How do you approach a patient with newly diagnosed high-grade osteosarcoma who received maximum cumulative dose of doxorubicin for a soft tissue sarcoma 10 years earlier?

Some chemo is better than no chemo for osteosarcoma.

That is what is known. After the first randomized study establishing that chemo was effective at improving survival for OS, all subsequent randomized studies have been statistical ties. No regimen or schedule or dose or drug has been proven to be better than another. 

Sticking to data, the French OS2006 study randomized persons with newly diagnosed osteosarcoma to MAP chemo vs. methotrexate ifosfamide and etoposide. Cites below. Outcomes were the same in both arms. I thought this was great at the time and started using it. Then I got nervous that MIE was never mentioned as an alternative in the ASCO reviews and such and thought maybe there was some problem with this study. There are more recent publications that reference it though. So: you can use no doxorubicin and no cisplatin and point to this study as your reference. Data!

Speculations and extrapolations to follow. It occurs to me that someone who got their life limit for doxorubicin for a soft tissue sarcoma might have been an adult who now has a radiation-induced osteosarcoma and so might be older and not so robust. If I were modifying the OS2006 regimen for an older and previously treated patient, I would drop the methotrexate. Which I might do anyway because I have become skeptical of high dose methotrexate - but there is no question it can be unpredictable in adults. The next thing I might do is drop the etoposide which is only questionable in the club of active agents vs. OS and also is pretty myelotoxic. That leaves ifosfamide. High dose ifosfamide is a fine drug for recurrent osteosarcoma. If you dose reduce high dose ifosfamide, you would get regular ifosfamide. I have used doxil in people who had their life limit of doxorubicin on the theory that it is less cardiotoxic than doxorubicin. I have used ifosfamide and doxil before for osteosarcoma. Doxil is easy on the marrow and the heart. I have not combined ifosfamide with cisplatin (given together) for OS but it is done all the time for germ cell tumors as TIP. I could imagine TIP with no taxol could be appropriate for an adult with healthy kidneys who should not get more doxorubicin. The cisplatin spread over 4 days is also better for an adult than the giant 120mg/m2/4 hours pediatric dose.

Bottom line: chemo is good. You can omit doxorubicin and still use chemo to improve the chance your OS patient is cured.

Toulmonde et al., PMID 28662235

Gaspar et al., PMID 29190507 

Marec-Berard et al., PMID 31702419 

Le Deley et al., PMID 17267204 

Koshy et al., PMID 16054775 

“The 5-year cause-specific and overall survival rate for patients who received treatment for R-OS involving chemotherapy alone, surgery alone, and surgery plus chemotherapy was 17.3% and 17.3%, 56.6% and 50.3%, and 71.0% and 68.3%, respectively (p < 0.0001, log-rank test).”

In planning for treatment for your patient, you might consider the following articles.

1. Anninga et al., PMID 21703851 - Of cisplatin, ifosfamide, doxorubicin, methotrexate, and etoposide, using 3 chemotherapeutic agents is better than 2, but 4 isn't better than 3 in treating osteosarcoma. Etoposide is probably the least active among the 5 though.
2. Jones et al., PMID 33632930 - Low risk of cardiotoxicity with co-administration of dexrazoxane, albeit with relatively short follow up (median 28 weeks).
3. Van Tine et al., PMID 33766818 - Low risk of cardiotoxicity with co-administration of dexrazoxane (smaller study with short follow up).
4. Benjamin and Minotti, PMID 33990361 - commentary on both of the above.

Of potential future relevance, Saro Armenian presented the results of the Children's Oncology Group study ALTE1621 at ASCO this year, which showed that among survivors of pediatric cancer who received doxorubicin, low dose carvedilol started years after completion of chemotherapy reduced risk of LV dysfunction. (NCT02717507)

Bottom line, you can consider pushing the cumulative dose of doxorubicin if you want to treat your patient with curative intent.

Secondarily, if this is a true second primary disease, rather than a secondary malignancy from RT, consider evaluating your patient for a cancer predisposition syndrome (i.e. Li-Fraumeni).