CNS carcinoma

Section editor
	Seema Nagpal, MD Stanford University Palo Alto, CA

1 regimens on this page 1 variants on this page

Guidelines

ASCO

• 2022: Schiff et al. Radiation Therapy for Brain Metastases: ASCO Guideline Endorsement of ASTRO Guideline
• 2022: Ramakrishna et al. Management of Advanced Human Epidermal Growth Factor Receptor 2–Positive Breast Cancer and Brain Metastases

Older

• 2018: Ramakrishna et al. Recommendations on disease management for patients with advanced human epidermal growth factor receptor 2-positive breast cancer and brain metastases: American Society of Clinical Oncology clinical practice guideline update PubMed
• 2014: Ramakrishna et al. Recommendations on disease management for patients with advanced human epidermal growth factor receptor 2-positive breast cancer and brain metastases: American Society of Clinical Oncology clinical practice guideline PubMed

ASCO/SNO/ASTRO

• 2021: Vogelbaum et al. Treatment for Brain Metastases

EANO/ESMO

• 2021: Le Rhun et al. EANO–ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up of patients with brain metastasis from solid tumours
• 2017: Le Rhun et al. EANO–ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up of patients with leptomeningeal metastasis from solid tumours

NCCN

• NCCN Guidelines - Central Nervous System Cancers

Unselected all lines of therapy

Whole brain irradiation

WBRT: Whole-Brain Radiation Therapy

Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Knisely et al. 2007 (RTOG 0118)	2002-2004	Phase 3 (C)	Thalidomide & WBRT	Did not meet primary endpoint of OS

Radiotherapy

• Whole-brain irradiation 2.5 Gy fractions x 15 (total dose: 37.5 Gy)

One course

References

1. RTOG 0118: Knisely JP, Berkey B, Chakravarti A, Yung AW, Curran WJ Jr, Robins HI, Movsas B, Brachman DG, Henderson RH, Mehta MP. A phase III study of conventional radiation therapy plus thalidomide versus conventional radiation therapy for multiple brain metastases (RTOG 0118). Int J Radiat Oncol Biol Phys. 2008 May 1;71(1):79-86. Epub 2007 Dec 31. link to original article contains dosing details in abstract PubMed NCT00033254

Breast cancer, HER2-positive, all lines of therapy

Capecitabine & Lapatinib

Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Pivot et al. 2015 (CEREBEL)	2009-2012	Phase 3 (E-switch-ic)	Capecitabine & Trastuzumab	Did not meet primary endpoint of CNS metastases as first site of relapse

Biomarker eligibility criteria

• Gene: HER2 Positive
• Clinical Trial Eligibility: score > 2.2 by fluorescence in situ hybridization and/or 3+ amplification by immunohistochemistry or chromogenic/silver in situ hybridization

Chemotherapy

• Capecitabine (Xeloda) 1000 mg/m² PO twice per day on days 1 to 14

Targeted therapy

• Lapatinib (Tykerb) 1250 mg PO once per day

21-day cycles

References

1. CEREBEL: Pivot X, Manikhas A, Żurawski B, Chmielowska E, Karaszewska B, Allerton R, Chan S, Fabi A, Bidoli P, Gori S, Ciruelos E, Dank M, Hornyak L, Margolin S, Nusch A, Parikh R, Nagi F, DeSilvio M, Santillana S, Swaby RF, Semiglazov V. CEREBEL (EGF111438): A phase III, randomized, open-label study of lapatinib plus capecitabine versus trastuzumab plus capecitabine in patients with human epidermal growth factor receptor 2-positive metastatic breast cancer. J Clin Oncol. 2015 May 10;33(14):1564-73. Epub 2015 Jan 20. link to original article PubMed NCT00820222

Capecitabine & Trastuzumab (XH)

XH: Xeloda (Capecitabine) & Herceptin

Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Pivot et al. 2015 (CEREBEL)	2009-2012	Phase 3 (C)	Capecitabine & Lapatanib	Did not meet primary endpoint of CNS metastases as first site of relapse

Biomarker eligibility criteria

• Gene HER2 Positive
• Clinical Trial Eligibility: score > 2.2 by fluorescence in situ hybridization and/or 3+ amplification by immunohistochemistry or chromogenic/silver in situ hybridization

Chemotherapy

• Capecitabine (Xeloda) 1250 mg/m² PO twice per day on days 1 to 14

Targeted therapy

• Trastuzumab (Herceptin) as follows:
  • Cycle 1: 8 mg/kg IV once on day 1
  • Cycle 2 onwards: 6 mg/kg IV once on day 1

21-day cycles

References

1. CEREBEL: Pivot X, Manikhas A, Żurawski B, Chmielowska E, Karaszewska B, Allerton R, Chan S, Fabi A, Bidoli P, Gori S, Ciruelos E, Dank M, Hornyak L, Margolin S, Nusch A, Parikh R, Nagi F, DeSilvio M, Santillana S, Swaby RF, Semiglazov V. CEREBEL (EGF111438): A phase III, randomized, open-label study of lapatinib plus capecitabine versus trastuzumab plus capecitabine in patients with human epidermal growth factor receptor 2-positive metastatic breast cancer. J Clin Oncol. 2015 May 10;33(14):1564-73. Epub 2015 Jan 20. link to original article contains dosing details in abstract PubMed NCT00820222

Capecitabine & Trastuzumab (XH) & Tucatinib

Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Murthy et al. 2019 (HER2CLIMB)	2016-2019	Phase 3 (E-RT-esc)	XH	Superior OS Median OS: 21.9 vs 17.4 mo (HR 0.66, 95% CI 0.50-0.88)

Chemotherapy

• Capecitabine (Xeloda) 1000 mg/m² PO twice per day on days 1 to 14

Targeted therapy

• Tucatinib (Tukysa) 300 mg PO twice per day
• Trastuzumab (Herceptin) as follows:
  • Cycle 1: 8 mg/kg IV once on day 1
  • Cycle 2 onwards: 6 mg/kg IV once on day 1

21-day cycles

References

1. HER2CLIMB: Murthy RK, Loi S, Okines A, Paplomata E, Hamilton E, Hurvitz SA, Lin NU, Borges V, Abramson V, Anders C, Bedard PL, Oliveira M, Jakobsen E, Bachelot T, Shachar SS, Müller V, Braga S, Duhoux FP, Greil R, Cameron D, Carey LA, Curigliano G, Gelmon K, Hortobagyi G, Krop I, Loibl S, Pegram M, Slamon D, Palanca-Wessels MC, Walker L, Feng W, Winer EP. Tucatinib, Trastuzumab, and Capecitabine for HER2-Positive Metastatic Breast Cancer. N Engl J Med. 2020 Feb 13;382(7):597-609. Epub 2019 Dec 11. Erratum in: N Engl J Med. 2020 Feb 6;382(6):586. link to original article contains dosing details in manuscript PubMed NCT02614794
   1. Subgroup analysis: Lin NU, Borges V, Anders C, Murthy RK, Paplomata E, Hamilton E, Hurvitz S, Loi S, Okines A, Abramson V, Bedard PL, Oliveira M, Mueller V, Zelnak A, DiGiovanna MP, Bachelot T, Chien AJ, O'Regan R, Wardley A, Conlin A, Cameron D, Carey L, Curigliano G, Gelmon K, Loibl S, Mayor J, McGoldrick S, An X, Winer EP. Intracranial Efficacy and Survival With Tucatinib Plus Trastuzumab and Capecitabine for Previously Treated HER2-Positive Breast Cancer With Brain Metastases in the HER2CLIMB Trial. J Clin Oncol. 2020 Aug 10;38(23):2610-2619. Epub 2020 May 29. link to original article link to PMC article PubMed