A need to simplify informed consent documents in cancer clinical trials. A position paper of the ARCAD Group.

Background: In respect of the principle of autonomy and the right of self-determination, obtaining an informed consent of potential participants before their inclusion in a study is a fundamental ethical obligation. The variations in national laws, regulations, and cultures contribute to complex informed consent documents for patients participating in clinical trials. Currently, only few ethics committees seem willing to address the complexity and the length of these documents and to request investigators and sponsors to revise them in a way to make them understandable for potential participants. The purpose of this work is to focus on the written information in the informed consent documentation for drug development clinical trials and suggests (i) to distinguish between necessary and not essential information, (ii) to define the optimal format allowing the best legibility of those documents. Methods: The Aide et Recherche en Cancérologie Digestive (ARCAD) Group, an international scientific committee involving oncologists from all over the world, addressed these issues and developed and uniformly accepted a simplified informed consent documentation for future clinical research. Results: A simplified form of informed consent with the leading part of 1200-1800 words containing all of the key information necessary to meet ethical and regulatory requirements and 'relevant supportive information appendix' of 2000-3000 words is provided. Conclusions: This position paper, on the basis of the ARCAD Group experts discussions, proposes our informed consent model and the rationale for its content.

Impact of on-site initiation visits on patient recruitment and data quality in a randomized trial of adjuvant chemotherapy for breast cancer.

PURPOSE: To provide empirical evidence on the impact of on-site initiation visits on the following outcomes: patient recruitment, quantity and quality of data submitted to the trial coordinating office, and patients' follow-up time. PATIENTS AND METHODS: This methodological study was performed as part of a randomized trial comparing two combination chemotherapies for adjuvant treatment of breast cancer. Centers participating to the trial were randomized to either receive systematic on-site visits (Visited group), or not (Non-visited group). RESULTS: The study was terminated after two years, while the main randomized trial continued. Of the 135 centers that had expressed an interest in the trial, only 69 randomized at least one patient (35/68 in the Visited group, 34/67 in the Non-visited group). Almost two-thirds of the patients were entered by 17 centers (10 in the Visited group, seven in the Non-visited group) that accrued more than 10 patients each. None of the prespecified outcomes favored the group of centers submitted to on-site initiation visits (ie, mean number of queries par patient: 6.1 +/- 9.7 versus 5.4 +/- 6.4, respectively for the Visited and Non-visited groups). Spontaneous transmittal of case report forms, although required by protocol, was low in both randomized groups (mean number of pages per patient: 1.5 +/- 2.0 versus 2.1 +/- 2.3, respectively), with investigators submitting about one-third of the expected forms on time (29% and 39%, respectively). LIMITATIONS: This study could not evaluate the impact of repeated on-site visits on clinical outcomes. CONCLUSION: Systematic on-site initiation visits did not contribute significantly to this clinical trial.

Phase II trial of anaxirone (TGU) in advanced colorectal cancer: an EORTC Early Clinical Trials Group (ECTG) study.

Anaxirone, a rationally synthesised triepoxide derivative, was given to 46 patients with metastatic colorectal cancer. Good risk patients received 800 mg/m2 as a rapid intravenous injection every 4 weeks, whereas poor risk patients received 650 mg/m2. Of 46 patients, 45 were evaluable for toxicity and 42 for efficacy analysis. There were 37/45 patients with poor risk, showing no difference in toxicity as compared to good risk patients. The major toxic effect was myelosuppression with 34% of all patients experiencing grade 3 or 4 leucopenia; thrombocytopenia was less frequent. Locoregional phlebitis occurred in 66% of the patients. There was no objective tumour response to anaxirone in 42 evaluable patients. Only 4 patients achieved stabilisation of the disease lasting maximally up to 248 days. Anaxirone is inactive in metastatic colorectal cancer.

Recombinant granulocyte colony stimulating factor reduces the infectious complications of cytotoxic chemotherapy.

The aim of this study was to determine the usefulness of recombinant human granulocyte colony stimulating factor (r-metHuG-CSF) following conventional chemotherapy for small cell lung cancer. 130 previously untreated patients were randomised to receive either r-metHuG-CSF (230 micrograms/m2) or placebo on days 4-17 following CDE (cyclophosphamide, doxorubicin and etoposide) chemotherapy. Over all cycles, 53% of 64 patients on placebo and only 26% of 65 patients on r-metHuG-CSF had at least one experience of neutropenia with fever defined as a neutrophil count less than 1.0 x 10(9)/l and a temperature > or = 38.2 degrees C (P < 0.002). It resulted in a reduction in the requirement for parenteral antibiotics from 58% in placebo patients compared with 37% in the r-metHuG-CSF group (P < 0.02), and a significant reduction in the incidence of infection-related hospitalisation. Chemotherapy doses were reduced by 15% or more at least once in 61% of the placebo group compared with 29% in the r-metHuG-CSF group (P < 0.001). 47% of the patients treated with placebo and 29% of the patients treated with r-metHuG-CSF experienced at least one cycle with a delay of 2 days or more in the administration of chemotherapy (P < 0.04). r-metHuG-CSF was well tolerated. There were no significant differences between the two groups in terms of response or survival.

Responses and toxic deaths in phase I clinical trials.

This review analysis consists of the antitumor activity and toxic deaths reported in single agent Phase I clinical trials using cytotoxic compounds published from 1972 to 1987. A total of 6639 patients with a variety of solid tumors and hematological malignancies were accrued in 211 trials studying 87 compounds. The median number of patients per trial was 28 (range: 7-111) and the median of the median ages reported in the individual trial was 56 (range of individual age: 2 to 93 years). Ten percent of the trials enrolled pediatric patients (less than 18 years), but the exact numbers of children were not always given or separated from the adult patients. Nine percent of the patients had received no prior treatment, 75% were pretreated either with chemotherapy alone (50%) or radio- plus chemotherapy (25%). Radiotherapy alone was administered to 11% of the patients and the remaining 5% of the patients received prior treatments which was not specified. The most frequent tumor types were those of the gastrointestinal tract (22%) and the respiratory tract (19%). The frequency of the remaining malignancies was less than 10% of all patients. There were 23 (0.3%) complete responders and 279 (4.2%) partial responders for an overall response rate of 4.5% among all entries. Toxic deaths were rare and reported in only 31 patients (0.5% of the entire population). Responses were usually observed in chemosensitive tumor types. Despite a low response rate reported during the first phase of cytotoxic drug development, the present analysis shows that some therapeutic benefit can be achieved.

Phase I-II trial of doxifluridine (5'DFUR) administered as long-term continuous infusion using a portable infusion pump for advanced colorectal cancer.

Doxifluridine, a new fluoropyrimidine analog, was administered to 21 patients with advanced colorectal carcinoma. The starting dose was 1.0 g/m2 given over 24 h for 90 consecutive days as a continuous infusion. Due to severe skin reactions (hand-foot syndrome), the dose was reduced stepwise to 0.75 g/m2/day. Twenty patients were evaluable for efficacy, one had an early non-toxic death. Seven out of 20 (35%) showed a partial response; disease stabilization was observed in 10 patients (50%) and three showed progressive disease after 3 months of treatment. All 17 patients who achieved a partial response or a stabilization of disease were treated until progressive disease was documented and some had therapy up to 46 weeks. Toxicity was minimal and mainly defined as hand-foot syndrome which occurred in 50% of the patients of whom three experienced severe reaction. There was no myelosuppression, renal or liver dysfunction, no cardiac alterations and only one patient experienced severe dizziness. Doxifluridine is active in advanced colorectal carcinoma when the drug is given as a continuous infusion for 90 consecutive days at a daily dose of 0.75 g/m2.

Phase II trial of menogaril in advanced colorectal cancer.

Menogaril, a new semisynthetic anthracycline antibiotic, was administered to 35 patients with advanced colorectal cancer. The drug was infused over 2 hr at a dose of 160 mg/sqm or 200 mg/sqm repeated every 4 weeks. Twenty-seven patients were evaluable for response and no objective responses were achieved. Myelosuppression, only leukopenia, was usually of mild-moderate degree and occurred in 63% of the patients. Twenty-seven percent of the patients experienced severe leukopenia. Local erythema and phlebitis were frequently observed and were severe in 13% of the patients. Nausea/vomiting (66%) and alopecia (50%) were. of mild-moderate degree. This study suggests that menogaril at these doses and schedule had no activity in advanced colorectal cancer.

Phase I study of triglycidylurazol given on a 5-day i.v. schedule.

Triglycidylurazol is a teroxirone derivative proposed for clinical trials on the basis of a broad spectrum of activity against murine tumors and a reduced potential for toxic manifestations at the injection site as compared to the parent compound. This phase I trial was designed to define the maximum tolerated dose of triglycidylurazol given by iv bolus on a 5-day schedule. Twenty-eight adult patients with a variety of solid tumors were entered. Their median performance status was 2 (range, 0-3), and most had received prior radiotherapy, chemotherapy, or both. A median of one course (range, one to four) was administered, for a total of 47 courses. Doses were escalated from 6 to 250 mg/m2/day. Leukopenia and thrombocytopenia were dose-related and -limiting, with a strong suggestion of increased myelosuppression with repeated courses. Nonhematologic toxic effects were generally mild to moderate. Nausea and vomiting were experienced by most patients. Local toxic effects consisting of venous discoloration, phlebitis, and/or sloughing were encountered in about one-half of the patients. Possible drug-related impairments in liver function were noted in three patients. Negligible alopecia and fatigue were also observed. Antitumor effect was detected in one patient with adenocarcinoma of unknown origin. A dose of 200 mg/m2/day for 5 consecutive days may be recommended for phase II trials.

Randomized phase II trial of carminomycin versus 4'-epidoxorubicin in advanced breast cancer.

Sixty-three evaluable patients with advanced breast cancer were randomly allocated to receive three-week intravenous courses of carminomycin (18 mg/m2) or 4'-epidoxorubicin (90 mg/m2). The former yielded one (3%) partial response for nine weeks among 29 patients whereas, in the other arm, nine (27%) of 34 patients achieved partial response for a median of 28 weeks (range, nine to 36 weeks; p less than 0.02). The major toxic effect of these anthracyclines was leukopenia with median white blood cell nadirs of 1,600/microL (range, 300-4,000/microL) versus 1,800/microL (range, 500-4,300/microL), respectively. Acute nonhematologic toxic effects were qualitatively similar but carminomycin produced significantly less gastrointestinal intolerance and alopecia. Patients whose disease failed to respond to first-line anthracycline received doxorubicin (60 mg/m2) every three weeks. Four partial responses were obtained among 19 patients previously treated with carminomycin. Following 4'-epidoxorubicin therapy, one of 12 evaluable patients also attained partial response. Survival curves were not affected by the initial treatment option. Carminomycin has marginal activity against breast cancer whereas 4'-epidoxorubicin deserves further evaluation of its therapeutic index relative to doxorubicin. The design used in this trial appears attractive for prompt phase II evaluation of anthracycline analogs.

Phase II study of carminomycin in a human tumor cloning assay.

The anticancer activity of carminomycin was investigated in a human tumor cloning assay. No efficacy could be identified in the WiDr and the MCF7 cell lines which were highly responsive to doxorubicin. In addition, drug testing experiments were carried out in samples of various malignancies freshly obtained from 86 patients of whom 54 had not received prior anthracyclines. A reduction in the number of tumor colony forming units by 50% or more was seen in 1/26 breast cancers, 1/22 ovarian cancers and 1/7 melanomas. Cross-resistance studies indicated that eight tumors were responsive to doxorubicin only and one to carminomycin only whereas two were sensitive to both and 73 were resistant to both. This in vitro Phase II study corroborates the disappointing clinical results achieved with carminomycin.

Preparation of delta 3-7 alpha-phenylacetamidodesacetoxycephalosporanic acid.

delta 3-7 alpha-Phenylacetamidodesacetoxycephalosporanic acid was prepared by ring expansion of 6-epi-benzylpenicillin-S-sulfoxide, using N,O-bis(trimethylsilyl)acetamide (BSA) as silylating and dehydrating agent and alpha-picoline/alpha-picoline hydrobromide as catalyst. In some experiments 7 alpha-phenylacetamido-3 beta-bromo-3 alpha-methylcepham-4 alpha-carboxylic acid was obtained as a side product. 7-Epimers in the desacetoxycephalosporanic series were also prepared by base-catalyzed epimerization of the benzyl 7 beta-(p-nitrobenzylideneimino)desacetoxycephalosporanate and of the S-sulfoxide of natural methyl 6-phenylacetamidodesacetoxycephalosporanate. In both reactions 1,5-diazabicyclo(4.3.0)non-5-ene (DBN) was used as epimerization catalyst.