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Adverse event (AE) reporting in oncology has evolved from informal descriptions to a highly systematized process. The Common Terminology Criteria for Adverse Events (CTCAE) is the predominant system for describing the severity of AEs commonly encountered in oncology clinical trials. CTCAE clinical descriptors have been developed empirically during more than 30 years of use. The method of data collection is clinician based. Limitations of the CTC system include potential for incomplete reporting and limited guidance on data analysis and presentation methods. The Medical Dictionary for Regulatory Activities (MedDRA) is a comprehensive medical terminology system used for regulatory reporting and drug labeling. MedDRA does not provide for severity ranking of AEs. CTC-based data presentations are the primary method of AE data reporting used in scientific journals and oncology meetings. Patient-reported outcome instruments (PROs) cover the subjective domain of AEs. Exploratory work suggests PROs can be used with a high degree of patient engagement and compliance. Additional studies are needed to determine how PROs can be used to complement current AE reporting systems. Potential models for integrating PROs into AE reporting are described in this review. AE reporting methods will continue to evolve in response to changing therapies and growing interest in measuring the impact of cancer treatment on health status. Although integration of PROs into AE reporting may ultimately improve the comprehensiveness and quality of collected data, it may also increase the administrative burden and cost of conducting trials. Therefore, care must be used when developing health outcomes and safety data collection plans.

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Immunotoxin LMB-1 is composed of monoclonal antibody B3 chemically linked to PE38, a genetically engineered form of Pseudomonas exotoxin. B3 recognizes a carbohydrate antigen (Le(Y)) present on many human solid tumors. LMB-1 has excellent antitumor activity in nude mice bearing Le(Y)-positive tumors. We conducted a phase I study of 38 patients with solid tumors who failed conventional therapy and whose tumors expressed the Le(Y) antigen. Objective antitumor activity was observed in 5 patients, 18 had stable disease, 15 progressed. A complete remission was observed in a patient with metastatic breast cancer to supraclavicular nodes. A greater than 75% tumor reduction and resolution of all clinical symptoms lasting for more than six months was observed in a colon cancer patient with extensive retroperitoneal and cervical metastasis. Three patients (two colon, one breast cancer) had minor responses. The maximum tolerated dose of LMB-1 is 75 microgram/kg given intravenously three times every other day. The major toxicity is vascular leak syndrome manifested by hypoalbuminemia, fluid retention, hypotension and, in one case, pulmonary edema. Although immunotoxins have been evaluated in clinical studies for more than two decades, this is the first report of antitumor activity in epithelial tumors.

A grading scale specific to EGFR inhibitor dermatologic AEs is presented for formal integration into future versions of CTCAE and for validation in clinical trial settings. The study group designed this scale to detect and report EGFRI-related toxicities with greater sensitivity, specificity, and range than the scales currently used. This scale should serve as a foundation for efforts to perform objective interdrug comparisons and assessments of supportive care treatment strategies more effectively than with current methods.

Purpose To assess the feasibility of measuring symptomatic adverse events (AEs) in a multicenter clinical trial using the National Cancer Institute’s Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE). Methods and Materials Patients enrolled in Trial XXXX (XXXX) were asked to self-report 53 PRO-CTCAE items representing 30 symptomatic AEs at 6 time points (baseline; weekly x4 during treatment; 12-weeks post-treatment). Reporting was conducted via wireless tablet computers in clinic waiting areas. Compliance was defined as the proportion of visits when an expected PRO-CTCAE assessment was completed. Results Among 226 study sites participating in Trial XXXX, 100% completed 35-minute PRO-CTCAE training for clinical research associates (CRAs); 80 sites enrolled patients of which 34 (43%) required tablet computers to be provided. All 152 patients in Trial XXXX agreed to self-report using the PRO-CTCAE (median age 66; 47% female; 84% white). Median time for CRAs to learn the system was 60 minutes (range 30–240), and median time for CRAs to teach a patient to self-report was 10 minutes (range 2–60). Compliance was high, particularly during active treatment when patients self-reported at 86% of expected time points, although compliance was lower post-treatment (72%). Common reasons for non-compliance were institutional errors such as forgetting to provide computers to participants; patients missing clinic visits; internet connectivity; and patients feeling “too sick”. Conclusions Most patients enrolled in a multicenter chemoradiotherapy trial were willing and able to self-report symptomatic adverse events at visits using tablet computers. Minimal effort was required by local site staff to support this system. The observed causes of missing data may be obviated by allowing patients to self-report electronically between-visits, and by employing central compliance monitoring. These approaches are being incorporated into ongoing studies.

Cyclopentenyl cytosine (CPE-C) is an investigational drug that is active against human solid tumor xenografts. The 5'-triphosphate of CPE-C inhibits CTP synthase, and depletes CTP and dCTP pools. We conducted a phase I clinical trial of CPE-C given as a 24-h continuous i.v. infusion every 3 weeks in 26 adults with solid tumors. The starting dose rate, 1 mg/m2 per h, was selected on the basis of both preclinical studies and pharmacokinetic data from two patients obtained after a test dose of 24 mg/m2 CPE-C as an i.v. bolus. Dose escalation was guided by clinical toxicity. A total of 87 cycles were given, and ten patients received four or more cycles. The mean CPE-C steady-state plasma levels (Cpss) increased linearly from 0.4 microM to 3.1 microM at dose levels ranging from 1 to 5.9 mg/m2 per h (actual body weight); the mean total body clearance was 146 +/- 38 ml/min per m2. CPE-C was eliminated by both renal excretion of intact drug and deamination to cyclopentenyl uracil in an apparent 2:1 ratio. CTP synthase activity in intact bone marrow mononuclear cells was inhibited by 58% to 100% at 22 h compared to matched pretreatment samples at all CPE-C dose levels. When all data were combined, flux through CTP synthase was decreased by 89.6% +/- 3.1% at 22 h (mean +/- SE, n = 16), and remained inhibited by 67.6% +/- 7.7% (n = 10) for at least 24 h post-CPE-C infusion. Granulocyte and platelet toxicities were dose-dependent, and dose-limiting myelosuppression occurred during the initial cycle in two of three patients treated with 5.9 mg/m2 per h. Four of 11 patients (4 of 20 cycles) who received 4.7 mg/m2 per h CPE-C experienced hypotension 24-48 h after completion of the CPE-C infusion during their first (n = 2), third (n = 1) and sixth cycles (n = 1), respectively. Two of these patients died with refractory hypotension despite aggressive hydration and cardiopulmonary resuscitation. One of 12 patients (28 total cycles) treated with 3.5 mg/m2 per h CPE-C experienced orthostatic hypotension during cycle 1, and this patient had a second episode of orthostatic hypotension at a lower dose (3.0 mg/m2 per h). Hypotension was not seen in patients receiving < or = 2.5 mg/m2 per h CPE-C.(ABSTRACT TRUNCATED AT 400 WORDS)

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