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Explaining Leptomeningeal Metastases

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Guest post by Seema Nagpal, MD, a Clinical Assistant Professor of Neurology in the Division of Neuro-oncology at Stanford University School of Medicine

Leptomeningeal metastases, also known as “LM”, carcinomatous meningitis, or neoplastic meningitis, are cancer metastases that have spread to the coating of the brain. Rather than growing as a ball, leptomeningeal metastases form a thin layer along the meninges. LM may occur with or without brain metastases, but is generally a complication that occurs after cancer has spread from its primary site to other organs.

LM can be a frightening diagnosis for patients and for doctors, alike. While we do not have a cure for LM, new drugs and a multi-disciplinary approach can dramatically alter outcomes. Doctors who see patients with LM are seeing longer and better survivals than we have in the past. Many of us can tell you about patients who have lived a number of years after coming to us very ill. Though this won’t be the case for every patient, seeing a doctor who treats LM frequently can assure you are getting information about all of the options. Clinical trials often exclude patients with LM, but this is also slowly changing, so be sure to check with your doctor and with clinicaltrials.gov if you are interested.

Symptoms of LM

The symptoms of LM can come from the brain, the nerves exiting the brain, or nerves exiting the spinal cord. The most common symptom is persistent headache, frequently accompanied by nausea. These symptoms may be worse in the morning and get slightly better through the day. Other symptoms can include double vision, difficulty walking, numbness or weakness not explained by other problems, and neck stiffness.

Diagnosis

Meningeal carcinomatosis in a patient with breast cancer

Meningeal carcinomatosis in a patient with breast cancer

Because symptoms of LM are varied and may be vague, LM can be tricky to diagnose. Patients and doctors need to be aware of this complication and consider a work-up for LM if symptoms are otherwise unexplained. MRI of the brain and spinal cord with contrast can be helpful in many cases, but may not be as accurate in patients with blood cancers as it is in solid organ cancers. MRIs should be performed with a high quality scanner and the radiologist should be aware of the possible diagnosis.

For some patients, the combination of MRI and symptoms is enough to make the diagnosis of LM. In patients where there is some doubt, the test that confirms diagnosis is a lumbar puncture or spinal tap. Despite the scary name, it’s usually performed in a doctor’s office using the same anesthetic your dentist uses. Patients go home within 20 minutes to 1 hour of the procedure. Again, the doctor performing the lumbar puncture needs to be aware of the possible diagnosis so that enough fluid can be tested and so that the sample can be tested right away (or it’s not accurate). Unfortunately, even in the best hands, a single lumbar puncture may only make the diagnosis 70% of the time. Sometimes, 2 lumbar punctures are needed. We are working on tests for DNA and RNA in the spinal fluid that may help make testing the spinal fluid more accurate.

Treatment

Treating LM is very individualized. The choice of treatment depends on the type of cancer, the patients’ symptoms and how well controlled the cancer is outside of the central nervous system. There are 3 general approaches. Most of the time, we use a combination of these, along with direct symptoms management, to help patients live better and longer:

1. Systemic Chemotherapy with central nervous system penetration: Most drugs do not enter the central nervous system due to the “blood-brain-barrier.” However, some drugs are able to enter the nervous system and effectively treat metastases in both the brain and leptomeninges. Patients with blood cancers who develop LM may receive high doses of methotrexate. Patients with specific types of lung cancer may get alternate dose regimens of oral drugs like erlotinib (Tarceva), or receive pemetrexed (Alimta) in combination with bevacizumab (Avastin). Patients with melanoma may receive vemurafenib (Zelboraf). Centers who see more patients with LM frequently have other alternatives they use for patients.

2. Radiation can be used to slow disease and relieve symptoms. This may mean whole brain radiation or radiation to specific areas of the spine.

3. “Intrathecal Chemotherapy” is chemotherapy that is given directly into the fluid that surrounds the brain and spinal cord. Usually, patients will have a port, called an Ommaya, surgically placed into the brain prior to this chemotherapy.

Symptom Management

The symptoms of LM are varied, depending on the most effected areas of the nervous system. For patients suffering nausea and vomiting from elevated pressure in the brain, a shunt from the brain to the abdomen can help reduce pressure. Medications that reduce irritation to the coating of the brain or decrease spinal fluid production can also help. I see my patients with LM often and frequently in conjunction with our supportive care oncologists. Controlling symptoms is important not only to quality of life, but can also increase survival.

Summary

This is a very basic overview of leptomeningeal metastases, or metastases to the coating of the brain. LM can cause a number of bothersome and vague symptoms, such as nausea or difficulty walking. Diagnosis can be tricky, but is usually made with MRI and a lumbar puncture. While LM is not curable, a multi-disciplinary treatment approach that includes a supportive care specialist and a doctor who sees many patients with LM can improve quality of life as well as survival.

 


GRACE Video

The Future of Cancer Immunotherapy: Combination Treatments

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Immunotherapy Forum Video #29: In part 2 of 2, Dr. Jason Luke discusses treating cancer with immunotherapy and another drug, such chemotherapy or targeted therapies, as well as what we know about biomarkers that predict if an immunotherapeutic will work.


GRACE Video

The Right Time for Cancer Immunotherapy: Before or After Surgery?

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Immunotherapy Forum Video #28: Doctors are still weighing the pros and cons of giving a cancer patient immunotherapy before or after resection surgery. In part 1 of 2 videos, Dr. Jason Luke details those risks and benefits.


Dr West

Is there a harm in discontinuing Avastin (bevacizumab)? The evidence says no.

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One question that has emerged with the increasing use of anti-angiogenic (blood vessel-inhibiting) therapy like Avastin (bevacizumab) for many different kinds of cancer is whether, as some lab-based research has suggested, the removal of the anti-angiogenic effect when the agent is discontinued leads to a rebound increase in pro-angiogenic signaling. If that happens, perhaps it will lead to an acceleration of the rate of progression and even potentially early death after stopping Avastin. Though it’s not part of the standard approach for managing Avastin, some physicians have patients continue Avastin after they’ve shown clear progression on it, potentially out of fear that there will be a harmful effect from stopping it. But now we’ve got some evidence that suggests this isn’t the case.

A new article just coming out in the Journal of Clinical Oncology reviewed the pooled results from five different randomized phase III trials, totaling over 4000 patients with either breast, colorectal, renal, or pancreatic cancer who received chemo or the same chemo with Avastin. The authors analyzed whether the patients who discontinued Avastin, either due to side effects or for any reason, experienced a faster time to progression and worse survival than patients who hadn’t been on Avastin.

The answer from this pooled analysis was that there was neither an earlier time to progression or worse overall survival when checked at multiple different time points after discontinuing Avastin, as shown below:

efs-for-bev-after-dc (click on image to enlarge)

mortality-after-dc-of-bev

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Dr West

Cancer Treatments with Big Benefits for Small Populations

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Earlier this week, I wrote about the very promising early work with the novel, still investigational agent crizotinib (PF-02341066) in treating the 4-5% of NSCLC patients with a tumor positive for an ALK rearrangement. For this minority of patients, the benefit was of a kind we don’t see enough in cancer and certainly not in lung cancer, with about 2/3 of patients showing a significant response in terms of tumor shrinkage, and 87% achieving at least stable disease; nearly 3 out of 4 remained on it without progression 6 months later, and many are on it now for much longer, with responses still ongoing.

These data, presented in the Plenary Session of our ASCO Annual Conference, were really not controversial, except for the question of whether crizotinib should be approved by the FDA (and potentially by other similar regulators in countries around the world) based on these overwhelmingly positive results, in a limited population. The larger studies are ongoing that I think are exceptionally likely to lead to its official FDA approval, but in the meantime, there is no question that many patients will miss the opportunity to benefit from it while it remains available in only very selected settings around the world. There will also be less awareness of the test for ALK rearrangements and the benefits of crizotinib in the appropriate target patients while it is not commercially available and marketed.

The biggest problem of all, though, is that having a very effective treatment for a limited segment of the population creates a whole new set of problems that we’ll see more and more. In many ways, we are fortunate to have found the right target for the right targeted therapy here. If crizotinib had been tested in a broad NSCLC population, as is the ritual default paradigm for our treatments, it would likely be just one more drug with a 3-4% response rate that would be discarded rather than progressing through additional clinical testing. How many other crizotinibs are there that just haven’t had their appropriate targets identified and remain undeveloped by a drug company because they appear to be minimally active in an overly broad population? We should also remember that many, many agents have now been tested in too broad a population and had safety problems. Many of the anti-angiogenic agents have been shown to have increased mortality compared with placebo in patients with squamous NSCLC; in fact, it’s easy to imagine that Avastin (bevacizumab) would be tainted as the drug that regularly kills people by hemoptysis if investigators hadn’t identified the problem early in its development in lung cancer (as reviewed in this post) and excluded patients with squamous NSCLC in the larger phase III studies that led to its ultimate approval.

But we should also be concerned that pharmaceutical and biotech companies will do the calculations of offering treatment to a smaller population and find that it isn’t worth their costs and efforts to pursue therapies for a small subset of patients. Here is one of the first slides from Dr. Pennell’s excellent podcast on molecular therapies for NSCLC, showing that until 10 years ago, NSCLC was essentially viewed as one entity with a market of 60-70,000 patients with advanced disease (and smaller numbers with other stages as well) in the US each year:

lc-classification-1900-2000 (click on image to enlarge)

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