Recently a dear friend was diagnosed with Leptomeningeal Disease.

This is  a terrifying diagnosis in an already difficult disease.  As the wonderful Emily Garnett has described so poignantly in her blog about how she felt when she had gotten the news of this diagnosis.

“So this was pretty terrible news. Actually it was the absolute worst news. Left untreated lepto mets can spread very rapidly, often causing someone to die in a matter of weeks, maybe months. Even with conventional treatment options, life expectancy is considered in the span of months.

I felt and continue to feel the narrowing of the lens through which I view my life. Making plans for weeks, even months ahead of the now, is a trigger for me. More often than not, when a well meaning acquaintance makes an offhanded remark about an indeterminate time in the future, I'm reduced to tears. I know the likelihood that I will see that time is very small.” 

Leptomeningeal disease (Lepto, LM or LMD) occurs when cancer cells had crossed into cerebral spinal fluid or CSF and are circulating within that fluid. It is a relatively rare complication of cancer and occurs in approximately 5–8% of patients with solid tumors.

So what do you say to a friend who just received this diagnosis? How can you help? What words do not sound like platitudes? What is that fine line  between encouragement and false hope?

I feel that the only help I can offer, is by sharing  my knowledge and understanding of metastatic breast cancer,  and my ability to disseminate important news and information.  I know my friend has a sound plan of action. She is in good hands and treated in one of the best cancer centers in the world.

Still…

I would probably start by saying this:

As survival rates from other cancers improve, more people are having to cope with this complication. Fortunately, recent advances in cancer therapies promise more options for effective treatment. I hope you understand that much of what you may hear and read is already outdated.

Here are some updates that are up-to-date, and you might find them helpful.

Introduction

On June 5th, 2023, a special education session, entitled “ Leptomeningeal Disease: Toward Patient-Centered Care and Research for a Pressing Clinical Problem” was held in Chicago’s McCormick Place, the site of the ASCO annual conference. Unfortunately, I was unable to attend this session in person, but luckily for me it was recorded and archived. I went over audio and slides many times and tried to understand and take in every word. It was that important.

I would like to share my notes with you, our community.

At the start of the session, its chair Dr. Adrienne Boire of MSKCC, posed a question:

“So why are we having a session in this enormous theater about Leptomeningeal Disease?” 

“This is promising,” I thought. LMD is a rare complication, that was often overlooked by the mainstream science. Why indeed? Is the number of people who get this diagnosis, growing? Does it have anything to do with better treatments and longer survivals for patients with CNS metastases? What about treatments themselves? Are there more of them and, and thus this timely ASCO discussion?

It turns out that the answer is “Yes” to all my questions. New opportunities for therapies and for predicting therapeutic response have recently become available. The number of clinical trials is growing and accelerating. Overall survival is also improving for patients.

And unfortunately, the answer is also “yes” to a question about increased incidents in the diagnosis of LMD.

One of the widely accepted explanations is that Leptomeningeal Disease is increasing in numbers as people are living longer with advanced cancer.

LMD is almost never the first site in metastatic setting, that happens only in 5–10% of patients. It is usually a result of advanced disease progression with the median time from the diagnosis of metastatic disease to LMD ranging from 1.2–2 years in solid tumors. Roughly 50 to 80 percent of people (depending on the study) who have LMD also have brain metastases (within the brain rather than within the spinal fluid).

Clearly, the organizers of ASCO 2023 feel that LMD was a pressing clinical problem and diagnostic challenge that required a special education session at the ASCO annual meeting.

This session provided updates on the diagnosis and management of leptomeningeal metastases including systemic and intrathecal therapies, radiotherapy, and palliative care, with a focus on bringing access to new technologies to all patients.

To sum up, LMD is still an area of a huge unmet need, but improving

• More trials

• Better Overall Survival

• Accelerating number of trials
  
  

Chapter 1: Advances in Diagnostics and Response Assessment for Leptomeningeal Disease

Dr. Adrienne Boire, Neurologist & Neuro-Oncologist, MSKCC

Leptomeningeal disease is also known as carcinomatous meningitis or neoplastic meningitis. Most often with this complication, people have multiple neurological symptoms including visual changes, speech problems, weakness or numbness of one side of the body, loss of balance, confusion, or seizures. Diagnosis is usually made with a combination of an MRI and spinal tap.

Unlike the spread of cancer to the brain itself (brain metastases), leptomeningeal metastases involve the spread of cancer cells to the cerebrospinal fluid (CSF) that bathes the brain and spinal cord. It arises due to the seeding of cancer cells into the leptomeninges, the two innermost membranes that cover and protect the brain. Cancer cells may float freely between these membranes (the subarachnoid space) in the cerebrospinal fluid (and hence travel throughout the brain and spinal cord). Because cerebrospinal fluid is rich in nutrients and oxygen, cancer cells don't need to form large tumors to be viable, as they do in other regions of the body.

Diagnosing leptomeningeal disease can be challenging, not only because of the overlap of symptoms with those of brain metastases, but because of the testing process. A high index of suspicion is necessary to ensure that the appropriate tests are run for a timely diagnosis.

Chapter 2: State of the Art Use of Systemic and Intrathecal Therapies for Patients With Leptomeningeal Disease

Dr. Emille La Rhun, Senior Specialist in the Department of Neurosurgery.

Best Treatment for LMD - Personalized Treatment

The treatment of leptomeningeal metastases depends on many factors, including severity of symptoms, type of primary cancer, the person's general health, presence of other metastases, and more.

Leptomeningeal metastases are challenging to treat for several reasons.

1. They often occur in advanced stages of cancer and after a person has been ill for a significant period. Because of that, those diagnosed with the disease, may be less able to tolerate treatments such as chemotherapy.

2. As with brain metastases, the blood-brain barrier poses problems in treatment. This tight network of capillaries is designed to prevent toxins from getting into the brain, but for the same reason it limits chemotherapy drug access in the brain and spinal cord. Some targeted therapies and immunotherapy drugs, however, can penetrate this barrier.

3. The symptoms related to leptomeningeal disease may progress rapidly, and many cancer treatments work relatively slowly compared to disease progression.

Intrathecal pharmacotherapy

Intravenously administered chemotherapy drugs don't usually cross the blood-brain barrier,

Example below shows how ineffective an IV infusion is in delivering the drug to CSF. The penetration is measured by the CSF/plasma ratio, the difference between what is given in IV and how much will penetrate into the CSF.

As an example, Trastuzumab,, if delivered intravenously will result in a maximum of 2% penetration.

Clinical Trials for Intrathecal Trastuzumab

With HER2-positive breast cancer, the HER2-targeted therapy trastuzumab (Herceptin) can also be administered intrathecally.

Systemic Treatments

It's important to control cancer in other regions of the body as well, so specialists often use additional treatments along with intrathecal chemotherapy and/or radiation.

So here are some data in breast cancer. Unfortunately, there are no Phase III trials.

To sum up,

Chapter 3: Use of Radiotherapy for Leptomeningeal Disease: Applying Trial Data to the Real World

Michelle Alonso-Basanta, MD, PhD, Chief of the Central Nervous System, Service in Radiation Oncology, UPenn

Photon involved-field radiotherapy (IFRT) of whole brain and spine is the standard-of-care radiotherapy for patients with leptomeningeal metastasis (LM) from solid tumors.

To an experienced radiation oncologist, the whole brain and spine fields are fairly simplistic for calculation of a 3-D simulation, and they can be calculated quickly. For this reason they've been considered palliative workhorse. That’s essential when a patient needs to get on treatment very quickly.

A serious limitation to this type of radiation - it assumes no prior radiation. In this day and age, doctors see very few patients with no prior radiation.

It does a very good job at relieving symptoms, but it does not have an impact on survival because, in essence, only a portion of the disease is being treated.

Craniospinal Irradiation or CSI is a much more complicated and calculated process and treatment. The transition for most radiation oncologists from children to adults was not easy. And traditionally, the prone (face down) position was used because of the techniques available at that time.

Historically, when the craniospinal irradiation was offered in the metastatic setting, it was usually over 4 weeks with at least 2 weeks of recovery

Patients who needed to control their systemic disease and had to resume their systemic treatments were not good candidates for this therapy.

So patient selection was always key. It was always part of the discussion and the overall performance status was essential, because doing this treatment is not inconsequential, both in the length of time on the table.

The biggest disadvantage of the prone position (face down) is that it is extremely uncomfortable to a patient.

For a radiation team, it had some advantages, but the disadvantages clearly outweighed the advantages, so there was a move in the field to treat supine.

Figuring out how to perform this technique in supine (face up) position was a great boost to craniospinal irradiation.

Still, this is not a technique that can be done in a day. So why are we even talking about it so much? About two years ago, the Phase IA/B trial came out from MSKCC looking at pCSI or proton craniospinal irradiation for both lung and non-small cell lung cancer with expected good overall survival and progression-free survival.

And last year, the Phase II data of pCSI versus involved fields, randomized in patients with primarily non-small cell lung cancer and breast metastases were presented.

And what they found was encouraging. Good CNS progression-free survival, good overall survival, and in essence, for first time this technique was seriously considered as a viable option for the LMD patients. Toxicity was very favorable.

They saw an improvement in progression-free survival, CNS progression-free survival from 7.5 to 2.3 in overall survival of 9.9 versus six with little differences in grade three, grade four.

Great news. But how will it be implemented? Depending on whee you are treated, your radiation oncology center may have forgotten how to do the craniospinal irradiation (CSI). Most teams, trained in that 3-D era who are doing palliative or involved fields, are not necessarily trained in CNS or pediatric radiation.

So you can have lots of varied technologies across the board, but what is essential, is using the right tools at the right time and having an efficient system.

• The panels below show the differences in dosimetry and technique for CSI.

• The 3-D era gave a lot of dose to a lot of area of the body that really didn't need it.

• And so when the field transitioned to an intensity modulated radiation technique or VMAT technique, it did increase the dose to the anterior organs.

• TomoTherapy, although very conformal, did spread a lot of dose as well.

• pCSI in the last panel looks a lot better.

And really that's why the MSKCC study used pCSI that spares anterior organs at risk.

Given that most patients have had prior radiation, either during their initial primary diagnosis or subsequent palliative radiation of metastases, it's important to try to limit as much as possible the dose to any other structure.

What are the challenges in adults?

Availability. Not everyone feels comfortable treating these patients and not only the physicians, but entire therapy staff.

It is time consuming, both in regards to simulation, in planning, in treating, usually more than 6 hours from simulation to start.

And then there are risks.

Every decision has to be made in conjunction with medical oncologists

It has to be a team decision with the following question to consider:

• What is our goal?

• How is the patient doing?

• What comes next?

It is a tough treatment. When we talk about fatigue, it's not fatigue that you're falling asleep on the couch an hour earlier.It is FATIGUE where you have to set an alarm clock to eat.

The other aspect is the steroid dependence. It has to be considered at all times. It is unacceptable to have a patient on four milligrams every six hours for literally no edema. Steroid dependence in these patients needs to bed decreased quickly.

PT/OT should be considered upfront as well as the dietitians. and social workers involved early on not just for the patients, but the caregivers.

Conclusion

Over the last three years, this podcast has not shied away from difficult subjects. As part of our Road to a Cure series, we have spoken with Dr. Priya Kumtekar, the neuro oncologist for North Western, about this diagnosis and her research.

On our website we have put together every episode that touches upon the subject of LMD.
Follow this link to listen.