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

The mean cognitive and behavioral outcomes for children aged 9 years who had prenatal exposure to their mother’s cancer were within normal ranges and comparable to the general population, at a long-term follow-up published in the 

Full scale intelligence quotient (FSIQ) was not found to be different by cancer treatment types (

 = .802) were found to have a significant impact. Moreover, for children who were exposed to therapy (n = 109), no associations between the FSIQ and chemotherapeutic agent, exposure level, or timing of treatment emerged.

On average, the FSIQ score increased by 1.6 points for each week increase in gestational age at birth (95% CI, 0.7-2.5; 

“Cognitive and behavioral outcomes of 9-year-old children born to mothers diagnosed with cancer during pregnancy did not differ with norms of the general population,” wrote Indra A. Van Assche, MSc, a PhD researcher in neuropsychology at the University of Leuven, in Leuven, Belgium, and co-investigators, in the study. “We reported average group scores for all intelligence index scores, verbal and visuospatial memory outcomes, attentional functioning outcomes, and behavioral questionnaire measures. We found no impact of sex, treatment type, and cancer stage.”

Previous reports from this study suggested that fetal exposure to chemotherapy was not associated with increased central nervous system, cardiac or auditory morbidity and that the impairments that these children faced in regard to their general health and growth were comparable to the general population.

 At the same time, subtle changes in cardiac and neurocognitive measurements emphasized the importance of long-term follow-up. In this analysis premature birth was the greatest driver of cognitive development impairments.

In total, investigators used neurocognitive tests and parent-reported behavioral questionnaires to assess 151 children (mean age, 9.3 years; range, 7.8-10.6), including 96 from Belgium, 24 from the Netherlands, 9 from Italy, 6 from the Czech Republic, and 7 from New Jersey. In this set of participants, 109 (72.2%) had been exposed to chemotherapy (alone or combination with other treatment modalities), 18 (11.9%) had surgery alone, 16 (10.6%) had been expressed to radiotherapy, 1 to trastuzumab (Herceptin), and 16 (10.6%) had not been exposed to cancer treatment.

As part of the International Network on Cancer, Infertility and Pregnancy Child Follow-up study, children were assessed longitudinally at the age of 18 months, 36 months, and again every 3 years until age 18. This current 9-year analysis used FISQ, which is derived from the Wechsler Intelligence Scale for Children. Secondary outcomes were neurocognitive test scores and behavioral questionnaire results. All children also underwent a clinical neurologic and general pediatric examinations, and parents filled out a survey regarding their children general health and education level. All tests were conducted in the child’s native language.

Of note, gestational age at birth did show a positive association with full FISQ. Observations were also observed with maternal death and maternal education.

Gestational age was linked to verbal intelligence (β, 1.49 points/week; CI, 0.6-2.4; 

= .02), performance intelligence (β, 1.39 points/week; CI, 0.6-2.2; 

 = .002), and processing speed (β, 1.21 points/week; CI, 0.3-2.1; 

Moreover, maternal bereavement was linked to lower FSIQ scores (

 = .022). Children whose mothers passed away before they age 2 years demonstrated lower FSIQs (93.13 ± 12.65) than those with a surviving mother (104.08 ± 14.88). However, adjustments for gestational age caused this association to disappear (

 < .3). Of note, children whose mother passed away before they were 2 years were, on average, born earlier (33.4 weeks ± 2.7), than those whose mother passed away after they were 2 years (37.1 weeks ± 1.7) and those with a surviving mother at the time of follow-up (36.4 weeks ± 2.5; 

In terms of general health, the patient-reported health questionnaire revealed no specific group across the population. Four children had been diagnosed with attention-deficit hyperactivity disorder, 3 of whom needed supportive medication. One child was on the autistic spectrum. Thirty-one children (24.4%) received remedial care, including speech therapy (n = 17), remedial teaching at school (n = 10), a type of physical or exercise therapy (n = 4), and neurofeedback therapy (n = 1).

Study authors noted that maternal death was not associated with not associated with a specific cancer type, cancer stage, or treatment type in this study and that, therefore, children who consequently developed cognitive development problems may have been equally affected by the maternal stress or an insecure mother-child attachment as they were by treatments. Moreover, for children who were prenatally exposed to chemotherapy, maternal education level was the only driving factor in FSIQ scores; prematurity was not found to have an effect, suggesting that more research into the effect of prematurity may be warranted in a larger chemotherapy group.

“Seventeen percent of the children in this study had lost their mother (of which almost 58% died before their child turned 2 years old),” study authors concluded. “The results suggest a relationship between maternal bereavement in the first 1000 days of life and full-scale intelligence, although a larger sample is necessary to disentangle effects of maternal loss and often coinciding premature birth.”

In accordance with the study guidelines, follow-up with this group of children will continue to be ongoing until they are age 18 years.

Van Assche IA, Huis In 't Veld EA, Van Calsteren K, et al. Cognitive and behavioral development of 9-year-old children after maternal cancer during pregnancy: a prospective multicenter cohort study. 

. Published online January 12, 2023. doi:10.1200/JCO.22.02005

Amant F, Van Calsteren K, Halaska MJ, et al: Long-term cognitive and cardiac outcomes after prenatal exposure to chemotherapy in children aged 18 months or older: An observational study. 

 2012;13(3):256-264. doi:10.1016/S1470-2045(11)70363-1

An analysis of 141 children who had prenatal exposure to maternal cancer showed promising cognitive and behavioral functions at age 9 years. 

Children Exposed to Maternal Cancer Show Normal Cognitive and Behavioral Outcomes

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 

Sunitinib (Sutent) was the most cost-effective immunotherapy treatment option for patients with metastatic renal cell carcinoma (mRCC) in an analysis of the drug and other approved immunotherapy (IO)/IO-tyrosine kinase inhibitor (TKI) drug combinations using public payer acquisition costs in the United States. Notably, nivolumab (Opdivo) plus ipilimumab (Yervoy) was deemed the most effective treatment option in the model but did not meet the willingness-to-pay threshold (WTP).

Sunitinib was ranked as the least expensive treatment in the model. Its costs were estimated to be between $357,948 USD and $656,100 USD across a 10-year span. Lenvatinib (Lenvima) plus pembrolizumab (Keytruda) or pembrolizumab plus axitinib (Inlyta) were ranked as the most expensive (range, $959,302 USD-$1,403,671 USD). Nivolumab plus ipilimumab garnered the highest number of quality-of-life years (QALYs; 3.6) and avelumab (Bavenzio) plus axitinib procured the least number of QALYs (2.5).

“Our results demonstrate that sunitinib was the most cost-effective first-line strategy at a WTP of $150,000 USD/QALY, which is the threshold typically used by the US Institute for Clinical and Economic Research because of lower drug-associated costs compared with all other approved IO-IO and IO-TKI combinations,” wrote Minkyoung Yoo, PhD, of the University of Utah Health Systems, and co-investigators, in the study. “Among combination therapies, [nivolumab plus ipilimumab] was the only strategy not dominated by sunitinib. [Nivolumab plus ipilimumab] was associated with higher QALYs over a 10-year time horizon vs all other options including sunitinib.”

In the United States, the estimated incidence of renal cell cancer for 2022 was 79,000, resulting in approximately 13,900 deaths. Significant advances have been made to treat this disease, including numerous immunotherapies and IO-based drug combinations, including combinations with TKIs. These treatments have demonstrated significant improvements in response rates, progression-free survival (PFS), and overall survival (OS). However, it is important to note the rates of immune-related adverse events (irAEs), which can affect overall treatment costs and therefore warrant financial considerations. In 1 systematic review of patients with urologic cancers who received immunotherapy or IO-TKI combination therapy, the rate of any-grade treatment-related AEs was 88.3%, including an any-grade irAE rate of 42.7%.

Investigators designed a decision model with a 10-year time horizon. They included 7 different treatment strategies; these were atezolizumab (Tecentriq) plus bevacizumab (Avastin); avelumab plus axitinib; pembrolizumab plus axitinib, nivolumab plus ipilimumab, nivolumab plus cabozantinib (Cometriq), lenvatinib plus pembrolizumab, and sunitinib alone. These treatments were measured in terms of QALYs with utility values, based on the published literature. The costs include the drug acquisition costs along with the management of grade 3 or 4 drug-related adverse events.

Study authors noted that with a higher willingness-to-pay threshold, nivolumab/ipilimumab would be the most cost-effective. These results were consistent across the VA Federal Supply Schedule Service (VA FSS) and the National Average Drug Acquisition Cost (NADAC) drug costs, and whether patients were assumed to receive second-line therapy after the failure of first-line treatment.

The model included a partitioned survival model, in which patients transitioned between 3 health states, progression-free, progressive disease, and death, at monthly intervals, on the basic of parametric survival function. There were estimated from published survival curves. Cost-effectiveness was determined by incremental cost-effectiveness ratios (ICERs) by dividing the difference in cost by the difference in effectiveness between nondenominated treatments.

Regardless of the perspective and the rate of subsequent therapy, sunitinib demonstrated the lowest 10-year total costs at $467,394 USD to $726,068 USD (including medications, administration costs, and drug-related adverse events), whereas lenvatinib/pembrolizumab or pembrolizumab/axitinib showed the highest (range, $1,116,302 USD-$1,502,129).

The estimated 10-year QALYs ranged from 2.52 for avelumab/axitinib to 3.60 years with nivolumab plus ipilimumab. Atezolizumab plus bevacizumab, avelumab plus axitinib, nivolumab plus cabozantinib, lenvatinib/pembrolizumab, and pembrolizumab/axitinib were not considered in this part of the analysis because they were both less effective and more expensive than sunitinib alone, and nivolumab/ipilimumab, or a linear combination of both treatments.

The incremental cost-effectiveness ratio for nivolumab/ipilimumab, was from $297,465 USD per QALY in a model where 30% of patients were receiving second-line therapy and the V FSS was used for pricing, to $422,220 USD/QALY in a version where all patients were Medicare/Medicaid beneficiaries and were receiving second-line therapy.

According to study authors, this study differs from other publish cost-effective analyses for mRCC, including Shay et al, which deemed nivolumab/ipilimumab to be most cost-effective, but did not include sunitinib as a comparator.3 One key difference with this study is that it used the NADAC and VA FSS to determine drug prices, whereas many other published analyses used the manufacturers’ list price, which does not include discounts and rebates. Moreover, this study ran a version of the model in which all patients received second-line therapy, as well a version in which only 30% did, they also included a total of all 7 first-line approved treatments, rather than a subset of therapies.

The study authors acknowledged that extrapolating survival data to a 10-year time horizon invites uncertainty. Although they tested various potential parametric survival functions, used 6 independent clinical trials to compare each IO-TKI combination against sunitinib, this uncertainty may still be present. Moreover, the Kaplan-Meier PFS and OS curves for sunitinib vary across each of these studies. Consequently, investigators used both the highest and lowest reported median PFS time from the 6 trials. 

Finally, although the VA FSSS and Average Sales Price/NADAC may represent the actual drugs costs better than the wholesale acquisitions, study authors acknowledge that drug prices still very greatly across payers in the United States—and the study did not include out-of-pocket costs.

Yoo M, Nelson RE, Cutshall Z, Dougherty M, Kohli M. Cost-effectiveness analysis of six immunotherapy-based regimens and sunitinib in metastatic renal cell carcinoma: a public payer perspective. 

. Published online January 4, 2023. doi:10.1200/OP.22.00447

Wu Z, Chen Q, Qu L, et al. Adverse events of immune checkpoint inhibitors therapy for urologic cancer patients in clinical trials: a collaborative systematic review and meta-analysis. 

 2022;81(4):414-425. doi:10.1016/j.eururo.2022.01.028

Shay RC, Nicklawsky A, Lam ET. Comparative effectiveness of combination first-line therapies for metastatic renal cell carcinoma (mRCC).

. 2021;39 (suppl 15):e16549. doi:10.1200/JCO.2021.39.15_suppl.e16549

A decision model with a 10-year time horizon found that nivolumab plus ipilimumab was the most effective combination for patients with metastatic renal cell carcinoma, but sunitinib was the most cost-effective approach. 

Nivolumab/Ipilimumab May Be Most Effective mRCC Treatment, Sunitinib Most Cost-Effective

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

In the age of social media, misinformation of all kinds is now more easily spread than ever, whether it is intentionally spread or not. Unfortunately, misinformation about cancer is no exception. Although most false information may seem obviously fake to those in the health care industry, it can be hard for the average person to discern fact from fiction. For patients who are scared of their cancer growing or recurring, taking matters of research into their own hands is often an intuitive choice. Therefore, conversations about misinformation are becoming increasingly relevant.

There are many different myths and unproven claims related to cancer—causes, ways to prevent it, and alleged cures alike. A few of the most common specific claims include the following:

Aluminum-based antiperspirants cause breast cancer.

Eating sugar “feeds” cancer and causes it to grow.

Cancer can be cured by eating a particular diet (e.g., Gerson therapy

) or cured by consuming particular herbs or supplements (e.g., Vitamin C infusions alone,

All of the above claims, along with many others, have either been proven false, oversimplify a complex or unclear cause-effect or, in most cases, have insufficient information to establish as either true or false. Ambiguity and misleading personal anecdotes can make it easier for misinformation to spread.

There are a few important things providers can do to better support patients who have concerns about lifestyle, environmental risks, or potential alternative therapies.

 It is imperative to appreciate the perspective of a patient who is concerned about their cancer risks. Many patients do not know how or why their cancer developed. This lack of known cause and effect can often be emotionally destabilizing, as the trust they had in their bodies is now broken. Those worried about future cancer risk are often motivated to maximize their chances either of curing their present cancer or preventing a future diagnosis. Oncology workers can create a safe, nonjudgmental space for patients to voice their questions or concerns about potentially false cancer information they’ve learned through social media or well-meaning loved ones. These professionals can empathize with the fear and confusion that contradicting information can create, especially for the cancer patient with a course of treatment already underway. Building this rapport will allow the patient to feel more comfortable bringing up additional concerns in the future, both relating to popular cancer claims and in general.

Provide any available, accurate information.

 When health care providers come from a place of empathy and understanding, they are able to empower clients with accurate health information. The 

 all have excellent online resources that discuss the truthfulness of many common myths and claims. Create time to compare treatment methods that are already fully evidence-based and FDA-approved vs other methods that may have the potential to be helpful but are not yet adequately researched. This can help patients fully understand if, how, or why a treatment may work. Although it is important to empower patients to make their own choices, it would be negligent for any health care professional to allow patients to make uninformed decisions.

When helping patients learn how to better identify potential misinformation, there are a few questions for patients to ask when assessing a claim for validity, whether a social media post, article, or other means of communication.

Does the individual presenting this information have any professional background in cancer or cancer research? If the post was not written by a specific person, is there an organization connected to the post? Is this organization known within the cancer community to be a reputable source of information?

Is the individual or online post appealing to your emotions?

 Appealing to emotions is a common tactic among those who purposely spread misinformation. Research suggests that those who rely on emotion over reason are more likely to believe false information.

Does the individual or post cite a source, or do they rely on personal anecdote? 

When a loved one offers a suggestion, it may be easier to take them at their word due to established trust. But even outside of that personal relationship, it’s important to know where they learned such information as they too may have picked up false information.

What motivation does the source have to share this information with you?

 Although most individuals share information in good faith, others may have a more selfish reason to convince you of certain information. Unfortunately, there are those that use sickness of all kinds, including cancer, for personal financial gain or to collect personal information.

Additional information on deciphering cancer information online or through social media can be found on National Cancer Institute’s website 

 also offers a library of resources about 

how a person can talk to their medical team

 social worker can also help break down information patients are seeing online and navigate them to verified information outlets.

1. Antiperspirants/deodorants and breast cancer. National Cancer Institute. August 9, 2016. Accessed November 29, 2022. 

1. Does sugar feed cancer? Dana-Farber Cancer Institute. Accessed November 29, 2022, from 

3. Gerson Therapy (PDQ®)–patient version. National Cancer Institute. January 7, 2015. Accessed November 29, 2022. 

4. De Santis, Andy. Dispelling the 3 most common cancer and Diet Myths. American Institute for Cancer Research. February 9, 2022. Accessed November 29, 2022. 

5. Intravenous vitamin C (PDQ®)–patient version. National Cancer Institute. June 24, 2022. Accessed November 29, 2022. 

6. Cannabis and cannabinoids (PDQ®)–patient version. National Cancer Institute. October 14, 2022. Accessed November 29, 2022. https://bit.ly/3CpTGeq


Oncology nurses can help their patients navigate misinformation that they may find online. 

Talking With Patients About Potential Cancer Misinformation

Compared with standard of care (SOC) treatment, neither pola-R-CHP (polatuzumab vedotin-piiq [Polivy] with rituximab [Rituxan], cyclophosphamide, doxorubicin, and prednisone), nor second-line CAR-T cell therapy represents the most cost-effective option for patients with diffuse large B-cell lymphoma (DLBCL) in the United States or Canada. However, both therapies have demonstrated improvements in progression-free survival (PFS) for this patient’s population, according to findings published in the 

In 10,000 simulations, each strategy was found to be incrementally more effective than its respective SOC, but also more costly. Adding pola-R-CHP to SOC incurred an incremental cost-effectiveness ratio (ICER) of $546,956 (range, $338,797-$1,199,923) USD/quality-of-life adjusted years (QALY) and $245,381 (range, $151,671-$573,250) CAD/QALY.

The addition of second-line CAR T-cell therapy to SOC led to an ICER of $309,813 (range, $190,197-$694,200) USD/QALY and $303,163 (range, $221,300-$1,063,864) CAD/QALY. Lastly, adding both pola-R-CHP and second-line CAR-T to the SOC yielded an ICER of $488,284 (range, $326,765-$840,157) USD/QALY and $267,050 (range, $182,832-$520,922) CAD/QALY.

“Although there is great excitement regarding the important PFS improvements in the frontline and second-line treatment of DLBCL reported by the POLARIX (NCT03274492), ZUMA-7 (NCT03391466), and TRANSFORM (NCT03575351) trials, this must be tempered with a realistic consideration of the costs of these therapies and their implementation,” Abi Vijenthira, MD, SM, a hematologist in the Division of Medical Oncology and Hematology at Princess Margaret Cancer Centre in Toronto, Canada, and co-investigators, wrote in the study. “On the basis of the current prices of these therapies, we found that alone or together, they were unlikely to be cost-effective from both a US and a Canadian payer perspective.”

R-CHOP [rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone] has been the SOC for DLBCL for nearly 2 decades, and autologous stem-cell transplant (ASCT) has been a SOC for relapsed disease for even longer. Recently, data from the POLARIX trial showed that pola-R-CHP yielded a super PFS benefit to R-CHOP, although a 2-year analysis did not show a survival benefit. Of note, polatuzumab vedotin is expensive: in the United States it is listed at $15,600 per 140-mg vial; representing a $93,600 price tag for a 6-cycle treatment for a 70-kg patient, which was the model used for the analysis.

Another recent development in the DLBCL space has been the recently published ZUMA-7 trial and the TRANSFORM studies, which compared axicabtagene ciloleucel (axi-cel; Yescarta) and lisocabtagene maraleucel (liso-cel; Carvykti) to salvage chemotherapy with or without ASCT for patients with primary refractory or early relapse of DLBCL within 12 months of frontline therapy. Both trials showcased significant PFS benefits for these patients; however, follow-up remains short and long-term survival is still largely undocumented. Like polatuzumab vedotin, CAR T-cell therapy comes with a significant cost. The drug costs can range from $399,000-$410,300 USD, not including additional inpatient supportive care costs.

The FDA approved these 2 CAR T-cell agents on 

, respectively, neither has yet been approved in Canada.

Investigators constructed a Markov model to compare 4 strategies or patients with newly diagnosed intermediate-to high-risk DLBCL. The first strategy consisted of pola-R-CHP plus second-line CAR T-cell therapy for early relapse (< 12 months); the second strategy was pola-R-CHP plus second-line salvage therapy with or without autologous stem-cell transplant; the third strategy was R-CHOP plus second-line CAR-T for early relapse; and the last strategy was SOC, which consisted of R-CHOP plus second-line salvage therapy with or without ASCT.

Trial data were used to estimate transition probabilities. Investigators then calculated lifetime costs, QALYs, and ICERs from an American and Canadian payer perspective. Willingness-to-pay (WTP) thresholds were also designed for both populations. The WTP thresholds were $150,000 USD and $150,000 CAD/QALY.

In the 10,000 simulations using the American WTP of $150,000 USD/QALY, strategy 3 was the most cost-effective strategies in 0.1% of iterations and strategy 4 was the most cost-effective option in 99.9% of iterations.

Investigators then conducted a one-way sensitivity analysis comparing the first 3 strategies against the SOC. Using the range of HR reported for pola-R-CHP compared with R-CHOP in POLARIX (0.56-0.95) the therapy did not represent a cost-effective strategy even when for American patients even when maximizing for efficacy at a 4.4% improvement. The 5-year OS improvement would need to be 7.4% for this treatment to be cost-effective.

Of note, from a Canadian perspective, this strategy became cost effective if the HR was less than 0.59 translating to a 5-year OS improvement of at least 4.1% with OS rates of 78.5% vs 74.4% for the therapies, respectively.

For the CAR T-cell therapies, varying the HR across the ranges reported in the ZUMA-7 trial (0.37-0.65) did not cross the WTP for either country. This meant that even if the 5-year OS improvement for second-line CAR T-cell therapy was maximized to 7.3% for a 5-year OS rate of 47.3% vs 40.0%, second-line CAR-T cell therapy would not be cost effective over SOC in either the US or Canada. The 5-year OS improvement over SOC would need to be 9.5% or 11.3% from a US or Canadian payer perspective, respectively.

Study authors acknowledged that the model had limitations. For instance, long-term follow-up was not available for all input in the model, meaning that assumptions regarding risk of relapse and probability of cure in the frontline and relapses settings had to be made. In addition, the efficacy of second-line CAR-T has not been studied in patients exposed to polatuzumab vedotin in the frontline, and so the efficacy in this setting had to be estimated. Further, CAR T-cell therapy tends to incur additional costs with inpatient supportive care, and insurance coverage is variable, making its cost hard to estimate.

An economic analysis showed that neither polatuzumab vedotin nor CD19-directed CAR T-cell therapy are likely to be the most cost-effective for patients with diffuse large B-cell lymphoma based on their high costs and current long-term survival estimates. 

Supportive Care