Significant survival gains for neoadjuvant chemotherapy for high risk soft tissue sarcoma
Dr Alessandro Gronchi - National Cancer Institute, Milan, Italy
Sarcoma is a rare disease, we are talking about 1% of all malignancies, so it’s rare and especially rare in the population at the age where normally cancer occurs, so in the 60s, in the 70s, while it’s one of the commonest cancers in the young adult population and in children. So it’s a disease which has a lot of impacts in the emotion and in the life of the people who, at the end, develop it.
Adjuvant chemotherapy, so chemotherapy given to prevent the risk of further relapse, to prevent the risk of dying after a patient is treated for his localised disease at the time of presentation, has been debated over the years. Its benefit is not uniformly accepted and the reason why it’s not uniformly accepted is because the largest studies on chemotherapy over the years were negative while the smallest were positive. So a lot of debate in the literature about that.
We Italians were the first to show a benefit in adjuvant chemotherapy in a small population of patients but affected by a very high risk of disease relapse. Based on this study which was carried out in the ‘90s we later developed this regimen which is a regimen employing conventional drugs, nothing new, nothing sexy in a way, but conventional drugs that were used at full doses proving to be effective. We decided to compare these drugs, which were not perfect but able to give some benefit, with an histologic tailored approach. Why so? Because soft tissue sarcomas are rare and also heterogeneous so they are made up by different diseases. So we wanted to see if conventional chemotherapy given to everybody, the same to everybody independently of the histological type, was as good or worse as compared to giving a histologic tailored chemotherapy, specific drugs to the specific histological subtype.
Where did we get these drugs to compare the conventional chemotherapy with? We derived information from the metastatic setting where these drugs, these specific drugs, have shown a selective activity in specific histologic subtypes. So we were able to select five regimens to compare the conventional chemotherapy with and these five regimens we used in the five histologic subtypes which are the commonest histologic types occurring in this disease. So altogether these represent 80% of soft tissue sarcoma with high risk of relapse.
What we saw, we recruited in five years 435 patients, 287 of which were randomised. You see that the median age is younger as compared to the one you were looking at before. Size tends to be big so these tumours tend to be quite large and we had 240 available patients and so on. So we were able to complete the pre-operative chemotherapy in almost 90% of the patients.
These are the results. Patients affected, surprisingly, patients that are affected by high risk soft tissue sarcoma of the extremity and trunk who were treated with conventional chemotherapy had a Kaplan-Meier probability or probability at four years higher as compared to those treated with histologic tailored chemotherapy. This also translated into a survival benefit so adjuvant chemotherapy, conventional adjuvant chemotherapy, seems to work. This was highly statistically significant.
So formally this is a negative trial because it was designed to test the superiority of the histologic tailored chemotherapy over the conventional chemotherapy. However, the presence of this statistically significant and clinically relevant difference in relapse free survival and overall survival at three years in favour of standard chemotherapy provides, for the first time, a strong and randomised evidence in support of its efficacy that is still, up to now, considered questionable. This is level 1c evidence which will be accommodated in the future guidelines.
So in a population of sarcomas selected by high risk of relapse averaging 60-70%, so patients who have a 60-70% chance of dying from their disease despite the fact that they have been treated for their local disease, the use of this chemotherapy is able to increase relapse free survival and overall survival by 20% and 10% respectively. Of course we await the final analysis when the follow-up is mature but we believe that the current clinical practice guidelines and future studies will have to accommodate this evidence in the future.