Abstract
Background:
Novel-fosfamides (NFOs) belong to active metabolites of ifosfamide that bypass the generation of toxic byproducts. In this analysis, we aimed to comprehensively assess the benefits and risks of NFO monotherapy or in combination with doxorubicin (DOX) versus single-drug DOX in previously untreated patients with advanced soft-tissue sarcoma (ASTS).
Methods:
Online PubMed, Web of Science, Embase, and Cochrane CENTRAL databases were systematically searched on April 26, 2022. Objective response rate and disease control rate were primary outcomes. Overall survival (OS), progression-free survival (PFS), and grade ≥ 3 treatment-related adverse events were secondary outcomes.
Results:
In all, 3 randomized clinical trials with a total of 1207 ASTS patients were eligible. DOX plus NFO combination therapy showed higher risk ratios of objective response rate (1.50, 95% CI 1.20–1.68, P = .0003) and disease control rate (1.15, 95% CI 1.05–1.27, P = .0030) compared with DOX monotherapy. Nevertheless, NFO-based monotherapy and combination therapy were found no improvements on OS (hazard ratio 0.93, 95% CI 0.52–1.65, P = .8050) and PFS (hazard ratio 0.88, 95% CI 0.54–1.43, P = .6088) against DOX. More incidences of grade 3 or worse anemia, thrombocytopenia, stomatitis, diarrhea, constipation, and febrile neutropenia were observed in NFO-based treatments.
Conclusion:
Adding NFO to DOX as first-line therapy improved the responses in ASTS patients but did not prolong OS and PFS. Grade 3 or worse treatment-related adverse events should be treated with caution during the NFO-based therapies.
Keywords: novel-fosfamide, response, soft tissue sarcoma, survival, treatment-related adverse event
1. Introduction
Soft tissue sarcoma (STS) encompasses a diverse group of mesenchymal tumors. The latest 5th edition of the World Health Organization (WHO) provides classifications of tumors of soft tissue and bone, including adipocytic tumors, fibroblastic and myofibroblastic tumors, so-called fibrohistiocytic tumors, vascular tumors, pericytic (perivascular) tumors, smooth muscle tumors, skeletal muscle tumors, gastrointestinal stromal tumors, chondro-osseous tumors, peripheral nerve sheath tumors, tumors of uncertain differentiation, and undifferentiated small round cell sarcomas of bone and soft tissues.[1,2] For most advanced STS (ASTS), the primary therapeutic strategy is conventional chemotherapy. Doxorubicin (DOX)-based treatments represent the first line option with anthracycline-based regimen.[3]
However, several studies have demonstrated that the addition of IFO to DOX failed to improve the overall responses and survival outcomes in ASTS patients.[4–7] In clinical practice for ASTS, DOX plus IFO chemotherapy is still recommended as a first-line option, especially for younger age (<65 years old) and well-performance (ECOG 0-1) patients.
For enhancing the efficacy and reducing the toxicities, different types of isophosphoramide mustard have been explored. To date, novel-fosfamides (NFOs) comprise evofosfamide, trofosfamide, palifosfamide, glufosfamide, aldoifosfamide, etc. These drugs are the active metabolites of IFO and can bypass the generation of toxic byproducts, including acrolein and chloracetaldehyde.[8,9]
NFOs are associated with specific antitumor effects as alkylating agents. Nevertheless, whether the addition of NFO to DOX as first-line therapy improves survival outcomes and responses compared with single-drug DOX in patients with ASTS remains unclear.
Thus, we conducted a pooled analysis to comprehensively evaluate the NFO monotherapy or plus DOX combination therapy versus DOX alone in ASTS patients.
2. Methods
This pooled analysis was conducted based on the guideline of the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA).[10] The data used in the analysis were not original raw data but were based on published clinical studies with ethical approval. Therefore, ethical approval was not necessary.
2.1. Search strategy
A systematic literature search was performed in online PubMed, Web of Science, Embase, and Cochrane CENTRAL databases on April 26, 2022. Search terms were (1) soft tissue sarcoma, (2) doxorubicin or adriamycin, and (3) prodrug OR isophosphoramide OR evofosfamide OR TH-302 OR trofosfamide OR palifosfamide OR ZIO-201 OR glufosfamide OR aldoifosfamide. References in relevant studies were reviewed for more eligible records.
2.2. Selection criteria
Inclusion criteria included (1) previously untreated ASTS patients (neoadjuvant therapy followed by surgery and adjuvant therapy was allowed, but should no disease progression within a period of 6 months), (2) eligible patients were treated with NFO-based monotherapy or in combination with DOX versus DOX alone, (3) prospective clinical studies, (4) data of responses, survivals, and toxicities were available.
Exclusion criteria were (1) review or comment or letter, (2) meeting abstract, (3) single-arm study, (4) study protocol, (5) subgroup analysis, and (6) basic research. Any disagreements were resolved by discussion.
2.3. Data extraction and quality assessment
Objective response rate (ORR) and disease control rate (DCR) were defined as the primary outcomes. Overall survival (OS), progression-free survival (PFS), and grade 3 or worse treatment-related adverse events (TRAEs) were the secondary outcomes. Two of us (Bi-Cheng Wang and Guo-He Lin) independently extracted trial name, year of publication, study design, groups, dose, number of patients, median age, median OS, median PFS, median treatment duration, response events, survival outcomes, and grade 3 or worse TRAEs. For unreported original time-to-event survival data, we used Engauge Digitizer software and the statistic formula reported by Jayne F Tierney to reconstruct the hazard ratio (HR) and 95% confidence interval (CI).[11] Bi-Cheng Wang and Guo-He Lin used the Jadad scale to assess the methodological quality of each eligible clinical study.[12]
2.4. Statistical analysis
Risk ratios (RRs) with 95% CIs were adopted to evaluate the ORR and DCR data. While HRs and 95% CIs were used to assess the data of OS and PFS. R software (version 4.1) and the “meta” package was applied to pooled-analyze the responses, survival outcomes, and toxicities.
Heterogeneities were evaluated by I2 and t2 statistic percentages. Both fixed effect and random effects models were calculated. When I2 < 50% or P < .1, the heterogeneity was low, and then the results calculated through a fixed effect model with Mantel-Haenszel method were extracted. Otherwise, results through random effects model were selected. Differences between the groups with P values < 0.05 were deemed statistically significant.
3. Results
3.1. Eligible clinical trials and basic characteristics
Our search identified 332 relevant records. Two hundred thirty-seven records remained after screening duplicated records (n = 95). 38 records were eligible for full-text assessment while 199 irrelevant records were excluded. Subsequently, 11 reviews/comments/letters, 10 meeting abstracts, 6 single-arm studies, 6 study protocols, 1 subgroup analysis, and 1 basic research were excluded. Finally, 3 prospective, multicenter, randomized clinical trials evolving 1207 ASTS patients were enrolled (Fig. 1).[13–15]
Figure 1.
Process of selecting eligible randomized clinical trials.
The basic characteristics of the eligible clinical trials were depicted in Table 1. Two studies were phase 3 trials, comparing NFO plus DOX with DOX alone, and one was a phase 2 trial, comparing NFO with DOX. The age of enrolled patients ranged from 18 to 89. According to the scores generated from Jadad scale (high quality ≥ 3), all studies were defined as high quality. The histologic subtypes of ASTS mainly included: leiomyosarcoma, synovial sarcoma, liposarcoma, angiosarcoma, myxofibrosarcoma, undifferentiated pleomorphic sarcoma, rhabdomyosarcoma, malignant peripheral nerve sheath tumor.
Table 1.
Basic characteristics of the eligible clinical trials.
| Trial | Year of publication | Design | Group | Dose | Number of patients | Median age (years, range) | Jadad score | |
|---|---|---|---|---|---|---|---|---|
| PICASSO III | 2016 | A multicenter, randomized, double-blind, phase 3 trial | Doxorubicin + Palifosfamide Doxorubicin + Placebo |
Doxorubicin: 75 mg/m2/d, i.v., d1 Palifosfamide 150 mg/m2/d, i.v., d1-3 q3w, for up to 6 cycles |
Doxorubicin: 75 mg/m2/d, i.v., d1 q3w, for up to six cycles |
226 221 |
58 (19–85) 56 (18–83) |
5 |
| TH CR-406/ SARC021 |
2017 | A multicenter, randomized, open-label, phase 3 trial | Doxorubicin + Evofosfamide Doxorubicin |
Doxorubicin: 75 mg/m2/d, i.v., d1 Evofosfamide 300 mg/m2/d, i.v., d1 and d8 q3w, for up to 6 cycles |
Doxorubicin: 75 mg/m2/d, i.v., d1 q3w, for up to six cycles |
317 323 |
60 (49–67) 58 (49–66) |
3 |
| AIO-STS-002 | 2020 | A multicenter, randomized, open-label, phase 2 trial | Trofosfamide Doxorubicin |
Trofosfamide: 300 mg/d, p.o., d1-7, 150 mg/d, p.o., continuously | Doxorubicin: 60 or 75 mg/m2/d, i.v., d1 q3w, for up to 6 cycles |
80 40 |
70 (60–89) 71 (60–84) |
3 |
3.2. Responses
Five hundred forty-three patients received NFO plus DOX combination therapy, 75 patients received NFO monotherapy, and 544 patients received DOX monotherapy. Compared with DOX alone, NFO plus DOX significantly increased the ORR (RR 1.50, 95% CI 1.20–1.86, fixed effect model, P = .0003) and DCR (RR 1.15, 95% CI 1.05–1.27, fixed effect model, P = .003) (Fig. 2). However, NFO monotherapy showed comparable responses compared with DOX monotherapy (ORR: RR 0.87, 95% CI 0.22–3.44, fixed effect model; DCR: RR 0.78, 95% CI 0.55–1.10, fixed effect model).
Figure 2.
Forest plots of the pooled risk ratios for objective response rate (A) and disease control rate (B) between noval-fosfamide monotherapy or plus doxorubicin combination therapy and single-drug doxorubicin therapy.
3.3. Survival outcomes
Table 2 depicted the median OS, PFS, and treatment duration in detail. In each study, both groups showed similar survival outcomes.
Table 2.
Median overall survival, progression-free survival, and treatment duration in the enrolled trials.
| Trial | Group | Median overall survival | Median progression-free survival | Median treatment duration |
|---|---|---|---|---|
| PICASSO III-2016 | Doxorubicin + Palifosfamide Doxorubicin + Placebo |
15.9 months (95% CI 13.7–19.4) 16.9 months (95% CI 14.8–22.9) |
6.0 months (95% CI 5.4–6.5) 5.2 months (95% CI 4.2–6.0) |
4.3 months 4.6 months |
| TH CR-406/SARC021–2017 | Doxorubicin + Evofosfamide Doxorubicin |
18.4 months (95% CI 15.6–22.1) 19.0 months (95% CI 16.2–22.4) |
6.3 months (95% CI 6.0–7.8) 6.0 months (95% CI 4.6–6.2) |
6.7 months (IQR 3.9–13.8) 6.2 months (IQR 3.7–10.4) |
| AIO-STS-002–2020 | Trofosfamide Doxorubicin |
12.3 months (95% CI 9.6–16.2) 9.8 months (95% CI 6.7–11.6) |
2.8 months (95% CI 1.7–3.6) 4.3 months (95% CI 2.2–6.3) |
2.8 months (95% CI 0.4–41.4) 2.8 months (95% CI 0–4.6) |
HR and 95% CI data in AIO-STS-002 trial were reconstructed according to the OS and PFS curves. Comparing NFO versus DOX, the reproduced HR for OS was 0.64, (95% CI 0.41–0.99), and for PFS was 1.41 (95% CI 1.00–1.98). The pooled HRs for OS were 1.06 (95% CI 0.54–2.05, fixed effect model, P = .8703) when comparing NFO plus DOX with DOX alone and 0.93 (95% CI 0.52–1.65, fixed effect model, P = .8050) when comparing all NFO-based therapies versus DOX monotherapy (Fig. 3A). The pooled HRs for PFS was 0.85 (95% CI 0.52–1.41, fixed effect model, P = .5354) when comparing NFO plus DOX with DOX alone and 0.88 (95% CI 0.54–1.43, fixed effect model, P = .6088) when comparing all NFO-based therapies versus DOX monotherapy (Fig. 3B). The forest plots showed that no survival benefits were found in the NFO-based treatments compared to DOX.
Figure 3.
Forest plots of the pooled hazard ratio for overall survival (A) and progression-free survival (B) between noval-fosfamide monotherapy or plus doxorubicin combination therapy and single-drug doxorubicin therapy.
3.4. Toxicities grade ≥ 3 treatment-related adverse events
Eleven grade 3 or worse TRAEs were pooled-analyzed and depicted in Table 3. Compared with DOX monotherapy, NFO-based therapy showed higher incidences of anemia (RR 2.11, 95% CI 1.70–2.62, fixed effect model, P < .0001), thrombocytopenia (RR 7.05, 95% CI 3.34–14.9, fixed effect model, P < .0001), stomatitis (RR 2.99, 95% CI 1.49–6.03, fixed effect model, P = .0021), and constipation (RR 6.22, 95% CI 1.13–34.34, fixed effect model, P = .0359).
Table 3.
Poole analyses of grade 3 or worse treatment-related adverse events.
| Trial | PICASSO III-2016 | TH CR-406/SARC021–2017 | subgroup RR (95% CI) | AIO-STS-002–2020 | subgroup RR (95% CI) | Total RR (95% CI) | |||
|---|---|---|---|---|---|---|---|---|---|
| Groups | Doxorubicin + Palifosfamide (n = 220) | Doxorubicin (n = 214) | Doxorubicin + Evofosfamide (n = 313) | Doxorubicin (n = 308) | Trofosfamide (n = 76) | Doxorubicin (n = 39) | |||
| Anemia | 37 | 19 | 150 | 65 |
Fixed effect model: 2.19 (1.75–2.73, P < .0001) Random effects model: 2.20 (1.76–2.74, P < .0001) |
7 | 4 | Fixed effect model: 0.90 (0.28–2.88) Random effects model: 0.90 (0.28–2.88) |
Fixed effect model: 2.11 (1.70–2.62, P < .0001) Random effects model: 2.04 (1.50–2.76, P < .0001) |
| Neutropenia | 65 | 45 | 47 | 92 | Fixed effect model: 0.80 (0.64–1.00, P = .0478) Random effects model: 0.84 (0.31–2.30, P = .7335) |
1 | 13 | Fixed effect model: 0.04 (0.01–0.29) Random effects model: 0.04 (0.01–0.29) |
Fixed effect model: 0.72 (0.58–0.89, P = .0022) Random effects model: 0.49 (0.17–1.45, P = .1995) |
| Thrombocytopenia | 9 | 3 | 45 | 4 | Fixed effect model: 7.57 (3.48–16.46, P < .001) Random effects model: 6.04 (1.61–22.74, P = .0078) |
1 | 0 | Fixed effect model: 1.56 (0.06–37.39) Random effects model: 1.55 (0.06–37.16) |
Fixed effect model: 7.05 (3.34–14.9, P < .0001) Random effects model: 5.25 (1.68–16.42, P = .0044) |
| Nausea | 10 | 4 | 5 | 2 |
Fixed effect model: 2.44 (0.96–6.23, P = .0619) Random effects model: 2.44 (0.96–6.23, P = .0619) |
3 | 0 | Fixed effect model: 3.64 (0.19–68.68) Random effects model: 3.61 (0.19–68.25) |
Fixed effect model: 2.56 (1.05–6.25, P = .0395) Random effects model: 2.53 (1.04–6.18, P = .0414) |
| Vomiting | 12 | 6 | 3 | 1 |
Fixed effect model: 2.09 (0.86–5.05, P = .1021) Random effects model: 2.07 (0.86–5.02, P = .1061) |
2 | 0 | Fixed effect model: 2.60 (0.13–52.81) Random effects model: 2.58 (0.13–52.48) |
Fixed effect model: 2.13 (0.91–4.98, P = .0802) Random effects model: 2.11 (0.90–4.93, P = .0846) |
| Fatigue | 10 | 10 | 16 | 11 |
Fixed effect model: 1.21 (0.69–2.13, P = .5021) Random effects model: 1.21 (0.69–2.13, P = .5085) |
4 | 2 | Fixed effect model: 1.03 (0.20–5.36) Random effects model: 1.03 (0.20–5.36) |
Fixed effect model: 1.19 (0.70–2.03, P = .5183) Random effects model: 1.19 (0.70–2.03, P = .5250) |
| Stomatitis | 4 | 1 | 26 | 7 |
Fixed effect model: 3.68 (1.71–7.94, P = .0009) Random effects model: 3.68 (1.71–7.93, P = .0009) |
0 | 1 | Fixed effect model: 0.17 (0.01–4.15) Random effects model: 0.17 (0.01–4.13) |
Fixed effect model: 2.99 (1.49–6.03, P = .0021) Random effects model: 2.34 (0.59–9.35, P = .2291) |
| Diarrhea | 6 | 0 | 4 | 1 |
Fixed effect model: 6.85 (1.24–37.81, P = .0272) Random effects model: 6.04 (1.06–34.38, P = .0426) |
0 | 1 | Fixed effect model: 0.17 (0.01–4.15) Random effects model: 0.17 (0.01–4.13) |
Fixed effect model: 3.07 (0.94–10.07, P = .0638) Random effects model: 2.35 (0.25–22.43, P = .4591) |
| Asthenia | 4 | 5 | 3 | 1 |
Fixed effect model: 1.14 (0.39–3.36, P = .8137) Random effects model: 1.09 (0.35–3.40, P = .8826) |
3 | 0 | Fixed effect model: 3.64 (0.19–68.68) Random effects model: 3.61 (0.19–68.25) |
Fixed effect model: 1.38 (0.51–3.76, P = .5253) Random effects model: 1.27 (0.44–3.63, P = .6602) |
| Constipation | 1 | 0 | 4 | 0 |
Fixed effect model: 5.88 (0.71–48.60, P = .1002) Random effects model: 5.35 (0.62–46.10, P = .1272) |
6 | 0 | Fixed effect model: 6.75 (0.39–116.86) Random effects model: 6.71 (0.39–116.12) |
Fixed effect model: 6.22 (1.13–34.34, P = .0359) Random effects model: 5.81 (1.04–32.39, P = .0449) |
| Febrile neutropenia | 44 | 25 | 57 | 34 |
Fixed effect model: 1.68 (1.24–2.26, P = .0007) Random effects model: 1.68 (1.24–2.26, P = .007) |
– | – | – | – |
The bold words meant the adopted model in the analysis. The underlines meant the differences were statistically significant.
RR = risk ratio.
In subgroup analysis, adding NFO to DOX increased the incidences of anemia (RR 2.19, 95% CI 1.75–2.73, fixed effect model, P < .0001), thrombocytopenia (RR 6.04, 95% CI 1.61–22.74, random effects model, P = .0078), stomatitis (RR 3.68, 95% CI 1.71–7.94, fixed effect model, P = .0009), diarrhea (RR 6.85, 95% CI 1.24–37.81, fixed effect model, P = .0272), and febrile neutropenia (RR 1.68, 95% CI 1.24–2.26, fixed effect model, P = .0007).
No significant differences between the groups in terms of neutropenia, nausea, fatigue, and asthenia were found.
4. Discussion
In this pooled analysis of randomized clinical trials, the addition of NFO to DOX enhanced the ORR (1.50, 95% CI 1.20–1.68, P = .0003) and DCR (1.15, 95% CI 1.05–1.27, P = .0030), whereas NFO-based monotherapy and combination therapy failed to significantly prolong OS (HR 0.93, 95% CI 0.52–1.65, P = .8050) and PFS (HR 0.88, 95% CI 0.54–1.43, P = .6088) against DOX alone in ASTS patients. In addition, more grade ≥ 3 TRAEs, including anemia, thrombocytopenia, stomatitis, diarrhea, constipation, and febrile neutropenia, were reported in the NFO group.
In contrast to IFO (ORR: RR 1.37, 95% CI 0.94–1.99, P = .10),[7] NFO seems more effective when combined with DOX in elevating the response rates in ASTS. However, up to now, no direct comparison studies between IFO and NFO have been conducted. Future network analyses may show us the answer.
In terms of the subgroup analysis in PICASSO III and TH CR-406/SARC021, survival outcomes showed no significant differences between the groups in any of the subgroups analyzed (age, sex, race, metastatic disease, grade, previous treatment, performance status, tumor type, etc), except HR for OS in synovial sarcoma (0.32, 95% CI 0.14–0.73). Thus, some types of ASTS did benefit from the addition of NFO to DOX.
For furtherly increasing the control rates, radiotherapy is crucial for ASTS. In Littau study, adjuvant radiotherapy was associated with improved OS for patients with larger than 10 cm retroperitoneal liposarcoma (HR 0.75, 95% CI 0.64–0.89).[16] Additionally, immunotherapy has been widely explored in sarcoma patients. However, the combination of immunotherapy and chemotherapy showed moderate antitumor effects (Nab-paclitaxel plus sintilimab; ORR: 25%; DCR: 50%; median PFS: 2.25 months) in ASTS, according to Tian report.[17] An ongoing phase 2 trial compares stereotactic body radiotherapy plus immunotherapy (atezolizumab) with stereotactic body radiotherapy alone in ASTS, intending to investigate whether the efficacy of immunotherapy would be enhanced by radiotherapy.[18] We are waiting for the upcoming data.
Treatment-related death is an essential issue that should be mentioned. In TH CR-406/SARC021 trial, 2 and 8 deaths due to TRAEs were recorded in the DOX and DOX plus NFO groups, respectively.[14] In PICASSO III trial, 7 deaths related to TRAEs were recorded (2 for thrombocytopenia in the DOX plus NFO group; 1 for right ventricular failure, 1 for hemorrhagic shock, and 3 for sepsis or septic shock in the DOX group).[13] Therefore, treatment-related deaths need constant caution during DOX-based treatments.
5. Limitations
Limitations existed in this analysis. Soft tissue sarcoma is a very diverse and complicated disease comprising over 100 histological subtypes. DOX or NFO-contained chemotherapies might not be the most optimal choice for all these subtypes. Additionally, the administration of subsequent systemic and local therapies after disease progression could have certain impacts on survival outcomes. However, this could be hard for researchers to balance the bias when trials have ended. At last, AIO-STS-002 trial compared NFO monotherapy with DOX monotherapy, which might bias the final results and reduce the benefits or toxicities. Therefore, subgroup analyses were applied to control the bias during this pooled study.
6. Conclusion
Compared with DOX alone, DOX plus NFO significantly increased response rates in ASTS patients. Meanwhile, NFO-related toxicities deserved serious attention. Future studies are necessary to investigate more effective subsequent strategies to improve the survival.
Acknowledgments
We thank the SNOWELL studio for helping to provide statistical support and improve the language.
Author contributions
Conceptualization: Bi-Cheng Wang.
Data curation: Xin-Xiu Liu, Guo-He Lin, Bi-Cheng Wang.
Formal analysis: Xin-Xiu Liu, Guo-He Lin, Bi-Cheng Wang.
Funding acquisition: Bi-Cheng Wang.
Investigation: Guo-He Lin, Bi-Cheng Wang.
Methodology: Xin-Xiu Liu, Bo-Hua Kuang, Guo-He Lin, Bi-Cheng Wang.
Project administration: Yan-Hong Han, Bo-Hua Kuang, Bi-Cheng Wang.
Resources: Yan-Hong Han, Bo-Hua Kuang, Guo-He Lin, Bi-Cheng Wang
Supervision: Xin-Xiu Liu, Yan-Hong Han, Bo-Hua Kuang, Guo-He Lin, Bi-Cheng Wang.
Software: Bo-Hua Kuang, Guo-He Lin, Bi-Cheng Wang.
Validation: Xin-Xiu Liu, Yan-Hong Han, Bo-Hua Kuang, Guo-He Lin, Bi-Cheng Wang.
Visualization: Xin-Xiu Liu, Bo-Hua Kuang, Guo-He Lin, Bi-Cheng Wang.
Writing – original draft: Xin-Xiu Liu, Yan-Hong Han, Bo-Hua Kuang, Guo-He Lin, Bi-Cheng Wang.
Writing – review & editing: Xin-Xiu Liu, Yan-Hong Han, Bo-Hua Kuang, Guo-He Lin, Bi-Cheng Wang.
Abbreviations:
- ASTS
- advanced soft-tissue sarcoma
- DCR
- disease control rate
- DOX
- doxorubicin
- HR
- hazard ratio
- NFOs
- novel-fosfamides
- ORR
- objective response rate
- OS
- overall survival
- PFS
- progression-free survival
- STS
- soft tissue sarcoma
- TRAEs
- treatment-related adverse events
The authors have no funding and conflicts of interest to disclose.
All data generated or analyzed during this study are included in this published article [and its supplementary information files].
How to cite this article: Liu X-X, Han Y-H, Kuang B-H, Lin G-H, Wang B-C. Novel-fosfamide monotherapy or in combination with doxorubicin versus doxorubicin alone in patients with advanced soft tissue sarcoma: A pooled analysis of randomized clinical trials. Medicine 2023;102:33(e34902).
Contributor Information
Xin-Xiu Liu, Email: whuhxinxiu@163.com.
Yan-Hong Han, Email: yanhonghan2015@163.com.
Bo-Hua Kuang, Email: kuangbohua@163.com.
Guo-He Lin, Email: linguohe2020@163.com.
References
- [1].Board WCoTE. WHO Classification of Tumours. Lyon, France: IARC Press. 2020;3. [Google Scholar]
- [2].Choi JH, Ro JY. The 2020 WHO classification of tumors of soft tissue: selected changes and new entities. Adv Anat Pathol. 2021;28:44–58. [DOI] [PubMed] [Google Scholar]
- [3].von Mehren M, Kane JM, Bui MM, et al. NCCN guidelines insights: soft tissue sarcoma, version 1.2021. J Natl Compr Canc Netw. 2020;18:1604–12. [DOI] [PubMed] [Google Scholar]
- [4].Judson I, Verweij J, Gelderblom H, et al. Doxorubicin alone versus intensified doxorubicin plus ifosfamide for first-line treatment of advanced or metastatic soft-tissue sarcoma: a randomised controlled phase 3 trial. Lancet Oncol. 2014;15:415–23. [DOI] [PubMed] [Google Scholar]
- [5].Santoro A, Tursz T, Mouridsen H, et al. Doxorubicin versus CYVADIC versus doxorubicin plus ifosfamide in first- line treatment of advanced soft tissue sarcomas: a randomized study of the European organization for research and treatment of cancer soft tissue and bone sarcoma group. J Clin Oncol. 1995;13:1537–45. [DOI] [PubMed] [Google Scholar]
- [6].Maurel J, López-Pousa A, De Las Peñas R, et al. Efficacy of sequential high-dose doxorubicin and ifosfamide compared with standard-dose doxorubicin in patients with advanced soft tissue sarcoma: an open-label randomized phase II study of the Spanish group for research on sarcomas. J Clin Oncol. 2009;27:1893–8. [DOI] [PubMed] [Google Scholar]
- [7].Wang BC, Kuang BH, Xiao BY, et al. Doxorubicin/adriamycin monotherapy or plus ifosfamide in first-line treatment for advanced soft tissue sarcoma: a pooled analysis of randomized trials. Front Oncol. 2021;11:762288. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [8].Tascilar M, Loos WJ, Seynaeve C, et al. The pharmacologic basis of ifosfamide use in adult patients with advanced soft tissue sarcomas. Oncologist. 2007;12:1351–60. [DOI] [PubMed] [Google Scholar]
- [9].Hingorani P, Zhang W, Piperdi S, et al. Preclinical activity of palifosfamide lysine (ZIO-201) in pediatric sarcomas including oxazaphosphorine-resistant osteosarcoma. Cancer Chemother Pharmacol. 2009;64:733–40. [DOI] [PubMed] [Google Scholar]
- [10].Moher D, Liberati A, Tetzlaff J, et al. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA Statement. Open Med. 2009;3:e123–130. [PMC free article] [PubMed] [Google Scholar]
- [11].Tierney JF, Stewart LA, Ghersi D, et al. Practical methods for incorporating summary time-to-event data into meta-analysis. Trials. 2007;8:16. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [12].Jadad AR, Moore RA, Carroll D, et al. Assessing the quality of reports of randomized clinical trials: is blinding necessary? Control Clin Trials. 1996;17:1–12. [DOI] [PubMed] [Google Scholar]
- [13].Ryan CW, Merimsky O, Agulnik M, et al. PICASSO III: a phase III, placebo-controlled study of doxorubicin with or without palifosfamide in patients with metastatic soft tissue sarcoma. J Clin Oncol. 2016;34:3898–905. [DOI] [PubMed] [Google Scholar]
- [14].Tap WD, Papai Z, Van Tine BA, et al. Doxorubicin plus evofosfamide versus doxorubicin alone in locally advanced, unresectable or metastatic soft-tissue sarcoma (TH CR-406/SARC021): an international, multicentre, open-label, randomised phase 3 trial. Lancet Oncol. 2017;18:1089–103. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [15].Hartmann JT, Kopp HG, Gruenwald V, et al. Randomised phase II trial of trofosfamide vs. doxorubicin in elderly patients with untreated metastatic soft-tissue sarcoma. Eur J Cancer. 2020;124:152–60. [DOI] [PubMed] [Google Scholar]
- [16].Littau MJ, Kulshrestha S, Bunn C, et al. The importance of the margin of resection and radiotherapy in retroperitoneal liposarcoma. Am J Surg. 2021;221:554–60. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [17].Tian Z, Dong S, Yang Y, et al. Nanoparticle albumin-bound paclitaxel and PD-1 inhibitor (sintilimab) combination therapy for soft tissue sarcoma: a retrospective study. BMC Cancer. 2022;22:56. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [18].Birdi HK, Jirovec A, Cortes-Kaplan S, et al. Immunotherapy for sarcomas: new frontiers and unveiled opportunities. J ImmunoTher Cancer. 2021;9:e001580. [DOI] [PMC free article] [PubMed] [Google Scholar]