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OBJECTIVE: The authors sought to empirically test whether relative health stock, a measure of patients' sense of loss in their health due to illness, influences the treatment decisions of patients facing life-threatening conditions. Specifically, they estimated the effect of relative health stock on advanced cancer patients' decisions to participate in phase I clinical trials. METHOD: A multicenter study was conducted to survey 328 advanced cancer patients who were offered the opportunity to participate in phase I trials. The authors asked patients to estimate the probabilities of therapeutic benefits and toxicity, their relative health stock, risk preference, and the importance of quality of life. RESULTS: Controlling for health-related quality of life, an increase in relative health stock by 10 percentage points reduced the odds of choosing to participate in a phase I trial by 16% (odds ratio = 0.84, 95% confidence interval = 0.72, 0.97). CONCLUSION: Relative health stock affects advanced cancer patients' treatment decisions. [ABSTRACT FROM AUTHOR]

A phase I trial of all-trans-retinoic acid (ATRA) was conducted to establish the maximum tolerable dose (MTD) of ATRA given once daily to patients with solid tumors. Cancer patients for whom no standard therapy was available were treated with ATRA once daily. Doses were escalated in cohorts of at least three patients. The pharmacokinetics of ATRA were assessed on day 1 for all patients and weekly for 31 patients who received doses of ≥110 mg/m2 per day. Patients were followed for toxicity and response. Correlations of toxicity frequency and grade with pharmacokinetic parameters were sought. In addition, correlation of changes in ATRA pharmacokinetics with the concentration of ATRA metabolites in plasma were sought. A total of 49 patients received ATRA at doses ranging from 45 to 309 mg/m2 per day. Hypertriglyceridemia was dose-limiting at 269 mg/m2 per day. Other frequent toxicities included mucocutaneous dryness and headache. With chronic dosing, plasma ATRA concentrations fell in 59% of patients. Stable, low, or variable [ATRA] were seen in 16%, 6%, and 16% of patients respectively. Age, gender, smoking, or concurrent medication did not correlate with the pharmacokinetic pattern. Severe toxicities tended to occur with initial peak [ATRA] of ≥0.5 μg/ml (1.7 μ M), and the toxicity frequency did not change if [ATRA] decreased with continued dosing. No consistent change in 4-oxo-ATRA or retinoid glucuronide concentrations was observed with decreases in plasma [ATRA]. The recommended once-daily ATRA dose is 215 mg/m2, although significant interpatient variability is observed in toxicity and plasma retinoid concentrations. Although not statistically significant, more frequent and severe toxicity tended to occur in patients with higher plasma peak ATRA concentrations. Other factors, such as responses at target tissues, may be at least as important as the plasma ATRA concentration in predicting toxicity and/or response. [ABSTRACT FROM AUTHOR]

A total of 21 patients with advanced cancer were entered into a phase I study to determine the maximum tolerable dose (MTD) of liposome-encapsulated doxorubicin (LED) given weekly for 3 consecutive weeks at doses of 20, 30, or 37.5 mg/m2 per week. For a comparison of the pharmacokinetic behavior of LED with that of standard-formulation doxorubicin, 13 patients received a dose of standard-formulation doxorubicin 2 weeks prior to the first dose of LED. All doses were given by 1-h infusion through a central vein. Toxicity was evaluated in 22 courses delivered to 17 patients. The MTD with this schedule was 30 mg/m2 per week x 3. The single patient treated at 37.5 mg/m2 weekly could not complete the entire course due to myelosuppression. At the dose of 30 mg/m2 per week, three of eight patients had grade > or = 3 leukopenia. Other toxicities included mild to moderate thrombocytopenia, nausea, vomiting, fever, alopecia, diarrhea, fatigue, stomatitis, and infection. At the dose of 30 mg/m2 per week, the total doxorubicin AUC and peak total doxorubicin concentrations in plasma were 8.75 +/- 8.80 microM h (mean +/- SD) and 3.07 +/- 1.45 microM, respectively, after LED administration. The total doxorubicin AUC and peak total doxorubicin concentrations in plasma were 3.92 +/- 2.47 microM h and 2.75 +/- 2.70 microM, respectively, after the infusion of standard-formulation doxorubicin. The total body clearance of doxorubicin was 18.42 +/- 11.23 l/h after the infusion of LED and 31.21 +/- 15.48 l/h after the infusion of standard-formulation doxorubicin. The mean elimination half-lives of doxorubicin were similar: 8.65 +/- 5.16 h for LED and 7.46 +/- 5.16 h for standard-formulation doxorubicin. Interpatient variability in pharmacokinetic parameters as demonstrated by the percentage of coefficients of variation was 33%-105%. There was no relationship between the percentage of WBC decrease or the duration of WBC suppression and the total doxorubicin or doxorubicinol AUC. There was no correlation between the duration of leukopenia and drug exposure as reflected by the AUC of liposome-associated doxorubicin. LED can be given in doses similar to those of standard-formulation doxorubicin and produces acute toxicities similar to those caused by standard doxorubicin. [ABSTRACT FROM AUTHOR]

Assessment of renal function prior to cisplatin chemotherapy has long been based on measurement of creatinine clearance by 24-hour urine collection (CrCmeas). Estimated creatinine clearance (CrCest) as calculated from the patient's age, weight, and serum creatinine level has been suggested as an adequate surrogate for CrCmeas, as it provides advantages of improved convenience, decreased cost, and possibly increased accuracy. We studied 847 patients receiving cisplatin-based chemotherapy on Cancer and Leukemia Group B (CALGB) protocols to determine whether the CrCmeas, CrCest, or serum creatinine value or the age of the patient would predict the subsequent genitourinary (GU) toxicity. Both CrCmeas (P = 0.001) and CrCest (P = 0.02) were predictive of subsequent grade 2+ GU toxicity, with CrCmeas being a slightly better predictor. Patient age also influenced subsequent GU toxicity, with the risk increasing with age (P = 0.0008). When patients were classified by age group and by CrCmeas, distinct subgroups were identified, with differences in the risk for grade 2+ GU toxicity ranging from 14% to 32%. Using a logistic model to assess the probability of grade 2+ GU toxicity, we found that an age of greater than or equal to 60 years (P = 0.005), a CrCmeas value of less than 75 ml/min (P = 0.004), and the risk characteristics of the individual cisplatin trial were important, whereas CrCest was not. Furthermore, CrCest proved to be a poor predictor of a CrCmeas value of less than 75 ml/min, "misclassifying" nearly half of the patients to a "lower-risk" subgroup. In summary, both CrCmeas and the patient's age independently provided predictive information concerning cisplatin GU toxicity. Our data support the continued clinical usefulness of determining the CrCmeas value prior to the administration of cisplatin-based chemotherapy to most patients. [ABSTRACT FROM AUTHOR]

Because of potential synergistic interactions, we added 25 mg/m2 i.v. cisplatin (P) 25 given on days 1-5 to the combination of 45 mg/m2 i.v. doxorubicin (A) given on day 1, 800 mg/m2 i.v. cyclophosphamide (C) given on day 1, and 50 mg/m2 i.v. etoposide (E) given on days 1-5. The resulting PACE regimen was given every 21 days for the first three courses and then every 28 days for the next five courses. PACE was used in two trials: the first, for both limited and extensive disease, was conducted at the University of Maryland Cancer Center and North Shore University Hospital; and the second, for extensive disease, was carried out as a Cancer and Leukemia Group B pilot study. Chest irradiation was not used. Prophylactic cranial irradiation at a dose of 3,000 cGy was given to all patients achieving a complete response (CR). A total of 33 subjects were entered in the first study; 8 of the 15 (53%) presenting with limited disease and 7 of the 18 (39%) exhibiting extensive disease achieved a CR. A partial response (PR) was obtained in 27% and 33% of cases, respectively. Of the 34 patients entered in the second study, 25 were eligible; 8 (32%) achieved a CR and 6 (24%) showed a PR. Toxicity was severe in both studies, including greater than 90% severe or life-threatening leukopenia and thrombocytopenia. Serial creatinine-clearance evaluations in the first study indicated progressive deterioration, which required discontinuation of the cisplatin before the planned completion of treatment in most cases. Since the response rate was no higher than the historic data reported for the three-drug ACE combination and because the toxicity was severe, the studies were stopped and patients were followed for survival. After a follow-up period of greater than 6 years, the median survival was 24 months for limited disease, with 33% and 27% of the patients being alive at 3 and 6.5 years, respectively. The median survival for extensive disease was 15 and 11 months in the first and second studies, respectively. These pilot studies suggest that the addition of cisplatin may augment the activity of the ACE regimen, but at the cost of severe toxicity. Further studies seem warranted if the myelotoxicity can be better controlled. [ABSTRACT FROM AUTHOR]

HMBA is a potent differentiating agent capable of causing > 95% morphological differentiation in cell lines in vitro. The induction of differentiation is dependent on both the concentration of and the duration of exposure to HMBA. However, acute toxicities (neurotoxicity and acidosis) have limited the maximal HMBA css value to < 2 mM, which is at the lower limit of effective in vitro concentrations. When HMBA css values have been maintained at 1-2 mM, thrombocytopenia has limited the duration of HMBA infusion to < or = 10 days. The present studies were performed to determine whether exposure to HMBA could be individualized and maximized without resulting in intolerable toxicity to patients and to determine which factors would predispose a patient to the development of acute toxicity during treatment with HMBA. For these investigations, patients were given HMBA at a target css using an adaptive-feedback-control method rather than at a set dose. Because HMBA administration produces large anion gaps, a simple maneuver such as alkalinization might enable the escalation of plasma HMBA css values to > 2 mM. HMBA was given as a 5-day CI to 14 patients (26 courses) at 2 target HMBA css levels near the maximal tolerated value in the presence or absence of concurrent alkalinization with sodium bicarbonate. Symptomatic acidosis occurred in one patient who did not receive bicarbonate. Neurotoxicity proved to be dose-limiting at the target HMBA css value of 1.5-2.0 mM in the absence of concurrent alkalinization and at a css level of > 2 mM, regardless of alkalinization. No neurotoxicity was seen at target HMBA css values of 1.5-2.0 mM in patients who did receive concurrent alkalinization. Alkalinization was not associated with any detectable changes in plasma HMBA metabolites. With the maximal tolerable 5-day HMBA css having thus been defined at 1.5-2.0 mM, we attempted to maximize exposure to HMBA by defining a tolerable duration of infusion. Individualization of the duration of HMBA infusion to a target nadir PLT was performed in patients who had received an initial 5-day CI of HMBA at a css 1.5-2.0 mM along with concurrent alkalinization. The AUC achieved and the thrombocytopenia produced during this first course were used to predict the duration of infusion that each patient would subsequently tolerate (at an HMBA css of 1-2 mM) to achieve a nadir PLT of 75,000-100,000/microliters.(ABSTRACT TRUNCATED AT 400 WORDS) [ABSTRACT FROM AUTHOR]

Three patients with advanced refractory malignancies were treated with whole-body hyperthermia (WBH: 42-42.3 degrees C) for 2 h during which time they also received an infusion of 60 or 80 mg/m2 of cis-diamminedichloroplatinum II (DDP). Each patient developed an elevated serum creatinine (2.7-13.6 mg/dl), with maximum creatinine occurring between days 7 and 12 after treatment. WBH did not alter plasma or urinary pharmacokinetics of total or ultrafilterable platinum compared with pharmacokinetic data of the same or other patients given DDP euthermically. Although the mechanism of the renal damage is unclear, it appears that WBH can potentiate the nephrotoxic actions of DDP and that further study of this combination is not warranted. [ABSTRACT FROM AUTHOR]

Twenty-nine patients with non-small cell lung cancer refractory to prior therapy were treated with either vindesine (VDS) alone (3 mg/m2 every week) or the combination of VDS plus cisplatin (DDP) (100 mg/m2 every 28 days). Serial blood and urine samples were collected to assess the pharmacokinetics of VDS and DDP. All patients were evaluable for toxicity and 27 were evaluable for response. No objective antitumor responses were observed. Peripheral neuropathy manifested by paresthesias, muscle weakness, and constipation were observed in 20 treated patients, and hematologic toxicity consisting of thrombocytopenia and/or leukopenia occurred in 18 patients. The plasma and urinary pharmacokinetics of VDS and DDP measured in this study indicate that VDS and DDP do not interfere with each other and that the pharmacokinetics in previously treated and untreated patients are similar. The antitumor responses and degree of toxicity observed in this trial compare unfavorably with previously reported VDS and VDS-DDP trials in previously untreated patients with this disease and suggest that prior exposure to chemotherapy might both decrease antitumor activity and enhance toxicity of these chemotherapeutic agents. [ABSTRACT FROM AUTHOR]

A phase II study of intermittent high-dose 6-thioguanine (6-TG) was undertaken in 19 patients with metastatic colorectal carcinoma. Fourteen patients had received prior myelosuppressive therapy. 6-TG was administered as a single dose by IV bolus over 15-30 min, with retreatment every 3 weeks. The starting dose was 700 mg/m in ten patients, 900 mg/m in one patient, 1,000 mg/m in four patients, and 1,200 mg/m in two patients. Two patients received reduced doses (350 mg/m) because of liver dysfunction. There was no regression of measurable disease after treatment with 6-TG in this study. Eight patients achieved stabilization of previously progressive disease for periods of 10-32 weeks. Toxicities were nausea and vomiting (19 patients), mucositis (3 patients), reversible renal dysfunction with creatinine>2 mg/dl (4 patients), nasal congestion (3 patients), diarrhea (1 patient), and skin blistering at the infusion site (1 patient). Seven patients had white blood count nadirs below 3,000/μl (the lowest nadir was 900/μl). Only one patient had a platelet count nadir below 100.000/μl. There were no infections or hemorrhage. 6-TG, as administered in this study, has no antitumor activity against colorectal carcinoma. Concentrations of 6-TG and metabolites were assessed in the plasma of six patients by a reversed-phase HPLC system. 6-TG and metabolites were extracted from human plasma at 50%-100% efficiency by cold 2 N perchloric acid (1 : 1). Neutralized extracts were chromatographed on a μ-Bondapak C column by two separate isocratic conditions. 6-TG, 6-thiouric acid, 6-thioguanosine, and 6-thioxanthine were analyzed with 0.01 M Na acetate, pH 3.5/10% methanol as the mobile phase and were detected at 340 nm. 6-Methyl TG and three unknown metabolites were eluted with Na acetate/25% methanol and were detected at 310 nm. External standard calibration was used for quantitation. The 6-TG detection limit was 0.8 nmol/ml. In six patients who received 1-1.2 g 6-TG/m IV, 6-TG achieved peak plasma concentrations of 61-118 nmol/ml (95.6 ± 23.0, mean ± SD). Plasma 6-TG concentrations decayed bi-exponentially, with initial t of 3 h and terminal t of 5.9 h. 6-Thiouric acid, 6-methyl TG, 6-thioguanosine, 6-thioxanthine, and three major unidenitified metabolites were also observed in plasma. The three unknowns were extracted with ethyl acetate from alkalinized pooled plasma extracts and were purified by HPLC. [ABSTRACT FROM AUTHOR]

The plasma pharmacokinetics of the antineoplastic anthracycline antibiotic aclacinomycin A (Acm) and its metabolites were studied in 12 patients treated with 60-120 mg/m2 during a phase I clinical trial. Total plasma drug fluorescence initially declined very rapidly, but from 2 to 24 h after injection, fluorescence rose progressively to intensities greater than those measured 1 min after Acm injection. Plasma total drug fluorescence slowly declined from 24 to 72 hours after Acm administration. These events reflected the rapid disappearance of Acm and the subsequent appearance of two highly fluorescent metabolites. One metabolite co-chromatographed with and had a fluorescence spectrum identical to known metabolite F1 (bisanhydroaklavinone). The other metabolite did not co-chromatograph with any previously described Acm metabolite. This metabolite had a fluorescence spectrum unlike any previously described Acm metabolite and was not altered by treatment for 60 min with 0.2 N HCl at 100 degrees C or by treatment for 24 h at 37 degrees C with bacterial beta-glucuronidase or limpet aryl sulfatase. [ABSTRACT FROM AUTHOR]

Pancreatic cancer is the fourth leading cause of cancer-related death with a median survival of 3-11 months when metastatic. We present a patient with metastatic pancreatic cancer and an exceptional response to initial systemic chemotherapy with FOLFIRINOX (fluorouracil, leucovorin, irinotecan, and oxaliplatin). Despite evidence of disease control on body imaging, he developed symptomatic leptomeningeal disease and brain metastases 29 months into treatment. He received aggressive treatment with capecitabine and irinotecan, intrathecal topotecan, and eventually bevacizumab. He did well for 36 weeks on this regimen until developing sepsis. This patient significantly outlived his expected survival and, moreover, did so with very good quality of life. This case demonstrates the natural history of pancreatic cancer progressing to involve the central nervous system when systemic disease is otherwise responsive to chemotherapy. It is the first case to demonstrate the potential effectiveness of intrathecal topotecan in combination with systemic chemotherapy for the treatment of leptomeningeal metastases of pancreatic cancer.

Chemotherapy is frequently used in the treatment of advanced breast cancer. The identification of patient-specific tumor characteristics that can improve the ability to predict response to chemotherapy would help optimize advanced breast cancer treatment approaches. Quantitative immunofluorescence (QIF) may be applied to the standardization of protein analysis, resulting in increased sensitivity and reproducibility. In the current pilot study, QIF was used to correlate the expression of beta tubulin III and thymidylate synthase with clinical outcome associated with taxane and capecitabine treatment, respectively. QIF analysis is based on fluorescent dye-labeled monoclonal antibody staining followed by computer-assisted microscopy to measure the expression of molecular markers in tumor samples derived from a retrospective database. The interpretation of the tumor marker expression levels results in classification of breast tumors as sensitive or resistant to a mechanistically related drug. Overall diagnostic accuracy of QIF for taxane based therapy was 88% (CI 75.0 - 95.3) with a positive predictive value of 86% and a negative predictive value of 100%, while diagnostic accuracy QIF for capecitabine therapy was 86% (CI 88.0-96.0) with a positive predictive value of 80% and a negative predictive value of 100%. In this study, QIF showed retrospectively a potential for predictive value when analyzing chemotherapeutic treatments for individual advanced stage breast cancer patients. The predictive power of the QIF for chemotherapy confirms that further studies utilizing larger clinical cohorts are warranted.

Objective: To investigate potential sources of gram-negative multidrug-resistant organisms (MDROs) in a deployed US military healthcare facility., Design: Active surveillance., Methods: Swab sampling of patients, hospital personnel, and environmental surfaces was performed before the opening of a new medical treatment facility in Iraq and then serially for the next 6 months. Multidrug resistant isolates were genotypically characterized using pulsed-field gel electrophoresis (PFGE). Univariate and multivariate analysis were performed to evaluate associations between patient characteristics and MDRO carriage., Setting: Deployed US military medical facility., Results: A total of 1,348 samples were obtained, yielding 654 isolates, 42 of which were MDROs. One hundred fifty-eight patients were sampled; swabs from 18 patients yielded 29 MDR isolates. Host nation patients comprised 89% of patients with MDROs and 37% of patients without MDROs (P < .001). Host nation patient status was also significantly associated with MDRO carriage in multivariate logistic regression analysis (adjusted odds ratio, 2.9; confidence interval, 1.3-6.3; P = .009). Bacteria with PFGE patterns matching those recovered from host nation patients were later isolated from environmental surfaces including recovery room patient monitors and the trauma bay floor., Conclusions: At this facility, MDRO isolation was predominantly obtained from newly admitted host nation patients, which may reflect baseline colonization with MDROs in the community. Patient MDRO carriage was linked to subsequent environmental contamination. These findings support intensive infection control efforts in forward deployed facilities.

Objectives: To evaluate whether two molecular biomarkers, thymidine phosphorylase (TP) and dihydropyrimidine dehydrogenase (DPD), could be clinically useful in predicting and improving the chemotherapeutic outcome of the oral fluoropyrimidine capecitabine (5'-DFUR or Xeloda), in the treatment of human head and neck squamous cell carcinoma (HNSCC)., Experimental Design: Quantitative reverse-transcriptase polymerase chain reaction was used to determine the TP and DPD expression levels in different HNSCC cell lines. The TP to DPD ratio was calculated and compared to the relative chemosensitivity between cell lines after treatment with 5'-DFUR. The effect of TP transgene expression to alter the TP to DPD ratio and hence optimize the therapeutic outcome of capecitabine treatment was further evaluated in a murine model of human HNSCC using immunohistochemistry to detect TP and DPD expression in vivo., Results: No correlation was detected between sensitivity to 5'-DFUR and the relative expression levels of TP or DPD in the multiple HNSCC cell lines tested. However, significant correlation was observed between the TP to DPD ratio versus drug resistance of the HNSCC cells (r = -0.914, p = 0.0281). In addition, we demonstrate that transgene expression of TP significantly enhanced the tumoricidal effect of capecitabine in HNSCC tumors with otherwise low endogenous TP to DPD ratios. This antitumor effect was observed up to 30 days after treatment., Conclusions: The results of this study suggest that HNSCC patients who would most benefit from capecitabine-based chemotherapy could be identified by examining the TP to DPD ratio of their tumors. Furthermore, we demonstrate the potential role of TP gene therapy in TP to DPD ratio manipulation to optimize the tumoricidal effect of capecitabine.

Vascular disrupting agents (VDAs) represent a novel approach to the treatment of cancer, resulting in the collapse of tumor vasculature and tumor death. 5,6-dimethylxanthenone-4-acetic acid (DMXAA) is a VDA currently in advanced phase II clinical trials, yet its precise mechanism of action is unknown despite extensive preclinical and clinical investigations. Our data demonstrate that DMXAA is a novel and specific activator of the TANK-binding kinase 1 (TBK1)-interferon (IFN) regulatory factor 3 (IRF-3) signaling pathway. DMXAA treatment of primary mouse macrophages resulted in robust IRF-3 activation and approximately 750-fold increase in IFN-beta mRNA, and in contrast to the potent Toll-like receptor 4 (TLR4) agonist lipopolysaccharide (LPS), signaling was independent of mitogen-activated protein kinase (MAPK) activation and elicited minimal nuclear factor kappaB-dependent gene expression. DMXAA-induced signaling was critically dependent on the IRF-3 kinase, TBK1, and IRF-3 but was myeloid differentiation factor 88-, Toll-interleukin 1 receptor domain-containing adaptor inducing IFN-beta-, IFN promoter-stimulator 1-, and inhibitor of kappaB kinase-independent, thus excluding all known TLRs and cytosolic helicase receptors. DMXAA pretreatment of mouse macrophages induced a state of tolerance to LPS and vice versa. In contrast to LPS stimulation, DMXAA-induced IRF-3 dimerization and IFN-beta expression were inhibited by salicylic acid. These findings detail a novel pathway for TBK1-mediated IRF-3 activation and provide new insights into the mechanism of this new class of chemotherapeutic drugs.

Concurrent chemotherapy and radiation has improved the outcome for patients presenting with locally advanced squamous cell carcinomas of the head and neck (SCCHN). These improvements have come at a cost of increased treatment-related toxicities. We previously reported the results of a phase II trial examining the role of concurrent carboplatin, paclitaxel, and daily radiotherapy (RT) in SCCHN. In an attempt to decrease these side effects, we conducted a prospective phase II trial evaluating the role of amifostine (Ethyol, MedImmune Oncology, Inc, Gaithersburg, MD) in patients treated with this concurrent chemoRT scheme. From April 2002 to September 2004, 19 patients with stage III-IV SCCHN were enrolled on a prospective phase II trial. Treatment consisted of daily RT delivered to 70.2 Gy (1.8 Gy/fx) with amifostine 500 mg IV (<1 hour before RT), and concurrent weekly carboplatin (100 mg/m2) and paclitaxel (40 mg/m2). Median age was 58.5 years (range, 48 to 70 years); male to female ratio was, 83%:17%; Caucasian versus other was, 61%/39%. Tumor characteristics based on histology were: primary cancers of the oropharynx (55.6%); supraglottic larynx (16.7%); hypopharynx (16.7%); oral cavity (5.6%); and unknown primaries (5.6%). All patients presented with locally advanced, unresectable disease T4 (50%), T3 (27.8%), and advanced nodal disease (N2b-N3) (78%). Toxicities were measured weekly during treatment and at each follow-up visit. Disease response to therapy was determined 2 months after completion of therapy. Seventeen patients are evaluable for response and survival at 2 months following completion of RT. Eighty-four percent completed the prescribed radiation treatment, and 84% of patients received more than six cycles of chemotherapy. The median number of missed chemotherapy cycles was 1.5 (range, 0 to 5 cycles). Fifty-six percent of patients received more than 90% of prescribed amifostine doses, with chemoRT-related toxicity being the most common reason for withholding the dose (77%). Median doses of missed amifostine were three (range, 0 to 30 doses). Grade 3 toxicities associated with therapy were: mucositis and dysphagia (40% of patients each), dehydration (27%), xerostomia (20%), and dermatitis (20%); 53% of patients experienced grade 3 leukopenia, while grade 3/4 neutropenia developed in 20%/13%. No grade 4/5 nonhematologic toxicities were encountered. Forty percent of patients completed RT without unscheduled treatment breaks secondary to treatment-related toxicity. Median treatment-break time was 5 days (range, 0 to 20 days). Clinical complete response at both the primary site of disease and neck was achieved in 75% of patients 2 months following completion of RT. Weekly carboplatin and paclitaxel administered concurrently with definitive RT and daily amifostine is well tolerated, with over 85% of patients completing therapy with acceptable toxicity. The addition of amifostine appears to decrease treatment-related toxicity without impacting efficacy.

Purpose: To describe and compare the perceptions of cancer patients and their physicians regarding phase I clinical trials., Methods: Eligible patients had been offered phase I trial participation and had decided to participate but had not yet begun treatment. Each patient's physician also served as a study subject. Patients and physicians completed questionnaires with domains including perceptions of potential benefit and harm from treatment (experimental and standard), relative value of quality and length of life, and perceived content of patient-physician consultations., Results: Three hundred twenty-eight patients and 48 physicians completed surveys. Patients had high expectations regarding treatment outcomes (eg, median 60% benefit from experimental therapy), with those choosing to participate in a phase I trial being more optimistic than those declining phase I participation. Patients predicted a higher likelihood of both benefit and adverse reactions from treatment (experimental and standard) than their physicians (P <.0001 for all comparisons). Although 95% of patients reported that quality of life was at least as important as length of life, only 28% reported that changes in quality of life with treatment were discussed with their physicians. In contrast, 73% of physicians reported that this topic was discussed (P <.0001)., Conclusion: Cancer patients offered phase I trial participation have expectations for treatment benefit that exceed those of their physicians. The discordant perceptions of patients and physicians may possibly be explained by patient optimism and confidence; however, the discrepancies in reports of consultation content, particularly given patients' stated values regarding quality of life, raise the possibility that communication in this context is suboptimal.

Purpose: Butyrate is a small polar compound able to produce terminal differentiation and apoptosis in a variety of in vitro models at levels above 50-100 microM. Previously our group demonstrated that daily oral administration of the prodrug, tributyrin, is able to briefly achieve levels >100 microM. Given in vitro data that differentiating activity requires continuous butyrate exposure, the short t1/2 of the drug and a desire to mimic the effects of an intravenous infusion, we evaluated a three times daily schedule., Patients and Methods: Enrolled in this study were 20 patients with advanced solid tumors for whom no other therapy was available, had life expectancy greater than 12 weeks, and normal organ function. They were treated with tributyrin at doses from 150 to 200 mg/kg three times daily. Blood was sampled for pharmacokinetic analysis prior to dosing and at 15 and 30 min and 1, 1.5, 2, 2.5, 3, 3.5 and 4 h thereafter., Results: The patients entered comprised 15 men and 5 women with a median age of 61 years (range 30-74 years). Prior therapy regimens included: chemotherapy (median two prior regimens, range none to five), radiation therapy (one), no prior therapy (one). There was no dose-limiting toxicity. Escalation was halted at the 200 mg/kg three times daily level due to the number of capsules required. A median butyrate concentration of 52 microM was obtained but there was considerable interpatient variability. No objective responses were seen. There were four patients with prolonged disease stabilization ranging from 3 to 23 months; median progression-free survival was 55 days. Two patients with chemotherapy-refractory non-small-cell lung cancer had survived for >1 year at the time of this report without evidence of progression., Conclusion: Tributyrin is well tolerated and levels associated with in vitro activity are achieved with three times daily dosing.

The authors report their experience with the Pleurx tunneled catheter in patients with end-stage abdominal carcinomatosis and intractable ascites. Ten patients with intractable ascites and abdominal carcinomatosis underwent placement of tunneled Pleurx catheters. The catheters were placed with combined US and fluoroscopic guidance. Patients' charts were reviewed for procedural complications, serum albumin levels, infection, efficacy of catheters in providing effective drainage of ascites, and duration of catheter patency. There were no procedural complications. The serum albumin level decreased from 2.7 g/L to 2.3 at 3 weeks and 2.4 g/L at 6 weeks. There were no catheter infections. Some patients required continuous drainage, whereas others were successfully treated by drainage once per week. Mean catheter survival was 70 days. In patients with end-stage abdominal carcinomatosis complicated by malignant ascites, the Pleurx tunneled catheter can provide effective palliation and alleviated the need for repeated percutaneous paracentesis.

Purpose: The sequence in which chemotherapeutic agents are administered can alter their pharmacokinetics, therapeutic effect, and toxicity. We evaluated the pharmacokinetics and pharmacodynamics of docetaxel and topotecan when coadministered on two different sequences of administration., Patients and Methods: On cycle 1, docetaxel was administered as a 1-hour infusion at 60 mg/m(2) without filgrastim and at 60, 70, and 80 mg/m(2) with filgrastim on day 1, and topotecan was administered at 0.75 mg/m(2) as a 0.5-hour infusion on days 1 to 4. On cycle 2, topotecan was administered on days 1 to 4, and docetaxel was administered on day 4. Cycles were repeated every 21 days. Blood samples for high-performance liquid chromatography measurement of docetaxel (CL(DOC)) and topotecan (CL(TPT)) total clearance were obtained on day 1 of cycle 1 and day 4 of cycle 2. CL(DOC) and CL(TPT) were calculated using compartmental methods., Results: Mean +/- SD CL(DOC) in cycles 1 and 2 were 75.9 +/- 79.6 L/h/m(2) and 29.2 +/- 17.3 L/h/m(2), respectively (P: <.046). Mean +/- SD CL(TPT) in cycles 1 and 2 were 8.5 +/- 4.4 L/h/m(2) and 9.3 +/- 3.4 L/h/m(2), respectively (P: >. 05). Mean +/- SD neutrophil nadir in cycles 1 and 2 were 4,857 +/- 6, 738/microL and 2,808 +/- 4,518/microL, respectively (P: =.02)., Conclusion: Administration of topotecan on days 1 to 4 and docetaxel on day 4 resulted in an approximately 50% decrease in docetaxel clearance and was associated with increased neutropenia.

Purpose: Unresectable squamous cell carcinomas of the head and neck (SCCHN) continue to pose a significant therapeutic challenge. This report defines the toxicities, efficacy, and prognostic factors associated with the combination of carboplatin (CBDCA), paclitaxel, and once-daily radiation for patients with locally advanced disease. Additionally, the pharmacokinetics of paclitaxel were investigated., Methods and Materials: From 1993-1998, 62 patients with Stage III-IV SCCHN were treated with 70.2 Gy of RT at 1.8 Gy/fraction/day to the primary site. Weekly chemotherapy was given during RT consisting of paclitaxel (45 mg/m(2)/wk) and CBDCA (100 mg/m(2)/wk). All patients presented with locally advanced disease; 77% had T4 disease and 21% had T3 disease. Fifty-eight percent had N2b-N3 disease., Results: Sixty patients were evaluable for response and survival with a median follow-up of 30 months (range 7-70). Ninety-eight percent of patients completed prescribed therapy. One patient died after refusing medical management for pseudomembranous colitis and is scored as a Grade 5 toxicity. Two patients suffered Grade 4 leukopenia. Median number of break days was two. A clinical complete response (CR) at the primary site was obtained in 82%, with a total (primary site and neck) CR rate of 75%. The median survival for the entire cohort is 33 months. Response to therapy and status of the neck at presentation were the only prognostic factors found to influence survival. The median survival for patients who attained a CR is 49 months versus 9 months in those who did not attain a CR (p < 0.0001). The 2- and 3-year overall survival for complete responders are 79% and 61%. Plasma paclitaxel concentrations in the range shown to be radiosensitizing were achieved., Conclusions: Weekly carboplatin and paclitaxel given concurrently with definitive once-daily external beam radiation therapy is well tolerated with over 90% of patients completing prescribed therapy. An ultimate CR rate of greater than 70% was obtained, which translated directly into improved survival. With 48% 3-year overall survival for the entire group, this regimen is an excellent option for this group of patients with a historically poor prognosis.

Although retinoids show promise for prevention of second primary upper aerodigestive tract tumors, the optimum retinoid, dose, and schedule are unknown. All-trans retinoic acid (ATRA) has greater affinity for retinoic acid receptors and may be more active than other retinoids but has a shorter plasma half life and may up-regulate its own metabolism. We defined the maximum long-term tolerable dose, dosing frequency, pharmacokinetics, and toxicity of ATRA in patients with treated squamous cell carcinoma of the head and neck (SCCHN). Twenty-one patients were randomized to 45, 90, or 150 mg/m2 ATRA either once daily, or as divided doses every 8 h, for 1 year. Pharmacokinetics were assessed periodically. Fourteen men and seven women with previous SCCHN of initial stage I-IV were treated. Grade > or =3 toxicities (reversible) included headache and hypertriglyceridemia in 5 and 6 patients each, mucositis in 2 patients, and hyperbilirubinemia, elevated alkaline phosphatase, colitis, lipasemia, xerostomia, eczema, and arthritis in 1 patient each. The 150-mg/m2 dose was not tolerable. Doses were reduced for grade > or =3 toxicity in seven of eight patients at 90 mg/m2 daily. Three of nine patients at 45 mg/m2/day required dose reduction, two at the once-daily dose. Day 1 ATRA area under the plasma concentration versus time curve (AUC) increased with dose, and after 1-2 months of continued dosing, the AUC declined in 7 of 13 patients (54%) studied. ATRA AUC did not correlate with toxicity severity or frequency. Fifteen mg/m2/day every 8 h is a tolerable dose for 1 year in patients with treated SCCHN. ATRA pharmacokinetics did not correlate with toxicity.

Purpose: Both docetaxel (DOC), a promoter and stabilizer of microtubule assembly, and topotecan (TOPO), a topoisomerase I inhibitor, have shown antitumor activity in a variety of solid tumor malignancies. This phase I trial was conducted to determine the overall and dose-limiting toxicities (DLT), the maximum tolerated dose (MTD) and the pharmacokinetics of the combination of DOC and TOPO in patients with advanced solid tumor malignancies., Methods: DOC was administered first at 60 mg/m2 without G-CSF and at 60, 70, and 80 mg/m2 with G-CSF by 1-h infusion on day 1 of the odd-numbered cycles (1, 3, 5, etc.) and on day 4 of the even-numbered cycles (2, 4, 6, etc.). TOPO 0.75 mg/m2 was administered as a 30-min infusion on days 1, 2, 3 and 4 of each cycle. G-CSF 300 micrograms was administered subcutaneously (s.c.) on days 5-14. Cycles were repeated every 21 days. All patients were premedicated with dexamethasone 8 mg orally every 12 h for a total of six doses starting on the day before DOC infusion., Results: A total of 22 patients were treated. Six patients were treated in cohort I with DOC and TOPO doses of 60 and 0.75 mg/m2, respectively, without G-CSF, and two patients developed DLT (febrile neutropenia). Four patients were treated in cohort II with DOC and TOPO doses of 60 and 0.75 mg/m2, respectively, with G-CSF, and no DLT was observed. Four patients were treated in cohort III with DOC and TOPO doses of 80 and 0.75 mg/m2, respectively, with G-CSF, and three developed DLT (febrile neutropenia). DOC was then de-escalated to 70 mg/m2 and delivered with TOPO 0.75 mg/m2 and G-CSF (cohort IV). Eight patients were treated at this dose level, and one DLT (febrile neutropenia) was observed. Two patients developed a severe hypersensitivity reaction shortly after the DOC infusion was started, one in cycle 1 and one in cycle 2. Both patients were removed from the study. Two patients developed severe dyspnea in the presence of progressive pulmonary metastases. Other nonhematological toxicities were mild. One patient with extensively pretreated ovarian carcinoma had a partial response, and eight patients with various solid tumor malignancies had stable disease with a median time to progression of 12 weeks (range 9-18 weeks). Administration of TOPO on days 1-4 and DOC on day 4 resulted in increased neutropenia., Conclusions: DOC 80 mg/m2 given first as a 1-h infusion on day 1 with TOPO 0.75 mg/m2 given as a 0.5-h infusion on days 1, 2, 3 and 4 with G-CSF was considered the MTD. The recommended phase II dose for DOC given on day 1 is 70 mg/m2 with TOPO 0.75 mg/m2 given on days 1, 2, 3 and 4 every 21 days with G-CSF 300 micrograms s.c. on days 5-14. The alternative schedule with DOC given on day 4 and TOPO on days 1-4 is not recommended.