Complementary therapies, such as acupuncture, may help patients alleviate cancer-related pain.

 Notably, auricular acupuncture has been noted to help certain patients not only manage pain, but reduce their opioid use, according to Heather Jackson, PhD, FNP-BC, NEA-BC, FAANP.

“When we think about treating pain, if you’re going to treat the whole person you have to think about all the different aspects of the [individual],” Jackson explained, noting that complementary therapies are not panacea, but can be useful in addressing certain symptoms and treating the person in a holistic fashion.

“I said [to my patient], this could be 1 piece of the pie and then we can look at alternative medicines while we’re doing the acupuncture.”

®, Jackson, the administrative director of advanced practice for the Vanderbilt Ingram Cancer Center, discussed forms of therapy with acupuncture as well as her experience using acupuncture for a thyroid cancer survivor and how it helped him achieve his goal of coming off pain management treatment with an opioid.

Please discuss this patient’s diagnosis and the treatment that was chosen.

I had a wonderful case study that came to my clinic: a 49-year-old male who had a history of thyroid cancer, and did not have current active disease. He had completed his treatment, had surgery, and was still having a lot of facial pain [in the] left cheek, neck, and temporomandibular joint. He’d been taking oxycodone 15 mg 4 times [daily] and he came to me and said, ‘I’m a father, I’m a husband, and it’s really sedating for me, I can’t sit down at meals, I can’t enjoy social activities, anything I do is uncomfortable.’ He didn't have his full energy level.

We said: What can we do to try to get him off of the oxycodone, but still functioning and interacting with his family? I said, ‘how about acupuncture?’ and he was really interested in it. I looked at his medicine regimen and said ‘it’s not the cure-all, but it could be a piece of the pie.’

What did the conversation look like when you mentioned acupuncture and what questions did the patient have?

It’s very common where patients will say, ‘I don’t understand why we are doing this now?’

I go over the evidence with them and then I build their confidence by saying, ‘I’ve done research in this and it's safe enough that I’ve done stickers on babies all the way to needles in adult’s ears. I’ve had success in getting patients off of opioids and even reducing anxiety and depression.’

He and I looked through Google and some PubMed articles. I said feel free to look through them, read up on it, [and] bring whatever you want back… and that’s what he did. He was a very motivated patient, and he came back to me [in] clinic and said, ‘I did look through this and there is some justification to what you’re talking about. Let’s try it, what do I have to lose?’

What did acupuncture treatment look like for this patient?

The acupuncture that we do in our clinic is a modified acupuncture technique; it’s not full body, it’s limited to the ear. They call it auricular acupuncture, and [the] protocol that I use is called the battlefield protocol. Battlefield protocol was developed by the Air Force for pilots who couldn’t be on opioids long term; they couldn’t be on sedating medicines.

The battlefield pain protocol is for pain treatment. They have studs that you can put in the ear and leave in—they’ll stay in the ear for up to 5 to 7 days.

I also have the NADA protocol which was developed for patients who were in detox programs, trying to do a methadone clinic, or [use] buprenorphine treat opioid use disorder. [Investigators] have seen that it helps with physiological symptoms as well as the psychological impact of being a dependent or having a use disorder.

I talked to him about both options, the pain was the issue here, so I went to the battlefield protocol and said ‘we don't have to be so aggressive that I put studs, the needles in your ears that you walk around with, I could put some milder needles in your ear on the point, [and] you can rest for 20 to 30 minutes.

I usually turn the lights down in the exam room and I have a sound maker to try to help them relax; I step out of the room, let them relax with the needles in their ear, and then I come back and take the needles out. I offer acupressure stickers that are like a little band aid that I can put on a couple of little spots that way they can go home, they can be pressing on the area [to] give a little bit more stimulation.

I’ll tell the patient, you can come back anytime you want. There are no adverse risks except maybe a little bruising and bleeding which is quickly resolved, the needles are so small—they’re smaller than a needle you would even thread with. I will let them sort of direct [if they] want to come back in 2 weeks, in 4 weeks, [etc]. I recommend a few sessions that way [they] can build on top of each other. It doesn’t work for everyone, but if it does work you will notice different things, every patient is different.

Some patients will say ‘well, Heather I didn’t get 100% pain relief, which would be a pretty unattainable goal, but I did notice that I didn't have to take my medicine 3 times a day; I took it 2 times a day’ or ‘usually I can't sleep more than 6 hours [but] I slept 8 hours’ or ‘I could only walk in a mall for an hour and a half but I noticed after your treatments I’m able to walk for 2 hours.’

Those are the things I tell the patient you need to be looking for, I don’t expect a cure-all, but oftentimes they do complete their treatment and they’ll say ‘preprocedure I was an 8 out of 10 and now I’m a 6 or now I'm a 2 [for pain].’ That’s the conversation we usually have and what I tell the patient to be monitoring.

How did you measure this patient’s pain and how did he respond to the acupuncture treatment?

We looked at medicine doses because he wanted to be off oxycodone, and he had been so motivated to get off of the oxycodone that he had quit it cold turkey and had some reactions because his body was used to that for so many years. He realized [he] needed some help coming off of it, we talked about that. I said ‘let’s do the acupuncture and then gradually come down on the medicine, but it’s going to be a timed thing. It’s not going to happen overnight, we have to be patient, [and] you can’t push yourself too hard because we also don’t want the pain to flare up.’ That was how we walked through it, and he was amenable to that.

He did feel some pain relief right after the intervention and we ended up doing a series of 3 [treatments] for the actual acupuncture and he felt the pain was getting under control. Then we were able to reduce and completely wean him off the oxycodone, he was very motivated, within 4 months. He reported 100% relief of his right-side face pain and 50% relief on the left side after he had completed his treatments, and this would be reported to me in the follow-up when he came in 4 weeks later.

A big point that he shared with me was: ‘Heather, I can eat with my family, now I can go out to eat.’ He had young kids, middle school teenage [aged and] you can imagine the quality of life that was being impacted. He was so thrilled to be able to say now I can eat with my family.

[Today] he is not in my clinic anymore because we got him off of everything and he [only] needed help getting through that period of getting off the medicine. He’s not in our clinic anymore for cancer pain, but he’s under surveillance and should we need to intervene in the future we absolutely will.

Is there any monitoring or questions that you ask patients when they’re undergoing treatment?

You [may] have concerns [if] the patient has hemophilia, [which] some patients [do on] very rare occasions, or, if you have a patient with a pain condition—sometimes stimulation with a needle are not a good idea. It depends on what type of pain a person has.

If a person has a central sensitization, where there's pain everywhere the body, sometimes an event like a needle will trigger more pain. That’s something to be cautious with. You sort of have to interview with the patient, to get a gut feeling for the patient and know if this is going to be a good fit or not. Usually, the patients that are very motivated that have tried chiropractic or massage are open to other options— that’s a good indicator that this is probably going to be a successful treatment.

Otherwise, [concerns] would be very mild bleeding that can occur. If that does occur, [use] a cotton swab or a tissue, hold it on there and take it off.

I’ve never [seen] any bruising [with my patients]. Some patients don’t like the stickers that I’ve put on for acupressure, so we don’t use them if they don’t like them, but most people like them.

Do you have any clinical pearls to wrap up what you learned from this case study?

My advice would be to always consider [acupuncture] as an adjunct [therapy]. There’s a lot of miscommunication with complementary therapies and people will assume that’s the only option and that’s not what we’re saying when we say complementary, we say complementary [as] in addition to. We can all work together, we can all collaborate like we do multidisciplinary treatments for our patients, but this could be an option to add too.

Jackson HJ, Peal K. Auricular acupuncture for the treatment of cancer-related pain. 

.2022;37(4):32-35. doi:10.1080/10463356.2022.2079353

Montgomery AD, Ottenbacher R. Battlefield acupuncture for chronic pain management in patients on long-term opioid therapy. 

. 2020;32(1):38-44. doi:10.1089/acu.2019.1382

Carter K, Olshan-Perlmutter M. NADA protocol: integrative acupuncture in addictions.

. 2014;25(4):182-287. doi:10.1097/JAN.0000000000000045

Articles

Heather Jackson, PhD, FNP-BC, NEA-BC, FAANP, provides a case-based perspective on the benefit of auricular acupuncture as a tool for managing cancer pain.

Auricular Acupuncture Offers Complimentary Approach to Manage Cancer Pain

Pain management is a core component of cancer care. However, use of agents to curb these effects, especially opioids present challenges in practice including stigma around opioid abuse, reimbursement issues, lack of availability, and patient fear of addiction. The American Society of Clinical Oncology (ASCO) has updated its guidelines providing recommendations for the management of cancer pain with opioids.

Approximately 55% of patients experience pain during active cancer treatment and more than 66% of patients with advanced disease will experience cancer-related pain. Although guidelines for managing cancer-related pain exist, there are few guidelines focused on exclusively on opioids. Opioids approved by the FDA are viable options for pain relief and use should be determined based on several factors including cost, half-life, pharmacokinetic properties, and route of administration. If a clinician is unsure of the best agent palliative care or pain specialists should be consulted.

A multidisciplinary expert panel consisting of patient representatives and an ASCO guidelines staff member with health research methodology expertise developed the guidelines that were informed by evidence including 16 randomized controlled trials and 31 systemic reviews from January 1, 2010, to February 17, 2022.

The supportive care guidelines addressed 7 key questions for patients with cancer pain under all of which fell under the umbrella of the leading question: “In what circumstances should opioids be used to manage cancer pain in adults, how should opioids be administered, and how should opioid adverse effects be prevented or managed?”

Regarding the circumstances under which opioids should be offered, an evidence-based strong recommendation was given by the panel that all patients with moderate-to-severe pain related to cancer or active treatments should be offered, unless otherwise determined, opioids to be given as needed as the benefits outweigh the harm. According to informal consensus, opioids should be administered at the lowest possible dose, early assessment and titration should occur as well; however, there is insufficient evidence to recommend a single set of ranges for escalation. The authors wrote, “In general, the minimum dose increase is 25% [to] 50%, but patient factors such as frailty, comorbidities, and organ function must be evaluated and considered when changing doses.”

In terms of opioid-induced adverse event (AE) management, the panel noted several events with recommendations for prevention and treatment. These events included constipation, delirium and neurotoxicity, endocrinopathy, nausea and vomiting, pruritus, sedation and respiratory depression, and urinary retention. Guidelines for opioid-induced constipation have been published and should be referenced.

 All others should be treated based on clinical experience.

The guidelines advised that patients with renal or hepatic impairment should receive more frequent dose adjustments and clinical observations. Patients with renal impairment who are currently undergoing treatment with an opioid may rotate to methadone as it is excreted fecally. For those who are given opioids that are primarily eliminated in urine, such as fentanyl, oxycodone, and hydromorphone, careful titration, and frequent risk monitoring for accumulation of the parent drug or active metabolites should occur. Both recommendations are supported by strong informal consensus.

Additional recommendations stated that patients who have been taking other analgesics such as nonsteroidal anti-inflammatory drugs, may continue taking them after initiating opioid use if they provide further pain relief. However, there is insufficient evidence on a set range for dose escalation and whether genetic testing should be performed to guide administration of opioids.

The panel noted that there is insufficient evidence to provide a recommendation for a specific short-acting opioid for breakthrough pain, but patients receiving opioids around the clock should be given immediate release agents at a dose of 5% to 20% of the daily regular morphine equivalent daily dose for breakthrough pain. As with the titration recommendation, there is insufficient evidence to support a specific opioid for breakthrough pain.

A strong evidence-based recommendation for opioid rotation is included in the guideline. Specifically, the evidence supports switching agents when AEs are poorly managed, there are logistical or cost concerns, trouble with the route of administration or absorption of an opioid, or patients have pain that is refractory to dose titration. As with the titration recommendation, there is insufficient evidence to support a specific opioid for breakthrough pain.

The guidelines also stated that because patients with multiple chronic conditions represent a diverse and complex population shared decision making is crucial and clinicians should review all chronic conditions present when determining a treatment plan. It was noted that patients with persistent noncancer pain who were already being treated with opioids and later developed cancer, may have a challenging time obtaining pain relief.

Prior to prescribing opioids, physicians, patients, and caregivers should discuss expectations, goals, pain, and concerns about the treatment; education as well as regular follow-up is key between clinicians and patients. Shared decision-making should also take cost into account and patients should be informed of financial counseling services. To prevent or manage AEs to opioid use, education, and strategies of prevention to known effects should be given by clinicians.

As there are few guidelines focused solely on opioids for pain management, evidence for several of the questions was limited leading the panel to reply on consensus or they could not make a recommendation; however, the panel noted that the use of opioids for cancer pain management has been routine. The panel recommended that to determine the best approach of pain management for patients with a substance use disorder, clinicians should discuss with a palliative care, pain, and/or substance abuse disorder specialist.

A draft of the recommendations was made available to the public for comment from July 8, 2022, through July 22, 2022, and for each recommendation, 88% to 100% of respondents agreed or agreed with slight modifications. Additionally, ASCO noted that most randomized controlled trials included in the analysis had an intermediate or high risk of bias and further questions remain about the use of opioids for cancer pain management.

Paice JA, Bohlke K, Barton D, et al. Use of opioids for adults with pain from cancer or cancer treatment: ASCO guideline. 

. Published online December 5, 2022. doi:10.1200/JCO.22.02198

Larkin PJ, Cherny NI, La Carpia D, et al; ESMO Guidelines Committee. Diagnosis, assessment and management of constipation in advanced cancer: ESMO clinical practice guidelines. 

. 2018;29(suppl 4):iv111-iv125. doi:10.1093/annonc/mdy148

The American Society of Clinical Oncology (ASCO) has updated its guidelines providing recommendations for the management of cancer pain with opioids.

ASCO Guidelines Provide Road Map for Cancer Pain Management With Opioids 

During end-of-life (EOL) care, patients of color were much less likely to receive treatment with opioids than White patients, according to a study of 318,548 Medicare patients with poor prognoses cancers published in the 

. In addition, Black patients, despite being prescribed lower doses of opioids, were more likely to undergo urine drug screenings (UDS).

Findings from the study showed that Black patients were 4.3 percentage points (95% CI, ­–4.8 to –3.6) less likely to receive any opioid and 3.1 percentage points (95% CI, –3.6 to –3.8) less likely to receive long-acting opioids near EOL compared with White patients. The differences were similar for Hispanic patients, who were 3.6 percentage points (95% CI, –4.4 to -2.9) less likely to receive any opioid and –2.2 percentage points (95% CI, –2.7 to –1.7) less likely to receive long-acting opioids compared with White patients. Investigators noted that by 2019, only 32.7% of patients overall received any opioid, and only 9.4% received a long-acting opioid near EOL.

“Most previous studies of inequities in cancer pain management were conducted before the full scope of the opioid crisis was recognized and regulations to curb opioid prescribing were put in place,” lead author Andrea Enzinger, MD, an assistant professor of Medical Oncology with Dana-Farber Cancer Institute (DFCI), in Boston, Massachusetts, said in a news release.

 “Over the past decade, there has been a seismic shift in prescribing practices and sharp declines in access to these medications for patients with cancer. But we know very little about the current state of disparities in access in this environment of increased regulation, and about the magnitude of disparities among patients with terminal cancer.”

In 2021, Enzinger et al determined that the proportion of patients with poor prognosis cancers receiving at least 1 opioid prescription near EOL dropped from 42.0% (95% CI, 41.4%-42.7%) in 2007 to 35.5% (95% CI, 34.9%-36.0%) by 2017. The proportion of these patients who received at least 1 long-acting opioid prescription declined from 18.1% (95% CI, 17.6%-18.6%) to 11.5% (95% CI, 11.1%-11.9%).

In this new study, Enzinger et al examined trends in opioid prescription fills and potency as measured by morphine milligram equivalents (MMEs) per day (MMEDs) near EOL, defined as 30 days before death or hospice enrollment. The study included White (n = 272,358), Black (n = 29,555), and Hispanic (n = 16,636) Medicare decedents older than 65 years with poor-prognosis cancers who died from 2007 to 2019. Compared with White patients, Black and Hispanic patients were more likely to live in the South, urban areas, and the most deprived Social Deprivation Index quintile as measured community-level socioeconomic deprivation.

The mean patient age was 77.6 years; 18.2% of the cohort were aged 85 years or older. Lung cancer was the most common malignancy in all racial groups. Investigators found that the racial cohorts were equally likely to have chronic illness such as acute myocardial infarction, ischemic heart disease, and chronic obstructive pulmonary disease.

Black and Hispanic decedents received fewer opioids at lower doses than White decedents throughout the study except in 2019. In that year, access to long-acting opioid was the same between Hispanic and White patients.

In keeping with the 2021 results, the proportion of patients near EOL receiving any opioid decreased from 42.2% to 32.7% over the study period. Patients receiving long-acting opioids declined from 17.9% to 9.4%.

The mean daily dose fell from 84.6 MMED to 51.8 MMED for all patients, and the total dose of opioids filled per decedent, averaged across those who did and did not fill an opioid prescription, fell from 1067 to 508 MME. Although dose levels fell for all patients, investigators found that Black and Hispanic patients received even weaker doses than their White counterparts.

Among those who filled at least 1 opioid prescription, Black patients received daily doses that were 10.5 MMEs lower (95% CI, –12.8 to –8.2) than White patients. Hispanic patients received daily doses that were 9.1 MMEs lower (95% CI, –12.1 to –6.1). Investigators said the difference was roughly equivalent to receiving 25 fewer 5-mg oxycodone tablets in the final month of life, which Enzinger said represented “a meaningful amount of pain control.”

Black patients were required to submit to UDS more often than White or Hispanic patients throughout the study period. From 2007 to 2019, the proportion of patients undergoing UDS in the 180 days before death or entry to hospice care increased from 0.6% to 6.7% for White patients compared with 1.0% to 7.9% for Black patients. Urine testing increased from 0.5% to 6.8% for Hispanic patients.

“The disparities in UDS are modest but important, because they hint at underlying systematic racism in recommending patients for screening,” senior author Alexi Wright, MD, MPH, a physician and director of Gynecologic Oncology Outcomes Research at DFCI, said in a news release. “Screening needs to either be applied uniformly or not at all for patients in this situation.”

Investigators noted that Black men were particularly affected by these disparities. White men were most likely and Black men were least likely to receive opioids. Black men and women and Hispanic women received statistically fewer opioids than White men and women across all measures.

Furthermore, compared with White women, White men filled a mean total opioid dose near EOL that was 150 MMEs more per decedent (95% CI, 130-169). In contrast, Black women filled 128 MMEs less (95% CI, 168-153) and Black men filled 153 MMEs less (95% CI, –195 to –110).

The disparities in treatment existed even after correcting for measures of poverty, community-level deprivation, or rurality. Notably, rural White patients were most likely to receive opioids, and Black patients living in urban areas were the least likely.

Investigators assessed dual-eligibility for Medicare and Medicaid as an indicator of low income. White dual-eligible patients received the most opioids across all measures, and Black non–dual-eligible patients generally received the least. Compared with White dual-eligible patients, Black non–dual-eligible patients were 13.1 percentage points (95% CI, –14.0 to –12.1) less likely to fill any opioid near EOL and 5.9 percentage points (95% CI, –6.6 to –5.3) less likely to fill a long-acting opioid. Furthermore, Black patients received lower daily and mean total opioid dose.

According to most measures of EOL, opioid receipt did not differ by dual-eligibility for Black patients. White non–dual-eligible patients, however, received more opioids across all measures.

Enzinger AC, Ghosh K, Keating NL, et al. Racial and ethnic disparities in opioid access and urine drug screening among older patients with poor-prognosis cancer near the end of life. 

. Published online January 10, 2023. doi:10.1200/JCO.22.01413

Study finds racial inequities in access to opioids among older patients with cancer near end of life. News release. Dana-Farber Cancer Institute. January 10, 2023. Accessed January 11, 2023. 

Enzinger AC, Ghosh K, Keating NL, Cutler DM, Landrum MB, Wright AA. US trends in opioid access among patients with poor prognosis cancer near the end-of-life. 

. 2021;39(26):2948-2958. doi:10.1200/JCO.21.00476

Findings showed that Black patients were 4.3 percentage points less likely to receive any opioid and 3.1 percentage points less likely to receive long-acting opioids near end-of-life compared with White patients. 



During End-of-Life Cancer Care, Patients of Color Less Likely To Receive Opioid Treatment

Patients experiencing tamoxifen-related side effects may benefit from cannabidiol (CBD) oil, according to a poster presentation from the 

2022 San Antonio Breast Cancer Symposium.

CBD led to decreases in several tamoxifen-related adverse effects (AEs). Without CBD, the percentage of patients (n = 26) who experienced grade 1 or 2 insomnia was 62% (n = 16) and 38% (n = 10), respectively. With CBD, the rates of grade 1 or 2 insomnia were 73% (n = 19) and 12% (n = 3). Similarly, with for hot flashes, tamoxifen alone induced grade 1 and grade 2 symptoms in 77% (n = 20) and 19% (n = 5) of patients, respectively, whereas the addition of CBD yielded grade 1 and 2 symptoms in 85% (n = 22) and 4% (n = 1) of the population.

Without CBD, the rates of arthralgia were 58% (n = 15) and 38% (n = 10), respectively. Following CBD, these rates were 81% (n = 21) and 12% (n = 3). The rate of grade 1 mood alterations decreased from 73% (n = 19) to 65% (n = 17) following CBD, and the rate of grade 2 mood alterations remained at 4% (n = 1). Similarly, with no CBD, the rate of grade 1 muscle cramps was 27% (n = 7) and the grade 2 rate was 4% (n = 1). Following CBD, no patients reported grade 2 muscle cramps and the rate of grade 1 muscle cramps was 31% (n = 8).

The rate of headache was consistent across the 2 groups: 4 patients (15%) experienced grade 1 headaches both with and without CBD. Vaginal dryness decreased from 2 patients (8%) and 1 (4%) patient with grade 1 or 2 severity without CBD, to 1 patient (4%) with grade 1 severity with CBD. Four patients (15%) and 2 patients (8%) experienced grade 1 amnesia without and without CBD, respectively. Where 2 patients (8%) experienced weight gain with tamoxifen alone, 1 patient (4%) did so with CBD.

Moreover, the mean heath related quality-of-life (HR-QOL) without CBD was 74.3 and the mean after 4 weeks of CBD was 79.0, translating to a 4.7-point increase in HR-QOL (95% CI, 1.8-7.6; 

 = .003). In terms of endocrine symptoms, the mean without CBD was 47.1 and the mean after 4 weeks of CBD was 53.8. In this population, endocrine symptoms improved by 6.7 points (95% CI 

Tamoxifen is often associated with bothersome AEs, which may negatively effect a patient’s QOL, as well as treatment adherence, wrote study authors. Many patients seeking relief from these AEs have fixes their attention to cannabinoids such as cannabidiol (CBD), they continued; however, the effects of CBD on tamoxifen-related AEs have not been investigated. Moreover, because tamoxifen is mainly metabolized through CYP2D6, and CBD is suggested to be an in-vitro inhibitor of CYP2D6, the use of CBD might affect tamoxifen pharmacokinetics.

“The aims of this study were to determine the pharmacokinetic interaction between CBD and tamoxifen, and to subsequently investigate where there is a beneficial influence of CBD on tamoxifen-related [AEs] and [QOL],” Sanne Buijs, MD, of the Department of Medical Oncology, Erasmus MC Cancer Institute, and co-investigators wrote.

To that end, investigators enrolled patients with endoxifen levels of at least 16 nM and at least one tamoxifen-related AE, including hot flashes, arthralgia, mood alterations, and insomnia.

Median patient age was 49.5 years [range, 47-54], the median BMI was 26.1 [range, 24-31], and the median months of tamoxifen use was 13 [range, 5-24]. Thirteen patients (50%) had received local treatment with lumpectomy plus radiotherapy, 4 (15%) had received mastectomy alone, and 9 (35%) had received mastectomy plus radiotherapy. Twenty patients (77%) had undergone neoadjuvant chemotherapy and one patient (4%) had received neoadjuvant anti-HER2 therapy.

Of note, CBD led to toxicities in 38% of patients, all of which were categorizes as grade 1 in accordance with Common Terminology Criteria for Adverse Events guidelines.

With no CBD, 3 patients experienced grade 1 and grade 2 fatigue (12% for both). However, with CBD, 8 patients (31%) experienced grade 1 and 1 patients (4%) experienced grade 2 fatigue. No patients experienced dry mouth or nausea with tamoxifen alone, but these toxicities were reported by 3 (12%) and 2 (8%) of patients receiving CBD.

Study authors acknowledged that 4 weeks of CBD use was a short amount of time for a study, and that a longer study period may yield better insights on CBD and clinically relevant improvements in HR-QOL.

Investigators also noted that the combination of CBD and tamoxifen did lead to a significant decrease in endoxifen plasma concentrations, but this decrease remains within bio-equivalence boundaries and is not considered clinically relevant.

Buijs S, Braal CL, Buck SAJ, et al. CBD-oil: a potential solution in case of severe tamoxifen-related side effects. Presented at: 2022 San Antonio Breast Cancer Symposium; December 6-10, 2022; San Antonio, TX. P1-02-08.

Cannabidiol oil may be useful in helping patients with breast cancer manage tamoxifen-related adverse effects. 


CBD Oil Shows Modest Improvements in Tamoxifen-Related Adverse Effects

Anemia is a common problem with myelofibrosis and can lead to a significant patient burden, according to Aaron T. Gerds, MD, MS. However, JAK inhibitors have demonstrated encouraging efficacy in this arena.

Gerds, who isan assistant professor in medicine (hematology and medical oncology) at the Cleveland Clinic Taussig Cancer Institute, recently presented findings from the phase 3 MOMENTUM trial (NCT04173494), which showed that in the open-label continuation phase, patients with myelofibrosis who have anemia and previously received a JAK inhibitor who stayed on momelotinib experienced durable transfusion independent, splenic response, and symptoms improvement. This was also observed in patients who or crossed over from danazol (Danocrine) to receive momelotinib.

®, Gerds discussed the findings from MOMENTUM, the trajectory of JAK inhibitors for the treatment of myelofibrosis, and whether momelotinib can contribute to the JAK inhibitor momentum; as well as the potential benefit these drugs can offer for patients with myelofibrosis who have anemia.

For patients on the momelotinib-to-momelotinib arm (n = 130), the week 24 symptom responses were sustained through week 48 of treatment in 97% of patients. This occurred in 100% of patients in the danazol-to-momelotinib arm (n = 40).

Additionally, for the patients who did not have a Total Symptom Score (TSS) response to danazol and therefore crossed over to momelotinib at week 24, 29% experienced a TSS at 48 weeks. Also at week 48, 20% of patients who continued momelotinib in the open-label phase from momelotinib in the double-blind phase experienced a TSS.

Early crossover to momelotinib was permitted if disease progression was confirmed. In the open-label crossover phase after 24 weeks of treatment, momelotinib was given at 200 mg daily.


“This study selected patients who had previous JAK inhibitor exposure, were anemic and also significantly symptomatic and had large spleens. It was looking to see if momelotinib was a better option for these patients,” Gerds explained. “Danazol was chosen as a comparator because it is an active agent in remedying anemia in these folks, and momelotinib is a special JAK inhibitor that not only can shrink spleens and improve symptom burden, but it can also have a potential effect on anemia through inhibition of ACVR1.”


“The first key take-home point from the data we presented was that there were no new toxicity or safety signal seen. The data was very consistent [with] what we saw in the original 24-week analysis. This is, of course, incredibly important when you think about the fact that these [patients] might be on this medication for a long time,” he added. “Moreover, the responses were quite durable. Patients who responded at week 24 continue to respond through week 48, whether we’re talking about transfusion independence, spleen volume response or symptom burden improvement.”

An interesting point from the data, according to Gerds, is that patients who did not show an original symptom response during their first 24 weeks of treatment did so during the next 24 weeks, indicating that additional therapy may be beneficial. Moreover, investigators looked at different platelet count cutoffs, and the response rates were similar no matter what the platelet count threshold was for that ad hoc analysis.

“That’s important because thrombocytopenia [can] often co-occur with anemia,” he noted. “So, if you have a drug that treats anemia, you also want [it to] have efficacy in patients who are thrombocytopenic.”

Gerds AT, Mesa RA, Vannucchi AM, et al. Updated results from the Momentum phase 3 study of momelotinib (MMB) versus danazol (DAN) in symptomatic and anemic myelofibrosis (MF) patients previously treated with a JAK inhibitor. 

. 2022;140(suppl 1):1514-1515. doi:10.1182/blood-2022-162783

Videos

Aaron T. Gerds, MD, MS, unpacks data seen with momelotinib for patients with anemic myelofibrosis. 

Aaron Gerds on JAK Inhibitor Therapy for Anemic Patients With Myelofibrosis

The common terminology criteria for adverse events (CATCAE) is a helpful tool for nurses when managing adverse events (AEs) in the treatment of melanoma with immunotherapies and targeted therapies, according to Caressa Valdueza, MSN, AGNP-BC, AOCNP.

Valdueza, a nurse practitioner at Weill Cornell Medicine, recently presented on managing such toxicities as part of an 

® State of the Science Summit™ that took place in November, 2022.In an interview with 

®, Valdueza highlighted key takeaways from her presentation, noting promising new advances that are arising in the treatment paradigm and common AEs that nurses may observe with these treatments.

“There are good guidelines out there [such as] the CTCAE criteria and the National Comprehensive Cancer Network guidelines [that] provide robust instructions and details on how to manage treatment toxicities,” Valdueza said. “I want people in this arena of immunotherapy and targeted therapy to be aware that there are a lot of promising treatments for melanoma, it's exciting.”

 Please provide an overview of your presentation.

 At the presentation I talked about the toxicities associated with the treatments for melanoma. I focused mainly on immunotherapy and targeted therapies such as the BRAF and MEK inhibitors. These treatments have been the cornerstone in advancing the treatment landscape for melanoma within the past decade.

What are the most common treatment related AEs that are seen with these treatments?

[To] start with immunotherapy, skin toxicities are number 1 and they present as a rash or itchiness or both. The next more common AEs that we see are gastrointestinal toxicities presenting as diarrhea or colitis; we also see endocrinopathies, the most common being hypothyroidism, followed by adrenal insufficiency. We also see liver toxicity.

With immunotherapy, any organ can be affected [and these AEs often] mimic autoimmune disorders. These are the most common ones we see in practice.

There are more rare AEs that are very important to know such as myocarditis, pneumonitis, and aseptic meningitis. These are other complications that we need to look out for.

Targeted therapies such as the BRAF and MEK inhibitors can cause skin reactions. In particular, BRAF inhibitors are well known to cause pyrexia—most notably with dabrafenib [Tafinlar]. BRAF inhibitors can also cause liver toxicity.

MEK inhibitors are more associated with ocular toxicities—when a patient reports eye pain or blurry vision they need to be referred to an ophthalmologist right away. With MEK inhibitors, cardiomyopathy is [another] potential AE [to be aware of].

How do you address treatment-related AEs?

For both immunotherapy and the targeted therapies, we go by the CTCAE criteria [and] this allows us to grade the toxicities. Grade 1 are mild and in this situation we continue with immunotherapy. Systemic steroid treatment is not indicated for grade 1 toxicities. 

When we reach grade 2 toxicities that's when we hit the gray area [and] we start thinking about holding the treatment; for immunotherapy we consider starting with systemic steroid treatment but starting with a low dose like half a milligram to a milligram per kilogram per day.

With grades 3 and 4, [which] are severe toxicities, we hold the treatments. If these are caused by immunotherapy, in addition to steroids, we also order additional immunosuppressant medication such as infliximab and mycophenolate.

What unmet needs remain in the space that you’d like to see addressed?

We’re looking forward to determining biomarkers that can predict significant toxicity with immunotherapy. We're also looking into the efficacy and tolerance of immunotherapy in patients with autoimmune disorders. I want to highlight that patients with autoimmune disorders should not be routinely excluded from immunotherapy. What we see in the literature and practice is that generally they are at higher risk for having the flares but with what we see these flares generally can be managed with steroid treatment. They are also at risk for the more common immune induced AEs such as colitis, skin toxicity. There is now a trial called AIM-NIVO [NCT03816345] that is exploring this and collecting data on nivolumab [Opdivo] in patients with autoimmune disorders.

[Additionally], we’re looking into cellular therapies, specifically tumor infiltrating lymphocytes and it's important to be knowledgeable and skilled on managing treatment toxicities so that our patients can get the optimal benefits from these new therapies.

Caressa Valdueza, MSN, AGNP-BC, AOCNP, discusses toxicity management with unfolding treatment options in melanoma. 
 


Caressa Valdueza Highlights Best Practices for the Management of Common Adverse Events in Melanoma

Regardless of menopause status, women with breast cancer who receive chemotherapy followed by endocrine therapy may be at a greater risk of cancer-related cognitive impairment than those receiving endocrine therapy alone, according to patients-reported outcomes (PROs) from the RxPONDER PRO substudy.

“Cancer-related cognitive impairment seems to persist over time in a significant proportion of patients,” said Irene Kang, MD, medical director of women’s health breast oncology at City of Hope Orange County in Irvine, California, during the presentation of the data.

In the RxPONDER study, 5,083 women with HR-positive, HER2-negative breast cancer with 1 to 3 positive lymph nodes without distant metastasis were randomly assigned to either chemotherapy followed by endocrine therapy or endocrine therapy alone. The PRO substudy included 274 patients from the chemotherapy followed by endocrine therapy group and 294 patients from the endocrine monotherapy group.

In the substudy, patients completed an 8-item questionnaire on a 5-point Likert scale assessing cognitive function at baseline, 6 months, 12 months, and 36 months.

The primary end point of the RxPONDER PRO substudy was mean cognitive function score by treatment arm and menopausal status. In particular, 139 women were premenopausal (median age, 48 years) and 429 women were postmenopausal (median age, 62 years).

Scores indicating perceived cognitive function concerns were similar between both treatment groups at baseline. In patients assigned endocrine therapy alone, these scores decreased from baseline to 6 months and 12 months but recovered to baseline at 36 months, according to the abstract. In contrast, patients assigned chemotherapy and endocrine therapy also had the same decrease at 6 months and 12 months, although their scores did not return to baseline at 36 months.

The mean score difference between the chemotherapy and endocrine therapy group and the endocrine therapy alone group was -3.02 (

 = .01) for premenopausal women and -2.36 for postmenopausal women (

Of note, 42% of premenopausal women assigned chemotherapy followed by endocrine therapy experienced a sustained and clinically significant decline in cognitive function as opposed to 28% for endocrine therapy. For postmenopausal women, these declines were 41% and 36%, respectively.

During the presentation, Kang noted that these results differ from the findings of a similar trial, TAILORx, which used a different cognitive function scale. Results from that trial demonstrated that the differences in cancer-related cognitive impairment between chemotherapy followed by endocrine therapy and endocrine therapy alone “vanished” at 12-month follow-up, she said.

Limitations to the study, as acknowledged by Kang, included patient drop-off over time, small sample size particularly in the premenopausal group, and that patients in the premenopausal group could theoretically have begun menopause at any point during the study’s duration. Patients were also overwhelmingly White (84.2%) and non-Hispanic (91.6%).

“Our study highlights the need for future investigation of cancer-related cognitive impairment in a more diverse population, as well as understanding who will develop cognitive impairment and who will recover,” Kang said during the presentation.

Kang I, Forschmiedt J, Loch M, et al. Patient-reported cognitive impairment in women participating in the RxPONDER trial (SWOG S1007) by menopausal status. Presented at: 2022 San Antonio Breast Cancer Symposium; December 6-10, 2022; San Antonio, TX. Abstract GS1-04.

Patients with breast cancer may be at risk for more intense cognitive impairment following treatment with chemotherapy plus endocrine therapy.

Chemotherapy Plus Endocrine Therapy Increases Cognitive Impairment in Breast Cancer 

Adjuvantado-trastuzumab emtansine (T-DM1; Kadcyla) with concurrent radiotherapy did not lead to a significant drop in ejection fraction or global longitudinal strain(GLS) in patients with early-stage, HER2-positive breast cancer, according to a poster that was presented at the 

In an analysis of 32 patients, 2 (6%) experienced a drop in ejection fraction following radiation. The median preradiation ejection fraction was 60% and the median ejection fraction radiation was 61%. In addition, paired t-testing revealed that there was no statistically significant difference in ejection fraction after radiation (

Among 16 patients who were evaluable for GLS measurements, there were no statistical differences with concurrent radiation (

 = .18). According to the study authors, most patients tolerated radiation. Most experienced grade 2 skin dermatitis, although 1 patient developed grade 3 skin dermatitis. Unfortunately, 1 patient had to discontinue radiation early because of grade 3 skin dermatitis.

HER2-positive breast cancers represent 20% of breast cancer and are linked to aggressive clinical behavior and poor prognoses, according to the study authors. Although HER2 targeted therapies have dramatically shifted the treatment landscape—reducing the risk of recurrence by 50% and improving survival by 33%—these therapies are often associated with cardiotoxicity.

Following neoadjuvant HER2-targeted therapy, adjuvant T-DM1 is the current standard of care in this setting. However, this targeted treatment is linked to an increased risk of cardiotoxicity, specifically a decline in left ventricular ejection fraction (LVEF). According to a pooled analysis from 7 metastatic breast cancer trials assessing T-DM1, there was a 3.37% incidence of congestive heart failure (CHF), cardiac ischemia, cardiac arrhythmia, or grade 1/2 LVEF drop with this treatment.

Moreover, patients who are at a high risk of recurrence often receive adjuvant breast radiation. Breast radiotherapy is also associated with a long-term risk elevation for cardiac disease, for even 10 years post therapy. The HERA trial (NCT00045032), which assessed adjuvant trastuzumab (Herceptin), revealed that patients who received trastuzumab in conjunction with concurrent radiation therapy had higher rates of cardiotoxicity than those receiving trastuzumab alone (left sides > right sides), thought the rates were not found to be statistically significant. A multivariate analysis of the study did not highlight baseline cardiovascular risk factors as significant risk factors for this toxicity, but radiation therapy did demonstrate a borderline correlation (HR, 1.258; 95% CI, 1.00-1.58; 

As T-DM1 is increasingly being used in the adjuvant setting, and with a lack of sufficient evidence surrounding the cardiotoxicity of the agent in combined use with radiotherapy, investigators sought to understand the combination’s cardio-toxic effects in patients with early-stage breast cancer.

In this study, investigators conducted a review of clinical database to identify patients who had received adjuvant T-DM1 with recurrent radiotherapy for patients with stage I-III breast cancer between January 2020 and January 2022. Age, date of diagnosis, history of cardiac disorders, echocardiogram findings, radiation dose, final pathologic stage, and molecular subtypes of cancer, were all clinical parameters. All evaluated patients had ejection fraction. Moreover, GLS, which the authors described to be a more sensitive and reproducible indicator of cardiac dysfunction than LVEF, was also collected.

Ultimately, 38% (n = 12), 50% (n = 16), and 12% (n = 4) of patients developed grade 1, 2 or 2, radiation dermatitis, respectively.

Study authors acknowledged that the sample size was small for this study; however, they asserted that the data still strong clinical implications and should be assessed on a broader scale.

George MA, Farooq F, Cason D, et al. Evaluating the risk of cardiotoxicity associated with concurrent trastuzumab emtansine (TDM1) and radiation therapy in patients with early-stage HER2 positive breast cancer. Presented at: San Antonio Breast Cancer Symposium 2022; December 6-10, 2022. San Antonio, TX. Abstract P5-07-08. 

Patients with early-stage, HER2-positive breast cancer who received both adjuvant ado-trastuzumab emtansine and concurrent radiotherapy did not experience a significant drop in ejection fraction or global longitudinal strain. 
 


Adjuvant T-DM1 With Concurrent Radiotherapy Is Not Associated with Cardiotoxic Concerns in Early-Stage HER2+ Breast Cancer

Black mulberry extract was more effective than sodium bicarbonate in significantly decreasing oral mucositis and dry mouth symptoms in patients receiving chemotherapy, according to findings published in the 

 Moreover, the intervention also yielded significant improvements in weight gain compared with controls.

In both the intervention (black mulberry extract) and control (sodium bicarbonate) group, there was a statistically significant decrease in mean scores in an oral assessment guide at 1-, 7-, and 15-days post-intervention (

 = .001). According to the Oral Assessment Guide, the mean scores in the intervention group at days 1-, 7-, and 15- was 1.92 (standard deviation [SD], 0.45; range, 1-3), 1.53 (SD, 0.32; range 1-3), and 1.21 (SD, 0.21; range, 1-3). In the control group, the mean scores at the same follow-up intervals were 2.06 (SD, 0.38; range, 1-3), 1.9 (SD, 0.27; range, 1-3), and 1.77 (SD, 0.76; range, 1-3).

In the Radiation Therapy Oncology Group/European Organization for Research and Treatment of Cancer (RTOG/EORTC) Late Radiation Morbidity Scoring Schema, the mean scores for dry mouth in the intervention group were 2.18 (SD, 0.5; range, 0-3), 1.31 (SD, 0.71; range, 0-2), and 0.54 (SD, 0.03; range, 0-1) and the mean scores in the control arm were 2.45 (SD, 0.75; range, 0-3), 2.05 (SD, 0.51; range 1-3), and 1.55 (SD, 0.51; range 1-2).

Investigators also determined that the weight gain in was significantly higher on days 7 and 15 among patients receiving the mulberry extract than among patients receiving the sodium bicarbonate. The mean scores in the experimental group, on days 7, and 15, were 65.3 (SD, 8.79), and 66.7 (SD, 7.98), and in the control group, were 68.47 (SD, 12.54), and 68.76 (SD, 12.51).

“Results from this study suggest that black mulberry extract may be effective in preventing or reducing mucositis for patients receiving chemotherapy and may also support weight gain," wrote Tuba Karabey, BSc, MSc, PhD, RN, assistant professor in the Faculty of Health Science at Tokat Gaziosmanpasa University and co-investigators, in the study.

“It is important to educate nurses and raise awareness about the use and importance of black mulberry extract in symptom management for patients with cancer [as] it is believed that recommending black mulberry extract to patients and their families for managing symptoms of oral mucositis and dry mouth, and continuing to apply it when they are discharged, can be effective in symptom control,” study authors added.

Chemotherapeutics agents—which suppress the growth and maturation of cells, disrupting the primary mucosal barrier in the mouth and throat—are often associated with oral mucositis. Oral mucositis can be linked to erythema, edema, bleeding, ulcerations, and hoarseness, as well as difficulty with breathing, chewing, and swallowing. It can also lead to inadequate nutrient intake, malnutrition, and communication problems, as of which can cause negative effects on a patient’s quality of life.

Black mulberry has been investigated in various settings as a management strategy for oral mucositis. The extract contains papiriflavonal A, kuraridin, saforaflavanon D, and saforaiso flavanon A—all of which have demonstrated antifungal and strong antimicrobial activity and are known to be effective in treating mouth and dental wounds. Black mulberry molasses demonstrated efficacy in decreasing oral mucositis in patient undergoing head and neck radiation, and black mulberry syrup reduced the toxicity in patients with obstructive pulmonary disease unrelated to cancer. However, Harman et al, found that black mulberry syrup did not prevent oral mucositis in patients undergoing stem cell transplantation,

 and Sari et al, found that the syrup did not reduce the toxicity in patients receiving head and neck cancer radiation.

The purpose of this study, therefore, was to assess the efficacy of black mulberry extract compared to sodium bicarbonate. In Turkey, where this study was conducted, sodium bicarbonate is one of the most common substances used to prevent mouth sores in patients undergoing chemotherapy (54.2%). Other common substances include chlorhexidine gluconate mouthwashes (68.2%); saltwater (51.7%); sage, chamomile, and fennel tea (46.7%); water with lemon (27.5%); black mulberry molasses (26.7%); honey (24.2%); and turmeric (17.5%).

A sample size of 40 patients were randomly assigned to either the sodium bicarbonate or black mulberry extract group. All patients were inpatients on the oncology unit, 18 years or older, and receiving their first course of treatment with methotrexate chemotherapy. The dose of methotrexate was 3.5 g/m

 of which was administered in 1000 mL 0.9% sodium chloride over 15 minutes, and the remaining 3 g/m

In the control group, nurse researchers applied 10 cc of 8.4% sodium bicarbonate mouthwash for 30 seconds 3 times daily for 15 days. In the intervention group, nurse researchers applied 5 ml of black mulberry extract for 60 seconds 3 times daily for 15 days. The extract contained ripe black mulberry fruit, citric acid, and about 9% fruit sugar. It did not contain glucose or preservatives. Patients were instructed not to consume anything within 15 to 20 minutes of extract application so as to not disturb the mucosal lining. Of note, the extract, which is approved by the Turkish Ministry of Agriculture and Rural Affairs, is not approved for the treatment of oral mucositis in the United States, but can be purchased by US residents through various online retailers, pharmacies, and grocery stores.

Based on the findings, study authors noted that nurses should educate patients about the potential benefits of complementary and nonpharmacologic treatments for symptom management, and to consider black mulberry extract in patients receiving chemotherapy.

Black mulberry extract represents a “cost-effective, evidence-based option to prevent oral mucositis caused by chemotherapy,” study authors concluded.

Karabey T, Karagözogli Ş, Aygün N, Sümer Z. The effect of oral care with black mulberry extract on oral mucositis, dry mouth, and weight gain in patients with cancer. 

. 2022;26(6):636-642. doi:10.1188/22.CJON.636-642

Harman M, Ovayolu N, Ovayolu O. The effect of three different solutions on preventing oral mucositis in cancer patients undergoing stem cell transplantation: a non-randomized controlled trial: a Turkish study - NON-RANDOMISED TRIAL. 

Yuce Sari S, Beduk Esen CS, Yazici G, Yuce D, Cengiz M, Ozyigit G. Do grape and black mulberry molasses have an effect on oral mucositis and quality of life in patients with head and neck cancer? 

. 2022;30(1):327-336. doi:10.1007/s00520-021-06411-6

Black mulberry extract may help patients manage oral mucositis, dry mouth, and weight gain, while receiving oral cancer medications.

Black Mulberry Extract Shows Efficacy in Oral Mucositis Management for Patients Receiving Chemotherapy 

Acupuncture should be recommended for aromatase inhibiter (AI)-related joint pain, according to a panel of experts across the Society of Integrative Oncology (SIO) and the American Society of Clinical Oncology (ASCO).

Moreover, acupuncture, reflexology, or acupressure may all be recommended for general cancer pain or musculoskeletal pain, and hypnosis may be recommended for those who experience procedural pain. Massage may also be recommended to those experiencing pain during palliative or hospice care.

These recommendations, which were published as part of a guideline update in the 

, note that the quality of evidence is low for mind-body interventions or natural products, and that the body of evidence is insufficient to make integrative medicine recommendations for pediatric patients. Authors also stated that more research is needed to better define the role of integrative medicine interventions throughout the cancer continuum.

An ASCO/SIO expert panel outlined evidence supporting integrative therapies for adults. There is insufficient evidence in the pediatric population.

Adverse Event Management