Chemotherapy-induced peripheral neuropathy (CIPN) is a common and potentially debilitating adverse effect of cancer treatment, often resulting in treatment delay, interruption or dose modifications, which can negatively impact cancer outcomes.¹ CIPN incidence varies widely, ranging from about 10% to over 80%,^2–4 based on several factors, including the cumulative dose of neurotoxic agents, drug combinations, treatment duration, follow-up time, the presence of comorbidities (e.g., diabetes) and lifestyle factors (e.g., smoking and alcohol use).^2,4,5

Cytotoxic agents commonly associated with CIPN include taxanes, vinca alkaloids, platinum agents, brentuximab vedotin, bortezomib, and eribulin.^1,6 According to a systematic review and meta-analysis involving over 4000 patients with cancer who received chemotherapy of any type, approximately 70% developed peripheral neuropathy by one month following the end of chemotherapy. Moreover, at six months or beyond, about 30% of patients were experiencing persistent peripheral neuropathy symptoms, leading to impairment of the quality of life of these patients.²

Existing data on CIPN in the United States (US) predominantly stem from clinical trials with small sample sizes and studies of older adult cancer survivors.^7–11 There are limited population-based data on the incidence of CIPN and its association with specific chemotherapy drugs among pediatric (<15 years) and adolescent and young adult (AYA, 15–39 years) cancer survivors.^12–15 To address this gap, we investigated peripheral neuropathy in children and AYAs with Medicaid insurance in California. For five common malignancies, we determined the cumulative incidence of peripheral neuropathy and the association of this condition with neurotoxic and non-neurotoxic agents adjusting for sociodemographic and clinical factors.

A total of 6,446 cancer survivors (418 children and 6028 AYAs) covered by Medicaid insurance were included in our study. During a median follow-up time of 4.8 years (interquartile range 2.7, 8.1), 1007 were diagnosed with peripheral neuropathy. The median time from cancer diagnosis to peripheral neuropathy onset varied from 8 months for NHL, 13 months for colorectal and testicular cancer, and 21 months for HL and breast cancer. Most patients were female (60%), resided in the lowest socioeconomic neighborhoods (53%), were identified as Hispanics (57%), and received neurotoxic chemotherapy (55%) (Table 1). Approximately 5% of patients had a history of diabetes. Among patients diagnosed with peripheral neuropathy, 71.5% received neurotoxic drugs, while 28.5% received non-neurotoxic chemotherapy.

In a large cohort involving over 6,000 children and AYAs with Medicaid insurance in California diagnosed with five types of cancer, our findings revealed a high 5-year cumulative incidence of peripheral neuropathy ranging from 17% to 70% among the 55% of patients receiving neurotoxic chemotherapy. Across each cancer type, the risk of developing peripheral neuropathy was 1.7 to 9.5 times greater among patients exposed to neurotoxic agents, particularly brentuximab in patients with HL or NHL, paclitaxel in patients with breast cancer, oxaliplatin in patients with colorectal cancer, and cisplatin and etoposide in those with testicular cancer. We identified a substantial risk of peripheral neuropathy in a young population of cancer survivors, despite that this population is thought to be at lower risk than older patients or those with diabetes.^1,8,23,31

We observed an increasing cumulative incidence of peripheral neuropathy from years 1 to 2 and continuing through year 5 across all cancer sites, particularly for patients who received neurotoxic drugs. This suggests that new diagnoses may occur later in the survivorship period. However, the increase may also reflect several factors, including delayed coding of a symptom that has been present for a long time, delayed diagnosis of peripheral neuropathy during therapy that progresses over time, or the persistence of lower-grade neuropathy (grade 2) even as more severe neuropathy (grades 3 or 4) resolve. We were unable to determine whether patients continued to receive chemotherapy during the follow-up period (e.g., due to relapsed or refractory disease) or neuropathy resolves over time, which could have influenced the observed increase in cumulative incidence. These findings underscore the importance of monitoring peripheral neuropathy, collecting patient-reported outcomes (PROs) on symptomatology, and adjusting treatment as recommended by clinical practice guidelines.³¹

Our findings align with those reported in prior studies. In patients with HL and NHL, those receiving brentuximab had a markedly high risk of being diagnosed with peripheral neuropathy.^24,33 To mitigate the risk, regimens that spare neurotoxic agents – such as replacing brentuximab with nivolumab in patients with newly diagnosed advanced-stage HL – may offer better survival outcomes with fewer adverse effects and lower rates of drug discontinuation.³⁴ Consistent with prior studies, paclitaxel was strongly associated with peripheral neuropathy in breast cancer survivors.^8,9 Given that paclitaxel dosing is based on body surface area, with high pharmacokinetic variability influenced by patient characteristics, such as age and gender,^10,35 therapeutic drug monitoring³⁵ and pharmacokinetically-guided dosing may help reduce paclitaxel-associated neuropathy.³⁶

Our study confirmed the significant association between oxaliplatin and peripheral neuropathy in patients with colorectal cancer, as previously reported.^37–39 A recent study found that factors, such as high body mass index, diabetes, and low physical activity, were associated with increased severity of oxaliplatin-induced peripheral neuropathy, highlighting potential areas for interventions to mitigate the risk and severity of CIPN.¹¹ We observed that AYAs with testicular cancer receiving cisplatin and etoposide had twice the risk of peripheral neuropathy than those receiving non-neurotoxic drugs. This is notable as these drugs are not typically considered to be as neurotoxic as the taxanes or vinca alkaloids. A recent European study showed that long-term survivors of testicular germ cell tumors who received ≥400 mg/m² of cisplatin reported poorer physical functioning,⁴⁰ suggesting that more work is needed to identify effective supportive care options for these patients.

The updated 2020 American Society of Clinical Oncology guidelines on Prevention and Management of CIPN reiterated that no agent is proven for the prevention of CIPN. Despite limited data, duloxetine remains the only agent recommended for the management of patients with established painful CIPN, whereas no treatment exists for sensory CIPN.³¹ Therefore, identifying early signs of nerve damage is crucial to guide interventions to prevent long-term or severe neurotoxicity. PRO measures are valid and reliable tools to help physicians and researchers detect clinically significant CIPN.^41,42 However, the absence of validated PRO measures for neuropathy in pediatric and AYA populations underscores the need for future research to either validate adult scales or develop new instruments for these age groups.¹²

In patients with underlying conditions that increase the risk of peripheral neuropathy, such as diabetes, pre-existing or family history of peripheral neuropathy,³¹ it is important to weigh the risks and benefits of using neurotoxic chemotherapy. Additionally, in patients who experience peripheral neuropathy during treatment, shared decision-making should consider the potential survival benefits when deciding whether or not to continue neurotoxic chemotherapy, particularly in cases of adjuvant treatment administered to patients with lower risk of recurrence, and thus less absolute survival benefit potential.

Our study has several limitations. First, physicians likely underreported peripheral neuropathy in Medicaid claims. This underreporting can result from patients not being asked about or not reporting peripheral neuropathy symptoms, or when physicians do not document this condition, either due to less severe symptoms or the absence of effective treatments.²³ Second, it is possible that some neurotoxic drugs were not fully captured in Medicaid claims, leading to some patients being classified as receiving non-neurotoxic drugs, which could result in an underestimation of the association we found between neurotoxic agents and peripheral neuropathy. Third, information on cumulative doses and treatment duration is not available in Medicaid claims, preventing us from considering these associations with neuropathy. Fourth, we could not individually evaluate the effect of some drugs (e.g., bortezomib, ixabepilone, trastuzumab emtansine) due to the small number of patients treated with these agents. Finally, our findings among Medicaid enrollees may not be generalizable to individuals with private insurance, other public insurance or those who are uninsured. However, Medicaid enrollees, who accounted for 40% of all children and AYAs with the selected cancers in our CCR cohort, represent a population at higher risk for late-stage diagnosis and treatment-related complications,^29,43 which makes this group particularly relevant for studying CIPN. Despite the limitations, we consistently demonstrated a high incidence of peripheral neuropathy in survivors treated with neurotoxic chemotherapy, using a large cohort of young patients, recent data, and the innovative linkage between Medicaid claims, CCR, and HCAI. This information is relevant for the next era of symptom prevention and management, for systematic collection of PROs, and for advising patients on what to expect.

In conclusion, our study revealed a substantial burden of peripheral neuropathy in low-income children and AYAs with common malignancies. Across each cancer site, the risk was higher among patients exposed to specific neurotoxic agents, highlighting the need for further for treatment regimens that reduce neurotoxicity and maintain efficacy. Additionally, close monitoring and early diagnosis of peripheral neuropathy are crucial for reducing symptoms and long-term debilitating effects of this common condition.