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1-(2'-Deoxy-2'-fluoro-1-beta-D-arabinofuranosyl)-5-methyluracil (FMAU), a new pyrimidine nucleoside, is of potential clinical interest both as an anticancer and as an antiviral drug. FMAU is active in vitro and in vivo against P815 and L1210 cell lines resistant to cytarabine. Moreover, in mice inoculated ic with herpes simplex virus Type II, FMAU is 100-fold more potent than vidarabine or acyclovir. We have conducted a phase I trial of FMAU in 17 patients with advanced cancer. The dose levels studied were 2, 4, 8, 16, 32, 64, and 128 mg/m2/day iv for 5 days. The dose-limiting toxic effect was drug-induced central nervous system dysfunction. Although 32 mg/m2/day for 5 days produced only transient, mild symptoms, severe encephalopathy with extrapyramidal dysfunction occurred at 64 and 128 mg/m2/day for 5 days and contributed to two deaths. No toxicity was observed at less than 32 mg/m2. A dose of 32 mg/m2/day for 5 days is suggested for phase II study. Because of its potent and selective antiviral activity, future trials of low doses of FMAU in immunosuppressed patients with herpes virus infections are under consideration.

5-Formyl-tetrahydrofolate [citrovorum factor (CF)] is commonly used for preventing or reversing toxicity due to treatment with high-dose methotrexate (HDMTX). In vivo, CF is converted to 5-methyltetrahydrofolate (MTHF) and then to the 5,10-methylene tetrahydrofolate, which is the active coenzyme involved in thymidine synthesis. In this study, MTHF was used for protection from toxicity following larger doses of MTX than previously studied, doses which could not be tolerated without effective "rescue." Fifteen patients were given 18 courses of MTX in escalating doses (1-24 g) followed by MTHF. The toxic effects observed included: leukopenia, thrombocytopenia, mucositis, nausea, vomiting, and elevation of serum creatinine and serum transaminase. The side effects were reversible and all patients recovered fully. "Matched pairs" comparison of CF and MTHF rescue in five patients showed no difference in rescue efficacy between the two agents. Since ten of the treatments consisted of 12 and 24 g of MTX, doses potentially fatal without rescue, MTHF is an effective agent for prevention of MTX toxicity.

We have previously reported that bisantrene has significant activity against a variety of tumors in the human tumor soft agar cloning assay. An update of that experience reveals that 26% of evaluable human breast cancer specimens were sensitive to bisantrene, which had activity equivalent or superior to that of doxorubicin. Because of the preclinical activity of bisantrene and its activity in the cloning assay, bisantrene was studied in a phase II clinical trial of 30 patients with advanced breast cancer refractory to standard agents. Six patients (20%) had objective complete or partial regressions, including one patient with complete regression of lymphangitic lung metastases lasting greater than 18 months, confirming the antitumor activity of this compound. Two of the six responding patients had failed doxorubicin treatment, implying a lack of complete cross-resistance. Bisantrene toxicity was acceptable in most patients, with reversible myelosuppression being the most frequent side effect. Phase III trials of this promising new agent are warranted.

A phase II study of 5-azacytidine given twice weekly as a rapid iv infusion was performed on 116 patients with different metastatic cancers of refractory lymphomas at a dose of 150 mg/m2 twice weekly x 6. Ninety-one patients were evaluable. Dose modifications were carried out depending on previous treatment status. Nausea and vomiting was a major side effect; significant granulocytopenia was observed in 35 patients. Responses were observed in only four patients. Our results indicate little effectiveness of this drug. The severe toxicity prevented escalation to potentially more effective dose levels.

Seven patients with germ cell tumors of the ovary were treated with four cycles of cisplatin, vinblastine, and bleomycin. Six patients were without evidence of disease 17+ to 37+ months after completion of the remission-induction chemotherapy, and one patient relapsed after 9 months. Substantial toxicity of the cisplatin, vinblastine, and bleomycin regimen was noted. Despite the high response rate suggested in this small series, the optimal chemotherapeutic treatment for this disease has yet to be determined.

Eighteen patients with histologically documented small cell carcinoma of the lung who had failed initial combination chemotherapy regimens were treated with single-agent cisplatin in a dose of 100 mg/m2 every 3 weeks, with mannitol and fluid diuresis. Tumor regression was limited to one partial response (response rate, 6%; 95% confidence limits. 1%-27%). Significant toxic effects were gastrointestinal (severe nausea and vomiting in 12 of 14 patients) and hematologic (severe leukopenia in one patient and severe thrombocytopenia in three). The antitumor efficacy of high-dose cisplatin in heavily pretreated patients with small cell carcinoma of the lung appears to be marginal.

We conducted a phase I study of 6-diazo-5-oxo-L-norleucine given iv on a twice weekly schedule. Twenty-six evaluable patients received 31 courses of the drug. Doses ranged from 100 to 500 mg/m2. Nausea with vomiting was the dose-limiting toxic effect, transient thrombocytopenia was seen frequently, and mucositis occurred in 39% of the patients. No definite therapeutic responses were observed in 18 patients with measurable lesions. The recommended dose for phase II studies is 200-300 mg/m2 iv twice weekly.

Fourteen patients (less than or equal to 35 years of age) with intra-abdominal undifferentiated lymphomas, without evidence of disease elsewhere, were treated by surgical resection and six cycles of combination chemotherapy which included cyclophosphamide, vincristine, doxorubicin, prednisone, and 42-hour methotrexate infusion with leucovorin rescue. One patient with very extensive retroperitoneal disease prior to surgery had rapid tumor regrowth and subsequently died. One patient has relapsed twice, but is currently alive and has been disease-free for 2 years. All other patients have remained in complete remission for 25-63 months from presentation. The major toxic effects encountered in this protocol were mucositis (which necessitated a reduction in methotrexate duration in two patients) and fever and neutropenia (which complicated chemotherapy in 15 of the total of 79 cycles delivered). There were three documented infections; all were diagnosed before chemotherapy was started, and all resolved with appropriate antibiotic treatment. The 92% actuarial survival rate in this protocol is comparable to results with more prolonged chemotherapy or a combination of prolonged chemotherapy and irradiation. Since prolonged maintenance therapy and irradiation were not utilized in our protocol, they appear to be unnecessary for patients with intra-abdominal undifferentiated lymphoma whose disease can be at least 90% resected.

Fifteen patients with advanced malignancy were treated with escalating doses of recombinant beta ser 17 interferon (IFN). Doses ranging from 0.006 to 500 X 10(6) units/m2 were administered according to a dosage escalation scheme by iv push twice weekly (starting 1 week after an initial dose) for a planned minimum of 5 weeks, to be continued as a function of response. Toxic effects were broad in scope but generally low in grade. They included fever, malaise, leukopenia, proteinuria, nausea/vomiting, diarrhea, and mild elevations of serum transaminases and creatinine. In one patient, transient hypotension with bradycardia ensued. Malaise and fever increased somewhat with increasing dose. Doses of up to 500 X 10(6) units/m2 were tolerated without severe toxicity. A maximum tolerated dose was not defined. IFN pharmacokinetics followed a biphasic decay curve, with a distribution phase alpha-half-life of 9 minutes and an elimination phase beta-half-life of 103 minutes. Anti-IFN antibodies by the ELISA technique were present in seven of 15 patients. Presence of antibody did not correlate with toxicity or response. 2',5'-Adenylate synthetase levels were increased 2 and 24 hours after the initial dose, with a trend toward higher increments with higher doses. Minimal anti-tumor responses were seen in two patients with melanoma.

From January 1978 to October 1982, 47 patients with histological diagnosis of epithelial cancer of the ovary received peptichemio (PTC) at a dose of 70 mg/m2 (maximum, 120 mg total) every 15 days. Forty-two patients are now evaluable: 27 with stage III and 15 with stage IV disease. All patients but four with stage IV disease had been pretreated and had received at least one drug combination (median, three drugs per patient, including alkylating agents). Before the administration of PTC, the tumor extension in the abdomen was carefully assessed in all patients: ten patients had residual tumor less than 2 cm in diameter, while 32 patients had tumor greater than 2 cm in diameter. Objective responses were obtained in ten patients (23.8%): six complete remissions and one partial remission were observed in stage III patients and one complete remission and two partial remissions were observed in stage IV patients. Of the ten responding patients, eight had tumors less than 2 cm in diameter before receiving PTC. The median duration of response was 16 months. The most frequent side effects were myelosuppression and phlebosclerosis. Bone marrow depression was a common finding after the third course in heavily pretreated patients. Accordingly, in these patients a schedule interval of 3 weeks should be more appropriate. Since most of the responders were in the "small tumor" category, PTC appears to be an active drug in patients with ovarian cancer having small tumors (less than 2 cm). On the other hand, the response rate in a nonselected population of patients remains to be clearly defined with further studies.

Twenty-five evaluable, ambulatory outpatients with disseminated malignant melanoma received tamoxifen at a dose of 40 mg orally each day. None of the patients had an objective regression and approximately 70% had disease progression within 30 days of starting treatment, including two patients with detectable estrogen receptor titers. Median survival time and time to progression were 4 months and 1 month respectively. Performance score was the most significant covariate for survival time (P < 0.01) and time to progression (P = 0.02).

A group of 47 patients with advanced breast cancer were treated with a combination of prednimustine, methotrexate, 5-FU, and tamoxifen. In this combination, with methotrexate and 5-FU administered at standard doses, hematologic toxicity of prednimustine at a dose of 100 mg/m2 orally on Days 1-5 repeated every 4 weeks was acceptable. Nausea and vomiting occurred in 40 of the 47 patients but was only grade 1-2 in 35 of these patients. Only one patient had alopecia to the extent of requiring a wig. Response to treatment could be evaluated in 28 patients; 21 achieved a response (complete or partial lasting a median of 13 months.

The early hope that L-asparaginase would be a breakthrough in medical treatment, with selective toxic effects based on the qualitative presence or absence of a specific enzyme (asparagine synthetase), has not been realized. Despite its failure to live up to early hopes, L-asparaginase is now commercially available because of its usefulness in treating selected forms of acute leukemia and T-cell lymphoid neoplasms. By and large, hints of useful activity in other tumors have not been confirmed, and L-asparaginase remains experimental for all other indications. It is variably toxic in man, and severe toxic effects are not unusual. Toxic reactions are generally hypersensitivity reactions or depression of protein synthesis.

AMSA an acridine derivative, was administered to 35 adults with previously treated advanced sarcomas. Patients with adequate bone marrow reserve received 120-150 mg/m2 of AMSA as a single dose repeated every 3 weeks. Patients with inadequate bone marrow reserve received 100-120 mg/m2 of AMSA. Among 31 evaluable patients, there was one partial response that lasted 6 months in a patient with intra-abdominal malignant fibrous histiocytoma with liver metastases. Thirteen patients had stable disease with a median time to disease progression of 5 months (range, 2-13), while 17 patients demonstrated progressive disease with a median time to disease progression of 2 months (range, 1-3). The median survival time for the 31 evaluable patients in this study was 5 months. The toxic effects were mild and included myelosuppression, nausea and vomiting, fever of unknown origin, and fatigue. At the dose and schedule used in this study, AMSA does not appear to have any significant activity in advanced sarcomas of adults.

Oral 6-thioguanine (6-TG) is an S-phase antimetabolite with significant activity against acute leukemia. Preliminary reports of activity of iv 6-TG indicated significant activity against advanced colorectal cancer. We conducted a phase II study of iv 6-TG in 29 patients with advanced measurable colorectal cancer. Only one transient partial response occurred. Toxic effects included mild myelosuppression, nausea, vomiting, and minor ECG changes. We discourage further use of iv 6-TG in the dose and schedule we used to treat advanced colorectal cancer.

Since July 1976, 19 patients with carcinoma of the bladder have been treated with adriamycin, 5-fluorouracil, and levamisole combined with radiotherapy (60 Gy [6000 radsA1/24 fractions/6 weeks). Chemotherapy and radiotherapy were initiated simultaneously, with the entire treatment lasting 7--8 months. Three months after the completion of radiotherapy, 14 of the 18 patients in whom cystoscopy was performed were found to be in complete remission. Overall, 17 of the 19 patients have responded to the treatment and 15 patients have at some time shown complete remission. The toxic effects seen were myelosuppression, nausea, vomiting, diarrhea, loss of weight, and alopecia. Thirteen patients received the entire treatment as outpatients while six patients had to be hospitalized for a period of 8--14 days because of severe side effects, especially in Weeks 3--8. Serious complications such as bowel perforation were not seen, but one patient died with septicemia as a result of agranulocytosis, which was attributed to the treatment with levamisole.

Twenty-three patients with metastatic melanoma were treated with combination therapy consisting of dacarbazine (220 mg/m2) and cisplatin (25 mg/m2) iv daily for 3 days every 3 weeks, carmustine (150 mg/m2) iv every 6 weeks, and tamoxifen (10 mg) orally twice daily. In 20 evaluable patients, there were no complete responses and ten partial responses. The median remission duration has not yet been reached but exceeds 7 months. Treatment was relatively well tolerated. However, six patients developed deep venous thrombosis, and four of these six suffered pulmonary emboli. Our data support a previous study and suggest that this combination warrants comparison with the active single components in a randomized prospective trial.

We have conducted a phase I study of the cyclic peptide echinomycin (Quinomycin A) on a schedule of administration of once every 4 weeks. Ten dose levels between 20 and 1800 micrograms/m2 were studied. Acute gastrointestinal toxicity, thrombocytopenia, and transient elevations of serum transaminases occurred at doses of greater than or equal to 1000 micrograms/m2. Gastrointestinal toxicity was severe and dose-limiting in several patients at doses of 1800 micrograms/m2. Thrombocytopenia was erratic, but generally increased with drug doses. Platelet count nadirs occurred 5-10 days after administration. Hepatic toxicity was reflected in transient elevations of serum transaminases without hyperbilirubinemia. Three patients experienced apparent anaphylactic reactions to doses of 1500 micrograms/m2. The maximum tolerated single dose of echinomycin was 1800 micrograms/m2. A starting phase II dose of 1500 micrograms/m2 is recommended.

Tiazofurin is a novel C-nucleoside with significant antitumor activity in murine tumor models. In a phase I clinical trial, patients received tiazofurin by bolus iv infusion daily for 5 days. Six doses ranging from 550 to 4100 mg/m2/day were evaluated. Thirty-one treatment courses were initiated in 21 patients. Tiazofurin induced multiple, transient toxic effects at all but the lowest dose level, and treatment interruption was a common result. Nine of 28 treatment courses initiated at doses greater than or equal to 1100 mg/m2/day were interrupted at less than 5 days; only five of eight courses initiated at 1100 mg/m2/day were completed. Symptoms leading to treatment interruption included headache, nausea and emesis, and lethargy and malaise. Other significant, transient toxic effects included skeletal muscle injury manifest as pain, weakness, or serum biochemical abnormalities; mucocutaneous effects; and mental or mood changes. One case each of transient pericarditis and fatal cardiomyopathy occurred at the highest dose. Myelosuppression was observed but was transient and not dose limiting. In addition to leukopenia and thrombocytopenia, unexpected declines in serum hemoglobin were observed, although these were of uncertain significance. Tiazofurin induced significant increases in uric acid production which could be reversed with coadministration of allopurinol. Pharmacokinetic analysis revealed tiazofurin plasma elimination to be at least biphasic, with a beta-half-time of 4.2 hours; most of an injected dose could be recovered from the urine as unaltered compound within 24 hours. From this study we conclude that an appropriate dose for phase II trials with this schedule is less than or equal to 1000 mg/m2/day. The schedule may be a difficult one for clinical evaluation of antitumor activity, however, because of the possibility of frequent treatment interruption due to multiple systemic toxic effects.

Fourteen patients with metastatic malignant melanoma localized to a lower extremity were treated with combined radiotherapy and intra-arterial infusion therapy with dacarbazine. All lesions that were included in radiation fields regressed completely. Two patients relapsed within radiation fields and six relapsed elsewhere. One patient had a serious intimal lesion caused by the catheter.

Eleven randomly hydrated patients with metastatic malignancies received iv bolus chemotherapy. Serial observations of plasma antidiuretic hormone (ADH), serum osmolality, blood pressure, and presence of nausea or emesis were made over the next 3-4 hours. Group 1 (four patients) had no nausea or emesis and no change in ADH, osmolality, or mean blood pressure. Group 2 (seven patients) had nausea and emesis following chemotherapy, with an increase in mean ADH from a baseline level of 5.53 pg/ml to a peak after emesis of 33.83 pg/ml. Group 2 had no significant increase in osmolality or decrease in mean blood pressure before emesis. ADH levels increased 0-40 minutes before emesis and peaked 28-115 minutes (mean, 66) after emesis. Emesis caused by chemotherapy agents is associated with rapid, significant increases in plasma ADH levels, independent of changes in osmolality or blood pressure.

Moderate doses of methotrexate and L-asparaginase were added to standard doses fo 5-fluorouracil, Adriamycin, and cyclophosphamide in an attempt to improve the overall response rate and survival following chemotherapy. In addition, nonspecific immunotherapy with either Corynebacterium parvum or Pseudomonas vaccine was integrated into this prospective randomized clinical trial. The overall toxicity (degree of granulocytopenia and thrombocytopenia, length of myelosuppression, and incidence of myelosuppression-related infection and infectious deaths) increased considerably and led to the termination of patient accrual. The incidence of stomatitis and diarrhea was also increased with the addition of methotrexate and L-asparaginase, and apparently was potentiated by the addition of Pseudomonas vaccine to this five-drug combination.

Pentamethylmelamine is a soluble monodemethylated derivative of hexamethylmelamine. Its activity in animal tumors is similar to that of hexamethylmelamine. When given iv at a dose of 1200 mg/m2 to patients with advanced cancer, it produced severe nausea and vomiting, severe psychotropic effects, and EEG changes. When this dose was given for 10 consecutive days, there was marked but reversible myelosuppression. The severe CNS effects which occurred at doses sufficient to produce myelosuppression cast doubt on the potential utility of pentamethylmelamine.

Ninety-eight patients with metastatic breast cancer, heavily pretreated with other agents, were entered in a phase II trial of hexamethylmelamine (HEX). Patients were randomized to receive HEX alone or combined with prophylactic pyridoxine. There was a 2% response rate in 89 partially or fully evaluable patients. Seven percent of these patients developed neurologic toxicity which occurred in the HEX-alone group only.

In a phase II trial, cisplatin was given by two randomly assigned dose schedules to 53 children with malignant solid tumors. Both schedules, 30 mg/m2/week and 90 mg/m2 every 3 weeks, were associated with drug-related toxic effects involving the renal, hematopoietic, and neuromuscular systems. Pharmacokinetic studies indicated that the initial serum half-life of total platinum was 27.6 minutes, with a terminal half-life of 44.4 hours. Significant antitumor effect was noted in patients with neuroblastoma and malignant germ cell tumors. Use of cisplatin in combination therapy for patients with these diseases is indicated.

To determine the incidence of anticipatory vomiting (AV) and postchemotherapy nausea and vomiting (PCNV) in women receiving cyclophosphamide, methotrexate, and 5-FU (CMF) adjuvant chemotherapy for breast carcinoma, we studied 52 women randomized to two regimens (standard-dose and low-dose) of CMF. Charts were reviewed for the cycle of onset of AV and PCNV, the severity of PCNV, and relationships of these syndromes to CMF dose and protocol compliance. Among the 52 patients, AV occurred in 17 (33%), while PCNV was experienced by 46 (88%). Severe PCNV (defined as uncontrolled nausea and/or vomiting interfering with performance of daily activities) occurred in 22 of 52 (42%) women. Eighteen of 23 (78%) women receiving standard-dose CMF experienced severe PCNV, and 13 of these had AV. Patients in whom severe PCNV began before cycle 4 were more likely to develop AV than women in whom PCNV began later (P less than 0.01). Ten of 52 (19%) patients discontinued CMF adjuvant chemotherapy because of nausea and vomiting; seven of the ten (70%) were receiving standard-dose CMF and seven had experienced AV. This study demonstrates that both AV an PCNV are significant toxic effects that not only affect the quality of life of a woman receiving CMF chemotherapy for breast cancer but also limit the ability of the clinician to provide maximum therapy to woman at high risk of recurrence of breast carcinoma.

ICRF-187, the enantiomer of ICRF-159 formulated for iv use, was administered to 23 patients in a phase I clinical trial. The dose ranged from 500 to 1500 mg/m2 every day for 3 days and was repeated every 28 days. The toxic effects included moderate to severe leukopenia and thrombocytopenia, which recovered by the 21st day of a treatment cycle. Myelosuppression was more severe in patients with prior nitrosourea treatment. Nonmyelosuppressive toxic effects included nausea and vomiting, transient elevations in liver function tests, alopecia, and increased urinary clearances of iron and zinc. The starting dose for phase II trials should be 1250 mg/m2 daily for 3 days repeated at 21-day intervals.

5-FU, semustine (MeCCNU), triazinate (TZT), and razoxane (ICRF-159) have each shown activity against advanced colorectal cancer in studies by at least two investigative groups. Objective response rates, however, have been low, without evidence of increased patient survival. The hope of this study was that enhanced activity might result from giving these agents in two-drug combinations. There were 167 eligible and evaluable patients randomized among the programs: 5-FU at a dose of 500 mg/m2/day by iv push X 5 (F); 5-FU at a dose of 400 mg/m2/day iv X 5 plus TZT at a dose of 175 mg/m2/day iv X 3 (FT); 5-FU at a dose of 400 mg/m2/day plus ICRF-159 at a dose of 600 mg/m2/day orally X 3 (FI); MeCCNU at a dose of 150 mg/m2/day orally plus TZT at a dose of 200 mg/m2/day iv X 3 (MT); MeCCNU at a dose of 150 mg/m2 orally plus ICRF-159 at a dose of 500 mg/m2/day orally X 3 (MI); and ICRF-159 at a dose of 425 mg/m2/day orally X 3 plus TZT at a dose of 125 mg/m2/day iv X 3 (IT). Patients with limiting conditions (serum creatinine greater than 1.5 mg/dl or elevated bilirubin) were randomized among programs F, FI, and MI. Objective response rates by treatment arm were: F--13% (four of 31 patients); FT--13% (four of 31); FI--15% (four of 27); MT--11% (three of 28); MI--13% (four of 32); and IT--6% (one of 17). Response rates of combination arms were not significantly larger than those of 5-FU alone. With regard to survival, patients initially treated with 5-FU alone had the most favorable experience (median, 10.8 mos). Multivariate analysis showed the following factors to have a significant and independent influence on survival: Eastern Cooperative Oncology Group performance score, grade, site of indicator lesion, and the presence of 5-FU in the treatment regimen. Toxic effects most frequently seen were nausea, vomiting, thrombocytopenia, leukopenia, diarrhea, stomatitis, alopecia, and dermatitis. The incidence and severity of toxicity were roughly comparable among the six treatment arms.

In a prospective study, 18 evaluable patients with recurrent osteosarcoma were treated with ifosfamide, 1.8 g/m2 daily for 5 consecutive days. Courses were repeated every 4 weeks. Additional mesna (2-mercaptoethane sulfonate) was given to prevent urotoxicity. All patients had measurable lung deposits and all but one had been pretreated with various cytotoxic agents. Six patients (33%) showed therapeutic response, two complete and four partial, with a median duration of 5.5 months (range, 3-47+). Toxicity included myelosuppression, alopecia, nausea, and vomiting. No severe urotoxicity or central nervous system toxicity was observed. Thus, high-dose ifosfamide in combination with mesna seems to be a safe and effective agent for the chemotherapy of osteosarcoma.

Twenty-five patients with stage III or IV locally advanced head and neck cancer were treated from February 1981 to November 1982 with a combined modality approach utilizing chemotherapy followed by irradiation and surgery. Induction therapy with cisplatin and bleomycin was followed by a sequence integrating weekly cisplatin into a program of locoregional irradiation. After the administration of 4800 cGy, patients received either "boost" irradiation or surgery. At the completion of all therapy, 20 of 23 patients evaluable for response had achieved complete remission. Toxicity was tolerable and all patients are being followed closely to assess durability of remission and overall survival.

We studied the prevalence of anticipatory nausea (AN) and anticipatory nausea and vomiting (ANV) in an ambulatory medical oncology population by self-report questionnaire over 7 weeks. Thirty-eight of 123 (31%) patients receiving parenteral chemotherapy reported anticipatory symptoms (AN or ANV). Twenty-one (17%) patients reported ANV and 17 (14%) reported AN only. Patients receiving parenteral chemotherapy (N = 123) with anticipatory symptoms (N = 38) were younger (45.1 +/- SE 1.9 vs 55.5 +/- 1.45, P less than 0.001) and more likely to be female (82% vs 61%, P = 0.04), unmarried (47% vs 26%, P = 0.03), and receiving adjuvant chemotherapy for breast cancer (42% vs 7% P less than 0.001) than patients without anticipatory symptoms (N = 85). A greater proportion of patients with both postchemotherapy nausea and vomiting and anticipatory symptoms reported greater than 12 hours of postchemotherapy nausea (65% vs 39%, P = 0.01) and postchemotherapy nausea and vomiting (37% vs 12%, P = 0.01) after their most recent cycle of chemotherapy than did patients with postchemotherapy symptoms only. In structured interviews with 23 patients with anticipatory symptoms, 16 identified specific stimuli associated with AN or ANV, taste being the most frequently mentioned (ten of 16 patients) sensory modality. In our clinic, patients receiving adjuvant chemotherapy for breast cancer develop anticipatory symptoms frequently and represent a relatively homogenous sample for further studies.

The Southwest Oncology Group evaluated 51 patients with a histologic diagnosis of metastatic adenocarcinoma and an occult primary tumor. Even though all patients received an extensive diagnostic evaluation, only six (12%) primary sites were found. Thirty-six patients whose primary tumor sites remained occult were randomized to receive either 5-FU or combination chemotherapy (5-FU, doxorubicin, and cyclophosphamide [FAC]). There were no responses in either group. The median survival with 5-FU was 105 days and with FAC was 95 days. Toxicity with FAC was more common and more severe.

Cis-dichlorodiammineplatinum(II) was used in the treatment of 34 patients with advanced adenocarcinoma of the ovary who were resistant to conventional chemotherapy. Two dose schedules were explored: a high-dose schedule with 30 mg/m2 given daily on 3 successive days every 4 weeks and a low-dose schedule with 30 mg/m2 given once every 2-3 weeks. Nine patients (26.5%) showed a therapeutic response with a median duration of 6 months (range, 3-15 months). The main toxic effects included myelosuppression, renal function impairment, and nausea and vomiting. The high-dose schedule proved to be more toxic without any therapeutic advantage.

Thirty-six patients with lung cancer, 24 with prior chemotherapy and 12 without prior chemotherapy, received iv melphalan at doses ranging from 20 to 40 mg/m2 of body surface area. Patients who showed moderate myelosuppression and remained in the study were also investigated to determine if cyclophosphamide (300 mg/m2) administered 1 week before the identical dose of i.v. melphalan modified the hematopoietic toxicity of melphalan (cyclophosphamide priming). In this study, the activity of melphalan was minimal, four minor responses with no partial or complete responses. Three of these minor responses were in previously untreated patients. The major toxicity was hematopoietic and the maximum tolerated i.v. dose was 20 mg/m2 in the patients previously treated with chemotherapy and 30 mg/m2 in those without prior chemotherapy. Cyclophosphamide priming did not reduce the myeloid toxicity. Myelosuppression was more severe in the course that included cyclophosphamide. Recovery, however, appeared to be similar in both courses. I.v. melphalan at these doses has minimal activity in lung cancer. Cyclophosphamide administered 1 week before i.v. melphalan does not decrease the myelosuppression but should be investigated further for its effect on the rate of wbc and neutrophil count recovery.

Pentamethylmelamine (PMM) is a water-soluble monodemethylated derivative of hexamethylmelamine and has a similar spectrum of activity against murine tumors. Unlike hexamethylmelamine, it is suitable for parenteral administration. We conducted a phase I trial of PMM given as a weekly 1-hour iv infusion to 34 extensively pretreated patients with advanced solid tumors. Eight dose levels ranging from 80 to 1500 mg/m2 were studied. A median of three infusions (mean, 4.2; range, 1-24) were given to each patient. Severe nausea and vomiting was dose-limiting at 1500 mg/m2; it was unresponsive to antiemetics and persisted up to 48 hours. Mild to moderately depressed levels of consciousness were seen in one third of the patients at dose levels of greater than or equal to 750 mg/m2. Consistent dose-related myelosuppression was not observed. Hepatocellular toxicity manifested by elevated serum transaminases occurred sporadically, usually in patients with liver metastases, but could not be unequivocally attributed to the drug. No complete or partial tumor responses were noted. At each dose level, the pharmacokinetics of PMM disappearance from plasma were studied in one to three patients with a gas chromatograph-mass spectrometer assay which exclusively measured the unmetabolized drug. The data obtained wee consistent with a two-compartment model of drug distribution, with a mean dose-independent terminal half-life of 143 minutes (range, 43-370). Peak drug levels were directly proportional to dose. The relative lack of myelotoxicity would make PMM an attractive candidate for addition to combination regimens if antitumor activity at tolerable doses could be documented. On this schedule, the recommended dose is 100 mg/m2 for phase II trials.

Forty-one patients with advanced squamous cell lung cancer and no prior chemotherapy were entered in a prospectively randomized trial comparing dianhydrogalactitol plus Adriamycin (DA) versus DA plus cis-dichlorodiammineplatinum(II) (DAP). The DAP regimen was superior to the DA regimen in regression rate (53% versus 27%), median regression duration (255 versus 122 days), median time to tumor progression (approximately 175 versus 58 days), and median survival time (185 versus 126 days). Patients who were greater than 60 years old responded particularly well to the DAP regimen and accounted for most of the survival advantage. Nausea, vomiting, and myelosuppression were more frequent and severe with the DAP regimen. This study seems to indicate a role of cis-dichlorodiammineplatinum(II) in patients with advanced squamous cell lung cancer. The particular advantage noted for older patients needs further evaluation.

A phase II clinical trial of high-dose cisplatin (120 mg/m2 iv every 3 weeks), with fluid and mannitol-induced diuresis, was conducted in 81 patients with advanced lung cancer. Partial remissions were documented in 26% of 75 evaluable cases for a median duration of 3.5 months. Adenocarcinoma and small cell anaplastic carcinoma were more responsive than epidermoid carcinoma, with partial response rates of 35%, 30%, and 18%, respectively. The median survival of responders (8.5 months) was significantly longer than the survival of nonresponders (4 months) (P less than 0.02). Myelosuppression was mild. Renal toxicity with peak serum creatinine greater than 2.5 mg/100 ml occurred in eight patients, with one death occurring due to toxicity. Cisplatin is an active drug in advanced lung cancer.

One hundred and six patients with advanced adenocarcinoma and large cell carcinoma of the lung with no prior chemotherapy were entered in a prospectively randomized trial comparing cyclophosphamide, doxorubicin, and cisplatin versus methotrexate, doxorubicin, cyclophosphamide, and lomustine. The two regimens resulted in nearly identical regression probabilities (36% vs 34%), distributions of time to progression, and survival distributions. The major toxic effects from both regimens consisted primarily of myelosuppression and nausea and vomiting, with severe vomiting occurring more frequently in patients treated with cyclophosphamide, doxorubicin, and cisplatin (43% vs 19%).

Ten patients with persistent or metastatic trophoblastic disease following molar pregnancy were treated with etoposide orally, administered on an outpatient basis. All patients achieved sustained biochemical remission. The mean duration of treatment was 8 weeks. The side effects were mild. The use of etoposide in patients resistant to conventional chemotherapy is discussed.

A phase I clinical study of tegafur (ftorafur) was conducted in 29 patients with various advanced solid tumors. To evaluate its efficacy and toxicity, the initial dose of 0.5 g/m2/day x 21 days at 3-week intervals was progressively increased to a maximum dose of 1.5 g/m2/day. Tegafur was administered orally in two or three divided doses. Diarrhea was the dose-limiting toxic effect and occurred more often in patients with abnormal pretreatment liver function. Nausea occurred in about one-half of the patients, but vomiting was infrequent. Skin rash and mucositis occurred in 10% and 7% of the patients, respectively. Neurologic toxic effects of tegafur were infrequent and mild. The hematologic toxicity of tegafur was minimal. Antitumor activity could be evaluated in 21 patients with measurable disease. One complete and three partial responses were observed in four of 17 patients who had adenocarcinoma of unknown primary origin. All responses occurred at doses greater tan or equal to 1.0 g/m2/day. The recommended dose of tegafur for this schedule of administration is 1.0 g/m2/day.