Phase I/II trial of high dose mitoxantrone in metastatic breast cancer: the M.D. Anderson Cancer Center experience.

Anthracyclines are among the most active agents in metastatic breast cancer. Mitoxantrone demonstrated a different toxicity profile when compared to doxorubicin. We performed a phase I/II study of single-agent high-dose mitoxantrone therapy for advanced breast cancer. Nineteen patients who had a diagnosis of metastatic breast cancer received treatment at the M.D. Anderson Cancer Center between June 1986 and December 1987. The patients received escalating doses of mitoxantrone until a maximum tolerated dose (MTD), defined as grade 3 or 4 nonhematologic toxicity or infection, was obtained. The starting dose of 25 mg/m2, given by short intravenous infusion, was escalated by 25% in each five-patient cohort if each patient in the previous cohort tolerated the initial course and 2 or fewer patients reached the MTD. The median cumulative dose of mitoxantrone was 93 mg/m2 (range, 25-205) and the maximum single dose was 39 mg/m2. Myelosuppression was the dose limiting toxicity. The median duration of granulocyte count < or = 250/microl was 5-7 days. Four patients (22%) had infections that required hospitalization, 3 patients (17%) had cardiac toxicity. One patient (6%) achieved a complete response, and 3 (17%) had a partial response, with an overall response rate of 22.3%. No apparent dose-response relationship was observed in our study. The mitoxantrone dosage recommended for phase II studies is 25 mg/m2 every 3-4 weeks. We conclude that high-dose mitoxantrone therapy for metastatic breast cancer was relatively well tolerated but was not associated with a higher response rate than that of standard dose mitoxantrone.

IDEC-C2B8 (Rituximab) anti-CD20 monoclonal antibody therapy in patients with relapsed low-grade non-Hodgkin's lymphoma.

IDEC-C2B8 is a chimeric monoclonal antibody (MoAb) directed against the B-cell-specific antigen CD20 expressed on non-Hodgkin's lymphomas (NHL). The MoAb mediates complement and antibody-dependent cell-mediated cytotoxicity and has direct antiproliferative effects against malignant B-cell lines in vitro. Phase I trials of single doses up to 500 mg/m2 and 4 weekly doses of 375 mg/m2 showed clinical responses with no dose-limiting toxicity. We conducted a phase II, multicenter study evaluating four weekly infusions of 375 mg/m2 IDEC-C2B8 in patients with relapsed low-grade or follicular NHL (Working Formulation groups A-D). Patients were monitored for adverse events, antibody pharmacokinetics, and clinical response. Thirty-seven patients with a median age of 58 years (range, 29 to 81 years) were treated. All patients had relapsed after chemotherapy (median of 2 prior regimens) and 54% had failed aggressive chemotherapy. Infusional side effects (grade 1-2) consisting of mild fever, chills, respiratory symptoms, and occasionally hypotension were observed mostly with the initial antibody infusion and were rare with subsequent doses. Peripheral blood B-cell depletion occurred rapidly, with recovery beginning 6 months posttreatment. There were no significant changes in mean IgG levels and infections were not increased over what would be expected in this population. Clinical remissions were observed in 17 patients (3 complete remissions and 14 partial remissions), yielding an intent to treat response rate of 46%. The onset of these tumor responses was as soon as 1 month posttreatment and reached a maximum by 4 months posttreatment. In the 17 responders, the median time to progression was 10.2 months (5 patients exceeding 20 months). Likelihood of tumor response was associated with a follicular histology, with the ability to sustain a high serum level of antibody after the first infusion, and with a longer duration of remission to prior chemotherapy. One patient developed a detectable but not quantifiable immune response to the antibody that had no clinical significance. IDEC-C2B8 in a dose of 375 mg/m2 weekly for 4 weeks has antitumor activity in patients with relapsed low-grade or follicular NHL. Results with this brief, outpatient treatment compare favorably with results with standard chemotherapy, and IDEC-C2B8 has a better safety profile. Further studies evaluating IDEC-C2B8 in other types of lymphoma either alone or combined with chemotherapy are warranted.

GM-CSF secretion in primary cultures of normal and cancerous human renal cells.

Rates of secretion of granulocyte-macrophage colony stimulating factor (GM-CSF) were measured in 50 primary cell cultures derived from cancerous and normal human kidneys. Mean rates of GM-CSF secretion measured by TF-1 cell proliferation assay (N = 21) and by ELISA (N = 31) were 2.5 and 7.8 ng/10(6) cells/24 hr, respectively. There was no significant difference between the mean rates of GM-CSF secretion by cancerous and normal renal cells. GM-CSF was also secreted by primary renal cell cultures grown in serum-free medium and by renal cell lines. GM-CSF mRNA was detected by RT-PCR in cultured renal cells, but not in undissociated kidney tissue. Rates of GM-CSF secretion were reduced up to 99% under conditions where the cellular density or substratum more closely resembled the in vivo environment. Some cultured human renal carcinoma cells (RCC) secreted GM-CSF at levels that occasionally overlapped the levels produced by the GM-CSF gene-modified human RCC vaccine now in phase I trial. The data indicate that GM-CSF is not expressed in vivo, and that stable GM-CSF secretion is induced by the dissociation and culture of human renal cells.

Randomized placebo-controlled trial of granulocyte-macrophage colony-stimulating-factor support for dose-intensive cyclophosphamide, etoposide, and cisplatin.

This is a double-blind randomized placebo-controlled trial to evaluate the efficacy and safety of granulocyte-macrophage colony-stimulating-factor (GM-CSF) after dose-intensive cyclophosphamide, etoposide, and cisplatin (DICEP). Fifty-six patients with lymphoma or breast carcinoma were randomized to receive GM-CSF 250 microg/m2 or placebo subcutaneously (SC) every 12 hr after each course of DICEP until recovery of absolute neutrophil count (ANC) of 1.5 x 10(9)/L. Each patient was to receive three courses of DICEP. There were 28 patients in each group. The median duration of ANC below 0.5 x 10(9)/L was 10 versus 12 days for Course 1 (P = 0.010), 10 versus 12 days for Course 2 (P = 0.248), and 16.5 versus 15 days for Course 3 (P = 0.126); platelet counts below 20 x 10(9)/L was 4 versus 4 days for Course 1 (P = 0.586), 8.5 versus 7 days for Course 2 (P = 0.013), and 23.5 versus 10.5 days for Course 3 (P = 0.104); hospitalization for patients readmitted with cytopenic fever were 4 versus 8 days for Course 1 (P = 0.035); 7 versus 6 days for Course 2 (P = 0.692); and 8 versus 12 days for Course 3 (P = 0.884) in the GM-CSF and placebo group, respectively. GM-CSF significantly shortens the duration of neutropenia and readmission only during the first course of DICEP. There was a delay in platelet recovery and an increase in transfusion requirement during subsequent courses in the GM-CSF group. The result cautions the routine use of lineage specific hematopoietic growth factors in supporting repeated cycles of dose-intensive chemotherapy.

Measurement of quality of life in patients with lung cancer in multicenter trials of new therapies. Psychometric assessment of the Lung Cancer Symptom Scale.

BACKGROUND: This study continued the development and psychometric testing of the Lung Cancer Symptom Scale (LCSS), a disease- and site-specific instrument primarily measuring the physical and functional dimensions of quality of life for individuals with lung cancer. The instrument contains two scales, one for patients and a counterpart for health professionals as observers. METHODS: Feasibility, reliability, construct validity, and criterion-related validity were evaluated with 207 patients with non-small cell lung cancer (NSCLC) from six cancer centers. Within an interview with an observer, patients completed part of a battery of instruments by self-report and were interviewed for the remaining measures. Observers also completed measures after the interview. RESULTS: Feasibility, reliability, and validity were well supported for this lung cancer population. Feasibility was demonstrated by patient and staff compliance in completion at all six cancer centers. Internal consistency was good, with coefficient alphas of 0.82 for the patient scale and 0.75 for the observer scale. Construct validity was supported by 1. contrasted groups approach: regression lines (with 95% confidence bands) were obtained between the Karnofsky performance scale (KPS) and each of the two LCSS scales; 2. as a refinement, relationship testing: significant correlations between the LCSS and KPS for each item (except hemoptysis for the patient scale); and 3. multitrait-multimethod approach: good reliability (alphas ranging from 0.75 to 0.93), good convergent validity for the two LCSS scales (r = 0.77), and a good discriminant validity pattern from the Brief Symptom Inventory (BSI). Criterion-related validity with relevant gold standard measures (American Thoracic Society Questionnaire [ATS] and McGill Pain questionnaire, KPS, Profiles of Mood States [POMS], and Sickness Impact Profile [SIP]) was supported with significant correlations (0.40-0.67 for the LCSS patient scale; 0.54-0.65 for the LCSS observer scale). CONCLUSIONS: These psychometric properties demonstrate that the LCSS patient and observer scales are feasible, reliable, and valid quality of life measures that are ready for research and clinical use with lung cancer populations.

Multiple cycles of dose-intensive cyclophosphamide, etoposide, and cisplatinum (DICEP) produce durable responses in refractory non-Hodgkin's lymphoma.

Patients whose lymphoma is resistant to standard treatment regimens continue to do poorly, with only an occasional patient achieving long-term remission even with bone marrow transplantation. Twenty-three patients with primarily refractory (11), or refractory relapsed (12) non-Hodgkin's lymphoma were treated with repeated cycles of dose-intensive cyclophosphamide, etoposide, and cisplatin (DICEP) without bone marrow transplantation. Each cycle of DICEP consisted of cyclophosphamide (2500 mg/m2/day, days 1-2), etoposide (500 mg/m2/day, days 1-3), and cisplatin (50 mg/m2/day, days 1-3). Twelve patients (52%) have achieved a complete response and 6 (26%)r a partial response. Three of the complete responders remain continuously free of disease for 19, 29, and 32 months, and 3 more are disease-free at 58, 59, and 65 months after receiving further therapy. Three-year survival for all patients is 45%. Patients with a good initial performance status (Zubrod 0 or 1) had a 58% complete response rate and a 2-year survival rate of 53%. One of 19 patients with an initial performance status of 0 or 1 had treatment-related mortality. Repeated cycles of DICEP can produce long-term responses in patients with refractory non-Hodgkin's lymphoma.

GM-CSF, carboplatin, doxorubicin: a phase I study.

Dose intensification has the potential to increase the response frequency of chemosensitive tumors to chemotherapy. G-CSF and GM-CSF offer the possibility of dose-intensifying chemotherapy without prohibitive myelosuppression. A phase I study was undertaken to identify the maximum tolerated dose (MTD) of carboplatin that could be administered with a fixed dose of doxorubicin, 60 mg/m2, administered every 28 days. Further escalation of the carboplatin dose was then attempted, with the concomitant addition of GM-CSF 10 mg/kg per day on days 1-21. We had 21 patients, 13 with prior therapy, who were eligible. In all, 60 courses of therapy were delivered, all with doxorubicin and with carboplatin doses of 250 mg/m2, 325 mg/m2 and 400 mg/m2. At carboplatin 400 mg/m2 and doxorubicin 60 mg/m2, thrombocytopenia was dose limiting. The addition of GM-CSF did not allow further escalation. Of the 6 patients treated with carboplatin 400 mg/m2, doxorubicin 60 mg/m2, and GM-CSF, grade 4 granulocytopenia and thrombocytopenia were seen in 4 and 5 patients, respectively. The severity of thrombocytopenia was related to the calculated carboplatin AUC and also to baseline platelet count and prior therapy. In addition, the interaction of GM-CSF and chemotherapy, especially carboplatin-based, may be more complex than originally anticipated.

Failure of GM-CSF to permit dose-escalation in an every other week dose-intensive regimen for advanced breast cancer.

BACKGROUND: In an attempt to improve dose intensity and therapeutic effectiveness in breast cancer, GM-CSF was incorporated into a multi-drug every other week chemotherapy regimen that had been previously reported to have promising activity, but whose dose-limiting toxicity was neutropenia. PATIENTS AND METHODS: A Phase I-II study in patients with locally advanced or metastatic breast cancer was initiated using GM-CSF and a 5-drug chemotherapy regimen employing oral cyclophosphamide daily for 7 days and doxorubicin, vincristine, methotrexate, 5-fluorouracil, and leucovorin IV every 2 weeks for 10 courses. In the first 8 patients, GM-CSF in escalating doses (1-20 micrograms/kg s.c. per day) was given on days 8-13 of each 2 week cycle. In the last 12 patients, GM-CSF was given on days 3-14 of each cycle in an attempt to improve its effectiveness by prolonging treatment duration. RESULTS: The regimen was poorly tolerated. Only 10 patients completed all 10 courses of treatment, and most of those required dose delays and/or reductions. GM-CSF failed to reduce neutropenia when given by either schedule. Furthermore, thrombocytopenia was severe and progressive, especially with the more prolonged GM-CSF schedule in which the mean lowest nadir platelet count was 15,000/microliters. Anemia, fatigue, mucositis, and neutropenic fevers were also common, and dose escalations were not possible in any patient. Central venous catheter complications were also common. Complete or partial remissions were observed in 15 of 20 patients, but response durations were brief. CONCLUSIONS: GM-CSF in two different schedules failed to ameliorate myelosuppression when used in combination with this multiple drug, every other week regimen. Neutropenia and, especially, thrombocytopenia remained dose limiting.

Hematopoietic cytokines. Current use in cancer therapy.

The introduction of hematopoietic cytokines into the clinic has been rapid with three currently approved by the Food and Drug Administration and perhaps a dozen more in clinical trials. Combinations of cytokines have been relatively unexplored in the clinics. Knowledge about the use of cytokines with chemotherapy has grown considerably in the past few years. The literature relating to use of cytokines in support of standard chemotherapy, marrow failure syndromes associated with malignant disease, and dose intensification not requiring progenitor cell replacement has been reviewed. This review does not address the use of cytokines to support bone marrow transplantation and collection of progenitor cells. Hematopoietic cytokines shorten the duration of cytopenia and decrease infectious complications when used to support standard chemotherapy regimens. However, several randomized trials have failed to show a benefit of such cytokine-supported treatment programs in terms of antitumor response, palliation, or survival. One exception is granulocyte-macrophage colony stimulating factor used with aggressive but standard chemotherapy for high-risk non-Hodgkin lymphoma. Cytokines decrease the infectious complications of myelodysplastic syndromes and may decrease transfusion requirements. Marked escalations in chemotherapy doses are possible with specific chemotherapy regimens. These increase complete remission rates although no benefit in survival or palliation has yet been proven. Cytokines have not been effective in allowing escalation of doses with certain chemotherapy agents and regimens. Cytokines decrease hematopoietic toxicity with standard or escalated chemotherapy doses. Randomized trials are now beginning to define the true patient benefit of this capability.

Granulocyte-macrophage colony-stimulating factor given before dose-intensive cyclophosphamide, etoposide, and cisplatin (DICEP).

Substantial increases in dose-intensity of chemotherapy yield a severalfold increase in complete remission rates and durable responses in several types of malignant disease. Hematopoietic colony-stimulating factors decrease the duration of the resultant severe neutropenia but optimal dosing regimens of these cytokines have not yet been determined. This study was designed to explore the use of both yeast-derived and E. coli-derived GM-CSF given pre- and postchemotherapy with an intensive combination chemotherapy regimen. The chemotherapeutic regimen consisted of cyclophosphamide 5000 mg/m2, etoposide 1500 mg/m2, and cisplatin 150 mg/m2 (DICEP). Patients receiving either yeast-derived GM-CSF (6.5 days) or E. coli-derived GM-CSF (6.0 days) had a shorter duration of severe granulocytopenia with an absolute granulocyte count below 300/microL than patients receiving no GM-CSF (11.0 days, p = 0.0001). Administration of GM-CSF for 6 days immediately preceding DICEP did not further shorten the duration of cytopenia. E. coli-derived GM-CSF given at doses above 5 micrograms/kg was poorly tolerated and offered no hematologic advantage. Lower doses (3 micrograms/kg) of the E. coli product were better tolerated but still produced more toxicities than yeast-derived GM-CSF. The yeast-derived product produced no local skin reactions and decreased the incidence of nonhematologic and all grade 3 or 4 toxicities compared to the control group.

Granulocyte-macrophage colony-stimulating factor with dose-intensified treatment of cancer.

GM-CSF decreases the hematopoietic toxicity of both nonablative and marrow ablative intensive chemotherapy regimens. Data are limited at this time, particularly in regard to optimal schedules and GM-CSF dosing regimens with particular chemotherapy programs. The importance of GM-CSF scheduling in relationship to chemotherapy is becoming more clear. The dose-intensive regimens supported by GM-CSF produce a high complete remission rate in several types of malignancy. Evidence that these remissions will be durable is still lacking. Future directions will include filling some of these voids in our knowledge, as well as exploring various cytokine combinations for improved hematopoietic recovery and other chemotherapeutic regimens for improved antitumor effect. The near complete cytoreduction produced by these dose-intensive regimens may also create a better setting for attempts at therapeutic immunomodulation. Yet another, but more difficult, task will be to identify those situations where progenitor cell replacement is beneficial and appropriate.

Dosing regimen of granulocyte-macrophage colony-stimulating factor to support dose-intensive chemotherapy.

PURPOSE: This trial evaluated the optimum dosing regimen for recombinant human granulocyte-macrophage colony-stimulating factor (rhu GM-CSF) to support a dose-intensive chemotherapy regimen given without progenitor cell replacement. PATIENTS AND METHODS: Fifty-one patients with refractory malignancy received cyclophosphamide 2,500 mg/m2 on days 1 and 2, etoposide 500 mg/m2 on days 1, 2, and 3, and cisplatin 50 mg/m2 on days 1, 2, and 3. Patients were hospitalized from cycle days 1 to 4 for chemotherapy and readmitted for cytopenic temperatures above 38.5 degrees C. Cycles were repeated every 35 days in patients who responded to a total of three cycles. GM-CSF was given at doses of 250 to 1,000 micrograms/m2 by continuous intravenous infusion (CIV) or subcutaneously starting on cycle days 3 to 6. Two nonrandomized control groups are used. RESULTS: The optimum regimen of GM-CSF for shortening the duration of leukopenia (WBC count less than 300/microL) was 500 micrograms/m2 given CIV. Duration of leukopenia was 5.9 days compared with 13.2 and 10.2 days in the controls (P less than .05). The optimum regimens for shortening duration of hospitalization, however, were 500 and 750 micrograms/m2/d given as divided (twice daily) subcutaneous injections. Durations of hospitalization were 9.6 and 9.8 days compared with 15.7 and 22.2 days in the controls (P less than .08). At the higher GM-CSF dose, only 36% of patients required readmission for cytopenic fever. Toxicities of GM-CSF at clinically useful doses were minimal. Twelve patients had complete response (24%) and 22 partial response (43%). CONCLUSIONS: This dose-intensive regimen can be given safely without progenitor replacement. rhu GM-CSF decreases the duration of severe leukopenia and decreases the need for hospitalization and antibiotic therapy.

Hematopoietic colony-stimulating factors. Uses in combination with standard chemotherapeutic regimens and in support of dose intensification.

BACKGROUND: Three hematopoietic colony-stimulating factors (CSF) are currently approved for clinical use and several more are being used in clinical trials. These factors have impressive quantitative and/or functional effects on their respective target cell lines, but their best clinical uses have not been defined. METHODS: The literature regarding the use of CSF in standard chemotherapy is reviewed data and from early Phase I-II studies the use of granulocyte-macrophage CSF (GM-CSF) in support of dose intensification without progenitor cell replacement are presented. Dose intensive cyclophosphamide (5000 mg/m2), etoposide (1500 mg/m2), and cisplatin (150 mg/m2) (DICEP) were administered during 3 days, followed by CSF until hematologic recovery was achieved. Patients had advanced types of cancer unlikely to respond to standard chemotherapy. RESULTS: CSF can shorten the duration of leukocyte nadirs when given with standard chemotherapy, but a benefit to patients in terms of improved survival or quality of life has not been shown. Dose intensification has increased partial and complete response rates in several tumor types. The higher complete remission rate may translate into improved survival; no convincing data have been published to date supporting that possibility. The duration of severe leukopenia (absolute neutrophil count, less than 100/microliters) after DICEP can be shortened from 8.5 days to 5-6 days with either granulocyte CSF (G-CSF) or GM-CSF. GM-CSF has been shown to decrease the duration of hospital stay from 18.7 to 9.6 days and to decrease the need for readmittance to the hospital for cytopenic fever. A high complete remission rate (35%) was seen in patients with breast cancer and durable complete remissions were achieved in patients with refractory non-Hodgkin lymphoma. CONCLUSIONS: CSF shortens the duration of postchemotherapy leukocyte nadirs and allows maintenance of dose when this is essential for a beneficial outcome. Substantial dose escalations are also possible with CSF support and can produce a high complete response rate that offers hope for improved survival in selected patients.

A Southwest Oncology Group Phase I study of the sequential combination of recombinant interferon-gamma and recombinant interleukin-2 in patients with cancer.

Thirty-seven patients with advanced malignancies were treated sequentially with recombinant interferon-gamma (rIFN-gamma) and recombinant interleukin-2 (rIL-2) in an outpatient dose escalation clinical trial. rIFN-gamma (0.1 or 0.25 mg/m2/day) was administered by intramuscular injection, days 1-7 and rIL-2 (12, 18, or 24 x 10(6) IU/m2/day) was administered by a 15-min intravenous bolus, days 8-12. Common toxicities encountered included fever, chills, fatigue, neutropenia, and elevations of SGOT, bilirubin, or creatinine. Hypotension and cardiac and pulmonary toxicities were rare. With repeated cycles of therapy, nausea/vomiting and diarrhea associated with the administration of rIL-2 were seen in greater frequency. There were no treatment-related deaths, and no patient required intensive care unit admission for toxicity management. A complete response was observed in one of 11 patients with renal cancer and a partial response was observed in one of seven patients with malignant melanoma. Due to problems with drug supply, further dose escalation could not be continued, and maximum tolerated doses (MTD) were not determined by strict criteria. However, the combination of rIFN-gamma, 0.25 mg/m2/day, and rIL-2, 24 x 10(6) IU/m2/day, appeared to be beyond the MTD, as three of six patients at this dose level could not complete one cycle of therapy due to toxicity. It is unlikely that higher doses of either agent would be tolerated, and for further study using this schedule, we recommend the doses: rIFN-gamma, 0.1 mg/m2/day, and rIL-2, 24 x 10(6) IU/m2/day.

Dose-intensive treatment of breast cancer supported by granulocyte-macrophage colony-stimulating factor (GM-CSF).

Substantial intensification of chemotherapy doses is a promising approach to the treatment of refractory malignancy currently receiving increasing attention. For the past 4 years we have used 3 repeated cycles of a combination of cyclophosphamide (5 g/m2), etoposide (1500 mg/m2), and cisplatin (150 mg/m2) without replacement of progenitor cells and with and without colony-stimulating factor support. The duration of threatening levels of granulocytopenia with this regimen averages 10.2 days, although an occasional patient has prolonged recovery (range, 5-20 days) and most patients require antibiotic therapy for cytopenic fever. We have not yet identified the optimal dose of GM-CSF, but 500 micrograms/m2 significantly shortens the duration of cytopenia (ANC less than 300/mm3) to 5.9 days with a resultant decrease in incidence and duration of cytopenic fever (from 10.8 to 1.7 days), use of antibiotics (from 10.8 to 7.6 days), and duration of hospitalization (from 22.2 to 16.3 days). Seventeen patients with metastatic breast cancer have received this regimen to date with a 35% complete response (CR) rate and a 53% partial response (PR) rate. Most of these patients were refractory to standard therapy. Four of six (67%) not refractory to standard therapy have achieved complete responses that are ongoing at 3.5 to 10.4 months. We conclude that dose-intensive therapy is an option that needs more careful exploration early in the treatment of advanced breast cancer and that GM-CSF decreases morbidity and risk of dose-intensive regimens.

Use of colony-stimulating factors in combination with high-dose chemotherapy.

Recent clinical trials of two hematopoietic cytokines, granulocyte- and granulocyte-macrophage colony stimulating factors, in combination with chemotherapy, have shown that they allow substantially higher doses of chemotherapeutic agents to be used. Administering cytokines decreased the length of time for granulocyte recovery, the incidence of infection, the need for antibiotics, as well as shortening the duration of hospitalizations. Current work is focusing on the use of cytokines to stimulate circulating progenitor cells for pheresis and replacement. There are still striking gaps, however, in our knowledge of the interactions of the various cytokines with each other and with chemotherapeutic agents.

Vinblastine fails to improve response of renal cancer to interferon alfa-n1: high response rate in patients with pulmonary metastases.

One hundred sixty-five patients were randomized to receive either interferon alfa-n1 (Wellferon; Burroughs Wellcome Co, Research Triangle Park, NC) alone or with vinblastine. An initial six-cycle induction treatment consisted of interferon given at daily doses of 3, 5, 20, 20, and 20 x 10(6) U/m2 every 2 weeks. Vinblastine at a dose of 10 mg/m2 (later decreased to 5 mg/m2) was given on day 1 of alternate cycles. Toxicities were generally well tolerated. The overall response rate was 10% with no significant difference between treatment arms. Survival was also not significantly different for the arms. A small subset of patients (16) with metastases only to the lungs had a high complete response (CR) and partial response (PR) rate of 44%. Responses were durable, and overall survival of this group was much better than that of the other patients.

Phase II study of pibenzimol in pancreatic cancer. A Southwest Oncology Group study.

Twenty-three patients with advanced pancreatic adenocarcinoma were treated with Pibenzimol utilizing a daily intravenous schedule for five days. There were no objective responses seen. The major toxicity was pancreatic with grade 3 hyperglycemia in eleven patients. Pibenzimol is inactive in patients with advanced pancreatic adenocarcinoma.

Phase I study of repeated cycles of high-dose cyclophosphamide, etoposide, and cisplatin administered without bone marrow transplantation.

Forty-two patients with advanced malignancy judged unlikely to respond to standard treatment received high-dose combination chemotherapy with cyclophosphamide, etoposide, and cisplatin in a phase I trial. Twenty-two of these patients who had at least a partial response (PR) to the first cycle of therapy received a second cycle, and eight patients received three or more cycles of therapy. Bone marrow replacement was not used. The maximum-tolerated doses (MTDs) were cyclophosphamide 2.5 g/m2 on days 1 and 2; etoposide 500 mg/m2 on days 1, 2, and 3; and cisplatin 50 mg/m2 on days 1, 2, and 3. Hematologic toxicity was not dose-limiting by study design. Recovery to an absolute granulocyte count above 100/microL occurred at a median of 9 days from onset (range, 3 to 23 days) at the MTD. Recovery was delayed after the third cycle. Only one patient on his third cycle failed to recover peripheral blood counts and died of sepsis an day 43. Hematologic toxicity was not dose-dependent. Nonhematologic toxicities included emesis, fatigue, alopecia, diarrhea, and anorexia and were generally well tolerated. The dose-limiting toxicities were fatal pulmonary or cardiac toxicities in five of nine patients treated at the highest dose level. Patients likely to do well can be selected by tumor type, response to prior therapy, and performance status. Nine of 36 assessable patients had a complete response (CR) and 13 a PR for a response rate of 61%. Five patients (12%) remain alive and free of disease at 15 to 32 months. Repeated cycles of dose-intensive combination therapy can produce long-term disease-free remissions in patients with refractory tumor types. The toxicity of the regimen is acceptable if patients are carefully selected.