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Postoperative Radiation Therapy for Lung Cancer

Postoperative Radiation Therapy for Lung Cancer

ABSTRACT: ABSTRACT: Lung cancer is the leading cause of cancer mortality in the United States. Local recurrence after surgery for operable disease has long been recognized as a hindrance to long-term survival. Postoperative radiation therapy was logically explored as a means to improve local control and survival. Multiple randomized trials were conducted, many showing improved local control, but none demonstrated a statistically significant survival benefit. In fact, a meta-analysis showed a rather large survival detriment, presumably from treatment-related complications. Radiation therapy has evolved over the years, and more modern treatment planning and delivery has the potential to treat sites deemed at high risk of recurrence while limiting the dose to critical intrathoracic structures, which should decrease the risk of treatment-related complications. Recent studies have supported this supposition. Similarly, since cancer is often a systemic disease, local control will become a more pressing issue as systemic micrometastatic disease is eradicated with effective chemotherapy. Unfortunately, randomized trials testing the effectiveness of modern postoperative radiation therapy in the chemotherapy era have not been performed. Clinicians must therefore counsel patients regarding the risk of disease recurrence after surgery, the potential but unproven benefit of postoperative radiation therapy, and the possibility of treatment-related complications.

Figure 1An extraordinarily influential and controversial 1998 report by the Postoperative Radiation Therapy (PORT) Meta-analysis Trialists Group showed that postoperative radiation therapy (RT) was associated with a 21% relative increased risk of death in patients with lung cancer.[1] Interestingly, this was not the first meta-analysis suggesting that an adjuvant treatment was potentially detrimental. Three years earlier, the Non-Small Cell Lung Cancer Collaborative Group published a meta-analysis of adjuvant chemotherapy trials,[2] demonstrating a 15% relative increased risk of death at 2 years with long-term alkylating agents. Knowing that distant metastases develop in a significant proportion of patients, further studies successfully sought to optimize chemotherapy delivery (appropriate agents, number of cycles, etc). Local failure, as will be shown, is also a considerable obstacle to cure in resected lung cancer. How postoperative RT can be optimized to safely decrease this risk and improve survival will be the focus of this review.

Local/Regional Failure: Defining the Risk
An accurate assessment of the risk of local (ie, local/regional) recurrence after surgery is necessary to guide postoperative therapy. In malignancies in which the risk of local recurrence is relatively high, postoperative RT generally improves outcomes (eg, cancers of the breast, rectum, and central nervous system). On the other hand, in malignancies with low rates of local recurrence after surgery, postoperative RT has not generally produced a benefit (eg, cancers of the colon, bladder, and kidney).

Table 1In lung cancer, unfortunately, determining the risk of local recurrence after surgery is not a straightforward task. Most prospective studies have not reported patterns of failure. When rates of local failure are reported, these are typically given as crude percentages in lieu of actuarial rates. Crude rates are influenced by the length of follow-up (Figure 1) and risk of death from other causes, and will always underestimate the true risk.

Furthermore, many studies only report first sites of failure. Distant metastases commonly develop after surgery for lung cancer and are typically easier to assess radiologically than local/regional failures. Unless there is a thorough evaluation at the time of relapse (to assess for a concurrent local failure), this may also underestimate the true risk.

Finally, the definition of local failure varies in both prospective and retrospective studies. For example, in the recently published Adjuvant Navelbine International Trialist Association (ANITA) trial,[3] local failure was defined as an "ipsilateral mediastinal relapse." Other sites of failure, such as the contralateral mediastinum, were scored as distant failures. This is clearly a narrow definition of "local" failure and is potentially misleading. Most investigators would define a local (ie, local/regional) relapse as a failure at the surgical margin or in ipsilateral hilar and/or mediastinal lymph nodes.

With an understanding of these limitations, an attempt to define the risk of local recurrence follows.

Table 2Stage I/II
It is generally believed that the risk of local recurrence after lobectomy for stage I non–small-cell lung cancer (NSCLC) is low. However, there is substantial variation in the literature, with rates ranging from 6% to 45% (Table 1 and Figure 1). It is noteworthy that studies with local control as a primary endpoint[4-6] have generally reported higher rates of local failure than those with other primary endpoints, such as disease-free survival.[7,8] It is likely that the diligence with which local control is assessed and recorded is affected by this detail.

Table 3The incidence of local recurrence after surgery for stage II NSCLC is generally higher than with stage I. Crude rates range from 7% to 55% (Table 2 and Figure 1). The only study reporting an actuarial rate was from the Mayo Clinic, which demonstrated a 38% risk of local failure at 5 years (crude rate was 23%).[9]

Stage III
Similar to early-stage disease, reported rates of local recurrence after surgery for stage III NSCLC vary dramatically (Table 3 and Figure 1). However, most studies, especially those reporting actuarial rates, indicate that the risk is substantial (> 50%). Such high rates of local failure are not surprising. Microscopic deposits of tumor likely infiltrate throughout the mediastinal lymphatic network, making a curative en bloc "cancer resection" impractical.

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