Results of a real-world analysis of patients with hepatocellular carcinoma (HCC) who received single-agent lenvatinib (Lenvima) showed that dose adjustments made during treatment course were feasible and starting patients at a lower dose did not effect outcomes. A poster on the data were presented during the 2022 International Liver Cancer Association Conference.

The recommended starting dose of lenvatinib for patients with HCC is based on body weight: patients weighing 60 kg or more receive 12 mg once daily and those weighing less than 60 kg receive 8 mg once daily. The retrospective study assessed the effect of adjusting the dosage of lenvatinib using data from 6 oncology centers in Hong Kong, China.

In 174 patients, 88 (50.5%) started lenvatinib at a lower dose and 86 (49.5%) started lenvatinib at the recommended dose. The median overall survival (OS) was 9.7 months (95% CI, 9.0-10.9) in the low-dose group and 7.6 months (95% CI, 5.6-13.5) in the recommended-dose group. The difference was not significant between the group with an HR of 0.882 (95% CI, 0.60-1.30; 

“In real-world practice, it is evident that clinicians may start lower doses of lenvatinib for selected patients and/or adjust the dose during treatment according to patients’ conditions and adverse events,” the authors of the study wrote in a poser of the findings. “There are no data on the clinical impact of dose adjustment during treatment course.”

In terms of dose-adjustment data, patients were placed in group A (n = 45) defined as having had dose escalation following either a lower starting dose or previous dose reduction during treatment or group B (n = 132) defined as having had never experienced dose escalation during treatment.

The median OS was significantly better for those who had dose escalation during treatment, with a HR of 0.31 (95% CI, 0.18-0.53; 

< .0001). In group A the median OS was 15.8 months (95% CI, 12.1-30.6) vs 8.0 months (95% CI, 6.4-9.5) for group B. “Patients with dose escalation during treatment remains an independent prognostic factor for OS after adjustment with other known significant prognosticators such as performance status, ALBI grading, portal vein thrombosis, and alpha fetoprotein,” the authors wrote.

In the study, 126 (71.2%) patients were Hepatitis B surface antigen–positive. Most patients had the following characteristics: Child-Pugh score A (n = 134; 75.7%), albumin-bilirubin grade 2 (n = 127, 71.8%) and BCLC stage C (n = 147; 83.0%). Over one-third of patients had advanced disease.

Investigators advised clinicians should assess patient’s conditions and determine if dose escalation of lenvatinib is a practical option, especially for those who had prior dose reduction during treatment or started with a lower dose at baseline than recommended. Introduced in 2007, sorafenib (Nexavar) was the first multikinase inhibitor approved for first line treatment of HCC. Lenvatinib was approved 2018 after showing noninferior but not statistically superior results compared with sorafenib in the REFLECT (NCT01761266) trial.2,3

A common adverse event with lenvatinib, unlike other TKIs, is associated with thyroid toxicity and monitoring for thyroid abnormalities during treatment is advised. Patients with HCC most commonly experience the adverse reactions (incidence ≥ 20%) of hypertension, fatigue, diarrhea, decreased appetite, arthralgia/myalgia, decreased weight, abdominal pain, palmar-plantar erythrodysesthesia syndrome, proteinuria, dysphonia, hemorrhagic events, hypothyroidism, and nausea.

Chan LL, Mo FKF, Law ALY, et all. Impact of dose adjustment on clinical outcomes of Lenvatinib-treated patients with advanced hepatocellular carcinoma (HCC). Poster presented at: 16th Annual International Liver Cancer Association Conference; September 1-4, 2022; Madrid, Spain. Accessed September 7, 2022. 

Feng MY, Chan LL, Chan SL. Drug treatment for advanced hepatocellular carcinoma: first-line and beyond. 

.2022;29(8):5489-5507. doi:10.3390/curroncol29080434

Lenvima. Prescribing information. Eisai Inc; 2021. Accessed September 7, 2022. 

Articles

In a real-world analysis of patients with hepatocellular carcinoma, the median overall survival with lenvatinib was 9.7 months in the low-dose group and 7.6 months in the recommended-dose group.

Lenvatinib Dose Escalation Is Associated With Favorable Outcomes in Patients with HCC

Results of retrospective analysis of previously treated patients with metastatic renal cell carcinoma (mRCC) who received nivolumab (Opdivo) in the second- and third-line showed that health-related quality of life (HRQOL) was maintained in the real-world setting. Results of the analysis were presented in a poster during the 

“Across all evaluated FKSI-19 and EQ-5D-3L scores, changes from baseline did not extend beyond the respective thresholds for clinically meaningful changes at any timepoint,” study authors wrote in a poster of the data. “These real-world findings add to the evidence base from the randomized, controlled CheckMate 025 trial [NCT01668784], and further our understanding of the impact of nivolumab on HRQOL in patients with previously treated mRCC.”

Investigators performed a pooled data analysis, IO-Synthesise RCC, using findings from the prospective real-world studies WITNESS (NCT03455452) and NORA (NCT02940639). Patients enrolled in the French WITNESS (n = 105) and the German NORA (n = 201) studies were aged 18 years or older at the start of nivolumab monotherapy and received treatment for mRCC as second- or third-line therapy. Patients were excluded if they received prior anti–PD-1/PD-L1 or ant-CTLA4 therapy.

Measurements used to analyze HRQOL outcomes were FKSI-19, which assesses kidney cancer disease-related symptoms, and EQ-5D-3L, which measures health status in the groups of mobility, self-care, usual activities, pain along with discomfort, and anxiety/depression. Higher scores from both measurement instruments indicate a better state of health and EQ-5D-3L also looks at the patient’s self-rated health on a visual analog score (VAS). FKSI-19 scores were very similar in the categories of disease-related symptoms (DRS); DRS-emotional (DRS-E); DRS-physical (DRS-P); functional well-being (FWB); treatment side effects (TSE).

Completion rates were comparable between the 2 assessments over time. FKSI-19 completion rates at week 6 ranging between 76.7% and 77.4% and completion rates at month 18 between 47.5% to 48.5%. For EQ-5D-3L week 6 rates were between 71.4% and 74.9% and were 46.5% at month 18.

Score ranges in the FKSI-19 assessment were: total score (range, 0-76); DRS (range,0-36); DRS-P (range, 0-48); DRS-E (range, 0-4); TSE (range, 0-12); FWB (range, 0-12). The baseline FKSI-19 scores were similar between the 2 studies. The pooled analysis mean scores were as follows:

Outcomes from the EQ-5D-3L assessment showed variation between the 2 studies. In terms of utility index (range, 0-1), the baseline score in the WITNESS study was 0.66 (SD, 0.30) compared with 0.69 (SD, 0.30) in the NORA study. The baseline VAS scores (range, 0-100) were 63.62 (SD, 18.52) and 56.64 (SD, 26.59), respectively.

“From months 6 to 9 onward, there was a numerical trend toward improved FKSI-19 total

and DRS subscale scores and a numerical trend toward worsened VAS, although these

changes did not reach the threshold for clinical meaningfulness,” the investigators wrote.

Although a notable number of patients were missing components of baseline data that may have affected HRQOL analysis, investigators reported that of the patients with available baseline data, 206 of 273 (75.5%) had a Karnofsky performance score (KPS) of more than 70%. Additionally, 262 of 302 (86.8%) had clear cell histology, and 240 of 303 (79.2%) had undergone previous nephrectomy.

Patients in the combined studies has a median age of 70 years (range, 38-89), 74.5% were men, and 83.3% of patients received nivolumab as second-line therapy. Prior to nivolumab treatment, 82.7% of patients reported receiving prior tyrosine kinase inhibitors, most common were sunitinib (Sutent; 55.9%) and/or pazopanib (Votrient; 51.6%).

There was some inconsistent data in the 2 groups before it was pooled including KPS where 62.4% of patients in the WITNESS study had a score greater than 70% and 83.1% of NORA patients had a score more than 70%. Patients who had previous nephrectomy were 65.7% compared with 86.4%, respectively. The stage of disease at initial diagnosis also had notable differences before the data was combined: 13.5%, 32.4%, 10.8%, and 43.2% of patients in the WITNESS study had stage I, II, III, and IV disease, respectively. These rates were 11%, 23.1%, 31.3%, and 34.6%, respectively, in the NORA study.

Limitations included bias that may occur during the real-world routine care in each country, the EQ-5D-3L utility index scores that were derived using a UK-based value set not specific to either group, or varying practice patterns in each country. The difficulty of collecting HQROL outcomes in a real-world setting also affected the pooled data as the collection of it was not mandatory in the WITNESS study resulting in a smaller sample size.

“Because there are limited data, additional exploratory analyses will be conducted on this data set to further investigate the relationship between baseline clinical factors along with clinical outcomes and HRQOL outcomes,” the authors concluded.

In CheckMate 025 nivolumab demonstrated efficacy as well as HRQOL outcomes compared with the agent everolimus (Afinitor). Specifically, patients who received nivolumab had an increase through week 136 in mean changes from baseline in Functional Assessment of Cancer Therapy–Kidney Symptom Index–Disease Related Symptoms score compared with those who received everolimus arm, who experienced a decrease. Scores using the EQ-5D for utility index and VAS showed improved outcomes for patients receiving nivolumab from baseline to week 104 vs those who received everolimus arm who had a decline in scores.

Guillaume M, Bedke J, Albigès L, et al. IO- Synthesise RCC: analysis of real-world health-related quality of life outcomes with nivolumab for previously treated metastatic renal cell carcinoma using pooled data from France and Germany. Poster presented at: 2022 European Society for Medical Oncology; September 9-13, 2022; Paris, France.

Results of retrospective analysis of previously treated patients with metastatic renal cell carcinoma who received nivolumab in the second- and third-line showed that health-related quality of life was maintained in the real-world setting

Real-World HRQOL Findings Support Nivolumab for Previously Treated mRCC

Cannabinoids are becoming more popular for patients with cancer as a pain management strategy. However, with inconsistent laws across states and federal bodies, it can be difficult for nurses and patients to comfortably discuss cannabinoids and cannabinoid use.

As the public perception and patient success stories with unconventional, alternative, and natural therapeutics shift consumer attitudes, it is important for nurses and their patients to understand the differences in the products and the adverse effects associated with each. According to a study by Butler et al in 2021, nearly half of individuals who participated in a survey who had consumed cannabidiol (CBD) did not disclose use to their health care provider.

“We see a lot of patients who have been trying to talk to us about CBD [cannabidiol], and cannabinoids and THC, [tetrahydrocannabinol]” Karen Hande, PhD(c), DNP, ANP-BC, CNE, FAANP, ANEF, a professor of nursing at Vanderbilt University School of Nursing, said in a presentation during the Oncology Nursing Society Bridge.

Although Hande stated in her presentation that she was no expert in cannabinoids or medical cannabis, her clinical research primarily focuses on helping patients effectively manage their cancer-related pain. Therefore, she has become very interested in cannabis and has dedicated a lot of time and research to best understand the evidence-based data that exists for these products. In her presentation, “Cannabinoids for Patients With Cancer,” Hande discussed the available evidence on CBD and the possible risks, particularly in vulnerable populations.

“I think it’s just important for under us to understand a kind of broad overview about cannabinoids and THC and CBD, because this gives us a better understanding of where the laws come into play,” Hande said. She added, “It took me quite some time to try to understand all the differences and trying to make sure I give the correct information to my patients.”

A key concept for oncology nurses to understand, according to Hande, is the variations of cannabinoids.

Cannabinoids are compounds found in the cannabis plant. These compounds interact with the human endocannabinoid system. The exact relationship still required further understanding.

“Cannabis has many names for [many] strains, and hemp and marijuana are under this big umbrella of cannabis plants; they are all considered to be 1 species: the cannabis sativa plant,” she said. “This is a genus of flowering plants. And these can contain about over 100 phytocannabinoids, [and] they have a wide range of effects on the body in the brain.”

The following products are derived from cannabis: marijuana, hemp, THC, and CBD. In addition, there are man-made synthetic cannabinoids (K2/Spice); however, these agents are designed to mimic the mind-altering effects of illicit drugs. For her talk, Hande chose to focus on the products derived from the plant itself, as oncology nurses are more likely to encounter patients using plant-derived products.

If a patient reports marijuana use, this means they are using the dried flowers, leaves, stems, and seeds of the cannabis plant. Marijuana is also known as cannabis, weed, pot, or dope. Specifically, it can be defined as a plant with at least 0.3% delta-9 THC by weight. It is consumed by smoking (joints, blunts, bongs), vaping (vaporizing electronics devices), or by mixing or infusing it into foods or drinks (edibles).

“This is an important differentiating factor that I’ll be highlighting regularly through this talk,” Hande said during her presentation. “Marijuana is more than 0.3% of THC by weight.”

Marijuana is the most used federally illegal drug in the United States, with approximately 18% of Americans reported using it at least once in 2019 (~48.2 million Americans).1

Because marijuana has THC, it is associated with the following health risks: alterations in memory, learning, attention, decision-making, coordination, emotion, and reaction times.2 In terms of long-term health, marijuana has been linked to an increased risk of psychosis and schizophrenia,3 and, like other drugs, it’s use during pregnancy may increase the risk of embryo-toxicities.4 Moreover, this drug, depending on where it is sourced, may be laced with other substances. Consumers may or may not be aware of other substances in their product.

Using marijuana in combination with other agents may also result in impairment and can increase the risk of overdose.

Federally, marijuana is illegal as a recreational drug. It is classified as a schedule 1 drug, per the Drug Enforcement Agency. Although it is legal in some states for medical for nonmedical adult use, this does not mean that is safe, Hande noted. Specifically, smoking marijuana can expose users to harmful chemicals, and insufficient evidence exists to document the safest method for consuming.

Legally, hemp must contain a THC concentration of less than 0.3% by dry wright. It is the same species of plant as the cannabis plant and, along with bamboo, it is one of the fastest growing plants on Earth. There are almost no restrictions on hundreds of compounds made by the plant. Industrial hemp is cannabis sativa plant grown specifically for industrial or medicinal use.

“Many states across the country have hemp cultivation,” Hande said. “This allows cultivation of hemp from commercial or research or pilot programs. There are only a few states that do not allow cultivation of hemp.”

In 2018, the farm bill legalized the production and sale of hemp and its extracts, removing the product from the controlled substance act. Of note, per federal law, hemp cannot contain greater than 0.3% THC. If the concentration of THC surpasses this measurement, it is classified as marijuana.

As of September 2022, 47 states have enacted legislation to establish hemp production programs or cultivation research.

THC is a compound of the cannabis plant. This psychoactive agent causes, what is known as a high. It is consumed via dabbing—a specific method for inhaling THC concentrates.

Unfortunately, the concentrated forms of THC mean that there is an increased risk of additives or contaminating substances existing in the product.

CBD is another active cannabinoid found in the cannabis plant. This agent is not psychoactive and consequently does not cause a high.

CBD can be derived either directly from the cannabis plant or from a hemp product. The key difference between cannabis- and hemp-derived CBD is the concentration of THC. Hemp-derived CBD must have a THC concentration less than 0.3% to be federally legal. CBD products containing greater concentrations are federally illegal but are legal under some states.

“The main difference between cannabis and hemp-derived CBD is the amount of THC that it can contain,” Hande stressed. “Hemp-derived CBD includes less than 0.3% of the THC. [Therefore,] it’s federally legal to use hemp-derived CBD, but CBD products that contain more than 0.3% of THC are federally illegal. This is where the conflict between the state and the federal laws [can arise].”

The extraction process for CBD and THC are similar; farmers harvest the hemp and it is sent to an extractor. If the extraction is not performed with pharmaceutical grade standards, the CBD may become contaminated with THC, chemical solvents, or even pesticides. This is compounded by the fact that the US does not hold CBD supplies to a standard, and federal enforcement is lacking.

CBD can be converted into delta-8-THC, delta-9 THC, and other THC isomers through a solvent, acid, and heat. These products end up with higher concentrations of delta-8 THC than those which occur naturally in the cannabis plant. Consequently, these products may create harmful by-products that presently are not well-characterized.

Delta-8 THC products are increasing in popularity, in both marijuana- and hemp-based markets. It is appearing in markets that are operating legally under state, territorial, or tribal laws.

As of 2022, most states and territories permit full and restricted marketplaces where consumers can purchase hemp and hemp-derived CBD products.

According to Hande, there are a wide variety of delta-8 THC-containing products in the market. For example, vapes, smokable hemp sprayed with delta-8 THC extract, distillates, tinctures, gummies, chocolates, and even infused beverages can fit into this category. Moreover, the testing method for these products are still under development. This means that Delta-8 THC products may not be systematically tested for contaminants such as heavy metals, solvents, or pesticides which can cause adverse health effects.

How to Talk to Your Patient About Cannabinoid Use

Nurses hold a key role in discussing not only the risks of cannabinoid use but providing educational information for the safe consumption. Should a patient be interested in trying CBD products, counsel on the lack of evidence, contaminants, misleading labels, and legal issues of surrounding use. One approach to counter the “buyer beware” notion is to provide evidence-based patient education and to screen for any drug/drug interactions that may occur should the patient consume CBD products.

Additionally, assessing the patient’s baseline knowledge base before use will be beneficial and open communication may help establish trust and increase reported use between the patient and the health care provider. Finally, addressing the topic early on in care may remove the barrier of the stigma surrounding cannabinoid use.

Hande concluded by adding that many trials are ongoing in the cannabinoid arena and that results are expected to be published over the next several years. She noted that the oncology nurses should be up-to-date on the latest findings to provide guidance.

Marijuana and public health data and statistics. Centers for Disease Control and Prevention. June 8, 2021. Accessed September 14, 2022. bit.ly/3ROqaoi

Testai FD, Gorelick PB, Aparicio HJ, et al. Use of marijuana: effect on brain health: a scientific statement from the American Heart Association. 

. 2022;53(4):e176-e187. doi:10.1161/STR.0000000000000396

Di Forti M, Quattrone D, Freeman TP, et al. The contribution of cannabis use to variation in the incidence of psychotic disorder across Europe (EU-GEI): a multicentre case-control study. 

. 2019;6(5):427-436. doi:10.1016/S2215-0366(19)30048-3

Health effects of marijuana and cannabis-derived products presented in new report. National Academies. January 12, 2017. Accessed September 14, 2022. 

Karen Hande, PhD(c), DNP, ANP-BC, CNE, FAANP, ANEF, explains the difference between some of the popular cannabinoid products that patients with cancer may be taking.

Oncology Nurses: What Cannabinoid Is Your Patient Taking?

A combination of pembrolizumab (Keytruda) and soluble EphB4-human serum albumin (sEphB4-HSA) may elicit superior overall survival (OS) and objective response rates (ORR) in patients with platinum-refractory metastatic urothelial carcinoma than PD-1/PD-L1 therapy alone, according to findings from a phase 2 trial (NCT02717156) published in the 

At a median follow up of 22.9 months (range, 1.3-54.7) in the intention-to-treat (ITT) analysis, the median OS was 14.6 months (95% CI, 9.2-21.5); the 

 value was .014 for rejecting the null hypothesis that the median survival would be 6.9 months or less. The median progression-free survival (PFS) was 4.1 (95% CI, 1.5-5.7) months, and 26 (37%) patients had an objective response (95% CI, 26%-48%).

The regimen also had acceptable toxicity, and the tolerability monitoring boundary was not crossed, with a total of 11 events in 11 patients.

“The combination of sEphB4-HSA and pembrolizumab can be administered with acceptable toxicity and improves key efficacy end points especially in [the] sEphB4-HSA drug target (EphrinB2)–positive subgroup and forms the basis for further investigation in high-grade urothelial carcinoma,” lead study author Sarmad Sadeghi, and coauthors, wrote in the publication.

Poor outcomes are associated with metastatic urothelial carcinoma following failure on standard frontline chemotherapy, and approved PD-1 inhibitors have low response rates in the second-line setting.

EphB4 is highly expressed in urothelial cancer and leads to increased tumor cell invasion, proliferation, and survival. Interaction of high EphrinB2 in tumor vessels and EphB4 on tumor cells promotes angiogenesis and impedes immune cell traffic into the tumor. sEphB4-HSA binds EphrinB2 and inhibits bidirectional signaling and tumor growth and increases immune cell trafficking into the tumor.

In preclinical models, the combination of sEphB4 and PD-1 inhibition was more active than either agent alone, supporting further evaluation.

In this phase 2 trial, 70 patients with metastatic urothelial carcinoma that recurred or progressed after platinum-based chemotherapy received sEphB4-HSA in combination with pembrolizumab.

To be eligible for enrollment, patients had to be at least 18 years of age and have histologically confirmed urothelial carcinoma with disease progression after platinum-based chemotherapy for advanced disease or recurrence within 12 months of receiving platinum-based adjuvant or neoadjuvant therapy for localized muscle-invasive disease; at least 1 measurable lesion according to RECIST v1.114 criteria, and an ECOG performance status (PS) of 0 or 1.

Patients received 200 mg of intravenous (IV) pembrolizumab once on day 1 and 10 mg/m2 of IV sEphB4-HSA once daily on days 1, 8, and 15 every 3 weeks. Treatment was continued until RECIST-defined disease progression, development of unacceptable toxicity, patient or investigator decision, or the completion of 2 years of therapy.

The primary end points of the trial were tolerability and OS. The secondary end points were PFS, ORR, duration of response (DOR), and toxicity.

The median age of participants was 67 years. Sixty-four patients received only 1 prior line of therapy; 6 patients received more than one line of therapy. Baseline sites of disease included the lymph nodes (n = 45; 64%), lungs (n = 24; 34%), liver (n = 18; 26%), and bone (n = 9; 13%).

Thirty-nine patients (56%) had an ECOG PS of 0 and 31 (44%) patients had an ECOG PS of 1. Stratification of Bellmunt risk demonstrated that 27% of patients had no risk factors, 37% had 1 risk factor, and 36% had 2 or more risk factors. Fourteen (20%) patients had upper-tract disease as their primary site of disease. Forty-six (66%) patients were EphrinB2 positive.

The median duration of therapy was 15 weeks (range, 3-120). Eight patients remain on treatment, and 37 patients (60%) discontinued treatment because of disease progression. Of the 25 patients who stopped treatment for reasons other than progressive disease, 15 remain without subsequent systemic treatment and 21 received subsequent systemic therapy.

Additional results indicated that at a median follow-up of 22.5 months (range, 3.5-54.7) among the patients with EphrinB2 expression, the median OS was 21.5 months (95% CI, 12.4–not reached), and the median PFS was 5.7 months (95% CI, 2.7-27.9). The ORR was 52% (95% CI, 37%-67%), which included a complete response rate of 24% (n = 11 of 46; 95% CI, 12%-36%).

Notably, response was maintained at 6, 12, and 24 months in 88%, 74%, and 69% of the patients, respectively.

The median DOR was not reached in either the ITT population or the EphrinB2-positive cohort.

Any-grade adverse effects (AEs) occurring in at least 10% of patients included hypertension (n = 52; 74%), fatigue (n = 31; 44%), anemia (n = 12; 17%), anorexia (n = 9; 13%), headache (n = 9; 13%), nausea (n = 9; 13%), proteinuria (n = 8; 11%), rash (n = 8; 11%), hyperuricemia (n = 7; 10%), increase in aspartate aminotransferase (AST; n = 7; 10%), and pruritus (n = 7; 10%).

Six patients (8.6%) discontinued treatment because of grade 3 toxicity: arthralgia (n = 1), edema (n = 1), abdominal pain (n = 1), and supraventricular tachycardia (n = 1), increase in AST and alanine aminotransferase (n = 1), and endocrine disorder (n = 1).

Four (6%) patients died on treatment because of organ failure attributed to pembrolizumab (n = 1), aspiration pneumonia (n = 1), and overall decline in health and clinical progression of disease (n = 2). Five patients withdrew from the trial, and 6 patients discontinued therapy per the recommendation of the treating physician.

Hypertension was the most common toxicity attributed to sEphB4-HSA; 74% of patients experienced any-grade hypertension, and 46% had grade 3 or 4 hypertension.

Severe immune-related AEs included myositis in 1 patient, which resulted in death. Grade 2 pneumonitis occurred in 1 patient. Other immune-mediated AEs resolved with corticosteroids and without sequelae.

“A larger controlled phase 3 trial is required to confirm the efficacy signal observed in this study,” the study authors concluded. “A phase 2 study of this combination in metastatic urothelial carcinoma is under way, which includes a frontline cohort and an EphrinB2-positive biomarker-selected previously treated cohort (NCT04486781).”

Sadeghi S, Quinn D, Dorff T, et al. EphrinB2 inhibition and pembrolizumab in metastatic urothelial carcinoma. 

. Published online August 19, 2022. doi:10.1200/JCO.21.02923

At a median follow-up of 22.9 months, patients with platinum-refractory metastatic urothelial carcinoma achieved a median overall survival of 14.6 months with EphB4-human serum albumin plus pembrolizumab.

EphrinB2 Inhibition With PD-1/PD-L1 Immunotherapy Induces Promising Responses in Progressive Metastatic Urothelial Cancer 

Before deciding on a single treatment strategy to manage vancomycin-infusion reactions (VIR), oncology providers should consider therapeutic implications, according to a report published in the 

Journal of Hematology and Oncology Pharmacy

Gram-positive bacterial infections represent a major mortality risk for patients with cancer. Vancomycin is an antibiotic that is administered intravenously (IV) to treat bacterial infections, making appropriate use a key factor in supporting this patient population.

VIR is a well-documented hypersensitivity reaction that is common across diverse patient populations. Key signs that a patient is experiencing VIR include flushing, pruritus, chest pain, muscle spasm, and hypotension. The typical onset time of reactions is 15 to 40 minutes into the infusion; they may continue for the duration of the infusion. The typical resolution time is 30 minutes after treatment.

Severity of VIR is typically classified into 3 different thresholds. A mild reaction is when a patient can tolerate flushing and other symptoms. A moderate reaction means a patient may be uncomfortable because of flushing or pruritis but is hemodynamically stable and is not experiencing muscle spasms and chest pain. A severe reaction, on the other hand, means a patient is experiencing muscle spasms, chest pains, and hypotension.

VIR, though common, is usually mild and easily treatable. However, it has the potential to cause severe reactions in some individuals. Severe VIR is more common in patients older than 40 years.

According to study authors, best management strategies may include premedication, infusion-rate adjustment, and, in some cases, alternative antibiotic therapy.

Multiple studies have assessed the efficacy of antihistamine pretreatment to prophylaxis against VIR severity. Rapid vancomycin administration, when the infusion rate is less than or equal to 10 mg/minute, is often required in an emergency or presurgical setting, but comes with inherent risk of VIR. Both oral and IV histamine type 1 antagonists, such as hydroxyzine or diphenhydramine below 1 mg/kg, and type 2 antagonists, such as cimetidine below 4 mg/kg have demonstrated promising efficacy in reducing the effects of rapid vancomycin administration, yet patients will still require careful monitoring for subsequent doses.3-6 These H1 and H2 antagonists have also showed promising efficacy in reducing the severity of VIR symptoms in patients who have already developed moderate or severe reactions. 

Concurrent Medication and Infusion-Rate Adjustments

For patients who develop moderate or severe VIR and need to hold medication, the introduction of 50-mg diphenhydramine (oral or IV) and 20-mg IV famotidine may be appropriate, according to clinical guidelines.5 Alternatively, the use of IV fluids may be successful in achieving hemodynamic stabilization in a hypotensive patient. Once a patient has returned to their precreation clinical status, vancomycin may be reintroduced. However, a reduced infusion rate is advised.

When restarting vancomycin infusion, either a 50% reduction in rate speed or a decrease to below 1000 mg/hour, with a target of 10 mg/minute, is advised. The slower the better. One possible strategy proposed by Healy et al extends the duration time from 1 hour to 2 hours, as trough concentrations and areas under the curve are similar for both these infusion times.

 Moreover, more frequent, lower doses of vancomycin may also be an effective strategy. For example, 500 mg every 6 hours instead of 1 g every 12 hours may be preferable. However, this method may pose some relevant pharmacokinetic, workflow, and financial implications.

If vancomycin is the only effective antibiotic available for a patient who experienced VIR with the first dose, they should be pretreated with a histamine type 1 antagonist and the infusion rate should be extended so that it lasts over 2 hours.

However, for patients with a history of VIR, antibiotics with similar activity and efficacy to vancomycin may be considered. It is important to note that patients receiving these treatments will still require routine monitoring and nuanced dosing and infusion rates.

Daptomycin, a cyclic lipopeptide antibiotic, or telavancin, dalbavancin, and oritavancin, all semisynthetic lipoglycopeptide antibiotics (and vancomycin analogs), are recommended alternative treatments for patients requiring antibiotic infusion.

For skin and skin-structure infections, the recommended daptomycin dose is 4 to 6 mg/kg once daily. For bloodstream infections, the standard dose increased to 8 to 10 mg/kg once daily. The standard duration with daptomycin is 5 to 14 days.

Alternatively, telavancin is typically prescribed at 10 mg/kg once daily for at least 14 days for blood stream infections. Oritavancin and dalbavancin represent long-acting antibiotic; for skin and soft-tissue infections, their recommended doses are 1.2 g and 1.5 g, respectively.

The adverse events associated with these alternative treatments are limited and less frequent than with vancomycin. Pseudoallergic VIR symptoms may occur and are best managed with slower infusion rates.

Teicoplanin is a drug with an antibacterial spectrum like vancomycin; however, this agent is currently only used outside the United States. Its profile suggests it may be a safer alternative for patients who cannot tolerate a vancomycin-induced release of histamine. The recommended loading dose for teicoplanin is 6 mg/kg twice daily for 48 hours for complicated infection, followed by a maintenance dose of 6 mg/kg once daily. Because this treatment is not widely available, it is recommended to consider the alternatives first.

“The percentage of patients who require an alternative therapy for VIR is generally low, but considerable variability exists in this area, because rarer forms of vancomycin hypersensitivity, which can manifest as IgE-mediated [immunologic] anaphylaxis, drug-induced hypersensitivity syndrome, or linear IgA bullous dermatosis, may still necessitate such treatment,” study authors noted.

“Appropriate precautions may also be taken before the use of an alternative antibiotic therapy is considered, including slowing the infusion rate and completing relevant premedication or coadministration of H1 and H2 antagonists. For patients with a history of anaphylaxis to vancomycin, alternative therapy with nonglycopeptide antibiotic is recommended whenever possible,” they concluded.

Haque S, Cubbison C, Pucik K, Bubalo J. Vancomycin infusion reaction: a clinical and therapeutic overview

Alqahtani S, Almatrafi A, Bin Aydan N, et al. Optimization of vancomycin dosing regimen in cancer patients using pharmacokinetic/pharmacodynamic modeling

 2020;40(12):1192-1200. doi:10.1002/phar.2475

Wallace MR, Mascola JR, Oldfield EC III. Red man syndrome: incidence, etiology, and prophylaxis

Weller PF. Vancomycin hypersensitivity. UpToDate. Wolters Kluwer; 2021. AccessedAugust 25, 2022

Renz CL, Thurn JD, Finn HA, et al. Oral antihistamines reduce the side effects from rapid vancomycin infusion. 

Sahai J, Healy DP, Shelton MJ, et al. Comparison of vancomycin- and teicoplanin-induced histamine release and “red man syndrome.” 

Best management strategies for vancomycin infusion reactions may include premedication, infusion-rate adjustment, and, in some cases, alternative antibiotic therapy. 

New Research Sheds Light on Optimal Management of Vancomycin Infusion Reactions

In August 2022, the relationship between nutrition and cancer was put to the test: myths surrounding sugar, soy, and vegan diets, and their ability to improve or injure patient outcomes were debunked. Similarly, the American Society of Clinical Oncology (ASCO) released updated guidelines with recommendations for diet and exercise for patients undergoing active treatment.

Oncology nurse research took center stage as new findings showed that taxane-based chemotherapy caused hearing loss in the majority of patients with breast, gastrointestinal, gynecological, or lung cancer. 

® discussed the findings and implications in clinical practice in an exclusive interview with principal investigator Christine Miaskowski, PhD, RN.

Finally, nurses play a powerful role in improving the quality of care for patients. Hear from experts how nurses can help ensure that patients with ovarian cancer receive optimized treatment plans, as well as help create an inclusive environment for all they attend to in their practice.

Dispelling Nutrition Myths for Patients With Cancer

Entering the words nutrition and cancer into Google returns as many as 718 million hits. With an overabundance of opinions, it can be challenging to separate fact from fiction. Therefore, in this feature, Nicole Franklin, MS, RDN, CSO, LDN, a registered dietician with the American Oncology Network, calls out 3 commonly held myths about nutrition and cancer and uncovers the bottom line.

Audiological Assessments May Be Vital Component of Cancer Survivorship Care Following Chemotherapy

New research efforts led Christine Miaskowski, PhD, RN, show that most adult cancer survivors who undergo treatment with either a platinum-based chemotherapy, taxane alone, or a combined regimen of platinum- and taxane-based treatment, experience some degree of hearing loss. In an interview with 

 Miaskowski, a professor in the Department of Physiological Nursing and Anesthesia at UCSF School of Nursing, highlights what these findings mean for clinical practice.

Nurses Play Key Role in Facilitating Maintenance Therapy With PARP Inhibitors in Ovarian Cancer

®, Paula Anastasia, RN, MN, AOCN, a gynecologic Oncology Clinical Nurse Specialist for UCLA Health, offers a recap of her presentation at 

. She discusses ways in which nurses can help facilitate maintenance therapy with PARP inhibitors such as olaparib (Lynparza), rucaparib (Rubraca), and niraparib (Zejula), and emphasizes the value of germline testing for this patient population.

ASCO Outlines Recommend Aerobic and Resistance Exercises for Patients Undergoing Active Cancer Treatment

ASCO recently convened a panel of experts to conduct a comprehensive literature review of existing data regarding the role of diet, weight, and exercise in defining patient outcomes. The updated guidelines formally recommend aerobic and resistance exercises for patient with cancer, although they note that this is an area of research that continues to be overlooked in clinical trial designs.

1. Addressing Disparities: Practicing Inclusion for LGBTQ+ Patients With Cancer

Identifying and acknowledging disparities helps providers work together to improve access to care and treatment and reduce the cancer risks. Among individuals in the LGBTQ+ community there is less access to care because of a lack of inclusive health care, underrepresentation and exclusions in clinical trials, and lack of coverage for appropriate screenings.

In this feature, our partners at Cancer Care outline key ways that nurses can improve their care delivery and create a practice that is inclusive for marginalized communities.

To stay on top of all the latest news and features

Each month, we take a look back at the most popular Oncology Nursing News® stories. Here are the top 5 stories from August 2022.

Oncology Nursing News Top Stories: August 2022

Most patients with unresectable or metastatic renal cell carcinoma (RCC) about to initiate VEGF tyrosine kinase inhibitor (TKI) therapy are prescribed a reduced dose, according to a retrospective chart review published in the 

Journal of Hematology Oncology Pharmacology.

 Moreover, study results indicate that a reduced TKI starting dose may improve therapy tolerability without compromising efficacy.

Among patients treated at the Georgia Cancer Center-Laney Walker campus who received a TKI between January 1, 2015, and June 30, 2020, 66.7% (n = 28) began therapy at a reduced dose and 33.3% (n = 14) began therapy at the full dose. No differences were observed in overall survival (OS; 

“Our study revealed that the majority of current patients at our institution are being started with a reduced dose of a TKI for the treatment of metastatic RCC,” the study authors wrote. “No differences were observed in overall survival or in the number of patients with dose reductions or treatment discontinuations between those who were started with a reduced-dose TKI and those who were started with a full-dose TKI. Similar to most previous reports, the lack of deleterious effect on patients’ outcomes further supports the use of an initial reduced-dose TKI strategy.”

Patients with relapsed or metastatic RCC regularly receive VEGF TKIs as first- or second-line therapy. Approved treatment options within this class of agents include sunitinib (Sutent), pazopanib (Votrient), cabozantinib (Cabometyx), lenvatinib (Lenvima), everolimus (Afinitor), and axitinib (Inlyta). Each of these treatments is associated with adverse events of any grade, which may lead to dose reductions, interruptions, or discontinuations. In the clinical trial setting, nearly 46% of patients will require a dose reduction because of an adverse event.

In light of this, ongoing research efforts are directed toward the dose optimization of TKIs. Previous research has examined the relationship between dose reductions and alternate dosing schedules and the relation with tolerability and efficacy. However, investigators at the Georgia Cancer Center sought to assess outcomes of patients who 

Collected patient data included baseline characteristics, history of immune checkpoint inhibitor therapy before or after TKI use, drug received, initial dose, start date, and the date and reasoning for dose reduction, temporary interruption, and/or treatment discontinuation.

The study’s primary end point was the percentage of patients who received first-line treatment with a TKI at a reduced dose. The secondary end point was the relationship between a reduced starting dose and duration of therapy, incidence of further reductions or interruptions, and OS. Any decrease in dose or frequency compared with the FDA indication was classified as a reduced dose.

The percentage of patients who died was 25% among those who began with a reduced dose and 42.9% among those who began with a full dose. The percentage was clinically different, but not statistically different. More than 50% of patients survived in each arm and as a result median survival and upper limit of 95% CI could not be estimated. The median time to death among these 2 groups was 20.1 months vs 25 months, respectively (


Most patients initiating with a reduced dose (78.5%; n = 22) were prescribed their treatment in 2017 or later and approximately 100% of patients (n = 14) receiving a full dose were prescribed their regimen prior to 2017. The median duration of treatment between these 2 groups was 6.6 months vs 13.9 months, respectively (

Many patients receiving frontline therapy required at least 1 intervention. Among those in the reduced-dose group, the percentage of patients requiring reductions and discontinuation were 47.8% (n = 11) and 82.6% (n = 19), respectively. In the full-dose group, the percentages were 55.6% (n = 5) and 100% (n = 9), respectively. In both groups, the most causes of dose reductions were adverse events and disease progression.

Stitt TM, Saunders KM, Rowling BC, Waller JL, Clemmons AB. Reduced starting dose of tyrosine kinase inhibitors in patients with metastatic renal-cell carcinoma

Starting patients with unresectable or metastatic renal cell carcinoma on a reduced dose of VEGF tyrosine kinase inhibitor (TKI) therapy did not compromise survival outcomes.

Reduced VEGF TKI Dose May Be Preferable in Treating Patients With Renal Cell Carcinoma

Phase 2 findings showed that rucaparib (Rubraca) may an effective maintenance option for patients with DNA repair–deficient (DRD)-positive, metastatic 

 whose disease has progressed following platinum-based chemotherapy. Findings from the ATLANTIS trial (ISRCTN25859465), which were published in the 

, showed that patients who received the PARP inhibitor achieved extended progression-free survival (PFS).

Twelve (60%) and 20 (100%) PFS events occurred among the 20 patients enrolled in the rucaparib and placebo arms, respectively. At a median follow-up of 94.6 weeks (range, 11.4-148.9) in patients still alive, the median PFS was 35.3 weeks (80% CI, 11.7-35.6) with rucaparib vs 15.1 weeks (80% CI, 11.9-22.6) with placebo (HR, 0.53; 80% CI, 0.30-0.92; one-sided 

“In this efficacy signal-seeking phase 2 trial, we found that switch maintenance treatment with rucaparib resulted in clinically meaningful improvement in the primary end point of PFS, despite small numbers,” lead study author Simon J. Crabb, PhD, MBBS, of Southampton Experimental Cancer Medicine Centre, and coauthors, wrote in the publication.

Platinum-based chemotherapy is the standard frontline treatment for patients with metastatic urothelial cancer, but disease progression remains an inevitable reality for almost all patients, and responses are difficult to salvage even with second-line therapy.

 has since become a standard of care following frontline chemotherapy, most patients will not benefit from immunotherapy, leaving an unmet need for molecularly-directed treatment approaches.

As such, investigators conceptualized the ATLANTIS trial, which is an adaptive, multicomparison, clinical trial platform. As part of this effort, investigators are evaluating several, biomarker-selected switch maintenance therapeutic approaches for patients with metastatic urothelial cancer without disease progression after completing 4 to 8 cycles of platinum-based chemotherapy in a series of parallel, randomized, double-blind, phase 2 comparisons.

To be eligible for enrollment within the rucaparib comparison, patients had to be at least 16 years of age and have a diagnosis of stage IV (stage T4b and/or N1-3 and/or M1), histologically confirmed, DRD-positive urothelial cancer ineligible for curative-intent treatment. Patients also had to have an ECOG performance status between 0 and 2 and were required to begin study treatment within 3 to 10 weeks of completing 4 to 8 cycles of first-line platinum-containing chemotherapy. Notably, patients were excluded for cancer progression during, or at completion of, first-line chemotherapy.

Patients were randomly assigned 1:1 to receive 600 mg of maintenance rucaparib twice a day orally, or placebo, until disease progression.

Patients were determined to be DRD positive if any of the following were present: at least 10% genome-wide loss of heterozygosity and/or alteration in a defined DRD associated gene (

ATM, BARD1, BRCA1, BRCA2, BRIP1, CDK12, CHEK2, FANCA, NBN, PALB2, RAD51, RAD51B, RAD51C, RAD51D,

) and/or prior confirmation of a germline alteration in 

The primary end point of the trial was PFS. Statistical analysis targeted a hazard ratio of 0.5, with a 20% one-sided α. PFS, which was investigator assessed by RECIST v1.1 criteria, was compared between trial arms in the intention-to-treat (ITT) population, within a Cox model. Secondary end points included overall survival (OS), confirmed response rates, maximum percentage decrease in measurable disease, safety, and tolerability.

Out of 248 patients, 74 (29.8%) were DRD positive and 40 were randomly assigned.

Within the ITT population, the median age was 70.5 years (range, 53-86); 35 (87.5%) patients had a primary bladder cancer and 18 (45%) had visceral metastases. Twenty-five patients (62.5%) received prior cisplatin-based chemotherapy and 36 (90%) achieved an objective response to first-line chemotherapy.

Additional results demonstrated that 9 (45%) and 14 (70%) patients in the rucaparib and placebo arms, respectively, had died. The median OS was not reached in the rucaparib arm and 72.3 weeks (80% CI, 51.7-85.4) in the placebo arm (HR, 1.22; 80% CI, 0.62-2.38; 

One confirmed partial response occurred in one patient (5%) treated with rucaparib. No other objective radiologic responses to treatment occurred on study, in either treatment group. The maximal percentage reduction in measurable disease was comparable between treatment arms, with medians of −5.8% (interquartile range [IQR], −21.2-36.3) and −4.9% (IQR, −17.9-37.7) for rucaparib and placebo, respectively.

In the safety population (n = 39), treatment-related adverse effects (TRAEs) were mostly low grade. Patients received a median of 10 cycles of rucaparib and 6 cycles of placebo.

All-grade TRAEs of fatigue (63.2% vs 30.0%; 

 = .04), and raised alanine aminotransferase (57.9% vs 10%; 

 = .003) were more common in the rucaparib arm.

Five (26.3%) patients on rucaparib and 1 (5%) on placebo discontinued treatment because of treatment-related toxicity or patient decision. At least 1 dose reduction was required in 7 (36.8%) patients receiving rucaparib and 4 (20%) receiving placebo. No treatment-related deaths occurred.

The additional toxicity linked with treatment was consistent with previous experience for PARP inhibition, and rucaparib specifically, according to the study authors.

“Further development of PARP inhibition in metastatic urothelial cancer is now warranted,” the authors concluded. “This may require combination strategies and will require further scrutiny of patient genomic phenotypes to optimally integrate into the increasingly complex treatment pathway for this disease.”

Crabb SJ, Hussain S, Soulis E, et al. A randomized, double-blind, biomarker-selected, phase II clinical trial of maintenance poly ADP-ribose polymerase inhibition with rucaparib following chemotherapy for metastatic urothelial carcinoma. 

. Published online August 12, 2022. doi:10.1200/JCO.22.00405

Rucaparib may be a viable maintenance therapy option for patients with DNA repair–deficient positive, metastatic urothelial cancer who are unlikely to benefit from avelumab immunotherapy. 

Patients With DRD+ Metastatic Urothelial Cancer Achieve Prolonged PFS with Rucaparib Maintenance Therapy 

A regimen of olaparib (Lynparza) plus abiraterone and prednisone or prednisolone has received priority review status for the indication of metastatic castration-resistant prostate cancer (mCRPC).

 Under the Prescription Drug User Fee Act date, the regulatory decision is anticipated by the final quarter of 2022.

The FDA has granted olaparib plus abiraterone priority review status for the indication of metastatic castration-resistant prostate cancer.

Genitourinary Cancer