Clinical Investigation
A Phase I/II Radiation Dose Escalation Study With Concurrent Chemotherapy for Patients With Inoperable Stages I to III Non-Small-Cell Lung Cancer: Phase I Results of RTOG 0117

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Purpose

In preparation for a Phase III comparison of high-dose versus standard-dose radiation therapy, this Phase I/II study was initiated to establish the maximum tolerated dose of radiation therapy in the setting of concurrent chemotherapy, using three-dimensional conformal radiation therapy for non-small-cell lung cancer.

Methods and Materials

Eligibility included patients with histologically proven, unresectable Stages I to III non-small-cell lung cancer. Concurrent chemotherapy consisted of paclitaxel, 50 mg/m2, and carboplatin, AUC of 2, given weekly. The radiation dose was to be sequentially intensified by increasing the daily fraction size, starting from 75.25 Gy/35 fractions.

Results

The Phase I portion of this study accrued 17 patients from 10 institutions and was closed in January 2004. After the initial 8 patients were accrued to cohort 1, the trial closed temporarily on September 26, 2002, due to reported toxicity. Two acute treatment-related dose-limiting toxicities (DLTs) were reported at the time: a case of grade 5 and grade 3 radiation pneumonitis. The protocol, therefore, was revised to de-escalate the radiation therapy dose (74 Gy/37 fractions). Patients in cohort 1 continued to develop toxicity, with 6/8 (75%) patients eventually developing grade ≥3 events. Cohort 2 accrued 9 patients. There was one DLT, a grade 3 esophagitis, in cohort 2 in the first 5 patients (1/5 patients) and no DLTs for the next 2 patients (0/2 patients).

Conclusions

The maximum tolerated dose was determined to be 74 Gy/37 fractions (2.0 Gy per fraction) using three-dimensional conformal radiation therapy with concurrent paclitaxel and carboplatin therapy. This dose level in the Phase II portion has been well tolerated, with low rates of acute and late lung toxicities.

Introduction

The standard dose, volume, and beam arrangements for the treatment of non-small-cell lung cancer (NSCLC) were established by Radiation Therapy Oncology Group (RTOG) dose escalation trial 7301 (1). This trial included patients with inoperable stage III disease, who received radiation therapy only. Since current radiation parameters were established by that trial, a number of changes in treatment have occurred, including the addition of concurrent chemotherapy and the application of three-dimensional conformal radiation therapy (3DCRT). RTOG 9311 was a subsequent protocol that escalated the radiation dose with 3DCRT without concurrent chemotherapy (2). The total dose was based on the percent volume of normal lung exceeding 20 Gy (V20). RTOG 9311 established that the maximum tolerated doses (MTD) of radiation alone were 83.8 Gy for patients with V20 values of <25% and 77.4 Gy for V20 values between 25 and 36%. Near the close of this study, results of randomized trials were reported that demonstrated a survival advantage in favor of concurrent chemotherapy compared to radiation alone or to sequential chemotherapy followed by radiation therapy 3, 4, 5, 6, 7. Therefore, the objectives for RTOG 0117 were to establish the MTD of radiation therapy in the setting of concurrent paclitaxel and carboplatin therapy, using 3DCRT for patients with inoperable NSCLC (Phase I), and to estimate the percentage of patients who survive at least 12 months with this regimen (Phase II). This report addresses the Phase I results of this trial.

Section snippets

Methods and Materials

Between July 13, 2001, and January 13, 2004, 17 patients were enrolled in the Phase I portion of the study. Eligible patients had histologically proven stage I to IIIB NSCLC, Zubrod performance status levels of 0 to 1, a weight loss of ≤5% within the previous 6 months, a forced expiratory volume at 1 second of ≤1 liter, and atelectasis involvement, if present, in less than one lung. Based on conformal treatment planning, the volume of the lung at or exceeding 20 Gy (V20) had to be ≤30% and a

Results

Accrual for the Phase I portion was from nine RTOG institutions (15 of 17 patients) and one RTOG community clinical oncology program.

The Phase I portion of this study had 8 eligible and evaluable patients in cohort 1 (receiving 75.25 Gy/35 fractions) and 9 patients in cohort 2 (receiving 74 Gy/37 fractions). The distributions of pretreatment characteristics for each of the Phase I arms are given in Table 2. Patients ranged in age from 48 to 81 years old. Cohort 1 had 4 (50%) patients with a

Discussion

The currently accepted “standard of care” for patients with locally advanced NSCLC is concurrent radiation plus chemotherapy. Recently, most research has focused on which chemotherapy drugs to use and how to integrate them with radiation therapy. Moreover, little attention has been given to optimizing radiation therapy. In particular, the nationally accepted standard radiation prescription dose has remained at the same level (60–63 Gy) for more than 30 years (1). Doses in this range provide

Conclusions

Based on the results of RTOG 0117, NCCTG N0028, and CALGB 30105, 74 Gy has been established as the MTD of radiation therapy when given with weekly concurrent carboplatin and paclitaxel chemotherapy. These three cooperative groups have initiated a Phase III intergroup trial (RTOG 0617/ NCCTG N0628/ CALGB 30609) testing 74 Gy versus 60 Gy with concurrent chemotherapy for patients with inoperable stage III NSCLC.

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    A DLT was defined as acute grade 3 or higher esophageal or pulmonary toxicity that was possibly, probably, or definitely related to radiation. We implemented a 5 + 2 stepwise design similar to that in RTOG 0117.16,17 The trial began by treating up to 5 patients on arm 1.

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This work was supported by National Cancer Institute grants RTOG U10 CA21661, CCOP U10 CA37422, Stat U10 CA32115, and ITC U24 CA081647.

Conflict of interest: none.

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