LOS ANGELES--Twice-daily chest irradiation concurrent with cycle 1 chemotherapy substantially improves survival and reduces the rate of local failure in limited stage small-cell lung cancer (SCLC), compared with a less intensive once-daily schedule, a large intergroup trial has shown.

Notably, patients who achieved a partial response with the twice-daily regimen had 2-year and 5-year survival rates virtually identical to those of patients who had a complete response, Andrew T.Turrisi III, MD, reported at an ASCO oral session.

While chemotherapy remains the cornerstone of treatment for SCLC, "thoracic radiotherapy is an integral partner," said Dr. Turrisi, professor of radiation oncology, Medical University of South Carolina, Charleston. However, questions about fractionation persist.

In this study, the investigators evaluated two regimens of radiation therapy given concurrently with cisplatin-etoposide chemotherapy. Half the 419 patients enrolled in the study received a 45 Gy radiation dose given in daily (QD) fractions over the 5 weeks of the first cycle of therapy. The remaining patients received an identical radiation dose given in twice-daily (BID) fractions for 3 weeks of the first cycle.

"Why did we use twice-daily dosing?" Dr. Turrisi asked. "Rapidly dividing tumor cells have fast cell cycle times, and certain cell cycle phases are relatively radioresistant," and thus might respond better to more frequent dosing. He added that although twice-daily fractions with smaller doses per fraction cause greater acute toxicity (primarily esophagitis), this schedule produces fewer late effects, such as strictures.

All patients received the same chemotherapy: cisplatin (Platinol), 60 mg/m² on day 1, and etoposide (VePesid), 120 mg/m² on days 1 to 3. The regimen was repeated for a maximum of four cycles. "I acknowledge that many centers throughout the world continue to use cyclophosphamide- or doxorubicin-based regimens," Dr. Turrisi said. "However, those regimens are rather incompatible with the use of concurrent radiation therapy."

Patients who had a complete response received a 25-Gy dose of prophylactic cranial irradiation (PCI), given in 10 fractions over 2 weeks. Follow-up continued for a minimum of 5 years in all patients, and data were analyzed on an intention-to-treat basis.

Response Rates and Outcomes

Response rates did not differ significantly between the two groups. Complete responses occurred in 53% of patients who received twice-daily irradiation vs 46% of those randomized to once-daily radiation therapy. The overall response rates were 82% with BID irradiation and 81% with QD irradiation.

Median survival in the once-daily radiation cohort was 19 months versus 22 months in the BID cohort. Two-year survival was 41% and 46% with once- and twice-daily irradiation, respectively, and 5-year survival was 19% in the QD group and 27% in the BID group.

At the end of 5 years, 85% of the QD patients had died, as had 76% of the BID group. However, the cumulative mortality for the trial fell short of projections. There were 335 deaths at 5 years whereas the researchers had predicted there would be 350 deaths at 2 years.

Local failure occurred less often in the BID group, 42% vs 75% in the QD group (see table). The incidence of local plus distant failure was significantly lower in the BID group. Brain metastasis occurred significantly more often in the BID cohort. However, Dr. Turrisi noted that not all patients received mandated PCI. Among those who did, the brain metas-tasis rate was 50% lower (15% vs 30%).

"The partial responders were very interesting in this trial," Dr. Turrisi said, since their outcomes differed dramatically in the two groups. Among the 71 patients who achieved PR in the QD arm, survival was 24% at 2 years and 8% at 5 years. "Not so bad," Dr. Turrisi said. "However, the data were even more dramatic in the BID arm." Two-year survival among the 61 BID patients with a partial response was 45%, virtually the same as seen in patients who had a complete response. Five-year survival was 23%.

"Thus," he said, "partial responders can do very well, and this might have confounded the data on local failure." Only the complete responders received PCI, he noted, even though these results suggest that many of the good partial responders might benefit from it.

Both arms had grade 3-4 myelotoxicity in 89% of patients. However, grade 3 esophagitis was significantly more common with BID irradiation, 27% vs 12%.

The findings do not resolve all the potential questions about fractionation and timing of irradiation, Dr. Turrisi said. "Is it the BID dosing or the compressed schedule?" he asked. "Would an equivalent dose given in an equal or shorter time period, once a day, produce the same results? Would a greater dose in standard time produce equal outcomes? Right now, all we can say is that four cycles of cisplatin-etoposide plus concomitant 45 Gy BID provides a standard of comparison for which we have long follow-up."