Because immunotherapy activates the immune system instead of suppressing it, immune-related adverse events (irAEs) are completely different than AEs typically associated with chemotherapy, explained Lisa A. Kottschade, MSN, APRN, CNP.

Kottschade, nurse practitioner-associate professor of oncology, Mayo Clinic-Rochester, recently presented at the ONS Bridge about irAE management. Her presentation, “The Long and the Short of it: Monitoring Immune Related Toxicity Across the Cancer Continuum” highlighted the 4 most common categories of irAEs, as well as some of the life-threatening irAEs oncology nurses should be aware of.

“I tell people to think of it as kind of like putting the pedal to the metal in the car,” described Kottschade in reference to irAEs. “They can attack any tissue organ or body system. They can be severe and there have been fatalities reported.”

“It's really important to remember that these are not the same mechanisms of action for side effect management, thereby treatments being very different. So how do we deal with this? Education, education, education. You know, we need to know and educate our patients. We need to educate other care providers outside of oncology. We need to recognize these immune-related adverse events very early because we know that if we delay that, we're going to have worsening adverse events.”

Dermatologic irAEs are most commonly associated with anti-CTLA4 and anti-PD1 blockades, shared Kottschade, noting that these events are seen about 40% of the time with single agent therapies and around 60% with combination therapies. Most patients will experience diffuse maculopapular rash and/or pruritus, as well as vitiligo. It is possible for patients to develop Stevens-Johnson syndrome or toxic epidermal necrolysis and between 10% to 30% of patients experience pruritus despite the absence of rash.

She advised that nurses take into consideration the percentage of body surface area covered by rash. Patients should be taught to report any skin peeling, fever, or lesions in their oral, anal, or genital area.

Immunotherapy will generally continue if the dermatologic irAE (rash, bullous pemphigoid, lichenoid reaction, pruritus) is a mild grade 1. Treatment for this grade irAE includes oral antihistamines and high dose topical steroids. Oral steroids are considered necessary if the rash progresses to grade 2, as well as treatment with moderate potency topical steroids and/or prednisone at a dosage of 0.5-1 mg/kg/day. It may be appropriate to consider holding immunotherapy.

When a patient experiences a rash that is grade 3 or higher, it becomes necessary to discuss the risk-benefit ratio with patients. Prednisone should be administered at 0.5-1 mg/kg/day and dosage increased to 2 mg/kg/day if the condition does not improve. At grade 3 or 4, it may become appropriate to admit the patient to inpatient care and to consult urgent dermatology.

Nurse management of rash or pruritus involves contacting the patient 1 to 2 times between treatments, assessing medication compliance with both topical and oral prescriptions, and instructing the patient to avoid hot showers, excessive drying, and anything that might further irritate the skin.

Diarrhea and colitis, the 2 common gastrointestinal irAEs, are more commonly associated with anti-CTLA-4 inhibitors (30%) than with PD1/PD-L1 inhibitors (15%) but are most common with combination therapy (50%). Colitis shares histologic features with Crohn’s disease and fatal bowel perforation is reported in 1% of patients treated with ipilimumab (Yervoy).

To manage GI irAEs, nurses should determine the number of stools over baseline, assess abdominal pain, if there is any blood or mucus present in the stool, fever, and promptly rule out any infectious etiology, taking care to not hold steroids while awaiting results. If any of the previously noted irAEs present themselves, bowel perforation should be ruled out immediately.

The CTCAE grading of diarrhea defines an increase of 4 stools over baseline per day as grade 1 severity. An increase of 4 to 6 stools is considered grade 2. An increase of 7 stools is considered grade 3 and is considered cause for hospitalization. An increase greater than 7 stools is considered life threatening.

Kottschade also presented an algorithm to manage diarrhea/colitis related to immune checkpoint inhibition. For all grade irAEs, other causes should first be ruled out through stool studies including C. difficile and enteric pathogens. Grade 1 irAEs should be managed with the BRAT diet. If the condition progresses but is still grade 1, then entocort 12 mg or uceris 9mg daily should be administered. Grade 2 irAEs should be treated with entocort 12 mg or uceris 9mg daily and, upon progression, prednisone should be added to treatment at 0.5-2.0 mg/kg daily.

Grade 3 gastrointestinal irAEs should be treated with entocort 12 mg or uceris 9mg daily plus, prednisone at 1.0-2.0 mg/kg daily. If the AE progresses, a gastroenterologist should be consulted and solumedrol should be given at 1 gm IV daily. If the severity becomes grade 4, not only should a gastroenterologist should be consulted and solumedrol should be given at 1 gm IV daily, but infliximab should be given at 5 mg/kg and colectomy should be considered if condition worsens.

Patient education should focus on increasing fluid intake and instructing them to report an increase in stool frequency, bloody stools, or abdominal pain. Patients should be contacted weekly between treatments and bi-weekly if they begin to present with higher grade irAEs.

Kottschade emphasized that with the diarrhea colitis, “many patients can have really good responses to steroids within 1 to 2 days. But they also can have rebound diarrhea. So patients we see in the hospital that we're giving high-dose steroids to intravenously and we switch them over to oral, a lot of times we will hang on to them another 24 to 48 hours because they have a lot of rebound diarrhea where they're back, having as many stools as they were at baseline. We generally don't start taper until the patients at grade 0 or 1. And if they have been started on both budesonide and systemic steroids are going to start tapering the systemic steroids first. We caution against giving antidiarrheals to patients with greater than grade 2 diarrhea because it can get toxic megacolon and are at higher risk for perforation.”

Hepatotoxicity, or asymptomatic transaminitis and/or hyperbilirubinemia is seen in 30% of patients treated with combination therapy (15% of which present with grade 3 or 4 severity) and less than 10% of patients treated with monotherapy, Kottschade explained.

Around 0.2% of patients experience hepatic failure. Nurses should rule out new or progressive hepatic involvement by malignancy. She also advised utilizing the algorithm-based treatment chart from the National Comprehensive Cancer Network (NCCN).

Nursing specific management of hepatitis involves assessing compliance with steroids and other immunosuppressants, instructing patients to avoid acetaminophen and alcohol, and emphasizing the need for patients to get their laboratory blood draws as instructed.

The 2 main classifications of endocrinopathies include thyroid dysfunction, which is most common with PD-L1 endocrinopathies, and pituitary dysfunction, which is most common with anti-CTLA-4 inhibitors.

Thyroid dysfunction accounts for between 0% and 15% of cases but is more associated with combination therapy (40%) than with single agent regimens.

Nurses should assess patients who experience thyroid disorders for fatigue, hair loss, weight fluctuations, palpitations, sweating, nervousness, cold intolerance, and tightness of clothing around neck.

“Again, assessing for kind of the normal side of side effects that we expect from hypo/hyperthyroidism, we're going to see fatigue in both, [as well as] hair loss, and weight gain. For hyperthyroidism, we're also going to see palpitations and sweating, it's going to be important to know if they're tachycardic because we do treat with that they may be cold and tolerant and both may experience feeling that tightness around their neck if they have cold in there.”

Nursing responsibilities in monitoring patients with thyroid disorders include monitoring patient compliance with medication, persistently reassessing symptoms, educating patients in proper method for thyroid replacement medications.

“This is really important,” Kottschade emphasized. “I find a lot of patients don't take this correctly. You know when our first thing upon rising and an hour prior to food or other medications and nothing but water, avoiding iron and acids and calcium supplements when they can.”

Nurses should also monitor for hypophysitis, sometimes known as the “run over by a truck” phenomenon.” “[These] patients are going to come in and say oh, you know, Lisa, I just feel like I got hit by a truck. I'm sleeping 18 hours a day. I can't do anything. I can barely get out of bed. I've got this horrible headache and I feel kind of sick to my stomach. These patients are going to have undetectable ACTH & AM cortisol levels,” advised Kottschade. In addition, 75% of these patients will show an enlarged pituitary gland on an MRI.

“We always want to make sure that we don't have new involvement of central nervous system (CNS), either cancer or worsening of their CNS disease if already present,” she reminded the audience. “Assess for the following things again, fatigue, nausea, vomiting, and the unrelenting headache. Patients may just tell you they feel weak. In patients who have primary adrenal insufficiency we may see abnormal sodium so low sodium and high potassium and low sugars.”

Because primary adrenal insufficiency (AI) is a medical emergency, these patients will need to immediately go to the ICU. Marked by volume depletion electrolyte abnormality and low or undetectable cortisol and high SCTH, these patients will require fluid replacement, electrolyte replenishment, and high dose steroids (1-2 mg/kg) once they are hospitalized. 

In comparison, patients with secondary AI will have low or undetectable am cortisol and low ACTH. This can come from hypophysitis or long-term steroids use.

Education for patients with adrenal insufficiency includes taking their steroids as directed and ensuring that patients understand that they will likely be needing their steroids lifelong. “We do this in conjunction with our endocrine colleagues, but it's great for oncology nurses to be able to reinforce that and know what that teaching is” she said.

Patients will need to understand “sick day” steroids, stress dose steroids, and will need to wear a medical alert bracelet since most pituitary and adrenal abnormalities do not resolve.

Pneumonitis may present asymptomatically, but symptoms include shortness of breath at rest, orthopnea, and dyspnea on exertion, and can also include dry nagging cough, chest pain and fever. Pneumonitis can be seen radiographically.

Although neurotoxicity is not a common irAE, when it occurs, it can be life-threatening.

The incidence rate for this irAE e is 3.8 % with CTLA-4 inhibitors, 6% with PD-1 inhibitors, 12% with combination therapy, Kottschade explained, and presentation can vary due to

nonspecific symptoms and a wide range of differentials.

Typical onset is anywhere between 3 days to 17 months, but the median is 6 weeks. Some of the conditions associated with neurotoxicity include Guillan Barre syndrome, myasthenia gravis, central or peripheral neuropathy, encephalitis, aseptic meningitis, and transverse myelitis.

Conditions associated with cardiac toxicity are myocarditis/pericarditis/cardiomyopathy. While exact incidence rates vary, once patients develop a cardiac toxicity, the fatality rate is about 50%.

“In summary, we know that immune checkpoint inhibitors are really great cancer therapies. And these target our host immune system, we need to carefully assess our patients prior to each ICI therapy,” concluded Kottschade. She reminded nurses that prior to immunotherapy initiation, patients should be assessed for their prior autoimmune conditions, transplant history, as well as vaccination or antibiotic status, because these factors can impact whether immunotherapy is appropriate for the individual.

Moving forward, Kottschade hopes to see better monitoring and early recognition of some of the life threatening irAEs. She also anticipates treatment optimization across tumor types that affect various organs.

The final point that Kottschade discussed was conversations surrounding survivorship issues. “It's hard to have a discussion with a 30-year-old patient who is going to get adjuvant nivolumab for her resected high-risk melanoma and look her in the eye and say, ‘Hey, if I happen to blow your pituitary or something else, you may not be able to get pregnant.’ [But] that's a big discussion that we should be having with our patients.”

“We don't know all the long-term side effects, especially in the adjuvant population, but it's something that I think in the [interest] of full disclosure, we should be talking with our patients with,” she concluded.

Kottschade LA. The long and the short of it: monitoring immune related toxicity across the cancer continuum. Present

Articles

An expert on immune toxicity management discusses dermatologic, gastrointestinal, hepatic, and endocrine irAEs and how nurses can help educate their patients to monitor these symptoms. 

Patient Education Key in Managing Immune-Related Adverse Events

The Food and Drug Administration (FDA) has approved luspatercept-aamt (Reblozyl) for the treatment of anemia in adult patients with beta thalassemia who require regular red blood cell (RBC) transfusions.

The approval is based on findings from the phase III BELIEVE study, which showed that treatment with luspatercept-aamt led to significant reductions in RBC transfusion burden in those with beta-thalassemia—associated anemia.

 Results specifically showed that 21.4% of patients who received luspatercept-aamt achieved a ≥33% reduction from baseline in RBC transfusion burden, with a reduction of ≥2 units, during weeks 13 to 24 after randomization compared with 4.5% of patients who received placebo (risk difference, 17.0; 95% CI, 10.4-23.6; 

“When patients receive multiple blood transfusions, there is a risk for iron overload, which can affect many organs,” Richard Pazdur, MD, director of the FDA’s Oncology Center of Excellence and acting director of the Office of Oncologic Diseases in the FDA’s Center for Drug Evaluation and Research, stated in a press release.

 “Today’s approval provides patients with a therapy that, for the first time, will help decrease the number of blood transfusions. This approval is an example of our continued progress for rare diseases and providing important new drugs to patients earlier.”

Beta thalassemia is a rare blood disorder that is caused by a genetic defect in hemoglobin; it is also associated with ineffective erythropoiesis, which leads to a production of fewer and less healthy RBCs and often leads to severe anemia. Luspatercept-aamt is a first-in-class erythroid maturation agent designed to regulate late-stage red blood cell maturation. 

In the double-blind, placebo-controlled, multicenter, BELIEVE study (NCT02604433), investigators explored the safety and efficacy of luspatercept-aamt in adult patients with beta thalassemia who regularly required RBC transfusions. To be eligible for enrollment, patients had to be aged ≥18 years, had beta thalassemia or hemoglobin (Hb) E/beta thalassemia, and required regular transfusions of 6 to 20 RBC units in the 24 weeks prior to randomization with no transfusion-free period ≥35 days during that time.

A total of 336 patients were randomized 2:1 to receive either luspatercept-aamt at a starting dose level of 1.0 mg/kg with titration up to 1.25 mg/kg (n = 224), or placebo (n = 112), subcutaneously every 3 weeks for ≥48 weeks; 332 patients were treated. Those in both arms continued to receive RBC transfusions and iron chelation therapy to maintain the same baseline Hb level.

The primary endpoint of this trial was a ≥33% reduction in transfusion burden, with a reduction of ≥2 RBC units, during weeks 13 to 24, when compared with a 12-week baseline period. Secondary endpoints included ≥33% reduction in RBC transfusion burden at weeks 37 to 48, ≥50% reduction in transfusion burden at weeks 13 to 24, ≥50% reduction in transfusion burden at weeks 37 to 48, and mean change in transfusion burden at weeks 13 to 24. Moreover, achievement of ≥33% reduction in RBC transfusion burden over any consecutive 12 weeks on study was also evaluated.

The median age was 30 years (range, 18-66) and 58% of patients were female. Additionally, patients received a median of 6 RBC units in the 12 weeks before treatment, and 58% of patients in each arm had undergone splenectomy. B0/B0 genotype was observed in 30.4% and 31.3% of patients in the luspatercept-aamt and placebo arms, respectively.

Additional results showed that 19.6% patients on luspatercept-aamt achieved a ≥33% reduction in RBC transfusion burden at weeks 37 to 48 compared with 3.6% of those receiving placebo (

 <.0001). Moreover, 7.6% and 10.3% achieved a ≥50% reduction in RBC transfusion burden at weeks 13 to 24 and 37 to 48, respectively, versus 1.8% and 0.9% of those on placebo (

Regarding safety, thromboembolic events occurred in 3.6% of patients on the luspatercept-aamt arm, and hypertension was reported in 10.7% of luspatercept-aamt—treated patients across the clinical development program. Serious adverse events (AEs) occurred in 3.6% of patients receiving luspatercept-aamt, and serious AEs in 1% of patients were cerebrovascular accident and deep vein thrombosis. There was 1 death due to an unconfirmed case of acute myeloid leukemia. The most common AEs were headache (26% with luspatercept-aamt vs 24% with placebo), bone pain (20% vs 8%, respectively), arthralgia (19% vs 12%), fatigue (14% vs 13%), cough (14% vs 11%), abdominal pain (14% vs 12%), diarrhea (12% vs 10%), and dizziness (11% vs 5%).

Treatment discontinuation due to an AE in grades 1 through 4 occurred in 5.4% of patients who received luspatercept-aamt. The most frequent AEs that required discontinuation in the luspatercept-aamt arm included arthralgia (1%), back pain (1%), bone pain (<1%), and headache (<1%). Furthermore, dose reductions due to an AE occurred in 2.7% of patients who received luspatercept-aamt, the most common were due to hypertension and headache. Dose interruptions due to AEs occurred in 15.2% of those on luspatercept-aamt; the most frequent AEs that led to dose interruptions were upper respiratory tract infection, alanine transaminase increase, and cough.

“Today’s approval is an important milestone and underscores our continued commitment to patients with hematology disorders,” Nadim Ahmed, president, Global Hematology and Oncology for Celgene, the developer of luspatercept-aamt, stated in a press release. “There are very limited options for patients living with anemia due to beta thalassemia who are dependent on long term red blood cell transfusions. We are pleased to make Reblozyl available as a new therapy for these patients to help address their anemia, a significant clinical complication of beta thalassemia.”

A version of this article appeared on OncLive

FDA Approves Luspatercept for Beta Thalassemia—Associated Anemia

FDA approves REBLOZYL® (luspatercept-aamt) for the treatment of anemia in adults with beta thalassemia who require regular red blood cell transfusions. Celgene. Published November 8, 2019. https://bit.ly/33vOhPo. Accessed November 8, 2019.

FDA approves first therapy to treat patients with rare blood disorder. FDA. Published November 8, 2019. https://bit.ly/2JZQeLZ. Accessed November 8, 2019. 

Cappelini MD, Viprakasit V, Taher A, et al. The BELIEVE Trial: results of a phase 3, randomized, double-blind, placebo-controlled study of luspatercept in adult beta-thalassemia patients who require regular red blood cell (RBC) transfusions. 

. 2018;132:163. doi: 10.1182/blood-2018-163.

The therapy is now approved for the treatment of anemia in adult patients with beta thalassemia who require regular red blood cell (RBC) transfusions.

Luspatercept Approved by the FDA to Treat Anemia in Patients With Beta Thalassemia

The FDA has approved the pegfilgrastim (Neulasta) biosimilar LA-EP2006 (pegfilgrastim-bmez; Ziextenzo) as a treatment to decrease the incidence of infection, exhibited from febrile neutropenia, in patients with nonmyeloid malignancies receiving myelosuppressive anti-cancer therapy that is associated with a clinically significant incidence of febrile neutropenia.

The approval is based on analytical, preclinical, and clinical studies, including data from the pivotal three-way pharmacokinetics (PK) and pharmacodynamics (PD) LA-EP06-104 trial comparing Sandoz's pegfilgrastim biosimilar with US-sourced reference pegfilgrastim; the pegfilgrastim biosimilar with European Union—sourced reference pegfilgrastim; and US- with EU-sourced reference pegfilgrastim.

Results showed that PK and PD similarity were demonstrated in all three comparisons, and there were no clinically meaningful differences observed in safety and immunogenicity among the groups.

"When a cancer patient with febrile neutropenia gets an infection, it can have serious consequences such as delays or dose reductions of chemotherapy," Carol Lynch, president of Sandoz Inc., the developer of the biosimilar, stated in a press release.

Pegfilgrastim is a long-acting version of filgrastim (Neupogen), which is indicated for select patients with cancer undergoing chemotherapy to enhance the production of infection-fighting white blood cells. The indication is specific to those receiving myelosuppressive anti-cancer drugs associated with a clinically significant incidence of febrile neutropenia.

In April 2019, Sandoz resubmitted a biologics license application to the FDA for LA-EP2006 to decrease the incidence of infection from febrile neutropenia in patients with nonmyeloid malignancies receiving myelosuppressive anticancer therapy.

 The resubmission addressed a complete response letter issued by the FDA in June 2016.

The resubmitted application included updated data from the LA-EP06-104 study, methodology of which was presented at the 2018 ESMO Congress. The study was sufficiently powered (90%) to achieve confidence intervals within margins 0.8 to 1.25 in co-primary endpoints pairwise comparisons. The investigators noted that due to historically known high intra- and inter-subject variabilities with reference biologic in area under the serum concentration-time curve (AUC)0-inf, the study, in healthy volunteers, is appropriate and establishes the scientific bridge to demonstrate similarity of PK/PD, safety, and immunogenicity between LA-EP2006, EU reference pegfilgrastim, and US reference pegfilgrastim. As of October 2018, the trial was ongoing in 5&thinsp;US and 1 Dutch study sites.

The European Commission approved LA-EP2006, known as Ziextenzo, as a treatment to reduce the duration of neutropenia and incidence of febrile neutropenia that is associated with anticancer chemotherapy in November 2018. With that approval, the biosimilar became indicated for use in the same proposed indications as reference pegfilgrastim, which is to prevent febrile neutropenia in patients receiving myelosuppressive chemotherapy, those with acute myeloid leukemia receiving induction or consolidation chemotherapy, patients with cancer undergoing bone marrow transplantation, those undergoing autologous peripheral blood progenitor cell collection and therapy, and those with severe chronic neutropenia.

The European approval was based on comprehensive analytical, preclinical and clinical data demonstrating the similarity between Ziextenzo and pegfilgrastim regarding safety, efficacy, and quality. Part of the submitted data was from a single-dose, double-blind, randomized, two-way crossover, phase I study, in which the biosimilar demonstrated similar PD, PK, immunogenicity, and safety as reference pegfilgrastim.

The study consisted of 2 treatment periods separated by an 8-week washout period. A total of 169 patients between the ages of 18 and 45 years were randomized to either the biosimilar or pegfilgrastim. Each treatment was administered at a 6-mg subcutaneous dose on day 1 of each treatment period.

PK/PD similarity was claimed if 90% PK and 95% PD confidence intervals (CIs) for geometric mean ratios of AUC from time of dosing and extrapolated to infinity (AUC0-inf), or to the last measurable concentration (AUC0-last), maximum observed serum concentration (Cmax), absolute neutrophil count (ANC) area under the effect curve from the time of dosing to the last measurable concentration (AUEC0-last), and ANC maximum effect attributable to the therapy under investigation (Emax) were completely contained within the predefined margin (0.8-1.25).

Results showed that similar PK/PD data were demonstrated: 90% CIs of geometric mean ratio of proposed biosimilar/reference for PK: AUC0-inf (1.0559-1.2244), AUC0-last (1.0607-1.2328), Cmax (1.0312-1.1909) and 95% CIs for PD (ANC): AUEC0-last (0.9948-1.0366), Emax (0.9737-1.0169) were contained within the predefined margin.

Moreover, the biosimilar and reference pegfilgrastim demonstrated similar safety profiles and were well tolerated, and there was no detection of neutralizing or clinically relevant antibodies.

FDA approved the first pegfilgrastim biosimilar CHS-1701

 (pegfilgrastim-cbqv; Udenyca) for patients with cancer receiving myelosuppressive chemotherapy.

A version of this article originally appeared on OncLive

FDA Approves Sandoz’s Pegfilgrastim Biosimilar

Sandoz receives US FDA approval for long-acting oncology supportive care biosimilar Ziextenzo™ (pegfilgrastim-bmez). Sandoz. Published November 5, 2019. https://bit.ly/2PP20Nh. Accessed November 5, 2019.

Nakov R, Schussler S, Schier-Mumzhiu S, et al. A large multi-center, randomized, double-blind, crossover study in healthy volunteers to compare pharmacokinetics and pharmacodynamics of a proposed biosimilar pegfilgrastim with EU and US reference pegfilgrastim: methodological approach. Ann Oncol. 2018;29(suppl 8; abstr 1796P). doi: 10.1093/annonc/mdy300.110.

Sandoz resubmits biosimilar pegfilgrastim application to US FDA. Sandoz. Published April 2, 2019. https://bit.ly/2FQQsCu. Accessed April 2, 2019.

Nakov R, Gattu S, Wang J, et al. Proposed biosimilar pegfilgrastim shows similarity in pharmacokinetics and pharmacodynamics to reference pegfilgrastim in healthy subjects [published online August 5, 2018]. Br J Clin Pharmacol. doi: 10.1111/bcp.13731.

The FDA has approved the biosimilar pegfilgrastim for treatment to decrease the incidence of infection exhibited from febrile neutropenia.

Pegfilgrastim Biosimilar Approved By FDA

The FDA has expanded the approval of aprepitant (Cinvanti) injectable emulsion for intravenous (IV) use to include the 130-mg single-dose regimen for patients receiving moderately epigenetic chemotherapy (MEC).

The label expansion standardizes the aprepitant 130 mg single-dose regimen for patients receiving highly emetogenic cancer chemotherapy (HEC) and/or MEC as an injection over 2 minutes or an infusion over 30 minutes, which eases the dosing and administration and eliminates the need to take oral aprepitant on days 2 and 3 following MEC administration.

The expansion also builds on the prior label expansion that introduced the 2-minute IV push, which enables physicians to utilize the operational advantages of this administrative method of and contributes to a reduction in total patient time spent at the infusion site, according to Heron Therapeutics, Inc., the developer of aprepitant, in a press release.

"This most recent label expansion to offer a simplified dosing regimen for MEC adds to the important advantages Cinvanti provides to patients as the only FDA-approved, IV NK

 RA available as a convenient 2-minute IV push for MEC and HEC," Rudolph M. Navari, MD, PhD, University of Alabama, Birmingham School of Medicine, Division of Hematology and Oncology, stated in a press release. "The simplified dosing in MEC removes the need for patients to take oral aprepitant on days 2 and 3, which can improve compliance and reduce costs. These benefits continue to improve the overall patient experience with Cinvanti."

Aprepitant is a polysorbate 80-free, IV formulation of an NK1 receptor antagonist, which is designed to significantly reduce CINV in both the acute and delayed phases following chemotherapy. The FDA previously approved aprepitant as a 30-minute IV infusion on November 2017, making it the first IV formulation to directly deliver aprepitant (Emend). In February 2019, the FDA has expanded the approval of aprepitant injectable emulsion to include a 2-minute IV use for the prevention of acute and delayed CINV.

The decision of the earlier approval is based on results of a two-part, phase I study that demonstrated bioequivalence and a similar safety profile for patients who received aprepitant as a standard 30-minute IV infusion compared with a 2-minute IV injection, which is also referred to as an IV push.

Part A of the study randomized 24 patients to receive aprepitant at 130 mg IV via injection over 15 minutes (cohort 1), 5 minutes (cohort 2), or 2 minutes (cohort 3). The primary endpoint was tolerability and safety of single doses of aprepitant across the 3 cohorts. Patients then progressed to Part B of the trial, which was a two-sequence crossover study, following the establishment of acceptable tolerability in cohorts 2 and 3.

In Part B, 50 patients were randomized to receive a 2-minute injection of 130 mg aprepitant at 9 ml/min or a 30-minute infusion at 296 ml/h. The primary endpoint was pharmacokinetics of plasma aprepitant following a single dose as an injection or infusion; secondary endpoints were safety and tolerability. The mean age of patients was 34; 19 patients were female and 31 were male.

Results showed bioequivalence between the 2 administration arms, confirming the short injection as an alternative method to administer aprepitant to patients. The values for area under the curve (AUC)0-last, AUC0-inf and t1/2 were similar between injections and infusions. Additionally, Cmax was higher in patients who received aprepitant via injection than in those who received it via infusion, and Tmax occurred earlier with the injection versus the infusion.

Regarding safety, 8 patients on the injection arm experienced 11 treatment-emergent adverse events (TEAEs; 6 related) versus 9 patients who experienced 14 TEAEs (9 related) in the infusion group. The most prevalent treatment-related TEAEs were headache and fatigue; 1 patient in each arm reported feeling hot ≤30 minutes following treatment.

The initial approval of aprepitant was based on findings from 2 randomized, crossover studies that demonstrated the bioequivalence of aprepitant to fosaprepitant IV for the prevention of acute and delayed CINV following highly emetogenic cancer (HEC) chemotherapy and moderately emetogenic cancer (MEC) chemotherapy.

Specifically, results showed that patients who received aprepitant reported fewer adverse events (AEs) than those who received IV fosaprepitant, including substantially fewer infusion-site reactions.

A version of this article originally appeared on OncLive as, “

FDA Approves Single-Dose Aprepitant Regimen for MES

Heron Announces FDA Approval of Supplemental New Drug Application to Expand CINVANTI

 Label for Single-Dose Regimen for Patients Receiving Moderately Emetogenic Chemotherapy (MEC). Heron Therapeutics, Inc. Published October 22, 2019. https://finance.yahoo.com/news/heron-announces-fda-approval-supplemental-123000083.html. Accessed October 22, 2019.

Ottoboni T, Lauw M, Keller MR, Cravets M, Manhard K, Clendeninn N, Quart B. HTX-019 via 2-min injection or 30-min infusion in healthy subjects [published online ahead of print December 21, 2018]. 

Heron Therapeutics Announces U.S. FDA Approval of CINVANTI (aprepitant) Injectable Emulsion for the Prevention of Acute and Delayed Chemotherapy-Induced Nausea and Vomiting (CINV). Heron Therapeutics. Published November 9, 2017. https://bit.ly/2NyINfA. Accessed February 28, 2019.

Ottoboni T, Boccia G, Keller MR, Cravets M, Clendeninn N, Quart B. Bioequivalence of HTX-019 (aprepitant IV) and fosaprepitant in healthy subjects. Presented at: 2017 Hematology/Oncology Pharmacy Association Annual Conference; March 29-April 1, 2017; Anaheim, CA.

The FDA has expanded the approval of aprepitant to include in its label the use of a single dose regimen in patients receiving moderately epigenetic chemotherapy.   

FDA Expands Aprepitant Approval For MEC

Opioids are top of mind for many oncology nurses when it comes to managing patients’ cancer-related pain. However, as the opioid epidemic continues to sweep the nation—claiming an average of 130 American lives every day

— healthcare providers must be aware of the risks of these popular painkillers, knowing when to use them, when not to, and how to identify biases, as well as recognizing the warning signs of potential misuse. Armed with thorough documentation and patient communication tools, nurses can be key players in the safe administration of opioids and other analgesics to patients with cancer.

“It’s our moral obligation to treat pain, and suffering is not a desired response at all,” said Tonya Edwards, MSN, MS, RN, FNP-C, a palliative care nurse at The University of Texas MD Anderson Cancer Center in Houston, in an interview with 

. “But there is a cascade of issues out there, especially with so many opioid-related deaths.”

Many individuals have biases against opioids and the patients who use them, and oncology nurses certainly are not the exception to this rule. But Edwards stressed that healthcare workers need to put their patients’ pasts aside and always provide the best and most appropriate care.

“It’s unfortunate that patients might have had an addiction issue before, but now they have cancer. So it’s a double whammy,” she said. “We are not here to judge them on whatever happened in the past. They are human. They walk through the door with cancer, and we need to gain their trust and, of course, use our ethical concerns if we have to have an exit strategy and get them off the medicine later.”

Edwards noted that if patients have a history of opioid misuse, healthcare providers will not treat them with opioids in the cancer setting. But regardless of an individual’s history, each patient deserves to be treated with compassionate care, she explained.

Gretchen McNally, PhD, ANP-BC, AOCNP, agrees and says that the language oncology nurses use can have a major impact on perceptions as well as patient care. “For example, someone with an opioid use disorder, is the correct terminology, versus ‘an addict’ or ‘a junkie,’” said McNally, a nurse practitioner at Arthur G. James Cancer Hospital, part of The Ohio State University Comprehensive Cancer Center, in Columbus, in an interview with 

. “The first step is just recognizing and [trying] to use different terminology that is more respectful. Try to reframe your perception, which will then influence your practices.”

Improved education is also key in caring for this patient population. “Healthcare providers know that substance use disorders are a medical diagnosis, but I really don’t know that we all understand how much of a chronic brain disease it is,” McNally said. “People can’t really control that at all. So that [recognition] is the first step.”

Oncology nurses can look for specific signs of drug misuse, Edwards said. These include asking for more opioids before a prescription is finished, repetitively stating that opioids were stolen or lost, not attending oncology visits, and calling the clinic or heading to the emergency department only for more opioids.

The majority of opioid misuse starts with a prescription, “either that a doctor gave patients or that wound up in the wrong hands,” Patrick I. Borgen, MD, chair of the Department of Surgery and director of the Breast Center Program at Maimonides Medical Center in Brooklyn, New York, said in an interview with 

. “So the healthcare profession is directly at the center of this.”

Edwards said that she and her team at MD Anderson tell all their patients to lock up their medications to reduce the risk that another individual will take them. Additionally, providers at the institution make it a point to educate patients and their caregivers about proper opioid use and even host annual Opioid Crisis Seminar events to spread the goal of safe use. “Opioid education is one of the most powerful lessons that anyone can always share and build upon in their own clinic or inpatient area,” Edwards said. “Everyone in the community is welcome to come. We have people coming from all over the United States, and we are more than happy to let them see the system that we have.”

McNally’s team focuses on harm reduction for at-risk patients. She established a multidisciplinary committee within the lymphoma department of her hospital, comprising inpatient and outpatient nurse practitioners, pharmacists, patient care resource managers, social workers, and other nurses. After reviewing literature on the topic, they realized that harm reduction would be the best strategy to address opioid misuse in the cancer clinic.

Harm reduction does not treat addiction or disease. Rather, as its name suggests, the strategy focuses on minimizing harm and is not abstinence-based. “We can use safer prescribing practices or maybe be more aware of red flags that may come up—for example, patients losing their prescription, having it stolen, asking for early refills, and things like that,” McNally said, echoing Edwards’ advice. “We’re providing education to patients for different strategies to minimize their use or their risk.”

Harm reduction strategies at Wexner Medical Center, also part of The Ohio State University, included safer prescribing practices, such as asking every patient about their current or past substance use or addiction; consideration of complementary or nonopioid therapy; using the Prescription Drug Monitoring Program and employing a controlled medicine management form; pain diaries for patients; urine toxicology screenings; pill quantity limits; and other initiatives.

Many patients with cancer may not even need opioids, especially because safer alternatives with similar efficacy are available, explained Borgen. After witnessing a growing number of opioid-related hospitalizations and deaths at its institution, Maimonides formed a group to determine how the healthcare staff could decrease the amount of opioids prescribed.

The group created the Enhanced Recovery After Surgery protocol, which it initially employed in the colorectal surgery space but then altered and applied to other areas of the

hospital, including breast cancer surgery. The protocol is focused on mitigating opioid use but still effectively treating patients’ pain.

“We did a pilot study. We had some surgeons who were naysayers, and they stayed out of it, but that gave us a control group. We were able to show dramatically better pain scores and really [use] zero opioids,” Borgen said. “So if you fast-forward now to 2019, we’ve just submitted a paper tracking 700 women who we’ve treated consecutively for their breast cancer without a single milligram of opioids being dispensed. I’m incredibly proud of that accomplishment." Borgen has found alternatives to opioids for his patients, such as liposomal bupivacaine (Exparel), which he describes as a “workhorse of a local anesthetic.” The bupivacaine is encased in liposomal microspheres that break over time, resulting in an operative field that is bathed in local anesthetic over days instead of just hours, giving patients who underwent breast cancer surgery about 72 hours of pain relief.

The team at Maimonides sets the expectation with patients that their pain will be managed but without the use of opioids. To put patients at ease—because this notion can make some appre- hensive, said Borgen&mdash;clinical staff members are available for patients by phone 24 hours a day, 7 days a week, if they need better pain manage- ment. But they almost never call. “I do think that these patients need peace of mind knowing that these pills are just a phone call away if they’re in pain. But it’s much better than our old mind-set, which was ‘Here are 50 pills. I hope you don’t need them,’” Borgen noted.

Edwards also cited alternatives to opioid use for pain management, such as referring patients to integrative medicine. “[The rehab team] can teach them certainexercises, or maybe they even need to  walk in a different way to take the pressure off a painful area,” Edwards said. “They have tricks and aids in their field that are able to help them minimize pain or discomfort and be more functional. That’s the whole point of it: restoring functional recovery for everyone to continue on and be able to fight their cancer, go to their kid’s soccer game, or just have a good night’s sleep.”

McNally added that pain is not only physical but can be emotional, too, so having a psychol- ogist, in addition to physical and occupational therapists, on the treatment team can be helpful.

“Really before the whole ‘pain is the fifth vital sign’ campaign, they were looking at these multimodality clinics to treat pain, but those are expensive. Then they started coming out with opioids, and it was much easier to take a pill, and it cost less. Going back to that [kind of care] isn’t easy, but things like psychosocial therapy, phys- ical therapy, and occupational therapy can really help,” McNally said.

The courts are beginning to push back against manufacturers of these painkillers, too. In August, Johnson & Johnson and its subsidiaries were ordered by an Oklahoma judge to pay $572 million for their contributions to the opioid crisis in the state. This is after 2 other rulings stating that Purdue Pharma and Teva Pharmaceutical Industries Ltd. were ordered to pay $270 million and $85 million, respectively.

Appropriate Opioid Use And The Future Of Care

Despite promising alternatives, some patients ultimately will need opioids. “I think that there are going to be times, maybe for trauma patients or patients under- going large, radical surgery, when we do have to use opioids. But our choice of opioid matters,” Borgen said.

Borgen noted an underused opioid called buprenorphine that controls pain but does not elicit the same euphoric feeling that other drugs such as oxycodone and morphine do, making it less likely to lead to addiction. Overall, he expressed optimism that through patient and provider education, the opioid crisis can improve. “We’ve got to change the mind-set, and I think that’s happening,” Borgen said. “I think being honest and transparent about these drugs, offering alternatives, is what is going to make a change.”  

Understanding the epidemic. Centers for Disease Control and Prevention website. cdc.gov/drugoverdose/epidemic/index.html. Updated December 19, 2018. Accessed June 26, 2019

McNally GA. Harm reduction: reframing perceptions and informing practices of hematology/oncology advance practice providers. Presented at: Oncology Nursing Society 44th Annual Congress; April 11-14, 2019. Anaheim, CA. 

Opioids are the go-to treatment for cancer-related pain. But is this mainstay poised to change as the opioid crisis continues to grow?

Nurses Can Change The Direction of The Opioid Crisis

5. Genetic Testing is Beneficial in Breast Cancer

Testing isn’t just beneficial for patients with a strong family history of the disease, says one expert. Some common myths about 

4. Managing CINV During and After Chemotherapy

In this interview, a researcher sheds some light on his work in managing 

 in patients with certain blood cancers. 

3. Animal Interventions May Be Beneficial for Patients and Providers 

man’s best friend may eventually be healthcare’s best friend

2. Addressing the Oncology Nursing Shortage

Learn more about what’s being done to address the growing challenge of 

recruitment and retention in oncology nursing

handling chemotherapy and other potentially dangerous anti-cancer drugs

, there are steps that oncology nurses should take to protect themselves and their colleagues. Learn more about them in this story.   

And as always, for links to all of our top stories and more, visit 

Here are the top 5 Oncology Nursing News stories for March 2019.

ONN's Top 5 Stories: March 2019

Jamie Fritz, RPh, Oral Pharmacy Manager, Compass Oncology, describes the vital role that oral oncology nurses play in cancer care, assisting with positive quality interventions (PQIs), a Quality Standard created by the National Community Oncology Dispensing Association (NCODA), managing adverse events, and collaborating with the rest of the care team.

Videos

Registered pharmacist Jamie Fritz, RPh, Oral Pharmacy Manager, Compass Oncology, describes the vital role that oral oncology nurses play in cancer care.

Role of the Oral Oncology Nurse

The FDA has issued a letter to healthcare providers about the risk of increased mortality associated with vascular balloons coated with paclitaxel or stents that release the agent in the femoropopliteal artery in the leg among patients with a type of peripheral arterial disease (PAD).

The letter follows a meta-analysis that was recently published in the 

Journal of the American Heart Association

 (JAHA; CRD42018099447), which suggested that there is a 

 ≥2 years in patients with PAD treated with these devices compared with control devices, which consist of noncoated balloons or bare metal stents. The specific cause of this mortality observation has not yet been determined, the agency stated.

In the letter, the agency recommended physicians monitor patients who have been treated with the coated balloons and eluting stents, and discuss the benefits and risks of all available therapies for patients with PAD. The FDA also said that, currently, the benefits continue to outweigh the risks when the devices are used as indicated. Additionally, all observed or suspected adverse events associated with these devices should be reported.

The paclitaxel-coated balloons and paclitaxel-eluting stents are approved by the FDA to treat obstructed lesions in arteries of the legs. Mechanistically, the balloon and stent operate to open the obstructed vessel, and paclitaxel is released from the balloon or stent to prevent scar tissue formation in the blood vessel that can re-obstruct the artery.

Intravenous paclitaxel is approved by the FDA for indications in 

The FDA also noted in a press release that it is currently evaluating the available long-term follow-up data to determine whether there are any associated long-term risks with paclitaxel-coated products. Additional statistical analyses are also being conducted to identify the magnitude and presence of any long-term risks.

 study, investigators conducted a systemic review and meta-analysis of 28 randomized controlled trials of paclitaxel-coated devices in the femoral and/or popliteal arteries with a primary endpoint of all-cause patient death. Risk ratios and risk differences were pooled with a random effects model, and 4663 patients (89% intermittent claudication) were analyzed.

Of 28 trials with 4432 cases, the all-cause patient death at 1 year was similar between paclitaxel-coated devices and the control arm at 2.3% versus 2.3% (Risk ratio, 1.08; 95% CI, 0.72-1.61). At 2 years, the all-cause death at 2 years—which was 12 trials and 2316 cases&mdash;was significantly higher in the paclitaxel arm (7.2%) than in the control arm (3.8%; risk ratio, 1.68; 95% CI, 1.15-2.47; number-needed-to-harm, 29 patients [95% CI, 19—59]).

Up to 5 years, the all-cause death of 3 trials and 863 cases continued to be higher in the paclitaxel-coated arm (14.7%) versus the control arm (8.1%; risk ratio, 1.93; 95% CI, 1.27-2.93—number-needed-to-harm, 14 patients [95% CI, 9—32]).

Moreover, meta-regression showed a significant link between exposure to paclitaxel (dose-time product) and absolute risk of death (0.40.1% excess risk of death per paclitaxel mg-year; 

<.001). A trial sequential analysis excluded false-positive findings with 99% certainty (2-sided a, 1.0%).

The study investigators concluded in the article that further investigations are warranted.

Treatment of Peripheral Arterial Disease with Paclitaxel-Coated Balloons and Paclitaxel-Eluting Stents Potentially Associated with Increased Mortality - Letter to Health Care Providers. FDA. Published January 17, 2019. https://bit.ly/2W0wr3B?rel=0". Accessed January 17, 2019.

Katsanos K, Spiliopoulos S, Kitrou P, Krokidis M, Karnabatidis D. Risk of death following application of paclitaxel-coated balloons and stents in the femoropopliteal artery of the leg: a systematic review and meta-analysis of randomized controlled trials. 

. 2018;7:e011245. doi: 10.1161/JAHA.118.011245.

FDA Issues Letter Regarding Safety Concerns With Paclitaxel-Coated Devices

The FDA has issued a letter about a possible risk of increased mortality among patients with a type of arterial disease who have paclitaxel-coated implants.

FDA Warns of Safety Concerns With Paclitaxel-Coated Devices

From financial toxicity to lifestyle, there are many factors that could prevent patients from consistently taking their medication. Kathy Oubre, MS, Chief Operating Officer, Pontchartrain Cancer Center in Covington, Louisiana, shares some barriers to adherence to oral oncolytics that patients may face.

There’s no way a checklist can be as comprehensive as it needs to be to cover all possible influential factors, Oubre said. Having a conversation with patients is the best way to get a clear understanding of what their barriers might be and how to overcome them.

Kathy Oubre, MS, Chief Operating Officer, Pontchartrain Cancer Center in Covington, Louisiana, shares some barriers to adherence to oral oncolytics that patients may face.

Assessing Barriers to Oral Oncolytic Adherence

With the explosion of immunotherapy and rapid changes in oncology treatment guidelines, it is all nurses can do to stay abreast of best practices. The Oncology Nursing Society (ONS) will soon fill this growing educational gap with a complete update of 

Chemotherapy and Biotherapy Guidelines and Recommendations for Practice

, a classic foundational volume now in its fourth edition. This fall, the ONS will publish the revamped and renamed volume as the first edition of the 

Chemotherapy and Immunotherapy Guidelines and Recommendations for Practice

The reorganized book includes a new chapter that focuses on the treatment of cancer using the immune system, immunotherapeutics. The chapter presents 6 categories of this approach: checkpoint inhibitors; chimeric antigen receptor (CAR) T-cell immunotherapy; cytokines; monoclonal antibodies, including radioimmunotherapy; immunomodulators; and oncolytic viral therapy.

Other chapters focus on chemotherapy, molecularly targeted anticancer agents, and hormonal therapy, with updates on unique toxicities such as colitis, pneumonitis, and dermatitis.

Chemotherapy and Immunotherapy Guidelines and Recommendations for Practice 

contains extensive details related to every toxicity of antineoplastic therapies, with evidence-based approaches for prevention and management. “It is critical that oncology nurses use the most current evidence when managing patients who have cancer,” said MiKaela Olsen MS, APRN-CNS, AOCNS, FAAN, lead editor of the new volume and an oncology and hematology clinical nurse specialist, Ambulatory Oncology, Sidney Kimmel Comprehensive Cancer Center, at Johns Hopkins Hospital and Greenspring Oncology, and lead editor of the new volume.

“These guidelines provide that evidence in a quick, easy-to-follow outline and tablet format. The book is also an excellent resource for nurses working in other fields who may administer these therapies and manage these patients after treatment.”

 incorporates major new content since the publication of the fourth edition of 

A foundational volume in oncology nursing gets an upgrade.

Drug Safety