A randomized clinical trial in bronchogenic small-cell carcinoma evaluating alternating maintenance therapy of vincristine, adriamycin, procarbazine, and etoposide (VAPE) with cyclophosphamide, CCNU, and methotrexate (CCM) versus CCM maintenance alone in complete responders following VAPE induction and late intensification.

Initially, 109 evaluable patients with locally advanced or metastatic small cell lung cancer (SCLC) were treated with vincristine, Adriamycin, procarbazine, and etoposide (VAPE). Partial (PR) or nonresponders (NR) were crossed to CCM (cyclophosphamide, CCNU, and methotrexate) and then to HMiVe (hexamethylmelamine, mitomycin C, vinblastine) sequentially at maximum response. Complete responders (CR) were intensified by 50% with VAPE primarily and randomized to VAPE, alternating with CCM or CCM alone during maintenance. CR patients with limited disease received local thoracic irradiation and prophylactic cranial irradiation (PCI), whereas those with extensive disease received PCI alone. There were 45 patients (41%) who achieved a CR to chemotherapy, and 27 patients were eligible for randomization. Of 12 CR patients randomized to alternating therapy (VAPE/CCM), the median survival was 25.9 months compared to 12.9 months for 15 CR patients randomized to continuous CCM (P = .049). In addition, 35 patients achieved a PR (32%) and 29 were NR (27%). Overall median survivals were significantly different for the CR patients (13.0 months) as compared to PR (7.6 months) and NR patients (6.4 months). Late intensification did not appear to add substantially to survival while contributing to toxicity. In summary, VAPE is a new outpatient regimen for SCLC, which is highly effective as an induction regimen with moderate hematologic toxicity and predominantly gastrointestinal nonhematologic toxicity.

A phase II clinical trial evaluating the use of two sequential, four-drug combination chemotherapy regimens in ambulatory bronchogenic adenocarcinoma patients.

Forty-three ambulatory patients with locally advanced or metastatic bronchogenic adenocarcinoma were sequentially treated with two potentially mutually non-cross-resistant chemotherapy regimens. A new regimen, MVPF (mitomycin-c, vinblastine, procarbazine, and 5-fluorouracil), was given until progressive disease occurred. Then, a second regimen--MOCC (methotrexate, vincristine [Oncovin], cyclophosphamide, and CCNU)--was initiated. At further progression, regional disease patients received radiotherapy, whereas extensive disease patients received Phase II agents. Of the 43 patients entered on the study, 40 were evaluable. Three patients withdrew early due to poor tolerance of the regimen. The response rate for MVPF was 33% (12 of 40 PR, 1 of 40 CR) compared to a 4% (1 of 23 PR) response for MOCC (difference: p < or = .03), for a total response rate of 35%. Although there was an initial improvement in survival for responders (31.7 weeks) versus nonresponders (15.7 weeks) at the 75th percentile (p < or = .05), there was no significant difference in median survival. The hematologic toxicity was equivalent for both groups, whereas nonhematologic toxicity revealed a high incidence of nausea and vomiting in the MVPF group. It is concluded that this approach lent itself well to ambulatory care, and MVPF could be considered an alternative to cyclophosphamide-based regimens. However, the absence of a meaningful CR rate and lack of influence of response on median survival were factors limiting its effectiveness.

Cisplatin-induced autonomic neuropathy.

A 57-year-old man with bronchogenic squamous cell carcinoma developed an autonomic neuropathy following treatment with a chemotherapy combination which included cisplatin. The autonomic neuropathy resolved following discontinuation of the cisplatin and treatment with dextroamphetamine. The following case represents a patient with bronchogenic carcinoma treated with cyclophosphamide, doxorubicin, and cisplatin, who developed a severe autonomic neuropathy following chemotherapy administration. This is the first report of cisplatin-associated autonomic neuropathy to appear in the literature.

Lobular carcinoma of the breast metastatic to bone with unusual clinical, radiologic, and pathologic features mimicking osteopoikilosis.

A 55-year-old woman who underwent a right radical mastectomy for infiltrating lobular carcinoma was found to have multiple diffuse osteoblastic bone lesions. Since she was asymptomatic, had no elevation of alkaline phosphatase, and the lesions did not take up technetium pyrophosphate on bone scan, she was thought to have osteopoikilosis. An iliac bone biopsy was performed that showed greatly thickened bony trabeculae with diffuse delicate marrow fibrosis entrapping easily overlooked short strands of small malignant cells. The histologic picture also closely resembled osteopoikilosis. Although infiltrating lobular carcinoma has been recognized as separate from ductal carcinoma in the primary site, its recognition in metastatic foci is still vague. Attention is drawn to its histologic appearance in skeletal metastases so that such lesions will be more recognizable in the future.

A controlled clinical trial testing two potentially non-cross-resistant chemotherapeutic regimens in small-cell carcinoma of the lung.

With the objectives of improving response rate, duration of response, and survival in small-cell carcinoma of the lung, 39 patients were randomized to remission-induction with either one of two potentially non-cross-resistant drug combinations: APE (consisting of adriamycin, 35 mg/m2 IV, D1 Q 3 weeks; procarbazine, 60 mg/m2 PO, D1-10 Q 3 weeks; and the epipodophyllotoxin (VP16-213), 130 mg/m2 IV, D8, 15 Q 3 weeks) or MOCC (composed of methotrexate, 15 mg/m2 IV (with [vincristine] Oncovin) or PO twice weekly D8-21 Q 3 weeks; Oncovin, 1.5 mg/m2 IV, D8, 15 Q 3 weeks; cyclophosphamide, 600 mg/m2 IV, D1 Q 3 weeks, and CCNU, 60 mg/m2 PO Q 6 weeks). A fixed crossover to the alternate regimen occurred at three months. Radiotherapy was delivered to the primary tumor (locoregional disease only) by a split course technique (1,750 rads for five days with a three-week split, followed by 3,400 rads over 17 days). The median survival including both arms was 11 months for regional and nine months for extensive disease. The chemotherapeutic activity of both regimens was comparable, with 15/17 (88 percent) of the patients responding to APE (including six complete) and 14/17 (82 percent) responding to MOCC (including five complete). The median survival for the complete responders was 11.7 months, while the partial responders survived for a median of 9.7 months. There were 2/9 (22 percent) responders to the alternate regimen at progressive disease. The overall incidence of CNS progression was 17 percent. The toxicity of the regimens was moderate, except for one instance of granulocytopenic death. This study establishes two equipotent drug combinations for the treatment of small-cell carcinoma of the lung.

Calcitonin as a marker for bronchogenic cancer: a prospective study.

A prospective study was done of serum calcitonin (HCT) levels in 61 patients with bronchogenic cancer. Initially, 52% of patients had hypercalcitonemia. Hypercalcitonemia was not confined to patients with any particular histologic type. Seventy-eight percent of those with high calcitonin remained normocalcemic. There was no correlation between high calcitonin levels and osseous metastases. Selective thyroid venous sampling delineated two types of hypercalcitonemia: thyroidal and ectopic. To date, the ectopic type has been associated with the small cell bronchogenic carcinoma. High initial calcitonin levels decreased significantly in 75% of patients on antitumor therapy. In 13 evaluable patients calcitonin levels mirrored clinical status changes 67% of the time. Calcitonin may be a useful marker to assess the results of therapy in patients with bronchogenic cancer.

Influence of chemotherapeutic agents on chorionic gonadotropin-alpha subunit secretion in a human lung cancer cell line (ChaGo): discordance of cytotoxic and secretory effects.

Cells from cultures of ChaGo, a cell line of a human lung cancer that ectopically produces chorionic gonadotropin (hCG) and its alpha subunit (hCG-alpha) were exposed to five different cancer chemotherapeutic agents in vitro in separate experiments (one drug/expt). The control doubling time averaged 4 days, with molar biphasic secretory rates of hCG-alpha ranging from a high of 58.1 to a low of 10.5 pmoles/10(6) cells/24 hours. Drug concentrations were chosen to induce a 30-60% inhibition of cell replication over a period of 8-10 days. Neither methotrexate nor vincristine demonstrated major effects on extracellular hCG-alpha production, but each agent moderately depressed cell number and each produced major inhibition of intracellular protein synthesis. Procarbazine inhibited marker production only in slight excess of inhibition of cell growth and cell protein. Actinomycin D and mechlorethamine, however, had profound effects on inhibition of hCG-alpha production in excess of cell growth. Our results indicated that cancer chemotherapeutic agents have specific and differing effects on cell growth and cell protein on the one hand and marker production on the other. These data suggested a mechanism for certain cases of discordance between hormone production and clinical status.

Vitamin A serum and dietary vitamin A intake in lung cancer patients.

Clinical and experimental evidence indicates a possible role for vitamin A deficiency in the pathogenesis of bronchogenic carcinoma. We, therefore, measured serum vitamin A levels in 67 newly diagnosed non-resectable lung cancer patients. In 43 of these patients daily vitamin A intake was also determined. Serum vitamin A levels were within the normal range of the general population of 66 of the 67 patients. Eighteen of 43 patients had daily vitamin A intakes less than 5000 IU/day while 25 patients had daily intake above this level. The serum vitamin A level did not correlate with histologic subtype, extent of disease or presence or absence of hepatic metastases. While these data suggest that vitamin A deficiency was not implicated in pulmonary carcinogenesis, more definitive conclusions await prospective evaluation of high risk individuals followed serially for many years.

Placental proteins and their subunits as tumor markers in prostatic carcinoma.

Sixteen patients with Stage D adenocarcinoma of the prostate were prospectively evaluated for the presence of human placental lactogen (hPL), placental alkaline phosphatase (PAP), and human chorionic gonadotropin (hCG). Ectopic production of hCG was found in one of the 16 cases and is described in detail. Serial serum hCG levels in that patient mirrored his course more reliably than concomitant acid phosphatase levels. Serum estradiol, testosterone, the hCG-alpha subunit, hPL and PAP were not elevated. There was a minimal elevation of serum FSH. There were no elevations of the other placental proteins in ten evaluable cases. A retrospective evaluation of serum bank specimens from 47 patients with prostatic carcinoma revealed no elevation of the placental proteins hPL, hCG-beta, and hCG-alpha. To our knowledge this report documents the first case of a chorionic gonadotropin-producing prostatic carcinoma appearing the literature.

Intensive chemotherapy of small cell bronchogenic carcinoma.

Thirty-two patients (27, extensive disease; five, regional disease) with histologically documented small cell carcinoma entered a randomized study to determine the efficacy of intensive induction chemotherapy. The necessity of a protected environment (laminar air flow room) during this treatment was also evaluated. Patients received high-dose or standard-dose cyclophosphamide, methotrexate, and CCNU (CMC) during the first 6 weeks of treatment. Subsequent maintenance therapy consisted of standard-dose CMC until disease progression. In 23 patients treated with high-dose chemotherapy there were responses in 96% (30% complete). Standard-dose chemotherapy gave responses in 45%, none of which were complete. Median survival correlated with completeness of response and was 16+ months for the seven complete responders. Patients receiving high-dose CMC spent an average of 10 days with neutrophil counts less than 1000/mm3. There was only one documented, non-fatal infection. High-dose chemotherapy gives better responses and longer survival than previously utilized standard doses of the same drugs. Patients could safely be treated in the hospital ward.

Pharmacokinetic considerations in the design of optimal chemotherapeutic regimens for the treatment of breast carcinoma: a comceptual approach.

Pharmacological data are currently available for a number of antineoplastic agents which have shown clinical activity in advanced breast carcincoma. Preclinical data reveal a relationship between therapeutic response and certain pharmacokinetic parameters such as time of effective cytotoxic exposure (Teff) and the product of concentration with time (Cxt). We have attempted to apply human pharmacologic data to get estimates of these parameters for 6 active agents in breast cancer, to relate them to response rates, and to suggest a method for estimating the role of individual drugs in a multidrug combination. The response rates for 6 single agents were obtained from literature review and related to estimates of Teff and Cxt. The Cxt-response relations for single drugs were linear for cyclophosphamide, 5-fluorouracil, and thiotepa; exponential for vincristine; and relatively flat for methotrexate and cytoxine arabinoside. Most Teff values for the active single agents clustered about 15 hr/dose. From the graphs of response rate vs Cxt, the individual contribution of each agent in a combination study was estimated to arrive at a predicted response rate. The predicted response rates for the combination studies correlated with the actual response rates determined in the clinical study, for 6 of 6 nonrandomized studies and for 12 of 14 randomized studies analyzed. In 2 studies, deviations from the predicted response rate were attributed to differences in study design or analysis. There was no correlation between Teff and predicted response rate. Analyses of pharmacokinetic data may be useful to simulate combination chemotherapy studies to predict the effectiveness of clinical trials in breast cancer. Since the pharmacologic data were not obtained for any of the agents in the actual clinical trials done, we can only speculate on the usefulness of this method. We would encourage the prospective collection of this data in future clinical trails.

Phase I study of thalicarpine (NAC-68075), a plant alkaloid of noval structure.

An initial clinical trial of daily and weekly X 6 ihtravenous infusions of thalicarpine, a plant alkaloid of novel structure, was carried out in 36 patients. Twenty-eight patients received 33 courses of single-dose administration at doses of 200-1900 mg/m2. At the maximum tolerable dose of 1400 mg/m2, toxic effects included arm pain (nine or ten), central nervous system depression (seven of ten), nausea and vomiting (two of ten), hypotension (two of ten), hypertension (two of ten), arrhythmia (premature ventricular contractions) (one of ten), and electrocardiographic changes (mainly T-wave flattening) (five of ten). At the maximum tolerable dose for weekly administration, 1100 mg/m2/week X 6, arm pain was seen in seven of eight, central nervous system depression in three of eight, hypotension in one of eight, and electrocardiographic changes in three of eight. The recommended dose for phase II trials is 1100 mg/m2/week by a 2-hour intravenous infusion.