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Systemic Therapy for Sarcomas

Oncology

Authors

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Elise F. Nassif, M.D., M.S.
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Emily Z. Keung, M.D., A.M.
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Introduction

Sarcomas are a group of rare cancers of mesenchymal origin. Over 100 distinct sarcoma subtypes are described, and advances in molecular characterization have led to continued refinement and characterization of sarcoma subtypes that historically had been lumped together [1].
Broadly, sarcomas can be differentiated into three main categories: soft tissue sarcoma, bone sarcoma, and gastrointestinal stromal tumor. Each category has its own generalized treatment paradigm that in recent years has become more subtype-specific with some subtypes now having specific treatments unique from the more generalized algorithms that up until recently guided most sarcoma management decisions. Here, we summarize the current management strategies with a focus on use of systemic therapies for different sarcoma subtypes. We also highlight specific sarcoma subtypes with management strategies that deviate from the more generalized approach.

Soft Tissue Sarcoma

Management of localized soft tissue sarcoma
Curative intent surgery consisting of complete en bloc tumor resection, with wide margins when feasible, is critical for patients with localized soft tissue sarcomas. Patients with an inadequate initial surgery are more likely to develop metastatic disease, so recognition of a sarcoma diagnosis and referral to experienced sarcoma centers when possible prior to an initial resection is highly recommended. For patients with primary sarcomas of the extremities or trunk, limb-sparing surgery is now considered standard of care if complete resection with negative margins can be achieved with adequate functional outcomes.
Often for large extremity sarcomas wide margins cannot be achieved. In these cases, preoperative or postoperative radiotherapy is recommended in conjunction with limb-sparing surgery as this has been shown to improve rates of local control. The role of radiotherapy is less certain for abdominal/retroperitoneal cases. A large, randomized trial failed to show benefit of radiation in these cases, although on post-hoc subgroup analysis there may be benefit of radiotherapy in patients with low grade liposarcomas [2].
In spite of many efforts to demonstrate benefit of adjuvant chemotherapy for resected, localized soft tissue sarcomas, no prospective studies have been able to clearly show such a benefit. A meta-analysis published in 1997 showed improvement in relapse-free survival (RFS) with a trend towards improvement in overall survival (OS) [3].
The largest prospective study evaluating adjuvant chemotherapy after adequate local control (surgery and radiation as indicated) randomized patients to either no chemotherapy or doxorubicin 75 mg/m2 and ifosfamide 5 g/m2 (whereas current standards use ifosfamide 10g/m2) [4].
Again, there was a non-significant trend towards improved OS with receipt of chemotherapy. Further analysis of this trial later demonstrated OS benefit specifically in the patients with high-risk tumors, defined as those having a 10-year predicted OS of 60% or less based on a validated risk nomogram [5]. A criticism of the studies performed to date is that they may have used sub-par chemotherapy dosing and, in many cases, included patients with lower grade disease who were less likely to benefit from chemotherapy. Collectively, these data fail to support universal use of adjuvant chemotherapy. However, it can be considered for patients with large (>5cm), high-grade tumors who are at increased risk of metastasis and poor outcomes.
For patients with large high-grade tumors for whom chemotherapy is being considered, neoadjuvant chemotherapy is now generally favored. One potential benefit of this approach is that it allows for direct assessment of any clinical benefit by direct tumor assessment. Neoadjuvant treatment has the possibility of facilitating surgery for patients with reduction in tumor size, which occurs in ~40% of patients receiving doxorubicin and ifosfamide. Histotype-tailored chemotherapy did not lead to improved outcomes [6], so if neoadjuvant chemotherapy is to be given the recommended regimen is doxorubicin (75 mg/m2 bolus with dexrazoxane) and ifosfamide (10 g/m2). When medically contraindicated or for IVC based leiomyosarcomas, dacarbazine can be substituted in place of ifosfamide.
Metastatic soft tissue sarcoma
For many years, multi-agent chemotherapy was a cornerstone of treatment for patients with most metastatic or unresectable soft tissue sarcoma. Specifically, (CyVADIC: cyclophosphamide, vincristine, adriamycin, dacarbazine), and then doxorubicin, ifosfamide, and dacarbazine were used in the recent past. Doxorubicin and ifosfamide then became standard, and now, after randomized trial demonstrated progression-free survival (PFS) benefit but limited OS benefit of combination doxorubicin and ifosfamide over single agent doxorubicin, single agent doxorubicin 75 mg/m2 is the recommended first systemic therapy for most metastatic soft tissue sarcomas [7].
However, in patients with oligo-metastatic disease, potentially amenable to local treatment of all macroscopic disease, doxorubicin and ifosfamide combination can be considered as it yields higher response rates than doxorubicin alone (26% vs 14%).
Second-line therapy generally consists of gemcitabine-based combinations. Gemcitabine and docetaxel led to a median PFS of 6.2 months and median OS of 17.9 months, an improvement over gemcitabine and is my favored approach for second-line therapy. However, this comes at the cost of increased toxicity with about 40% of patients discontinuing therapy due to toxicity alone [8]. An alternative combination is gemcitabine and dacarbazine, which has similar efficacy and a somewhat more favorable toxicity profile [9].
More recently, subtype-specific chemotherapies have been approved for later lines of therapy. One of the first was trabectedin, an agent that binds to the DNA minor groove. After initial studies showed activity in leiomyosarcoma and dedifferentiated liposarcomas, a larger trial demonstrated that trabectedin has a median PFS of 4.2 months, significant over dacarbazine, but demonstrated a similar median OS of slightly over 1 year and modest objective response rate (ORR) [10].
In spite of the modest result, trabectedin was approved for use by European and US regulatory agencies based on the PFS benefit. Of note, trabectedin has higher clinical activity in myxoid/round cell liposarcoma and is a preferred systemic therapy for that subtype. Additionally, trabectedin can be used for translocation-associated sarcomas based on a demonstrated survival benefit over best supportive care in a randomized study in Japan [11].
Pazopanib is a multi-tyrosine kinase inhibitor (TKI). In the pivotal PALETTE study which randomized patients to pazopanib or placebo, pazopanib demonstrated a median PFS of 4.6 months (compared to 1.5 months) with a trend towards improved OS. ORR was low with just 6% having a radiographic response by RECIST criteria. However, 67% had stable disease as best response and pazopanib is now used for non-adipocytic soft tissue sarcomas [12].
Eribulin is a microtubule destabilizing agent that, initially, demonstrated activity in leiomyosarcoma and liposarcoma. A large randomized trial in these 2 subtypes showed OS benefit but not PFS benefit. In subgroup analysis, the OS benefit was largely driven by the liposarcoma subgroup with improvement over dacarbazine in LPS patients, whereas the leiomyosarcoma patients had survival similar to that seen in dacarbazine [13]. Therefore, although eribulin can be considered for both leiomyosarcoma and liposarcoma, its approval in the US is only for liposarcoma after progression or intolerance to 2 prior lines of systemic therapy.
Other agents are actively being explored. Based on the presence of CDK4 amplification in liposarcomas, CDK4 inhibitors palbociclib and abemaciclib have demonstrated activity with favorable PFS in single-arm phase 2 trials [14,15]. Immune checkpoint inhibitors, which have revolutionized care for many different cancer types, have been less successful in soft tissue sarcomas but hints of activity yield promise for future study. Pembrolizumab has an ORR of ~20% in undifferentiated pleomorphic sarcoma [16] and is a preferred treatment for that sarcoma subtype.
Angiosarcoma is generally managed outside of the above soft tissue sarcoma paradigms. Paclitaxel has a high response rate and is often used as first line therapy, especially in cutaneous angiosarcomas, due to its efficacy and generally favorable toxicity profile. However, the median duration of response with paclitaxel is low at around 4-6 months [17].
Immune checkpoint inhibition has recently been shown to be active in some angiosarcomas – particularly cutaneous tumors of the scalp or face, and is a preferred option for these patients [18]. Epithelioid sarcoma is characterized by INI-1 loss. This led to development of tazemetostat, an EZH2 inhibitor for this disease. After demonstrating a response rate of 15% and median PFS of 5.5 months, tazemetostat is now a preferred first line option [19]. Subsequent therapies for both angiosarcoma and epithelioid sarcoma follow the refractory soft tissue sarcoma pathways as described previously.
Figure 1. Management Schematic for Soft Tissue Sarcoma

Gastrointestinal Stromal Tumor (GIST)

Gastrointestinal stromal tumors are thought to originate in the interstitial cells of Cajal and can arise anywhere within the gastrointestinal tract (GI) [20]. Management of GIST was revolutionized by the identification of its molecular drivers – namely KIT and PDGFR-alpha mutations – and effective TKIs. While molecular drivers can be identified for most cases, diagnosis remains histological with GISTs characterized by KIT (CD117) and DOG1 expression.
The mainstay of treatment for resectable disease is surgery. Historically, patients with resected GIST had about a 50% chance of distant recurrence [21]. Now, several nomograms exist to stratify patients into those at high- versus low-risk of recurrence following GIST resection. These nomograms are based on key variables including tumor size, origin in the GI tract, and perhaps most importantly the mitotic index. Low-risk patients do not need adjuvant imatinib and can be followed with regular surveillance imaging of the abdomen and pelvis. However, the cutoff between high- and low-risk is not well defined, leaving many patients in an “intermediate” risk group.
Discussion of the potential risks versus benefits of imatinib and shared decision-making is critical for these patients in deciding upon a plan. For patients with high-risk disease, Joensuu et al. demonstrated a 20% RFS and 5% OS benefit with 3 years of adjuvant imatinib 400 mg daily compared to 1 year of adjuvant imatinib [22], and 3 years of adjuvant imatinib is considered standard treatment. Although the optimal treatment duration with imatinib in the adjuvant setting is not known, based on these and other data many believe that longer treatment is even better and will continue patients on adjuvant imatinib for as long as they are tolerating the drug and there is no tumor recurrence [23].
When technically possible, KIT and PDGFR-alpha mutations testing should be performed on all patients for whom systemic therapy with a TKI is being considered. 80% of patients will have a mutation in KIT, with the most common primary driver mutations in KIT exon 11, followed by KIT exon 9 mutations. Notably, patients with a KIT exon 9 mutation require a higher daily dose of imatinib – 800 mg daily. 10% of patients will have mutations in PDGFR-alpha, most of which are also sensitive to 400 mg imatinib. However, it is now recognized that some mutations in PDGFR-alpha exon 18 (especially D842V) confer resistance to imatinib. Several TKIs were developed to have activity against this mutation, and now avapritinib is approved in the United States for upfront treatment of unresectable or metastatic PDGFR-alpha exon 18 mutated GIST due to an overall response rate of 86% in this population [24].
A series of randomized phase 3 clinical trials established a standard sequencing of TKIs for upfront treatment of metastatic GIST. First, imatinib demonstrated a dramatic OS benefit over doxorubicin [25]. After progression or intolerance to imatinib, sunitinib 50 mg every 4 weeks with a 2 week break improved PFS over placebo with a median PFS of 27 weeks compared to 6.4 weeks with placebo [26]. An alternate regimen of continuous sunitinib 37.5 mg daily can be considered to improve tolerance. After sunitinib, regorafenib is considered standard based on PFS advantage of 4.8 months versus 0.9 months with placebo [27]. Finally, ripretinib was recently approved in the US after demonstrating an OS of 15 month versus 6.6 months for placebo in 4th line or later [28].
When multifocal progression occurs on ripretinib, one option is to escalate the dose of ripretinib to 150 mg twice daily [29]. Dose escalation led to partial metabolic response in 13 of 37 patients, with a median PFS from the point of dose escalation of 4.6 months for patients at or beyond the 4th line of therapy. If progression is localized to one or few spots, then it could be reasonable to maximize the benefit of any given TKI with targeted intervention such as surgery, ablation, or radiation to limited sites of progression. Other TKIs can also be used – avapritinib [30], dasatinib [31], and pazopanib [32]. Immunotherapy can also be considered, with rare responses and some patients deriving clinical benefit [33]. Repeat tumor genetic testing may be beneficial and could be considered to guide management of refractory disease.
Treatment of patients without activating KIT or PDGFR-alpha mutations is less well established. When no mutations are found on initial sequencing, we recommend broader mutation testing as several other conditions or mutations can be associated with this so called “wild-type” GIST. These include mutations resulting in SDH-deficiency, BRAF or NF1 mutations, NTRK fusions, and others [34]. Although these tumors are less likely to respond to TKIs, the treatment paradigms are generally the same as those used for GISTs with the more common KIT or PDGFR mutations.
Figure 2. Management Schematic for Gastrointestinal Stromal Tumor

Bone Sarcoma

Most malignant bone sarcomas in adults are osteosarcoma, Ewing sarcoma, or chondrosarcoma. Unlike the soft tissue tumors described above, all patients with conventional osteosarcoma or Ewing sarcoma require long courses of multi-agent chemotherapy.
The EURAMOS trial established 10 weeks of neoadjuvant doxorubicin, cisplatin, and methotrexate followed by surgery (limb sparing if possible) and additional adjuvant chemotherapy as the preferred management for localized osteosarcoma [35]. Chemotherapy for metastatic disease is the same as that used for localized disease but is given with palliative intent. After progression on front-line chemotherapy, high dose ifosfamide [36], gemcitabine-based regimens [37], and regorafenib [38] are some options with demonstrated efficacy. Osteosarcoma is considered a radioresistant tumor, although radiation can be used in cases where other options have been exhausted.
Ewing sarcoma chemotherapy consists of vincristine, doxorubicin, and ifosfamide, followed by definitive local therapy, and then additional VDC/IE (vincristine, doxorubicin, cyclophosphamide, alternating with ifosfamide and etoposide). Compressed interval dosing has a survival advantage, although this dosing is difficult for adults to tolerate and often needs to be modified for toxicity [39].
An alternative in adult populations is vincristine, doxorubicin, and ifosfamide every 3 weeks, as tolerance of interval compressed VDC/IE is challenging in this population [40]. In contrast to osteosarcoma, Ewing sarcoma is a radiosensitive disease and definitive radiation can be used when surgery would carry unacceptable morbidity with curative intent. The rEECur trial established high dose ifosfamide as the preferred regimen for refractory, metastatic Ewing sarcoma [41].
Chondrosarcoma is considered a chemo-resistant cancer. Surgery should be considered when possible, including for oligometastatic disease. For unresectable disease, clinical trials are a preferred option. A subset of chondrosarcomas (65%) harbor mutations in IDH1 or IDH2, and some clinical activity was seen with the IDH inhibitor ivosidenib [42].
Figure 3. Management Schematic for Malignant Bone Tumors

Other “indolent” Histologies

Advances in our understanding of the biology of many sarcoma subtypes has led to many exceptions to the general strategies mentioned above. Some of these and their associated systemic therapies and rationale are listed here:

PEComa

PEComas are the most aggressive of a spectrum of myoepithelial tumors ranging from angiolipoma to angiomyolipoma to PEComa. About 40% of PEComas harbor loss-of-function mutations in TSC1 or TSC2, resulting in marked enhancement of signaling through the PI3K/mTOR pathway. The consequent activation of mTOR resulting from these TSC1/2 mutations can be targeted with the mTOR inhibitors rapamycin or nab-rapamycin [43,44].

Desmoid

Desmoid fibromatosis is a “benign” proliferation that can cause significant morbidity. Historically, surgical resection was often performed for these tumors but associated with high local recurrence risk and is in the current era no longer the favored initial approach to desmoid management. Systemic therapy choices are driven by the severity of symptoms and whether critical structures are threatened. Patients who have minor or no symptoms may be observed without intervention. Placebo controlled trials for desmoid tumors have shown a 8-20% ORR in the placebo group [45,46].
For patients with moderate symptoms, the TKIs sorafenib [46] or imatinib [47] can be considered for first line therapy. Hormonal therapy with tamoxifen or non-steroidal anti-inflammatory drugs (NSAIDs), either as single agent or in combination, were previously used widely but are now falling out of favor. Newer agents including gamma-secretase inhibitors are actively being studied, with encouraging early results [45]. Other non-systemic interventions like cryoablation or radiation can also be effective for controlling desmoid tumors and improving pain and can therefore be considered.

Giant Cell Tumor of Bone

Giant cell tumor of bone is a locally destructive neoplasm that rarely metastasizes but has a high rate of local recurrence. Denosumab, a RANK-L inhibitor, is effective in this disease with a response rate of 35% when using RECIST criteria but as high as 82% as assessed by the modified EORTC criteria [48,49].

Tenosynovial Giant Cell Tumor

Tenosynovial giant cell tumor (TGCT), previously known as pigmented villonodular synovitis (PVNS) is another locally aggressive tumor with high recurrence rate after surgery. In particular, the diffuse type of TGCT which typically affects larger joints is difficult to definitively manage surgically. Molecularly, TGCT overexpresses CSF-1. Pexidartinib is a potent CSF1R inhibitor that yielded responses in 39% of patients after 25 weeks compared to no responses seen with placebo [50].

Solitary fibrous tumor

Solitary fibrous tumor is another tumor with varying behavior. It is defined by a characteristic fusion of NAB2 and STAT6. SFTs that are unresectable or metastatic can be treated with inhibitors of the VEGF pathway. Regimens include pazopanib which has 58% response rate by Choi criteria [51], sunitinib which has a 53% response rate by Choi criteria [52], or bevacizumab with temozolomide which had a 79% response rate by Choi criteria in a retrospective analysis [53].
Table 1. Other special histologies
Epithelioid SarcomaTazemetostat
Alveolar Soft Parts SarcomaAtezolizumab, Axitinib+Pembrolizumab
PEComamTOR inhibitors (nab-rapamycin, rapamycin, everolimus)
Tenosynovial Giant Cell Tumor (TGCT), previously PVNSPexidartinib (CSF1R inhibitor)
Giant Cell Tumor of BoneDenosumab
Desmoid FibromatosisSorafenib, Pazopanib, Nirogacestat
Solitary Fibrous TumorPazopanib, Sunitinib, Temozolomide+Bevacizumab
Pleomorphic RhabdomyosarcomaTreat like STS (Figure 1)
Pediatric type rhabdomyosarcoma (Alveolar, Embryonal)Multi-agent chemotherapy

Summary

Sarcomas are a heterogenous group of diseases for which systemic therapies are often used. When localized, curative intent surgery is the mainstay of management for most sarcoma subtypes with radiotherapy administered in the neoadjuvant or adjuvant setting for appropriate clinical scenarios/indications.
Chemotherapy is controversial for localized soft tissue sarcomas, although patients with large high-grade tumors may benefit from anthracycline-based combination chemotherapy in the neoadjuvant or adjuvant setting.
Anthracycline remains the first systemic therapy of choice for most metastatic soft tissue sarcoma, with preferred subsequent lines of therapy evolving as newer data is becoming more and more subtype specific.
Unlike soft tissue sarcoma, the bone sarcomas osteosarcoma and Ewing sarcoma are systemic diseases and multi-agent chemotherapy is required for all patients regardless of extent of disease at presentation.
Gastrointestinal stromal tumor does not respond to chemotherapy but can be very sensitive to tyrosine kinase inhibitors. When possible, multidisciplinary evaluation at a sarcoma specialty center should be considered for all patients with sarcoma diagnosis.

References

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