Metastatic Soft Tissue Sarcoma: What to Ask

This page is for adults with soft tissue sarcoma that has spread (stage IV), and their families. It explains what the National Cancer Institute (NCI) says about testing and treatment, and suggests questions for your sarcoma team.

Soft tissue sarcoma is not one illness. It is a large family of tumors that are unrelated to each other. They share only a starting place: connective tissue, such as fat, muscle, or blood vessels.

That has a strange result, and NCI states it directly. Staging is mainly used as a research tool. It does not routinely drive decisions beyond four things:

• The subtype.
• The grade.
• Where the tumor started.
• How far it has gone.

So the first question is not "what stage?" It is "what exactly is this?"

This page covers adult soft tissue sarcoma, which is the group NCI's stage IV evidence comes from. Bone sarcomas such as osteosarcoma and Ewing sarcoma are treated on entirely different protocols. If that is your diagnosis, ask your team for guidance written for it.

The evidence on where treatment happens is unusually clear.

NCI reports a Swedish series of 375 patients. Local recurrence (the cancer coming back in the same place) was:

• 45 percent in people never referred to a specialist center.
• 24 percent in those referred after a first operation or biopsy.
• 18 percent in those referred before any surgery at all.

A British series of 260 patients found the same pattern from another angle. Local recurrence was 19 percent at the specialist center and 39 percent across 38 district hospitals. This was even though the district tumors were smaller and of lower grade. Patients at the specialist center also had a small survival advantage once other factors were accounted for (multivariate analysis).

Grade is worth asking about by name. Grade describes how aggressive the cells look. The AJCC recommends the three-tier FNCLCC system, which scores three things:

• How closely the tumor resembles normal tissue.
• How fast the cells divide.
• How much of the tumor has died off.

NCI says the point of that score is to predict who will develop metastasis (spread to other parts of the body).

NCI says spread to nearby lymph nodes is rare in adult soft tissue sarcoma, though some types do it more often. When sarcoma spreads to distant organs, it most often goes to the lung.

NCI calls the lung the most common site of distant spread. It lists a chest CT scan for high-grade sarcoma to look there. It also names the exceptions. A PET scan helps with the subtypes that do favor lymph nodes: synovial sarcoma, clear cell sarcoma, angiosarcoma, rhabdomyosarcoma and epithelioid sarcoma.

That is worth knowing when a scan is ordered. Where the team looks depends on which sarcoma this is.

NCI lists three kinds of options for stage IV disease:

• Chemotherapy.
• Targeted or immunotherapy treatment matched to the subtype (histology).
• Surgery.

Doxorubicin has been the standard chemotherapy drug for decades. NCI names others that work against sarcoma: ifosfamide, epirubicin, pegylated liposomal doxorubicin, gemcitabine, trabectedin, eribulin, pazopanib, dacarbazine and the taxanes.

Then it makes a point that surprises people. Combining anthracyclines (the drug family doxorubicin belongs to) with other drugs raises response rates. It also raises side effects markedly, without helping people live longer, except in some specific subtypes. So in most settings NCI prefers single drugs used one after another.

• Adding ifosfamide raises the response rate and progression-free survival (time without the cancer growing). It has not been shown to lengthen life.
• Adding trabectedin to doxorubicin does improve progression-free survival in metastatic or unresectable (not removable by surgery) leiomyosarcoma.

Gemcitabine with docetaxel is one of several regimens NCI lists for second line and beyond. Others are ifosfamide, trabectedin, eribulin, pazopanib, dacarbazine and pegylated liposomal doxorubicin. Which one comes next depends heavily on your subtype.

One randomized phase II study of gemcitabine with docetaxel enrolled 122 patients. Compared with gemcitabine alone:

• The response rate was 16 percent, against 8 percent.
• Median progression-free survival was 6.2 months, against 3.0.
• Median overall survival was 17.9 months, against 11.5.

But the GeDDis trial put it head to head with doxorubicin in 257 untreated patients. Progression-free survival came out identical.

This is the list worth photographing. NCI lists sarcoma subtypes that respond better to particular drugs:

• Alveolar soft-part sarcoma: kinase inhibitors including sunitinib and pazopanib. Also immunotherapy, including atezolizumab and pembrolizumab.
• Angiosarcoma: taxanes.
• Dermatofibrosarcoma protuberans: imatinib.
• Inflammatory myofibroblastic tumor: ALK inhibitors.
• PEComa: mTOR inhibitors, including nab-sirolimus.
• Sarcomas with an NTRK fusion: larotrectinib.
• Epithelioid sarcoma: tazemetostat.
• Desmoid tumor: nirogacestat, or the kinase inhibitor sorafenib. Desmoid tumors sit slightly apart from the rest of this page. They can grow into nearby tissue and come back locally. But they do not spread to distant organs, so "metastatic" does not apply to them.

Synovial sarcoma has its own route, and it is often described wrongly. The T-cell therapy afamitresgene autoleucel is directed against a protein called MAGE-A4. It is not aimed at the SS18-SSX fusion that defines the diagnosis. The label sets several conditions:

• The disease must be unresectable or metastatic.
• Chemotherapy must have come first.
• The patient must be 12 or older.
• They must carry one of four specific HLA-A*02 types (an inherited immune marker).
• A companion test must confirm MAGE-A4.

It carries a boxed warning for cytokine release syndrome, a serious immune reaction. It must not be used in anyone carrying HLA-A*02:05P. Two separate tests decide eligibility, and neither is the diagnostic fusion. Biomarker testing is doing real work here.

Removing metastases is not routine. It is not fringe either.

NCI's position is careful. Removing lung metastases may bring long-term disease-free survival if the primary tumor is under control. That applies to favorable disease biology, which in NCI's words means few nodules and slow growth. NCI then adds an honest caveat. It is unclear how much of the benefit comes from the operation. It may come instead from choosing patients whose disease was already gentle.

Retroperitoneal sarcoma (sarcoma deep in the back of the abdomen) is the harder case. NCI notes that complete removal is often difficult. These tumors are large by the time they are found, and they sit among organs and vessels that cannot be removed freely.

• What is the exact subtype, and who reviewed the slides?
• What is the FNCLCC grade, and which component drove it?
• Is my subtype one of the eight in NCI's table with a matched agent?
• Was molecular testing sent, including NTRK fusion testing?
• Is doxorubicin first here, or does my subtype justify starting elsewhere?
• If the disease is only in my lungs, is removing the nodules being considered?
• Which trial would be the alternative to standard chemotherapy right now?

• Call 911 or go to an emergency department if you cough up blood, or breathlessness or chest pain comes on suddenly. CDC lists these among the signs of a blood clot in the lung, and cancer raises the risk of clots. Do not drive yourself.
• Phone your sarcoma team right away, at any hour, if you have a temperature of 100.4°F (38°C) or higher, or shaking chills, during chemotherapy. CDC says a fever during chemotherapy is a medical emergency, because fever may be the only sign of an infection and an infection during chemotherapy can be life-threatening. Doxorubicin can cause a severe drop in blood cells. If you cannot reach your team quickly, go to an emergency department and tell them you are on chemotherapy.
• Get medical help at once after afamitresgene autoleucel if you have fever, shaking chills, a fast or irregular heartbeat, dizziness, shortness of breath, confusion, trouble speaking or a seizure. The label says these can be signs of cytokine release syndrome or a nerve-system reaction, and tells patients to seek immediate medical attention.
• Call your care team right away if you are short of breath, your hands, feet or ankles swell, or your heartbeat is fast, irregular or pounding. MedlinePlus says doxorubicin can cause serious heart problems, during treatment or long after, and lists these as reasons to call immediately.
• Call your care team soon, within a day or two, if a known lump grows noticeably, a new lump appears, or a limb aches deeply at night. Your team may want to move a scan forward.

For the wider picture, see sarcoma and getting a second opinion.

• National Cancer Institute — Soft Tissue Sarcoma Treatment (PDQ®), Health Professional Version
• DailyMed (NIH) — TECELRA (afamitresgene autoleucel) prescribing information
• NCI — Infection and Neutropenia During Cancer Treatment
• CDC — Watch Out for Fever
• CDC — About Blood Clots
• MedlinePlus — Doxorubicin
• NCI — Desmoid Tumor