Is paclitaxel less cardiotoxic in the treatment of breast cancer before or after doxorubicin? / Qual estratégia terapêutica é menos cardiotóxica no tratamento do câncer de mama: uso de paclitaxel antes ou depois da doxorrubicina?

Background: The combination of doxorubicin (DOX) with paclitaxel (PTX) effectively treats breast cancer (BC). However, DOX-associated cardiotoxicity (CTX) is aggravated by the use of PTX. Consensus is lacking about which drug sequence involves the most CTX. Objectives: To evaluate whether DOX followed by PXT or the reverse sequence has the greatest cardiotoxic potential in the treatment of BC. Methods: Prospective study of women with primary BC who received four cycles of DOX and 12 infusions of PTX. Participants were divided into Group 1 (G1; PXT before DOX) and Group 2 (G2; DOX before PXT) at the discretion of the oncologist. CTX was defined as an absolute reduction in left ventricular ejection fraction (LVEF) > 10% to a value <53%. Patients underwentclinical evaluations and echocardiography before treatment (Phase 1) and one year after treatment (Phase 2). Results: Sixty-nine women were evaluated: 19 in G1 and 50 in G2. The groups had similar clinical characteristics. The doses of radiation, DOX, and PTX used were similar. Eight (11.6%) patients developed CTX: two (10.5%) in G1 and six (12.0%) in G2 (p=0.62). The mean LVEF was similar between groups in Phase 1 (G1=65.1±3.5%; G2=65.2±3.9%; p=0.96), with a significant reduction noted after one year in both groups: G1=61.4±8.1% (p=0.021) and G2=60.8±7.6% (p<0,001). Although lower, mean LVEF remained similar between groups after Phase 2 (p=0.79). Conclusions: In women with BC who underwent chemotherapy, the incidence of CTX at the end of the first year of treatment was similar regardless of whether DOX was used before or after PTX. (AU)

Perda visual irreversível após uso de paclitaxel / Irreversible visual loss after use of paclitaxel

Descrevemos um caso de perda visual irreversível bilateral em uma paciente de 64 anos após uso prolongado de paclitaxel. Ao exame oftalmológico paciente apresentou acuidade visual (AV) de 20/400 em ambos os olhos (AO) na primeira consulta. À tomografia de coerência óptica (TCO) evidenciou espessamento macular AO. Após seis meses da suspensão do paclitaxel, a paciente apresentava melhora discreta da AV atingindo 20/200 com correção em AO, além da TCO demonstrando resolução do espessamento retiniano.

We describe a case of bilateral irreversible visual loss of a 64 year-old patient after prolonged use of paclitaxel. Patient presented best corrected visual acuity of 20/400 in both eyes at first visit and optical coherence tomography showed increased macular in both eyes.After six months of the interruption of -paclitaxel therapy, the patient showed slight improvement of visual acuity reaching 20/200 in both eyes, while OCT demonstrated resolution of macular edema.

Ganglioside GM1 (porcine) ameliorates paclitaxel-induced neuropathy in rats.

BACKGROUND: Paclitaxel, an anti-neoplastic agent effective against several solid tumors, has several side effects including peripheral neuropathy. So far, there are no effective treatments for this complication. Monosialic acid ganglioside (GM1) has been shown to protect neurons against injuries and degeneration. However, its efficacy in the treatment of paclitaxel-induced neuropathy has not been verified. OBJECTIVE: To evaluate the effect of porcine GM1 on neurophysiological abnormalities in rats receiving paclitaxel. MATERIAL AND METHOD: Fifty-four Wistar rats were divided into control, vehicle for paclitaxel (Cremophor EL), paclitaxel, and paclitaxel + GM1 groups. Paclitaxel 16 mg/kg/week for five consecutive weeks was given intraperitoneally. Treatment with 30 mg/kg 5 days per week of GM1 was started 3 days prior to the first dose and continued until 3 days after the last dose of paclitaxel. Tail and hind paw thermal thresholds including tail motor nerve conduction velocity (MNCV) were measured prior to and after the start of treatments. Histopathology of the sciatic nerve was also examined. RESULTS: Paclitaxel alone induced thermal hypoalgesia and reduced tail MNCV Less severe abnormalities were also found with the vehicle. GM1 appeared to prevent the development of hypoalgesia and ameliorated the decreased MNCV without any evidence of Guillain-Barre Syndrome. Mild endoneurial edema and axonal degeneration in the sciatic nerve sections were seen in paclitaxel treated rats. Microtubule accumulation and activated Schwann cell were also presented in the paclitaxel treated groups. CONCLUSION: These data suggest that porcine GM1 may be useful in the prevention and treatment of paclitaxel-induced neuropathy. However the adverse effect of Cremophor EL should be of concern.

the therapeutic index better with paclitaxel plus carboplatin than with paclitaxel plus cisplatin in initial treatment of advanced ovarian cancer?

Retrospective analysis and comparison of the side effects, efficacy and feasibility of cisplatin and carboplatin each in combination with paclitaxel as front-line therapy in advanced epithelial ovarian cancer. Between January 2001 and January 2006, 39 patients with advanced epithelial ovarian cancer were allocated to receive paclitaxel 175mg/m[2] intravenously as a 3-hour infusion followed by either cisplatin 75mg/m[2] or carboplalin [area under the plasma concentration-time curve of 5] both on day [1]. The schedule was repeated every 3 weeks for at least six cycles to the majority of the patients. The primary endpoint was the proportion of patients without progression at 2 years. Secondary endpoints included toxicity, tolerability, response to treatment, and overall and progression-free survival time. Kaplan-Meier method estimated overall and time to disease progression. Log rank test compared survival curves with p value 230 had 92.3% sensitivity and 100% specificity [p=<0.001] and tumor size at start of chemotherapy had 96.3% sensitivity and 100% specificity [p<0.001]. The 2-years progression-free survival [PFS] of all patients was 39.4% and the median time to disease progression was 23.3 months. While the median overall survival time of all patients was 37.5 months and the 2-years overall survival [OAS] was 62.9%. The 2-years PFS and OAS were 35.2% and 44.4%, respectively, for TC arm compared with 44.4% and 83.3%, respectively, for paclitaxel-cisplatin [TP] arm. The relative risk [RR] of progression for patients with incomplete response was 6.9 [95%- CI, 2.052 to 23.11] and the RR of death for TC arm was 6.3 [95% CI, 1.7 to 9.0]. The small number of patients entered onto the study caused wide CI around the hazards ratio for RR of death with delayed treatment [hazards ratio, 4.0; 95% CI, 1.7 to 23.3] and did not allow conclusions about efficacy. Age >60 [p=0.05], stage IIIB, IIIC and IV disease [p=0.02], and delayed treatment [0.001] had statistically significant adverse effect on the OAS, while response to chemotherapy [p=0.03] had statistically significant effect on prolonging the OAS. Presence of residual disease >1cm had borderline significance [p=0.06] on the OAS. However elevated level of CA[125] >230, tumor grade, pathological subtype, Karnofsky performance status [KPS] had no statistically significant effect on the OAS [all p=NS]. Univariate analysis of factors that might affect PFS showed that patients with a residual tumor of less than 1cm before chemotherapy [p=0.0003], KPS [p=0.0268], FIGO stage II or IIIa [p=0.0018], had statistically significant longer PFS while CA125 >230 [p=0.0012] and incomplete response [p=0.002] had a significant adverse impact on PFS. In patients with advanced ovarian cancer, a chemotherapy regimen consisting of TC results in less toxicity, is easier to administer, and has similar median time to disease progression [23.3 months], when compared with TP regimen, however a longer follow-up is required for a definitive statement on survival

Weekly paclitaxel and paraplatin as first line chemotherapy in patients with advanced NSCLC

Optimal platinum based combination regimen for advanced NSCLC remains to be defined. Weekly Taxol and paraplatin is an effective and generally well tolerated regimen for first line treatment for stage III and IV NSCLC and affords potential for lower toxicity and increases exposure to drugs with alternative cytotoxic/cytostatic mechanisms. Thirty patients with histologically or cytologically proven NSCLC stages IIIb and IV were included during the period between March 2001-March 2003 with the following criteria, median age was 55 years, measurable or evaluable disease, PS

Paclitaxel as induction chemotherapy plus radiation for locally advanced sequamous cell carcinoma of the head and neck

The primary objective of this study was to asses the complete response [CR] rate to a new innovative induction regimen plus combined chemoradiation in patients with locally advanced head and neck cancer [LA-HNC]. From April 2003 to March 2005, 66 eligible patients with LA-HNC referred mainly from Oncosurgery Department to Clinical Oncology and Nuclear Medicine Department, Mansoura University Hospital were treated by three cycles of induction chemotherapy [IC] with paclitaxel 175mg/m[2] in 3-h infusion on d1, leucovorin [LV] 200mg/m[2] over 20min immediately followed by fluorouracil [FU] 400mg/m[2] bolus and then 600mg/m[2] as 24h continuous infusion on d1 and 2, cisplatin 75mg/m[2] over 1-h infusion on d2 every 3 weeks. This was followed by radiation [70Gy] am weekly cisplatin 20mg/m[2]. After the completion of IC, 12/66 [18.2%] patient had CR. The CR rate was increased to [53.03%] post concomitant chemoradiotherapy [CCRT]. Hematologic toxicity, alopecia and mucositis were the most common complications of treatment. Median time to progression was 10 months and median survival was 18 months. This novel induction regimen is active, well tolerated and can be successfully followed by CCRT with weekly cisplatin. CCRT should remain standard treatment for patients with LA-HNC

Vinorelbine, 5 fluorouracil and folinic acid [fufol-nav] versus paclitaxel [p] as first line treatment in metastatic breast cancer patients pre-treated with anthracycline

The aim of this study was to investigate the efficacy and safety of Vinorelbine, 5 Fluorouracil and Folinic acid [Fu Fol-Nav] versus Paclitaxel [P] in patients with metastatic breast cancer [MBC] previously treated with Anthracycline. Between January 2001 and September 2003, 50 eligible patients with MBC were randomized to either Folinic acid 3Omg/m2 followed by 5Fu 600 mg/m2 given as intravenous holus injection then Vinorelbine 25 mglm2 [10 minute-infusion] q3 weeks [group A], or Paclitaxel 175 mg/m2 [3 hour infusion] q3 weeks [group B]. Eligibility criteri included: measurable MBC previous treatment with Anthracycline in [neo] adjuvant setting. The two randomized arms were well balanced for FuFol-Nav vs. P, median age [44 vs. 51], nearly three quarter of patients in each group had ECOG performance status 0,1. Hormonal receptor positivity for group A was 60% vs. 72% for group B, about half the patients had one metastatic site [56% vs. 47%] with predominant visceral sites in 68% vs. 60% in groups A and B respectively. Overall, both regimens were relatively well tolerated, grade 314 toxicities for group A vs. B: neutropenia and alopecia were significantly higher in group B: [28% vs. 8, 24% vs. 0] hut neurosensory [4% vs. 8%] and mucositis [8% vs. 4%] were not significantly different between the 2 groups. Other toxicities were mild and manageable and no treatment related mortality has been reported in both arms. Overall response rate was 44% [95% CI 42.1 to 45.9] for group A versus 48% [95% CI 46.9 to 50.1] in group B [P> 0.05]. Median time to progression TTP was 7.5 ms vs. 8ms in groups A and B respectively, median duration of response was comparable in both groups [8.5 vs 9ms]. Notably the median OS was similar in both arms [l3ms]. The present study failed to demonstrate a significant difference in response rate, median time to progression and overall survival between the two regimens, so FuFol-Nav is a well tolerated regimen with comparable efficiency as Paclitaxel hut with less cost burden in the treatment of MBC patients

Concurrent weekly paclitaxel and carboplatin with thoracic radiation followed by consolidation chemotherapy for locally advanced non-small cell lung cancer [NSCLC]

To assess the feasibility and activity of chemoradiation program using paclitaxel and carboplatin-based combined-modality therapy based on the unique radiation-sensitizing properties of these agents in locally advanced unresectable stage III NSCLC. Twenty-seven patients with unresectable NSCLC were evaluable, with a median age of 54 years [range 44-69]. Eleven patients [41%] had stage IIIA and 16 [59%] had stage IIIB. Treatment consisted of paclitaxel [50 mg/m[2] i.v. infusion over 1 hour] followed by carboplatin [AUC 2.0 i.v. bolus infusion over 30 min.] administered weekly concurrently with radiation on days 1,8,15,22,29,36. Thoracic radiation was delivered in daily doses of 2 Gy to a total dose of 65 Gy over 6.5 weeks. Consolidation chemotherapy: After chemoradiation therapy, patients received an additional 4 cycles of paclitaxel 175 mg/m[2] I.V infusion over 3 hours and carboplatin at AUC 6 every 3 weeks. The overall response rate was 77.8% with CR in 7 patients [25.9%] PR in 14 patients [51.9%], SD in 5 patients [18.5%] and 1 patient [3.7%] showed progressive disease. The median overall survival was 13.5 months and 1 year and 2 year survival rates were 58% and 26% respectively. The most frequent and significantly noted toxicity in this study was esophagitis [85.2%]. The other nonhematologic toxicities included nausea and vomiting [59.2%], peripheral neuropathy [25.9%], fatigue [33.3%] and pneumonitis [11.1%]. Hematologic toxicity consisted of anemia in 12 patients [44.4%], leucopenia in 8 patients [29.6%] and thrombocytopenia in 6 patients [22.2%]. These data together with our experience suggest that, in patients with unresectable stage IIIA-IIIB NSCLC, concomitant weekly chemoradiotherapy with paclitaxel and carboplatin, followed by consolidation chemotherapy with the same regimen is feasible, generally well tolerated, and yields therapeutic results that compare favorably to those reported for other regimens. However, further randomized studies are needed to identify the optimal chemoradiotherapy regimens and schedules for treatment of unresectable stage IIIA-IIIB NSCLC patients

Toxicity profile and objective response of paclitaxel in metastatic breast cancer

To evaluate the efficacy and toxicity of 1-hour weekly Paclitaxel in metastatic breast cancer along with evaluation of overall survival. A phase II interventional trial. Oncology Department, Combined Military Hospital, Rawalpindi, between August 2001 to July 2003. Thirtysix patients were enrolled in the study. All patients with histologically confirmed and bidimensionally measurable metastatic breast cancer who had received previously either chemotherapy or hormone therapy were included in the study. Paclitaxel was administered in 1-hour weekly infusion in a dose of 100 mg/m2 for 12 doses. All patients had received previous chemotherapy with either CAF or CMF. Twenty five patients had also received hormone therapy, 61% had two or more metastatic sites involved, and lung was the common site of involvement. Complete response was observed in 4 [11.1%] patients, partial response in 14 [38.8%] patients, with an overall response rate of 50.0%. Clinical benefit was 94.4% and median overall survival was 11 months. Treatment was well-tolerated with no grade 3 or 4 toxicity. Common side effects were arthralgias, myalgias and neutropenia. Treatment with 1-hour weekly infusion of Paclitaxel is a well-tolerated chemotherapy with a substantial degree of efficacy in patients with metastatic breast cancer

Reversal of paclitaxel induced neutropenia by Withania somnifera in mice.

The effect of aqueous extract of Withania somnifera (L. Solanaceae) was studied against paclitaxel induced neutropenia in mice. After paclitaxel 1 mg/kg, i.v. administration significant fall in total WBC and absolute neutrophil count was observed on day 3 and day 5. W. Somnifera (200 mg/kg, p.o.) per se produced significant increase in neutrophil counts. W. somnifera (200 mg/kg, p.o.) when administered for 4 days before paclitaxel treatment and continued for 12 days caused significant reversal of neutropenia of paclitaxel. The findings of the study suggest the potential of W. somnifera as an adjuvant during cancer chemotherapy for the prevention of bone marrow depression associated with anticancer drugs.

Alteraciones electrocardiográficas inducidas por paclitaxel (taxol) / Electrocardiographic alterations induced by paclitaxel (taxol)

Objetivo. Identificar repercusiones clínicas y alteraciones electrocardiográficas inducidas por la infusión de placlitaxel durante 24 horas. Pacientes y métodos. De enero de 1993 a enero de 1996, en los Departamentos de Medicina Interna del Hospital ABC y de Oncología del Hospital General de México, se estudiaron a 35 pacientes entre 18 y 75 años de edad, con diversas neoplasias karnofsky > 60 por ciento, que previamente habrían recibido uno o más esquemas de quimioterapia. Todos recibieron paclitaxel en infusión continua de 24 horas, cada 21 días, con dosis de 125-225 mg/m², y profilaxis para tratamiento de hipersensibilidad con dexametasona, ranitidina y clorfeniramina. Se practicó electrocardiograma antes y después de cada infusión del taxano. El grado de cardiotoxicidad se calificó de acuerdo con los criterios del national Cancer Institute. Resultados. Treinta y cinco pacientes con edad promedio de 50 ñ 8.8 años, 28 mujeres (80 por ciento) y siete hombres (20 por ciento), recibieron 110 ciclos. Diecinueve pacientes (54.2 por ciento) habían recibido doxorrubicina previamente y 10 habían sido sometidos a radioterapia mediastinal. Un paciente presentó infarto agudo al miocardio un año antes del tratamiento. Se encontró disminución de la frecuencia cardiaca en 37.1 por ciento de los pacientes y 26.3 por ciento de los ciclos con dosis de 125 y 150 mg/m². En 25.7 por ciento de los pacientes y 19 ciclos se detectó prolongación del intervalo QTc con dosis mayores de 150 mg/m². Hubo extrasístoles supraventriculares en cuatro pacientes durante ocho ciclos de tratamiento y extrasístoles ventriculares, en un paciente, durante un ciclo. Se detectó disminusión del voltaje del complejo QRS en 3.6 por ciento de los ciclos y en 5.7 por ciento de los pacientes con dosis de 135 y 175 mg/m². La inversión de la onda T se presentó en tres casos durante cuatro ciclos, sin repercusión hemodinámica ni traducción enzímatica. Se registró aumento de la frecuencia cardiaca en 28.5 por ciento de los pacientes y 18.1 por ciento de los ciclos con dosis superiores a 175 mg/m². Hubo un caso de taquicardia supraventricular con dosis de 225 mg/m². Todas las alteraciones se calificaron como grado I, sin repercusión hemodinámica ni significancia estadística...

Toxicidad con paclitaxel en infusión de 24 horas / Paclitaxel toxicity in infussion of 24 hours

Antecedentes: El paclitaxel(Taxol) ha mostrado ser efectivo para el tratamiento de algunas neoplasias; sin embargo, su utilización provoca reacciones tóxicas. Objetivo: Valorar los efectos tóxicos del paclitaxel. Método: Se administró, con escalamiento, en infusión de 24 horas y ciclos de 21 días, dosis entre 125 y 250 mg/m² a pacientes con neoplasias avanzadas y Karnofsky mayor a 60 por ciento que previamente habían recibido otros regímenes de quimioterapia. Se suministró premedicación profiláctica a base de dexametasona, ranitidina y clorfeniramina. Resultados: Se inclyeron 24 pacientes con edad promedio de 53.5 años; 19 mujeres (79 por ciento) y cinco hombres (21 por ciento). Fueron evaluados 93 ciclos: 63.4 por ciento a dosis de 150 a 175 mg/m², 18,3 por ciento en dosis menores a 150mg/m² y 18.3 por ciento con dosis mayores a 175 mg/m². Toxicidad observada: neutropenia grado II en 25.8 y grados III y IV en 74.2 por ciento. Se presentó neutropenia grados III y IV en 52.93 por ciento con dosis < 150 mg/m², en 72.97 por ciento con 15 mg/m² y en 84.61 por ciento con dosis ò 175 mg/m², hubo diferencia significativa (p<0.01) entre el grupo que recibió < 150 mg/m² y el que recibió ò 175 mg/m². Se registraron dos casos de neutropenia con fiebre. El 47.3 por ciento requirió de factor estimulante de colonias. Se registró neuropatía sensorial, leve reversible, en 33.3 por ciento, con 125 a 175 mg/m². Dos pacientes (8.33 por ciento) manifestaron reacciones de hipersensibilidad, por omisión de profilaxis. Hubo cambios cardioléctricos en 19 pacientes (79.2 por ciento), pero no se registró repercusión clínica. El 62.5 por ciento cursó con mucositis grados II y III por dosis mayores a 175 mg/m². Se presentó aumento de aminotransferasa grado III en un paciente. Todos los sujetos experimentaron alopecia. Conclusiones:; El paclitaxel provocó neutropenia importante a dosis mayores a 150 mg/m², por lo que se requirió de estimuladores de colonia. Se observaron alteraciones electrocardiográficas notorias in repercusión clínica. Hubo mucositis en más del 50 por ciento de los pacientes y neuropatía sensorial en una tercera parte. Se precisan estudios prospectivos controlados para evaluar duración de infusión y dosis, respecto a efecto tumoral y manifestaciones tóxicas