Sequential biochemical modulation of fluorouracil with folinic acid, N-phosphonacetyl-L-aspartic acid, and interferon alfa-2a in advanced colorectal cancer.

PURPOSE: Several agents have been evaluated for their effect as biochemical modulators of fluorouracil (5-FU) in the treatment of metastatic colorectal carcinoma. In this study, we used folinic acid (FA), N-phosphonacetyl-L-aspartic acid (PALA), and recombinant interferon alfa-2a (IFNalpha-2a) in a sequential order to assess the efficacy of this approach in patients with metastatic colorectal carcinoma. PATIENTS AND METHODS: Forty-four patients with metastatic colorectal carcinoma were enrolled onto the study. The treatment course consisted of three cycles: (cycle 1) FA 20 mg/m(2) followed by 5-FU 425 mg/m(2) on days 1 to 5; (cycle 2) PALA 250 mg/m(2) on days 29, 36, 43, and 50 and 5-FU 2,600 mg/m(2) as a 24-hour infusion on days 30, 37, 44, and 51; and (cycle 3) IFNalpha-2a 9 million units (MU) three times a week for 5 weeks beginning on day 57, with a continuous infusion of 5-FU 750 mg/m(2) on days 57 to 61, and then weekly bolus of 5-FU 750 mg/m(2)/wk on days 71, 78, and 85. Response was determined after cycle 3. RESULTS: All patients had a Zubrod performance status >/= 2, measurable disease, and had received no prior chemotherapy for their metastatic disease. A total of 212 cycles were given. Thirty-six patients were assessable for response. No complete responses were seen. Seven patients had a partial response, eight had stable disease, and 15 had progressive disease. The median duration of response was 25 weeks, and the median survival was 53 weeks. Grade 3 and 4 toxic effects included granulocytopenia, stomatitis, diarrhea, rash, nausea, and fatigue. CONCLUSION: This trial provided no evidence that sequential biochemical modulation of 5-FU in patients with metastatic colorectal carcinoma had any therapeutic advantage over conventional treatment regimens of 5-FU plus FA.

Randomized study of CODE versus alternating CAV/EP for extensive-stage small-cell lung cancer: an Intergroup Study of the National Cancer Institute of Canada Clinical Trials Group and the Southwest Oncology Group.

PURPOSE: To determine whether an intensive weekly chemotherapy regimen plus thoracic irradiation is superior to standard chemotherapy in the treatment of extensive-stage small-cell lung cancer (ESCLC). PATIENTS AND METHODS: Patients with ESCLC were considered eligible for the study if they were younger than 68 years, had a performance status of 0 to 2, and were free of brain metastases. Patients were randomized to receive cisplatin, vincristine, doxorubicin, and etoposide (CODE) or alternating cyclophosphamide, doxorubicin, vincristine/etoposide and cisplatin (CAV/EP). Consolidative thoracic irradiation and prophylactic cranial irradiation were given to patients responding to CODE and according to investigator discretion on the CAV/EP arm. RESULTS: The fidelity of drug delivery on both drug regimens was equal, and more than 70% of all patients received the intended protocol chemotherapy. Although rates of neutropenic fever were similar, nine (8.2%) of 110 patients on the CODE arm died during chemotherapy, whereas one (0.9%) of 109 patients died on the CAV/EP arm. Response rates after chemotherapy were higher (P =.006) with CODE (87%) than with CAV/EP (70%). However, progression-free survival (median of 0.66 years on both arms) and overall survival (median, 0.98 years for CODE and 0. 91 years for CAV/EP) were not statistically different. CONCLUSION: The CODE regimen increased two-fold the received dose-intensity of four of the most active drugs in small-cell lung cancer compared with the standard CAV/EP regimen while maintaining an approximately equal total dose. Despite supportive care (but not routine prophylactic use of granulocyte colony-stimulating factor), there was excessive toxic mortality with the CODE regimen. The response rate with CODE was higher than that of CAV/EP, but progression-free and overall survival were not significantly improved. In view of increased toxicity and similar efficacy, the CODE chemotherapy regimen is not recommended for treatment of ESCLC.

Second-line treatment of advanced measurable ovarian cancer with iproplatin: a Southwest Oncology Group study.

105 patients with advanced ovarian cancer previously treated with cisplatin or carboplatin were entered into a study of iproplatin as second-line therapy. Patients were either clinically resistant to cisplatin or carboplatin, or had relapsed after complete response to these agents. Patients were treated intravenously at an initial dosage of 270 mg/m2 with dosage adjustments to 340, 200 or 135 based on observed toxicity. Of 101 eligible patients, 7 responses (3 complete, 4 partial; 12%) were observed in 60 patients resistant to cisplatin. 2 partial responses (11%) occurred in 18 patients resistant to carboplatin. 2 complete and 3 partial responses were observed in 19 patients (26%) previously treated with but not resistant to cisplatin. Response durations were 2-20 months. Toxicities of iproplatin included thrombocytopenia in 93% of patients, leukopenia in 76% of patients, anaemia in 68% of patients, and diarrhoea in 40% of patients. Thus iproplatin shares cross-resistance with cisplatin and carboplatin in the treatment of ovarian cancer and is not recommended as an effective second-line agent for platinum-resistant ovarian cancer.

Phase I-II pilot of whole abdominal radiation and concomitant 5-FU as an adjuvant in colon cancer: a Southwest Oncology Group Study.

Thirty-eight patients with Stage B2, C1 or C2 colon cancer (Astler-Coller Modification of Dukes) received 3000 rads whole abdominal radiation and concomitant intermittent bolus 5-FU as part of a phase I-II adjuvant trial. Patients whose tumor penetrated the serosa (B2 or C2) in addition received a 1600 rad boost to the tumor bed. 5-FU was administered only during radiation. It was given at a dose of 300 mg/m2 days 1-5 and 28-32 in 21 patients (Group A) and day 1-3 and 28-31 in 17 patients (Group B). Median follow-up time for Group A is 44 months. Group A patients have a disease-free survival of 66% and overall survival of 73% at 44 months. The 16 C2 patients in Group A have a disease-free survival of 54% and overall survival of 65% at 44 months. There was a 26% incidence of moderate to severe acute toxicity in Group A but no long term bowel, liver, or hematologic toxicity. One patient developed acute myelogenous leukemia 2 years after treatment. Group B patients had only a 6% incidence of moderate to severe toxicity, but had a disease-free survival of 60% and overall survival of 100% at median follow-up of 23 months. Group B Stage C2 patients had a disease-free survival of 53% and overall survival of 100% at this same follow-up period. Disease-free and overall survival in Group A Stage C2 patients is superior to that in several published trials. Given the manageable toxicity, adjuvant whole abdominal radiation with concomitant 5-FU and tumor bed boost should be tested in a randomized fashion for possible therapeutic benefits.

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.

The addition of tamoxifen to dacarbazine and cisplatin in metastatic malignant melanoma. A phase II trial of the Southwest Oncology Group, (SWOG-8921).

Based on the reports of substantial improvement in the response rate w ith the addition of tamoxifen to a multiagent chemotherapy regimen for metastatic melanoma, Southwest Oncology Group (SWOG)-8921 was initiated. A prior regimen (SWOG-8804) of dacarbazine (DTIC) 750 mg/m(2) i.v. day 1 and cisplatin 100 mg/m(2) day 1 repeated every 3 weeks produced a 13% response rate in patients with metastatic melanoma without brain metastasis. SWOG-8921 using identical chemotherapy and schedule added tamoxifen 10 mg twice daily. There were 55 eligible patients registered, median age 52, with 37 men and 18 women. Fifty (91%) patients had evidence of visceral metastasis at registration. There were 10 responders (2 complete and 8 partial responses) for an 18% response rate (95% CI, 9-31%). The response rate in women was 28% (95% CI, 10-53%; in men, 14% (95% CI, 5-29%). Tamoxifen has produced a small increase in the response rate when added to the present combination and schedule of chemotherapy. Further Phase III trials will be necessary to assess whether there is a statistical advantage to the use of tamoxifen when combined with chemotherapy and whether there are statistical differences between men and women.

Rheology of acrylic denture-base polymers.

The aim of this study was to investigate the changing rheological behavior of a denture-base polymer from mixing to setting. In addition, monomer evaporation and exothermic behavior of the mix were evaluated. The results show that the material behaves as a pseudoplastic fluid. It is shown that the viscosity increases at different rates with respect to lapsed time, and increases with higher temperature. Also, it is shown that polymerization and monomer evaporation both play a part in dough formation.

Studies on the preparation and characterization of monodisperse polystyrene latices. VI. Preparation of zwitterionic latices.

The preparation of zwitterionic latex particles is reported by using a mixed anionic and cationic initiator system without requiring surface-active agents. Isoelectric points were found from microelectrophoresis experiments and were in the pH range of 3.5-5. Close to the isoelectric point, the latices coagulated as expected, and good stability was achieved outside this narrow range. This range of stability was in good agreement with predictions from current theory. Redispersion after coagulation was found to be difficult as was expected for a hydrophobic colloid. The electrokinetic behavior did not result in the maximum in zeta potential at an electrolyte concentration of 1 mM unlike the situation for other hydrophobic polystyrene latex particles, and hence these systems may be even better models for other colloidal studies.

The strategy of fetal risk management.

Current concepts of perinatal intensive care seem to place disproportionate emphasis on sophisticated electronic and biochemical techniques. There is a need for a balanced approach to the strategy of fetal risk management: the planning, the timing, and the decision making. Ten basic principles underlying good perinatal care are presented. All pregnancies should be assumed to be at risk until it can be proved otherwise. Ideally, no fetus should be submitted to the acknowledged risks of labor until one has some reasonably precise information of the extent to which that fetus is at risk before labor begins. A plea is made for greater communication between the attending physician and those physicians who may well be involved with the care of the infant during and after labor and delivery.

Quantitative indices of short- and long-term heart rate variability.

Two quantitative indices of heart rate variability are proposed. Instantaneous variability is defined as the average of the absolute value of instantaneous rate differences over a 30 second interval. It is sensitive to short-term variability changes. Bandwidth variability is defined as twice the standard deviation of instantaneous heart rates over a 30 second interval, and it is a measure of long-term variability. The rationale for the choice of these indices is discussed, and they are compared with other published indices of variability. Samples of computer printout of instantaneous and bandwidth variability obtained from fetal heart rate records are given.

Chemotherapy sensitivity assessment of leukemic colony-forming cells with in vitro simultaneous exposure to multiple drugs: clinical correlations in acute nonlymphocytic leukemia.

For 13 patients with acute nonlymphocytic leukemia receiving four-drug combination chemotherapy (14 chemotherapy trials), leukemic bone marrow cells were obtained before treatment and were exposed in vitro to all four-drug-mixture solutions simultaneously followed by the survival assessment of leukemic colony-forming cells (L-CFU). Survival of normal marrow colony-forming cells (CFU-C) was also assessed concurrently, and the sensitivity index (SI) of leukemic cells was determined as the ratio of the survival of CFU-C to that of L-CFU. Correlations of in vitro results to clinical results were excellent: four of five trials resulting in complete remission had high SI and eight of nine trials without complete remission had low SI (P = 0.02). The potential advantages of this method of exposing cells to drug mixture are discussed in terms of detecting drug synergism and improving the efficiency of in vitro chemotherapy sensitivity studies.

Chemotherapy of malignant fibrous histiocytoma: a Southwest Oncology Group report.

Malignant fibrous histiocytoma is a rare tumor, which constitutes 3-4% of the soft tissue sarcomas. It occurs with maximum frequency in the sixth and seventh decades of life and has a distinct male preponderance. In two-thirds of the patients an extremity is the primary site and approximately one-half develop local recurrences and one-half, distant metastases. Response to combination chemotherapy occurred in 33%, a rate similar to that seen in other sarcomas.

A phase II evaluation of tamoxifen in unresectable or refractory meningiomas: a Southwest Oncology Group study.

Twenty-one patients with nonresectable refractory meningiomas were registered on a study giving tamoxifen 40 mg per M2 b.i.d. for four days, then 10 mg b.i.d. thereafter. Nineteen were eligible and evaluated for response. One patient (5%) achieved an MRI-documented partial response while two had a minor response measured on CT scan which was of short duration (4 and 20 months). Six patients (32%) remained stable for a median duration of 31 + months while ten (53%) demonstrated progression. Twenty-two percent (22%) reported subjective improvement though this did not correlate with objective improvement in all cases. At present, a definite recommendation for the use of tamoxifen in refractory meningiomas cannot be made. Further evaluation of hormonal therapy of meningiomas with a consensus for definition of endpoints for evaluation of response in view of the difficulty of evaluating radiologic findings with clinical outcome, is needed.

A weekly cisplatin-based induction regimen for extensive non-small cell lung cancer. A Southwest Oncology Group study.

The purpose of this Phase II pilot study was to determine whether a dose-intensive regimen of weekly cisplatin combined with other active non-cross-resistant agents would improve the response rate and survival time of patients with extensive non-small cell lung cancer. Patients received cisplatin (50 mg/m2/wk) on days 1, 8, 15, 22, 36, 43, 50, and 57 combined with mitomycin C (8 mg/m2) on days 1 and 36, vinblastine (3 mg/m2) on days 8 and 43, and 5-fluorouracil (5-FU) (1 g/m2) by continuous infusion over 24 hours on days 15 and 50. Responding patients received consolidation therapy with cisplatin and etoposide (VP-16). Of 82 registered patients, 80 were eligible and 77 were evaluable for response. The overall response rate was 23% with 1 patient achieving a complete response (CR) and 17 patients achieving a partial response (PR). The median survival time was 4.6 months. The toxicity profile was not different from that described for standard-dose regimens. Although this regimen does not offer any benefit over standard-dose cisplatin regimens for patients with extensive non-small lung cancer, the weekly schedule permits a dose-intensive regimen with acceptable toxicity for tumors that may benefit from this approach.

Cisplatin and novobiocin in the treatment of non-small cell lung cancer. A Southwest Oncology Group study.

Novobiocin, a commercially available oral antibiotic, inhibits DNA topoisomerase II in a manner shown in cell culture to enhance the cytotoxicity of alkylating agents and cisplatin. Thirty-six patients were entered on a Phase II trial using high-dose cisplatin (100 mg/m2 on days 1 and 8 for four cycles) after steady-state dosing with novobiocin (1000 mg or four 250-mg capsules every 12 hours for six doses, four of which were administered before each dose of cisplatin). One patient remains on study and cannot be evaluated for response. No complete responses were seen. Three patients (8%) had partial responses and an additional patient had an unconfirmed partial response. The median survival time of all patients was just less than 7 months. These results are comparable with those of other concurrent Southwest Oncology Group (SWOG) Phase II and III trials of high-dose cisplatin in non-small cell lung cancer (NSCLC). Novobiocin plasma levels were obtained for three patients and were approximately 50% of the optimal concentration as reported in cell culture for potentiation of cytotoxicity. It was concluded that an optimum test of novobiocin as a modulator of cytotoxicity may require the availability of an intravenous preparation.

Prediction of chemotherapy response in human leukemia using an in vitro chemotherapy sensitivity test on the leukemic colony-forming cells.

An in vitro test system to quantitatively assess the chemotherapy sensitivity of human acute leukemic colony-forming cells (L-CFU) in relation to normal granulocytic precursor cells (CFU-C) has been developed. After simultaneous exposure of leukemic and normal bone marrow cells to individual drugs in vitro, cells were grown using an improved agar culture method with daily feeding. A sensitivity index (SI) was determined as the ratio of survival fraction of CFU-C to that of L-CFU, L-CFU being more (or less) sensitive than CFU-C if the SI were higher (or lower) than unity. Thirty SI were determined for 6 single drugs actually given in various combinations to a total of 9 patients (8 with acute nonlymphocytic leukemia and 1 with chronic myelomonocytic leukemia). A highly significant correlation was observed between high (or low) SI and achievement of (or failure to achieve) complete remission, with only 6 false correlations (p = 0.0013). Also, the mean of these SI (MSI) for the multiple single drugs given to each patient as components of a combination chemotherapy was used to indicate an overall sensitivity for each trial of the chemotherapy. Among the 10 chemotherapy trials (1 trial each for 8 patients and 2 trials for 1 patient), 4 trials resulting in complete remission had MSI higher than 1.0, and 6 trials not resulting in complete remission had MSI lower than 1.0 (p = 0.0048). This assay system appears useful in predicting the response of patients to chemotherapy and in the selection of the most effective drugs for use in individual patients.

Phase II evaluation of echinomycin (NSC-526417) in patients with central nervous system malignancies. A Southwest Oncology Group study.

The objective of this trial was to determine the efficacy of echinomycin (1.2 mg/m2) administered on a weekly times four schedule in the treatment of patients with recurrent or progressive central nervous malignancies despite adequate radiotherapy. Thirty-five patients were registered on study. The majority of patients (20) had glioblastoma multiforme. Ten had anaplastic astrocytoma. Eight patients had received prior nitrosoureas. SWOG performance status was 1 in 11 patients and 2 in 22. The median age was 51 years (25-75 years). One patient had a partial remission (3%:95% confidence interval: 1%-16%). Twenty two patients had progressive disease. The median survival was 5.9 months. Toxicity was primarily gastrointestinal with nausea and vomiting in 13 patients and nausea only in 11 patients. Hepatotoxicity occurred in 10 patients. Echinomycin given at this dose and schedule is not effective in treating patients with recurrent or progressive glioblastoma multiforme or anaplastic astrocytomas.