Risk of comorbidities and chemotherapy-induced peripheral neuropathy in participants aged 65 years or older in the Southwest Oncology Group clinical trial
background
Neuropathy is a debilitating toxicity associated with various chemotherapy drugs. We assessed the association between common comorbidities and the development of peripheral neuropathy in patients receiving taxane chemotherapy.
way
We examined the Southwest Oncology Group database to identify phase II and III trials that included taxane therapy between 1999 and 2011. We linked Southwest Oncology Group clinical records to Medicare claims data based on social security number, gender, and date of birth. The following disease conditions that may be associated with peripheral neuropathy were evaluated: diabetes mellitus, hypothyroidism, hypercholesterolemia, hypertension, varicella zoster, peripheral vascular disease, and autoimmune disease. Multivariate logistic regression was used to model the probability of developing grade 2 to 4 neuropathy.
outcome
A total of 1,401 patients from 23 studies were included in the analysis. Patients in the paclitaxel group were more likely to develop grade 2 to 4 neuropathy compared with docetaxel (25% versus 12%, respectively; OR, 2.20; 95% CI, 1.52 to 3.18; P < .001). The addition of platinum-based agents was also associated with an increased incidence of neuropathy (OR, 1.68; 95% CI, 1.18 to 2.40; P = .004). The chance of neuropathy increased by 4% for each 1 year increase in age (P = .006). Patients with diabetic complications were more than twice as likely to develop neuropathy compared with those without diabetes (OR, 2.13; 95% CI, 1.31 to 3.46; P = .002). In contrast, patients with autoimmune diseases were half as likely to develop neuropathy (OR, 0.49; 95% CI, 0.24 to 1.02; P = .06). Other diseases are not associated with neuropathy.
conclusion
We found that, in addition to drug-related factors, age and diabetes history were independent predictors of chemotherapy-induced peripheral neuropathy. Interestingly, we also observed that a history of autoimmune disease was associated with a reduced incidence of neuropathy. Patients with diabetes complications may choose to avoid paclitaxel or taxane-plus platinum-based combination therapy if other effective options are available.
introduce
Chemotherapy-induced peripheral neuropathy (CIPN) is a debilitating toxicity associated with a variety of drugs that are widely used to treat cancer. These toxicities have a significant impact on quality of life. Clinical trials of taxanes have shown a grade 2 to 4 neuropathy of 15% to 23%, with a high incidence according to the Common Terminology Standard Adverse Events system, with specific drugs, doses, treatment regimens, and duration of treatment correlated. Patients with grade 2 neuropathy have impaired functioning (e.g., difficulty buttoning shirts), patients with grade 3 neuropathy can interfere with activities of daily living (e.g., brushing teeth), and patients with grade 4 neuropathy have permanent and disabling symptoms.
Currently, there is a paucity of effective therapies to treat and prevent CIPN. Identifying patients at risk for CIPN is important for a number of reasons. First, it can help to personalize treatment based on toxicity risk. In addition, understanding the factors that contribute to risk may help uncover potential underlying mechanisms that could serve as targets for CIPN treatment or prevention trials.
Most studies assessing risk factors for CIPN are retrospective, from a single institution, or inconsistent in the definition of CIPN. Preliminary studies suggest that race, age, and obesity are risk factors for CIPN; However, other studies have not confirmed these findings. It may also be a history of other conditions that predispose the patient to peripheral neuropathy, resulting in an increased risk of developing CIPN. There have been no reports of a comprehensive evaluation of prior diseases or conditions associated with peripheral neuropathy such as hypothyroidism, varicella zoster, and autoimmune diseases.
Using a new link between data from older patients and Medicare claims enrolled in the Southwest Oncology Group (SWOG), we examined whether specific demographic, clinical, treatment, and comorbid conditions at the start of treatment could predict the development of CIPN in patients aged 65 years or older enrolled in a clinical trial that included taxane-containing therapies.
discuss
By establishing a new link between the large number of older patients recruited in SWOG clinical trials and Medicare claims, we found that patients with a history of diabetes, especially those with a history of diabetes complications, were at significantly increased risk of developing CIPN. We have also observed that patients with autoimmune diseases may have a lower risk of developing CIPN. In addition, patients treated with paclitaxel more than doubled their risk of developing CIPN compared with docetaxel, while those who were added platinum had more than two-thirds more of the chance of developing CIPN.
Diabetic peripheral neuropathy is the most common complication in people with diabetes and the most common cause of neuropathy worldwide. Early metabolic abnormalities of nerves are thought to be due to direct exposure of nerve tissue or its vascular bed to high concentrations of glucose. If blood sugar control is poor, its incidence and severity can increase over time. Most of the previous studies evaluating the association between diabetes and CIPN have come from retrospective trials in which it is difficult to determine which components of neuropathy are from diabetes and which are from exposure. To assess the association of diabetes with CIPN, the researchers evaluated the development of hyperglycemia as a surrogate indicator of diabetes. They found that patients with hyperglycemia while treated with taxanes had a 1.47 chance of developing grade 2 to 4 CIPN. Prospective trials that include drugs known to cause CIPN will generally exclude patients with severe neuropathy; In this study, more than two-thirds of the patients were from trials that excluded patients with pre-existing neuropathy. In addition, we found no neuropathy in the control group that did not receive taxane-naïve treatment. Therefore, we are convinced that the neuropathy observed in diabetic patients occurs while receiving taxane treatment.
In addition to diabetes, peripheral neuropathy is caused by many other diseases and conditions. Insufficient thyroid hormone production slows metabolism and causes fluid to build up, which puts pressure on peripheral nerves. Vasculitis impairs blood flow to nerves, which reduces the supply of oxygen to peripheral nerves, leading to subsequent nerve damage. Infections such as chickenpox-zoster and HIV can damage sensory nerves. In addition, medications commonly used to treat high blood pressure and high cholesterol can also cause peripheral neuropathy. We did not find an increased risk of CIPN in patients with a history of these conditions.
We found no other demographic factors other than age, such as gender, ethnicity, or self-reported ethnicity, to be associated with the development of CIPN. Our sample includes only patients aged 65 years and older who receive Medicare. Other studies assessing the association between age and CIPN have reported conflicting results; However, the average age of these studies was significantly younger than in our cohort. The association between black race and the development of CIPN is also inconsistent. Analysis of patients with early-stage breast cancer did not show an association between self-reported black ethnicity and CIPN; However, genome-wide association studies of patients in the same study found an association between genetically determined African ancestry and taxane-induced CIPN. Similarly, in an analysis of a SWOG-assisted breast cancer trial, African-American specific haplotypes were associated with a nearly threefold increased risk of CIPN. There was no information on baseline diabetes in these studies. It is difficult to determine the independent effects of black ethnicity due to the higher prevalence of diabetes, poorly controlled diabetes, and higher rates of diabetes-related complications among ethnic minorities. The current analysis provides a detailed assessment of diabetes-related risks.
We are curious about the critical, significant protective effect of a history of autoimmune disease on the development of CIPN. Sjögren's syndrome, rheumatoid arthritis, and lupus can produce autoantibodies that directly cause nerve damage. Although the mechanisms that lead to the development of CIPN are unknown, there may be a relationship between the immune system, inflammation, and peripheral neuropathy. If so, then previous anti-inflammatory therapy may have a protective effect on these patients against the development of CIPN. It has been hypothesized that activation of the inflammatory cascade, upregulation of pro-inflammatory cytokines, and neuroimmune communication pathways may play an important role in the initiation and progression of CIPN. Paclitaxel-induced CIPN has been found to be associated with microglial activation following spinal cord dorsal horn expression and release of pro-inflammatory cytokines. If these pathways are already active in patients with autoimmune diseases, the effects of chemotherapy may not be as pronounced.
We acknowledge that there are some limitations to our study, as well as to the Medicare database as a whole. All patients were over 65 years of age, while older patients were not usually included in clinical trials. Patients must also have a continuous Medicare claim for 6 months or more prior to enrollment in the study. This may affect the generalizability of the findings. Although we require patients to have two claims to reduce misclassification bias (which is a routine process for seeking diagnosis), not all patients with Medicare claims may have comorbidities to which we are assigned. Other factors known to be associated with neuropathy, such as medications, obesity, and alcohol history, are not available. In addition, some comorbidities are rare; As a result, the ability to determine their relationship to neuropathy is limited. Our results may not be applicable to younger patients. All patients were enrolled in clinical trials; Therefore, these results may not be applicable to all patients who do not meet the eligibility criteria for a SWOG trial, as most patients have a performance status of 0 or 1 and do not have end-organ damage or any uncontrolled disease at the time of enrollment. Finally, our goal is to identify potential predictors of neuropathy for future investigation; As a result, no multiple comparison adjustments were made. However, in some cases (e.g., taxane type, diabetes mellitus), the strength of the association between predictors and neuropathy was statistically significant, even under a conservative multiple comparison approach.
In conclusion, we have shown that, in addition to drug-related factors and duration of treatment, age and history of diabetes are independent predictors of the development of CIPN. Interestingly, we also found that a past history of autoimmune disease was associated with a lower incidence of neuropathy. Future research should understand the role of immune system and cytokine activation in the development and prevention of CIPN. Also, patients with diabetic complications should consider avoiding paclitaxel or taxane-plus platinum combinations if other options are available.
Comorbidities and Risk of Chemotherapy-Induced Peripheral Neuropathy Among Participants 65 Years or Older in Southwest Oncology Group Clinical Trials - PubMed