A randomized, multicenter study of subcutaneous and intravenous darbepoetin alfa for the treatment of chemotherapy-induced anemia.

BACKGROUND: This randomized, open-label study evaluated the efficacy, safety and pharmacokinetics of darbepoetin alfa administered intravenously (i.v.) or subcutaneously (s.c.) in chemotherapy-induced anemia. PATIENTS AND METHODS: Patients received darbepoetin alfa i.v. (n=59) or s.c. (n=59) at a dose of 4.5 mug/kg once weekly for 6 weeks (correction phase) followed by 4.5 mug/kg once every 3 weeks for the remainder of the 18-week treatment period (maintenance phase). RESULTS: During the correction phase, the mean [95% confidence interval (CI)] change in hemoglobin (intention-to-treat) was 1.1 (0.6-1.5) g/dl in the i.v. group and 1.3 (0.9-1.7) g/dl in the s.c. group; using available data, the mean change was 1.4 (1-1.9) g/dl and 1.6 (1.2-2) g/dl, respectively. The percentage (95% CI) of patients maintaining hemoglobin (i.e. average decrease < or =0.5 g/dl) during the maintenance phase was similar between the i.v. (82%; 95% CI 66% to 92%) and s.c. (80%; 95% CI 66% to 90%) groups. Thirty-five per cent (95% CI 20% to 50%) of patients in the i.v. group and 32% of patients in the s.c. group (95% CI 18% to 45%) received red blood cell transfusions during week 5 to the end of the treatment period. Darbepoetin alfa was well tolerated in both groups. No significant difference (P=0.36) in weekly darbepoetin alfa serum concentrations was observed between groups. CONCLUSIONS: Darbepoetin alfa can be administered i.v. or s.c. at equal doses for the treatment of anemia in this setting.

Assessment of psychological distress in prospective bone marrow transplant patients.

Patient psychological distress is associated with many aspects of the bone marrow transplantation (BMT) process and has been linked with poor treatment outcomes. We assessed psychological distress in potential BMT candidates, and compared patient and nurse coordinator ratings of emotional distress at the time of initial BMT consultation. Fifty patients self-reported psychological distress using both the NCCN Distress Thermometer (DT) and the Hospital Anxiety and Depression Scale (HADS). Coordinators rated patient emotional distress using the DT and Coordinator Rating Scales that measure anxiety and depression. Fifty and 51% of patients self-reported clinically significant levels of emotional distress and anxiety, respectively, but only 20% self-reported clinically significant levels of depression. There was good correlation between ratings using the brief DT and the more comprehensive HADS. There was significant but only moderate agreement between patient and coordinator ratings of emotional distress and anxiety, with coordinators underestimating the number of patients with high levels of emotional distress. In addition, coordinator ratings of patient emotional distress primarily reflected anxiety, whereas anxiety and depression together only minimally accounted for patient self-reports of psychological distress. These findings suggest that: (1) the DT can be a useful screening device; (2) approximately half of patients at the time of initial consultation for BMT already experience significant levels of psychological distress; and (3) coordinators observe emotional distress primarily as anxiety, but patients experience psychological distress as something more than anxiety and depression.

Frequency and clinical significance of the expression of the multidrug resistance proteins MDR1/P-glycoprotein, MRP1, and LRP in acute myeloid leukemia: a Southwest Oncology Group Study.

Therapeutic resistance is a major obstacle in the treatment of acute myeloid leukemia (AML). Such resistance has been associated with rapid drug efflux mediated by the multidrug resistance gene 1 (MDR1; encoding P-glycoprotein) and more recently with expression of other novel proteins conferring multidrug resistance such as MRP1 (multidrug resistance-associated protein 1) and LRP (lung resistance protein). To determine the frequency and clinical significance of MDR1, MRP1, and LRP in younger AML patients, we developed multiparameter flow cytometric assays to quantify expression of these proteins in pretreatment leukemic blasts from 352 newly diagnosed AML patients (median age, 44 years) registered to a single clinical trial (SWOG 8600). Protein expression was further correlated with functional efflux by leukemic blasts [assessed using two substrates: Di(OC)(2) and Rhodamine 123] and with the ability of MDR-reversing agents to inhibit efflux in vitro. MDR1/P-glycoprotein expression, which was highly correlated with cyclosporine-inhibited efflux, was noted in only 35% of these younger AML patients, distinctly lower than the frequency of 71% we previously reported in AML in the elderly (Blood 89:3323, 1997). Interestingly, MDR1 expression and functional drug efflux increased with patient age, from a frequency of only 17% in patients less than 35 years old to 39% in patients aged 50 years (P =.010). In contrast, MRP1 was expressed in only 10% of cases and decreased with patient age (P =. 024). LRP was detected in 43% of cases and increased significantly with increasing white blood cell counts (P =.0015). LRP was also marginally associated with favorable cytogenetics (P =.012) and French-American-British (FAB) AML FAB subtypes (P =.013), being particularly frequent in M4/M5 cases. Only MDR1/P-glycoprotein expression and cyclosporine-inhibited efflux were significantly associated with complete remission (CR) rate (P(MDR1) =.012; P(efflux) =.039) and resistant disease (RD; P(MDR1) =.0007; P(efflux) =.0092). No such correlations were observed for MRP1 (P(CR) =.93; P(RD) =.55) or LRP (P(CR) =.50; P(RD) =.53). None of these parameters were associated with overall or relapse-free survival. Unexpectedly, a distinct and nonoverlapping phenotype was detected in 18% of these cases: cyclosporine-resistant efflux not associated with MDR1, MRP1, or LRP expression, implying the existence of other as yet undefined efflux mechanisms in AML. In summary, MDR1 is less frequent in younger AML patients, which may in part explain their better response to therapy. Neither MRP1 nor LRP are significant predictors of outcome in this patient group. Thus, inclusion of MDR1-modulators alone may benefit younger AML patients with MDR1(+) disease.

Estrogen receptor methylation is associated with improved survival in adult acute myeloid leukemia.

Estrogen receptor methylation (ERM) is a frequent molecular alteration in adult acute myeloid leukemia (AML). In this study, we sought to determine the clinical characteristics and prognostic significance of ERM in AML. ERM was determined for 268 patients who had leukemic blasts available for molecular analysis. ERM was measured by Southern blot analysis, and results were obtained for 261 patients (ages 17-69). ERM ranged from 0-99.1%, with a median of 25%. One hundred sixty patients (61%) had ERM values over 15% and were considered ERM+. In a subset of patients analyzed, ERM+ samples had markedly lower ER gene expression compared with ERM- samples. In multiple regression analyses of patient and disease characteristics at diagnosis, two factors had significant independent association with ERM: ERM decreased with increasing age (P = 0.0001) and was significantly lower in patients with French-American-British classification M4 or M5 (P = 0.0019). In regression analyses of outcome measures, ERM had no significant impact on complete remission rate after initial induction therapy. However, ERM+ patients had significantly better overall survival [OS; 18% at 6 years; 95% confidence interval (CI), 12-24% versus 9%; CI, 3-14% for ERM- patients; P = 0.022]. In multiple regression analyses, OS increased with increasing ERM (P = 0.0044). Similar results were seen for relapse-free survival (23% at 6 years; CI, 15-32% for ERM+ versus 10%; CI, 2-19% for ERM-), although the effect of ERM was not statistically significant (P = 0.15 in multiple regression analysis). Our results indicate that ERM at diagnosis may be a favorable prognostic factor for OS in adult AML.

A randomized investigation of high-dose versus standard-dose cytosine arabinoside with daunorubicin in patients with previously untreated acute myeloid leukemia: a Southwest Oncology Group study.

Interest in high-dose cytarabine (HDAC) for both induction and postremission therapy for acute myeloid leukemia (AML) prompted the Southwest Oncology Group (SWOG) to initiate a randomized trial comparing HDAC with standard-dose cytarabine (SDAC) for remission induction of previously untreated AML and to compare high-dose treatment versus conventional doses for consolidation therapy. Patients less than 65 years of age with de novo or secondary AML were randomized for induction between SDAC 200 mg/ m2/d for 7 days by continuous infusion or HDAC at 2 g/ m2 intravenously every 12 hours for 12 doses; both groups received daunorubicin (DNR) at 45 mg/m2/d intravenously for 3 days. Complete responders to SDAC were randomized to receive either two additional courses of SDAC plus DNR or one course of HDAC plus DNR. Complete responders to HDAC were nonrandomly assigned to receive one additional course of HDAC plus DNR. Of patients randomized between SDAC (n = 493) and HDAC (n = 172) induction, 361 achieved complete remission (CR). The CR rate was slightly poorer with HDAC: 55% versus 58% with SDAC for patients aged less than 50, and 45% (HDAC) versus 53% (SDAC) for patients aged 50 to 64 (age-adjusted one-tailed P = .96). With a median follow-up time of 51 months, survival was not significantly better with HDAC (P = .41); the estimated survival rate at 4 years was 32% (HDAC) versus 22% (SDAC) for those aged less than 50, and 13% (HDAC) versus 11% (SDAC) for those aged 50 to 64. However, relapse-free survival was somewhat better following HDAC Induction (P = .049): 33% (HDAC) versus 21% (SDAC) at 4 years for those aged less than 50, and 21% (HDAC) versus 9% (SDAC) for those aged 50 to 64. Induction with HDAC was associated with a significantly increased risk of fatal (P = .0033) and neurologic (P < .0001) toxicity. Among patients who achieved CR with SDAC, survival and disease-free survival (DFS) following consolidation randomization were not significantly better with HDAC compared with SDAC (P = .77 and .46, respectively). Patients who received both HDAC induction and consolidation had the best postremission outcomes; however, the proportion of CR patients who did not go on to protocol consolidation therapy was more than twice as high after HDAC induction compared with SDAC. Induction therapy with HDAC plus DNR was associated with greater toxicity than SDAC plus DNR, but with no improvement in CR rate or survival. Following CR induction with SDAC, consolidation with HDAC increased toxicity but not survival or DFS. In a nonrandomized comparison, patients who received both HDAC induction and consolidation had superior survival and DFS compared with those who received SDAC induction with either SDAC or HDAC consolidation.

Correlation of multidrug resistance (MDR1) protein expression with functional dye/drug efflux in acute myeloid leukemia by multiparameter flow cytometry: identification of discordant MDR-/efflux+ and MDR1+/efflux- cases.

Resistance to chemotherapy is a major factor limiting successful treatment of acute myeloid leukemia (AML); one of the best characterized drug resistance mechanisms is extrusion of drugs by the energy-dependent multidrug resistance (MDR1) transport protein. Expression of MDR1 is common in AML and has been linked to lower remission induction rates and decreased remission durations. Because MDR1 efflux function may be modified by drugs such as cyclosporin A, accurate identification of MDR1+/efflux+ AML cases will be critical to identify patients who may benefit from therapies that contain such MDR1 modulators. We have optimized single and multiparameter flow cytometric assays to detect efflux of drugs or fluorescent dyes by previously cryopreserved AML blasts. These assays allowed precise identification of efflux by leukemic blasts, and correlation with CD34 and MDR1 expression. We subsequently studied a series of 60 previously untreated AML cases. Functional efflux was identified in 39 cases and was significantly correlated with MDR1 expression (P = .0002). However, discrepant cases were identified; 10 cases were efflux+ without significant MDR1 expression, whereas 6 MDR1+ cases were efflux-. There was also a highly significant correlation of efflux with CD34; 31 (79%) of the 39 efflux+ cases were CD34+ in comparison with only 5 (24%) of the 21 efflux- cases (P < .0001). Multivariate analysis showed that efflux was significantly associated with independent effects of both CD34 (P = .0011) and MDR1 expression (P = .034); the majority of efflux+ cases were CD34+, whereas 5 of the 6 MDR1+ efflux- cases lacked CD34 expression. Cyclosporin A blocked efflux in all but 2 cases regardless of MDR1 expression. Functional efflux in AML is frequently detected without the classic MDR1+ phenotype indicating that alternate non-MDR1-mediated efflux mechanisms may be important. Efflux assays may better identify patients who would benefit from therapies that include efflux modulators.

Effect of aggressive daunomycin therapy on survival in acute promyelocytic leukemia.

The Southwest Oncology Group analyzed outcome with cytotoxic chemotherapy for previously untreated acute myeloblastic leukemia (AML) from 1982 through 1986. Results with acute promyelocytic leukemia (APL) prompted comparison with patients from 1986 through 1991 and analysis of factors contributing to APL results. Patient and disease characteristics and treatment outcome were compared for all evaluable patients, with more detailed analysis of factors affecting APL treatment outcome. From 1982 through 1986, median survival and disease-free survival in 45 APL patients were 106 months and greater than 105 months, respectively, versus 6 and 14 months for 417 other AML patients. Such differences were not seen from 1986 through 1991. In the 141 APL patients from 1982 through 1991, after adjusting for significant patient and disease characteristics, higher daunomycin (DNR) doses during induction were significantly associated with higher complete remission rates (P < .0001), longer survival (P < .0001), and longer DFS (P < .0001). Cytosine arabinoside (Ara-C) induction dose, the inclusion of other chemotherapy agents in induction, postremission therapy (consolidation, maintenance, or bone marrow transplantation) other than DNR, APL subtype, and patient age did not appear to significantly affect outcome of APL, except for a significant detrimental effect of high-dose Ara-C in consolidation (P = .0042). Morphologic AML subtypes other than APL did not affect outcome. We conclude that high-dose DNR selectively increases survival in APL. This good survival is important for evaluation of combined all-trans retinoic acid (ATRA)/chemotherapy protocols and for planning future combinations of chemotherapy and ATRA. These results illustrate the need to individualize chemotherapy for subtypes of AML. Therapeutic response of APL is independent of age. Except for APL, morphologic subclassification of AML contributed little prognostic information.

Concurrent cisplatin/etoposide plus chest radiotherapy followed by surgery for stages IIIA (N2) and IIIB non-small-cell lung cancer: mature results of Southwest Oncology Group phase II study 8805.

PURPOSE: To assess the feasibility of concurrent chemotherapy and irradiation (chemoRT) followed by surgery in locally advanced non-small-cell lung cancer (NSCLC) in a cooperative group setting, and to estimate response, resection rates, relapse patterns, and survival for stage subsets IIIA(N2) versus IIIB. PATIENTS AND METHODS: Biopsy proof of either positive N2 nodes (IIIAN2) or of N3 nodes or T4 primary lesions (IIIB) was required. Induction was two cycles of cisplatin and etoposide plus concurrent chest RT to 45 Gy. Resection was attempted if response or stable disease occurred. A chemoRT boost was given if either unresectable disease or positive margins or nodes was found. RESULTS: The median follow-up time for 126 eligible patients [75 stage IIIA(N2) and 51 IIIB] was 2.4 years. The objective response rate to induction was 59%, and 29% were stable. Resectability was 85% for the IIIA(N2) group eligible for surgery and 80% for the IIIB group. Reversible grade 4 toxicity occurred in 13% of patients. There were 13 treatment-related deaths (10%) and 19 others (15%) died of causes not related to toxicity or tumor. Of 65 relapses, 11% were only locoregional and 61% were only distant. There were 26 brain relapses, of which 19 were the sole site or cause of death. There was no survival difference (P = .81) between stage IIIA(N2) versus stage IIIB (median survivals, 13 and 17 months; 2-year survival rates, 37% and 39%; 3-year survival rates, 27% and 24%). The strongest predictor of long-term survival after thoracotomy was absence of tumor in the mediastinal nodes at surgery (median survivals, 30 v 10 months; 3-year survival rates, 44% v 18%; P = .0005). CONCLUSION: This trimodality approach was feasible in this Southwest Oncology Group (SWOG) study, with an encouraging 26% 3-year survival rate. An Intergroup study is currently being conducted to determine whether surgery adds more to the risk or to the benefit of chemoRT.

Aggressive multimodality therapy for malignant pleural mesothelioma.

Nineteen patients with clinical stage I malignant pleural mesothelioma were treated with aggressive multimodality therapy. Nine patients underwent pleurectomy and decortication followed by immediate intrapleural chemotherapy with cisplatin and mitomycin C. Ten patients required pleuropneumonectomy followed within 1 week to 2 weeks by intrapleural administration of cisplatin (100 mg). Four to 8 weeks after operation, 15 patients underwent postoperative adjuvant cisplatin-based systemic chemotherapy. There were three postoperative complications (16%) requiring reoperation and one postoperative death (5%). Intrapleural chemotherapy was well tolerated with no complications. Systemic chemotherapy was poorly tolerated, and there was one chemotherapy-related death. Sixteen patients (84%) experienced good to excellent palliation. Three patients are currently alive with no evidence of recurrent disease at 10, 35, and 43 months. The median overall survival was 13 months and the median disease-free survival, 11 months. Overall and disease-free 3-year survivals were 17% and 22%, respectively. Patients with epithelial malignant pleural mesothelioma had significantly better overall survival (p = 0.037) and disease-free survival (p = 0.02) than patients with sarcomatous or biphasic malignant pleural mesothelioma. We conclude that despite major toxicity, in select patients with clinical stage I malignant pleural mesothelioma, aggressive multimodality therapy offers effective palliation and occasional long-term disease-free survival.

Phase II study of carboplatin (CBDCA) in refractory multiple myeloma. A Southwest Oncology Group study.

Nineteen patients with multiple myeloma resistant to standard alkylating agent therapy or to the VAD regimen received carboplatin at a planned daily dose of 100 mg/M2 on four successive days. Two patients erroneously received a four-fold higher drug dose resulting in bone marrow aplasia and death without antitumor effect in one patient with post-mortem examination. No anti-tumor effect was observed among 15 patients evaluable for response (two lacked follow-up examination of tumor markers). Major toxicities were hematologic and included grade > or = III, leukopenia in 9, thrombocytopenia in 6 and anemia in 3 of the 17 evaluable patients. Their median survival was 9 months. These results indicate that carboplatin is inactive in refractory multiple myeloma.

Extended administration of oral etoposide and oral cyclophosphamide for the treatment of advanced non-small-cell lung cancer: a Southwest Oncology Group study.

PURPOSE: We designed an all-oral regimen of etoposide and cyclophosphamide for use in advanced non-small-cell lung cancer. PATIENTS AND METHODS: Eligible patients were chemotherapy-naive and had histologically confirmed assessable or measurable stage IV non-small-cell lung cancer. Patients received etoposide 50 mg/m2/d orally days 1 through 14 and cyclophosphamide 50 mg/m2/d orally days 1 through 14 every 28 days. Doses on later cycles were adjusted for myelosuppression. RESULTS: Sixty-six patients (64 eligible patients) received 192 cycles of oral extended etoposide/cyclophosphamide therapy (median, two cycles; range, zero to 15). Therapy was well tolerated with the mean dose per cycle being 104% of the originally scheduled dose. Two patients (3%) achieved a complete response and six (9%) achieved a partial response. Leukopenia, anemia, nausea/vomiting, and alopecia were the most common toxicities. Median survival was 6 months, and the 1-year survival rate was 25.6%, comparable to more intensive treatments. CONCLUSION: Oral extended etoposide/cyclophosphamide is a well-tolerated alternative for the treatment of stage IV non-small-cell lung cancer and can be used as a basis for the design of further outpatient regimens.

A phase I trial of combination fludarabine monophosphate and chlorambucil in chronic lymphocytic leukemia: a Southwest Oncology Group study.

Fludarabine monophosphate is a new antimetabolite with demonstrated activity in chronic lymphocytic leukemia (CLL). We have investigated the practicality of utilizing fludarabine in combination with chlorambucil in a disease-specific phase I trial. Twenty-one patients with advanced and previously treated, relapsed or refractory CLL were treated with chlorambucil plus fludarabine. Chlorambucil was given day 1 at 15 or 20 mg/m2 per os and fludarabine days 1-5 at 10, 15, or 20 mg/m2 intravenously, every 28 days. We concluded that with chlorambucil 15 mg/m2, the maximum tolerated dose for fludarabine was 20 mg/m2 in this patient population with this scheduling. Dose-limiting toxicity was thrombocytopenia. A low incidence of peripheral neuropathy, rash, pulmonary fungal infection, and acute tumor lysis syndrome was also encountered. Although responses were observed, it was impossible from this study to determine whether the combination was better than fludarabine alone in this heavily pretreated population. This study does, however, demonstrate the feasibility of exploring the utility of such a combination in previously untreated patients. An intergroup phase III trial utilizing this combination has been initiated.

Phase II trial of ifosfamide and cisplatin in the treatment of metastatic sarcomas: a Southwest Oncology Group study.

The Southwest Oncology Group (SWOG) performed a phase II trial of a combination of ifosfamide/mesna/cisplatin in patients with metastatic soft-tissue sarcoma who had previously received one chemotherapeutic regimen. A total of 39 patients were registered in the study, including 7 treated during a limited-institution pilot phase; 38 patients were fully eligible and evaluable. During the pilot phase, patients were treated with 2.5 g/m2 ifosfamide daily on days 1-3, 2.5 g/m2 mesna daily on days 1-4, and 100 mg/m2 cisplatin on days 2 and 9. Due to excessive myelosuppression, the day-9 cisplatin dose was dropped when the study was opened groupwide, and the subsequent 32 patients were treated at 3- to 4-week intervals with 2.5 g/m2 ifosfamide daily on days 1-3, 2.5 g/m2 mesna daily on days 1-4, and 100 mg/m2 cisplatin on day 2. Myelosuppression was severe, with granulocytopenia (< 0.5 x 10(9)/l) being observed in 26 of 38 patients. Three cases of National Cancer Institute grade 3 or 4 nephrotoxicity (serum creatinine, > 3 times the normal value) and three cases of grade 3 or 4 central nervous system toxicity were reported. Overall, three complete and five partial responses were achieved, for a major response rate of 21%. The median survival of all patients was 11 months. We conclude that ifosfamide-based chemotherapy can produce objective responses in previously treated patients with metastatic soft-tissue sarcoma but that cisplatin increases the toxicity of therapy. Phase II trials of new agents are needed to identify drugs with clinical activity in the treatment of soft-tissue sarcomas.

Phase I study of WR-2721 and carboplatin.

Because WR-2721 reduces the toxicity of cisplatin and carboplatin in preclinical systems, we have treated 35 patients in a phase I study of WR-2721 and carboplatin. As the plasma half-life of WR-2721 is short relative to that of carboplatin, WR-2721 was administered in two divided doses. This schedule produced acceptable toxicity in 24 patients treated with carboplatin 400 mg/m2 and escalating doses of WR-2721. In the subsequent 11 patients, WR-2721 was fixed at 740 mg/m2/dose and the dose of carboplatin was escalated. With WR-2721, grade 3-4 thrombopenia (platelets < 50 x 10(9)/l) was produced in 4/5 patients treated with carboplatin 625 mg/m2 and in 1/6 patients treated with carboplatin 500 mg/m2. Carboplatin pharmacokinetic parameters in 4 patients were similar to those reported for carboplatin alone. These results suggest that WR-2721 might increase the maximum tolerated dose of carboplatin from 400 to 500 mg/m2.

Precursor Langerhans cell histiocytosis. An unusual histiocytic proliferation in a patient with persistent non-Hodgkin lymphoma and terminal acute monocytic leukemia.

BACKGROUND: Langerhans cell precursors are considered to be identical to their mature counterparts except for the lack of Birbeck granules. Proliferations composed of such histiocytes appear to be uncommon. METHODS: Standard immunophenotypic, molecular genetic, and DNA content studies were used to characterize various hematopoietic disorders, including a proliferation of precursor Langerhans cells, which arose sequentially in a patient. RESULTS: The patient studied initially had a low-grade, B-cell, non-Hodgkin lymphoma and subsequently had an unusual histiocytic proliferation (precursor Langerhans cell histiocytosis) in cutaneous and lymph node sites. The patient eventually died of acute myelogenous leukemia (FAB, M5). CONCLUSIONS: A larger series is required to determine the significance of the precursor Langerhans cell phenotype, particularly with respect to the development of acute myelogenous leukemia.

Comparison of cisternal and lumbar CSF examination in leptomeningeal metastasis.

We compared cisternal and lumbar CSF examination in 14 patients suspected of having leptomeningeal metastasis from cancer. Malignant cells were present in 12 patients--in both cisternal and lumbar CSF in nine patients and only in cisternal CSF in three. Cisternal CSF cytologic examination should be considered in patients suspected of having leptomeningeal metastasis if lumbar CSF is nondiagnostic.

Current dermatologic laser applications in patient care.

Laser is an acronym for Light Amplification by Stimulated Emission of Radiation. Current clinical applications of lasers are changing the practice of dermatology. Research and the changing practice significantly impact dermatologic nursing practice.

A Southwest Oncology Group phase II Trial of recombinant tumor necrosis factor in metastatic breast cancer.

New approaches are needed in the treatment of advanced breast cancer. In vitro studies have shown that recombinant tumor necrosis factor (TNF) is a growth inhibitor for the MCF-7, ZR-75-1, and BT-20 human breast cancer cell lines. Based on these considerations, the Southwest Oncology Group performed a Phase II trial of recombinant TNF (Genentech) (150 micrograms/m2) given by 30-minute intravenous infusion on days 1 to 5 of every other week for 8 weeks. Patients with metastatic breast cancer who had received one prior chemotherapy regimen for advanced disease were eligible. Of the 22 patients who were entered, 3 were ineligible. Nineteen patients who had a performance status of 2 or less could be examined (median age, 53 years). One possible fatal toxic reaction has been seen in a patient who had intracranial bleeding caused by a previously undiagnosed brain metastasis; no other treatment-related deaths have occurred. Toxicity has included nausea, vomiting, fever, chills, myalgia, and fatigue. No Grade 4 toxicity has been observed. Grade 3 toxic reactions have included hypotension (two patients), diarrhea (one patient), transient leukopenia (two patients), and reversible elevations of liver function test values (two patients). No objective responses have been observed. Twelve of 19 patients have died (median survival time, 8.5 months). Recombinant TNF is inactive as a single agent in patients with previously treated metastatic breast cancer.

A randomized trial of five cisplatin-containing treatments in patients with metastatic non-small-cell lung cancer: a Southwest Oncology Group study.

Six hundred eighty assessable patients with measureable stage III M1, non-small-cell lung cancer (NSCLC) were randomized to one of five treatment arms including cisplatin, etoposide (VP-16) +/- methylglyoxal bisguanylhydrazone (MGBG; PVp, PVpM); cisplatin, vinblastine (PVe); or PVe alternating with vinblastine, mitomycin (PVeMi); or fluorouracil, vincristine, mitomycin/cyclophosphamide, doxorubicin, cisplatin (FOMi/CAP). The overall response rate was 20% with 3% complete responses and 17% partial remissions. The duration of these responses was not statistically different by treatment regimen and varied from 2.7 months to 5.0 months. The overall median survival for all patients was 5.3 months and is not different by treatment. Toxicity was greater in PVpM. The similarity of results for response, duration of response, and survival does not establish the superiority of any of these platinum-based regimens for standard clinical usage.