Leiomyosarcoma in 2018 – where we are and where we need to go.

Good afternoon readers!

Having recently teamed up with the National Leiomyosarcoma Foundation as an advisory board member, for this posting I thought we’d focus on leiomyosarcoma, including some of the most common questions coming in from patients, caretakers and providers.

What is leiomyosarcoma?

Leiomyosarcoma is probably the fourth most common sarcoma behind gastrointestinal stromal tumor (GIST), pleomorphic sarcomas, and liposarcomas.  These tumors arise from smooth muscle, which is the muscle that forms the walls of organs, not muscles that contract under our own control (which are called skeletal muscles).  Contractions of smooth muscles are what push food along in our digestive tracts, force blood to travel through our veins and arteries, and in the uterus, allow childbirth as well as annoying menstrual cramps.  Leiomyosarcoma can arise in a wide variety of places, usually from a blood vessel wall when occurring in an arm or leg, or inside of our abdominal cavities, from the wall of an organ like stomach, intestine, or bladder, and from the uterus muscles.  It is unknown what causes these tumors to form.  Additionally, when we look at the genetic mistakes or mutations in leiomyosarcomas, there are a wide variety of mistakes that can occur, making treatment of these diseases challenging.

What kinds of treatments are used in leiomyosarcomas?

In my practice, I think of leiomyosarcomas as three main types – soft tissue (often in extremities, such as an arm, leg, head/neck, chest wall, etc), vascular (growing from a blood vessel usually deep in a body cavity, most commonly the abdominal cavity), and uterine. These three main groups really present their own unique challenges for treatment. Like other sarcomas, surgery is the most important component for cure. If the leiomyosarcoma can be removed completely with surgery, that’s the best chance for cure, regardless of where the tumor is located.  However, that’s often much easier said than done, especially for the big ones that are vascular and deep in the abdominal cavity.  A major problem with uterine leiomyosarcomas is that these can be mistaken for fibroids, which are BENIGN growths of uterine smooth muscle that are NOT cancer.  Now before you panic, a very large series reported that the risk of this happening was really only about 1 out of 2000 (Pritts et al, Gynecol Surg 2015).  If the surgery done is a typical hysterectomy, often this doesn’t tremendously impact the surgical outcome – but previously some surgeons were performing something called morcellation, which is the equivalent of an immersion blender that chewed up the fibroid before pulling the material out of the body – a very bad idea if you were the 1 in 2000 people that actually had a cancer that has now been flung around the body.  Fortunately, this has largely fallen out of favor.  In a perfect world, every soft tissue mass would be biopsied before an attempt at surgery would happen… but that’s a challenging obstacle to overcome.

I had a leiomyosarcoma removed by surgery.  Do I need chemotherapy afterwards?

So it depends! There were two giant studies that included up to 18 different clinical trials and about 2000 sarcoma patients all together.  They lumped all of the data together, and tried to determine if using chemotherapy after surgery (called adjuvant chemotherapy) helped prevent sarcomas from coming back, and whether people would live longer if they did so.  The problem is that there were LOTS of different sarcoma types included in these studies, and different chemotherapy regimens including drugs like doxorubicin and ifosfamide. Basically, this was a giant fruit basket.  If everyone was averaged together, overall patients with sarcomas in the extremities did better if they received chemotherapy, whereas patients with abdominal sarcomas did not have any difference in the chance of recurrence after surgery whether or not they received chemotherapy.  In terms of benefit, there generally was some improvement in the risk of being free from cancer at 10 years with chemo, but people didn’t necessarily live longer because of it.  (confusing and weird to think about.)  In general chemotherapy bought about a 10% improvement in the chances of being cancer free at that point.  Not a lot, when you think about the side effects that come from the chemotherapy cocktails.

Newer chemo combos like gemcitabine/docetaxel are commonly used for uterine leiomyosarcoma after surgery.  Although it is widely used, there has still been no randomized clinical trial to prove that patients do better with or without it.  Since patients with chemotherapy did better than historical patients who did not get chemotherapy, many gynecologist oncologists often use this regimen now in the adjuvant setting.

My ongoing gripe about using averages comes down to this – we are not talking about breast cancer here, where 40,000 women can get put into databases and exact risks of cancer return can be calculated with a reasonable degree of certainty.  Most likely, in the much smaller numbers of sarcoma patients there are people that do much better than the average, and people that do worse.  There are people that will get a lot MORE benefit from chemo than the average of 10%, and there are people that will get a lot LESS benefit from chemo.  So how do we figure these things out?  These are my unofficial, non-validated “good risk” and “bad risk” features that I use to counsel patients on whether we should think about chemotherapy for them:

LMS risk factors unofficial

These assume that we are talking about a first diagnosis, and no metastatic disease (spread of cancer) that is already found on scans.  Any of the “really bad” qualities (except high grade by itself) will lead me to recommend chemotherapy, because I think these people are almost guaranteed to have their cancer recur and spread.  Also, remember that we have to take the patient into account!  Someone with lots of medical problems or who is not in great shape may need gentler chemo, or even no chemo.  It’s a discussion to have with your oncologist to look at you as an individual patient, including your individual tumor and surgery result!

Should I have my leiomyosarcoma genetically tested?

This is a common question.  Genetic testing means that we take the old tumor preserved in a pathology lab after surgery (for up to 10 years!) OR a new biopsy and we send it for mapping – to figure out what proteins and genes are broken and driving the tumor growth.  Usually there are companies, like Foundation Medicine or Caris, and some institutions like MD Anderson, Memorial Sloan Kettering, and others are doing their own testing but usually a smaller number of targets.  Why should you have this done?

  1. If the diagnosis is in question – is this really a leiomyosarcoma OR another type of sarcoma? Different sarcomas can have different genes that are broken so these tests can help to clarify which type you have.
  2. If you are looking for potential clinical trial options. Some of the newer clinical trials have drugs that are designed to block specific broken genes or proteins, rather than to treat specific types of cancer.  So if you happened to be in the 0.1% of sarcomas that have a broken NTRK (N-track) fusion gene, there are new NTRK specific drugs that are extremely effective. MOST of the time we do not find these “Achilles’ heel” types of mistakes in leiomyosarcomas.  About 40% of the time there will be NO matchable genetic treatment to a mistake in your tumor. Lots of work still to do.
  3. SO FAR we do not use genetic testing in leiomyosarcoma to pick the best chemotherapy, to predict whether chemotherapy is likely to help you, or if your leiomyosarcoma is likely to recur. More work to do.

Overall, genetic testing can be helpful but I tend to get it for my metastatic (or stage IV) patients where I am thinking about clinical trials, rather than newly diagnosed or adjuvant treatments.

My leiomyosarcoma was in my uterus and my surgeon told me it had estrogen receptors on it – can’t I just go on estrogen blockers instead of chemotherapy?

Estrogen is the female reproductive hormone – which is all over our normal uterus including the inner lining that nourishes during pregnancy and bleeds during menstruation, as well as the uterine muscle which contracts during childbirth and menstrual cramps.  So, some leiomyosarcomas may hang onto the estrogen receptors that are designed to respond to estrogen.  Now, other estrogen positive cancers like breast cancer have been shown to benefit in prevention using drugs that block estrogen activity, called aromatase inhibitors (some names of drugs include Arimidex, Aromasin, Femara), or tamoxifen.  Other options include using progesterone therapies that also can suppress estrogen, like the drug Megace.  The best summary I found of the chances of success with this is from one of my personal heroes, Dr. Martee Hensley at Memorial Sloan Kettering.  Her group looked back at 40 patients with uterine leiomyosarcoma treated with various hormonal options listed above in this paper.  Overall, most patients with leiomyosarcoma have developed other genetic problems that drive their growth, and generally no longer depend much on estrogen. That being said, some of the less aggressive, slow growing, lower grade leiomyosarcomas can have benefit from estrogen blockers.  For metastatic leiomyosarcoma, the chance of shrinkage with estrogen blockers in this group was only 9%, and half of all patients had tumors grow within 3 months after starting. A few patients (case reports) HAVE had long periods of stable disease (months to years).  So my opinion is that for highly aggressive leiomyosarcomas with any of the “worse” or “very bad” features listed above, or metastatic patients that are growing quickly, the chance of response to estrogen blockers is very low and I usually would prefer to move on to chemotherapy or targeted therapies.

We’ve had a few questions about combining hormone blockers and drugs like Ibrance (palbociclib) which are approved and active in breast cancer – but again, unless your leiomyosarcoma has been sequenced and is KNOWN to have a mistake in the protein that palbociclib is designed to act against, I think the chances of benefit are very low when compared to traditional chemo.

I have metastatic leiomyosarcoma and it can’t be removed by surgery. What are my treatment options in 2018?

Fortunately we have more options now than we used to!  Here are some of the ones I discuss with my patients –

#2 chemo regimens for LMS

How do you pick what’s right for you?  First – what is the goal of treatment???  It is the most important thing to make these decisions with the doctors that know you and your case the best!

Some patients might have only a couple sites of disease, or a big mass that has come back and is not able to be removed by surgery now, but COULD be if it shrunk. Those patients should consider strong chemotherapy because rapid shrinkage is more important in their case and might allow complete removal of all sarcoma (always the best option if it exists.)

However, other patients might have a lot of distant sites that cannot be removed.  In these settings, the goal might be disease control, stability, good quality of life, and TIME to allow for newer research to hopefully find better treatments.  In those situations, probably better to pick something stabilizing, but with a more manageable side effect cluster that is easier to live with long term.

What are the new clinical trials and research going on in the leiomyosarcoma world that I should know about?

It’s always good to know about clinical trials and research, because more and more patients are choosing to participate in trials earlier on in their treatments.  But it needs to be a clinical trial that makes sense for you.

What about immunotherapy?  See my prior post for the basics of immunotherapy.  The newest and hottest technology for cancer treatment, new drugs that boost the immune system to fight cancer have created near-cures for patients with aggressive stage IV cancers like melanoma, lung cancer and kidney cancer even after traditional chemotherapy doesn’t work. These are drugs like checkpoint inhibitors (nivolumab, pembrolizumab, ipilimumab, atezolizumab, durvalumab, tremelimumab, and dozens and dozens of ones with numbers and letters instead of names…)  The problem is that cancer is smart – and there isn’t just one way that it shuts down our immune system for most patients. So new clinical trials are combining multiple drugs or therapies to boost the immune system in different ways and trying to increase the chances of success.

Unfortunately, so far leiomyosarcoma has not been a home run with checkpoint inhibitors.  There are a few patients who have responded, but chances probably run about 1 in 40.  However, Seth Pollack at the Fred Hutchinson Cancer Research Center in Seattle and his colleagues recently looked back at leiomyosarcoma tissue samples, and showed that there IS evidence that the immune system can recognize that the sarcoma is a bad thing and actually does try to attack it – but it’s hitting roadblocks.  So my recommendation is that leiomyosarcoma patients should ONLY participate in immune therapy clinical trials with combinations – it makes no sense to try these drugs off label with such low chances of success.  For example…

  • SARC028, the first sarcoma study with pembrolizumab enrolled 10 patients with leiomyosarcoma – no patients responded.
  • Dr. Suzanne George from Dana Farber published a study of 12 women with uterine leiomyosarcomas treated with nivolumab – no patients responded.
  • In Miami, I led a study of combination axitinib (a blood vessel blocking drug like pazopanib) and the checkpoint inhibitor pembrolizumab.  We included 2 patients with soft tissue leiomyosarcoma and 4 patients with uterine leiomyosarcoma.  The soft tissue patients actually did pretty well – one patient had shrinkage of her tumors that lasted for 15 months, and my other patient had shrinkage of her tumors but developed side effects and had to come off the drugs.  I’m in the process of trying to develop a specific trial for soft tissue leiomyosarcoma patients to explore this in more detail.  Unfortunately none of our uterine leiomyosarcoma patients responded.
  • Dr. D’Angelo from Memorial Sloan Kettering and her colleagues recently published the results from the Alliance trial studying nivolumab and ipilimumab or nivolumab alone.  Out of 29 patients with leiomyosarcomas, there were only two significant tumor shrinkages, including 1 uterine leiomyosarcoma and 1 non-uterine.
  • Others have reported results from trabectedin plus nivolumab, tough to tell whether the effect is coming from the immune drug or the trabectedin…


Trial options LMS

Now that I’ve gone on forever, hopefully this has answered some of your most common questions about leiomyosarcoma.  If you have more specific questions, I highly recommend checking out the National LeioMyoSarcoma Foundation Research Website which is loaded with information, and on the front lines of funding for promising new research.  If you have other questions for follow up blogs, feel free to comment.  Please realize that I cannot comment on personal situations, only because as you’ve hopefully seen in this post, one size does not fit all!

Onwards to a cure…

33 thoughts on “Leiomyosarcoma in 2018 – where we are and where we need to go.

  1. As usual, it’s great that you can pack so much information into a blog post that patients can understand! Here’s a link to Dr. Hensley’s editorial on no adjuvant therapy for women with “good” risk factors, for anyone who wants to check it out. https://www.ncbi.nlm.nih.gov/pubmed/29417238 For those who don’t know me, I’d like to give some hope to people with “bad” risk factors. My vaginal LMS — in the same category as uterine LMS — was 12cm with positive margins. (To get clear margins, the surgeon would have had to remove my bladder. My bladder did end up getting removed later.) A gyn oncologist did my surgery but was familiar with sarcoma. Mine was considered very high grade, or “dedifferentiated.” (Mitotic index of 52/10.) The surgeon cut my tumor into a couple of pieces to remove it, but I don’t think cutting or rupture has proved bad in the vagina, as opposed to doing that in the uterus. My LMS did go to my right lung twice. The first time, gemcitabine/taxotere got rid of it. The second time I had lung surgery to remove it. I’m happy to have survived 16 years. Tomorrow I’m headed to New Orleans to the annual meeting of the Society of Gynecologic Oncology. This will be my 10th time. I’ll have a table with information on the Sarcoma Alliance and the Sarcoma Foundation of America, the two nonprofits I volunteer for. I’m also familiar with NLMSF.org and LMSdr.org, the two national LMS nonprofits. I regularly tweet on LMS @SuzieSiegel and I’m a longtime peer volunteer, if anyone wants to contact me. I hope Dr. Wilky doesn’t mind this long comment, but I’ll also add that there is some very exciting genomic profiling going on for LMS. She heard the presentation of research out of Germany at a big sarcoma conference in November. At the New Orleans conference, Dr. Alex Lazar and Dr. Matt Anderson will be presenting on genomic profiling of uterine LMS, including the already published information from The Cancer Genome Atlas. This gives me hope for immunotherapy in the future.


    • Thanks so much for your response! Yes, I agree- you are living proof that even with the scariest risk factors nothing is absolute!! Those are just some things that make me more likely to recommend chemo to try to kill any left behind cancers.


  2. Dr. Wilky,
    You reference: ” Dr. Suzanne George from Dana Farber published a study of 12 women with uterine leiomyosarcomas treated with nivolumab – no patients responded.”

    What are your thoughts then on the current Phase II Trial that Dana Farber (Suzanne George is the principal investigator) NCT02428192 (Sponsored by NCI) “Nivolumab Alone or in Combination With Ipilimumab in Treating Patients With Advanced Uterine Leiomyosarcoma”


    • So there were some patients that responded to the combination with uterine leiomyosarcoma so that parts makes sense to me- I don’t know exactly about the design of the study, but for me it would be hard to put a patient on that trial unless they could cross over (meaning have the chance to get the combination) if the computer put them on the nivolumab only arm first.


  3. Dr. Wilky,
    Re: Your table listing the current clinical trials to keep an eye on:
    The listing for “Ribociclib plus Everolimus for LMS-target treatments-get sequencing first!”
    What does “get sequencing first” mean- for specific mutations or biomarkers?-what are they looking for?


    • So, before I would recommend this study for a patient, it would be helpful to look at their genetic sequencing first to see if they have mistakes in the key genes that are involved in the pathways that these drugs regulate. Only because the side effects of these drugs can be very strong and I would feel better if there was some biological reason to put someone on it. Just my opinion though!


  4. How does the axtinib combination look so far? What are your thoughts on votrient and keytruda? I’m anxious to add immunotherapy to votrient but am waiting to get the votrient to hopefully stabilize the cells coming up to my brain from somewhere. I actually think hitting the whole body with an HIV medicine first for a few weeks, then stopping the day before treatment with yondellis so there’s no conflict in medicine and following up with an imunotherapy is the best bet after hearing your explanation on YouTube about cocktails. Since not all tumors react at the same rate like HIV, it’s important to get them on the same page then attack them.


  5. Hi, firstly wanted to say that this is the most comprehensive article about Leiomyosarcoma that I have read after tons of research, congrats on that! Regarding the clinical trials, nr. 2 trabectadin + doxorubicin is extremely toxic, my mother had 3 rounds of it and died due tumor lysis syndrome caused by it. She was in great health state before starting chemo, even though stage 4 uterine leiomyosarcoma. Was wondering, are there any other findings so far regarding this clinical trial? Based on what criteria you chose a specific chemo regimen for different patient with the same diagnosis?


    • Thank you! I am sorry to hear about your mother. Yes I also learned quickly that trabectedin can be a very tricky drug. Some people do so well with it with almost no side effects, and other people, even young and healthy, can get incredibly sick. This trial hasn’t started yet but we purposely decreased the doses to start because of concerns for the side effects.


  6. Great article, thank you. My wife has retroperitoneal leiomayosarcoma, and it became clear to us that the subtypes need to be further understood given we received 4 different chemo regimen recommendations by 4 different oncologist, 3 of which have significant experience with sarcomas. The rarity of each doesn’t help with getting significance on trials either. Thanks again.


  7. Thank you so much for this article. We as patients SO appreciate every minute of research that goes into treating this disease! I am wondering about your thoughts on the Phase 2 trial of Doxyrubicin + Keytruda, being conducted by Dr. Pollack in Seattle. I went to meet with Dr. Pollack and it sounds like the responses from Phase 1 have been quite good. I’m specifically wondering about the pros and cons of this trial vs. just doing the Doxy with Olaratumab?


  8. Dr Wilky, thanks so much for this article! It is sooooo important especially to those left alone, in countries (like Poland) where there is no one to turn to 😦 Or maybe you know about a place where they would have some expertise on LMS? In our global world it is stull not easy to get access to up-to-date know-how.


    • Hi Mirania! I just came across your post and might have an answer for you. My name is Kathrin and I am from the network of sarcoma patient organisations called Sarcoma Patients EuroNet (SPAEN). If you are looking for someone to turn to in Poland, get in touch with the Polish Sarcoma patient organisation. They are very active and well connected in Poland. The web address is http://www.sarcoma.pl/. Other groups can be found here: http://www.sarcoma-patients.eu/en/our-members-2/group-profiles.
      Please don’t hesitate to contact us or the groups directly.
      Breelyn, I hope you don’t mind my answering to Mirania!
      Warm regards, Kathrin


  9. After a surgery 2007 July, I had a 2th one not operable June 2013, located on the door vein of the liver with 2 metastasis in the liver, 4 months receiving epirubicin, it growed. 4 months Gemzar taxoter, 2 weeks in palliative care. Out of hospital I started yondelis. September 2016 the inoperable tumour on the vein cave an door vein of liver disapered with 1 metastasis in the liver, the other one removed November 2016 by radio frequency, an other one appeared near the same spot and removed by radio frequency November this year. Leiomyosarcoma high grade. I,m now 70 year old, back from a trip in the south. My physicians said a,m a champion. I live in Canada


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  11. Best source of information on this specific condition, and I really have gone through a lot out there. I´d like to congratulate Dr. Breelyn Wilky for employing her time and thoughts on this very elucidative great piece of article. Thank you! Really glad I’ve got an appointment coming soon.


  12. I had read that propranolol is effective for angiosarcoma. I would think that beta receptors may be present in smooth muscle as well. Has anyone looked to see if leiomyosarcomas express beta-receptors? How does propanolol have its therapeutic effect in angiosarcoma? Thanks.


    • Thanks for your comment… propranolol is tricky to interpret in angiosarcoma because usually the studies combine it with chemotherapy- so tough to tell what benefit the propranolol is actually adding. While angios and maybe other sarcomas have the receptors remember we are battling a complex genetic machinery that is overproducing many other signals which may overpower the beta receptors. Need more research …


  13. Dear Dr Wilky,

    I would really appreciate your advice on this. My mother have a tumor on the ovary (10cm) and one on the kidney (7cm). She also have metastasis in liver, lung and bones. The biopsy in the liver revealed that she have LMS however the source is not clear (ovary or kidney). All the oncologist that she have seen recommends her palliative care only. She is 60 years old and and very active and with good health: no hypertension, kidneys working as they should, no diabetes or any other complication. I would like to know if, based on your experience, would you recommend surgery to remove the tumors and then chemotherapy or radiotherapy.
    Thanks a lot


    • Thanks for writing! I can’t provide any specific recommendations without seeing her as a patient but there are definitely many treatment options if she has leiomyosarcoma that may not be curative, but certainly can slow the progression of the disease. Traditional chemotherapy as well as newer targeted treatment options and clinical trials. She should be seen by a sarcoma specialist. If you would like specific recommendations based on where you live please email me at breelynwilkymd@gmail.com.


  14. I am recently diagnosed with Soft tissue sarcoma which initially presented as a uterine tumor, biopsy indicated was benign but was wrong. Now six weeks later, I have a mass in one lung and spots in the other lung. My doctor now refuses to perform surgery and tells me I have just weeks to live with no hope of More time.
    What should I do if I want to prolong my life ?


    • There are many options for treatment and weeks to live is generally not accurate. I would recommend that you seek out a sarcoma center for a consultation. There’s a link to these through sarcoma foundation of America on my homepage or email me directly and I can help you.


  15. I was diagnosed with leiomyosarcoma cancer in Oct. of 2014 and had a large tumor removed on my upper left arm followed by 33 sessions of radiation starting in May of 2015. After a few months 5 nodules appeared on left side of my lungs. I was advised to have surgery to remove these nodules but after reading the risk and thanks to reading on UCLA’S website I discovered Cyber-Knife radiation. I had 3 sessions of 90 minutes on each of the 5 nodules and today after 3 successful ct scans no new nodules have appeared and I’ll have another scan next month 1/2019. I refused any type of chemo and could have been included in a clinical trial but decided not to participate. Just thought I would leave a message and many thanks to UCLA Medical Center. Gerry Wambold Colorado Springs Colorado


  16. Hi Dr Wilky,
    Thanks so much for such an informative and LMS-specific article. I had a morcellation hysterectomy in 2016 for undiagnosed uLMS of 10 cm. It was well differentiated but had tumor necrosis and mitotic index of 15-20 which makes it (??) intermediate grade. It would have been stage 1b but for morcellation. I had pelvic radiation for 5 weeks and then letrezole and a bucket of supplements including metformin, curcumin etc, and am so far recurrence free. I notice you don’t talk much about pelvic radiation which I imagine may have been about the RCT which showed no benefit in adjuvent radiation in early stages.. however my reading of the morcellation data is that much of the excess mortality in this group is early and due to local recurrence- which from my understanding is reduced by radiation…?


  17. Hi, pls advise which chemo is suitable for my mother she has Retroperitional Leiomyosarcoma it started in 2007 as uterine LMS. she had hysterectomy done due to it, later recurrence surgery in 2012, 3rd surgery in 2014 and her 4th surgery in 2015. The tumor grew back and she had radiation which rapidly increased tumor size within 1 month from 9cm to 12cm, she also had radiofrequency ablation. CAT scan says areas of necrosis within tumor, tumor is growing towards spine, high concern of neoplastic infiltration. As a palliative treatment doctors advise to immediately start chemo,. Another surgeon is ready to preform debulking surgery on her but it can only happen after 3 to 4 months, meanwhile her current doc wants her to start chemo and asked us to choose the chemotherapy we preferred.


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