Motor Neurotoxicity Research Articles

Efficacy of cryotherapy on chemotherapy-induced peripheral neuropathy in patients with breast cancer: a propensity score-matched study.

This study investigated the effectiveness of cryotherapy in preventing CIPN and its effect on the quality of life (QoL) during chemotherapy. Eligible participants are cancer patients who began therapy with carboplatin, docetaxel, or paclitaxel in the Breast Oncology Unit between May 2022 and October 2022. Patients were distributed into intervention groups that utilized cryotherapy with ice gloves and ice boots and control groups that did not receive cryotherapy. Patient self-report questionnaires were used to quantify patients' symptoms and QoL after treatment. The intervention group exhibited significantly less cold sensitivity, hand and foot numbness, and hand tingling than the control group. Daily CIPN symptoms were substantially milder in the intervention group. Before and after treatment, nerve pain, balance, and muscle and joint discomfort were similar. Intervention and control groups have varied neurotoxicity adverse reaction scores. 2.4% of controls had grade 4 motor neurotoxicity impairment. Physical function and QoL improved in the intervention group. Cryotherapy relieves CIPN symptoms in breast cancer patients receiving carboplatin and paclitaxel chemotherapy. More thorough trials should be carried out to determine the best time limit and duration of cryotherapy.

Prospective Assessment of Motor Neurotoxicity and Sarcopenia in CD30+ Lymphoma Patients Treated with Brentuximab Vedotin. Single Center Multidisciplinary Unit Experience

Introduction: Brentuximab Vedotin (BV), a CD30-targeting antibody-drug conjugate, has been increasingly used for the treatment of several CD30+ lymphomas, being BV-induced motor peripheral neurotoxicity (BVIMN) one of the greatest concerns for treating physicians. Patients may develop weakness with hand and foot paresis as most severe manifestation. Risk factors associated with BVIMN are scarcely known. Before treatment, severe muscle mass depletion (sarcopenia) has been associated with increased chemotherapy-related toxicity in several cancer types. To date, the association between BVIMN and sarcopenia is unknown. Aim: to assess in a multidisciplinary approach the BVIN development in CD30+ lymphoma patients treated at our institution and try to identify those risk factors associated with motor BVIMN development. Material and Methods: Since January 2019, adult patients from our institution receiving BV are prospectively evaluated in a multidisciplinary unit including hematologists, neurologists and nutritionists. Patients are assessed periodically before, during and after completion of treatment. Neurological assessment includes the clinical version of the Total Neuropathy Score (TNSc©), including muscle strength, NCI.CTC gradation scale, patient reported outcomes (PROMs), handgrip dynamometry and conventional nerve conduction studies (NCS) at upper and lower extremities. Nutritional assessment includes anthropometry, laboratory parameters, and body composition analysis of the cross-sectional CT o CT-PET scan at the level of the 3rd lumbar vertebra (L3). Skeletal muscle index (SMI), reflecting muscle mass, and skeletal muscle density (SMD), associated with muscle strength, are used to determine sarcopenia. The association between sarcopenia and BVIMN are evaluated. Results: A total of 58 patients were included in the analysis, of which, 62% had Hodgkin lymphoma and 38% had CD30+ T cell lymphomas, including 8 patients with Mycosis Fungoides. The median age at BV-based treatment initiation was 45 years [21-92], with a predominance of men (55.2%). ECOG was 0,1,2 in 59.6%, 29.8% and 10.6% of patients. In 24% and 76% of patients, BV was administered in monotherapy or in combination with chemotherapy, respectively. The mean total dose of BV received was 856.85 +/- 170 mg. At baseline, 45.2% of patients had sarcopenia. Serum albumin was 42 g/L [28-50]. No differences in cumulated received BV dose between patients with or without sarcopenia were identified. At finishing chemotherapy, BVIN was developed in 72.2% patients, mostly of mild severity (66.7%). Rates of sensory BVIN were: 44.4% grade 1, 22.4% grade 2 and 3.7% grade 3. Motor BVIN was observed in one third (27.8%) of patients: 7.4% (grade 1), 14.8% (grade 2) and 5.6% (grade 3). Patients with moderate (> grade 2) motor BVIN were younger (37 vs 59 years old, p=0.04). Baseline sarcopenia was more frequent in the group of patients developing moderate BVIMN (35% vs 6%, p=0.06). No association with baseline demographic, anthropometric characteristics, or handgrip results were identified. Motor neurotoxicity correlated significatively with motor NCS impairment in upper (r= -0.472, p=0.023) and lower (r=-0.331, p=0.07) extremities. Conclusions: Motor neurotoxicity may develop in one third of patients receiving BV alone or in combination. Sarcopenia, which is common (45.2%) in BV candidates, could be associated with a higher risk of developing motor BVIN. Motor severity of BVIN can be objectively assessed with neurophysiological tests.

Retrograde axonal transport of poliovirus and EV71 in motor neurons

Poliovirus (PV) can spread through neural pathway to the central nervous system and replicates in motor neurons, which leads to poliomyelitis. Enterovirus 71 (EV71), which is closely related to PV, is one of the causative agents of hand-foot-and-mouth disease and can cause severe neurological diseases similar to poliomyelitis. Since PV is similar to EV71 in its motor neurotoxicity, we tried to understand if the results obtained with PV are of general applicability to EV71 and other viruses with similar characteristics. Using microfluidic devices, we demonstrated that both PV capsid and the PV genome undergo axonal retrograde transport with human PV receptor (hPVR), and the transported virus replicated in the soma of hPVR-expressing motor neurons. Similar to PV in hPVR-transgenic (Tg) mice, neural pathway ensuring spreading of EV71 has been shown in adult human scavenger receptor class B, member 2 (hSCARB2)-Tg mice. We have validated this finding in microfluidic devices by showing that EV71 is retrogradely transported together with hSCARB2 to the cell body where it replicates in an hSCARB2-dependent manner.

Prevention of taxane-associated acute pain syndrome with etoricoxib for patients with breast cancer: A phase II randomised trial

BackgroundFor patients with breast cancer who receive docetaxel chemotherapy, taxane-associated acute pain syndrome (T-APS), considered a form of neural pathology, is a significant clinical problem. We evaluated the effect of prophylactic etoricoxib on T-APS in patients with breast cancer. Materials and methodsWe conducted a phase II randomised trial including 144 patients with breast cancer receiving four cycles of docetaxel-based chemotherapy. Patients were randomised in the ratio 1:1 to receive prophylactic etoricoxib (60 mg, Day 1 to Day 8) or no prophylactic treatment. The primary end-point was the overall incidence of T-APS across all cycles. Secondary end-points included the incidence of severe pain (greater than 5 on a scale 0–10); severity and duration of T-APS; Functional Assessment of Cancer Therapy-Breast subscale; chronic sensory and motor neurotoxicity and adverse events. ResultsThe overall incidence of T-APS across all cycles of chemotherapy in the etoricoxib group was 57.1%, while that in the control group was 91.5% (P < 0.001). The incidences of severe T-APS were 11.4% and 54.9% for the etoricoxib and control groups, respectively (P < 0.001). The mean Functional Assessment of Cancer Therapy-Breast subscale score of the etoricoxib group (103.79–107.24) was significantly higher than that of the control group (93.88–96.71) (P = 0.001 at cycle 1 and P < 0.001 at cycles 2–4). After four cycles of docetaxel chemotherapy, the etoricoxib group demonstrated a significantly higher mean Functional Assessment of Cancer Treatment Neurotoxicity subscale score than the control group (38.46, 95% CI: 37.63–39.29; 34.59, 95% CI: 33.73–35.45, respectively; P < 0.001). Electromyography showed that most peripheral sensory nerves in the etoricoxib group had significantly improved action potential amplitudes and conduction velocities compared with those in the control group. ConclusionProphylactic use of etoricoxib could significantly reduce the incidence and severity of docetaxel-induced acute pain syndrome and potentially decrease docetaxel-induced peripheral neuropathy. Trial registrationClinicalTrials.gov, NCT04565600.

Are we mis-estimating chemotherapy-induced peripheral neuropathy? Analysis of assessment methodologies from a prospective, multinational, longitudinal cohort study of patients receiving neurotoxic chemotherapy

BackgroundThere are inconsistencies in the literature regarding the prevalence and assessment of chemotherapy-induced peripheral neuropathy (CIPN). This study explored CIPN natural history and its characteristics in patients receiving taxane- and platinum-based chemotherapy.Patients and methodsMulti-country multisite prospective longitudinal observational study. Patients were assessed before commencing and three weekly during chemotherapy for up to six cycles, and at 6,9, and 12 months using clinician-based scales (NCI-CTCAE; WHO-CIPN criterion), objective assessments (cotton wool test;10 g monofilament); patient-reported outcome measures (FACT/GOG-Ntx; EORTC-CIPN20), and Nerve Conduction Studies.ResultsIn total, 343 patients were recruited in the cohort, providing 2399 observations. There was wide variation in CIPN prevalence rates using different assessments (14.2–53.4%). Prevalence of sensory neuropathy (and associated symptom profile) was also different in each type of chemotherapy, with paclitaxel (up to 63%) and oxaliplatin (up to 71.4%) showing the highest CIPN rates in most assessments and a more complex symptom profile. Peak prevalence was around the 6-month assessment (up to 71.4%). Motor neurotoxicity was common, particularly in the docetaxel subgroup (up to 22.1%; detected by NCI-CTCAE). There were relatively moderately-to-low correlations between scales (rs = 0.15,p < 0.05-rs = 0.48 p < 0.001), suggesting that they measure different neurotoxicity aspects from each other. Cumulative chemotherapy dose was not associated with onset and course of CIPN.ConclusionThe historical variation reported in CIPN incidence and prevalence is possibly confounded by disagreement between assessment modalities. Clinical practice should consider assessment of motor neuropathy for neurotoxic chemotherapy. Current scales may not be all appropriate to measure CIPN in a valid way, and a combination of scales are needed.

Mir-pharmacogenetics of Vincristine and peripheral neurotoxicity in childhood B-cell acute lymphoblastic leukemia.

Vincristine (VCR), an important component of childhood acute lymphoblastic leukemia (ALL) therapy, can cause sensory and motor neurotoxicity. This neurotoxicity could lead to dose reduction or treatment discontinuation, which could in turn reduce survival. In this line, several studies associated peripheral neurotoxicity and polymorphisms in genes involved in pharmacokinetics (PK) and pharmacodynamics (PD) of VCR. Nowadays, it is well known that these genes are regulated by microRNAs (miRNAs) and SNPs in miRNAs could modify their levels or function. Therefore, the aim of this study was to determine whether SNPs in miRNAs could be associated with VCR-induced neurotoxicity. To achieve this aim, we analyzed all the SNPs in miRNAs (minor allele frequency (MAF) ≥ 0.01) which could regulate VCR-related genes in a large cohort of Spanish children with B-cell precursor ALL (B-ALL) homogeneously treated with LAL/SHOP protocols. We identified the A allele of rs12402181 in the seed region of miR-3117-3p, that could affect the binding with ABCC1 and RALBP1 gene, and C allele of rs7896283 in pre-mature sequence of miR-4481, which could be involved in peripheral nerve regeneration, significantly associated with VCR-induced neurotoxicity. These findings point out the possible involvement of two SNPs in miRNA associated with VCR-related neurotoxicity.

Abstract PD4-08: Efficacy of compression therapy using surgical gloves for nanoparticle albumin-bound-paclitaxel-induced peripheral neuropathy: A phase II multicenter study by the Kamigata breast cancer study group

Abstract PURPOSE: Chemotherapy-induced peripheral neuropathy (CIPN) is an adverse effect of many commonly used chemotherapeutic agents, including taxanes. However, there is currently no established effective prophylactic management for CIPN. Thus, we investigated the efficacy of using surgical glove (SG) compression therapy to prevent nanoparticle albumin-bound-paclitaxel (nab-PTX)-induced peripheral neuropathy. PATIENTS AND METHODS: Patients with primary and recurrent breast cancer who received 260 mg/m2 of nab-PTX were eligible for this case-control study. The patients wore two SGs of the same size, that is, one size smaller than the size that fit, on their dominant hand for 90 minutes. They did not wear SGs on the non-dominant hand, which served as the control hand. Peripheral neuropathy was evaluated at each treatment cycle using Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 and the Patient Neurotoxicity Questionnaire (PNQ). The temperatures of each fingertip of the compression SG-protected and control hands were measured by using thermography. RESULTS: Between August 2013 and January 2016, 43 patients were enrolled, and 42 were evaluated. As shown in Table 1, the overall occurrence of ≥grade 2 sensory and motor peripheral neuropathy according to the CTCAE was significantly lower in the SG-protected hands than in the control hands (76.1% vs. 21.4% and 57.1% vs. 26.2%, respectively, p &amp;lt; 0.0001). The PNQ results showed that the incidence of ≥grade 4 neuropathy was significantly higher in the control hands than in the SG-protected hands in terms of both sensory and motor neurotoxicity (p &amp;lt; 0.0001, Table 2). As the treatment cycles of nab-PTX increased, the mean CTCAE and PNQ grades of the control hands gradually increased. However, the SG-protected hands maintained significantly lower mean grades than the control hands over time (p &amp;lt; 0.0001). No patients withdrew from this study because they could not tolerate the compression from the SGs. The mean temperature of each fingertip significantly decreased (1.42–2.60 °C) in the SG-protected hands compared to in the control hands. CONCLUSIONS: SG compression therapy appears effective for reducing nab-PTX-induced peripheral neuropathy. The nab-PTX exposure to the peripheral nerve may be decreased because the SG decreases microvascular flow to the fingertip. Table 1: Comparison of the overall occurrences of the different grades of peripheral neuropathy according to CTCAE version 4.0 between the compression surgical glove-protected hands and control handsCTCAE v.4.0SensoryMotorGradeSurgical GloveControlSurgical GloveControl012418712161311292411163080840000 Table 2: Changes in the overall occurrence of the Patient Neurotoxicity Questionnaire (PNQ) grade with surgical glove compression therapyPNQSensoryMotorGradeSurgical gloveControlSurgical gloveControl194209223512113717912431611050000 Citation Format: Tsuyuki S, Senda N, Kanng Y, Yamaguchi A, Yoshibayashi H, Kikawa Y, Katakami N, Kato H, Hashimoto T, Okuno T, Yamauchi A, Inamoto T. Efficacy of compression therapy using surgical gloves for nanoparticle albumin-bound-paclitaxel-induced peripheral neuropathy: A phase II multicenter study by the Kamigata breast cancer study group [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr PD4-08.

Protective effect of rosemary on acrylamide motor neurotoxicity in spinal cord of rat offspring: postnatal follow-up study.

The direct interactive effects of rosemary and acrylamide on the development of motor neurons in the spinal cord remains unknown. Our goal is to confirm the protective effects of rosemary against motor neuronal degeneration induced by acrylamide in the developing postnatal rat spinal cord using a postnatal rat model. We assigned the offspring of treated female rats into control, rosemary; acrylamide group; and recovery groups. This work depended on clinical, histopathological, morphometrically, immunohistochemical and genetic methods. In the acrylamide group, we observed oxidation, motor neuron degeneration, apoptosis, myelin degeneration, neurofilament reduction, reactive gliosis. Whoever, concomitant rosemary intake and withdrawal of acrylamide modulate these effects. These findings proof that dietary rosemary can directly protect motor neuron against acrylamide toxicity in the mammalian developing spinal cord.

Erectile Dysfunction Associated With Bortezomib Treatment in a Patient With Multiple Myeloma and Amyloidosis

Case Report Peripheral neuropathy (PN) is the dose-limiting toxicity of bortezomib, a reversible selective proteasome inhibitor approved for the treatment of MM. The incidence of new or worsening bortezomibinduced PN in untreated and relapsed or refractory MM is 44% and 36%, respectively, with Grade 3–4 neuropathy occurring in up to 15% of patients. Bortezomib-induced PN (BiPN) is most commonly sensory and although less frequent, motor PN has been eported, including life-threatening motor neurotoxicity. Still less ommon is autonomic neuropathy, including cutaneous hyperemia, ostural hypotension, paralytic ileus, abdominal distention, and uriary retention. We herein present the first detailed report of a patient with MM who developed erectile dysfunction (ED) after bortezomib treatment. A 60-year-old man without significant past medical history was found during a routine dental workup to have prolonged bleeding, with laboratory tests revealing iron deficiency with mild anemia and a protein gap. Work-up revealed asymptomatic IgG MM. Though a fat pad aspiration was positive for amyloidosis, biopsies taken during esophagogastroduodenoscopy and colonoscopy were Congo Red negative. Despite resolution of iron deficiency with iron

P5-18-04: Safety Profile of Ixabepilone as Adjuvant Treatment for Poor Prognosis Early Breast Cancer: First Results of the Unicancer-PACS 08 Trial.

Abstract Purpose: PACS 01 trial demonstrated that the sequential adjuvant chemotherapy with FEC100 followed by docetaxel (D) significantly improves disease-free and overall survival in node-positive(N+) early breast cancer (BC). However, Triple negative (TN) and ER+/ PR-/HER2− subgroups are significantly associated to a worse prognosis even after adjunction of D. As Ixabepilone (Ixa) has notable preclinical and clinical activity in these subgroups, the PACS 08 trial aims to compare standard FEC100-D regimen to 3 cycles of FEC100 followed by 3 cycles of Ixa. We report the preliminary results of the toxicity profile. Patients and methods: Patients (pts) had localized resectable unilateral ER-/PR-/HER2− or ER+/PR-/HER2− BC. Main inclusion criteria were: age&amp;lt;70 years, normal cardiac, hepatic, haematological and renal functions. Arm A: pts received 3 cycles of FEC100 (F and C, each at 500 mg/m2, E 100 mg/m2, every 3 weeks) followed by 3 cycles of D (100 mg/m2 every 3 weeks); Arm B, Ixa 40 mg/m2 replaced D. Radiotherapy was mandatory after conservative surgery and endocrine therapy was given to ER+ pts. A 5% absolute difference in disease-free survival at 5 years is the main statistical end-point. Results: Between October 2007 and September 2010, 762 pts with TNBC or ER+/PR-/HER2− BC were enrolled. Recruitment was interrupted due to BMS decision to stop Ixa development in adjuvant setting. Main pts characteristics were well balanced between the 2 arms: median age 53 years, postmenopausal 57.8%, conservative surgery 68.4%, node positive 59.5%. A total of 755 pts were evaluable for safety. Treatment was completed for 93.4% and 86.1% of pts in arms A and B, respectively. During FEC100 sequence, toxicities were well balanced between the two arms. From cycle 4, whereas Gr3/4 sensory neurotoxicity (12pts; 3.5%) and thrombopenia (7pts; 2%) were reported in Ixa arm, none of these toxicities was reported in the D arm (p0.001). There were significantly more Gr3/4 neutropenia on day 21 in Ixa arm (13pts, 6.6% vs 4pts, 1.9%; p&amp;lt;10.005). No significant difference was observed for febrile neutropenia. Fewer cutaneous toxicities were observed in Ixa arm (2pts, 0.6% vs 10pts, 2.6%; p&amp;lt;0.05). No significant difference was observed neither for motor neurotoxicity or hepatic function between two arms. More pts discontinued treatment in Ixa arm compared to D arm (49pts (13%) vs 26pts (7%), p&amp;lt;0.05). Main reasons were Gr3/4 haematological adverse events (AE) and Gr3/4 neurotoxicities for Ixa arm and due to GR3/4 haematological AE for D arm. One non expected Gr4 bullous dermatitis was reported during the first Ixa cycle. 2 deaths due to septic shock occured in Ixa arm (both at cycle 4 for a 56- and a 66-year-old woman). However, according to the IDMC no obvious precipitating factor questioning the Ixa arm was identified. Conclusion: Our results indicate that D arm is more often associated to significant haematological toxicities, whereas both neurotoxicities and haematological toxicities are reported in the Ixa arm. Although significantly more pts discontinued treatment due to adverse events in Ixa arm compared to D arm, Ixa may still represent a promising therapeutic option for pts in the adjuvant setting especially for poor prognosis BC. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P5-18-04.

Phase III Trial of Observation Versus Six Courses of Paclitaxel in Patients With Advanced Epithelial Ovarian Cancer in Complete Response After Six Courses of Paclitaxel/Platinum-Based Chemotherapy: Final Results of the After-6 Protocol 1

To assess whether six courses of paclitaxel are effective as consolidation treatment in patients with advanced epithelial ovarian cancer who are in complete response after first-line paclitaxel/platinum-based chemotherapy. Patients with stages IIb to IV disease in clinical or pathologic complete response after six courses of paclitaxel/platinum-based chemotherapy were randomly allocated to either observation (ie, control) or six courses of paclitaxel 175 mg/m(2) every 3 weeks (ie, maintenance). Two hundred patients were randomly assigned from March 1999 to July 2006. Because of the low accrual rate, an unplanned interim analysis of futility according to the Bayesian approach was performed. Grade 2 or greater motor neurotoxicity and sensory neurotoxicity were reported in 11.3% and 28.0% of the paclitaxel-arm patients, respectively. After a median follow-up of 43.5 months, 107 patients (53%) had experienced relapse, and 48 patients (24%) had died. Two-year progression-free survival rates were 54% (95% CI, 43% to 64%) and 59% (95% CI, 49% to 69%; P = not significant) in the control and maintenance arms, respectively. Corresponding 2-year overall survival rates were 90% (95% CI, 84% to 97%) and 87% (95% CI, 80% to 94%; P = not significant), respectively. The Cox model showed that residual disease after initial surgery (macroscopic v no macroscopic residuum; hazard ratio [HR], 1.91; 95%CI, 1.21 to 3.03) and stage (IIIc to IV v others; HR, 3.10; 95% CI, 1.13 to 8.48) were independent prognostic factors for progression-free survival, whereas the treatment arm (maintenance v control) had no prognostic relevance. A consolidation treatment with six cycles of paclitaxel does not prolong progression-free survival or overall survival in patients in complete response after first-line paclitaxel/platinum-based regimens.

Weekly Low-Dose Paclitaxel as Maintenance Treatment in Patients With Advanced Ovarian Cancer Who Had Microscopic Residual Disease at Second-Look Surgery After 6 Cycles of Paclitaxel/Platinum-Based Chemotherapy

The aim of this paper was to assess whether weekly intravenous 60-mg/m2 paclitaxel for 21 weeks is feasible and effective as maintenance treatment in 64 patients with advanced ovarian cancer who had microscopic residual disease after 6 cycles of paclitaxel/platinum-based chemotherapy. Forty-eight patients completed the planned cycles of weekly paclitaxel. The worst toxicities were grade 2 leukopenia in 22.4% of the patients, grade 2 neutropenia in 25.9%, grade 2 sensorial neurotoxicity in 20.7%, and grade 2 motor neurotoxicity in 6.9%. Seventeen patients underwent a third-look surgery that showed a pathological complete response in 6 (35.3%, 95% confidence interval [CI], 17.3%-59.0%) cases. The 3-year progression-free survival rate was 18% (95% CI, 9.6%-33.8%), and the 3-year overall survival rate was 64% (95% CI, 52.0%-78.0%). Weekly low-dose paclitaxel is a feasible and well-tolerated maintenance treatment.

Residual neurotoxicity in patients with ovarian cancer in clinical remission after first-line chemotherapy with carboplatin and paclitaxel: The Multicenter Italian Trials in Ovarian cancer (MITO-4) retrospective study

5015 Background: carboplatin/paclitaxel (CP) is the chemotherapy (CT) of choice for advanced ovarian cancer. Although a significant proportion of patients (pts) have some neurotoxicity during treatment, the long-term outcome of CT-induced neuropathy has been scantly studied. We retrospectively assessed the prevalence of residual neuropathy in a cohort of pts in clinical remission after first-line CP for advanced ovarian cancer. Patients and Methods: 120 consecutive pts have been enclosed in this study. All pts received C (AUC 5) plus P (175 mg/m2) every 3 weeks for 6 cycles, completing treatment between 1998 and 2003. 49 pts (41%), assigned to the experimental arm of the MITO-1 study, had received 4 courses of topotecan (1.5 mg/m2 for 5 days every 3 weeks) after CP, as consolidation therapy. Data have been collected between May and September 2004. Residual sensory and motor neurotoxicity have been coded according to the NCI CTC v2.0. Results: 55 pts (46%) did not experience any grade of neurological toxicity during CT: none of them had signs of neuropathy during follow up. The other 65 pts (54%) had CT-induced neurotoxicity during treatment and follow-up data are available for 60 of them. 46/60 pts (77%) had no residual neuropathy at the moment of interview: in detail, recovery from neurotoxicity had occurred in the first 2 months after the end of CT in 22 (37%), between 2 and 6 months in 15 (25%), or after more than 6 months in 9 (15%). The remaining 14/60 pts (23%) referred residual neuropathy at the most recent follow-up visit, after a median follow up of 18 months (range, 7–58 months): 12 pts had G1 and 2 pts G2 peripheral sensory neuropathy; 3 pts had also G1 motor neuropathy. Overall, at 6 months, 23 out of 120 pts (19%) had some residual neurotoxicity. Conclusions: our data indicate that a significant proportion of patients with advanced ovarian cancer treated with first-line CT with carboplatin/paclitaxel suffer long-term residual neuropathy. This issue should be carefully taken into account before considering a re-treatment with the same agents in sensitive recurrent disease. No significant financial relationships to disclose.

Treatment of primary advanced and recurrent endometrial carcinoma with a combination of carboplatin and paclitaxel

5110 Background: Primary advanced endometrial carcinomas constitute approximately 10% of all diagnosed cases. Of all treated tumors 15–20% will recur, mainly within 3 years, with locoregional or distant metastases. Chemotherapy is a treatment option for these cases. A platinum and an anthracycline have been a standard regimen at many centers. A response rate of 40–50% and short survival time are frequently reported. To improve the results a combination of carboplatin and paclitaxel was used in a consecutive series of endometrial carcinomas. Methods: A non-randomized, prospective, phase II trial was conducted at 5 Swedish departments for gynecological oncology during the period 2000–2003. Sixty-six consecutive primary advanced (n = 18) or recurrent (n = 48) carcinomas were treated with a combination of carboplatin (AUC = 5) and paclitaxel (175 mg/m2, 3h infusion) given every 3 weeks for at least 6 courses. A combination of CT scans, chest X-rays, ultrasound and clinical examinations were used during the follow-up. No patients were lost to follow-up. Results: In the complete series 19 complete responses (29%) and 25 partial responses (38%) were recorded. The overall response rate was 67% (95% CI: 55–78%). For the primary advanced carcinomas the response rate was 83% and for the recurrent tumors 60%. For primary advanced endometrioid carcinomas the overall response rate was 86% (95% CI: 67–100%). The overall 2 year survival rate was 57% (95% CI: 44–69%) and the 3 year survival rate 29% (95% CI: 17–42%) in the complete series. The median overall survival time was 26.4 months. Grades 2–3 neutropenia was recorded in 12% after 6 courses. Thrombocytopenia was infrequent and only grade 1 reactions occurred. Neurosensory symptoms were more frequent (grade 1: 42%, grade 2: 26% and grade 3: 8%) and the most serious toxicity recorded. Grades 2–3 motor neurotoxicity occurred in 7 out of 53 evaluable patients (13%). Conclusions: The carboplatin-paclitaxel combination seems to be more effective than prior used regimes in treatment of primary advanced endometrial carcinoma. However, the majority of the patients were not cured from their disease and the neurotoxicity was a significant problem in this series of patients. No significant financial relationships to disclose.

Factors affecting grip strength testing

The rodent grip strength test was developed decades ago and is a putative measure of muscular strength. This test has been included in the functional observational battery (FOB) to screen for neurobehavioral toxicity, and changes in grip strength have been interpreted as evidence of motor neurotoxicity. Despite its widespread use, questions remain about what the grip strength test actually measures. In this study, potential confounders of the grip strength test were identified and tested, including operational parameters, disruption of peripheral sensory function and changes in body weight. Operational parameters (sampling rate, system type and trial angle but not trial speed) had dramatic effects on grip strength data. Doxorubicin (DX, 10 mg/kg iv) was used to cause sensory impairment. It decreased forelimb and hindlimb grip strength (by 27% and 32%, respectively, compared with controls), an effect that was correlated with degeneration of peripheral and central sensory components (distal tibial and sural nerves, dorsal funiculus of the spinal cord and dorsal, but not ventral, spinal roots). Feed restriction-induced loss of body weight (26% compared with controls) and muscle mass (20% compared with controls) reversibly decreased both forelimb and hindlimb grip strength (18% and 17%, respectively, compared with controls). Ignoring these confounding factors could potentially lead to increased data variability and inconsistency within single studies, across studies and in historical control data sets. To assist in data interpretation and evaluation of grip strength results, it is suggested that exact conditions of application of the test be reported in greater detail. Furthermore, given that the grip strength test can be influenced by factors other than true muscular strength, use of the term grip performance is proposed to better reflect the apical nature of this test.

Radical cytoreductive surgery combined with platinums-carboplatin and cisplatin chemotherapy for advanced ovarian cancer.

In an attempt to improve the therapeutic outcome for patients with advanced ovarian cancer, primary radical cytoreductive surgery consisting of hysterectomy, bilateral salpingo-oophorectomy, omentectomy and retroperitoneal lymph node resection, with optimal cytoreduction in case of metastatic lesions, was followed by five courses of chemotherapy of carboplatin 280 mg/m2 i.v. on day 1 and cisplatin 70 mg/m2 i.v. on day 2, every four weeks. A total of 51 patients with advanced epithelial ovarian cancer comprised the study (6 with stage IIC, 32 with stage III, and 13 with stage IV). Following radical cytoreductive surgery, 29 patients (57%) showed 2 cm or less of residual disease. There was a low incidence of severe complications and no postoperative mortality. An overall response rate of 76% of patients consisting of 42% pathologic complete response and 34% partial response was observed. The overall four-year survival rate for patients with stage III cancer was 70%. The dose-limiting toxicity was identified to be hematologic toxicity, which showed grade 3/4 of leuopenia 37% (neutropenia 73%) and thrombocytopenia 24%. The incidence of peripheral neurotoxicity was comparatively low. An evaluation of nerve conduction velocity revealed that motor neurotoxicity was liable to appear in the lower extremity, while sensory nerve damage was often noted in the periphery in both the upper and lower extremities. The combined chemo-surgery treatment resulted in good response and good survival without fatal toxicity for patients with advanced ovarian cancer.

Oxaliplatin in ovarian cancer

Oxaliplatin in ovarian cancer

Phase II study with Docetaxel (Taxotere®) in advanced soft tissue sarcomas of the adult

Current regimens for treatment of distant metastases of soft tissues sarcomas result in response rates of about 25%. Therefore the search for active drugs remains a task for investigational groups. Taxoids offer a new class of cytostatic drugs. Docetaxel has been studied as a second line chemotherapy in advanced soft tissue sarcomas of the adult. In a multi-center non-randomized phase II study docetaxel was administered at a dose of 100 mg/m2 in a 1-hour i.v. infusion q 3 weeks. Twenty-nine patients (pts), median age 52 yr, performance status WHO 0: 16 pts, WHO 1: 11 pts, WHO 2: 2 pts, were eligible. One patient had early death due to malignant disease, 1 patient died due to toxicity and progression, 1 pt refused after 1 course. Five partial responses (5/29 = 17%, C.I. 6%-36%) have been observed. Grade > or = 3 leucopenia occurred in 76% of patients and grade > or = 3 thrombopenia did not occur. Median nadir of neutrophils was 0.23 x 10(9)/l. Episodes of fever and documented infection have been observed in 10 and 5 pts respectively. Anaphylactoid type reactions occurred in 5 patients: ranging from flushing in 5 pts to cardiovascular symptoms in 1 pt. Sensory neurotoxicity was observed in 14 pts grade 1: 10 pts, grade 2: 3 pts, grade 3: 1 pt). Grade 1 motor neurotoxicity was experienced by 3 pts. Skin reactions (pruritus, erythema, urticaria, exfoliation grade 1: 11 pts, grade 2: 7 pts, grade 3: 1 pt, grade 4: 1 pt) in 20 pts, among them 9 patients with nail changes. Peripheral edema and fluid retention has been observed in 12 pts. Taxotere has activity in adult soft tissue sarcoma in second line, warranting studies on first line efficacy.

A pilot study of intensive weekly chemotherapy for extensive disease small-cell lung carcinoma.

An intensive weekly chemotherapeutic treatment for extensive disease small-cell lung cancer was piloted in 14 patients. The regimen consisted of 6 drugs. Two drugs were given each week for a total of 12 weeks of treatment. Modifications were required in the protocol to attempt to overcome excessive toxicity. Unexpected toxicity included anemia requiring transfusions in 8 of 10 patients completing treatment, sepsis in 8 of 14 with 3 related deaths, and prolonged grade III motor neurotoxicity in 2 patients. All 3 patients who died of sepsis had shown evidence of response, and 8 of the remaining 11 had 90% or greater tumor shrinkage. Two others had a partial response. Median survival time for all patients was 9.3 months.