High-grade, advanced, soft-tissue sarcoma (STS) is an aggressive disease with poor prognosis. In this population, single-agent doxorubicin (DOXO) has been considered the standard in detriment of combination regimens [
Testing this strategy, the first sequential (dose dense) STS study was shown to be feasible with manageable toxicity [
In this scenario, one STS trial has demonstrated that patients with positive ezrin expression presented poor survival [
The present study explored the activity and safety of front-line sequential dose-dense DOXO- and IFO-based chemotherapy in advanced, high-grade STS adult patients in an outpatient basis, and we tried to confirm if ezrin could identify those patients with worse prognosis. The primary endpoint of the trial, response rate, was evaluated by RECIST version 1.0 [
This study included metastatic (META) or locally advanced (LOCA), chemotherapy-naïve, histologically confirmed, high-grade STS patients according to the WHO classification. Patients were deemed eligible who were 18–60 years of age, had at least one unidimensionally measurable lesion, an ECOG performance status of 0–2, adequate bone marrow, and renal, liver, and cardiac functions (neutrophils count >1.0 × 109 per liter and left ventricle ejection fraction >55%). Patients with malignant mesothelioma, juvenile types of rhabdomyosarcoma, neuroblastoma, PNET/Ewing, carcinosarcoma, and gastrointestinal stromal tumor were excluded.
The protocol was reviewed and approved by the Ethics Committee for Research Project Analysis from University of Sao Paulo, and conducted according to the International Conference on Harmonization Good Clinical Practice guideline. All participants were advised about the procedures and gave informed consent.
As cited previously, all chemotherapy was administered on an outpatient basis. Three cycles of 30 mg/m2/day
This trial required 39 patients to achieve 80% statistical power at a significance level of
Ezrin was analyzed immunohistochemically on formalin-fixed, paraffin-embedded biopsy slides as described elsewhere [
In this uni-institutional, single-arm phase II study, 25 patients with high-grade STS were screened between August 2005 and January 2007, and 20 entered (Figure
Patient characteristics.
METAa | LOCAb | Total | |
---|---|---|---|
Total | 13 (65) | 7 (35) | 20 (100) |
Sex | |||
Male | 7 (35) | 5 (25) | 12 (60) |
Female | 6 (30) | 2 (10) | 8 (40) |
Age (years) | |||
Median | 47 | 28 | 39 |
Range | 26–60 | 25–45 | 25–60 |
Performance status | |||
0 | 4 | 4 | 8 |
1 | 6 | 3 | 9 |
2 | 3 | 0 | 3 |
Histological subtype | |||
Synovial | 1 | 4 | 5 |
Leiomyo | 5 | 0 | 5 |
Unclassified | 2 | 2 | 4 |
Malignant fibrohistiocytoma | 2 | 0 | 2 |
Myxoid | 1 | 1 | 2 |
Otherc | 1 | 1 | 2 |
Primary site | |||
Lower limbs | 3 | 5 | 8 |
Retroperitoneal | 5 | 0 | 5 |
Upper limbs | 2 | 2 | 4 |
Otherd | 3 | 0 | 3 |
Size of primary tumor (cm) | |||
Median | 12.4 | 11.7 | 12 |
Range | 2–18 | 6.1–15 | 2–18 |
Metastatic site | |||
Lung | 11 | NA | 11 |
Lymph node | 5 | NA | 5 |
Liver | 4 | NA | 4 |
Bone | 4 | NA | 4 |
Othere | 4 | NA | 4 |
Number of metastatic sites | |||
1 | 5 | NA | 5 |
2 | 3 | NA | 3 |
≥3 | 5 | NA | 5 |
aMETA: metastatic disease.
bLOCA: locally advanced disease.
cEpithelioid, malignant peripheral nerve sheath tumor.
dLung, uterus, scalp.
eSpleen, adrenal gland, pleura.
NA: not applicable.
Patient inclusion. LVEF: left ventricular ejection fraction. PE: pulmonary embolism. PR: partial response. PD: progressive disease.
In total, 105 cycles were delivered, 54 during the first phase and 51 during the second. Fourteen patients (70%) received all planned chemotherapy. Six META patients did not complete the protocol; this was due to disease progression in three patients, two early deaths (see discussion below), and in one patient DOXO was halted after a single cycle due to unexplained cough. This patient presented a pretreatment left ventricle ejection fraction (LVEF) of 58% and diffuse myocardial hypocontractility. He underwent a new LVEF evaluation, which remained unchanged; he became asymptomatic and received six IFO cycles at a dose of 10 g/m2 at the investigators’ discretion. He presented stable disease and underwent resection of lung metastases.
A median of six cycles (1–7) were administered per patient. Median dose intensities for DOXO and IFO for the entire cohort were 42 mg/m2/week (27–45) and 3.6 g/m2/week (1.3–4.1), respectively, which corresponded to 93% (61–101%) and 87% (32–100%) of the planned dose intensities.
In an intention-to-treat analysis, we observed three partial responses, 10 stable diseases, and seven disease progressions, translating to a response rate of 15% (3 out of 20). As mentioned previously, because this fell short of the six responses required to complete accrual, the study closed accrual on January 31st 2007. The histologic subtypes of the patients who presented partial responses were synovial sarcoma, unclassified sarcoma, and malignant fibrous histiocytoma (MFH). Median duration of response was 2.1 months (1.3–4.9).
Survival information was locked on August 31st 2007. After a median follow-up of 11 months with 10 patients remaining alive, progression-free survival (PFS) and overall survival (OS) were 8.1 months (1.5–22.6) and 20.1 months (2.3–22.6), respectively. Subgroup analyses showed longer PFS for those patients in the LOCA group as compared to META patients, not reached versus 6 months, HR 0.07 (95% CI 0.04–0.43)
The toxicities that occurred in more than 10 cycles are detailed in Table
Adverse events occurring in more than 10 cycles.
Event | Grade 1–4-related events ( | |||
1 | 2 | 3 | 4 | |
Alopecia | 7 | 12 | NA | NA |
Anorexia | 6 | 6 | 0 | 0 |
Asthenia | 1 | 16 | 4 | 0 |
Canalicular enzymes | 34 | 5 | 2 | 0 |
Constipation | 5 | 16 | 1 | 0 |
Dermatitis | 9 | 5 | 0 | 0 |
Diarrhea | 7 | 1 | 3 | 0 |
Dysgeusia | 8 | 5 | 0 | 0 |
Haematuria | 12 | 2 | 2 | 0 |
Hypobicarbonatemia | 13 | 0 | 0 | 0 |
Mucositis | 17 | 12 | 3 | 0 |
Nausea | 23 | 15 | 3 | 0 |
Transaminitis | 18 | 3 | 1 | 0 |
Vomiting | 20 | 8 | 6 | 0 |
Anemia | 41 | 20 | 5 | 0 |
Thrombocytopenia | 7 | 3 | 2 | 0 |
Febrile Neutropenia | NA | NA | 5 | 1 |
NA: not applicable.
Ezrin expression was positive in 10 patients (Table
Ezrin expression according to histology.
Histology | Ezrin expression |
---|---|
Leiomyosarcoma | |
Leiomyosarcoma | 0 |
Leiomyosarcoma | 0 |
Leiomyosarcoma | 0 |
Leiomyosarcoma | 0 |
Synovial | |
Synovial | |
Synovial | |
Synovial | + |
Synovial | + |
Unclassified | |
Unclassified | 0 |
Unclassified | 0 |
Unclassified | 0 |
MFHa | + |
MFHa | 0 |
Myxoid | |
Myxoid | 0 |
Epithelioid | + |
MPNSTb | 0 |
aMalignant fibrohistiocytoma.
bMalignant peripheral nerve sheath tumor.
Overall survival according to immunohistochemical ezrin expression. Median overall survival for soft-tissue sarcomas patients whose tumors were classified as positive for ezrin was 21.1 months, compared to 8.6 months for ezrin-negative patients; HR 0.39, 95% CI 0.08–1.31;
In this phase II study investigating a sequential dose-dense DOXO/IFO schedule in high-grade STS patients, a low response rate has been observed, determining patients’ accrual discontinuation. Unexpectedly, none of the LOCA patients responded; however, all but one was alive at the time of study closure. On the other hand, two of the three patients presenting partial response had died, raising the question whether response rate will represent an appropriate endpoint in future STS trials.
Despite a high degree of grade 3/4 toxicities observed, febrile neutropenia rate was similar to that observed in the literature [
The median OS was longer than those described in two previous studies with similar dose-dense strategies [
In a scenario of doubts in which STS trials are inserted, some questions arise. (1) Are there patients who might benefit from DOXO and IFO in first-line chemotherapy? (2) Are these patients among the ones with poor prognosis? (3) How could we find them? The answer for the first two questions is “perhaps” and for the third one, we will use selected histologic subtypes as examples. Leiomyosarcoma patients may show response rate (RR) as low as zero [
We have observed that, besides being 100% ezrin positive, those patients with synovial histology had most often locally advanced disease (with a better prognosis than metastatic disease), and we believe that this clearly confounds this data. However, we also believe that ezrin may have positively influenced survival among those patients. Corroborating these results, a better outcome was also observed for patients with ovarian cancer and positive for ezrin [
In accordance to the literature [
The fact that STS are heterogeneous and cannot be grouped and treated as the same way is the new paradigm. In the near future, the identification of one (or more) biologic (molecular) marker(s) will tailor treatment in an attempt to predict compliance, response, and survival.
The authors have no conflict of interests, neither financial nor personal relationships with people or organizations that might inappropriately influence (bias) this paper.
We thank Radiology Institute from Clinics Hospital University of Sao Paulo where the image scans were performed, analyzed and reviewed. This study was supported by funds of the host institution.