L. Herbert Maurer

Isolation and growth characteristics of continuous cell lines from small-cell carcinoma of the lung

Sixteen continuous tumor‐cell cultures have been isolated from 91 tissue specimens from patients with small‐cell carcinoma of the lung. Biopsy and autopsy specimens of primary and metastatic tumors have been utilized. The developing cell lines were recognized by proliferation of tumor cells in the culture from one to 14 weeks after explantation and have been maintained for up to four years. Primary lung tumor, bone marrow aspirations, pleural effusions and other metastases have all been productive explant material for the development of cell lines. Their human origin has been demonstrated by chromosome and/or isoenzyme analysis. Dense core vesicles, characteristically found in small‐cell tumor cells were observed by electron microscopic examination of cultured cells. Growth rates in vitro have been measured and the in vitro cycle time in tumors of one cell line (DMS 79) has been compared with in vivo cycle time in tumors arising from DMS 79 cells in nude athymic mice.

Cytogenetics of small cell carcinoma of the lung

Nineteen cell lines derived from various malignant tissues of 15 patients with small cell carcinoma of the lung (SCCL) have been studied. The results showed heterogeneity in all cell lines, with no one consistent abnormality among them. Cell lines from 11 of the patients had minute and double minute chromosomes, and cell lines from 2 patients had abnormally banding regions, designated as ABRs, as distinguished from homogeneously staining regions (HSRs). The latter 2 and several of the former cell lines were derived from specimens taken before the patients were placed on therapy. All but 2 of the cell lines had a constant marker load, consisting of 24%-35% of the complement. Some markers remained stable through months and years of culture life, while other markers came and went. Chromosomes #1, #6 and #11 were most frequently involved in marker formation in the cell lines, and these were compared to similar markers in direct bone marrow preparations. Chromosome #1 markers were of variable structure, whereas #6 and #11 most often took the form of 6q- and 11p+ markers, with breakpoints most frequently at 6q23-25 and 11p11-12. A 3p- marker was found in a minority of cell lines. All of these markers were also found in direct marrow preparations from some patients with SCCL. Nonmonoclonal tumors arose from inoculation of bimodal cell lines into nude mice, but population selection by undetermined mechanism was evident. Cytogenetic parameters showed no positive correlation with hormone production by these cell lines.

A Feasibility Study of Extended Chemotherapy for Locally Advanced Non-Small Cell Lung Cancer: A Phase II Trial of Cancer and Leukemia Group B

The purpose of this study was to determine the feasibility of additional chemotherapy beyond 5 weeks of vinblastine-cisplatin followed by radiation therapy for patients with stage III non-small cell lung cancer. In this randomized phase II trial, the goal was to determine, in a similar population of patients, the toxicity of either of two additional chemotherapy programs. Ninety-one patients with stage III non-small cell lung cancer received the same induction regime of vinblastine/cisplatin/radiotherapy. In patients randomized to regime 1, an additional four cycles of vinblastine/cisplatin were given after the radiotherapy. In regimen 2, six weekly doses of carboplatin were given concurrent with the radiotherapy. The additional four cycles of vinblastine and cisplatin were completed by 34% of patients; the concurrent carboplatin program was completed by 70% of patients. Grade 3 or 4 granulocytopenia occurred in 53% of patients on regime 1 versus 17% on regime 2 (p < 0.003); grade 3 or 4 nausea/vomiting occurred in 20% of those on regime 1 versus 7% on regimen 2 (p = 0.175). Response rates and survival were similar for the two regimens, with approximately 30% of patients surviving at 2 years. Given the reduced toxicity and the improved capacity to complete the planned therapy with the concurrent carboplatin treatment, this regimen will be further examined in a phase III trial.

The Neurophysins and Small Cell Lung Cancer

Neurophysins are single chain proteins of about 10,000 daltons in size that are normally produced by neurons in the hypothalamus. These proteins are rich in cysteine, glycine, and glutamic acid, and all of those so-far studied have an N-terminal alanine. Most of the neurons that produce neurophysins are located in the supraoptic and paraventricular nuclei of the anterior hypothalamus. Two other well-characterized products of these neurons are the hormones oxytocin and vasopressin (antidiuretic hormone, ADH).

Phase I trial of etoposide, carboplatin, and GM-CSF in extensive small-cell lung cancer: a Cancer and Leukemia Group B study (CALGB 8832).

The maximum tolerated dose (MTD) of etoposide and carboplatin without growth factor support was previously defined by Cancer and Leukemia Group B (CALGB) as 200 and 125 mg/m2/day x 3, respectively, given every 28 days to previously untreated patients who have extensive, small-cell lung cancer (SCLC). Myelosuppression was dose-limiting. The purpose of this phase I trial was to determine if granulocyte macrophage colony-stimulating factor (GM-CSF) support allows the dosage of the combination of etoposide and carboplatin to be increased above the previously determined MTD. In this CALGB study of 44 evaluable patients with performance status 0-2, cohorts were treated with etoposide and carboplatin given intravenously on days 1-3 followed by GM-CSF (molgramostim) given subcutaneously on days 4-18. Four dose levels of bacteria-derived recombinant GM-CSF (5, 10, 20 microg/kg/day and 5 microg/kg every 12 h), three dose levels of etoposide (200, 250, and 300 mg/m2/day x 3), and two dose levels of carboplatin (125 and 150 mg/m2/day x 3) were evaluated. There was no chemotherapy dose escalation in individual patients. With 5 microg/kg/d GM-CSF, the first etoposide and carboplatin cycle of 300 and 150 mg/m2/day x 3, respectively, could be administered with acceptable toxicity. However, GM-CSF did not allow repeated administration of this dose-escalated regimen every 21 days, since delayed platelet and/or neutrophil recovery was dose limiting in later cycles. These results demonstrate that GM-CSF alone has limited capability to support the repeated administration of high doses of etoposide and carboplatin. CALGB currently is testing the ability of interleukin (IL)-6 given with GM-CSF to ameliorate the cumulative myelosuppression of this intense regimen.

A phase I II trial of etoposide and cisplatin in extensive small cell lung cancer: A cancer and Leukemia Group B study

Patients with untreated extensive small cell lung cancer (SCLC) with CALGB performance scores 0-2 were treated with etoposide 200 mg/m2/day on days 1-3 and cisplatin doses of 20, 30, or 35 mg/m2/day days 1-3 in a Phase I/II format. Of the nine patients treated at the 35 mg/m2/day cisplatin dose in the Phase I portion of the study, Grade 4 leukopenia occurred in five patients and Grade 4 thrombocytopenia in four. There were two deaths due to myelosuppression and sepsis. This dose was thus considered the maximum tolerated dose (MTD), and a Phase II trial was then conducted using this treatment program. In the Phase II trial of 39 patients, the objective response rate was 67% (95% confidence interval, 50-81%) with 21% complete responses (CI 9-36%). Median survival was 10.5 months. Grade 4-5 leukopenia was seen in 57% and Grade 4-5 thrombocytopenia in 56%. The MTD defined by this Phase I trial represents a 67-100% increase in etoposide and a 32-42% increase in cisplatin dosage compared to prior studies. The observed objective response rates with this regimen are comparable to studies using conventional doses, but hematological toxicity was higher.