Severity Of Paclitaxel-induced Peripheral Neuropathy Research Articles

Relation between Vitamin D Level and Severity of Paclitaxel-Induced Peripheral Neuropathy in Breast Cancer Patients

Relation between Vitamin D Level and Severity of Paclitaxel-Induced Peripheral Neuropathy in Breast Cancer Patients

A Prospective Study on the Incidence and Severity of Paclitaxel-induced Peripheral Neuropathy in the Indian Population

Background: Despite the high efficacy rate of paclitaxel, physicians are compelled to discontinue the regimen due to its prevailing neurotoxicity and myelosuppressive effects, thus not achieving the desired clinical outcomes. The neurotoxicity studies of paclitaxel have been mostly performed on upper dose limits (>275mg/m2), and little information is available on lower doses. Since there is a lack of such studies on the Indian population, the medical professionals are unable to analyze at what cumulative dose does paclitaxel show maximum severity of peripheral neuropathy. Methods: This is a prospective observational study conducted for 1 year in patients undergoing paclitaxel therapy. These patients were evaluated for the incidence and severity of paclitaxel-induced peripheral neuropathy during the first 6 cycles using the QLQ-CIPN questionnaire. We also identified the cumulative dose at which most patients developed peripheral neuropathy and each patient’s quality of life using EORTC QLQ C30. Results: Out of 85 patients, 76 developed peripheral neuropathy during the first 6 cycles. It was observed that the severity of peripheral neuropathy increased in each cycle of therapy. The overall quality of life of patients decreased with therapy, and at a cumulative dose of 525mg/m2, most of the patients (40%) developed symptoms of peripheral neuropathy. Conclusion: The incidence and severity of peripheral neuropathy increased with each cycle, leading to a significant reduction in the quality of life of patients post 6 cycles. Moreover, a high cumulative dose may limit the paclitaxel therapy.

EVALUATION OF THE EFFICIENCY OF ALPHA-LIPOIC ACID AND IPIDACRINE HYDROCHLORIDE FOR THE PREVENTION OF PACLITAXEL-INDUCED PERIPHERAL NEUROPATHY ACCORDING TO THE TOTAL NEUROPATHY SCORE.

To evaluate the efficacy of combination of alpha-lipoic acid and acetylcholinesterase inhibitor (ipidacrine hydrochloride) to prevent the development and improve the course of paclitaxel-induced peripheral neuropathy (PIPN) in patients with breast cancer according to the Total Neuropathy Score. 32patients with breast cancer T1-4N0-3M0received six cycles of polychemotherapy according to the AT scheme (paclitaxel, doxorubicin) or ET scheme (paclitaxel, epirubicin). Patients were randomized into two groups- without (group I) or with (group II) medication for prevention of neuropathy. A comprehensive neurological examination of patients was performed according to all ten parameters of the Total Neuropathy Score before chemotherapy, and after third and sixth cycles of chemotherapy. Each parameter was evaluated from 0 (no deficit) to 4 (no function/the most severe deficit). The scores obtained from the scale were summarized to obtain a total score from 0to 40. The use of alpha-lipoic acid in combination with an acetylcholinesterase inhibitor (ipidacrine hydrochloride) significantly reduces the symptoms and severity of PIPN. The manifestations of PIPN in patients of the control group were significantly more severe compared to the group in which the study drugs were used. The average severity of neuropathy after 3and 6cycles was 1.75and 2.62in groupI, and 1.12and 1.62- in group II, respectively (improvement by 15.75% (p < 0.05) and 25.00% (p < 0.001) after3and 6cycles). Proposed combination of alpha-lipoic acid and ipidacrine hydrochloride led to a statistically significant reduction in the severity of PIPN, and thus to improvement of the functional capacity and quality of life of patients.

Effects of combined chemotherapy and anti-programmed cell death protein 1 treatment on peripheral neuropathy and neuroinflammation in mice.

A modern approach for cancer treatment is the use of immunotherapy, and particularly immune checkpoint inhibitors, such as anti-programmed cell death protein 1 (PD-1), alone and in combination with chemotherapy. The PD-1 pathway plays a crucial role in inhibiting immune responses and recently has been shown to modulate neuronal activity. However, the impact of PD-1 blockade on the development of chemotherapy-induced peripheral neuropathy is currently unknown. In this study, we show that C57BL/6 mice treated with the chemotherapeutic drug paclitaxel or cotherapy (paclitaxel and anti-PD-1), but not with anti-PD-1 alone, exhibited increased mechanical sensitivity of the hind paw. Both chemotherapy and immunotherapy caused a reduction in neurite outgrowth of dorsal root ganglion (DRG) explants derived from treated mice, whereas only paclitaxel reduced the neurite outgrowth after direct in vitro treatment. Mice treated with anti-PD-1 or cotherapy exhibited distinct T-cell changes in the lymph nodes and increased T-cell infiltration into the DRG. Mice treated with paclitaxel or cotherapy had increased macrophage presence in the DRG, and all treated groups presented an altered expression of microglia markers in the dorsal horn of the spinal cord. We conclude that combining anti-PD-1 immunotherapy with paclitaxel does not increase the severity of paclitaxel-induced peripheral neuropathy. However, because anti-PD-1 treatment caused significant changes in DRG and spinal cord immunity, caution is warranted when considering immune checkpoint inhibitors therapy in patients with a high risk of developing neuropathy.

Vitamin D deficiency increases severity of paclitaxel-induced peripheral neuropathy.

Approximately 25% of patients receiving weekly paclitaxel for breast cancer require treatment disruptions to avoid severe, irreversible peripheral neuropathy (PN). Vitamin insufficiencies are PN risk factors in many diseases, but their relevance to chemotherapy-induced PN is unknown. We investigated whether baseline insufficiency of vitamin D, vitamin B12, folate, or homocysteine increased PN in patients with breast cancer receiving weekly paclitaxel in a retrospective analysis of a prospective observational study. Patient-reported PN was collected at baseline and during treatment on the Quality of Life Questionnaire Chemotherapy-Induced Peripheral Neuropathy (CIPN20). The primary analysis tested associations between vitamin deficiency and the maximum increase from baseline in the CIPN20 sensory subscale (ΔCIPN8). Secondary analyses tested for association with PN-induced treatment disruptions and adjusted associations for treatment and clinical variables. 25-hydroxy-vitamin D was the only nutrient with sufficient deficiency (< 20ng/mL) for analysis (15/37 = 41%). Vitamin D-deficient patients had a greater mean PN increase than non-deficient patients (ΔCIPN8 ± SD, 36 ± 23 vs. 16 ± 16, p = 0.003) and a non-significant, approximately threefold increase in risk of treatment disruption (OR 2.98, 95% CI [0.72, 12.34], p = 0.16). In multivariable models adjusted for clinical and treatment variables, baseline vitamin D level was inversely associated with PN (β = -0.04, p = 0.02). Pre-treatment vitamin D deficiency was associated with PN in women receiving weekly paclitaxel for breast cancer. Vitamin D deficiency may be an easily detected PN risk factor that could be resolved prior to treatment to prevent PN, avoid treatment disruptions, and improve treatment outcomes.

Impact of Exogenous Neurotropic Factor Administration on Occurrence and Severity of Paclitaxel-Induce Neuropathy in Breast Cancer Patients. An open label Pilot Study.

Background: Paclitaxel-induced peripheral neuropathy (PIPN) is a common toxicity with no proven agent beneficial for prevention. The potentiality of Nerve Growth Factor (NGF) as a protective agent for PIPN was suggested by several studies. Aim: This study aimed to test the impact of exogenously administered NGF on PIPN and to assess NGF levels in relation to PIPN severity. Methods: Forty patients were prospectively randomly allocated to paclitaxel alone (control group) or paclitaxel + exogenous NGF (test group). Neuropathy occurrence and severity was assessed before enrollment and after each cycle using the European Association for Treatment of Cancer Quality of Life Questionnaire for Chemotherapy Induced Peripheral Neuropathy (EORTC QLQ-CIPN20). Nerve Growth Factor level was assessed in both groups at baseline and at the end of the study. Nerve Growth Factor safety was assessed by laboratory investigations and the occurrence of adverse drug reactions. Results: There was significant increase in the EORTC QLQ-CIPN20 score in the control group (p < 0.001) and a stabilization in the score in the test group. Nerve Growth Factor levels significantly increased in the test group (p < 0.001) and declined in the control group. A highly significant negative correlation existed between NGF level and the EORTC QLQ-CIPN20 score (r=-0.781, p < 0.001). No significant difference was observed between the two groups in the occurrence of adverse drug reactions or other toxicities. Conclusion: Exogenous NGF may have a potential neuroprotective effect against PIPN in breast cancer patients. Higher endogenous NGF level is inversely correlated with the occurrence and severity of PIPN.

The Incidence and Severity of Paclitaxel-induced Peripheral Neuropathy in Patients with Ovarian Cancer: a Retrospective Study

The Incidence and Severity of Paclitaxel-induced Peripheral Neuropathy in Patients with Ovarian Cancer: a Retrospective Study

Delayed recovery and increased severity of Paclitaxel-induced peripheral neuropathy in patients with diabetes.

Although diabetes mellitus (DM) is recognized as a risk factor for chemotherapy-induced neurotoxicity, its true impact on intensity and time course of peripheral neuropathy is still unclear. The goal was to analyze the relevance of preexisting DM to weekly paclitaxel-induced peripheral neuropathy (PIPN). We performed a retrospective case-control study (1:2) including a total of 129 patients with breast cancer (43 with DM and 86 controls) treated with single-agent weekly paclitaxel (wP). Compared with controls, patients with DM treated with wP experienced PIPN more frequently (74.4% vs 58.4%; P=.016) and with higher severity (grade 2-3: 51.2% vs 27.7%; P=.014). A significant delay in PIPN resolution was observed in women with DM (P=.001) and, in a multivariate analysis, DM was the only independent predictor for delayed recovery (hazard ratio [HR], 0.16; 95% CI, 0.05-0.55; P=.003). After 2 years, 68.7% of patients with DM (vs 29.2% of women without DM) still experienced PIPN, which was functionally significant (grade 2-3) in 18.2%. Significantly more dose delays and reductions because of PIPN occurred in patients with DM. Preexisting DM associates with long-lasting significant PIPN in patients treated with wP. Benefits and risks of long-term significant PIPN should be carefully balanced in patients with DM before starting wP chemotherapy.

Omega-3 fatty acids are protective against paclitaxel-induced peripheral neuropathy: A randomized double-blind placebo controlled trial

BackgroundAxonal sensory peripheral neuropathy is the major dose-limiting side effect of paclitaxel.Omega-3 fatty acids have beneficial effects on neurological disorders from their effects on neurons cells and inhibition of the formation of proinflammatory cytokines involved in peripheral neuropathy.MethodsThis study was a randomized double blind placebo controlled trial to investigate the efficacy of omega-3 fatty acids in reducing incidence and severity of paclitaxel-induced peripheral neuropathy (PIPN). Eligible patients with breast cancer randomly assigned to take omega-3 fatty acid pearls, 640 mg t.i.d during chemotherapy with paclitaxel and one month after the end of the treatment or placebo. Clinical and electrophysiological studies were performed before the onset of chemotherapy and one month after cessation of therapy to evaluate PIPN based on "reduced Total Neuropathy Score".ResultsTwenty one patients (70%) of the group taking omega-3 fatty acid supplement (n = 30) did not develop PN while it was 40.7%( 11 patients) in the placebo group(n = 27). A significant difference was seen in PN incidence (OR = 0.3, .95% CI = (0.10-0.88), p = 0.029). There was a non-significant trend for differences of PIPN severity between the two study groups but the frequencies of PN in all scoring categories were higher in the placebo group (0.95% CI = (−2.06 -0.02), p = 0.054).ConclusionsOmega-3 fatty acids may be an efficient neuroprotective agent for prophylaxis against PIPN. Patients with breast cancer have a longer disease free survival rate with the aid of therapeutical agents. Finding a way to solve the disabling effects of PIPN would significantly improve the patients’ quality of life.Trial registrationThis trial was registered at ClinicalTrials.gov (NCT01049295)

Paclitaxel-induced peripheral neuropathy in patients receiving adjuvant chemotherapy for breast cancer

The long-term outcomes and risk factors of paclitaxel-induced peripheral neuropathy (PIPN) have not yet been fully elucidated. We identified 219 breast cancer patients who received paclitaxel as adjuvant chemotherapy between 2002 and 2009. We retrospectively analyzed the incidence, time to onset, duration, and risk factors for PIPN by chart review. Of the 219 patients, 212 developed PIPN (97%) during a median follow-up time of 57 months (range 5.3-95.5). Median time to PIPN onset was 21 days (range 11-101) for the entire patient population: 35 days (range 14-77) for weekly administration and 21 days (range 11-101) for tri-weekly administration. PIPN caused termination of paclitaxel treatment in 7 patients (4%). Median duration of PIPN was 727 days (range 14-2621 days). PIPN persisted in 64 and 41% of patients at 1 and 3 years after initiating paclitaxel, respectively. Age ≥60 years and severity of PIPN were significantly associated with PIPN duration. PIPN persists longer in older patients and in those who experience severe neuropathy. Further studies to identify the risk factors for PIPN are warranted.

Preventing Paclitaxel-Induced Peripheral Neuropathy: A Phase II Trial of Vitamin E Supplementation

A randomized, controlled trial was performed to assess the efficacy and safety of vitamin E supplementation for prophylaxis against paclitaxel-induced peripheral neuropathy (PIPN). Thirty-two patients undergoing six courses of paclitaxel-based chemotherapy were randomly assigned to receive either chemotherapy with vitamin E (300 mg twice a day, Group I) or chemotherapy without vitamin E supplementation (Group II). A detailed neurological examination and electrophysiological study was performed during and 3 months after chemotherapy. The severity of PIPN was summarized by means of a modified Peripheral Neuropathy (PNP) score. The incidence of neurotoxicity differed significantly between groups, occurring in 3/16 (18.7%) patients assigned to the vitamin E supplementation group and in 10/16 (62.5%) controls ( P = 0.03). The relative risk (RR) of developing PIPN was significantly higher in controls than in vitamin E group patients (RR = 0.3, 95% confidence interval (CI) = 0.1–0.9). Mean PNP scores were 2.25 ± 5.1 (range 0–15) for patients in Group I and 11 ± 11.63 (range 0–32) for those in Group II ( P = 0.01). Vitamin E supplementation was well tolerated and showed an excellent safety profile. This study shows that vitamin E effectively and safely protects patients with cancer from the occurrence of paclitaxel-induced peripheral nerve damage. A double-blind, placebo-controlled trial is needed to confirm these results.