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

Pain management of those with cancer still remains a challenge, according to Judith A. Paice, PhD, RN.

“Unrelieved pain is a huge public health crisis,” said Paice, Division of Hematology, Northwestern University, Feinberg School of Medicine, during a recent presentation at the Oncology Nursing Society Bridge virtual meeting.

 “Opioid misuse and overdose deaths are emergencies... [but]efforts to reduce the opioid overdoses have resulted in stigma and unrelieved pain for people who might use opioids to relieve their pain.”


Paice’s presentation “Safe and Effective Use of Opioids to Treat Cancer Pain” highlighted how the media attention surrounding opioids has made pain management potentially more difficult for patients with cancer, as well as effective ways to prescribe and titrate opioids, and how the COVID-19 pandemic has further affected pain management.

The Impact of Current CDC Opioid Guidelines

In 2016, the CDC released guidelines for prescribing opioids.

“These were pretty controversial for many of us who were working in the world of significant pain, like people treating people with cancer-related pain,” explained Paice. When the guidelines came out, there was not an omission for people at end-of-life care or patients receiving active cancer treatment.

Eventually a caveat was added for these specific populations, but there were still 2 guidelines that concerned oncology health care workers. The first guidelines stated that only a 3 to 5 days’ supply should be dispensed at a given time, and the second advised only using a very small amount of drug-less than 50 milligrams.

Paice explained the ramifications this had on her patients experiencing acute pain. “We met with significant problems with access; insurance would not allow us to give [our patient] the dose that was needed on there without pay for that amount, saying that the dose exceeds the CDC guidelines… This patient [with metastatic prostate cancer and a large tumor impacting his spinal cord] really became very anxious about his use of opioids [and] was very fearful and upset about the stigma when he would go to the retail pharmacies and not be given the medications that had been rightfully ordered for him. And he was extremely fearful of running out of the medication.”

Paice was not the only nurse observing these access barriers. “ASCO conducted a survey of oncology practices,” she shared. “And they found that 40% of U.S. oncology practices stated that their patients were having difficulty filling opioid prescriptions.” These barriers included pill limits, maximum dosages, and medications not being unbillable at local pharmacies.

Opioid Prescriptions for Patients and Survivors

While there are different definitions, some literature defines survivorship as beginning at the moment of a patient’s diagnosis and continuing through the rest of their lives.

 By this definition, there are 16 million cancer survivors in the United States alone, and it has been demonstrated that pain in this population is 40% or higher.

With so many advanced treatment options, more patients are viewing their cancer as more of a chronic illness, adding another challenge to developing clinical practice guidelines, she added.

Current guidelines emphasize the non-pharmacologic interventions. Paice highlighted physical interventions, such as physical therapy, occupational therapy, recreational therapy, orthotics, heat packs and ice, etc. Other therapies can include integrative therapies such as acupuncture, music, massage, and more, depending on the institution. “A wide array of professionals can deliver nerve blocks, kyphoplasty and different kinds of peripheral infusions, psychological approaches,” she added. “We still struggle with a shortage of mental health practitioners, particularly practitioners who have expertise in the special needs of those who are experiencing a malignancy, but cognitive behavioral therapies, mindfulness imagery, relaxation, all can be exquisitely helpful for that person with cancer related pain.”

Opioids are usually considered after describing and reminding patients about the non-pharmacologic techniques used to manage pain. Patients should be reminded that there are long-term adverse events (AEs) associated with opioids, such as constipation, upper GI symptoms, mental clouding, endocrinopathies, etc. and as well sexual side effects including reduced libido, infertility, and more.

One significant change in pain assessment has been a transition from number-related pain assessments to task-oriented pain rating. For example, nurses might now ask their patients “What is your pain preventing you from doing that you want to be doing?” Outcomes and goals are defined by the patient. This can include returning to work, or even just walking around the block, being able to sit at a hard chair in a restaurant for dinner, or holding a grandchild. This style of approach allows for a more structured and measurable evaluation of treatment efficacy.

Another important change is risk assessment for potential misuse. This includes conversations about current or past misuse of prescription or illicit drugs, alcohol, smoking, gambling, etc.

“I also ask about family,” Paice shared. “And this helps me to get a very crude measure of genetics, if we find that very large number of biologic family members have had substance use disorder, then there's likely a high risk for this patient.”

Some conversations can be a little more sensitive. “I usually give people a little bit of a warning shot,” said Paice. “[I’ll say] I need to ask you a difficult question, and I stop for a second so I really have their attention, [and ask] ‘Have you ever been abused?’ ... And I'll explain to them that we know that someone who has been abused, particularly as a child, or an early teen, has a very high risk of substance misuse or addiction.”

Some patients are worried about becoming addicted to their pain medications, she said, but there is a prescription drug monitoring program that is available in 49 out of 50 states that Paice finds useful. She does however recommend using systems like these universally to avoid falling into traps of implicit bias. Additional useful monitoring tools include urine toxicology, and verbal or written patient agreement contracts.

“That’s another thing that most of us didn't learn in our basic training related to pain management or opioids,” Paice said, regarding how to help patients wean themselves off opioid use. “I use a very slow downward titration note, [but] I'm primarily working in an outpatient practice.”

Paice shared that she helps around 200 patients in the outpatient hematology oncology clinics and that nurses can reduce prescription as quickly as 10% per week, but that 10% per month is often her preferred method of titration. She emphasized offering lots of coaching, as well as psychosocial support and encouragement, and to remind patients about why this is important, as well as getting the assistance of cognitive behavior therapists. Her team uses antidepressants rather than benzodiazepine to treat irritability and prefers to give their patients clear verbal treatment plans so they can understand how the process will look.

“It's about 5% to 20% every month, and you know what, if it's a holiday, we'll pause, we'll plateau, if it's an important day, you know, this month, their child is getting married, and they really want to not be going through any kind of change in their pain management. I understand that. But we're going to then resume with our reduction.”

Paice also discussed talking to patients about safe use. She shared that despite the media attentions surrounding opioid misuse, many patients are surprised when she describes locking up their pain medicines.

She also discussed nasal naloxone. While nasal naloxone prescription varies by state, there remains to be a consensus on who needs it. “I'm feeling more comfortable now than I was 2 to 3 years ago, when many patients were having to pay out-of-pocket and it was about $150 for the nasal Naloxone.

“Now most insurance companies are paying for it I would say maybe about 10% of my patients are having to pay a pretty significant copay. Some recommendations [say] that if the patient is getting more than 50 milligrams per day of oral morphine equivalents, then we should be prescribing nasal Naloxone.”

The Effects of COVID-19 on Cancer-Related Pain Management

The COVID-19 pandemic has exacerbated preexisting issues in unrelieved pain, summarized Paice. “We're seeing additional symptoms, some of them pain. So, in one of the early papers that documented the symptoms seen in COVID-19 as you would imagine breathlessness, agitation, drowsiness, pain, and then after hospitalization, muscle pain was common in more than half of the population.”

Common symptoms seen in patients referred to palliative care have included breathlessness (67%), agitation (43%), drowsiness (36%), and pain (23%). Post hospitalization symptoms have included fatigue (55%), dyspnea (45%) and muscle pain (51%).

“Whether you are a primary palliative care nurse which all oncology nurses should be, or whether you are a specialty palliative care nurse. All of us have an enormous role, regardless of our settings of care in providing stellar care for people with COVID-19, and particularly for our patients with the additional serious illness of cancer,” said Paice, urging listeners to mobilize staff with pain and palliative care training, provide brief education related to symptom control and to engage allied health to provide emotional support to patients, families and staff impacted by the pandemic.

“Go out there and change the world of pain management for your patients,” she concluded.

1. Paice JA. Safe and effective use of opioids to treat cancer pain. Presented at: Virtual ONS Bridge; Sept 9-16

2. Dowell D. Haegerich TN, Chou R.CDC Guideline for Prescribing Opioids for Chronic Pain MMWR. CDC. 2016; 65:1-50

3. Opioids and cancer pain: patient needs and access challenges. ASCO. Accessed October 8, 2021. 

https://www.asco.org/sites/new-www.asco.org/files/content-files/blog-release/images/opioids-cancer-pain-infographic-%202137x2755.pdf

4. Mayer DK, Nasso SF, Earp JA. Defining cancer survivors, their needs, and perspectives on survivorship health care in the USA

 2017: 18 e11-18. doi: 10.1016/S1470-2045(16)30573-3.

5. Van den Beuken-van Everdingen MH, et al. Update on Prevalence of Pain in Patients With Cancer: Systematic Review and Meta-Analysis

. 51: 1070-1090, 2016. doi: 10.1016/j.jpainsymman.2015.12.340.

An expert on pain management discusses safe and effective opioid prescriptions to manage cancer-related pain. 


Unrelieved Pain Management Remains Critical Issue in Patients with Cancer

Medical cannabis can help alleviate adverse events from cancer treatment, like vomiting, nausea, appetite loss, and sleeping difficulty, explained Eloise Theisen, RN, MSN, AGPCNP-BC. Unfortunately, due to a lack of federal standardization for medical cannabis, navigating the cannabinoid system can be a challenge for nurses and patients alike.

Theisen, current president of the American Cannabis Nurses Association (ACNA), recently spoke to 

 about the appeal of medical cannabis for patients with cancer, as well as transparency on cannabis use between patients and providers, and the direction she hopes to see in cannabis research in the coming years.

 What are some reasons that medical cannabis might be appealing to patients with cancer?

That's a great question. And it's a question I get a lot. Often when patients come to see me in my private practice, it's because they're looking for something to help manage their symptoms that are either related to the cancer treatment or the cancer itself. It may be because they're not getting the relief that they want from traditional therapies. They may be looking for something “more natural,” or they have family members who are insistent that they consider cannabis as a treatment option.

What are some of the advantages to cannabis as opposed to a more traditional treatment option?

We have limited research in some areas. The areas that we have really good data are with nausea and vomiting, appetite loss, chronic pain, [and] sleep. We're starting to see more research come out around chemotherapy-induced peripheral neuropathy. And one of the advantages of working with cannabis is you can really personalize the treatment plan to the patient's needs and goals. So, there's a lot of flexibility [and] there's a lot of individuality. It really allows patients to find a dose that may produce the best benefit with the least amount of side effects.

Do you believe that there might be some patients who might be interested in medical cannabis, but are nervous to ask their providers about it out of fear of the stigma?

Yeah, actually, that happens quite a bit. You know, I've been doing this work since 2013. And I've seen an evolution of how patients have come to cannabis. And there are still some that really struggle with the stigma; they're afraid that their health care provider will judge them or potentially no longer treat them if they are using it or want to use it. And we've found that, in some states, oncology providers are more favorable to their patients using cannabis, but many of them are unsure of dosages or side effects, or even different profiles to recommend to their patient. So many patients, unfortunately, end up looking to dispensary staff or “Dr. Google” or [even] friends or family to start their treatment. I always encourage [patients] to start the conversation with their health care provider, even if that health care provider doesn't know a lot about it. At least there's some transparency there.

For health care professionals looking for resources for dosage, what might be some good first steps?

Dosage is one of those things. It's very individualized and personalized, and it's an area of research that we're lacking. We don't have good double-blind, placebo studies to demonstrate what dosage should be applied for what condition.

At the American Cannabis Nurses Association (ACNA), our mission is to help educate health care professionals, particularly nurses, on the endocannabinoid system. We also have the National Council of State Boards of Nursing, who issued guidelines in 2018 on how to care for the patient using medical cannabis. We also have resources through the American Cannabis Nurses Association that we've vetted. It is challenging right now to find programs that are evidence based. And that's part of the work that the American cannabis nurses does as well. All of our companies that we work with are vetted to make sure that they're evidence based and [have] reliable information, because there's so much misinformation out there. We want to make sure that people get the right information.

Can you discuss some of the work that your organization does to try and obtain these evidence-based answers?

We've been around since 2010 and we are now about 1,500 members strong, predominantly in the United States, in all 50 states. We also have a couple members outside of United States, like the United Kingdom and Canada. And again, our mission really is to educate, collaborate, increase research, and partnerships. We do a lot of vetting around products, manufacturers, different sponsors, and education, to really ensure that, again, members are getting the most accurate and up-to-date information. We're also doing a lot of work to become an anti-racist organization, because a lot of the history in cannabis is rooted in racism, and prohibition as well.

We’re largely focusing on education because about 60% of our members consider themselves novices when it comes to cannabis. We really want to provide that foundational information to them so that they can become more empowered to talk to their patients or health care providers, lobbyists, etc. So, we're trying to educate our members, as well, on a lot of the political challenges out there around cannabis.

In states where medical cannabis is legal, what is the process like for patients to get that recommendation or prescription and then to get the actual product?

Well, it's not universal. It's not standardized. It really depends on what the state has determined to be a qualifying condition. We have 36 states, plus the District of Columbia, that have a medical cannabis program. And they vary. Some states like Oklahoma and California, that have medical programs [that] essentially allow anyone to qualify if that physician feels that their condition would benefit from the use of cannabis. And then we have other states like Texas, where they have a medical program that's incredibly restrictive, and only a few qualifying conditions. You can always check out the state website to determine whether somebody qualifies or not.

Then we have 18 states and the District of Columbia that allow for adult use, which also makes it [for] anybody over the age of 21 [who] can access it. But of course, most of those people are using it for symptom management because of an underlying health condition, but they're not getting medical guidance. So, it is challenging, overwhelming, and confusing for patients right now to navigate the space for sure.

What tips or advice would you give to these patients who are attempting to navigate the space?

Look for qualified health care professionals in their area that are knowledgeable in cannabis and the endocannabinoid system. There's a growing group of providers that have the specialized knowledge. I would really discourage them from using the internet to try to figure out what they need. There are some trusted sources out there are some nonprofit organizations that are dedicated to helping patients specifically like leaf411.org, and projectcbd.org. These are organizations that are consumer facing that are trying to help patients navigate the space and they do it free of charge.

Is there any research that you’ve seen that you are excited about?

We did have the National Academy of Sciences, Engineering, and Medicine report come out in 2017. They looked at over 10,000 peer reviewed studies. And they did publish their recommendations. They found conclusive evidence that cannabinoids are effective for chronic pain in adults. And they listed their report, you can also find where there's moderate evidence for sleep and other conditions. It also talks about some of the adverse effects, that you can get from using cannabinoids.

But I'm most excited to see the evolution of research. We are anticipating in the next few years, either for decriminalization or legalization at the Federal level, which will really open up our ability to research. We did see the DEA come out and say that they will start allowing researchers to use cannabis that is sold in dispensaries versus the cannabis that's grown by the government because there's a huge difference in the potency and the quality. So, we're going to start to really see, when patients are using these products from dispensaries, what the risks and benefits are of those products.

Should nurses be monitoring their patients for specific adverse events if they are taking medical cannabis?

It all depends on dosing. Cannabis has a biphasic or bidirectional effect. So low doses can produce 1 effect and a large dose can produce the opposite. So, you know, we always want to monitor our patients for adverse effects and whether or not they're receiving any benefits. Often, we will see many side effects, but we should always be monitoring for increased depression, increased anxiety, potential psychosis, or any suicidal ideation. Those are some of the adverse effects that we can see. There's also a condition called cannabinoid hyperemesis syndrome, where a chronic user can start having vomiting like cyclical vomiting. So those are other things that we want to monitor our patients for. And [also] make sure it's working because it's expensive, [and patients] don’t get insurance coverage for it. So, if the benefit is not there, we should really be encouraging them to discontinue their use.

And is there anything else that I haven't asked you that you feel would be useful for oncology nurses to know?

Our patients are using it. So, it's really important that we become educated on the endocannabinoid system so that we can help patients navigate this because right now, they really are relying on the internet or dispensary staff and we want to make sure that they get the most current, up to date evidence-based information so that they can be making informed choices and not potentially increasing their harm.

An expert weighs in on the advantages of cannabis treatment for patients with cancer, and how nurses can help patients navigate the cannabis-oncology space, in spite of certain research limitations.  

Cannabis May Help Manage Cancer-Related Symptoms and AEs, But Clinical Research Remains a Challenge

Chronic graft-versus- host disease (cGVHD) management has advanced greatly in recent years. Not only have experts gained valuable insight into the pathophysiology of the disease, but new treatment modalities continue to be better understood, explained Daniel R. Couriel, MD, MS, in a presentation as part of the 2021 Society of Hematologic Oncology (SOHO) Annual Meeting.

Couriel showed that there are options for patients with cGVHD through to the second line of therapy.

Therapies for primary treatment of cGVHD have an average objective response rate of 50% which are achieved over 2 to 3 years of treatment. After 6 months of treatment, research shows <40% of patients are still alive, on lower doses of steroids, and do not require additional steroid of cGVHD therapy. This status of treatment in the field has come long way since the studies of historical agents, Couriel explained.

Multiple studies of historic agents used for the frontline treatment of cGVHD failed to show a survival benefit. Instead, these studies demonstrated decreased survival, limited benefit, unacceptable toxicity, or no benefit at all.

The most recent study highlighted during Couriel‘s presentation was the phase 3 BMT CTN 0801 clinical trial (NCT01106833) of sirolimus (Rapamune) plus prednisone with or without a calcineurin inhibitor. In 138 evaluable patients, the study showed that failure-free survival and overall survival were similar regardless of inclusion of a calcineurin inhibitor. There was all no difference in response rate between the 2 treatment arms, leading investigators of the study to conclude that the results were insufficient to warrant a randomized controlled trial, and the study was terminated early.

According to Couriel, BMT CTN 0801 and other studies of frontline treatment for cGVHD are no longer relevant because the agents are not widely used in the space. Further, if effective primary treatment does not bring patients into remission, there is opportunity to treat these patients in later-line settings.

Everyday treatment of steroid-refractory cGVHD can include off-label use of agents that are not FDA approved for the treatment of this patient population. This is because after failure on corticosteroids, agents like rituximab (Rituxan), mycophenolate mofetil, sirolimus, and others have shown the ability to induce high response rates in retrospective and prospective studies.

“Traditionally, we've used these treatments for steroid-refractory chronic GVHD. These modalities are not FDA approved, but we're still using them. For instance, in my case, especially Rituxan, and then the list continues with mTOR inhibitors, specifically sirolimus, more than everolimus [Afinitor] in the case of our patients. The overall response rate is around 60% to 70%, with the exception of modalities that seem to be on the lower end of the range, like imatinib,” Couriel stated during his presentation.

The challenge with these agents, according to Couriel, is that the study results are difficult to understand because the study designs are not always curated in a way that can translate to clinical practice. Further, oncologists select treatment based on experience, ease of use, need for monitoring, and risk of toxicity.

Treatment with rituximab is FDA approved for the treatment of steroid-refractory acute GVHD and was considered a potential option for steroid-refractory cGVHD following results from a phase1/2 study.

 In the study, 21 patients received 38 cycles of rituximab and the objective response rate achieved was 70%. Responses included 2 complete responses. In terms of toxicity, the treatment was well-tolerated. There were 9 grade 3/4 adverse events observed. AEs included infectious toxicity like hepatitis B reactivation in 1 patients and septic arthritis in a clinically uninvolved hip joint in 1 patient, infectious diarrhea in 3 patients, and viral conjunctivitis in 1 patient. Non-infectious AEs included gastrointestinal hemorrhage, nephrolithiasis with acute renal colic in, and acute infusion reaction to rituximab in 1 patient each.

One agent is now making progress with the FDA for the potential treatment of steroid-refractory cGVHD; ruxolitinib (Jakafi). A new drug application for the agent was granted priority review by the FDA in February 2021 based on data from the phase 3 REACH-3 clinical trial (NCT03112603). Ruxolitinib led to a higher response rate of 49.7% compared with 25.6% in the best available therapy arm and showed a trend toward improvement in FFS. The FDA plans to make a decision on the potential approval at the end of September 2021.

Further progress in the armamentarium of cGVHD has been shown with second-line therapies, explained Couriel.

Based on findings from a multicenter, open-label, phase 2 study (PCYC-1129-CA; NCT02195869), ibrutinib (Imbruvica) was granted FDA approval for the treatment cGVHD after failure of first-line corticosteroid therapy and requiring additional therapy in 2017.

Regarding the study, Couriel said: “It was well designed and included steroid refractory chronic GVHD patients, and the primary endpoint was response using the chronic GVHD response criteria. There was a documented 60 something response rate. This was in 28 patients, 9 of whom had complete remission, and 7 patients had stable disease.”

Of the 42 patients envaulted on oral ibrutinib 420 mg once daily, the 67% responded to therapy (95% CI, 51%-80%). Notably, 88% of the patient population had 2 organs involved at baseline. Responses were observed in all involved areas, which included the mouth, skin, gastrointestinal tract, and liver. The median time to response was 12.3 weeks (range, 4.1-42.1 weeks).

More than 20% of patients in the study experienced AEs. The most common AE observed with second-line ibrutinib in patients with cGVHD included fatigue, bruising, diarrhea, thrombocytopenia, stomatitis, muscle spasms, nausea, hemorrhage, anemia, and pneumonia.

Since, 2017, 1 additional therapy was granted FDA approval for the second-line treatment f cGVHD which is belumosudil (Rezurock) for the treatment of adult and pediatric patients 12 years and older with cGVHD after failure of at least two prior lines of systemic therapy.

Approval was granted based on results from the ROCKstar study (NCT03640481) during which the ORR was assessed as the primary end point, and the key secondary end points evaluated were duration of response, change in Lee Symptom Scale Score, OS, FFS, and change in GVHD severity.

ROCKstar showed a 75% ORR with belumosudil (95% CI, 63%-85%). Response included CRs in 6% of patients and partial responses in 69%. The treatment was also determined to be well-tolerate and consistent with prior reports of the agent in patients with cGVHD.

Now that the treatment landscape for cGVHD appears to be well-populating with treatment options, Couriel explains that questions about sequencing linger.

“We still need to establish a more or less standard algorithm in terms of how we position them in in the middle of the traditional therapies. And the treatment choices are still based on physician experience, ease of use need for monitoring, risk of toxicity, and now with new agents’ cost. FDA-approved agents are 2 factors that I would include in the equation,” Couriel stated.

In the pipeline for cGVHD, JAK-1/JAK2 inhibition is very promising, Couriel stated, and oncologists await the FDA decision on whether to approve ruxolitinib for cGVHD indications.

Couriel, DR. Chronic GVHD - New Therapies. Presented at: 2021 Society of Hematology Oncology Annual Meeting September 8-11, 2021; virtual.

Carpenter PA, Logan BR, Lee SJ, et al. A phase II/III randomized, multicenter trial of prednisone/sirolimus versus prednisone/ sirolimus/calcineurin inhibitor for the treatment of chronic graft-versus-host disease: BMT CTN 0801. 

.2018;103(11). Doi: 10.3324/haematol.2018.195123

Cutler C, Miklos D, Kim HT, et al. Rituximab for steroid-refractory chronic graft-versus-host disease. 

. 2016;108(2):756-762. doi: 10.1182/blood-2006-01-0233

Incyte announces acceptance and Priority Review of sNDA for Jakafi® (ruxolitinib) as a treatment for patients with chronic graft-versus-host disease, News release. Incyte. February 22, 2021. Accessed September 8, 2021. https://bit.ly/2ZEOors

Incyte announces U.S. FDA has extended the sNDA review period for ruxolitinib (Jakafi®) in chronic graft-versus-host disease (GVHD). News release. Incyte. June 8, 2021. September 8, 2021. https://bit.ly/3iBiKpk.

FDA expands ibrutinib indications to chronic GVHD. News release. FDA. August 2, 2017. Accessed September 8, 2021. https://bit.ly/2X9RK89

US FDA grants full approval of REZUROCK (TM) (belumosudil) for the treatment of patients with chronic graft-versus-host disease (cGVHD). News release. Kadmon Holdings, Inc. July 16, 2021. Accessed September 8. 2021. 

Cutler CS, Lee SJ, Arai S, et al. Belumosudil for chronic graft-versus-host disease (cgvhd) after 2 or more prior lines of therapy: the ROCKstar study. 

. 2020;136(suppl 1). doi: 10.1182/blood.2021012021

Chronic graft-versus-host disease management has continued to advance in recent years, with new and anticipated treatment options for its treatment landscape. 



Advancements in cGVHD Yield New and Anticipated Treatment Options

The use of roxadustat (Evrenzo) conferred effective and tolerable results for the treatment of chemotherapy-induced anemia in patients with non-myeloid malignancies, according to topline results of the phase 2 WHITNEY trial.

The oral agent is the first in a new class of agents including HIF-PH inhibitors that encourage erythropoiesis through amplified endogenous production of erythropoietin, better iron absorption and mobilization, and downregulation of hepcidin.

“Roxadustat is a promising new approach for treating chemotherapy induced anemia, which complicates the treatment of many [patients with] cancer,” Mark D. Eisner, MD, MPH, chief medical officer at FibroGen, Inc., stated in a press release. “Further studies will be necessary to evaluate whether roxadustat can effectively and safely treat this important type of anemia.”

In the open-label phase 2 trial, investigators examined the safety and efficacy of roxadustat as a treatment for anemia in 92 patients concurrently receiving chemotherapy for non-myeloid malignancies.

Patients enrolled to the trial had a hemoglobin level at, or below, 10 g/dL. To be eligible for inclusion, patients needed to have a diagnosis of a non-myeloid malignancy, anemia caused by cancer treatment defined as a hemoglobin of 10.0 g/dL or less at screening, planned concurrent treatment of cancer with chemotherapy for at least 8 additional weeks, and an estimated life expectancy of 6 months or more.

Patients who were receiving chemotherapy with an anticipated cure outcome; who were only receiving hormonal products, biological products, immunotherapy, radiation; or who had a history of leukemia were excluded. Other exclusion criteria included those who received a red blood cell transfusion or erythropoietic therapy within 4 weeks of enrollment, any investigational agent within 8 weeks before study treatment, or who anemia because of other etiologies or cardiovascular risks.

Study participants were given roxadustat at a starting dose of either 2.0 mg/kg or 2.5 mg/kg three times per week for 16 weeks, with an additional follow-up period of 4 weeks. Notably, doses were allowed to be titrated every 4 weeks.

The primary end point of the trial, which was met, was maximum change in hemoglobin within 16 weeks from baseline without red blood cell transfusion. Other secondary outcomes of interest include examining the mean change in hemoglobin level from baseline to week 16, change in hemoglobin in this timeframe, and red blood cell transfusion between week 5 and week 16.

The agent was found to be well tolerated with no significant differences in treatment-emergent adverse effects observed between the 2 starting doses examined.

Full data from the trial will be shared at a medical conference later this year, according to FibroGen, Inc.

Roxadustat has received regulatory approval for use in the European Union member states, including European Economic Area countries, and in Japan, China, Chile, and South Korea for use in the treatment of anemia of chronic kidney disease in adult patients, irrespective of whether they are on dialysis.

FibroGen announces positive topline results from phase 2 clinical trial of roxadustat for the treatment of chemotherapy induced anemia. News release. FibroGen, Inc. August 25, 2021. Accessed August 25, 2021. 

Evaluation of efficacy and safety of roxadustat for the treatment of chemotherapy induced anemia. ClinicalTrials.gov. Updated August 2, 2021. Accessed August 25, 2021. 

https://clinicaltrials.gov/ct2/show/NCT04076943

This article was originally published on OncLive as “Roxadustat Shows Activity Against Chemotherapy-Induced Anemia in Non-Myeloid Malignancies”

Treatment with Roxadustat was associated with promising results in chemotherapy-induced anemia in non-myeloid malignancies. 

Roxadustat Appears Safe and Effective in Treating Chemotherapy-Induced Anemia in Non-Myeloid Malignancies

Data from the phase 2 trial ROCKstar clinical trial (NCT03640481) demonstrated that patients with chronic graft-versus-host-disease (GVHD) and were treated with belumosudil (Rezurock) experienced clinically meaningful, durable responses. These results were consistent among patients despite differences in prior treatments, severity of disease and number of organs affected, according to the published study in 

The best overall response rate (ORR) achieved with belumosudil at a once-daily dose of 200 mg was 74% (95% CI, 62%-84%) and 77% (95% CI, 65%-87%) when given at a twice-daily dose of 200 mg. High ORRs, ranging from 61% to 85%, were reported in all subgroups analyzed.

The efficacy demonstrated with belumosudil was maintained, regardless of previous treatment with ibrutinib (Imbruvica; n = 46) or ruxolitinib (Jakafi; n = 38). The ORRs in the ruxolitinib and ibrutinib subsets were 68% (95% CI, 51%-83%) and 74% (95% CI, 59%-86%), respectively.

Additionally, best ORR was observed across all affected organs. The ORRs observed in the skin, eyes, mouth, liver, lungs, joint/fascia, upper gastrointestinal (GI) tract, lower GI tract, and the esophagus at 37%, 42%, 55%, 39%, 26%, 71%, 52%, 69%, and 45%, respectively.

“Belumosudil is very effective in inducing responses across all organs affected by chronic GVHD and is safe and well tolerated. It is exciting to see the development of new interventions that can help patients,” study investigator Corey Cutler, MD, MPH, FRCPC, associate professor of medicine at Harvard Medical School and medical director of the Adult Stem Cell Transplantation Program at Dana-Farber Cancer Institute, stated in a press release.

An oral selective inhibitor of ROCK2, belumosudil was designed to reduce type 17 and follicular helper T cells through downregulation of STAT3 and to strengthen regulatory T cells through the upregulation of STAT5.

In July 2021, the FDA approved belumosudi

 for use in adult and pediatric patients aged 12 years and older with chronic GVHD following failure of at least 2 prior lines of systemic therapy.

The regulatory decision was supported by data from ROCKstar.

In the multicenter registration phase 2 trial, investigators examined 2 doses of belumosudil, at 200 mg daily (n = 66) and 200 mg twice daily (n = 66) in patients with chronic GVHD who had previously received 2 to 5 lines of treatment.

To be eligible for participation, patients needed to have received an allogeneic hematopoietic cell transplant, be at least 12 years of age, and have persistent chronic GVHD manifestations following 2 to 5 previous systemic lines of therapy. Patients needed to be on stable corticosteroids for 2 weeks before screening, and they needed to have a Karnofsky or Lansky Performance Status Scale score of 60 or higher.

If patients experienced a relapse of their underlying malignancy, had a National Institutes of Health (NIH) lung symptom score of 3, and had developed lymphoproliferative disease following transplant, they were excluded. Other exclusion criteria included liver transaminases greater than 3 times the upper limit of normal (ULN), a total bilirubin of more than 1.5 times the ULN for any reason, current receipt of ibrutinib.

Study participants received belumosudil at either once-daily 200 mg or twice-daily 200 mg in patients with chronic GVHD. Patients were stratified 1:1 by chronic GVHD severity and previous exposure to ibrutinib. Patients received belumosudil continuously until significant disease progression or intolerable toxicity.

The primary end point of the trial was best ORR at any time, and important secondary end points comprised duration of response (DOR), time to response (TTR), changes in Lee Symptom Scale (LSS), failure-free survival (FFS), corticosteroid dose reductions, overall survival, and safety.

A total of 132 patients were enrolled to the trial between October 2018 and August 2019. Baseline demographics and clinical characteristics were found to be comparable across the arms. The median age of participants was 56 years (range, 21-77), and the overall median time from diagnosis to enrollment was 28 months (range, 2-162).

At the time of screening, 31% of patients had moderate disease and 67% had severe disease. Moreover, 52% had involvement of 4 or more organs. Additionally, 36% of patients were found to have lung involvement at baseline; 38% of these patients had a NIH lung symptom score of 2. Patients received a median of 3 prior systemic lines of treatment. Additionally, 72% of patients had disease that was refractory to their last systemic line of treatment received, 34% had prior ibrutinib, 29% had prior ruxolitinib, and 72% had 3 or more prior lines of therapy. The median corticosteroid dose at baseline was 0.2 mg/kg/day of prednisone equivalent; the mean dose was 0.25 mg/kg/day.

At the time of the data analysis, 37% of patients were still on belumosudil treatment. Patients who discontinued treatment did so because of disease progression (n = 21), voluntary withdrawal (n = 13), toxicities (n = 16), physician decision (n = 11), progression of an underlying malignancy (n = 5), death because of an underlying malignancy or progression (n = 4), other (n = 7), and nonadherence to treatment (n = 3).

Additional data from the study showed that 7 patients experienced a complete response (CR) in all affected organs. Of 12 patients with lung responses based on normalization of FEV1, 3 achieved a CR and there were an additional 3 CRs based on a reduction in NIH lung symptom score from 1 to 0. Six additional patients achieved a partial response (PR).

Of the 41 patients who experienced skin responses, 11 were noted to have a decrease in sclerotic features, 15 had a decrease in body surface area (BSA) involvement, and 13 had improvements in both BSA involvement and sclerotic features.

Responses were found to occur rapidly. The median TTR was 5 weeks (range, 4-66). Within 6 months of treatment, 91% of patients experienced responses; the remaining 9% of patients experienced responses after 6 to 12 months of treatment. Notably, 59% of patients who responded to belumosudil continued to respond for 20 weeks or longer. The median DOR was 54 weeks in responders. The FFS rates achieved with the agent at 6 months and 12 months were 75% (95% CI, 66%-81%) and 56% (95% CI, 47%-64%), respectively.

With belumosudil, 65% of patients reduced their corticosteroid dose. The mean dose resulted in a 45% reduction in the modified intention-to-treat (mITT) population; the mean dose reduction was 54% in responders. Moreover, 21% of patients discontinued treatment with corticosteroids. Twenty-two percent of patients were able to discontinue treatment with calcineurin inhibitors; 20% discontinued sirolimus (Rapamune) and 21% discontinued mycophenolate mofetil.

Lastly, treatment with belumosudil at a daily-dose of 200 mg and a twice-daily dose of 200 mg improved the 7-day LSS summary score by 59% and 62%, respectively, from baseline in the mITT population. Among responders, the rates with the once-daily and twice-daily doses were 69% and 71%, respectively; in nonresponders, these rates were 29% and 33%, respectively.

Belumosudil was well tolerated, with toxicities consistent with those expected in patient with chronic GVHD who were receiving corticosteroid therapy. Thirty-eight percent of patients experienced 1 or more serious adverse effects (AEs), with pneumonia being the most frequently reported (7%). The most common grade 3 or 4 toxicities comprised pneumonia (8%), hypertension (6%), and hyperglycemia (5%).

Of 83 patients who discontinued treatment with belumosudil, 21% did so because of toxicity, 12% because of potential drug-related toxicities, 4% because of progression of underlying malignant disease, and 16% because of progression of chronic GVHD.

“Based on the similar efficacy and safety observed in this study, 200 mg once daily is the preferred dosage for the treatment of chronic GVHD. Although the 200-mg twice-daily dose showed higher responses in certain organs, such as the skin, and slightly fewer AEs, the difference compared with the 200-mg twice-daily dose was not deemed significant,” the studfy authors concluded. “Because of its unique mechanism of action, belumosudil may have broad therapeutic potential beyond chronic GVHD and is currently being studied in systemic sclerosis, with plans for additional studies in other immune disorders.”

Cutler CS, Lee SJ, Arai S, et al. Belumosudil for chronic graft-versus-host disease (cGVHD) after 2 or more prior lines of therapy: the ROCKstar study. 

. Published online July 15, 2021. doi:10.1182/blood.2021012021

Kadmon announces pivotal trial data published in the journal Blood for REZUROCK (belumosudil) in chronic graft-versus-host disease (cGVHD). News release. Kadmon Holdings, Inc. July 19, 2021. Accessed July 19, 2021. 

US FDA grants full approval of REZUROCK (TM) (belumosudil) for the treatment of patients with chronic graft-versus-host disease (cGVHD). News release. Kadmon Holdings, Inc. July 16, 2021. Accessed July 19, 2021. 

This article was originally published as 

“Belumosudil Represents Promising Newly-Approved Option for Chronic GVHD”

A recent study showed that belumosudil induced clinically meaningful, durable responses among a varied cohort of patients with chronic graft-versus-host-disease. 

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