Preoperative Chemotherapy + Surgery for Sarcoma

(STRASS2 Trial)

Recruiting at 148 trial locations

Overseen By EORTC HQ

Age: 18+

Sex: Any

Trial Phase: Phase 3

Sponsor: European Organisation for Research and Treatment of Cancer - EORTC

Must not be taking: Anthracyclines, Anthracenediones

Disqualifiers: Metastatic disease, Congestive heart failure, Uncontrolled hypertension, others

Stay on Your Current Meds You can continue your current medications while participating

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Pivotal Trial (Near Approval) This treatment is in the last trial phase before FDA approval

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: 3

Duration: 9-12 weeks

250 Participants Needed

Trial Summary

What is the purpose of this trial?

This is a multicenter, randomized, open label phase lll trial to assess whether preoperative chemotherapy, as an adjunct to curative-intent surgery, improves the prognosis of high risk DDLPS (dedifferentiated Liposarcoma) and LMS (Leiomyosarcoma) patients as measured by disease free survival. After confirmation of eligibility criteria, patients will be randomized to either the standard arm or experimental arm.

Do I need to stop my current medications for this trial?

The trial protocol does not specify if you need to stop taking your current medications. However, if you have uncontrolled high blood pressure, you may need to adjust your antihypertensive medication before joining the study. It's best to discuss your current medications with the trial team.

What data supports the idea that Preoperative Chemotherapy + Surgery for Sarcoma is an effective treatment?

The available research shows that using preoperative chemotherapy before surgery for sarcoma can lead to better outcomes. For example, in osteosarcoma, this approach has resulted in a 93% disease-free survival rate over a median of 20 months. This means that most patients did not show signs of the disease during this period. Additionally, preoperative chemotherapy can make surgery less invasive, allowing for limb-sparing procedures instead of more drastic surgeries. This treatment strategy also helps identify patients who might need different therapies if the initial chemotherapy isn't effective, improving overall treatment results. ^{1 2 3 4 5}

What safety data exists for preoperative chemotherapy and surgery for sarcoma?

The safety data for preoperative chemotherapy and surgery for sarcoma is limited and varies. Real-world data suggests that perioperative chemotherapy is used in high-risk, localized soft tissue sarcoma, but potential toxicity from cytotoxic chemotherapy is substantial. There is little consensus on the indications for chemotherapy in the adjuvant/neoadjuvant setting. Some studies have evaluated toxicity and survival outcomes, but the efficacy and safety remain controversial, with few prospective studies available. Adjuvant chemotherapy is standard for certain sarcoma subtypes, but not for low- and intermediate-risk disease, and the benefits for high-risk disease are not convincingly demonstrated. ^{6 7 8 9 10}

Is surgery a promising treatment for sarcoma?

Yes, surgery is a promising treatment for sarcoma, especially when combined with preoperative chemotherapy. This approach can make surgeries easier and safer, potentially allowing for less invasive procedures and better outcomes. ^{1 7 11 12 13}

Research Team

Alessandro Gronchi

Principal Investigator

Fondazione IRCCS Istituto Nazionale dei Tumori, Milano

Winan van Houdt

Principal Investigator

The Netherlands Cancer Institute-Antoni Van Leeuwenhoekziekenhuis

Eligibility Criteria

This trial is for adults with high-risk leiomyosarcoma or liposarcoma in the retroperitoneal or pelvic spaces, who haven't had previous treatments. Tumors must be a certain size and meet specific criteria. Patients need to have good organ function, no severe illnesses, not be pregnant or breastfeeding, and agree to use effective birth control.

Inclusion Criteria

My diagnosis was confirmed with specific tests for MDM2 and CDK4.

I have a specific type of sarcoma (DDLPS) that is considered high risk but operable.

Criteria for non-resectability are: Involvement of the superior mesenteric artery, aorta, coeliac trunk and/or portal vein. Involvement of bone. Growth into the spinal canal. Progression of retro-hepatic inferior vena cava leiomyosarcoma towards the right atrium. Infiltration of multiple major organs like liver, pancreas and/or major vessels. Tumor not previously treated (no previous surgery (excluding diagnostic biopsy), radiotherapy or systemic therapy). Patient must have radiologically measurable disease (RECIST 1.1), as confirmed by imaging within the 28 days prior to randomization. CT thorax abdomen pelvis with IV contrast is the preferred imaging modality. In case of any contra-indications (medical or regulatory), it is allowed to perform a non-contrast CT thorax + MRI abdomen & pelvis. ≥ 18 years old (no upper age limit). WHO (World Health Organization) performance status ≤ 2. Adequate haematological and organ function: Haematological: haemoglobin > 9.0 g/dL or 5.6 mmol/L, absolute neutrophils > 1.5 x 109/L, platelets > 100 x 109/L Note: Platelet transfusions is allowed to achieve these baseline values. Renal: estimated glomerular filtration rate (eGFR) > 50 ml/min/m2; No proteinuria CTCAE ≥ grade 2. Hepatic: Bilirubin ≤ 1.0 times upper limit of normal (1.0xULN) of institutional limits, ALT (alanine aminotransferase) and/or AST (aspartate transaminase) ≤1.5 x ULN. If isolated elevated bilirubin <2 x ULN and Gilberts syndrome suspected, suggest repeating bloods after food. If bilirubin improves to meet the criteria above this is acceptable. More severe persistent hepatic impairment of whatever cause would exclude the patient from treatment till resolved. Heart: Clinically normal cardiac function based on left ventricular ejection fraction (LVEF ≥ 50%) as assessed either by multi-gated acquisition scan (MUGA) or cardiac ultrasound and 12 lead ECG without clinically relevant abnormalities. American Society of Anesthesiologist (ASA) score < 3. Women of child bearing potential (WOCBP) must have a negative serum pregnancy test within 7 days prior to the first dose of study treatment or surgery. Note: a woman is considered of childbearing potential (WOCBP), i.e. fertile, following menarche and until becoming post menopausal unless permanently sterile. Permanent sterilisation methods include hysterectomy, bilateral salpingectomy and bilateral oophorectomy. A postmenopausal state is defined as no menses for 12 months without an alternative medical cause. A high follicle stimulating hormone (FSH) level in the postmenopausal range may be used to confirm a post-menopausal state in women not using hormonal contraception or hormonal replacement therapy. However in the absence of 12 months of amenorrhea, a single FSH measurement is insufficient. Patients of childbearing / reproductive potential should use highly effective birth control measures, as defined by the investigator, during the study treatment period and for at least 6 months after the last dose of treatment or date of surgery. A highly effective method of birth control is defined as a method which results in a low failure rate (i.e. less than 1% per year) when used consistently and correctly. Such methods include: Combined (oestrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation (oral, intravaginal, transdermal). Progestogen-only hormonal contraception associated with inhibition of ovulation (oral, injectable, implantable). Intrauterine device (IUD). Intrauterine hormone-releasing system (IUS). Bilateral tubal occlusion. Vasectomized partner. Sexual abstinence (the reliability of sexual abstinence needs to be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the patient). Female subjects who are breast feeding should discontinue nursing prior to the first day of study treatment and until 6 months after the last study treatment. Before patient registration/randomization, written informed consent must be given according to ICH/GCP, and national/local regulations.

Exclusion Criteria

You have certain types of sarcoma that originated from bone, abdominal or gynecological organs, and it has spread to other parts of the body. You have a history of severe allergic reactions to certain medications used to treat sarcoma. You have experienced long-term suppression of your bone marrow. You have had a heart attack within the past 6 months. You have uncontrolled heart rhythm problems. You have already received the maximum allowed doses of certain chemotherapy drugs. You have active and uncontrolled infections. You have received live vaccines within the past month. You have bladder inflammation or blockage of urine flow. You have had another type of cancer within the past 5 years, except for certain types of skin, cervical, or prostate cancer that have been treated and cured. You have uncontrolled severe illness or medical conditions other than the specific type of sarcoma being studied. If you are a female patient, you are pregnant or breastfeeding, or if you are a male or female patient capable of having children, you are not willing to use effective birth control methods. You have any psychological, family, social, or geographical circumstances that could make it difficult for you to follow the study's instructions and schedule. You have known allergies to certain imaging agents and magnetic resonance imaging (MRI).

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants in the experimental arm receive 3 cycles of neoadjuvant chemotherapy followed by surgery. The standard arm undergoes surgery alone.

9-12 weeks

3 visits (in-person) for chemotherapy, 1 visit (in-person) for surgery

Follow-up

Participants are monitored for safety, effectiveness, and recurrence after treatment

8 years

Treatment Details

Interventions

• Preoperative chemotherapy
• Surgery

Trial Overview The study is testing if adding preoperative chemotherapy before surgery can improve disease-free survival for patients with high-risk sarcomas. Participants will be randomly assigned to either receive standard surgery alone (control group) or chemotherapy followed by surgery (experimental group).

Participant Groups

Group I: Standard arm Experimental Treatment 1 Intervention

Surgery alone

Group II: Experimental arm Experimental Treatment 1 Intervention

Preoperative chemotherapy and surgery

Who Is Running the Clinical Trial?

European Organisation for Research and Treatment of Cancer - EORTC

Lead Sponsor

Trials

417

Recruited

166,000+

Eastern Cooperative Oncology Group

Collaborator

Trials

272

Recruited

153,000+

ECOG-ACRIN Cancer Research Group

Collaborator

Trials

122

Recruited

160,000+

Canadian Cancer Trials Group

Collaborator

Trials

135

Recruited

70,300+

Japan Clinical Oncology Group

Collaborator

Trials

20

Recruited

4,700+

Australia and New Zealand Sarcoma Association

Collaborator

Trials

1

Recruited

250+

Anticancer Fund, Belgium

Collaborator

Trials

16

Recruited

1,900+

Findings from Research

Preoperative chemotherapy for soft tissue sarcoma can help determine the effectiveness of treatment, potentially allowing for less invasive surgical options and reducing major surgical complications.

The approach to using chemotherapy, surgery, and radiation therapy must be tailored to each patient based on tumor stage and grade, ensuring optimal tumor control while minimizing side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Preoperative chemotherapy in soft tissue sarcoma. Lokich, JJ.[2013]

Primary systemic chemotherapy followed by delayed surgery has shown better outcomes for osteogenic sarcomas compared to immediate surgery, allowing for limb preservation and reducing the time lost to postoperative therapy.

At Memorial Sloan Kettering Cancer Center, patients who did not respond favorably to preoperative chemotherapy were switched to alternative regimens, resulting in a 93% disease-free survival rate over a median of 20 months, suggesting that this tailored approach could be beneficial for treating other aggressive tumors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[New therapeutic results in osteosarcoma]. Urban, C., Rosen, G.[2022]

In a study of 81 sarcoma patients who underwent pulmonary metastasectomy after chemotherapy, measurable progression of lung metastases post-chemotherapy was identified as a significant predictor of poor survival outcomes, with a hazard ratio of 4.025.

Patients who experienced progression after chemotherapy had a five-year survival rate of 0%, compared to 32% for those without progression, highlighting the critical impact of post-chemotherapy disease status on prognosis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Progression after chemotherapy is a novel predictor of poor outcomes after pulmonary metastasectomy in sarcoma patients. Stephens, EH., Blackmon, SH., Correa, AM., et al.[2022]

The prognosis for patients with bone and soft tissue sarcomas has improved significantly due to the use of chemotherapy and radical surgery, regardless of whether radiotherapy is included.

Sensitivity to preoperative adjuvant chemotherapy is a key prognostic factor, highlighting its importance in the overall treatment strategy for these cancers.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Prognostic factors of bone and soft tissue sarcomas]. Furuse, K.[2006]

Surgical resection is a crucial treatment for lung metastases from sarcoma, and having multiple bilateral metastases does not prevent surgery from being a viable option.

The effectiveness of preoperative chemotherapy can be assessed through tumor doubling time, which helps predict how well the tumor will respond to treatment and correlates with patient prognosis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pulmonary resection for metastatic sarcoma. Huth, JF., Holmes, EC., Vernon, SE., et al.[2019]

In a study of 806 patients with localized soft tissue sarcoma, those who received perioperative chemotherapy had a 5-year metastasis-free survival rate of 58%, indicating that this treatment can be effective in real-world settings.

While the long-term outcomes of patients receiving perioperative chemotherapy in routine clinical practice were similar to those in clinical trials, there were notable risks of secondary malignancies and cardiac toxicity, highlighting the importance of considering these potential side effects in treatment decisions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Real-world evidence on perioperative chemotherapy in localized soft tissue sarcoma of the extremities and trunk wall; a population-based study. Boye, K., Lobmaier, I., Kobbeltvedt, MR., et al.[2022]

Preoperative chemotherapy has been shown to improve outcomes for certain pediatric sarcomas, leading to interest in applying similar strategies to adult soft tissue sarcomas, especially for tumors larger than 10 cm.

Despite the potential benefits of neoadjuvant chemotherapy in reducing the risk of recurrence and death, there is significant concern about the toxicity of these treatments and a lack of consensus on when they should be used in adult soft tissue sarcoma cases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Chemotherapy: Does Neoadjuvant or Adjuvant Therapy Improve Outcomes? Canter, RJ.[2018]

In a study of 38 patients with soft tissue sarcoma, preoperative therapy, including neoadjuvant radiotherapy and chemotherapy, demonstrated effective local control with only 5.2% experiencing local recurrence after surgery.

The study showed that preoperative treatment was safe and feasible, with most patients undergoing limb-sparing surgeries, and the results suggest that lower limb involvement and marginal excision are associated with worse disease-free survival outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Neoadjuvant treatment of soft tissue sarcoma. Greto, D., Livi, L., Saieva, C., et al.[2021]

In a Phase II study involving 70 patients with Stage III non-round cell soft tissue sarcomas in the extremities, pre-operative chemotherapy with doxorubicin and ifosfamide showed promising outcomes, with 5-year overall survival rates of 82.6%.

Despite significant hematological toxicities, including leukopenia and neutropenia, the treatment was feasible and resulted in favorable progression-free survival rates of 75.7% at 2 years and 63.8% at 5 years, indicating potential for further research.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Perioperative chemotherapy with ifosfamide and doxorubicin for high-grade soft tissue sarcomas in the extremities (JCOG0304). Tanaka, K., Mizusawa, J., Fukuda, H., et al.[2022]

The treatment of soft tissue sarcomas has shifted from radical surgeries like amputation to more conservative approaches that combine surgery with radiotherapy, supported by small randomized trials showing better outcomes.

For patients with localized soft tissue sarcomas, adjuvant chemotherapy is standard for certain high-risk subtypes, but its benefits for stage III patients remain unclear, necessitating careful discussion of risks and benefits with these patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Evidence-based recommendations for local therapy for soft tissue sarcomas. Pisters, PW., O'Sullivan, B., Maki, RG.[2022]

The study discusses a new preoperative adjuvant chemotherapy regimen using intra-arterial cisplatin (CDDP) combined with high-dose methotrexate (HDMTX) and adriamycin (ADR) to effectively shrink primary skeletal and soft tissue sarcomas, potentially leading to safer limb-salvage procedures.

This approach aims to not only identify effective postoperative treatments but also to eliminate micrometastatic disease, enhancing overall treatment efficacy for patients with sarcomas.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Preoperative adjuvant chemotherapy of skeletal and soft tissue sarcomas]. Maeyama, I., Furuse, K., Morimoto, K., et al.[2016]

In a study involving eight patients with osteosarcoma and Ewing's sarcoma, early surgery (1 to 4 days after the last chemotherapy dose) was performed without any wound healing or infection complications, suggesting that the timing of surgery after preoperative chemotherapy can be safely adjusted.

The study indicates that combining neoadjuvant chemotherapy with early surgical intervention is feasible and does not delay subsequent chemotherapy treatments, which could improve overall management strategies for high-grade primary bone sarcomas.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Perioperative chemotherapy for primary sarcoma of bone. Chan, KW., Knowling, M., Beauchamp, CP.[2015]

Preoperative chemotherapy was found to be effective in evaluating treatment outcomes for patients with osteosarcoma and malignant soft tissue tumors, based on a study of 28 patients.

While changes in radiographic images were similar for malignant bone and soft tissue tumors, the response to chemotherapy was more pronounced in soft tissue tumors, suggesting the need for further research on malignant bone tumors beyond osteosarcoma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Application of preoperative chemotherapy to postoperative chemotherapy in malignant bone and soft tissue tumors]. Furuse, K., Morimoto, K., Yamamoto, K., et al.[2006]

References

1. United States pubmed.ncbi.nlm.nih.gov

Preoperative chemotherapy in soft tissue sarcoma. [2013]

2. Austria pubmed.ncbi.nlm.nih.gov

[New therapeutic results in osteosarcoma]. [2022]

3. United States pubmed.ncbi.nlm.nih.gov

Progression after chemotherapy is a novel predictor of poor outcomes after pulmonary metastasectomy in sarcoma patients. [2022]

4. Japan pubmed.ncbi.nlm.nih.gov

[Prognostic factors of bone and soft tissue sarcomas]. [2006]

5. United States pubmed.ncbi.nlm.nih.gov

Pulmonary resection for metastatic sarcoma. [2019]

6. England pubmed.ncbi.nlm.nih.gov

Real-world evidence on perioperative chemotherapy in localized soft tissue sarcoma of the extremities and trunk wall; a population-based study. [2022]

7. United States pubmed.ncbi.nlm.nih.gov

Chemotherapy: Does Neoadjuvant or Adjuvant Therapy Improve Outcomes? [2018]

8. Italy pubmed.ncbi.nlm.nih.gov

Neoadjuvant treatment of soft tissue sarcoma. [2021]

9. England pubmed.ncbi.nlm.nih.gov

Perioperative chemotherapy with ifosfamide and doxorubicin for high-grade soft tissue sarcomas in the extremities (JCOG0304). [2022]

10. United States pubmed.ncbi.nlm.nih.gov

Evidence-based recommendations for local therapy for soft tissue sarcomas. [2022]

11. Japan pubmed.ncbi.nlm.nih.gov

[Preoperative adjuvant chemotherapy of skeletal and soft tissue sarcomas]. [2016]

12. Canada pubmed.ncbi.nlm.nih.gov

Perioperative chemotherapy for primary sarcoma of bone. [2015]

13. Japan pubmed.ncbi.nlm.nih.gov

[Application of preoperative chemotherapy to postoperative chemotherapy in malignant bone and soft tissue tumors]. [2006]