When I first started OncTalk, my first priority was to get some basic posts on the site that provided a quick and dirty assessment of the best standards we had for different stages of lung cancer. But not only did several of these gloss over a lot of material very quickly, that was really before I could add figures. I'm going to try to go over some issues that are on the site in a more thorough manner; how chemo and radiation concurrently became the preferred approach for stage III NSCLC is a good place to start.

Why give chemo and radiation? We need to beat the cancer in two arenas: local and distant. We know we want to cover the tumor we can see with radiation, which can be quite effective in the area it covers, but it can't treat any micrometastases, living cancer cells that are outside of the radiation field. Chemo can potentially eradicate disease we can't see that is elsewhere in the body, poised to develop distant metastases. It can also work as a radiation sensitizer (or radiosensitizer), making radiation more effective in the area that receives it, if it's given at the same time as radiation. So chemo may improve both local and distant control when added to radiation.

Way back in the 1980s, radiation was the standard approach for most stage III NSCLC (we might consider this the "Dark Ages" of lung cancer, since chemo didn't have a role yet -- but as a chemo-administering medical oncologist, I may be biased). There was less effort to classify locally advanced as stage IIIA or stage IIIB, and the trials of that time basically just pooled a large group of patients with "stage III unresectable NSCLC" together. Then an influential study from the Cancer and Leukemia Group B, or CALGB, tested the value of adding chemo, old school chemo with cisplatin and vinblastine, a drug rarely used in NSCLC anymore, to radiation. The so-called Dillman trial (named after the lead investigator) tested radiation alone to two cycles of chemo followed by radiation in 155 patients:

(Click to enlarge)

It was published in the very influential NEJM (abstract here) because it had results that were felt to arguably change the standard of care, showing a significant benefit for the patients who received chemo for two cycles before radiation:

These results also held up with longer follow-up (full text here).

After that, the next question was whether giving chemo and radiation at the same time led to patients doing better than if they received chemo followed by radiation. A Japanese trial by Furuse and colleagues in the West Japan Lung Cancer Group (abstract here) tested this concept in just over 300 patients and found a significant survival advantage for the group that received concurrent chemo and radiation rather than a sequential approach:

There were actually a few limitations with this trial. One, the radiation dose was rather low, at 56 Gray (Gy), and we try to use a minimum of 60 Gy (and a difference of just 4 can make a difference); this was equal between the two arms. But the second point is that the people who got concurrent chemo and radiation had a break in their radiation, but the folks who received sequential chemo and radiation did not. We know that radiation is most effective if given without a break (not counting weekends, when the radiation oncologists tell us the machines don't work), so this should have favored the people getting sequential chemo and radiation, with no break in the radiation. Despite that advantage, the concurrent chemoradiation arm did better.

In fact, these results have been very consistent in a wide range of trials, run in Asia, North America, and also in Europe. These trials have consistently shown an improvement in median survival of about three months (and also, importantly, a greater proportion of patients alive several years out from treatment) if they received chemo and concurrent radiation (each colored bar is a different study):

So we've established that there is a survival benefit when chemo and radiation are given together. Great, but you never get something for nothing. There is a short term toxicity increase, primarily in severe esophagitis (inflammation of the esophagus). Radiation causes a burn inside the radiation field, which includes some of the esophagus that runs behind the windpipe and mediastinal lymph nodes. Grade 3 or 4 (moderately severe to severe) esophagitis is many times more common in patients who get concurrent chemo/radiation, seen across these same trials:

Fortunately, there are no significant differences in long-term toxicities seen in patients getting concurrent instead of sequential chemo and radiation. But because of the challenges of getting through the acute 6-7 week process, which sometimes leaves people hospitalized (with a rare fatality as well), this concurrent approach is still most appropriate for people well enough to get through the rigors of it. While sequential chemo and radiation is not quite as optimal for more fit patients, those who are too frail can be better served by a less intensive sequential approach that can still be curative, even if not quite as often.

Most of these trials included just a couple of cycles of chemo, along with radiation. Next we'll explore the question of whether adding more chemo before or after the chemoradiation is beneficial beyond just the 6-7 weeks of chemo and radiation together.