Phase I study of carboplatin given on a five-day intravenous schedule.

Twenty-six adult patients were entered in a phase I trial of carboplatin, a new cisplatin derivative with reduced potential for nephrotoxicity. All patients had solid tumors and the median World Health Organization performance score was 2 (0-3). Twelve patients had not received prior chemotherapy. The drug was administered as a 15-minute IV infusion, without pre- or posthydration, at daily doses of 40-125 mg/m2 for five consecutive days. Antiemetics were given only if needed. Thrombocytopenia and neutropenia were dose related and dose limiting. One patient died from septic shock at the highest dose level. Nonhemolytic anemia was also encountered. Nausea and vomiting were experienced by most patients but gastrointestinal intolerance was severe in only two patients. One patient had hypercreatininemia, which was minor and rapidly reversible. Other toxic effects consisted of negligible fatigue, paresthesia, pruritus, local pain, stomatitis, headache, and alopecia. Although none of the patients achieved a partial or complete response, antitumor effect was strongly suggested in two patients with thyroid and cervix cancer, respectively. Carboplatin is an attractive candidate for phase II trials. In good-risk patients, such trials could be initiated at a daily dose of 100 mg/m2 for five consecutive days every five to six weeks.

Clinical studies with a THC analog (BRL-4664) in the prevention of cisplatin-induced vomiting.

BRL-4664, a THC analog, has been administered to 23 patients at a dose of 10 or 15 mg repeated twice. All patients were on cisplatin therapy, and 16 of them had experienced severe vomiting during the previous course of cisplatin. There was a statistically significant difference between the group with prior cisplatin therapy and without prior therapy in terms of number of vomiting episodes, emphasizing the role of conditioned reflexes. The dose of 15 mg administered before and twice after the infusion of cisplatin was well tolerated. Only minor side effects were observed.

In vitro chemosensitivity of brain tumors to cisplatin and its analogues, iproplatin and carboplatin.

The human tumor stem-cell assay was used to investigate the in vitro chemosensitivity of 27 evaluable samples to cisplatin and its analogues, iproplatin and carboplatin, as well as to BCNU, teniposide, vindesine, and dibromodulcitol. All agents exhibited some antitumor activity with the exception of dibromodulcitol (zero response out of 19 evaluable samples). Vindesine, BCNU, and carboplatin were the three most active compounds, with response rates of 29%, 23%, and 22%, respectively. There was a lack of complete cross-resistance between carboplatin and cisplatin as well as between carboplatin and BCNU. Our data suggest that clinical studies with carboplatin and combinations of vindesine plus cisplatin and its analogues may be worthwhile.

Phase I trials of single agents in adult solid tumours: preclinical and clinical aspects.

Considerable progress has been made in the treatment of cancer. However, there is still a need for new drug development. The preclinical antitumour activity of new anticancer agents is evaluated by sequential testing in murine tumours and human xenografts in mice. More recently, the human tumour stem cell assay has been introduced into the preclinical screen. Toxicology studies are done in animals in order to characterize qualitatively and quantitatively the side effects of the new compounds. These toxicology studies allow an appropriate starting dose to be selected for clinical trials. Most commonly, the starting dose for clinical trials corresponds to 1/10 of the dose that will induce a 10% lethality in the mouse (LD10), if that dose is tolerated by the dog. The escalation scheme for clinical trials must be a compromise between the safety of the patient and quickly reaching biologically active doses. This may be achieved by using the so-called modified Fibonacci scheme. A slightly more rapid alternative is to increase the dose by 100% until the equivalent of the LD10 in the mouse is reached, and then by 50% until toxic effects are observed. Further dose increases depend on the type and severity of these toxic side-effects. Patients included in phase I clinical trials of anticancer agents must have histologically proven malignant disease that cannot be treated by conventional therapeutic modalities. They should have normal haematological, renal and hepatic functions and should be expected to live long enough to evaluate properly the toxic effects of the new compounds.(ABSTRACT TRUNCATED AT 250 WORDS)

Regional chemotherapy of maxillofacial malignant melanoma with intracarotid artery infusion of DTIC.

Six intracarotid artery infusions of DTIC were performed in 4 patients with invasive malignant melanoma of the maxillo-facial region. A total dose of 3.5 to 7 g was well tolerated. Only 1 patient who received 9.5 g in 25 days developed a reversible bone marrow depletion. Two out of the 4 patients presented a transient 50% tumor surface regression, but no response was seen after the second infusion. Of the 2 remaining patients, 1 had no measurable effect and 1 experienced tumor progression.

Hyperthermic isolation-perfusion with melphalan, a preliminary appraisal of local and general effects in malignant melanoma.

Ten hyperthermic isolation-perfusions with melphalan were performed for invasive malignant malenoma of the limbs. Four cases at stage II and with in transit metastases (up to 15 cm in diameter) had a complete regression. However, no improvement of survival was noticed: 4 out of 5 stage II patients who died, within 1 year after perfusion, developed a generalized disease. Systemic chemotherapy was administered in 3 patients after perfusion, but they died from distant metastases. The need for an adequate adjuvant treatment added to isolation perfusion is discussed.

[Medical decision in clinical oncology: the example of drug therapy of gastric cancer in the advanced stage during the last decade]. / La décision médicale en cancérologie clinique: l'exemple de la chimiothérapie du cancer gastrique à un stade avancé au cours de la dernière décennie.

The therapy of advanced stomach cancer is used to exemplify the clinicians' thoughts when confronted with the decision of adapting a standard treatment for a particular disease. This example shows that the different steps of clinical trials are not chosen on a rational basis and that the concern of rapidity may lead to untimely conclusions which force the clinician to set off useless therapeutic trials. We conclude that, unfortunately, the clinical practise in oncology remains to be largely improved.

[Cervical adenopathies of malignant lymphomas and especially Hodgkin's disease]. / Les adénopathies cervicales des lymphomes malins et en particulier de la maladie de Hodgkin.

Cervical lymph nodes are frequently involved in malignant lymphomas, especially in Hodgkin's disease. The surgeon who performs a lymph node biopsy should be aware of the technical problems concerning fixation, conservation, and transport of the surgical specimen in order to allow special immunologic and histochemical techniques, if there is a high degree of suspicion of malignant lymphoma. Staging laparotomy should be considered only if non invasive diagnostic methods have been non contributory and if the potential change in staging involves a change in treatment. Radiotherapy is the main part of the therapeutic strategy in stage I/II whereas chemotherapy is primarily considered for stage III/IV. Stage I/II, with B symptoms, with massive mediastinal involvement, and/or with a large number of nodal sites, may benefit from the combination of chemotherapy and radiotherapy. On the other hand, irradiation of residual disease after chemotherapy should be considered in disseminated disease.