Clinical investigation: lung
Can elective nodal irradiation be omitted in stage III non-small-cell lung cancer? analysis of recurrences in a phase II study of induction chemotherapy and involved-field radiotherapy

Presented at the 37th Annual Meeting of the American Society of Clinical Oncology, San Francisco, California, May 12–15, 2001, and at the 43rd Annual Meeting of the American Society for Therapeutic Radiology and Oncology, San Francisco, California, November 4–8, 2001.
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Abstract

Purpose: To establish the recurrence patterns when elective mediastinal irradiation was omitted, patients with Stage III non-small-cell lung cancer were treated with sequential chemotherapy (CHT) and involved-field radiotherapy (RT).

Methods and Materials: Fifty patients were treated with either two or four cycles of induction CHT, followed by once-daily involved-field RT to 70 Gy, delivered using three-dimensional treatment planning. The contoured gross tumor volume consisted of the pre-CHT tumor volume and nodes with a short-axis diameter of ≥1 cm. Patients were reevaluated at 3 and 6 months after RT using bronchoscopy and chest CT. Elective nodal failure was defined as recurrence in the regional nodes outside the clinical target volume, in the absence of in-field failure.

Results: Of 43 patients who received doses ≥50 Gy, 35% were disease free at last follow-up; in-field recurrences developed in 27% (of whom 16% had exclusively in-field recurrences); 18% had distant metastases exclusively. No elective nodal failure was observed. The median actuarial overall survival was 18 months (95% confidence interval 14–22) and the median progression-free survival was 12 months (95% confidence interval 6–18).

Conclusion: Omitting elective mediastinal irradiation did not result in isolated nodal failure. Future studies of concurrent CHT and RT for Stage III non-small-cell lung cancer should use involved-field RT to limit toxicity.

Introduction

The combination of chemotherapy (CHT) and radiotherapy (RT) is the standard of care for patients with unresectable Stage III non-small-cell lung cancer (NSCLC). Recently, concurrent CHT and RT (CHT-RT) was shown to be superior to the sequential administration of the two modalities 1, 2. However, overall survival remains poor because of both local and distant failure, and future strategies must be directed toward both of these patterns of relapse. CHT reduces the incidence of distant metastases but has only a modest effect on survival because of the high incidence of local recurrence (3). In NSCLC, improvements in local tumor control improve survival 4, 5. However, strategies directed toward improving local control should not unduly increase the toxicity or compromise the ability to deliver optimal doses of systemic CHT. Both radiation dose escalation 6, 7 and concurrent CHT-RT are accompanied by increases in the incidence of treatment-related radiation pneumonitis and esophagitis. For example, the modest survival gain of 2.5 months in the concurrent CHT and once-daily RT arm of the Radiation Therapy Oncology Group (RTOG) 94-10 study was accompanied by a 48% incidence of Grade 3-4 acute toxicity vs. a 30% incidence with sequential CHT-RT (2). Therefore, future approaches should be accompanied by measures to avoid increases in toxicity.

An obvious measure to reduce toxicity in a volume-dependent organ such as the lung is to reduce the amount of normal lung tissue in the planning target volume (PTV). This can be achieved by omitting elective nodal irradiation (ENI). Currently, elective irradiation of radiologically uninvolved mediastinal nodes is widely considered standard for Stage III NSCLC 8, 9. Proponents of ENI justify this practice because unenlarged mediastinal nodes may contain occult metastases. However, the use of ENI in Stage III NSCLC is not based on firm scientific evidence (10), and ENI limits the ability to escalate radiation doses (11). In addition, the risk of failure arising from occult metastases in unenlarged mediastinal nodes must be offset against the failure to achieve histologically confirmed complete remissions in >80% of patients with Stage III NSCLC (12). This argues for more intensive treatment directed at the clinical target volume, which may only be possible if ENI is omitted because this reduces the risk of radiation pneumonitis and esophagitis 7, 11. An 8% recurrence rate has been reported in the initially uninvolved mediastinum when ENI is performed (6). To establish the risk of recurrence in unirradiated mediastinal nodes of patients with Stage III NSCLC, we performed a Phase II study of induction CHT, followed by involved-field (IF)-RT to a dose of 70 Gy.

Section snippets

Methods and materials

Between 1997 and the end of 2000, patients with Stage III tumors were treated in a Phase II trial in which either two or four cycles of induction CHT were administered, followed by IF-RT. The Medical Ethics Committee of the University Hospital Rotterdam approved the study, which was labeled DDHK 97-11. All patients gave written informed consent before enrollment in the study and were jointly evaluated by a pulmonary oncologist and a radiation oncologist before the start of treatment.

Results

The study closed in early 2001 after 50 eligible patients had been recruited. Four other patients were considered ineligible because of distant metastases that manifested before the second cycle of CHT and in 1 patient because of a synchronous second primary. The baseline characteristics of the 50 patients, and the details of RT and CHT, are summarized in Table 1. Of the 50 patients, 76% had Stage IIIB disease, and the locally advanced disease indicates that regions of the mediastinum outside

Discussion

The practice of ENI became standard in the era before CT-based RT planning was available, and it was reinforced by analyses of failure patterns in RTOG trials (22). However, accurate restaging using bronchoscopy has revealed that earlier studies had grossly overestimated local control after RT (3). This Phase II study was performed to establish whether the use of IF-RT would result in an unacceptable increase in out-of-field regional failure.

The main arguments for omitting ENI are as follows:

  • 1.

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