009. Safe use of fluoroquinolones: A focus on limiting CNS and peripheral neuropathy adverse events

Background: Bortezomib is used as first-line therapy for multiple myeloma. Observational studies based on the FDA Adverse Event Reporting System (FAERS) database analysis and systematic reviews indicate that the incidence of peripheral neuropathy and tumor lysis syndrome (TLS) tends to be higher with bortezomib than that of other drugs. In a comprehensive analysis assessing drugs that cause peripheral neuropathy in Japanese patients, the incidence of bortezomib-induced adverse events (AEs) was reportedly high. However, a comprehensive assessment of bortezomib is lacking. Objectives: The purpose of this study was to determine the frequency of bortezomib AEs in Japanese patients and to determine the incidence, time to onset, and post hoc outcomes of unique AEs using the Japanese Adverse Drug Event Report (JADER) database. Method: To investigate the association between bortezomib and AEs, we analyzed the JADER database, which contains spontaneous AE reports submitted to the Pharmaceuticals and Medical Devices Agency from April 2004 to December 2020. Criteria indicating the presence of an AE signal were met when the following requirements were fulfilled: proportional reporting ratios (PRR) ≥ 2 and χ2 ≥ 4. Time to onset and post-event outcomes were analyzed for characteristic AEs. Results: Among 26 extracted AEs, 13 presented AE signals. The post-exposure outcomes of 12 AEs showed fatal outcomes at rates exceeding 10%, including cardiac failure (30%), lung disorder (24%), pneumonia (18%), and TLS (10%). Furthermore, a histogram of time to onset revealed that the 12 AEs were concentrated from the beginning to approximately one month after bortezomib administration. The median onset times for cardiac failure, lung disorder, pneumonia, and TLS were 28, 13, 42, and 5 days, respectively. Conclusions: Cardiac failure, lung disorder, pneumonia, and TLS had a higher rate of fatal clinical outcomes after onset than other AEs. These AEs exhibited a greater onset tendency in the early post-dose period. This study suggests that there is a need to monitor signs of cardiac failure, lung disorder, pneumonia, and TLS, potentially resulting in serious outcomes.

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Innovative Approach for the Prevention of Chemotherapy-Induced Peripheral Neuropathy in Cancer Patients: A Pilot Study With the Hilotherm Device, the Poliambulanza Hospital Experience

Integrative Cancer Therapies ◽

10.1177/1534735420943287 ◽

2020 ◽

Vol 19 ◽

pp. 153473542094328

Author(s):

Ester Oneda ◽

Fausto Meriggi ◽

Laura Zanotti ◽

Elisabetta Zaina ◽

Sara Bighè ◽

...

Keyword(s):

Quality Of Life ◽

Peripheral Neuropathy ◽

Adverse Events ◽

Negative Impact ◽

Life Questionnaire ◽

European Organization ◽

Effective Prevention ◽

The Common ◽

Hands And Feet

Background: Chemotherapy-induced peripheral neuropathy (CIPN) is an adverse event of taxanes, with no effective prevention or treatment available and a highly negative impact on patient quality of life. The aim of this study is to asses that the constant application of cooled cuffs on the hands and feet prevent and mitigate CIPN. Methods: Patients with breast, gynecologic, and pancreatic cancer who received weekly paclitaxel (PTX), PTX/carboplatin, and nab-paclitaxel (nab-PTX)/gemcitabine for any indication at the therapeutic scheduled dosage were included in this prospective study. Hilotherm Chemo care device forms a closed-loop system with cuffs and tubes through which a coolant flows at a temperature of 10 °C. CIPN was monitored using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (edition 3.0), and the tolerability and side effects were scored by using the Common Terminology Criteria for Adverse Events (T4.03 2017). Results: To date, we have enrolled 64 patients. Of these, 54 (84%) completed all cooling cycles. Continuous cooling was well tolerated by all patients. No patients had grade >2 CIPN or had serious or lasting adverse events as a result of Hilotherapy. The median time to CIPN onset was 77 days for the entire population. Conclusion: Hilotherapy has good effectiveness and tolerability and seems to be able to prevent or reduce the symptoms of CIPN. We are still recruiting patients to obtain more data and to collect data at 3 months after the end of chemotherapy. Prospective studies seem to be warranted.

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The Relationship Between Evaluation Methods for Chemotherapy-Induced Peripheral Neuropathy

Scientific Reports ◽

10.1038/s41598-019-56969-9 ◽

2019 ◽

Vol 9 (1) ◽

Cited By ~ 3

Author(s):

Yoichiro Yoshida ◽

Atsushi Satoh ◽

Teppei Yamada ◽

Naoya Aisu ◽

Taisuke Matsuoka ◽

...

Keyword(s):

Colorectal Cancer ◽

Peripheral Neuropathy ◽

Visual Analogue Scale ◽

Adverse Events ◽

Analogue Scale ◽

Evaluation Methods ◽

Sense Perception ◽

Analytical Instrument ◽

The Relationship ◽

Monofilament Test

AbstractNumbness and pain are currently evaluated using subjective methods such as the visual analogue scale (VAS). PainVision (PV) is an analytical instrument that was designed to quantitatively assess sense perception and nociception in patients. Chemotherapy-induced peripheral neuropathy (CIPN) is one of the most important adverse events that renders prolonged chemotherapy difficult. To assess the features of CIPN, we aimed to compare PV methods with existing methods. A total of 73 patients received oxaliplatin for metastatic colorectal cancer. Registered patients included 37 men and 36 women in the range of 37 to 89 years (median 70). CIPN was evaluated a total of 483 times (median per patient six times). Our study examined the correlation between evaluation methods of CIPN using VAS and PV, respectively. The average VAS (hand), VAS (foot) and PV scores of CIPN were 18.4 (range: 0–100), 23.8 (range: 0–100), and 24.7 (range: 0–496), respectively. VAS (hand), VAS (foot), and FACT/GOG-NTX (NTX2, NTX4 and NTX8) were significantly correlated with PV. PV showed no correlation with a Disk-Criminator or the monofilament test used as a quantitative evaluation. The evaluation of CIPN is complex, and further improvement is required for evaluation with PV.

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Phase II Study of Thalidomide in Escalating Doses for Follicular (F-NHL) and Small Lymphocytic Lymphoma (Sll): CALGB Study 50002.

Blood ◽

10.1182/blood.v104.11.3284.3284 ◽

2004 ◽

Vol 104 (11) ◽

pp. 3284-3284 ◽

Cited By ~ 4

Author(s):

David L. Grinblatt ◽

Jeffrey Johnson ◽

Donna Niedzwicki ◽

David A. Rizzieri ◽

Nancy Bartlett ◽

...

Keyword(s):

Peripheral Neuropathy ◽

Adverse Events ◽

Phase Ii ◽

Performance Status ◽

Sensory Neuropathy ◽

Complete Response ◽

Lymph Node Biopsy ◽

Prior Therapy ◽

Median Daily Dose ◽

Grade 3

Abstract Background: Thalidomide has marked activity in both untreated and heavily pretreated myeloma. Its activity in part is believed to be due to inhibition of bFGF and VEGF induced angiogenesis. Elevated levels of bFGF in serum and urine have correlated with decreased survival in lymphoma possibly through up-regulation of BCL-2. Methods: 25 patients (pts) with previously treated F-NHL and SLL were registered and treated on this multi-institutional study from July 2001–April 2004 to evaluate the efficacy and safety of oral thalidomide in this patient group. Pts had B-cell SLL (7: 36.8%), F-NHL grade 1 (7: 36.8%), grade 2 (3: 15.8%) and grade 3 (2: 10.1%) NHL. Pts were eligible for entry with up to 3 prior chemotherapy (CT) and 2 immunotherapy (IT) regimens provided performance status was ≥ 1. Pts with new onset of B-symptoms, rising LDH, rapid tumor growth or greater than one year from initial diagnosis were required to undergo repeat lymph node biopsy to exclude recent transformation. Pts with CNS involvement, prior peripheral neuropathy >gr 1, HIV+, and pregnant or nursing women were also excluded. Pts were required to have Cr <2 x ULN, AST/ALT <2.5 x ULN and an ANC > 750. Median age at study entry was 60 years (36–87). Prior therapy was evaluated in 20 pts and 17/20 had received multi-agent CT while 12/20 pts received prior IT. Thalidomide was initiated at a dose of 200 mg daily and escalated by 100 mg daily every 1–2 weeks as tolerated with a maximal dose of 800 mg/d. If ≥ gr 2 peripheral neuropathy or ≥ gr 3 somnolence or mood changes occurred, the dose was held for one week and restarted at 50% of the prior daily dosage. Results: The median daily dose was 400 mg (range 50–800 mg). There was 1 complete response (CRu-residual abnormality) in a pt with SLL and one partial response in a pt with F-NHL grade 1 (ORR 8%: 95%CI: 1–26%). 16 pts had progressive disease during therapy and 2 died of disease soon after stopping therapy due to adverse events. One patient continues on therapy without progression of disease to date. The remaining 4 pts were taken off of therapy prior to the first 3 month evaluation. The reason for withdrawal was pt refusal (2) and adverse events (2). The median event free survival was 2.6 months (95% CI:1.4–4.4 mos) with a median overall survival of 23.3 months. Toxicity information on 24/25 pts revealed 4 (17%) with grade 4 neutropenia with 1/4 febrile as well. The most common grade 3 toxicities were anemia (13%), dyspnea (13%), fatigue (8%) and neurologic toxicities consisting of somnolence, dizziness, depression and anxiety (21%). Peripheral sensory neuropathy was reported as gr 2 in 8% and gr 3 in 8%. However, 38% of pts were reported as experiencing gr 2 fatigue. There were no grade 5 toxicities. Conclusion: These phase II trial results in a pretreated pt population demonstrate that, despite an acceptable toxicity profile, thalidomide has only minimal efficacy in F- NHL and SLL.

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A Systematic Review and Meta-Analysis of Thalidomide in Patients with Previously Untreated Multiple Myeloma.

Blood ◽

10.1182/blood.v108.11.3570.3570 ◽

2006 ◽

Vol 108 (11) ◽

pp. 3570-3570 ◽

Cited By ~ 1

Author(s):

Lisa Hicks ◽

Adam Haynes ◽

Donna E. Reece ◽

Irwin Walker ◽

Jordan A. Herst ◽

...

Keyword(s):

Multiple Myeloma ◽

Relative Risk ◽

Peripheral Neuropathy ◽

Adverse Events ◽

Response Rate ◽

Meta Analysis ◽

Cochrane Library ◽

Number Needed To Treat ◽

Vte Prophylaxis ◽

American Society

Abstract Background: Multiple myeloma disproportionately affects the elderly and is currently an incurable malignancy. New therapies for myeloma, particularly oral therapies, are urgently needed. Objectives: To determine if thalidomide with or without other agents, improves response rate (≥ 50% reduction in monoclonal protein), survival, and/or progression in patients with previously untreated myeloma. To determine the frequency and significance of major adverse events associated with thalidomide in this setting. Methods: A literature search of Medline (1966–June 2006), Embase (1980–June 2006), the Cochrane Library, abstracts from the annual meetings of the American Society of Hematology (1999–2005) and the American Society of Oncology (1999–2006) was completed with a pre-specified search strategy. No language restrictions were applied. Randomized controlled trials of induction thalidomide (any dose, any duration) for adults with previously untreated multiple myeloma were included. Trials of exclusively maintenance therapy were excluded. Two reviewers independently extracted data. The methodological quality of selected trials was assessed and summarized. Weighted data was expressed as relative risk, risk difference, number needed to treat (NNT), and number needed to harm (NNH). A random-effects model was used. Results: Six eligible studies involving almost two thousand patients (N=1875) were identified and meta-analyzed. Two studies were published and four were reported in abstract form only. Five studies reported overall response rate (ORR); the four largest trials reported statistically significant improvements in ORR with the addition of thalidomide to standard therapy. The weighted relative risk of responding to a thalidomide-containing regimen versus control was 1.50 (95% CI 1.21 to 1.86). The NNT to achieve one additional response with thalidomide was 4 (95% CI 2.9 to 8.3). Two trials reported improvements in EFS/PFS. One trial reported an improvement in OS. The risk of VTE, peripheral neuropathy, and constipation was consistently elevated with thalidomide such that for every 50 patients treated with a thalidomide-containing-regimen, one could expect 12 to 13 additional patients to respond, 4 additional patients to develop VTE (NNH 12.5; 95% CI 8.3 to 20), 2 additional patients to develop peripheral neuropathy (NNH 25; 95% CI 16.7 to 50), and 4 additional patients to develop constipation (NNH14; 95% CI 10 to 25). In our analyses, prophylactic anticoagulation appeared to decrease, but not abolish, the risk of VTE with thalidomide. Conclusions: Thalidomide improves response rate and possibly progression free and overall survival in patients with previously untreated myeloma. It also increases the incidence of VTE, neuropathy, constipation and other adverse events. Further studies are required to confirm the survival advantage seen in one study, and to determine the optimum strategy for VTE prophylaxis.

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Effect of Mirogabalin on Chemotherapy-Induced Peripheral Neuropathy Caused by Gemcitabine Plus Nab-Paclitaxel Therapy in Pancreatic Cancer Patients: A Pilot Study

10.21203/rs.3.rs-948459/v1 ◽

2021 ◽

Author(s):

Yusuke Takasaki ◽

Toshio Fujisawa ◽

Mako Ushio ◽

Sho Takahashi ◽

Wataru Yamagata ◽

...

Keyword(s):

Pancreatic Cancer ◽

Peripheral Neuropathy ◽

Pilot Study ◽

Adverse Events ◽

Rating Scale ◽

Numerical Rating Scale ◽

Sensory Neuropathy ◽

Life Questionnaire ◽

European Organization ◽

Patient Reported

Abstract Purpose: Gemcitabine/nab-paclitaxel (GnP) therapy is widely used to treat pancreatic cancer (PC), but chemotherapy-induced peripheral neuropathy (CIPN) is common. Mirogabalin is a novel drug for treating peripheral neuropathy. We investigated the effects of mirogabalin on CIPN due to GnP therapy in PC patients.Methods: This was a single-center retrospective pilot study. Patients who had previously received or were currently receiving GnP for PC and had taken mirogabalin for at least 2 weeks for CIPN, were included. Patients completed a questionnaire about their symptoms before and after taking mirogabalin. The primary outcome was the change in numbness and tingling scores on the patient-reported outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE). Secondary outcomes were the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire–Chemotherapy-Induced Peripheral Neuropathy (QLQ-CIPN20) (Japanese version) score, numerical rating scale (NRS) pain score, and adverse events (AEs).Results: Increased numbness and tingling severity (1.84 vs. 1.76; P=0.63) and interference with daily life (1.42 vs. 1.44; P=0.80) were not seen in any of the 25 enrolled patients. The scores on the sensory subscale of the QLQ-CIPN improved significantly after treatment (17.5 vs. 15.7; P=0.02). AEs occurred in 22 patients (88%), but there were no serious AEs (≥ grade 3).Conclusions: Mirogabalin may control the progression of CIPN caused by GnP therapy in PC patients, and improved sensory neuropathy significantly in our patients. However, since the incidence of AEs is high, mirogabalin should be used with caution.

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GSTP1 as a potential predictive factor for adverse events associated with platinum‑based antitumor agent‑induced peripheral neuropathy

Oncology Letters ◽

10.3892/ol.2019.9907 ◽

2019 ◽

Cited By ~ 3

Author(s):

Sou Katayanagi ◽

Kenji Katsumata ◽

Yasuharu Mori ◽

Katsunori Narahara ◽

Masatoshi Shigoka ◽

...

Keyword(s):

Peripheral Neuropathy ◽

Adverse Events ◽

Predictive Factor ◽

Antitumor Agent

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A phase II trial of low-dose nab-paclitaxel for patients with previously treated or recurrent advanced gastric cancer (OGSG1302).

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.4_suppl.350 ◽

2020 ◽

Vol 38 (4_suppl) ◽

pp. 350-350

Author(s):

Masashi Hirota ◽

Shigeyuki Tamura ◽

Hirokazu Taniguchi ◽

Atsushi Takeno ◽

Hiroshi Imamura ◽

...

Keyword(s):

Gastric Cancer ◽

Peripheral Neuropathy ◽

Adverse Events ◽

Phase Ii ◽

Low Dose ◽

Response Rate ◽

Phase Ii Trial ◽

Dose Intensity ◽

Relative Dose Intensity ◽

Grade 3

350 Background: Paclitaxel is a key drug in second-line chemotherapy for advanced or recurrent gastric cancer (AGC) and nanoparticle albumin-bound paclitaxel (nab-PTX) is also widely used in Japan. A previous phase II trial in Japan showed the effectiveness of nab-PTX (260 mg/m2) administered every 3 weeks (q3w) in patients with AGC with a response rate (RR) of 27.8%; however, toxicity was major concern with grade ≥3 neutropenia (49.1%) and peripheral neuropathy (23.6%). To solve this problem, we investigated the efficacy and safety of low-dose q3w nab-PTX regimen in AGC. Methods: Eligibility requirements included: aged ≥20 years, HER2-negative, histologically confirmed, unresectable or recurrent gastric adenocarcinoma, one or more prior chemotherapy containing fluoropyrimidine regimens, presence of measurable lesion(s) according to RECIST ver. 1.1, ECOG PS of 0–2, and adequate organ function. Nab-PTX was administered at a dose of 220 mg/m2 every 3 weeks. The primary endpoint was the RR. Secondary endpoints were overall survival (OS), progression-free survival (PFS), disease-control rate (DCR), incidence of adverse events, relative dose intensity and proportion of patients who received subsequent chemotherapy. Results: Thirty-three patients were enrolled from 10 institutions in Japan. Of the 32 patients treated with protocol therapy, RR (CR, PR) was 3.1% (95% CI, 0–16.2%), which was not reached the protocol-specified threshold (p = 0.966). DCR (CR, PR, SD) was 37.5% (95% CI, 21.1–56.3%), median OS and PFS were 6.3 months (95% CI, 4.4–14.2) and 2.2 months (95% CI, 1.8-3.1). Relative dose intensity was 97.8% (215 mg/m2). 62.5% of patients received subsequent chemotherapy. Most common grade ≥3 adverse events were neutropenia (38%), anemia (13%), fatigue (19%), anorexia (16%), and peripheral neuropathy (13%). Conclusions: Low-dose regimen of q3w nab-PTX was slightly less toxic, although it did not demonstrate the same effect as the original regimen in response rate. Therefore, it is not recommended for AGC in second or later line setting. Clinical trial information: UMIN 000012701.

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A Phase II Study of Pegylated Liposomal Doxorubicin, Bortezomib and Dexamethasone (DVD) for Patients with Previously Untreated Multiple Myeloma (MM).

Blood ◽

10.1182/blood.v114.22.4936.4936 ◽

2009 ◽

Vol 114 (22) ◽

pp. 4936-4936

Author(s):

James R. Berenson ◽

Ori Yellin ◽

Ravi Patel ◽

Chien-Shing Chen ◽

Ralph Vincent Boccia ◽

...

Keyword(s):

Multiple Myeloma ◽

Peripheral Neuropathy ◽

Adverse Events ◽

Phase Ii ◽

Liposomal Doxorubicin ◽

Phase Ii Study ◽

Severe Combined Immunodeficiency ◽

Pegylated Liposomal Doxorubicin ◽

Pulmonary Interstitial Fibrosis ◽

Grade 3

Abstract Abstract 4936 Despite recent advances in the treatment of MM, the disease remains incurable and many of the most effective, newer combination therapies are accompanied by significant side effects that have a major negative impact on the patient's quality of life. Pegylated liposomal doxorubicin (PLD) and bortezomib have shown anti-MM efficacy in the laboratory and for the treatment of previously treated MM patients, leading to FDA approval for patients who have failed one prior therapy. Using our severe combined immunodeficiency-hu murine models of human MM, we have previously demonstrated that lower doses of PLD administered daily are more effective and better tolerated than higher amounts given weekly. Moreover, the combination of bortezomib and dexamethasone has been shown to be effective for previously untreated MM patients. Prior studies by our group have shown that combining chemotherapy including PLD with bortezomib administered at 1.0 mg/m2 on days 1, 4, 8, and 11 of a 28-day cycle rather than the standard 1.3 mg/m2 on the same days of a 21-day schedule is effective for MM patients with relapsed or refractory disease and associated with a reduction in the incidence and severity of peripheral neuropathy. Thus, we conducted a single-arm multi-center phase II study for previously untreated MM patients to evaluate the combination of intravenously administered dexamethasone, bortezomib and PLD (DVD). The treatment consisted of intravenous administration of 40 mg dexamethasone followed by 1.0 mg/m2 bortezomib and finally 5.0 mg/m2 PLD on days 1, 4, 8, and 11 of a 28-day cycle. Patients were treated to a maximum response plus two additional cycles or completed a maximum of eight cycles of therapy without disease progression. To date, 22 (of 35 planned) patients have been enrolled with a median age of 64 years (range, 42-79 years). The majority of those on study (68 %) were diagnosed with International Staging System II or III MM. Four patients are too early to assess for response. To date, among the 18 evaluable patients, 16 (89%) have shown objective responses to the DVD regimen, including 2 complete responses (11%), 8 partial responses (44%) and 6 minimal responses (33%). The other 2 patients (11%) had stable disease, with one of these subjects showing a continuing reduction in M-protein after 2 cycles of therapy to date. Thus, disease control was achieved in all patients. To date, no patient has shown progressive disease after 2+ - 12+ months of follow-up. Six patients experienced grade 3 adverse events and one patient with a prior history of pulmonary interstitial fibrosis developed a grade 4 toxicity (shortness of breath). Grade 3 adverse events in three of the six patients were judged not to be related to the study treatment. The most common grade 3 adverse event was reversible neutropenia (n=2). To date, only 2 patients (9%) have developed peripheral neuropathy (grade 1). Notably, there have been no cases of stomatitis or hand-foot syndrome. Thus, these results suggest that the DVD regimen using a modified schedule and doses of the combination of intravenous dexamethasone, bortezomib and PLD is a well tolerated treatment that produces high response rates for previously untreated patients with multiple myeloma. Disclosures Berenson: Millennium Pharmaceuticals: Consultancy, Research Funding, Speakers Bureau; Centocor Ortho Biotech: Consultancy, Speakers Bureau. Hilger:Millennium Pharmaceutcals: Employment.

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