Treatments

Soft Tissue Sarcoma Treatment Based on Tumor Stage¹

 

Stage I sarcomas: Surgery is recommended as primary treatment to remove the tumor. This is often curative. If positive margins are found, follow-up treatment may include a second surgery, observation, or radiation.

Stage II sarcomas: Surgery may be an option for stage II tumors. Stage II tumors may be treated with surgery alone, or radiation therapy may be needed after surgery if the margins are positive. Radiation therapy may also be used before surgery to reduce tumor size and decrease the chance of relapse. If surgery is not possible, radiation, chemotherapy, chemoradiation, or isolated limb infusion/perfusion are recommended.

Stage III sarcomas: Surgery may be an option for stage III tumors. If the tumor can be resected, neoadjuvant treatments to reduce the tumor size include chemotherapy, radiation, or chemoradiation. Radiation before surgery is recommended by NCCN guidelines. If margins are positive after surgery, radiation with or without adjuvant chemotherapy is recommended. If surgery is not possible, radiation, chemotherapy, chemoradiation, or isolated limb infusion/perfusion are recommended.

Stage IV sarcomas: It is still unclear what treatments are most effective for stage IV sarcomas. Clinical trials are the preferred treatment option. If the metastases have spread to one organ, local treatment options used for stage II and III may be used. Alternatively, surgery can be used to remove the metastases along with chemotherapy before or after surgery, with or without radiation. Other options include ablation, embolization, stereotactic body radiation therapy (SBRT), or observation. For widespread stage IV sarcoma, observation is an option if asymptomatic. If symptomatic, palliative care may be necessary. Chemotherapy, radiation, surgery, ablation or embolization may also be used to slow tumor growth in widespread stage IV cancer.

Challenges in the Personalization of Patient Treatment

The current version of the National Comprehensive Cancer Center guidelines includes a wide range of regimens that lack supporting randomized trial evidence, and there are few treatment pathways to guide treatment decision making.²

Individualizing treatment strategies for patients with advanced soft tissue sarcomas (STSs) can be a daunting challenge for oncologists unfamiliar with this group of rare heterogeneous cancers. Oncologists need to take into account not only the large number of available therapeutic agents, but also their potential combinatorial and/or sequential use (Table 1). Additionally, and perhaps most importantly, clinicians must be mindful of patient-specific factors that make some treatments more likely than others to fail or succeed.

Table 1. Proposed treatment sequence for advanced or metastatic, high-grade STSs^1,3,4

Sarcoma subtype	First line	Second line	Third line	Fourth line
UPS	aAnthracycline-based regimen	Gemcitabine + docetaxel	Pazopanib	PDL-1
LPS	aAnthracycline-based regimen	bTrabectedin or eribulin	Eribulin or trabectedin
LMS	aAnthracycline-based regimen	cGemcitabine + docetaxel	Trabectedin	Pazopanib
SS	aAnthracycline-based regimen	dHigh-dose ifosfamide	Pazopanib
MPNST	aAnthracycline-based regimen	Pazopanib

^aAnthracycline-based regimens include: single-agent doxorubicin, doxorubicin and ifosfamide, doxorubicin and olaratumab, or liposomal doxorubicin.

^bTrabectedin particularly effective for myxoid/round cell LPS.

^cGemcitabine + docetaxel particularly effective for uterine LMS.

^dHigh-dose ifosfamide only recommended for select patients with good performance status and preserved renal function.

UPS, undifferentiated pleomorphic sarcoma; LPS, liposarcoma; LMS, leiomyosarcoma; SS, synovial sarcoma; MPNST, malignant peripheral nerve sheath tumor.

Doxorubicin (± ifosfamide) is the standard first-line systemic treatment for advanced STSs; however, newer chemotherapeutic agents may improve outcomes achieved with single-agent doxorubicin.^4,5 The recent addition of olaratumab/doxorubicin for patients with non-specific histology to the NCCN guidelines reflect the phase II study results in 133 patients with advanced/metastatic STS.¹ Specifically, the improved metastatic progression free survival of 6.6 months compared to 4.1 months and median overall survival of 26.5 compared to 14.7 months, combination arm versus the doxorubicin only arm, respectively.⁶ Agents for second- and further lines include trabectedin, which combines long-term tumor stabilization with good quality of life, and gemcitabine + docetaxel, which can produce a marked clinical response although at the cost of high toxicity. Pazopanib, eribulin, aldoxorubicin and regorafenib are other options for use in advanced STSs.^4,5

Mounting evidence from phase III clinical trials supports the selection of histology-driven treatment, particularly in the setting of advanced disease, and the current version of the NCCN STS guidelines recommends that “Treatment options should be decided by a multidisciplinary team with extensive experience in the treatment of patients with STS,based on the patient’s age, performance status, comorbidities, location, and histologic subtype of the tumor.” ² For example, second- and later-line medical therapy for advanced STS is increasingly histology driven, with a tendency for available active agents to be used in specific histologies⁵. In a multicenter phase III trial comparing trabectedin and dacarbazine in patients with advanced liposarcoma or leiomyosarcoma, the risk of disease progression or death in the final analysis of progression free survival was reduced by 45% with trabectedin.⁷An interim analysis of overall survival indicated a nonsignificant 13% reduction in the risk of death favoring trabectedin. These results support the use of trabectedin over dacarbazine in advanced liposarcoma and leiomyosarcoma after failure of prior chemotherapy. Eribulin, was compared with dacarbazine in a phase III study of patients with advanced liposarcoma and leiomyosarcoma.⁸ Median overall survival was significantly improved in patients randomized to eribulin, although the advantage over dacarbazine occurred mainly in the patient subset with liposarcoma (15 vs. 8 months). Treatment arms differed significantly only for median overall survival, not for progression free survival or objective response rate.

REFERENCES

1. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology. Soft Tissue Sarcoma. V2.2019. https://www.nccn.org/professionals/physician_gls/pdf/sarcoma.pdf. Accessed March 14, 2019.
2. von Mehren M, Randall RL, Benjamin RS, et al. Soft Tissue Sarcoma, Version 2.2018, NCCN Clinical Practice Guidelines in Oncology. J Natl Compr Canc Netw. 2018;16:536-563.
3. In G, Hu J, Tseng W. Treatment of advanced, metastatic soft tissue sarcoma: latest evidence and clinical consideration. Ther Adv Med Oncol. 2017;9:533-550.
4. Seetharam M, Kolla K, Chawla S. Metastatic Soft Tissue Sarcomas: A review of treatments and new pharmacotherapies. Clin Oncol. 2018;3: Article1426.
5. Blay J. Getting up-to-date in the management of soft tissue sarcoma. Future Oncol. 2018;14:3-13.
6. Tap W, Jones R, Van Tine B, et al. Olaratumab and doxorubicin versus doxorubicin alone for treatment of soft-tissue sarcoma: an open-label phase 1b and randomised phase 2 trial. Lancet. 2016a;388:488-497.
7. Moroncini G, Maccaroni E, Fiordoliva I, et al. Developments in the management of advanced soft-tissue sarcoma – olaratumab in context. Onco Targets Ther. 2018;11:833-842.
8. Demetri G, von Mehren M, Jones R, et al. Efficacy and safety of trabectedin or dacarbazine for metastatic liposarcoma or leiomyosarcoma after failure of conventional chemotherapy: results of a Phase III randomized multicenter clinical trial. J Clin Oncol. 2016;34:786-793.
9. Schöffski P, Chawla S, Maki R, et al. Eribulin versus dacarbazine in previously treated patients with advanced liposarcoma or leiomyosarcoma: a randomised, open-label, multicentre, Phase 3 trial. Lancet. 2016; 387:1629-1637.