Randomized phase III study of docetaxel compared with paclitaxel in metastatic breast cancer.

PURPOSE: This randomized, controlled, multicenter, open-label, phase III study compared docetaxel versus paclitaxel in patients with advanced breast cancer that had progressed after an anthracycline-containing chemotherapy regimen. PATIENTS AND METHODS: Patients (n = 449) were randomly assigned to receive either docetaxel 100 mg/m2 (n = 225) or paclitaxel 175 mg/m2 (n = 224) on day 1, every 21 days until tumor progression, unacceptable toxicity, or withdrawal of consent. RESULTS: In the intent-to-treat population, both the median overall survival (OS, 15.4 v 12.7 months; hazard ratio [HR], 1.41; 95% CI, 1.15 to 1.73; P = .03) and the median time to progression (TTP, 5.7 months v 3.6 months; HR, 1.64; 95% CI, 1.33 to 2.02; P < .0001) for docetaxel were significantly longer than for paclitaxel, and the overall response rate (ORR, 32% v 25%; P = .10) was higher for docetaxel. These results were confirmed by multivariate analyses. The incidence of treatment-related hematologic and nonhematologic toxicities was greater for docetaxel than for paclitaxel; however, quality-of-life scores were not statistically different between treatment groups over time. CONCLUSION: Docetaxel was superior to paclitaxel in terms of OS and TTP. ORR was higher for docetaxel. Hematologic and nonhematologic toxicities occurred more frequently in the docetaxel group. The global quality-of-life scores were similar for both agents over time.

Leucovorin plus 5-fluorouracil: an effective treatment for metastatic colon cancer.

In Columbus, OH, 46 patients with measurable metastatic colorectal cancer were treated with leucovorin (LV) 80 mg/m2/20 h intravenous (IV) infusion followed by 5-fluorouracil (5-FU) 400 mg/m2 IV bolus daily for three days and then once weekly. Many patients had liver (62%) and/or multisite metastases (53%), carcinoembryonic antigen (CEA) greater than 10 (76%), documented tumor progression before entry (51%), and tumor-related symptoms (36%), but also good performance status (84%). Prior therapy consisted of radiotherapy (RT) in 18%, chemotherapy in 22%, both in 4%, and none in 56%. There were 36% objective responses and 31% stabilization, which we believe is a significant change in the natural history of these patients. Median survival was 8 months. Improved survival was seen in patients with single- rather than multiple-site involvement. Decreasing CEA levels were seen in 59% (always in responders or patients with stable disease), and correlated with longer survival time (11.0 v 5.5 months, P = 0.01). Palliation of tumor related symptoms occurred in 75%, with or without antitumor effect. One patient with prior RT died of neutropenic sepsis after only the three-day load, so we now recommend only weekly therapy in previously radiated patients. Otherwise, toxicity was mild, manifest as weakness in 62%, nausea in 53%, or diarrhea in 47%, which was the most common dose-limiting side effect. The occurrence or absence of toxicity did not predict outcome. Because of equivalent efficacy, mild toxicity, and less expense, this regimen should be considered for patients who desire therapy.

Phase I study of docetaxel dose escalation in combination with fixed weekly gemcitabine in patients with advanced malignancies.

PURPOSE: To determine the maximum-tolerated dose of monthly docetaxel combined with fixed-dose weekly gemcitabine and describe the dose-limiting toxicities (DLTs) of the combination. PATIENTS AND METHODS: Patients with refractory solid tumors were treated with gemcitabine days 1, 8, and 15 every 4 weeks at a fixed dose of 800 mg/m2. Two docetaxel administration schedules were studied, with the drug administered either day 1 or day 15 at doses of 45, 60, 75, and 100 mg/m2 per cycle. RESULTS: Forty patients received 132 cycles of chemotherapy. On the day-1 schedule, the maximum-tolerated docetaxel dose was the highest planned dose of 100 mg/m2 with two DLT episodes among 12 patients treated with 34 cycles at this dose level. On the day-15 schedule, delivery of the planned docetaxel doses was not feasible because of thrombocytopenia and hepatic dysfunction. Hematologic toxicities included grade 4 neutropenia in 16 patients, with three episodes of febrile neutropenia; grades 3 to 4 thrombocytopenia in nine patients; and anemia that required RBC transfusions in 10 patients. For patients treated at the highest docetaxel dose level, myelosuppression was not dose limiting and only one of 34 cycles was complicated by febrile neutropenia. The most common nonhematologic toxicities were asthenia, flu-like symptoms, and fluid retention. Antineoplastic activity was noteworthy, with partial responses in nine of 21 patients with pretreated non-small-cell lung cancer (NSCLC; 43%; 95% confidence interval, 22 to 66), in four of seven patients with breast cancer, and in one patient with esophageal adenocarcinoma. CONCLUSION: Gemcitabine 800 mg/m2 days 1,8, and 15 can be safely combined with docetaxel 100 mg/m2 day 1 of a 28-day cycle. The observed antitumor activity warrants phase II evaluation.

Hepatic artery ligation and portal vein infusion for liver metastases from colon cancer.

Localized treatment of liver metastases from colon cancer has yielded better results than has systemic therapy. We report 19 patients with metastatic colon cancer whose bulk disease was limited to the liver, but was not amenable to surgical resection. Many of these patients had poor prognostic features: 14 had greater than 30% replacement of the liver, five had poorly differentiated tumor, and five had previously failed to respond to systemic chemotherapy. All were treated with hepatic artery ligation and portal vein infusion of chemotherapy (mitomycin C and 5-fluorouracil). Two patients (10%) died within one month postoperatively. The remaining 17 patients all improved clinically and demonstrated a marked decrease in carcinoembryonic antigen (CEA) levels. Based on follow-up physical exam, liver function tests, computed tomographic scan, and/or laparotomy, there were two complete responses, ten partial responses, four improved, and one indeterminate, for an objective response rate of 63%. Median survival of all patients was 13 months after hepatic artery ligation, and 14 months after diagnosis of liver metastases, with four patients still alive at 13+, 16+, 41+, and 61+ months after hepatic artery ligation. We believe that this form of therapy is an effective, well-tolerated alternative for patients with unresectable liver metastases.

Chemotherapy of drug-resistant ovarian cancer: a Southwest Oncology Group Study.

We present a final analysis, including pathology review, of a cooperative group study of drug-resistant ovarian cancer. Of 200 patients registered, 112 were eligible and evaluable, with a response rate of 26% and median survival of 7 months. Because these results are poorer than those reported in the preliminary and interim analyses of this study, we scrutinized the 88 excluded patients, most of whom failed to meet our strict pathologic criteria for a diagnosis of ovarian cancer of epithelial type, and who, as a heterogeneous group, fared better than patients who did meet the eligibility criteria. We believe this analysis provides insight into the spectrum of diseases that are frequently called ovarian cancer, but might be more properly labeled abdominal carcinomatosis.

A randomized, double-blind trial of fluorouracil plus placebo versus fluorouracil plus oral leucovorin in patients with metastatic colorectal cancer.

PURPOSE: A prospectively randomized trial was performed to determine whether the combination of fluorouracil (FU) plus leucovorin (FU-LV) administered orally is more effective than equitoxic FU for patients with metastatic colorectal cancer. PATIENTS AND METHODS: A double-blind, placebo-controlled trial design was used to eliminate observer bias. An escalating FU dosing schedule was used to achieve equal toxicity. End points were response, time to treatment failure (TTF), and eight quality-of-life (QL) parameters. A crossover arm allowed FU-treated patients to receive FU-LV combination treatment after treatment failure. RESULTS: Response rate was 32% for FU-LV versus 23% for FU (P = .15). Median TTF was 22 versus 16 weeks (P = .27). Median survival time was 44 versus 54 weeks (P = .26). QL was the same for both treatments, except for days of hospitalization, which was greater for FU-LV (P < .001). Toxicities were similar to those previously reported for FU-LV and FU alone. CONCLUSION: Oral LV-FU produces the same efficacy and toxicity pattern as has been reported for intravenous LV-FU. When FU-LV is compared with equitoxic doses of FU, there is no difference in patient outcome. These results suggest that patients with advanced disease should receive FU at doses adequate to produce toxicity.

Randomized comparison of vinorelbine and melphalan in anthracycline-refractory advanced breast cancer.

PURPOSE: This prospective multicenter randomized trial was performed to compare the effectiveness and safety of intravenous (i.v.) vinorelbine tartrate (Navelbine [NVB]; Burroughs Wellcome Co, Research Triangle Park, NC) with i.v. melphalan (Alkeran [ALK]; Burroughs Wellcome Co) in a heavily pretreated population of patients with anthracycline-refractory advanced breast cancer (ABC). Efficacy end points included time to disease progression (TDP), time to treatment failure (TTF), survival, tumor response rates, and quality of life (QL) and relief of cancer-related symptoms. PATIENTS AND METHODS: Between August 24, 1990, and December 1, 1992, 183 patients were randomized (2:1) to treatment with NVB (30 mg/m2 weekly) or ALK (25 mg/m2 every 4 weeks) i.v. Patients were stratified by measurable or nonmeasurable-assessable disease and by treatment center. RESULTS: Time to disease progression was significantly longer with NVB than with ALK, with a median 12 weeks versus 8 weeks, respectively (P < .001). NVB patients also had significantly longer time to treatment failure than ALK patients, with a median 12 weeks versus 8 weeks, respectively (P < .001). The effect of NVB on survival was also statistically significant (P = .034): 1-year survival rates were 35.7% with NVB and 21.7% with ALK and the median survival rate was 35 weeks and 31 weeks, respectively. In total, 46.5% of NVB patients and 28.2% of ALK patients achieved an objective response or stabilization of disease (P = .06). No intergroup differences were noted in patient-assessed QL and cancer-related symptoms. The most common toxicities were hematologic, including granulocytopenia with NVB and thrombocytopenia and granulocytopenia with ALK. Both drugs were generally well tolerated, and no septic deaths were reported. CONCLUSION: This randomized trial demonstrates a survival benefit in anthracycline-refractory ABC. NVB was well tolerated and demonstrated activity superior to ALK in anthracycline-refractory ABC, without compromising QL. Based on activity of single-agent NVB in this difficult-to-treat patient population, investigations of NVB in combination with other anticancer drugs are warranted.

Evaluation of topotecan in resistant and relapsing multiple myeloma: a Southwest Oncology Group study.

PURPOSE: Topotecan is a topoisomerase I inhibitor with antitumor activity against hematologic and solid tumor malignancies. We evaluated its activity in refractory and relapsing multiple myeloma patients who had received one prior chemotherapeutic regimen. PATIENTS AND METHODS: Toptecan 1.25 mg/m2/d was administered as a 30-minute infusion for 5 days repeated every 3 weeks. Granulocyte colony-stimulating factor (G-CSF) 5 microg/kg/d subcutaneously was administered after the first course of treatment if neutropenia was dose-limiting. RESULTS: Forty-six patients entered the study, with 43 patients eligible. The major toxicity was granulocytopenia with grade 3 or better occurring in 40 of 43 patients treated; 21 of 43 patients developed grade 3 or greater thrombocytopenia. Other significant toxicity included mild nausea in 23 patients and mild vomiting in 13 patients. The overall response rate (partial response or better) was 16% (95% confidence interval, 7% to 31%), with responses occurring in both relapsed and refractory patients. Responses have lasted 70 to 477+ days, with a median progression-free survival duration of 13 months and median survival time of 28 months. CONCLUSION: Topotecan has activity in refractory and relapsing multiple myeloma. Future investigation of topotecan in multiple myeloma including combination therapy and the study of other topoismerase I inhibitors is warranted.

Adjuvant therapy in large bowel adenocarcinoma: long-term results of a Southwest Oncology Group Study.

The Southwest Oncology Group (SWOG) colorectal adjuvant study 7510 went through two phases. From 1975 to 1977, 309 patients were randomized to chemotherapy alone or the same chemotherapy plus immunotherapy. From 1977 until 1980, 317 patients were randomized among the same two therapy programs and a control group. With a minimum follow-up in either phase of greater than 7 years, data are now mature. They show no difference in relapse-free survival (RFS) nor overall survival (OS) in either the two-way phase or in the three-way phase. There is no indication, except possibly in one very small subset, that the addition of immunotherapy to chemotherapy provides an improvement in OS or in RFS. Using data from patients accrued after randomization to the control group, we fail to find evidence that either chemotherapy alone or chemoimmunotherapy improves OS or RFS when contrasted to outcomes obtained by patients on the control arm. In fact, we have significant evidence, at the P = .016 level, that chemotherapy does not improve OS by at least 50%; we also have significant evidence, at the P = .011 level, that chemoimmunotherapy will not improve OS by at least 25%. No evidence of efficacy was demonstrated for either treatment regimen, even though enough therapy was given to result in significant toxicities. Acute toxicity was at least moderate, but not fatal, in 75% of patients. Recognizable delayed toxicity included rare cases of fatal renal failure and acute leukemia.

Adenovirus-mediated wild-type p53 gene transfer in patients receiving chemotherapy for advanced non-small-cell lung cancer: results of a multicenter phase II study.

PURPOSE: To study the additional benefit from adenoviral p53 gene therapy in patients undergoing first-line chemotherapy for advanced non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: Twenty-five patients with nonresectable NSCLC were enrolled in an open-label, multicenter phase II study of three cycles of regimen A, carboplatin (area under the curve, 6; day 1) plus paclitaxel (175 mg/m(2), day 1), or regimen B, cisplatin (100 mg/m(2), day 1) plus vinorelbine (25 mg/m(2), days 1, 8, 15, and 22) in combination with intratumoral injection of 7.5 x 10(12) particles of SCH 58500 (rAd/p53, day 1). Responses of individual tumor lesions were assessed after each cycle, and gene transfer was examined in posttreatment tumor biopsies using reverse transcriptase polymerase chain reaction. RESULTS: There was no difference between the response rate of lesions treated with p53 gene therapy in addition to chemotherapy (52% objective responses) and lesions treated with chemotherapy alone (48% objective responses). Subgroup analysis according to the chemotherapy regimens revealed evidence for increased mean local tumor regressions in response to additional p53 gene therapy in patients receiving regimen B, but not in patients receiving regimen A. There was no survival difference between the two chemotherapy regimens, and the median survival of the cohort was 10.5 months (1-year survival, 44%). Transgene expression was confirmed in tumor samples from 68% of patients, and toxicities attributable to gene therapy were mild to moderate. CONCLUSION: Intratumoral adenoviral p53 gene therapy appears to provide no additional benefit in patients receiving an effective first-line chemotherapy for advanced NSCLC.

Further evaluation of intensified and increased total dose of cyclophosphamide for the treatment of primary breast cancer: findings from National Surgical Adjuvant Breast and Bowel Project B-25.

PURPOSE: In 1989, the National Surgical Adjuvant Breast and Bowel Project initiated the B-22 trial to determine whether intensifying or intensifying and increasing the total dose of cyclophosphamide in a doxorubicin-cyclophosphamide combination would benefit women with primary breast cancer and positive axillary nodes. B-25 was initiated to determine whether further intensifying and increasing the cyclophosphamide dose would yield more favorable results. PATIENTS AND METHODS: Patients (n = 2,548) were randomly assigned to three groups. The dose and intensity of doxorubicin were similar in all groups. Group 1 received four courses, ie, double the dose and intensity of cyclophosphamide given in the B-22 standard therapy group; group 2 received the same dose of cyclophosphamide as in group 1, administered in two courses (intensified); group 3 received double the dose of cyclophosphamide (intensified and increased) given in group 1. All patients received recombinant human granulocyte colony-stimulating factor. Life-table estimates were used to determine disease-free survival (DFS) and overall survival. RESULTS: No significant difference was observed in DFS (P =.20), distant DFS (P =.31), or survival (P =.76) among the three groups. At 5 years, the DFS in groups 1 and 2 (61% v 64%, respectively; P =. 29) was similar to but slightly lower than that in group 3 (61% v 66%, respectively; P = 08). Survival in group 1 was concordant with that in groups 2 (78% v 77%, respectively; P =.71) and 3 (78% v 79%, respectively; P =.86). Grade 4 toxicity was 20%, 34%, and 49% in groups 1, 2, and 3, respectively. Severe infection and septic episodes increased in group 3. The decrease in the amount and intensity of cyclophosphamide and delays in therapy were greatest in courses 3 and 4 in group 3. The incidence of acute myeloid leukemia increased in all groups. CONCLUSION: Because intensifying and increasing cyclophosphamide two or four times that given in standard clinical practice did not substantively improve outcome, such therapy should be reserved for the clinical trial setting.

Concurrent cisplatin, prolonged oral etoposide, and vincristine plus chest and brain irradiation for limited small cell lung cancer: a phase II study of the Southwest Oncology Group (SWOG-9229).

PURPOSE: The primary objectives of the study were to evaluate the efficacy and safety of prolonged oral (PO) etoposide as part of cisplatin-based chemotherapy plus concurrent chest/brain irradiation induction, followed by CAV consolidation, in the treatment of patients with limited-stage small cell lung cancer (SCLC-LD) within a cooperative group setting. METHODS AND MATERIALS: Fifty-six eligible patients with SCLC-LD received three 28-day cycles of cisplatin 50 mg/m2 i.v. (days 1, 8; 29, 36; and 57, 64), PO etoposide 50 mg/m2 (days 1-14, 29-42, and 57-70), and vincristine 2 mg i.v. (days 1, 29, and 57). Thoracic irradiation (TRT) was administered at 1.8 Gy in 25 daily fractions to a total dose of 45 Gy via an AP:PA arrangement, to begin concomitantly with induction chemotherapy. Prophylactic cranial irradiation (PCI) was started on day 15 of induction therapy. Fifteen daily fractions of 2.0 Gy were administered to the entire brain to a total dose of 30 Gy to finish at approximately the same time as TRT. Two 21-day cycles of consolidation cyclophosphamide 750 mg/m2 i.v., doxorubicin 50 mg/m2 i.v., and vincristine 2 mg i.v. (all on days 1 and 22), were given beginning on day 106 or week 16, from the start of induction therapy. RESULTS: Among 56 eligible patients, 93% had SWOG performance status 0-1. All had adequate organ function and had not received prior therapy. The overall confirmed response rate was 46%, including 16% complete responders and 30% partial responders. After a minimum follow-up duration of 17 months, the Kaplan-Meier median progression-free (PFS) and overall survival (OS) were 10 and 15 months, respectively. Two-year survival is 28%. Only 28 of 56 patients (50%) completed chemotherapy per protocol, while 52 of 56 patients (93%) completed radiation per protocol. Eleven patients (20%) discontinued secondary to toxicity and two patients died from treatment. The major toxicity was hematologic. The two deaths were secondary to infection. Of the nonhematologic toxicities, there were 10 cases of pulmonary fibrosis (including one Grade 3) and six cases of pneumonitis (including one Grade 3). CONCLUSION: Concomitant chemoradiation with oral etoposide as part of a platinum-based chemotherapy and TRT induction regimen is toxic. The CR rate is not better than our prior best group-wide experience. The progression-free and overall survival are similar to published trials utilizing short-course i.v. etoposide. As in chemotherapy for extensive-stage SCLC, there is no apparent advantage to prolonged exposure to etoposide, and toxicity resulted in an inferior therapeutic index compared to programs with shortened exposure.

Photodynamic therapy for cutaneous and subcutaneous malignant neoplasms.

Twenty-seven patients with cutaneous and subcutaneous malignant neoplasms were treated with photodynamic therapy. Therapy was administered to 248 areas during a total of 72 separate treatment sessions after patients received a total of 45 injections of sensitizer. Seven patients had basal cell carcinoma, three had squamous cell carcinoma, three had malignant melanoma, one had liposarcoma, and 12 had breast cancers. One patient had Bowen's disease. Treatment was given either by surface radiation or interstitially. One month after treatment, 48 (67%) of the treatment sessions resulted in a complete response (no clinical evidence of tumor), and 19 (26%) resulted in a partial response (greater than 50% reduction in the number or size of tumors). Fifteen patients were examinable 12 months after treatment, and in this group, 31 treatment sessions were evaluated as a complete response one month after therapy, 15 (48%) of which retained this status at one year after treatment. By comparing the ability of different light-delivery instrumentation, it was concluded that the Yellow Springs radiometer (Yellow Springs Instruments, model 65A, Yellow Springs, Ohio) provided the most reliable spot power density readings. Straight-tipped fibers are nonhomogeneous and can result in overtreatment of the central area with necrosis and pain and in undertreatment of the periphery.

Photodynamic therapy for esophageal tumors.

Between 1982 and 1987, 40 patients with esophageal tumors (19 adenocarcinomas, 19 squamous carcinomas, and two melanomas) in whom conventional treatments were unsuccessful were treated with photodynamic therapy (PDT) after injection with either hematoporphyrin derivative or dihematoporphyrin ether. Patients underwent endoscopy again two to three days and one month after PDT and as needed when symptoms recurred. At one month, the average minimal diameter opening of 28 assessable tumors increased from 6 to 9 mm. Of the 35 patients who could be evaluated one month after PDT, the average improvement in food intake was from a liquid to a soft diet. Average survival time (from time of first treatment) was 7.7 months (n = 17) for adenocarcinoma, 5.8 months (n = 12) for squamous cell carcinoma, and 25 months (n = 2) for melanoma. Two patients with stage I adenocarcinoma were alive with no evidence of disease at 11 and 23 months. One patient with stage I squamous cell cancer died 18 months after PDT, with recurrence of tumor above the treated area noted eight months after treatment. One patient with stage I melanoma died of a synchronous colon cancer 31 months after PDT, with no evidence of residual melanoma.

Photodynamic therapy for esophageal malignancy: a prospective twelve-year study.

BACKGROUND: We wanted to determine factors affecting survival rates of benefits to, and complications in patients with esophageal cancer treated with photodynamic therapy. METHODS: From 1982 to January 1994, we used photodynamic therapy to treat 77 patients with esophageal carcinoma and evaluated survival to July 1994. All patients had failed, refused, or were ineligible for surgical intervention, ionizing radiation therapy, or chemotherapy. RESULTS: The only significant variable affecting survival was clinical stage. Median survival after photodynamic therapy was as follows: all patients, 6.3 months (mean survival, 9.2 months); stage I, not reached; stage II, 12 months; stage III, 6.2 months; and stage IV, 3.5 months. For stages III and IV, a Karnofsky performance status of 70 or higher had a significant effect. For stage III, the median survival was 6.3 months when the Karnofsky performance status was equal to or greater than 70 and 3.5 months when it was less than 70. For stage IV, the median survival was 5.5 months when the Karnofsky performance status was equal to or greater than 70 and 2.5 months when it was lower than 70. Seven stage I patients with no treatment prior to photodynamic therapy had an estimated 5-year survival rate of 62%. Three patients with stage I invasive adenocarcinoma and Barrett's mucosa diagnosed when they underwent endoscopy for dysphagia were alive with no evidence of disease 17, 44, and 59 months after photodynamic therapy. CONCLUSIONS: Photodynamic therapy for esophageal carcinoma caused minimal complications and no procedure-related deaths. Photodynamic therapy can be considered an alternative treatment for patients with Barrett's esophagus with severe dysplasia or patients with stage I carcinoma who are under consideration for operation but are high surgical risks. The length of palliation for patients having "noncurative" treatment was equal to or better than that reported historically for most other treatment regimens.

Adenosine mediates spinal norepinephrine-produced antinociception as revealed by nociceptive discharges in parafascicular neurons in rats.

The effects of intrathecal pretreatment with aminophylline on intrathecal norepinephrine-produced or serotonin-produced suppression of noxiously evoked discharges in thalamic parafascicular neurons were investigated in 35 urethane-anesthetized rats. The results showed that: (1) both intrathecal norepinephrine (15 nmol) or serotonin (20 nmol) produced significant suppression of noxiously evoked discharges in parafascicular neurons; (2) intrathecal aminophylline (120 nmol) blocked the norepinephrine-produced suppression of noxiously evoked discharges, while the same dose of aminophylline exhibited no significant effect on the serotonin-produced suppression of these discharges in parafascicular neurons. The results suggest that spinal norepinephrine-produced, but not serotonin-produced, antinociceptive effects may be mediated by adenosine as one of successive chemical links in the spinal dorsal horn circuitry.

Docetaxel and gemcitabine combinations in chemotherapy-pretreated non small-cell lung cancer.

Both docetaxel and gemcitabine are active against chemotherapy-pretreated non small-cell lung cancer (NSCLC). We previously demonstrated that weekly gemcitabine can be safely combined with monthly docetaxel with promising antineoplastic activity. In a recently completed phase II trial, 38 NSCLC patients failing upfront chemotherapy were treated with gemcitabine 800 mg/m2 on days 1, 8, and 15 and docetaxel 100 mg/m2 on day 1 every 4 weeks. The intent-to-treat response rate was 33% (95% CI: 19%-55%), with one complete and 11 confirmed partial responses. Responses were seen at all disease sites and in 31% of patients refractory to front-line chemotherapy. The median time to disease progression for the responders was 8 months, and two have remained progression-free for longer than a year. Hematological toxicities included grade 4 neutropenia in half of patients, febrile neutropenia in 10%, and grade 3-4 thrombocytopenia in 25%. The most prominent nonhematological toxicity was asthenia. We conclude that this doublet is active and safe, producing durable responses at all disease sites and in patients with platinum-refractory NSCLC.

Quality of life in patients with metastatic colorectal cancer receiving chemotherapy: a randomized, double-blind trial comparing 5-FU versus 5-FU with leucovorin.

We compared health-related quality of life (HQL) measures in 210 patients with metastatic colorectal cancer who were receiving equitoxic regimens of weekly 5-fluorouracil (5-FU) plus leucovorin (LV) or 5-FU alone in a multicenter, placebo-controlled, double-blind, randomized trial. The HQL was assessed during the first 120 days of treatment by the patient-generated functional living index-cancer (FLIC) questionnaire. Also assessed were clinician-generated measures to evaluate physical functioning and suffering: Karnofsky performance status (KPS), body weight, disease symptoms, and hospitalization. No significant difference was detected between treatment groups in HQL or in any measurement of efficacy or toxicity. The number of patients hospitalized was similar in both groups, 35 patients receiving 5-FU-LV, 32 receiving 5-FU-placebo, but those receiving 5-FU-LV were hospitalized longer (450 vs 315 total days). The KPS improved or stabilized in 23% and 37% of patients, respectively. Overall, FLIC scores significantly improved in 27% or remained stable in 62% of all patients; disease symptoms improved in 19-49%; a weight increase of 2 kg or more occurred in 27%. A change in FLIC was not associated with tumor response or improvement in pain, but a decline in FLIC was associated with improved survival. An improvement in KPS or weight was associated with tumor response and strongly correlated with survival. Improvement of pain was associated with a stable or increase in weight, and worsening of pain correlated with lack of tumor response.

Different GABA-receptor types are involved in the 5-HT-induced antinociception at the spinal level: a behavioral study.

The effects of intrathecally (i.t.) administered GABA(A)-receptor antagonist picrotoxin or bicuculline on the antinociception produced by i.t. serotonin (5-HT), gamma-aminobutyric acid (GABA), muscimol--the GABA(A) agonist or baclofen--the GABA(B) agonist were investigated and compared using the tail-flick assay in rats. The results showed that 1) both i.t. picrotoxin (1.5 nmol) and i.t. bicuculline (0.5 nmol) exhibited a partial and later-emerged blockade on the antinociception produced by 5-HT (120 nmol) or GABA (1.5 nmol); 2) both i.t. picrotoxin and i.t. bicuculline, with the same dosages, completely blocked the antinociception produced by muscimol (1.0 nmol), but showed no effects on that produced by baclofen (0.3 nmol). The results suggest that GABA may mediate the 5-HT-induced antinociception at the spinal level, with the GABA(B)-receptors exhibiting the effect at the early-stage and the GABA(A)-receptors at the later stage of the 5-HT-induced antinociception.

Hispanic women's breast and cervical cancer knowledge, attitudes, and screening behaviors.

PURPOSE: This study examined breast and cervical cancer knowledge, attitudes, and screening behaviors among different Hispanic populations in the United States. DESIGN: Data were collected from a random digit dial telephone survey of 8903 Hispanic adults from eight U.S. sites. Across sites, the average response rate was 83%. SETTING: Data were collected as part of the baseline assessment in a national Hispanic cancer control and prevention intervention study. SUBJECTS: Analysis was restricted to 2239 Hispanic women age 40 and older who were self-identified as either Central American (n = 174), Cuban (n = 279), Mexican American (n = 1550), or Puerto Rican (n = 236). MEASURES: A bilingual survey instrument was used to solicit information on age, education, income, health insurance coverage, language use, U.S.-born status, knowledge of screening guidelines, attitudes toward cancer, and screening participation. Differences in knowledge and attitudes across Hispanic groups were assessed by either chi-square tests or analysis of variance. Logistic regression models assessed the influence of knowledge and attitudes on screening participation. RESULTS: The level of knowledge of guidelines ranged from 58.3% (Mexican Americans) to 71.8% (Cubans) for mammography, and from 41.1% (Puerto Ricans) to 55.6% (Cubans) for Pap smear among the different Hispanic populations. Attitudes also varied, with Mexican Americans and Puerto Ricans having more negative or fatalistic views of cancer than Cuban or Central Americans. Knowledge was significantly related to age, education, income, language preference, and recent screening history. Overall, attitudes were not predictive of mammography and Pap smear behavior. CONCLUSIONS: Factors related to mammography and Pap smear screening vary among the different Hispanic populations. Limitations include the cross-sectional nature of the study, self-reported measures of screening, and the limited assessment of attitudes. The data and diversity of Hispanic groups reinforce the position that ethno-regional characteristics should be clarified and addressed in cancer screening promotion efforts. The practical relationships among knowledge, attitudes, and cancer screening are not altogether clear and require further research.