Sarcoma Recurrence: What to Ask

NCI's PDQ summary for health professionals frames sarcoma recurrence in one sentence. Treatment depends on the clinical presentation of the disease and on previous treatment.

Those two things carry most of the decision. Where the cancer came back matters. So does what was already used, because it limits what can be used again.

PDQ groups the options into four headings: surgery with or without radiation, chemotherapy and targeted therapy, three named drugs, and immune checkpoint inhibitor therapy.

PDQ cites a review of 174 patients with limb sarcoma followed at one center from 2003 to 2009. It grades it Level of evidence C2, meaning a look back rather than a trial.

Of those, 82 patients, or 47%, relapsed. More than 80% of relapses happened within the first 2 years of follow-up.

Two findings from that series shape what to ask.

Local returns at the original site were found by hand and eye. Of 31 local recurrences, 30 were detected clinically. MRI found exactly one.

Lung spread was found by imaging. Isolated lung metastases developed in 28 patients, or 16%. Chest x-ray found 19 of them, CT found 3, and clinical exam found 11.

PDQ adds that PET and CT imaging may be more sensitive than contrast-enhanced CT alone when recurrence is suspected. And it is honest about the limit: the effect of finding metastases early on survival or quality of life is unknown.

PDQ says patients who develop a local recurrence can often be treated with local therapy.

Which local therapy depends on history. After light earlier treatment, PDQ describes surgery plus radiation. After heavy earlier treatment, it describes amputation.

Lung metastases get their own line. PDQ says removing a limited number of lung metastases may be associated with favorable disease-free survival, graded Level of evidence C3.

It then supplies the caveat that makes those results readable. The contribution of selection factors is not known. PDQ names three: low tumor burden, slow tumor growth, and a long disease-free interval. People who do well after lung surgery may be doing well partly because they were chosen for it.

Single-agent chemotherapy may be used at recurrence. PDQ names ifosfamide and gemcitabine as agents that may be used in sequence at recurrence or progression, graded Level of evidence C3.

Then it states the reason to consider a trial instead. None of these agents has been shown to increase overall survival in this setting.

That single sentence changes what a conversation about second-line chemotherapy should cover.

PDQ lists further options after first-line chemo. Ifosfamide, with or without etoposide. Dacarbazine. Temozolomide. Vinorelbine. And regorafenib.

PDQ says FDA has approved eribulin, trabectedin, and pazopanib after failure of a first-line chemotherapy regimen. Each has a phase III trial behind it, and each result is worth reading closely.

Eribulin is a microtubule inhibitor, approved in 2016. Its use is for liposarcoma that cannot be removed or has spread, after anthracycline chemo. Its trial enrolled 452 patients with advanced leiomyosarcoma or adipocytic sarcoma. Eribulin was given by vein on days 1 and 8 every 3 weeks, at an amount worked out from body size. The comparison was dacarbazine. Median overall survival was 13.5 months against 11.5, with a hazard ratio of 0.77. A preplanned subset told a different story. In liposarcoma, median survival was 15.6 months against 8.4. Time before growth was identical in both groups, at 2.6 months.

Trabectedin is approved as second-line treatment for advanced liposarcoma and leiomyosarcoma. Its trial enrolled 518 patients. It was given as a 24-hour infusion on day 1, every 21 days, at an amount based on body size. The comparison was dacarbazine. Time before growth improved, at 4.2 months against 1.5. But overall survival, the main endpoint, was not statistically different. It was 12.4 months against 12.9. Response rates were low in both arms, 10% against 7%. Clinical benefit, counting response plus stable disease, was 34% against 19%. The most common grade 3 and 4 problems were low blood counts and a temporary rise in liver enzymes. Phase II studies showed a high response rate in myxoid or round cell liposarcoma, up to 51%. The 6-month rate without growth was 88%.

Pazopanib is a pill that blocks several tyrosine kinases. The phase III PALETTE study compared 800 mg daily against placebo in 369 patients. It excluded adipocytic sarcomas and gastrointestinal stromal tumors. All had progressed on a first-line anthracycline regimen. Median time before growth was 4.6 months against 1.6. Overall survival was not statistically different, at 12.5 months against 10.7. Response rate was 6% against 0%. Disease stability was 67% against 38%. The most common grade 3 or 4 problems were fatigue, high blood pressure, diarrhea, loss of appetite, and a temporary rise in liver enzymes. FDA approved it in 2012, for soft tissue sarcomas other than the adipocytic subtypes, after earlier chemo. Pazopanib is a tablet you take at home. Go by the amount your sarcoma team prescribed, not by the trial figure.

Pazopanib is a tablet taken at home. The study amount is quoted here for the record; your own sarcoma team sets what you take and often reduces it for blood pressure or liver problems.

Read together, a pattern shows. Two of the three improved time before growth without improving survival. Subtype decided who benefited most.

PDQ is direct. Two trials have explored pembrolizumab, nivolumab, and ipilimumab in soft tissue sarcoma.

Some activity has been shown in selected subtypes. But the factors that might predict who responds remain unknown. PDQ states their use cannot be routinely recommended.

That is a specific statement, not a general caution. It means asking which subtype and which trial, rather than asking whether immunotherapy is available.

Almost every option above is keyed to histology. Liposarcoma. Leiomyosarcoma. Myxoid or round cell liposarcoma. The adipocytic subtypes. Each appears in a different eligibility line.

PDQ also names two histologies where recurrence more than 5 years after diagnosis is a known pattern: synovial sarcoma and alveolar soft-part sarcoma.

So the first question at a suspected recurrence is not which drug. It is what the pathology report names, and whether that name has been re-confirmed on the new tissue.

• Call 911 or go to an emergency department if you cough up blood, or become suddenly short of breath, or have chest pain. The lung is where sarcoma most often spreads, and in the series above isolated lung metastases developed in 16 percent.
• Call 911 or go to an emergency department if a limb becomes cold, pale, numb, or suddenly very painful, or if you cannot move it.
• Call your sarcoma team at once, at any hour, if you have a temperature of 100.4°F (38°C) or higher, or chills, while on chemotherapy such as ifosfamide or gemcitabine. Those drugs flatten the white cells that hold infection back, so the CDC counts fever during chemotherapy as a medical emergency. Do not wait for the clinic to ring back, and if you cannot get through, go to an emergency department and say you are on chemotherapy.
• Call your care team the same day if an old surgical site opens, leaks fluid, or becomes newly red, swollen, and painful.
• Call your care team within a day or two if you find a new or growing lump at or near the original site. Of 31 local recurrences in that series, 30 were found clinically rather than on a scan, so what you feel matters.
• Call your care team within a day or two if you have a cough that will not clear, or you are breathless doing things you managed a month ago.

The disease itself is described in sarcoma. Long-term monitoring is covered in sarcoma survivorship. The general shape of a return workup is in when cancer comes back.

• NCI PDQ: soft tissue sarcoma, HP version
• NCI: drugs for soft tissue sarcoma
• NCI: Infection and Neutropenia During Cancer Treatment