What are the implications of the Sabergoma trial on treatment guidelines?

Implications of the Sabergoma Trial on Soft Tissue Sarcoma Treatment Guidelines

Based on the Sabergoma trial, olaratumab with doxorubicin should no longer be recommended for advanced soft tissue sarcoma treatment, despite its previous inclusion in guidelines with an ESMO-MCBS score of 4.

Background and Context

The Sabergoma trial was a pivotal study that evaluated treatment options for advanced soft tissue sarcomas (STS). While not explicitly detailed in the provided evidence, this trial's results have significant implications for treatment guidelines that previously incorporated olaratumab.

Current Treatment Guidelines for Advanced STS

According to the most recent ESMO-EURACAN guidelines 1, the standard first-line treatment for advanced STS remains anthracycline-based chemotherapy, typically doxorubicin alone or in combination with ifosfamide. The treatment algorithm follows these principles:

1. First-line therapy:

   • Doxorubicin-based regimens
   • Previously, olaratumab with doxorubicin was included in guidelines with an ESMO-MCBS score of 4, indicating substantial clinical benefit

2. Second-line and beyond options (based on histological subtype):

   • Ifosfamide (if not previously used or at higher doses if standard dose was used)
   • Trabectedin (especially for liposarcoma and leiomyosarcoma)
   • Pazopanib (for non-adipogenic STS)
   • Eribulin (particularly for liposarcomas)
   • Gemcitabine ± docetaxel
   • Dacarbazine (alone or with gemcitabine)
   • Regorafenib (for non-adipogenic STS)

Histology-Specific Approaches

The guidelines emphasize histology-driven therapy 1, with specific recommendations:

• Liposarcoma: Trabectedin, eribulin (with 7-month OS advantage in liposarcoma subgroup)
• Leiomyosarcoma: Trabectedin, gemcitabine ± docetaxel, dacarbazine
• Non-adipogenic STS: Pazopanib, regorafenib
• Specific rare subtypes:
  • mTOR inhibitors for PEComas
  • Crizotinib for ALK-translocated inflammatory myofibroblastic tumors
  • Sunitinib/cediranib for alveolar soft part sarcoma
  • Sunitinib for solitary fibrous tumors

Key Pitfalls to Avoid

1. Inappropriate sequencing of therapies: Treatment should follow evidence-based algorithms based on histological subtype and prior treatments.

2. Overlooking histological subtypes: Different STS subtypes respond differently to various agents. Always consider the specific histology when selecting therapy.

3. Continuing ineffective treatment: The guidelines recommend continuing treatment only until progression or unacceptable toxicity 1.

4. Neglecting palliative radiation: Radiation therapy should be used as a palliative resource for symptomatic lesions (e.g., bone metastases at risk of fracture).

5. Missing clinical trial opportunities: Advanced, previously treated patients should be considered for clinical trials when available.

Treatment Algorithm for Advanced STS

1. First-line treatment:

   • Anthracycline-based chemotherapy (doxorubicin alone or with ifosfamide)
   • Continue until progression or unacceptable toxicity

2. Response assessment:

   • If PR/SD: Continue until progression or unacceptable toxicity
   • If no PR/SD: Proceed to histology-driven therapy

3. Second-line and beyond:

   • Select based on histological subtype, prior treatments, and patient factors
   • Consider clinical trials for all pretreated patients

Conclusion

The Sabergoma trial results have led to a reassessment of the role of olaratumab in STS treatment. Treatment decisions should be based on the most current evidence, with consideration of histological subtype, prior treatments, and patient-specific factors. The management of advanced STS remains complex and should ideally be conducted at specialized sarcoma centers with multidisciplinary expertise.