Treatment Of Advanced Sarcoma Research Articles

Efficacy and safety of Anlotinib in the treatment of advanced sarcoma

Objective: Patients with advanced sarcomas have a dismal prognosis with few effective therapies. The purpose of this study was to evaluate the efficacy and safety of anlotinib in the treatment of advanced sarcoma and to explore the relationship between adverse events (AEs) and efficacy. Methods: Data from 45 advanced sarcoma patients who received anlotinib monotherapy at Affiliated Cancer Hospital of Zhengzhou University between June 2018 and August 2021 were retrospectively analyzed. According to Response Evaluation Criteria In Solid Tumors (RECIST) Version 1.1, the objective remission rate (ORR) and disease control rate (DCR) were calculated, and the progression free survival (PFS) and treatment-related AEs were recorded and analyzed. Survival analysis was conducted using the Kaplan-Meier survival rates were compared using the Log rank test. Results: Forty patients were treated for more than 1.5 months and received efficacy evaluation. The ORR and DCR after 3 months were 7.5%(3/40) and 80.0%(32/40), respectively. The overall ORR was 2.5%(1/40), the total DCR was 27.5%(11/40), and the median progression-free survival (m-PFS) was 6.70 months; The m-PFS of alveolar soft tissue sarcoma (ASPS) was 10.27 months, which was significantly longer than that of other subtypes of sarcoma (P=0.048). In addition, the DCR of ASPS and synovial sarcoma (SS) was significantly better than that of osteosarcoma (P<0.05). The most common AEs were elevated thyroid stimulating hormone (17.8%, 8/45), anemia (15.6%, 7/45), fatigue (11.1%, 5/45). Five patients developed grade 3 AEs after treatment; The PFS of patients with hand-foot syndrome after treatment was significantly longer than that of patients without hand-foot syndrome (14.10 vs 6.00, P=0.024). Conclusions: The efficacy of anlotinib in the treatment of ASPS and SS is better than that of other subtypes. The PFS in the group with hand-foot syndrome was significantly longer than that of the group without hand-foot syndrome.

The Outcome of Discontinuing Tyrosine Kinase Inhibitors in Advanced Sarcoma Following a Favorable Tumor Response to Antiangiogenics Therapy.

(1) Background: The use of antiangiogenic TKIs (AA-TKIs) has recently emerged as a major paradigm shift in the treatment of advanced sarcoma. However, the feasibility of drug holidays for patients demonstrating a very favorable response remains unknown. (2) Methods: We aim to explore the outcomes of patients with advanced sarcoma who discontinued AA-TKIs after a (near-) complete remission or were long-term responders. Patients with advanced disease were included if they had bilateral or multiple lung metastases, extrapulmonary recurrence, a short disease-free interval, etc., at the initiation of AA-TKIs. (3) Results: A total of 22 patients with AA-TKI discontinuation were analyzed, with a median follow-up of 22.3 months post-discontinuation. Prior to discontinuation, there were four drug-induced complete remissions (CRs), twelve surgical CRs, and six long-term responders. Disease progression was observed in 17/22 (77.3%) patients, with a median of 4.2 months. However, since the majority were still sensitive to the original AA-TKIs and amenable to a second surgical remission, 7 out of these 17 patients achieved a second CR after disease progression and were thus considered as relapse-free post-discontinuation (pd-RFS). Therefore, the pd-RFS and post-discontinuation overall survival (pd-OS) in the last follow-up were 12/22 (54.5%) and 16/22 (72.7%), respectively. Remarkably, surgical CR and drug tapering off (versus abrupt stopping) were associated with a greater pd-RFS and pd-OS (p < 0.05). Furthermore, higher necrosis rates (p = 0.040) and lower neutrophil-to-lymphocyte ratios (NLR) (p = 0.060) before discontinuation tend to have a better pd-RFS. (4) Conclusions: Our results suggest that AA-TKI discontinuation with a taper-off strategy might be safe and feasible in highly selected patients with advanced sarcoma. Surgical CR, NLR, and tumor necrosis rates before discontinuation were potential biomarkers for AA-TKI withdrawal.

Inflammatory Surrogate Parameters for Predicting Ifosfamide-Induced Neurotoxicity in Sarcoma Patients.

Sarcomas compromise a heterogenous group of tumors of a mesenchymal origin. Although treatment options in many solid tumors have evolved over the past decades, the treatment of advanced sarcoma is still based on conventional chemotherapeutic agents. Beside anthracyclines, alkylating agents such as ifosfamide are frequently used in sarcoma treatment. However, treatment with ifosfamide can cause severe dose- and treatment-limiting side effects, such as ifosfamide-induced neurotoxicity (IIN). Especially in sarcoma, consecutive risk assessment analyses investigating the individual factors associated with the increased incidence in IIN, remain insufficient so far. In this retrospective analysis, we investigated 172 sarcoma patients treated with ifosfamide. Out of 172 patients, 49 patients (28.5%) developed IIN. While gender, age, histologic origin, and tumor stage were not associated with the occurrence of IIN, infusion times, simultaneous radiotherapy, and concomitant use of opioids or anticonvulsants affected the risk of developing IIN. Sarcoma patients with IIN showed an alteration in several inflammatory markers, including a lower lymphocyte count, hemoglobin levels, and calcium levels, as well as elevated GGT, sodium, and CRP levels. Remarkably, the occurrence of IIN was associated with a worse prognosis regarding progression free and overall survival. In addition, high CTCAE grades were negatively associated with overall survival in sarcoma. The observation that an inflammatory state is associated with an increased risk of IIN in sarcoma patients can be used prospectively to further investigate the relationship of inflammation and IIN. In addition, the easily accessible blood markers used in our study to predict IIN can be incorporated into clinical decision making.

Albumin-Bound Paclitaxel: Worthy of Further Study in Sarcomas.

Taxanes (paclitaxel and docetaxel) play an important role in the treatment of advanced sarcomas. Albumin-bound paclitaxel (nab-paclitaxel) is a new kind of taxane and has many advantages compared with paclitaxel and docetaxel. Nab-paclitaxel is currently approved for the treatment of advanced breast, non-small cell lung, and pancreatic cancers. However, the efficacy of nab-paclitaxel in sarcomas has not been reviewed. In this review, we first compare the similarities and differences among nab-paclitaxel, paclitaxel, and docetaxel and then summarize the efficacy of nab-paclitaxel against various non-sarcoma malignancies based on clinical trials with reported results. The efficacy and clinical research progress on nab-paclitaxel in sarcomas are also summarized. This review will serve as a good reference for the application of nab-paclitaxel in clinical sarcoma treatment studies and the design of clinical trials.

Preliminary evaluate the safety and efficacy of anlotinib in advanced sarcoma patients in multi-line therapy.

11526 Background: Patients with advanced bone and soft tissue sarcoma are mostly treated with chemotherapy, but the effect is poor. Anlotinib hydrochloride is a multi-targeted receptor of tyrosine kinase inhibitors (TKI), which has demonstrated therapeutic effects on a variety of sarcoma subtypes, and is approved for the treatment of advanced soft tissue sarcomas in China. Methods: This is a single-arm, prospective, single-center clinical study. The included criteria were patients with pathological diagnose of bone and soft tissue sarcoma, at least one measurable lesion (according to RECIST 1.1), failed of more than first-line therapy (except for alveolar soft tissue sarcoma) in the last 6 months, with the normal function of main organs. All patients received anlotinib for more than 1 month. The primary study endpoint was objective response rate (ORR). Disease control rate (DCR) and side effects was also calculated. Results: At the latest follow up in Jan. 20th, 2020, a total of 31 patients were enrolled. The median age of the patients was 38 (8-79) years. The main subtypes included osteosarcoma (25.8%), undifferentiated pleomorphic sarcoma (19.4%), synovial sarcoma (16.1%), fibrosarcoma (12.9%). 83.9% of patients received for at least third-line therapy of anlotinib. The oral administration time was 1.5-15 months, with the average of 4.34 months. The ORR was 29%. The DCR was 77.4%. Patients who had received other TKI drugs had an ORR of 20% and a DCR of 70% in 10 cases (32.2%) in this group. mPFS and mOS have not been reached. Adverse events were mainly in grades I and II, including 6 (19.4%) of anorexia or diarrhea, 5 (16.1%) of pain, 4 (12.9%) of hand-foot syndrome, 3 (9.7%)of hypertension, fatigue and mucosa ulcer each. One case had hypertension in grades III. Conclusions: Anlotinib has shown a definite effect in the treatment of advanced sarcomas. Effectiveness can also be observed in patients who have failed in other targeted therapy. The adverse events are minor and can be tolerated. Clinical trial information: NCT04223583 .

Selinexor in Combination With Ixazomib for the Treatment of Advanced Sarcoma

Selinexor in Combination With Ixazomib for the Treatment of Advanced Sarcoma

Clinical Utility of Genomic Profiling in the Treatment of Advanced Sarcomas: A Single-Center Experience.

Sarcomas are a diverse group of malignant tumors that arise from soft tissues or bone. For most advanced cases, there is a substantial need for improved therapeutic options and, therefore, a desire to more precisely tailor therapy in individual cases. In this study, we review our institutional experience with next-generation sequencing (NGS)-based molecular profiling for non-GI stromal tumors sarcomas, with a focus on the clinical utility of the results. We retrospectively analyzed results of NGS performed on tumors from 114 patients with a diagnosis of sarcoma. A chart review was conducted to review the clinical impact of NGS findings. A median of three putatively oncogenic gene alterations were identified per tumor sample (range, 0 to 19) and at least one mutation was detected in 96.7% of tumors. Fifty-six patients (49.1%) harbored a finding that was felt to be actionable after review by a molecular tumor board. Five patients (4.4%) had a diagnosis change as a result of NGS findings. In 15 patients (13.2%), therapeutic selection was influenced by NGS findings. Four of 15 (26.7%) of the NGS-influenced systemic therapies resulted in clinical benefit. Putatively oncogenic mutations are readily detected in the majority of sarcomas. Genetic profiling affected the diagnosis and/or treatment approach in a sizeable minority of patients with sarcoma treated at our center. Additional study is required to determine if genetic profiling leads to improved clinical outcomes.

Olaratumab (LARTRUVO®) as a new therapeutic option in the treatment of patients with advanced soft tissue sarcomas

Olaratumab is a newly approved human monoclonal IgG1 antibody against platelet-derived growth factor alpha (PDGFR-α). In a relatively small, randomised phase 2 trial the drug given in combination with doxorubicin produced an overall survival improvement in patients with unresectable and/or metastatic soft tissue sarcomas. Further studies are necessary to establish the role of this agent in the treatment of advanced sarcomas. In this paper the current clinical data on olaratumab are presented.

Trabectedin: novel insights in the treatment of advanced sarcoma.

Soft tissue sarcomas are a heterogenous group of malignancies with relatively high mortality rates. The outlook for these patients has been poor, with only a few drugs showing measurable activity. Trabectedin is a new alkylating agent with significant activity in sarcomas, but particularly in liposarcomas and leiomyosarcomas, both as a single agent or in combination with other drugs. Phase I and II studies of trabectedin have shown measurable benefit. Currently there are several Phase III trials which have completed accrual to better study its use as a single agent or in combination therapy, although outcomes have not yet been reported. Trabectedin (Yondelis) is approved for the treatment of sarcomas by the EMEA, but is not yet approved by the FDA, pending the results of the currently maturing phase III trials.

AOS12 Efficacy and safety of trabectedin versus gemcitabine/docetaxel in patients with sarcoma after failure of anthracycline and/or ifosfamide

<h3>Background</h3> Trabectedin and gemcitabine/docetaxel are routinely used in the treatment of advanced sarcoma after failure of anthracycline and/or ifosfamide. The optimum regimen remains unclear. We aimed to assess the efficacy and safety of trabectedin versus gemcitabine/docetaxel in patients with sarcoma after failure of standard therapy. <h3>Methods</h3> Twenty-nine patients with advanced sarcoma who had received trabectedin or gemcitabine/docetaxel after failure of anthracycline and/or ifosfamide were included in this single-centre study. Three patients received both regimens and were included in the initial treatment group for the purpose of this analysis. Per institutional guidelines, imaging studies were repeated after 2–3 cycles of treatment; response rates and drug-emergent toxicity were evaluated using Response Evaluation Criteria in Solid Tumors (RECIST) (version 1.1) and CTACE (version 4), respectively. <h3>Findings</h3> Sixteen and 13 patients received trabectedin and gemcitabine/docetaxel, respectively. Median age (53 versus 56 years) and sex (44% versus 46% males) were not significantly different between the two groups. Patients in both cohorts had previously received a median of 1 line of chemotherapy (range 1–3). A median of two cycles were administered in both cohorts (range 1–10 and 1–6, respectively). Median administered dose of trabectedin was 1.2mg/<mml:math><mml:mrow><mml:msup><mml:mrow><mml:mi>m</mml:mi></mml:mrow><mml:mrow><mml:mn>2</mml:mn></mml:mrow></mml:msup></mml:mrow></mml:math> (range 0.9–1.5mg/<mml:math><mml:mrow><mml:msup><mml:mrow><mml:mi>m</mml:mi></mml:mrow><mml:mrow><mml:mn>2</mml:mn></mml:mrow></mml:msup><mml:mo>\)</mml:mo></mml:mrow></mml:math> and, per institutional practice, gemcitabine was administered routinely at 900mg/<mml:math><mml:mrow><mml:msup><mml:mrow><mml:mi>m</mml:mi></mml:mrow><mml:mrow><mml:mn>2</mml:mn></mml:mrow></mml:msup></mml:mrow></mml:math> on days 1 and 8 and docetaxel at 75mg/<mml:math><mml:mrow><mml:msup><mml:mrow><mml:mi>m</mml:mi></mml:mrow><mml:mrow><mml:mn>2</mml:mn></mml:mrow></mml:msup></mml:mrow></mml:math> day 8, supported by growth factors. With the exception of self-limiting grade 3/4 ALT elevations in 50% of patients in the trabectedin group versus none in the gemcitabine/docetaxel (<i>p</i>=0.003), both treatments were generally well tolerated with no significant differences in toxicity profiles. Objective response rates were 6% (trabectedin) versus none (gemcitabine/docetaxel). Overall median PFS was 1.5 months with no significant difference in the two groups (1.4 versus 1.9 months, respectively); 31% versus 15% of patients in the trabectedin and gemcitabine/docetaxel groups, respectively, did not have disease progression at 4 months. <h3>Interpretation</h3> Encouraging anti-tumour activity was noted in both treatment groups with subsets of patients achieving prolonged clinical benefit. Prospective studies are urgently needed to clarify the optimum strategy in this clinical setting. <h3>Funding</h3> National Cancer Centre Research Fund and Janssen Singapore. The authors declared no conflicts of interest.

Trabectedin: Safety and Efficacy in the Treatment of Advanced Sarcoma

Soft tissue sarcomas (STS) are a rare group of malignancies with multiple different subtypes. Close to half of intermediate or high grade STS develop metastatic disease. Treatment of recurrent/metastatic sarcomas is quite challenging with only a few drugs showing measurable benefits. Trabectedin (ecteinascidin 743, ET-743, Yondelis) is a newly developed alkylating agent that has shown significant broad spectrum potential as a single agent second line drug alone or in combination particularly in the treatment of liposarcomas and leiomyosarcomas. Clinical benefit rates seem to favor its use especially in pretreated patients with recurrent/metastatic disease. The drug is well tolerated in general but hepatotoxicity and hematologic side effects are common. Approved in Europe, the currently ongoing Phase III trials along with the already existing clinical evidence may provide enough data for the Food and Drug Administration for an approval in the US.

Sirolimus reduced tumor-related morbidity and resulted in biochemical and radiographic response in patients with progressive sarcoma

9503 Background: Chemotherapy options for palliative treatment of advanced sarcomas are limited and studies are underway to identify new classes of active agents. Second generation inhibitors of the mammalian target of rapamycin (mTOR) are being tested in phase II trials. Objective responses of sarcomas to the mTOR inhibitor AP23573 have been reported. Sirolimus (rapamycin) is a macrocyclic triene antibiotic that inhibits activation of S6 kinase, the cdk2/cyclinE complex and phosphorylation of retinoblastoma protein and causes cell cycle arrest in G1-S phase. Methods: We report the cases of four (out of 20) patients (pts) with progressive, metastatic sarcoma failing 2–6 chemotherapies treated with sirolimus and followed for clinical benefit. Sirolimus was self-administered daily with (n=2) or without (n=2) daily oral cyclophosphamide 200 mg every other week. Patients were followed in clinic for disease and toxicity assessments every 2 weeks. Molecular analysis of mTOR targets will be performed. Results: Patients with MFH, leiomyosarcoma, angiosarcoma and osteosarcoma were treated using 4–8 mg sirolimus daily for a median of 16 weeks (range 8–28 wks). Three pts were symptomatic from disease and had reduced performance status prior to treatment. All 3 pts had subjective improvement in tumor-related symptoms and 2 had improvement in performance status. LDH and bilirubin fell from 1,712 u/L and 5.6 mg/dl to 388 u/L and 1.1 mg/dl, respectively, in the pt with angiosarcoma during 3 months of sirolimus and cyclophosphamide. Alkaline phosphatase fell from 791 u/L to 120 u/L in the pt with osteosarcoma over 6 weeks of simolimus and cyclophosphamide. Three pts had minor radiographic improvement in tumor and remain on treatment. One pt has died of disease progression. Treatment was well tolerated. Conclusions: Sirolimus treatment was associated with improvement in tumor-related symptoms, performance status and biochemical markers of disease activity and inhibited tumor growth in pts with advanced sarcoma failing multiple prior therapies. Phase I studies of sirolimus in advanced cancer are underway at the University of Chicago. Formal study of sirolimus in advanced sarcoma is contemplated. No significant financial relationships to disclose.

The treatment of advanced sarcomas with cytotoxic drugs.

Abstract The treatment of 6 patients is described. In sarcomas treated with cyclophosphamide it is suggested that regular daily doses throughout may offer a better form of treatment than repeated intensive courses of treatment.

Phase I multicenter study of combined high-dose ifosfamide and doxorubicin in the treatment of advanced sarcomas

Ifosfamide and doxorubicin are the most active agents in the treatment of sarcomas and are characterized by a marked dose-response relationship. The objective of this study was to determine the maximum tolerated dose (MTD) of both agents in combination under granulocyte-macrophage colony-stimulating factor (GM-CSF) cover. Thirty-three patients with untreated sarcomas (soft tissue: n = 20; gynecological: n = 11; bone: n = 2) were treated with ifosfamide 12 g/m2 by continuous i.v. infusion over five days and doxorubicin with dose escalation from 50 mg/m2 i.v. bolus divided on two days, then to 60 mg/m2 bolus divided on three days. Ifosfamide was reduced to 10 g/m2 and doxorubicin was further escalated up to 90 mg/m2. GM-CSF (5 micrograms/kg/day subcutaneously) was started 24 hours after chemotherapy and continued for 10 days. The MTD was reached with the combination of ifosfamide at 12 g/m2 and doxorubicin at 60 mg/m2. But with ifosfamide 10 g/m2 and doxorubicin 90 mg/m2 the MTD was not obtained. While severe leukopenia and granulopenia were observed at all-dose levels, severe anemia was more frequently related to the highest dose of ifosfamide. Severe thrombopenia and mucositis were more commonly observed at the highest dose of doxorubicin. Ifosfamide 10 g/m2 and doxorubicin 90 mg/m2 induced WHO grade 4 leukopenia in 58%, grade 3-4 thrombopenia in 42%, and anemia in 31% of cycles. Mucositis was minor in 50% of cycles. The overall response rate among 31 evaluable patients was 55% (95 confidence interval (CI): 36%-73%), with four (13%) complete responders and 13 (42%) partial responders. Response rates based on soft-tissue sarcomas or gynecological sarcomas alone were similar. Ten patients could be treated by elective surgery and/or radiotherapy. The total group of patients reached a median survival of two years, with 25% (SE 8%) survivors after three years. The dose level of ifosfamide 10 g/m2 and doxorubicin 90 mg/m2 with supportive GM-CSF is manageable in a multicenter setting and should be further tested in regular phase II trials, including patients with gynecological and soft-tissue sarcomas. Transient toxicity with myelosuppression should be accepted in order to obtain a high antitumor activity of this regimen and a potential improvement in survival.

A useful high-dose intermittent schedule of adriamycin and DTIC in the treatment of advanced sarcomas.

One-hundred-fourteen evaluable patients with metastatic soft tissue or bony sarcoma with measurable disease were treated with Adriamycin (doxorubicin) administered intravenously at a dose of 60 mg/M2 on day 1, followed by DTIC (dacarbazine) at a dose of 750 mg/M2; courses were administered at 3-week intervals. Ten complete remissions and 17 partial remissions were observed. The most responsive cell type was malignant fibrous histiocytoma with a response rate of 54%. This treatment schedule was very well tolerated, with only moderate myelosuppression and moderate nausea and vomiting. Cardiac toxicity was identified in three patients, with two patients demonstrating electrocardiogram (EKG) changes and arrhythmias and only one patient developing heart failure. The 24% overall response rate suggests no compromise in activity on this schedule, with a significant reduction in toxicity.

A phase II evaluation of methyl CCNU and actinomycin D in the treatment of advanced sarcomas in adults

Twenty-nine patients with metastatic sarcoma were treated with a combination of methyl CCNU and actinomycin D. Patients with adequate bone marrow reserve received methyl CCNU 100 mg/m2 orally on day 1 and actinomycin D 0.3 mg/m2/day intravenously for five days. Both drugs were repeated every four weeks. Patients with inadequate bone marrow reserve received methyl CCNU 75 mg/m2 and actinomycin D 0.2 mg/m2/day for five days. All patients had received prior chemotherapy and had progressive disease at the start of the study. There was one complete response in a patient with peritoneal mesothelioma which lasted 18 months and the patient is still alive at 38+ months. Ten patients had stable disease including three patients who had responses between 25% to 50%. No responses were seen in 18 patients. The median time to progression for patients with stable disease was five months and for those with progressive disease was two months (P = 0.001). The median survival for patients with stable disease was 20 months compared with three months for patients with progressive disease (P = 0.001). The combination was generally very well tolerated and myelosuppression was insignificant. However, with the dosages and schedule used in this study, the combination of methyl CCNU and actinomycin D does not appear to have significant activity in advanced soft tissue sarcomas. Further studies with this combination are indicated in patients with mesothelioma.

Chemotherapy of sarcomas with a combination of adriamycin and dimethyl triazeno imidazole carboxamide

During the initial therapeutic evaluations of adriamycin and DIC, efficacy was noted with each in the treatment of advanced sarcomas. Preclinical studies suggested possible synergism without additive toxicity. This lead to our evaluating the two agents in combination in metastatic sarcomas. Adriamycin at 60 mg/m2 was given I.V. on day 1 and DIC 250 mg/m2 I.V. on days 1 to 5, with the entire regimen repeated every 21 days. The dosage of both drugs was reduced 25% in patients with extensive prior therapy. Of 120 patients entered, 100 were evaluable for therapeutic efficacy. Five complete and 36 partial remissions (> 50%) were observed for a response rate of 41% including the following diagnoses: synovial cell sarcoma 2/2; rhabdomyosarcoma 3/5; undifferentiated sarcoma 6/13; fibrosarcoma 5/11; osteogenic sarcoma 8/18; liposarcoma 3/7; mesothelioma 3/7; neurofibrosarcoma 4/10; leiomyosarcoma 6/16; angiosarcoma 1/5; chondrosarcoma 0/4, and miscellaneous sarcomas 0/2. The median duration for complete remission was 5+ months (range—3+ to 7+ months) and for partial remission was 31/2+ months (1–10+ months) with 29/41 still in remission. Toxicity was limited predominantly to vomiting, alopecia, and myelosuppression. Leukocyte depression was maximum by median day 15, with prompt recovery permitting retreatment at a 3-week interval in all but 8% of courses. Combination therapy with adriamycin and DIC appears to be an effective and promising regimen in the treatment of metastatic sarcomas.