Advances of Systemic Treatment for Adult Soft-Tissue Sarcoma

Wenshuai Liu; Quan Jiang; Yuhong Zhou

Disclosures

Chin Clin Oncol. 2018;7(4) 

In This Article

Chemotherapy in Metastatic STS

First-line Chemotherapy

For the majority of patients with unresectable and metastatic disease, systemic therapy is administered with palliative intention. As in the adjuvant setting, anthracycline and ifosfamide remain the cornerstone for more than 30 years regardless of subtype. However, there are few studies directly assessed whether doxorubicin should be administered alone or in combination with ifosfamide. The randomized phase III EORTC 62012 trial was conducted, a total of 455 locally advanced or metastatic, grade 2 or 3 soft-tissue sarcoma patients were randomly assigned to receive either single-agent doxorubicin (75 mg/m2) or doxorubicin (75 mg/m2) with ifosfamide (10 g/m2 over 4 days) with growth factor support.[16] Patients were treated every 3 weeks for a maximum of 6 cycles or until progression. At a median follow-up of 56 months, the difference of OS did not achieve statistical significance. Median OS was 14.3 months with the combination and 12.8 months with doxorubicin alone (HR =0.83; P=0.076). Median PFS, however, was 7.4 months with the combination and 4.6 months with doxorubicin alone, for a 26% reduction in risk that was statistically significant (HR =0.74; P=0.003). The objective response rate (RR) was 26.5% with the combination and 13.6% with doxorubicin. Despite colony-stimulating factor support, the most common grade 3 and 4 toxic effects were all more common in the combination than in the doxorubicin alone group: leucopenia (43% vs. 18%), neutropenia (42% vs. 37%), febrile neutropenia (46% vs. 13%), anemia (35% vs. 5%), and thrombocytopenia (33% vs. <1%). The lack of OS advantage but with more toxicities for combination regimen do not support its routine use in the setting of advanced incurable disease unless there is an immediate need to decrease tumor bulk, improve symptoms or translate into resection.

Until now, the standard first-line treatment for STS has been doxorubicin. Is there any choice to consider when selecting first-line treatment beyond doxorubicin?

According to phase II and retrospective studies, the combination of gemcitabine and docetaxel may be effective in treating STS. The GeDDiS trial was a phase III, randomized, multicenter study to compare the combination of gemcitabine and docetaxel with doxorubicin in patients with previously untreated advanced unresectable or metastatic STS.[17] Patients were randomly assigned to the control arm (75 mg/m2 of doxorubicin) or the investigational arm (675 mg/m2 of gemcitabine on days 1 and 8 plus 75 mg/m2 of docetaxel on day 8 every 21 days). A total of 257 patients were enrolled, the median follow-up was 19 months. The primary endpoint of 24-week PFS was identical between arms, 46% each. However, patients in the investigational arm had lower dose intensity (83.3% vs. 94.6% for doxorubicin), more dose delays (55.5% vs. 45.7% for doxorubicin), and more withdrawals because of unacceptable toxicity (10.2% vs. 0.8% for doxorubicin). Moreover, no differences in efficacy were found between histology subtype groups, such as LMS or nonleiomyosarcoma. This result again confirmed that single agent doxorubicin should be the preferred first-line option, given greater tolerability and potentially favourable efficacy.

Although doxorubicin remains a backbone for sarcoma treatment, its RR is relatively low while with significant toxicities. As doses exceeding 75 mg/m2, doxorubicin is associated with cardiotoxicities, myelosuppression and mucositis. Several types of anthracycline have been recently tested in first-line treatment to improve its efficacy in STS. Aldoxorubicin is a novel albumin-binding prodrug of doxorubicin which contains a carboxylic hydrazone and covalently binds to albumin in the blood until reaching into tumor tissue, where the acidic microenvironment breaks the covalent bond with albumin and release doxorubicin. This allows for greater doses (3.5–4 times of the standard doxorubicin dose) of doxorubicin to be administered while reducing its side effects. An international multicenter phase 2b randomized study has evaluated the efficacy and safety of aldoxorubicin vs. doxorubicin in patients with advanced STS.[18] A total of 123 patients with histologically confirmed metastatic, locally advanced unresectable STS were randomized 2:1 to receive 350 mg/m2 aldoxorubicin (260 mg/m2 doxorubicin equivalents) intravenous (IV) or 75 mg/m2 doxorubicin every 3 weeks for up to 6 cycles. In this study, aldoxorubicin was associated with more than a doubling of both overall RR (ORR: 25% vs. 0%) and PFS (5.6 vs. 2.7 months; P=0.02). A similar percentage of neutropenic fever between two arms (15% vs. 16%), and a higher rate of decreased cardiac output was observed in doxorubicin arm (22%) compared with aldoxorubicin arm (11%). No patient treated with aldoxorubicin had ejection fractions below 50% versus 9.4% of patients that had received doxorubicin. Most importantly, there was no clinically significant reduction in cardiac function in the aldoxorubicin patients despite receiving high equivalent of doxorubicin dose. Aldoxorubicin represents a promising drug for treatment of sarcomas. The drug has minimal cardiac toxicity, which represents a significant advantage to doxorubicin. Preliminary phase 3 study results demonstrate PFS advantage in patients with LMS and liposarcoma. However, more studies are needed to establish the role of aldoxorubicin in sarcoma treatment.

Amrubicin is a third-generation anthracycline, which has been suggested to be less toxic than doxorubicin, especially for cardiac toxicity. A phase II multicenter single arm study was done to evaluate the efficacy and tolerability of amrubicin in advanced STS.[19] A total of 24 patients were treated with amrubicin 40 mg/m2 for 3 days in 21 days cycles in first-line therapy. The best ORR was 13%, median PFS was 5.8 months, and median OS was 26 months. Grade 3 to 4 toxicities of febrile neutropenia and anemia occurred in 21% of treated patients. There was no significant cardiac toxicity up to a cumulative dose of 4,800 mg/m2. One patient with metastatic MLPS with TLS-CHOP translocation had a durable response thus indicate further study is warranted in this subtype.

Similar to aldoxorubicin and amrubicin, newer fosfamides, namely evofosfamide and palifosfamide have not yet led to substantial progress. Two randomised phase III clinical trials named SARC021[20] and PICASSO[21] have tested doxorubicin in combination with evofosfamide or palifosfamide, respectively. In these two studies, the combination arm produced higher RR but more toxicity. Moreover, same as EORTC 62012 trial, there were no OS or PFS in favour of the combination arm.

Until now, doxorubicin with or without ifosfamide remains the standard first-line chemotherapy for most of STS.

Histology-based Second-line Chemotherapy

There is no standard regimen in second line treatment for STS. Beside anthracyclines and ifosfamide, there are other drugs with moderate activity in this disease. As different subtypes may have different sensitivity to different cytotoxic agents, beyond the first line, the treatment for STS is being increasingly driven by histology. For example, there is evidence of efficacy of gemcitabine in LMS and angiosarcoma; dacarbazine in LMS and solitary fibrous tumors (SFT); trabectedin in LMS and liposarcomas, especially in MLPS; taxanes and gemcitabine in angiosarcoma, eribulin in liposarcoma, etc.

Eribulin

Eribulin mesylate is an antimitotic agent, which acts by inhibiting microtubules' growth. A phase 2 trial assessed the safety and efficacy of eribulin in pretreated STS 128 patients who received eribulin 1.4 mg/m2 over 2–5 min at days 1 and 8 for every 3 weeks. The subtypes including adipocytic sarcoma (37 patients), LMS (40 patients), synovial sarcoma (19 patients), and other sarcomas (32 patients). The result was positive for primary goal (3-month PFS), in the group of adipocytic sarcoma with 46.9% patients were progression free at 12 weeks, and LMS [3-month progression-free rate (PFR): 31.6%].[22] Anther randomized phase 3 trial in 452 advanced pretreated adipocytic sarcoma and LMS patients, 50% of patients received eribulin (1.4 mg/m2, intravenous on days 1 and 8), the left over received dacarbazine (850–1,200 mg/m2, IV on day 1) for every 21 days.[23] The median OS for eribulin and dacarbazine was 13.5 and 11.5 months, respectively (HR =0.768, 95% CI: 0.618–0.954; P=0.017). The OS was significantly improved (15.6 vs. 8.4 months) in liposarcoma cohorts, while no sense was seen in LMS. Based on these results, the FDA approved the using of eribulin in advanced pretreated liposarcoma in 2016 (http://www.fda.gov/.fda.gov). The most common grade 3–4 adverse events were neutropenia, anemia, fatigue, and febrile neutropenia.

Trabectedin

Trabectedin, derived from the marine ascidian, Ecteinascidia turbinata, is a natural alkaloid with multiple complex mechanisms of effects. Trabectedin, mainly binds to the minor groove of DNA and binds to guanine in N2 position, different from traditional alkylating agents which binds to the major groove of DNA and predominantly form crosslink to guanine in the N7 or O6 position.[24] Trabectedin disturbs tumor cell cycle progression by retarding S-phase progression and inducing G2/M arrest.[25]

In 2001, Delaloge et al. first reported the activity of trabectedin in 29 advanced STS patients who had failed in prior doxorubicin-based chemotherapy.[26] In this investigation, there were 34.5% (10/29) stable disease (SD) sustaining more than 2 months and median time to progression of 2.8 months, 13.8% (4/29) PR, 6.9% (2/29) minor responses with shrinking at least 30% in size. A late study recommended the dosage of trabectedin to be 1.5 mg/m2 as 24-H continuous intravenous infusion (CIV) once every 3 weeks.[27] Morgan et al.[28] compared 580 μg/m2 per week schedule with the "standard" 1.5 mg/m2 24-H CIV every 3 weeks schedule, the results indicated that every 3 weeks schedule superior to per week in median PFS (3.3 vs. 2.3 months; P=0.0418).

Several phase 2 clinical trials have been conducted to verify the efficacy of trabectedin alone or combine with other chemotherapy drugs in advanced STS patients who fielded in previous first-line chemotherapy.[29–32] In a retrospective study,[31] 885 advanced STS patients received the "standard" q3 weeks regime, and 227 of them continued trabectedin up to disease progression. The longer trabectedin treatment until disease progression is associated with a significantly improved PFS (11.7 vs. 4.4 months) and OS (24.9 vs. 12.2 months). In an expanded access program for 1,895 advanced STS following failure of prior chemotherapy, suggested the patients with LMS and liposarcoma had significantly longer OS (16.2 vs. 8.4 months, respectively) compared to all other histological subtypes, as well as higher RR (6.9% vs. 4%, respectively). Several trials tried to verified the efficacy of trabectedin in specific STS subtypes, mainly concentrated on LMS and MLPS.[33–36]

In 2015, Demetri et al. launched critical randomized phase 3 study using trabectedin (n=345) vs. dacarbazine (n=173) in locally advanced, unresectable or metastatic LMS and liposarcoma.[37] In the trabectedin arm, trabectedin (1.5 mg/m2) was administered as a 24-H CIV on day 1 of every 3 weeks, whereas in the dacarbazine arm, dacarbazine (1 g/m2) was administered by intravenous infusion over 20–120 min on day 1 of every 21-day cycle. OS was the primary end-point, and PFS was a secondary end-point. Fortunately, treatment with trabectedin resulted in a statistically significant improvement in PFS, with a PFS of 4.2 months and 1.5 months for trabectedin and dacarbazine, respectively (HR =0.55; 95% CI: 0.44–0.70; P<0.001). However, the primary end-point, interim analysis indicated no improvement in OS (HR =0.87; P=0.37). Based on these dates, the United States Food and Drug Administration (FDA) approved the trabectedin for the treatment of unresectable or metastatic liposarcoma or LMS that has failed a prior anthracycline-containing regimen.

MLPS is, characteristically associated with t(12;16) FUS-CHOP translocation which accounting for 90% variants of MLPS, a STS subtype which is particularly sensitive to trabectedin. The chimeric product of this translocation modulates the activity of the C/EBP pathway, which is implicated in G1-S phase cell cycle progression, growth arrest, apoptosis, and developmental programs.[38] Some of transcription play a crucial role in adipocytic differentiation, the trabectedin may interfere with the activity of modulation and induce expression or accumulation of some proteins which associated with terminal adipocytic differentiation. While in Europe, the drug is approved for all STS, and it brought the experiences in treatment of other subtypes of STS. In a retrospect study of the using trabectedin in 61 patients with synovial sarcoma, 9 of them had a partial response (PR), and 21 of them had SD.[39]

Although trabectedin brings new hope for specific subtypes of STS, the side effects also have to be taken into consideration. In previous investigation,[37] the most common adverse reactions are nausea (75%), fatigue (69%), vomiting (46%), constipation and decreased appetite (37%), diarrhea (35%). Less common adverse reactions were dyspnea and headache (25%), arthralgia and insomnia (15%), and myalgia (12%). The grade 3–4 side effects were, less than 10%, neutropenia, thrombocytopenia, anemia, elevated liver enzymes. Thus, an important method in reducing toxicity is the use of dexamethasone prophylaxis 4 mg po BID the day before the trabectedin CIV, and markedly decreased the grade 3–4 advanced effects (P=0.0001).[40,41] At the same time, don't forget to follow up blood biochemistry during trabectedin infusion.

With the efficacy of trabectedin and doxorubicin has firmly established in advanced STS, does the two drugs powerful combination will bring new hope for metastatic STS? In 2001, Takahashi and colleagues reported that the combination appeared to result in synergistic cytotoxicity in a sarcoma cell line. The trabectedin 24-H CIV prior to doxorubicin seemed to enhance the cytotoxic activity of the combination.[42] Blay et al. studied a 60-mg dose of doxorubicin administered as a bolus with subsequent 3-H CIV of trabectedin. The results indicated that 83% of patients had SD, 12% of them had PR, but all patients presented dosing limiting neutropenia, and all need hematopoietic growth factor support, and the maximum tolerated dose was doxorubicin 60 mg/m2 with trabectedin 1.1 mg/m2.[43] Another nonrandomized phase II study of the combination of trabectedin and doxorubicin in soft tissue and uterine LMS adopted the dosing the same with Blay et al. 59.6% patients with PR and 27.7% with PR in the uterine LMS cohort, while 36.1% patients with PR and 52.6% having SD in the soft-tissue LMS cohort. The median PFS (8.2 vs. 12.9 months) and median OS (20.2 vs. 35.5 months) for uterine LMS and soft-tissue LMS respectively. Although lacking the date about the outcomes of patients with soft-tissue LMS, the authors still pointed out that the RR, PFS and OS in the uterine LMS cohort did compare favorably to other uterine LMS cohorts treated with combinations like gemcitabine and docetaxel or doxorubicin and ifosfamide.[44–46] In a randomized phase II study compared the doxorubicin 75 mg/m2 single agents with the combination of doxorubicin 60 mg/m2 and trabectedin 1.1 mg/m2 in a broader range of STS. Frustratedly, the study was stopped early because of the worsening expected PFS in experimental arm.[47] The PFS in experimental arm and the control group was 5.5 vs. 5.8 months respectively. The second endpoints, RR and OS, were also no sense.

Above all, trabectedin is one of effective alternative chemotherapeutic drugs for unresectable or metastatic STS, especially in liposarcoma or LMS. If trabectedin is used in combination with other agents, special attention should be paid to the toxic reaction and the dosage of the drug, and at the same time take appropriately methods to reduce and monitor the toxicity.

Others

Both temozolomide and dacarbazine (DTIC), are alkylating agents, with temozolomide being a prodrug of dacarbazine which interferes with the biosynthesis of purine, showed activity in monotherapy in pretreated STS.[48] In a prolonged schedule of temozolomide (75–100 mg/m2 per day during 6 consecutive weeks) in 48 pretreated STS patients, the 3-month PFR was 39.5% and RECIST RR was 15.5%, and the efficacy lasting for a long time (median of 12.5 months) in responding patients.[49] Another study indicated modest activity in pretreated STS, and the LMS group had a median PFS and OS of 3.9 and 30.8 months, respectively.[50] These drugs could be especially interesting in LMS. What's more, SFT also seems to benefit from dacarbazine and temozolomide based regimens[51,52]

The combination of dacarbazine and doxorubicin is one of the oldest drugs to have shown efficacy in STS. Primarily, DTIC was used as a monotherapy in advanced STS, and had a RR of 18%; but a short time to progression.[53] A study compared doxorubicin alone with the combination of doxorubicin and DTIC, showed increase in RR in advanced STS.[54] In 2013, a systematic review investigated the using of DTIC as second line therapy with and without gemcitabine.[55] The results indicated the combination had a high rate of disease free progression at 3 months (54.2% vs. 35.2%, respectively).

Paclitaxel has widely used in tumor chemotherapy and also shown activity in STS. In a phase 2 trial conducted by French sarcoma group, 30 advanced angiosarcoma patients were treated with weekly paclitaxel 80 mg/m2 days 1, 8, and the results showed that the 4-month PFS reached 45%. The same group also launched a combination trial of bevacizumab and paclitaxel, but failed to show the superiority to weekly paclitaxel.[56] Another clinical trial also showed the activity in Kaposi sarcoma.[57]

Thus, when we carry out chemotherapy regiments for STS, we'd better take the subtype, location, histological grade, tumor size, surgical margin, tumor metastasis, and previous treatment into consideration. In addition, patient's factors should not be ignored, factors including, but not limited to, patients' willingness, physical status, potential toxic risks related to the treatment, as well as possible quality-of-life impairments. Therefore, a multi-disciplinary team discussion is essential for all advanced STS in order to propose appropriate strategies and maximize the therapeutic effects.

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