Chemoradiation versus radiation alone in head and neck cancer

Prof Esat Mahmut Özsahin - Service de Radio-Oncologie Bugnon, Lausanne, Switzerland

In head and neck cancer after following surgery we have patients with low risk, patients with high risk and patients with intermediate risk, in between us. So high risk patients are who have extracapsular extension or positive margins; low risk are small tumours without any lymph node invasion etc. So for low risk patients surgery is enough, you don’t do anything more; for high risk patients you should do your whole treatment that you have and intermediate risk there’s still discussion but some of them you do postoperative chemoradiotherapy, some of them you do definitely postoperative radiotherapy. For low risk you don’t do anything after surgery and high risk you do chemoradiotherapy.

So there are two big trials, phase III randomised trials, comparing chemoradiotherapy versus radiotherapy. I presented these two trials; I’m one of the co-authors of one of these trials. They were both published in The New England Journal of Medicine a long time ago and these two trials show that the use of chemoradiotherapy in high risk patients or even intermediate risk patients is better than the postoperative radiotherapy alone. But the European trial was positive in local regional controlled disease free survival and survival and the American trial was not positive for survival but it was disease free survival and local regional control. Then we did a meta-analysis by putting these two trials that was published in Head and Neck that the American group and the EORTC get together. We saw that both trials, the common inclusion criteria patients in both trials, they have a significant effect of chemoradiotherapy compared to radiotherapy alone in overall survival, disease free survival and local regional control. But patients who were outside of the intersection of these two trials, because the European trial had different factors other than extracapsular extension and positive margins like lymphovascular invasion, perineural invasion etc and the American trial had two or more positive lymph nodes other than extracapsular extension and postive margins. So we observed that if you look at only those patients you didn’t see so much influence of chemoradiotherapy, a little bit more for the European type of secondary inclusion criteria but much less for the two or more positive lymph nodes.

Then in 2007 there was another meta-analysis. We put these two trials plus two other small trials, randomised trials, done in France and Hungary and they published in Head and Neck in 2007 saying that the p-value was significant for local regional control and overall survival when you have the data from these four trials. Also I presented a little bit what is going on currently.

The current clinical practice for head and neck cancer globally is when you have a positive margin and extracapsular extension you do definitely postoperative chemoradiotherapy. So for an intermediate risk patient you do postoperative radiotherapy but it depends if the patient is young and has a little bit more risky disease than the other ones, for example if she or he has perineural invasion, lymphovascular invasion, then you might include chemotherapy as well to the radiotherapy. But if it’s not a very fit patient or some age, because we know from the meta-analysis from the definitive chemoradiotherapy that patients who are more than 65-70 years old, they don’t benefit so much from chemotherapy. We don’t have this data for the postoperative but you can make the link between them. You may give only postoperative radiotherapy in these kinds of patients. But if there is an extracapsular extension and positive margins then you do definitely chemoradiotherapy if the patient is medically possible to do the chemotherapy.

In the future is this likely to change?

The next step we were thinking to do anti-EGFR treatment. We had a phase III study that was planned and it came to just a couple of days before it started, everything was ready, the 22071 EORTC study which wanted to compare radiochemotherapy plus or minus panitumumab, which is an anti-EGFR antibody, the commercial name is Vectibix. This study was ready, everything was done but at the last moment Amgen, which was the sponsor of the trial, decided not to do the study because of another study, a phase III study, which negatively resulted in the metastatic patients.

There is a phase II randomised American study, the RTOG-0234 study, which didn’t compare. The two arms, experimental arms, combining cetuximab with cisplatin or cetuximab with docetaxel and they observed that docetaxel plus cetuximab in the postoperative setting gave better results. So they opened now a phase III study on that so I hope we will see what will happen.

There is another issue that the period, the time, between surgery and radiotherapy is important. Ideally it should be between 4-6 weeks and if it’s longer then you have a less outcome. So maybe there might be a possibility to do some, give some chemotherapy during this period in order to get rid of this bad influence of this time factor. Because some patients with big tumours, when you operate they don’t come out easily from the hospital, they have complications etc. etc. So that’s not because you have a waiting list time or something like that, that you are waiting for eight weeks, but you cannot treat the patient if you have to wait for the healing. So there is a phase II American RTOG study which used docetaxel in these patients during the postoperative period which is also an interesting way to go.

There was a phase III study presented at ASCO last year using lapatinib, which is a tyrosine kinase inhibitor, combined to radiochemotherapy. So a huge phase III study, more than 800 patients; radiochemotherapy versus radiochemotherapy plus lapatinib during treatment and thereafter which was negative as well, the curves were completely similar.

Maybe immunotherapy, but we don’t have anything on the postoperative setting. Now we know in the metastatic setting it works so probably there will be some phase I/II… not phase I but phase II trials on the definitive setting. Maybe we’ll come to the postoperative as well, that can be also very interesting.

Do you have a take home message for cancer doctors?

For advanced disease, operated advanced disease, the postoperative chemoradiotherapy is important. We have to give it if possible, whenever it’s possible medically. For oral cavity cancers the use of induction chemotherapy may be interesting. There is a Chinese phase III randomised study published in the JCO two years ago which showed that in terms of overall survival doing induction chemotherapy before surgery and then do tailored radiochemotherapy or chemoradiotherapy after the surgical specimen, compared to up-front surgery and postoperative chemoradiotherapy, there was no difference at all. But the issue is not to have a difference at all because probably the induction chemotherapy will not bring anything to the overall survival. We were expecting in the beginning to maybe have less metastatic disease later on but the issue is that some part of these patients who are not… this trial was done in patients who were… all patients were operable, so to randomisation, but for inoperable patients or where you can also operable but your organ functionality may be better, these kinds of patients may benefit from induction chemotherapy. Even if it doesn’t change the final outcome you may do less aggressive surgery and compensate this with postoperative radiotherapy etc. So that can be an interesting issue for the future.