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Feb 25, 2016 03:17PM
I am sorry to hear of your wife's diagnosis, and it is very loving of you to reach out on her behalf. Below from my MBC Guide is a list of possible therapies. You (and others) are welcome to request a complimentary copy of the 115 page booklet by visiting the top of this page: https://community.breastcancer.org/forum/8/topics/831507?page=2#idx_32
A unique hurdle in the development of therapies for BCBM is the presence of the blood-brain barrier (BBB), a tight layer of endothelial cells that acts as a selective barrier to the diffusion of systemic therapies such as chemotherapy.
Despite the presence of the BBB, there is considerable information about the use of drugs for people with brain metastasis in this section.
In May 2014, ASCO issued the following treatment guidelines for HER2 positive MBC patients with brain metastasis (the author was unable to find similar guidelines for HER2 negative MBC):
- For patients with favorable prognosis for survival, surgery and/or radiotherapy are recommended, depending on the size and number of metastases, resectability, and symptoms.(Note: No specific mention was made here for targeted and/or chemotherapy, so it might be worth discussing the pros and cons of systemic with one's doctor).
- For patients with a poor prognosis for survival, options include surgery, Whole Brain Radiation (WBR) therapy, and systemic therapies with some evidence of activity in the setting of brain metastases such as Tykerb and Xeloda.
- Additional options include best supportive care, enrollment in a Clinical Trial, and/or palliative care.
Brain metastasis may be treated through non-drug techniques, medications, or both.
Non-Drug treatments for brain metastasis
- Brain Surgery
- Proton Therapy
- Radiosurgery such as:
- Whole Brain Radiation Therapy (WBR or WBRT)
These procedures are described below:
- Proton (Pencil Beam) Therapy: Traditional radiation therapy affects everything in its path, so doctors have to limit the dose delivered to the tumor in order to minimize damage to surrounding healthy tissue.In proton therapy, protons enter the body with a low dose of radiation which increases when the beam slows down within the tumor, and then the protons stop without going any further to harm further tissue. Compared to an X-ray beam, a proton beam has a low "entrance dose" (the dose delivered from the surface of the skin to the front of the tumor), a high dose designed to cover the entire tumor, and no "exit dose" beyond the tumor.The combined effect is claimed to provide greater precision in targeting the tumor with a more potent dose of radiation. The accuracy of proton therapy for treatment delivery is within approximately one millimeter. MD Anderson is currently using pencil beam scanning to treat cancers of the prostate, brain, base of the skull and eye, and this therapy may be worth inquiring about for MBC patients with brain metastases. From: http://www.mdanderson.org/patient-and-cancer-information/cancer-information/cancer-topics/cancer-treatment/radiation/proton-therapy/index.html
- Radiosurgery (SRS): Radiosurgery, also called Stereotactic RadioSurgery or SRS: The term "radiosurgery" is misleading because the procedure does not involve surgery. Radiation is given from the outside the head without having to cut into the skull. This is a procedure that aims very high doses of radiation (higher than WBRT) directly at brain metastases. Because the beams of radiation converge from many different directions, the rest of the brain is spared these high doses. Unlike WBRT, only the metastases is targeted, not the entire brain, which minimizes toxicities. It can be used to treat metastases deep within the brain (such as in the brainstem), where regular surgery cannot be done safely. It is considered to be at least as effective as surgical resection, although that has not been completely proven.
Radiosurgery is generally not used for more than three metastases at a time, or for metastases that are larger than approximately 3 centimeters.However, more and more patients and their doctors are going outside these guidelines, treating more than three metastases as well as metastases larger than 3 centimeters. Severe side effects occur in only 1-2% of those treated with radiosurgery. These include seizures, edema, hemorrhage, and radionecrosis (dead tumor tissue).Radionecrosis from radiosurgery can be hard to distinguish from recurring brain metastasis.Usually radionecrosis is treated with a corticosteroid, so sometimes surgery is necessary to biopsy the lesion to determine if it is, in fact, radionecrosis or recurring metastases.
Radiosurgery can be repeated if new brain metastases appear, and it can also be used after regular surgery or WBRT as a "boost" to prevent brain metastases from recurring in the same location.From: http://www.brainmetsbc.org/en/content/current-treatments-brain-metastasis
Forms of Radiosurgery include:
- CyberKnife is a form of SRS. It is a non-invasive alternative to surgery for the treatment of both cancerous and non-cancerous tumors anywhere in the body, including the head.The treatment – which delivers beams of high dose radiation to tumors with extreme accuracy – offers new hope to patients worldwide.The CyberKnife treatment involves no cutting and claims to be the world's first and only robotic radiosurgery system designed to treat tumors throughout the body non-invasively.It provides a pain-free, non-surgical option for patients who have inoperable or surgically complex tumors, or who may be looking for an alternative to surgery. From: http://www.cyberknife.com/faq/index.aspxThe CyberKnife differs from the Gamma Knife (below) by employing real-time X-ray images to guide treatment; and as a result has expanded SRS to sites outside the brain.It does not require a head frame screwed into the skull for immobilization, thus avoiding the pain, headache, nausea and risk of infection seen at times with stereotactic frames. Instead, a non-invasive thermoplastic head mask and image guidance allows stereotactic immobilization. From: http://csn.cancer.org/node/189965
- Gamma Knife is also a form of SRS. It is a blade-free radiosurgical treatment that delivers a dose of gamma radiation to the target with surgical precision.Gamma Knife radiosurgery delivers more than 200 precise radiation beams that converge deep within the brain to shrink or even destroy diseased or damaged tissue.Alone, each of the beams contains harmless doses of radiation so surrounding tissue remains unaffected, protecting the important functions of the brain. From: www.pennmedicine.org/neurosurg...
- Whole Brain Radiation Therapy (WBR or WBRT): Whole brain radiation therapy is used for the treatment of multiple and larger brain metastases.It is also used for those patients with rapidly progressing metastatic disease outside of the brain and for what is known as "poor performance status" (ability to take care of oneself).As its name indicates, radiation is delivered to the entire brain.WBR has been shown in research studies to extend life and improve the quality of life for patients whose brain metastases are causing symptoms.30% to 40% of patients will achieve a complete reversal of symptoms, while 75% to 85% of patients will experience some improvement or stabilization of their symptoms, especially headache and seizure. From: http://www.brainmetsbc.org/en/content/current-treatments-brain-metastasis
Preservation of Memory with WBR:There is a type of WBR that is a "hippocampus sparing procedure" which may help to preserve a degree of memory that might otherwise be lost as a result of the procedure.In a study of 113 patients, at four months after undergoing the hippocampus sparing procedure, the decline in recall (as compared to baseline) was 7%, significantly better than the 30% cognitive decline in the historical control group that received WBR without the hippocampus sparing procedure.From:http://jco.ascopubs.org/content/early/2014/10/21/JCO.2014.57.2909
Increased Overall Survival in patients who have undergone WBR:A retrospective study reviewed the status of 253 breast cancer patients with brain metastases who were treated with WBR.The results were consistent with mounting evidence that histone deacetylase (HDAC) inhibitors such as Valproic Acid (VPA) synergize with radiation to improve patient outcomes. VPA and its derivative, divalproex, are oral drugs that are currently used for the treatment of convulsions, migraines and bipolar disorder.The study found that breast cancer patients who received VPA with WBR had a 6-month longer Overall Survival than those who did not receive VPA.From: http://www.sciencedirect.com/science/article/pii/S0167814015005514
Additional information about radiation options for brain metastasis can be found at:www.texasoncology.com/types-of...
Drug treatments for brain metastasis
Despite the presence of the Blood Brain Barrier (BBB), some drugs appear helpful in treating brain metastasis and/or side effects from treatment include:
- Abemaciclib (LY2835219 or Bemacicilib) – Not Yet FDA-Approved
- Ang1005 – Not Yet FDA-Approved
- Boswellia Serrata
- Chemotherapy Drugs
- Dexamethasone (Decadron)
- Emend (Apripitant)
- Herceptin (Trastuzumab) given Intrathecally
- Hormonal Therapies
- Kadcyla (TDM-1)
- Lapatinib (Tykerb) and Xeloda (Capecitabine)
- NKTR-102 (Etirinotecan Pegol) – Not Yet FDA-Approved
- ONT-380– Not Yet FDA-Approved
- Abemaciclib (LY2835219 or Bemaciclib): In October 2015, this experimental oral drug was granted a "Breakthrough Therapy Designation" by the FDA, which is a form of Fast Track Designation intended to facilitate the development and review of new drugs intended to treat serious conditions. Abemaciclib may have strong single-agent activity in MBC, meaning that it may potentially be used alone instead of in combination with other drugs (although it may also work in combination with other drugs), and as of January 2015 it is in Clinical Trials.With any luck, it may be available in 2017.
One study included 47 patients with MBC who received a median of seven prior therapies. The majority had two or more metastatic sites and 74% had visceral (internal organ) metastases. Among Hormone Receptor positive patients, 9 (25%) had confirmed partial responses and 20 (56%) had stable disease, including 2 with unconfirmed partial responses.Thee clinical benefit rate was 61%, and disease control rate was 81%.
A unique characteristic of Abemaciclib is its ability to cross the blood-brain barrier, making it a potentially attractive treatment option for brain metastasis.From: http://www.onclive.com/publications/contemporary-oncology/2014/november-2014/targeting-cell-cycle-progression-cdk46-inhibition-in-breast-cancer/3#sthash.wCkkuV7J.dpuf
- ANG1005: This Taxol-like drug, which is being studied as of October 2015 in a clinical trial for mbc patients with brain metastasis,is providing encouraging results in this population.In a Phase II study of 10 patients with a total of 32 metastatic brain lesions, 15 of the 32 lesions showed a 20% or greater reduction within a specified timeframe.Among patients who went on to additional cycles of ANG1005, two of the 10 patients had confirmed partial responses and seven patients had stable disease. Unfortunately as of December 2015, no open clinical trials were identified. From: http://www.reuters.com/article/2015/06/01/angiochem-idUSnBw015944a+100+BSW20150601
- Boswellia Serrata (BS) is not a treatment.Instead, it is used to help relieve edema (swelling):Patients irradiated for brain tumors often suffer from cerebral edema and are usually treated with Dexamethasone, a steroid which has various side effects and can promote tumor growth..In one study, 44 patients with primary or secondary malignant cerebral tumors were randomly assigned to radiotherapy plus either BS or placebo.Blood samples were taken to analyze the serum concentration of boswellic acids (AKBA and KBA).Compared with baseline, a reduction of cerebral edema of more than 75% was found in 60% of patients receiving BS, and in only 26% of patients receiving placebo.These findings may be based on an additional antitumor effect. There were no severe adverse events in either group.BS did not have a significant impact on quality of life or cognitive function.Therefore, Boswellia Serrata could potentially be steroid-sparing for patients receiving brain irradiation.From:http://www.ncbi.nlm.nih.gov/pubmed/21287538One patient wrote that the Dexamethasone initially helped her enormously, but she subsequently began reacting badly to it the longer she was on it. She weaned off it in less than two weeks by taking Boswellia Serreta and found that 1,800 mg was comparable to half a dose of Dexamethasone.So she boosted her Boswellia intake to two caplets 4 times a day during radiation no longer needed to take any steroids.(Note: Patients interested in taking Boswellia should confer with their doctor about dosage and frequency).
- Chemotherapy Drugs: Some studies have suggested that Xeloda (Capecitabine), high-dose Methotrexate, the Platinum drugs Carboplatin and Cisplatin, and Adriamycin (Doxorubicin) can be effective in shrinking brain metastases. From: http://www.brainmetsbc.org/index.php?q=content/current-treatments-brain-metastases#HT
- Dexamethasone (Decadron): Although not a cancer treatment in and of itself, a steroid called Dexamethasone is given to patients with brain metastasis (often at the time of diagnosis) to reduce cerebral edema (swelling). Patients with small, completely asymptomatic lesions may not need steroids; however, steroids may reduce the acute side effects of radiation and are rarely harmful in most patients for short periods of time.The beneficial effects of steroids are noticeable within 6 to 24 hours after the first dose and reach maximum effect in 3 to 7 days. More than 70% of patients improve symptomatically after starting steroids.From: http://www.medmerits.com/index.php/article/brain_metastases/P11/That said, Dexamethasone may bind to a segment of DNA that may activate genes associated with drug resistance and poor patient outcomes, so alternative anti-inflammatories should be considered.From:http://www.eurekalert.org/pub_releases/2015-10/osuw-ssn100615.php
- Emend (Apripitant): This is an anti-nausea drug that may help combat brain metastasis in addition to reducing nausea.In the laboratory (not human) setting, Emend was associated with a reduction in brain tumor growth, and it also caused cell death in the tumor cells.This drug may offer further opportunities to study possible brain tumor treatments over the coming years. From:www.sciencedaily.com/releases/...
- Herceptin (Trastuzumab) given Intrathecally (in the spinal canal): Studies have shown that HER2+ patients treated with IV Herceptin have significantly lower concentrations of the drug in their Cerebral Spinal Fluid (CSF) than elsewhere in their bodies.This could explain the subsequent development of CNS metastases when non-CNS metastases are under control. Researchers hypothesized that the lack of efficacy of IV Herceptin with respect to brain metastasis in HER2-overexpressing breast cancers may result from a deficient Blood Brain Barrier (BBB) passage, and that Intrathecal Herceptin administration might overcome this deficiency. A study of one HER2+ patient who had liver metastases for 6 years and brain metastases for 2.5 years, showed that after 6 months with an efficacious Intrathecal Herceptin concentration, she was still alive without treatment toxicity, and the progression of her brain and epidural metastases had halted. From: http://jco.ascopubs.org/content/early/2014/12/29/JCO.2012.44.8894.full
- Hormonal Therapies:Hormonal therapies such as Tamoxifen, Letrozole, and Megace have been shown to be effective in treating breast cancer brain metastasis in some women with ER-positive tumors. From: http://www.brainmetsbc.org/index.php?q=content/current-treatments-brain-metastases#HT
- Kadcyla (TDM-1) for pre-treated Asymptomatic HER2+ MBC:One study indicated that patients with HER2 positive MBC with pre-treated CNS metastasis and no symptoms who took Kadcyla experienced significantly longer Overall Survival (OS) than those assigned Xeloda plus Tykerb.From: http://www.healio.com/hematology-oncology/breast-cancer/news/online/%7B6433cb8b-e23f-4134-b2e9-ed9fe37a6005%7D/ado-trastuzumab-emtansine-significantly-extended-os-in-HER2positive-breast-cancer-with-cns-metastasis
- Lapatinib (Tykerb) and Xeloda (Capecitabine): The studies that have explored the combination of Lapatinib and are generally small in size, ranging from 13 to 138 patients. In nearly all studies, 85–100% of patients received prior Herceptin and WBR. CNS response ranged from 20 to 30%, which appears to be an improvement over responses observed with Lapatinib alone.One study addressed the role of the Lapatinib and Xeloda combination prior to WBRT.In this study, 45 patients with newly diagnosed Brain Metastases (BM) were enrolled, of which 36 (80%) patients had two or more BM and 42 (93%) patients received prior Herceptin. This study showed an impressive (67%) CNS response rate, defined as 50% volumetric reduction of CNS lesions. Median time to progression was 5.5 months and median time to whole-brain irradiation was 8.3 months. From: http://www.medscape.com/viewarticle/759026_5
- Mannitol (a diuretic) is not a cancer treatment.Instead, it helps remove fluid from the brain (and reduce swelling) by drawing it into the blood vessels from the tissues, and assisting the kidneys to eliminate it through the urine. From: www.livestrong.com/article/162... swelling/
- Namenda (Memantine HCL) is an Alzheimer's drug that may help preserve cognitive skills after WBR. Results of a study demonstrated that Namenda delays cognitive decline in areas of recognition memory, global function, executive function and processing speed, since patients in the Namenda group experienced 17% less cognitive reduction at 24 weeks compared to those in the placebo group. There was no difference in patients' Overall Survival or Progression Free Survival between the treatment groups. From: www.astro.org/News-and-Media/N...
- NKTR-102 (Etirinotecan Pegol) – Not Yet FDA-Approved: In a clinical trial called BEACON, 852 patients with advanced breast cancer who had any type of ER/HER-2 status were enrolled.Patients were randomly assigned to receive either NKTR-102 or a physician's choice of standard chemotherapy. The study found that NKTR-102 doubled Overall Survival in patients with brain metastases when compared to the physician's choice chemotherapy.Furthermore, NKTR-102 was less toxic than standard chemotherapy. As of May 2015, the author was unable to locate a clinical trial of this drug for MBC patients with brain metastasis, so interested patients are encouraged speak with their doctor.
- ONT-380: ONT-380 is a small molecule inhibitor of the HER2 growth factor receptor. The drug works by targeting the HER2 "tyrosine kinase" - a link in the chain of communication that allows HER2 receptors to signal the growth of the cell. The fact that it is a small molecule means the drug is able to pass through the blood-brain barrier to act against brain metastases of the disease.In the first study of ONT-380 with TDM-1, all 8 evaluable patients with brain metastases experienced more than 50% reduction in primary brain tumor size.In another study of 33 evaluable patients with metastatic HER2+ breast cancer (with and without brain metastases), 19 (58 percent) showed clinical benefit, with 16 achieving at least "stable disease" (i.e. no tumor progression while on trial), 11 patients experienced "partial response" (i.e. tumor shrinkage of more than 30%). Of 8 patients with brain metastases, 5 achieved at least stable disease, with 2 partial responses and one complete response in which existing brain metastases were undetectable after treatment. From:http://www.eurekalert.org/pub_releases/2015-05/uocd-ohs052915.phpandhttp://www.eurekalert.org/pub_releases/2015-12/uoca-spp120915.phpAs of Dec. 2015, there is at least one recruiting clinical trial (NCT02025192) of ONT-380 for HER2+ MBC patients: https://www.clinicaltrials.gov/ct2/show/NCT02025192?term=ont-380&recr=Recruiting&rank=2
- Temodar (Temozolomide) has recently been used as a single agent to treat brain metastasis from breast cancer in Clinical Trials. In one study, complete remission was achieved in 36% of patients, and an additional 58% had a partial response. From: http://emedicine.medscape.com/article/1157902-treatmentClinical Trials: A list of Clinical Trials solely for brain metastasis is located at: http://brainmetsbc.org/en/content/available-clinical-trials-linksA new clinical trial for patients receiving WBR entails the use of an additional experimental drug called RRx-001, which appears to sensitize (or re-sensitize) tumors to treatment.In a study of 25 patients with advanced malignant incurable tumors that were rapidly progressing, disease control was evident in 71% of patients, with stable disease for more than 4 months in 28% of patients. From: http://www.targetedonc.com/news/epigentic-targeted-agent-may-combat-resistance-in-many-cancers In the clinical trial specifically for patients undergoing WBR, the rationale for using RRx-001 is that RRx-001 releases a gas called nitric oxide, which widens the diameter of blood vessels and allows the delivery of more oxygen to tumors. The presence of oxygen in tumors is critical for the effectiveness of radiation therapy, since cancer cells are about two to three times more vulnerable to radiation when oxygen is present.Hence it is hoped that WBR will be more effective when combined with this experimental drug.From: https://www.clinicaltrials.gov/ct2/show/NCT02215512?term=rrx-001&rank=1
Clinical Trials: A list of Clinical Trials solely for brain metastasis is located at: http://brainmetsbc.org/en/content/available-clinical-trials-links
A new clinical trial for patients receiving WBR entails the use of an additional experimental drug called RRx-001, which appears to sensitize (or re-sensitize) tumors to treatment.In a study of 25 patients with advanced malignant incurable tumors that were rapidly progressing, disease control was evident in 71% of patients, with stable disease for more than 4 months in 28% of patients. From: http://www.targetedonc.com/news/epigentic-targeted-agent-may-combat-resistance-in-many-cancers
In the clinical trial specifically for patients undergoing WBR, the rationale for using RRx-001 is that RRx-001 releases a gas called nitric oxide, which widens the diameter of blood vessels and allows the delivery of more oxygen to tumors. The presence of oxygen in tumors is critical for the effectiveness of radiation therapy, since cancer cells are about two to three times more vulnerable to radiation when oxygen is present.Hence it is hoped that WBR will be more effective when combined with this experimental drug.From: https://www.clinicaltrials.gov/ct2/show/NCT02215512?term=rrx-001&rank=1
10/6/2011, IDC, Left, Stage IV, ER+/PR+, HER2-