Lucyna Kepka1, Terisa Luo2
1Department of Radiotherapy, Military Institute of Medicine, Warsaw, Poland; 2JTD Editorial Office, AME Publishing Company
Correspondence to: Terisa Luo. JTD Editorial Office, AME Publishing Company. Email: jtd@amepc.org.
Editor’s note
Journal of Thoracic Disease (JTD) has published a number of special series in recent years, receiving overwhelming responses from academic readers around the world. Our success cannot be achieved without the contribution of our distinguished guest editors. This year JTD launched a new column, “Interviews with Guest Editors”, to better present our guest editors and to further promote the special series. We also hope to express our heartfelt gratitude for their tremendous effort and to further uncover the stories behind the special series.
The special series “Radiotherapy for Brain Metastases from Lung Cancer (1) led by Prof. Lucyna Kepka (Figure 1) from Military Institute of Medicine has attracted many readers since its publication. This special series have discussed multiple therapeutic strategies for brain metastases in lung cancer, hoping to be helpful to clinicians in their daily practice. At this moment, we are honored to have an interview with Prof. Kepka to share her scientific career experience and insights on this special series.
Figure 1 Prof. Lucyna Kepka.
Expert introduction
Prof. Lucyna Kepka is the head of the Department of Radiotherapy in the Military Institute of Medicine in Warsaw, Poland.
Her main field of interest is the radiotherapy of lung cancer, sarcomas, and brain tumors with a special focus on brain metastases. From the very beginning, she was interested in the introduction of new radiotherapy technologies into routine use and also in the limited resources setting. She has published on target definition in radiotherapy of lung cancer (postoperative radiotherapy, elective nodal irradiation, hypofractionated radiotherapy with and without chemotherapy for NSCLC, and 4D-radiotherapy planning). She also performed research on the cost-effectiveness in radiotherapy of lung cancer and brain tumors within the projects of the IAEA. She conducted a randomized trial comparing whole brain radiotherapy (WBRT) with radiosurgery of the cavity after surgery for brain metastases. She is a teacher in the European School of Oncology refresher courses on lung cancer. Overall, her research resulted in 145 publications (total H-index 32).
Interview
JTD: What motivated you to specialize in the field of radiotherapy?
Prof. Kepka: I made this choice more than 30 years ago. The rationale and motivation behind my final choice were rather complex, a mixture of the possibilities of employment at that time and my interest in research on cancer. I was driven primarily by my desire of treating patients with cancer. First, I thought about medical oncology, because I had not got enough knowledge about radiation oncology during my medical studies. During my residency in the oncological centers, I got an opportunity to get familiar with the treatment of cancer with radiation. Thus progressively, I was abandoning my thinking about getting a specialty in medical oncology and finally, I specialized in radiation oncology. I am currently very happy with this choice. Radiotherapy is a constantly evolving form of treatment, making use of all new technologies. Progress in radiation oncology is driven by advances in medical imaging, and computer science, currently also in artificial intelligence. At the same time, we don’t stop being medical doctors, treating people with cancer, and we are so satisfied that we may offer our patients not only our knowledge about oncology, and radiobiology, but also all these advances which make their treatment more effective and less toxic. I think that radiation oncology is an exciting career at the cutting edge of patient care, technology, and research.
JTD: As stated in the series that novel therapies such as targeted agents for brain metastases in lung cancer with driver mutations and the immune checkpoint inhibitors were revealed to have greater intracranial efficacy compared with conventional chemotherapy. Could you provide a brief introduction on current status of targeted and immunotherapy in non-small cell lung cancer (NSCLC)?
Prof. Kepka: Patients with disseminated NSCLC (stage IV) and good performance status (PS:0-2) are candidates for systemic therapy. Currently, we have a choice between cytotoxic chemotherapy (CHT), targeted therapy, and immunotherapy (IO). The choice of treatment strategy is driven by the molecular characteristics of the disease. Patients with the presence of actionable molecular biomarkers as epidermal growth factor receptor (EGFR), ROS1 mutations, or anaplastic lymphoma kinase (ALK) rearrangement receive targeted therapy with appropriate inhibitors. Such therapy is not only better tolerated than traditional CHT and increases patients’ survival, but also increases the role of radical radiotherapy in metastatic disease. In patients with negative test results for actionable driver mutations, the choice of treatment between CHT, IO, or a combination of both depends on the programmed death protein-1 ligand (PD-L1) level. Depending on the level of PD-L1 (> 50% or > 1% and < 50%) patients receive IO with immune checkpoint inhibitors (ICIs), as single agent IO, or IO-CHT with the continuation of mono-IO. Patients with PD-L1 level <1% do not receive ICIs as a first-line treatment. These strategies revolutionized the therapy landscape of NSCLC by prolonging patients' survival and providing more therapeutical arms. Additionally, tolerance of these drugs is much better than that of traditional CHT, giving patients the long-standing preservation of their quality of life (QoL).
JTD: Could you share with us the recent advances in targeted and immunotherapy for brain metastases from NSCLC?
Prof. Kepka: Local treatment including whole-brain radiotherapy (WBRT), stereotactic radiosurgery (SRS), or in selected cases surgery followed by radiotherapy has been a gold standard of management of brain metastases from NSCLC. CHT has not been considered as an appropriate strategy due to the poor penetration of the drugs through the blood-brain barrier, low response rate with shortly lasting effects, and significant toxicity. Local treatment through effective may have also meaningful toxicity. WBRT causes neurocognitive sequelae. The use of SRS spares some volume of the brain from radiation limiting the risk of cognitive deterioration, however, giving high doses to the brain increases the risk of brain necrosis. Radionecrosis may seriously affect the QoL of patients causing focal neurological deficits, headaches, seizures, and requiring the use of corticosteroids or even surgery. Thus, deferring or limiting the extent of local treatment with the use of effective systemic treatment is an attractive option. In patients with brain metastases from oncogene-driven NSCLC, such as those harboring EGFR mutations or ALK rearrangement, we have now new generation target agents with demonstrated significant penetration to the brain with about 70% response rate and potential to reduce the risk of the occurrence of brain metastases. This has significantly increased our armamentarium against brain metastases from oncogene-addicted NSCLC. In asymptomatic patients with brain metastases non-suitable for SRS, when the new generation TKIs with stronger CNS activity are used as a first-line treatment, upfront WBRT may be deferred. The combination of SRS with new-generation TKIs is realized on an individual basis, always keeping in mind that giving TKIs first may reduce the volume of brain metastases making SRS less toxic. Omission (or long-lasting deferral) of local treatment in case of complete response after targeted therapy is also sometimes achievable. We have less evidence on the effectiveness of ICIs in the management of brain metastases because patients with brain metastases were rarely included in the trials evaluating the effectiveness of IO in NSCLC. Evidence coming from retrospective analyses suggests that the combination of ICIs with radiation for brain metastases is superior in terms of tumor response to radiation alone or systemic treatment alone. Another issue is the safety of such combinations. Some reports demonstrated the increased risk of radionecrosis with such combinations, others did not confirm that. Certainly, we need more prospective data on the proper combination of local treatment of brain metastases with ICIs in NSCLC. I would like to stress that even when potentially effective for brain metastases target agents or ICIs in selected patients are used, there is practically no cure with systemic treatment, and ultimately, the disease recurs. The relapses occur the most frequently in the initial sites of the disease. Thus a proper combination and sequencing of local treatment strategies with systemic treatment is crucial and should be carefully planned for each patient taking into account the patient's condition, presence of symptoms, the extent of the disease in the brain, level of PD-L1 in oncogene-negative NSCLC, and drugs we have still to our disposition.
JTD: Looking towards the future, what do you believe is the most important direction for the treatment of brain metastases from lung cancer? Specifically, what treatment do you think hold the greatest promise for improving outcomes for patients?
Prof. Kepka: I would not select one specific treatment for that. I think that combined treatment strategies are the most promising. The treatment armamentarium should be large to the point that various treatment tools are available at the different stages of the disease course. Actually, we work on the development of both – local and systemic treatment. A progress in the development of new radiotherapy technologies has been already enormous. Actually, we are able to deliver high doses of radiotherapy to the tumor volume with rapid dose fall-off outside the target which considerably spares healthy brain tissue from radiation, limiting the risk of damage in the brain. Also, the advances in technologies led to the possibility of treating multiple brain metastases with radiosurgery in one session with the omission of WBRT. WBRT with hippocampal region avoidance realized with IMRT technology is also a possible strategy to reduce the risk of cognitive impairment, as the hippocampal zone is responsible for memory. Despite all these advances, still, radiotherapy even if it is much less toxic than in the past, may cause brain damage, mainly by the risk of radionecrosis in the region of the highest dose. Thus, it is crucial to develop effective systemic treatment strategies with drugs penetrating into the brain that may limit the extent of the irradiated volume, and defer or omit, in some cases, local treatment. In oncogene-addicted NSCLC, it is already happening. However, still it is a room for improvement, especially we need more drugs that have in their characteristics the possibility of overcoming the acquired resistance to the previous lines of targeted therapy, keeping at the same time the CNS activity. This may prolong the time of effective systemic treatment of brain metastases and further delay the need for local treatment. In patients receiving IO, further research is needed on the combination of local and systemic treatment strategies. Up to now, we still have no evidence that a delay of local treatment and the use of ICIs alone is a safe strategy and such a policy may be only adopted on at very individual basis. For patients with brain metastases from oncogene-negative and PD-L1 levels less than 1%, we have no effective systemic strategy, and this is the least favorable from the molecular point of view group of patients (2), for whom only local treatment may be effectively adopted. This is an urgent need of the research on the molecular characteristics of these types of NSCLC in order to find effective, active in CNS drugs targeting any mutations driving cancer progression. For now, we do have not yet such molecules, but the research is ongoing.
JTD: Is the topic of this special series associated with any of your recent research projects? Would you please share some significant researches you are working on?
Prof. Kepka: Currently, we have no ongoing prospective studies on brain metastases from lung cancer in our department. However, as all radiation oncologists we are facing the complex problem of patients with synchronous or induced oligometastatic disease of oncogene-positive and oncogene-negative NSCLC referred for local treatment in different stages of their disease course. Some of them have also brain metastases. There are no strict recommendations for the management of such patients in the experts’ guidelines. Thus, we are recording all their disease and treatment characteristics and then following them prospectively with emphasis on the treatment outcome and toxicity. Patients who are finally not qualified for local treatment are also included. We hope that with such a database we will be able to select the best candidates for local treatment and this will be a hypothesis-generating study to launch a prospective trial on the proper timing of radiotherapy and systemic therapy with regard to the molecular characteristics of the NSCLC. Another interesting issue is the comparison of the toxicity of SRS of multiple metastases with WBRT. Impairment of neurocognitive functioning with the use of WBRT compared with SRS limited to up to 3 lesions was demonstrated (3). However, when we are treating multiple metastases (> 4) with high doses of SRS we cannot, even with the use of new technologies, disregard incidental doses received by the brain tissue. Mean brain dose may also matter and be meaningful, finally leading to neurocognitive impairment. Thus, it is not demonstrated how neurocognitive functioning is preserved with SRS of multiple metastases compared with WBRT. Such a study is at the phase of preparation in our department.
JTD: If given an opportunity to update this special series, what would you like to moderate, add or emphasize to provide a more informative series?
Prof. Kepka: There were no recent publications of the results of large clinical trials on brain metastases from NSCLC. General treatment policy remains the same: to limit as far as possible toxicity of local treatment by reducing the volume of irradiated brain and using systemic (active in CNS) treatment whenever possible. However, as I have already mentioned, only in EGFR-, or ALK-positive NSCLC, do we have new-generation drugs with demonstrated CNS activity. In other types, an issue of delaying local treatment is more complex and is rarely indicated. An area of combining IO with brain radiotherapy deserves more prospective data. Theoretical background supports combining ICIs with radiation for the management of brain metastases from NSCLC, presumably due to the immunologic effects of radiotherapy in the tumor microenvironment. Some retrospective studies also support the use of such a combination. On the other side, still this is a concern among radiation oncologists about safety of such an approach. The management of side-effects of brain radiotherapy with steroids during IO is a subject to debate. Steroids and ICIs exert opposite effects on the immune system. However, in two meta-analyses, it was shown that steroids used to mitigate adverse events during IO did not impact survival (4, 5). Certainly, in clinical practice, more data on the safety, possible interactions, and timing of radiation in relation to systemic treatment with emphasis on the targeted therapy and IO is needed. Despite a lack of robust evidence on this issue, different forms of brain radiotherapy are given to patients in this new therapeutic landscape. Thus, meanwhile, a series presenting cases with brain metastases from NSCLC in patients suitable for targeted therapy or IO with expert discussion on the proposed treatment strategy would be of interest to clinical practitioners. I think about something like written multidisciplinary tumor board discussions and conclusions. This probably will not bring any firm solutions as would do the results of prospective studies, however, sharing experience in the limited evidence setting may be worthwhile.
Reference
- Radiotherapy for Brain Metastases from Lung Cancer. Available online: https://jtd.amegroups.org/post/view/radiotherapy-for-brain-metastases-from-lung-cancer
- Sperduto PW, De B, Carpenter D, et al. Graded patients with lung cancer and brain metastases: Initial report of the small cell lung cancer GPA and update of the non-small cell lung cancer GPA including the effect of programmed death ligand 1 and other prognostic factors. Int J Radiat Oncol Biol Phys. 2022; 114: 60–74.
- Brown PD, Jaeckle K, Ballman KV, et al. Effect of Radiosurgery Alone vs Radiosurgery With Whole Brain Radiation Therapy on Cognitive Function in Patients With 1 to 3 Brain Metastases: A Randomized Clinical Trial. JAMA 2016; 316: 401-9.
- Ricciuti B, Dahlberg SE, Adeni A, et al. Immune checkpoint inhibitor outcomes for patients with non-small-cell lung cancer receiving baseline corticosteroids for palliative versus nonpalliative indications. J Clin Oncol 2019; 37: 1927-34.
- Petrelli F, Signorelli D, Ghidini M, et al. Association of steroids use with survival in patients treated with immune checkpoint inhibitors: a systematic review and meta-analysis. Cancers 2020; 12: 546.