Genetic Predictors of Chemotherapy-Induced Peripheral Neuropathy from Paclitaxel, Carboplatin and Oxaliplatin: NCCTG/Alliance N08C1, N08CA and N08CB Study.

Chemotherapy-induced peripheral neuropathy (CIPN) is a common and potentially permanent adverse effect of chemotherapeutic agents including taxanes such as paclitaxel and platinum-based compounds such as oxaliplatin and carboplatin. Previous studies have suggested that genetics may impact the risk of CIPN. We conducted genome-wide association studies (GWASs) for CIPN in two independent populations who had completed European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ)-CIPN20 assessments (a CIPN-specific 20-item questionnaire which includes three scales that evaluate sensory, autonomic, and motor symptoms). The study population N08Cx included 692 participants from three clinical trials (North Central Cancer Treatment Group (NCCTG) N08C1, N08CA, and N08CB) who had been treated with paclitaxel, paclitaxel plus carboplatin, or oxaliplatin. The primary endpoint for the GWAS was the change from pre-chemotherapy CIPN20 sensory score to the worse score over the following 18 weeks. Study population The Mayo Clinic Breast Disease Registry (MCBDR) consisted of 381 Mayo Clinic Breast Disease Registry enrollees who had been treated with taxane or platinum-based chemotherapy. The primary endpoint for the GWAS assessed was the earliest CIPN20 sensory score available after the completion of chemotherapy. In multivariate model analyses, chemotherapy regimen (p = 3.0 × 10-8) and genetic ancestry (p = 0.007) were significantly associated with CIPN in the N08Cx population. Only age (p = 0.0004) was significantly associated with CIPN in the MCBDR population. The SNP most associated with CIPN was rs56360211 near PDE6C (p =7.92 × 10-8) in N08Cx and rs113807868 near TMEM150C in the MCBDR (p = 1.27 × 10-8). Due to a lack of replication, we cannot conclude that we identified any genetic predictors of CIPN.

Genetic Variations and Health-Related Quality of Life (HRQOL): A Genome-Wide Study Approach.

Health-related quality of life (HRQOL) is an important prognostic patient-reported outcome in oncology. Because prior studies suggest that HRQOL is, in part, heritable, we performed a GWAS to elucidate genetic factors associated with HRQOL in breast cancer survivors. Physical and mental HRQOL were measured via paper surveys that included the PROMIS-10 physical and mental health domain scales in 1442 breast cancer survivors participating in the Mayo Clinic Breast Disease Registry (MCBDR). In multivariable regression analyses, age and financial concerns were significantly associated with global physical health (age: p = 1.6 × 10-23; financial concerns: p = 4.8 × 10-40) and mental health (age: p = 3.5 × 10-7; financial concerns: p = 2.0 × 10-69). Chemotherapy was associated with worse global mental health (p = 0.01). In the GWAS, none of the SNPs reached the genome-wide association significance threshold of 5 × 10-8 for associations with either global physical or global mental health, however, a cluster of SNPs in SCN10A, particularly rs112718371, appeared to be linked to worse global physical health (p = 5.21 × 10-8). Additionally, SNPs in LMX1B, SGCD, PARP12 and SEMA5A were also moderately associated with worse physical and mental health (p < 10-6). These biologically plausible candidate SNPs warrant further study as possible predictors of HRQOL.

Genetic variation in Charcot-Marie-Tooth genes contributes to sensitivity to paclitaxel-induced peripheral neuropathy.

Aim: This study explored whether inherited variants in genes causing the hereditary neuropathy condition Charcot-Marie-Tooth disease are associated with sensitivity to paclitaxel-induced peripheral neuropathy (PN). Patients & methods: Hereditary neuropathy genes previously associated with risk of paclitaxel-induced PN were sequenced in paclitaxel-treated patients. Eight putative genetic predictors in five hereditary neuropathy genes (ARHGEF10, SBF2, FGD4, FZD3 and NXN) were tested for association with PN sensitivity after accounting for systemic exposure and clinical variables. Results:FZD3 rs7833751, a proxy for rs7001034, decreased PN sensitivity (additive model, ß = -0.41; 95% CI: -0.66 to -0.17; p = 0.0011). None of the other genetic predictors were associated with PN sensitivity. Conclusion: Our results support prior evidence that FZD3 rs7001034 is protective of PN and may be useful for individualizing paclitaxel treatment to prevent PN.

Patient factors associated with discrepancies between patient-reported and clinician-documented peripheral neuropathy in women with breast cancer receiving paclitaxel: A pilot study.

PURPOSE: Discrepancies between clinicians' assessment of chemotherapy-induced peripheral neuropathy (CIPN) and patient-reported outcomes (PRO) have been described, though the underlying reasons are unknown. Our objective was to identify potential patient-specific factors associated with under-describing of CIPN to clinicians in women with non-metastatic breast cancer treated with paclitaxel. METHODS: Patients enrolled in an observational study (n = 60) completed weekly CIPN PRO using the EORTC CIPN20. Clinician-documented CIPN using the NCI CTCAE were abstracted from the electronic medical record and paired with CIPN20 data at weeks 7 and 10. Patients were classified as under-describers if their CIPN20 was above the 80th percentile of the CIPN20 distribution for that CTCAE grade from an independent clinical trial (N08CA). Demographics, Assessment of Survivor Concerns (ASC), Trust in Oncologist Scale (TiOS), and health literacy assessment were collected post-treatment via survey. Repeated measures cumulative logistic regression models were used to identify factors associated with under-describing CIPN. RESULTS: Forty-two women completed the survey (response rate 70%). Three and 9 patients were categorized as under-describers at weeks 7 and 10, respectively. Women who were not working (OR = 9.00, 95%CI 1.06-76.15), had lower income (OR = 7.04, 95%CI 1.5-32.99), and displayed higher trust in their oncologist's competence (OR = 1.29, 95%CI 1.03-1.62 for a 0.1-unit increase in score) were more likely to under-describe CIPN symptoms. CONCLUSIONS: This preliminary study identified non-working status, low income and trust in oncologist's competence as potential factors influencing under-description of CIPN to the clinical team. Further work is needed to clarify these relationships and test additional factors.

Neurological safety of oxaliplatin in patients with uncommon variants in Charcot-Marie-tooth disease genes.

Oxaliplatin therapy can be complicated by chemotherapy-induced peripheral neuropathy (CIPN). Other neurotoxic chemotherapies have been linked to single nucleotide variants (SNV) in Charcot-Marie-Tooth disease (CMT) genes. Whether oxaliplatin carries increased risks of CIPN due to SNV in CMT-associated genes is unknown. 353 patients receiving oxaliplatin in NCCTG N08CB were serially evaluated for CIPN using a validated patient-reported outcome (PRO) instrument, the CIPN20 questionnaire (sensory scale). 49 canonical CMT-associated genes were analyzed for rare and common SNV by nextgen sequencing. The 157 patients with the highest and lowest susceptibility to CIPN (cases and controls) harbored 270 non-synonymous SNV in CMT-associated genes (coding regions). 143 of these were rare, occurring only once ("singletons"). CIPN cases had 0.84 singletons per patient compared with 0.98 in controls. An imbalance in favor of cases was noted only in few genes including PRX, which was previously highlighted as a candidate CIPN gene in patients receiving paclitaxel. However, the imbalance was only modest (5 singleton SNV in cases and 2 in controls). Therefore, while singleton SNV were common, they did overall not portend an increased risk of CIPN. Furthermore, testing CMT-associated genes using recurrent non-synonymous SNV did not reveal any significant association with CIPN. Genetic analysis of patients from N08CB provides clinical guidance that oxaliplatin chemotherapy decisions should not be altered by the majority of SNV that may be encountered in CMT-associated genes when common genetic tests are performed, such as exome or genome sequencing. Oxaliplatin's CIPN risk appears unrelated to CMT-associated genes.

Scrambler therapy for chemotherapy neuropathy: a randomized phase II pilot trial.

INTRODUCTION: Chemotherapy-induced peripheral neuropathy (CIPN) is a prominent clinical problem, with limited effective therapies. Preliminary non-randomized clinical trial data support that Scrambler Therapy is helpful in this situation. METHODS: Patients were eligible if they had CIPN symptoms for at least 3 months and CIPN-related tingling or pain at least 4/10 in severity during the week prior to registration. They were randomized to receive Scrambler Therapy versus transcutaneous electrical nerve stimulation (TENS) for 2 weeks. Patient-reported outcomes (PROs) were utilized to measure efficacy and toxicity daily for 2 weeks during therapy and then weekly for 8 additional weeks. RESULTS: This study accrued 50 patients, 25 to each of the 2 study arms; 46 patients were evaluable. There were twice as many Scrambler-treated patients who had at least a 50% documented improvement during the 2 treatment weeks, from their baseline pain, tingling, and numbness scores, when compared with the TENS-treated patients (from 36 to 56% compared with 16-28% for each symptom). Global Impression of Change scores for "neuropathy symptoms," pain, and quality of life were similarly improved during the treatment weeks. Patients in the Scrambler group were more likely than those in the TENS group to recommend their treatment to other patients, during both the 2-week treatment period and the 8-week follow-up period (p < 0.0001). Minimal toxicity was observed. CONCLUSIONS: The results from this pilot trial were positive, supporting the conduct of further investigations regarding the use of Scrambler Therapy for treating CIPN.

Genetic variation in EPHA contributes to sensitivity to paclitaxel-induced peripheral neuropathy.

AIMS: Chemotherapy-induced peripheral neuropathy (PN) is a treatment limiting toxicity of paclitaxel. We evaluated if EPHA genetic variation (EPHA4, EPHA5, EPHA6, and EPHA8) is associated with PN sensitivity by accounting for variability in systemic paclitaxel exposure (time above threshold). METHODS: Germline DNA from 60 patients with breast cancer was sequenced. PN was measured using the 8-item sensory subscale (CIPN8) of the patient-reported CIPN20. Associations for 3 genetic models were tested by incorporating genetics into previously published PN prediction models integrating measured paclitaxel exposure and cumulative treatment. Significant associations were then tested for association with PN-related treatment disruption. RESULTS: EPHA5 rs7349683 (minor allele frequency = 0.32) was associated with increased PN sensitivity (ß-coefficient = 0.39, 95% confidence interval 0.11-0.67, p = 0.007). Setting a maximum tolerable threshold of CIPN8 = 30, optimal paclitaxel exposure target is shorter for rs7349683 homozygous (11.6 h) than heterozygous (12.6 h) or wild-type (13.6 h) patients. Total number of missense variants (median = 0, range 0-2) was associated with decreased PN sensitivity (ß-coefficient: -0.42, 95% confidence interval -0.72 to -0.12, P = .006). No association with treatment disruption was detected for the total number of missense variants or rs7349683. CONCLUSION: Isolating toxicity sensitivity by accounting for exposure is a novel approach, and rs7349683 represents a promising marker for PN sensitivity that may be used to individualize paclitaxel treatment.

Randomized controlled trial of cryotherapy to prevent paclitaxel-induced peripheral neuropathy (RU221511I); an ACCRU trial.

PURPOSE: This pilot trial aimed to assess if cooling hands and feet with crushed ice during receipt of paclitaxel helps prevent peripheral neuropathy. METHODS: This prospective, randomized trial compared cryotherapy to standard care in patients initiating paclitaxel weekly x 12. For those on cryotherapy, hands and feet were cooled starting 15 min prior to and ending 15 min after each paclitaxel dose. EORTC QLQ-CIPN20 was completed at baseline, weekly x12, then monthly x6. Area under the curve (AUC) was calculated for subscale scores, adjusting for baseline, and compared between arms (Wilcoxon rank-sum test). Cross-study comparisons used data from 2 prior similarly-conducted neuropathy trials. RESULTS: Forty-six patients were accrued. Three withdrew and one was ineligible. Of the remaining 42 (21 cryotherapy, 21 control), 39 (19 cryotherapy, 20 control) were analyzable for AUC. Cryotherapy was well tolerated, but the AUC of the CIPN20 sensory scores over 12 weeks of paclitaxel was not found to differ between the study arms (mean difference 3.45, 95% CI -3.13 to 10.02, p = 0.26). However, the control arm of the current trial experienced less neuropathy than did the placebo arms of two previous similar trials. When our cryotherapy arm was compared to the combined control arms from all three trials, the cryotherapy arm had less neuropathy (Wilcoxon Rank-Sum p = 0.01). CONCLUSION: While there was no difference in CIPN20 scores identified between the 2 study arms in the current phase II trial, further investigation is needed given that the control arm experienced less neuropathy than was expected.

Biological predictors of chemotherapy-induced peripheral neuropathy (CIPN): MASCC neurological complications working group overview.

Chemotherapy-induced peripheral neuropathy (CIPN) is a common and debilitating condition associated with a number of chemotherapeutic agents. Drugs commonly implicated in the development of CIPN include platinum agents, taxanes, vinca alkaloids, bortezomib, and thalidomide analogues. As a drug response can vary between individuals, it is hypothesized that an individual's specific genetic variants could impact the regulation of genes involved in drug pharmacokinetics, ion channel functioning, neurotoxicity, and DNA repair, which in turn affect CIPN development and severity. Variations of other molecular markers may also affect the incidence and severity of CIPN. Hence, the objective of this review was to summarize the known biological (molecular and genomic) predictors of CIPN and discuss the means to facilitate progress in this field.

MRI guidance technology development in a large animal model for hyperlocal analgesics delivery to the epidural space and dorsal root ganglion.

BACKGROUND: Development of new analgesic drugs or gene therapy vectors for spinal delivery will be facilitated by "hyperlocal" targeting of small therapeutic injectate volumes if spine imaging technology can be used that is ready for future clinical translation. NEW METHOD: This study provides methods for MRI-guided drug delivery to the periganglionic epidural space and the dorsal root ganglion (DRG) in the Yucatan swine. RESULTS: Phantom studies showed artifact-corrected needle localization with frequency encoding parallel to the needle shaft, while maximizing bandwidth (125 KHz) minimized needle artifact. A custom constructed 8-12 element surface coil (phased array) wrapped over the spine in conjunction with lateral recumbent positioning achieved diagnostic quality signal to noise ratio at the depth of the DRG and afforded transforaminal access via anterolateral or posterolateral vectors, as well as interlaminar access. Swine epidural anatomy was homologous with human anatomy. Injectate containing 2% gadolinium allowed imaging of injectate volumes in increments as small as 10 microliters and discrimination of epidural flow from intraparenchymal injectate delivery into a DRG. All technical and technological elements of the procedure appear clinically translatable. COMPARISON WITH EXISTING METHODS: Computed tomographic or fluoroscopic guidance cannot directly visualize drug delivery into the DRG due to contrast medium toxicity, nor reliably identify epidural injection volumes of < 50 microliters. CONCLUSIONS: MRI-guided hyperlocal delivery in swine provides a translatable and faithful model of future human spinal novel drug- or gene therapy vector delivery.

Unilateral Epidural Targeting of Resiniferatoxin Induces Bilateral Neurolysis of Spinal Nociceptive Afferents.

OBJECTIVE: This study modeled image-guided epidural drug delivery to test whether intraprocedural distribution of pre-injected contrast reliably predicts the neuroanatomical reach of resiniferatoxin-mediated nociceptive neurolysis. METHODS: Swine (N = 12) received unilateral L4-S2 computed tomography fluoroscopy injections by a blinded neuroradiologist; 0.25 mL of contrast was pre-injected to confirm dorsal periganglionic targeting, followed by a 0.5-mL injection of 5 µg of resiniferatoxin/Tween80 or vehicle control. Epidural contrast distribution was graded according to maximum medial excursion. Spinal cord substance P immunostaining quantified the magnitude and anatomical range of resiniferatoxin activity. RESULTS: Periganglionic injection was well tolerated by all animals without development of neurological deficits or other complications. Swine were a suitable model of human clinical spinal intervention. The transforaminal approach was used at all L4 and 50% of L5 segments; the remaining segments were approached by the interlaminar route. All injections were successful with unilateral contrast distribution for all resiniferatoxin injections (N = 28). Immunohistochemistry showed bilateral ablation of substance P+ fibers entering the spinal cord of all resiniferatoxin-treated segments. The intensity of substance P immunostaining in treated segments fell below the lower 99% confidence interval of controls, defining the knockout phenotype. Substance P knockout occurred over a narrow range and was uncorrelated to the anatomical distribution of pre-injected contrast. CONCLUSIONS: Periganglionic resiniferatoxin/Tween80 induced bilateral ablation of spinal cord substance P despite exclusively unilateral targeting. These data suggest that the location of pre-injected contrast is an imperfect surrogate for the neuroanatomical range of drugs delivered to the dorsal epidural compartment that may fail to predict contralateral drug effects.

Clinical magnetic resonance-enabled characterization of mono-iodoacetate-induced osteoarthritis in a large animal species.

INTRODUCTION: Osteoarthritis (OA) is the most common form of arthritis. Medical and surgical treatments have yet to substantially diminish the global health and economic burden of OA. Due to recent advances in clinical imaging, including magnetic resonance imaging (MRI), a correlation has been established between structural joint damage and OA-related pain and disability. Existing preclinical animal models of OA are useful tools but each suffers specific roadblocks when translating structural MRI data to humans. Intraarticular injection of mono-iodoacetate (MIA) is a reliable, well-studied method to induce OA in small animals but joint size discrepancy precludes the use of clinical grade MRI to study structural disease. The porcine knee is suited for clinical MRI and demonstrates homology with humans. We set out to establish the first large animal model of MIA-induced knee OA in swine characterized by structural MRI. MATERIALS AND METHODS: Yucatan swine (n = 27) underwent ultrasound-guided injection of knees with 1.2, 4, 12, or 40 mg MIA. MRI was performed at several time points over 12 weeks (n = 54 knees) and images were assessed according to a modified clinical grading scheme. Knees were harvested and graded up to 35 weeks after injection. RESULTS: MIA-injected knees (n = 25) but not control knees (n = 29) developed gross degeneration. A total of n = 6,000 MRI measurements were recorded by two radiologists. MRI revealed progressive cartilage damage, bone marrow edema, erosions, and effusions in MIA-injected knees. Lesion severity and progression was influenced by time, dose, and inter-individual variability. CONCLUSIONS: Intraarticular injection of MIA produced structural knee degradation that was reliably characterized using clinical MRI in swine. Destruction was progressive and, similar to human OA, lesion severity was heterogeneous between and within treatment groups.

Human interleukin-10 delivered intrathecally by self-complementary adeno-associated virus 8 induces xenogeneic transgene immunity without clinical neurotoxicity in swine.

INTRODUCTION: Intrathecal interleukin (IL)-10 delivered by plasmid or viral gene vectors has been proposed for clinical testing because it is effective for chronic pain in rodents, is a potential therapeutic for various human diseases, and was found to be nontoxic in dogs, when the human IL-10 ortholog was tested. However, recent studies in swine testing porcine IL-10 demonstrated fatal neurotoxicity. The present study aimed to deliver vector-encoded human IL-10 in swine, measure expression of the transgene in cerebrospinal fluid and monitor animals for signs of neurotoxicity. RESULTS: Human IL-10 levels peaked 2 weeks after vector administration followed by a rapid decline that occurred concomitant with the emergence of anti-human IL-10 antibodies in the cerebrospinal fluid and serum. Animals remained neurologically healthy throughout the study period. CONCLUSIONS: The findings of the present study suggest that swine are not idiosyncratically sensitive to intrathecal IL-10 because, recapitulating previous reports in dogs, they suffered no clinical neurotoxicity from the human ortholog. These results strongly infer that toxicity of intrathecal IL-10 in large animal models was previously overlooked because of a species mismatch between transgene and host. The present study further suggests that swine were protected from interleukin-10 by a humoral immune response against the xenogeneic cytokine. Future safety studies of IL-10 or related therapeutics may require syngeneic large animal models.

Laminotomy for Lumbar Dorsal Root Ganglion Access and Injection in Swine.

Dorsal root ganglia (DRG) are anatomically well defined structures that contain all primary sensory neurons below the head. This fact makes DRG attractive targets for injection of novel therapeutics aimed at treating chronic pain. In small animal models, laminectomy has been used to facilitate DRG injection because it involves surgical removal of the vertebral bone surrounding each DRG. We demonstrate a technique for intraganglionic injection of lumbar DRG in a large animal species, namely, swine. Laminotomy is performed to allow direct access to DRG using standard neurosurgical techniques, instruments, and materials. Compared with more extensive bone removal via laminectomy, we implement laminotomy to conserve spinal anatomy while achieving sufficient DRG access. Intraoperative progress of DRG injection is monitored using a non-toxic dye. Following euthanasia on post-operative day 21, the success of injection is determined by histology for intraganglionic distribution of 4',6-diamidino-2-phenylindole (DAPI). We inject a biologically inactive solution to demonstrate the protocol. This method could be applied in future preclinical studies to target therapeutic solutions to DRG. Our methodology should facilitate testing the translatability of intraganglionic small animal paradigms in a large animal species. Additionally, this protocol may serve as a key resource for those planning preclinical studies of DRG injection in swine.

Fatal Meningitis in Swine after Intrathecal Administration of Adeno-associated Virus Expressing Syngeneic Interleukin-10.

Interleukin-10 (IL-10) delivered by intrathecal (i.t.) gene vectors is a candidate investigational new drug (IND) for several chronic neurological disorders such as neuropathic pain. We performed a preclinical safety study of IL-10. A syngeneic large animal model was used delivering porcine IL-10 (pIL-10) to the i.t. space in swine by adeno-associated virus serotype 8 (AAV8), a gene vector that was previously found to be nontoxic in the i.t. space. Unexpectedly, animals became ill, developing ataxia, seizures, and an inability to feed and drink, and required euthanasia. Necropsy demonstrated lymphocytic meningitis without evidence of infection in the presence of normal laboratory findings for body fluids and normal histopathology of peripheral organs. Results were replicated in a second animal cohort by a team of independent experimenters. An extensive infectious disease and neuropathology workup consisting of comprehensive testing of tissues and body fluids in a specialized research veterinary pathology environment did not identify a pathogen. These observations raise the concern that i.t. IL-10 therapy may not be benign, that previously used xenogeneic models testing the human homolog of IL-10 may not have been sensitive enough to detect toxicity, and that additional preclinical studies may be needed before clinical testing of IL-10 can be considered.

Oxaliplatin-Induced Peripheral Neuropathy and Identification of Unique Severity Groups in Colorectal Cancer.

CONTEXT: Oxaliplatin-induced peripheral neuropathy (OIPN) is a dose-limiting toxicity of oxaliplatin and affects most colorectal cancer patients. OIPN is commonly evaluated by patient symptom report, using scales to reflect impairment. They do not discriminate between unique grouping of symptoms and signs, which impedes prompt identification of OIPN. OBJECTIVE: The objective of this study was to identify clusters of symptoms and signs that differentiated underlying clinical severity and segregated patients within our population into OIPN subgroups. METHODS: Chemotherapy-naive colorectal cancer patients (N = 148) receiving oxaliplatin were administered the Total Neuropathy Score clinical (TNSc©), which includes symptom report (sensory, motor, autonomic) and sensory examination (pin sense, vibration, reflexes). The TNSc was administered before chemotherapy initiation (T0) and after cumulative doses of oxaliplatin 510-520 mg/m2 (T1) and 1020-1040 mg/m2 of oxaliplatin (T2). Using mean T2 TNSc scores, latent class analysis grouped patients into OIPN severity cohorts. RESULTS: Latent class analysis categorized patients into four distinct OIPN groups: low symptoms and low signs (n = 54); low symptoms and intermediate signs (n = 44); low symptoms and high signs (n = 21); and high symptoms and high signs (n = 29). No differences were noted among OIPN groups on age, sex, chemotherapy regimen, or cumulative oxaliplatin dose. CONCLUSION: We identified OIPN patient groups with distinct symptoms/signs, demonstrating variability of OIPN presentation regardless of cumulative oxaliplatin dose. Over half of the sample had positive findings on OIPN examination despite little or no symptoms. Sensory examination of all patients receiving oxaliplatin is indicated for timely identification of OIPN, which will allow earlier symptom management.

Patient-reported (EORTC QLQ-CIPN20) versus physician-reported (CTCAE) quantification of oxaliplatin- and paclitaxel/carboplatin-induced peripheral neuropathy in NCCTG/Alliance clinical trials.

PURPOSE: Clinical practice guidelines on chemotherapy-induced peripheral neuropathy (CIPN) use the NCI Common Terminology Criteria for Adverse Events (CTCAE), while recent clinical trials employ a potentially superior measure, the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-CIPN twenty-item scale (QLQ-CIPN20), a patient-reported outcome (PRO). Practitioners and researchers lack guidance, regarding how QLQ-CIPN20 results relate to the traditional CTCAE during the serial assessment of patients undergoing chemotherapy. METHODS: Two large CIPN clinical trial datasets (538 patients) pairing QLQ-CIPN20 and CTCAE outcomes were analyzed using a multivariable linear mixed model with QLQ-CIPN20 score as the outcome variable, CTCAE grade as the main effect, and patient as random effect (accounting for internal correlation of serial measures). RESULTS: The association between QLQ-CIPN20 scores and CTCAE grades was strong (p < 0.0001), whereby patients with higher CTCAE grade had worse QLQ-CIPN20 scores. Some variation of QLQ-CIPN20 scores was observed based on drug, treatment, and cycle. While there was a marked difference in the mean QLQ-CIPN20 scores between CTCAE grades, the ranges of QLQ-CIPN20 scores within each CTCAE grade were large, leading to large overlap in CIPN20 scores across CTCAE grades. CONCLUSIONS: A strong positive association of QLQ-CIPN20 scores and CTCAE grade provides evidence of convergent validity as well as practical guidance, as to how to quantitatively interpret QLQ-CIPN20 scores at the study level in terms of the traditional CTCAE. The present results also highlight an important clinical caveat, specifically, that conversion of a specific QLQ-CIPN20 score to a specific CTCAE score may not be reliable at the level of an individual patient.

A pilot study of minocycline for the prevention of paclitaxel-associated neuropathy: ACCRU study RU221408I.

PURPOSE: Paclitaxel is associated with both an acute pain syndrome (P-APS) and chronic chemotherapy-induced peripheral neuropathy (CIPN). Given that extensive animal data suggest that minocycline may prevent chemotherapy-induced neurotoxicity, the purpose of this pilot study was to investigate the efficacy of minocycline for the prevention of CIPN and the P-APS. METHODS: Patients with breast cancer were enrolled prior to initiating neoadjuvant or adjuvant weekly paclitaxel for 12 weeks and were randomized to receive minocycline 200 mg on day 1 followed by 100 mg twice daily or a matching placebo. Patients completed (1) an acute pain syndrome questionnaire daily during chemotherapy to measure P-APS and (2) the EORTC QLQ-CIPN20 questionnaire at baseline, prior to each dose of paclitaxel, and monthly for 6 months post treatment, to measure CIPN. RESULTS: Forty-seven patients were randomized. There were no remarkable differences noted between the minocycline and placebo groups for the overall sensory neuropathy score of the EORTC QLQ-CIPN20 or its individual components, which evaluate tingling, numbness and shooting/burning pain in hands and feet. However, patients taking minocycline had a significant reduction in the daily average pain score attributed to P-APS (p = 0.02). Not only were no increased toxicities reported with minocycline, but there was a significant reduction in fatigue (p = 0.02). CONCLUSIONS: Results of this pilot study do not support the use of minocycline to prevent CIPN, but suggest that it may reduce P-APS and decrease fatigue; further study of the impact of this agent on those endpoints may be warranted.

Comparison of oxaliplatin and paclitaxel-induced neuropathy (Alliance A151505).

PURPOSE: Oxaliplatin and paclitaxel are commonly used chemotherapies associated with acute and chronic neuropathies. There is a need to better understand the similarities and differences of these clinical syndromes. METHODS: Neuropathy data were pooled from patients receiving adjuvant oxaliplatin and weekly paclitaxel or every 3 weeks of paclitaxel. Patients completed daily questionnaires after each chemotherapy dose and the European Organization for Research and Treatment of Cancer quality-of-life questionnaire for patients with chemotherapy-induced peripheral neuropathy before each chemotherapy cycle and for 12 months post-treatment. RESULTS: Acute neuropathy symptoms from both drugs peaked around day 3. Acute symptoms experienced in cycle 1 predicted occurrence in subsequent cycles. Paclitaxel-induced acute symptoms were similar in intensity in each cycle and largely resolved between cycles. Oxaliplatin-induced acute symptoms were about half as severe in the first cycle as in later cycles and did not resolve completely between cycles. Both drugs caused a predominantly sensory chronic neuropathy (with numbness and tingling being more common than pain). Oxaliplatin-induced neuropathy worsened after the completion of treatment and began to improve 3 months post-treatment. In contrast, paclitaxel-induced neuropathy began improving immediately after chemotherapy cessation. During treatment, the incidence of paclitaxel sensory symptoms was similar in the hands and feet; with oxaliplatin, the hands were affected more than the feet. Both paclitaxel- and oxaliplatin-induced acute neurotoxicity appeared to predict the severity of chronic neuropathy, more prominently with oxaliplatin. CONCLUSIONS: Knowledge of the similarities and differences between neuropathy syndromes may provide insight into their underlying pathophysiology and inform future research to identify preventative treatment approaches.