Paclitaxel Infusion Research Articles

Weekly paclitaxel, cisplatin, and 24-hour infusion of high-dose 5-fluorouracil plus leucovorin (weekly TP-HDFL) in patients with metastatic or recurrent esophageal cancer

15165 Background: Paclitaxel (T), cisplatin (P), and 5-fluorouracil (5-FU) are active chemotherapy drugs for esophageal cancer. The 3-drug combination using a conventional 3-weekly schedule was active in patients with advanced esophageal cancer with response rate of 46% (Ilson DH et al: J Clin Oncol 1998;16:1826). The toxicity was substantial, with 57% grade 3/4 hematologic toxicities and 18% grade 3/4 peripheral neuropathy. We reported a multifractionated schedule using twice-weekly TP and weekly 5-FU (Lin CC et al: Anticancer Drugs 2007;18: in press). The multifractionated schedule, while induced comparable antitumor activity, had similar hematologic toxicities, less neuropathy, but more diarrhea than conventional 3-weekly schedule. The optimal way of combining T, P, and 5-FU remains to be defined. Methods: Patients with metastatic or recurrent esophageal cancer treated with weekly T, P, high-dose 5-FU plus leucovorin (weekly TP- HDFL) were retrospectively analyzed. The regimen consisted of T 70–80 mg/m2 IV 1h D1, P 35 mg/m2 IV 3h D2, 5-FU 2000 mg/m2 plus leucovorin 300 mg/m2 IV 24h D2, for 2 or 3 weeks followed by 1 week off. Results: Between Dec 2004 and Sep 2006, a total of 15 patients (male 14, squamous cell carcinoma 12) with a median age of 54 (range 37–76) were included. Eleven patients had de novo metastatic disease and 4 had recurrent disease. The disease extent included local esophageal tumor, lymph nodes, lung, liver, and bone in 13, 13, 5, 4, and 5 patients, respectively. The patients received an average of 3 cycles (range 1–5). Grade 3/4 neutropenia, leukopenia, thrombocytopenia, and infection occurred in 4, 3, 1, and 5 patients, respectively. No grade 3/4 vomiting, mucositis, diarrhea, and peripheral neuropathy occurred. The overall response rate was 33% (95% CI 12–87) (PR 5, SD 6, PD 4). With a median follow-up of 5 months, the median progression-free and overall survival were 3 (range 2–7) and 12.5 months (range 3+-12.5), respectively. Conclusions: Weekly TP-HDFL has a comparable activity and a better toxicity profile in patients with advanced esophageal cancer compared to previously reported 3-weekly or multifractionated schedule. (The study was supported by the grant of DOH95-TD-B-111- 001) No significant financial relationships to disclose.

Cystatin C, an additional marker of ovarian cancer extent: A pilot study

16080 Background: Cystatin C is a cysteine protease inhibitor which has been recommended as the marker of glomerular filtration rate (GFR). We investigated significance of cystatin C in relation to ovarian cancer extent and its feasibility in assessment of renal function in patient with ovarian cancer (OC) who underwent chemotherapy. Methods: We prospectively included consecutive patients with OC who underwent chemotherapy : cisplatin 75 mg/m2 plus 24-hour infusion of paclitaxel 135 mg/m2 every three week after surgery. Before chemotherapy serum renal markers were noted as: creatinine (Cr), cystatin C (Cys C), albumin, creatinine clearance (ClCr) calculated by using 24-hour urine collection per 1.73 m2, creatinine clearance estimated with formulas Cocroft- Gault (ClCG) and Modification of Renal Disease (MDRD1), respectively. Results: Between February 2003 and January 2006 37 patients were enrolled onto this study. Median age 54 year (range from 28 to 68). Cystatin C and CrCl weakly correlated (R Spearman= -0.36; p=0,03). There were no correlation between cystatin C and other markers of GFR (serum creatinine, ClCG, MDRD1). We showed correlation between cystatin C and tumor extent revealed by spiral CT- scan (> 1 cm diameter) after surgery (R Spearman= 0.4; p=0.01), and CA 125 (R Spearman= 0.4, p=0.03). Cut-off values were established as medians for both factors, and patients with high and low values had no statistical differences in overall survival (log- rank test, p=0.9). Conclusions: We believe that cystatin C could imply OC extent in patients.This factor weakly was correlated with CrCl, and no correlated with other GFR parameters. No significant financial relationships to disclose.

Comparative phase II study of intraperitoneal (IP) versus intravenous (IV) carboplatin administration with IV paclitaxel in patients with bulky residual disease after primary debulking surgery for epithelial ovarian or primary peritoneal cancer: A Sankai Gynecology Study Group (SGSG) study

5584 Background: To assess the anti-tumor effect and safety of IP carboplatin (C) administration comparing with IV C administration in combination with IV infusion of paclitaxel (P). Methods: This is a non-randomized comparative phase II trial. Eligible patients were those with histologically confirmed epithelial ovarian or primary peritoneal cancer who received initial surgery and ended up with residual disease >= 2 cm. They must have reasonable hematological, hepatic, renal function before receiving chemotherapy. The patients received either of the following treatment arms; IP Arm: IV P 175 mg/m2 over 3h followed by IP C AUC6, IV Arm: IV P 175 mg/m2 over 3h followed by IV C AUC6. The treatments were scheduled to repeat 6–8 cycles. Interval debulking surgery was allowed after 3 to 5 cycle of treatment. Each participating institution had to declare, before the study was opened, which of the treatment arms the patients from the institution would be entered. Primary endpoint was a response. Secondary endpoints were toxicity and progression-free survival (PFS) and overall survival (OS). Target accrual was 30 patients in each arm. Results: Total accrual was 26 patients for IP arm and 30 patients for IV arm between 2001 and 2005. The study was closed early, because of the conflict of protocols for IP treatment. Eligible patients were 24 in IP Arm and 25 for IV arm. Median number of treatment cycle was 6 for both arms. Although the difference was not statistically significant, response rate was better in the IP Arm. Response rates were 83.3% (95%CI: 62.6%-95.3%) for IP Arm and 60.0% (95%CI: 38.7%-78.9%) for IV Arm. As of median followup of 31 months, median PFS is 25 months for IP Arm and 21 months for IV Arm,. Median OS is not reached for IP Arm, and 52 months for IV arm. Incidences of hematological and non-hematological toxicities were essentially the same on both arms. Conclusions: IP administration of C may be a better treatment strategy for epithelial ovarian and primary peritoneal cancer patients. A randomized phase III trial including bulky residual disease for comparison of IP and IV carboplatin treatment. No significant financial relationships to disclose.

Sequential therapy with carboplatin (C) followed by paclitaxel (P) as first-line chemotherapy in 105 patients with advanced ovarian cancer (AOC): Results of a multicenter phase II study of the Northeastern German Society of Gynecological Oncology

5533 Background: For the adjuvant setting of AOC after primary radical surgery the combination of paclitaxel and platinum in a three weeks schedule has emerged as the current standard. Exposition duration of the drug is important for cell death. In animal model additional anti-angionetic effects of low dose paclitaxel infusion was observed. A sequential schedule of these agents can potentially yield in an improved therapeutic index. Methods: In this multicenter-phase II trial after primary radical surgery 4 cycles of Carboplatin at a dose of AUC 5 (d1/q21d) followed by 12 cycles weekly paclitaxel at a dose of 80mg/m2 (d1/q7d) was applied. All patients with haemoglobin levels < 12mg/dl get primary erythropoietin. No primary use of other growth factors were allowed. Eligibility criteria were: AOC (FIGO IIb-IV), ECOG performance status 0–2, normal organ functions. Results: Between 07/2003 and 05/2005, 105 patients from 27 institutions were enrolled. The median age was 60 years (23–80). FIGO-stages were: II: 11.4%, III: 67.6%, IV: 14.2%. 1,441 cycles were analyzed and in median 16 courses were applied (range 0–16). The incidence of non-hematological toxicities was very low. 25 % of all patients experienced alopecia (grade 1–2). Neurotoxicity and nausea/vomiting (grade III-IV) occurred in no patients. Grade 3–4 hematological toxicity (% of all pts) included: thrombocytopenia (16 %), anemia (3%), leucopenia (22%), neutropenic fever (0%). 96% received erythropoietin. Thromboembolic events (5%) were not increased in patients who received erythropoietin. After a median follow-up interval of 10 months (range: 1–27 months) 20 patients died, the median overall survival is already not reached. The progression free survival is 19 months (range:10–23 months). Conclusions: These results suggest that this sequential regimen using weekly paclitaxel represents an efficacious and well-tolerated regimen. A randomized study comparing this new schedule with the conventional 3-week protocol is warranted. (Supported by Bristol Myers Squibb Germany and Ortho Biotech Germany) No significant financial relationships to disclose.

The effect of five different administration intervals on the pharmacokinetics (pk) of paclitaxel (PTX) and pegylated liposomal doxorubicin (PLD) association regimen

13012 Background: The PTX-PLD association is a promising schedule for recurrent head/neck cancer. Their pk behavior could be dependent not only on PTX excipient (polyethoxylated castor oil) interference, but even on different i.v. administration intervals between the two drugs. This study evaluated any possible administration interval-dependent pk interaction, when PLD infusion started 0, 1, 3, 12 or 24 h after PTX infusion end. Methods: 25 patients, affected by recurrent cisplatin pre-treated squamous cell head/neck cancer, were randomized to receive PTX 80 mg/m2 q1w and PLD 12.5 mg/m2 q2w at administration intervals of 0, 1, 3, 12 or 24 h. Pk parameters were evaluated during the first course by non-compartmental analysis, while statistical analysis was performed by non-parametric Kruskal Wallis test. Results: Median PK parameters are reported in the table . PTX pk profile is strongly affected by PLD administration. PTX total exposure is highly reduced, with a consequent increase in Cltot; this alteration is totally due to Kel modifications. On the other side, no statistically significant interactions affected PLD pk parameters. Some in vitro experiments indicate that PLD is able to partially absorb PTX, driving to PTX plasmatic concentration reduction, when PLD is administered at 0–1 h intervals. Conclusions: PLD liposomal components seem to be able to entrap PTX, therefore reducing PTX plasmatic concentrations; so, it is very important to choose the ideal administration interval. In order to avoid pk interaction, the i.v. administration interval between PTX and PLD had to be 3 h at least. For shorter intervals, patients could be underexposed to PTX, with lesser clinical efficacy. [Table: see text] No significant financial relationships to disclose.

Pilot study of regional, hepatic intra‐arterial paclitaxel in patients with breast carcinoma metastatic to the liver

Approximately 25% of patients with metastatic breast carcinoma develop hepatic involvement during the course of their disease that further affects their survival. Systemic paclitaxel is safe and has demonstrated good antitumor activity against breast carcinoma. The objective of this prospective study was to determine the safety and antitumor activity of hepatic intra-arterial paclitaxel therapy. Ten patients with breast carcinoma and dominant liver metastases received monthly, inpatient, 24-hour, continuous hepatic infusions of paclitaxel at 200 mg/m(2) through an intra-arterial catheter, which was placed using a percutaneous transfemoral approach. The mean patient age at the time of treatment was 51 years. Fifty-six courses of paclitaxel were delivered. The most common treatment-related toxicities were leukopenia, fatigue, nausea, and vomiting. No procedure-related complications were observed. Three patients (30%) attained partial responses that lasted for 6 months, 7 months, and 48 months; and 4 other patients had stable disease for 5 months to 9 months. One patient underwent liver resection after receiving hepatic arterial infusions of paclitaxel and remained disease free for 48 months. Eight patients had received prior systemic taxane therapy alone or with other cytotoxic agents. However, no association between previous taxane exposure and the efficacy of the current regimen was established. Hepatic intra-arterial therapy with paclitaxel at the dose level and on the schedule used in this study was safe and well tolerated and had reasonable antitumor activity against breast carcinoma involving the liver. Previous taxane exposure did not hamper the potential benefit of this approach. This regimen alone or in combination with targeted therapies deserves further investigation in patients with dominant liver metastases from breast carcinoma.

Weekly paclitaxel and high-dose 5-fluorouracil plus leucovorin in hormone-refractory prostate cancer: In vitro combined effects and a Phase II trial

Purpose Paclitaxel and 5-fluorouracil have been used to treat hormone-refractory prostate cancer with some success. In vitro data suggest that the combined cytotoxicity may be sequence dependent. Thus, we explored the combined effects of the 2 agents, both in vitro and in vivo. Patients and Methods The combined cytotoxicity of paclitaxel and 5-fluorouracil, and the possible schedule dependence were studied in vitro using PC-3 and DU145 cells and the microculture tetrazolium assay. There were 23 patients with hormone-refractory prostate cancer treated with the regimen T-HDFL: paclitaxel 90 mg/m 2 intravenously 1 hour on days 1 and 8; 5-fluorouracil 2000 mg/m 2; and leucovorin 300 mg/m 2 intravenous 24-hour infusion on days 2 and 9, which repeated every 21 days. The allowed percentage of bone marrow irradiation was 50%. Results Significant synergistic cytotoxicity was seen only when paclitaxel was given 24 hours before 5-fluorouracil. With the T-HDFL regimen, 11 (52%) of the 21 evaluable patients had ≥50% reduction of prostate-specific antigen, lasting for 6 weeks. Of the 7 patients with measurable disease, 2 had a partial response. Median overall survival was 14.1 months. Grade III/IV leukopenia occurred in 2 patients. There was no treatment-related death. Toxicities were well tolerated. Conclusions The combined cytotoxicity of paclitaxel and 5-fluorouracil is schedule dependent. It is feasible to administer weekly paclitaxel and high-dose 5-fluorouracil infusions in patients with hormone-refractory prostate cancer. Our findings may serve as an important rationale for future trial design.

Doxifluridine combined with weekly paclitaxel for second-line treatment in patients with gastric cancer resistant to TS-1

Many patients with gastric cancer respond to TS-1, but some fail to respond or have recurrence. Second-line therapy is needed. We performed a pilot study in patients with advanced gastric cancer who did not respond to TS-1 or who had disease recurrence. The patients received oral doxifluridine (600 mg/day) on days 1 to 21 and an intravenous infusion of paclitaxel (70 mg/m(2)) on days 7, 14, and 21 of a 28-day cycle. The treatment was repeated until disease progression or prohibitive toxicity. Response rate, duration of response, median survival time (MST), effects on pleural effusion, ascites, and other signs, and toxicity were evaluated. The study group comprised 52 patients. The response rate was 28%. The duration of response was 103 days. The MST after the start of second-line treatment was 175 days (95% confidence interval, 135 to 224 days). Pleural effusion or ascites resolved or decreased in 73% of the patients. Hair loss occurred in 32 patients (62%), and leukopenia developed in 28 (54%, grade 3 in 1 patient and grade 2 or lower in the others). The MST after the start of treatment with TS-1 was about 16 months. A combination of doxifluridine and weekly paclitaxel is expected to be an effective second-line treatment for gastric cancer not responding to TS-1, especially in patients with malignant ascites or pleural effusion. However, it remains unclear whether paclitaxel plus doxifluridine results in a better response and survival benefit than paclitaxel alone in this subgroup of patients. Further studies are therefore necessary.

Cross-reactivity between paclitaxel and hazelnut: a case report

A 73-year-old Caucasian woman with metastatic bladder cancer developed hives, itching, difficulty in breathing, and general ill-feeling during the first 10 min of her first infusion of paclitaxel. Paclitaxel was discontinued and the symptoms resolved after intravenous diphenhydramine and hydrocortisone treatment. Upon discussion with the patient, she described the sensation as similar to her reaction to hazelnuts. The patient's only other allergy was to azithromycin, which presented as hives. A PubMed literature search revealed that paclitaxel is found in the components of the hazelnut tree and its nuts. While a nut-protein allergy cannot be ruled out, a cross-reaction between paclitaxel and hazelnuts is a possibility. Patients who describe an allergy to hazelnuts must be carefully observed while being treated with paclitaxel. The hazelnut allergy may not be a nut-protein allergy at all, but rather an allergy to the components of paclitaxel that reside in the hazelnut itself.

A phase I study evaluating the safety and pharmacokinetics of weekly paclitaxel and carboplatin in relapsed ovarian cancer

This phase I study sought to determine the toxicity profile, pharmacokinetics, and antitumor activity of giving carboplatin every 3 weeks and paclitaxel weekly in patients with relapsed ovarian cancer. Eligible patients with relapsed epithelial ovarian cancer and prior treatment with platinum- and paclitaxel-based therapy were treated with an escalating regimen of carboplatin (day 1) at an area under the curve (AUC) of 4-6 and 1-h infusions of paclitaxel (days 1, 8, and 15) at 50-80 mg/m(2) cycled at 3-week intervals. Pharmacokinetic studies were performed on the first day of cycles 1 and 2. All patients had a platinum-free interval of greater than 6 months from the most recent platinum treatment. A total of 77 cycles were administered to 16 patients, with a similar median number of cycles per patient at each dose level varying from 4.6 to 5.3. Febrile neutropenia and grade 4 thrombocytopenia were the dose-limiting toxicities at dose levels 3 and 4 after the third cycle, with no mucositis, nausea, vomiting, or peripheral neuropathy observed greater than grade 2. The maximum tolerated dose of carboplatin was an AUC of 5 and 80 mg/m(2) for paclitaxel. Pharmacokinetic analysis showed a marginal statistical difference with regard to reduced systemic paclitaxel concentration after cycle 2 compared with cycle 1 (P= 0.06). Of nine patients evaluable for a radiographic response, the response rate was 66.6% with a complete response of 33.3%. All five patients with nonmeasurable disease achieved a biochemical response. The combination of carboplatin given every 3 weeks at an AUC of 5 and 1-h weekly paclitaxel at 80 mg/m(2) is a feasible and reasonably well-tolerated regimen and may have significant antitumor activity in relapsed ovarian cancer patients.

Physical and chemical stability of paclitaxel infusions in different container types

To determine the physicochemical stability of generic (Teva Pharmaceuticals) paclitaxel infusions (0.3 and 1.2 mg/mL) in 0.9% sodium chloride or 5% glucose in polyolefin (Viaflo), low-density polyethylene (Ecoflac), and glass containers at 2-8 and 25 degrees C. Paclitaxel infusions of various concentration/diluent/container combinations were prepared. Containers were light-protected and incubated at test temperatures with further analysis at predetermined intervals of 1-3 days for up to 30 days. Infusions were monitored for pH, weight loss, precipitation, colour change, and subvisual particulates as indicators of physical stability, and assayed for drug concentration to determine chemical stability. Precipitation was the limiting factor. Infusions of paclitaxel (0.3 mg/mL) in 0.9% sodium chloride remained stable for 13, 16 and 13 days at 2-8 degrees C in polyolefin, low-density polyethylene and glass containers, respectively; in 5% glucose for 13, 18, and 20 days, respectively. At 25 degrees C, paclitaxel infusions (0.3 mg/mL) remained stable for 3 days in all diluent/container combinations with the exception of 5% glucose in glass, where stability reached 7 days. Paclitaxel infusions (1.2 mg/mL) in 0.9% sodium chloride remained stable for 9, 12, and 8 days at 2-8 degrees C in polyolefin, low-density polyethylene and glass containers, respectively; in 5% glucose for 10, 12, and 10 days, respectively. At 25 degrees C, paclitaxel 1.2 mg/mL remained stable for 3 days in all diluent/container combinations with the exception of glass, where stability reached 5 days in 0.9% sodium chloride diluent, and 7 days in 5% glucose. Paclitaxel stability was influenced by storage temperature, with longer shelf-life at 2-8 degrees C, and also by drug concentration, where 0.3 mg/mL infusions were more stable than 1.2 mg/mL for all diluent/container combinations. Physical stability (precipitation) was the limiting parameter in each case.

Successful treatment of malignant pericardial effusion, using weekly paclitaxel, in a patient with breast cancer

We report a case of metastatic breast cancer with pericardial effusion that was successfully treated with weekly paclitaxel. A 46-year-old woman underwent modified radical mastectomy in April 1997 and was readmitted to the hospital for dyspnea in March 2002. A diagnosis of cardiac tamponade due to breast cancer relapse was made, and the patient was treated with weekly paclitaxel (80 mg/m2) and insertion of a drainage catheter. This treatment was effective in preventing reaccumulation of the pericardial effusion until her death. The concentration of paclitaxel in the cardiac effusion was 45 ng/ml at 3 h, 15 ng/ml at 12 h, and less than 10 ng/ml at 24 h after paclitaxel infusion, indicating good transportation of the drug from the blood to the pericardial effusion. These findings suggest that weekly intravenous infusion of paclitaxel could be effective for the treatment of patients with malignant pericardial effusion.

Intravenous paclitaxel administration in the rat induces a peripheral sensory neuropathy characterized by macrophage infiltration and injury to sensory neurons and their supporting cells

Paclitaxel-induced peripheral neuropathy (PN) can be a significant problem for patients receiving chemotherapeutic regimens for the treatment of breast, ovarian, and lung cancer as PN can influence the quality of life and survivorship in these patients. To begin to understand the cellular changes that occur within the peripheral and central nervous system as PN develops, we intravenously infused rats with clinically relevant doses of paclitaxel. Ten days later, behavioral changes indicative of PN became evident that included mechanical allodynia, cold hyperalgesia, and deficits in ambulation/coordination. These behaviors were accompanied by increased expression of activating transcription factor 3 (ATF3; a marker of cellular injury) in a population of large > medium > small diameter sensory neurons, a population of satellite cells in the lumbar dorsal root ganglia (DRG) and in myelinating Schwann cells in the sciatic nerve. In addition, there was an increase in the expression of glial fibrillary acidic protein (GFAP) in DRG satellite cells and an increase in the number of CD68 positive activated macrophages within the DRG and peripheral nerve. Within lamina III–IV of the lumbar spinal cord, there was an increase in OX42 positive microglia. These data suggest that intravenous infusion of paclitaxel induces a peripheral neuropathy characterized by injury of neuronal and non-neuronal cells in the peripheral nervous system, macrophage activation in both the DRG and peripheral nerve, and microglial activation within the spinal cord. An understanding of the factors involved in the development and maintenance of PN may lead to mechanism based therapies that prevent/treat PN and thus improve the survival and quality of life of patients receiving chemotherapy.

Pharmacokinetics of paclitaxel in a hemodialysis patient with advanced gastric cancer: A case report.

We report for the first time the possibility of weekly paclitaxel chemotherapy for a patient with advanced, nonresectable gastric cancer undergoing hemodialysis. A 50-year-old man with chronic renal failure due to bilateral polycystic kidneys, who had undergone hemodialysis three times a week for 5 years, presented with hematemesis in December 2004. Based on the diagnosis of gastric cancer with lymph node metastases, surgery was performed. On the 15th postoperative day, the patient was treated with chemotherapy using paclitaxel. Paclitaxel was administered at a dose of 60 mg/m2 as a 1 h iv infusion in 250 mL of saline. Hemodialysis was started 1 h after the completion of the paclitaxel infusion and was performed for 3 h. Paclitaxel was administered weekly on d 1, 8, and 15 on a 28-d cycle. The maximum plasma concentration of paclitaxel was 1390 microg/L. The area under the curve of paclitaxel was 4398.6 microg x h/L. Grade 2 leukopenia was encountered during the first cycle. The plasma concentrations of paclitaxel from 6 to over 24 h after the infusion were 0.01 to 0.1 micromol/L in our patient, and these concentrations have been shown to be effective on inhibiting the growth of gastric cancer cells without producing adverse side effects in the patient. The plasma concentration of paclitaxel was not influenced by hemodialysis. We conclude that the pharmacokinetics of paclitaxel is not altered in a patient with renal failure, and that weekly paclitaxel is a suitable treatment regimen for hemodialysis patients with advanced gastric cancer.

Sensory neurons and their supporting cells located in the trigeminal, thoracic and lumbar ganglia differentially express markers of injury following intravenous administration of paclitaxel in the rat

Paclitaxel-induced peripheral neuropathy is a sensory neuropathy that affects thousands of cancer patients each year as paclitaxel is commonly used to treat breast, non-small cell lung and ovarian cancer. To begin to define the type and location of sensory neurons most impacted by paclitaxel, we examined rat trigeminal ganglion, thoracic and lumbar dorsal root ganglion (DRG) 10 days following intravenous infusion of clinically relevant doses of paclitaxel. To define the population of cells injured by paclitaxel, we examined the expression of activating transcription factor-3 (ATF3), a marker of cell injury; to define the hypertrophy of satellite cells, we quantified the expression of the intermediate filament protein glial fibrillary acidic protein (GFAP); and to define the activation of macrophages, we examined the expression of the lysosomal protein CD68. Intravenous infusion of paclitaxel induced a significant increase of ATF3 in mainly but not exclusively large and medium sensory neurons in all sensory ganglia. An increase in both GFAP immunofluorescence in satellite cells and the number of activated macrophages occurred in lumbar > thoracic > trigeminal ganglia of paclitaxel-treated rats. This differential expression of cellular markers suggests that the largest sensory cell bodies with the longest axons are the most at risk of being injured by paclitaxel (size and length dependent pathology). These results provide a pathological basis for the anatomical distribution of paclitaxel-induced symptoms in patients receiving therapeutic regimens of paclitaxel.

A phase II evaluation of a 3‐hour infusion of paclitaxel, cisplatin, and 5‐fluorouracil in patients with advanced or recurrent squamous cell carcinoma of the head and neck

Previous data from an institutional pilot study in patients with advanced or recurrent squamous cell carcinoma of the head and neck (SCCHN) who received treated a combined chemotherapy regimen of paclitaxel, cisplatin, and 5-fluorouracil indicated an overall response rate of 60% and a median survival of 6 months. To validate these results and to determine the feasibility of this combination, a Phase II study was conducted by the Southwest Oncology Group (SWOG S0007). Patients with advanced or recurrent SCCHN were eligible if they had received 1 previous regimen of induction/adjuvant chemotherapy or no prior systemic therapy. Patients received treatment with paclitaxel (135 mg/m(2) on Day 1), followed by cisplatin (75 mg/m(2) on Day 1), and 5-fluorouracil (1000 mg/m(2)per day as a 96-hour continuous infusion on Days 1-4) every 21 days. Seventy-six patients received a combined total of 286 cycles of chemotherapy. Sixty-nine patients were evaluable for response. There were 5 complete responses (7%) and 23 partial responses (33%) partial responses, for an overall response rate of 41%. The median progression-free survival was 4 months, and the median overall survival was 10 months. Six treatment-related deaths were documented, including deaths in 2 patients who had a Zubrod PS of 2. Grade 3 or 4 neutropenia (according to National Cancer Institute Common Toxicity Criteria [version 2.0]) was observed in 47% of patients. Other Grade 3 or 4 adverse events included mucositis (34% of patients), nausea (20% of patients), anemia (9% of patients), and neuropathy (8% of patients). The combination of paclitaxel, cisplatin, and 5-fluorouracil had efficacy similar to that of standard treatment regimens in patients with advanced or recurrent SCCHN but with increased toxicity.

Paclitaxel, 5-fluorouracil and hydroxyurea concurrent with radiation in locally advanced nasopharyngeal carcinoma

Background: Concurrent chemoradiotherapy (CRT) is the standard treatment for locally advanced nasopharyngeal carcinoma (NPC). We conducted a phase II trial using paclitaxel, 5-fluorouracil and hydroxyurea concurrent with radiation (TFHX).Patients and methods: Fifty-nine patients with locally advanced NPC were treated with CRT consisting of 4-day continuous infusions of paclitaxel (20mg/m2/d) and 5-fluorouracil (600mg/m2/d), and oral hydroxyurea 500mg bid for nine doses, every 3 weeks concurrent with radiotherapy (RT). RT consisted of once daily 200cGy fractions 5 times per week to a total of 7000cGy.Results: Complete response was seen in 86% and 71% of patients at 4 and 12 months after CRT. The median follow-up was 34 months. Twenty-three patients experienced relapse. Sixteen deaths occurred: 13 from progressive disease. Three-year overall survival and progression-free survival were 72% and 54% respectively, with locoregional and distant control rates of 83% and 64% at 3 years respectively. Grade 3 to 4 acute toxicities included oropharyngeal mucositis in 81% of patients treated, dermatitis in 63%, weight loss in 32%, and neutropenia in 22%. Neutropenic fever was seen in 14%. There were no treatment-related deaths from acute toxicity.Conclusions: TFHX is shown to be feasible in NPC. Non-cross resistant induction chemotherapy should be further studied with this regimen.

A phase I study of S-1 administration and a 24-h infusion of cisplatin plus paclitaxel in patients with advanced gastric cancer

4074 Background: S-1 may have a major role in the treatment of gastric cancer as single agent or as a component of combination chemotherapy in Japan. We previously reported a multicentric phase II study of S-1 combined with a 24-h infusion of cisplatin in patients with advanced gastric cancer. This combination was active, safe and had the possibility of being combined with other anticancer drug. Combination chemotherapy with S-1 and cisplatin plus paclitaxel for advanced gastric cancer might yield a stronger antitumor effect. The objective of this study was to determine the dose-limiting toxicity (DLT), the maximum tolerated dose (MTD), the recommended dose (RD), and the preliminary antitumor activity of S-1 and cisplatin plus paclitaxel for advanced gastric cancer. Methods: Paclitaxel was administered on day 1. A fixed dose of S-1 (70 mg/m2/day) was orally administered for 14 consecutive days from day 1, and a 24-h infusion of a fixed dose of cisplatin (60 mg/m2) was administered on day 14 of every 28-day cycle. Four dose escalation levels of paclitaxcel were studied (120, 140, 160, and 180 mg/m2). The DLT was defined as any of the following: grade 3 neutropenia lasting more than 5 days, grade 4 hematological toxicity, grade 3 non-hematological toxicity, or treatment delay of greater than 2 weeks as a result of toxicity. Results: Twenty patients were enrolled. Hematological and non- hematological toxicity of over grade 2 was not observed at dose level 1 and 2. Three patients started at dose level 3. One developed grade 3 neutropenia for 5 days following by grade 2 neutropenia lasted more than 10 days. Five more patients were added at this level. The treatment was delayed over 2 weeks in 1 out of 8 patients. Three patients started at dose level 4. One developed grade 3 neutropenia and needed longer than 14 days to recover. Three patients added this level. In total, at dose level 4 the treatment was delayed over 2 weeks in 3 out of 6 patients as a result of neutropenia. We considered level 4 is the MTD and the RD of paclitaxcel was 160 mg/m2 (dose level 3). The overall response rate was 75%. Conclusions: Triple combination chemotherapy consisting of S-1, cisplatin, and paclitaxel showed a tolerable dose of adverse reactions and favorable antitumor activity for gastric cancer. No significant financial relationships to disclose.

Pilot study of regional hepatic intra-arterial (HIA) paclitaxel in patients (Pts) with breast carcinoma metastatic to the liver

10626 Background: Approximately 50% of pts with metastatic breast carcinoma develop hepatic involvement during the course of their disease. Their median survival is 1–14 months (mo). Systemic paclitaxel has good anti-tumor activity against breast carcinoma and is safe. We sought to prospectively determine the safety and anti-tumor activity of HIA paclitaxel therapy. Methods: Ten pts with breast carcinoma and dominant liver metastases received monthly inpatient 24 hr-continuous HIA infusions of paclitaxel at 200 mg/m2 through intra-arterial catheters placed via percutaneous transfemoral approach. WHO tumor assessment guidelines were used. Results: Nine pts enrolled in this study had infiltrating ductal carcinoma and their median age at the time of treatment was 51 years. The group had received a mean of 3.8 previous treatment regimens including adjuvant regimens. Therapy was well tolerated. Fifty-six courses were delivered. Mean hospital stay was 3 days. No procedure related complications were observed. Most common treatment related toxicities included leukopenia, fatigue, nausea, and vomiting. Three pts attained partial responses (50% decrease in tumors) lasting 6, 7, and 48 months whereas in 4 others disease stabilization lasted 5 to 9 mo. One pt underwent liver resection and remained NED for 48 mo. Eight pts had received prior systemic taxane therapy alone or in combination with other cytotoxics (3 adjuvant; 5 palliative). However, no association between previous taxane exposure and clinical efficacy of this regimen was not established. Conclusions: Hepatic arterial therapy with paclitaxel at this dose and schedule is safe and well tolerated and has reasonable anti-tumor activity against breast carcinoma involving the liver. Previous taxane exposure does not hamper the potential benefit of this approach. This regimen deserves further investigation alone or in combination with targeted strategies in patients with dominant liver involvement from breast carcinoma. No significant financial relationships to disclose.

Paclitaxel and pegylated liposomal doxorubicin in recurrent head/neck cancer: An unexpected administration interval-dependent pharmacokinetic interaction

2042 Background: Combination of paclitaxel (PTX) with pegylated liposomal doxorubicin (PLD) is an interesting opportunity for recurrent head/neck cancer treatment. Their pharmacokinetic (PK) behavior could be dependent not only on PTX excipient (polyethoxylated castor oil) interference, but also on different iv administration interval between the two drugs. The study endpoint was to evaluate any possible administration interval-dependent PK interaction, when PLD infusion start is delayed from 0 to 24 h after PTX infusion end. Methods: 24 patients affected by recurrent cisplatin pre-treated squamous cellhead/neck cancer were enrolled, receiving PTX 80 mg/m2 q 1w and PLD 12.5 mg/m2 q 2w for 6w/2w rest. Administration interval was 0 h at d1 (PTX-PLD 0) and 24 h at d15 (PTX-PLD 24). Blood sampling was performed at d1–15, PTX and PLD blood levels were analyzed by high performance liquid chromatography techniques, while PK parameters by non-compartmental analysis. Results: PTX PK parameters had large statistically significant differences (median/IQR, PTX-PLD 0 vs. PTX-PLD 24, Mann-Whitney test): Cmax 261/219–531 vs. 407/250–1473 ng/ml p=0.142, AUC 869/688–1331 vs. 3361/969–7853 ng*h/ml p=0.013, Kel 0.39/0.26–0.57 vs. 0.11/0.02–0.26 h⁁−1 p=0.001, Cl 153/89–198 vs. 41/17–138 l/h p=0.013. Similarly, PLD Cmax and AUC were higher in PTX-PLD 24 (Cmax 5.1/3.3–8.1 vs. 6.8/5.3–7.8 mg/l p=0.043, AUC 341/104–1472 vs. 603/106–1006 mg*h/l p=1.000). The overall response rate was 37.5%, including 1 CR (4%); median response duration was 5.5 months (range, 2–16), median overall survival 10 months (range, 2–25+). Conclusions: This exploratory study, having a favourable palliative role in heavily pre-treated patients, showed that PTX PK profile is unexpectedly affected by a different administration interval. In PTX-PLD 0, PTX AUC is fourfold reduced, with a similar increase in Cl, totally due to Kel alteration: therefore, patients could be underexposed to PTX. PLD PK behavior confirmed previous studies results, in which PTX modified PLD disposition, prolonging the duration of its elimination phase and increasing total body exposure to PLD. No significant financial relationships to disclose.