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

Thirty-six patients with advanced unresectable carcinoma of the head and neck were treated with a combination of three courses of chemotherapy and low doses of radiation, followed after 3 weeks by definitive irradiation. Each course was repeated every 3 weeks with the following sequence. Cisplatin (20 mg/m2) was given in a 20-minute infusion, followed by a 2-hour infusion of 5-fluorouracil (400mg/m2), on days 1,2,5, and 6. Low doses of radiation were given on days 3 and 4, followed by a 2-hour infusion of 5-fluorouracil (400 mg/m2) with a dose of 3 Gy on the target volume. For definitive irradiation, a total dose of 60 Gy was delivered in 30 fractions within 6 weeks. The complete response rate reached 30%, and the partial response rate was 30%. With a median follow-up of 11 months, median overall survival was 10 months; median survival was 21 months for patients with complete response, 9 months for patients with partial response, and 6 months for those with no response (P=.02).

The important chemotherapeutic agent cisplatin is currently being combined with radiation therapy (RT) in clinical protocols intended to exploit the potential for this drug to potentiate radiation-induced tumor cell kill. This paper reviews the reports from preclinical studies leading to the design of combined modality protocols and describes the effects produced when platinum complexes are combined with RT. Two interactions that are receiving considerable attention since they might produce an improved therapeutic ratio are the radiosensitization of hypoxic cells and post-RT potentiation of cell kill. This latter effect might include the inhibition of recovery from RT-induced potentially lethal or sublethal damage. However, platinum-radiation interactions are complex and probably include several mechanisms that are unknown at this time. The potential for platinum complexes will be especially promising if results of ongoing phase III combined modality trials show them to be efficacious, since it is unlikely that current protocol designs are optimal. Furthermore, second-generation platinum analogs or other metal complexes designed as potentiators of RT may prove to be more interactive with RT.

Cisplatin was administered as a single iv dose of 5 mg/kg in WAG/Rij female rats at intervals of 7 days or 30 minutes before or 7 days after graded irradiation of the left kidney. The unirradiated right kidney was removed 4 weeks after the x-ray treatment. Kidney function was determined by measuring urine osmolality and plasma urea. The kidney function parameters did not change measurably in animals treated with cisplatin alone. Only differences in urine osmolality were observed between the groups that received combined treatment or irradiation only. Long-term renal fibrosis was assessed by measuring the hydroxyproline content. Significant increases in renal hydroxyproline content were observed in animals receiving treatment with cisplatin either 7 days before or 7 days after irradiation, compared with animals receiving irradiation alone.

Spirogermanium (SPG) was investigated in the 9L rat brain tumor model in vivo and in vitro. Used at a single ip dose of 50 or 60 mg/kg or at 5 daily doses of 10 mg/kg, SPG was ineffective in prolonging survival of rats burdened with the intracerebrally implanted tumor, i.e., the median survival time (MST) was the same as that for the controls. Only a schedule of 3 X 20 mg SPG/kg every other day improved the MST compared with controls. Single-dose (20-Gy) radiation therapy (RT, cesium-137 whole-head irradiation) did prolong survival. However, when single-dose SPG was combined with RT (1 hr or 1 day before, or 1 hr after RT), the survival response was worse than after RT alone. When the daily SPG was combined with daily RT (5 doses of 6 Gy), survival was no better than after daily RT alone. In vitro, SPG produces a concentration-dependent, exponential decrease in cell survival as measured by colony formation assay. When combined with radiation, there is an additive effect on cell lethality. Aside from the possibility that SPG does not penetrate the rat brain tumor itself, we have no explanation why SPG shows some activity against human brain tumors and is cytotoxic against 9L cells in vitro, yet is both ineffective by itself and fails to potentiate RT in the 9L rat brain tumor model.

Thirty-three second cancers, excluding basal cell carcinomas of skin and in situ carcinomas of the cervix uteri, were observed among 1,084 patients in first complete remission from Hodgkin's disease treated from 1964 to 1981 by the Lymphoma Group of the European Organization for Research and Treatment of Cancer and the Groupe Pierre et Marie Curie. Five of these second cancers were acute nonlymphocytic leukemias (ANLL), and five were non-Hodgkin's lymphomas (NHL). The 15-year cumulative proportion was 7.6% for second cancers; 0.7% for ANLL; and 1.2% for NHL. For solid tumors (ST) occurring in a previously irradiated area, it was 1.0% after regional radiotherapy (RT); after extended-field RT, it was 8.2% (P = .009). The relative risk (RR) of ANLL after combined chemotherapy with mechlorethamine, vincristine, procarbazine, and prednisone plus RT (relative to the general population incidence rates) was 39 (P less than .001) during the first 4-year period; it was not significantly increased in patients treated by RT without combined chemotherapy. Similar RR was observed for NHL (RR = 31; P less than .001). Moreover, an increased RR of NHL (RR = 53; P less than .001) was observed in patients treated by RT without combined chemotherapy after 10 years. For ST, no significant increased risk was observed regardless of the treatment. There is, however, a slight tendency for the risk of ST related to extended-field RT to increase after 10 years.

We have been using the 9L rat brain tumor model to investigate the effect of the combination of a perfluorochemical emulsion, Fluosol-DA 20%, and carbogen breathing on the therapy of brain tumors. The combination of Fluosol, carbogen breathing, and carmustine (BCNU) was more effective at prolonging survival than was BCNU alone. This difference was small but significant (P less than 0.25). neither Fluosol without carbogen nor carbogen without Fluosol significantly altered the effect of BCNU. Fluosol and carbogen alone did not affect the survival of tumor-burdened rats. Fluosol and carbogen breathing did not alter the effect of single doses of radiation on these tumors. This result supports the hypothesis that 9L brain tumors contain few, if any, critical hypoxic cells. However, these tumors may contain cells which are oxygen deficient but not radiobiologically hypoxic. The Fluosol-carbogen combination may be changing the intratumor environment in such a way that the metabolism or activity of BCNU is altered.

Limited clinical stage C (T3 NX M0) disease can be treated surgically, and morbidity can be acceptable. When appropriate adjuvant therapy (orchiectomy and/or radiation) is administered, residual cancer can be controlled locally for at least a limited period. The incidence of local progression in pathologic stage C or D1 disease may be negligible after early adjuvant orchiectomy and/or radiation treatment. The combination of immediate orchiectomy and radical prostatectomy has been shown to limit progression significantly (P = .0009) in many patients with D1 (T0-3 N1,2 M0) disease. However, some patients do not respond to this combination treatment, which suggests that systemic dissemination of heterogeneous tumor cells is unresponsive to adjuvant androgen ablation therapy. The DNA ploidy pattern may be a valuable predictor of disease outcome after treatment in stage D1 disease. Other pathologic variables (including acid phosphatase levels) have not been useful in predicting disease outcome or treatment response. Finally, patients with limited clinical stage C disease and those with pathologic C or D1 disease should be enrolled in a prospective randomized protocol so that the possible beneficial effects of adjuvant treatment programs can be evaluated. Apart from the usual pathologic variables and prostate-specific antigen testing, the DNA pattern should be included as a stratification factor.

Lymphography demonstrates the size, position, and internal architecture of the external iliac, common iliac, para-aortic, and paracaval lymph nodes. Importantly, the "surgical obturator" nodes are also routinely opacified because they are part of the external iliac chain. Analysis of the internal architecture permits detection of metastases in nodes of normal size, an advantage over cross-sectional imaging techniques. In a prospective study of 89 unselected, previously untreated patients with carcinoma limited to the prostate or periprostatic bed, lymphography was compared with histology of lymph nodes removed at surgical staging. The sensitivity was 53% (17 of 32), specificity 93% (53 of 57), accuracy 79% (70 of 89), and positive and negative predictive values were 81% (17 of 21) and 78% (53 of 68), respectively.

Pelvic lymphadenectomy is valuable as a staging procedure prior to radical prostatectomy in patients with clinical stages A2, B1 (except low-grade lesions), and B2 prostate cancer who seem to be good candidates for an attempt at curative surgery. Survival rates are promising in patients with negative pelvic lymph nodes and local tumors who undergo radical prostatectomy. In the presence of positive nodes, there is little reason to proceed with radical prostatectomy. Noninvasive alternatives to pelvic node dissection are appealing, but lymphangiography, ultrasound, computed tomography scanning, and magnetic resonance imaging are all less reliable than pelvic lymphadenectomy. Some morbidity is associated with surgical staging, and it is important that this be minimized. Pelvic lymph node dissection can play a role in treatment planning for patients who will be given external-beam radiation therapy. However, the role depends on the physician's treatment philosophy. In a recently reported series of patients receiving radiation therapy for localized prostate carcinoma, prior surgical staging by pelvic lymphadenectomy is uncommonly performed.