31

Medical Oncology

INTRODUCTION

While surgery ± radiation therapy remains the definitive therapy for localized, resectable, low-risk sarcomas, a significant portion of patients will require additional treatment with systemic agents owing to high risk for recurrence or development of metastatic disease. Systemic therapy of sarcoma can be broadly classified to have three separate, but often coincident goals: downstaging of a localized tumor to improve the prospects for local control with better preservation of function, treatment of high-risk localized disease to decrease the risk of distant metastatic recurrence, and treatment of metastatic and unresectable disease with the goal of symptom palliation and life prolongation. Appropriate selection of therapy used in a given scenario will take into account which of these goals are pertinent to the patient being treated, the age and comorbid conditions of that patient, acceptability of the toxicity profile of the agent or combination of agents, previous agents with which the patient may have been treated, and increasingly, specific histologic type of the tumor to be treated.

Interpreting the literature with respect to efficacy of agents also depends on thoughtful consideration of endpoints examined in clinical trials and in the clinic. The gold standard endpoint for patients treated on clinical trials is the median overall survival (OS), commonly defined as the time from initiation of treatment to the death of half the patients treated. While intuitively important, a change in OS by the agent under study can be difficult to prove in clinical trials as every intervention a patient receives before and after an experimental treatment is also going to impact survival. Patients may go on to receive multiple additional lines of systemic therapy, radiation treatments, and surgery, which may be applied to both arms in a comparison study and may make a survival improvement less observable or statistically significant. This issue is particularly pronounced in patients who are treated in a clinical trial with crossover design in which the intervention is made available to both groups, but in a different sequence. Thus, OS is most reliable in patient populations with limited treatment options, without a crossover study design, or in patients who are likely to be cured by the intervention and not require additional therapy.

To get around some of the limitations inherent in proving a better OS associated with a treatment, many trials have also reported median progression-free survival (PFS), defined as the time from initiation of therapy to progression of disease of half the treated patients, with progression defined by specified criteria (in modern studies, this is usually RECIST 1.1). PFS is often viewed as a surrogate endpoint for OS, in that if a patient’s cancer is slowed by a certain amount of time, one might assume that the patient’s life has been prolonged by the same amount of time. This may not hold true if (a) the treatment causes late toxicity that results in death or (b) the patient receives less subsequent treatment (e.g., high rates of a lethal second cancer, months or years after treatment) or (c) there is organ dysfunction that precludes additional systemic therapy or (d) the treatment somehow modifies future disease biology (making the tumor more or less susceptible to subsequent lines of therapy or more or less likely to metastasize).

Other endpoints are also of interest in specific situations. In a patient who has a tumor that is unresectable or borderline resectable, one may be most likely to use a therapy associated with higher dimensional response rate (RR), defined as the percentage of patients receiving a response based on imaging (usually RECIST 1.1). RR is also likely to be important for patients with highly symptomatic disease for which tumor shrinkage could help achieve palliation.

Measurement of RR and PFS is reliant on accurate criteria by which to determine patients who are responding or progressing on therapy. In earlier eras of treatment, physicians relied on clinical response (e.g., a patient’s clinically evident tumor is smaller, softer, or less painful) or dimensions on plain x-rays. With the widespread use of CT and MRI for following disease, most modern studies have employed 4World Health Organization (WHO) or, more recently, the RECIST criteria (Response Evaluation Criteria in Solid Tumors), which rely on bidimensional or unidimensional cross-sectional measurements of selected lesions. These criteria are not without their downfalls. It is a well-described phenomenon that a responding tumor may not decrease in size, even though at the time of surgery after treatment, 100% necrosis is observed with acellular matrix being the only remnant of the tumor. This is particularly common in gastrointestinal stromal tumor (GIST), in which lesions will often remain stable in size or even get larger and more cystic as they respond. These responding tumors often demonstrate decreased density and decreased enhancement on cross-sectional imaging. Consequently, in many studies of GIST, RECIST measurements are supplemented by Choi criteria measurements, which examine both size and decrease in attenuation when judging response. Tumors treated with immunotherapy also sometimes demonstrate apparent increase in size related to immune infiltration prior to stabilizing or shrinking. Immune-related response criteria (irRC) have been proposed and are now in common usage in immunotherapy-based clinical trials to identify false progression and capture delayed responses in these patients.

Given the rarity of soft tissue sarcoma in general and even more so for specific subtypes, oncologists are frequently asked to make decisions regarding systemic therapy treatment options in the absence of proven survival benefit and often based on small or underpowered studies. This holds for all scenarios, but is particularly pronounced in the adjuvant and neoadjuvant setting, where clinical trials have, as a rule, been underpowered to demonstrate statistical significance of what would be considered clinically meaningful improvements in OS.

What follows is a discussion of the agents commonly used to treat most soft tissue sarcomas, with a discussion of data surrounding each agent and combination, and situations in which they are commonly used. We also discuss the adjuvant and neoadjuvant treatment of sarcomas, a historically controversial proposition in which we believe improved patient selection tools and supportive therapies are making the approach more appealing for the right patient.

AGENTS IN THE TREATMENT OF METASTATIC DISEASE

Doxorubicin

Most first-line regimens employ doxorubicin as a single agent or in combination. The drug has been used since the 1970s, and early in its history, it became apparent that higher doses result in higher RRs, an effect that was less pronounced in other studied malignancies.¹

Often discussed is cardiac toxicity related to high lifetime doses of doxorubicin. Given that most modern sarcoma regimens employ doxorubicin at 75 mg/m², six doses get patients to 450 mg/m², the dose at which the incidence of heart failure seems to increase. Several strategies have been employed to decrease this apparent cardiac risk. The 450 mg/m² threshold is based on bolus administration of the drug without dexrazoxane cardioprotection. When the drug is administered over longer periods of time (48–72 hours in our practice), the incidence of cardiac damage declines. This comes at the cost of increased mucositis, which, in some patients, can be severe enough to interfere with oral intake or serve as a source of fever in the setting of neutropenia, which may result in hospitalization. Another strategy to mitigate cardiac toxicity from doxorubicin has been administration of the chelating agent, dexrazoxane. Theoretical concerns with dexrazoxane include theoretical protection of the tumor from the cytotoxic effects of doxorubicin and increased risk of secondary malignancies. Long-term follow-up of survivors of childhood cancers treated with dexrazoxane does not demonstrate worse cancer outcomes, and data regarding secondary malignancies are equivocal. Either of these approaches raises the cumulative dose at which the incidence of cardiomyopathy begins to increase. The cumulative dose of 450 mg/m² is not an absolute limit, but may be exceeded in situations in which the potential benefit of doxorubicin outweighs the potential risk of cardiomyopathy.

Dacarbazine

Initially demonstrated to have anticancer effect around the same time as doxorubicin, dacarbazine remains in common use today both as a single agent and in combination for the treatment of soft tissue sarcoma. Contemporary clinical trials have used dacarbazine as a comparator arm in randomized studies for agents being examined in pretreated patients (trabectedin and eribulin) and demonstrated median PFS of 1.5 to 2.6 months and RRs in the range of 5% to 7% using RECIST criteria. Subgroup analysis suggests the drug may be more active in leiomyosarcomas than other treated subtypes (notably, liposarcomas).^2,3 The side effect profile of the drug as a single agent is generally mild, though it is highly emetogenic and does require appropriate nausea prophylaxis.

5Cyclophosphamide and Ifosfamide

Cyclophosphamide has a long-standing history of use in the treatment of sarcomas. In modern therapy, it remains a cornerstone of combinations directed at the treatment of pediatric sarcomas like Ewing sarcoma and rhabdomyosarcoma.

In other sarcoma subtypes seen more commonly in adults and in relapsed pediatric sarcomas, ifosfamide came to be of interest because of its clear single-agent activity in the relapsed setting. Similar to doxorubicin, RRs appear to increase as the dose of ifosfamide administered increases. A randomized study comparing ifosfamide 5 g/m² (a low to moderate dose in the era of hematopoietic growth factors) to cyclophosphamide 1,200 mg/m² (the dose used in most modern regimens) demonstrated a significantly increased RR in the group of patients receiving ifosfamide.⁴ Most subsequent soft tissue sarcoma combination regimens have integrated ifosfamide rather than cyclophosphamide. In pediatric tumors, particularly Ewing sarcoma, addition of ifosfamide and etoposide to a cyclophosphamide-containing regimen improved the OS for children with localized disease and is now the standard regimen in the United States.⁵ Ifosfamide, however, is more cumbersome to administer and requires experience and expertise, given the possibilities of significant myelosuppression, nephrotoxicity, central neurotoxicity, and an increased risk of hemorrhagic cystitis.

MAID, AIM, and Other Anthracycline-Based Combinations

As such drugs as doxorubicin, cyclophosphamide, ifosfamide, and dacarbazine have come into common use in the treatment of soft tissue sarcomas, there has been interest in combinations of these agents that may be additive or synergistic and provide incremental benefit either in likelihood of response, PFS, and/or OS.

Initially available around the same time period as doxorubicin, dacarbazine was the first agent to be studied as an addition to doxorubicin in the treatment of soft tissue sarcomas. Several studies demonstrated improved RR and PFS, but none were adequately powered to demonstrate OS benefit.^6–8

Other combinations incorporated cyclophosphamide or ifosfamide, either to doxorubicin alone or to doxorubicin and dacarbazine. In the 1980s, a combination of cyclophosphamide, vincristine, doxorubicin, and dacarbazine was the most active combination available with respect to RR, though without a demonstrated OS benefit.⁹ As ifosfamide gradually replaced cyclophosphamide as the more active agent in treatment of soft tissue sarcoma, investigators removed vincristine (with its limited single-agent activity in non-small cell soft tissue sarcoma) and replaced cyclophosphamide with ifosfamide. The resulting mesna, Adriamycin (doxorubicin), ifosfamide, and dacarbazine (MAID) regimen demonstrated a high RR, though again without a statistically significant survival benefit, and became the standard combination therapy through the 1990s.⁷ The availability of hematopoietic growth factors allowed for yet another advance, the intensification of dose in agents with a dose–response curve (doxorubicin and ifosfamide). In order to maximize the doses of these agents, dacarbazine was removed from the regimen. The resulting Adriamycin (doxorubicin), ifosfamide, and mesna (AIM) regimen has the highest RRs of any combination reported in soft tissue sarcoma and remains the regimen of choice when inducing a response, which is the primary objective of treatment.^10,11

The choice of whether to use a doxorubicin-based combination or single-agent doxorubicin in patients with asymptomatic metastatic disease remains controversial. A recent clinical trial attempted to settle this controversy by randomizing 455 patients with advanced soft tissue sarcoma to receive doxorubicin and ifosfamide versus doxorubicin alone. The study demonstrated a longer median PFS for the combination (7.4 vs. 4.6 months, p = .003) and overall RR (26% vs. 14%, p = .0006). OS also trended toward improvement, but fell short of statistical significance (14.3 vs. 12.8 months, p = .076). The results leave room for interpretation, with proponents of combination therapy citing the PFS and RR benefit and nearly statistically improved survival. Opponents of the approach cite the lack of demonstrated OS benefit and clearly increased toxicity with combination therapy.

Gemcitabine and Gemcitabine-Based Combinations

Gemcitabine is a nucleoside analog originally developed as an antiviral agent, but ultimately approved as an antineoplastic drug. It was approved by the U.S. Food and Drug Administration (FDA) in 1996 for the treatment of pancreatic cancer. Several subsequent clinical studies demonstrated the activity of single-agent gemcitabine in soft tissue sarcoma, with RRs ranging from 3% to 18%.¹² The addition of docetaxel to gemcitabine, despite little to no activity of the former as a single agent, also seemed to improve the RRs, with initial nonrandomized studies demonstrating RRs of 14% to 53%.¹² Given the uncontrolled nature of these studies, controversy existed as to whether the higher observed RRs with the 6combination of gemcitabine and docetaxel were related to synergy between the drugs or that these later combination studies utilized fixed dose rate gemcitabine, administered at 10 mg/m²/min, which has been noted to improve intracellular concentrations of the active metabolite, gemcitabine triphosphate.¹³

To settle this debate, the Sarcoma Alliance for Research through Collaboration (SARC) ran a study using a Bayesian adaptive approach to randomize patients to gemcitabine alone versus gemcitabine and docetaxel. The study demonstrated improved outcomes with the addition of docetaxel to single-agent gemcitabine, including a PFS of 6.2 versus 3.0 months and an OS of 17.9 versus 11.5 months, establishing the combination of gemcitabine and docetaxel as a standard treatment for soft tissue sarcoma in the United States. Of note, the addition of docetaxel was also associated with many more treatment discontinuations related to toxicity.¹⁴ The critique of the study included its small sample size and the statistical design.

Another study performed by the French Sarcoma Group randomized patients with leiomyosarcoma to gemcitabine alone or to the combination of gemcitabine and docetaxel. In contrast to the American study, no improvements in outcomes including RR, PFS, or OS were seen with the addition of docetaxel.¹⁵ These conflicting results have tempered enthusiasm for the gemcitabine and docetaxel combination, especially in light of the added toxicity from docetaxel, and prompted searches for other agents that might be used in combination with gemcitabine. These include drugs such as dacarbazine and vinorelbine.^16,17 Interestingly, the Spanish study randomizing patients to dacarbazine alone versus gemcitabine plus dacarbazine showed improved PFS and OS in favor of the doublet.¹⁶

Trabectedin

Trabectedin is a novel antineoplastic agent derived from the marine tunicate Ecteinascidia turbinata. The mechanism of action is complex; it covalently binds the minor groove of the DNA strand, interfering with DNA replication and the cell cycle, and may also have a myriad of other effects, including disruption of microtubule networks, inhibition of transcription, and other less understood effects on tumor microenvironment.

Early studies demonstrated responses in sarcoma and also established a 24-hour infusion of the agent every 3 weeks as more efficacious than weekly bolus administration. The agent was approved in 2007 by the European regulatory agency for patients with previously treated soft tissue sarcomas. A more recent study conducted in patients with leiomyosarcoma and liposarcoma, in which the efficacy of the drug seemed most pronounced, randomized pretreated patients to receive either single-agent dacarbazine or trabectedin. The study failed to meet its OS endpoint, with a median survival of 12.9 months for trabectedin and 12.4 months for patients receiving dacarbazine. Median PFS, however, was improved at 4.2 versus 1.5 months,² which ultimately resulted in approval of trabectedin in the United States for liposarcoma and leiomyosarcoma previously treated with anthracycline.

In several studies conducted prior to the approval of trabectedin and in the subsequent clinical experience with the drug, it has been noted that patients with myxoid/round cell liposarcoma (MRCL) appear to have particularly robust response to trabectedin.^2,18 In a recent study of trabectedin versus doxorubicin-based frontline therapy in translocation-associated sarcomas (approximately a third of which were MRCL), PFS was similar between the two arms. Further interpretation of the data was limited by high attrition rate, related in large part to patients undergoing surgical removal of their tumors, the incidence of this being higher in the trabectedin subgroup.¹⁹ For MRCL, the drug has also been studied in small neoadjuvant studies, in which the overall RR was found to range from 24% to 38%.²⁰

Eribulin

Eribulin, a modified analog of halichondrin B, a compound isolated from a marine sponge, was approved for the treatment of breast cancer in 2010 based on data from the EMBRACE study, where it was noted to improve OS in metastatic breast cancer patients. The drug is predominantly felt to be a microtubule dynamics inhibitor, though other mechanisms of action may be important in its clinical effect. Preclinical data demonstrating efficacy in sarcoma subtypes ultimately led to a Phase 2 study conducted by the European Organisation for Research and Treatment of Cancer (EORTC), which demonstrated that leiomyosarcomas and adipocytic tumors (liposarcomas) achieved a 12-week PFS of >30%, which was the prespecified endpoint. These subtypes were subsequently studied in a Phase 3 confirmatory study.²¹ This study, enrolling patients with liposarcoma and leiomyosarcoma, randomized patients to treatment with the standard 1.4 mg/m² dose of eribulin or dacarbazine at doses of 850 to 1,200 mg/m². The trial met its primary endpoint of a 2-month improvement in OS with eribulin over dacarbazine (13.5 vs. 11.5 months, p = .0169). PFS (X vs. Y months) in the overall study cohort was not improved, suggesting perhaps a mechanism of action other than direct cytotoxicity. Mechanisms 7including vascular remodeling, improved delivery of subsequent lines of chemotherapy, and modification of metastatic potential have been raised as possibly contributing to the demonstrated survival benefit in the absence of PFS improvement.^22,23

The subgroup analysis reported in the initial study demonstrated that the OS benefit of eribulin over dacarbazine was limited to patients with liposarcoma, and for this reason, the FDA elected to approve eribulin for liposarcoma only. Subsequent post hoc analysis of only the liposarcoma group from the Phase 3 study demonstrated that among these patients, PFS was improved (2.9 vs. 1.4 months, p = .0015) and the magnitude of the OS benefit was larger than in the entire study population (15.6 vs. 8.4 months, p < .001).²⁴

Of note, despite the lack of improvement seen in clinical endpoints in the study on patients with leiomyosarcoma, an interpretation of the available data may be that eribulin is as efficacious as dacarbazine in patients with leiomyosarcoma, and more effective than dacarbazine in patients with liposarcoma. Despite the lack of FDA approval for this specific histologic diagnosis, eribulin remains an option for treatment of leiomyosarcoma in treatment guidelines.^25,26

Tyrosine Kinase Inhibitors

Among the so-called targeted agents, the drugs that have had the most impact in the treatment of soft tissue sarcoma are tyrosine kinase inhibitors used in the treatment of GIST. These include FDA approvals for agents such as imatinib, sunitinib, and regorafenib. Their use in the treatment of GIST is discussed elsewhere in this textbook.

For other soft tissue sarcomas, the most commonly used multitargeted tyrosine kinase inhibitor is pazopanib. Based on earlier-phase clinical trials showing promising activity in multiple soft tissue sarcoma subtypes, the drug was studied in the Phase 3 PALLETTE study, which enrolled patients with a wide variety of soft tissue sarcomas and excluded patients with liposarcoma. Compared to placebo, median PFS was improved at 4.6 versus 1.6 months, and there was a trend toward improved OS that was not statistically significant. Dimensional partial responses by RECIST were rare (6% for pazopanib vs. 0% with placebo).²⁷ Given the paucity of available lines of treatment, its relatively favorable toxicity profile, and its broad approval for most sarcoma subtypes by regulatory agencies, pazopanib continues to be a commonly used agent in pretreated metastatic soft tissue sarcoma, except liposarcomas and GIST.

Immunotherapy

Representing a paradigm shift from traditional cytotoxic therapies and antiangiogenic tyrosine kinase inhibitors, therapies that modulate the endogenous immune system or confer adoptive immunity are of increasing interest across a broad range of tumor types.

The most broadly utilized of these is immune checkpoint blockade. In certain diseases, most notably melanoma, anti-PD1–, anti-PD-L1–, and anti-CTLA-4–directed therapies^* have revolutionized treatment and drastically improved outcomes for patients, with long-term responses in patients who previously had few treatment options. PD-1/PD-L1–directed therapies are now approved for a host of malignancies including non-small cell and small cell lung cancers, bladder carcinomas, renal cell carcinoma, squamous cell carcinomas of the head and neck, Hodgkin lymphoma, and cancers with high microsatellite instability. This list continues to grow as additional cancer types are studied. In many of these cases, expression of PD-L1 is used as a biomarker to predict response.

In sarcoma, the largest study reported to date using checkpoint blockade is a study of single-agent pembrolizumab, which examined four cohorts of soft tissue sarcoma patients with leiomyosarcoma, unclassified pleomorphic sarcoma (UPS), synovial sarcoma, and “other” miscellaneous histologic types in addition to three cohorts of patients with bone tumors. Among the soft tissue sarcoma patients, there was an 18% RR and 38% stable disease (SD) rate overall. Responses were primarily seen in the cohorts of patients with UPS and dedifferentiated liposarcoma.²⁸ Combined checkpoint blockade with nivolumab and ipilimumab has also shown activity, more so than nivolumab alone (RR of 16% vs. 8%) in a study of 85 patients with various sarcoma subtypes, though at the cost of increased toxicity.²⁹

Another area of particular interest for immune checkpoint blockade-based therapies has been alveolar soft part sarcoma (ASPS). A Phase 2 study of pembrolizumab and axitinib demonstrated an overall RR of 45.5%.³⁰ Several other studies have also reported small numbers of patients with this rare sarcoma subtype who responded to therapy with immune checkpoint inhibitors alone or in combination 8with other agents.^31,32 In general, these have been small studies that have not resulted in approval of this agent in any sarcoma subtype, but interest remains in pursuing and improving checkpoint blockade-based therapy, particularly in apparently responsive tumors including ASPS, dedifferentiated liposarcoma, and UPS.

Another area of active investigation for immune-based therapies in soft tissue sarcoma is cellular therapies and vaccines directed against the cancer testis antigen NY-ESO-1, which is found with high frequency in patients with myxoid liposarcoma and synovial sarcoma, and with less frequency in other sarcoma subtypes.³³ NY-ESO-1 is not expressed in normal adult tissues outside the testis, making it an ideal target for immune-based approaches.

LV305 is a dendritic cell (DC)-targeted vaccine that aims to induce an endogenous tumor-specific T-cell response. It is an engineered lentiviral particle that selectively targets immature DCs and induces the expression of NY-ESO-1, which is then processed and displayed by major histocompatibility complex (MHC) class I and II molecules that can elicit a T-cell response. In the Phase 1 study, a single partial response (PR) was seen in 24 sarcoma patients treated with the drug; however, over half experienced stable disease and lived longer than might have been expected based on historical comparisons.³⁴ Subsequent work has focused on combining LV305 with a Toll-like receptor 4 (TLR4) agonist, glucopyranosyl lipid adjuvant (GLA), and recombinant NY-ESO-1, referred to as CMB305. A study of synovial sarcoma and myxoid liposarcoma patients treated with this regimen demonstrated stable disease in 53% of synovial sarcoma patients and 75% of MRCL patients.³⁴

While vaccines remain promising, another strategy under active investigation is the use of modified T-cell receptors with affinity for the NY-ESO-1 protein. Small studies utilizing this approach have resulted in meaningful RRs as high as 61% in synovial sarcoma and it remains under active investigation.³⁵

Adjuvant and Neoadjuvant Therapy

Given that development and progression of metastatic disease is the largest driver of poor outcomes in soft tissue sarcoma, considerable efforts have been made to examine the utility of chemotherapy in the neoadjuvant or adjuvant setting. These efforts have been hampered by the overall rarity of soft tissue sarcoma in general and specific subtypes of interest in particular, heterogeneous inclusion criteria in studies that do not always reliably identify high-risk patients for treatment, and lack of equipoise at the treating centers, which had made enrollment into randomized studies of adjuvant therapy difficult.

Given the challenges with a small sample size in various studies, perhaps the most compelling evidence of the efficacy of adjuvant chemotherapy comes from two important meta-analyses. The first, published by the Sarcoma Meta-analysis Collaboration (SMAC) in 1997, included 1,568 patients from 14 studies conducted from 1973 to 1990, all having received a doxorubicin-based adjuvant treatment regimen, all at doses lower than those used in modern regimens with growth factor support. This analysis demonstrated an improvement in local recurrence risk, distant (metastatic) recurrence risk, and overall recurrence-free survival. Risk of death also trended lower, but did not achieve statistical significance.³⁶

An update to this analysis was reported in 2008. This new report incorporated not only the original 14 doxorubicin-based adjuvant studies discussed in the original SMAC analysis but also four new studies using anthracycline and ifosfamide (though at doses lower than the modern AIM regimen). In addition to again demonstrating improvement in local recurrence rates, distant recurrence rates, and overall recurrence rates, the authors were able to demonstrate an improvement in OS for patients receiving doxorubicin and ifosfamide-based treatments, with an absolute risk reduction of death of 11% in the patients who received doxorubicin and ifosfamide over no treatment.³⁷

Since the reporting of this updated meta-analysis, another randomized study was conducted by the EORTC, this time using a more modern regimen of doxorubicin 75 mg/m² and ifosfamide 5 g/m² (although the dose of ifosfamide was half the dose used in AIM). The study enrolled patients with grade II–III soft tissue sarcomas, with malignant fibrous histiocytoma, liposarcoma, leiomyosarcoma, and synovial sarcoma accounting for 67% of the 176 patients in the control arm and 61% of the 145 patients in the treatment arm. Just under half the patients in each arm had grade III tumors at the central review of pathology. Tumor size ranged from 0.3 to 35 cm in the chemotherapy arm and from 1.2 to 38 cm in the control arm, with the median size being 8.6 and 7.5 cm, respectively. The study failed to show any improvement in relapse-free survival or OS with adjuvant chemotherapy.³⁸ The major criticism of the study stemmed from the inclusion criteria that allowed patients with lower risk for recurrence (small tumors, intermediate grade, all anatomic sites) to be enrolled in the study and the lower dose of ifosfamide used.

9A reanalysis of the data from this EORTC study has recently been reported using a risk stratification tool to better understand the pool of patients enrolled in the study. Using the Sarculator, a recently developed and validated risk assessment nomogram, patients treated on the EORTC adjuvant study with tumors in the extremities and trunk were stratified by their predicted-OS (pr-OS). Patients in the high-risk group had a 10-year pr-OS of ≤51%, the low-risk group had a pr-OS of ≥66%, and the intermediate prognosis patients had a pr-OS from 51% to 66%. This analysis demonstrated half the risk of death (hazard ratio [HR]: 0.46, 95% confidence interval [CI]: 0.23–0.94) in the high-risk group when chemotherapy was given, with the 8-year absolute risk reduction for death being 21.3%, an effect that was not replicated in the intermediate- or low-risk groups.³⁹

Similar findings have also been subsequently obtained in the results of ISG-GEIS-FSG-1001, a study of epirubicin and ifosfamide versus subtype-specific neoadjuvant therapy in five sarcoma subtypes (malignant peripheral nerve sheath tumor, myxoid liposarcoma, leiomyosarcoma, synovial sarcoma, and undifferentiated pleomorphic sarcoma). Patients were treated with either three cycles of epirubicin 120 mg/m² and ifosfamide 9 g/m² or a histology-specific regimen. In this study, the patient’s tumors had to be at least 5 cm and deep to investing fascia. Median size of the enrolled tumors was approximately 11 cm in both treatment groups, and the population of tumor types was less heterogeneous than in EORTC 62931, given that it was restricted to only these five tumor types. In this study, patients receiving epirubicin and ifosfamide-based neoadjuvant therapy had a better 46-month disease-free survival rate at 62%, higher than the 36% in the histotype-tailored active chemotherapy group. OS at 46 months was similarly better in the anthracycline plus ifosfamide treatment group. While the study demonstrated that histotype-tailored adjuvant treatment was not better than epirubicin and ifosfamide-based therapy, the most notable finding was the prospectively demonstrated benefit in the epirubicin and ifosfamide arm, the first convincing demonstration of a survival benefit with anthracycline and ifosfamide in a prospective, randomized clinical trial, even when compared to an active control group.⁴⁰

While adjuvant therapy remains in some respects controversial for patients with soft tissue sarcoma, the preponderance of evidence to date does suggest a measurable improvement in disease-free survival and OS. A more pertinent discussion may be how to appropriately risk-stratify patients with localized sarcomas. The Sarculator is a reasonable tool, but remains limited to patients with retroperitoneal, extremity, and trunk sarcomas and only incorporates more common histologic types. Other sites such as the head and neck, the female reproductive tract, intra-abdominal, and intrathoracic locations are not well characterized by the nomogram. In some of these locations, where wide margins may be difficult to obtain, there may be additional benefits to chemotherapy; a consistent finding in adjuvant/neoadjuvant studies has been an improvement in local relapse-free survival.³⁶

SUMMARY

Localized approaches such as surgery and radiation therapy are the mainstay for localized, resectable, low-risk sarcoma patients. However, a significant portion of patients requires systemic therapy owing to a high risk for recurrence or the presence of metastatic disease. Systemic therapy for sarcoma patients is generally used to facilitate limb (or organ)-sparing surgery, neoadjuvant/adjuvant treatment of high-risk localized disease to decrease the risk of metastases, and for the treatment of metastatic and locally advanced disease with the objective of symptom palliation and prolongation of life. As discussed previously, many new agents with new mechanisms of action are available to sarcoma patients. A goal in medical oncology is to select the appropriate agent and administer it at the appropriate dose for the appropriate patient. The selection of therapy in a given scenario will consider the overall goals of the patient being treated, the patient’s ability to tolerate a treatment, the acceptability of the toxicity profile to the patient, any previous therapies, and, increasingly, the specific histologic subtype of the patient’s tumor. In conclusion, we have entered an era with new systemic agents that are offering hope for our patients impacted by sarcoma.

  *  PD-1 is programmed cell death protein-1, PDL-1 is programmed cell death protein -1 ligand, and CTLA is cytotoxic t-lymphocyte associated protein.

---

Only gold members can continue reading. Log In or Register to continue

Share this:

• Click to share on Twitter (Opens in new window)
• Click to share on Facebook (Opens in new window)

Related

Related posts:

Alveolar Soft Part Sarcoma Immunotherapy for Sarcoma Undifferentiated Pleomorphic Sarcoma/Myxofibrosarcoma/Other Fibrosarcomas Malignant Peripheral Nerve Sheath Tumor Interventional Radiology Myxoid Liposarcoma

Stay updated, free articles. Join our Telegram channel

Join