Neoadjuvant Chemotherapy for High Grade Myxoid Liposarcoma
Some answers, more questions
Obligatory—this is not medical advice
The role of neoadjuvant chemotherapy, that is chemotherapy given specifically before an intended surgery or procedure, is highly debated within the sarcoma world. This question has been evaluated numerous times and in as many ways.1 Because of the breadth of diagnoses incorporated into the field, as well as the variability in interpretation and designation of a pathologic diagnosis, results of studies on perioperative chemotherapy have been mixed.23 There have been hints at perhaps a role for systemic treatment in some patients, relying on various models, but the perception has often been that these are limited datasets contingent upon subgroup analyses that in themselves have wide confidence intervals (meaning are not the most statistically reliable basis for treatment decisions).4 Therefore, it is vital that we practice shared decision-making.
Myxoid Liposarcoma
I have written about liposarcoma previously, and that it is very roughly divided into three separate diagnoses. Myxoid liposarcoma has a very demographic basis, pathophysiology, as well as sensitivity to therapy (radiation and chemotherapy) when compared to its liposarcoma cousins. It is somewhat defined by a FUS-DDIT3 fusion which can be detected on FISH. Please forgive my analogies, but I do want to emphasize this point, these subtypes of liposarcoma are an etymological grouping of convenience, with a presumed though yet unproven possible similarity in progenitors. It is perhaps the human equivalent of calling someone a Chicagoan or New Yorker. They are from that place—but they may be very different.
Trabectedin
I have written about trabectedin and its role in the treatment of leiomyosarcoma, particularly in conjunction with doxorubicin, here. Loosely speaking, trabectedin is an alkylating agent—which is an oversimplification as we frequently see for our chemotherapies. Certainly, it plays many parts, one of which being placement of an alkyl group on the N2 position of guanine. It interferes with DNA transcription and perhaps has a unique ability to reduce DNA binding of transcription factors—though not all equally, of course.5
Neoadjuvant Chemotherapy in High-Grade Myxoid Liposarcoma
So, enough of all this yammering about things. What was this trial?
Patients with localized high-grade myxoid liposarcoma (high grade defined as cellular component >5%). Size >5cm, deeply seated
Primary end point: disease free survival (that is time until recurrence) with secondary endpoint of survival
Randomized, noninferiority Bayesian design to show that trabectedin was not inferior to anthracycline and ifosfamide (hazard ratio of 1.25, that is an allowable possibility of 25% decrement in efficacy).
So, all that aside, these are relatively specialized terms designed to convey the fact that this was not a 1:1 randomization and was an expansion of a subgroup within a larger study.6 As with any study, you must prospectively set thresholds for efficacy and determine your alpha (ie the probability this occurred by chance). What is also different about this study is that it is ‘non-inferiority,’ which is to say that we are proving that it is not worse than the prevailing standard of care. These are trickier trials as they tend to need larger numbers of patients, and the results can be nebulous. It is not infrequent that we get a conclusion that states, ‘x was not non-inferior to y,’ which implies that x was not proven to be equivalent to y within certain parameters. We must know those parameters so that we might judge the wherewithal of the trial. To say that a trial determines what is best is an oversimplification.
My apologies for the dissertation. I am merely reflecting my enthusiasm for the concepts and that as physicians we must understand more than just the indications for a treatment, but how it has been shown to work. Sadly, we cannot always trust the FDA to make worthwhile decisions, and so it falls on our shoulders to interpret the data rigorously.
Within those bounds, we see that trabectedin was non-inferior to more typical anthracycline + ifosfamide based treatment. The authors go on to write, eloquently, about the errors that might have led to this result. Furthermore, they extrapolate to known models of survival and recurrence that are frequently used (sarculator). It is a well-done paper. I would argue that it is perhaps one of the more ‘human’ manuscripts I have read in some time, though somewhat off the beaten path for many oncologists.
Conclusions
Neoadjuvant systemic therapy for soft tissue sarcoma is highly debated. Its role, and whether it may lead to improved functional or survival outcomes for patients remains relatively unknown. Within this study, with named limitations, trabectedin was non-inferior to anthracycline and ifosfamide for high-grade myxoid liposarcoma. Nonetheless, determination about the application of these findings very much should be done in a multidisciplinary group and with the true informed perspective of the patient.
https://pubmed.ncbi.nlm.nih.gov/32421444/
https://pubmed.ncbi.nlm.nih.gov/27733375/
https://pubmed.ncbi.nlm.nih.gov/18521899/
https://pubmed.ncbi.nlm.nih.gov/30690293/
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6584455/
https://pubmed.ncbi.nlm.nih.gov/11502318/