Supplement 12
Abstract: Although pancreatic cancer is rare, it is the fourth-leading cause of cancer-related mortality. Pancreatic adenocarcinoma is the most common type of pancreatic cancer, accounting for approximately 95% of cases. At diagnosis, it is estimated that less than 10% of patients have localized disease, 29% have regional disease, and 52% have distant metastases and might be eligible for palliative treatment only. Optimal management of pancreatic cancer requires early referral to a medical oncologist. Therapeutic goals should address both symptom improvement and survival. In the metastatic setting, advances in systemic therapy are improving outcome. For years, the standard therapy was single-agent gemcitabine, and this approach is still used for patients who have a poor performance status, who are elderly, or who have comorbidities. More recent strategies include oxaliplatin, irinotecan, fluorouracil, and leucovorin (FOLFIRINOX) and gemcitabine plus albumin-bound (nab)-paclitaxel. In 2015, the US Food and Drug Administration approved the use of nanoliposomal irinotecan in combination with fluorouracil and leucovorin for the treatment of patients with metastatic adenocarcinoma of the pancreas after disease progression following gemcitabine-based therapy. Multiple novel strategies are being evaluated for patients with pancreatic cancer. A multidisciplinary team that includes an interventional gastroenterologist is appropriate for all patients with pancreatic cancer, regardless of disease stage. Proactive management of potential complications is essential for maintaining adherence to treatment and maximizing clinical outcomes.
Unmet Needs in the Management of Pancreatic Adenocarcinoma
Fadi Braiteh, MD
Director of the Translational Oncology Program, Phase I and GI Malignancies Program
Comprehensive Cancer Centers of Nevada
Clinical Associate Professor
University of Nevada School of Medicine
Las Vegas, Nevada
Although pancreatic cancer accounts for only 3% of new cancer diagnoses in the United States, it is the fourth-leading cause of cancer-related death.1 The incidence of pancreatic cancer is increasing, and outcomes remain poor. By 2030, pancreatic cancer is expected to become the second-leading cause of cancer-related mortality.2 The incidence is highest among individuals ages 65 to 74 years.3
Pancreatic adenocarcinoma is the most common type of pancreatic cancer, accounting for approximately 95% of cases. Another 4% are pancreatic neuroendocrine tumors, which include functional tumors that secrete neuroendocrine substances and nonsecreting or nonfunctional tumors. The remaining pancreatic tumor types are uncommon histologies, such as acinar cell carcinoma, as well as metastases to the pancreas arising from the kidney and other organs.
Detection of pancreatic cancer is hampered by a lack of available screening modalities and the absence of hereditary factors in most patients.4 A small fraction of pancreatic cancers can be attributed to inherited genetic causes, such as the very rare hereditary pancreatitis syndrome. However, other prevalent conditions include Lynch syndrome (germline mutations of MLH1, MSH2, MSH3, EPCAM, PMS2, or MSH6 genes), hereditary breast and ovarian cancer syndrome (germline BRCA1, BRCA2, or PALB2 mutations), Li–Fraumeni syndrome (germline TP53 mutation), ataxia-telangiectasia syndrome (ATM mutation), familial melanoma (CDKN2A germline mutation), familial adenomatous polyposis (germline APC mutation), and Peutz–Jeghers syndrome (germline STK11 mutation), among others.4
Most patients with pancreatic cancer are diagnosed with locally advanced unresectable disease or metastatic disease. At diagnosis, it is estimated that only less than 10% of patients have resectable disease, while 29% have regional/borderline resectable disease. Approximately 52% present with distant metastases and might be eligible for palliative treatment only.3 In the past 10 years, a new category known as borderline resectable has been delineated. Borderline resectable refers to patients in whom neoadjuvant chemotherapy, with or without radiation therapy, has the potential to allow conversion to surgical resectability.5
Outcome for patients with pancreatic cancer remains dismal. The median overall survival for patients with locally advanced disease is approximately 20 months, even with adjuvant therapy.6 Adjuvant chemotherapy has shown clinical benefit in patients with resectable pancreatic adenocarcinoma, with gemcitabine demonstrating a significant survival advantage compared with observation.7 For many years, single-agent gemcitabine had been the only standard-of-care systemic adjuvant therapy, and it was added to radiation therapy when indicated (based on the status of lymph nodes and resection margins). Data from the ESPAC-4 trial (European Study Group for Pancreatic Cancer trial 4) recently showed that the combination of gemcitabine plus capecitabine improved overall survival vs gemcitabine alone (median overall survival, 28.0 vs 25.5 months; hazard ratio, 0.82; P=.032).8
In the metastatic setting, a variety of systemic ther-apies are used. For years, the standard therapy was single-agent gemcitabine, and this approach is still used for patients who have a poor performance status, who are elderly, or who have comorbidities.9 For patients eligible for more aggressive therapy, the National Comprehensive Cancer Network (NCCN) guidelines9 recommend oxaliplatin, irinotecan, fluorouracil, and leucovorin (FOLFIRINOX), based on results from the ACCORD trial (Actions Concertées dans les Cancers Colorectaux et Digestifs),10 or gemcitabine plus albumin-bound (nab)-paclitaxel, based on results of the MPACT trial (A Randomized Phase III Study of Weekly ABI-007 Plus Gemcitabine Versus Gemcitabine Alone in Patients
With Metastatic Adenocarcinoma of the Pancreas).11,12
In a real-world analysis of patients receiving selected therapies for metastatic pancreatic cancer, 49% received nab-paclitaxel, 32% received FOLFIRINOX, and 19% received single-agent gemcitabine.13 In this analysis, nab-paclitaxel plus gemcitabine and FOLFIRINOX appeared to have comparable effectiveness. Patients treated with nab-paclitaxel plus gemcitabine remained on therapy longer than patients who were treated with gemcitabine alone (Figure 1). Nab-paclitaxel plus gemcitabine was associated with a lower incidence of adverse events and fewer requirements for granulocyte-colony stimulating factor support. However, this regimen required more frequent use of erythropoiesis-stimulating agents, antiemetic agents, and corticosteroids (Table 1).
The combination of gemcitabine and erlotinib, which targets the human epidermal receptor growth
factor receptor 1/epidermal growth factor receptor, is also included in the NCCN guidelines.9 However, the combination provides only a 2-week improvement in survival over gemcitabine alone.14
Clearly, there is an unmet clinical need for additional options for the treatment of pancreatic cancer. In the second-line setting, clinical trials had been limited primarily to small institutional and single-arm studies. Regimens under evaluation in clinical trials have included FOLFIRINOX10; oxaliplatin, folinic acid, and fluorouracil (5-FU)15; oxaliplatin plus 5-FU and leucovorin (LV; FOLFOX)16; and capecitabine plus oxaliplatin.17 None of these trials led to significant changes in the treatment landscape. One regimen that has demonstrated a sig-nificant survival benefit is the combination of nanoliposomal irinotecan plus 5-FU/LV, which showed a significant survival improvement over 5-FU/LV alone in the randomized, phase 3 NAPOLI-1 trial (Nanoliposomal Irinotecan).18
Challenges in Pancreatic Cancer Treatment
Several other factors negatively impact outcomes for patients with pancreatic cancer. Studies have shown undertreatment of patients with both localized and advanced disease.19 In a 2013 survey of patients with pancreatic cancer and their caregivers, 20.4% of respondents reported that the diagnosing physician did not discuss treatment options (Figure 2).20 The most common reasons for not receiving treatment were that the doctor said nothing could be done (42.1%) and the patient did not think therapy would help (36.8%).20 Undertreatment is particularly relevant to older patients, in whom comorbidities and polypharmacy are more common than younger patients.21 Older patients are also less likely to enroll in clinical trials.21
The state of patients’ general health can present challenges for the treatment of pancreatic cancer. There is often a high burden of symptoms at diagnosis, including cachexia, weight loss, anorexia, immune system dysfunction, and thromboembolic disease. These conditions can interfere with treatment and quality of life, particularly in older patients with comorbidities.
Pancreatic cancer is associated with a high incidence of depression. Although this association may not be surprising given the prognosis, approximately half of patients have signs of depression in the year prior to diagnosis, suggesting that there is a physiologic component.22 Pancreatic cancer is also associated with a high incidence of pancreatic exocrine insufficiency, a condition in which pancreatic enzymes important for digestion are not properly secreted by the pancreas, resulting in malnutrition caused by a lack of vitamins and other nutrients.23 In some cases, the onset of pancreatic exocrine insufficiency precedes the diagnosis of pancreatic cancer. Pancreatic exocrine insufficiency is often overlooked by physicians, who may not address the condition until it progresses to steatorrhea, the presence of high fat content in the stool that is associated with abdominal pain, flatulence, and weight loss.23 However, once steatorrhea is identified, the patient’s vitamin and nutrient absorption has already been compromised.
Another challenge for patients with pancreatic cancer is pain. Even patients with locally advanced disease can develop complex pain that includes visceral, somatic, and neuropathic components.24 Pain associated with pancreatic cancer requires early introduction of opioids, with dose adjustments as appropriate and measures to prevent opioid-induced constipation, which can exacerbate symptoms. Interventional pain services may be considered to assist in pain control.
These symptoms and others not only cause problems for patients, but they also can interfere with the delivery of appropriate treatment.25 It is essential that patients receive appropriate care to maximize outcomes. Early palliative care consultations have been shown to improve pain management and reduce visits to emergency departments related to pain.25 A multidisciplinary care team that includes an interventional gastroenterologist is appropriate for all patients with pancreatic cancer, regardless of disease stage. Proactive management of potential complications (eg, opioid-induced constipation, cholestasis, stent infection, and pancreatic exocrine steatorrhea) is essential for maintaining adherence to treatment and maximizing clinical outcomes. Thus, therapeutic goals should address both symptom improvement and survival. Enrollment in clinical trials should always be considered when formulating the treatment plan.
Disclosure
Dr Braiteh has received honoraria from Amgen, BMS, Genentech, AstraZeneca, Insys, Incyte, Ipsen, and Tesaro. He is a consultant or advisor for Amgen, Genentech, AstraZeneca, Insys, Incyte, Ipsen, and Lexicon. He is a member of the speakers bureaus of Amgen, BMS, Genentech, Boehringer Ingelheim, AbbVie, AstraZeneca, Celgene, Pfizer, Clovis, Lexicon, and Taiho.
References
1. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2017. CA Cancer J Clin. 2017;67(1):7-30.
2. 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.
3. National Cancer Institute. Cancer stat facts: pancreas cancer. https://seer.cancer.gov/statfacts/html/pancreas.html. Accessed September 20, 2017.
4. Carrera S, Sancho A, Azkona E, Azkuna J, Lopez-Vivanco G. Hereditary pancreatic cancer: related syndromes and clinical perspective. Hered Cancer Clin Pract. 2017;15:9.
5. Lopez NE, Prendergast C, Lowy AM. Borderline resectable pancreatic cancer: definitions and management. World J Gastroenterol. 2014;20(31):10740-10751.
6. D’Angelo FA, Antolino L, La Rocca M, et al. Adjuvant and neoadjuvant therapies in resectable pancreatic cancer: a systematic review of randomized controlled trials. Med Oncol. 2016;33(3):28.
7. Oettle H, Neuhaus P, Hochhaus A, et al. Adjuvant chemotherapy with gemcitabine and long-term outcomes among patients with resected pancreatic cancer: the CONKO-001 randomized trial. JAMA. 2013;310(14):1473-1481.
8. Neoptolemos JP, Palmer DH, Ghaneh P, et al; European Study Group for Pancreatic Cancer. Comparison of adjuvant gemcitabine and capecitabine with gemcitabine monotherapy in patients with resected pancreatic cancer (ESPAC-4): a multicentre, open-label, randomised, phase 3 trial. Lancet. 2017;389(10073):1011-1024.
9. NCCN Clinical Practice Guidelines in Oncology. Pancreatic adenocarcinoma. Version 3.2017. https://www.nccn.org/professionals/physician_gls/pdf/pancreatic.pdf. Updated September 11, 2017. Accessed September 20, 2017.
10. 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.
11. Goldstein D, El-Maraghi RH, Hammel P, et al. nab-Paclitaxel plus gemcitabine for metastatic pancreatic cancer: long-term survival from a phase III trial. J Natl Cancer Inst. 2015;107(2).
12. 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.
13. 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.
14. 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.
15. Pelzer U, Schwaner I, Stieler J, et al. Best supportive care (BSC) versus oxaliplatin, folinic acid and 5-fluorouracil (OFF) plus BSC in patients for second-line advanced pancreatic cancer: a phase III-study from the German CONKO-study group. Eur J Cancer. 2011;47(11):1676-1681.
16. Gill S, Ko YJ, Cripps C, et al. PANCREOX: a randomized phase III study of 5-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.
17. Xiong HQ, Varadhachary GR, Blais JC, Hess KR, Abbruzzese JL, Wolff RA. Phase 2 trial of oxaliplatin plus capecitabine (XELOX) as second-line therapy for patients with advanced pancreatic cancer. Cancer. 2008;113(8):2046-2052.
18. 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.
19. Enewold L, Harlan LC, Tucker T, McKenzie S. Pancreatic cancer in the USA: persistence of undertreatment and poor outcome. J Gastrointest Cancer. 2015;46(1):9-20.
20. Engebretson A, Matrisian L, Thompson C. Patient and caregiver awareness of pancreatic cancer treatments and clinical trials. J Gastrointest Oncol. 2016;7(2):228-233.
21. Higuera O, Ghanem I, Nasimi R, Prieto I, Koren L, Feliu J. Management of pancreatic cancer in the elderly. World J Gastroenterol. 2016;22(2):764-775.
22. Mayr M, Schmid RM. Pancreatic cancer and depression: myth and truth. BMC Cancer. 2010;10:569.
23. Vujasinovic M, Valente R, Del Chiaro M, Permert J, Löhr JM. Pancreatic exocrine insufficiency in pancreatic cancer. Nutrients. 2017;9(3).
24. Lahoud MJ, Kourie HR, Antoun J, El Osta L, Ghosn M. Road map for pain management in pancreatic cancer: a review. World J Gastrointest Oncol. 2016;8(8):599-606.
25. Hui D, Bruera E. Integrating palliative care into the trajectory of cancer care. Nat Rev Clin Oncol. 2016;13(3):159-171.
Development of New Pharmaceutical Therapies for Pancreatic Adenocarcinoma
Ramesh K. Ramanathan, MD
Professor of Medicine
Mayo Medical School
Mayo Clinic Cancer Center
Phoenix, Arizona
Despite substantial research efforts undertaken to identify new effective therapies for the treatment of pancreatic adenocarcinoma, progress has been slow. Among the novel approaches that have shown initial activity but yielded negative results in randomized trials are the hypoxia-activated prodrug evofosfamide,1 the Janus kinase 1/2 inhibitor ruxolitinib,2 the oral tyrosine kinase inhibitor masitinib,3 the vaccine product algenpantucel-L,4 the radiolabeled 90Y-clivatuzumab tetraxetan,5 and PEGPH20 administered in combination with FOLFIRINOX.6
One approach that has shown a significant benefit in overall survival in patients with pancreatic cancer is nanoliposomal irinotecan, which is approved by the US Food and Drug Administration (FDA) for use in combination with 5-FU/LV for the treatment of patients with metastatic adenocarcinoma of the pancreas after disease progression following gemcitabine-based therapy.7 This indication encompasses not only the second-line setting, but also patients who have received prior gemcitabine as an adjuvant treatment. For these patients, nanoliposomal irinotecan can be used in the first-line metastatic setting. The irinotecan preparation uses a novel nanoliposomal product that has been designed to enhance drug delivery to tumors.8
Preclinical Rationale for Nanoliposomal Drug Delivery
The development of nanoliposomal drug delivery systems was based on the observation that liposomes deposited into tumors are scavenged by tumor-resident macrophages that take in the encapsulated product. Nanoliposomal irinotecan is converted by macrophages to its more active metabolite, SN-38. The nanoliposomal drug is also passively targeted to tumor sites owing to the hypervascular nature of tumors and their enhanced permeability to macromolecules, a property known as the enhanced permeability and retention effect.8,9 In animal studies, nanoliposomal irinotecan demonstrated a 70-fold increase in the area under the curve compared with conventional irinotecan; increased drug concentrations were detectable in the plasma, blood, and tumor.10 Together, these data provided a strong rationale for the investigation of a nanoliposomal drug delivery system in pancreatic cancer.
Clinical Trials of Nanoliposomal Irinotecan in Pancreatic Cancer
Nanoliposomal irinotecan was initially evaluated in a phase 1 dose-escalation study, which showed favorable pharmacokinetics and suggested potential antitumor activity in patients with solid tumors.11 Subsequently, a phase 2 trial evaluated the activity and safety of nanoliposomal irinotecan as monotherapy in 40 patients with gemcitabine-refractory pancreatic cancer.12 The agent was associated with a 3-month overall survival rate of 75%. Median progression-free survival was 2.4 months, and median overall survival was 5.2 months. The safety profile was acceptable.
Outcomes in the phase 2 trial led to the initiation of the global, randomized, open-label, phase 3 NAPOLI-1 trial, in which 417 patients with metastatic pancreatic ductal adenocarcinoma previously treated with gemcitabine-based therapy were randomly assigned to nanoliposomal irinotecan plus 5-FU/LV (n=117), nanoliposomal irinotecan monotherapy (n=151), or 5-FU/LV (n=149).13 The combination of nanoliposomal irinotecan plus 5-FU/LV was significantly more effective than 5-FU/LV. Median overall survival was 6.1 months with nanoliposomal irinotecan plus 5-FU/LV vs 4.2 months for 5-FU/LV alone (hazard ratio, 0.67; 95% CI, 0.49-0.92; P=.012; Figure 3).13 Nanoliposomal irinotecan plus 5-FU/LV also improved median progression-free survival compared with 5-FU/LV alone (3.1 months vs 1.5 months; unstratified hazard ratio, 0.56; 95% CI, 0.41-0.75; P=.0001; Figure 4). The median overall survival with single-agent nanoliposomal irinotecan was 4.2 months. A per-protocol analysis of the NAPOLI trial included patients who had received at least 80% of the scheduled doses during the first 6 weeks of treatment (n=66 in the nanoliposomal irinotecan plus 5-FU/LV arm vs n=71 in the 5-FU/LV arm).14 The median overall survival was 8.9 months in patients treated with nanoliposomal irinotecan plus 5-FU/LV vs 5.1 months for those treated with 5-FU/LV alone (stratified hazard ratio, 0.47; P=.0018).
The grade 3/4 toxicities that were more common with nanoliposomal irinotecan plus 5-FU/LV compared with the control arm of 5-FU were neutropenia (27% vs 1%), diarrhea (13% vs 4%), vomiting (11% vs 3%), and fatigue (14% vs 4%).
Based on the trial results and subsequent FDA approval of nanoliposomal irinotecan, this regimen should be considered a standard second-line regimen for patients who develop progressive disease after gemcitabine. One notable point about the NAPOLI-1 trial is the treatment history of enrolled participants. Because the trial was initiated before the common use of gemcitabine and nab-paclitaxel, only 13% of patients had received this combination as first-line therapy. However, 55% had received combination therapy with gemcitabine, and based on the nonoverlapping mechanisms of action with gemcitabine and nab-paclitaxel, the combination of nanoliposomal irinotecan plus 5-FU/LV as second-line therapy is reasonable and supported by the NCCN guidelines.15
Other Novel Strategies
Multiple other novel strategies are being evaluated for patients with pancreatic cancer. PEGPH20 combined with FOLFIRINOX showed no benefit at the interim futility analysis of a phase 2 trial,6 but it continues to be evaluated in combination with other active agents based on promising activity in preclinical studies. One trial is evaluating PEGPH20 in combination with gemcitabine and nab-paclitaxel.16 A recent abstract presentation of the HALO-109-201 study suggested that high levels of tumor hyaluronan may predict benefit from PEGPH20 used in combination with gemcitabine/nab-paclitaxel, indicating a potential biomarker for PEGPH20 responses.17 Based on the encouraging results of the HALO-109-201 study, a randomized, placebo-controlled phase 3 study known as HALO-109-301 has been initiated in patients with tumors showing high expression of hyaluronan.18
Ibrutinib, a Bruton tyrosine kinase inhibitor, is also being evaluated in combination with gemcitabine/nab-paclitaxel in late-stage clinical trials.19 Ibrutinib inhibits mast cell degranulation, causing stromal weakening, and it may also have immunostimulatory properties.
Another promising agent being evaluated in phase 3 trials is the signal transducer and activator of transcription 3 (STAT 3)-targeting drug napabucasin, which aims to inhibit cancer stem cell signaling pathways. In a phase 1/2 study in 66 patients with metastatic pancreatic cancer, the combination of napabucasin, nab-paclitaxel, and gemcitabine appeared to have antitumor activity, with an overall response rate of 55%.20 The randomized, open-label, multinational CanStem111P trial is evaluating the addition of napabucasin to gemcitabine and nab-paclitaxel in approximately 1132 patients with metastatic pancreatic cancer.21
Work is also ongoing to develop biomarkers to assess the activity of nanoliposomal irinotecan. Tumors with high concentrations of macrophages in the stroma may be more susceptible to nanoliposomal irinotecan based on higher concentrations of SN-38. One potential tool for measuring local macrophage concentrations is uptake of the iron-replacement agent ferumoxytol. The level of ferumoxytol in the tumor, as assessed by quantitative magnetic resonance imaging, appeared to correlate with responses to nanoliposomal irinotecan in preliminary studies (Figures 5 and 6).22 Work is ongoing to further evaluate ferumoxytol as a biomarker for response to nanoliposomal irinotecan.
Disclosure
Dr Ramanathan is a consultant for Pharmacyclics. He has rec-eived research support from AbbVie, Merck, Celgene, Berg, Boston Biomedical, and Ipsen.
References
1. Van Cutsem E, Lenz H, Furuse J, et al. MAESTRO: a randomized, double-blind phase III study of evofosfamide (evo) in combination with gemcitabine (gem) in previously untreated patients (pts) with metastatic or locally advanced unresectable pancreatic ductal adenocarcinoma (PDAC) [ASCO abstract 4007]. J Clin Oncol. 2016;34(15 suppl).
2. Hurwitz H, Van Cutsem E, Bendell JC, et al. Two randomized, placebo-controlled phase 3 studies of ruxolitinib (Rux) + capecitabine (C) in patients (pts) with advanced/metastatic pancreatic cancer (mPC) after failure/intolerance of first-line chemotherapy: JANUS 1 (J1) and JANUS 2 (J2) [ASCO GI abstract 343]. J Clin Oncol. 2017;35(suppl 4S).
3. Deplanque G, Demarchi M, Hebbar M, et al. A randomized, placebo-controlled phase III trial of masitinib plus gemcitabine in the treatment of advanced pancreatic cancer. Ann Oncol. 2015;26(6):1194-1200.
4. NewLink Genetics. NewLink Genetics announces results from phase 3 IMPRESS trial of algenpantucel-l for patients with resected pancreatic cancer. http://investors.linkp.com/releasedetail.cfm?releaseid=969978. Posted May 10, 2016. Accessed September 20, 2017.
5. Globe Newswire. Immunomedics provides update on phase 3 PANCRIT-1 trial of clivatuzumab tetraxetan in patients with advanced pancreatic cancer. https://globenewswire.com/news-release/2016/03/14/819641/0/en/Immunomedics-Provides-Update-on-Phase-3-PANCRIT-1-Trial-of-Clivatuzumab-Tetraxetan-in-Patients-With-Advanced-Pancreatic-Cancer.html. Posted March 14, 2016. Accessed September 20, 2017.
6. PRNewswire. Halozyme provides update on SWOG collaborative group clinical study. http://www.halozyme.com/investors/news-releases/news-release-details/2017/Halozyme-Provides-Update-On-SWOG-Collaborative-Group-Clinical-Study/default.aspx. Posted March 30, 2017. Accessed September 20, 2017.
7. Onivyde [package insert]. Basking Ridge, New Jersey: Ipsen Biopharmaceuticals, Inc; 2015.
8. 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.
9. Matsumura Y, Maeda H. A new concept for macromolecular therapeutics in cancer chemotherapy: mechanism of tumoritropic accumulation of proteins and the antitumor agent smancs. Cancer Res. 1986;46(12 Pt 1):6387-6392.
10. Center for Drug Evaluation and Research. Application number: 207793Orig1s000. Clinical Pharmacology and Biopharmaceutics Review(s). https://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/207793Orig1s000ClinPharmR.pdf. Submission date: April 24, 2015. Accessed September 21, 2017.
11. Chang TC, Shiah HS, Yang CH, et al. Phase I study of nanoliposomal irinotecan (PEP02) in advanced solid tumor patients. Cancer Chemother Pharmacol. 2015;75(3):579-586.
12. Ko AH, Tempero MA, Shan YS, et al. A multinational phase 2 study of nanoliposomal irinotecan sucrosofate (PEP02, MM-398) for patients with gemcitabine-refractory metastatic pancreatic cancer. Br J Cancer. 2013;109(4):920-925.
13. 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.
14. Chen L-T, Von Hoff DD, Li C-P, 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(3 suppl).
15. NCCN Clinical Practice Guidelines in Oncology. Pancreatic adenocarcinoma. Version 3.2017. https://www.nccn.org/professionals/physician_gls/pdf/pancreatic.pdf. Updated September 11, 2017. Accessed September 20, 2017.
16. ClinicalTrials.gov. PEGPH20 plus nab-paclitaxel plus gemcitabine compared with nab-paclitaxel plus gemcitabine in subjects with stage IV untreated pancreatic cancer (HALO-109-202). https://clinicaltrials.gov/ct2/show/NCT01839487. Identifier: NCT01839487. Accessed September 20, 2017.
17. Hendifar A, Bullock A, Seery T, et al. Tumor hyaluronan may predict benefit from PEGPH20 when added to nab paclitaxel/gemcitabine in patients with previously untreated metastatic pancreatic ductal adenocarcinoma (mPDA) [ESMO WGI Abstract O-028]. Ann Oncol. 2017;28(suppl 3).
18. ClinicalTrials.gov. A study of PEGylated recombinant human hyaluronidase in combination with nab-paclitaxel plus gemcitabine compared with placebo plus nab-paclitaxel and gemcitabine in participants with hyaluronan-high stage IV previously untreated pancreatic ductal adenocarcinoma. https://clinicaltrials.gov/ct2/show/NCT02715804. Identifier: NCT02715804. Accessed October 4, 2017.
19. ClinicalTrials.gov. Study of ibrutinib vs placebo, in combination with nab-paclitaxel and gemcitabine, in the first line treatment of patients with metastatic pancreatic adenocarcinoma (RESOLVE). https://clinicaltrials.gov/ct2/show/NCT02436668. Identifier: NCT02436668. Accessed October 4, 2017.
20. Bekaii-Saab T, Starodub A, El-Rayes B, et al. A phase 1b/II study of cancer stemness inhibitor napabucasin in combination with gemcitabine (gem) & nab-paclitaxel (nabptx) in metastatic pancreatic adenocarcinoma (mpdac) patients (pts) [ESMO abstract LBA-002]. Ann Oncol. 2017;28(suppl 3).
21. ClinicalTrials.gov. A study of napabucasin plus nab-paclitaxel with gemcitabine in adult patients with metastatic pancreatic adenocarcinoma (CanStem111P). https://clinicaltrials.gov/ct2/show/NCT02993731. Identifier: NCT02993731. Accessed September 20, 2017.
22. Ramanathan RK, Korn RL, Raghunand N, et al. Correlation between ferumoxytol uptake in tumor lesions by MRI and response to nanoliposomal irinotecan in patients with advanced solid tumors: a pilot study. Clin Cancer Res. 2017;23(14):3638-3648.
Advances in the Management of Pancreatic Adenocarcinoma: Guidelines and Clinical Practice
Tanios Bekaii-Saab, MD
Professor, Mayo Clinic College of Medicine and Science
Program Co-Leader, GI Cancer, Mayo Clinic Cancer Center
Senior Associate Consultant, Mayo Clinic Arizona
Phoenix, Arizona
Optimal management of pancreatic cancer hinges upon early referral to a medical oncologist for a proper assessment. Performance status is a key consideration in treatment planning. Patients with a poor performance status (>2) are not likely to benefit from anticancer therapy and should instead receive best supportive care. It should be noted, however, that patients with a new diagnosis of pancreatic cancer could have functional limitations related to symptoms caused by the cancer itself. In such patients, it may be possible to improve performance status so that active treatment may become an option.
It is also important that, whenever possible, patients with pancreatic cancer receive care in a specialized center that is familiar with current practices. This approach may reduce the likelihood of less-optimal treatment.1 Although treatment in specialized cancer centers was thought to benefit primarily those with early-stage cancers, recent data suggest that patients with complex conditions, such as pancreatic cancer, benefit from referral to specialized care centers regardless of stage.2
Clinical trial participation is a key aspect of pancreatic cancer treatment, as addressed in multiple treatment guidelines. Clinical guidelines from the NCCN3 clearly state that a clinical trial is the best management option for patients with a diagnosis of cancer, and those from the National Cancer Institute4 recommend that patients always be considered for clinical trials prior to initiating palliative therapy. Participation in clinical trials remains a challenge, as they are often available only in larger academic centers, and many eligible patients may not have access for various reasons. Unfortunately, only approximately 12% of US patients with pancreatic cancer enroll in clinical trials.5 Efforts to educate physicians as well as patients regarding the importance of referral to a clinical trial, whenever possible, may improve access and overall outcomes.
Although survival rates for patients with pancreatic cancer remain bleak, outcomes have improved, albeit mod-estly, in recent years, with 5-year overall survival rates improving from approximately 4% in the early 2000s to 8% following the year 2010.6 These trends highlight that, in small steps, strides are being made in the treatment of pancreatic cancer, primarily owing to improvements in systemic therapy. Newer treatment reg-imens, including gemcitabine and nab-paclitaxel, FOLFIRINOX, and nanoliposomal irinotecan plus 5-FU/LV, have changed the landscape in such a way that a small percentage of patients are surviving for multiple years after a diagnosis of metastatic pancreatic cancer. For example, in the phase 3 MPACT trial, 3% to 4% of patients receiving gemcitabine and nab-paclitaxel were still alive after 3 years, compared with no patients receiving gemcitabine alone.7 These outcomes reflect a slow movement toward survival targets that were thought to be impossible in this disease.
Clinical Guidelines for Pancreatic Cancer
The guidelines primarily utilized in the community are those from the NCCN, which are updated frequently (most recently in September 2017), and those from the European Society for Medical Oncology (ESMO), which are published approximately every 3 years.3,8,9 The ESMO guidelines are occasionally updated electronically to reflect treatment advances; they were most recently updated in June 2017 to add nanoliposomal irinotecan and 5-FU/LV for pancreatic cancer.8,9
The NCCN guidelines tend to be more extensive than the ESMO guidelines. They categorize treatments based on levels of evidence. Current NCCN guidelines recommend nanoliposomal irinotecan and 5-FU/LV as a category 1 option for the second-line treatment of patients with metastatic pancreatic cancer who have good performance status and disease progression.3
Selecting Systemic Therapy in Pancreatic Cancer
Although there are some differences between the guidelines from the NCCN and ESMO, both promote the general aim of treating the right patient with the right regimen, with the goal of providing adequate palliation and extending survival. As newer regimens are introduced, treatment decisions become more complicated. The optimal sequencing of therapies has recently been brought into question. Clinicians often use FOLFIRINOX as initial therapy for patients who are relatively younger (typically <70 years old) and/or those with a great performance status. Another approach would be to start with gemcitabine plus nab-paclitaxel, regardless of the patient’s age and performance status, leaving more therapy options for the second-line or even third-line settings. The choice between FOLFIRINOX and gemcitabine plus nab-paclitaxel in the first-line setting is largely driven by relative physician bias, given that the 2 regimens have not been compared in randomized studies. Historically and in separate studies, the median overall survival was 11.1 months with FOLFIRINOX vs 6.8 months with gemcitabine (P<.001),10 and 8.7 months with gemcitabine plus nab-paclitaxel vs 6.6 months with gemcitabine (P<.0001).7 However, a number of notable differences make the interpretation of the historical results very difficult, including the fact that the FOLFIRINOX trial enrolled a more highly selected patient population and included only subjects treated in French Centers of Excellence.10
In a real-world analysis of outcomes in patients with metastatic pancreatic cancer, Braiteh and colleagues found similar outcomes whether patients started with FOLFIRINOX or gemcitabine plus nab-paclitaxel.11 The widespread use of FOLFIRINOX in the first-line setting is limited by the greater level of toxicity, and decreases salvage options beyond the first-line setting. In my practice, I tend to generally use a less-intensive biweekly regimen of gemcitabine plus nab-paclitaxel in the first-line setting,12 reserving other therapies for later lines. This approach allows the use of nanoliposomal irinotecan plus 5-FU/LV as a second-line option. It is then possible to utilize a platinum-based therapy in the third-line setting, allowing a potential path for 3 lines of therapy while using a “gentler” treatment approach that maintains clinical benefit. Sequencing strategies, rather than a “kitchen-sink approach,” are already widely adopted in the palliative setting of most other malignancies. Real-world data suggest that this approach does not compromise survival compared with the use of more aggressive initial therapy.11
Treatment Considerations for Patients With BRCA Mutations
A group of patients who require consideration of a different course of initial treatment are those with BRCA1/2 mutations. These patients have an enhanced sensitivity to platinum agents and/or topoisomerase inhibitors, and therefore a regimen such as FOLFIRINOX or gemcitabine/cisplatin may be more beneficial earlier in the disease course.13
Choice of Second-Line Therapy
The selection of a second-line regimen depends on the type of exposure in the first-line setting. Historically, selection had been an ongoing challenge for oncologists. Traditionally, after gemcitabine/nab-paclitaxel, most clinicians in the United States have tended to use FOLFOX, based on the German Charité Onkologie (CONKO) study group trial showing a significant benefit with oxaliplatin, folinic acid, and 5-FU (OFF) vs supportive care in the second-line setting (Figure 7).14 In contrast, the PANCREOX study (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) showed no benefit and added toxicities with the addition of oxaliplatin to 5-FU/LV vs 5-FU/LV alone.15
We recently published a meta-analysis evaluating all randomized, controlled trials of oxaliplatin-based and irinotecan-based regimens for the treatment of patients with progressive disease after first-line treatment of metastatic pancreatic cancer.16 Only irinotecan-containing combinations appear to improve overall survival compared with fluoropyrimidine monotherapy (Figure 8), suggesting that nanoliposomal irinotecan plus 5-FU/LV should be the preferred option over FOLFOX for second-line treatment following disease progression on a gemcitabine-based regimen.
Managing Adverse Events
Combination regimens for the treatment of pancreatic cancer can have substantial toxicities. Patients who develop toxicities during treatment with FOLFIRINOX often require multiple dose reductions and growth-factor support.10 Additionally, the regimen of gemcitabine and nab-paclitaxel has its own limiting toxicities. In particular, adequate delivery of weekly gemcitabine singly or in combination is notoriously difficult to maintain. Dose interruptions may be needed to manage cytopenias or other toxicities, as observed in clinical trials.7 Neuropathy is of particular concern with nab-paclitaxel. Grade 3/4 peripheral neuropathy occurs in approximately 17% of patients receiving weekly gemcitabine and nab-paclitaxel.7 Among patients treated with nab-paclitaxel, peripheral neuropathy leads to dose reductions in 10% and discontinuations in another 8%.7 A modified biweekly regimen can be considered as a possible alternative. In a retrospective analysis, biweekly administration of gemcitabine and nab-paclitaxel was better tolerated while maintaining efficacy when compared with the historical weekly regimen (Figure 9).12 Efforts are underway to have a direct comparison between biweekly and weekly dosing regimens. The toxicities associated with the nanoliposomal irinotecan and 5-FU/LV regimen are similar to what would be expected from an irinotecan-based regimen, aside from a much lower rate of alopecia with the formulation.17 Overall, it is essential to follow patients very closely, intervene with supportive measures, and use dose modifications as indicated to ensure exposure to optimal dose intensity while maximizing a balance between treatment efficacy and tolerability. With this comprehensive approach, one would maximize a balanced outcome of palliation and prolongation of survival.
Disclosure
Dr Bekaii-Saab has no real or apparent conflicts of interest to report.
References
1. Enewold L, Harlan LC, Tucker T, McKenzie S. Pancreatic cancer in the USA: persistence of undertreatment and poor outcome. J Gastrointest Cancer. 2015;46(1):9-20.
2. Haj Mohammad N, Bernards N, Besselink MG, et al. Volume matters in the systemic treatment of metastatic pancreatic cancer: a population-based study in the Netherlands. J Cancer Res Clin Oncol. 2016;142(6):1353-1360.
3. NCCN Clinical Practice Guidelines in Oncology. Pancreatic adenocarcinoma. Version 3.2017. https://www.nccn.org/professionals/physician_gls/pdf/pancreatic.pdf. Updated September 11, 2017. Accessed September 20, 2017.
4. National Cancer Institute. Pancreatic cancer treatment (PDQ®)—Health Professional Version. https://www.cancer.gov/types/pancreatic/hp/pancreatic-treatment-pdq. Updated July 11, 2017. Accessed September 20, 2017.
5. Engebretson A, Matrisian L, Thompson C. Patient and caregiver awareness of pancreatic cancer treatments and clinical trials. J Gastrointest Oncol. 2016;7(2):228-233.
6. National Cancer Institute. Cancer stat facts: pancreas cancer. https://seer.cancer.gov/statfacts/html/pancreas.html. Accessed September 20, 2017.
7. 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.
8. Ducreux M, Cuhna AS, Caramella C, et al. Cancer of the pancreas: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2015;26(suppl 5):v56-v68.
9. ESMO Guidelines Committee. eUpdate—cancer of the pancreas treatment recommendations. http://www.esmo.org/Guidelines/Gastrointestinal-Cancers/Cancer-of-the-Pancreas/eUpdate-Treatment-Recommendations. Posted June 20, 2017. Accessed September 20, 2017.
10. 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.
11. 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.
12. 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.
13. Lowery MA, Kelsen DP, Stadler ZK, et al. An emerging entity: pancreatic adenocarcinoma associated with a known BRCA mutation: clinical descriptors, treatment implications, and future directions. Oncologist. 2011;16(10):1397-1402.
14. Pelzer U, Schwaner I, Stieler J, et al. Best supportive care (BSC) versus oxaliplatin, folinic acid and 5-fluorouracil (OFF) plus BSC in patients for second-line advanced pancreatic cancer: a phase III-study from the German CONKO-study group. Eur J Cancer. 2011;47(11):1676-1681.
15. Gill S, Ko YJ, Cripps C, et al. PANCREOX: a randomized phase III study of 5-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.
16. Sonbol MB, Firwana B, Wang Z, et al. Second-line treatment in patients with pancreatic ductal adenocarcinoma: a meta-analysis [published online August 17, 2017]. Cancer. doi:10.1002/cncr.30927.
17. 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.
18. Mizuno N, Yamao K, Komatsu Y, et al. Randomized phase II trial of S-1 versus S-1 plus irinotecan (IRIS) in patients with gemcitabine-refractory pancreatic cancer [ASCO GI abstract 263]. J Clin Oncol. 2013;31(4 suppl).
19. 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.
20. Ohkawa S, Okusaka T, Isayama H, et al. Randomised phase II trial of S-1 plus oxaliplatin vs S-1 in patients with gemcitabine-refractory pancreatic cancer. Br J Cancer. 2015;112(9):1428-1434.
Recent Advances in the Treatment of Pancreatic Adenocarcinoma: Further Observations
Ramesh K. Ramanathan, MD, and Tanios Bekaii-Saab, MD
H&O How might drug development in pancreatic cancer evolve?
Ramesh K. Ramanathan, MD The development of new drugs for pancreatic cancer has been difficult—more so than for other cancers. Researchers have struggled to develop targeted agents and immunotherapeutic approaches that are effective in pancreatic cancer. Multiple targeted and immunotherapeutic approaches have shown a lack of efficacy in clinical trials; this does include some agents that showed only minimal activity in early studies. Perhaps there was too much of a rush on some of these agents. In order to effectively employ immunotherapy against pancreatic cancer, researchers will need to devise rational combinations of costimulatory molecules and understand the mechanisms behind the poor immune responses observed in pancreatic cancer.1
Tanios Bekaii-Saab, MD I agree; pancreatic cancer has the unfortunate reputation of being the “graveyard” of drug development. However, in the past few years, several studies have shown that we have the ability to move the needle and improve outcomes with a lot of work and more investment in this space.
Today, we know of 2 subsets of pancreatic cancer patients who will respond to specific therapies. Less than 1% of patients with pancreatic cancers have high expression of microsatellite instability (MSI-H), either in the setting of Lynch syndrome or through somatic acquisition. In this setting, the checkpoint inhibitor pembrolizumab, which binds to the programmed cell death protein 1 (PD-1) receptor, has shown significant activity2 and is now approved by the FDA. I have firsthand experience treating a patient with a history of Lynch syndrome, who eventually developed MSI-H pancreatic cancer. She was initially treated with chemotherapy. She rapidly progressed and then was referred to my clinic for further management. She received single-agent pembrolizumab, and attained a complete response lasting more than 2 years now.
The other subset of patients includes those with tumors harboring BRCA/PALB mutations. Patients with germline BRCA mutations represent only approximately 3% to 4% of all cases, and another 5% to 6% have somatic mutations. There is another subset of patients who will have other homologous repair deficiencies (HRDs), accounting for close to 10% of pancreatic cancers. Patients with BRCA/PALB mutations exhibit significant responses to platinum-based and/or irinotecan-based therapies. Additionally, ongoing efforts to evaluate poly (ADP-ribose) polymerase (PARP) inhibitors in this subset of patients (with BRCA/PALB mutations and other HRDs) are underway. Olaparib3 and rucaparib,4 but not veliparib, have demonstrated preliminary single-agent activity in patients with pancreatic cancer with BRCA mutations.
We have a great need to continue expanding our understanding of the molecular biology and genetics of pancreatic cancer. Recent research suggests that as we further refine different subgroups, we may be able to target these cancers more precisely.
Disclosures
Dr Ramanathan is a consultant for Pharmacyclics. He has rec-eived research support from AbbVie, Merck, Celgene, Berg, Boston Biomedical, and Ipsen. Dr Bekaii-Saab has no real or apparent conflicts of interest to report.
References
1. Guo S, Contratto M, Miller G, Leichman L, Wu J. Immunotherapy in pancreatic cancer: unleash its potential through novel combinations. World J Clin Oncol. 2017;8(3):230-240.
2. Diaz LA, Marabelle A, Delord JP, et al. Pembrolizumab therapy for microsatellite instability high (MSI-H) colorectal cancer (CRC) and non-CRC [ASCO abstract 3017]. J Clin Oncol. 2016;34(15 suppl).
3. 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.
4. 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 4100]. J Clin Oncol. 2016;34(15 suppl).