Looking for the Most Effective Osteosarcoma Treatment?

This article describes how chemotherapy drastically increased the survival of osteosarcoma patients , but also why the standard chemotherapy combination may not be best for everyone and what you can do about it.

Three years ago, a 38-year-old man was diagnosed with osteosarcoma in his shoulder.  The surgery went well and he received adjuvant chemotherapy to reduce the risk of recurrence called MAP (a combination of high-dose methotrexate, doxorubicin and cisplatin).  For two years everything looked good. Then the tumor returned.

How chemotherapy transformed osteosarcoma treatment

Historically, surgery was the only treatment for osteoscarcoma and often involve the amputation of whole limbs.  However, microscopic and undetectable cancer cells had frequently already spread to other parts of the body (metastases) so that only about 15–20% of patients remained free of recurrence.

Then, in a landmark randomized trial, 66% of patients who received multidrug chemotherapy remained relapse-free at two years.¹  This was an extraordinary advance. Surgery plus adjuvant chemotherapy became critical to curing localized, high-grade osteosarcoma.

But the adjuvant chemotherapy regimen (MAP) was not created in a single, well-designed trial that tested methotrexate (M), doxorubicin (A) and cisplatin (P) separately and in every possible combination. Instead, it evolved step by step from small studies conducted more than 50 years ago.

Year	Treatment	Initial Setting	Early Evidence
1972	Doxorubicin	Visible lung metastases	Among 13 patients, one had a complete response and three had partial responses: 4 of 13, or 31%.²
1972–77	High-dose methotrexate	Visible primary tumors or lung metastases	Early reports described tumor regressions. A later vincristine-plus-methotrexate series reported responses in 7 of 8 patients, but it was a small sample of patients and did not test methotrexate alone.³
1974–77	Methotrexate plus doxorubicin	Metastatic and postoperative treatment	The drugs were combined without a randomized trial showing that the combination was better than either drug alone. Early postoperative studies relied on historical controls and short follow-up.³⁻⁴
Late 1970s	Cisplatin	Previously treated advanced disease	Cisplatin also shrank some tumors. A later phase II study found responses in 7 of 37 patients, or 19%.⁵
1980s	MAP-like multidrug protocols	Before and after surgery	Active drugs and schedules were assembled into institutional protocols. Multiple components changed together, so the independent contribution of each drug was never established.

Do we really need all three drugs?

In a randomized European trial of 198 patients, MAP was compared to just doxorubicin plus cisplatin (AP). To everyone's surprise, the 5-year overall survival was 50% with MAP but 64% with AP. In other words, leaving out methotrexate increased overall 5-year survival by 14%.⁶ 

That triggered a second randomized trial with 407 patients, where a more complex MAP regimen which included methotrexate, doxorubicin, cisplatin and several additional drugs was compared to AP. This time, 5-year survival was 55% in both groups, but toxicity was higher in the more complex MAP regimen leading to only half of the patients completing their treatment. The investigators concluded that AP was shorter, better tolerated and should be preferred.⁷

These studies do not prove that AP is best for every patient. But the findings demonstrate that more chemotherapy was not better and whether adding methotrexate to AP is really beneficial was never convincingly established.

Why did MAP remain the more commonly used standard?

Clinical standards acquire momentum. Physicians understandably fear the regret of omitting a drug if a patient later relapses. Giving the established combination is also easier to defend to colleagues, guidelines and insurers, this created a one-way bias: adding treatment feels proactive, while removing treatment can feel like undertreatment, even when a simpler regimen produces comparable survival outcomes.

The result is remarkable: a chemotherapy backbone assembled during the 1970s and 1980s remains dominant almost 50 years later, despite substantial toxicity and little improvement for patients whose cancer is resistant or has already spread. Of course, if you tell your oncologist that you'd prefer AP over MAP, your oncologist would most likely be perfectly fine with it.  But you shouldn't have to ask.  

When the patient’s cancer returned

Despite surgery and the full MAP protocol, this patient’s cancer returned, now classified as a  metastatic chondrosarcoma with an IDH1 mutation, the latter providing a biological rationale for treatment with ivosidenib, a targeted drug that inhibits mutant IDH1.  But “targeted” does not mean “guaranteed to work” (see "Got a Mutation but Your Targeted Therapie isn't working?) In a small chondrosarcoma study evaluating ivosidenib, only 3 of 13 patients, 23% experienced measurable tumor shrinkage, although some achieved prolonged disease control.⁸  After two months of ivosidenib, this patient’s tumor continued to grow.

This time, the living tumor was tested for the most effective therapy. 

Tissue from the progressing axillary tumor was sent for the SAGE Oncotests™, which exposes a patient’s living tumor tissue to multiple treatment options.  The test confirmed resistance to ivosidenib, consistent with what had already happened clinically, but it also identified a different path forward. Among standard chemotherapies, gemcitabine plus docetaxel produced a much more favorable profile, with strong inhibition of tumor growth (as shown in the SAGE Oncotest Reveal™). 

In addition to the standard therapies, other FDA-approved and clinical trial drugs were tested.  Among those, eprenetapopt (APR-246) stood out as it produced the strongest overall response.

Summary: To gain clarity about your treatment choices, plan to include functional profiling before an upcoming biopsy or surgery.

Osteosarcoma chemotherapy is one of oncology’s great achievements. It changed a disease that was usually fatal despite surgery into one that can often be cured when localized. But the history of MAP also illustrates the limitations of a one-size-fits-all treatment. A regimen may become standard without every component having been rigorously proven necessary for every patient.

If your treatment has stopped working or a biopsy or surgery is upcoming, check out our 5-min SAGE eligibility questionnaire to see whether fresh tumor may be used for functional drug testing.

Functional testing cannot guarantee a clinical response. But it can provide patient-specific evidence before another consequential treatment decision is made.

References

1. Link MP, et al. The effect of adjuvant chemotherapy on relapse-free survival in patients with osteosarcoma of the extremity. N Engl J Med. 1986;314:1600–1606. https://doi.org/10.1056/NEJM198606193142502

2. Cortes EP, et al. Doxorubicin in disseminated osteosarcoma. JAMA. 1972;221:1132–1138. https://doi.org/10.1001/jama.1972.03200230020005

3. Jaffe N, et al. High-dose methotrexate with citrovorum factor in osteogenic sarcoma—progress report II.Cancer Treat Rep. 1977;61:675–679. https://pubmed.ncbi.nlm.nih.gov/301780/

4. Rosen G, et al. High-dose methotrexate with citrovorum factor rescue and adriamycin in childhood osteogenic sarcoma. Cancer. 1974;33:1151–1163.

5. Oosterhuis JW, et al. Phase II study of cisplatin in advanced osteogenic sarcoma. Cancer Treat Rep.1985;69:119–121. https://pubmed.ncbi.nlm.nih.gov/3855699/

6. Bramwell VHC, et al. A comparison of two short intensive adjuvant chemotherapy regimens in operable osteosarcoma. J Clin Oncol. 1992;10:1579–1591. https://pubmed.ncbi.nlm.nih.gov/1403038/

7. Souhami RL, et al. Randomised trial of two regimens of chemotherapy in operable osteosarcoma. Lancet.1997;350:911–917. https://pubmed.ncbi.nlm.nih.gov/9314869/

8. Tap WD, et al. Phase I study of the mutant IDH1 inhibitor ivosidenib: long-term safety and clinical activity in patients with conventional chondrosarcoma. Clin Cancer Res. 2025;31:2108–2116. https://doi.org/10.1158/1078-0432.CCR-24-3298

Medical note: This article is educational and does not replace advice from an osteosarcoma specialist. The SAGE Oncotest is a laboratory-developed test whose results should be considered together with pathology, imaging, clinical evidence and physician judgment.