Suresh Senan, MD: In nonresectable locally advanced non—small cell lung cancer, the standard of care is concurrent chemoradiotherapy supported by metaanalysis. So, we give a dose of about 60 gray, 6 weeks of radiation with at least 2 cycles of platinum-based combination chemotherapy, and in patients who are fit to tolerate the treatment. So, the patient has to be fit for both. And in radiation oncology, for the radiation aspect, the radiation esophagitis is the most troublesome toxicity. And depending on the study, it could range from about 6% to 15%, grade 3 or higher, which means the patients need a feeding tube. But it’s often a self-limiting toxicity. But that is often an impediment, and in centers who do not have experience, they may only choose the most fit patients, and for the rest, they may not do it as concurrent treatment, they may do it to sequential treatment.

So, until recently, the trial suggested that the survival benefit was in the order of about 4% at 5 years; sequential was concurrent. But that’s not a true reflection because often patients come for sequential treatment if their disease has not progressed where they’re being treated elsewhere in another department with chemotherapy. So, the preference is always with concurrent. But if the patient is not fit or there are doubts, sequential is a good option. First the chemotherapy, between 2 and 4 cycles of systemic therapy, followed thereafter by radiation therapy to about 6 weeks of radiation therapy.

And in patients who are unfit to receive any chemotherapy, radiotherapy is an option, but partly due to selection and partly because a single-modality treatment in locally advanced non—small cell lung cancer is insufficient for cure for many patients; the survivals are far poorer. We’re talking about a median survival of about between 11 to 14 months in patients who’ve had a brain MRI and a PET scan to exclude occult disease. So, if I were to summarize, I would say anyone who can receive it should receive concurrent platinum-based chemotherapy to a dose of about 60 gray.

In unresectable stage 3 disease, the role of higher doses of radiation has been a subject of randomized RTOG trials, and the surprising conclusion for some radiation oncologists was that a higher dose of 74 gray was actually inferior to a standard dose of 60 gray. So, 60 gray given in once-daily fractions of 2 gray. And these data have now been updated with 5-year follow-up at the ESTRO meeting this year. And that showed that with standard chemoradiotherapy, carboplatin-based therapy for 6 weeks, patients have a 5-year survival of about 30%. Unfortunately, the 5-year progression-free survival is only 18%. And that was far superior to patients getting a higher dose. Not only did they have more recurrences, but also more toxicity during treatment. It may be reflected by a number; there may be a number of explanations for this, including the fact that perhaps with delivery of higher techniques, people were more careful about sparing, avoiding normal organs to the extent they have avoided part of the tumor. But it could also be toxicity of very high dose radiation, which has also been shown in the past for esophageal tumors; for example, tumors in the same location.

So, the dose question has been answered. It’s 60 gray. The other question is how you deliver it. You could deliver it with 3-dimensional radiotherapy with just a CT scan, but the delivery of the radiation can be modulated to avoid certain organs or to better cover the tumor. There was not a stratification factor, but in the RTOG trial, about half the patients had the so-called intensity-modulated radiotherapy, or IMRT. And there was a suggestion that they had less pneumonitis and they had less decreases in quality of life but they made no differences in the survival. It’s also good to know that there have been 3 other large trials for locally advanced small-cell and non—small cell lung cancer where very little intensity-modulated radiotherapy was used. And even then, the incidence of radiation pneumonitis was low and the esophagitis was under the 15%. So, I think we have been getting better at eradiating tumors, limiting our tumor volumes, better staging information, and avoiding healthy tissue, even without the use of intensity modulator radiotherapy.

I do believe, however, the intensity-modulated radiotherapy has a role, if it’s available, in even better sparing of organs at risk, like the heart or the esophagus. But it’s not mandatory. Nobody should delay implementing concurrent chemoradiotherapy just because they lack intensity-modulated radiotherapy. It’s quite easy to implement now, with the upgraded software and knowledge of your personnel, but it’s not a reason not to do it because the survival with 3-dimensional radiotherapy or standard radiotherapy is also excellent in these randomized trials.

For a long time now, many radiation oncologists have felt that the introduction of proton beam therapy could represent a breakthrough in locally advanced non—small cell lung cancer simply because protons can be much more precise in delivering radiation and in sparing normal organs at risk. Unfortunately, the only randomized study to date shows that it was, in fact, inferior to conventional IMRT. The study was presented at the ASCO meeting 2 years ago and conducted by very reputable investigators in North America. Some have argued that the unexpected findings came about because they used an older generation of proton technology with new proton technology becoming available now. But it could also be a reflection of the fact that the organs in the thorax move considerably. Moving organs, varying amount of air in the chest wall, is not good for proton dose distributions. It could be a technical challenge.

Because we have a negative trial for protons at present, I think we can quite confidently say that patients are not being deprived of good care because they do not have access to protons. In fact, the reverse is true. Those advocating protons have to prove that it’s not inferior to standard IMRT.

Solange Peters, MD, PhD: In stage 3 or locally advanced unresectable disease, you still have to try to find a way to treat the whole disease to cure the patient. And the best way, defined by all guidelines, is the combination of radiotherapy and chemotherapy. We needed some meta-analysis to show us that ideally, you should deliver them together in the same time. So, basically, it means radiotherapy for more or less 30 fractions, so 30 sessions, and more or less 2 cycles of chemotherapy that you deliver every 3 weeks. This is basically the minimal denominator. But what is interesting is that lots of trials have tried to put more chemotherapy before; we call it induction. More chemotherapy after, we call it consolidation—which doesn’t change anything. Try to have this backbone of chemotherapy and radiotherapy. The American colleagues use weekly chemotherapy, paclitaxel, and carboplatin. That’s not really in the European way to do it, but this is also feasible and has some good results. But we never adopted this kind of thing.

But this is a scenario for good performance status patients because concurrent radiochemotherapy is giving rise to fatigue, some inflammation of the esophagus, some cough. It’s not an easy way to go. So, if you have to face patients who are probably older or elderly, we have more and more. If you have to face patients with lower performance status, you probably have to find other ways to deliver a kind of multimodal treatment. So, the easiest way is to go sequential. You start with chemotherapy and you give radiotherapy afterwards. I prefer to start with chemotherapy because you can imagine a shrinkage of the disease; so you have a volume a bit easier to encompass in your radiotherapy field afterwards. And then you can minimize the cumulative toxicities of the modality. That’s probably the best way.

Some trials have shown that you can try to reduce the dose of chemotherapy. There’s even a trial where they give daily carboplatin, very small doses, but it’s not very strong evidence that you can do that. But sometimes we start to negotiate these kinds of things. What if you cannot give both modalities? It’s interesting. But to me, the main risk in stage 3 disease, if you cannot deliver radiotherapy and chemotherapy, is really to become a metastatic patient. You cannot cure. If you don’t give both, the probability of cure is very low. So probably you should give an efficient systemic treatment in order to keep the disease under control, being here to the chest or being distant sites. So, usually we start with some kind of low-dose chemotherapy or well-tolerated chemotherapy and we control everything over CT scans over time.

When you have a patient who is considered as being the fragile group in guidelines or elsewhere suffering from stage 3 disease, you probably will not be able to really go for the standard of care, radiotherapy and chemotherapy in the same time, even with cisplatin sometimes. These patients don’t fit or don’t suit this scenario, so you have to kind of negotiate your intensive treatment or compromise your intensive treatment somehow by doing something else. So, the simplest thing is to go back to what we have been doing some decades ago, which is to give sequential treatment: chemotherapy then radiotherapy. Probably better to start with the chemotherapy because you can hope for shrinkage of the disease, so you know a little bit more about the biology, too. And then reduction of the radiotherapy fields, subsequently. So, that’s a good strategy to start with the chemotherapy, but you also can do the other way around. But I prefer to start with the chemotherapy.

And sometimes you cannot deliver both or sometimes you cannot deliver radiotherapy because the lung function is too low. So sometimes you have to give up the idea to give the tumor the RT. It’s difficult to know what to do there, and there’s no clinical trials, of course. But probably you have to keep in mind that this disease is threatening because it can give rise to some local invasion, of course, but also give rise in a high percentage of patients. Meaning that if you have to favor one modality because you can only give one, maybe you should just control the disease by giving a well-tolerated systemic treatment and just observe the disease and maybe adapt over time but to be sure that the next step is not liver metastases or bone metastases.

Marina Chiara Garassino, MD: I don’t think that there are great differences between Europe and the United States, because the right decision for the patients is to go with chemoradiation or to go to surgery. So, you can use a variety of regimens for the treatment of chemoradiation. All of the regimens are quite similar. Maybe in the United States there is more use of the carboplatin/Taxol, and maybe in Europe there is more use of the cisplatin/gemcitabine. Or cisplatin and vinorelbine.

Transcript Edited for Clarity