“We are not necessarily moving the needle on the survival curve by rushing to whole-brain radiation therapy. In the era of improved therapies, we have to rethink our use of whole-brain radiation therapy.”

— Kimberly Blackwell, MD

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FOR PATIENTS WITH BREAST CANCER who have metastases to the central nervous system (CNS), clinicians should think twice before administering whole-brain radiotherapy, according to Kimberly Blackwell, MD, Professor of Medicine and Assistant Professor of Radiation Oncology at Duke University Medical Center.¹ 

Speaking at the 2017 Miami Breast Cancer Conference, Dr. Blackwell suggested that whole-brain radiation is often the first response to the patient who “arrives at 5 PM with symptoms.” She said that “rather than sitting tight with intravenous steroids, we feel compelled to take this step.” The results of two studies, in particular, have convinced her that “rushing to whole-brain radiation” is often not the right course. 

Two Pivotal Trials 

THE PHASE III QUARTZ TRIAL evaluated dexamethasone and supportive care, with or without whole-brain radiation therapy, in 538 patients with non–small cell lung cancer and brain metastases unsuitable for resection or stereotactic radiotherapy.² The study found no difference in overall survival with the use of whole-brain radiation therapy. “Patients who got only best supportive care did as well as those getting whole-brain radiation therapy, and, in fact, quality of life at 24 weeks was actually better for the supportive care arm,” revealed Dr. Blackwell. 

The N0574 study randomized 213 patients with a variety of solid tumors and 1 to 3 brain metastases to undergo stereotactic radiosurgery alone or with whole-brain radiation therapy.³ The N0574 study differed from some previous ones in that the treatment was prospectively assigned and not determined by clinician’s choice or retrospectively analyzed. The primary endpoint was the effect on cognitive function with the addition of whole-brain radiation therapy to stereotactic radiosurgery. 

The use of stereotactic radiosurgery alone, compared with stereotactic radiosurgery plus whole-brain radiation therapy, resulted in less cognitive deterioration at 3 months and better quality of life, and there was no difference in overall survival. Cognitive deterioration after stereotactic radiosurgery alone was observed in 40 of 63 patients (63.5%), compared with 44 of 48 patients (91.7%) who also received whole-brain radiation therapy (P < .001). 

Dr. Blackwell continued: “But there continues to be an active dialogue about whether we should add whole-brain radiation therapy after stereotactic radiosurgery.” In part, this dialogue is being driven by another finding from the same study—that the cumulative incidence of intracranial tumor progression was three times higher (> 50% vs 20% at 18 months) with stereotactic radiosurgery alone. “This highlights the dilemma,” she said. “With whole-brain radiotherapy, there was significantly higher tumor control within the brain, and you would assume this would improve overall survival, but in reality it had no impact.” 

“These two studies suggest we are not necessarily moving the needle on the survival curve by rushing to whole-brain radiation therapy,” she concluded. “That doesn’t mean, however, the patient with multiple brain metastases who is highly symptomatic should not get it, but in the era of improved therapies, we have to rethink our use of whole-brain radiation therapy.” 

Difficulty Assessing Disease Progression 

DR. BLACKWELL also discussed the difficulty in deciphering tumor progression from necrosis at the stereotactic radiosurgery site. “In our experience, spots on magnetic resonance imaging that appear to have grown after stereotactic radiosurgery are often radiation-based necrosis or gliosis of the brain,” she explained. “This is well known in the radiation literature, but many surgical and medical oncologists may not be aware of this.” 

She and her colleagues at Duke University Medical Center evaluated patients who underwent brain biopsy after stereotactic radiosurgery. The prebiopsy impression was that 67% of these lesions were tumor progression; the impression postbiopsy, however, was that 68% indicated radiation necrosis. 

“Although it’s tempting, you don’t automatically re-administer stereotactic radiosurgery in these cases,” she indicated. “If the patient is otherwise doing well, without evidence of disease progression in other sites, a stereotactic brain biopsy can serve the patient well.” 

Chemotherapy and CNS Metastases 

“DON’T FORGET ABOUT TRADITIONAL AGENTS that might cross into the brain,” Dr. Blackwell continued. They include (though not necessarily for breast cancer) temozolomide, tamoxifen, idarubicin, liposomal doxorubicin, methotrexate, gemcitabine, and platinums. Newer (more breast cancer–specific) agents with CNS penetration include capecitabine, aromatase inhibitors, everolimus (Afinitor), and inhibitors of cyclin-dependent kinases 4 and 6 (CDK4/6) and poly (ADP-ribose) polymerase (PARP). 

The most progress in therapeutically targeting brain metastases appears to be in the setting of HER2-positive disease. “This is a pressing issue, because as trastuzumab [Herceptin] and pertuzumab [Perjeta] have improved overall survival ‘from the neck down,’ there are patients who die due to consequences of CNS metastases, despite otherwise well-controlled disease,” she said. 

“We have moved the needle a little bit in this area,” she added, but acknowledged that CNS response rates with most of these drugs remain “a bit lackluster”: lapatinib (Tykerb) alone: 6%; lapatinib plus capecitabine: 20%; lapatinib plus capecitabine plus everolimus: 11%; neratinib: 8%; and ado-trastuzumab emtansine (Kadcyla; T-DM1): 24%.

But newer agents show more promise, especially tucatinib (formerly ONT-380), a selective HER2-specific small molecule inhibitor “that we are all excited about,” she said. A small study reported at the 2016 San Antonio Breast Cancer Symposium evaluated tucatinib combined with capecitabine and trastuzumab.⁴ In 12 patients with measurable CNS lesions at baseline, 5 (42%) had a response to treatment. One patient had a complete response, and one patient had almost a 60% reduction in tumor size. 

Dr. Blackwell reminded clinicians that when HER2-positive patients develop progressive brain metastases, but disease is controlled elsewhere, it is not recommended to change systemic therapy to treat the brain lesions. “I see patients who’ve been doing great on a drug, such as pertuzumab or T-DM1; but when they are switched to a different drug, they progress from the neck down. We need to follow the guidelines.” 

Clinical trials of breast cancer with brain metastases are critical to improving the state of this disease. For example, SWOG 1416 is enrolling patients with triple-negative disease for treatment with cisplatin and veliparib, including a cohort with new or progressing CNS lesions after prior intracranial radiotherapy. Dr. Blackwell encourages clinicians to consider enrolling patients in this study. ■

DISCLOSURE: Dr. Blackwell reported no conflicts of interest. 

REFERENCES 

1. Blackwell K: Assessment and treatment of CNS metastases. Invited Lecture. 2017 Miami Breast Cancer Conference. Presented March 9, 2017. 

2. Mulvenna P, Nankivell M, Barton R, et al: Dexamethasone and supportive care with or without whole brain radiotherapy in treating patients with non-small cell lung cancer with brain metastases unsuitable for resection or stereotactic radiotherapy (QUARTZ): Results from a phase 3, non-inferiority, randomised trial. Lancet 388:2004-2014, 2016. 

3. 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 316:401-409, 2016. 

4. Hamilton E, Borges V, Conlin A, et al: Efficacy results of a phase 1b study of ONT-380, an oral HER2-specific inhibitor, in combination with capecitabine and trastuzumab in HER2+ metastatic breast cancer, including patients with brain metastases. 2016 San Antonio Breast Cancer Symposium. Abstract P4- 21-01. Presented December 9, 2016.