Tyrosine kinase inhibitors and signal transduction modulators: Rationale and current status as chemopreventive agents for prostate cancer.

Cell growth and differentiation are processes intimately associated with carcinogenesis and regulated by tyrosine kinases and other signaling proteins. Identification of drugs that target signaling molecules is hampered by both the large number of targets and the complex nature of signaling cascades. Optimal development of chemopreventive agents must take into account affinity for the target, pharmacology, and safety profile of the agent. Validated biomarkers will allow the optimal implementation of chemopreventive trials. Directed epidemiologic studies can lead to the identification of lead compounds for chemoprevention, such as genistein. Therefore, agents targeted to pathways and molecules of known biological importance in the prostate hold the promise of clinical efficacy against prostate cancer in a chemopreventive setting.

Clinical strategy for the development of angiogenesis inhibitors.

Angiogenesis inhibitors differ from conventional cytotoxic chemotherapy agents by targeting normal cells rather than tumor cells, which may contain multiple mutations. Because of this, the traditional strategy used in clinical development of cytotoxic agents may not be appropriate for these novel agents. Many clinical studies are now evaluating these agents with a new approach, referred to as the cytostatic paradigm. The cornerstone of the cytostatic paradigm is the use of time to progression (TTP) of disease as the decision-making criterion for "go/no go" in the early phases of clinical development. However, the use of TTP as the main criterion for clinical trials is complicated for a variety of reasons, including: A) the lack of standardized criteria accepted by regulatory authorities; B) the heterogeneity of the historical database, and C) the larger number of patients needed for the "go/no go" decision-making process. In addition, clinical trials of cytotoxic agents have traditionally used objective response (despite the controversy regarding objective response as a surrogate for clinical activity) as the main criterion for determining whether the results of phase II studies justify the pivotal phase III studies. Another aspect of the clinical development strategy is combining angiogenesis inhibitors with cytotoxic chemotherapy. The rationale for combination of angiogenesis inhibitors with cytotoxic agents is based on: A) different targets for these agents; B) lack of cross-resistance patterns; C) lack of myelosuppression with angiogenesis inhibitors allows administration of full doses of all agents, and D) the assumption that combining these agents will result in additive antitumor activity. Combination therapy with angiogenesis inhibitors may be attractive to both clinicians and their patients because it allows cytostatic agents to be used upfront in treatment while contributing to drug registration strategy (cytostatic/cytotoxic combination therapy versus cytotoxic therapy). The clinical development of the angiogenesis inhibitor SU5416, a small molecule inhibitor of vascular endothelial growth factor, is currently ongoing. In phase I trials, SU5416 demonstrated activity in both colorectal and non-small-cell lung cancer patients. Based on these encouraging results, phase III studies to evaluate combination of SU5416 with established cytotoxic therapy are planned. These studies will include an interim analysis, the equivalent of a phase II evaluation of clinical activity. If successful, this strategic approach will save significant time in the clinical development process.

Clinical research and drug development of antivirals in HIV: an industry perspective.

Clinical research can be viewed from three perspectives: research, patient care, and regulatory. Clinical research strategies can be either drug oriented, following the traditional phase I-II-III flow, or disease oriented. The drug-oriented strategy has as its goal regulatory approval, which means widespread patient-care usage. The disease-oriented strategy focuses on improving the overall care of the disease in question. At times, a dynamic tension exists between the two strategies. In HIV, as in all diseases, industry mainly is involved in drug-oriented studies emphasizing the regulatory perspective. In HIV a critical issue involves accelerated approval, following expanded access, based on surrogate markers. This initial approval is for end-stage therapy (the expanded access population). Additional claims require a full supplemental New Drug Application utilizing clinical end points. This leads to a situation in which the label, over time, becomes less relevant to how the drug is used in actual practice. This has caused concern among the patient advocates and is becoming a major challenge for the industry.

Phase III trial of irradiation plus chemotherapy for patients with hepatic metastases and hepatoma: experience of the Northern California Oncology Group.

The effects of iv or intra-arterial chemotherapy added to hepatic irradiation were evaluated in a 3-arm randomized trial. Patients with predominantly hepatic metastases or with hepatoma were eligible. They were randomized to receive 2,100 cGy in seven fractions alone or with 5-fluorouracil given either intra-arterially or by iv infusion; doxorubicin and mitomycin were given by bolus simultaneously with the radiation in a single course. A total of 166 patients were entered in the study. Toxicity was acceptable, with no sign of enhanced radiation damage. Response was evaluated 4-6 weeks after treatment. No complete responses were seen, but partial responses greater than or equal to 50% were observed in the groups treated with radiation only (17%), radiation plus drug given iv (25%), and radiation plus drug given intra-arterially (20%) (P greater than .3). Disease progression occurred in a larger number of patients who received radiation only (29%) at 6 weeks than in the other 2 groups (7% and 18%, respectively; P less than .03). Thus, in terms of local response duration, the addition of chemotherapy enhanced the effect of the radiation. Survival was not different among the 3 groups.

Combined radiotherapy and chemotherapy with bleomycin and methotrexate for advanced inoperable head and neck cancer: update of a Northern California Oncology Group randomized trial.

Between 1978 and 1984, the Northern California Oncology Group (NCOG) conducted a randomized trial to study the efficacy of combined radiotherapy (RT) and chemotherapy (CT) for stage III or IV inoperable head and neck cancer. One hundred four patients were randomized to receive: (1) RT alone, or (2) RT plus CT. RT consisted of 7,000 cGy to the involved areas and 5,000 cGy to uninvolved neck at 180 cGy/fraction, five fractions/wk. CT consisted of bleomycin, 5 U intravenously (IV), twice weekly during RT, followed by bleomycin, 15 U IV, and methotrexate, 25 mg/m2 IV weekly for 16 weeks after completion of RT. Fifty-one patients in the RT alone group and 45 in the combined treatment group were evaluable. The local-regional complete response (CR) rate was 45% v 67% (P = .056); the 2-year local-regional control rate, including salvage surgery, was 26% v 64% (P = .001); and the incidence of distant metastasis was 24% v 38% (P greater than .25), for the RT alone and RT plus CT groups, respectively. The relapse-free survival curves were significantly different (P = .041), favoring the combined treatment. However, the survival curves were not significantly different (P = .16). Patient compliance to maintenance CT was poor. Bleomycin significantly increased the acute radiation mucositis, although the difference in late normal tissue toxicity was not statistically significant. Thus, bleomycin and concurrent RT produced a more favorable CR rate, local-regional control rate, and relapse-free survival, but the difference in survival was not statistically significant.

Calibrated phase II clinical trials in oncology.

This paper proposes the use of calibrated designs in phase II oncological clinical trials and evaluates their statistical properties in terms of power recovery and cost. A calibrated phase II design for a new cancer treatment for a specific tumour, e.g. colo-rectal, consists of random allocation of patients to receive either the investigational treatment or a standard treatment known to have activity at a certain level in phase II trials (e.g. 5 FU, expected response proportion = 0.20). Patients assigned to the standard treatment form the calibration group. The calibration group is not a control group in the traditional sense and one does not conduct a formal efficacy comparison between the investigational treatment group and the calibration group. Instead, one uses the calibration group to evaluate whether the sample of patients who receive the investigational treatment has the capability of showing a response. If the data do not support the hypothesis that the expected response proportion prevails in the calibration group, one declares the investigational group results suspect and recommends a second trial. Assuming acceptable results of the second trial, we use binomial calculations to find the effect of the calibration design on power recovery and relative cost. We show that when an unrepresentative sample occurs, calibration designs generally recover 90 per cent or more of nominal power at a cost of three to fivefold increase in sample size. We recommend for calibrated phase II trials a 'master protocol' approach in which several investigational treatment arms share one concurrent calibration group.

Cardiotoxicity of epirubicin and doxorubicin: assessment by endomyocardial biopsy.

Forty-two evaluable endomyocardial biopsies were obtained from 29 patients treated with epirubicin, the 4'-epimer of doxorubicin in cumulative doses ranging from 147 mg/m2 to 888 mg/m2. In this study of the Northern California Oncology Group, myofibrillar loss and sarcoplasmic vacuolization were identified and shown to be identical to those previously described for doxorubicin. However, when these biopsies were compared to 119 biopsies obtained from 98 patients treated with doxorubicin, milligram for milligram, epirubicin caused less endomyocardial injury than doxorubicin (P = 0.0013). Age, sex, type of primary malignancy, prior cardiac disease, and hypertension did not influence the degree of histologically demonstrated anthracycline injury induced by epirubicin.

Adjuvant chemotherapy of cancer. A review of its current status.

Adjuvant chemotherapy can be defined as the use of drugs immediately after local control therapy to attempt eradication of residual micrometastatic disease. Conceptually, the micrometastatic disease is presumed to be outside the field of surgical excision or the area of curative intent of radiation therapy. Adjuvant chemotherapy designed to eradicate established micrometastases is a relatively new area of clinical research which began to be seriously considered in the late 1960s and reached a peak of enthusiasm a decade later. However, the early promise of adjuvant chemotherapy has not been fulfilled and the entire concept, and its biological underpinnings, are now under re-evaluation. This review considers the biological rationale for adjuvant chemotherapy and the current status of the large-scale clinical trial data base which now exists in 4 major diseases: breast cancer, osteogenic sarcoma, large bowel cancer, and gastric cancer.

A randomized study of doxorubicin versus doxorubicin plus cisplatin in endocrine-unresponsive metastatic prostatic carcinoma.

Thirty-seven patients with hormonally refractory prostatic carcinoma entered a randomized trial comparing doxorubicin and doxorubicin plus cisplatin. All patients had failed prior hormonal treatment. Mean Karnofsky performance status (76% doxorubicin versus 75% combination), percent of patients with prior palliative irradiation (40% doxorubicin versus 35% combination), and hemoglobin levels of less than or equal to 12 g/dl (30% doxorubicin versus 24% combination) were roughly equivalent in the two treatment groups. More patients treated with doxorubicin than the combination treatment had an elevated acid phosphatase level at study entry (90% versus 65%). Measurable bidimensional tumors were present in 13 patients in 16 sites in the doxorubicin arm and in 10 patients in 11 sites in the combination arm. Partial responses were seen in 1 of 13 patients in the doxorubicin arm and 2 (20%) of 10 patients in the combination arm. Improvement in Karnofsky performance status of 20% or greater was rarely observed with either treatment (7% doxorubicin versus 8% combination). Acid phosphatase levels normalized or improved by 50% in 39% of patients who received doxorubicin and 27% of patients who received the combination. The overall response rate by National Prostatic Cancer Project Criteria was 53% for doxorubicin and 59% for doxorubicin plus cisplatin. Myelotoxicity and gastrointestinal toxicity were severe, particularly in the combination arm, and required discontinuation of treatment in some patients who responded to treatment. Moderate renal dysfunction (creatinine value 2.0-3.0 mg/dl) occurred only in the combination arm at an incidence of 23%. Time to progression and survival were similar for the two treatment groups. In this small group of 37 patients, the combination of cisplatin and doxorubicin showed no improvement over doxorubicin alone in response, response duration, or survival, and was difficult to administer in this patient population.

Carboplatin: the clinical spectrum to date.

The existing literature data base on carboplatin updated to June, 1985 has been reviewed. The compound seems to retain the same spectrum of activity as cisplatin, and a definite set of efficacy data is available for ovarian cancer of epithelial origin, small cell carcinoma of the lung and epidermoid carcinoma of the head and neck. A yet unpublished toxicity data base on carboplatin suggests that the compound has an improved therapeutic index over the parent compound, cisplatin, and that it does not seem inferior to another platinum coordination compound currently in clinical trials, iproplatin.