen.12 The median overall survival was 6.1 months in the arm with nanoliposomal irinotecan vs 4.2 months in the arm without nanoliposomal irinotecan (HR, 0.67; 95% CI, 0.49-0.92; P=.012).12 The median PFS was 3.1 months vs 1.5 months (HR, 0.56; 95% CI, 0.41-0.75; P=.0001).12
To elucidate the role of oxaliplatin in the second-line setting, a meta-analysis identified randomized controlled trials comparing single-agent fluoropyrimidine to combination therapy that included fluoropyrimidine and either oxaliplatin or different formulations of irinotecan.13 The overall survival was not significantly different between fluoropyrimidine and regimens containing oxaliplatin (P=.9), but the overall survival was improved in regimens containing irinotecan compared with single-agent fluoropyrimidine (P=.004).13 Compared with fluoropyrimidine, the PFS was improved in regimens containing oxaliplatin (P=.02) or irinotecan (P=.005).13
There is no clinically validated second-line option after frontline FOLFIRINOX. Frontline gemcitabine plus nab-paclitaxel allows for second-line irinotecan plus 5-FU in patients with good performance status.3 In patients with poor performance status, options are 5-FU, capecitabine, or best supportive care.
Emerging Therapies in Pancreatic Cancer
The microenvironment of pancreatic cancer is hypovascular, hypoxic, and chemoresistant, in part because of the physical barrier formed by hyaluronan, a component of the extracellular matrix.14,15 In a preclinical model, depletion of hyaluronan with PEGylated recombinant human hyaluronidase PH20 (PEGPH20) reversed chemoresistance of pancreatic tumors and permitted successful treatment with gemcitabine.14,15 In a phase 2 trial that evaluated the addition of PEGPH20 to nab-paclitaxel plus gemcitabine in patients with metastatic pancreatic cancer, there was no difference in median overall survival between the 2 arms.16 There was, however, an improvement in median PFS in the PEGPH20 arm, for both the overall study population and the subset of patients with tumors that had high levels of hyaluronan. An ongoing phase 3 trial is investigating the same treatment regimen in patients with high levels of hyaluronan.17
Another emerging therapeutic approach uses cancer stemness inhibitors, such as napabucasin, to mitigate chemoresistance in pancreatic cancer. A phase 1b/2 trial assessed napabucasin with nab-paclitaxel and gemcitabine in metastatic pancreatic cancer.18 The ORR was 55%, the median PFS exceeded 7 months, and the median overall survival was longer than 10.5 months.18 A phase 3 trial is evaluating the addition of napabucasin to nab-paclitaxel plus gemcitabine in patients with metastatic disease.19 The target enrollment is 1132 patients.
Disclosure
Dr Bekaii-Saab is an advisor or consultant for Amgen, ARMO, Bristol-Myers Squibb, Celgene, Exelixis, Genentech, Glenmark, Ipsen, Merck & Co, Merrimack, Roche, and SillaJen.
References
1. Hackeng WM, Hruban RH, Offerhaus GJ, Brosens LA. Surgical and molecular pathology of pancreatic neoplasms. Diagn Pathol. 2016;11(1):47.
2. Golan T, Sella T, Margalit O, et al. Short- and long-term survival in metastatic pancreatic adenocarcinoma, 1993-2013. J Natl Compr Canc Netw. 2017;
15(8):1022-1027.
3. NCCN Clinical Practice Guidelines in Oncology. Pancreatic adenocarcinoma. Version 2.2018. https://www.nccn.org/professionals/physician_gls/pdf/pancreatic.pdf. Updated July 10, 2018. Accessed July 11, 2018.
4. Burris HA III, Moore MJ, Andersen J, et al. Improvements in survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced pancreas cancer: a randomized trial. J Clin Oncol. 1997;15(6):2403-2413.
5. Boeck S, Heinemann V. Second-line therapy in gemcitabine-pretreated patients with advanced pancreatic cancer. J Clin Oncol. 2008;26(7):1178-1179.
6. Bayraktar S, Rocha-Lima CM. Advanced or metastatic pancreatic cancer: molecular targeted therapies. Mt Sinai J Med. 2010;77(6):606-619.
7. Conroy T, Desseigne F, Ychou M, et al; Groupe Tumeurs Digestives of Unicancer; PRODIGE Intergroup. FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. N Engl J Med. 2011;364(19):1817-1825.
8. Von Hoff DD, Ervin T, Arena FP, et al. Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine. N Engl J Med. 2013;369(18):1691-1703.
9. Braiteh F, Patel MB, Parisi M, Ni Q, Park S, Faria C. Comparative effectiveness and resource utilization of nab-paclitaxel plus gemcitabine vs FOLFIRINOX or gemcitabine for the first-line treatment of metastatic pancreatic adenocarcinoma in a US community setting. Cancer Manag Res. 2017;9:141-148.
10. Scheithauer W, Ramanathan RK, Moore M, et al. Dose modification and efficacy of nab-paclitaxel plus gemcitabine vs. gemcitabine for patients with metastatic pancreatic cancer: phase III MPACT trial. J Gastrointest Oncol. 2016;7(3):
469-478.
11. Ahn DH, Krishna K, Blazer M, et al. A modified regimen of biweekly gemcitabine and nab-paclitaxel in patients with metastatic pancreatic cancer is both tolerable and effective: a retrospective analysis. Ther Adv Med Oncol. 2017;9(2):
75-82.
12. Wang-Gillam A, Li CP, Bodoky G, et al; NAPOLI-1 Study Group. Nanoliposomal irinotecan with fluorouracil and folinic acid in metastatic pancreatic cancer after previous gemcitabine-based therapy (NAPOLI-1): a global, randomised, open-label, phase 3 trial. Lancet. 2016;387(10018):545-557.
13. Sonbol MB, Firwana B, Wang Z, et al. Second-line treatment in patients with pancreatic ductal adenocarcinoma: a meta-analysis. Cancer. 2017;123(23):
4680-4686.
14. Jacobetz MA, Chan DS, Neesse A, et al. Hyaluronan impairs vascular function and drug delivery in a mouse model of pancreatic cancer. Gut. 2013;62(1):
112-120.
15. Provenzano PP, Cuevas C, Chang AE, Goel VK, Von Hoff DD, Hingorani SR. Enzymatic targeting of the stroma ablates physical barriers to treatment of pancreatic ductal adenocarcinoma. Cancer Cell. 2012;21(3):418-429.
16. Hingorani AR, Bullock AJ, Seery TE, et al. Randomized phase II study of PEGPH20 plus nab-paclitaxel/gemcitabine (PAG) vs AG in patients (pts) with untreated, metastatic pancreatic ductal adenocarcinoma (mPDA) [ASCO abstract 4008]. J Clin Oncol. 2017;35(suppl 15).
17. Doherty GJ, Tempero M, Corrie PG. HALO-109-301: a phase III trial of PEGPH20 (with gemcitabine and nab-paclitaxel) in hyaluronic acid-high stage IV pancreatic cancer. Future Oncol. 2018;14(1):13-22.
18. Bekaii-Saab TS, Starodub A, El-Rayes BF, et al. Phase 1b/2 trial of cancer stemness inhibitor napabucasin (NAPA) + nab-paclitaxel (nPTX) and gemcitabine (gem) in metastatic pancreatic adenocarcinoma (mPDAC) [ASCO abstract 4110]. J Clin Oncol. 2018;36(suppl 15).
19. Bekaii-Saab TS, Li CP, Okusaka T, et al. CanStem111P: a phase III study of napabucasin (BBI-608) plus nab-paclitaxel (nab-ptx) with gemcitabine (gem) in adult patients with metastatic pancreatic adenocarcinoma (mPDAC) [ASCO abstract TPS4148]. J Clin Oncol. 2017;35(suppl 15).
Identifying Ideal Candidates for Nanoliposomal Topoisomerase Inhibitors in Metastatic Pancreatic Adenocarcinoma
Kenneth Yu, MD, MSc
Throughout the previous decade, treatment combinations and sequencing in pancreatic adenocarcinoma have become more complicated. Patients can now receive multiple lines of therapy, including combination chemotherapy. NCCN guidelines have recommendations for first- and second-line treatment.1 FOLFIRINOX and nab-paclitaxel plus gemcitabine are the 2 first-line options.1-4 Nanoliposomal irinotecan with 5-FU/leucovorin is recommended for second-line therapy.
Results from the phase 3 NAPOLI-1 trial of nanoliposomal irinotecan plus 5-FU/leucovorin vs 5-FU/leucovorin showed no significant difference in clinical outcomes based on performance status.4 A retrospective real-world study from Memorial Sloan Kettering Cancer Center assessed patients with pancreatic cancer who started treatment with nanoliposomal irinotecan plus 5-FU/leucovorin between October 2015 and June 2017 at the cancer center and regional network sites.5 A total of 56 patients were identified from pharmacy inquiries regarding prescriptions for nanoliposomal irinotecan, which is FDA-approved only for pancreatic adenocarcinoma. At the regional centers, some patients were treated by clinicians who were generalists rather than specialists. All patients had advanced pancreatic adenocarcinoma. The median PFS was 2.9 months, and the median overall survival was 5.3 months. A partial response was seen in 5% of patients, stable disease in 41%, and progressive disease in 41%.
Clinical outcomes were improved in patients receiving nanoliposomal irinotecan plus 5-FU/leucovorin in the frontline setting. The median PFS was 10.8 months in the frontline setting, 4.3 months in the second-line setting, 2.4 months in the third-line setting, and 2.5 months beyond the third-line setting (P=.0031; Figure 4). The median overall survival was not reached, 8.4 months, 3.9 months, and 4.5 months, respectively (P=.0002).
More than half of these patients (59%) had received prior irinotecan, which predicted a lack of efficacy for nanoliposomal irinotecan. The median overall survival across different therapy sequences was approximately 24 months. Additionally, there was no correlation between the starting dose of nanoliposomal irinotecan and the median PFS or overall survival. Patients who received 2 dose reductions had a higher probability for PFS, but these patients were also exposed to the drug for a longer time.
Compared with the NAPOLI-1 study, the patients in this analysis experienced fewer grade 3/4 adverse events, including nausea (4%) and vomiting (4%).5 Notably, these patients were on lower doses of nanoliposomal irinotecan than patients in the NAPOLI-1 study.4
This real-world evidence supports the survival benefit of adding nanoliposomal irinotecan to 5-FU/leucovorin.5 Survival was improved when nanoliposomal irinotecan was given earlier, and when the disease was not refractory to irinotecan. The treatment was safe and efficacious, even at lower doses and with dose reductions. Future studies should address whether multiple lines of active therapy affect disease biology.
Disclosure
Dr Yu is a consultant for Ipsen and Halozyme, and receives research support from Halozyme.
References
1. NCCN Clinical Practice Guidelines in Oncology. Pancreatic adenocarcinoma. Version 2.2018. https://www.nccn.org/professionals/physician_gls/pdf/pancreatic.pdf. Updated July 10, 2018. Accessed July 11, 2018.
2. Scheithauer W, Ramanathan RK, Moore M, et al. Dose modification and efficacy of nab-paclitaxel plus gemcitabine vs gemcitabine for patients with metastatic pancreatic cancer: phase III MPACT trial. J Gastrointest Oncol. 2016;7(3):
469-478.
3. Conroy T, Desseigne F, Ychou M, et al; Groupe Tumeurs Digestives of Unicancer; PRODIGE Intergroup. FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. N Engl J Med. 2011;364(19):1817-1825.
4. Wang-Gillam A, Li CP, Bodoky G, et al; NAPOLI-1 Study Group. Nanoliposomal irinotecan with fluorouracil and folinic acid in metastatic pancreatic cancer after previous gemcitabine-based therapy (NAPOLI-1): a global, randomised, open-label, phase 3 trial. Lancet. 2016;387(10018):545-557.
5. Glassman DC, Desai AM, Ku GY, et al. Nano-liposomal irinotecan and 5-FU/LV (N+F) for the treatment of advanced PDAC: Memorial Sloan Kettering (MSK) Single Cancer Center Evaluation [ASCO GI abstract 471]. J Clin Oncol. 2018;36(suppl 4S).
Real-World Approaches for Extending Progression-Free Survival in Patients With Metastatic Pancreatic Neuroendocrine Tumors: Focus on Timing, Sequencing, Regimen Initiation, and Maintenance Strategies Using Somatostatin Analogs, Targeted Agents, and Peptide Receptor Radiotherapy
Edward M. Wolin, MD
Neuroendocrine tumors (NETs) arise from cells in the endocrine system, and they most commonly occur in gastroenteropancreatic (GEP) sites. The incidence of GEP-NETs has increased by more than 500% in the previous 3 decades, and NETs are the second most prevalent gastrointestinal malignancy (after colon cancer).1 Early diagnosis of NETs enables initiation of therapy that can lead to long-term survival or even a cure.2 However, a study showed that the correct diagnosis of NETs took longer than 2 years in 53% of patients and longer than 5 years in 34%.2 The mean time to diagnosis of pancreatic NETs is 53.4 months. GEP-NETs often have metastasized by the time of diagnosis.
Prognosis varies and depends on stage, grade, primary site, and age at diagnosis.3 The 2010 classification from the World Health Organization divided NETs into 3 grades based on tumor differentiation.4,5 Between 20% and 100% of NETs were classified as grade 3, the highest grade. A large heterogeneity of tumors and prognoses were seen within this grade. In 2017, the World Health Organization updated its classification of NETs, splitting grade 3 into 2 different grades.6 The 2 new grades are grade 3 well-differentiated neuroendocrine tumors and grade 3 poorly differentiated neuroendocrine carcinomas.6 Poorly differentiated neuroendocrine carcinoma refers to either a small-cell or large-cell type with more than 20 mitoses per high-power field.6 Grade 3 well-differentiated neuroendocrine tumors are similar to grade 1 and grade 2 tumors.6
Genetics and Genomics of NETs
Pancreatic NETs can harbor mutations in DAXX, ATRX, and MEN1, which are genes involved in chromatin remodeling, and in genes in the mammalian target of rapamycin (mTOR) pathway, such as PTEN and TSC2.7 Mutations in both the mTOR pathway and in DAXX or ATRX correlate with excellent survival, with a 10-year survival rate close to 100%.8 Mutations in genes involved in DNA repair (eg, BRCA2, CHEK2, MUTYH) have been associated with poorly differentiated neuroendocrine carcinoma, as have mutations in RB1 and TP53.9,10 In contrast, small bowel NETs harbor a lower mutational burden, with only 14 mutations detected during a sequence of 48 tumors.11 Mutated genes included those involved in the mTOR pathway, DNA repair, chromatin remodeling, and apoptosis.11
Assessing Grade and Functionality of NETs
The treatment plan begins with identification of the grade and functionality of NETs. Pancreatic NETs are usually subdivided into 2 groups.12,13 Functional NETs cause clinical syndromes associated with excessive secretion of hormones.12,13 Nonfunctional NETs do not cause syndromes associated with excessive secretion of hormones, and they are usually asymptomatic until the patient develops advanced disease.12-14 Nonfunctional tumors are the most common, accounting for 40% to 90% of pancreatic NETs.14 Functional pancreatic NETs secrete bioactive peptides or hormones, with the type of hormone secreted dependent on the type of cell of origin.13 Syndromes caused by secreted peptides or hormones in functional NETs can be fatal, independent of the tumor proliferation.
Insulinomas account for approximately 70% of pancreatic functional NETs.15 Less common types include glucagonomas, which account for approximately 15%, and gastrinomas and somatostatinomas, each accounting for approximately 5% to 10%.15 VIPomas are more rare.
Approved Systemic Therapies for Pancreatic NETS
Treatment of NETs involves a multidisciplinary team from oncology, surgery, cardiology, radiation oncology, pathology, nuclear medicine, endocrinology, and other areas. Treatment regimens depend on the location of the NET, its grade and spread, and whether it is functional. The antiproliferative drugs streptozocin, everolimus, sunitinib, lanreotide depot/autogel, and Lu 177 dotatate are FDA-approved to treat pancreatic NETs. Additionally, short-acting octreotide, octreotide long-acting release, lanreotide depot/autogel, and telotristat ethyl can provide relief of hormonal syndromes. Sequencing of treatment and the integration of locoregional therapies remain challenging.
Incorporating Current Therapies Into Clinical Practice
Targeting the Somatostatin Receptor in NETs
Somatostatin is a peptide hormone with activity that is mediated through somatostatin receptors. Approximately 80% to 90% of NETs express somatostatin receptors (of which there are 5 known subtypes). Somatostatin and somatostatin analogues send signals through somatostatin receptors to arrest the cell cycle at G1, resulting in apoptosis. These features make somatostatin receptors a target for the development of therapies for NETs. Somatostatin receptor type 2 is the most important subtype to target for the treatment of NETs.
Although human somatostatin has a relatively short half-life of 3 minutes, the somatostatin analogue octreotide has a half-life of 90 minutes.16,17 Octreotide and lanreotide are both somatostatin analogues that bind to somatostatin receptor type 2 with a high affinity and are antineoplastic in their activity.17,18 The long-term acting formulations of each allow for injections once every 4 weeks.17,18 Somatostatin inhibitors have a manageable toxicity profile, and most adverse events are transient.19 Diarrhea, steatorrhea, flatulence, and injection site pain are the most frequent adverse events (>20%).19 Diarrhea and flatulence are related to the steatorrhea, and can be treated with the administration of pancreatic enzymes before meals.
The phase 3 CLARINET trial (Controlled Study of Lanreotide Antiproliferative Response in Neuroendocrine Tumors) established the efficacy and safety of lanreotide depot/autogel in patients with metastatic GEP-NETs.20 CLARINET enrolled 204 patients with advanced, well- or moderately differentiated, nonfunctioning, somatostatin receptor–positive, grade 1 to 2, progressive GEP-NETs.20 Patients were randomly assigned to receive either extended-release lanreotide depot/autogel or placebo once every 4 weeks for 96 weeks.20
The median PFS was not reached with lanreotide depot/autogel vs 18.0 months with placebo (HR, 0.47; P<.001; Figure 5).20 The benefit of lanreotide depot/autogel was not significant in the subgroup of patients with pancreatic NETs, but this subgroup was small.20 In general, lanreotide depot/autogel improved clinical outcomes across subgroups, including divisions based on liver tumor burden, disease stage, and extent of differentiation.20 Neither overall survival nor quality of life were significantly different between the 2 treatment arms.20 A decrease in chromogranin A of at least 50% from baseline was seen in 42% of the lanreotide depot/autogel arm vs 5% of the placebo arm (P<.001).20 Based on results of the CLARINET trial, the FDA approved lanreotide depot/autogel for pancreatic NETs. Although octreotide is a similar somatostatin analogue, it does not have the same level 1 clinical evidence that CLARINET provided for lanreotide depot/autogel.
The phase 2/3 REMINET trial (A Study Evaluating Lanreotide as Maintenance Therapy in Patients With Non-Resectable Duodeno-Pancreatic Neuroendocrine Tumors) is currently recruiting patients with metastatic or locally advanced, nonresectable, grade 1 or 2 NETs.21 At least 4 weeks before randomization, patients must have controlled disease after 1 line of chemotherapy. Results from REMINET should elucidate whether long-term maintenance with lanreotide after primary therapy should be part of an overall treatment approach.
Somatostatin analogues can also be linked to radioisotopes. This approach can enable delivery of highly accurate radiotherapy. The phase 3 NETTER-1 trial (A Study Comparing Treatment With 177Lu-DOTA0-Tyr3-Octreotate to Octreotide LAR [Control] in Patients With Inoperable, Progressive, Somatostatin Receptor Positive Midgut Carcinoid Tumors) compared the radioisotope-linked somatostatin analogue Lu 177 dotatate plus best supportive care vs long-acting octreotide.22 A total of 229 patients with well-differentiated, metastatic, midgut NETs received either Lu 177 dotatate (n=116) at 7.4 GBq every 8 weeks plus best supportive care, including octreotide, or long-acting octreotide (n=113) at 60 mg once every 4 weeks.22 At data cut-off for the primary analysis, the estimated PFS at 20 months was 65.2% in the Lu 177 dotatate arm (95% CI, 50.0%-76.8%) and 10.8% in the control arm (95% CI, 3.5%-23.0%).22 The response rate was 18% in the Lu 177 dotatate arm and 3% in the control arm (P<.001).22 In the planned interim analysis of overall survival, there were 14 deaths in the Lu 177 dotatate arm vs 26 deaths in the control arm (P=.004).22 Grade 3 or 4 neutropenia, thrombocytopenia, and lymphopenia occurred in less than 10% of the Lu 177 dotatate arm and in no patients in the control arm.22 Lu 177 dotatate is now FDA-approved for the treatment of pancreatic NETs in patients with progressive disease after primary therapy with a somatostatin analogue. Patients without somatostatin receptors are not candidates for this treatment.
Radiotherapy-linked somatostatin analogues can also enable imaging of tumors just a few millimeters wide. Theranostics of NETs using molecular imaging with positron emission tomography/computed tomography (PET/CT) with (68)Ga-labeled somatostatin analogues can allow highly accurate detection of NETs and metastases with diagnostic specificity and sensitivity.23 The reproducible and quantitative data can identify patients who are well-suited for treatment with agents such as Lu 177 dotatate.23 Among the benefits are a fast imaging time (60-90 minutes), low radiation burden, flexibility in daily use, decreased cost compared with octreotide scintigraphy, and quick, routine quantification of tumors during PET/CT scans.23
Targeting the mTOR Pathway
The product of the TSC2 gene inhibits mTOR activation. Patients with defective TSC2 develop pancreatic NETs.24 Decreased expression of TSC2 and another mTOR inhibitor, PTEN, has been associated with shorter disease-free survival and overall survival.25 NF1 also regulates mTOR, and patients with NF1 gene loss develop pancreatic NETs characterized by neurofibromatosis.26
Everolimus is an inhibitor of mTOR. The phase 3 RADIANT-3 trial (Efficacy and Safety of Everolimus Compared to Placebo in Patients With Advanced Neuroendocrine Tumors) was a prospective, double-blind, randomized, placebo-controlled trial enrolling 410 patients with advanced pancreatic NETs who exhibited radiologically confirmed progression within 12 months.27 Patients were randomly assigned to treatment with everolimus once daily (n=207) or placebo (n=203), until disease progression, unacceptable toxicity, or withdrawal.27 Both treatment arms received best supportive care (that could include somatostatin analogues). Upon disease progression, treatment was unblinded, and patients in the control arm could cross over to receive everolimus.27
The median PFS was 11.0 months in the everolimus arm vs 4.6 months in the placebo arm (HR, 0.35; 95% CI, 0.27-0.45; P<.001), which represented a 65% reduction in the risk for death or progression.27 The estimated proportion of patients alive and progression-free at 18 months was 34% (95% CI, 26%-43%) in the everolimus arm vs 9% (95% CI, 4%-16%) in the placebo arm.27 Treatment-related adverse events were primarily grade 1 or 2.27 The median exposure to everolimus was 38 weeks, and the median exposure to placebo was 16 weeks.27
Targeting Tumor Vascularity in NETs
Unlike pancreatic adenocarcinoma, GEP-NETs are usually hypervascular and express growth factors that promote angiogenesis, such as the vascular endothelial growth factor (VEGF).28 Sunitinib inhibits multiple kinases, including VEGF and the epidermal growth factor receptor. In a phase 3, randomized, double-blind trial, 171 patients with advanced, well-differentiated pancreatic NETs and disease progression within the previous 12 months received sunitinib at 37.5 mg/day or placebo.29 All patients also received best supportive care. The study was discontinued early, after the independent data and safety monitoring committee observed more serious adverse events and deaths in the placebo arm, as well as improved PFS with sunitinib.29 The median PFS was 11.4 months in the sunitinib arm vs 5.5 months in the placebo arm (HR, 0.42; 95% CI, 0.26-0.66; P<.001). Analysis of PFS favored sunitinib across all subgroups. The ORR was 9.3% with sunitinib vs 0% with placebo. The most frequent adverse events in the sunitinib arm were diarrhea, nausea, vomiting, asthenia, and fatigue.
A randomized phase 2 study from the Cancer and Leukemia Group B, known as 80701, evaluated whether the VEGF inhibitor bevacizumab improved outcomes when added to everolimus and octreotide.30 ORR was 31% among patients in the bevacizumab arm vs 12% among those treated with everolimus and octreotide alone (P=.005). No significant differences between the 2 arms were seen in median PFS (16.7 vs 14.0 months; P=.12) or median overall survival (36.7 vs 35.0 months; P=.16).30 A single-arm phase 2 study of the mTOR inhibitor temsirolimus plus bevacizumab in patients with advanced, progressive pancreatic NETs showed an ORR of 41%, a 6-month PFS rate of 79%, and a median PFS of 11.7 months.31 The potential of combination therapies to improve survival must be weighed against the possibility that they may have intolerable toxicity profiles.
Disclosure
Dr Wolin is on the advisory boards of Novartis, Ipsen, and Lexicon.
References
1. Yao JC, Hassan M, Phan A, et al. One hundred years after “carcinoid”: epidemiology of and prognostic factors for neuroendocrine tumors in 35,825 cases in the United States. J Clin Oncol. 2008;26(18):3063-3072.
2. Wolin E, Hollander R, Leyden J, et al. Delays in neuroendocrine tumor (NET) diagnosis: U.S. results from the first global NET patient survey—a collaboration between the International Neuroendocrine Cancer Alliance (INCA) and Novartis Pharmaceuticals [DDW abstract 668]. Gastroenterology. 2015;148(suppl 1).
3. Dasari A, Shen C, Halperin D, et al. Trends in the incidence, prevalence, and survival outcomes in patients with neuroendocrine tumors in the United States. JAMA Oncol. 2017;3(10):1335-1342.
4. Bosman FT, Carneiro F, Hruban RH, Theise ND, eds. World Health Organization (WHO) Classification of Tumours of the Digestive System. 4th edition. Lyon, France: International Agency for Research on Cancer; 2010.
5. Sorbye H, Welin S, Langer SW, et al. Predictive and prognostic factors for treatment and survival in 305 patients with advanced gastrointestinal neuroendocrine carcinoma (WHO G3): the NORDIC NEC study. Ann Oncol. 2013;24(1):
152-160.
6. Lloyd RV, Osamura RY, Klöppel G, Rosai J, eds. WHO Classification of Tumours of Endocrine Organs. 4th edition. Lyon, France: International Agency for Research on Cancer; 2017.
7. Jiao Y, Shi C, Edil BH, et al. DAXX/ATRX, MEN1, and mTOR pathway genes are frequently altered in pancreatic neuroendocrine tumors. Science. 2011;331(6021):1199-1203.
8. de Wilde RF, Edil BH, Hruban RH, Maitra A. Well-differentiated pancreatic neuroendocrine tumors: from genetics to therapy. Nat Rev Gastroenterol Hepatol. 2012;9(4):199-208.
9. Scarpa A, Chang DK, Nones K, et al; Australian Pancreatic Cancer Genome Initiative. Whole-genome landscape of pancreatic neuroendocrine tumours. Nature. 2017;543(7643):65-71.
10. Tang LH, Basturk O, Sue JJ, Klimstra DS. A practical approach to the classification of WHO grade 3 (G3) well-differentiated neuroendocrine tumor (WD-NET) and poorly differentiated neuroendocrine carcinoma (PD-NEC) of the pancreas. Am J Surg Pathol. 2016;40(9):1192-1202.
11. Banck MS, Kanwar R, Kulkarni AA, et al. The genomic landscape of small intestine neuroendocrine tumors. J Clin Invest. 2013;123(6):2502-2508.
12. Kulke MH, Anthony LB, Bushnell DL, et al; North American Neuroendocrine Tumor Society (NANETS). NANETS treatment guidelines: well-differentiated neuroendocrine tumors of the stomach and pancreas. Pancreas. 2010;39(6):
735-752.
13. Ehehalt F, Saeger HD, Schmidt CM, Grützmann R. Neuroendocrine tumors of the pancreas. Oncologist. 2009;14(5):456-467.
14. Vinik AI, Woltering EA, Warner RR, et al; North American Neuroendocrine Tumor Society (NANETS). NANETS consensus guidelines for the diagnosis of neuroendocrine tumor. Pancreas. 2010;39(6):713-734.
15. Strosberg JR, Nasir A, Hodul P, Kvols L. Biology and treatment of metastatic gastrointestinal neuroendocrine tumors. Gastrointest Cancer Res. 2008;2(3):113-125.
16. Dogliotti L, Tampellini M, Stivanello M, Gorzegno G, Fabiani L. The clinical management of neuroendocrine tumors with long-acting repeatable (LAR) octreotide: comparison with standard subcutaneous octreotide therapy. Ann Oncol. 2001;12(suppl 2):S105-S109.
17. Rosenberg JM. Octreotide: a synthetic analog of somatostatin. Drug Intell Clin Pharm. 1988;22(10):748-754.
18. Wolin EM, Manon A, Chassaing C, et al. Lanreotide depot: an antineoplastic treatment of carcinoid or neuroendocrine tumors. J Gastrointest Cancer. 2016;47(4):366-374.
19. Pavel MA. Treatment landscape and ongoing clinical trials in NET. Ann Oncol. 2014;25(suppl 4):iv27-iv28.
20. Caplin ME, Pavel M, Ćwikła JB, et al; CLARINET Investigators. Lanreotide in metastatic enteropancreatic neuroendocrine tumors. N Engl J Med. 2014;371(3):224-233.
21. Lepage C, Dahan L, Bouarioua N, et al. Evaluating lanreotide as maintenance therapy after first-line treatment in patients with non-resectable duodeno-pancreatic neuroendocrine tumours. Dig Liver Dis. 2017;49(5):568-571.
22. Strosberg J, El-Haddad G, Wolin E, et al; NETTER-1 Trial Investigators. Phase 3 trial of 177Lu-dotatate for midgut neuroendocrine tumors. N Engl J Med. 2017;376(2):125-135.
23. Baum RP, Kulkarni HR, Carreras C. Peptides and receptors in image-guided therapy: theranostics for neuroendocrine neoplasms. Semin Nucl Med. 2012;42(3):190-207.
24. O’Reilly T, McSheehy PM. Biomarker development for the clinical activity of the mTOR inhibitor everolimus (RAD001): processes, limitations, and future proposals. Transl Oncol. 2010;3(2):65-79.
25. Missiaglia E, Dalai I, Barbi S, et al. Pancreatic endocrine tumors: expression profiling evidences a role for AKT-mTOR pathway. J Clin Oncol. 2010;28(2):
245-255.
26. Meric-Bernstam F, Gonzalez-Angulo AM. Targeting the mTOR signaling network for cancer therapy. J Clin Oncol. 2009;27(13):2278-2287.
27. Yao JC, Shah MH, Ito T, et al; RAD001 in Advanced Neuroendocrine Tumors, Third Trial (RADIANT-3) Study Group. Everolimus for advanced pancreatic neuroendocrine tumors. N Engl J Med. 2011;364(6):514-523.
28. Briest F, Grabowski P. PI3K-AKT-mTOR-signaling and beyond: the complex network in gastroenteropancreatic neuroendocrine neoplasms. Theranostics. 2014;4(4):336-365.
29. Raymond E, Dahan L, Raoul JL, et al. Sunitinib malate for the treatment of pancreatic neuroendocrine tumors. N Engl J Med. 2011;364(6):501-513.
30. Kulke MH, Niedzwiecki D, Foster NR, et al. Randomized phase II study of everolimus (E) versus everolimus plus bevacizumab (E+B) in patients (pts) with locally advanced or metastatic pancreatic neuroendocrine tumors (pNET). CALGB 80701 (Alliance) [ASCO abstract 4005]. J Clin Oncol. 2015;33(suppl).
31. Hobday TJ, Qin R, Reidy-Lagunes D, et al. Multicenter phase II trial of temsirolimus and bevacizumab in pancreatic neuroendocrine tumors. J Clin Oncol. 2015;33(14):1551-1556.