Evaluation of a somatostatin analog in the treatment of lymphoproliferative disorders: results of a phase II North Central Cancer Treatment Group trial.

PURPOSE: Malignant cells from non-Hodgkin's lymphomas (NHL) have been shown to express the somatostatin receptor on their cell surface and most NHL are visible on somatostatin radioscintigraphy scans. This provided the rationale to conduct a phase II trial of a somatostatin analog in patients with B- and T-cell lymphoproliferative disorders. PATIENTS AND METHODS: Sixty-one patients with measurable or assessable lymphoproliferative disorders (31 stage III or IV low-grade NHL; 21 chronic lymphocytic leukemia [CLL]; and nine cutaneous T-cell NHL [CTCL]) were enrolled. Patients were treated with somatostatin 150 micrograms subcutaneously (SQ) every 8 hours for 1 month. Patients with stable or responding disease received 2 additional months of therapy; those who responded after 3 months were treated for an additional > or = 3 months. RESULTS: Sixty patients were assessable for toxicity and 56 for response. There were no complete remissions. In the low-grade NHL group, 36% (10 of 28 patients; 95% confidence interval [CI], 19% to 56%) had a partial remission. Forty-four percent (four of nine; 95% CI, 14% to 79%) of patients with CTCL had a partial response. No patients with CLL had a partial remission. Among 45 patients with stable disease or a partial remission, the mean time to progression (TTP) was 10.9 months (median, 6.2; range, 1.6 to 48.5). The drug was well tolerated, with the most common side effects being diarrhea and hyperglycemia. CONCLUSION: Somatostatin at a dose of 150 micrograms every 8 hours is well tolerated and has activity in low-grade NHL.

A phase III clinical trial comparing the combination cyclophosphamide, adriamycin, cisplatin with cyclophosphamide, 5-fluorouracil, prednisone in patients with advanced breast cancer.

We assessed the efficacy of a regimen consisting of four cycles of cyclophosphamide, Adriamycin (Adria Laboratories, Inc, Columbus, Ohio), cisplatin (CAP) followed by maintenance with cyclophosphamide, 5-fluorouracil, prednisone (CFP) compared with CFP alone in a randomized trial of 86 patients with advanced breast cancer. The objective regression rates were 46% (CFP) and 49% (CAP with CFP) which included complete regression rates of 7% (CFP) and 4% (CAP with CFP). The median time to progression was nine months for CFP and six months for CAP with CFP. Median survival in the CFP group was 18 months v 11 months in the CAP recipients. Due to the therapeutic trend in favor of patients receiving CFP, we terminated the study before achieving our initially projected accrual. We observed over a twofold excess of substantial nausea and vomiting among patients receiving the platinum-based regimen. In our view, the CAP followed by the CFP regimen is a more toxic program that offers no clinically meaningful improvement over CFP to patients with advanced breast cancer.

Randomized clinical trial of tamoxifen alone or combined with fluoxymesterone in postmenopausal women with metastatic breast cancer.

A randomized clinical trial was performed to determine if combination hormonal therapy with tamoxifen (TAM) and fluoxymesterone (FLU) was more efficacious than TAM alone for the treatment of postmenopausal women with metastatic breast cancer. Patients failing TAM could subsequently receive FLU. The dose of both drugs was 10 mg orally twice daily. Objective responses were seen in 50 of 119 TAM patients (42%) and 63 of 119 TAM plus FLU patients (53%) (one-sided P = .05). Time to disease progression distributions were better for TAM plus FLU (median, 350 days v 199 days), but the log rank test only approached statistical significance (one-sided P = .07). Duration of response and survival distributions were similar between the two treatment arms. Toxicities, in terms of androgenic side effects, were greater on the TAM plus FLU regimen. Fifty-two patients are evaluable for response with FLU following TAM and 21 (40%) have achieved a response. We conclude that the advantages in terms of response rate and time to progression observed with TAM plus FLU probably represent a biological effect, but are not of sufficient magnitude to justify the routine clinical use of this combination given the lack of survival advantage and side effects encountered.

A controlled evaluation of recent approaches to biochemical modulation or enhancement of 5-fluorouracil therapy in colorectal carcinoma.

Three hundred thirty-five previously untreated patients with advanced colorectal carcinoma were randomly assigned to treatment with 5-fluorouracil (5-FU) alone, 5-FU plus N-(phosphonacetyl)-L-aspartic acid (PALA), 5-FU plus high-dose thymidine, 5-FU plus levamisole, or 5-FU plus methyl CCNU, vincristine, and streptozotocin (MOF-Strept). Dosages were designed to produce definite toxicity in the majority of patients, although the nature of dose-limiting reactions varied considerably among regimens. 5-FU alone and 5-FU plus levamisole produced mucocutaneous reactions, diarrhea, and leukopenia; 5-FU plus PALA produced primarily mucocutaneous reactions and diarrhea; 5-FU plus thymidine produced leukopenia with occasional neurotoxicity and hypotension; and MOF-Strept produced substantial nausea and vomiting with both thrombocytopenia and leukopenia. Objective response rates among patients with measurable disease varied from 12% (5-FU plus PALA) to 34% (MOF-Strept), but none of the regimens were significantly superior to 5-FU alone. Both interval to progression and survival were comparable among the five regimens with no reasonable chance that any combination regimen could produce as much as a 50% improvement when compared with 5-FU alone. Whereas we observed definite modulation of 5-FU dose--toxicity relationships, particularly with the thymidine and PALA combinations, this did not result in a detectable improvement in therapeutic effect. None of the combination regimens, administered in the dosages and schedules we used, can be recommended as standard therapy of advanced colorectal carcinoma.

Treatment of limited-stage small-cell lung cancer with cyclophosphamide, doxorubicin, and vincristine with or without etoposide: a randomized trial of the North Central Cancer Treatment Group.

In this randomized study involving patients with limited-stage small-cell lung cancer (LD-SCC), we compared treatment with either cyclophosphamide; doxorubicin, and vincristine (CAV) or CAV plus etoposide (CAVE). All patients received identical thoracic radiation consisting of 3,750 cGy in 15 fractions and prophylactic cranial radiation (3,000 cGy in 10 fractions). Among 231 evaluable patients, the two treatment arms were well matched with respect to sex, age, performance score, and presence or absence of heart disease. A major regression (REGR) was observed in 83% of all patients and a complete response (CR) in 60%. There was no difference in the response rate between the two treatment regimens. The median time to progression is 10.4 months (95% confidence interval [Cl], 8.9 to 12 months) for CAVE versus 8.9 months (95% Cl, 7.9 to 10.4 months) for CAV (P = .04). The median survival is 15.1 months (95% Cl, 11.7 to 17.8 months) for CAVE versus 12.4 months (95% Cl, 11 to 14.4 months) for CAV. This difference is not significantly different (P = .13). Toxicity was primarily myelosuppression and was significantly greater for the four-drug regimen. Fatal treatment-related toxicity was observed in two patients on the CAVE regimen and no treatment-related deaths were observed on the CAV treatment. In conclusion, the addition of etoposide to the CAV regimen resulted in increased toxicity but did not lead to a meaningful improvement in survival.

A controlled evaluation of combined 5-fluorouracil, doxorubicin, and mitomycin C (FAM) for the treatment of advanced non-small-cell lung cancer.

One hundred eighty-six patients with advanced non-small-cell lung cancer were randomly assigned to treatment with combined 5-fluorouracil, doxorubicin, and mitomycin C (FAM) or combined methotrexate, doxorubicin, cyclophosphamide, and lomustine (MACC). Respective objective regression rates were comparable at 20% and 16%. Distribution of intervals to progression (overall median, 2.8 months) and survival times (overall median, 5.0 months) were essentially identical between the two regimens. The comparability of therapeutic effect was also evident within the subset of 81 patients who had adenocarcinoma cell type, although MACC showed a small advantage in survival after covariate analysis. In large-cell carcinoma, MACC showed a higher regression rate than that of FAM as well as a small advantage in survival. In squamous-cell carcinoma, however, FAM was superior to MACC in regression rates (32% v 4%) and also provided somewhat longer survival. With regard to toxicity, MACC produced a higher incidence of nausea and vomiting, whereas FAM produced more frequent and severe thrombocytopenia. From an overall standpoint, the therapeutic accomplishments of both regimens were disappointing. Our study does, however, provide additional evidence that mitomycin C-containing regimens may be selectively effective for squamous-cell carcinoma of the lung.

Prospective phase I evaluation of radiation therapy, 5-fluorouracil, and levamisole in locally advanced gastrointestinal cancer.

PURPOSE: A recent clinical trial in patients with resected node-positive colon cancer demonstrated a clear survival advantage for patients treated with adjuvant 5-fluorouracil and levamisole. This finding led to interest in development of a Phase III trial comparing 5-fluorouracil and levamisole with 5-fluorouracil, levamisole, and radiation therapy in colon cancer patients at high risk for local recurrence. A prospective evaluation of 5-fluorouracil, levamisole, and radiation therapy was undertaken with the goal of establishing a satisfactorily tolerated regimen. METHODS AND MATERIALS: Fifteen patients were studied who had locally advanced or locally recurrent upper abdominal gastrointestinal cancer (11 patients) or large bowel cancer confined to the pelvis (4 patients). The tumor and regional lymph nodes received 45 Gy in 25 fractions. Patients with pelvic tumors subsequently were treated with a radiation boost of 5.4-9 Gy in 3-5 fractions. Systemic therapy consisted of 5-fluorouracil, 450 mg/m2, given intravenously for 3 consecutive days during the first and last weeks of radiation therapy. Levamisole, 50 mg, given orally 3 times daily was used for 3 consecutive days concurrent with initiation of radiation therapy and 5-fluorouracil, at the beginning of the third week of radiation therapy, and concurrent with the final 3-day course of 5-fluorouracil. RESULTS: Therapy was generally well tolerated. In two patients, > or = grade 3 nonhematologic toxicity developed and consisted of transient small bowel obstruction in one and severe nausea and vomiting related to levamisole administration in another. One patient experienced grade 3 hematologic toxicity with a leukocyte count nadir of 1,600 cells/microL. CONCLUSIONS: These results are similar to the toxicity profile reported elsewhere for radiation therapy and 5-fluorouracil. The addition of levamisole to radiation therapy and 5-fluorouracil does not appear to increase toxicity significantly.

Systemic adjuvant therapy in women with resected node-negative breast cancer.

Currently, the role of adjuvant systemic therapy in women with node-negative breast cancer is being determined. Several studies of adjuvant hormonal therapy and adjuvant chemotherapy have demonstrated a moderate reduction in the risk of recurrence in the treated patients. With relatively limited follow-up, however, overall survival has not improved with use of adjuvant therapy. The use of prognostic factors to select those patients at highest risk for relapse is an active area of oncologic research. The decision to recommend adjuvant therapy necessitates assessment of the probability of recurrence, the expected reduction of risk with adjuvant therapy, the toxic effects of therapy, and the influence of treatment on the patient's overall quality of life.

Etiologic considerations in superior vena cava syndrome.

The Mayo Clinic experience with superior vena cava obstruction during the last 20 years was reviewed. The diagnosis of superior vena cava obstruction is often made at the bedside. Typical symptoms include suffusion, dyspnea, cough, and, less commonly, pain, syncope, dysphagia, and hemoptysis. The most important physical findings are the increased collateral veins covering the anterior chest wall and the dilated neck veins with edema of the face, arms, and chest. The chest x-ray film usually shows widening of the superior mediastinum. Of our 86 cases of superior vena cava obstruction, 67 (78%) were due to malignancy and 19 (22%) to benign causes. The cause of obstruction is usually established by bronchoscopy, open lung biopsy, or biopsy of the superficial lymph node. Radiotherapy remains the standard approach for the treatment of superior vena cava obstruction due to malignant disease. It is of particular interest to note that of the six benign cases resulting from thrombosis of the superior vena cava, three were due to the use of central venous catheters. Physicians should be aware of this association.

A randomized phase II trial of two schedules of topotecan for the treatment of advanced stage non-small cell lung cancer.

We conducted a randomized phase II trial of two different schedules of topotecan in patients with advanced-stage non small lung cancer (NSCLC) without prior cytotoxic chemotherapy. All patients had histologic or cytologic confirmation of stage IV (M1) or III-B NSCLC. Patients were stratified by performance status, stage and weight loss. Patients were randomized to receive topotecan at intravenous doses of 1.5 mg/m(2)/day over 30 min for 5 days every 3 weeks (Arm A) or 1.3 mg/m(2)grade 3 in both arms included leukopenia, thrombocytopenia, malaise, constipation, diarrhea, lethargy, pulmonary, vomiting, infection and myalgia. Severe (> or = grade 3) thrombocytopenia occurred in 15.8% of Arm A patients and 37.8% of Arm B patients and this difference was statistically significant (P=0.03). The median times to progression are 101 and 63 days (P=0. 75) and the median survival times are 257 and 179 days (P=0.83) for Arms A and B, respectively. These differences in time to progression and overall survival are not statistically significant. Topotecan has limited, single agent activity in advanced NSCLC when given as 1. 5 mg/m(2)/day over 30 min for 5 days every 3 weeks. We do not intend to pursue further investigations with topotecan in patients with NSCLC.

Evaluation of fludarabine phosphate in patients with recurrent glioma.

Fifteen patients with recurrent primary brain tumors were treated with fludarabine phosphate. There were no responses seen. Toxicity was mild and primarily hematological. Fludarabine phosphate would appear to be ineffective in recurrent gliomas.

Phase II study of combined levamisole with recombinant interleukin-2 in patients with advanced malignant melanoma.

Adoptive immunotherapy (AI) with interleukin-2 (IL-2) and lymphokine-activated killer cells (LAK) is an antineoplastic modality in which immune-activated cells are administered to a host with advanced cancer in an attempt to mediate tumor regression. Levamisole (LEV), an immune stimulant, has been suggested to have therapeutic effectiveness in a variety of cancers. After a phase I trial of recombinant IL-2 plus LEV, a phase II trial of this combination was conducted in patients with advanced malignant melanoma. Nineteen patients were entered in the trial. They received IL-2 at 3 x 10(6) U/m2 subcutaneously daily x 5 plus LEV 50 mg/ m2 orally three times daily (p.o. t.i.d.) x 5. Patients were reevaluated at four-week intervals. None of the patients achieved a partial or complete regression (PR, CR). The median time to treatment failure (refusal, progression, or off study due to toxicity) was 56 days. Grade IV toxicities included vomiting (3 patients), lethargy (1 patient), and musculoskellar pain (1 patient). This regimen is not recommended for further testing in patients with advanced malignant melanoma.

Evaluation of intravenous 6-thioguanine as first-line chemotherapy in women with metastatic breast cancer.

6-Thioguanine (6-TG) is a purine analog that has marked variability in plasma concentration after oral administration. Following the development of a multiple-day i.v. regimen, we performed a phase II trial of this agent as first-line chemotherapy in women with metastatic breast cancer. Forty-one patients with measurable (31 patients) or evaluable (10 patients) disease were entered into this trial. 6-TG was administered i.v. over a 10 min period daily for 5 consecutive days, with a planned cycle length of 35 days. The daily dosage level was 55 mg/m2 in the first 15 patients, but this was increased to 65 mg/m2 in the remaining patients due to inadequate myelosuppression at the lower dose. Six patients, all with measurable disease, achieved a complete response (CR) (two patients) or a partial response (PR) (four patients). Three responses occurred at the 55 mg/m2 level and three at the 65 mg/m2 level. The 95% confidence interval (CI) for the true response rate among patients with measurable disease was 6-39%. The median time to progression was 140 days and median survival time was 460 days. The regimen was well tolerated. We conclude that 6-TG, as given in this study, has limited activity as first-line chemotherapy for women with metastatic breast cancer.

Randomized trial of doxorubicin alone or combined with vincristine and mitomycin C in women with metastatic breast cancer.

A randomized clinical trial was performed to determine if combination therapy with doxorubicin, vincristine, and mitomycin C (DVM) was superior to doxorubicin alone in women with metastatic breast cancer for whom prior chemotherapy had failed. A total of 185 women were randomized to monthly courses of D (60 mg/m2, observation after 500 mg/m2); or D (50 mg/m2, maximum cumulative dose 500 mg/m2), V (1 mg/m2), and M (10 mg/m2, given every other cycle). Patients failing after D alone could receive V (1 mg weekly for 5 weeks, then 1.2 mg/m2 every 5 weeks) plus M (12 mg/m2 every 5 weeks). Objective responses were seen in 24 of 95 patients (25%) on D alone and 39 of 90 patients (43%) on DVM (two-sided p = 0.01). The time to disease progression distribution was significantly better for DVM (two-sided p = 0.02), but the magnitude of the advantage was small with the medians being 2.7 months for D and 4.2 months for DVM. There was no significant difference in survival between the two regimens. The degree of leukopenia was greater for DVM both in terms of median white blood cell nadir (1,300/microL versus 1,700/microL) and percentage of patients with a nadir less than 1,000/microL (33% versus 16%). A total of 45 patients received VM following D alone, and only seven (16%) achieved an objective response. We conclude that, despite a significantly higher response rate and longer time to progression, the degree of clinical benefit is not sufficient to recommend the combination of DVM over D alone as second-line therapy for women with metastatic breast cancer. The level of efficacy seen with VM as tertiary therapy is low and is of such a magnitude to suggest that V adds little but toxicity to M.

Phase II trial of topotecan for the treatment of mesothelioma.

The North Central Cancer Treatment Group designed a phase II trial to assess the efficacy and toxicity of topotecan in patients with unresectable malignant pleural mesothelioma. Twenty-two previously untreated patients with unresectable pleural mesothelioma and good performance status (Eastern Cooperative Oncology Group performance status 0, 1, or 2) were enrolled on this trial from October 1993 through July 1994. Nineteen men and three women, median age 66 years (range, 44-78 years), were treated with topotecan 1.5 mg/m2 intravenously over 30 minutes daily for 5 days at 3-week intervals until toxicity, progression of disease, or a patient decided to discontinue treatment. There were seven patients with measurable disease and 15 with evaluable disease; all were assessable for response and toxicity. A total of 113 cycles of treatment were given, for a median of three cycles (range, 1-26 cycles). Myelosuppression was the most frequent toxicity. Eighteen of 21 patients (86%) experienced grade 3 or 4 neutropenia during the initial treatment cycle. The median neutrophil nadir was 0.5 x 10(3)/microl (range, 0.1-1.6 x 10(3)/microl), and the median platelet nadir was 127 x 10(3)/microl (range, 18-460 x 10(3)/microl). Other toxicities more than grade 2 included malaise (two patients), and anorexia, infection, fever, pulmonary, and cardiac in one patient each. There were no objective responses, and 18 patients had stable disease for a median of 74 days. The median survival for all patients was 230 days, with 23% alive at 1 year. Topotecan as administered in this trial is reasonably well tolerated; however, the response rate was insufficient to warrant additional study in pleural mesothelioma.

Randomized clinical trial of doxorubicin alone or combined with mitolactol in women with advanced breast cancer and prior chemotherapy exposure.

One hundred fifty-one women with advanced breast cancer who had failed prior chemotherapy were randomized to monthly courses of doxorubicin (60 mg/m2 I.V. day 1, observation after 500 mg/m2) or doxorubicin (40 mg/m2 I.V. day 1; maximum 500 mg/m2) and mitolactol (135 mg/m2 orally, days 1-10; 180 mg/m2 after maximum doxorubicin). Median survival times were 232 days for doxorubicin and 225 days for doxorubicin + mitolactol, and median times to progression were 112 days and 97 days, respectively. Results are inconsistent with a 25% improvement in survival or time to progression for doxorubicin + mitolactol (p = 0.04 and 0.02, respectively, adjusted for stratification factors but not multiple testing). Regression rates for all patients, both measurable and evaluable, were 30% for doxorubicin alone and 26% for doxorubicin + mitolactol. Regression rates were significantly higher in patients with measurable indicator lesions. Cardiac toxicity was seen in four patients, all of whom were receiving doxorubicin alone. It appears that the combination of doxorubicin + mitolactol is not substantially more effective than doxorubicin alone in women with advanced breast cancer and prior chemotherapy exposure.

Phase II study of high-dose somatostatin analogue in patients either previously treated or untreated who have extensive-stage small cell lung cancer.

The authors conducted a phase II study of somatostatin analogue in 18 patients with extensive stage small cell lung cancer (four with previous treatment, 14 without previous treatment). Patients received 2,000 mg subcutaneously thrice daily. They were required to have an Eastern Cooperative Oncology Group performance score of 0-2 and acceptable pretreatment biochemical parameters. No patient responded to treatment. The median time to progression was 44 days. The median survival was 106 days. Toxicity related to treatment consisted of mild diarrhea and anorexia. Somatostatin analogue is not active as a single agent in the treatment of extensive-stage small cell lung cancer.

Combined levamisole with recombinant interleukin-2 (IL-2) in patients with advanced renal cell carcinoma: a phase II study.

Adoptive immunotherapy (AI) with interleukin-2 (IL-2) and lymphokine-activated killer (LAK) cells is an antineoplastic modality in which immune-activated cells are administered to a host having cancer in an attempt to mediate tumor regression. Levamisole (LEV), an immune stimulant, has been suggested as having therapeutic effectiveness in a variety of cancers. After a phase I trial of recombinant IL-2 plus LEV, a phase II trial of this combination was conducted in patients who had advanced renal cell carcinoma. The regimen was IL-2 at 3 x 10(6) U/m2 daily x 5 plus LEV at 50 mg/m2 perorally three times a day x 5. Only one of the 22 eligible patients had a regression. It was a partial regression, 85 days in duration. The median time to treatment failure (refusal, progression, or off study because of toxicity) was 36 days. The only grade 4 toxicity reported was lethargy. This regimen is not recommended for further testing in patients who have advanced renal cell carcinoma.

Phase II study of bisantrene administered by continuous 72-hour infusion for advanced pancreatic adenocarcinoma.

Eighteen ambulatory patients who had proven metastatic adenocarcinoma of the pancreas and measurable disease but no previous chemotherapy were treated with bisantrene given by constant central intravenous infusion over 72 hours at a total dose of 300 mg/m2 repeated every 3 to 4 weeks. No objective regression was seen. The median interval to progression was 6 weeks; the median survival was 14 weeks. Primary toxic reactions were nausea, vomiting, and leukopenia. In no instance were these life-threatening. When administered by the method we used, bisantrene cannot be recommended for treatment of advanced pancreatic adenocarcinoma.