Final results of phase III trial in regionally advanced unresectable non-small cell lung cancer: Radiation Therapy Oncology Group, Eastern Cooperative Oncology Group, and Southwest Oncology Group.

STUDY OBJECTIVES: The purpose of this phase III clinical trial was to test whether chemotherapy followed by radiation therapy resulted in superior survival to either hyperfractionated radiation or standard radiation in surgically unresectable non-small cell lung cancer. DESIGN: Patients were prospectively randomized to 2 months of cisplatin, vinblastine chemotherapy followed by 60 Gy of radiation at 2.0 Gy per fraction or 1.2 Gy per fraction radiation delivered twice daily to a total dose of 69.6 Gy, or 2.0 Gy per fraction of radiation once daily to 60 Gy. Patients were enrolled from January 1989 through January 1992, and followed for a potential minimum period of 5 years. SETTING: This trial was an intergroup National Cancer Institute-funded trial within the Radiation Therapy Oncology Group, the Eastern Cooperative Oncology Group, and the Southwest Oncology Group. PATIENTS: Patients with surgically unresectable non-small cell lung cancer, clinical stage II, IIIA, and IIIB, were required to have a Karnofsky Performance Status of > or = 70 and a weight loss of < 5% for 3 months before study entry. Four hundred ninety patients were registered on trial, of which 458 patients were eligible. CONCLUSION: Overall survival was statistically superior for the patients receiving chemotherapy and radiation vs the other two arms of the study. The twice-daily radiation therapy arm, although better, was not statistically superior in survival for those patients receiving standard radiation. Median survival for standard radiation was 11.4 months; for chemotherapy and irradiation, 13.2 months; and for hyperfractionated irradiation, 12 months. The respective 5-year survivals were 5% for standard radiation therapy, 8% for chemotherapy followed by radiation therapy, and 6% for hyperfractionated irradiation.

Cyclin D1 expression in squamous cell carcinomas of the head and neck and in oral mucosa in relation to proliferation and apoptosis.

Deregulation of expression of the cell cycle regulator cyclin D1 (cD1) may be responsible for rapid proliferation of squamous cell carcinoma of the head and neck (SCCHN). We have studied the expression of cD1 in 46 SCCHNs using immunohistochemistry. Before biopsy, the patients received an in vivo infusion of iododeoxyuridine (IdUrd) for cell proliferation assessment. Additionally, the level of apoptosis was estimated using in situ end labeling (ISEL). Among 33 tumors, the proportion of cD1(+) cells varied from 0.5 to 51.3% (19.9 +/- 2.2%). Thirteen tumors did not express cD1. The fraction of S-phase (IdUrd-positive) cells was 26.3 +/- 1.8% in cD1(+) versus 20.0 +/- 2.4% in cD1(-) tumors (P = 0.06). The percentages of cD1(+) cells and of S-phase cells were not correlated (P = 0.37). Apoptosis was detected by ISEL in 15 of 33 tumors studied. ISEL-positive tumors contained a significantly higher proportion of cD1(+) cells (14.9 +/- 2.6%) than cD1(-) ones (7.9 +/- 2.8%; P = 0.03). There was a positive correlation between the percentage of cD1(+) cells and the degree of ISEL (r = 0.54; P < 0.001). In noninvolved oral mucosa, cD1(+) cells were located primarily in the suprabasal layers (29.3 +/- 3.8% versus 1.2 +/- 0. 2% in the basal layer). Only 23 of 44 mucosal specimens contained cD1(+) cells. All cD1(-) samples were proliferatively active and contained IdUrd-labeled cells. The percentage of cD1(+) cells in the oral epithelium from nontumor controls (uvula samples) was significantly higher than in the SCCHN group in both basal (2.4 +/- 0.4%; P = 0.008) and suprabasal (42.7 +/- 3.3%; P = 0.005) layers. Additionally, whereas in uvuli, cD1(+) cells were distributed evenly along the epithelial lining, in SCCHN samples the regions showing cD1 expression alternated with areas in which cD1 expression was undetectable. These data indicate that cD1 expression in SCCHN varies among tumors and is not correlated with cell proliferation. In noninvolved oral mucosa, cD1 expression differs from that in truly normal epithelium obtained from nontumor patients. A correlation between cD1 expression and the extent of ISEL positivity suggests a possible involvement of cD1 expression in the apoptotic pathways.

Cell kinetics of head and neck cancers.

We measured the tumor cell proliferative rate in 26 patients with head and neck cancer, 22 of which were squamous cell carcinomas (SCCs). Patients received sequential infusions of iododeoxyuridine and bromodeoxyuridine, after which the tumor was biopsied and studied. The percentage of labeled cells [labeling index (LI)] in well-differentiated SCCs was 20.4 +/- 2.7% (mean +/- SE) and 23.8 +/- 2.1% in moderately differentiated SCCs (P = 0.135). The LIs of two poorly differentiated SCCs were 39.4 and 55.9%. The LI was 2.5% in a high-grade lymphoepithelioma and 24.8% in a malignant lymphoma. In one well-differentiated and one poorly differentiated mucoepidermoid tumor, the LIs were 3.0% and 29.1%, respectively. S-phase duration time measurements ranged from 5.1-21.5 h (12.8 +/- 1.5). The calculated potential doubling times ranged from 18.8-84.5 h (47.3 +/- 6.7). The duration of G2 was between 90 and 180 min. To track the fate of labeled cells, in four patients a repeat biopsy was obtained 7-14 days after the iododeoxyuridine/bromodeoxyuridine infusion. These patients did not receive treatment between the biopsies. Due to the dilution of the label, most labeled cells in the second biopsy demonstrated a "fragmented" pattern resulting from repeated cell divisions. In two patients, however, 25% of cells in the second biopsy had undiluted label, suggesting that these cells had not divided after incorporating iododeoxyuridine/bromodeoxyuridine. On Day 7 labeled cells migrated to keratinized parts of tumors and to necrotic foci. Thus, the arrest of cell cycle transition, tumor cell differentiation, and cell death may be major routes of tumor cell loss from the proliferative compartment. This may explain the difference between very short potential doubling times and the actual rate of tumor growth.