Weekly paclitaxel with trastuzumab and pertuzumab in patients with HER2-overexpressing metastatic breast cancer: overall survival and updated progression-free survival results from a phase II study.

We previously reported progression-free survival (PFS) results on a phase II trial of weekly paclitaxel, trastuzumab, and pertuzumab in patients with human epidermal growth factor receptor 2(HER2)-positive metastatic breast cancer (MBC) treated in the first- and second-line setting. Here, we report results for overall survival (OS) and updated PFS after an additional year of follow-up. Patients with HER2-positive MBC with 0-1 prior treatment were eligible. Treatment consisted of paclitaxel (80 mg/m(2)) weekly, and trastuzumab (loading dose 8 mg/kg â†’ 6 mg/kg) and pertuzumab (loading dose 840 mg â†’ 420 mg) every 3 weeks, all given intravenously. Primary endpoint was 6-month PFS. Secondary endpoints included median PFS, 6-month and median OS. Evaluable patients received at least one full dose of treatment. From January 2011 to December 2013, 69 patients were enrolled: 51 (74 %) and 18 (26 %) treated in first- and second-line metastatic settings, respectively. As of July 1, 2015, the median follow-up was 33 months (range 3-49 months; 67 patients were evaluable for efficacy). The median OS was 44 months (95 % CI 37.5-NR) overall and 44 months (95 % CI 38.3-NR) and 37.5 months (95 % CI 30.3-NR) for patients with 0 and 1 prior metastatic treatment, respectively; 6-month OS was 98 % (95 % CI 90-1). The 6-month PFS was 86 % (95 % CI 75-93) overall and 89 % (95 % CI 76-95) and 78 % (95 % CI 51-91) for patients with 0 and 1 prior therapy, respectively; and median PFS was 21.4 months (95 % CI 14.1-NR) overall and 25.7 months (95 % CI 14.1-NR) and 16.9 months (95 % CI 8.5-NR) for patients with 0-1 prior treatment, respectively. Treatment was well tolerated. Updated analysis demonstrates that weekly paclitaxel, when added to trastuzumab and pertuzumab, is associated with a favorable OS and PFS and offers an alternative to docetaxel-based therapy. http://www.ClinicalTrials.gov NCT0127604.

The Internet's role in a biodosimetric response to a radiation mass casualty event.

Response to a large-scale radiological incident could require timely medical interventions to minimize radiation casualties. Proper medical care requires knowing the victim's radiation dose. When physical dosimetry is absent, radiation-specific chromosome aberration analysis can serve to estimate the absorbed dose in order to assist physicians in the medical management of radiation injuries. A mock exercise scenario was presented to six participating biodosimetry laboratories as one individual acutely exposed to Co under conditions suggesting whole-body exposure. The individual was not wearing a dosimeter and within 2-3 h of the incident began vomiting. The individual also had other medical symptoms indicating likelihood of a significant dose. Physicians managing the patient requested a dose estimate in order to develop a treatment plan. Participating laboratories in North and South America, Europe, and Asia were asked to evaluate more than 800 electronic images of metaphase cells from the patient to determine the dicentric yield and calculate a dose estimate with 95% confidence limits. All participants were blind to the physical dose until after submitting their estimates based on the dicentric chromosome assay (DCA). The exercise was successful since the mean biological dose estimate was 1.89 Gy whereas the actual physical dose was 2 Gy. This is well within the requirements for guidance of medical management. The exercise demonstrated that the most labor-intensive step in the entire process (visual evaluation of images) can be accelerated by taking advantage of world-wide expertise available on the Internet.

Dose coefficients for intakes of radionuclides via contaminated wounds.

The NCRP Wound Model, which describes the retention of selected radionuclides at the site of a contaminated wound and their uptake into the transfer compartment, has been combined with the ICRP element-specific systemic models for those radionuclides to derive dose coefficients for intakes via contaminated wounds. These coefficients can be used to generate derived regulatory guidance (i.e., the activity in a wound that would result in an effective dose of 20 or 50 mSv, or in some cases, a organ-equivalent dose of 500 mSv) and clinical decision guidance (i.e., activity levels that would indicate the need for consideration of medical intervention to remove activity from the wound site, administration of decorporation therapy or both). Data are provided for 38 radionuclides commonly encountered in various activities such as nuclear weapons, fuel fabrication or recycling, waste disposal, medicine, research, and nuclear power. These include 3H, 14C, 32P, 35S, 59Fe, 57,58,60Co, 85,89,90Sr, 99mTc, 106Ru, 125,129,131I, 134,137Cs, 192Ir, 201Tl, 210Po, 226,228Ra, 228,230,232Th, 234,235,238U, 237Np, 238,239,240,241Pu, 241Am, 242,244Cm, and 252Cf.

No more business as usual: enticing companies to sharply lower the public health costs of the products they sell.

Cigarettes, alcohol, junk food and motor vehicles cause a staggeringly high level of death, injury and disease. Business leaders from the industries that make these products currently try to frame these negative outcomes as 'collateral damage' that is someone else's problem. That framing is not only morally objectionable, but also overlooks the possibility that, with proper prodding, industry could substantially mitigate these public health disasters. A promising regulatory tool called 'performance-based regulation' is a new approach to combating the problem. Simply put, performance-based regulation would impose a legal obligation on manufacturers to reduce their negative social costs. Rather than suing the firms for damages, or telling them how they should run their businesses differently (as typical 'command and control' regimes do), performance-based regulation allows the firms to determine how best to decrease today's negative public health consequences. Like other public health strategies, performance-based regulation shifts the focus away from individual consumers on to those who are far more likely to achieve real public health gains. Analogous to a tax on causing harm that exceeds a threshold level, performance-based regulation seeks to harness private initiative in pursuit of the public good.

Phase I chemotherapy study of biochemical modulation of folinic acid and fluorouracil by gemcitabine in patients with solid tumor malignancies.

PURPOSE: This phase I biochemical modulation study evaluated the maximum-tolerated dose (MTD), toxicity, and effectiveness of the combination of folinic acid (FA)/fluorouracil (5-FU) followed by escalated dose levels of gemcitabine (FFG) in patients with advanced solid tumors. PATIENTS AND METHODS: Patients were refractory to primary treatment and/or without effective treatment options. Twenty-eight patients received an intravenous (IV) infusion of FA 100 mg/m(2) over 1 hour and a 5-FU 450 mg/m(2) IV bolus in the middle of the FA infusion. After the FA infusion, gemcitabine was administered at a steady rate of infusion of 10 mg/m(2)/min over initially 30 minutes and with increases of an additional 15 minutes at each given level. One cycle consisted of six weekly treatments followed by a 2-week rest. RESULTS: The MTD of gemcitabine was established at 900 mg/m(2) given over 90 minutes. Eight patients of 21 with metastatic colorectal cancer achieved responses (one complete response; seven partial responses), for a response rate of 38%. Responses were seen across the gemcitabine doses of 300 to 900 mg/m(2). One patient had prior treatment with FA/5-FU for advanced disease. Patients with colorectal carcinoma had a median survival of 18 months, and the patient with lung carcinoma has been alive for 24+ months. CONCLUSION: The combination chemotherapy of FFG was well tolerated and may benefit patients with advanced colorectal carcinoma. A phase II evaluation in this patient population is in progress.

Identification of tamoxifen-DNA adducts in the endometrium of women treated with tamoxifen.

The risk of developing endometrial cancer increases significantly for women treated with tamoxifen (TAM); the present study was designed to investigate the mechanism of this carcinogenic effect. Endometrial tissue was obtained from 16 women treated for varying lengths of time with TAM and from 15 untreated control subjects. DNA was analyzed with a (32)P-post-labeling/HPLC on-line monitoring assay capable of detecting 2.5 adducts/10(10) nucleotides. Using this sensitive and specific assay, TAM-DNA adducts were detected in eight women. The major adducts found were trans and cis epimers of alpha-(N(2)-deoxyguanosinyl) tamoxifen (dG-N(2)-TAM); levels ranged between 0.2-12 and 1.6-8.3 adducts/10(8) nucleotides, respectively. There was marked inter-individual variation in the relative amounts of cis and trans adducts present. Low levels (0.74-1.1 adducts/10(8) nucleotides) of trans and cis forms of dG-N(2)-TAM N-oxide were detected in one patient. DNA adducts derived from 4-hydroxytamoxifen quinone methide were not observed. We conclude from this analysis that trans and cis dG-N(2)-TAMs accumulate in significant amounts in the endometrium of many, but not all, women treated with this drug. The level of adducts found, coupled with the previous demonstration of their mutagenicity [Cancer Res., 59, 2091, 1999], suggest that a genotoxic mechanism may be responsible for TAM-induced endometrial cancer.

Phase I trial of the anti-Lewis Y drug immunoconjugate BR96-doxorubicin in patients with lewis Y-expressing epithelial tumors.

PURPOSE: We conducted a phase I clinical trial of BR96-Doxorubicin (BR96-Dox), a chimeric anti-Lewis Y (Le(Y)) monoclonal antibody conjugated to doxorubicin, in patients whose tumors expressed the Le(Y) antigen. The study aimed to determine the toxicity, maximum-tolerated dose, pharmacokinetics, and immunogenicity of BR96-Dox. PATIENTS AND METHODS: This was a phase I dose escalation study. BR96-Dox was initially administered alone as a 2-hour infusion every 3 weeks. The occurrence of gastrointestinal (GI) toxicity necessitated the administration of BR96-Dox as a continuous infusion over 24 hours and use of antiemetics and antigastritis premedication. Patients experiencing severe GI toxicity underwent GI endoscopy. All patients underwent restaging after two cycles. RESULTS: A total of 66 patients predominantly with metastatic colon and breast cancer were enrolled onto the study. The most common side effects were GI toxicity, fever, and elevation of pancreatic lipase. At higher doses, BR96-Dox was associated with nausea, vomiting, and endoscopically documented exudative gastritis of the upper GI tract, which was dose-limiting at a maximum dose of 875 mg/m(2) (doxorubicin equivalent, 25 mg/m(2)) administered every 3 weeks. Toxicity was reversible and generally of short duration. Premedication with the antiemetic Kytril (granisetron hydrochloride; SmithKline Beecham, Philadelphia, PA), the antacid omeprazole, and dexamethasone was most effective in ameliorating GI toxicity. A dose of 700 mg/m(2) BR96-Dox (doxorubicin equivalent, 19 mg/m(2)) every 3 weeks was determined to be the optimal phase II dose when administered with antiemetic and antigastritis prophylaxis. BR96-Dox deposition on tumor tissue was documented immunohistochemically and by confocal microscopy. At the 550-mg/m(2) dose, the half-life (mean +/- SD) of BR96 and doxorubicin was 300 +/- 95 hours and 43 +/- 4 hours, respectively. BR96-Dox elicited a weak immune response in 37% of patients. Objective clinical responses were seen in two patients. CONCLUSION: BR96-Dox provides a unique strategy to deliver doxorubicin to Le(Y)-expressing tumor and was well tolerated at doses of 700 mg/m(2) every 3 weeks. BR96-Dox was not associated with the typical side-effect profile of native doxorubicin and can potentially deliver high doses of doxorubicin to antigen-expressing tumors. A phase II study in doxorubicin-sensitive tumors is warranted.

Tamoxifen-DNA adducts detected in the endometrium of women treated with tamoxifen.

Women treated for breast cancer with tamoxifen are at increased risk of developing endometrial cancer. This carcinogenic effect has been attributed to estrogenic stimulation and/or to a genotoxic effect of this drug. To examine genotoxicity, we developed a (32)P-postlabeling TLCL/HPLC procedure for quantitative analysis of tamoxifen-DNA adducts in endometrial tissue. This assay is several orders of magnitude more sensitive than those previously used for this purpose; with it, we can detect five tamoxifen-DNA adducts in 10(11) bases. Endometrial tissue was obtained from women undergoing tamoxifen therapy and from untreated control subjects. DNA adducts, identified as trans and cis epimers of alpha-(N(2)-deoxyguanosinyl)tamoxifen, were detected in six of thirteen patients in the tamoxifen-treated group. Levels of trans and cis adducts ranged from 0.5 to 8.3 and from 0.4 to 4.8 adducts/10(8) nucleotides, respectively. Tamoxifen-DNA adducts were not detected in endometrial tissue obtained from the control subjects. We conclude from this study that one or more tamoxifen metabolites react with endometrial DNA to form covalent adducts, establishing the potential genotoxicity of this drug for women and suggesting the use of TAM-DNA adducts as biomarkers for investigations of tamoxifen-induced endometrial cancer.

Randomized phase II study of BR96-doxorubicin conjugate in patients with metastatic breast cancer.

PURPOSE: BMS-182248-1 (BR96-doxorubicin immunoconjugate) is a chimeric human/mouse monoclonal antibody linked to approximately eight doxorubicin molecules. The antibody is directed against the Lewis-Y antigen, which is expressed on 75% of all breast cancers but is limited in expression on normal tissues. Preclinical xenograft models demonstrated significant antitumor activity, including cures. A randomized phase II design was chosen to estimate the activity of the BR96-doxorubicin conjugate in metastatic breast cancer in a study population with confirmed sensitivity to single-agent doxorubicin. PATIENTS AND METHODS: Patients with measurable metastatic breast cancer and immunohistochemical evidence of Lewis-Y expression on their tumor received either BR96-doxorubicin conjugate 700 mg/m2 IV over 24 hours or doxorubicin 60 mg/m2 every 3 weeks. Patients were stratified on the basis of prior doxorubicin exposure, visceral disease, and institution. Cross-over to the opposite treatment arm was allowed with progressive or persistently stable disease. RESULTS: Twenty-three patients who had received a median of one prior chemotherapy regimen were assessable. There was one partial response (7%) in 14 patients receiving the BR96-doxorubicin conjugate and one complete response and three partial responses (44%) in nine assessable patients receiving doxorubicin. No patient experienced a clinically significant hypersensitivity reaction. The toxicities were significantly different between the two treatment groups, with the BR96-doxorubicin conjugate group having limited hematologic toxicity, whereas gastrointestinal toxicities, including marked serum amylase and lipase elevations, nausea, and vomiting with gastritis, were prominent. CONCLUSION: The BR96-doxorubicin immunoconjugate has limited clinical antitumor activity in metastatic breast cancer. The gastrointestinal toxicities likely represent binding of the agent to normal tissues expressing the target antigen and may have compromised the delivery of the immunoconjugate to the tumor sites.

Phase I clinical and plasma and cellular pharmacological study of topotecan without and with granulocyte colony-stimulating factor.

Topotecan, a semisynthetic water-soluble analogue of camptothecin, inhibits human topoisomerase I (topo I). We performed a Phase I clinical and plasma pharmacological study of topotecan administered by 24-h continuous infusion without and with granulocyte colony-stimulating factor (G-CSF). We also measured topo I-DNA complexes in peripheral blood mononuclear cells (PBMCs) in an attempt to correlate formation of topo I-DNA complexes in patients treated with topotecan with toxicity and/or response. One hundred four courses of topotecan at doses of 2.5-15.0 mg/m2 were administered to 44 patients with solid tumors. The maximum tolerated dose without G-CSF was 10.0 mg/m2; granulocytopenia was the dose-limiting toxic effect. The maximum tolerated dose could not be increased with G-CSF because of severe thrombocytopenia. Plasma pharmacology was obtained in 11 patients treated at 12.5 mg/m2 and 15.0 mg/m2. The topotecan lactone end-infusion plasma levels correlated strongly with the area under the curve. Lactone elimination was biexponential with a mean t1/2alpha of 28 min and a t1/2beta of 3.8 h at 12.5 mg/m2. Topo I-DNA complexes were measured before and after treatment in PBMCs from seven patients. Pretopotecan topo I-DNA complexes were available on two additional patients treated at 15 mg/m2. The mean increase in topo I-DNA complexes at the end of the topotecan infusion was 1.25 times the pretreatment value. There was a statistically significant relationship (P = 0.02) between lack of disease progression and the level of topo I-DNA complexes measured in PBMCs before therapy. For Phase II studies of minimally treated adults with solid tumors, the recommended topotecan starting dose administered by 24-h continuous infusion is 10 mg/m2 without G-CSF.

Lipid-complexed camptothecin: formulation and initial biodistribution and antitumor activity studies.

Water-soluble derivatives of camptothecin, and active topoisomerase I inhibitor, have shown a broad spectrum of activity against human tumors. Early clinical trials with the water-soluble sodium salt of camptothecin were hindered by significant cystitis, gastroenteritis, and leukopenia. Furthermore, the sodium salt of camptothecin has been shown to have significantly less activity than the water-insoluble lactone form of the compound. We describe a formulation of lipid-complexed CPT (LC-CPT; particle size range 20.8-208.1 nm) that is very easy to prepare and allows for intravenous administration in vivo in clinically relevant lipid-drug ratios (12.5:1 w/w). The lipid formulation had in vitro antitumor activity similar to that of CPT formulated without lipids and displayed similar cytotoxicity against MDR-1-negative and -positive tumor cells. The biodistribution of CPT was profoundly affected by lipid complexation; free CPT achieved the greatest concentration in the pulmonary parenchyma while LC-CPT achieved the highest concentration in the gastrointestinal tract. LC-CPT had significant antitumor activity in vivo against intraperitoneal L1210 and P338 leukemia and appeared to be more potent then free CPT.

Pilot phase II trial of 13-cis-retinoic acid and interferon-alpha combination therapy for advanced pancreatic adenocarcinoma.

The combination of interferons (IFNs) and retinoids in antineoplastic therapy is based upon preclinical, in vitro, and in vivo observations. Retinoid-IFN combinations have shown significant antitumor activity against advanced cutaneous and cervical squamous cell carcinoma (SCC), and the toxic effects do not appear to overlap. Based on in vitro evidence of synergy and observed clinical activity, we conducted a pilot phase II trial of 13-cis-retinoic acid (1 mg/kg/day) and IFN alpha (6 million units/day) in patients with advanced pancreatic adenocarcinoma. No objective responses occurred among six evaluable patients. The toxicities were mild and reversible, and grade 3 fatigue occurred in only one patient. No objective antitumor activity was noted against pancreatic adenocarcinomas at the dose and schedule utilized. Further exploration of this this purely biological approach is not warranted for pancreatic adenocarcinomas.

Phase II trial of isotretinoin and recombinant interferon alfa-2a in metastatic colorectal carcinoma.

Phase II trials of the novel biologic combination isotretinoin (13-cis-retinoic aid) plus recombinant interferon alfa-2a have demonstrated this combination's major activity against advanced squamous cell carcinoma of the skin and cervix. Because this combination has had limited study in other tumors, we initiated a phase II trial of this regimen in patients with metastatic colorectal adenocarcinoma. Sixteen patients with measurable metastatic colon carcinoma who had received no previous chemotherapy were entered on the trial. Patients received recombinant interferon alfa-2a, 6 million units a day subcutaneously, and isotretinoin, 1 mg/kg per day orally in two divided doses. Patients were evaluated for response after 8 weeks of treatment and then continued on therapy until progressive disease was documented. We did not observe complete or partial responses. Two patients experienced minor responses in measurable pulmonary metastases lasting 12 and 8 weeks. Grade 3-4 toxic reactions included fatigue (5 patients), granulocytopenia (6 patients), neurotoxicity (2 patients), and elevated serum triglyceride levels (2 patients). Although this combination has demonstrated significant activity in squamous cell carcinomas of the skin and cervix, our results suggest that it has little therapeutic activity against advanced colorectal adenocarcinomas.

Role of adjuvant therapy in surgically resected colorectal carcinoma.

An important advance in cancer treatment has been made in recent years with the finding that adjuvant therapy can significantly improve the survival of patients with colorectal cancer. In patients with resected lymph node-positive colon carcinomas (TNM stage 3), adjuvant 5-fluorouracil and levamisole produced an unequivocal survival advantage that established this combination as the standard of clinical practice. Given that biochemical modulation of fluorouracil by leucovorin can increase response rates in advanced disease, this combination is undergoing evaluation as an adjuvant treatment. Preliminary results indicate that 5-fluorouracil and leucovorin are effective in reducing disease relapse; however, the effect of this regimen on patient survival rates awaits extended follow-up. In the treatment of stages 2 and 3 rectal cancer, significant reductions in local recurrence and death rates have been achieved with the combination of 5-fluorouracil and radiation therapy. Immunologic approaches and newer chemotherapeutic agents may further improve patient outcome and are under investigation, as are efforts to reduce the toxic effects of cancer chemotherapy. Increased understanding of the biology of these diseases is likely to yield prognostic markers capable of identifying subgroups of earlier stage patients at high risk of disease relapse who may also benefit from adjuvant therapy.

Cisplatin, 5-Fluorouracil, and leucovorin in the therapy of adenocarcinomas of the pancreas.

Pancreatic cancer is resistant to most chemotherapeutic regimens. Based upon evidence of synergy between 5-fluorouracil (5-FU) and cisplatin (CDDP), and of enhanced 5-FU activity in the presence of leucovorin in other neoplasms, a phase II study of CDDP, 5-FU, and leucovorin was conducted to determine the efficacy of this regimen in patients with unresectable adenocarcinomas of the pancreas. Nineteen patients were enrolled, and all were evaluable for toxicity and response. One complete and two partial responses were observed (15.8%). Adverse effects were reversible and tolerable. This regimen has limited activity against pancreatic cancer, and cannot be recommended as standard therapy in this disease.

Phase II trial of uracil and tegafur plus oral leucovorin: an effective oral regimen in the treatment of metastatic colorectal carcinoma.

PURPOSE: To determine the activity and evaluate the toxicity of uracil and tegafur in a 4:1 molar concentration (UFT; Taiho Pharmaceutical Ltd, Tokyo, Japan) plus oral calcium leucovorin in the treatment of patients with advanced colorectal carcinoma. PATIENTS AND METHODS: Forty-five patients with advanced, bidimensionally measurable metastatic colorectal carcinoma were enrolled onto the trial. None of the patients had received prior chemotherapy or biologic therapy for advanced disease. Patients received either 350 or 300 mg/m2/d UFT plus 150 mg/d leucovorin administered orally in divided daily doses every 8 hours for 28 days followed by a 7-day rest period. Response was evaluated after two courses of therapy. RESULTS: Eighteen patients (three treated at 350 mg/m2/d and 15 at 300 mg/m2/d) had partial responses, and one patient had a complete response (response rate, 42.2%; 95% confidence interval, 28% to 58%). Responses were observed in sites that included liver (n = 18), lung (n = 6), and bone (n = 1). Of seven patients who received 350 mg/m2 UFT, prolonged grade 3 diarrhea developed in five; this resulted in a reduction in the UFT starting dose to 300 mg/m2/d in the remaining 38 patients. Grade 1 or 2 toxic effects included diarrhea, nausea, vomiting, abdominal cramping, anorexia, fatigue, oral mucositis, excessive lacrimation, and rash. Among 38 patients who received the 300-mg/m2/d dose, grade 3 toxic reactions included diarrhea (n = 4), vomiting (n = 2), abdominal cramping (n = 1), and fatigue (n = 2). CONCLUSION: UFT 300 mg/m2/d plus oral leucovorin 150 mg/d administered for 28 days demonstrated significant activity against metastatic colorectal carcinoma. This oral regimen was well tolerated and devoid of the neutropenia or significant oral mucositis that complicates intravenous schedules of fluorouracil (5-FU) plus leucovorin. The results of this clinical trial will serve as the basis for a randomized phase III study to compare this oral schedule of UFT plus leucovorin with intravenous 5-FU plus leucovorin to determine the relative efficacy, impact on quality of life, and cost of the two regimens.

Phase II trial of docetaxel (Taxotere) in metastatic colorectal carcinoma.

BACKGROUND: Docetaxel (Taxotere) is prepared from a noncytotoxic precursor extracted from the needles of the Taxus baccata. Preclinical investigations have demonstrated that docetaxel is very active in colon adenocarcinoma murine models. Phase I studies revealed granulocytopenia to be the dose-limiting toxicity. Initial clinical trials also demonstrated docetaxel's activity in ovarian, breast, and non-small cell lung cancer. Because of this encouraging preclinical and clinical activity, we initiated a phase II study of docetaxel in patients with metastatic colorectal carcinoma. PATIENTS AND METHODS: Docetaxel, 100 mg/m2, was administered as a 1-hour intravenous infusion every 21 days. Nineteen patients were entered on the trial. All patients had measurable disease and had not received prior chemotherapy for metastatic disease. RESULTS: No complete or partial responses were observed. Granulocytopenia was the dose-limiting toxic effect. Seventeen patients had grade 4 granulocytopenia; 8 of these patients received antibiotics for neutropenic fevers. Twelve patients experienced hypersensitivity reactions, and 15 patients experienced cutaneous toxic reactions. One patient demonstrated evidence of fluid retention. CONCLUSIONS: Administered at the stated dose and schedule, docetaxel has little activity against metastatic colorectal carcinomas. The toxicity profile, consisting of granulocytopenia, hypersensitivity reactions, cutaneous reactions, and edema, has been previously described in patients receiving docetaxel.

Liposomes in the treatment of malignancy: a clinical perspective.

Technological advances in liposomal preparation and efficient drug entrapment, along with supportive preclinical studies, have led to a number of recent clinical trials utilizing liposomes as drug carriers in the treatment of human malignancy. Although the results of these trials must be considered preliminary, it is clear that liposomal delivery of chemotherapeutic agents is safe at the doses administered. Aside from minor constitutional symptoms, virtually all toxicity could be attributed to release of the incorporated drug. Myelosuppression tends to be the dose-limiting toxicity with free drug, whereas constitutional symptoms are more likely to occur with encapsulated biologic therapy. Prior to human trials, there was fear that intravenous injection of liposomes could result in pulmonary emboli. No cases of pulmonary embolism secondary to liposome therapy have been recorded. The objective response rate in the patients studied appears to be minimal. This is not surprising, since the overwhelming majority of patients studied had disease that was advanced and previously shown to be refractory to therapy. Subgroups of patients that appear to benefit most include those with breast cancer who were treated with liposomal doxorubicin and those with advanced melanoma treated with liposomal tumor vaccines. Additional phase II and III clinical trials will better define the effectiveness of treatment modalities incorporating liposomes. VI-A. Future directions One of the earliest applications of liposomes may be in the amelioration of drug toxicity. Although not yet proven, the clinical studies reviewed suggest that liposomal delivery of doxorubicin reduces cardiotoxicity without sacrificing antitumor effect. Although similar claims have been made in support of continuous infusion doxorubicin [11], one can avoid unnecessary hospitalization or the bulk and expense of portable infusion devices by a single administration of the liposomal preparation. Liposome encapsulation can markedly alter the biodistribution and pharmacokinetics of well-known chemotherapeutic agents. The effectiveness of liposomal drug delivery in human trials thus far has probably been more closely related to altered pharmacokinetics rather than enhanced drug delivery to tumor or increased tumor responsiveness. As demonstrated by Gabizon [19], increased liposome circulating time in the murine model can be achieved by using small unilamellar vesicles containing a phosphatidylcholine of high phase-transition temperature and a small molar fraction of monosialoganglioside or hydrogenated phosphatidylinositol.(ABSTRACT TRUNCATED AT 400 WORDS)

The need to reform personal injury law leaving scientific disputes to scientists.

Personal injury law is staggeringly inefficient as a system of victim compensation. There is little reason to assume that it importantly curtails unreasonably dangerous conduct, yet there is good reason to conclude that it promotes socially undesirable behavior. Moreover, the tort law system ill serves the goal of individual justice, in part because it assumes that lay juries can correctly decide complex scientific issues. Several methods of replacing tort law with other compensation systems are surveyed and a specific, balanced reform package is proposed.