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

Drug-resistant mammalian tumor cell lines have been derived by either fractionated x-irradiation treatment or exposure to vincristine or etoposide (VP-16-213) in vitro. Analyses of the patterns of responses expressed by these differently derived, resistant cell lines have shown variations in responses to a range of antitumor drugs depending upon the agent used to induce resistance. However, all treated cell lines express resistance to vincristine and, with one exception, to VP-16-213. Preliminary evidence has indicated that resistance to vincristine in drug-treated cells, but not x-irradiation-treated cells, is associated with impaired vincristine uptake; resistance to VP-16-213 in both differently derived, resistant sublines is associated with a reduction of VP-16-213-induced DNA single-strand breakage; and collateral sensitivity to cisplatin in x-irradiation-treated cells is associated with enhanced drug-induced DNA cross-linking. These data indicate that patterns of responses to antitumor drugs and the mechanisms associated with these altered responses differ depending upon the agent used to induce resistance.

Previously, investigators at this institute have studied the use of upper hemibody irradiation as a consolidation agent following combination chemotherapy for small cell lung cancer. There was no improvement in survival compared to that in the group treated with chemotherapy alone. In our present pilot study, we are investigating the toxicity and efficacy of using hemibody irradiation (HBI) as a non-cross-resistant agent early in a program of alternating chemotherapy consisting of six treatment cycles. Toxicity due to the combined effects of chemotherapy (cisplatin and etoposide plus cyclophosphamide, doxorubicin, and vincristine) plus HBI is reported. The HBI was given at a dose of 1,000 cGy in four fractions for limited disease or as a single 800-cGy dose for extensive disease. Bone marrow suppression following HBI necessitated a subsequent delay in the chemotherapy cycle or dose reduction in 55% of the 33 patients. Six patients developed diffuse interstitial pneumonitis following chemotherapy and HBI; 3 have died, and in 2 of these, the etiology was opportunistic infection. In our previous studies utilizing HBI either alone or as consolidation therapy after induction chemotherapy, a low incidence of lung toxicity occurred. This increased incidence suggests a possible drug-radiation interaction when HBI is used as an alternating agent with doxorubicin and cisplatin.

Based on our experience with head and neck cancer, we have developed an every-other-week, split-course schedule for giving combined cisplatin and 5-fluorouracil infusion and radiation to patients with regionally advanced non-small cell lung cancer for a limited number of cycles prior to planned resection. Sixty-four patients having stage III disease without distant metastases were treated with 4 cycles of combined chemotherapy and radiation to 40 Gy and were offered surgical resection. Thirty-nine patients (61%) underwent surgery. Nine had no residual cancer. No correlation was noted between clinical and histologic responses in the surgery group, but histologic response correlated with subsequent outcome. Survival was 58% at 1 year, 33% at 2 years, and 22% at 3 years. Although encouraging, the overall dismal prognosis of this disease has led us to pursue further improvements in protocol design prior to phase III testing of this concept. To this end, etoposide has been added to the above regimen, extending the cycles from every other week to every third week.

The diagnosis of prostate carcinoma by imaging is still fraught with problems, even with the advent of highly sophisticated techniques. Despite enthusiastic preliminary reports, no one imaging method reliably screens for this condition. The staging of prostate carcinoma is feasible, but the best imaging method remains a subject of debate. The transabdominal sonographic approach lacks the resolution required for detailed intraglandular anatomic delineation. The transrectal sonographic approach excels in guiding needle biopsy and in evaluating transcapsular and seminal vesicle extension of known tumors. Computed tomography lags behind other tomographic imaging modalities in its accuracy for local tumor staging, but it is excellent, although nonspecific, in the detection of lymph node enlargement. Magnetic resonance detects abnormalities in the prostate in a high percentage of cases but is nonspecific. However, it can stage prostate carcinoma and detect lymphadenopathy reliably.

Over 900 patients have been treated with radiation therapy in the 30-year Stanford prostate study. Overall survival, i.e., scoring death due to all causes, was 45%, 35%, 33%, 20%, and 10% for Stanford stages T0, T1, T2, T3, and T4 (nominal stages A, B1, B2, C) at 15 years; lymph node status was unknown. Disease-specific survival at 15 years was 85%, 64%, 45%, 33%, and 15%, respectively, for the same patients. In 141 patients with restricted nodular disease (lymph node status unknown) equal to or less than one-half of one lobe involved (stage B1), the 15-year overall survival was 50% and identical to the expected survival of an age-matched cohort of males. Potency was preserved in 86% of the patients at 15 months posttreatment, and 50% of the patients maintained erectile potency for 7 years posttherapy. Other sequelae and complications are analyzed. The incidence of second neoplasms did not exceed expectations for an age-matched population.

Morphometric reconstruction of 122 consecutive radical prostatectomy specimens were analyzed for cancer volume and grade, seminal vesicle (SV) invasion, lymph node (LN) metastasis, and complete capsular penetration. The mean cancer volume for 91 specimens without SV invasion or LN metastasis was 3.7 cm3; for 14 with only SV invasion, 9.0 cm3; for 17 with LN metastasis, 15.2 cm3; and for 12 with both SV invasion and LN metastasis, 17.8 cm3. The mean cancer volume for 60 specimens without capsular penetration was 2.5 cm3, and for 62 it was 9.0 cm3. Grade of cancer correlated well with tumor volume. We believe that radical prostatectomy for cure should be performed on patients with tumors less than 3.8 cm3 in volume. Methods for accurate assessment of tumor volume before surgery should be given research priorities.

The outcome for the first 57 successive patients who underwent total perineal prostatectomy for clinically localized prostate cancer at the Virginia Mason Clinic and who have been followed up for a minimum of 15 years is reviewed for evaluation of the long-term impact of this operation on the disease. Twenty percent of the patients had pathologic stage C disease. Recurrence developed in 11 of the 55 patients (20%) who could be evaluated, and death from prostate cancer occurred in 6 (11%) during this interval. The actual observed overall survival at 15 years or more was 60%, the actuarial survival 67%, and the cause-specific survival 89%. The current morbidity of this operation was evaluated by review of the last 50 consecutive patients who underwent this procedure and had follow-up of at least 6 months. Operative time averaged 140 minutes, and blood loss averaged 660 ml; 22% of the patients required a transfusion. Average postoperative hospitalization was 5 days. Two patients required a temporary colostomy for unrecognized rectal injury, and 2 developed a stricture requiring more than one dilation. Three patients (6%) wear pads for mild stress incontinence. One patient died of a cerebral vascular accident.

The morbidity of radical retropubic prostatectomy for prostate cancer has been reduced through improved understanding of the surgical anatomy of the prostate. Delineation of the anatomy of the dorsal vein complex has led to modifications in the surgical technique that have reduced blood loss and improved surgical exposure. The addition of epidural anesthesia and presurgical donation of autologous blood has limited the need for the homologous transfusion of blood to 2% of the patients and has reduced the frequency of serious perioperative complications such as pulmonary emboli to 0.3%. Delineation of the anatomy of the pelvic plexus and identification of the neurovascular bundles as the macroscopic landmark of the microscopic cavernous nerves have made it possible for the surgeon to make an informed decision at the time of surgery whether the neurovascular bundles can be preserved safely or excised widely with the specimen. In all surgical approaches to prostate cancer, the primary goal must be excision of all tumor; preservation of sexual function should be of secondary concern. These considerations were addressed in the treatment of 320 consecutive patients; 74% of the men are potent postoperatively. It was necessary to excise one neurovascular bundle widely in 49 patients; 69% are potent. In addition to improvements in postoperative sexual function, the incidence of incontinence following surgery has been reduced. The total medical expenses for patients undergoing radical prostatectomy range from $8,500 to $9,500 and are similar to those for external-beam radiotherapy.(ABSTRACT TRUNCATED AT 250 WORDS)

In defined-flora, barrier-maintained rats (WAG/RijMCW males), radiation nephritis is the principal late toxicity seen after high-dose-rate, total-body irradiation (TBI) when hematologic toxicity is prevented by bone marrow transplantation. Pneumonitis develops only if rats are exposed to a conventional environment during and after bone marrow transplantation. Low-dose-rate TBI gives similar toxicity at doses twice as large. Rats surviving for 9 months after TBI show decreased tolerance for cisplatin. This decreased tolerance is related to dose and dose rate and is seen for radiation doses that show little or no renal toxicity. Evidence suggests that the decrease in renal tolerance is due to decreased renal platinum clearance in the irradiated kidneys.

Doxorubicin was initially administered alone by continuous infusion for 5 days every 3 weeks in escalating doses to 13 patients with advanced metastatic and/or recurrent malignancies. The maximum tolerable dosage was 13 mg/m2 per day for 5 days. Kinetic data showed a steady level of 60 ng/ml for 4 days and a biphasic disappearance curve. Radiation therapy (150-200 cGy per session) was then administered in 5-day cycles, every 3 weeks, concomitantly with continuous infusion of doxorubicin (12 mg/m2 per day) to 21 patients with various advanced unresectable recurrent or metastatic malignancies. Four of 9 patients with soft tissue sarcomas achieved complete response after a radiation dose of 2,206 +/- 590 (SD) cGy and 3 had partial response; the median durations of the response were 142 +/- 65 (SD) weeks for complete response and 28 +/- 10 weeks for partial response. Of 4 patients with primary hepatoma, 2 achieved partial response after 1,290 +/- 210 cGy. No response was seen in any of the 7 patients with adenocarcinoma of the gastrointestinal tract or breast. Complications of this regimen included moderate leukopenia and thrombocytopenia, mucositis, skin erythema, and decrease of the ventricular ejection fraction at a cumulative doxorubicin dose of 840 mg/m2. We conclude that doxorubicin given by protracted infusion can be safely administered with concomitant radiation and appears to enhance the effects of radiation on most soft tissue sarcomas and on some hepatocellular carcinomas.