NCI monographs : a publication of the National Cancer Institute最新文献

Definitive radiation therapy was administered to 577 patients with histologically confirmed carcinoma of the prostate localized to the pelvis between January 1967 and December 1983. All patients were available for a minimal 3-year follow-up, and the median period of observation is 6.5 years. The actuarial survival without tumor in stages A2 and B at 5 years was 78% and at 10 years 60%. In stage C, the corresponding survival figures were 60% at 5 and 40% at 10 years. The overall actuarial survival in stage B patients was 76% at 5 and 56% at 10 years, which is similar to the life expectancy of a comparable cohort of normal males. In stage C, the actuarial survival was 65% at 5 and 35% at 10 years. The pelvic failure rate in stage A2 was 12% (5 of 41), 17% in stage B (31 of 185), 28% (93 of 328) in stage C, and 48% (11 of 23) in stage D1. Distant metastases were noted in 12% of the patients with stage A2, 20% stage B, 42% stage C, and 65% stage D1. In stage B, patients who had control of the pelvic tumor exhibited an 85% actuarial 5-year survival and a 60% one at 10 years. This compares with an actuarial survival of 30% at 5 and 10 years when there was evidence of pelvic recurrence alone or combined with distant metastases. In stage C patients with pelvic tumor control, actuarial survival was 81% at 5 and 50% at 10 years, in comparison with 25% at 5 and 10% at 10 years when there was development of pelvic recurrence or distant metastases or a combination of both. There was a strong correlation between the survival and appearance of distant metastases with the histologic degree of differentiation of the tumor in all stages. However, the probability of tumor control in the pelvis was not significantly correlated with this parameter. The administration of hormones concomitantly with radiation therapy did not significantly influence the probability of tumor control, appearance of distant metastases, or survival. Major sequelae of therapy were noted in 2.2% of the patients, whereas minor sequelae were observed in approximately 12% of the patients. Radiation therapy has been shown to be an effective therapeutic alternative to radical prostatectomy or hormonal manipulation in patients with carcinoma of the prostate.

The objectives of our retrospective long-term analysis of radical prostatectomy at The Johns Hopkins Hospital are to determine the efficacy of radical prostatectomy and the optimal statistical method for ascertaining survival following therapeutic intervention for men with clinically localized prostate cancer. The duration of survival and the cause of death were ascertained for 57 men with clinical stage B1 prostate cancer who had radical prostatectomies at The Johns Hopkins Hospital between 1951 and 1963. The absence of metastatic disease was determined by radiographic survey of the bones only. The survival curve determined by the direct method was virtually identical to the projected survival curve for a 62-year-old man in 1960. The cause-specific actuarial survival analysis indicated that only 14% of the men with stage B1 disease and a 15-year life expectancy will develop metastatic prostate cancer following radical prostatectomy. The cause-specific survival curve plateaued after 10 years, which indicated that the majority of men surviving 10 years free of disease are cured of the disease. Survival analysis was also determined by the direct method for 48 men with clinical stage B2 prostate cancer who had undergone radical prostatectomy between 1951 and 1963. Overall, the survival rates for these men were considerably lower than those for similarly treated men with clinical stage B1 disease. The survival curves following radical prostatectomy for men with stage B1 disease and clinical stage B2 disease pathologically confined to the prostate were similar. Radical prostatectomy for stage B1 disease was performed with minimal morbidity, and potency was preserved in most patients with the use of nerve-sparing modifications.(ABSTRACT TRUNCATED AT 250 WORDS)

Our purpose of this study was to determine whether whole-body, continuous low-dose-rate irradiation (CLDRI) alters the plasma and/or tumor platinum pharmacokinetics after ip bolus injection or ip infusion as a possible mechanism of interaction between CLDRI and cisplatin. The C3Hf/Sed mice bearing SCCVII/SF tumors were given 6 mg cisplatin/kg ip by bolus injection or an ip infusion of 0.25 mg cisplatin.kg-1.hour-1 for 48 hours with and without CLDRI at 0.56 Gy/hr for 24 or 48 hours. Plasma and tumor platinum concentrations were determined with an atomic absorption spectrophotometer at appropriate intervals during infusion and up to 48 hours after drug administration. Both total and ultrafilterable plasma platinum followed a biphasic elimination after ip bolus injection, whereas only a prolonged single-phase elimination was seen after ip infusion. Tumor uptake of platinum appeared to follow a passive diffusion pattern with a prolonged cellular retention of platinum. Whole-body CLDRI had no apparent effect on the pharmacokinetics of plasma and tumor platinum administered by ip bolus injection or prolonged continuous infusion.

The combination of radiotherapy and chemotherapy is aimed at improving local control and eradicating distant metastases by using cytostatic drugs as radiosensitizing or independent cell-killing agents. This approach has been successful in some areas but has failed in a large number of trials. The failure can be attributed to biologic and clinical factors; the low drug uptake in the tumor is one of the most limiting factors. New approaches should therefore include the improvement of drug targeting and the use of predictive assays; these efforts should proceed with the performance of pharmacokinetic studies and experiments testing the effects of combined treatment on tumors and normal tissues. Pharmacokinetic studies should include measurement of the intracellular drug uptake, preferably at the target. This is now possible for cisplatin; DNA adducts induced by this drug can now be measured with an immunocytochemical technique. The experimental animal studies should include testing of the effects of fractionated irradiation with drugs on tumors and on early- and late-responding normal tissues.

DNA damage and repair were assessed by alkaline sucrose gradients in the nonstimulated circulating mononuclear cells of 7 patients receiving high-dose cyclophosphamide (HDCy) and fractionated whole-body irradiation. Measurable damage produced by HDCy appeared to be repaired in about 60 hours. Damage from a radiation dose of 2 Gy was not completely repaired within 24 hours because DNA molecular weight was found to be decreased by an average of 22%. We attempted to assess the impact of HDCy on radiation damage repair by comparing blood irradiated and incubated in vitro before therapy with in vivo incubation following HDCy administration. Two hours after a radiation dose, repair appeared increased following HDCy. These results suggest the possibility that significant interaction at the DNA level may occur when HDCy and irradiation are administered together.

The effectiveness of fractionated total body irradiation (TBI) in treatment of non-Hodgkin's lymphoma is limited by bone marrow toxicity. Because WR-2721 effectively protects bone marrow, we tested its potential in treatment of I-347 lymphoma in BALB/c mice, using various single and fractionated TBI regimens. In most treatment schedules, WR-2721 did not cause net lymphoma protection; in fact, it was cytotoxic. Lymphoma regrowth delay times for the 21 treatment groups were quite effectively fitted by a mathematical model with three components: 1) a dose-dependent radiation effect; 2) a small radioprotective effect by WR-2721; and 3) significant cytotoxicity of WR-2721. Bone marrow radioprotection was reduced when TBI was fractionated, but there was no evidence of WR-2721 cytotoxicity to marrow. The therapeutic gain due to WR-2721 was 2.5 for the five-fraction regimen, compared to 2.3 for a single fraction. The cumulative WR-2721 toxicity to lymphoma combined with marrow protection suggests that WR-2721 could increase the clinical therapeutic ratio of TBI, particularly fractionated TBI, in treatment of lymphoma.

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.

Cells of three human tumors irradiated in situ in athymic nude mice are more radioresistant at all doses than are corresponding cells irradiated in vitro. The tumors investigated were Na11 melanoma and two colorectal adenocarcinomas, HRT18 and HT29. While the Na11 tumor contains an exceptionally large hypoxic fraction, this is not true for the other two tumors, and other mechanisms have been proposed to explain these findings. Results of experiments described here suggest that the effect is not dependent on intercellular contact or on the age distribution of the cells in vivo. Tumor cells irradiated in situ were sensitized by both high-pressure oxygen and misonidazole, and the effect of the two agents together was greater than that of either used alone. It is concluded from the shape of the survival curve and from the response to high-pressure oxygen and/or misonidazole that the tumor cell population contains cells ranging from acutely hypoxic to fully oxygenated and includes a subpopulation of partially hypoxic cells of intermediate radiosensitivity.

Five squamous cell carcinomas were induced in the lungs of WAG/Rij rats by radiation emitted from isotopes iridium-192 or iodine-125. Tumor fragments were transplanted subcutaneously in syngeneic hosts for propagation of the tumors. A lung cancer model based on implantation of tumor fragments in the lung has been developed. Tumor implants in the lung grew into large invasive squamous cell carcinomas. Metastases in the renal cortex were frequently observed. Tumor growth was determined from repeated chest radiographs. Volume changes after cytostatic treatment could be monitored accurately up to several months. Squamous cell carcinomas transplanted subcutaneously responded as heterogeneously to a variety of cytostatic drugs as did their human counterparts. Responses of the tumor line L17 to doxorubicin were similar when tumors were growing intrapulmonarily or subcutaneously. However, the response of L33 tumors to cisplatin was different, depending on the location. The tumors growing in the lungs provide a model for realistic testing of regimens involving radiation doses, cytostatic drugs, and combinations thereof.

The interaction of doxorubicin and radiation has been systematically studied in the Dunning R3327G prostatic adenocarcinoma, the preeminent animal model for human prostatic cancer. Subcutaneous tumors (produced by injection of 10(7) cells) were treated when about 1 cm3 in volume (19-22 days postimplant). Each modality was used at 1 of 3 dose levels; 2, 4, and 9 mg/kg for doxorubicin; and 5, 15, and 25 Gy for radiation. Single treatment with each agent was combined, in both sequences and five delay times (0.5, 12, 24, 48, and 120 hr) between agents. Growth of individual tumors was fit to a quadratic exponential growth model which was solved for the growth delay and growth rate at twice initial volume. Analysis of variance identified significant interactions for doxorubicin and radiation (due to drug toxicity), sequence and delay, and sequence and radiation, in addition to the four factors individually. The effect on the tumor of combined doxorubicin and radiation is basically additive. Sequence and delay are important in overall tumor control.