Combination chemotherapy (5-fluorouracil, methyl-CCNU, mitomycin C) versus 5-fluorouracil alone for advanced previously untreated colorectal carcinoma. A phase III study of the Piedmont Oncology Association.

One-hundred thirty eligible patients with advanced colorectal carcinoma who had received no prior chemotherapy were randomized to either methyl-CCNU, 70 mg/m2 orally every 6 weeks on day 1, mitomycin C, 10 mg/m2 intravenously every 6 weeks on day 1, and 5-fluorouracil (5-FU), 400 mg/m2 intravenously weekly--(MMF)--or 5-FU, 600 mg/m2 intravenously weekly (5-FU). One hundred twenty-six patients are evaluable for response. Of 62 patients treated with MMF, one (2%) achieved complete remission, and three (5%) attained partial remission. Of 64 patients treated with 5-FU, two (3%) achieved complete remission, and eight (13%) attained partial remission. The median survival for patients receiving MMF was 9.5 months compared with 10.3 months for patients receiving 5-FU. The survival distributions for the two regimens were not significantly different, either unadjusted or adjusted for pretreatment characteristics. Performance status and lactic dehydrogenase (LDH) were both significantly associated with survival. Patients with liver metastases only and normal liver function tests had a median survival of 19.8 months and a 40% response rate. This randomized phase III trial did not show any therapeutic advantage for MMF compared to 5-FU therapy alone in advanced colorectal cancer. In addition, hematologic toxicity was significantly greater with the combination (MMF) regimen.

Recombinant alfa interferon in renal cell carcinoma: a randomized trial of two routes of administration.

Ninety-seven patients with recurrent or metastatic renal cell carcinoma were randomized to receive recombinant interferon (IFN) alfa-2b (Intron A; Schering-Plough, Kenilworth, NJ) by either the subcutaneous (SC) or intravenous (IV) route. The SC dosage was 2 X 10(6) IU/m2 three times weekly, and the IV dose 30 X 10(6) IU/m2 for five consecutive days every 3 weeks. Dose escalation to a maximum of 10 X 10(6) IU/m2 SC and 50 X 10(6) IU/m2 IV was allowed for patients with minimal or absent toxicity. Five of 51 of the SC-treated patients (10%) and three of 46 of the IV-treated patients (7%) had a partial response (PR) or complete response (CR). Patients with prior nephrectomy, no prior treatment, and lack of bone metastases were most likely to respond, and a retrospective analysis of this subgroup revealed a 23% response rate. Achievement of response took from 3 weeks to 11 months, while response duration lasted from 3 to 31+ months. All responders had prior nephrectomy; six of eight had no prior chemotherapy or hormonal therapy; five had lung metastases, and none had bone metastases. Regardless of route, almost all patients developed a flu-like syndrome; however, grade 3 or greater toxicity was much more common for IV-treated patients. This trial demonstrates modest, but definite antitumor activity for recombinant interferon in advanced renal cell carcinoma. SC administration with lower dose and toxicity is as effective as treatment administered IV.

Improvement of long-term survival in extensive small-cell lung cancer.

The effect of adding the epipodophyllotoxin etoposide (VP-16-213) to a standard chemotherapy regimen for patients with extensive stage small-cell lung cancer was evaluated during a randomized trial. Chemotherapy consisted of vincristine, doxorubicin, and cyclophosphamide (VAC) alone or with etoposide (EVAC). Of 139 patients enrolled, 136 patients were eligible for study and all but five were evaluable for response. The overall objective response was 46% in the VAC group v 70% in the etoposide-treated group (P = .008) with complete response (CR) rates of 12% v 29%, respectively (P = .030). Although the time to the observation of disease progression was significantly longer in the group of patients receiving etoposide (9.6 v 6.5 months, P = .010), overall survival was similar; this was probably due to administration of other agents including etoposide at the time of VAC failure. However, there were noteworthy differences in long-term (greater than or equal to 2 year) survival. Whereas only four (6%) patients treated with VAC lived 2 years, 11 (16%) of the etoposide-treated group did so (P = .100). Two-year failure-free survival was attained in one (2%) of the VAC patients and eight (11%) of the patients treated with etoposide (P = .034). Long-term survivorship, heretofore usually reported in patients with limited stage disease after a variety of treatments, may be possible with this drug combination in the setting of extensive disease.

VP-16-213 in combination chemotherapy with chest irradiation for small-cell lung cancer: a randomized trial of the Piedmont Oncology Association.

The role of etoposide epipodophyllotoxin (VP-16-213) in a combined modality treatment program incorporating local chest irradiation and combination chemotherapy with cyclophosphamide, Adriamycin (Adria Laboratories, Columbus, Ohio), and vincristine has been evaluated in a randomized trial of 165 patients with small-cell lung cancer. The overall response rate (complete response [CR] plus partial response [PR]) was significantly greater in the VP-16-213 arm (85% v 64%, P = .005) primarily as a consequence of improved response in patients with extensive disease (85% v 38%, P = .002 and 30% v 8% for CR only, P = .045). No differences in the response rates were observed in limited disease. The duration of response (months) was greater in the VP-16-213 arm (8.6 v 7.0 overall and 14.4 v 11.5 for CR) but not significantly so. Median survival times (months) were consistently greater in the group receiving VP-16-213 when analyzed according to extent of disease and response (10.6 v 9.5 overall; 15.0 v 13.6 for limited disease; 9.0 v 6.7 for extensive disease; 18.5 v 16.2 for CR overall; and 18.6 v 16.1 for CR in limited disease); the results were not statistically significant. The median survival of extensive disease patients attaining a CR was 15.3 months (range 3.2 to 34.3 + months) in the VP-16-213 arm and 7.4+ and 8.1+ months for the two patients with CR in the other group. Anemia and leukopenia occurred to a greater degree in the four-drug regimen, but no unusual or significant compounding toxicity (ie, neurotoxicity) was observed otherwise. Further investigation of this agent in combination chemotherapy programs for small-cell lung cancer appears to be warranted.

Amelioration of vincristine neurotoxicity by glutamic acid.

Neurotoxicity is the principal limiting side effect of the widely used antitumor agent, vincristine. Following evaluation of glutamic acid as a potential modifier of vincristine toxicity in preclinical studies in mice and a preliminary clinical trial, a prospective, double-blind, placebo-controlled, randomized trial was conducted by the Piedmont Oncology Association. Of 87 patients entered into the study, 84 were evaluable, including 42 patients who were randomly assigned to receive vincristine 1.0 mg/m2 weekly for six doses and 42 patients who were assigned to receive glutamic acid 500 mg orally three times daily plus vincristine. The following neurotoxic signs and symptoms were evaluated before each dose of vincristine: reflex changes, paresthesias, constipation, strength, and mental changes. Loss of the Achilles tendon reflex, an objective parameter, was noted in 19 percent of patients receiving glutamic acid and 42 percent of control subjects (p = 0.03). Development of moderate to severe paresthesias, a subjective parameter, occurred in 19 percent of the glutamic acid group and 36 percent of the placebo group (p = 0.09). Overall moderate neurotoxicity (6 units or more), determined by adding the grade of each neurotoxic parameter for the weekly clinic visit in which maximum neurotoxicity occurred, was observed in 21 percent of patients receiving glutamic acid and 43 percent of those in the control group (p = 0.04). Hematologic and gastrointestinal side effects occurred with similar frequency in the two groups. The administration of glutamic acid has decreased vincristine-induced neurotoxicity without any attendant side effects.

Clinical trial of folinic acid to reduce vincristine neurotoxicity.

In a murine model system, folinic acid demonstrated host-protective properties during administration of repetitive and lethal doses of vincristine (VCR). Subsequently, folinic acid was evaluated in patients receiving VCR during an adjuvant chemotherapy program for stage II carcinoma of the breast. The toxicities, cumulative VCR dosage, and percentage of ideal dosage observed in 18 patients receiving folinic acid have been compared with those observed in 70 patients who previously received VCR without folinic acid in the same chemotherapy program. All patients ideally were intended to receive VCR 1.0 mg/m2 weekly for 6 weeks, with dose modification for neurotoxicity. Treatment patients received folinic acid 800 mg PO daily in three divided doses during the 6-week course. The degree of neurotoxic manifestations of VCR was similar in the treatment and comparison patients. Absent to mild neurotoxicity was observed in approximately 70% of patients in both groups; moderate or greater neurotoxicity occurred in about 30% of patients in both groups. Full dosage (6.0 mg/m2) was attained in 7 (39%) treatment patients and 17 (24%) comparison patients (P = 0.21). The mean percentage of the ideal dosage of VCR was 73.7 +/- 28.7 in patients receiving folinic acid and 76.1 +/- 20.5 in those given only VCR (P = 0.69). Hematologic toxicities were similar in both groups, but nausea occurred more frequently in the folinic acid group. Folinic acid in this dose and schedule afforded no protection from the neurotoxic side effects of VCR.

Phase I study of high-dose cytosine arabinoside and etoposide in patients with advanced malignancies.

Cytosine arabinoside (ara-C) and etoposide (VP-16) display synergy in the laboratory. Twenty-six patients participated in a phase I study of high-dose ara-C in combination with VP-16. The dose of VP-16 was held constant at 50 mg/m2 as an intermittent infusion over 33 h; escalating doses of ara-C were given as infusions during hours 9-12 and 21-24. Myelosuppression was the dose-limiting toxicity and occurred with doses considerably less than those expected from studies of the two drugs as single agents. The suggested initial doses for phase II trials with this schedule are 750 mg/m2 X 2 doses of ara-C and 50 mg/m2 of VP-16. Nonhematologic toxicity was minimal; therefore, further dose escalation is feasible in patients in whom myelosuppression is acceptable.

Fluoxymesterone as third line endocrine therapy for advanced breast cancer. A phase II trial of the Piedmont Oncology Association.

The Piedmont Oncology Association conducted a Phase II trial of fluoxymesterone (Halotestin) in 28 patients who failed to respond to prior hormonal therapy with tamoxifen and a progestational agent. Of nine patients who had responded to prior endocrine therapy, one had a partial response (PR) as defined by strict criteria and remains on study at 17 + months for an 11% response rate [95% confidence interval (CI), complete response (CR) + PR, 0-48%]. None of 19 previously unresponsive patients achieved remission (95% CI, CR + PR, 0-18%). Eleven patients' performance status deteriorated during therapy. Five of them had not received prior chemotherapy, and their response to subsequent chemotherapy may have been adversely affected. Third-line hormonal therapy with fluoxymesterone can be recommended only as a temporizing measure in patients with indolent disease who have responded to prior hormonal therapy.

Cytotoxic chemotherapy and androgen priming in patients with advanced carcinoma of the prostate. A phase II trial of the Piedmont Oncology Association.

Twenty-three patients with advanced prostatic cancer refractory to hormonal therapy were entered into a phase II study of cytotoxic chemotherapy combined with androgen priming. Patients received vincristine 0.5 mg on day 1; fluoxymesterone 10 mg p.o. TID, days 1-5; methotrexate 4 mg/m2 p.o., days 1-7; and cyclophosphamide 500 mg/m2 I.V., day 8. Patients entered had no prior chemotherapy, most were symptomatic but ambulatory (18/23), and almost all had bone metastases (22/23). There were two stable responses and 14 progressions in 16 patients evaluable for response. Hematologic and gastrointestinal toxicities were substantial. Androgen priming was an unsatisfactory method of improving response in this trial.

Phase II trial of high-dose cytosine arabinoside and cisplatin in recurrent squamous carcinoma of the head and neck. A Piedmont Oncology Association Study.

Fifteen patients with recurrent squamous carcinoma of the head and neck received high-dose cytosine arabinoside (ara-C) (3 g/m2) and cisplatin (100 mg/m2) every 3 weeks in an attempt to explore the dose-dependent synergy between these two agents. A partial response was attained in one patient; there were no complete responses. The major toxicity was myelosuppression. With the current schedule, high-dose ara-C failed to improve the response rate achieved with cisplatin alone.

Carcinosarcoma of the colon. Report of a unique case with light and immunohistochemical studies.

A unique case of carcinosarcoma of the colon is reported. The tumor invaded the bowel wall deeply, metastasized widely, resisted multi-agent chemotherapy, and caused the patient's death 4 years later. The tumor was composed of adenosquamous carcinoma admixed with sarcoma showing osseous, cartilaginous, and nonspecific spindle-cell differentiation. Although carcinoembryonic antigen appeared limited to carcinoma cells, cytokeratin immunoreactivity was observed in both carcinoma and sarcoma cells. Like carcinosarcomas at other body sites, the finding of cytokeratin in sarcoma cells supports partial epithelial differentiation in this component, likely retained from carcinoma precursor cells.

Ara-C syndrome during low-dose continuous infusion therapy.

Four patients with acute nonlymphocytic leukemia developed one or more components of the "ara-C syndrome" including fever, peritonitis, pericarditis, and a maculopapular rash during therapy with continuous infusions of low-dose (20 mg/m2/d) cytosine arabinoside (ara-C). These complications, described with standard and high doses of ara-C, have not been previously noted with low-dose regimens.

Mitoxantrone and high-dose ara-C in refractory malignancies: a phase I trial.

On the basis of in vitro studies demonstrating marked synergy between mitoxantrone and high-dose cytosine arabinoside (ara-C) (HiDAC) against L5178Y murine leukemia and clinical studies showing usefulness of the combination in patients with refractory acute myeloid leukemia, a phase I study was initiated to find tolerable doses for use in patients with refractory solid tumors. Initial dose levels were mitoxantrone 2 mg/m2 infused over 30 minutes, followed by high-dose ara-C 750 mg/m2 infused over 3 hours repeated once at 24 hours (total dose 4 mg/m2 mitoxantrone and 1,500 mg/m2 HiDAC per 2-day course), with planned subsequent escalation of mitoxantrone. Moderate-to-severe myelosuppression, however, required sequential dose reduction of both agents. Nonhematologic toxicity was restricted to manageable nausea and vomiting in one-half the patients and a single episode of transient delirium of uncertain etiology. No responses were observed in 23 heavily pretreated patients with a wide variety of malignancies. On the basis of this study, doses of 187-375 mg/m2 ara-C given every 24 hours for two doses following mitoxantrone 1 mg/m2 every 24 hours for two doses would be tolerated by most patients with subsequent dose escalation in some as allowed by myelosuppression.

Phase I study of vincristine and escalating doses of etoposide.

A phase I trial of vincristine and etoposide was designed following the identification of a potentially synergistic antitumor effect in a murine model. The dose of vincristine was fixed (0.5 mg daily for 3 days). Etoposide was given at 1 of 3 total dose levels (250, 500, or 750 mg/m2) per treatment. Each dose was given in 3 equal fractions and each fraction was given daily for 3 days, i.e., 83.3 mg/m2/d x 3d, 166.7 mg/m2/d x 3d, or 250 mg/m2/d x 3d. A total of 31 patients were entered into study including 10, 18, and 3 patients treated at the 250, 500, and 750 mg/m2 dose levels, respectively. Dose-limiting toxicity occurred at the 750 mg/m2 level, in which Grade 4 myelosuppression developed in all of the patients. Life-threatening gram negative sepsis occurred in two of these patients and both required platelet transfusions. Grade 3-4 WBC toxicity was observed in 9 of 16 (56%) evaluable patients treated at the 500 mg/m2 level, but reversal of toxicity was generally rapid with repeat courses given at 3 week intervals in most patients. Non-hematologic toxicity was negligible. Objective responses were observed in 2 of 4 patients with Hodgkin's disease. The starting dose of etoposide recommended for phase II trials of this agent in combination with vincristine is 500 mg/m2; dose escalation may be possible in some patients.

Recombinant gamma interferon in advanced breast cancer: a phase II trial.

Fifteen patients with advanced carcinoma of the breast who had failed prior chemotherapy, were treated with recombinant gamma interferon at a dose of 2mg/m2 (1mg = 2.4 X 10(7) international units) intravenously for five consecutive days every other week. The median patient age was 51 and all patients had a performance status of 0-2 (Karnofsky greater than or equal to 50). Thirteen patients had two or three sites of metastatic disease and seven were estrogen receptor positive. No complete or partial responses were noted. Although some patients had brief periods of stable disease, almost all patients progressed after one or two courses. Only one patient was able to receive six courses of induction therapy and a brief course of maintenance. Flu-like symptoms and nausea were seen in all patients; vomiting and anorexia were frequent. Hepatic toxicity manifested by enzyme elevation was common and was most severe in patients with liver metastases. In this study a highly purified biologically active gamma interferon was not associated with anti-tumor activity in previously treated women with metastatic breast cancer.

Vinblastine infusion in non-Hodgkin's lymphomas: lack of total cross-resistance with vincristine.

Historically, vinblastine given by intravenous bolus injection has not been an effective treatment for non-Hodgkin's lymphomas; vincristine has displayed greater activity. Also, vinblastine has generally been considered to be cross-resistant with vincristine in such patients. In an attempt to overcome these obstacles, a protracted infusion of vinblastine was administered (0.5-1.5 mg/m2 per day for 5 days) and repeated every 3 weeks. Partial responses were observed in 4 of 29 (14%) patients with a variety of non-Hodgkin's lymphoma lasting 2.4, 2.4, 5.5, and 9.0 months. Just prior to treatment the responding patients had received and eventually become refractory to vincristine. These data show a lack of total cross-resistance between vinblastine and vincristine which might have important therapeutic implications in this disease.

Chemoinfusion of the hepatic artery for metastases to the liver.

During a five year period, 69 patients were treated for carcinoma of the liver (seven primary tumors and 62 metastatic tumors) with 5-fluorodeoxyuridine (5-FUDR) administered through a hepatic artery (n = 62) or portal vein (n = 3) implantable infusion pump. Ten patients proved to have previously unsuspected extrahepatic nodal metastases at laparotomy for pump insertion. 5-FUDR was given in 14 day cycles for three months. At the end of that period and at three month intervals thereafter (mean follow-up time of 18 months, a range of one to 60 months), patients were evaluated with roentgenograms of the chest, liver function tests, carcinoembryonic antigen levels, radionuclide scans and computed tomography. Thirty-five patients had a partial response, nine had stabilization of the disease and 25 had progression of the disease (five during therapy, who were given mitomycin C). Median regression was 6.8 months (a range of three to 18 months). Six of the 35 partial responders, three of the nine patients with stabilization and ten of the 25 patients with progression had extrahepatic visceral disease. Survival time averaged 18.4 months (a range of five to 60 months) for the partial responders, 12.6 months (a range of two to 40 months) for patients with stabilization and seven months (a range of one to 17 months) for those with progression of the disease.

Menogaril in the treatment of relapsed multiple myeloma. A phase II trial of the Cancer Center of Wake Forest University.

Fifteen patients with relapsed multiple myeloma (MM) were treated with menogaril 160 mg/m2 intravenously (IV) every 28 days. No responses were seen: 8 patients had stable disease, 4 progressed after one course of therapy, and 3 patients were removed from study after 1 course for other reasons. Four of the 8 patients with stable disease had an improved performance status, and 3 had a decrease in analgesic use. The major toxicity was myelosuppression. The median progression-free interval was 3.0 months with a range of 0.7 to 22 months and median survival was 11.3 months with a range of 0.7 to 39+ months. Menogaril displays little activity in patients with previously treated MM.