Neuropathy After Breast Cancer Chemo Can Last for Years

Liam Davenport

September 01, 2017

Early-stage breast cancer (ESBC) patients who receive adjuvant chemotherapy can experience symptoms of peripheral neuropathy even years after completing therapy, resulting in reduced quality of life, say US researchers, who call for clinicians to consider the long-term impact of their therapeutic choices.

After a systematic review of current evidence on peripheral neuropathy in ESBC turned up precious little information, the team studied data on more than 1500 women who had received various combinations of adjuvant chemotherapy as part of a randomized clinical trial.

They found that women given either adjuvant doxorubicin and docetaxel or concurrent doxorubicin, cyclophosphamide, and docetaxel, rather than a regimen with higher cumulative doses of docetaxel, were approximately half as likely to develop severe, long-term peripheral neuropathy, an outcome that was associated with significant reductions in quality-of-life scores.

The systematic review and study were both published online August 24 in the Journal of the National Cancer Institute.

Patricia Ganz, MD, director of the Center for Cancer Prevention and Control Research at the Jonsson Comprehensive Cancer Center, University of California, Los Angeles, who was an author on both articles, said: "There is very little treatment for neuropathy, and there's nothing that's actually proven to work."

Since we don't have an effective treatment, ideally, it would be best to prevent it from happening. Dr Patricia Ganz

"Since we don't have an effective treatment, ideally, it would be best to prevent it from happening by not administering chemotherapy if it is likely to have minimal additional benefit," she continued.

"Alternatively, this class of drugs could be avoided in patients who are at higher risk for persistent neuropathy. At the minimum, patients need to be informed about the likelihood of persistent symptoms," Dr Ganz said in a statement.

The findings also highlight the need for further research into peripheral neuropathy and the impact of other chemotherapy regimens, so as to identify which treatments can eradicate the cancer without resulting in long-term reductions in quality of life.

Coauthor Joy Melnikow, MD, director of the Center for Healthcare Policy and Research at University of California, Davis, said that their findings are "a call to action."

"We can't definitively define the frequency of peripheral neuropathy or understand the differences between chemotherapy regimens with the data we have," Dr Melnikow commented.

"This issue of adverse effects in survivors goes beyond peripheral neuropathy. There are other effects that need to be considered while women are making treatment decisions," she added.

Review Showed How Few Data Are Available

To examine the current evidence on the incidence and prevalence of peripheral neuropathy among women receiving adjuvant chemotherapy for ESBC and its impact on patient-reported outcomes and quality of life, the researchers searched the MEDLINE, PubMed, and Embase databases and the Cochrane Library for relevant studies published between 1990 and 2016.

The investigators focused on current adjuvant regimes with anthracyclines, taxanes, and cyclophosphamide and platinum compounds. Initially, 364 articles were identified; 60 full- text articles were considered, of which only five contained data on outcomes for at least 1 year after diagnosis.

Using the Newcastle-Ottawa Scale for nonrandomized studies and the Cochrane criteria for randomized controlled trials, the team rated three publications, detailing two studies, as being of good quality and two as being of fair quality.

The most striking finding from the review was how little data were out there. Dr Joy Melnikow

Dr Melnikow observed: "The most striking finding from the review was how little data were out there. And these studies report a wide range of frequency for peripheral neuropathy, from as low as 11% to more than 80% of patients at 1 to 3 years after treatment."

The investigators noted a high degree of variability in the studies. They identified six different measures used to assess peripheral neuropathy and large variations in study design, chemotherapy regimens used, drug dosing, variables collected, follow-up time, and outcome measures.

Focus on One Large Clinical Trial

To obtain a clearer picture of the long-term impact of peripheral neuropathy for breast cancer patients, the researchers focused on one large clinical trial. They examined data from the National Surgical Adjuvant Breast and Bowel Project Protocol B-30, in which women with node-positive ESBC were randomly assigned in a 1:1:1 ratio to the following:

  • four cycles of doxorubicin 60 mg/m2 plus cyclophosphamide 600 mg/m2 every 3 weeks, followed by four cycles of docetaxel 100 mg/m2 every 3 weeks (AC→T);

  • four cycles of doxorubicin 60 mg/m2 plus cyclophosphamide 600 mg/m2 plus docetaxel 60 mg/m 2 every 3 weeks (ACT); or

  • four cycles of doxorubicin 60 mg/m2 plus docetaxel 60 mg/m2 every 3 weeks (AT).

Quality of life was assessed using the Functional Assessment of Cancer Therapy-Breast Trial Outcome Index at baseline, during chemotherapy, and at follow-up visits at 6, 12, 18, and 14 months.

Symptoms were measured using the Breast Cancer Prevention Trial symptom checklist, with the severity of peripheral neuropathy determined from the response to a question on how much the patients were bothered by numbness or tingling in the hands or feet.

Of 5351 patients, 2156 were included in the quality of life substudy, and 2051 patients were eligible for analysis. There were no significant differences between the treatment groups in terms of demographic and tumor characteristics.

Peripheral neuropathy at baseline was reported by 18.5% of patients, at 15.8% in the AC→T group, 20.7% in patients treated with ACT, and 19.1% in patients given AT.

At 2 years, complete data were available for 1512 patients. Of those, 41.9% reported peripheral neuropathy, with 10.3% reporting a severe symptom. Patients treated with AC→T a reported higher rate of peripheral neuropathy than those in the other treatment groups, at 49.8% vs approximately 35%.

On univariate analysis, factors associated with the severity of peripheral neuropathy at 24 months included patient age, body mass index (BMI), menopausal status, the chemotherapy regimen administered, the presence of neuropathy symptoms at baseline, type of surgery, receipt of radiotherapy, and nodal status.

Multivariate analysis revealed that, compared with AC→T, receipt of ACT and AT was associated with a lower risk for severe, long-term peripheral neuropathy, at odds ratios of 0.59 and 0.45, respectively (P < .001).

Peripheral neuropathy at baseline was associated with a significantly increased risk for long-term symptoms, at an odds ratio of 2.67 ( P < .001). Age of at least 50 years (P = .005), nodal status ≥4 (P = .01), undergoing mastectomy rather than lumpectomy (P = .002), and a BMI ≥25 kg/m2 (P < .001) were also associated with an increased risk for long-term neuropathy.

The researchers note that long-term neuropathy of greater severity was significantly associated with lower quality of life (P for trend <.001), with scores ranging from 57.9 in patients who were "very much" bothered by peripheral neuropathy and 76.79 in those without symptoms.

The authors conclude, "The lower rate of peripheral neuropathy in patients who received adjuvant doxorubicin and docetaxel or concurrent doxorubicin, cyclophosphamide, and docetaxel, both of which employed lower cumulative doses of docetaxel, might be an important factor to support the choice of these therapies for individuals with preexisting neuropathic symptoms or other risk factors for neuropathy because the differences in survival and disease-free trial outcomes for these regimens were of modest magnitude compared with the higher-dose taxane-containing regimen.

"The choice of chemotherapy regimen should include consideration of long-term adverse effects and informed decision-making that involves patients in the process," they add.

The review was supported by a National Cancer Institute contract, by the National Institute of Health, and the Breast Cancer Research Foundation. The study was funded by the National Institutes of Health, the National Cancer Institute (NCI), the Department of Health and Human Services, the Public Health Service, the Breast Cancer Research Foundation, and through an NCI contract.

Dr Ganz is a member of the Scientific Advisory Board of the Breast Cancer Research Foundation. One coauthor has various ties with industry, as listed in the published article.

J Natl Cancer Inst. published online August 24, 2017. Review abstract; Study abstract

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