Chemotherapy for Soft-Tissue Sarcomas

Table: Conventional Chemotherapy for Adjuvant Treatment of Soft Tissue Sarcomas: Summary of Outcomes of Selected Trials

Cytotoxic chemotherapy with doxorubicin in combination with ifosfamide or dacarbazine, or gemcitabine in combination with docetaxel, continues to be the mainstay of treatment of metastatic soft-tissue sarcomas. A goal-oriented approach that includes careful consideration of histology, performance status, sites of disease, patient goals, and intent of treatment is vital to the formulation of an effective treatment plan. Both single-agent and combination chemotherapy regimens are available and should be chosen carefully to fit the clinical situation and patient goals. In patients with localized soft-tissue sarcoma who have a high likelihood of recurrent disease, systemic therapy should be strongly considered. The ability to demonstrate efficacy in the neoadjuvant setting may help avoid unnecessary treatment-related toxicity in patients with poor response and maximize recurrence-free survival in patients who do demonstrate an excellent response to therapy.

Introduction

Soft-tissue sarcomas are a heterogeneous group of rare tumors that arise from or differentiate toward tissues of mesodermal origin. These tumors can occur in any part of the body and have the potential for establishing metastatic disease. Their biologic behavior is dependent upon the histopathologic subtype; it can range from indolent disease with low metastatic potential and a course of progression spanning several years, to aggressive disease that is fatal within a few months. In addition to histopathologic subtype, the size and grade of these tumors also have an impact on the risk of developing metastatic disease. Multidisciplinary care at a high-volume center is required for optimal outcomes in patients with this rare disease. Patients with localized disease should be treated using surgical resection with curative intent, with incorporation of radiation and chemotherapy depending on the risk of local and distant recurrence. In patients with high-risk localized disease, the use of systemic chemotherapy should be strongly considered to delay recurrence and/or reduce the patient’s risk of developing metastatic disease. In patients with metastatic disease, systemic chemotherapy remains the mainstay of treatment.

Systemic Therapy of Metastatic Soft-Tissue Sarcoma

Systemic treatment of metastatic sarcoma can involve cytotoxic chemotherapy and/or targeted therapies with limited toxicity. While the idea of administering targeted therapies that have more favorable toxicity profiles than cytotoxic chemotherapy is attractive, use of such agents (for example, pazopanib and imatinib) in an unselected population of sarcoma patients has yielded limited results thus far. Cytotoxic chemotherapy may achieve higher response rates than targeted agents in unselected patient populations that are not enriched for presence of a driver molecular target relevant to the agent in use.

Cytotoxic chemotherapy

Both single-agent and combination chemotherapy options are available for the treatment of patients with metastatic soft-tissue sarcoma. The question of optimal initial (and subsequent) therapy is largely one of sequencing, given that during the course of their illness most patients receive all the available agents shown to have activity in soft-tissue sarcoma, since complete durable responses to any specific agent are rare. Choice of therapy should be made using a goal-based approach, as outlined below, with particular attention paid to the histologic subtype and the performance status of the patient.

Single-agent chemotherapy

While the reported single-agent activity of a wide variety of agents studied in soft-tissue sarcoma has been marginal, with response rates of 10% or less, doxorubicin and ifosfamide have stood out as promising, with response rates ranging from 20% to 35%. Several other chemotherapeutic agents, such as dacarbazine, temozolomide, cisplatin, carboplatin, and vinorelbine, have been studied in the treatment of soft-tissue sarcomas but tend to yield response rates of less than 20%.

Doxorubicin. Doxorubicin has been in use for the treatment of sarcomas since the 1970s,[1] and it continues to be used to this day in the management of these tumors. While many potential adverse effects are associated with doxorubicin, it remains the single most effective chemotherapeutic agent available against multiple histopathologic subtypes of sarcomas. In the 1970s, single-agent activity of doxorubicin at 60 mg/m² was initially reported, showing complete remission in 9% and partial remission in 32% of patients with metastatic sarcomas.[1] A dose-response relationship has been identified in sarcomas, with lower doses such as 25 mg/m² producing response rates as low as 12% in poor-risk patients, and higher doses of 60–75 mg/m² producing higher response rates of 25% to 27%.[2] Doxorubicin can cause cardiac toxicity, mucositis, myelosuppression, alopecia, nausea, and vomiting; the manifestation and severity of these toxicities are directly proportional to the schedule and dose administered. Choice of therapy should, therefore, include consideration of the performance status of the patient, and the quality of life (QoL) desired by the patient. Although doxorubicin is typically administered as a continuous infusion over a period of 48 to 72 hours, bolus administration is associated with less mucositis and more cardiac toxicity. Risk of cardiotoxicity can be reduced by concomitant use of dexrazoxane.[3]

Pegylated liposomal doxorubicin is also active in soft-tissue sarcomas, but it is unclear whether the response rates are equivalent to those achieved with doxorubicin. Doses higher than 60 mg/m² per cycle are difficult to administer, due to debilitating mucocutaneous toxicity (eg, hand-foot syndrome), and this is a limitation in a disease in which a dose-response relationship has been demonstrated for the nonliposomal preparation of the drug. In a randomized phase II trial of pegylated liposomal doxorubicin vs doxorubicin in patients with advanced/metastatic soft-tissue sarcoma-with leiomyosarcoma (33%), angiosarcoma (12%), and synovial sarcoma (12%) representing the top three histologies of the patients enrolled-the response rates of the two groups were equivalent. The overall response rate (ORR) in both groups was lower than normally expected (approximately 10%), a result thought to be due to both inclusion of patients with gastrointestinal stromal tumor (GIST) and stringent response-review procedures.[4] Another phase II trial of pegylated liposomal doxorubicin showed responses in 3 of 47 patients with advanced/metastatic sarcoma. This study was also limited by the fact that 15 patients with GIST were included in the study. Excluding these patients, the response rate was still low, at 9.3%.[5]

Ifosfamide. Sequential studies with single-agent ifosfamide performed at The University of Texas MD Anderson Cancer Center suggest a dose-response relationship, with incremental increases in response rates from 6 g/m², to 8 g/m², to 10 g/m² per cycle.[6] Data on single-agent activity of high-dose ifosfamide come from two simultaneous prospective clinical trials at MD Anderson Cancer Center that enrolled a total of 37 patients with soft-tissue sarcoma. A continuous infusion of high-dose ifosfamide at a dose of 14 g/m² produced a 19% response rate in patients with soft-tissue sarcoma, while the same dose administrated as a bolus produced a 45% response rate.[7] Investigators at the Dana-Farber Cancer Institute have demonstrated similar results in a phase II clinical trial of ifosfamide at 8 g/m² that showed a response rate of 26% with a bolus-infusion schedule and a 9% response rate with a continuous-infusion schedule.[8] Due to the results of these studies, at our center we have chosen to administer ifosfamide as a 2–3 hour “bolus” rather than a 24-hour continuous infusion. Single-agent ifosfamide produces results similar to those seen with doxorubicin monotherapy, with no differences in progression-free survival (PFS), overall survival (OS), or response rates, as shown by a phase III clinical trial that compared doxorubicin at 75 mg/m² with ifosfamide at a dose of 9 g/m².[9]

Ifosfamide does show a dose-response relationship, with high-dose therapy circumventing the resistance to standard-dose ifosfamide.[10] Toxicities commonly associated with ifosfamide include neurotoxicity, nephrotoxicity, and reversible hematologic toxicity. Hemorrhagic cystitis is an uncommon problem with concurrent administration of optimal doses of the mesna, which is considered standard of care with ifosfamide.

Gemcitabine. Gemcitabine as a single agent has a broad range of activity in several histologic subtypes of soft-tissue sarcoma. Some histopathologic subtypes are particularly sensitive, eg, leiomyosarcoma and angiosarcoma. A phase II clinical trial in soft-tissue sarcoma showed an ORR of 18%, with a median duration of response of 3.5 months.[11] Other trials have shown response rates as low as 4% to 7%,[12-15] reflecting the variability of response in clinical trials whose enrolled patients represent a mixture of different sarcoma histologies. In well-selected histologies, the response rate for single-agent gemcitabine can be quite high, as shown by Stacchiotti et al, who demonstrated an ORR of 68% in patients with angiosarcoma.[16] Gemcitabine is well tolerated by patients with sarcoma, especially the elderly. In patients with a poor performance status who may not tolerate combination chemotherapy, single-agent gemcitabine is a viable choice.

Dacarbazine and temozolomide. Dacarbazine as single-agent therapy in the treatment of soft-tissue sarcomas has been reported to achieve an ORR of 17%[17] to 18%.[18] In contrast, a phase II trial of temozolomide in 49 patients with pretreated soft-tissue sarcomas showed an ORR of 15.5%. In uterine leiomyosarcomas treated with temozolomide, however, the ORR was higher, at 45%.[19]

Vinorelbine. Use of this agent in pediatric sarcomas yielded an ORR of 29%, with 6 of 12 patients with rhabdomyosarcoma showing objective responses.[20] In adults, a retrospective study showed a much lower ORR of 6%, and stable disease was observed in 26% of patients.[21]

Cisplatin and carboplatin. Both cisplatin and carboplatin are poorly studied in soft-tissue sarcomas and appear to have minimal activity. A phase II trial of cisplatin as first-line therapy in patients with advanced or recurrent uterine sarcoma showed a 3% response rate.[22] In a phase II trial of carboplatin, a 16% response rate was observed in soft-tissue sarcoma patients who had received doxorubicin as their only prior systemic therapy.[23]

Trabectedin. Trabectedin has activity in myxoid liposarcoma and leiomyosarcoma. A phase II trial of trabectedin in advanced/recurrent uterine leiomyosarcoma by the Gynecologic Oncology Group (GOG) showed a partial response rate of 10% and stable disease in 50% of patients. Median PFS and OS were 5.8 months and > 26.1 months, respectively.[24] In patients with myxoid liposarcoma, a phase II clinical trial of neoadjuvant trabectedin showed a 13% pathologic complete response (CR), with an objective response rate of 24% by Response Evaluation Criteria in Solid Tumors (RECIST). No progression was noted in the study; trabectedin was administered at a dose of 1.5 mg/m², given as a 24-hour IV infusion every 3 weeks.[25] At the time of writing this review, the drug remains without US Food and Drug Administration (FDA) approval (for any indication) and therefore is unavailable to US patients with sarcoma.

Paclitaxel. While paclitaxel has limited utility in the management of most soft-tissue sarcomas, it is highly effective in the management of angiosarcoma. In a phase II trial of paclitaxel in soft-tissue sarcomas, two partial responses (7%) were observed among 28 patients, one of whom had angiosarcoma.[26] The clinical activity of paclitaxel in angiosarcomas of the head and neck was subsequently confirmed in a group of 9 patients treated with paclitaxel; 8 of these had a major response lasting more than 5 months.[27] In the ANGIOTAX study, a phase II trial that enrolled 30 patients with angiosarcoma, paclitaxel administered at 80 mg/m² (on days 1, 8, and 15 of a 4-week cycle) yielded a response rate of only 18% at 4 months, with a median time to progression (TTP) of 4 months. The lower level of paclitaxel activity observed in this trial may be related to the higher proportion of visceral angiosarcomas, the mean dose-intensity of 53.4 mg/m²/wk, and/or the strict response criteria employed in a formal study such as this one.[28] Paclitaxel appears to have better activity in patients with cutaneous angiosarcomas; a retrospective review of 117 patients with metastatic angiosarcoma has shown that paclitaxel activity may be comparable to that of single-agent doxorubicin in patients with cutaneous angiosarcoma. In this study, 53% of the 68 patients had a response to treatment, and an additional 29.5% had stable disease.[29] Paclitaxel should therefore be considered for use in patients with angiosarcoma, especially cutaneous angiosarcoma.

Combination chemotherapy

Several combination chemotherapy regimens are used in the treatment of soft-tissue sarcomas. They may be classified into doxorubicin-based regimens and non–doxorubicin-based regimens.

Doxorubicin-based regimens include:

• Doxorubicin and ifosfamide.
• Doxorubicin, ifosfamide, dacarbazine.
• Doxorubicin and dacarbazine.

The non–doxorubicin-based regimens include:

• Gemcitabine and docetaxel.
• Ifosfamide and etoposide.
• Cyclophosphamide and topotecan.

Doxorubicin and ifosfamide with or without dacarbazine. The superiority of doxorubicin and ifosfamide combination therapy over single-agent doxorubicin was demonstrated by an Eastern Cooperative Oncology Group (ECOG) study that included 262 assessable patients randomized to single-agent doxorubicin (at 80 mg/m²) vs doxorubicin (at 60 mg/m²) plus ifosfamide (at 7.5 g/m²) vs mitomycin (at 8 mg/m²), doxorubicin (at 40 mg/m²), and cisplatin (at 60 mg/m²). This trial demonstrated a statistically significant increase in response rate for doxorubicin plus ifosfamide over single-agent doxorubicin (34% vs 20%, P = .03). However, no statistically significant differences were noted in survival between all three arms of the study.[30] The addition of ifosfamide to multiagent chemotherapy was looked into in a large Intergroup study that randomized 305 patients to doxorubicin at 60 mg/m² plus dacarbazine at 1,000 mg/m² vs doxorubicin at 60 mg/m² plus ifosfamide at 6–7.5 g/m² plus dacarbazine at 1,000 mg/m²; statistically significant improvements in response rate (17% vs 32%; P < .002) and TTP (4 vs 6 months; P < .02) were observed in favor of combination therapy with doxorubicin, ifosfamide, and dacarbazine.[31] These trials suggest that the addition of ifosfamide to doxorubicin-based chemotherapy regimens is associated with an improvement in response rate and possibly PFS. In patients with limited metastatic disease in whom surgical resection of residual disease is planned after chemotherapy, a doxorubicin and ifosfamide–containing regimen should be considered for first-line therapy, as it increases the probability of response. Dose intensity may also be a critical factor in obtaining optimal results, as indicated by the European Organisation for Research and Treatment of Cancer (EORTC) trial that randomized 605 patients to single-agent doxorubicin (at 75 mg/m²); vs cyclophosphamide, vincristine, doxorubicin, and dacarbazine; vs doxorubicin (at 50 mg/m²) plus ifosfamide (at 5 g/m²). This large trial failed to show any differences between the three arms in terms of response rate, duration of response, or survival. Therefore, lower doses of the combination of doxorubicin and ifosfamide have no advantages over higher doses of single-agent doxorubicin.[32] Investigators at MD Anderson Cancer Center have evaluated a dose-intensive combination of doxorubicin (at 75–90 mg/m²) and ifosfamide (at 10 g/m²) with growth factor support in two serial pilot studies; they report higher rates of both CR (9%) and ORR (64%) with this treatment.[33] The 2014 EORTC phase III randomized trial (N = 455) that compared doxorubicin at 75 mg/m² with a combination of doxorubicin (at 75 mg/m²) and ifosfamide (at 10 g/m²) showed statistically significant improvements in PFS (4.6 mo vs 7.4 mo) and ORR (14% vs 26%). While OS was not statistically superior at the sample size that was examined, there was certainly a trend towards better survival with combination therapy (12.8 mo vs 14.3 mo).[34] The statistical significance of OS depends upon the sample size and the effect size chosen by the investigators; in addition, it measures the cumulative effects of all therapies received by the patient, making this endpoint harder to interpret.[35] Based on these findings, at our institution carefully selected patients (< 65 years of age, performance status 0–2) with metastatic soft-tissue sarcoma are treated with a combination of doxorubicin (75 mg/m²) and ifosfamide (10 g/m²), especially if additional surgery is planned.

Doxorubicin and dacarbazine. Doxorubicin and dacarbazine each have single-agent activity in soft-tissue sarcomas; consequently, the utility of the dacarbazine combination has been explored in a number of clinical trials. Borden and colleagues randomized patients with metastatic soft-tissue sarcoma to three groups, in order to compare the efficacy of combination therapy that included doxorubicin with that of single-agent doxorubicin: there were two groups utilizing different dosing schedules of single-agent doxorubicin and a third group treated with doxorubicin and dacarbazine. Patients treated with combination therapy were found to have a 30% response rate, while those in the two arms treated with single-agent doxorubicin had comparable response rates (16% and 18%). The median survival time was equivalent for both single-agent and combination chemotherapy (8 months). The largest histologic subtype in this study was leiomyosarcoma, and the doxorubicin/dacarbazine combination produced a 44% response rate in this group, a higher response than was observed for patients with any other histologic subtype.[36] In a randomized trial of doxorubicin with and without dacarbazine in patients with recurrent uterine sarcoma, Omura and colleagues reported a 16% response rate with single-agent doxorubicin compared with a 24% response with a combination of doxorubicin and dacarbazine.[37] Similar to the results of Borden et al, there was no survival advantage for combination therapy over single-agent doxorubicin in this study. Based on the improved response rates observed, however, combination therapy may have a role in patients with unresectable tumors who desire surgical resection of their disease. This regimen is also a reasonable choice for patients with poor renal function (who are not candidates for ifosfamide) and patients over 65 years of age, in whom the nephrotoxicity of ifosfamide is considerable. From a toxicity standpoint, the combination is better tolerated compared with doxorubicin + ifosfamide and therefore safe to use in patients with poor performance status. This regimen is also preferred for patients with nonuterine leiomyosarcoma, in whom the activity of ifosfamide may be suboptimal.[8]

Gemcitabine and docetaxel. This combination is widely used by medical oncologists for the treatment of patients with sarcoma, due to its broad spectrum of activity and a favorable toxicity profile (compared with the combination of doxorubicin and ifosfamide). The combination of gemcitabine and docetaxel was initially studied in leiomyosarcomas by Hensley and colleagues,[38] who reported a 53% ORR. Subsequent studies have identified a broader range of activity in other histologic subtypes. The French Sarcoma Group published a retrospective study evaluating the activity of gemcitabine + docetaxel in 133 patients with soft-tissue sarcoma (76 with leiomyosarcomas and 57 with other histologies). The ORR was 18% (with a 24% response rate for patients with leiomyosarcomas and a 10% response rate for those with other sarcoma histologies), and median survival time was 12 months.[39]

The utility of adding docetaxel to single-agent gemcitabine was examined in a phase III randomized controlled trial that showed the combination to be superior to single-agent gemcitabine. OS with single-agent gemcitabine was 11.5 months, while patients treated with the combination had a median OS of 17.9 months.[40] In patients with metastatic soft-tissue sarcoma who have good performance status, the combination of gemcitabine and docetaxel is therefore standard of care.

Ifosfamide and etoposide. The combination of ifosfamide and etoposide has been used to treat high-grade sarcomas, with a partial response rate of 40% and median TTP of 8 months.[41] While this combination has significant activity in small-cell sarcomas, its utility in other high-grade sarcomas may be more pronounced in patients without prior exposure to ifosfamide, either given alone or in combination with doxorubicin. The combination of ifosfamide and etoposide is widely used in the treatment of Ewing sarcoma, either alone or alternating with vincristine, doxorubicin, and cyclophosphamide. This regimen, alternating with vincristine, doxorubicin, and cyclophosphamide, has been investigated in the treatment of high-grade soft-tissue sarcomas, and has shown a comparable response rate and marginally improved survival.[42]

Cyclophosphamide and topotecan. This combination therapy appears to have activity in patients with pediatric sarcomas, especially rhabdomyosarcoma, neuroblastoma, and Ewing sarcoma.[43-46] Based on a phase II study in adults, this combination is active in adults with the same histologies for which it is observed to be effective in the pediatric population, ie, Ewing sarcoma and rhabdomyosarcoma. Partial responses were observed in two of six patients with rhabdomyosarcomas, and in one patient with synovial sarcoma. Stable disease was observed in Ewing sarcoma (40%), desmoplastic small round cell tumor and synovial sarcoma.[47] Very little is known about the role of combination therapy with cyclophosphamide and topotecan in the treatment of other high-grade sarcomas.

Goal-Based Treatment Planning

Systemic therapy is the primary approach to disease control in patients with multifocal disease or systemic dissemination. Most patients with metastatic soft-tissue sarcoma will die from disease progression. Long-term survivors among patients with metastatic sarcoma are rare. Prolonged survival in the setting of metastatic disease occurs with a CR to chemotherapy or in the setting of small-volume metastasis treated with surgery following a significant response to chemotherapy.

The intent of treatment in the metastatic setting is to improve/maintain QoL; to reduce symptom burden; and, when possible, to extend life. The small possibility of long-term survival may be an important factor for patients to consider when assessing treatment options.

Several factors must be considered prior to treatment planning, including:

• Natural history of the histologic subtype that is being treated.
• Current rate of progression of disease in the patient.
• Sites of disease.
• Performance status of the patient.
• Prioritization of treatment goals (such as QoL, reduction of symptoms, improvement of survival) based on their relative importance to the patient.
• Patient preferences regarding the level of acceptable vs unacceptable treatment-related toxicity.

A high-volume sarcoma center can be of tremendous help in treating these rare diseases, as its physicians have greater familiarity with the clinical behavior of various histopathologic subtypes and can assist the treating medical oncologist in selecting the most appropriate therapy, given both the clinical situation and the patient’s preferences.

Systemic Therapy for Localized Soft-Tissue Sarcoma: Adjuvant and Neoadjuvant Chemotherapy

Overview

Use of systemic chemotherapy in the management of localized soft-tissue sarcomas remains controversial even after evaluation of results of multiple clinical trials conducted over a period of 25 years. The primary goal of neoadjuvant/adjuvant therapy is to reduce the risk of local and distant recurrences, eventually resulting in prolonged OS within the treatment group. The Table highlights some of the trials that have explored the utility of adjuvant systemic therapy in soft-tissue sarcomas.

With the exception of a few trials that have shown a statistically significant improvement in disease-free survival[48-50] and OS with this approach,[48,50] most trials have only been able to demonstrate a trend towards improved survival. Even in trials that have shown a statistically significant improvement in survival, this benefit was not sustained past 5 years on long-term follow-up.[51]

In the most recent study published by Woll and colleagues, 351 patients were randomized to receive either adjuvant chemotherapy (doxorubicin at 75 mg/m² with ifosfamide at 5 g/m²) or no additional systemic chemotherapy following surgical resection of high-grade sarcoma. The results showed no definitive evidence of a relapse-free survival or OS benefit with the use of chemotherapy.[52] Because of these findings, some authors have concluded that there is no additional benefit to adjuvant chemotherapy in patients with sarcomas. However, we believe that the lack of benefit reported by Woll et al is most likely related to the heterogeneous patient population; suboptimal chemotherapy, especially with regard to duration; the relatively small sample size; and poor patient selection, with inclusion of low-risk tumors that are less likely to need or benefit from adjuvant chemotherapy. Clinical trials that have enrolled homogeneous patient populations at high risk for metastatic disease have shown significant benefit.[48] When histology-specific therapies are available, adjuvant therapy can be very effective. Adjuvant therapy of GIST, rhabdomyosarcoma, Ewing sarcoma, and osteosarcoma are excellent examples of this approach.

Indications for adjuvant vs neoadjuvant therapy

In patients with high-risk disease in whom adjuvant chemotherapy is being actively considered, a neoadjuvant approach is strongly recommended. In the preoperative setting, there is a unique opportunity to assess response to therapy in any given patient, with the potential to change chemotherapy if the response is inadequate.

Patients who have a suboptimal response to preoperative chemotherapy are less likely to derive long-standing survival benefit from systemic therapy and can be transitioned to early surgery or other systemic therapy options based on the clinical setting. Look et al published their experience with neoadjuvant chemotherapy of soft-tissue sarcomas over a 10-year period with 66 patients. They reported an 89% rate of margin-negative resection following surgery, as well as locoregional and distant 5-year relapse-free survival rates of 91% and 64%, respectively. The 5-year OS and disease-specific survival rates were 86% and 89%, respectively, suggesting high rates of survival with neoadjuvant chemotherapy in this setting.[54] With the aid of functional imaging such as positron emission tomography (PET)/CT, early identification of responders most likely to benefit from neoadjuvant chemotherapy is now possible.

Summary

Cytotoxic chemotherapy continues to be the mainstay of treatment for metastatic soft-tissue sarcomas. A goal-oriented approach that includes careful consideration of histology, performance status, sites of disease, patient goals, and intent of treatment is vital to the formulation of an effective treatment plan. Both single-agent and combination chemotherapy regimens are available and should be chosen carefully to fit the clinical situation and patient goals.

In patients with localized soft-tissue sarcomas who have a high likelihood of recurrent disease, systemic therapy should be strongly considered. The ability to demonstrate efficacy in the neoadjuvant setting may help avoid unnecessary treatment-related toxicity for patients with poor response and maximize recurrence-free survival in patients who do demonstrate an excellent response to therapy.

Financial Disclosure:Dr. Patel is a consultant to Johnson & Johnson and Novartis. Dr. Ravi and Dr. Benjamin have no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.

References:

1. Benjamin RS, Wiernik PH, Bachur NR. Adriamycin: a new effective agent in the therapy of disseminated sarcomas. Med Pediatr Oncol. 1975;1:63-76.

2. O’Bryan RM, Baker LH, Gottlieb JE, et al. Dose response evaluation of Adriamycin in human neoplasia. Cancer. 1977;39:1940-8.

3. Huh WW, Jaffe N, Durand JB, et al. Comparison of doxorubicin cardiotoxicity in pediatric sarcoma patients when given with dexrazoxane versus as continuous infusion. Pediatr Hematol Oncol. 2010;27:546-57.

4. Judson I, Radford JA, Harris M, et al. Randomised phase II trial of pegylated liposomal doxorubicin (DOXIL/CAELYX) versus doxorubicin in the treatment of advanced or metastatic soft tissue sarcoma: a study by the EORTC Soft Tissue and Bone Sarcoma Group. Eur J Cancer. 2001;37:870-7.

5. Skubitz KM. Phase II trial of pegylated-liposomal doxorubicin (Doxil) in sarcoma. Cancer Invest. 2003;21:167-76.

6. Benjamin RS, Legha SS, Patel SR, Nicaise C. Single-agent ifosfamide studies in sarcomas of soft tissue and bone: the M.D. Anderson experience. Cancer Chemother Pharmacol. 1993;31(Suppl 2):S174-9.

7. Patel SR, Vadhan-Raj S, Papadopolous N, et al. High-dose ifosfamide in bone and soft tissue sarcomas: results of phase II and pilot studies--dose-response and schedule dependence. J Clin Oncol. 1997;15:2378-84.

8. Antman KH, Ryan L, Elias A, et al. Response to ifosfamide and mesna: 124 previously treated patients with metastatic or unresectable sarcoma. J Clin Oncol. 1989;7:126-31.

9. Lorigan P, Verweij J, Papai Z, et al. Phase III trial of two investigational schedules of ifosfamide compared with standard-dose doxorubicin in advanced or metastatic soft tissue sarcoma: a European Organisation for Research and Treatment of Cancer Soft Tissue and Bone Sarcoma Group Study. J Clin Oncol. 2007;25:3144-50.

10. Le Cesne A, Antoine E, Spielmann M, et al. High-dose ifosfamide: circumvention of resistance to standard-dose ifosfamide in advanced soft tissue sarcomas. J Clin Oncol. 1995;13:1600-8.

11. Patel SR, Gandhi V, Jenkins J, et al. Phase II clinical investigation of gemcitabine in advanced soft tissue sarcomas and window evaluation of dose rate on gemcitabine triphosphate accumulation. J Clin Oncol. 2001;19:3483-9.

12. Hartmann JT, Oechsle K, Huober J, et al. An open label, non-comparative phase II study of gemcitabine as salvage treatment for patients with pretreated adult type soft tissue sarcoma. Invest New Drugs. 2006;24:249-53.

13. Ferraresi V, Ciccarese M, Cercato MC, et al. Gemcitabine at fixed dose-rate in patients with advanced soft-tissue sarcomas: a mono-institutional phase II study. Cancer Chemother Pharmacol. 2008;63:149-55.

14. Okuno S, Ryan LM, Edmonson JH, et al. Phase II trial of gemcitabine in patients with advanced sarcomas (E1797): a trial of the Eastern Cooperative Oncology Group. Cancer. 2003;97:1969-73.

15. Von Burton G, Rankin C, Zalupski MM, et al. Phase II trial of gemcitabine as first line chemotherapy in patients with metastatic or unresectable soft tissue sarcoma. Am J Clin Oncol. 2006;29:59-61.

16. Stacchiotti S, Palassini E, Sanfilippo R, et al. Gemcitabine in advanced angiosarcoma: a retrospective case series analysis from the Italian Rare Cancer Network. Ann Oncol. 2012;23:501-8.

17. Gottlieb JA, Benjamin RS, Baker LH, et al. Role of DTIC (NSC-45388) in the chemotherapy of sarcomas. Cancer Treat Rep. 1976;60:199-203.

18. Buesa JM, Mouridsen HT, van Oosterom AT, et al. High-dose DTIC in advanced soft-tissue sarcomas in the adult. A phase II study of the E.O.R.T.C. Soft Tissue and Bone Sarcoma Group. Ann Oncol. 1991;2:307-9.

19. Garcia del Muro X, Lopez-Pousa A, Martin J, et al. A phase II trial of temozolomide as a 6-week, continuous, oral schedule in patients with advanced soft tissue sarcoma: a study by the Spanish Group for Research on Sarcomas. Cancer. 2005;104:1706-12.

20. Casanova M, Ferrari A, Spreafico F, et al. Vinorelbine in previously treated advanced childhood sarcomas: evidence of activity in rhabdomyosarcoma. Cancer. 2002;94:3263-8.

21. Anderson SE, Keohan ML, D’Adamo DR, Maki RG. A retrospective analysis of vinorelbine chemotherapy for patients with previously treated soft-tissue sarcomas. Sarcoma. 2006;2006:15947.

22. Thigpen JT, Blessing JA, Beecham J, et al. Phase II trial of cisplatin as first-line chemotherapy in patients with advanced or recurrent uterine sarcomas: a Gynecologic Oncology Group study. J Clin Oncol. 1991;9:1962-6.

23. Goldstein D, Cheuvart B, Trump DL, et al. Phase II trial of carboplatin in soft-tissue sarcoma. Am J Clin Oncol. 1990;13:420-3.

24. Monk BJ, Blessing JA, Street DG, et al. A phase II evaluation of trabectedin in the treatment of advanced, persistent, or recurrent uterine leiomyosarcoma: a Gynecologic Oncology Group study. Gynecol Oncol. 2012;124:48-52.

25. Gronchi A, Bui BN, Bonvalot S, et al. Phase II clinical trial of neoadjuvant trabectedin in patients with advanced localized myxoid liposarcoma. Ann Oncol. 2012;23:771-6.

26. Casper ES, Waltzman RJ, Schwartz GK, et al. Phase II trial of paclitaxel in patients with soft-tissue sarcoma. Cancer Invest. 1998;16:442-6.

27. Fata F, O’Reilly E, Ilson D, et al. Paclitaxel in the treatment of patients with angiosarcoma of the scalp or face. Cancer. 1999;86:2034-7.

28. Penel N, Bui BN, Bay JO, et al. Phase II trial of weekly paclitaxel for unresectable angiosarcoma: the ANGIOTAX Study. J Clin Oncol. 2008;26:5269-74.

29. Italiano A, Cioffi A, Penel N, et al. Comparison of doxorubicin and weekly paclitaxel efficacy in metastatic angiosarcomas. Cancer. 2012;118:3330-6.

30. Edmonson JH, Ryan LM, Blum RH, et al. Randomized comparison of doxorubicin alone versus ifosfamide plus doxorubicin or mitomycin, doxorubicin, and cisplatin against advanced soft tissue sarcomas. J Clin Oncol. 1993;11:1269-75.

31. Antman K, Crowley J, Balcerzak SP, et al. An intergroup phase III randomized study of doxorubicin and dacarbazine with or without ifosfamide and mesna in advanced soft tissue and bone sarcomas. J Clin Oncol. 1993;11:1276-85.

32. 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.

33. Patel SR, Vadhan-Raj S, Burgess MA, et al. Results of two consecutive trials of dose-intensive chemotherapy with doxorubicin and ifosfamide in patients with sarcomas. Am J Clin Oncol. 1998;21:317-21.

34. 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.

35. Benjamin RS, Lee JJ. One step forward, two steps back. Lancet Oncol. 2014;15:366-7.

36. Borden EC, Amato DA, Rosenbaum C, et al. Randomized comparison of three adriamycin regimens for metastatic soft tissue sarcomas. J Clin Oncol. 1987;5:840-50.

37. Omura GA, Major FJ, Blessing JA, et al. A randomized study of Adriamycin with and without dimethyl triazenoimidazole carboxamide in advanced uterine sarcomas. Cancer. 1983;52:626-32.

38. Hensley ML, Maki R, Venkatraman E, et al. Gemcitabine and docetaxel in patients with unresectable leiomyosarcoma: results of a phase II trial. J Clin Oncol. 2002;20:2824-31.

39. Bay JO, Ray-Coquard I, Fayette J, et al. Docetaxel and gemcitabine combination in 133 advanced soft-tissue sarcomas: a retrospective analysis. Int J Cancer. 2006;119:706-11.

40. Maki RG, Wathen JK, Patel SR, et al. Randomized phase II study of gemcitabine and docetaxel compared with gemcitabine alone in patients with metastatic soft tissue sarcomas: results of Sarcoma Alliance for Research Through Collaboration study 002 [corrected]. J Clin Oncol. 2007;25:2755-63.

41. Saeter G, Talle K, Solheim OP. Treatment of advanced, high-grade soft-tissue sarcoma with ifosfamide and continuous-infusion etoposide. Cancer Chemother Pharmacol. 1995;36:172-5.

42. Palumbo R, Palmeri S, Gatti C, et al. Combination chemotherapy using vincristine, Adriamycin, cyclophosphamide (VAC) alternating with ifosfamide and etoposide (IE) for advanced soft tissue sarcomas: a phase II study. Oncol Rep. 1998;5:69-72.

43. Hunold A, Weddeling N, Paulussen M, et al. Topotecan and cyclophosphamide in patients with refractory or relapsed Ewing tumors. Pediatr Blood Cancer. 2006;47:795-800.

44. Kushner BH, Kramer K, Meyers PA, et al. Pilot study of topotecan and high-dose cyclophosphamide for resistant pediatric solid tumors. Med Pediatr Oncol. 2000;35:468-74.

45. Saylors RL 3rd, Stine KC, Sullivan J, et al. Cyclophosphamide plus topotecan in children with recurrent or refractory solid tumors: a Pediatric Oncology Group phase II study. J Clin Oncol. 2001;19:3463-9.

46. Walterhouse DO, Lyden ER, Breitfeld PP, et al. Efficacy of topotecan and cyclophosphamide given in a phase II window trial in children with newly diagnosed metastatic rhabdomyosarcoma: a Children’s Oncology Group study. J Clin Oncol. 2004;22:1398-403.

47. Blanchette P, Hogg D, Ferguson P, et al. Topotecan and cyclophosphamide in adults with relapsed sarcoma. Sarcoma. 2012;2012:749067.

48. Frustaci S, Gherlinzoni F, De Paoli A, et al. Adjuvant chemotherapy for adult soft tissue sarcomas of the extremities and girdles: results of the Italian randomized cooperative trial. J Clin Oncol. 2001;19:1238-47.

49. Gherlinzoni F, Bacci G, Picci P, et al. A randomized trial for the treatment of high-grade soft-tissue sarcomas of the extremities: preliminary observations. J Clin Oncol. 1986;4:552-8.

50. Rosenberg SA, Tepper J, Glatstein E, et al. Prospective randomized evaluation of adjuvant chemotherapy in adults with soft tissue sarcomas of the extremities. Cancer. 1983;52:424-34.

51. Frustaci S, De Paoli A, Bidoli E, et al. Ifosfamide in the adjuvant therapy of soft tissue sarcomas. Oncology. 2003;65(suppl 2):80-4.

52. Woll PJ, Reichardt P, Le Cesne A, et al. Adjuvant chemotherapy with doxorubicin, ifosfamide, and lenograstim for resected soft-tissue sarcoma (EORTC 62931): a multicentre randomised controlled trial. Lancet Oncol. 2012;13:1045-54.

53. Look Hong NJ, Hornicek FJ, Harmon DC, et al. Neoadjuvant chemoradiotherapy for patients with high-risk extremity and truncal sarcomas: a 10-year single institution retrospective study. Eur J Cancer. 2013;49:875-83.