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After two editions without celebrating due to the Covid pandemic, this weekend Madrid hosts the ‘GESE: Generating Evidence and Sharing Experience’ congress, organized by PharmaMar, in which the main European oncologists and medical specialists meet to share the latest advances in the treatment and diagnosis of sarcomaa rare type of cancer that includes more than 80 different subtypes and can appear at any time in life.
Among those who will not miss the appointment is the doctor Javier Martin-BrotoSarcoma medical oncologist at the Fundación Jiménez Díaz University Hospital in Madrid and director of the ATBsarc Research Group dedicated to sarcoma research at CITIUS III in Seville.
-Two editions without meeting due to the pandemic, what news has there been in sarcoma during this period?
-It has been investigated. They have taken longer sometimes because studies in Covid have been prioritized, but it has not been an absolute brake. We have recent changes in the last two years and not much: in Ewing’s sarcoma we have defined a first line. Before, there were two different first-line treatment strategies, but the European Ewing Consortium carried out an academic study, with more than 600 pediatric and adult patients, and it was confirmed that one of the schemes, the one we call VDCIE, is the one with the best results gives. On the other hand, in soft tissue sarcomas, the first line for 30-40 years was always in absolute dominance with doxorubicin, because there was no combination that had shown advantages in progression-free survival/overall survival, with some exceptions. This year we know that the combination of trabectedin with doxorubicin is an option that is more effective in leiomyosarcoma.
It is true that in soft tissue sarcomas, today, in metastatic disease, the survival expectancy is two years, but eight years ago it was one. We have gained one year in median survival expectancy and this has been due to the advent of second-line drugs. Because more research is being done, we can also offer patients new treatment opportunities and this is essentially an effort of cooperative groups at the national and international level.
Also in diseases that, within the 80 subtypes, we call ultra rare, we have had some recent success. For example, in giant cell tenosynovial tumors, drugs have been developed that inhibit a signaling pathway called CSF1 and that has been a before and after in this disease. We are also having recent successes with sorafenib and with a gamma secretase inhibitor in desmoid tumors. These are molecular target therapies and I think they have made a qualitative change in this disease.
In other ultra-rare cases, we have some recent success, such as EZH2 inhibitors (tazemtostat), a highly effective targeted therapy in epithelioid sarcoma. And, following this line, we have inhibitors of a gene that is amplified in some sarcomas called MDM2 and, from this group of drugs, which are now much better tuned (better tolerance and more effective), patients with liposarcoma will benefit dedifferentiated and with intimal sarcomas.
Finally, I would say that immunomodulation, which has been an absolute revolution in other tumors, has its niche in sarcoma for very rare sarcomas (soft tissue violation, dedifferentiated chondrosarcoma, rhabdoid tumors) for which we change the natural history of the disease .
-With more than 80 subtypes of sarcoma, is it difficult to diagnose?
Sarcomas occur anywhere in the body, from the head to the feet. It affects both muscular and visceral territory. Depending on in which territory the sarcoma emerges, it will give one symptom or another. The most frequent are extremity and trunk wall sarcomas, and the typical is a lump that emerges. That lump is normally not painful, but we have to suspect that that lump may be a sarcoma when it has more than 3 centimetersexperience a recent growthand when is it deep and not movable sideways. These are warning signs that serve to refer that patient to an expert center for imaging tests and a biopsy to better diagnose and plan treatment. However, in bone tumors, pain is the most important.
-What is the general prognosis for sarcomas?
-Speaking of localized soft tissue sarcomas of the limbs and trunk wall, which is the most common scenario, the cure rate is 60-65%, which means that they will never recur or, if they recur, they will not. it will be deadly
-At what point is the treatment of sarcoma in Spain?
-In Spain we have very good centers that have multidisciplinary teams, with training of surgical teams, radiologists and pathologists, and oncologists. In terms of assistance, quality is assured. Regarding systemic treatments, Spain is not one of the countries in which a drug is approved the fastest since the European Medicines Agency gives the go-ahead. There is a time lag, the law says that in three months the price should be established in Spain to be able to prescribe it, but the truth is that the delay is years. Something that does not happen in France, Italy, the United Kingdom or Germany. There are very sad examples such as the case of highly directed drugs against very specific targets such as tumors that have NTRK mutations, which have not been approved in Spain after 3 years of approval by the European Agency. In Europe, only Spain and Portugal remain, and in our country they have dismissed it for both pediatrics and adults, despite being hyperactive drugs when you have the mutation. A patient who now has a positive NTRK sarcoma in our country is going to have to go to other places and pay for it because the Spanish Medicines Agency has dismissed it. These are differences that call our attention.
In the research section, the Spanish Sarcoma Research Group (GEIS) is one of the most active groups worldwide, which is now developing study number 86 and that is new treatment opportunities for patients. Therefore, in the sense of having access to innovative and experimental drugs, Spain is in the top 5 of countries of the world. Our country is one of the five that can most offer innovative drugs in sarcomas.
-What predisposes us to develop a sarcoma?
98% of sarcomas are sporadic, they are not linked to any hereditary syndrome. There are recognizable hereditary syndromes where sarcomas can emerge with a fairly high frequency, but together they account for 2-5% of all cases. The vast majority are sporadic.
Although there is no recognizable external agent, it is true that in many sarcomas, especially pleomorphic and synovial sarcomas, there is often a previous traumatic history. Not everyone who hits himself will obviously get a sarcoma, but in certain contexts that is a trigger. We also know that a third of sarcomas have a specific translocation: there are two genes that fuse abnormally and that constitutes the driver of that tumor. Why they stick abnormally is what we need to know. We intuit that they are genes that are trying to correct some problem in their environment. We still need to know the final mechanism by which these fusion transcripts take place and are recurrent in sarcomas.
-What is the patient’s profile?
It can happen to anyone. We have sarcomas that can affect children or adolescents or young adults more, as is the case with osteosarcomas, rhabdomyosarcomas or Ewing’s sarcomas. We have subtypes that affect senile age more (conventional chondrosarcomas). And speaking of all soft tissue sarcomas, the average age is 60 years.
-In children, the pain of a sarcoma can be confused at first with other pathologies of childhood…
-In children, the most frequent somatic sarcomas are bone and these, like Ewing or osteosarcoma, begin with pain. In a growth stage there can be pain for many reasons. This symptom is very nonspecific, but the antenna must always be on. If that pain is not temporary, if it settles, or if it is accompanied by functional impotence or a palpable lump, in those cases it is necessary to request resonance, imaging tests, to perform a biopsy, diagnosis and treatment.
-Has the Covid pandemic affected the diagnosis and treatment of sarcomas?
-Our team at the Foundation has developed a study at the level of several hospitals in Spain to see the specific impact on sarcomas comparing 2018 with 2020. We are more than convinced that the fact that there were many telematic consultations meant that many patients could not appraise perfectly fine. Tests or surgeries were relegated because sometimes operating rooms housed Covid patients because they had ventilators. It has been a tragedy. Now we can say that we have returned to the normal rhythm in general.
-In sarcoma, are we going to increase survival as in other more prevalent cancers?
-We handle the figures for metastatic disease, but the global figures from the onset of the disease to follow-up for years escape us because there are very few records. Now we are looking at France because the French government supports rare tumor registries and we will be able to see how they evolve. In our country we have provincial records, not even autonomous, which does not include all of Spain and that means that we do not have very robust figures. When we analyze at European level what happens with sarcomas compared to other tumors, since sarcomas belong to the rare ones with an incidence of less than 6 new cases per hundred thousand inhabitants per year, there is a 10% higher mortality rate in rare tumors compared to tumors frequent. We also know from European registries that the trend in sarcomas in terms of improving survival is not that of the most frequent tumors. We are stable or in some figures a little worse. We will be very attentive to the French registries because the support of the French Government is very solid in rare tumors.
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