Soft tissue sarcomas (STSs) are a rare form of cancer which originate in various sites of the body [
We retrospectively reviewed patients with advanced or metastatic STS of nonextremities who received doxorubicin-based chemotherapies at the Department of Medical Oncology in our institution from October 2005 to April 2016. A histopathological diagnosis was done by a biopsy or surgery which was reviewed by a well-trained pathologist in our institution. The regimens included a single agent of doxorubicin, a combination mostly with cyclophosphamide/vincristine/dacarbazine (CYVADIC), or ifosfamide (AI). The dose of doxorubicin monotherapy varied from 60 mg/m2 to 75 mg/m2, and CYVADIC consisted of 50 mg/m2 doxorubicin, 1.5 mg/m2 vincristine (max 2.0 mg/body, Day 1), 250 mg/m2 dacarbazine (Day 1–5), and 500 mg/m2 cyclophosphamide (Day 2), and AI consisted of 30 mg/m2 doxorubicin (Day 1–2) and 2 g/m2 ifosfamide (Day 1–5). The treatment regimen and the doxorubicin dose were chosen by a physician’s choice. The doxorubicin monotherapy was chosen for the purpose of extending the patient’s life, whereas the combination therapy was chosen with the purpose of shrinking the tumor. The patient’s age, PS, organ functions, and risks such as the risk of myelosuppression were taken into consideration when determining the treatment regimen and the dose of chemotherapy. Clinical evidence in regard to the benefit of OS is based on some randomized clinical trials, such as EORTC62012. These trials in turn possibly affected the preference of physicians’ choices regarding the use of doxorubicin monotherapy. The doxorubicin-based chemotherapy was discontinued until progressive disease (PD), unacceptable adverse events, or the cumulative dose was reached up to 450 mg/m2. Imaging studies were performed every 2 to 3 months, or whenever the patients’ presented with exacerbated symptoms. Objective responses, according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, were assessed by computed tomography (CT) or magnetic resonance imaging (MRI). Time to treatment failure (TTF) and overall survival (OS) were assessed by the Kaplan–Meier method. A univariate log-rank analysis was used to assess potential prognostic factors for OS, and the independent significant factors were investigated by multivariate Cox regression analyses for which the
Between October 2005 and April 2016, a total of 75 patients were enrolled for analysis. The baseline characteristics of the patients treated with the doxorubicin-based chemotherapy are shown in Table
The baseline characteristics of the patients treated with the doxorubicin-based chemotherapy.
No. (%) | |
---|---|
|
|
Male | 40 (53) |
Female | 35 (46) |
|
|
Median age, years | 55 (21–75) |
|
|
0 | 57 (76) |
1 | 15 (20) |
2 | 3 (4) |
|
|
Head and neck | 14 (19) |
Thorax | 7 (9) |
Abdomen | 23 (31) |
Retroperitoneum | 19 (25) |
Genital organs | 4 (5) |
Others | 4 (5) |
Unknown | 4 (5) |
|
|
1 | 22 (29) |
2 | 26 (35) |
3 | 13 (17) |
4 | 10 (13) |
≧5 | 4 (5) |
| |
Head and neck | 11 (15) |
Intra-abdomen | 30 (40) |
Retroperitoneum | 15 (20) |
Lung | 35 (47) |
Liver | 22 (29) |
Bone | 18 (24) |
Lymph node | 16 (21) |
Others | 29 (39) |
|
|
Median (cm) | 5.3 (0–21.7) |
>5 cm | 40 (53) |
|
|
Operation | 49 (65) |
Radiation | 21 (28) |
Chemotherapy | 8 (11) |
None | 18 (24) |
|
|
Leiomyosarcoma | 17 (23) |
Liposarcoma | 15 (20) |
Spindle cell sarcoma, NOS | 14 (19) |
Pleomorphic sarcoma | 6 (8) |
Synovial sarcoma | 5 (7) |
Others |
18 (24) |
The median follow-up time was 14.3 months. Of the enrolled patients, 48 were alive and 15% were maintaining the treatment effect or under the treatment at the data cutoff of April 2016. Nine percent were keeping more than stable disease (SD) after the doxorubicin-based chemotherapy, including one partial response (PR) and one complete response (CR), respectively. One patient showed PR after the treatment but moved on to the second-line therapy, without break by the physician’s decision. The median TTF was 4.7 months (Figure
Median TTF.
Median OS.
Overall response rate.
Best overall response | No. (%) |
---|---|
Complete response | 3 (4) |
Partial response | 12 (16) |
Overall response | 15 (20) |
Stable disease | 31 (41) |
Progressive disease | 27 (36) |
Not evaluable or not assessed | 2 (3) |
Doses of doxorubicin monotherapy administering 75 mg/m2 or less than 75 mg/m2 did not show significant difference either in TTF or in OS (Figure
Difference of (a) TTF and (b) OS in doses of doxorubicin monotherapy.
Tumor response for different doses of doxorubicin monotherapy.
Best overall response | Doxorubicin ≧ 75 mg/m2 ( |
Doxorubicin < 75 mg/m2 ( |
---|---|---|
Complete response | 0 (0) | 0 (0) |
Partial response | 2 (13) | 2 (6) |
Overall response | 2 (13) | 2 (6) |
Stable disease | 5 (31) | 14 (44) |
Progressive disease | 8 (50) | 6 (19) |
Not evaluable or not assessed | 1 (6) | 0 (0) |
Difference of (a) TTF and (b) OS in combination therapy and monotherapy.
Overall response rate for doxorubicin monotherapy and combination therapy.
Best overall response | A single agent ( |
Combination therapy ( |
---|---|---|
Complete response | 0 (0) | 3 (8) |
Partial response | 4 (11) | 8 (22) |
Overall response | 4 (11) | 11 (30) |
Stable disease | 19 (50) | 12 (32) |
Progressive disease | 14 (37) | 13 (35) |
Not evaluable or not assessed | 1 (3) | 1 (3) |
Prognostic factors by univariate analysis and multivariate analysis.
Prognostic factors | Univariate analysis | Multivariate analysis | |
---|---|---|---|
|
Relative risk (95% CI) |
|
|
Male | 0.55 | — | — |
Age (<40) | 0.15 | — | — |
PS (0) | 0.012 | — | 0.54 |
Number of involved organs (<3) | 0.013 | 0.31 (0.15–0.65) | 0.0019 |
Head and neck | 0.28 | — | — |
Intra-abdomen | 0.25 | — | — |
Retroperitoneum | 0.17 | — | — |
Lung | 0.34 | — | — |
Liver | 0.30 | — | — |
Bone | 0.60 | — | — |
Lymph node | 0.84 | — | — |
No bulky mass (<5 cm) | 0.009 | 0.27 (0.12–0.60) | 0.0013 |
Pretreatment | 0.73 | — | — |
Normal, N/l | 0.44 | — | — |
Normal Hb level (≧11.6 g/dl) | 0.18 | — | — |
Normal LDH level (<222 mg/dl) | 0.61 | — | — |
Normal ALP level (<322 IU/l) | 0.12 | — | — |
Normal CRP level (<0.14 mg/dl) | 0.020 | 0.43 (0.20–0.93) | 0.032 |
Locally advanced or metastatic STS of nonextremities is generally considered to be incurable and has poor prognosis. Salvage therapies such as systemic therapy and operation and radiation therapies are usually performed to such patients, and doxorubicin remains the most active single agent in STS for systemic chemotherapy. However, the optimal dose of doxorubicin in regard to doxorubicin monotherapy is unclear, neither is the role of combination therapy, especially when it is restricted to nonextremities STS. A number of trials comparing doxorubicin as a single agent with combination chemotherapy were performed, and a few studies showed a better overall response rate. However, according to those trials, combination chemotherapy has not indicated survival advantage compared to a single-agent chemotherapy [
We acknowledge that there are several limitations in this study since this was a retrospective study. Some of the decisions were made by individual physicians. For example, when imaging studies were performed, they may influence TTF. Furthermore, chemotherapy regimens and the dose of chemotherapy were chosen by a physician’s choice. As a result, the dose of doxorubicin, in our study, was lower than the standard dose, in a high proportion of the patients. A further investigation which includes a prospective randomized study is needed.
In conclusion, doses of doxorubicin and doxorubicin monotherapy or combination therapy did not show significant differences in OS, but combination therapy showed a better overall response rate and longer TTF compared to monotherapy. Furthermore, less number of involved organs, no bulky mass, and normal CRP level were found to be independent favorable prognostic factors.
The authors declare that they have no conflicts of interest.