Managed Care & Clinical Updates: February 2023

Revised Classification Criteria for Melanoma Are Needed

The increasing rate of melanoma diagnosis in the United States may not be due to actual disease, but possibly it is due to overdiagnosis of patients with an actual very low risk of death, authors of a new study posit. The growing numbers of melanoma diagnosis in recent years may be due to overdiagnosis of skin cancer in patients with a very low risk of death and stage I lesions that are 1 mm or smaller, according to study findings published in Cancer.

“Evidence exists that escalating melanoma incidence is due in part to overdiagnosis, the diagnosis of lesions that will not lead to symptoms or death,” the authors wrote. “Although melanoma is the most serious skin cancer, most patients have high chances of survival. There is evidence that some lesions diagnosed as melanoma would never have caused symptoms or death.”

Investigators used data from the Surveillance, Epidemiology, and End Results Program database. Patients were included in analyses if their melanoma was diagnosed in 2010 or 2011; they had negative clinical lymph nodes; and they had early-stage, small lesions. Risk of death was estimated out to 7 years—patients had to have complete 7-year follow-up data—and logistic models identified a subset of patients in this group who may have had a higher risk of death. Of the 11,594 patients in the study, 46% were women. The median (IQR) age for all participants was 58 years (range, 48-68).

“Patients with very low risk of dying from melanoma within 7 years of diagnosis were identified,” they concluded. “Such cases warrant further study and consensus discussion to develop classification criteria, with the potential to be categorized using an alternative term such as ‘melanocytic neoplasms of low malignant potential.’ ”

The median Breslow thickness was 0.45 mm (range, 0.30-0.65). Breslow depth ranges from 1.0 mm or less (skin surface) to more than 4 mm (subcutaneous fat). Stage Ia was the assigned melanoma stage in 71% of the patients. Four percent of these cases involved ulceration, 27% were mitogenic, and 45% were Clark level II.

The entire patient cohort was divided into a training set (67%) and a testing set (33%), with the testing data “reserved until after the final selection of candidate models developed using the training data.”

The authors developed 4 models—3 classification and regression tree (CART) models and 1 risk prediction model—to estimate patient outcomes using the training data set:

• Model 1A, a CART model, classified patients by age, with cutoff of 69 years.
• Model 1B was an extension of Model 1A, with second age cutoff
  of 43 years.
• Model 2, the risk prediction model, used continuous age, sex, Clark level, ulceration, and mitogenicity.
• Model 3, another CART model, classified patients by age (cutoff of 69 years), Clark level, ulceration, and mitogenicity.

“Based on final results,” they wrote, “we focused on Model 1A, 1B, and 2.”
In Model 1A, 35% of patients were classified as having a very low risk of death of 0.58% (95% CI, 0.29%-1.14%); in Model 1B, 25% had a very low mortality risk of 0.40% (95% CI, 0.16%-1.03%); and in Model 2, 25% had a very low mortality risk of 0.52% (95% CI, 0.22%-1.20%).

Overall, 2.5% of all patients died of melanoma within the 7-year follow-up.
“The favorable survival estimates we report are comparable to ultrathin melanomas with Breslow thickness ≤ 0.5 mm studied previously,” the authors concluded. “Besides physical effects of unwarranted treatment, overdiagnosis can falsely import psychological burden of disease. This retrospective study indicates the need for prospective studies to better characterize melanocytic neoplasms of low malignant potential.” 

Reference
Eguchi MM, Elder DE, Barnhill RL, et al. Prognostic modeling of cutaneous melanoma stage I patients using cancer registry data identifies subsets with very-low melanoma mortality. Cancer. 2023;129(1):89-97. doi:10.1002/cncr.34490


Concurrent Antibiotics, Steroids Raise CDI Risk in Patients With Lung Cancer Receiving EGFR-TKI Therapy

Findings from a new study shed light on the risk of Clostridioides difficile infection (CDI) among patients with lung cancer who are receiving EGFR tyrosine kinase inhibitor (EGFR-TKI) therapy. Results of the study, believed to be the first of its kind, suggest that concurrent antibiotics and systemic steroids increase the risk of CDI and that patients who become infected have higher rates of intensive care unit (ICU) admissions and mortality. The study was published in OncoTargets and Therapy.¹

CDI is relatively common in patients receiving treatment for lung cancer, the authors explained. Results of another study found that CDI is the cause of nearly a quarter of all diarrhea cases among patients receiving chemotherapy for lung cancer.² TKIs also can cause diarrhea, and such patients are often treated with antimotility agents.

“However, the use of antimotility agents in patients with active CDI has traditionally been avoided because of possible gastrointestinal complications,” the study authors wrote. “Therefore, it is necessary to distinguish whether a patient is suffering from CDI or TKI-associated diarrhea so that the appropriate treatment can be administered to reduce unnecessary complications.”

Currently, the investigators said, few data are available on the incidence of CDI in patients receiving EGFR-TKIs. Most of the existing data come from case reports and adverse event databases in the United States and Japan. The authors therefore embarked on a retrospective analysis of existing data in hopes of drawing concrete insights about the issue of CDI among patients with lung cancer receiving EGFR-TKIs.

The authors used a multi-institutional electronic health records database to search for patients 20 years or older with lung cancer who were treated with EGFR-TKIs at several hospitals in Taiwan. Patients were followed from the start of TKI treatment through the occurrence of diarrhea, ICU admission, death, or the cutoff point for data, which was the end of 2019.

Altogether, the investigators identified 2242 patients with lung cancer who experienced diarrhea following treatment with TKIs. Just 51 of those patients had CDI. The data showed that key risk factors for those developing CDI included the concurrent use of antibiotics (HR, 3.30; 95% CI, 1.67-6.50) and the concurrent use of systemic steroids (HR, 4.90; 95% CI, 2.65-9.06).

The study investigators also looked at whether a particular TKI used affected CDI risk. They noted that the second-generation TKI afatinib (Gilotrif) has been associated with gastrointestinal toxicities, and so they wondered whether it might also be linked to higher rates of CDI.³

However, the data revealed no such association. In fact, the data suggested that first-generation TKIs gefitinib (Iressa) and erlotinib (Tarceva) tended to be associated with CDI at higher rates than afatinib (HR, 1.81, 95% CI, 0.94-3.47).3 Afatinib was not associated with an increased CDI risk compared with first-generation TKIs, they found.

As expected, when patients had CDI-associated diarrhea, they were much more likely to be admitted to the ICU or to die. The investigators said these data lend important context to the risks associated with lung cancer treatment. They said clinicians should be careful to determine the cause of diarrhea when patients develop the symptom during treatment.

“Physicians should be aware of CDI in these patients to attain an early diagnosis, proper treatment, and reduced complications,” they concluded. 

References
1. Chung YS, Lin YC, Hung MS, Ho MC, Fang YH. Clinical impact of epidermal growth factor receptor tyrosine kinase inhibitor associated Clostridioides difficile infection among patients with lung cancer. Onco Targets Ther. 2022;15:1563-1571. doi:10.2147/OTT.S386807
2. Toi Y, Kobayashi T, Harada T, et al. Prospective multicenter study of chemotherapy-induced Clostridium (Clostridioides) difficile infection in patients with lung cancer: North Japan Lung Cancer Study Group trial 1204. Front Oncol. 2021;11:685320. doi:10.3389/fonc.2021.685320
3. Neha R, Subeesh V, Beulah E, et al. Existence of Notoriety Bias in FDA adverse event reporting system database and its impact on signal strength. Hosp Pharm. 2021;56(3):152-158. doi:10.1177/0018578719882323

Targeted Therapies for NSCLC May Be Underused in Medicaid Programs, Study Results Suggest

Targeted therapies for non–small cell lung cancer (NSCLC) may be underused in many state Medicaid programs, according to study results published in JAMA Network Open.

Drugs targeting specific mutations can significantly improve outcomes for certain patients, including subsets of patients with NSCLC. EGFR variants and ALK rearrangements are the most common targetable variations in NSCLC, and there are currently 8 approved drugs indicated for tumors with these genomic alternations, the study authors noted.

Despite the potential benefits of targeted therapy for cancers with certain mutations, prior research suggests that they are underused for patients insured by Medicaid. The high cost of these drugs—both have a list price of more than $150,000 per year of treatment—is a significant barrier to uptake within Medicaid programs, which have fixed overall budgets and are required to cover drugs for almost every FDA-approved indication, the study authors wrote.

Considering that prior research has shown that prescription of expensive drugs varies significantly across state Medicaid programs, the new study specifically explored patterns of use of novel oncology therapies among state Medicaid programs, where data are historically lacking. The authors also aimed to describe factors that may be associated with state-level variation in targeted therapy use for Medicaid patients.

In 2020 and 2021, a total of 2281 person-years of therapies targeting EGFR and ALK were dispensed in state Medicaid programs overall. However, there were 3461 expected person-years of first-line targeted therapy during the same time frame based on real-world treatment durations of osimertinib (Tagrisso) and alectinib (Alecensa), which are standard-of-care first line treatments targeting EGFR and ALK, respectively.

This suggests that Medicaid beneficiaries with EGFR or ALK alterations received targeted therapy an estimated 66% of the person-time that was expected. Osimertinib and alectinib accounted for 83% of EGFR- and ALK-targeted therapy, the authors noted.

States with at least 20 estimated person-years of EGFR-altered NSCLC in the study time frame were included in the analysis, and 33 states met this threshold. There were 3258 expected person-years of targeted therapy use in these states overall, but only 1991 person-years of osimertinib and alectinib prescription.

In these states, Medicaid beneficiaries received osimertinib or alectinib an estimated 61% of the expected person-time. The proportions varied substantially by state, with the lowest being 18% in Arkansas and the highest being 113% in Massachusetts. Three states showed dispensing rates similar to those that were expected. These variations were associated with factors including Medicaid policies, state gross domestic product per capita, and the per-capita number of oncologists in each state.

Overall, the findings suggest targeted therapies are underused for Medicaid beneficiaries and that there is significant variation in targeted therapy use in this patient population across states.

“Just 66% of person-years in whom targeted therapies were indicated in 2020 and 2021 were associated with use of those medications, suggesting that at least 500 Medicaid patients with a diagnosis of EGFR- or ALK-altered metastatic NSCLC during these years did not receive targeted therapy when indicated,” the authors wrote. “Given the efficacy of targeted therapies, this underuse could have led to an estimated 855 preventable years of life lost during the period of analysis.”

Several factors could affect these rates, according to the authors. Ensuring that patients and clinicians have access to genomic testing to identify alterations and that prior authorization policies do not deter oncologists from using targeted therapies are both important aspects of more widespread access. Especially in states where underuse is confirmed, the onus should be on policy makers to examine these programs and ensure patient access to these standard of care therapies, the authors concluded. 

Reference
Roberts TJ, Kesselheim AS, Avorn J. Variation in use of lung cancer targeted therapies across state Medicaid programs, 2020-2021. JAMA Netw Open. Published online January 25, 2023. doi:10.1001/jamanetworkopen.2022.52562