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While complete remission may be achieved in 65% of adults with de novo AML, such remissions lack durability when conventional post-remission therapy is administered. Uncontrolled trials have suggested that intensive post-remission therapy may prolong these responses. To assess this concept, the Cancer and Leukemia Group B administered induction therapy (cytarabine and daunoribucin) to 1088 adults (median age: 52 years). Of these 1088 patients, 693 (64%) achieved complete remission of whom 596 were randomly assigned to receive four courses of single-agent cytarabine in one of three dose schedules: 3 gm/m2 in a 3-h infusion every 12 h x 2 on days 1, 3, and 5 (HiDAc; 187 patients); 400 mg/m2 per day x 5 days continuous infusion (206 patients); or 100 mg/m2 per day x 5 days continuous infusion (203 patients). All patients then received four courses of monthly maintenance treatment. After a median follow-up time of 63.5 months, the three treatment cohorts had significantly different disease-free survivals (p = 0.001). The probability of remaining in continuous complete remission after 5 years for patients 60 years of age or younger was 42% for HiDAc, 29% for 400 mg/m2, and 19% for 100 mg/m2 (p = 0.0007). In contrast, for patients older than age 60 years, the probability of continuous complete remission after 4 years was 14% or less in each of the three cytarabine groups. With further maturation of the data, the outcome of this trial continues to support the concept of a doseresponse effect for cytarabine in patients with AML and 60 years of age or younger. The results observed with the HiDAc dose schedule in this age group are similar to those reported in patients with AML who undergo allogeneic or autologous bone marrow transplantation during first remission.

In 1891 Brown-Sequard attempted to augment human bone marrow orally [1]. Over the next five decades allogeneic marrow was administered intramuscularly [2] and by intramedullary injection [3], before the intravenous route was found to be optimal in 1939 [4]. Between 1945 and 1965 the effects of total body radiotherapy were studied and the immunocompatibility complex was identified. The first series of patients transplanted for relapsed leukemia and aplastic anemia was published in 1968 [5]. In 1977, Thomas and colleagues in Seattle reported that 13 of 100 patients with relapsed acute leukemia at the time of transplant were disease free 1–4.5 years later [6]. Today more than half of acute myelogenous leukemia patients transplanted during first remission with HLA-matched sibling donor marrow are now cured [7–8]. Substantial gains made in the prevention of graft-versus-host disease and in supportive care (platelet transfusions and a wider variety of effective antibiotics) have considerably decreased the risks of high dose therapy.

Optimum treatment for osteogenic sarcoma involves a rapid definitive attack upon the primary tumor and systemic treatment to destroy pulmonary metastases [2, 4, 5, 6, 10, 11, 13, 14, 16]. Traditionally, the first objective is attempted by amputation, although radiation therapy has also been employed [1]. The latter, however, has not met with universal approval since osteogenic sarcoma is generally considered a radioresistant tumor, and retention of an uninhibited source of metastases is contrary to sound principles of cancer management. Not infrequently, tumor growth after irradiation required amputation for palliation [9].

Thirty years ago, chemotherapy had little to offer patients with solid tumors and in general patients were treated after failure of surgery or radiotherapy when advanced overt metastatic disease was already present. As progress was made in the chemotherapy of the childhood solid tumors, and of certain adult tumors, such as metastatic breast cancer, the investigation of chemotherapy in the adjuvant situation developed. This was stimulated by the fact that, for example, patients with stage II breast cancer or osteogenic sarcoma are at high risk of having micrometastatic dissemination at the time of diagnosis, so that potentially definitive treatment must include not only control of the primary with surgery and/ or radiotherapy (S/R), but also systemic chemotherapy (C), the latter to control disseminated micrometastatic disease. The experimental basis for this was the observation that chemotherapy for in vivo transplanted tumors was capable of cytoeradication (cure) in inverse relationship to the tumor burden. Thus chemotherapy which produced only partial regression of advanced tumor was frequently curative when applied to the same tumor in microscopic form (Goldin et al. 1956). This was also demonstrated in experimental in vivo systems, wherein the primary in the extremity was controlled by amputation, following which the cure rate could be increased in many circumstances by chemotherapy addressed to micrometastatic disease (Skipper 1978).

During the past decade, the combination of an anthracycline and continuous infusion cytosine arabinoside chemotherapy has been associated with an increase in the complete response rate of patients under age 60 having acute myelocytic leukemia (AML) from 35%-55% (Carey et al. 1975; Clarkson et al. 1975) to approximately 75% (Evans et al. 1975; Gale 1979; Haghbin et al. 1977; Preisler et al. 1979; Rees and Hayhoe 1978; Yates et al. 1973). This encouraging advance, however, has not led to prolonged periods of remission and indefinite survival as seen in childhood acute lymphocytic leukemia. The median duration of complete remission in most recent studies in AML is in the range of 12-14 months (Armitage and Burns 1976; Evans et al. 1975; Haghbin et al. 1977; Moreno et al. 1977; Peterson and Bloomfield 1977; Preisler et al. 1979; Rees and Hayhoe 1978; Spiers et al. 1977). In early 1976 a therapeutic program (VAPA 10 protocol) was initiated in an attempt to overcome the causes of relapse in patients with AML. It was postulated that the high failure rate in AML patients in complete remission might be the result of inadequate cytoreduction during the maintenance period, the development of drug resistance, the presence of “sanctuaries” into which effective chemotherapy could not penetrate, and the presence of a mutant myeloid progenitor cell which over a period of time would progressively replace or even suppress the growth of the differentiated product of normal hematopoiesis. It was appreciated that if the latter possibility were true, it would be unlikely that intensive chemotherapy would have any longterm beneficial effect in patients with AML and that the only rational therapeutic option would be replacement of these progenitor cells through a maneuver such as bone marrow transplantion. Others are presently testing the utility of marrow transplantation in patients with AML shortly after complete remission is obtained (Blume et al. 1980; Powles et al. 1980; Thomas et al. 1979).

Preclinical experimental models of dose response in breast cancer will be presented. Dose response differs according to the agent. For example, for the alkylating agents drug resistance is generally difficult to produce experimentally, and a steep dose-response curve both in vitro and in vivo is maintained through multiple logs of cell kill (Frei et al. 1985, Frei et al., in press; Teicher et al. 1986). In contrast using nonalkylating agents, drug resistance of a high degree can be produced readily. Related to this is the fact that fractional cytoreduction is progressively compromised with increasing doses through a multilog cell kill model. In this regard, the alkylating agents more closely resemble radiotherapy. The lack of cross-resistance among the alkylating agents in both in vitro and in vivo models has important implications for clinical treatment strategies (Frei et al. 1985; Frei et al., in press; Teicher et al. 1986).

The preclinical and clinical data for the adriamycin analog (AD 32) will be reviewed and compared to adriamycin. Emphasis will be placed on demonstrated biologic differences that may make AD 32 the better compound for clinical use.

Major progress in the treatment of acute myelogenous leukemia (AML) has occurred during the past decade. Advances in chemotherapy and supportive care have been associated with an increase in the complete remission rate of patients under the age of 60 with AML from 35%–55% [5, 7] to approximately 75% [2, 9, 16]. More importantly, the median duration of complete remission and the percentage of patients in long-term continuous complete remission has steadily improved. This has resulted from postinduction combination chemotherapy [10, 13, 18, 20] or chemoradiotherapy and transplantation of marrow from histocompatible siblings [4, 15, 21]. In 1976 the VAPA protocol was initiated to specifically improve the duration of complete remission for children and adults (< 50 years) with AML. In 1980 we reported encouraging results obtained with this approach [12, 22], and this report is an update of the study.

There is increasing emphasis on cytokinetic studies as a basis for constructing treatment programs for cancer. In the present study various pretreatment cytokinetic factors were analyzed with respect to their correlation with response to treatment and prognosis.

There are four basic parameters for evaluating objective response to chemotherapy. These are listed on the ordinate of Fig. 1. Remission induction consists of the initial period of chemotherapy and is generally continued until maximum tumor regression has occurred. Remission duration is divided into “unmaintained remisssion” and “maintained remission”. The former is the remission duration after remission induction therapy has been discontinued and the latter (maintained remission) is defined as the duration of remission when antitumor agent therapy is continued during remission. The ultimate parameter is survival and this, of course, is the major parameter for the evaluation of potentially curative therapy.