When I met my first lung cancer patient in medical school, I found it difficult to grasp the wording of the diagnosis non-small cell lung cancer (and its associated acronym, NSCLC). Why was the diagnosis named so specifically for what it is not, rather than what it is?

As it turns out, small cell lung cancer is a unique type of cancer, which tends to spread rapidly, though which is typically very sensitive (at least initially) to both conventional irradiation and chemotherapy. Thus, for small cell lung cancers, because of their tendency to spread quickly beyond a surgeon's grasp and the relative success of nonsurgical therapy, radiation and chemotherapy were historically the treatment of choice for most patients.

For most other cancers originating in the lung (commonly including variants such as adenocarcinoma and squamous cell carcinoma), of all possible historic treatments, an "operation" designed to surgically remove all known cancer offered the best chance of cure - making therapy for all of these cancers distinctly different from that for SCLC. Unfortunately however, many patients with NSCLC still developed recurrence of their disease in the chest after surgery, and eventually died of their disease.

Given the high risk of cancer recurrence in the chest after surgery for NSCLC, radiation therapy evolved as a common secondary treatment. Radiotherapy was targeted at the lymph node regions within the chest for the majority of NSCLC patients, including those with early stage disease to more advanced stages of disease. In this situation, where radiation therapy is performed relatively immediately after surgery, it is referred to as an adjuvant (meaning "helper") treatment (think of it as an attempt to enhance the potentially curative effect of the primary or definitive therapy, which is surgery).

Unfortunately for many patients, a study published in 1998 which compiled outcomes for over 2,000 patients treated from the late 1960's to the early 1990's indicated that for patients with early stage, completely resected lung cancers (nodal stages N0 (no lymph nodes involved) or N1 (hilar lymph nodes within the lung)), long term survival was worse among patients that underwent radiotherapy after surgery. Among patients in that study with cancer that had already spread to the lymph nodes in the center of the chest (the mediastinum, or nodal stage N2), there was no detriment to survival for patients treated with radiation after surgery, but no apparent survival benefit to radiotherapy either. This study is commonly known as the PORT meta-analysis, with PORT referring to Post-Operative Radiation Therapy, and meta-analysis referring to the fact that the study is a compendium of smaller studies.

The historic problem with radiation therapy for lung cancer (alone or after surgery) has been the often serious side effect of lung inflammation and scarring, which has the potential to threaten quality of life and can even be fatal. Six weeks to 6 months after radiation therapy, patients can develop a radiation-induced pneumonia like process termed radiation pneumonitis. The inflammation of early pneumonitis can progress to scarring which can significantly impede lung function - typically referred to as fibrosis.

Fortunately, since publication of the 1998 PORT meta-analysis, and now more than two decades since most of those patients were treated, postoperative radiation therapy techniques in NSCLC have dramatically improved; additional studies during this interval have shown a shift toward potential benefit of postoperative radiation therapy for patients with advanced cancers. Nowadays, radiation oncologists can specifically target lymph node areas while limiting radiation dose to normal lung to levels which can preserve normal lung function. With three dimensional imaging, volumetric analysis of lung tissue and relative dosing can be calculated. Known metrics for lung damage assessed are assessed to be sure that the risks for harm are understood and minimized. This is far different than treatment for patients in the era of the 1970's and 1980's.

Although our technology is dramatically more sophisticated and has made radiotherapy for lung cancer safer, whether post-operative radiation therapy is beneficial to a patient remains controversial. For patients with node negative (N0) or limited nodal involvement (N1), more contemporary series have continued to suggest a negative impact of postoperative radiation therapy. However, multiple recent large studies (examples here and here) have indicated a significant survival benefit of radiotherapy after surgery for patients with more advanced nodal disease (N2).

The crux of the matter is this: the problem with interpreting these studies is potential selection bias for patients undergoing postoperative radiation therapy. Selection bias can obscure the true benefit or detriment of postoperative radiation for both early stage (N0-N1) patients, as well as more advanced patients, because these studies were retrospective, rather than randomized. When looking at patient outcomes, cancer stage can be helpful, but does not tell the whole story, and in fact, can mask some of the reality. For example, in a patient with NSCLC and stage No or N1 disease that was very difficult to remove surgically, perhaps because it had invaded close to the spinal cord or major blood vessels, that cancer is potentially more aggressive and life threatening than one that is removed more easily and completely with surgery. For the former patient with an aggressive cancer, treating physicians may be more likely to recommend radiotherapy. However, despite more aggressive therapy including radiation, that patient may not have the same chance to outlive his or her disease simply because it was more dangerous cancer. But if one looked simply at whether radiation was helpful, it may appear as though it was harmful, if the patient with the more aggressive cancer did not fare as well as a patient with a less aggressive cancer that did not undergo radiation therapy (even though the nodal stage for the patient was technically the same).

For patients with more advanced cancers, ambiguity also persists. Selection bias is potentially again manifest, though this time in the reverse. Among patients with more advanced disease, only those already likely to do better may be fit enough to make it to (and through) a course of fractionated radiotherapy... this time biasing the apparent effect of radiation favorably.

Statistics are applied to try to control for bias in both directions - considering a variety of patient factors when trying to determine the benefit of radiotherapy after surgery. However, the capability of statistics to get it exactly right and fully control for all various features of a patient and a cancer is...well...a challenge.

Selection bias and the resultant difficulties in interpreting more recent studies highlight the need for a randomized trial to help address this question. In a randomized setting, patients and physicians would not choose which patients underwent radiotherapy after surgery, but it would be dictated essentially by the flip of a coin. In this setting, if the study is large enough, other factors of patients and cancers influencing outcome are more evenly balanced. At the same time, the reason that we don't have data from a randomized trial to date is clear: patients and physicians tend to be reluctant to leave the decision to a randomized choice if conventional opinion views the treatment as presumably helpful or harmful.

Overall, here is my opinion: In patients with locally advanced (N2) NSCLC, the cancer all too often wins out after even quite good surgery and chemotherapy alone. Many of these patients have progression of their disease in the chest, which can be life threatening, painful, or a source of distant metastases. Given the relative safety of modern radiation techniques and the data we do have suggesting a benefit of radiotherapy in this situation, such patients should meet with a radiation oncologist to discuss the specific risks and benefits of adding radiation therapy after surgery. In my experience, I have seen patients with advanced (N2) disease after surgery and chemotherapy undergo radiotherapy directed at the mediastinum with excellent outcomes: they are alive years after treatment with no apparent radiotherapy related side effects. It cannot be proved that radiotherapy added benefit to surgery and chemotherapy, but they are certainly are doing well enough that, to me, PORT remains an appropriate option in some clinical situations and shouldn't be presumed to be detrimental based on very old, arguably outdated evidence.