Current Trends in Proton RT of Head and Neck Tumors: Aiming to Preserve T Lymphocytes, Without Them, Treatment is Ineffective

Which malignant tumors fall into the group of oropharyngeal cancers? Are they defined only anatomically, or are there other specifics?

We are talking about tumors of the base of the tongue, tonsils, and possibly the back wall of the pharynx. We distinguish two types of tumor diseases here. The distinguishing criterion is whether they are associated with human papillomavirus (HPV) or not. Thus, these are tumors related or unrelated to HPV infection, and the biological behavior of these two groups is entirely different. For non-HPV-related tumors, the prognosis is significantly worse, the intensity of treatment must be significantly higher, and there is a higher risk of side effects. In other words, we treat an aggressive and difficult-to-cure tumor. Conversely, HPV-16-positive tumors respond very well to therapy, and there is a high probability of cure. Therefore, in these cases, we emphasize reducing the risk of permanent side effects of treatment and de-escalation of therapy.

What is the incidence ratio of these two groups?

I can't tell you exactly, but in recent years the ratio has significantly shifted toward HPV-positive tumors. A significant factor is that the groups of patients with these two types of tumors are socioeconomically different. HPV-16-negative are usually lifelong smokers, frequent alcohol consumers, with rather lower socioeconomic status. On the other hand, HPV-16-positive patients tend to be younger, non-smokers, athletes, with a good background.

Head and neck tumors are often diagnosed at an advanced stage. Is the situation changing for patients thanks to modern diagnostic options?

There have been no fundamental changes. In the field of ENT tumors, there are no screening programs and preventive examinations that would detect less advanced diseases. Earlier diagnosis is possible for HPV-positive tumors, which are characterized by early metastasis to the neck lymph nodes and the formation of large tumor nodes.

What is the position of radiotherapy in the management of care? In which stages is it most effective?

For HPV-negative tumors, its position remains the same. It is a method used as an adjunct to surgery, in combination with chemotherapy. Or, if surgery is not possible, it is the main treatment method. HPV-negative tumors do not have such high sensitivity to ionizing radiation as HPV-16-positive ones. And this is where radiotherapy comes to the forefront, or rather is an alternative to primary surgery. The therapeutic results of combined radiotherapy or radiochemotherapy are comparable to the results of surgical procedures followed by radiation.

What side effects does ionizing radiation have on the head and neck area?

These tumors are among the most complicated for any treatment, including ionizing radiation. No dose of radiation is without risk for the body. The current trend is to irradiate relatively large areas not only of the primary tumor but also of the draining lymphatic regions, usually bilaterally. Essentially, all organs in this area can be sources of post-radiation toxicity. It is necessary to decide what level of risk we are willing to take in the treatment algorithm.

As part of treatment de-escalation for patients with HPV-16-positive tumors, there are two options to reduce the extent of late consequences. One discusses reducing the overall radiation dose, i.e., dose de-escalation, and volume de-escalation, where nodes are irradiated unilaterally. Alternatively, it can be approached differently, by using a technique that less burdens healthy tissues, which is particle radiotherapy.

For which oropharyngeal tumors is proton therapy currently used, and with what results?

At the Prague Proton Center, we initially defined a circle of four diagnoses that we consider standard indications for proton radiotherapy. We irradiate tumors of the paranasal sinuses, nasopharynx, salivary glands, and also postoperatively tumors of the base of the tongue or tonsils. Globally, the indication circle is slightly broader. It also includes non-operated oropharyngeal tumors, where proton radiotherapy has similar efficacy to other methods but with less acute and late toxicity.

Does the prognosis of patients change with the use of proton therapy compared to other radiotherapeutic modalities?

Yes, and it has been primarily demonstrated in tumors of the paranasal sinuses. Particle radiotherapy, compared to photon, shows better survival and survival without disease recurrence. This has not yet been confirmed for other oropharyngeal tumors. In the case of HPV-16-positive patients, who are mostly cured, improvement is hard to prove. The goal of new procedures is not to improve the cure rate, which is already very high, but to reduce side effects.

When we talk about HPV-positive tumors, what role does vaccination play here?

Vaccination of women against HPV-16 has undoubtedly reduced the incidence of cervical cancer. And it is highly likely to reduce the incidence of HPV-16-positive oropharyngeal tumors as well. Hence, boys are also being vaccinated nowadays. This should also impact other HPV-16-associated cancers, such as anal, penile tumors, etc. There is also talk about therapeutic vaccination, but I do not have the latest conclusions.

How have insights into proton radiotherapy generally evolved recently, and what does this mean for practice?

New factors continue to emerge showing why it is more advantageous than standard radiation. Proton therapy probably spares T lymphocytes much more significantly. These are the main components of the immune system, responsible for antitumor immune responses. At the same time, they are extremely sensitive to ionizing radiation. It has been found that their number drops steeply after radiotherapy. One course of radiotherapy can reduce T lymphocyte counts to 5% of their original value. With proton radiotherapy, this reduction also occurs but is not as intense. This means that the patient leaves this treatment with a more effective immune system and has a better chance of the tumor not returning.

Meta-analyses show that the risk of death for a patient with an oropharyngeal tumor is three times higher if severe lymphopenia occurs than if it does not. This is a very high number and similar figures apply to other cancers, such as pancreatic carcinoma, bladder cancer, glioblastoma, lung tumors... In the future, this might play a crucial role because modern immunotherapy is based on functional T lymphocytes. So, if a patient doesn't have them, this therapy won't work either.

How does proton radiation spare T lymphocytes?

The reason is probably the lesser burden on healthy tissues with lower radiation doses. Although we do not yet know exactly whether it is solely the burden of the area with radiation dose, or whether the blood flow through the area or the irradiation of the lymphatic system also plays a role.

How many patients are affected by post-radiation lymphopenia?

Unfortunately, almost all. Until recently, this was a relatively unknown concept, but with the advent of immunotherapy, it is becoming evident that lymphopenia will be one of the major problems modern treatment methods will face. However, it also has another side. If only immunotherapy is administered, the lymphocytes cannot recognize the tumor. So, methods need to be combined.

And how effective is the combination of immunotherapy and proton therapy?

That's not yet clear. However, reports from around the world are very, very positive.

How could these two methods specifically be combined?

Probably in close temporal sequence. Currently, immunotherapy is not usually indicated in primary treatment, but only in recurrences and after irradiation. However, we think that soon it will be different. That the key will be the local "smashing of the tumor" with a combination of treatment methods and subsequent irradiation. This could be very effective if lymphocytes are not destroyed and if it is combined with immunotherapy. One of the most fantastic discussed trends in oncology is the effort to leave the tumor in the body for some time to activate the immune system even against possible metastases, and only then operate on it. This is a completely new concept.

MUDr. Andrea Skálová
redakce proLékaře.cz