Clinical trialPhase 3Sarcoma (soft tissue and bone cancer)

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 · 2016618 poor responders randomised (310 MAP and 308 MAPIE) out of 2,260 patients registered at 325 sites in 17 countries

Marina NM, Smeland S, Bielack SS, et al. Lancet Oncol. 2016. 17:1396-1408

Study type: Clinical trial
Study name: EURAMOS-1
Phase: Phase 3
Design: International, open-label, randomised controlled phase 3 trial run by four groups (COG, COSS, EOI and SSG); patients registered before chemotherapy and randomised 1:1 after surgery using concealed permuted blocks, stratified by trial group, tumour site and presence of metastases
Sample size: 618 poor responders randomised (310 MAP and 308 MAPIE) out of 2,260 patients registered at 325 sites in 17 countries
Source: Lancet Oncol · 2016
Trial registration: NCT00134030

In plain words

Teenagers and young adults with osteosarcoma whose tumour had not responded well enough to chemotherapy before surgery received, after surgery, either the same three drugs as before (MAP) or MAP with two extra drugs. Adding the drugs did not improve results and caused more side effects, so continuing the same MAP after surgery remained the standard treatment.

Key results

HR 0.98 (95% CI 0.78–1.23)

Event-free survival (MAPIE vs MAP)

p=0.86; non-proportional hazards (p=0.0003); 307 events

53% (MAPIE) vs 55% (MAP)

3-year event-free survival

RMST difference 0.8 months (95% CI −3.3 to 4.9); p=0.69

57% vs 60%

3-year event-free survival in localised disease

HR 1.03 (0.81–1.33); 541 patients

18% vs 24%

3-year event-free survival with metastases at registration

MAPIE vs MAP

77% vs 72%

3-year overall survival

HR 0.97 (0.73–1.29); p=0.86; immature data

10 vs 3 patients

Second malignancies

Cause-specific HR 3.24 (0.87–12.06); p=0.079

62.1 months

Median follow-up

IQR 46.6–76.6

Drugs in this study:Cisplatin (Platinol)Doxorubicin (Adriamycin)Etoposide

Dose and schedule cards

MAP (osteosarcoma)

Resectable high-grade osteosarcoma, aged 40 or younger (the EURAMOS-1 population); before and after surgery; continue the same MAP after surgery even with a poor histological responseOn the page “Sarcoma (soft tissue and bone cancer)” · Osteosarcoma: MAP chemotherapy

Resectable high-grade osteosarcoma, aged 40 or younger (the EURAMOS-1 population); before and after surgery; continue the same MAP after surgery even with a poor histological response

Drug	Dose	Route	Schedule
Each 5-week MAP cycle
Cisplatin	120 mg/m²	IV: 60 mg/m² per day over 4 hours for 2 days, or a 72-hour continuous infusion	Week 1
Doxorubicin	37.5 mg/m² per day (total 75 mg/m²)	IV (in the trial registry: 48-hour continuous infusion)	Days 1 and 2 of week 1
High-dose methotrexate	12 g/m² (maximum 20 g per dose)	4-hour IV infusion with hyperhydration and urine alkalinisation	Weeks 4 and 5
Leucovorin	15 mg/m²	Per protocol	From 24–48 hours after methotrexate until the level is below 0.1 micromolar

Cycle length: Each cycle lasts 5 weeks: cisplatin and doxorubicin in week 1, methotrexate in weeks 4 and 5
Duration: Before surgery 2 cycles (10 weeks): cisplatin and doxorubicin in weeks 1 and 6, methotrexate in weeks 4, 5, 9 and 10; then surgery. After surgery: cisplatin in weeks 12 and 17, doxorubicin in weeks 12, 17, 22 and 26 and methotrexate in weeks 15, 16, 20, 21, 24, 25, 28 and 29; 29 weeks in all (4 MAP cycles and 2 cycles of methotrexate and doxorubicin); cumulative cisplatin 480 mg/m²

Doses per the EURAMOS-1 full text (maximum methotrexate dose 20 g at COG centres); FDA methotrexate label: typically 12 g/m² (maximum 20 g per dose) as a 4-hour infusion with leucovorin rescue. Start cisplatin–doxorubicin cycles with ANC 750 and platelets 75,000, and HD-MTX with ANC 250 and platelets 50,000 per microlitre. Timing of the postoperative cycles per the trial registration on ClinicalTrials.gov. In patients over 40, HD-MTX is more difficult and regimens of doxorubicin, cisplatin and ifosfamide are alternatives.

On the page “Sarcoma (soft tissue and bone cancer)” · Osteosarcoma: MAP chemotherapy

Doses follow the trial protocol, guideline or official drug label (source given in the notes of each regimen). Before prescribing, check blood counts, renal and hepatic function, drug interactions and the patient’s condition, and adjust the dose according to the drug label.

Treatment arms and regimens

1MAP (310 patients)

Before surgery (all patients, 10 weeks): cisplatin 120 mg/m² (60 mg/m² per day over 4 hours for 2 days at COG sites or a 72-hour continuous infusion at other sites) and doxorubicin 37.5 mg/m² per day on days 1 and 2 (weeks 1 and 6), followed by high-dose methotrexate 12 g/m² over 4 hours (maximum 20 g at COG sites) with hyperhydration, alkalinisation and leucovorin 15 mg/m² from 24–48 hours after methotrexate until the level was below 0.1 micromolar (weeks 4, 5, 9 and 10). After surgery: the same doses; 29 weeks of treatment in total, comprising 4 MAP cycles and 2 cycles of methotrexate and doxorubicin; cisplatin was stopped after a cumulative dose of 480 mg/m². Per the ClinicalTrials.gov record: doxorubicin as a 48-hour continuous infusion in weeks 12, 17, 22 and 26, cisplatin over 4 hours on days 1 and 2 of weeks 12 and 17, and methotrexate over 4 hours in weeks 15, 16, 20, 21, 24, 25, 28 and 29.

2MAPIE (308 patients)

Postoperative MAP as the base, plus high-dose ifosfamide 14 g/m² (2.8 g/m² per day) with equidose mesna, followed by etoposide 100 mg/m² per day over 1 hour on days 1 to 5 (three postoperative cycles); two further cycles of ifosfamide 3 g/m² per day on days 1 to 3 (9 g/m²) with mesna, together with standard doxorubicin. Treatment lasted 40 weeks. Myeloid growth factors were allowed per local practice.

Source of the regimen details: Full text of the article (Lancet Oncol 2016; open access in PMC) and ClinicalTrials.gov NCT00134030 (week-by-week postoperative schedule)

Doses are given for the information of specialists, as in this study’s protocol, and are not a prescription. Every drug must be prescribed by the treating physician for the individual patient.

Study population

Patients aged 40 or younger with newly diagnosed high-grade osteosarcoma, localised or metastatic, of the limbs or axial skeleton and considered resectable by the treating team; Karnofsky or Lansky performance status of at least 60, normal cardiac function (shortening fraction above 28%), normal hearing and normal bone marrow. Randomisation required a poor histological response (10% or more viable tumour), exactly 2 courses of cisplatin and doxorubicin and at least 2 and no more than 6 doses of methotrexate before surgery, macroscopically complete resection of the primary tumour and randomisation within 35 days of surgery.

Endpoints

Primary endpoint: event-free survival from randomisation (local recurrence, new or progressing metastases, second malignancy or death) in the intention-to-treat population. Secondary endpoints: overall survival, short-‎ and long-term toxicity and quality of life. Because hazards were non-proportional, the difference was estimated with the restricted mean survival time (RMST).

Safety and side effects

Grade 3–4 neutropenia: 89% (MAP) and 90% (MAPIE); thrombocytopenia: 78% and 83%; febrile neutropenia without documented infection: 50% and 73%. Grade 4 non-haematological toxicity: 12% (35 of 301) vs 24% (71 of 298), mainly infection with neutropenia, febrile neutropenia and hypophosphataemia. Grade 3 or worse toxicity in 95% and 94%. Two deaths during postoperative therapy: infection (MAP) and left ventricular systolic dysfunction (MAPIE); one bone marrow infarction due to methotrexate. In long-term follow-up, grade 3 (4 patients) and grade 4 (1 patient) renal failure were reported only with MAPIE.

Clinical significance and place in guidelines

EURAMOS-1 is the largest osteosarcoma trial and showed that changing postoperative chemotherapy because of a poor histological response (adding ifosfamide and etoposide) brings no benefit; MAP before and after surgery is the standard of care for these patients. The ESMO–EURACAN–GENTURIS–ERN PaedCan 2021 guideline does not recommend adding ifosfamide and etoposide in poor responders outside clinical trials [I, D]. In the whole EURAMOS-1 cohort (more than 2,000 patients), 5-year overall survival from biopsy was 71%.

Limitations

Fewer patients were randomised than planned (618 vs 693) and 42% of poor responders were not randomised; there were also fewer events than planned (307 vs 378), which reduced statistical power. Outcomes were not centrally reviewed and overall survival data were immature. The intervention may have come too late (first ifosfamide in week 17). Only patients aged 40 or younger were included.

Original article (DOI)PubMed ClinicalTrials.gov

This summary was prepared by the editorial team from the published paper; the original paper is the final reference. Read the original abstract on PubMed.