Release Date: August 22, 2019
STATEMENT OF NEED
Expiration Date: August 22, 2020
This activity is provided free of charge.
This CE article is designed to serve as an update on cancer detection and prevention and to facilitate clinical awareness of current and new research regarding state-of-the-art care for those with or at risk for cancer.
Advanced practice nurses, registered nurses, and other healthcare professionals who care for cancer patients may participate in this CE activity.
Upon completion, participants should be able to:
ACCREDITATION/CREDIT DESIGNATION STATEMENT
- Describe new preventive options and treatments for patients with cancer
- Identify options for individualizing the treatment for patients with cancer
- Assess new evidence to facilitate survivorship and supportive care for patients with cancer
Physicians’ Education Resource®
, LLC is approved by the California Board of Registered Nursing, Provider #16669 for 1 Contact Hour.
DISCLOSURES/RESOLUTION OF COI
It is the policy of Physicians’ Education Resource®
, LLC (PER®
) to ensure the fair balance, independence, objectivity, and scientific objectivity in all of our CE activities. Everyone who is in a position to control the content of an educational activity is required to disclose all relevant financial relationships with any commercial interest as part of the activity planning process. PER®
has implemented mechanisms to identify and resolve all conflicts of interest prior to release of this activity.The planners and authors of this CE activity have disclosed no relevant financial relationships with any commercial interests pertaining to this activity.
METHOD OF PARTICIPATION
- Read the articles in this section in its entirety.
- Go to www.gotoper.com/go/ONN19August
- Complete and submit the CE posttest and activity evaluation.
- Print your CE Certificate.
This CE activity may or may not discuss investigational, unapproved, or off-label use of drugs. Participants are advised to consult prescribing information for any products discussed. The information provided in this CE activity is for continuing medical nursing purposes only and is not meant to substitute for the independent medical judgment of a nurse or other healthcare provider relative to diagnostic, treatment, or management options for a specific patient’s medical condition. The opinions expressed in the content are solely those of the individual authors and do not reflect those of PER®
Low-Dose Drug Regimen Is Effective for Older, Frail Patients With Gastroesophageal Cancer
The average age of diagnosis for advanced gastroesophageal cancer is 75 years in the United Kingdom, and many of these patients are frail and experiencing additional medical conditions. However, the clinical trials that led to the standard treatment for the disease often included patients who were a decade younger and in better health, according to Peter S. Hall, PhD, clinical senior lecturer at the University of Edinburgh. As a result, many elderly or frail patients are treated with reduced doses of chemotherapy that are not evidence-based.
“A number of years ago, we audited practices in the UK. We surveyed oncologists and found that elderly and frail patients with this condition were being treated with a wide range of chemotherapy regimens, including dose-modified regimes, but without any really good evidence-based supporting practice, thus leading to a wide variation in practice,” Hall said.
To address this problem, a group of investigators in the United Kingdom sought to determine the benefits of a reduced-dose regimen of oxaliplatin (Eloxatin) and capecitabine (Xeloda) in this patient population through the randomized, phase III GO2 clinical trial. Hall presented his team’s results in a presscast in advance of the 2019 ASCO Annual Meeting in Chicago, Illinois.1 The goal of GO2 was to find the optimal dose of oxaliplatin, which inhibits DNA replication, plus capecitabine, which inhibits tumor cell division. The investigators also evaluated optimal clinical benefit, tolerability, quality of life, and patient satisfaction for the drug duo to determine overall treatment utility (OTU).
OTU was classified as poor, intermediate, or good according to a combination of clinician- and patient-assessed criteria. A determination of good OTU required the following 6 outcomes: no cancer progression on scans; oncologist’s assessment of benefit; lack of severe toxicity; lack of deterioration in patient’s global quality of life; treatment considered worthwhile by patient; and treatment not interfering with patient’s daily activities.
The 514 trial participants were between 51 and 96 years of age and were randomly assigned to 1 of 3 dosage levels: Level A, 130 mg/m2 of oxaliplatin administered once every 21 days and 625 mg/m2 of capecitabine twice a day, every day; Level B, which was 80% of the Level A dose; and Level C, which was 60% of the Level A dose. Patients who had decreased kidney function received 75% of the suggested dose of capecitabine.
The primary endpoint of progression-free survival (PFS) was met; a lack of substantial variation between the 3 groups demonstrated that the lower doses were noninferior to the Level A dose. PFS was 4.9, 4.1, and 4.3 months for Levels A, B, and C, respectively. Non-inferiority of PFS is confirmed for Level B vs A (HR 1.09, CI, 0.89-1.32) and for Level C vs A (HR 1.10, CI, 0.90-1.33).
At a 9-week follow-up, patients randomized to Level C had fewer toxic reactions and better OTU outcomes than the other groups, with a higher percentage of good OTU scores (43%) in Level C than in Levels A (35%) and B (36%). Younger and less frail patients tended to have the best OTU, and no patient group benefited from the higher doses given in Level A.
Overall survival (OS)—a secondary endpoint—was also met, with minimal differences among the groups. OS was 7.5, 6.7, and 7.6 months for patients in Levels A, B, and C, respectively. Additionally, slightly more than one-third of patients in Level C (37%) experienced grade 3 or higher adverse events, compared with 56% in Levels A and B.
“We found that the lowest dose tested was noninferior in terms of progression-free survival. It produced less toxicity and better overall treatment utility,” Hall said.
Hall PS, Swinson D, Waters JS, et al. Alternative chemotherapy for frail or elderly patients with advanced gastric or esophageal cancer. Presented at: 2019 ASCO Annual Meeting; May 31-June 4, 2019; Chicago. Abstract 4006.
Spartalizumab Plus Dabrafenib/Trametinib Is Active in BRAF-Mutant Melanoma
The PD-1 inhibitor spartalizumab, taken along with dabrafenib (Tafinlar) and trametinib (Mekinist), led to a complete response (CR) in more than 40% of patients with previously untreated unresectable or metastatic BRAF V600–mutant melanoma, according to a pooled analysis of part 1 (run-in cohort) and part 2 (biomarker cohort) of the 3-part COMBI-i study. In a total of 36 patients (9 from part 1 and 27 from part 2), first-line treatment with the triplet was associated with an overall response rate (ORR) of 78% by investigator assessment and a CR in 42% of patients at a median follow-up of 19.9 months.1
As of April 8, 2019, the median progression-free survival (PFS) was 23.7 months and the overall survival (OS) was not evaluable.1 Eight (22%) of the 36 patients had died. COMBI-i is investigating first-line spartalizumab, 400 mg every 4 weeks, plus the BRAF inhibitor dabrafenib at 150 mg twice daily and the MEK inhibitor trametinib at 2 mg daily, in patients with unresectable or metastatic BRAF V600–mutant melanoma. Treatment was continued until disease progression, death, unacceptable toxicity, loss to follow-up, or withdrawal of consent.2
Of the 36 patients in this analysis, 22% had stage IIIC disease according to the American Joint Committee on Cancer (AJCC), 7th edition; 22% had stage IV M1a; 36% had stage IV M1b; 36% had stage IV M1c with elevated levels of lactate dehydrogenase (LDH); and 19% had stage IV M1c with normal LDH levels. Nineteen (53%) patients overall had an LDH level <1 x the upper limit of normal (ULN), 9 (25%) had LDH ≥1 to <2 x ULN, and 6 (17%) had LDH ≥2 x ULN. At data cutoff, of the 15 patients with CR, the CR was ongoing in 10 (66.7%), and 3 (20%) had elevated LDH.
The 12-month PFS rate was 66.7%. Among the 15 patients with elevated LDH at baseline, the median PFS was 10.7 months, with progression events in 10 of the 15 (66.7%). The median PFS in patients with stage IV M1c disease was 12.9 months.
The median OS was not evaluable in patients with elevated LDH at baseline, with 7 (47%) deaths in this group.
The median duration of response (DOR) was 20.7 months. The 12-month DOR rate was 80.3%. The median DOR was not evaluable in patients with elevated baseline LDH or stage IV M1c disease.
All patients experienced at least 1 adverse event (AE) of any grade, and serious AEs occurred in 64%. Pyrexia was the most common AE, occurring in 32 (89%) patients. The most common serious AEs were pyrexia (n = 8) and grade ≥3 pancreatitis, cellulitis, pneumonia, and a decrease in ejection fraction (n = 2 for each). There were no treatment-related grade 5 AEs.
AEs led to discontinuation of any study drug in 17 (47%) patients and discontinuation of all 3 study drugs in 6 (17%) patients. These AEs included increased gamma-glutamyltransferase, elevated aspartate aminotransferase (AST) or alanine aminotransferase (ALT), dermatitis, hyperkalemia, paresthesia, immune-mediated hepatitis, and interstitial lung disease. Adverse events leading to dose adjustments or interruptions occurred in 100% of patients. There were no treatment-related deaths.
Correlative biomarker data from the run-in and biomarker cohorts were presented in a separate poster by a team led by Reinhard Dummer, MD, professor of dermatologic oncology, University Hospital Zurich Skin Cancer Center, Switzerland.2 All patients had a consistent increase in T-cell-inflamed gene expression signature levels from baseline to biopsy at 2 to 3 weeks.
At data cutoff, 5 of 22 patients with DNA- and RNA-sequencing data available had a PFS event within the first 12 months. Heatmap analysis showed that those with a PFS event prior to 12 months had relatively cold tumors at baseline, characterized by low tumor mutational burden values, low T-cell-inflamed gene expression signature levels, or high levels of immunosuppressive tumor microenvironment signatures compared with the patients without a PFS event in the first 12 months.
The global placebo-controlled, randomized part 3 of COMBI-i is ongoing.
1. Long GV, Lebbe C, Atkinson V, et al. The anti–PD-1 antibody spartalizumab (S) in combination with dabrafenib (D) and trametinib (T) in previously untreated patients (pts) with advanced BRAF V600–mutant melanoma: updated efficacy and safety from parts 1 and 2 of COMBI-i. J Clin Oncol 37, 2019 (suppl; abstr 9531).
2. ClinicalTrials.gov. A study of the anti-PD1 antibody PDR001 in combination with dabrafenib and trametinib in advanced melanoma (COMBI-i) https://clinicaltrials.gov/ct2/show/NCT02967692.
3. Dummer R, Gusenleitner D, Campbell CD, et al. Tumor microenvironment (TME), longitudinal biomarker changes, and clinical outcome in patients (pts) with advanced BRAF V600-mutant melanoma treated with first-line spartalizumab (S) + dabrafenib (D) + trametinib (T). J Clin Oncol 37, 2019 (suppl; abstr 9515).
Jayshree Shah, MSN, BSN, BS, RN, APN-C, AOCNP
As new combination therapies are approved, it is vital for oncology nurses to both keep up with upcoming research and understand the drug-drug interactions involved so that they can teach and address any symptoms that may develop. This is important as we become more specialized and provide precision medicine to our patients.
In the COMBI-i trial, adding a PD-1 inhibitor to untreated, advanced BRAF V600–mutant melanoma provides another opportunity for oncology nurses to learn about the role and impact of using a PD-1 inhibitor with known oral dabrafenib and trametinib agents.
First, however, oncology nurses, in the office and infusion settings, must understand melanoma pathophysiology and using specific biomarkers to identify patients who have the BRAF V600 mutation so they can offer a more targeted patient-driven treatment plan. Once an eligible patient is identified, an oncology nurse can begin to explain how combination immunotherapy and targeted therapies fight mutation-positive cancer and activate the immune system using immunotherapy.
The next step is for the oncology nurse to begin explaining the timing of the regimen and how to take the oral kinase inhibitors on schedule. Ordering, processing, and receiving the oral kinases in a timely manner involves proper follow-up to make sure the patient has the medication and is taking it as advised.
Reviewing the adverse event (AE) profile becomes another top priority as combination therapies are introduced. The oncology nurse has to learn the targeted therapy’s AE profile, as well as the potential immunotherapy AEs in order to assure the patient and caregiver understand the importance of utilizing combination therapies.
Scheduling a visit and monitoring for AEs during and after treatment mean that the treatment center or medical office always properly communicate with the patients, beginning with the scheduler of an appointment and including the medical assistant, oncology nurses, and the treating physician.
Chronic Lymphocytic Leukemia
Acalabrutinib Combo Induces High Responses in CLL
Oncology Nursing News®
Simultaneous targeting of Bruton’s tyrosine kinase (BTK) and the CD20 antigen led to objective responses in more than 90% of patients with chronic lymphocytic leukemia (CLL), including those with previously untreated and relapsed/refractory (R/R) disease, a small preliminary trial showed.1
Patients with previously untreated disease had an overall response rate (ORR) of 95%, which declined slightly to 92% in patients with relapsed/refractory CLL treated with the combination of the BTK inhibitor acalabrutinib (Calquence) and the anti-CD20 antibody obinutuzumab (Gazyva). Median duration of response (DoR) had yet to be reached.
Patients with no prior treatment had a 39-month progression-free survival (PFS) rate of 94.4%, and those with previously treated disease had a 42-month PFS rate of 72.7%, as reported at the 2019 American Society of Clinical Oncology (ASCO) Annual meeting.
“Treatment with acalabrutinib plus obinutuzumab yielded high response rates that were durable and deepened over time in both R/R and treatment-naïve patients,” said Jennifer Woyach, MD, of The Ohio State University Comprehensive Cancer Center in Columbus, Ohio. “This combination was well tolerated in both cohorts, with low rates of grade 3 or higher adverse events and grade 3 or higher bleeding, and only one case of atrial fibrillation. Most patients remain on treatment after a median follow-up of 3.5 years.”
BTK has an essential role in B-cell receptor signaling and has become a validated therapeutic target for CLL. In phase I/II clinical trials, acalabrutinib achieved objective response rates exceeding 90% as a single-agent therapy for patients with untreated and relapsed/refractory CLL.2-4 Obinutuzumab has approved indications for follicular lymphoma and untreated CLL. Woyach reported findings from the 3.5-year follow-up of a single-arm trial involving 45 patients with CLL: 19 with untreated disease and 26 with relapsed/refractory CLL. In the group with R/R disease, prior treatment with a BTK inhibitor was allowed except in the case of discontinuation for on-treatment disease progression.
The study population median age was about 61 years, 51% had bulky disease, and only 1 patient had small lymphocytic lymphoma. Twenty-one percent had 17p deletion (del[17p]), 32% had del(11q), 61% had unmutated immunoglobulin heavy chain variable region, and half had a complex karyotype.
Seventy-eight percent of the patients remained on treatment. Woyach said that 10 patients discontinued acalabrutinib: 5 because of adverse events (AEs), 3 because of Richter transformation, 1 because of disease progression, and 1 because of death. All but 2 patients completed treatment with obinutuzumab.
The ORR in patients with previously untreated CLL consisted of complete responses (CR) in 31.6% and partial responses (PRs) in 63.2%. In the R/R group, 7.1% had CRs and 84.8% had PRs. Woyach said the CR rate in the previously untreated patients increased from 15% at 22 months to 32% at 39 months, reflecting conversion from PR to CR in 3 patients. The median time to CR was 18 months in the untreated patients and 12.9 months in the R/R group. Median DoR had yet to be reached in either group. At the last follow-up visit, DoR was 82.1% in patients with untreated and R/R disease.
With regard to minimal residual disease (MRD) status in bone marrow, 26% of previously untreated patients had MRD ≤0.01%, 21% had MRD >0.01% to ≤1%, and 42% had MRD >1%. The most common AEs (all grades) were upper respiratory tract infections (71%), weight gain (71%), maculopapular rash (67%), cough (64%), diarrhea (62%), headache (56%), nausea (53%), arthralgia (51%), dizziness (46%), constipation (45%), contusion (42%), fall (42%), infusion-related reaction (42%), sinusitis (42%), vomiting (42%), and fatigue (40%). The most common grade ≥3 AEs were neutropenia (24%); syncope (11%); decreased platelet count, cellulitis, and weight gain (9% each); and hypertension and hypophosphatemia (7% each).
1. Woyach JA, Rogers KA, Bhat SA, et al. Acalabrutinib with obinutuzumab (Ob) in treatment-naive (TN) and relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL): Three-year follow-up. J Clin Oncol 37, 2019 (suppl; abstr 7500).
2. Byrd JC, Harrington B, O’Brien S, et al. Acalabrutinib (ACP-196) in Relapsed Chronic Lymphocytic Leukemia. N Engl J Med 2016;374:323-332.
3. Byrd JC, Weirda WG, Schuh A, et al Acalabrutinib Monotherapy in Patients with Relapsed/Refractory Chronic Lymphocytic Leukemia: Updated Results from the Phase 1/2 ACE-CL-001 Study. Blood2017;130;498.
4. Byrd JC, Woyach JA, Furman, RR, et al. Acalabrutinib in Treatment-Naive (TN) Chronic Lymphocytic Leukemia (CLL): Updated Results from the Phase 1/2 ACE-CL-001 Study. Blood 2018;132-692).
Low-Fat Diet Reduces Risk of Breast Cancer Death
The results of a large, randomized clinical trial demonstrating a positive impact of a low-fat diet on breast cancer incidence and mortality are in, and they are encouraging, say researchers. According to data presented at the 2019 ASCO 55th Annual Meeting in Chicago, Illinois, a balanced diet that is low in fat and includes daily portions of vegetables, fruit, and grains leads to a 21% lower risk of dying from breast cancer.
Additionally, the risk of death from any cause after a breast cancer diagnosis was reduced by 15% for women who followed this diet, according to a press release about the findings.1 At a presscast ahead of the meeting, lead author Rowan Chlebowski, MD, PhD, FASCO, explained that the inconsistent findings of previous studies and the tendency of countries with lower-fat diets to see fewer instances of breast cancer led to the creation of the Women’s Health Initiative (WHI) Dietary Modification (DM) clinical trial, which examined the impact of a low-fat diet on breast cancer incidence and mortality.
From 1993 to 1998, investigators enrolled 48,835 postmenopausal women aged 50 to 79 years, with no previous breast cancer history, from 40 clinical centers across the United States. An analysis of these women’s diets revealed that they derived 32% or more of their daily calories from fat.
Participants were then randomly placed into 2 groups: 29,294 (60%) were assigned to a usual diet comparison group, while 19,541 (40%) were placed in a dietary intervention group with the goal of increasing their daily intake of fruits, vegetables, and grains and reducing their daily fat intake to 20% of their calories.
The comparison group was seen once a year by investigators, while the intervention group was seen at 18 visits over the course of a year, followed by quarterly follow-up visits, Chlebowski explained. The dietary intervention ended after 8.5 years (in 2005), and the trial has followed participants for a median of 19.6 years.
Between 1993 and 2013, a total of 3,374 cases of breast cancer were diagnosed. Investigators found that the women in the intervention group saw more health benefits than those in the control group. Most notably, the risk of death from any cause after a breast cancer diagnosis was reduced by 15%, and the risk of death directly from breast cancer was reduced by 21%. Throughout the dietary intervention period of 8.5 years, the investigators found 8% fewer breast cancer diagnoses overall, though the abstract noted that this was not statistically significant.
Chlebowski, investigator, and chief of the Division of Medical Oncology and Hematology at the Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center in Torrance, California, and professor of Medicine at the David Geffen School of medicine at UCLA, noted that these findings were particularly interesting given that although the intervention group did not hit its target goal of reducing fat intake to 20% of total energy, it still managed to see significant benefits while only reducing fat intake to 24.5%.
This research shows that dietary changes can significantly influence a woman’s risk of dying from breast cancer, said Chlebowski. “The balanced diet we designed is one of moderation, and after nearly 20 years of follow-up, the health benefits are still accruing.”
Lidia Schapira, MD, FASCO, medical oncologist at the Gillette Center for Breast Oncology at the Massachusetts General Hospital Cancer Center and assistant professor of medicine at Harvard Medical School, was also on the presscast and echoed Chlebowski’s statements with comments that could also ring true to oncology nurses.
“This helps us understand that what we put on our plates matters,” Schapira said. “It helps us, in general, to say that it is worth coaching our patients to put fruits, vegetables, and grains on their plates.”
Chlebowski RT, Aragaki AK, Anderson GL, et al. Low-fat dietary pattern and long-term breast cancer incidence and mortality: The Women’s Health Initiative randomized clinical trial. Presented at: ASCO Annual Meeting; May 31-June 4, 2019; Chicago, IL.; Abstract 520. Nurse Perspective
Interaction Between Socioeconomics and Multiple Myeloma Outcomes
Higher regional income and insurance type were associated with a significantly greater probability of survival for patients with multiple myeloma (MM), according to results from a recent study.1
After a median 30.2 months of treatment, patients living in areas with a median annual income ≥$46,000 had a 16% greater chance of survival compared with those living in less wealthy areas (HR, 1.16; 95% CI, 1.08-1.25; P<.0001).1
“We can clearly see that patients living in higher-income areas had a survival advantage,” said lead author Kamal Chamoun, MD, a fellow in the Hematologic Malignancies and Stem Cell Transplant Program at University Hospitals Seidman Cancer Center in Cleveland, Ohio, in a presentation at the 2019 ASCO Annual Meeting. The study was based on an analysis of demographic statistics collected by the National Cancer Database.
Those with private insurance had a 59% greater probability of survival than those insured through Medicaid and a 62% greater probability of survival than the uninsured. Among patients aged 65 years and older, those with private insurance also had median survival superior to those with Medicare (41.9 vs 30.8 months; P<.0001). However, Chamoun said that the survival difference was not statistically significant between private insurance and Medicare after adjusting for factors including age, race, median income based on zip code, comorbidities, and hospital type. Neither race nor gender played a significant role in survival.
Chamoun et al highlighted the presence of a survival disadvantage for people who cannot afford their treatment costs. Chamoun said that survival for patients with MM has increased greatly over the past 30 years. However, he said that “prices of oral cancer drugs have been rapidly escalating, especially for patients and survivors of [MM], and we need to take action to limit and reverse the disparity for those who cannot afford private insurance or have lower incomes.”
Lenalidomide (Revlimid), administered in combination with dexamethasone, is commonly used to treat MM. Celgene, the manufacturer of lenalidomide, raised the price of a 10-mm dose to $719.82 in January 2019. Bloomberg noted that the same dose in 2007 cost $247.28. The overall cost for a year of treatment is close to $200,000, a 3.5% increase since 2019.2
Chamoun said that oral agents for MM are covered under prescription drug plans. People on Medicare may find it more difficult to pay for long-term use of these medications, he said, which can lead to higher rates of treatment interruption or discontinuation. The investigators hypothesized that insurance status could explain the differences in survival.
People with Medicare or Medicaid were less likely to travel more than 120 miles to treatment centers compared with those with private coverage. This lack of access to treatment may play a role in the survival disparities between these patients and those with private insurance, especially for patients with Medicare or Medicaid in rural settings who often must travel 200 miles round trip to reach a primary care facility, according to the investigators.
Chamoun et al assessed data collected from 2005 to 2014 on 117,926 patients living with MM. The median age at diagnosis was 67 years, and 55% of the cohort was male. Fifty-seven percent of patients lived in areas with an annual median income of less than $46,000. 52% of patients were on Medicare, 35% had private insurance, 5% were on Medicaid, and 3% were uninsured.
Investigators also found that practice setting affected survival. Forty percent of patients were treated in an academic institution, 39% in a comprehensive community program, 10% in an integrated network cancer program offering comprehensive services, and 9% in a community cancer program. Those treated in an academic setting had a 49% greater probability of survival compared with patients treated in other settings (HR, 1.49; 95% CI, 1.39-1.59; P <.0001).
“Where you live and what insurance you have should not affect the length of time you survive [MM], though unfortunately it seems from Dr. Chamoun’s study that it does,” said ASCO expert Catherine M. Diefenbach, MD, director of the Clinical Lymphoma Program at the Perlmutter Cancer Center in New York.
In her practice, Diefenbach treated a patient with MM whose medication would have cost $20,000 per month. Her staff was able to reduce the cost to about $40 per month, but she noted that not every patient has access to that kind of support system. Some patients are forced to decide whether to take their medication as prescribed or to take their pills less often to stretch out the therapy.
“We’re seeing from Dr. Chamoun’s study that these challenges are creating real differences in survival,” she said. “As a society, we should strive to ensure that every patient, no matter their location or socioeconomic status, receives equal access to high-quality cancer care.”
1. Chamoun K, De Lima MJG, Caimi PF, et al. Insurance status and survival of multiple myeloma (MM) patients. Presented at: 2019 ASCO Annual Meeting; May 31-June 4, 2019; Chicago, IL. Abstract LBA107.
2. Spalding R. Celgene boosted the price of its top cancer drug on the same day of mega-deal. Bloomberg. www.bloomberg.com/news/articles/2019-01-04/celgene-boosted-price-of-its-top-cancer-drug-on-day-of-mega-deal. Published January 4, 2019. Accessed May 31, 2019.