Efficacy and Safety of Paclitaxel versus Cisplatin with Concurrent Radiotherapy in Central India Patients with Locally Advanced Head-and-neck Cancers: A Randomized, Open-label Study
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A BSTRACT Background: In India, majority of the patients with head-and-neck cancers are diagnosed in the locally advanced stage. The aim of this study was to compare the efficacy and safety of paclitaxel versus cisplatin with concurrent radiotherapy (RT) in patients with locally advanced head-and-neck squamous cell carcinomas (LAHNSCCs). Materials and Methods: This was an open-label, randomized study involving 100 patients with LAHNSCC who were randomly divided into two groups: the first group received paclitaxel (Tax, n = 50, 30 mg/m 2 /week for 7 weeks) and the second group received cisplatin (Cis, n = 50; 40 mg/m 2 /week for 7 weeks). Both the groups received concurrent RT in a total dose of 66.6 Gy in 37 fractions of 5 days/week over a period of 7.5 weeks. Results: The complete (46% vs. 36%) and partial (40% vs. 50%) response rates in the Tax + RT group and Cis + RT group were not significantly different (both P > 0.05). Cis + RT resulted in significantly greater Grade I adverse events (AEs) ( P < 0.05). While, Grade II, III, and IV AEs were significantly greater with Tax + RT (all P < 0.05). Overall analysis revealed that the use of Cis + RT was associated with a significantly greater number of patients who were free from AEs ( P < 0.05). Conclusions: Tax + RT and Cis + RT were equi-efficacious in patients with LAHNSCC. However, Cis + RT had a better safety profile.Keywords:
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Abstract The established antitumor efficacy of paclitaxel and cisplatin as single agents and their distinctly different mechanisms of action have prompted laboratory and clinical research into their use in combination. Our in vivo study was performed to investigate the importance of sequence of administration and inter‐agent interval. C3Hf/Kam mice bearing OCa‐1 tumors received paclitaxel and cisplatin. The antitumor efficacy of the combination, measured as re‐growth delay and expressed as the enhancement factor (EF), was determined for inter‐agent intervals of I, 9, 24, 48 and 72 hr. Morphometric analysis was used to determine the contribution of induced apoptosis. Our findings showed an additive effect when cisplatin preceded paclitaxel by 1 and 24 hr, producing EF of 1.1 and 1.0, respectively, and a greater than additive effect for 9 and 48 hr, producing EF of 1.3 and 1.8, respectively. This sequence, however, was associated with significant morbidity and mortality. When paclitaxel preceded cisplatin the effect was greater than additive with the EF for I, 9 and 24 hr, being 1.2, 1.5 and 1.5, respectively, and increasing to a maximum of 1.9 at 48 hr. Thus, for this combination, the therapeutic ratio was improved when paclitaxel preceded cisplatin and was greatest when a 48 hr interval was allowed between drugs. We were unable to attribute the efficacy of the drug combination to increased induction of apoptosis and suggest other possible mechanisms. © 1995 Wiley‐Liss, Inc.
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瞄准：由于源于先进胃的癌症的腹膜炎 carcinomatosa 与腹水在病人在它的静脉内的管理以后在血浆和腹水检验 paclitaxel 集中。方法：有腹水的二个病人在这研究由于源于胃的癌症的腹膜炎 carcinomatosa 被包括。在血浆和腹水的 paclitaxel 集中为 72 h 被调查以防 1 和 168 h 以防 2 在静脉内的管理以后。结果：在血浆的 paclitaxel 集中在管理以后立即达到顶点，在 24 h 以内在 0.1 微摩尔(85 ng/mL ) 的阀值价值下面由快速的减少列在后面。相反，在腹水的 paclitaxel 集中在管理以后为 24 h 逐渐地增加了到与在血浆发现的水平一致的水平。在 24 h 以后，在腹水和血浆的 paclitaxel 的水平变得类似，与被维持直到 72 h 追随者管理的最佳的水平。结论：在腹水的 paclitaxel 的集中在静脉内的管理以后为多达 72 h 为癌症房间的治疗在最佳的水平以内被维持。Paclitaxel 是为胃的癌症的恶意的腹水的治疗的有希望的药。
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目的将在周期性的颈的癌症的治疗加 cisplatin 观察 paclitaxel 的功效和毒性。方法有周期性的颈的癌症的诊断的 23 个病人是合格的。三周刊的化疗政体由 paclitaxel 组成了为白天 1 上的 3 h 的 135 150 mg/m2 注入， cisplatin 白天 1 ～ 3 上的 25 mg/m2 注入。所有病人接受了至少二周期治疗。反应评估的结果是 47.8% 包括 CR 2 盒子(8.7%) ， PR 9 盒子(39.1%) 。主要毒性包括了嗜中性白血球减少症，呕吐的恶心，关节痛，肌痛和脱发。与 cisplatin 相结合的结论 Paclitaxel 是有为周期性的颈的癌症的可接受的不利反应的有效治疗。
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Paclitaxel, an effective antitumor agent, is formulated in various vehicles serving as carriers to deliver the hydrophobic paclitaxel to tissue. The approved formulations in the U.S. are paclitaxel formulated in Cremophor EL (currently known as Kolliphor EL) and nanoparticle albumin-bound paclitaxel (nab–paclitaxel). Despite having the same active ingredient (paclitaxel), different formulations produce distinct products with unique efficacy and safety profiles. A semimechanistic model was developed to describe the pharmacologic sensitivity of paclitaxel under different formulations. Circulating paclitaxel concentration data from patients treated with nab–paclitaxel or Cremophor EL–paclitaxel were analyzed in NONMEM using a semimechanistic model with simultaneous disposition of paclitaxel–carrier complexes and the total paclitaxel released from the complexes. The key factors driving paclitaxel exposure in circulation and peripheral tissues were explored via sensitivity analysis. The rapid decline of total paclitaxel concentration following intravenous administration of nab–paclitaxel and Cremophor EL–paclitaxel was attributed to rapid tissue distribution of the paclitaxel–carrier complexes, with minor contribution of free and protein-bound paclitaxel. Distribution of nab–paclitaxel to peripheral tissue was 4-fold faster and 10-fold more extensive than that of Cremophor EL–paclitaxel micelles, resulting in distinct tissue paclitaxel profiles. Sensitivity analyses showed the plasma paclitaxel–time profile was insensitive to the rapid rates of tissue distribution and decomposition of paclitaxel–carrier complexes but that the tissue distribution profile of paclitaxel was highly sensitive. Tissue distribution of paclitaxel is carrier complex system-dependent. Different delivery systems result in distinct tissue paclitaxel profiles but similar paclitaxel concentration–time profiles in plasma or blood, rendering the paclitaxel plasma profile a poor surrogate for its clinical outcome.
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Pharmacokinetics of paclitaxel in a hemodialysis patient with advanced gastric cancer： A case report
我们第一次为一个病人报导每周的 paclitaxel 化疗的可能性与先进， nonresectable 胃的癌症经历牙齿过敏细胞溶解。有长期的肾衰竭的一个 50 岁的人由于双边的 polycystic，一个星期经历牙齿过敏细胞溶解三次 5 年了，在 2004 年 12 月与吐血介绍了。与淋巴节点转移基于胃的癌症的诊断，外科被执行。在第 15 手术后的天，病人用 paclitaxel 与化疗被对待。Paclitaxel 在 saline 的 250 mL 作为 1 h iv 注入在 60 mg/m2 的剂量被管理。血液透析被开始在 paclitaxel 注入的结束以后的 1 h 并且为 3 h 被执行。Paclitaxel 在 d 上每周被管理 1， 8，和 15 在 28-d 上骑车。paclitaxel 的最大的血浆集中是 1390 microg/L。在 paclitaxel 的曲线下面的区域是 4398.6 microg x h/L。等级 2 白细胞减少在第一个周期期间被遇到。到在注入以后的超过 24 h 的从 6 的 paclitaxel 的血浆集中是在我们的病人的 0.01 ～ 0.1 micromol/L，并且这些集中被显示了在没有在病人生产不利副作用，禁止胃的癌症房间的生长上有效。paclitaxel 的血浆集中没被牙齿过敏细胞溶解影响。我们断定 paclitaxel 的 pharmacokinetics 没与肾衰竭在一个病人被改变，并且那每周的 paclitaxel 是为有先进胃的癌症的牙齿过敏细胞溶解病人的合适的治疗政体。
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Paclitaxel and cisplatin are associated with dose‐limiting neurotoxicity that may result from their differing effects on microtubule stability in peripheral nerves. We hypothesized that such different actions of paclitaxel and cisplatin could be exploited to minimize their neurotoxicity by giving them in combination. Paclitaxel (9–18 micromol/kg/week or 7.7–15.4 mg/kg/week) and cisplatin (5–10 micromol/kg/week or 1.5–3 mg/kg/week) were given alone and in combination to female Wistar rats. Treatment was given once per week for a total of 7–10 weeks. Paclitaxel and cisplatin were given 24 h apart when they were given in combination. Changes in sensory nerve conduction velocity (SNCV) and dorsal root ganglia (DRG) morphology were measured. The nature of their interaction was analyzed using an isobologram. Their antitumor activity alone or in combination was also determined in C57B1/6 mice bearing colon 38 tumors. Reductions in SNCV occurred with paclitaxel alone (P = 0.009), cisplatin alone (P = 0.012), and cisplatin given 24 h before paclitaxel (P < 0.0001). In contrast, there was no significant change in SNCV with paclitaxel given 24 h before cisplatin (P = 0.11). An isobologram showed that the SNCV effects of the drug combinations were less than additive or antagonistic. Cisplatin‐induced morphometric changes in DRG neurons were less marked when cisplatin was given with paclitaxel (P = 0.004). Concentrations of platinum in dorsal root ganglia, sural nerves, and sciatic nerves were not altered by giving paclitaxel before cisplatin. Tumor growth delays (TGD) were greater after treatment with paclitaxel (23.4 mu mol/kg or 20 mg/kg) given 24 h before cisplatin (23.3 micromol/kg or 7 mg/kg) (TGD = 7.5 days) than after paclitaxel (23.4 micromol/kg or 20 mg/kg) (TGD = 2.0 days) or cisplatin (23.3 micromol/kg or 7 mg/kg) (TGD = 3.5 days) alone. Paclitaxel and cisplatin antagonized each other's neurotoxicity in Wistar rats. Combining cytotoxic agents with opposing effects on peripheral nerves has potential for minimizing neurotoxicity in patients.
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