The purpose of RTOG 97–12 was to determine the maximum tolerated dose (MTD) of thoracic radiation therapy (RT) with concurrent chemotherapy for patients with limited-stage small-cell lung cancer.

Sixty-four patients received four cycles of cisplatin (60 mg/m2 i.v.) and etoposide (120 mg/m2 i.v. Days 1–3) (PE), with concurrent thoracic RT starting on Day 1. Thoracic RT was given during the first two cycles with 1.8 Gy/fraction daily to the clinical target volume, followed by thoracic RT to the gross tumor volume b.i.d. for the last 3, 5, 7, 9, or 11 treatment days (total dose 50.4, 54.0, 57.6, 61.2, or 64.8 Gy, respectively). The MTD was based on the dose that produced Grades 3–4 nonhematologic toxicity (mainly esophagitis and pneumonitis) in greater than 50% of patients.

Results: After the first 8 patients were enrolled in Arm 1, administration of etoposide was changed from 120 mg/m2 i.v. on Days 2 and 3 of each cycle to 240 mg/m2 p.o. for patient convenience as outpatients. Total thoracic RT doses from 50.4 Gy to 61.2 Gy over 5 weeks given with PE were well tolerated. Three of the first 5 patients in the 64.8 Gy arm developed Grade 3 acute esophagitis; the MTD was determined to be 61.2 Gy. Fifty-four (87%) of the 62 evaluable patients achieved a complete (68%) or partial (19%) tumor response. The 18-month survival was 25% for patients receiving 50.4 Gy and 82% for those receiving 61.2 Gy.

Conclusions: The MTD for this accelerated thoracic RT regimen with concurrent PE was 61.2 Gy over 5 weeks.

It is now widely accepted that radiation therapy (RT) to the thorax, combined with chemotherapy, is the treatment of choice for patients with disease limited to the chest. Data from a trial conducted by the National Cancer Institute of Canada (3) demonstrated that administration of thoracic RT early in the course of chemotherapy was superior to thoracic RT administered after many more cycles of chemotherapy. Two pilot studies of concurrent chemotherapy and RT beginning concurrently on Day 1 suggested a benefit in short-term survival. Turrisi studied thoracic RT with accelerated fractionation using 1.5 Gy twice daily to a total dose of 45 Gy in 3 weeks, concurrent with cisplatin and etoposide (PE), and found a 2-year survival rate to be 44%. McCormick et al. from the Southwest Oncology Group  showed encouraging benefit with daily thoracic RT using 1.8 Gy per fraction to a total dose of 45 Gy in 5 weeks concurrent with chemotherapy.

Whether accelerating the thoracic RT with concurrent chemotherapy reduced intrathoracic failure and improved survival in patients with limited SCLC was addressed by Intergroup Studies 0096 (ECOG 3588/RTOG 88–15) (4). Twice-daily thoracic RT was compared with once-daily thoracic RT for limited small-cell lung cancer treated concurrently with cisplatin and etoposide. In that study, 417 such patients received thoracic RT to a total dose of 45 Gy either with standard fractionation at 1.8 Gy per fraction for 5 weeks (SD) or with accelerated fractionation (AHFX); with the latter, 1.5 Gy per fraction was given twice daily over 3 weeks (total dose 45 Gy). Patients in the accelerated fractionation arm had a median survival of 23 months compared with 19 months in the standard fractionation arm. More importantly, survival at 5 years was 26% for AHFX compared with 16% for SD (p = 0.04). The AHFX regimen resulted in a 27% incidence of Grade 3 esophagitis compared with 11% with SD and PE (p < 0.01). Moreover, the local failure rate in the AHFX arm was still 36%. Although this was better than the 56% local failure rate in the SD arm, it was still unacceptably high.

Strategies were considered that might increase the local control rate with concurrent chemotherapy and RT without increasing the esophageal toxicity rate to unacceptable levels. One strategy considered was to increase the total dose with daily thoracic RT to higher levels. This strategy, advocated by Choi et al., is being studied by the Cancer and Leukemia Group B . Considering the value demonstrated by accelerated fractionation even to a total dose of just 45 Gy in 3 weeks, there was concern that the overall duration of thoracic RT might be disadvantageous. Accelerated fractionation via concomitant boost has been successfully used to treat patients with head-and-neck cancer without chemotherapy. This strategy uses once-daily irradiation early in the course of treatment and then twice-daily irradiation toward the end. Therefore, a strategy that increased the total dose above 45 Gy but also accelerated the delivery of thoracic RT concurrent with chemotherapy was sought.

The hypothesis was that local failure could be reduced without increasing the incidence of acute Grade 3 esophagitis, the major nonhematologic (NH) toxicity in the earlier trials. A Phase I trial in which the chemotherapy was kept consistent and the thoracic RT dose was escalated was considered appropriate. Patients would be treated with once-a-day fractionation initially encompassing both the gross tumor volume (GTV) and a clinical target volume (CTV) that included sites of suspected metastases to lymph nodes. Toward the end of the 5-week course of treatment, a second fraction would be delivered each day using a concomitant boost technique encompassing only the GTV. Successive increases in the number of fractions delivered by the concomitant boost would constitute the dose escalation. The overall course of treatment would never exceed 5 weeks unless there were interruptions due to toxicity. Thus, the primary objective of this Phase I trial was to determine the maximum tolerated dose (MTD) of increasing doses of thoracic RT administered by concomitant boost.

Recently, attention has been focused on the use of prolonged administration of oral etoposide (VP-16) to take advantage of the apparent schedule dependency of this drug, which is phase-specific and acts in the late S or early G2 phase of the cell cycle (8–10). In vitro studies indicate that the degree of cell kill is related to the duration of exposure of the cells to the drug. In murine L 1210 leukemia, for example, exposure to the drug every 3 hours for 24 hours was superior to use of a single dose, and the cytotoxic effects of this simulated continuous infusion were also greater than the effects of smaller daily doses given consecutively for 5 days (11).

When etoposide was given orally for 21 days (of a 28-day cycle), the MTD was 50 mg/m2/day in a recently reported Phase I study. Most patients were able to receive their next course of treatment by Day 28. In a Phase II study of 17 patients with previously treated SCLC (14 with prior treatment with i.v. etoposide), Johnson et al. (10) reported a 47% response rate (including two complete responses), with a median response duration of 3 months. Median white blood count and platelet nadirs were 1,700/mm3 and 98,000/mm3, respectively, and occurred between Days 21 and 28. Einhorn ) reported a similar experience with oral etoposide in 26 previously treated patients with SCLC (objective response rate 23%, including one complete response).

In a separate study, Clark treated 20 patients with previously untreated SCLC and reported an 85% overall response rate. Dose schedule was 50 mg p.o. b.i.d. × 14 days of a 21-day cycle. Myelosuppression was minimal, with a median white blood count nadir of 3,400 and no significant thrombocytopenia. When etoposide was given twice a day (50 mg b.i.d.), the plasma concentration was maintained above the 1.0 ?g/mL level in most of the patients.

Etoposide and i.v. cisplatin combined have been shown to have synergistic antitumor effects in preclinical studies (14), and this has been borne out by numerous clinical studies in patients with SCLC (15, 16) and patients with non-small-cell lung carcinoma (17). In addition, preclinical data suggest a correlation between sensitivity to ionizing radiation and sensitivity to topoisomerase II inhibitors such as VP-16, which stabilizes the cleavable complex between the enzyme (topoisomerase II) and DNA (18).

Discussion

The primary purpose of this trial was to identify the MTD of thoracic RT, given in combination with chemotherapy (PE), that would induce acute esophagitis and pneumonitis in patients with limited SCLC. We found that dose escalation to 61.2 Gy within 5 weeks was possible with concurrent PE without exceeding our set maximum of 40% of patients developing Grade 3 or higher esophagitis at that dose. In our protocol, a total dose of 61.2 Gy was given as follows: 11 1.8-Gy fractions were given to large fields, 5 days a week, followed by 4 days of twice-daily RT in which one 1.8-Gy fraction was given in the morning to large fields and another 1.8-Gy fraction was delivered to boost fields 6 hours later. For the final 5 days, twice-daily 1.8-Gy fractions were given to the boost fields. This 5-week radiation-plus-chemotherapy period was followed by two more cycles of chemotherapy

Two meta-analyses of randomized clinical trials comparing chemotherapy with chemotherapy plus thoracic RT have shown that that combination has improved survival among patients with limited SCLC (2, 19). In one of these meta-analyses (2), data on 2-year survival accumulated from 11 randomized trials showed an odds-ratio benefit of 1.53 for the addition of thoracic RT to chemotherapy (p < 0.001); expressed in terms of risk difference, the addition of RT to chemotherapy improved 2-year survival by 5.4%.

Although the findings from these meta-analyses confirmed the usefulness of thoracic RT in improving local tumor control as well as survival in patients with limited SCLC, the optimal timing of thoracic RT relative to chemotherapy remains controversial. In a randomized comparison of 308 patients by the Canada Clinical Trial Group (3), those who underwent early thoracic RT had better survival and fewer brain metastases than did those who underwent thoracic RT late in the course of chemotherapy.

Whether accelerating the RT given with chemotherapy would improve local control or survival in patients with limited SCLC was investigated by Turrisi et al. (20) and Johnson et al. (21). Reasoning that SCLC cells proliferate quickly, these investigators chose to accelerate the RT, given in combination with concurrent cisplatin and etoposide, to twice-daily 1.5-Gy fractions, given 5 days a week over 3 weeks, for a total dose of 45 Gy. The 2-year survival rate was 57% in the study by Turrisi et al. (20) and 65% in the study by Johnson et al. (21); the 4-year survival rate in both studies was 36%. As noted earlier, the Intergroup comparison (4) of once-daily (SD) and twice-daily RT for SCLC showed that the twice-daily RT schedule improved the progression-free survival rate at 5 years compared with SD (26% compared with 16%, respectively, p < 0.04).

In our present study (RTOG 97–12), there was a suggestion of improvement in the estimated short-term survival rate (18 months) by dose escalation from 50.4 Gy to 61.2 Gy (25% compared with 82%, respectively).

The issue of normal tissue tolerance of twice-daily vs. once-daily RT for limited SCLC was addressed by Choi et al. (22). In that Phase I study, the MTD for hyperfractionated RT was 45 Gy, given in 30 fractions over 19 days. Because no MTD was reached for daily fractionation to 66 Gy given in 33 fractions over 45 days, a third schedule was tested in which 70 Gy was given in 35 fractions over 47 days. The response rates in this study ranged from 78% to 100% and did not differ depending on various dosage groups. Severe (Grades 3–4) esophagitis and granulocytopenia were more marked in the hyperfractionated and accelerated fractionation groups.

In addition to fractionation, the duration of RT is critical for controlling rapidly proliferating malignant cells, as has been shown in clinical trials involving patients with non-small-cell lung cancer and head-and-neck cancer (23–26). Concomitant boost has been attempted at The University of Texas M. D. Anderson Cancer Center for the treatment of locally advanced cancer of the head and neck (27); the efficacy of this approach was compared with that of hyperfractionated (twice daily) or standard RT in the RTOG randomized trial 9003. In that study, 1,113 patients with locally advanced head-and-neck cancer were randomly assigned to undergo one of four treatments: (1) standard RT, given in once-daily 2-Gy fractions 5 days a week to a total dose of 70 Gy in 35 fractions over 7 weeks; (2) accelerated high-dose RT, given in twice-daily 1.2-Gy fractions to a total dose of 81.6 Gy in 68 fractions over 7 weeks; (3) accelerated fractionated split RT, given in twice-daily 1.6-Gy fractions 5 days a week to 38.4 Gy, followed by a 2-week break, and continuing in the same schedule to a total dose of 67.2 Gy in 42 fractions over 6 weeks; and (4) accelerated fractionated RT with a concomitant boost, given as once-daily 1.8-Gy fractions 5 days a week plus another 1.5-Gy fraction to a boost field as a second daily treatment for the last 12 treatment days, to a total dose of 72 Gy in 42 fractions over 6 weeks. The median follow-up for all 1,073 patients with analyzable results was 23 months; that for living patients was 41 months. Patients given hyperfractionated or accelerated fractionation with concomitant boost (Arms 2 and 4) had better local-regional disease control and perhaps better disease-free survival, although this last apparent difference was not tested statistically. Outcomes were similar in Arms 1 and 3 (standard vs. accelerated split-course fractionation). However, all three modified fractionation schedules were associated with more acute side effects and more severe acute effects than was daily fractionation, but none led to an increase in late toxic effects (7).
Conclusions
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In this attempt to improve local control by increasing the dose of thoracic RT given with concurrent etoposide and cisplatin without increasing the incidence of acute severe esophagitis among patients with limited SCLC, we found that 61.2 Gy was the MTD of daily fractionation followed by accelerated hyperfractionated RT to the boost GTV with concurrent cisplatin and etoposide over a 5-week period. The efficacy of this regimen relative to that of accelerated twice-daily radiation with cisplatin and etoposide chemotherapy is being tested in a current Phase II trial through RTOG institutions. Should the results of such a study prove promising, a prospective Phase III trial will be warranted.
References