Estrogen plus progestin increase superoxide dismutase and total antioxidant capacity in postmenopausal women.

OBJECTIVE: This cross-sectional study aimed to evaluate the behavior of blood antioxidant enzymes (superoxide dismutase (SOD), catalase and glutathione peroxidase), plasma total antioxidant capacity and oxidative damage (lipid oxidation and protein carbonyl levels) and their relationship with the serum levels of steroid hormones in premenopausal and postmenopausal women without and with estrogen alone (ET) or estrogen plus progestin therapy (EPT). METHODS: Blood was collected from four groups of subjects: premenopausal women (n = 24), postmenopausal women without hormone therapy (n = 31), postmenopausal women with ET (n = 12) and postmenopausal women with EPT (n = 16). RESULTS: The activities of the different SOD isoforms (CuZnSOD and MnSOD) and the plasma total antioxidant power were significantly higher in the postmenopausal women under EPT than in the postmenopausal women without hormone replacement therapy (HRT). Only CuZnSOD activity was increased in women receiving ET compared to the postmenopausal women without HRT. However, no differences were observed in the levels of lipid or protein oxidation or in the non-enzymatic plasma antioxidants (uric acid and albumin) among the groups. The duration of HRT and serum estrogen levels were positively correlated to the blood CuZnSOD activity and to plasma total antioxidant power, whereas the serum progesterone levels were positively correlated to CuZnSOD activity and negatively correlated to protein carbonyl groups. Interestingly, the total antioxidant power of plasma was positively correlated to CuZnSOD and glutathione peroxidase activities. CONCLUSION: We conclude that EPT increases blood MnSOD and CuZnSOD activity in postmenopausal women, leading to an increased plasma total antioxidant capacity. This finding may be relevant to the prevention of oxidative stress-related disorders in postmenopausal women.

Non-genomic, direct modulatory effect of 17ß-estradiol, progesterone and their synthetic derivatives on the activity of human erythrocyte CuZn superoxide dismutase.

This study aimed to evaluate whether natural or synthetic steroid hormones could directly modulate the activity of the different superoxide dismutase (SOD) isoforms found in human blood fractions without changing enzyme expression. Enzyme samples of human erythrocytes, the human platelet-rich plasma fraction (PRP) or isolated CuZnSOD, which was purified from human erythrocytes were pre-incubated with natural steroids (17ß-estradiol 17-acetate and progesterone) and their synthetic derivatives (ß-estradiol 3-benzoate and medroxyprogesterone 17-acetate). Then, CuZn and MnSOD activities were measured using the xanthine/xanthine oxidase/nitroblue tetrazolium method. Hormones had no effect on MnSOD activity from the PRP, but we show for the first time that natural and synthetic steroid hormones have a direct, bell-shaped effect on the activity of CuZnSOD from both male and female human erythrocytes. Low (physiological) hormone concentrations caused a dose-dependent increase in enzyme activity, which disappeared at higher hormone concentrations. In addition, the combination of synthetic and natural estrogens and progestins had a synergistic stimulatory effect on the activity of CuZnSOD from human erythrocytes. The molecular interaction between CuZnSOD and steroid hormones was preliminarily studied. Natural hormones did not change the electrophoretic mobility of SOD under denaturing conditions, but they did increase the absorption spectra of SOD in the 230-290 nm range. These data suggest that hormone-mediated modulation of CuZnSOD is related to subtle changes in protein conformation, possibly related to Trp and Phe residues. We propose that this effect may account for the physiological regulation of enzyme activity during conditions where steroid hormones undergo alterations as the ovulatory cycle.

Clinical trials in a rural population: professional education aspects.

BACKGROUND: While the majority of cancer patients in rural New Hampshire and Vermont are treated in community hospitals, few have entered clinical trials. This report describes a rural hospital consortium as a single Cancer and Leukemia Group B (CALGB) affiliate that used local cancer teams and itinerant oncologists to develop a clinical trials program. METHOD: Grafted onto an existing oncology outreach program, educational programs were developed to help identify patients and recruit them to cooperative group clinical trials. Outcomes included the number of patients accrued to clinical trials, and a comparison of the quality of audited research records with those of affiliated institutions of the CALGB. The consequences of the program were to measure changes in patterns of care of breast, prostate, colorectal, and lung cancers during the study period. These included diagnostic, staging, and treatment changes that occurred over time. RESULTS: 3.3% of incident cases were accrued to clinical trials during the study period, more often for breast and colorectal than for lung and prostate cancers. Reasons that were identified for low accrual were lack of clinical trials for the majority of cases, including the elderly. More than 65% of the patients in the outreach population were older than 65, compared with 50% at the cancer center. Patterns of care did change for breast and prostate cancers, but were similar to national trends.

Dyspnea, anxiety, body consciousness, and quality of life in patients with lung cancer.

Dyspnea is a common symptom of lung cancer that can impact patient physical, social, and psychological well-being. Study goals were to evaluate quality of life (QOL) and dyspnea in patients with lung cancer and the relationships between QOL, dyspnea, trait anxiety, and body consciousness. Sociodemographic and cancer-related variables (stage, cell type, performance status) were evaluated. One hundred twenty outpatients with stage I-IV lung cancer participated in the study. Patients completed 5 questionnaires assessing QOL, dyspnea, trait anxiety, body consciousness, and pain. Eighty-seven percent of study participants experienced dyspnea. Patients with high dyspnea scores had lower QOL (P = 0.04). Dyspnea was worse in men than in women (P = 0.02), and there was a trend towards older patients reporting more severe dyspnea than younger patients (P = 0.06). There was no difference in dyspnea based on cancer stage, cell type, or performance status. Pain and anxiety scores were higher in patients with high dyspnea (P = 0.02, P = 0.03). Dyspnea was more severe in patients taking opioid analgesics when compared to non-opioids or no pain medications (P = 0.03). No significant association was found between dyspnea, anxiety, and private body consciousness.

Psychologic and neuropsychologic functioning of patients with limited small-cell lung cancer treated with chemotherapy and radiation therapy with or without warfarin: a study by the Cancer and Leukemia Group B.

PURPOSE: The current study assessed the psychologic and neuropsychologic functioning of patients with small-cell lung cancer who were randomized in a large clinical trial to receive intensive doxorubicin, cyclophosphamide, etoposide (ACE)/cisplatin, cyclophosphamide, etoposide (PCE) chemotherapy and radiation therapy (RT) to the primary tumor and prophylactic whole-brain irradiation with (regimen I) or without (regimen II) warfarin. PATIENTS AND METHODS: Patients' emotional states and cognitive functioning were assessed using the Profile of Mood States (POMS) and Trail Making B Test (Trails B), respectively. Two hundred ninety-five patients completed the POMS and Trails B at pretreatment, 224 patients after the completion of the ACE course of chemotherapy (week 9), and 177 patients after the completion of the PCE chemotherapy and RT (week 17). RESULTS: No differences on the POMS or Trails B measures were found between the two treatment arms as predicted, given that the only difference between the two treatment arms was the presence or absence of warfarin. Analysis of the POMS revealed that, overall, mean scores remained stable over the course of treatment; however, women showed a trend toward higher mean scores, which indicated a higher level of distress, compared with men at the pretreatment assessment. Examination of cognitive functioning, measured by the Trails B, revealed improved performance from baseline to post-ACE chemotherapy, which is consistent with a practice effect, but a significant worsening of Trails B scores post-RT compared with the pre-RT assessments, which is consistent with impaired cognitive functioning because of treatment (P < .0001). CONCLUSION: Emotional state, measured by the POMS, did not differ between the groups or change significantly over time in this study of small-cell lung cancer patients treated with a combination of chemotherapy and RT plus or minus warfarin. However, the pattern of relatively stable POMS scores and poorer Trails B performance post-RT suggested that this combination of chemotherapy and RT had a negative impact on cognitive functioning.

Randomized trial of chemotherapy and radiation therapy with or without warfarin for limited-stage small-cell lung cancer: a Cancer and Leukemia Group B study.

PURPOSE: Studies by the Veterans Administration Cooperative Studies Program and Cancer and Leukemia Group B (CALGB) suggested that the addition of warfarin to chemotherapy might enhance response and/or survival in small-cell lung cancer (SCLC). This randomized study evaluated the effect of warfarin with chemotherapy and radiation therapy in limited-stage SCLC. PATIENTS AND METHODS: Patients were randomized to receive warfarin or no warfarin. All patients received three cycles of doxorubicin, cyclophosphamide, and etoposide (ACE). Cycles 4 and 5 (cisplatin, cyclophosphamide, and etoposide [PCE]) were given concurrently with radiation therapy. Three cycles of ACE were given after chemoradiation therapy, but were discontinued due to a high rate of pulmonary toxicity. RESULTS: There were no significant differences in response rates, survival, failure-free survival, disease-free survival, or patterns of relapse between the warfarin-treated and control groups. In patients treated according to the initial design, an increase in failure-free survival seen with warfarin treatment approached significance (P = .07). Preamendment results, while not significant, did not have superimposable treatment survival curves. A landmark analysis at 8 months showed a median survival time after the landmark for complete responders of 33 months with warfarin treatment compared with < or = 13.75 months for complete or partial responders not treated with warfarin (P = .05). Differences between the complete responders in this preamendment population were not significant (P = .103). CONCLUSION: Warfarin does not appear to improve outcome significantly in limited-stage SCLC. However, the differences in some variables between populations before the protocol amendment correspond to the favorable effects of anticoagulants observed in previous studies.

Phase I trial of etoposide, carboplatin, and GM-CSF in extensive small-cell lung cancer: a Cancer and Leukemia Group B study (CALGB 8832).

The maximum tolerated dose (MTD) of etoposide and carboplatin without growth factor support was previously defined by Cancer and Leukemia Group B (CALGB) as 200 and 125 mg/m2/day x 3, respectively, given every 28 days to previously untreated patients who have extensive, small-cell lung cancer (SCLC). Myelosuppression was dose-limiting. The purpose of this phase I trial was to determine if granulocyte macrophage colony-stimulating factor (GM-CSF) support allows the dosage of the combination of etoposide and carboplatin to be increased above the previously determined MTD. In this CALGB study of 44 evaluable patients with performance status 0-2, cohorts were treated with etoposide and carboplatin given intravenously on days 1-3 followed by GM-CSF (molgramostim) given subcutaneously on days 4-18. Four dose levels of bacteria-derived recombinant GM-CSF (5, 10, 20 microg/kg/day and 5 microg/kg every 12 h), three dose levels of etoposide (200, 250, and 300 mg/m2/day x 3), and two dose levels of carboplatin (125 and 150 mg/m2/day x 3) were evaluated. There was no chemotherapy dose escalation in individual patients. With 5 microg/kg/d GM-CSF, the first etoposide and carboplatin cycle of 300 and 150 mg/m2/day x 3, respectively, could be administered with acceptable toxicity. However, GM-CSF did not allow repeated administration of this dose-escalated regimen every 21 days, since delayed platelet and/or neutrophil recovery was dose limiting in later cycles. These results demonstrate that GM-CSF alone has limited capability to support the repeated administration of high doses of etoposide and carboplatin. CALGB currently is testing the ability of interleukin (IL)-6 given with GM-CSF to ameliorate the cumulative myelosuppression of this intense regimen.

Non-small cell lung cancer at the extremes of age: impact on diagnosis and treatment.

BACKGROUND: Early detection and surgical resection offers the highest likelihood of cure for patients with lung cancer. Patients presenting at the extremes of age may fail to benefit maximally from these interventions. To study the impact of age on stage, histology, symptom, and treatment of patients with non-small cell lung cancer, we undertook a retrospective review. METHODS: One thousand eight hundred two patients with non-small cell lung cancer were identified between 1983 and 1993. Patients were selected by age as less than 45 years (55 patients) and 80 years or more (108 patients), and their medical records were reviewed. RESULTS: Three younger patients (6%) presented with stage I or II disease, yet 15 (32%) underwent thoracic operation. Twenty-seven elderly patients (33%) presented with early stage disease and only 6% underwent operation. The median survival was significantly longer for the younger population with surgically resectable stages of disease (stage I to IIIA) (p < 0.05), whereas no significant difference in survival was seen for the two groups with advanced disease (stage IIIB and IV). CONCLUSIONS: Age significantly affects the presentation and treatment of non-small cell lung cancer patients. Although thoracic operation imparts the greatest survival advantage, this benefit is diminished due to advanced disease in the younger patients and lack of surgical intervention in the elderly.

Phase II trial of tamoxifen, etoposide, mitoxantrone, and cisplatin in patients with metastatic breast carcinoma.

BACKGROUND: Based on previous data demonstrating a potentially synergistic interaction between tamoxifen and cisplatin in metastatic melanoma therapy, a Phase II study was performed to assess the activity of tamoxifen, etoposide, mitoxantrone, and cisplatin (TEMP) in patients with metastatic breast carcinoma. METHODS: Forty-six patients with metastatic breast carcinoma were treated with tamoxifen, 10 mg orally, twice a day for 28 days; etoposide, 100 mg/m2, on Days 1-3; mitoxantrone, 10 mg/m2, on Day 1; and cisplatin, 30 mg/m2, on Days 1 and 2. Forty-four patients (7 with bone only disease) were evaluable for response and toxicity after at least 1 cycle of therapy. All patients had previously received doxorubicin-containing regimens in either the adjuvant or metastatic setting. RESULTS: The overall objective response rate for the 37 patients with visceral and/ or soft tissue disease was 41% (95% confidence interval, 25-58%). The objective response rate among women previously treated with doxorubicin in the adjuvant setting was 56% (14 of 24). Only 1 of 13 patients with metastatic carcinoma who had failed doxorubicin responded. Five of seven patients with bone-only disease had subjective improvement of bone pain without worsening of bone scans. Approximately 59% of patients had Grade 3 or 4 neutropenia at some time in their therapy and 1 patient died of neuropenic sepsis. Logistic regression analysis (n = 37) revealed that response was not related to estrogen receptor (ER) status or to the presence of visceral metastases. CONCLUSIONS: TEMP appears to be an active regimen for patients with either ER positive (tamoxifen-resistant) or ER negative metastatic breast carcinoma that progresses after adjuvant doxorubicin therapy. Moreover, among patients who developed metastatic disease either during or < 12 months after adjuvant doxorubicin therapy, TEMP had a higher response rate than would have been predicted from previous studies. Although the mechanism remains to be elucidated, these results suggest a potentially synergistic role for tamoxifen in etoposide/cisplatin-based chemotherapy of breast carcinoma.

A phase I/II trial of etoposide and cisplatin in extensive small cell lung cancer: a cancer and leukemia group B study.

Patients with untreated extensive small cell lung cancer (SCLC) with CALGB performance scores 0-2 were treated with etoposide 200 mg/m2/day on days 1-3 and cisplatin doses of 20, 30, or 35 mg/m2/day days 1-3 in a Phase I/II format. Of the nine patients treated at the 35 mg/m2/day cisplatin dose in the Phase I portion of the study, Grade 4 leukopenia occurred in five patients and Grade 4 thrombocytopenia in four. There were two deaths due to myelosuppression and sepsis. This dose was thus considered the maximum tolerated dose (MTD), and a Phase II trial was then conducted using this treatment program. In the Phase II trial of 39 patients, the objective response rate was 67% (95% confidence interval, 50-81%) with 21% complete responses (CI 9-36%). Median survival was 10.5 months. Grade 4-5 leukopenia was seen in 57% and Grade 4-5 thrombocytopenia in 56%. The MTD defined by this Phase I trial represents a 67-100% increase in etoposide and a 32-42% increase in cisplatin dosage compared to prior studies. The observed objective response rates with this regimen are comparable to studies using conventional doses, but hematological toxicity was higher.

Dacarbazine, cisplatin and carmustine, with or without tamoxifen, for metastatic melanoma: 5-year follow-up.

Metastatic melanoma has a grim prognosis. Response rates and survival of patients treated with combination chemotherapy are not superior to single-agent chemotherapy. This study seeks to evaluate the objective response rate and survival of patients with metastatic melanoma treated with multiagent chemotherapy, with or without tamoxifen. Forty-two patients with metastatic melanoma were treated from March 1982 to February 1988 with dacarbazine, cisplatin and carmustine, with or without tamoxifen. An overall objective response rate of 43% was seen (complete response rate 17%; partial response rate, 26%). The response rate was 54% for patients treated with tamoxifen and 25% for patients treated without tamoxifen, but the results did not achieve statistical significance. Median overall survival was 412 days, and was significantly longer in the tamoxifen-treated group. Combination chemotherapy as described in this study is well-tolerated. The observation that tamoxifen appears to impact on survival should be interpreted with great caution due to the deficiencies in the design of the trial and small patient numbers. A randomized trial of this regimen vs single-agent chemotherapy is indicated and is currently being conducted.

Studies of possible mechanisms for the effect of urokinase therapy in small cell carcinoma of the lung.

Urokinase-type plasminogen activator has been administered by other investigators to patients with small cell carcinoma of the lung (SCCL) in an attempt to induce lysis of fibrin that is known to exist in the connective tissue stroma of this tumour type and that may support tumour growth. To study the fate of infused urokinase in this disease, a biopsy of a scalp metastasis was obtained from a patient with SCCL (entered on a phase I clinical trial of urokinase plus combination chemotherapy) immediately following urokinase infusion during the fourth course of therapy a time when this tumour mass had decreased to approximately 25% of its original size. Immunohistochemical procedures revealed abundant stromal fibrin in accord with previous observations from this laboratory. By contrast, urokinase, that is not a feature of small cell tumour cells, was present on the tumour cells in this specimen. Urokinase infusion was associated with a rapid increase in the amount of this enzyme associated with isolated peripheral blood monocytes. These results are consistent with uptake of infused urokinase onto monocytes and possibly tumour cells. It is postulated that substantial tumour fibrinolysis may not accompany such therapy and that urokinase, or its amino terminal fragment that bears the growth factor domain of this molecule, may bind to and alter the growth of the tumour cells.

Germline RET mutations in MEN 2A and FMTC and their detection by simple DNA diagnostic tests.

Multiple endocrine neoplasia type 2A (MEN 2A) and familial medullary thyroid carcinoma (FMTC) are two closely related cancer syndromes inherited in an autosomal dominant manner. Mutations in the RET proto-oncogene were found in MEN 2A and FMTC families. In this study we report seven different germline mutations in the RET proto-oncogene in five of five MEN 2A and five of six FMTC families. Each of the mutations involves a cysteine residue in the extracellular cysteine-rich domain of the RET receptor tyrosine kinase. We developed simple polymerase chain reaction based diagnostic tests for all seven mutations in these families.

A feasibility study of extended chemotherapy for locally advanced non-small cell lung cancer: a phase II trial of cancer and leukemia group B.

The purpose of this study was to determine the feasibility of additional chemotherapy beyond 5 weeks of vinblastine-cisplatin followed by radiation therapy for patients with stage III non-small cell lung cancer. In this randomized phase II trial, the goal was to determine, in a similar population of patients, the toxicity of either of two additional chemotherapy programs. Ninety-one patients with stage III non-small cell lung cancer received the same induction regime of vinblastine/cisplatin/radiotherapy. In patients randomized to regime 1, an additional four cycles of vinblastine/cisplatin were given after the radiotherapy. In regimen 2, six weekly doses of carboplatin were given concurrent with the radiotherapy. The additional four cycles of vinblastine and cisplatin were completed by 34% of patients; the concurrent carboplatin program was completed by 70% of patients. Grade 3 or 4 granulocytopenia occurred in 53% of patients on regime 1 versus 17% on regime 2 (p < 0.003); grade 3 or 4 nausea/vomiting occurred in 20% of those on regime 1 versus 7% on regimen 2 (p = 0.175). Response rates and survival were similar for the two regimens, with approximately 30% of patients surviving at 2 years. Given the reduced toxicity and the improved capacity to complete the planned therapy with the concurrent carboplatin treatment, this regimen will be further examined in a phase III trial.

Intensive combination chemotherapy, concurrent chest irradiation, and warfarin for the treatment of limited-disease small-cell lung cancer: a Cancer and Leukemia Group B pilot study.

PURPOSE: In prior Cancer and Leukemia Group B (CALGB) studies, combined chemotherapy and thoracic irradiation was superior to chemotherapy alone in limited-disease (LD) small-cell lung cancer (SCLC). A combined modality pilot study was performed to test the feasibility of adding warfarin to aggressive chemoradiotherapy for LD SCLC. PATIENTS AND METHODS: Combination chemotherapy with doxorubicin 45 mg/m2 intravenously (IV) on day 1, cyclophosphamide 800 mg/m2 IV on day 1, and etoposide (ACE) 80 mg/m2 on days 1 to 3 was given every 21 days for the first three courses. The fourth and fifth courses substituted cisplatin 33 mg/m2 IV on days 1 to 3 for the doxorubicin, with concurrent chest irradiation to a total of 4,000 cGy given in 20 fractions during a 4-week period followed by a boost of 1,000 cGy in five fractions during a 1-week period. Prophylactic cranial irradiation, 3,000 cGy was given concurrently in 10 fractions during a 2-week period. Courses 6 to 8 again used ACE chemotherapy, but courses 4 to 8 were given on a 28-day schedule with dose adjustment for hematologic or renal toxicity. Warfarin was given throughout the treatment period titrated to achieve a prothrombin time (PT) of 1.5 to 2 times the control. Patients with histologically proven limited-stage SCLC, good performance status, and normal renal, hematologic, and hepatic functions were eligible. RESULTS: Sixty-one of 66 patients entered onto the study were eligible and assessable. Fifty-four (89%) (95%) confidence interval [CI], 78% to 95%) experienced an objective response, 35 (57%) achieved a complete response (CR) (95% CI, 44% to 70%), and 17 (28%) achieved a partial response (95% CI, 16% to 39%). Median durations were CR, 26.3 months; failure-free survival, 11.8 months; and survival, 18 months. Forty-one percent of the patients were alive at 2 years, 33% were alive at 3 years, and 25% were alive at 4 or more years. Median follow-up for survivors is 5 years (range, 3.5 to 5.9 years). Severe or life-threatening myelosuppression occurred in 90%, infection occurred in 34%, fever without documented infection occurred in 26%, and pulmonary toxicity occurred in 6%. Another 6% of patients experienced severe or life-threatening hemorrhages. There were four treatment-related fatalities. The pulmonary toxicities have been associated with the resumption of ACE chemotherapy after chest irradiation. CONCLUSIONS: These highly encouraging response and survival results compare favorably with any prior CALGB group study. Although they are somewhat more toxic, they are comparable to the best published results. A randomized study that examines the role of warfarin is underway.

Socioeconomic status and cancer survival.

Survival data from eight Cancer and Leukemia Group B (CALGB) protocols were examined for patients with lung cancer (N = 961), multiple myeloma (N = 577), gastric cancer (N = 231), pancreatic cancer (N = 174), breast cancer (N = 87), and Hodgkin's disease (N = 58). After accounting for differences in survival rate attributable to type of cancer, initial performance status, age, and 14 other protocol-specific prognostic indicators, the additional predictive value of socioeconomic status (SES) was evaluated. Race (white v non-white) was not a significant predictor of survival time, but income and education were. People with lower annual incomes (below $5,000 per year in the years 1977 to 1981) and those with lower educational level (grade school only) showed survival times significantly shorter than those with higher income or education, respectively. These survival differences were associated with, but could not be fully explained by, severity of disease at initial presentation. SES continued to exert a small but significant impact on cancer survival, even after controlling for all known prognostic variables. Economically and educationally disadvantaged cancer patients may require treatment programs that include education about treatment and compliance, even after an initial diagnosis is made and treatment is initiated. Because SES is related to survival independent of all known prognostic variables, it should be included in the data bases of clinical trial groups to provide a more accurate test of the effectiveness of new therapies.

Continuous intratumoral infusion of methotrexate for recurrent glioblastoma: a pilot study.

Five patients with documented recurrences of glioblastoma multiforme were given continuous infusions of methotrexate delivered intratumorally using implantable catheters and subcutaneous refillable pumps. A continuous infusion of methotrexate (1 mg/d) was begun with concomitant oral administration of folinic acid. The methotrexate dose was increased every 2 weeks to 3, 10, 30, and, ultimately, 75 mg/d in two patients. Samples of serum and ventricular cerebrospinal fluid (CSF) were obtained to determine the levels of methotrexate and total bioactive folates, and brain tissue was obtained from two patients for determination of methotrexate concentration. The patients survived from 7 to 49 weeks after the implantation of the infusion device. Neither the clinical examination nor sequential radiological studies gave clear evidence of reduction in tumor size. Pneumonia developed in one patient, and mild hepatitis and increased seizure frequency in another. Methotrexate was stable in the delivery system over 12 days, and ventricular CSF reached steady-state levels by 5 days. Steady-state ventricular CSF levels of methotrexate were higher than serum levels in some patients, while the reverse was true in others. Levels of total bioactive folates in the CSF did not increase above the normal range. Methotrexate concentrations were highest at the center of the tumor, but measurable amounts of methotrexate were detectable in all areas of the brain. At autopsy in four patients, variable liquefactive necrosis of the brain tumors was seen, and viable tumor was found at the periphery of the tumor bed. These preliminary results suggest that it is technically feasible to infuse methotrexate into brain tumor cavities, and show that little central nervous system or systemic toxicity was encountered in five patients. Better delineation of the safety and efficacy of this therapeutic approach will require further clinical trials.

Lack of acute toxicity associated with a multimodality treatment of stage III ovarian epithelial carcinoma.

Eleven patients with advanced stage III ovarian epithelial carcinoma were treated primarily according to an aggressive multimodality plan utilizing cytoreductive surgery, chemotherapy (high-dose cisplatin and Cytoxan), and consolidative radiation therapy (abdominopelvic "bath" plus pelvic boost). The treatment was tolerated remarkably well. There was no evidence of progressive disease during treatment, and all patients showed a positive response. There was a notable lack of significant acute morbidity, with the exception of a severe symptomatic peripheral neuropathy associated with cisplatin doses of 200 mg/m2. This was not evident with doses of cisplatin up to 150 mg/m2.

Prognostic factors in small-cell carcinoma of the lung: an analysis of 1,521 patients.

Cancer and Leukemia Group B (CALGB) accrued 1,745 patients with limited (LD) or extensive (ED) small-cell lung cancer (SCCL) to five separate trials between 1972 and 1986. We reviewed these data to evaluate the impact of pretreatment prognostic factors on outcome. In multivariate analysis, female gender was predictive of improved response (LD, P = .01; ED, P = .04) and survival (LD, P = .01; ED, P = .02). A performance status of 0 or 1 was associated with improved response rates in both subsets, but was statistically significant (P = .04) only for overall objective response in LD patients. Performance status was a highly significant predictor of survival in both LD and ED groups (P less than .001). Supraclavicular lymph node involvement, while still LD, had a borderline unfavorable impact on survival (P = .06) compared with a lesser extent of LD involvement. In ED patients, a decrease in survival rates was associated with an increased number of metastatic sites (P = .01). Changes in the patient population were noted with time: the percentage of women increased from 21% to greater than 35%; an increased number of metastatic sites was identified among ED patients; mean performance status improved for both LD and ED subsets. These trends reflect the changing demographics of lung cancer, improved lung cancer staging, and probably lead-time bias. Response rates, overall survival, and long-term (greater than 2-year) survival varied significantly among the five protocols, both before and after multivariate correction for identified prognostic variables. However, the changing character of the study population limits the ability to determine retrospectively how much improvements in therapy contributed to the positive changes in failure-free survival, overall survival, and long-term survival observed in our sequentially studied population.