Maximum benefit of chemotherapy for osteosarcoma achieved—what are the next steps?
Authors: Eugenie Kleinerman
Journal: The Lancet Oncology (2016)

The survival rates for osteosarcoma have remained stagnant at 60–65% for more than 25 years. The three-drug chemotherapy regimen of cisplatin, doxorubicin, and methotrexate (MAP) form the backbone therapy, and response to induction chemotherapy correlates with patient outcome.1Bacci G Mercuri M Longhi A et al.Grade of chemotherapy-induced necrosis as a predictor of local and systemic control in 881 patients with non-metastatic osteosarcoma of the extremities treated with neoadjuvant chemotherapy in a single institution.Eur J Cancer. 2005; 41: 2079-2085Summary Full Text Full Text PDF PubMed Scopus (91) Google Scholar Debate remains about the usefulness of adding dose-intensive ifosphamide with or without etoposide to the three-drug MAP regimen (MAPIE) to improve the outcome of patients with a poor response (defined as ≤90% tumour necrosis) to induction chemotherapy. The results of the EURAMOS-1 international trial presented in The Lancet Oncology,2Marina N Smeland S Bielack S et al.Comparison of MAPIE versus MAP in patients with a poor response to preoperative chemotherapy for newly diagnosed high-grade osteosarcoma (EURAMOS-1): an open-label, international, randomised controlled trial.Lancet Oncol. 2016; (published online Aug 25.)http://dx.doi.org/10.1016/S1470-2045(16)30214-5PubMed Google Scholar focused on patients with newly diagnosed, non-metastatic osteosarcoma, who had a poor response (≤90% tumour necrosis) after neoadjuvant three-drug chemotherapy (MAP) and were randomly assigned postoperatively to MAP or MAP plus high dose ifosphamide (dose used was 14 g/m2 at 2·8 g/m2 per day) and etoposide (MAPIE). The study aimed to establish whether the addition of ifosphamide and etoposide, previously thought to improve outcome, would have a significant effect on event-free (the primary endpoint) and overall survival. No difference in either event-free survival (hazard ratio [HR] 0·98 [95% CI 0·78–1·23]) or overall survival was seen between the two groups. The EURAMOS-1 study shows that international collaborations are feasible, can be used to increase accrual of patient numbers, and are a powerful approach to studying rare cancers. This is the first randomised trial to investigate this important question, and not only shows that there was no patient benefit from ifosphamide and etoposide but also that there was an significant increase in regimen toxicity for high-grade non-haematological adverse events (p=0·0024), particularly in grade 4 non-haematological adverse events (35 [12%] of 301 in the MAP group vs 71 [24%] of 298 in the MAPIE group). This study is both timely and important because it provides crucial information for oncologists on how to approach the care of paediatric, adolescent, and young adult patients with osteosarcoma who have responded poorly to preoperative chemotherapy. Two other randomised trials3Meyers PA Schwartz CL Krailo MD et al.Osteosarcoma: the addition of muramyl tripeptide to chemotherapy improves overall survival—a report from the Children's Oncology Group.J Clin Oncol. 2008; 26: 633-638Crossref PubMed Scopus (581) Google Scholar, 4Ferrari S Ruggieri P Cefalo G et al.Neoadjuvant chemotherapy with methotrexate, cisplatin, and doxorubicin with or without ifosfamide in nonmetastatic osteosarcoma of the extremity: an Italian sarcoma group trial ISG/OS-1.J Clin Oncol. 2012; 30: 2112-2118Crossref PubMed Scopus (145) Google Scholar investigated whether the addition of ifosphamide at the standard dose improved the 60–65% survival of patients with osteosarcoma achieved with the three-drug regimen. Similar to the EURAMOS-1 trial, the Children's Oncology Group (COG) trial reported in 2008,3Meyers PA Schwartz CL Krailo MD et al.Osteosarcoma: the addition of muramyl tripeptide to chemotherapy improves overall survival—a report from the Children's Oncology Group.J Clin Oncol. 2008; 26: 633-638Crossref PubMed Scopus (581) Google Scholar and the Italian Sarcoma Group trial reported in 2012,4Ferrari S Ruggieri P Cefalo G et al.Neoadjuvant chemotherapy with methotrexate, cisplatin, and doxorubicin with or without ifosfamide in nonmetastatic osteosarcoma of the extremity: an Italian sarcoma group trial ISG/OS-1.J Clin Oncol. 2012; 30: 2112-2118Crossref PubMed Scopus (145) Google Scholar showed no benefit in adding ifosphamide to the three drug regimen as judged by event-free survival and overall survival. A meta-analysis published in 2011 showed that although treatment with three drugs is superior to that with two drugs, no benefit existed for using four drugs compared with three drugs.5Anninga JK Gelderblom H Fiocco M et al.Chemotherapeutic adjuvant treatment for osteosarcoma: where do we stand?.Eur J Cancer. 2011; 47: 2431-2445Summary Full Text Full Text PDF PubMed Scopus (325) Google Scholar Therefore, despite increasing the dose of ifosphamide and adding etoposide to the postoperative treatment, the EURAMOS-1 study corroborated the previous findings. The authors suggested that because ifosphamide and etoposide therapy was not initiated until week five postoperatively, this delay might account for the lack of benefit of the more intensive regimen. However, this theory is questionable in light of these two trials, which initiated therapy with ifosphamide earlier than the EURAMOS-1 study.3Meyers PA Schwartz CL Krailo MD et al.Osteosarcoma: the addition of muramyl tripeptide to chemotherapy improves overall survival—a report from the Children's Oncology Group.J Clin Oncol. 2008; 26: 633-638Crossref PubMed Scopus (581) Google Scholar, 4Ferrari S Ruggieri P Cefalo G et al.Neoadjuvant chemotherapy with methotrexate, cisplatin, and doxorubicin with or without ifosfamide in nonmetastatic osteosarcoma of the extremity: an Italian sarcoma group trial ISG/OS-1.J Clin Oncol. 2012; 30: 2112-2118Crossref PubMed Scopus (145) Google Scholar Although the study design for the COG trial was different to that of the EURAMOS-1 trial in that ifosphamide was substituted for cisplatin in the preoperative regimen, the number of courses of cisplatin, doxorubicin, and methotrexate administered to patients was the same in both groups. The only difference was the addition of ifosphamide, and in this trial, ifosphamide was administered early in the course of treatment.3Meyers PA Schwartz CL Krailo MD et al.Osteosarcoma: the addition of muramyl tripeptide to chemotherapy improves overall survival—a report from the Children's Oncology Group.J Clin Oncol. 2008; 26: 633-638Crossref PubMed Scopus (581) Google Scholar In addition to showing no improvement in event-free survival and overall survival, the COG trial also showed that there was no benefit in use of ifosphamide preoperatively because the percentage of patients with a good response to induction therapy was the same with or without ifosphamide. Because response to induction chemotherapy is the only reliable marker of patient outcome,1Bacci G Mercuri M Longhi A et al.Grade of chemotherapy-induced necrosis as a predictor of local and systemic control in 881 patients with non-metastatic osteosarcoma of the extremities treated with neoadjuvant chemotherapy in a single institution.Eur J Cancer. 2005; 41: 2079-2085Summary Full Text Full Text PDF PubMed Scopus (91) Google Scholar these findings support the conclusion that ifosphamide at either the standard-dose or high-dose provides no patient benefit. The time has come to put aside the hope that the addition of ifosphamide (standard-dose or high-dose, with or without etoposide) will provide the long sought answer to improving the 65–70% overall survival achieved with the three-drug regimen, cisplatin, doxorubicin, and methotrexate. Ifosphamide was introduced more than 30 years ago and tested in multiple randomised and non-randomised trials. Although responses to ifosphamide have been observed, this has not been translated into longer survival, the most important variable.6Lewis IJ Nooij MA Whelan J et al.Improvement in histologic response but not survival in osteosarcoma patients treated with intensified chemotherapy: a randomized phase III trial of the european osteosarcoma intergroup.J Natl Cancer Inst. 2007; 99: 112-128Crossref PubMed Scopus (299) Google Scholar The toxicity of adding ifosphamide with or without etopiside has also been documented many times, most recently in the EURAMOS-1 study. The addition of high-dose ifosphamide plus etoposide resulted in increased toxicity and more cases of secondary leukaemia, which is by stark contrast with the addition of the immunotherapy mifamuride to the three-drug regimen, which resulted in a reduction in mortality (HR 0·71 [95% CI 0·52–0·96])and an increase in survival from 70% to 78% at 8 years.3Meyers PA Schwartz CL Krailo MD et al.Osteosarcoma: the addition of muramyl tripeptide to chemotherapy improves overall survival—a report from the Children's Oncology Group.J Clin Oncol. 2008; 26: 633-638Crossref PubMed Scopus (581) Google Scholar The success of mifamurtide shows that osteosarcoma is sensitive to immunotherapy, suggesting that this should be the focus for future international trials. I declare no competing interests. Comparison of MAPIE versus MAP in patients with a poor response to preoperative chemotherapy for newly diagnosed high-grade osteosarcoma (EURAMOS-1): an open-label, international, randomised controlled trialEURAMOS-1 results do not support the addition of ifosfamide and etoposide to postoperative chemotherapy in patients with poorly responding osteosarcoma because its administration was associated with increased toxicity without improving event-free survival. The results define standard of care for this population. New strategies are required to improve outcomes in this setting. Full-Text PDF Open Access