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A phase I-II study of isotopic immunoglobulin therapy was performed in 18 patients with primary liver cancer; 14 were evaluable for toxicity. The patients received a dose of 37-157 millicuries of 131I-labeled antibody. The dose-limiting factor appears to be hematologic toxicity, especially thrombocytopenia. An objective antitumor effect was seen in six of nine patients who were evaluable for response. Present results suggest that further clinical studies with isotopic immunoglobulin are indicated.

Seventy-three patients with small cell lung carcinoma refractory to standard chemotherapy were entered in this phase II randomized study of cisplatin, maytansine, and chlorozotocin. Of the 58 evaluable patients, only one partial response was observed among 21 patients given cisplatin, and no responses were seen among 19 given maytansine or 18 given chlorozotocin. One patient treated with chlorozotocin and two treated with cisplatin experienced life-threatening thrombocytopenia. One third of the maytansine-treated patients experienced moderate or severe neurologic toxicity. The overall median survival was 9.7 weeks. Chlorozotocin treatment was associated with inferior survival (7.7 weeks).

Taxol is a unique plant-derived antineoplastic agent that appears to exert its cytotoxic effect by interfering with microtubule structure and function. In this phase I trial, in which the drug was given as a brief iv infusion every 3 weeks, the dose-limiting toxicity was leukopenia, with thrombocytopenia being seen much less frequently. Sensory neuropathy was frequently seen at the highest dosage, with numbness and paresthesias appearing in a glove-and-stocking distribution. In some cases, this appeared to be a cumulative effect. Total alopecia was common. Other toxic effects observed included nausea and vomiting, mucositis, myalgias, and phlebitis. The frequent occurrence early in the study of acute cardiovascular and pulmonary toxicity suggestive of hypersensitivity reactions was decreased in frequency and severity by prolonging the infusions and premedication with corticosteroids and antihistamines. Two heavily treated patients appeared to respond to this agent, one with non-small cell lung cancer and one with ovarian cancer. Based on these data, we recommend a starting dose in phase II trials of 212 mg/m2 in patients with minimal prior therapy and 170 mg/m2 in heavily treated patients. At least initially, these trials should be carried out in institutions familiar with the use of this drug.

Taxol is a unique antineoplastic agent which appears to exert its cytotoxic action as a result of interference with microtubular structure and function. Clinical development of this drug will be facilitated by the availability of sensitive and specific methods for its quantitation in biological fluids. We have developed a reverse-phase high-performance liquid chromatographic assay for taxol capable of detecting concentrations as low as 50 nM, which can be automated using readily available equipment. With this assay we have performed pharmacologic studies of taxol during the conduct of a phase I trial of this compound at The Johns Hopkins Oncology Center. Following a 60- to 360-minute infusion, the plasma disappearance is biexponential, with harmonic mean alpha half-life and beta half-life values of 16.2 minutes and 6.4 hours, respectively. Volumes of distribution for the theoretical central compartment (VDc) and at steady state (VDss) were 8.6 and 67.1 L/m2. Mean plasma clearance was 253 ml/minute/m2. Urinary clearance was 29.3 ml/minute/m2 and 5.9% +/- 8.8% of the drug was identified in 48-hour urine collections. No metabolites have been identified. Over the 18-fold dose range studied, there was no evidence of nonlinearity or dose-dependent behavior. A rough correlation between area under the plasma disappearance curve and hematologic toxicity was observed.

Twenty-three patients with small cell carcinoma of the lung (15 with limited disease and eight with extensive disease) were randomized into one of two induction schedules of high-dose cyclophosphamide (CY), 60 mg/kg iv, given either on Days 1 and 2 or on Days 1 and 8. Following the high-dose CY, patients were treated with a sequence of three monthly courses of COMB (CY, 800 mg/m2; vincristine [Oncovin], 1.4 mg/m2; methotrexate, 20 mg/m2; and BCNU, 60 mg/m2) alternating with high-dose CY. The overall response rate to the high-dose CY was 70% with 17% being complete responses (CRs). COMB produced no additional responses. There was no significant difference in response rate with either high-dose CY schedule. There was no unexpected morbidity associated with the intensive regiment despite marked myelosuppression. The high-dose CY administered on Days 1 and 8 appeared less toxic than that given on Days 1 and 2. Laboratory studies demonstrated that small cell carcinoma cells respond to drug-induced humoral stimulation in vitro; and that tumor proliferation in vivo temporally coincides with increased serum stimulatory activity. This study demonstrates that high-dose CY is a safe and effective induction therapy for small cell carcinoma of the lung although the low CR rate obtained is disappointing.

We studied the course of nausea and vomiting after high-dose cyclophosphamide (50-75 mg/kg) in 25 patients. Nausea was assessed with a visual analog scale and vomiting by patient report. The reliability and validity of these methods of assessment were established in separate studies of oncology patients. Nausea and vomiting developed between 6 and 12 hours after the start of a 1-hour cyclophosphamide infusion in about two thirds of the patients. Peak symptoms were at 12 hours. Vomiting had subsided in most of the patients by 24 hours, but nausea persisted. Although there was significant individual variation in the course of nausea and vomiting, we could identify no demographic, disease, drug, or treatment factors which were associated with more significant nausea and vomiting. Some of the variability in the onset, severity, and duration of nausea and vomiting may be related to individual differences in the metabolism of and susceptibility to cyclophosphamide. The visual analog scale may provide information about nausea not obtained by the more frequently employed categoric verbal rating scales. Suggestions for the treatment of nausea and vomiting after high-dose cyclophosphamide are made on the basis of the findings.

Nonthrombocytopenic purpura developed in a patient receiving hexamethylene bisacetamide, a tumor-differentiating agent in vitro that is in phase I clinical trials. Histopathological examination revealed features of leukocytoclastic vasculitis with deposition of IgA and complement in the dermal vasculature. Leukocytoclastic vasculitis, an extremely rare complication of therapy with antineoplastic agents, is reported to alert others using this compound of this association.

Twenty-eight patients with inoperable non-small cell carcinoma of the lung were treated with high-dose methotrexate with citrovorum factor rescue. One patient (4%) responded with a partial regression of the tumor. Three patients had severe or life-threatening complications: acute renal failure, acute shortness of breath, and bone marrow suppression, respectively. There is 98% confidence that the true response rate for this therapy is less than 20%. The results of this study demonstrate that high-dose methotrexate with citrovorum factor rescue, in the schedule utilized, is not effective in the treatment of patients with non-small cell carcinoma of the lung.

Eighty-two patients with small cell lung carcinoma refractory to standard chemotherapy were entered in this phase II randomized study of PALA, amsacrine, teniposide, and zinostatin. Of the 66 evaluable patients, one partial response occurred among 17 patients treated with teniposide and no responses occurred with the other drugs. Two patients each treated with amsacrine and teniposide experienced life-threatening hematologic toxic effects and one patient treated with zinostatin died of thrombocytopenic pulmonary hemorrhage. The overall median patient survival was 9.6 weeks. Weight loss greater than or equal to 5% prior to therapy, extensive disease, and a nonambulatory status were associated with poor survival.

Fifty-four patients with localized and extensive small cell carcinoma of the lung and no prior therapy were treated with intensive induction chemotherapy. The induction regimen consisted of two courses of high-dose cyclophosphamide, doxorubicin, and VP-16-213. The objective response rate was 78% (42 responses among 54 patients), with 14 complete (26%) and 28 partial (52%) responses. The median survival time for the entire group of patients is 378 days, with a projected 2-year survival rate of 22%. The most significant determinant of survival was the attainment of a complete response. Tumor progression in most relapsing patients occurred at the sites of initial involvement. Toxicity was significant, as expected, but treatment-related mortality did not exceed that of less intense regimens. Despite the use of such intensive induction regimens, the major challenge in the therapy for small cell carcinoma remains the achievement of more durable complete remissions.

Dosimetric studies are reported for 22 patients with hepatoma who received treatment with 131I-labeled antiferritin IgG. Studies included liver and tumor volume computations based on computerized axial tomographic scan analysis, in-vivo quantitation of the activity deposited in hepatic tumors and normal liver tissue, and effective half-life measurements of the activity in the tumor, liver, and total body. Administered activities of polyclonal and affinity-column purified 131I-labeled antiferritin IgG ranged from 32 to 157 mCi. Tumor volumes at the time of radioimmunoglobulin infusion ranged from 220 to 3020 cm3 and total liver volumes ranged from 900 to 4620 cm3. For tumor volumes ranging from 220 to 1700 cm3, the maximum tumor activity was linearly proportional to tumor volume, but independent of antiferritin preparations and administered activities. In this range of tumor volumes, the mean value of tumor-to-liver ratios of specific activities was 4.8:1. Hepatomas ranging from 2290 to 3020 cm3 had reduced tumor uptake of radiolabeled antiferritin IgG and had a tumor-to-liver ratio of specific activities of 1.6:1. For all patients studied there was a linear relationship between the volume of normal liver tissue and the maximum activity deposited. These data, in conjunction with toxicity studies and tumor effective half-life measurements, led to the present treatment regimen of administering 30 mCi of polyclonal antiferritin IgG on Day 0 and 20 mCi on Day 5 following the first injection. This has resulted in the same range of absorbed dose to the tumor as was achieved with larger administered activities, but with a significant reduction of total-body irradiation to the patient.

N-Methylformamide (N-MF) belongs to a class of polar-planar compounds which induce cellular differentiation. Preclinical antitumor activity was demonstrated against human mammary, colon, and lung tumor xenografts and L1210 and P388 murine leukemias. This phase I study used a single bolus infusion of N-MF given weekly X 3 doses every 6 weeks. Thirty-five patients were treated with N-MF at doses which ranged from 125 to 3125 mg/m2/week. The dose-limiting toxic effects included nausea and vomiting, anorexia, malaise, and liver function abnormalities. No myelosuppression was seen. The recommended dose for phase II trials of N-MF with this schedule is to initiate therapy at 2000 mg/m2 weekly X 3 and escalate to 2500 mg/m2 if the initial dose was well tolerated.

Fifteen patients with extensive small cell carcinoma of the lung and no prior therapy were treated with a chemotherapeutic regimen similar in intensity to the approach used in acute myelocytic leukemia. The patients received intensive induction therapy with cyclophosphamide, adriamycin, and VP-16-213 followed by treatment with a combination of BCNU, vincristine, methotrexate, and procarbazine. The objective response rate was 87% (13 of 15 patients) with three complete responses and ten partial responses. With the exception of one patient, the maximal response to therapy was achieved during therapy with the intensive cyclophosphamide, adriamycin, and VP-16-213 regimen. The three complete responders remain in remission for 159, 351, and 285 days but seven of the ten partial responders have relapsed and five of these have died. There was no unexpected morbidity associated with the intensive chemotherapy despite marked bone marrow suppression. This study demonstrates that very intensive combination chemotherapy can be safely used to achieve a high objective response rate in patients with extensive small cell carcinoma, but the complete response rate is low. An analysis of treatment failures and future directions is presented.

Nine patients with advanced epithelial ovarian cancer, classified as either stage III with macrometastatic residual disease or stage IV, received combination chemotherapy in conjunction with ip rabbit-derived human ovarian antitumor serum (HOATS). The HOATS regimen consisted of the ip instillation of 100 ml of ovarian antitumor serum on Days 1 and 3 of the first chemotherapy cycle. Side effects attributable to HOATS were low-grade fever in three patients and diffuse skin rash in two. The 1-year cumulative survival was 87%, with a clinical response rate of 80%. No significant toxic reactions to HOATS have been observed. Continuation of the present study seems justified.

The manufacturer's recommended dose of methadone, which is 2.5-10 mg every 3-4 hours, is excessive. Methadone has an average primary-phase half-life of 14.3 hours and a slower secondary-phase half-life averaging 54.8 hours. Administering the recommended dose of methadone and escalating doses within 2-3 days may lead to very high plasma levels of the drug. In addition, factors such as drug-drug interaction and/or hepatic and renal dysfunction may affect the metabolism of methadone and result in its accumulation. Methadone is an effective analgesic whose pharmacokinetics must be appreciated in order for it to be used safely and effectively. Three cases of methadone overdose are presented.

Thirty-four patients with metastatic breast cancer and no prior chemotherapy were treated with an induction regimen of four courses of adriamycin-cyclophosphamide followed by a fixed sequence of three courses of methotrexate-5-fluorouracil alternating with each course of adriamycin-cyclophosphamide. In this protocol, adriamycin can be administered for a minimum of 18 months before the dose of 550 mg/m2 is reached. The objective response rate was 56% (19 of 34 patients) with three complete responses and 16 partial responses. The median duration of response is 219 days and six of 19 patients remain in remission. The median survival of responders is 469 days while the nonresponders and progressors have a median survival of 273 days. The chemotherapy was administered in the outpatient department and was well tolerated. The scheduling of drugs in this study does not appear to result in significantly different response rates, duration of responses, or survival compared to those protocols in which these drugs are administered simultaneously.