This article is a review of Postoperative Radiation Therapy for Lung Cancer: Where Do We Stand?
Kelsey et al have written an excellent review on postoperative radiotherapy (PORT) for non–small-cell lung cancer (NSCLC). As pointed out in this thorough yet concise review, there are inconsistencies in the recommendation of PORT for NSCLC. These are the result of (1) inconsistencies in the assessment, definition, and report of the risk of local/regional recurrence after surgery, (2) inconsistencies in patient selection for PORT, and (3) a lack of well designed, adequately powered, prospectively randomized trials in the era of conformal radiation therapy.
Since the 1998 publication of the Trialists Group meta-analysis that showed a detrimental effect of PORT for NSCLC on overall patient survival,[1,2] the use of PORT has declined significantly in the United States. The meta-analysis was performed with data from 2,128 patients in nine randomized trials (published or unpublished) based on intention to treat. The results showed a significant adverse effect of PORT on survival (hazard ratio [HR] = 1.21; 95% confidence interval [CI] 1.08–1.34). Subgroup analyses suggested that this adverse effect was greatest for patients with stage I/II, N0/N1 disease, whereas for those with stage III, N2 disease there was no clear evidence of an adverse effect.
A recent update from the Trialists Group that included 2,232 patients from 10 randomized trials confirmed that PORT was detrimental for patients with early-stage (stage I/II) completely resected NSCLC, whereas for patients with stage III, N2 disease there was no clear evidence of an adverse effect. Based on these results, radiation oncologists generally agree that PORT is not indicated for completely resected stage I/II, N0/N1 NSCLC.
Survival Benefit in N2 Patients?
Patients with incidentally discovered N2 disease and patients with N2 disease after induction chemotherapy and complete surgical resection are at high risk of local recurrence (40%–60%) and distant metastases, as pointed out in the review by Kelsey and colleagues. Adjuvant treatments are considered a critical component of combined-modality therapy. The benefit of postoperative chemotherapy has been confirmed in several large trials of patients with stage II/III disease.[4,5] However, the benefit of PORT, especially on survival, remains inconclusive.
Recently, several large retrospective studies suggested a survival benefit of PORT in N2 patients. In the Adjuvant Navelbine International Trialist Association (ANITA) randomized trial evaluating adjuvant chemotherapy in stage IB–IIIA patients, PORT was an option left up to the individual institution before entering any patient in the trial. The descriptive analysis suggested that PORT had a survival benefit in patients with N2 disease. Another piece of evidence comes from Lally and colleagues, who selected patients treated between 1988 and 2002 from the Surveillance, Epidemiology and End Results (SEER) database, of which 47% received PORT. A significant improvement in survival was suggested in N2 patients.
However, practice guidelines for PORT have been inconsistent for patients with N2 disease. The National Comprehensive Cancer Network (NCCN) guidelines recommend adjuvant chemotherapy followed by PORT for patients with negative margins, postoperative chemoradiation for positive margins, and upfront PORT followed by chemotherapy for close margins and grossly involved N2 disease, based on limited evidence.
A 2004 guideline by the Lung Cancer Disease Site Group of the Cancer Care Ontario Program in Evidence-Based Care concluded that no evidence of a survival benefit and conflicting evidence on local/regional control was found for PORT in completely resected N2 patients. Therefore, the Canadian investigators concluded, the decision regarding PORT should be individualized.
More recently, the American College of Chest Physicians (ACCP) guidelines stated that “postoperative radiation therapy cannot be recommended on the basis of any proof of improved survival, but it should be considered in selected patients to reduce the risk of local recurrence, particularly when there is involvement of multiple nodal stations, extracapsular tumor spread, or close or microscopically positive resection margins, especially as assessed by the surgeon performing the resection.” PORT is generally recommended after adjuvant chemotherapy, and adjuvant concurrent chemoradiation is not recommended except in a clinical trial setting per the ACCP guidelines.
Taken together, these studies and guidelines suggest that PORT, like any other treatment, has its indications. At our institution, we use three indications to recommend PORT for patients with completely resected NSCLC: (1) positive N2 node(s), (2) a positive surgical margin, and/or (3) tumor at a location where a negative surgical margin is unlikely, even though the pathologic report does not indicate a positive margin (such as in cases of superior sulcus tumor). Eventually, a randomized trial using modern radiation therapy techniques will be needed to clarify these muddy waters.
—Zhongxing Liao, MD