Dose intensity of uracil and tegafur in postoperative chemotherapy for patients with poorly differentiated gastric cancer

A retrospective analysis of postoperative chemotherapy had shown the continuous administration of UFT, an oral preparation of 1-(2-tetrahydrofuryl)-5-fluorouracil (tegafur) and uracil at a molar ratio of 1:4, to be effective for poorly differentiated gastric cancer. We therefore sought to determine prospectively the effective dose of postoperative chemotherapy with UFT for patients with poorly differentiated gastric cancer following a curative resection. We determined the effect of the combined intravenous administration of mitomycin C (MMC) and oral treatment with protein-bound polysaccharide Kreha (PSK), extracted from the basidiomycete Coriolus versicolor, and UFT at a dose of either 8 mg/kg or 12 mg/kg daily for 1 year. A total of 224 patients with poorly differentiated stage II–IV gastric cancer were entered into this study after undergoing a curative resection. No differences were observed between the two treatment groups in terms of prognostic factors, the toxicity rate or the doses of the drugs prescribed, other than UFT. The higher dose of UFT in maintenance therapy led to a decrease in the recurrence rate (P < 0.05), and increases in disease-free survival and cause-specific survival (P < 0.05). UFT at 12 mg/␣kg in postoperative chemotherapy was thus found- to improve the postoperative results with no increase in toxicity for poorly differentiated gastric cancer, and is also cost-effective for outpatients. Received: 8 February 1996 / Accepted: 27 November 1996     

Optimizing interstitial delivery of BCNU from controlled release polymers for the treatment of brain tumors

 Two approaches for improving the interstitial administration of carmustine (BCNU) using 3.8% loaded poly(carboxyphenoxypropane-sebacic acid), an implantable biodegradable anhydride which significantly prolongs survival in patients with recurrent malignant gliomas, were evaluated. First, increasing the ratio of carboxyphenoxypropane (CPP) to sebacic acid (SA) in the polymer increases its hydrolytic stability, thus prolonging its half-life in vivo, and extending the period of drug release. A second approach is to increase the dose of drug loaded into the polymer. This study evaluated the relative merits of these two approaches by comparing release kinetics, safety, and efficacy of escalating BCNU doses in polymers with 20:80 and 50:50 ratios of CPP to SA. At the highest dose tested, the 50:50 polymer released BCNU 2.5 times as long in vitro as the 20:80 polymer. Both formulations were nontoxic in rat brains for all BCNU doses tested except 32%. The 20:80 and 50:50 polymers were equally effective in the rat intracranial 9L-glioma model. A dose-response relationship for BCNU was observed (hazard ratio 0.8354 for each mg/kg increase, P<0.001). The two highest loading doses of BCNU improved survival 40-fold (P<0.001). The 20% BCNU-loaded 20:80 polymer achieved the best balance of toxicity and antitumor efficacy, yielding a 75% long-term survival rate. Further evaluation of this polymer in monkeys suggests that it might be used with acceptable toxicity. This study establishes that a dose-escalation strategy for improving BCNU controlled-release polymers is more effective than adjusting the ratio of CPP to SA to prolong drug release. Received: 21 February 1996/Accepted: 14 August 1996     

A phase II study of pegylated liposomal doxorubicin for treatment of advanced hepatocellular carcinoma

Background:Pegylated liposomal doxorubicin has an enhancedefficacy and reduced toxicity compared with free doxorubicin. The efficacy andtoxicity of pegylated liposomal doxorubicin was investigated in patients withhepatocellular carcinoma. Patients and methods:Patients with histologically confirmed,locally advanced or metastatic hepatocellular carcinoma and a Karnofsky index>60% were included in this prospective single-arm study. Exclusioncriteria were liver cirrhosis stage Child–Pugh C, previous chemotherapy,or chemoembolization. Pegylated liposomal doxorubicin was given in a dose of30 mg/m² every three weeks until progression of disease. Afterinclusion of five patients the dose could be escalated to 40 mg/m²in absence of toxicity grade 3 and 4. Results:Sixteen patients were evaluable for response. Noobjective response was achieved. The median survival time was 140 days(95% confidence interval: 126–154 days). Treatment toxicitiesgrade 3 comprised increased liver enzymes in patients with preexistinggrade 1 or 2 elevation (n = 6), hematologic toxicity (n =5), and hypersensitivity (n = 2). Conclusions:Pegylated liposomal doxorubicin is not effective fortreatment of advanced hepatocellular carcinoma. The favorable toxicity profilewas confirmed even in patients with underlying liver disease.     

Toxicity, pathological effects, and antineoplastic activity of a non-toxic dose of 5-fluorouracil in combination with methotrexate

The survival time of CF-1 mice bearing Ehrlich ascites tumor cells was increased significantly by i.p. administration of a non-toxic dose of 5-fluorouracil (25 mg/kg) followed by methotrexate (40 mg/kg). The effects of 5-fluorouracil (FU) and methotrexate (MTX), singly and in combination, were examined on the hematopoietic system (platelets, erythrocytes, leukocytes, and hematocrit), body weight, and the crypt of Liberkühn to assess toxicity, and on survival of tumor-bearing animals to assess antineoplastic activity. Sequential treatment with a non-toxic dose of FU followed by MTX for 3 consecutive days produced no significant adverse effect. MTX alone and the scheduling of FU after a priming dose of MTX resulted in: (a) a marked decrease in the hematopoietic parameters; (b) significant morphological changes in ileal tissue; and (c) a reduction in body weight. The survival of tumor-bearing animals treated with FU alone and FU 2 hours before MTX was 124% and 139% greater than control, respectively. The survival rate of animals treated with MTX alone was less than that of untreated tumor animals. This study suggests the feasibility of designing FU and MTX regimens that will have little or no systemic toxicity while maintaining antineoplastic activity.     

Influence of vesicle size, lipid composition, and drug-to-lipid ratio on the biological activity of liposomal doxorubicin in mice

The effects of vesicle size, lipid composition, and drug-to-lipid ratio on the biological activity of liposomal doxorubicin in mice have been investigated using a versatile procedure for encapsulating doxorubicin inside liposomes. In this procedure, vesicles exhibiting transmembrane pH gradients (acidic inside) were employed to achieve drug trapping efficiencies in excess of 98%. Drug-to-lipid ratios as high as 0.3:1 (wt:wt) could be obtained in a manner that is relatively independent of lipid composition and vesicle size. Egg phosphatidylcholine (EPC)/cholesterol (55:45; mol/mol) vesicles sized through filters with a 200-nm pore size and loaded employing transmembrane pH gradients to achieve a doxorubicin-to-lipid ratio of 0.3:1 (wt/wt) increased the LD50 of free drug by approximately twofold. Removing cholesterol or decreasing the drug-to-lipid ratio in EPC/cholesterol preparations led to significant decreases in the LD50 of liposomal doxorubicin whereas, the LD50 increased 4- to 6-fold when distearoylphosphatidylcholine was substituted for EPC. The results suggest that the stability of liposomally entrapped doxorubicin in the circulation is an important factor in the toxicity of this drug in liposomal form. In contrast, the antitumor activity of liposomal doxorubicin is not influenced dramatically by alterations in lipid composition. Liposomal doxorubicin preparations of EPC, EPC/cholesterol (55:45; mol:mol), EPC/egg phosphatidylglycerol (EPG)/cholesterol (27.5:27.5:45; mol:mol), and distearoylphosphatidylcholine/cholesterol (55:45; mol:mol) all demonstrated similar efficacy to that of free drug when given at doses of 20 mg/kg and below. Higher dose levels of the less toxic formulations could be administered, leading to enhanced increases in life span (ILS) values. Variations in vesicle size, however, strongly influenced the antitumor activity of liposomal doxorubicin. At a dose of 20 mg/kg, large EPC/cholesterol systems are significantly less effective than free drug (with ILS values of 65% and 145%, respectively). In contrast, small systems sized through filters with a 100-nm pore size are more effective than free drug, resulting in an ILS of 375% and a 30% long term (greater than 60 days) survival rate when administered at a dose of 20 mg/kg. Similar size-dependent effects are observed for distearoylphosphatidylcholine/cholesterol systems.     

Eight-hour infusion versus bolus injection of doxorubicin in the EAP regimen in patients with advanced gastric cancer: A prospective randomised trial

Background:Doxorubicin (40 mg/m²/cycle), etoposide(360 mg/m²/cycle) and cisplatin (80 mg/m²/cycle)comprise an efficient regimen in patients with advanced gastric cancer (AGC).However, its excessive hematological toxicity led doctors to avoid using thecombination. Doxorubicin is the main cause of myelotoxicity in the EAPregimen. The aim of this study was to compare an eight-hour infusion ofdoxorubicin (arm A) with intravenous injection of doxorubicin (arm B) in theEAP regimen with respect to toxicity, objective responses, time to progression(TTP) and survival in patients with AGC. Patients and methods:One-hundred twenty chemotherapy-naïvepatients with measurable AGC were randomised between September 1994 and August1998. Sixty patients in arm A and sixty patients in arm B were considered asfully evaluable. The arms were well balanced for age, sex distribution,previous therapy, histological grade and performance status. One-hundredeighty cycles were applied in arm A (median 2) and 201 in arm B (median 4). Results:No difference was detected (P = 0.28) in theresponse rate of arm A 20% (CR 3; PR 9; 95% CI: 10–30) andB 28% (CR 3; PR 14; 95% CI: 17–40). But there was asignificant difference in PD (P = 0.005) between arm A (51%)and arm B (36%). TTP (P = 0.01) and survival (P =0.02) analyses detected an advantage for arm B vs. arm A. Grades 3–4toxicity were as follows (arms A%/B%): anemia 8/10, leukopenia24/26, thrombocytopenia 6/16 (significance, P = 0.05),nausea/vomiting 5/8, diarrhea 6/2, mucositis 8/5. Apart from thetrombocytopenia, there was no significant difference in toxicity grades3–4 between the two arms. Four treatment-related deaths occurred, twoin each arm. Conclusions:Bolus injection of doxorubicin is superior toeight-hour doxorubicin infusion in the EAP regimen in terms of survival, TTPand PD without being significantly more toxic.     

A phase I/II study of vinorelbine, doxorubicin, and methotrexate with leucovorin rescue as first-line treatment for metastatic breast cancer

Purpose: This study was performed to determine the maximum tolerated dose (MTD) and toxicity of vinorelbine when used in combination with doxorubicin and methotrexate with leucovorin rescue in women with metastatic breast cancer. Methods: Enrolled in the study were 23 women with metastatic breast cancer who had not received prior chemotherapy for metastatic disease. Patients treated at the first dose level received vinorelbine 20 mg/m² on day 1, doxorubicin 40 mg/m² on day 1, methotrexate 100 mg/m² on day 1 and leucovorin 20 mg orally every 6 h for six doses beginning on day 2. Treatment was repeated every 21 days. The vinorelbine dose was escalated by 5 mg/m² for patients treated at subsequent dose levels. The MTD was defined as the dose level at which fewer than one-third of patients enrolled experienced dose-limiting toxicity (DLT). When the MTD of vinorelbine had been determined, the doxorubicin dose was then escalated by 10 mg/m² with the vinorelbine dose held at its MTD. Results: total of 98 courses of treatment (median of 4 per patient, range 2–8) were administered. The MTD of this regimen was found to be vinorelbine 25 mg/m², doxorubicin 40 mg/m², and methotrexate 100 mg/m² with leucovorin rescue. At higher doses of vinorelbine, neutropenia, fatigue, arm pain, malaise, nausea and vomiting were dose-limiting. Higher doses of doxorubicin resulted in universal dose limiting neutropenia, and frequent nonhematologic DLT consisting of arm pain, malaise, stomatitis, nausea and vomiting. Amongst the 20 patients with measurable disease, there were 3 complete responses (15%, 95% confidence interval 3%–38%), 5 partial responses (25%, 95% confidence interval 9%–49%) and an overall response rate of 40% (95% confidence interval 19%–64%). The median survival was estimated to be 25 months from the start of chemotherapy. Conclusions: Vinorelbine at 25 mg/m² can be safely administered with doxorubicin at 40 mg/m² and methotrexate at 100 mg/m² with leucovorin rescue. Response rates observed with this regimen suggest that this combination of chemotherapeutic agents may not be more effective than the combination of vinorelbine and doxorubicin. Received: 27 April 1998 / Accepted: 17 September 1998     

Tumor necrosis factor-alpha (TNF alpha) enhances cisplatin cytotoxicity to ovarian carcinoma xenografts

Antitumor effect was compared between administration schedule of once a day dosing of cisplatin (DDP) for 2 consecutive days (q40d) with or without TNF alpha. In two controls, TNF alpha or dilutor alone was administered. Against the ovarian carcinoma 2008 cells, DDP given at dose level of daily x 2 (3.5 mg/kg/day q40d) combined with TNF alpha (50 mu g/kg/day) schedule showed 6.08-fold tumor growth delay (TGD) (17.10+/-1.65; P<0.01), produced 3.17-fold greater cell kill [ratio of tumor volume of treated and control groups (T:C)=0.148; P<0.01] and resulted in longer survival [median survival (MS)=166; P<0.01] than DDP alone. These are superior to even high dose DDP (7.0 mg/kg/day x 2d) without TNF alpha administration schedule showing TGD=11.38 days T:C=0.271 and MS=97 days. High dose DDP (7.0 mg/kg/day q40d) with TNF alpha showed further DDP antitumor potency (TGD=29.74+/-2.08, P<0.01), however, this schedule showed only 2.56-fold TGD extension and no improvement was found in survival because of its severe toxicity. TNF alpha did not alter DDP induced systemic toxicity. These data indicate that optimal antitumor activity, tolerance and survival improvement occured on a schedule of low dose DDP combined with TNF alpha, and this has prompted the clinical evaluation of this administration schedule.     

Effect on liver tumor growth in rats of allopurinol and 5-fluorouracil in combination with hepatic artery ligation

Summary Rats with an experimental solitary liver tumor of a nitrosoguanidine-induced colonic adenocarcinoma were subjected to hepatic artery ligation (HAL) alone or in combination with 5-fluorouracil (5-FU) in three different doses, with or without the addition of allopurinol. The drugs were injected i.p. on 3 consecutive days before or after the HAL procedure. HAL alone significantly reduced the tumor growth compared with the control procedure (P<0.001). This observation was correlated with a significantly prolonged survival for the ligated animals (P<0.01). The administration of a low dose of 5-FU (15 mg/kg per day) in combination with allopurinol (100 mg/kg per day) enhanced tumor growth compared with that in animals treated with 5-FU only (P<0.01) or nontreated animals (P<0.05). A significant increase in survival was observed in animals given a high dose of 5-FU (60 mg/kg per day) after HAL compared with nontreated animals (P<0.001) as well as animals subjected to HAL alone (P<0.02). All animals receiving more than 15 mg/kg per day 5-FU before HAL succumbed within 10 days. The addition of allopurinol did not protect the animals against this mortality. These observations indicate that the effect of HAL followed by 5-FU is dose-dependent and that, at least in this treatment modality, allopurinol does not modulate the toxicity of 5-FU.This study was supported by Swedish Medical Research Council grants B85-17X-07184-01A, B86-04X-07155-02B, and B87-04X-07155-03A and the Wellcome Foundation     

The influence of ranitidine on the pharmacokinetics and toxicity of doxorubicin in rabbits

Summary The influence of ranitidine on the pharmacokinetics and toxicity of doxorubicin was studied in six female New Zealand white rabbits. Plasma pharmacokinetic data were first obtained from rabbits given 3 mg/kg doxorubicin. After 1 month, the same rabbits were treated with ranitidine, 2.5 mg/kg or 25 mg/kg, before and during doxorubicin administration. The plasma doxorubicin assays to determine pharmacokinetic parameters were repeated. Drug toxicity was evaluated using complete blood counts, and hepatic function was measured using a ¹⁴C-aminopyrine breath test. High-dose ranitidine increased the total exposure to doxorubicin (area under the curve of doxorubicin alone =1.44±0.88 M·h/ml vs 4.49±2.35 M·hr/ml for doxorubicin given with high-dose ranitidine; P=0.06). Low-dose ranitidine did not alter doxorubicin pharmacokinetics. Exposure to doxorubicinol was altered by either high-dose or low-dose ranitidine. ¹⁴C-Aminopyrine half-life was altered by a raniditine dose of 25 mg/kg (aminopyrine half-life after placebo control =97±6 min as against aminopyrine half-life after ranitidine =121±7 min; mean±SEM; P<0.02). Low-dose ranitidine did not exacerbate doxorubicin-induced myelosuppression. High-dose ranitidine enhanced doxorubicin-induced erythroid suppression while sparing the myeloid series. At cytochrome P-450-inhibitory doses, ranitidine's effects upon doxorubicin plasma pharmacokinetics are similar to those previously seen with cimetidine. These changes did not appear to alter drug detoxification and are not related to microsomal inhibition of doxorubicin detoxification. Low doses of ranitidine do not alter doxorubicin plasma pharmacokinetics or toxicity in rabbits.Grant support: Glaxo Inc., Veterans Administration, NIH BRSG RR-05424, NIH Grant RR-00095, Clinical Research Center. American Cancer Society Institutional Grant IN25V     

Heart fatty acid-binding protein may not be an early biomarker for anthracycline-induced cardiotoxicity in rabbits

The objective of this study was to investigate the feasibility of using serum heart fatty acid-binding protein (H-FABP) concentrations as an early biomarker for doxorubicin-induced myocardial damage. Forty-four male rabbits were randomly divided into a control (8 rabbits) or one of four doxorubicin groups (8 rabbits in each group). Rabbits in the control group received saline, whereas rabbits in the doxorubicin group received 2?mg/kg doxorubicin weekly for 1?C8?weeks. Rabbits in the doxorubicin groups received doxorubicin 2?mg/kg for one (Group 1, 8 rabbits), two (Group 2, 8 rabbits), four (Group 3, 9 rabbits), or eight (Group 4, 11 rabbits) weeks. Echocardiography was performed to measure left ventricular ejection fraction (LVEF), shortening fraction (FS), and E/A ratio. Cardiotoxicity scores were assessed by light microscopy using Billingham??s method and also by electron microscopy. Serum H-FABP concentrations were quantified by a rabbit-specific enzyme-linked immunosorbent assay. Decreased LVEF, FS, and E/A ratio were detected in Group 4 (P?<?0.05). Billingham cardiomyopathy scores of the rabbits in Group 3 were significantly higher (P?<?0.05) than those of rabbits in the control group or Groups 1 or 2. Billingham cardiomyopathy scores in Group 4 were the highest of all groups (P?<?0.05). Myocardial injury was demonstrable by electron microscopy in rabbits in Groups 2, 3, and 4. Compared with the control group, serum H-FABP concentrations increased only in Group 4 (P?<?0.05). Serum H-FABP concentrations may not be a sensitive method for assessing early cardiotoxicity of doxorubicin.     

Phase I Study of Nonpegylated Liposomal Doxorubicin plus Trastuzumab in Patients with HER2-Positive Breast Cancer

BackgroundThis was an open-label, nonrandomized, multicenter, 2-stage phase I trial of safety and preliminary efficacy of nonpegylated liposomal doxorubicin (NLD) in combination with trastuzumab in advanced breast cancer, with emphasis on cardiac toxicity.Patients and MethodsForty patients (median age, 48 years; range, 30–74 years) with HER2/neu 2+ or 3+ tumors (by immunohistochemistry) were recruited December 1999 to November 2002. Patients were eligible if they received ≤ 1 previous trastuzumab regimen, ≤ 2 cytotoxic regimens for advanced breast cancer, and lifetime cumulative anthracycline doses ≤ 240 mg/m². The study regimen comprised NLD 60 mg/m² every 3 weeks and trastuzumab loading dose 4 mg/kg followed by 2 mg/kg weekly. Treatment cycles lasted 21 days. Clinical cardiac assessments were performed with multigated acquisition scans every 2 cycles. Patients were evaluated for cardiac toxicity after receiving ≥ 1 cycle. Cardiac safety was assessed after completing ≥ 4 full treatment cycles.ResultsThirty out of 40 patients (75%) received ≥ 4 treatment cycles and were evaluable for cardiac safety. Five patients (13%), 4 who were doxorubicin pretreated, developed left ventricular ejection fraction reductions to < 50%, and 2 (5%) of these patients experienced clinical cardiac toxicity. Fifty percent of the patients had objective tumor responses; median progression-free survival was approximately 21 weeks. Twenty-six patients (65%) had grade 3/4 neutropenia; 2 patients experienced febrile neutropenia.ConclusionNonpegylated liposomal doxorubicin plus trastuzumab is active in HER2-positive patients with advanced breast cancer and is associated with a lower risk of cardiac toxicity than conventional doxorubicin plus trastuzumab.     

Doxorubicin plus the IGF-1R antibody cixutumumab in soft tissue sarcoma: a phase I study using the TITE-CRM model

BackgroundInsulin-like growth factor receptor (IGF-1R) has been studied as an oncologic target in soft tissue sarcoma (STS), but its role in sarcoma biology is unclear. Anti-IGF-1R antibody cixutumumab demonstrated acceptable toxicity but limited activity as a single agent in STS. We carried out a dose-escalation study of cixutumumab with doxorubicin to evaluate safety and dosing of the combination.Patients and methodsEligible patients with advanced STS were treated with cixutumumab intravenously on days 1/8/15 at one of three dose levels (A: 1 mg/kg, B: 3 mg/kg, C: 6 mg/kg) with doxorubicin at 75 mg/m² as a 48 h infusion on day 1 of a 21 day cycle. After six cycles of the combination, patients could receive cixutumumab alone. The Time-to-Event Continual Reassessment Method was used to estimate the probability of dose-limiting toxicity (DLT) and to assign patients to the dose with an estimated probability of DLT≤20%.ResultsBetween September 2008 and January 2012, 30 patients with advanced STS received a median of six cycles of therapy (range <1–22). Two DLTs were observed, grade 3 mucositis (dose level B) and grade 4 hyperglycemia (dose level C). Grade 2 and 3 reduced left ventricular ejection fraction was seen in three and two patients, respectively. Five partial responses were observed, and estimated progression-free survival was 5.3 months (95% confidence interval 3.0–6.3) in 26 response-assessable patients. Immunohistochemical staining of 11 available tumor samples for IGF-1R and phospho-IGF-1R was not significantly different among responders and non-responders, and serum analysis of select single-nucleotide polymorphisms did not predict for cardiotoxicity.ConclusionThe maximum tolerated dose was doxorubicin 75 mg/m² on day 1 and cixitumumab 6 mg/kg on days 1/8/15 of a 21 day cycle. Cardiac toxicity was observed and should be monitored in subsequent studies, which should be considered in STS only if a predictive biomarker of benefit to anti-IGF-1R therapy is identified.Trial registrationClinicalTrials.gov:NCT00789633.     

Hyperthermic isolated limb perfusion in locally advanced limb soft tissue sarcoma: A 24-year single-centre experience

Background: Hyperthermic isolated limb perfusion (HILP) is a locoregional treatment aimed at avoiding amputation in patients with advanced extremity soft tissue sarcomas (STS). Over the last 25 years, HILP procedure has been implemented to maximise its therapeutic ratio. Methods: A retrospective analysis including 117 patients who underwent HILP from 1989 to 2013 was performed. Three different drug schedules were applied: 1) doxorubicin (n?=?47), 2) high dose (3–4?mg) tumour necrosis factor-alpha (TNF-α) plus doxorubicin (n?=?30), 3) low dose (1?mg) TNF-α plus melphalan (L-PAM) (n?=?40). Tumour response was evaluated by MRI or CT and surgical specimens. Toxicity and local progression-free survival (LPFS) were also evaluated. Results: In total 92 (78.6%) patients had primary, 25 (21.4%) had recurrent and 17 (14.5%) had metastatic disease. The subjects in the three groups were homogeneous for clinical-pathological features. Pathological response was complete in 55 patients (47%), partial in 35 (29.9%), regardless of drug schedule (p?=?0.501) and tumour presentation (p?=?0.094). Wieberdink III–V toxicity was registered in 19.1%, 20% and 2.5% of patients, respectively (p?<?0.051). Twenty-eight patients (23.9%) received adjuvant radiotherapy with no relevant toxicity. Five-year LPFS was 81.6% and 74.2% in patients with primary or recurrent disease, respectively (p?=?0.652). After a median follow-up of 36.5 months, the limb sparing rate was 77.8%. Conclusions: HILP performed with different drugs was equally active, either in primary, recurrent or metastatic STS, providing effective limb sparing and durable local control. Low dose TNF-α plus L-PAM had the most favourable toxicity profile. Adjuvant radiotherapy was not associated with relevant toxicity.     

Dose-finding study of docetaxel and doxorubicin in first-line treatment of patients with metastatic breast cancer

Purpose: To determine the maximum tolerated dose (MTD), the dose-limiting toxicity (DLT) and the recommended dose of docetaxel in combination with doxorubicin, and to evaluate the activity in patients with advanced breast cancer.Patients and methods: Forty-two women with untreated metastatic breast cancer (79% with visceral metastases; 52% with prior adjuvant anthracycline therapy) were treated with doxorubicin (40–60 mg/m2) i.v. bolus followed one hour later by docetaxel (50–85 mg/m2) one-hour i.v. infusion every three weeks, without G-CSF support.Results: The MTD occurred at the dose level combining 85 mg/m2 of docetaxel and 50 mg/m2 of doxorubicin, with the DLT being neutropenic sepsis. Neutropenia and/or its complications were manageable and no grade 3–4 or severe non-hematological toxicities were observed. Fluid retention was frequent but never severe. With a median cumulative dose of doxorubicin of 392 mg/m2 (240–559 mg/m2) and a median follow-up time of 29 months (9+–41), no congestive heart failure was observed. High activity was observed at all dose levels, particularly the last four, with a response rate of 81% (95% confidence interval (95% CI): 62.5–92.5). Median time to progression was 46 weeks (6+–62). Two-year survival was 66%, and median survival has not yet been reached.Conclusions: Docetaxel–doxorubicin is feasible, safe and highly active. The incidence of febrile neutropenia without G-CSF requires careful monitoring but is acceptable in this setting. There does not appear to be an increase in the cardiac toxicity of doxorubicin. The recommended dose is either docetaxel 75 mg/m2 and doxorubicin 50 mg/m2 or docetaxel 60 mg/m2 and doxorubicin 60 mg/m2, administered every three weeks.     

Antitumor and toxicity evaluation of free doxorubicin and doxorubicin entrapped in cardiolipin liposomes

Summary The antitumor activity of free doxorubicin and doxorubicin entrapped in cardiolipin liposomes was evaluated in P388 ascitic leukemia, disseminated Gross leukemia, and advanced mammary carcinoma. In P388 leukemia, free drug and drug entrapped in liposomes demonstrated equivalent antitumor activity at doses of 2.2 and 4.4 mg/kg, demonstrating 52% and 69% ILS (increase in life-span), respectively. Free doxorubicin at a dose of 10 mg/kg was superior, producing a 185% ILS against 82% with liposomal doxorubicin. With an increase in administered dose the antitumor response with liposomal doxorubicin was much more pronounced; at doses of 20 and 25 mg/kg the ILS was in excess of 376%, with five of ten mice surviving tumor-free. In Gross leukemia, the optimum dose of free doxorubicin, 10 mg/kg, brought about 186% T/C (median survival in treated mice over that in controls, x100), whereas with liposomal doxorubicin the optimum dose was 16.9 mg/kg, which yielded 214% T/C. In advanced mammary carcinoma, the maximum tumor regression with free doxorubicin was at a dose of 7.5 mg/kg, with two of six mice dying of toxicity. Liposomal doxorubicin caused maximum tumor regression at 10.8 mg/kg dose with no toxic deaths. Doxorubicin entrapped in cardiolipin liposomes was much less toxic than free drug at high doses in normal mice.This work was supported by a grant from the American Heart Association (82-922) and by PHSCA 5P30 CA 1-4626     

Frontline treatment of localized osteosarcoma without methotrexate: results of the St. Jude Children's Research Hospital OS99 trial

BACKGROUND:

The standard treatment of osteosarcoma includes cisplatin and high‐dose methotrexate (HDMTX); both agents exert significant toxicity, and HDMTX requires complex pharmacokinetic monitoring and leucovorin rescue. In the previous OS91 trial, the treatment of localized disease with carboplatin, ifosfamide, doxorubicin, and HDMTX yielded outcomes comparable to those of cisplatin‐based regimens and caused less toxicity. To build on this experience, the authors conducted a multi‐institutional trial (OS99) that evaluated the efficacy of carboplatin, ifosfamide, and doxorubicin without HDMTX in patients with newly diagnosed, localized, resectable osteosarcoma.

METHODS:

Treatment was comprised of 12 cycles of chemotherapy administered over 35 weeks: 3 cycles of carboplatin (dose targeted to area under the concentration‐time curve of 8 mg/mL × min on Day 1) and ifosfamide (at a dose of 2.65 g/m² daily ×3 days) and 1 cycle of doxorubicin (at a dose of 25 mg/m² daily ×3 days) before surgical resection, followed by 2 additional cycles of the combination of carboplatin and ifosfamide and 3 cycles each of doxorubicin (25 mg/m² daily ×2 days) combined with ifosfamide or carboplatin.

RESULTS:

A total of 72 eligible patients (median age, 13.4 years) were enrolled between May 1999 and May 2006. Forty of the 66 (60.6%) evaluable patients had good histologic responses (>90% tumor necrosis) to preoperative chemotherapy. The estimated 5‐year event‐free survival rate was 66.7% ± 7.0% for the OS99 trial compared with 66.0% ± 6.8% for the OS91 trial (P = .98). The estimated 5‐year survival rate was 78.9% ± 6.3% for the OS99 trial and 74.5% ± 6.3% for the OS91 trial (P = .40).

CONCLUSIONS:

The regimen used in the OS99 trial was found to produce outcomes comparable to those of cisplatin‐containing or HDMTX‐containing regimens. This therapy offers a good alternative for patients, particularly those who demonstrate an intolerance of HDMTX, and for institutions that cannot provide pharmacokinetic monitoring for MTX. Cancer 2011. © 2011 American Cancer Society.     

Preclinical pharmacology, toxicology and efficacy of sphingomyelin/cholesterol liposomal vincristine for therapeutic treatment of cancer

Purpose: To establish the pharmacodynamic relationships between drug biodistribution and drug toxicity/efficacy, a comprehensive preclinical evaluation of sphingomyelin/cholesterol (SM/chol) liposomal vincristine and unencapsulated vincristine in mice was undertaken. Methods: Pharmaceutically acceptable formulations of unencapsulated vincristine and liposomal vincristine at drug/lipid ratios of 0.05 or 0.10 (wt/wt) were evaluated for toxicity, antitumor activity and pharmacokinetics following intravenous administration. Results: Mice given liposomal vincristine at 2 mg/kg vincristine had concentrations of vincristine in blood and plasma at least two orders of magnitude greater then those achieved after an identical dose of unencapsulated drug. One day after administration of the liposomal vincristine, there were at least tenfold greater drug quantities, relative to unencapsulated vincristine, in the axillary lymph nodes, heart, inguinal lymph nodes, kidney, liver, skin, small intestines and spleen. Increased plasma and tissue exposure to vincristine as a result of encapsulation in SM/chol liposomes was not associated with increased drug toxicities. Treatment of the murine P388 ascitic tumor with a single intravenous dose of unencapsulated drug at 2, 3 and 4 mg/kg, initiated 1 day after tumor cell inoculation, resulted in a 33 to 38% increase in lifespan. In contrast, long-term survival rates of 50% or more were achieved in all groups treated with the SM/chol liposomal vincristine formulations at doses of 2, 3 and 4 mg/kg. At the 4 mg/kg dose, eight of ten and nine of ten animals survived past day 60 when treated with SM/chol liposomal vincristine prepared at the 0.05 and 0.1 drug/lipid ratios, respectively. Conclusions: Overall, increased and prolonged plasma concentrations of vincristine achieved by liposomal encapsulation were correlated with dramatically increased antitumor activity in comparison with the unencapsulated drug, but no correlations could be established between pharmacokinetic parameters and toxicity. Received: 30 September 1997 / Accepted: 9 March 1998     

Pegylated liposome-encapsulated doxorubicin and cisplatin in the treatment of head and neck xenograft tumours

Purpose: To evaluate the in vitro and in vivo activity of unencapsulated doxorubicin (DOX) and cisplatin (CDDP) and their pegylated liposome encapsulated counterparts (PLED and PLEC) in a subcutaneous model of human squamous cell cancer of the head and neck. Methods: In vitro cytotoxicity was determined by means of the sulphorhodamine B assay and in vivo activity was assessed in terms of tumour growth delay following single intravenous doses of the various agents. Treatment-related toxicity was evaluated by means of serial weight measurement. Results: The IC₅₀ values for DOX (12.1-fold) and CDDP (21.5-fold) were lower than for their liposome-encapsulated counterparts. When the two unencapsulated agents were compared, the IC₅₀ value for DOX was 16-fold lower than that for CDDP. In the in vivo studies, liposomes containing DTPA (PLEDTPA) exerted no effect on KB xenograft tumours when compared to untreated controls (P > 0.1). PLED was significantly more effective than DOX at doses of 2 mg/kg, 4 mg/kg and 8 mg/kg (P < 0.001 for all comparisons). At the 8 mg/kg dose, 7/13 animals treated with PLED were free of disease at 60 days, compared to 0/12 treated with DOX. PLEC displayed superior activity in comparison to CDDP at the 4 mg/kg dose level (P < 0.001), although at doses of 2 mg/kg and 10 mg/kg this comparison only reached borderline statistical significance (0.1 > P > 0.05). The highest dose level of 20 mg/kg was fatal to all animals in the CDDP group but well-tolerated by the animals in the PLEC group. On the basis of serial weight measurements, both PLED and PLEC were shown to be tolerated better than DOX and CDDP. Conclusion: Both PLED and PLEC were shown to exert significant activity against head and neck xenograft tumours, with PLED showing particular efficacy. Received: 2 November 1999 / Accepted: 14 February 2000     

Pegylated liposomal doxorubicin, vincristine, and dexamethasone provide significant reduction in toxicity compared with doxorubicin, vincristine, and dexamethasone in patients with newly diagnosed multiple myeloma: a Phase III multicenter randomized trial

BACKGROUND: Pegylated liposomal doxorubicin has pharmacologic and safety advantages over conventional doxorubicin. METHODS: For this noninferiority trial, 192 patients with newly diagnosed, active multiple myeloma were randomized to receive either combined pegylated liposomal doxorubicin (40 mg/m(2)) and vincristine (1.4 mg/m(2); maximum, 2.0 mg) as an intravenous infusion on Day 1 plus reduced-dose dexamethasone (40 mg) orally on Days 1-4 (DVd) (n = 97 patients) or combined vincristine (0.4 mg per day) and conventional doxorubicin (9 mg/m(2) per day) as a continuous intravenous infusion on Days 1-4 plus reduced-dose dexamethasone (VAd) (n = 95 patients) for at least 4 cycles. Treatment was repeated every 4 weeks until patients either achieved maximal response, disease progression, or unacceptable toxicity or underwent transplantation. The primary endpoints were response and toxicity. RESULTS: Objective response rates (DVd, 44%; VAd, 41%), progression-free survival (hazard ratio, 1.11; P = 0.69), and overall survival (hazard ratio, 0.88; P = 0.67) were similar between the treatment groups. However, DVd was associated with significantly less Grade 3/4 neutropenia or neutropenic fever (10% vs. 24%; P = 0.01), a lower incidence of sepsis, and less antibiotic use. Compared with VAd, DVd also significantly decreased the need for central venous access (P < 0.0001) and growth-factor support (P = 0.03) and resulted in less alopecia (20% vs. 44%; P < 0.001) but more hand-foot syndrome (25% vs. 1%; P < 0.001), mainly Grade 1/2. CONCLUSIONS: The DVd regimen demonstrated similar efficacy with less toxicity and supportive care compared with VAd, which should improve clinical utility and optimize the opportunity for transplantation.