David Gerber, MD, professor of internal medicine, co-director of the Experimental Therapeutics Program, University of Texas (UT) Southwestern Medical Center, UT Southwestern Simmons Cancer Center, and Chika Nwachukwu, MD, PhD, associate program director, Medical Residency, Harold C. Simmons Comprehensive Cancer Center, assistant professor, Radiation Oncology, UT Southwestern Medical Center, discuss their role within the Stand Up To Cancer® (SU2C) 4-team initiative, focusing on diversity in early-phase clinical trials.

Within the initiative, Gerber and Nwachukwu will focus their transferring care to enhance access to early-phase cancer clinical trials at UT Southwestern Medical Center and community treatment centers.

Enrolling a patient to a cancer clinical trial can still represent a real challenge, Gerber begins. As a clinician thinks about the eligibility of a patient for different trials, conducting research, and eventually finding the right trial, the clinician can often feel like they have run a marathon, despite this being only the initial steps of a patient, Gerber emphasizes. This makes it important to find ways to make this process smoother as possible and trials more accessible for patients, Gerber emphasizes.

Moreover, it must be understood what the barriers and the facilitators to clinical trial participation are by examining individual steps, Gerber notes. Overall, clinicians are hoping to learn about access to trials, particularly through the question of availability, which is one of the most important and least studied facets of the process, Gerber says.

Additionally, given the proximity of existing relationships between safety-net hospitals and National Cancer Institute–designated cancer centers, plus the existence of companies willing to cover the cost of care for clinical trials, these initiatives to improve the enrollment process and transfer care to community centers will be beneficial, Nwachukwu notes. Transferring care for complex trials to a smaller population could be feasible, effective, and efficient with this support. The initiative will aim to examine the timeliness and cost effectiveness for enrolling patients on clinical trials at smaller centers, Nwachukwu adds. Overall, these initiatives could help make it easier for more patients to gain access to early-phase clinical trials, Nwachukwu concludes.

Editor’s note: Dr Gerber reports serving as an advisory board member for Janssen Pharmaceuticals.

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David Gerber, MD, and Chika Nwachukwu, MD, PhD, discuss their role within the Stand Up To Cancer® 4-team initiative, focusing on diversity in early-phase clinical trials.

Drs Gerber and Nwachukwu on the Importance of Streamlining Clinical Research in Cancer Care

 Dr Vernino, do you have any thoughts on any pearls, take-home messages, closing comments, or future directions that our listeners should be aware of?

There are several things that I wanted to mention in terms of the initial evaluation. One is the recognition that patients come in complaining of weakness, describing difficulty getting up and down, fatigue, and yet their neurologic examination of strength appears normal or quite normal. It’s remarkable for someone who clearly has a lot of difficulty in their ability to do things to get upstairs, etc, but if you test those proximal muscles directly, they are normal. There’s a lot of debate about why that is, but that should not turn you away from the diagnosis. If someone comes in complaining about weakness and you test them and they appear strong, you might think it is just fatigue. This is one of those examples and perhaps it’s facilitation because the way we test patients in the office is that we have them make a maximal effort, which may induce facilitation of strength. This is more for neurologists to be very careful about your reflex examination because the absence of reflex is a strong clue about the diagnosis.

The other pearl, which you’ve talked about a few times, is to establish a relationship with your local oncologist. Oncologists often need our help as neurologists, and we certainly need guidance from them as we manage cases like this and other paraneoplastic disorders.

 LEMS [Lambert-Eaton myasthenic syndrome] itself is a particularly rare condition, but it speaks to the principles of autoimmune paraneoplastic conditions and other neurologic issues that can arise in patients with cancer. Many things that we’ve discussed can be applied to those scenarios as well.

That brings us to the end of our session. Dr Vernino, thank you for your time and expertise, and to those of you who’ve tuned in, I hope this has been helpful.

Experts provide clinical pearls on treating Lambert-Eaton myasthenic syndrome and small cell lung cancer and share upcoming advances and trials they look forward to.

Clinical Pearls and the Future of LEMS

 Let’s continue to the second case because it raises an important point—perhaps the most important point of this entire session. In our second case, a 57-year-old man presents to his primary care physician [PCP]; he is experiencing weakness in his legs and arms over the last 2 months, he’s able to walk, but he finds it difficult to stand up at his desk. He smoked 40 pack-years, and he has some well-controlled hypertension. The PCP refers him to a neurologist.

The neurologist does as you described, repetitive nerve stimulation tests, and finds abnormal detrimental responses with low-rates stimulation and incremental responses with high-rate stimulation, suggestive of LEMS [Lambert-Eaton myasthenic syndrome]. The patient begins treatment and experiences improvement in the symptoms. Six months later, the patient presents to his PCP with chest pain… and a cough. He’s referred to oncology, and the work-up reveals small cell lung carcinoma.

When I read this case, it made me cringe. Does this bother you as much as it does me?

It does because they forgot an important part of this work-up.

 If you were that neurologist, I’m sure you would perform similar neurologic diagnostic analyses and start similar treatments, but what else might you have done at that point?

When we consider the diagnosis of Lambert-Eaton myasthenic syndrome, we recognize that some of them will be autoimmune, not cancer related, and others will be paraneoplastic and often related to small cell lung cancer. This is a case where after making the diagnosis of Lambert-Eaton myasthenic syndrome, we should recognize that this is an older man with a smoking history and the chances of him having paraneoplastic are extremely high. Just because he doesn’t currently have chest symptoms, I would look at that as an opportunity to make an early cancer diagnosis. The error here was waiting around until the cancer presented itself. 

My approach to this would be chest imaging to start with, and in a case like this, I am highly suspicious for a paraneoplastic form, even if a chest x-ray and routine CT are not revealing that. I might proceed with a PET [positron emission tomography] imaging scan because we know that it’s more likely to pick up localized or low-volume small cell lung cancer earlier than routine CT imaging.

 We’ve shared a couple of these cases—whether you’re calling me and ordering the initial imaging study or vice versa, one of us gets it done. I often go straight to a PET scan, and people listening may ask how I get a PET CT scan on a patient who doesn’t have symptoms, but it’s because the likelihood of diagnosing small cell lung cancer is so high.

When small cell lung cancer is early stage, it may be embedded in the soft tissues of the media Steiner, not out in the [INAUDIBLE] of the lungs, surrounded by air, and the PET CT helps you pick it out. This is 1 of the 2 reasons why patients with small cell lung cancer who also have an aplastic neurologic condition like LEMS do better than patients who don’t have the paraneoplastic condition. We can diagnose it at an exceptionally early stage. You may say limited stages are limited stage, but if it’s a single area of tumor, we could be more aggressive with our radiation. There’s a decreased risk for toxicity, and we can aim for a cure. The other aspect of their better outcomes is probably the cross-reactivity. If their body has reacted to the cancer and it’s cross-reacting with the nervous system, some of that heightened immune status is also attacking the cancer as well. When it comes to paraneoplastic syndromes with cancers, the humoral ones that I discussed, those are the chemical high-calcium, low-sodium, Cushing syndrome, they’re almost always diagnosed after the cancer is recognized.

Paraneoplastic neurologic syndromes almost always come to clinical attention before the cancer, which is why if someone’s diagnosed with LEMS, we’re immediately looking for small cell lung cancer. If someone’s found to have myasthenia gravis, we’re immediately looking for a thymic tumor, for example.

On the neurologic side, there’s been a consensus expert opinion on this topic in Lambert-Eaton myasthenic syndrome. It’s recommended to start with at least CT chest imaging and repeat that every 3 months for at least 2 years before you can say that you didn’t find a cancer. In high-risk cases, those with antibodies and those with cancer risk factors, should proceed immediately to a PET scan in the current state.

This is a time that we should mention the importance of having a relationship between neurology and oncology. If you don’t have that as a neurologist, there can be frustration when you contact your local oncologist and ask, “Can you screen this patient for small cell lung cancer?” because, unfortunately, some oncology practices say they don’t see patients who don’t have cancer and will turn them away. It’s crucial to have an oncologist that knows that this is a special situation, where the likelihood of cancer is high and that it’s important to evaluate this patient. Ultimately, we may not find a cancer, but that is not wasted effort.

An oncologist reviews the case of a 57-year-old man diagnosed with small cell lung cancer after Lambert-Eaton myasthenic syndrome.

Case Review: Small Cell Lung Cancer Following LEMS

 It’s important to discuss that most cases that present symptomatically will require treatment. When I think about small cell lung cancer, they’re the paraneoplastic neurologic syndromes that are autoimmune. There are also paraneoplastic humeral syndromes. SIADH, the syndrome of inappropriate antidiuretic hormone [secretion], presents with low sodium or paraneoplastic cushions, and patients have high ACTH [adrenocorticotropic hormone] and cortisol. It’s important to remember with paraneoplastic humeral syndrome that when I treat the cancer, [the] paraneoplastic syndrome improves within days because when the cancer begins to shrink and die, the source of the syndrome goes away (the produced protein or chemical that was causing it).

The sodium can rise spontaneously on its own within days to normal levels, but with these paraneoplastic neurologic conditions, whether it’s LEMS [Lambert-Eaton myasthenic syndrome] or another one—maybe because there’s already damage to that component of the nervous system or maybe because the antibodies are preformed—we must go in hoping that there will be improvement and potentially resolution. We expect that we’re going to need to manage this besides just giving the cancer treatment.

My approach has been, even after we get clinical oncologic remission, we anticipate we will need a few more years of immunotherapy before we’re satisfied that the autoimmune condition has settled down and abated. That leads us into monitoring, and I’ll start with the neurological aspect of that.

It’s important that we monitor patients symptomatically. There are people who monitor the antibody levels, but there’s evidence that the clinical symptoms severity of weakness don’t correlate with the levels of the voltage-gated calcium-channel antibodies. It’s a great diagnostic test but not one that is useful for monitoring.

The physical exam and discussion with patients about their physical capabilities are the best way to monitor LEMS neurologically. In some cases, we may take them back to the EMG [electromyographic] laboratory, but that’s usually if we are not sure if their persistent fatigue, for example, is residual Lambert-Eaton syndrome or and adverse effect of chemotherapy and other issues. We’re monitoring them neurologically based on their symptom approach. If we’re using an immunotherapy agent, we will monitor blood counts and alike to ensure that we’re doing that safely.

 In cases that we’ve shared where you’re giving long-term therapy, and I may give episodic treatments of my own, it seems relatively feasible. Sometimes we worry about overlapping nephrotoxicity, hepatotoxicity, or myelosuppression, but usually we’re able to do it effectively. After I finish my early treatment, I will follow them clinically and with scans every few months. I might get a scan earlier than every 3 to 6 months wherever I am in the monitoring period due to new symptoms or if you inform me that the neurological condition has worsened because we know that can be a harbinger of cancer recurrence or progression.

Drs. Steven Vernino and David Gerber continue their conversation on their preferred treatment approaches and monitoring strategies for Lambert-Eaton myasthenic syndrome and small cell lung cancer.

Monitoring Patients with SCLC and LEMS

 David has explained the approach we would take for treating small cell lung cancer in the most appropriate way. In terms of the Lambert-Eaton myasthenic syndrome, we have a number of options that we can consider. This is a condition where the communication between the nerve and muscle at the neuromuscular junction is impaired. What can we do to strengthen that connection? That’s why we have many symptomatic medications for that purpose. Probably the oldest of those are the acetylcholinesterase inhibitors. Today we use pyridostigmine, but there are other varieties of that. That’s a medicine that increases the availability of acetylcholine, and once it’s released, allows it to stay in the neuromuscular junction a bit longer. That’s typically used for the postsynaptic neuromuscular junction disorders like myasthenia gravis.

Then we have a treatment that can help to increase the presynaptic function, the amount of acetylcholine that’s released with each action potential, by inhibiting the potassium channels at the presynaptic terminal, which prolongs the action potential and helps the calcium channels that are still there stay open longer. We get more calcium influx and more acetylcholine release. Those potassium channel inhibitors, the aminopyridines, the one that’s typically used in the cases of neuromuscular junction disorders is amifampridine, or 3,4-diaminopyridine. We don’t want these potassium channel inhibitors getting into the central nervous system because overstimulation of nerves there can lead to seizures. The monopyridines, like 4-aminopyridine, cross the blood-brain barrier, but diaminopyridine does not. Amifampridine is thought to largely remain in the peripheral nerve system, where it can strengthen this neuromuscular junction transmission. Sometimes we’ll use both amifampridine and pyridostigmine together to strengthen both the presynaptic and the postsynaptic side of the neuromuscular junction, and for many patients that is enough to give them the strength to function well.

Beyond that, we think about what we can do to treat this autoimmune condition and get rid of these antibodies that are causing problems with the voltage-gated calcium channel. When someone’s in cancer therapy, many of the chemotherapy drugs are providing some degree of immunosuppression, checkpoint inhibitors notwithstanding. We generally don’t add additional immunotherapy, with the exception of patients who are having a hard time acutely, perhaps they need a surgical procedure where we worry about clinical worsening because of the anesthesia.

We can use short-term therapies like plasma exchange, plasmapheresis, or intravenous immunoglobulin [IVIG]; these are treatments that will help remove or neutralize these pathogenic antibodies in the short term. Plasmapheresis is a treatment where we take the blood out, we do a bit of a dialysis procedure to remove the plasma and the antibodies in the plasma, and that can help in the very short term, after just a few treatments. But unfortunately, the antibodies will return over the course of several weeks, and the symptoms generally return. Similarly with IVIG, which is an infusion of normal antibodies, it works in a variety of different ways, but essentially to reduce the levels of pathogenic antibodies in the circulation. Those are good short-term treatments to get someone out of a difficult situation, to help them through a procedure, or to offset some worsening due to adverse effects of their cancer treatment. Those are very valuable sorts of treatments.

For patients who do not have cancer, we usually initiate some sort of immunotherapy longer term that could include an immunosuppressant agent like azathioprine, mycophenolate, or cyclosporine, or a newer agent like rituximab. Because Lambert-Eaton syndrome is rare, almost none of these have been studied in double-blind placebo-controlled trials and proven to be effective. The exception is amifampridine, where there have been trials that show the drug—amifampridine, again, is the presynaptic inhibitor of calcium channel function—improves symptoms in Lambert-Eaton syndrome and has been FDA approved for that purpose. We use that in combination with other off-label treatments to help our patients. And again, it’s individualized based on the situation.

Key opinion leaders detail the treatment options available for Lambert-Eaton myasthenic syndrome.

Treatment Options for LEMS

 Steve, I’m interested in your thoughts. When I have patients who have paraneoplastic peripheral neuropathy, because I know cisplatin can cause peripheral neuropathy, I’m likely to change out the cisplatin and substitute carboplatin. I don’t know if I automatically would do that with LEMS [Lambert-Eaton myasthenic syndrome], where I’m not sure if it’s the peripheral nerve so much as the neuromuscular junction. And what about whole-brain radiation or prophylactic cranial irradiation? When I have a patient with paraneoplastic limbic encephalitis, where the pathology of that syndrome is in the brain, I likely won’t do PCI, or prophylactic cranial irradiation, but if it were LEMS, where the pathology is outside of the brain, I might consider it. Steve, am I crazy to think about it that way?

 No, not at all. These are all great questions, but I’m not sure we have definitive answers for them. It requires a case-by-case approach and good communication and discussion between not only the patient and their physicians, but between the oncologist and the neurologist. For Lambert-Eaton myasthenic syndrome, the ultimate treatment goal is to try to remove the stimulus to the immune system, which is the small cell lung cancer, and then manage the symptoms. That’s what we would want to do, we’d want to be aggressive about the lung cancer treatment, and follow the approach that gives the patient the best chance of freedom from the malignancy. In my experience, because I’m looking at this from a different aspect, where everyone I’m seeing has a paraneoplastic neurologic syndrome, I’ve been struck over the years by the number of patients with small cell lung cancer who do have a long-term remission of their tumor and sometimes no recurrences, which is almost unheard of in small cell lung cancer, except in the scenario of a paraneoplastic immunological syndrome.

The thoughts about treating the LEMS, the neurologic aspect of this should focus on how much disability this person is having based on their weakness. This is a classic case with the symptoms we described, difficulty getting up the stairs, out of a chair, fatigability, and so on. Those are symptoms that are probably giving him a lot of trouble, and we’d want to be aggressive in terms of the symptomatic management while he’s undergoing cancer treatment. What I would do as a neurologist while seeing this patient, I would think about the other possible paraneoplastic syndromes we see in patients with small cell lung cancer and do a good thorough neurologic examination to establish what the baseline is. Yes, we can find things that help us to make the diagnosis of LEMS, but we should check cognition, cerebellar function, and do a careful sensory examination to see if there are signs of a peripheral neuropathy even before chemotherapy has started. That is helpful for the oncologist to know, that there’s already a significant neuropathy. Some patients with small cell lung cancer can get a paraneoplastic sensory neuropathy, which can be disabling, and we wouldn’t want to make that worse.

On the other hand, to treat the Lambert-Eaton myasthenic syndrome, I want to use the strongest cancer therapy that will treat the cancer and provide immunosuppression to reduce the activity of the immune system. That’s where we get into a bit of a conflict, like do we want to use checkpoint inhibitors, which can be valuable and revolutionary in improving the outcome of the malignancy, but are basically unleashing an immune system that already has a tendency of attacking normal tissues in the nervous system? I would encourage my colleagues in oncology to avoid a checkpoint inhibitor in this patient until we really need it and we’re pretty sure that we have the neurological syndrome under good management.

 As an oncologist, when I decide whether to give immunotherapy, a checkpoint inhibitor, I’m considering the potential benefit and risk. Unfortunately, the additional benefit of immunotherapy in small cell lung cancer is relatively limited. It’s not what we see in non–small cell lung cancer, and definitely not what we see in melanoma, where it has turned a devastating disease into something that can be cured in a substantial proportion of metastatic cases. I’m not necessarily putting the patient at a great disadvantage by not starting with upfront immunotherapy, if that’s otherwise indicated. I also ask myself, what is the risk? This comes up with autoimmune disease frequently. If I have a patient with psoriasis, and I trigger or worsen their autoimmune disease, their skin will get worse. We can handle that clinically. If they have a difficult to control myasthenia gravis, and I give them checkpoint inhibitor therapy, they may go into phrenic nerve paralysis, diaphragmatic failure, and hypoxic death. I worry more about LEMS as an autoimmune condition in the nervous system than I do about others, such as rheumatoid arthritis or those skin conditions that I mentioned.

 I think that’s right. You weigh the risks and benefits.

Steven Vernino, MD, describes the first-line treatment options for small cell lung cancer with Lambert-Eaton myasthenic syndrome.

Front-line Treatment Options for SCLC

 That’s a great overview of the condition. We have several cases to discuss. The first one is of a 64-year-old man who’s admitted to the hospital with a 3-month history of shortness of breath, fatigue, and difficulty standing up from a chair. He said his legs felt weak, and he’d been having trouble climbing the stairs in his house for the past month, especially in the evening. His medical history is significant for about 40 pack-years of smoking since the age of 25, chest imaging is performed and the CT scan shows a subcarinal mass. A bronchoscopic biopsy is performed and demonstrates small cell carcinoma. He’s referred to medical oncology and neurology, and the neurologist orders the antibody study, the voltage-gated calcium channel, which is positive, suggesting Lambert-Eaton myasthenic syndrome, or LEMS.

Let me start by thinking about this as a small cell lung cancer case, which is a minority of lung cancer cases. It’s about 15% of lung cancer cases; 40 years ago it was 30% of cases. Why is the incidence falling? It’s the type most closely linked to heavy tobacco use, especially unfiltered cigarettes. We learn in medical school that small cell lung cancer is the most aggressive type of lung cancer, but it is also the most responsive to chemotherapy and radiation. When someone’s in the ICU [intensive care unit] with small cell lung cancer, on a ventilator, the answer is never hospice. We will give that patient chemotherapy, and it’s likely that they could come off the ventilator within 48 hours. The issue is that, almost universally, it will recur in the future. At that point, it’s extremely difficult to treat.

Considering this case, so far there’s a mass in the chest that’s small cell lung cancer. I’ll want to do a brain MRI [magnetic response imaging] and a PET [positron emission tomography]/CT scan. If this is limited to the chest, what we call localized disease or limited-stage small cell lung cancer, we will treat it with concurrent chest radiation, thoracic radiation, for about 6 weeks, and 4 cycles of platinum-based chemotherapy, typically cisplatin and etoposide. If you think people are doing well, following the completion of that treatment, we may offer them prophylactic cranial irradiation, that’s whole-brain radiation, after the chemotherapy is done, to decrease the likelihood of future brain metastases. Doing that is also associated with improved overall survival.

What if it’s not limited stage? What if when we do additional staging, we see cancer outside of the chest area, like two-thirds of the extensive-stage cases that are diagnosed in small cell lung cancer? We will leave out the chest radiation, and we’ll give a platinum and etoposide chemotherapy. But today if the patient is considered eligible, we would also add an immune checkpoint inhibitor, immunotherapy, which is given at the same schedule every 3 weeks as the chemotherapy, but is continued as maintenance therapy after the chemotherapy is finished. How would I factor in the different options for patients who might have a paraneoplastic neurologic syndrome? With Lambert-Eaton myasthenic syndrome, I have to ask myself, would cisplatin possibly make it worse, and would giving whole-brain radiation possibly make it worse?

Drs. David Gerber and Steven Vernino review the case of a 64-year-old man with Lambert-Eaton myasthenic syndrome.

LEMS Case Review

 Steve, this brings up many questions because there have been cases in my practice where I have been the one to clinically recognize neuromuscular junction pathology, either myasthenia or LEMS [Lambert-Eaton myasthenic syndrome]. The patients never come in and say, “I have fatigable, proximal lower-extremity weakness.” They say, “I’m tired.” When you’re a medical oncologist, people can be tired because they have frequent appointments, they’re anemic from chemotherapy, or they are hypoxic from the small cell lung cancer in their chest. The most recent patient I diagnosed told me that she had been telling her outside oncologist for 6 months that she was tired, and nothing was being done, and I asked her to get up from the examination chair and go over to the table. She had to push with her hands for 5 seconds to get out of the chair. I said, “That’s not fatigue; that’s something different,” and we went from there. It makes me wonder, in the era of telemedicine, which we’ve done a lot more of in the last 2 years, how do we make sure we’re not missing those things? It’s hard to sense what is going on in the body. The other questions I had were in general when it comes to diagnosis. In many institutions, there’s not only a single antibody test, but you can order a paraneoplastic panel with 20 or more different antibodies looking for LEMS, myasthenia, or other cerebellar dysfunction types of conditions. What are your thoughts on the comprehensive panel versus a single test?

 You’re right about telemedicine. As neuromuscular doctors interested in muscles, it’s terrible because you can’t see the muscles and you can’t test them directly. It’s particularly difficult with Lambert-Eaton syndrome because unlike myasthenia, these patients don’t have much facial weakness or changes in their speech. Many of our patients with myasthenia have a droopy eyelid, or they have a very nasal speech, which tips you off. If the weakness is predominantly in the hip girdle muscles, and they’re usually sitting at their computer, you don’t see that. I like your approach with the patient in front of you who’s complaining of a nonspecific weakness, fatigue, or tiredness, and having them stand up and walk across the room. I also like to ask for specifics on telemedicine. “What things can or can’t you do that you used to be able to?” It’s interesting to ask about getting out of a chair and going up the stairs because those are activities that require some good proximal lower-extremity strength. When someone says they can’t get out of a chair or go up the stairs, that’s a clue that there’s some real weakness as opposed to just feeling tired. Tired people will say, “if I have to, I can get up the stairs, but I don’t want to do it constantly.” People who really have weakness can’t. Those are good and important things.

With respect to antibody testing, it’s a critical piece to think about. We have access to a whole battery of tests. Small cell lung cancer has been associated with more than one paraneoplastic disorder, ranging from ataxia, encephalitis, neuropathies, as well as Lambert-Eaton myasthenic syndrome. It’s difficult to know whether there are more than one of those going on at the same time. Our general approach, if you’re coming from the cancer side, or we have a constellation of symptoms that’s hard to put your finger on, is a panel of antibody testing because you have the highest yield. Any individual antibody in that panel is probably rare. We talk about things like anti-Hu and anti-Yo antibodies as being pathognomonic for particular disorders, but they are rarely encountered. You’re more likely to pick something up if you look at a broad panel. Conversely, if we’re in the room on the neuromuscular side of things, and you’ve done the EMG [electromyography] and we know there’s a neuromuscular junction disorder, we might limit our testing to antibodies for myasthenia or Lambert-Eaton myasthenic syndrome rather than other antibodies that are more relevant for brain- or spinal cord-related paraneoplastic syndromes.

It’s great to have that kind of sensitive testing available, where we can do a whole panel and be sure not to miss anything, but it does raise some concerns about specificity. Patients with small cell lung cancer may have low levels of various antibodies, even without a symptomatic or definable neurological condition occurring. That is not surprising, it reflects that the immune system is responding to these cancers appropriately and doing its job to generate antibodies and cell-mediated response against the tumor cells, which is good. It’s helping to fight off cancer. We must ensure we’re using our clinical judgment as well. When we talk about misdiagnosis of Lambert-Eaton syndrome, there’s a lack of recognition of the disease and underdiagnosing. But there’s also the risk that if you send the big antibody panel for everybody who’s a little fatigued or tired, you’ll occasionally turn up some antibodies. We’ll see many cases where someone has a low level of voltage-gated calcium channel antibodies, and someone has labeled them with Lambert-Eaton myasthenic syndrome when they had none of the symptoms or physical findings to go along with that.

These tests are useful tools, but the antibody is not 100% diagnostic of the condition. It’s very sensitive, if you have Lambert-Eaton you’re likely to have the antibodies, but in our practice, many people who have the antibodies don’t have Lambert-Eaton syndrome. We must put these things into context: our clinical judgment, the antibody testing, and the ancillary testing, whether it be electrodiagnostic testing or imaging.

 It’s almost analogous to the rheumatologist whose clinic panel is filled with asymptomatic people with positive ANA [antinuclear antibody], and not knowing where to go next.

Two experts debate the preferred testing options for Lambert-Eaton myasthenic syndrome presenting with small cell lung cancer.

LEMS Diagnosis: Patient Presentation and Testing

 Steve, it might be helpful at this point to go over how we diagnose and test for LEMS [Lambert-Eaton myasthenic syndrome].

 As neurologists, when we see conditions that make us think about paraneoplastic neurological syndromes, a number of cancers come to mind, but small cell lung cancer is at the top of that list for all the reasons you mentioned. We know that, relevant to LEMS, many small cell lung cancer lines have been studied that express neuronal channels, including a voltage-gated calcium channel, which is important for the survival of those cells. When the immune system wants to identify and kill cancer cells, it sees these antigens in that context, and that starts an appropriate immune response in some cases. Patients who have paraneoplastic syndromes like Lambert-Eaton myasthenic syndrome may have a better outcome with respect to their cancer for a variety of reasons. This is an autoimmune condition, and that means that it’s caused by the immune system. In this case we can associate Lambert-Eaton myasthenic syndrome with the production of an antibody against a particular voltage-gated calcium channel, one that’s present in small cell lung cancer cells in many cases, and in the same calcium channel that’s present at the neuromuscular junction, in particular on the presynaptic side, so the side of the synapse of the neuromuscular junction where the acetylcholine will be released. These calcium channels are responsible for letting calcium into the presynaptic junction, and that calcium leads to the release of the acetylcholine molecules, which ultimately binds to the muscle and causes it to contract. You can imagine that if you have something that’s binding to the voltage-gated calcium channels at that spot, preventing them from working well, there’s less calcium that comes into the presynaptic junction, fewer of the acetylcholine neurotransmitters that get released, and as a result, the muscle will not react in the typical way. That produces weakness because of this impaired communication.

That leads to our techniques in diagnosing and testing for Lambert-Eaton myasthenic syndrome because we’re looking for that characteristic impairment in the communication between the motor nerve and the muscle. We can do that many ways, but for the most part it starts with our neurological examination. We try to identify weakness of certain muscles in these patients and particularly the proximal muscles where they’re complaining of weakness. These patients may have a peculiar phenomenon called facilitation, where the muscle may be initially weak, but with repetitive testing and exertions, the muscle may get stronger. This is a subtle finding that could be difficult for people who aren’t trained as neuromuscular physicians to pick up on. Patients will describe this phenomenon, that they have a lot of trouble getting up and going, but once they’ve walked a little, they feel better. The other area where we can see facilitation is in testing for reflexes. When you test reflexes, like tapping the patellar tendon, many patients with Lambert-Eaton syndrome have no response; they have reduced or no reflexes. If you exert the muscle, having them do quadriceps contractions, and then immediately test, the reflex may return for a few seconds but then go away again. That’s almost pathognomonic of Lambert-Eaton myasthenic syndrome. But it takes experience and a good reflex hammer; we don’t expect oncologists to pick up that sort of thing.

There’s the initial suspicion based on the patient’s history or neurological examination of the muscles, and then we have several tools that we can use. One is electrodiagnostic testing, where we can take the patient to the EMG [electromyography] laboratory. Two major tests we do are nerve conduction studies and the needle electromyography test. In the nerve conduction test, we place electrodes on the skin, over the muscle, and send a shock to the muscle nerve, recording the amount of contraction, this is called the compound muscle action potential [CMAP]. In Lambert-Eaton myasthenic syndrome, CMAPs are usually small, maybe 10% of normal, in all muscles, not just in the ones that are clinically weak. If we give a test called repetitive stimulation, where we give repeated stimulations of that nerve 2 to 3 times a second, we’ll see that that muscle response become even smaller. We see a decremental response on the repetitive stimulation, which is like what we see in the other neuromuscular junction disorder, myasthenia gravis, or in a condition like botulism that causes a poisoning of the neuromuscular junction. You see this decremental response, and that’s diagnostic of a problem in the neuromuscular junction, not Lambert-Eaton particularly. In Lambert-Eaton syndrome, you can look for this facilitation by having the patient do contractions of the muscle, or by giving a high-frequency stimulation to get some of that calcium mobilized in the neuromuscular junction. You’ll see the size of that muscle action potential get larger and then gradually get smaller again. The decrement on repetitive nerve stimulation and a facilitation after exercise is convincing for Lambert-Eaton myasthenic syndrome, or perhaps some other rare conditions, but it’s suspicious.

For the other part of electrodiagnostic testing, the needle EMG, we stick a needle into the muscle of interest and look at the little muscle action potentials as they occur. What we see in these neuromuscular junction disorders, and especially in Lambert-Eaton myasthenic syndrome, is variability or what’s called jitter of the muscle action potentials. In other words, they’re not stable. They don’t fire at the same every time, they vary between getting bigger and smaller because there’s instability in that communication between the nerves and muscles. Those 2 tests can be diagnostic of Lambert-Eaton myasthenic syndrome. We also have a serological test. We’ve discussed the autoimmune nature of LEMS, and the association with antibodies against the voltage-gated calcium channel, in particular the P/Q-type channel. Antibodies against the P/Q-type voltage-gated calcium channel are commonly found in Lambert-Eaton myasthenic syndrome, regardless of whether it’s autoimmune- or cancer-related. That test, in some cases is considered to be 90% to 95% sensitive. If we suspect Lambert-Eaton syndrome and the antibody test is negative, we often scratch our head and wonder if that’s not the right diagnosis. The antibody test is available at commercial labs, at various places, so that’s often the first test people will do because sometimes the advanced electrodiagnostic testing is not readily available. Those are the 2 tools we use, but you have to suspect the diagnosis to think about order those tests. They are good at confirming the diagnosis of Lambert-Eaton syndrome. We’ll return later to discuss the pros and cons, or pitfalls, about the antibody testing.

A neurologist explains how to test for and diagnose Lambert-Eaton myasthenic syndrome.

Testing for LEMS

 program on “Lambert-Eaton Myasthenic Syndrome and Associated Cancers.” I’m David Gerber, professor of internal medicine within the hematology/oncology division and associate director of clinical research in the Simmons Comprehensive Cancer Center at [University of Texas] Southwestern Medical Center in Dallas, Texas. I’m happy to discuss this topic and case scenarios with my colleague, Dr Steven Vernino, distinguished teaching professor and executive vice chair for academic affairs in the Department of Neurology at UT Southwestern Medical Center. Before we review the cases, I want to go over information on the disease and testing. Could you start by defining Lambert-Eaton myasthenic syndrome, or LEMS?

 Lambert-Eaton myasthenic syndrome is a type of neuromuscular disorder that affects the communication between nerves and muscles. This was first described in the 1950s by various people, but most notably by [Edward] Lambert and [Lee] Eaton, who were neurologists at the Mayo Clinic. Lambert-Eaton myasthenic syndrome characteristically presents as fatigable weakness; patients often come in complaining of weakness in their lower limbs, around their hips, and they have trouble walking, getting up from a chair, or climbing the stairs due to weakness in their proximal legs. They often complain of generalized fatigue, which is a nonspecific symptom, but particularly when they try to do things. These complaints are like many other neuromuscular diseases that we see in neurology. Patients with Lambert-Eaton myasthenic syndrome also complain of other vague symptoms, including things like dry mouth, constipation, and others. It can be a difficult diagnosis, but it’s an important one to think about and to diagnose.

There are different types of Lambert-Eaton myasthenic syndrome. We’re going to discuss Lambert-Eaton that’s associated with cancers, or the paraneoplastic form of LEMS, but this can also occur in a nonparaneoplastic or autoimmune scenario. LEMS is a rare disease; it’s considered to be about 10 times less common than myasthenia gravis, which is the more recognizable and appreciated disorder of this neuromuscular junction. It can occur frequently in patients with small cell lung cancer. It’s estimated that up to 2% to 3% of all patients with small cell lung cancer have Lambert-Eaton myasthenic syndrome, which makes it more common among the rare paraneoplastic neurological syndromes. About half of LEMS cases are cancer-related, and the other half are noncancer autoimmune diseases. Having small cell lung cancer is a major risk factor for getting Lambert-Eaton syndrome, and those patients tend to be older men who have a smoking history; those were the patient types who were originally described by Lambert and Eaton. If we see younger patients, meaning middle-aged people and women, we start to think about nonparaneoplastic or autoimmune LEMS, particularly if the patient is a nonsmoker and has no other cancer risk factors. David, can you talk more about the association with cancer and LEMS and paraneoplastic syndromes?

 My perspective is skewed because I am a thoracic medical oncologist; most of my patients have lung cancer, including small cell lung cancer. Any of the patients in my practice who have paraneoplastic LEMS have lung cancer. I know it can also be seen rarely in other cancers, maybe gynecological cancers or lymphomas, but small cell lung cancer will be the dominant cause in terms of a cancer association. It raises the question, what is the link mechanistically or biologically between small cell lung cancer and LEMS? For me, it helps to think of this condition as an autoimmune process. When it comes to paraneoplastic conditions, one category of them is autoimmune, including most of the neurologic ones. Something is happening in these patients when they have a cancer diagnosis that’s making their body attack healthy, normal cells, tissues, and organs, including the nervous system. I break down the reasons for that happening into a couple of different possibilities. The first is that the cancer produces a protein that resembles part of the nervous system, that’s the case for small cell lung cancer; it’s almost cross-reactivity or tricking the immune system. The second, this is far less common, is that a tumor could contain nervous system components. An example of that is a teratoma; these are rare tumors that can grow slowly and quite large and can feature normal types of tissue like hair, teeth, and nervous system tissues. Then there are the types of tumors that involve organs that are usually involved in the regulation of the immune system; that’s the thymus and thymoma, why we see myasthenia gravis.

Lastly, there are the tumors that involve the production of immunoglobulins or antibodies, and that can be myeloma or lymphoma, which is potentially why we see LEMS with lymphoma cases. Why is it that small cell lung cancer tricks the body into thinking that it’s part of the nervous system? Neuroendocrine tumors look like and have antigen similar to the nervous system. When we diagnose small cell lung cancer, besides the pathologists looking under the microscope, they perform special immunohistochemical staining, or IHC. One of the most frequently used stains is CD56, which is the same as NCAM, neural cell adhesion molecule. This is why as small cell lung cancer develops, with those cells looking similar to the body’s immune system as the nervous system components, that you can not only get LEMS, but multiple other autoimmune paraneoplastic conditions affecting other components of the nervous system.

David Gerber, MD, and Steven Vernino, MD, PhD, provide an overview of Lambert-Eaton myasthenic syndrome and its association with cancers.

Defining LEMS

David Gerber, MD, professor of internal medicine, Hematology/Oncology Division, co-director, Experimental Therapeutics Program, UT Southwestern Medical Center, discusses the rationale to combine immunotherapy with radiation therapy in lung cancer. 

According to Gerber, there has always been clinical interest in combining these treatment modalities.

It appears that the efficacy of radiation therapy is dependent on aspects of the immune system, Gerber explains. Moreover, concurrent immunotherapy and radiation therapy can lead to synergistic effects. The radiation may result in the release of more antigens, which will make the cancer more recognizable by the immune system, concludes Gerber.

David Gerber, MD, discusses the rationale to combine immunotherapy with radiation therapy in lung cancer.  



David Gerber, MD

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