Circadian rhythms characterize murine tolerance for 18 anticancer agents, including radiations and chemotherapeutic drugs. Such rhythms usually exhibit a large amplitude. Moreover, the circadian time of highest host tolerance for several cytostatics was similar to that of their optimal antitumor effectiveness in four different experimental models. Mechanisms of such rhythms involve predictable temporal changes in drug pharmacokinetics as well as rhythms in the susceptibility of both tumor and host tissues. Studies performed in mice or rats led to an adequate prediction of the optimal time to administer adriamycin, 4'tetrahydropyranyl-adriamycin and cis-dichlorodiammine platinum, provided that the rest-activity cycle of either species be considered. Since the dosing time of these agents also influenced largely the extent of human tolerance for these drugs, the extension of circadian timed therapy appears as inescapable. Programmable delivery systems have been developed to render such goal feasible, and their need has been emphasized in preliminary studies. Since interindividual differences may characterize, to some extent, host chronotolerance, and to a larger extent, tumor chronosusceptibility, a circadian monitoring of marker variables ("marker rhythms") constitutes a further challenge for individualizing cancer chronotherapy.

Control of anti-cancer chemotherapeutic management is facilitated by the use of micro-computers. The authors have devised a program in which are entered, as separate records, all data required concerning the patient, the drugs administered, the therapeutic regimens and the controls to be applied during treatment. The computer commands appointments, examinations to be performed, prescriptions and protocols, making all the calculations needed and taking into account those data which restrict the use of drugs. At the end of each course, each record is updated by entering control parameters and new events, so that a detailed history of all the treatments received by all patients is obtained. This last record can be used for statistical purposes and to test compliance with, and response to treatment. The program, produced and distributed by a data-processing service firm, can be used with various micro-computers. It is available to medical groups interested in the treatment of cancer.

In a phase I-II trial, 38 patients with acute myeloid leukemia (AML) were given single drug induction therapy with aclarubicin (ACM) according to two dosing schedules: treatment 1: 10 to 30 mg/m2/d to a maximum total dose of 300 mg/m2 or until development of unacceptable toxicity: treatment 2: 15 mg/m2/d in ten-day courses separated by ten-day intervals. Response rates were 15% with treatment 1 and 44% with treatment 2 (overall response rate 34%). Complete remission (CR) was achieved in 6 patients who had previously failed to respond to adriamycin (ADM). Toxicity was more frequent and more severe in those patients given more than 150 mg/m2 ACM per course. The main side effects were oropharyngeal mucositis and diarrhea. Three patients exhibited T wave inversion and one had an episode of auricular flutter. In a separate trial in 16 patients with AML we used cyclic chemotherapy combining ACM (20 mg/m2/d) and ARA-C (200 mg/m2/d) for seven consecutive days. Complete remission rate was 50%. Severe ventricular rhythm disorders were seen in two patients. In a phase I-II study, 19 patients with acute lymphoid leukemia (ALL) and 8 patients with non-Hodgkin lymphoma (NHL) were given ACM alone according to the regimen designated treatment 1 described above. Response rates were 11% (2/19) in ALL and 25% (2/8) in NHL. A review of the literature is presented in the discussion of the original trials reported herein.

Association between radiotherapy and anthracyclines (especially adriamycin) early showed major toxicity on critical normal tissues so that its antitumor activity was concealed. This toxicity proved to be acute toxicity, recall phenomenon and cardiac toxicity. Clinical and experimental studies showed synergistic effect when drug and radiation are administered concomitantly and additive effect in sequential administration. So concomitant association must be rejected. The main point is the time interval between adriamycin injection and radiotherapy (at least seven days). These conditions are respected when alternating treatment schedule is applied: radiation split courses are integrated between two chemotherapy cycles including adriamycin. At this time new anthracycline analogs were not associated to radiotherapy.

Since the first discovery of antitumor properties of daunorubicin in 1962, several hundreds of anthracyclines have been evaluated. In 1969, the primary screening on L1210 leukemia allowed to detect doxorubicin which is more active than daunorubicin and has been found clinically active on several human solid tumors. Therefore, L1210 leukemia appeared to be a useful model for evaluating experimental antitumor activity of anthracyclines, indicating a possible correlation between this model and the clinic. Analogs which are equally or more active than doxorubicin in the primary screening are tested in the secondary screening, then eventually in models of cardiotoxicity in order to evaluate their therapeutic index. The secondary screening includes murine solid tumors (B16 melanoma, Lewis lung carcinoma, mammary adenocarcinomas, colon adenocarcinomas 26 and 38) and human tumor xenografts into nude mice or under the renal capsule of normal mice (LX1, lung - CX1, colon - MX1, breast). Various tumor localizations (i.p., i.v., s.c., i.m., i.c.), various routes of administration (mainly i.v. and p.o.), various schedules of treatment (early or delayed, repeated or intermittent) and models of polychemotherapy are used to obtain a better evaluation of the compound. P388 leukemia resistant to doxorubicin is useful to test cross resistance in vivo and also to screen compounds able to reverse this phenomenon. Until now, 17 new anthracyclines have been introduced into clinical trials. Aclacinomycin has a different mechanism of action from that of doxorubicin (induction of tumor cell differentiation, inhibition of B and T suppressor lymphocytes); it is less myelotoxic and it is not mutagenic in vitro. THP-doxorubicin is more active than doxorubicin against L1210 leukemia and some solid tumors; it seems less cardiotoxic.(ABSTRACT TRUNCATED AT 250 WORDS)

The rate of the anthracycline uptake and retention differs with the drug structure and with the cell type. Here we present evidence to show that as compared to carcinoma cells, normal epithelial cells are naturally resistant to adriamycin. Moreover, it is shown that uptake of demethoxy-daunorubicin and THP-ADM is a very rapid process as compared to ADM, epi-ADM or DNR. Cytotoxicity correlates with the intracellular concentration. The relevance of these in vitro findings is considered in the in vivo situation. Resistance to anthracyclines is in part related to decrease accumulation and retention. This resistance can be reversed not only by calcium transport and calmodulin inhibitors but also by co-treatment with aclacinomycin. Wether changes which occurred in acquired resistance can be found in cells with natural resistance to adriamycin remain to be determined.

With loco-regional chemotherapy high local concentration of antineoplastic products can be achieved without systemic toxicity. However local toxicity and technical problems are frequent and limit its use. Intra arterial chemotherapy (IAC) is interesting when the drugs used have a high total body clearance. One of the best indication of IAC is the intra-hepatic chemotherapy with anthracyclin for hepatocellularcarcinoma (40-60% objective response) and metastatic carcinoid. Among other IAC the IA limbs perfusions for soft tissue sarcoma have given interesting results. Chemoembolization with lipiodol and/or gelfoam mixed with anthracyclin is an interesting field of investigation in liver tumor and metastases. Intraperitoneal chemotherapy is used essentially for peritoneal carcinomatosis from ovarian origin and gives some positive results. However, intra peritoneal Adriamycin is not well tolerated and other anthracyclines are to be investigated.

In haematology, randomized clinical trials often use survival or disease-free interval as response criterion (censored data). For ethical reasons, interim analyses are usually performed, but these interim analyses lead to an increasing Type I error. Sequential methods allow for repeated testing. Three sequential methods are well-adapted to censored data: group sequential analysis, the sequential probability ratio test and the triangular test. The triangular test has the best properties: it allows an early termination of the trial whatever the difference between the treatment groups and without the risk of long duration trials. Sequential analyses can be performed at the same frequency as the usual interim analyses. These three sequential procedures have been applied to the analysis of two cooperative trials in haematology. It appears that the use of sequential methods has to be recommended in the design of randomized clinical trials with a censored response criterion.

A total of 91 patients with acute monoblastic leukemia (AML) were treated following two induction regimens (ARA-C + RBZ, with of without CPA), and a unique maintenance therapy (CNS prophylaxis and reinductions every 6 weeks, for 36 months). Complete remission (CR) was obtained in 84% of patients. The only prognostic factor significantly influencing the CR rate was age, with 92% for the less than 40 years group and 75% for the greater than or equal to 40 years group. CR was not influenced by sex, tumoral syndrome, leukocytosis, cytological subclassification (M5A, M5B), or induction regimen with or without CPA. The duration of CR in these forms which have a traditionally poor prognosis, was no different from other forms of AML (21 months), and the disease-free survival at 50 months was 45%. These results, pertaining to the largest published series treated by the same protocol, are the best reported in literature and confirm the role of induction and maintenance therapy in CR.

Surgical treatment of skin ulcers from extravasation of chemotherapeutic agents produces a chronic ulcer. The origin of the disease and the techniques of wide local excision and of skin cover are discussed.

Thirty-one totally implantable venous access system were investigated in patients who required intravenous administration of chemotherapy, drugs, nutrients solutions, blood products and blood sampling. Mean duration of venous access was 179 days (ranged from 9 to 429 days). Eight complications were observed, five benign without consequence on port system use, three severe (infections) requiring its removal. No death occurred during implantation and port system use. Patient acceptance was better than with other methods for repeated vascular access. In patients requiring prolonged chemotherapy, totally implantable venous access systems represent a new technique of long term venous access, with easy implantation and lack of restriction of daily activities. Review of literature show that complications are most frequently local and easy to manage. Four types of complications may have severe consequences for patient and/or port system use: catheter occlusion, venous thrombosis, local and/or general infection, and skin necrosis subsequent or not to extravasation. They represent the major cause of port system removal, but this is seldom necessary. Acquired experience allow to justify an earlier implantation of totally implantable venous access systems before chemotherapy and destruction of available surface vessels.