Neoadjuvant anthracycline plus ifosfamide shows survival advantage in high-risk soft tissue sarcoma

“Patients with 60-70% risk of developing distant disease and dying from it had on average a 20% improvement if treated with conventional chemotherapy as opposed to histologically driven chemotherapy.” Dr Alessondro Gronchi, Chair of Sarcoma Surgery at the National Cancer Institute, Milan, Italy.

However, he continued by saying that the presence of a statistically significant and clinically relevant difference in RFS and OS at over 3 years in favour of standard chemotherapy, “provides strong, randomised evidence in support of its efficacy, that is still considered questionable.”

As a rare disease, STS accounts for 1% of malignancies with five to six new cases per 100,000 of the population annually. In spite of this, it is one of the most common tumours in the younger population and can be found all over the body, but more commonly in the extremities and superficial trunk. “It is not a single disease but is heterogeneous both in terms of site of origin and histological subtypes,” explained Dr Gronchi.
Localised tumours are treated with surgery and radiotherapy, and with chemotherapy if distant metastases develop. “We lack a treatment in the localised setting that can help to increase the cure rate for this disease,” said Dr Gronchi. He explained that there has been controversy over the use of adjuvant chemotherapy in order to prevent or lower risk of distant metastases in patients surgically treated for localised disease.
“Previous trial results are conflicting. Larger studies are negative and smaller ones positive,” he said. “This is why we found ourselves in a situation where we wanted to know whether histologically-driven chemotherapy was any better than conventional chemotherapy for subtypes of the disease,” said Dr Gronchi, explaining the study rationale.
In total, 435 patients were registered from 32 sites in four countries. Of these, 287 were randomised to standard chemotherapy (n=145), or to histology-driven chemotherapy (n=142). Median patient age across all groups was 50 years.

The researchers identified five different histological strata, each of which responded to different combinations of histologically-tailored therapy. Patients received three cycles of one of five regimens: gemcitabine plus docetaxel in undifferentiated pleomorphic sarcoma (n=97); trabectedin in high-grade myxoid liposarcoma (n=65); high-dose prolonged-infusion ifosfamide in synovial sarcoma (n=70); etoposide plus ifosfamide in malignant peripheral nerve sheath tumors (n=27); or gemcitabine plus dacarbazine in leiomyosarcoma (n=28). All regimens were given pre-operatively. “These five strata represent 80% of all high risk STS.”
The five regimens were compared to three cycles of epirubicin (120 mg/sqm) plus ifosfamide (9 g/sqm). The primary endpoint was RFS, and secondary endpoints were OS and response rate. This treatment was placed in the neo-adjuvant setting.
Dr Gronchi described the results that took them by surprise. At the third interim analysis, with a median follow-up of 12.3 months, the researchers found that the conventional chemotherapy performed better than the histologically-driven chemotherapies. “Patients with 60-70% risk of developing distant disease and dying from it had on average a 20% improvement if treated with conventional chemotherapy as opposed to histologically driven chemotherapy.
Projecting to 46 months, the RFS probability was estimated at 0.62 and 0.38 (p=0.004), and OS had an estimated probability 0.89 and 0.64 (p=0.033), in the conventional chemotherapy (anthracycline plus ifosfamide) and in the histology-driven arm, respectively. Of 21 deaths, 6 were in the standard chemotherapy arm, and 15 in the histologically-driven arm.
Several explanations are possible for these results, for example, it could be that the number of cycles for the histologically-driven therapies was insufficient, remarked Dr Gronchi. “However, in the end, even if the study is formally negative, it provides, for the first time, strong randomised evidence in favour of the use of standard chemotherapy in patients with soft tissue sarcoma (STS) at high-risk of relapse.”
Upon further analysis of the data, one sub-group suggested that patients with high-grade myxoid liposarcoma, which occurs in patients aged on average 40 years, who were treated with trabectedin had similar PFS and OS to those treated with epirubicin plus ifosfamide.
“Trabectedin is far less toxic than conventional chemotherapy, with no effect on alopecia or fertility among other things, so we will now reopen this stratum to assess if there is any difference between the two in terms of outcomes,” Dr Gronchi said.
Finally, he pointed out that given the findings, “We need to accommodate this into the guidelines in the future.”

The final analysis will be performed when the follow-up is mature.

Commenting on the study, Professor Thomas Brodowicz, Program Director of the Bone and Soft Tissue-Sarcoma Unit, Medical University Vienna, Austria, said, “Investigators wanted to show a one-third reduction in the relapse risk in favour of histology-driven therapy, so that means the trial did not meet the primary objective.”
“What we can conclude out of this is that the neoadjuvant anthracycline plus ifosfamide is better than the histology-driven regimens, but the question still is, is it better in comparison to no treatment?” Dr Brodowicz asked. “Furthermore, are three cycles of histology-driven therapy enough and is the neoadjuvant approach the right approach for all high risk patients?”

Based on Gronchi A, Ferrari S et al. Full-dose neoadjuvant anthracycline + ifosfamide chemotherapy is associated with a relapse free survival (RFS) and overall survival (OS) benefit in localized high-risk adult soft tissue sarcomas (STS) of the extremities and trunk wall: Interim analysis of a prospective randomized trial (LBA6_PR). Presented on Monday 10 October 2016.

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