Pulmonologist Dr Lizza Hendriks (Maastricht UMC+) specializes in thoracic oncology and conducts research into the personalized prevention and treatment of brain metastases in lung cancer. “Doctors should not be too nihilistic, but on the other hand remain realistic.”
Brain metastases in lung cancer are anything but rare, says lung specialist Lizza Hendriks. As a treating lung specialist, she prefers to prevent brain metastases. “Prophylactic cranial irradiation (PCI) has been shown to significantly reduce the incidence of brain metastases. However, some of the patients develop neurocognitive complaints. That is why you want to be able to predict who has a high risk of brain metastases as well as of neurocognitive complaints after PCI, in order to make a personalized treatment decision together with the patient.”
Predicting brain metastases
For stage III and IV small cell lung cancer, Hendriks and colleagues are investigating whether radiomics (advanced quantitative analysis of standard imaging) can predict who will develop brain metastases. “The idea is that the primary tumor is already pre-programmed to spread or not to the brain and we hope to be able to detect this with radiomics analysis. In a small series of 105 patients, we were able to predict reasonably well who will in any case not develop brain metastases with a negative predictive value of 0.81. We are now evaluating the results internationally in a larger group of patients. If this is eventually validated prospectively, you can better educate patients about the usefulness of PCI. We are now also trying to more systematically map the risk factors for neurocognitive decline after PCI. An earlier review of ours showed that risk factors, such as certain co-medication and cardiovascular diseases, are not always properly looked at.”
Prophylactic Skull Irradiation
Hendriks also focuses on locally advanced non-small cell lung carcinoma (NSCLC stage III). The standard treatment consists of chemoradiotherapy, followed by a year of immunotherapy. “Despite the curative intention, these people have about a 15% chance of brain metastases. In the pre-immunotherapy era, PCI has been shown to reduce the incidence of brain metastases in this group, resulting in longer progression-free survival. PCI also proved cost-effective.” Due to the lack of survival benefit, PCI has not become standard of care. The Dutch multicenter NVALT28 study, with Hendriks and Prof. Dirk de Ruysscher (Maastro Clinic) as principal investigators, is now investigating whether adding low-dose PCI compared to adjuvant immunotherapy alone can reduce the percentage of brain metastases from 15% to 5%. “We opt for half the radiation dose, because immunotherapy and radiation reinforce each other. In this way we hope to maintain the effectiveness, with fewer side effects.”
Targeted therapy and local radiation
Hendriks also focuses her research on patients with metastatic NSCLC. After all, a quarter of these patients already have brain metastases at the time of first diagnosis. “There are also many new treatment options for this group. Targeted therapy can mean a lot for patients with specific mutations, others can benefit from immunotherapy, possibly in combination with chemotherapy.”
However, there are still many open questions. “For example, with targeted therapy, after an initial response, the brain metastases grow again, while the rest of the disease remains under control. Ideally, you want to treat the brain metastases locally. The question is: should you temporarily interrupt the targeted therapy to prevent the combination from causing additional neurocognitive side effects? Or is it better to continue, so that the cancer does not grow again? We are now conducting a multicenter study in the group of patients for whom we choose to continue with targeted therapy. We conduct extensive memory tests, before and after radiation. If we find no indications of harmful effects of combining radiation and targeted therapy, we can safely continue with targeted therapy from now on.”
Screening for brain metastases
Finally, Hendriks is interested in the desirability of screening for brain metastases in metastatic lung cancer. “American and European guidelines recommend this, preferably with MRI. However, it has never been shown that people then live better or longer,” Hendriks notes. “At the same time, you do incriminating research to people, and some of them then have to live in the knowledge that something is growing in their heads. We have recently discussed this issue in focus groups with patients with asymptomatic brain metastases and relatives. This shows that patients do appreciate the MRI scan – even if the diagnosis is hard, the majority still want to know and even pay an MRI scan for it. Patients like the feeling that they are being watched and hope that intervention can be taken before they develop headaches or epilepsy, for example. They can also better prepare for the future. The question remains whether the screening is clinically meaningful, and how exactly you should define ‘clinical benefit’. I hope to establish endpoints for this in the future together with the patient association.”
Not nihilism, but realism
When asked for a message for the readers of MedNet Oncology, Hendriks emphasizes that the prognosis of lung cancer patients with brain metastases is often much better than before, thanks to targeted or immunotherapy. “Doctors should therefore not be too nihilistic, but on the other hand remain realistic,” she advises. “People with a Karnofsky score below 70 who are not eligible for targeted therapy will very often have a short survival. The guideline prescribes to only provide supportive care, and I fully agree with that,” she says. “So take a good look at the individual patient with all his characteristics and especially discuss the patient in an MDT in order to arrive at an optimal treatment plan.”