Our topic today is dedifferentiated liposarcoma.  To begin with, could you please explain to us what this is?

Liposarcomas are cancers of fatty origin. They are a more common subtype of soft tissue sarcomas. But there are different types of liposarcoma. First, there are the well differentiated liposarcoma that are usually low-grade tumors, which means that they very rarely spread to other parts of the body.  Secondly, dedifferentiated liposarcoma are higher grade and thus more aggressive types of cancer. They have a higher propensity to recur and to spread elsewhere in the body.  Sometimes there is a combination of dedifferentiated and well differentiated liposarcoma. There are other types of liposarcoma, including myxoid and pleomorphic liposarcoma.

Is there any information on how many people are suffering from a dedifferentiated liposarcoma?

There are no clear statistics, but to give you an indication of the rarity:  Sarcomas in general are accounting for about 1% of adult cancers.  Liposarcomas in turn account for about 15% of all sarcomas.

What are current standard therapies for patients with dedifferentiated liposarcoma?

If the sarcoma has not spread to other parts of the body, the standard treatment is complete surgical removal. The first operation is the most important. The tumor needs to be removed completely.  So, it's very, very important that a patient is treated at a high-volume sarcoma center, particularly for their surgery.  And the patient groups can help to identify where best to go.  Depending on the location, sometimes radiation is also used. A current trial by the European Organisation for Research and Treatment of Cancer (EORTC) looks at the role of preoperative chemotherapy in retroperitoneal dedifferentiated liposarcoma.  It is open for recruitment for patients with operable tumors to receive either doxorubicin and ifosfamide prior the operation, or no chemotherapy drugs.

If the sarcoma has spread to other parts of the body, the cornerstone of treatment is systemic therapy or chemotherapy, sometimes combined with surgery or radiation.  There are several drugs available that we can use for metastatic or advanced disease, and it's a case of weighing up the pros and cons, the side effects of each treatment with an individual person.  Currently, we can use following drugs in these cases: doxorubicin, gemcitabine, trabectedin, eribulin, dacarbazine.  Each drug works differently and may have an advantage over the others in a specific case.   They may be used sequentially, if needed.   A group of experienced doctors should look after a particular patient and using every modality to the best that we can.

But in general, efficacy is limited. There's a real need for improved treatments that can be better tolerated and be more effective, in particular for patients with advanced dedifferentiated liposarcoma.

This is where so-called targeted therapies may come into the picture? 

Yes. Historically, chemotherapy has been used as a systemic approach to treat cancer by targeting a lot of pathways and molecular abnormalities.  Often, there are challenging side effects.   Targeted therapy on the contrary focuses on one specific molecular problem activating the cancer and making it grow.  Thus, efficacy should be better and side effects reduced.  There have been already success stories with this approach, such as in the case of gastrointestinal stromal tumors (GIST) where we have drugs that can target activating mutations and therefore stop the growth of cancer cells.

Similarly, the thinking has been that in the case of dedifferentiated liposarcoma, targeted therapy might prevent or stop growth of cancer cells.  Dedifferentiated and well differentiated liposarcoma are characterized by amplification in genes called MDM2 and CDK4. These have led to a lot of interest in drugs targeting these molecular abnormalities.

The Connective Tissue Oncology Society (CTOS), a leading group of world’s sarcoma specialists, discussed progress in this field, among others,  at the recent annual conference in San Diego in November 2024.  They had selected dedifferentiated liposarcoma as Sarcoma of the Year.  Why?

There had been several studies looking at drugs and treatments specifically for dedifferentiated liposarcoma which can be an aggressive cancer. CTOS wanted to enable the sarcoma community to discuss in detail the results of these trials.  Of particular interest are trials of MDM2 and CDK4 inhibitors, as they disrupt tumor suppressing functions of the body.  Hence, by targeting them, it is hoped that cancer growth can be stopped. And indeed, in some patients these drugs work really well and obviously target the molecular activator in that particular cancer.

What was the main outcome of this meeting?

The major result disclosed at the annual meeting of CTOS were for me certainly the findings of a trial in advanced and metastatic dedifferentiated liposarcoma, the Brightline study. This major trial that aimed to lead to the approval of an MDM2 inhibitor - brigimadlin - for dedifferentiated liposarcoma was negative. We still need to work out more about this trial and its implications.

Essentially, the trial randomized people to either receive doxorubicin or the MDM2 inhibitor brigimadlin as a first line treatment for advanced or metastatic dedifferentiated liposarcoma.  The aim was to compare these two drugs and their effect on progression free survival, that is, the time for the cancer to grow above a set threshold on scans.   Independent radiologists looked at scans and defined whether the tumor was responding or whether there was cancer progression.  And they did not find a statistically significant difference between the two arms of the trial.  The median progression free survival for patients treated with brigimadlin was 8.38 months compared to doxorubicin with 7.16 months, based on the blinded radiological assessment.

Having said that, one of my points regarding dedifferentiated liposarcoma is that it is very difficult to evaluate the response to drugs using scans for these tumors. Firstly, there can be both dedifferentiated and well differentiated components.  Secondly, some tumors can be very big and increase above the set threshold requires a considerable degree of growth. Whereas for smaller tumors, sometimes very little growth is required to exceed the threshold. For a 20 cm tumor to increase by 20%, it can take much longer than for a 4-5 cm tumor.   For all these reasons, it can be very difficult to disentangle what the benefit is for the individual patient.

There were also positive signals of activity from the trial. The response rate to brigimadlin was 22% compared to 8.6% with doxorubicin.  Using standard criteria, a partial response is defined as 30% or greater decrease in size of measured tumors. This suggests that some patients really benefit from this treatment.

Lastly, the oncologists treating patients found better results, namely 9.4 months progression free survival for brigimadlin compared to 7.16 months for doxorubicin.  The important thing to note here is that this was not a blinded trial. The oncologists knew that their patients were taking the drug and this could factor into their assessment.

In conclusion, we as a community need to try and work on finding better ways of assessing response in this disease.

So, why not stick then to Doxorubicin?

 It seems that doxorubicin is more effective than we thought. The progression free survival was much better than expected from the retrospective studies that had been done previously.   But again, as I said earlier there are caveats regarding the evaluation of response.

How do side effects of the two drugs compare?

We know that doxorubicin can have an impact on the heart muscle, cause hair loss, lower blood counts, provoke nausea and vomiting.  But MDM2 inhibitors can have side effects as well, particularly in terms of hematological function: platelet count, white cell count and hemoglobin, and also gastrointestinal side effects. Many patients had to have dose reductions with brigimadlin because of these side effects. Both drugs have side effects.

What is the way ahead then? 

The crucial point for regulatory agencies regarding this trial was that the primary end point was progression free survival.  While we know that brigimadlin has helped a lot of people, we cannot identify right now who is more likely to benefit from it, or who is more like to benefit from doxorubicin.

This is a disappointing trial result but there's clearly work that we can do to try and make things better in the future. I suggest three main points:

1. We need to develop a better way of understanding the tumors’ response and resistance to these treatments.

2. We need to think about combination therapy with these agents, which might be challenging due to the hematological toxicity. Therefore, we should try to develop combination schedules that avoid overlapping toxicity.

3. We need to identify markers of response in the laboratory to understand which is the best treatment for individual patients with dedifferentiated liposarcoma.

How long may this process take?

It's not a straightforward process and these tumors are challenging to treat. I hope it's sooner but realistically it can take years.   The consequence is that it is likely that there will not be another new option for patients for some time to come.   This has been a difficult result to take in.  We need to be thoughtful about the design of such important trials that could lead to approval- or not - of new treatments for sarcoma patients.

Questions by Gabi Ott, Editor-in-Chief of the Voices of Sarcoma blog