Przerzuty do mózgu – Zapobieganie i profilaktyka

Przerzuty do mózgu
Zapobieganie i profilaktyka

Przerzuty do mózgu występują u 9-17% pacjentów z nowotworami złośliwymi, co stanowi poważne wyzwanie kliniczne ze względu na niekorzystne rokowanie i wpływ na funkcje poznawcze. Profilaktyczna radioterapia mózgu (PCI) pozostaje standardem u pacjentów z drobnokomórkowym rakiem płuca (SCLC) w stadium ograniczonym po odpowiedzi na chemioterapię, redukując ryzyko przerzutów z HR około 0,35. W niedrobnokomórkowym raku płuca (NSCLC) PCI zmniejsza częstość objawowych przerzutów, jednak nie poprawia przeżycia całkowitego, dlatego nie jest standardem. Neurotoksyczność PCI, występująca u około 30% pacjentów, stanowi istotne ograniczenie, co skłania do stosowania technik oszczędzających hipokamp (HA) oraz leków neuroprotekcyjnych, takich jak memantyna. Nowe badania wskazują, że PCI u pacjentów z NSCLC wysokiego ryzyka może zmniejszyć częstość przerzutów (7% vs 38%) i poprawić medianę przeżycia całkowitego (64,5 vs 19,8 miesiąca).

Profilaktyka przerzutów do mózgu

Przerzuty do mózgu stanowią poważne powikłanie wielu typów nowotworów złośliwych, a ich występowanie wzrasta pomimo postępów w leczeniu systemowym. Ogólna częstość występowania przerzutów do mózgu wynosi od 9% do 17%, co przekłada się na ponad 150 000 przypadków rocznie. Ze względu na niekorzystne rokowanie i wpływ na jakość życia pacjentów, opracowanie skutecznych strategii profilaktycznych staje się priorytetem w onkologii¹².

Profilaktyczna radioterapia ośrodkowego układu nerwowego

Profilaktyczna radioterapia mózgu (PCI – Prophylactic Cranial Irradiation) jest najdłużej stosowaną metodą zapobiegania przerzutom do mózgu. PCI polega na napromienianiu całego mózgu (WBRT – Whole Brain Radiation Therapy) u pacjentów bez klinicznych objawów przerzutów, szczególnie w określonych typach nowotworów¹.

W drobnokomórkowym raku płuca (SCLC) PCI jest standardem postępowania u pacjentów z chorobą ograniczoną, którzy odpowiedzieli na chemioterapię. Metoda ta znacząco zmniejsza częstość występowania przerzutów do mózgu, z współczynnikiem ryzyka (HR) około 0,35. W SCLC PCI stała się standardem leczenia ze względu na zmniejszenie częstości występowania przerzutów do mózgu i łączny wpływ na przeżycie całkowite¹².

W niedrobnokomórkowym raku płuca (NSCLC) badanie NVALT-11/DLCRG-02 wykazało, że PCI zmniejsza częstość występowania objawowych przerzutów do mózgu. Jednakże, przegląd randomizowanych badań u pacjentów z NSCLC wykazał brak korzyści w zakresie przeżycia całkowitego, co sprawia, że PCI nie jest zalecana jako standardowe postępowanie w NSCLC¹².

Istotnym ograniczeniem PCI są zaburzenia funkcji poznawczych, które mogą wystąpić u nawet 30% pacjentów. Neurotoksyczność związana z WBRT i PCI pozostaje trudna do przewidzenia i stanowi poważny problem kliniczny¹².

Nowe podejścia do radioterapii profilaktycznej

Ze względu na ryzyko zaburzeń funkcji poznawczych, opracowywane są nowe podejścia do radioterapii mózgu, które mogą zmniejszyć neurotoksyczność¹:

Technika oszczędzająca hipokamp (HA – Hippocampal Avoidance) – zmniejsza dawkę promieniowania podawaną w obszarze hipokampa, który jest kluczowy dla funkcji poznawczych. Technika ta, zwłaszcza w połączeniu z memantyną, wydaje się obiecująca dla pacjentów z rakiem płuca i przerzutami do mózgu, którzy mają dobre rokowanie¹.
Leki neuroprotekcyjne – stosowanie leków takich jak memantyna i donepezil może zmniejszać ryzyko uszkodzenia funkcji poznawczych².
Modyfikacje schematów frakcjonowania – badania wykazały, że różne schematy dawkowania i frakcjonowania PCI mogą wpływać na stopień neurotoksyczności³.

Nowe badanie u pacjentów z NSCLC wysokiego ryzyka wykazało, że PCI znacząco zmniejsza częstość występowania przerzutów do mózgu w ciągu 24 miesięcy (7% vs 38%) oraz poprawia przeżycie całkowite (mediana 64,5 vs 19,8 miesiąca)¹.

Profilaktyka farmakologiczna

Postępy w profilowaniu molekularnym nowotworów doprowadziły do odkrycia mutacji kierujących i terapii celowanych, które mogą zapobiegać przerzutom do mózgu. Ta strategia, nazywana „chemoprewencją”, zyskuje coraz większe zainteresowanie, szczególnie w określonych podtypach molekularnych NSCLC, raka piersi i czerniaka¹.

W raku płuca z mutacjami kierującymi, kilka terapii celowanych wykazało potencjał w zapobieganiu przerzutom do mózgu¹²:

Ozymertynib w porównaniu ze standardowymi inhibitorami EGFR-TKI w badaniu FLAURA – tylko 3% pacjentów bez przerzutów do mózgu na początku badania rozwinęło przerzuty podczas obserwacji w grupie ozymertynibu, w porównaniu do 7% w grupie standardowych EGFR-TKI. Ponadto, 19% pacjentów z przerzutami do mózgu na początku badania rozwinęło nowe lub postępujące przerzuty w grupie ozymertynibu, w porównaniu do 43% w grupie standardowych EGFR-TKI¹.
Alektynib w porównaniu z kryzotynibem w badaniu ALEXA u pacjentów z ALK-dodatnim NSCLC – 4,6% pacjentów bez przerzutów do mózgu na początku badania rozwinęło przerzuty podczas obserwacji w grupie alektynibu, w porównaniu do 31,5% w grupie kryzotynibu¹.
Entrektynib u pacjentów z ROS1-dodatnim NSCLC – skumulowana częstość progresji w OUN po 6, 12, 18, 24 i 36 miesiącach wynosiła odpowiednio 3%, 10%, 17%, 17% i 20%¹.
Durwalumab dodany do radiochemioterapii w stadium III NSCLC – związany z poprawą pierwotnej profilaktyki przerzutów do mózgu, gdyż 5,5% pacjentów w ramieniu durwalumabu rozwinęło przerzuty do mózgu w porównaniu do 11,0% w ramieniu kontrolnym¹.

W HER2-dodatnim raku piersi przerzuty do mózgu występują u 25-55% pacjentów z chorobą przerzutową. Kilka strategii profilaktycznych jest obecnie badanych¹²:

Temozolomid (TMZ) – lek przenikający barierę krew-mózg, stosowany w niskich dawkach w sposób metronomiczny, wykazał znaczne zapobieganie rozwojowi przerzutów do mózgu w modelach mysich raka piersi. Badanie kliniczne I fazy z TMZ u kobiet z zaawansowanym rakiem piersi wykazało, że kombinacja leków była dobrze tolerowana, a tylko u dwóch pacjentek rozwinęły się nowe guzy w tkance mózgowej¹².
Tukatynib – badanie BRIDGET ocenia skuteczność dodania tukatynibu do standardowego leczenia trastuzumabem/pertuzumabem lub T-DM1 u pacjentów z HER2-dodatnim rakiem piersi po pierwszym lub drugim epizodzie choroby wewnątrzczaszkowej¹².
Trastuzumab derukstekan (T-DXd) – badanie DESTINY-Breast12 wykazało, że T-DXd może być skuteczny u pacjentów z HER2-dodatnim rakiem piersi i przerzutami do mózgu¹.

Retrospektywna analiza danych z badania klinicznego sorafenibu u pacjentów z przerzutami raka nerki do mózgu wykazała 75% zapobieganie rozwojowi przerzutów do mózgu¹.

Nowe mechanizmy i strategie profilaktyczne

Badania prowadzone są nad kilkoma obiecującymi mechanizmami zapobiegania przerzutom do mózgu¹²:

Hamowanie angiogenezy (tworzenia naczyń krwionośnych) – badania kliniczne wykazały, że hamowanie angiogenezy skutecznie hamuje wzrost guzów przerzutowych¹.
Hamowanie szlaku sygnałowego CDK (kinazy zależne od cyklin) może również pomóc w hamowaniu tworzenia przerzutów do mózgu¹.
Leki przeciwzakrzepowe – badania na myszach wykazały, że środki przeciwzakrzepowe zmniejszają liczbę przerzutów do mózgu. Wprowadza to koncepcję stosowania antykoagulantów i/lub inhibitorów czynnika von Willebranda w zapobieganiu przerzutom do mózgu¹².
Hamowanie szlaku HIF1A – badania wykazały, że blokowanie szlaku sygnałowego HIF1A może zmniejszyć częstość przerzutów do mózgu lub nawet całkowicie im zapobiec¹.
Kwas mykofenolowy i podobne związki – badania wykazały, że mogą zapobiegać rozwojowi przerzutów do mózgu poprzez oddziaływanie na szlaki metaboliczne komórek nowotworowych¹².

Profilaktyka wobec przerzutów do mózgu wymaga zrozumienia mechanizmów molekularnych, które przyczyniają się do tworzenia przerzutów. W przyszłości, przy wystarczającym zrozumieniu tych mechanizmów, możliwe będzie hamowanie różnych aktywowanych szlaków sygnałowych, aby chronić mózg przed atakiem komórek nowotworowych¹.

Profilaktyka przeciwdrgawkowa

Pacjenci z przerzutami do mózgu mają zwiększone ryzyko napadów padaczkowych. Jednakże, obecnie dostępne wytyczne nie zalecają rutynowego stosowania leków przeciwpadaczkowych (AEDs) u pacjentów bez wcześniejszych napadów¹²:

Profilaktyczne AEDs nie są zalecane dla pacjentów z przerzutami do mózgu, którzy nie przeszli resekcji chirurgicznej i są wolni od napadów padaczkowych¹.
Rutynowe pooperacyjne stosowanie AEDs u pacjentów z przerzutami do mózgu, którzy są wolni od napadów padaczkowych, nie jest zalecane¹.
Metaanaliza sześciu randomizowanych badań kontrolowanych, obejmujących 547 pacjentów z guzami mózgu, wykazała, że pacjenci, którzy otrzymali profilaktyczne AEDs, nie mieli znacząco niższej częstości występowania napadów padaczkowych w porównaniu z grupą, która nie otrzymała profilaktycznych AEDs¹.

Jednakże, w przypadku czerniaka, który ma dużą skłonność do przerzutów do mózgu, jedno badanie wykazało, że profilaktyka AED była znacząco związana ze zmniejszonym ryzykiem napadów (p = 0,03), z 3-miesięczną częstością napadów wynoszącą 0% w porównaniu do 17% bez profilaktyki AED. Sugeruje to, że profilaktyka AED może być skuteczna u wybranych pacjentów i powinna być przedmiotem randomizowanych badań kontrolowanych¹.

Badania przesiewowe i wczesne wykrywanie

Wczesne wykrywanie przerzutów do mózgu może umożliwić wcześniejsze leczenie i potencjalnie poprawić wyniki. Badania przesiewowe za pomocą rezonansu magnetycznego (MRI) u pacjentów bezobjawowych z wysokim ryzykiem przerzutów do mózgu jest podkreślane w wielu pracach¹².

Identyfikacja i leczenie bezobjawowych przerzutów do mózgu może zapobiec powikłaniom neurologicznym, poprawiając jakość życia i zmniejszając potrzebę WBRT lub operacji. Jednak starsze badanie na małej liczbie pacjentów nie wykazało różnicy w przeżyciu między pacjentami z bezobjawowymi a objawowymi przerzutami do mózgu¹.

Korzyści i wady strategii badań przesiewowych muszą być starannie rozważone. Obecnie nie ma jednoznacznych zaleceń dotyczących badań przesiewowych w kierunku bezobjawowych przerzutów do mózgu u pacjentów z grupy wysokiego ryzyka¹.

Przyszłe kierunki badań

Przyszłe strategie zapobiegania przerzutom do mózgu koncentrują się na kilku obszarach¹²:

Nowe projekty badań klinicznych – badania wtórnej profilaktyki reprezentują dotychczas niewypróbowaną metodę badania skuteczności leków w zapobieganiu przerzutom do mózgu. Nowe projekty badań mogłyby testować leki do zapobiegania przerzutom do mózgu¹².
Włączanie pacjentów z przerzutami do mózgu do badań klinicznych – badacze powinni rozważyć aktywne przerzuty do mózgu jako automatyczne wykluczenie z kwalifikowalności do badania, ponieważ wykluczenie tych pacjentów uniemożliwia badanie populacji z największą potrzebą terapii opartych na dowodach¹².
Uwzględnienie czasu do rozwoju przerzutów do OUN jako potencjalnego punktu końcowego przy testowaniu nowych terapii w zaawansowanym raku¹.
Identyfikacja biomarkerów i czynników ryzyka – określenie populacji pacjentów zagrożonych wysokim ryzykiem rozwoju przerzutów do mózgu¹.
Rozwój leków przenikających barierę krew-mózg – opracowanie związków, które selektywnie celują w komórki nowotworowe i przenikają przez barierę krew-mózg¹.

W przyszłości, lepsze zrozumienie biologii rozprzestrzeniania się przerzutów do OUN oraz włączanie pacjentów z przerzutami do OUN do badań klinicznych lub przeprowadzanie badań specjalnie dla pacjentów z rakiem piersi z zajęciem OUN, pozwoli nam ograniczyć to potencjalnie niszczące powikłanie¹.

Profilaktyka u pacjentów z określonymi typami nowotworów

Drobnokomórkowy rak płuca (SCLC)

Przerzuty do OUN rozwiną się u 50% pacjentów z SCLC w trakcie choroby. U tych pacjentów PCI jest standardem postępowania w chorobie ograniczonej, po odpowiedzi na chemioterapię i radioterapię, podczas gdy w chorobie rozległej PCI może być rozważona po korzystnej odpowiedzi na leczenie początkowe¹.

Jednak rola PCI w chorobie rozległej została zakwestionowana na podstawie japońskiego badania III fazy, które wykazało, że chociaż częstość występowania przerzutów do mózgu zmniejszyła się przy zastosowaniu PCI plus obserwacji MRI w porównaniu z samą obserwacją MRI, sama PCI nie przyniosła korzyści w zakresie przeżycia całkowitego¹.

Ze względu na skutki uboczne WBRT, wielu lekarzy decyduje się na częste badania MRI, aby ściśle obserwować mózg u pacjentów z SCLC, zamiast leczyć ich za pomocą WBRT¹.

Niedrobnokomórkowy rak płuca (NSCLC)

Profilowanie molekularne NSCLC doprowadziło do odkrycia mutacji kierujących i terapii celowanych. Inhibitory ALK trzeciej generacji, takie jak alektynib, wykazały znaczącą aktywność w zapobieganiu przerzutom do mózgu. Skumulowana częstość występowania progresji OUN była znacząco niższa dla alektynibu, z 12-miesięczną częstością wynoszącą 9,4% w porównaniu do 41,4% dla kryzotynibu¹.

Podobnie, ozymertynib wykazał lepszą profilaktykę pierwotną i wtórną przerzutów do mózgu w porównaniu ze standardowymi inhibitorami EGFR-TKI¹.

Rak piersi HER2-dodatni

Przerzuty do mózgu występują u 25-55% pacjentów z przerzutowym HER2-dodatnim rakiem piersi. Badania kliniczne oceniają obecnie skuteczność kilku strategii profilaktycznych¹:

Badanie CEREBEL porównywało lapatynib plus kapecytabinę vs trastuzumab plus kapecytabinę u pacjentów bez przerzutów do mózgu, z rozwojem przerzutów do OUN jako pierwotnym punktem końcowym. Nie wykazano istotnej różnicy między grupami¹².
Badanie wtórnej profilaktyki z doustnym TMZ podawanym pacjentom z HER2-dodatnim rakiem piersi z przerzutami do mózgu po niedawnym leczeniu miejscowym, w połączeniu z T-DM1 do kontroli systemowej choroby. Pierwotnym punktem końcowym jest brak nowych przerzutów do mózgu po 1 roku¹.
Badanie BRIDGET ocenia skuteczność dodania tukatynibu do standardowego leczenia trastuzumabem/pertuzumabem lub T-DM1 u pacjentów po pierwszym lub drugim epizodzie choroby wewnątrzczaszkowej¹.

Lepsza kontrola systemowa w HER2-dodatniej chorobie pozostaje kluczowa, a nowe, bardziej skuteczne leczenie systemowe we wczesnym stadium choroby może opóźnić lub zapobiec przerzutom do OUN w późniejszym okresie¹.

Czerniak

Czerniak ma wysoką skłonność do przerzutów do mózgu. Obecne wytyczne odradzają profilaktykę lekami przeciwpadaczkowymi (AED) u pacjentów bez historii napadów padaczkowych, ale badania sugerują, że profilaktyka AED może być skuteczna u wybranych pacjentów¹.

Pacjenci z przerzutami do OUN muszą być włączani do badań klinicznych czerniaka, a projekty badań muszą być ulepszone, aby były bardziej inkluzywne¹.

Wnioski i rekomendacje

Zapobieganie przerzutom do mózgu staje się coraz ważniejszym obszarem badań w onkologii. Obecne strategie obejmują PCI u wybranych pacjentów, terapie celowane molekularnie oraz badania przesiewowe za pomocą MRI u pacjentów bezobjawowych z wysokim ryzykiem¹.

Główne rekomendacje obejmują¹²:

PCI pozostaje standardem postępowania u pacjentów z SCLC, którzy odpowiedzieli na chemioterapię, ale kosztem późniejszego pogorszenia funkcji poznawczych¹.
Techniki oszczędzające hipokamp i leki neuroprotekcyjne mogą zmniejszyć neurotoksyczność związaną z radioterapią¹.
Terapie celowane molekularnie, szczególnie nowej generacji inhibitory TKI i inhibitory punktów kontrolnych immunologicznych, wykazują obiecującą skuteczność wewnątrzczaszkową i potencjał w zapobieganiu przerzutom do mózgu¹.
Profilaktyka lekami przeciwpadaczkowymi nie jest zalecana dla pacjentów z przerzutami do mózgu, którzy nie przeszli resekcji chirurgicznej i są wolni od napadów padaczkowych¹.
Pacjenci z przerzutami do OUN powinni być włączani do badań klinicznych, aby rozwijać terapie oparte na dowodach dla tej populacji¹.

Przyszłe badania powinny koncentrować się na identyfikacji biomarkerów i czynników ryzyka dla przerzutów do mózgu, opracowaniu leków przenikających barierę krew-mózg oraz projektowaniu badań klinicznych, które uwzględniają pacjentów z przerzutami do mózgu¹.

Ostatecznie, celem jest nie tylko leczenie pacjentów z przerzutami do mózgu, ale całkowite zapobieganie występowaniu przerzutów do mózgu¹.

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Materiały źródłowe

#1
https://esmed.org/MRA/mra/article/view/994
Brain metastases are common sequelae of many adult cancers, with reported overall incidence of 9%17% [1], which accounts for more than 150,000 cases per year (NCI). […] Prevention of brain metastases therefore has been an important topic in oncology. This article addresses the role of radiation therapy as a strategy in prevention of brain metastasis.
#1 Prevention of Brain Metastases: A New Frontier
https://www.mdpi.com/2072-6694/16/11/2134
This review discusses the topic of prevention of brain metastases from the most frequent solid tumor types, i.e., lung cancer, breast cancer and melanoma. Within each tumor type, the issues of screening in asymptomatic patients, prophylactic strategies with radiation and secondary chemoprevention with targeted agents are discussed. […] Prophylactic cranial irradiation is the standard of care in patients in small cell lung cancer responsive to chemotherapy but at the price of late neurocognitive decline. More recently, several molecular agents with the capability to target molecular alterations driving tumor growth have proven as effective in the prevention of secondary relapse into the brain in clinical trials. […] The need for screening with an MRI in asymptomatic patients at risk of brain metastases is emphasized.
#1 Hippocampal-Sparing Brain Irradiation: The Future of Brain Metastases Treatment and Prevention? – ILCN.org (ILCN/WCLC)
https://www.ilcn.org/hippocampal-sparing-brain-irradiation-the-future-of-brain-metastases-treatment-and-prevention/
Brain metastases (BMs) are frequently diagnosed in patients with SCLC and NSCLC, although the incidence is highest in SCLC. Therefore, it is important to prevent or to treat them early. Prophylactic cranial irradiation (PCI) significantly reduces BM incidence in both NSCLC and SCLC, with a hazard ratio (HR) of approximately 0.35. However, PCI comes with a 30% risk of irreversible neurocognitive decline (NCD; linked to hippocampal dose), resulting in a negative impact on QoL. To reduce the risk of neurotoxicity after PCI or WBRT, hippocampal avoidance (HA) has been evaluated, both alone and in combination with neuroprotective drugs. […] Because of a decrease in the incidence of BMs, combined with an aggregate OS benefit, PCI became standard-of-care for patients with SCLC whose disease responded to initial treatment. However, the role of PCI in extensive disease has been challenged on the basis of a Japanese phase III trial demonstrating that although the incidence of BMs decreased with PCI plus MRI follow-up compared with MRI follow-up alone, PCI alone did not result in an OS benefit. Furthermore, as stated above, PCI has been associated with a risk of NCD. To reduce this NCD, HA has also been evaluated in this setting. […] In conclusion, HA, especially when combined with memantine, may prove promising for patients with lung cancer and BMs who have a good prognosis. Future trials should specifically focus on this patient subgroup and include the evaluation of risk factors and biomarkers for NCD.
#1 Prevention of Brain Metastases: A New Frontier
https://www.mdpi.com/2072-6694/16/11/2134
Prevention strategies were initially developed for tumors with a high propensity to relapse into the brain, such as small cell lung cancer (SCLC), and consisted of the so-called prophylactic cranial irradiation (PCI). This modality has been proven effective in reducing the risk of brain metastasis (BM) but at the price of cognitive decline in long-surviving patients. […] More recently, it has emerged that some molecular subgroups of patients with non-small cell lung cancer (NSCLC), breast cancer and melanoma have a higher propensity to develop brain metastases and, at the same time, are treatable with new effective inhibitors with an increased capacity to cross the BBB. Thus, preventive strategies using molecular agents (âchemopreventionâ) are gaining increasing interest. […] The phase III NVALT-11/DLCRG-02 trial showed that PCI reduces the incidence of symptomatic brain metastases.
#1 Brain metastases: advances over the decades – Tsao – Annals of Palliative Medicine
https://apm.amegroups.org/article/view/7757/8901
The addition of radiosensitizers does not improve overall survival or brain response as compared to WBRT alone. Outside clinical trials, radiosensitizers is not recommended with WBRT. […] Randomized trials support the use of surgery to improve survival as compared to WBRT alone in selected patients with controlled systemic disease and a resectable single brain metastasis. […] The use of postoperative WBRT for patients with resected brain metastasis improves overall brain control but does not improve survival. […] However, the use of WBRT has been shown to negatively affect neurocognition and quality of life, such that experimental strategies to avoid WBRT have emerged. […] In order to spare neurocognitive function with WBRT, a few experimental strategies such as hippocampal radiation sparing, and the use of medications such as memantine and donepezil have been used. […] The targeted agents have not been used routinely for the initial management of newly diagnosed brain metastases patients.
#1 Prophylactic Radiotherapy: A Case for Patients at High Risk of Brain Metastases – ILCN.org (ILCN/WCLC)
https://www.ilcn.org/prophylactic-radiotherapy-a-case-for-patients-at-high-risk-of-brain-metastases/
Prophylactic radiotherapy for the prevention of brain metastases has not been considered a standard practice outside of limited stage SCLC, particularly amid the surge and approval of novel targeted therapies that have shifted the outlook for patients with oncogene-addicted lung adenocarcinomas. […] The continued search for strategies to prevent the development of brain metastases in patients with NSCLC has been a prioritized area of research for many years. […] The study, which recruited 84 individuals, showed for the first time that high-risk patients treated with PCI have a significantly reduced incidence of brain metastases at 24 months compared with those who undergo observation (7% vs. 38%) as well as improved OS (median = 64.5 vs. 19.8 months). […] It is important to highlight that some PCI studies identified low-grade toxicity in neurocognitive function associated with the experimental arm; however, these studies used higher PCI doses and different fractioning schemas, as well as surgical approaches in addition to the radiotherapy.
#1
https://link.springer.com/article/10.1007/s12254-021-00709-1
As the treatment of symptomatic BM is challenging and the overall survival prognosis still poor, secondary and primary prevention of BM by systemic treatment came into the focus in recent years. […] In the FLAURA trial, comparing osimertinib with standard EGFR-TKI, 3% of patients without BM at baseline developed BM during the follow-up in the osimertinib group compared to 7% in the standard EGFR-TKI group. Furthermore, 19% of patients with BM at baseline developed new or progressive BM in the osimertinib group compared to 43% in the standard EGFR-TKI group. […] Primary BM prevention of third generation ALK inhibitor alectinib compared to crizotinib was investigated in the ALEXA trial. In the crizotinib arm, 31.5% of the patients without BM at study entry developed BM during further course of the study, compared to only 4.6% of the patients in the alectinib group.
#1 Prevention of Brain Metastases: A New Frontier
https://www.mdpi.com/2072-6694/16/11/2134
Therefore, PCI is not a guideline management for NSCLC, since it offers no survival benefit. […] In recent years, the molecular profiling of NSCLC has resulted in the discovery of driver mutations and, subsequently, therapies targeting such mutations. Since there are limited data on the primary prevention of brain metastases, we have focused on secondary prevention. […] The cumulative incidence of CNS progression was significantly lower with alectinib, with a 12-month rate of 9.4% vs. 41.4% with crizotinib. […] A pooled analysis of the ALKA-372-001, STARTRK-1 and STARTRK-2 trials assessed entrectinib in patients with ROS1-driven NSCLC BM. […] The cumulative incidence rates for CNS progression at 6, 12, 18, 24 and 36 months were 3%, 10%, 17%, 17% and 20, respectively. […] In general, there are pros and cons regarding the usefulness of screening strategies. Identifying and treating asymptomatic BM might prevent neurologic complications, thus improving QoL and reducing the need for WBRT or surgery.
#1
https://link.springer.com/article/10.1007/s12254-021-00709-1
Furthermore, the addition of durvalumab to radiochemotherapy in stage III NSCLC was associated with an improved primary BM prevention as 5.5% of patients in the durvalumab arm developed BM compared to 11.0% in the control arm. […] Remarkable intracranial efficacies were observed for several next-generation TKIs and immune checkpoint inhibitorsespecially in patients with asymptomatic BM. Therefore, in case of available systemic treatment option with proven high intracranial efficacy, upfront systemic treatment can be evaluated in BM patients with asymptomatic disease. […] Furthermore, based on the promising primary and secondary BM preventions in some new therapeutic agents, effective prevention of BM also needs to be addressed in future trials.
#1 Temozolomide in secondary prevention of HER2-positive breast cancer brain metastases.
https://vivo.weill.cornell.edu/display/pubid32270710
Brain metastases occur in up to 25-55% of patients with metastatic HER2-positive breast cancer. […] Temozolomide (TMZ) is known to penetrate the blood-brain barrier and is US FDA approved for treatment of glioblastoma. […] Our group has demonstrated that low doses of TMZ administered in a prophylactic, metronomic fashion can significantly prevent development of brain metastases in murine models of breast cancer. […] Based on these findings, we initiated a secondary-prevention clinical trial with oral TMZ given to HER2-positive breast cancer patients with brain metastases after recent local treatment in combination with T-DM1 for systemic control of disease. Primary end point is freedom from new brain metastases at 1 year.
#1 BRIDGET: Secondary BRain metastases prevention after Isolated intracranial progression on Trastuzumab/Pertuzumab or T-DM1 in patients with aDvanced human epidermal Growth factor receptor 2+ brEast cancer with the addition of Tucatinib | Dana-Farber Cancer
https://www.dana-farber.org/clinical-trials/22-671
Patients with advanced HER2+ breast cancer on maintenance trastuzumab/pertuzumab or T-DM1 with 1st or 2nd intracranial disease event (brain metastases) and stable extracranial disease will be enrolled. […] They will receive local therapy with stereotactic radiosurgery surgical resection if indicated followed by enrollment. […] Patients will continue standard of care trastuzumab/pertuzumab or T-DM1 with the addition of tucatinib. […] Patients on trial with extracranial disease progression with stable intracranial disease should continue tucatinib into next line of therapy. […] Adequate local therapy to existing brain lesions 5mm including surgical resection and/or stereotactic radiosurgery. […] Prior radiation is required within 12 weeks of enrollment to at least 1 brain lesion.
#1 Expert consensus on the prevention of brain metastases in patients withâ¦ | Evandro de Azambuja
https://www.linkedin.com/posts/evandro-de-azambuja-bb37264_expert-consensus-on-the-prevention-of-brain-activity-7267906836656230400-NlsI?utm_source=share&utm_medium=member_desktop
Our expert consensus on the prevention of brain metastases in patients with HER2-positive breast cancer is out! […] The DESTINY-Breast12 trial showed trastuzumab deruxtecan, or T-DXd can be effective in patients with HER2-positive breast cancer and brain metastases. […] These findings highlight T-DXd’s substantial activity, particularly for patients with brain metastases who usually have limited treatment options.
#1 Brain metastases as preventive and therapeutic targets
https://pmc.ncbi.nlm.nih.gov/articles/PMC7351203/
WBRT also has a role in preventing brain metastases (prophylactic cranial irradiation (PCI)). […] A review of randomized trials in patients with non-small-cell lung cancer (NSCLC) showed a reduction in the incidence of brain metastases, without any survival benefit. […] The most profound preclinical observation that has been reported, however, is that prevention of the outgrowth of brain metastases is partially achievable. […] A retrospective analysis of the clinical trial data from sorafenib in patients with renal cancer brain metastases revealed a 75% prevention of brain metastasis development. […] Secondary prevention trials represent an as yet untried method for examining the efficacy of drugs at preventing brain metastases.
#1 Azthena logo with the word Azthena
https://www.news-medical.net/news/20190628/Promising-new-approaches-in-the-fight-against-brain-metastasis.aspx
Research is currently pursuing several highly promising approaches in the fight against cancers that give rise to metastases in the brain. „Our aim must be to prevent brain metastasis from occurring in the first place,” says oncologist Matthias Preusser from MedUni Vienna. […] An important starting point is therefore to inhibit such brain metastases or to prevent them occurring in the first place. […] Research is currently pursuing several approaches to prevention. […] There are already clinical studies showing that suppressing angiogenesis (blood vessel formation) successfully inhibits the growth of metastatic tumors. […] „If we have sufficient understanding of the molecular mechanisms that contribute to brain metastasis, then, in future, we would be able to suppress various activated signaling pathways, to protect the brain against attack by cancer cells,” says Preusser, describing this method.
#1 Azthena logo with the word Azthena
https://www.news-medical.net/news/20190628/Promising-new-approaches-in-the-fight-against-brain-metastasis.aspx
Inhibition of the CDK (cyclin-dependent kinases) signaling pathway might also help to inhibit the formation of brain metastases. […] „In a paper in which we participated and which was recently published in Nature Genetics, it was also demonstrated that some cancer cells can settle in the brain early on in the disease so that early targeted treatment could be expedient to prevent seeding of brain metastases.” […] Some chemotherapy drugs are also suitable for preventing or delaying metastasis. […] It was found in animal models that temozolomide, a chemotherapy drug commonly used against glioblastomas (brain tumors) prevents metastasis, if taken in low doses on a long-term basis. […] „Particularly in the area of brain metastasis, our aim is to prevent it occurring in the first place,” explains Preusser, „we want to be able to identify risk groups and provide them with preventive protection against metastasis.”
#1 Anticoagulants reduce the number of brain metastases in mice – German Cancer Research Center
https://www.dkfz.de/en/news/press-releases/detail/anticoagulants-reduce-the-number-of-brain-metastases-in-mice
Brain metastases can only develop if cancer cells first exit the fine blood vessels and enter into the brain tissue. […] For patients with cancers that often spread to the brain, it would be extremely helpful if we had a treatment available that could prevent brain metastases from developing, explains Frank Winker, head of a research group at the German Cancer Research Center and managing senior physician at Heidelberg University Neurological Hospital. […] An drug that inhibits thrombin would therefore have to suppress metastasis because it prevents the tumor cells from penetrating into the brain tissue. […] These experiments show that it is primarily the influence of the cancer cells on the plasmatic coagulation factors that promotes the development of brain metastases. This is why a preventive drug should target precisely this process, explains Manuel Feinauer, first author of the current publication. […] Our goal is to identify drugs for the prevention of brain metastases in high-risk patients, says Winkler. […] In the long term, we then want to test these substances in clinical trials.
#1 Research Highlight: Preventing Breast Cancer Brain Metastasis – NFCR
https://www.nfcr.org/blog/research-highlight-preventing-breast-cancer-brain-metastasis/
Dr. Haber and his team shared their exciting findings on how brain metastasis, or the spread of cancer to the brain, may be prevented. […] Simply put, blocking the HIF1A signaling pathway could reduce the rate of brain metastasis or even prevent it all together. […] Theoretically, a drug could be developed to suppress HIF1A and, in turn, prevent the spread of cancer. […] However, we would have to expand this to multiple different models and systems before we could contemplate an intervention.
#1 HemOnc Today’s PharmAnalysis
https://www.healio.com/news/hematology-oncology/20241107/novel-approach-shows-promising-potential-to-prevent-brain-metastases
Researchers identified a new approach that may help prevent cancer from metastasizing to the brain. […] The approach could serve as the basis for molecular-targeted therapies for brain metastases. […] A novel therapeutic approach could intercept rogue cancer cells before they develop into brain metastases, according to study findings. […] There are no molecular-targeted therapies [for brain metastases], Singh said. Weve just discovered the basis for one. […] Our rationale became, what if we could treat the cells and kill them before they get into the brain. […] Mycophenolic acid could be used to prevent the development of brain metastases now, but researchers acknowledge the drug leads to toxicities and adverse effects. […] The question were asking is: Can we develop a better version of mycophenolic acid that somehow could selectively target IMPDH in the cancer cells and not so much in the normal cells?
#1 Guidelines for the Treatment of Adults with Metastatic Brain Tumors
https://www.cns.org/guidelines/treatment-adults-metastatic-brain-tumors/role-of-prophylactic-anticonvulsants-in-treatment-
Prophylactic AEDs are not recommended for patients with brain metastases who did not undergo surgical resection and are otherwise seizure-free. […] Routine post-craniotomy anti-epileptic drug use for seizure-free patients with brain metastases is not recommended. […] The objective of this guideline is to address the role of AED prophylaxis in patients with brain metastases without prior seizures in the 1) non-surgical and 2) postoperative settings. […] These studies are Class III evidence, leading to the Level 3 recommendation that the use of prophylactic AEDs is not justified for patients with brain metastases who did not undergo surgical resection and are otherwise seizure-free. […] The remaining 2 studies enrolled/reviewed a similar number of patients as the terminated study, but did not provide metastases-specific analyses. These works are Class III evidence, leading to the Level 3 recommendation that routine use of prophylactic postoperative AEDs is not justified for patients with brain metastases who are otherwise seizure-free.
#1 Brain metastases: advances over the decades – Tsao – Annals of Palliative Medicine
https://apm.amegroups.org/article/view/7757/8901
Steroids provide relief of symptoms due to intra-cerebral edema. […] Anti-seizure medications should not be given as prophylaxis but instead be given for treatment of seizures. […] A meta-analysis of six randomized controlled trials including 547 patients with brain tumours reported that those patients with brain tumours who received prophylactic antiepileptic drugs did not significantly lower seizure incidence as compared to the group who did not receive prophylactic antiepileptic drugs. As such, there is evidence to support not using prophylactic anti-seizure medications in patients with a diagnosis of brain metastases but without a history of seizures. […] Similarly, a Cochrane meta-analysis found no difference between the use of prophylactic anti-seizure medications vs. no anti-seizure prophylaxis in preventing a first seizure in patients with brain tumours.
#1
https://link.springer.com/article/10.1007/s11060-012-0802-y
Melanoma has a high propensity to metastasize to the brain. […] Current guidelines recommend against antiepileptic drug prophylaxis (AED PPX) in patients without a history of seizure. […] On univariate analysis among patients without a seizure at diagnosis, AED-PPX was significantly associated with decreased risk of seizure (P = 0.03) with 3-month seizure rate of 0% compared to 17% without AED-PPX. […] AED PPX may be effective in selected patients, and should be addressed in a randomized controlled trial.
#1 Management of Breast Cancer Brain Metastases Is Moving Forward, but New Options Are Still Needed
https://www.cancernetwork.com/view/management-breast-cancer-brain-metastases-moving-forward-new-options-are-still-needed
Prevention of CNS seeding early in the metastatic disease course using drugs with both intra- and extracranial activity will be crucial to improving outcomes in patients with breast cancer brain metastases. […] Currently recommendations do not exist for screening of occult brain metastases in these high-risk patients. […] Prevention of CNS seeding early in the metastatic disease course using drugs with both intra- and extracranial activity will be crucial to improving outcomes in patients with BCBMs. […] The CEREBEL trial addressed the issue of primary prevention of brain metastases in HER2-positive MBC patients who had not yet developed brain metastases, comparing lapatinib plus capecitabine vs trastuzumab plus capecitabine, with development of CNS metastases as the primary endpoint.
#1 Brain metastases as preventive and therapeutic targets
https://pmc.ncbi.nlm.nih.gov/articles/PMC7351203/
The incidence of metastasis to the brain is apparently rising in cancer patients and threatens to limit the gains that have been made by new systemic treatments. […] Advances in the chemoprevention of brain metastases, the validation of tumour radiation sensitizers and the amelioration of cognitive deficits caused by whole-brain radiation therapy are discussed. […] Whole-brain radiation therapy (WBRT) has been shown to prevent lung cancer brain metastases, but causes cognitive decline. […] Prevention of brain metastasis formation in mice has been observed in response to lapatinib, vorinostat, pazopanib, signal transducer and activator of transcription 3 (STAT3) inhibitors and VEGF receptor (VEGFR) inhibitors. […] New trial designs could test drugs for the prevention of brain metastases.
#1
https://www.soc-neuro-onc.org/WEB/WEB/About_Content/News_Pages/ThirdBrainMets.aspx
Mechanisms of cancer cell entry and survival in the CNS is a domain of critical importance, as discoveries into metastasis invasion and propagation within the brain may provide novel strategies in brain tumor prevention and treatment. […] Such findings introduce the concept of anticoagulation and/or von Willebrand Factor inhibitors in the prevention of brain metastases. […] The concept of brain metastasis prevention was revisited, this time with focus on application to clinical trials. […] The scientific community has become increasingly cognizant of the need to study pharmacologic agents in patients with brain metastases. Accordingly, investigators should not consider active brain metastases as an automatic exclusion from trial eligibility, because doing so excludes the very patient population with the greatest need for evidence-based CNS-penetrant therapies.
#1 Management of Breast Cancer Brain Metastases Is Moving Forward, but New Options Are Still Needed
https://www.cancernetwork.com/view/management-breast-cancer-brain-metastases-moving-forward-new-options-are-still-needed
Nonetheless, the important lesson learned was that systemic control remains of key importance in HER2-positive disease, and we hope that new, more effective systemic treatment early in the disease course can delay or prevent CNS metastases later. […] Efficacy of novel systemic therapies in BCBMs should be incorporated routinely into clinical trials, early in the process. […] Time to development of CNS metastases is a potential endpoint to examine when testing new therapies in the setting of advanced breast cancer. […] With better understanding of the biology of CNS spread, and by either continuing to conduct studies specifically for breast cancer patients with CNS involvement or allowing patients with CNS metastases to be enrolled in clinical trials, we will persist in making the strides needed to limit this potentially devastating complication.
#1 HemOnc Today’s PharmAnalysis
https://www.healio.com/news/hematology-oncology/20241107/novel-approach-shows-promising-potential-to-prevent-brain-metastases
We are making compounds that are blood-brain barrier penetrant now. […] The most important thing is weve started a biomarker campaign. We have to figure out how to define the patient population that are at high risk for getting brain metastases after theyve finished their treatment for their lung cancer. […] Im hoping that we will develop therapies that are more helpful than anything thats being used to treat these patients right now, because they face a very grim prognosis.
#1
https://journals.lww.com/amjclinicaloncology/fulltext/2021/12000/treatment_and_prevention_of_brain_metastases_in.6.aspx
Central nervous system (CNS) metastasis will develop in 50% of small cell lung cancer (SCLC) patients throughout disease course. […] To prevent development of CNS metastasis prophylactic cranial irradiation (PCI) is recommended in limited stage disease, after response to chemotherapy and radiation, while PCI may be considered in extensive stage disease after favorable response to upfront treatment. […] Neurocognitive toxicity with whole brain radiotherapy and PCI is a concern and remains difficult to predict.
#1 Brain Metastasis from Lung Cancer | American Lung Association
https://www.lung.org/lung-health-diseases/lung-disease-lookup/lung-cancer/symptoms-diagnosis/lung-cancer-staging/brain-metastasis
There are a variety of treatment options for lung cancer that has spread to the brain. […] Sometimes WBRT is done to prevent brain mets in small cell lung cancer (SCLC) patients, who have a higher risk of brain mets and is called prophylactic cranial irradiation. […] Because of the side effects of WBRT, many physicians opt to use frequent MRIs to watch the brain closely in patients with SCLC instead of treating them with WBRT.
#1 Combating Melanoma Brain Metastases and Leptomeningeal Disease – Melanoma Research Alliance
https://www.curemelanoma.org/blog/combating-melanoma-brain-metastases-and-leptomeningeal-disease
Dr. Eva Hernando of the New York University School of Medicine commented that we used to think that we could go to the primary tumor and develop ways to stop them from spreading to other places in the body. However, emerging data suggests that most primary tumor cells can spread right away and can remain dormant in the brain for long periods of time. One of the major challenges is the need to stop the melanoma tumor cells that have already reached the brain before they come out of dormancy and become actively metastatic tumors, said Dr. Hernando. This is a tall task, but it is important for the research community to focus on this unmet need. […] The roundtable participants agreed that more patients with CNS metastases must be included in melanoma clinical trials, and that trial designs need improvements to make them more inclusive.
#1 HER2CLIMB Breast Cancer Brain Metastases | BCRF
https://www.bcrf.org/blog/nancy-lin-brain-metastases-her2-positive-breast-cancer-study/
As many as half of patients diagnosed with metastatic HER2-positive breast cancer will see their cancer spread to their brain. […] For a long time, we have wanted more effective treatment options for these patients. […] Until this point, there has been a fair amount of nihilism that these treatments are not going to be enough or they’re not going to work for patients with brain metastases. So, I hope that this result will really open up the door to more active inclusion of patients with brain metastases in clinical trials. […] Ultimately, we want to not just to treat patients with brain metastases, but to prevent brain metastases from happening altogether.
#2 Brain metastases: advances over the decades – Tsao – Annals of Palliative Medicine
https://apm.amegroups.org/article/view/7757/8901
Steroids provide relief of symptoms due to intra-cerebral edema. […] Anti-seizure medications should not be given as prophylaxis but instead be given for treatment of seizures. […] A meta-analysis of six randomized controlled trials including 547 patients with brain tumours reported that those patients with brain tumours who received prophylactic antiepileptic drugs did not significantly lower seizure incidence as compared to the group who did not receive prophylactic antiepileptic drugs. As such, there is evidence to support not using prophylactic anti-seizure medications in patients with a diagnosis of brain metastases but without a history of seizures. […] Similarly, a Cochrane meta-analysis found no difference between the use of prophylactic anti-seizure medications vs. no anti-seizure prophylaxis in preventing a first seizure in patients with brain tumours.
#2
https://journals.lww.com/amjclinicaloncology/fulltext/2021/12000/treatment_and_prevention_of_brain_metastases_in.6.aspx
Central nervous system (CNS) metastasis will develop in 50% of small cell lung cancer (SCLC) patients throughout disease course. […] To prevent development of CNS metastasis prophylactic cranial irradiation (PCI) is recommended in limited stage disease, after response to chemotherapy and radiation, while PCI may be considered in extensive stage disease after favorable response to upfront treatment. […] Neurocognitive toxicity with whole brain radiotherapy and PCI is a concern and remains difficult to predict.
#2 Prevention of Brain Metastases: A New Frontier
https://www.mdpi.com/2072-6694/16/11/2134
Therefore, PCI is not a guideline management for NSCLC, since it offers no survival benefit. […] In recent years, the molecular profiling of NSCLC has resulted in the discovery of driver mutations and, subsequently, therapies targeting such mutations. Since there are limited data on the primary prevention of brain metastases, we have focused on secondary prevention. […] The cumulative incidence of CNS progression was significantly lower with alectinib, with a 12-month rate of 9.4% vs. 41.4% with crizotinib. […] A pooled analysis of the ALKA-372-001, STARTRK-1 and STARTRK-2 trials assessed entrectinib in patients with ROS1-driven NSCLC BM. […] The cumulative incidence rates for CNS progression at 6, 12, 18, 24 and 36 months were 3%, 10%, 17%, 17% and 20, respectively. […] In general, there are pros and cons regarding the usefulness of screening strategies. Identifying and treating asymptomatic BM might prevent neurologic complications, thus improving QoL and reducing the need for WBRT or surgery.
#2 Brain metastases: advances over the decades – Tsao – Annals of Palliative Medicine
https://apm.amegroups.org/article/view/7757/8901
The addition of radiosensitizers does not improve overall survival or brain response as compared to WBRT alone. Outside clinical trials, radiosensitizers is not recommended with WBRT. […] Randomized trials support the use of surgery to improve survival as compared to WBRT alone in selected patients with controlled systemic disease and a resectable single brain metastasis. […] The use of postoperative WBRT for patients with resected brain metastasis improves overall brain control but does not improve survival. […] However, the use of WBRT has been shown to negatively affect neurocognition and quality of life, such that experimental strategies to avoid WBRT have emerged. […] In order to spare neurocognitive function with WBRT, a few experimental strategies such as hippocampal radiation sparing, and the use of medications such as memantine and donepezil have been used. […] The targeted agents have not been used routinely for the initial management of newly diagnosed brain metastases patients.
#2
https://link.springer.com/article/10.1007/s12254-021-00709-1
Furthermore, the addition of durvalumab to radiochemotherapy in stage III NSCLC was associated with an improved primary BM prevention as 5.5% of patients in the durvalumab arm developed BM compared to 11.0% in the control arm. […] Remarkable intracranial efficacies were observed for several next-generation TKIs and immune checkpoint inhibitorsespecially in patients with asymptomatic BM. Therefore, in case of available systemic treatment option with proven high intracranial efficacy, upfront systemic treatment can be evaluated in BM patients with asymptomatic disease. […] Furthermore, based on the promising primary and secondary BM preventions in some new therapeutic agents, effective prevention of BM also needs to be addressed in future trials.
#2 Expert consensus on the prevention of brain metastases in patients withâ¦ | Evandro de Azambuja
https://www.linkedin.com/posts/evandro-de-azambuja-bb37264_expert-consensus-on-the-prevention-of-brain-activity-7267906836656230400-NlsI?utm_source=share&utm_medium=member_desktop
Our expert consensus on the prevention of brain metastases in patients with HER2-positive breast cancer is out! […] The DESTINY-Breast12 trial showed trastuzumab deruxtecan, or T-DXd can be effective in patients with HER2-positive breast cancer and brain metastases. […] These findings highlight T-DXd’s substantial activity, particularly for patients with brain metastases who usually have limited treatment options.
#2 First clinical trial testing a prevention for breast cancer metastasis to the brain yields encouraging results | Center for Cancer Research
https://ccr.cancer.gov/news/article/first-clinical-trial-testing-a-prevention-for-breast-cancer-metastasis-to-the-brain-yields-encouraging-results
In a phase I clinical trial of a drug combination that aims to prevent metastatic tumors from recurring in the brains of women with advanced breast cancer, 83 percent of patients developed no new brain metastases. […] For the first clinical test of TMZ as a potential prevention for breast cancer brain metastases, Steeg, Zimmer, and their colleagues focused on a particularly high-risk group: women who had already developed and been treated for metastatic lesions in the brain. […] The drug combination was well tolerated and only two patients developed new tumors in their brain tissue. […] The team is now exploring a possible phase I clinical trial to evaluate a drug combination that includes TMZ as a prevention for secondary breast cancer metastasis in women with triple-negative breast cancer.
#2 UCSF Brain Cancer Trial â Secondary BRain Metastases Prevention After Isolated Intracranial Progression on Trastuzumab/Pertuzumab or T-DM1 in Patients with ADvanced Human Epidermal Growth Factor Receptor 2+ BrEast Cancer with the Addition of Tucatinib
https://clinicaltrials.ucsf.edu/trial/NCT05323955
Patients with advanced HER2+ breast cancer on maintenance trastuzumab/pertuzumab or T-DM1 with 1st or 2nd intracranial disease event (brain metastases) and stable extracranial disease will be enrolled. […] They will receive local therapy with stereotactic radiosurgery surgical resection if indicated followed by enrollment. […] Patients will continue standard of care trastuzumab/pertuzumab or T-DM1 with the addition of tucatinib. […] Study treatment will continue until intercranial disease progression or intolerable side effects. […] Patients with extracranial disease progression while on trial with stable intracranial disease should continue tucatinib into the next line of therapy as described in protocol. […] Patients with de novo metastatic disease and brain metastases or isolated intracranial recurrence can enter upon initiation of maintenance trastuzumab/pertuzumab after chemotherapy if deemed necessary by treating oncologist and meeting other inclusion criteria.
#2 Azthena logo with the word Azthena
https://www.news-medical.net/news/20190628/Promising-new-approaches-in-the-fight-against-brain-metastasis.aspx
Inhibition of the CDK (cyclin-dependent kinases) signaling pathway might also help to inhibit the formation of brain metastases. […] „In a paper in which we participated and which was recently published in Nature Genetics, it was also demonstrated that some cancer cells can settle in the brain early on in the disease so that early targeted treatment could be expedient to prevent seeding of brain metastases.” […] Some chemotherapy drugs are also suitable for preventing or delaying metastasis. […] It was found in animal models that temozolomide, a chemotherapy drug commonly used against glioblastomas (brain tumors) prevents metastasis, if taken in low doses on a long-term basis. […] „Particularly in the area of brain metastasis, our aim is to prevent it occurring in the first place,” explains Preusser, „we want to be able to identify risk groups and provide them with preventive protection against metastasis.”
#2
https://www.soc-neuro-onc.org/WEB/WEB/About_Content/News_Pages/ThirdBrainMets.aspx
Mechanisms of cancer cell entry and survival in the CNS is a domain of critical importance, as discoveries into metastasis invasion and propagation within the brain may provide novel strategies in brain tumor prevention and treatment. […] Such findings introduce the concept of anticoagulation and/or von Willebrand Factor inhibitors in the prevention of brain metastases. […] The concept of brain metastasis prevention was revisited, this time with focus on application to clinical trials. […] The scientific community has become increasingly cognizant of the need to study pharmacologic agents in patients with brain metastases. Accordingly, investigators should not consider active brain metastases as an automatic exclusion from trial eligibility, because doing so excludes the very patient population with the greatest need for evidence-based CNS-penetrant therapies.
#2 HemOnc Today’s PharmAnalysis
https://www.healio.com/news/hematology-oncology/20241107/novel-approach-shows-promising-potential-to-prevent-brain-metastases
We are making compounds that are blood-brain barrier penetrant now. […] The most important thing is weve started a biomarker campaign. We have to figure out how to define the patient population that are at high risk for getting brain metastases after theyve finished their treatment for their lung cancer. […] Im hoping that we will develop therapies that are more helpful than anything thats being used to treat these patients right now, because they face a very grim prognosis.
#2 Anticonvulsant Prophylaxis and Steroid Use in Adults With Metastatic Brain Tumors
https://www.mdcalc.com/guidelines/10253/other/anticonvulsant-prophylaxis-steroid-use-adults-metastatic-brain-tumors
Prophylactic antiepileptic drugs are not recommended for routine use in patients with brain metastases who did not undergo surgical resection and who are otherwise seizure free. […] Routine postcraniotomy antiepileptic drug use for seizure-free patients with brain metastases is not recommended. […] For asymptomatic brain metastases patients without mass effect, insufficient evidence exists to make a treatment recommendation for this clinical scenario. […] For brain metastases patients with mild symptoms related to mass effect, corticosteroids are recommended to provide temporary symptomatic relief of symptoms related to increased intracranial pressure and edema secondary to brain metastases. It is recommended for patients who are symptomatic from metastatic disease to the brain that a starting dose of dexamethasone 4 to 8 mg/day be considered.
#2 Prevention of Brain Metastases: A New Frontier
https://scholarlycommons.baptisthealth.net/se-all-publications/5271/
This review discusses the topic of prevention of brain metastases from the most frequent solid tumor types, i.e., lung cancer, breast cancer and melanoma. […] Prophylactic cranial irradiation is the standard of care in patients in small cell lung cancer responsive to chemotherapy but at the price of late neurocognitive decline. […] More recently, several molecular agents with the capability to target molecular alterations driving tumor growth have proven as effective in the prevention of secondary relapse into the brain in clinical trials. […] The need for screening with an MRI in asymptomatic patients at risk of brain metastases is emphasized.
#2 News & Events | DCTD
https://dctd.cancer.gov/NewsEvents/20221206_shaping_the_landscape.htm
Advances in cancer research and systemic therapy have increased survival for people with cancer but also the subsequent diagnosis of brain metastases. […] Distant treatment failure (new brain metastases) is an issue, and optimal prevention strategies, selection, or sequencing of standard and emerging therapies are unknown. […] What are the most promising strategies to predict response to standard therapies and to prevent local and distant intracranial treatment failure? […] Is there a role for WBRT for primary or secondary prevention? […] Right metastasis models (in vitro, such as HTS, and in vivo) for discovery of new systemic agents that help to prevent metastasis and augment standard of care. […] Science of CSF will help in prevention of metastasis.
#2 Brain metastases as preventive and therapeutic targets
https://pmc.ncbi.nlm.nih.gov/articles/PMC7351203/
WBRT also has a role in preventing brain metastases (prophylactic cranial irradiation (PCI)). […] A review of randomized trials in patients with non-small-cell lung cancer (NSCLC) showed a reduction in the incidence of brain metastases, without any survival benefit. […] The most profound preclinical observation that has been reported, however, is that prevention of the outgrowth of brain metastases is partially achievable. […] A retrospective analysis of the clinical trial data from sorafenib in patients with renal cancer brain metastases revealed a 75% prevention of brain metastasis development. […] Secondary prevention trials represent an as yet untried method for examining the efficacy of drugs at preventing brain metastases.
#2 Combating Melanoma Brain Metastases and Leptomeningeal Disease – Melanoma Research Alliance
https://www.curemelanoma.org/blog/combating-melanoma-brain-metastases-and-leptomeningeal-disease
The FDA recognized that this is a special patient population that has not been historically included in clinical trials due to a hesitancy of including them in a primary analysis based on how they do clinically. However, the agency notes to sponsors that by including these patients we are able to capture really important information that is contributing to our growing understanding of how to address this population with unmet needs.
#2 Update on Managing Brain Metastases in Breast Cancer â Hematology & Oncology
https://www.hematologyandoncology.net/archives/september-2018/update-on-managing-brain-metastases-in-breast-cancer/
We do not have a proven prevention strategy at this time. […] We had hoped that lapatinib/capecitabine, which has activity in the brain of patients with established brain metastases, might help prevent brain metastases. However, CEREBEL (Lapatinib Plus Capecitabine Versus Trastuzumab Plus Capecitabine in ErbB2 Positive Metastatic Breast Cancer), a randomized trial of capecitabine in combination with either trastuzumab or lapatinib in patients without evidence of brain metastases, found no difference between rates of CNS progression in the 2 groupsâalthough this could have been a consequence of the small number of patients with CNS progression overall.
#2 Management of Breast Cancer Brain Metastases Is Moving Forward, but New Options Are Still Needed
https://www.cancernetwork.com/view/management-breast-cancer-brain-metastases-moving-forward-new-options-are-still-needed
Nonetheless, the important lesson learned was that systemic control remains of key importance in HER2-positive disease, and we hope that new, more effective systemic treatment early in the disease course can delay or prevent CNS metastases later. […] Efficacy of novel systemic therapies in BCBMs should be incorporated routinely into clinical trials, early in the process. […] Time to development of CNS metastases is a potential endpoint to examine when testing new therapies in the setting of advanced breast cancer. […] With better understanding of the biology of CNS spread, and by either continuing to conduct studies specifically for breast cancer patients with CNS involvement or allowing patients with CNS metastases to be enrolled in clinical trials, we will persist in making the strides needed to limit this potentially devastating complication.
#3 Prophylactic Radiotherapy: A Case for Patients at High Risk of Brain Metastases – ILCN.org (ILCN/WCLC)
https://www.ilcn.org/prophylactic-radiotherapy-a-case-for-patients-at-high-risk-of-brain-metastases/
Prophylactic radiotherapy for the prevention of brain metastases has not been considered a standard practice outside of limited stage SCLC, particularly amid the surge and approval of novel targeted therapies that have shifted the outlook for patients with oncogene-addicted lung adenocarcinomas. […] The continued search for strategies to prevent the development of brain metastases in patients with NSCLC has been a prioritized area of research for many years. […] The study, which recruited 84 individuals, showed for the first time that high-risk patients treated with PCI have a significantly reduced incidence of brain metastases at 24 months compared with those who undergo observation (7% vs. 38%) as well as improved OS (median = 64.5 vs. 19.8 months). […] It is important to highlight that some PCI studies identified low-grade toxicity in neurocognitive function associated with the experimental arm; however, these studies used higher PCI doses and different fractioning schemas, as well as surgical approaches in addition to the radiotherapy.