Improved osteosarcoma survival with addition of mifamurtide to conventional chemotherapy – a prospective single institution analysis.

Background Conventional osteosarcoma is rare disease. Current treatment approaches have been set decades ago and include combination of three drug chemotherapy schedule and surgery. Three and five years event free survival in localized disease is roughly 59-54%, respectively. An immunotherapy agent mifamurtide was introduced to clinical practice after registration study which reported survival benefit, but some methodological controversies have been unsufficient for Food and Drug Administration market authorization Methods We report here prospective single center analysis of mifamurtide addition to conventional therapy in 16 patients during 5.5 year enrollment period. Results Adverse event profile was as expected with no dose limiting toxicities. All patients were given mifamurtide according to planned treatment schedule. There were no local relapses observed, one patient died in first complete remission due to doxorubicine cardiotoxicity, one patient had pulmonary metastatic relapse. Observed three and five years event free survival was 82,6 (CI 70-100%) and 82,6% (CI 70-100%), progression free survival was 92,3% (CI 78,9-100%) and 92,3% (CI 78,9-100%), overall survival was 93,3 (CI 81,5-100) and 74,7 (CI 47,2-100), respectively. Conclusions Survival benefit of mifamurtide is reported herein. Addition of mifamurtide should be considered as best treatment option for patients with localized osteosarcoma.


Abstract
Background Conventional osteosarcoma is rare disease. Current treatment approaches have been set decades ago and include combination of three drug chemotherapy schedule and surgery. Three and five years event free survival in localized disease is roughly 59-54%, respectively. An immunotherapy agent mifamurtide was introduced to clinical practice after registration study which reported survival benefit, but some methodological controversies have been unsufficient for Food and Drug Administration market authorization Methods We report here prospective single center analysis of mifamurtide addition to conventional therapy in 16 patients during 5.5 year enrollment period.
Conclusions Survival benefit of mifamurtide is reported herein. Addition of mifamurtide should be considered as best treatment option for patients with localized osteosarcoma.

Background
Osteosarcoma is the most common malignant mesenchymal tumor of the bone in pediatric population. That can arise from any bone, but most often localization of tumor´s origin is in metafyseal area of long bones. Osteosarcoma is composed of malignant osteoblasts, which produce immature bone tissue and osteoid. In histological point of view osteosarcoma can be subdivided into high grade forms such as conventional, telangiectatic or chondroblastic and into more indolent forms like parosteal or periosteal osteosarcoma.
Incidence of that disease is very rare of 4.0 (3.5-4.6) for the range 0-14 years and 5.0 (4.6-5.6) for the range 0-19 years per year per million persons and it varies with age (1).
There are well known two incidence peaks. First during skeletal growth spurt in age of 15-19 years and second one is during elderly age. osteosarcoma. Eight out of 16 diagnosed patients (50%) were in adolescent age, male:female ratio was 11:5 and most common sites were proximal humerus (31%) and proximal tibia (25%). Six of them (37,5%) had unspecific nodules in lungs at diagnosis, three of them with nodules size in range 1-5 mm, other three with size of 6-9 mm.
Histologically, 12 out of 16 (75%) tumors were conventional osteoblastic type, rest of them belonged to other histological subgroups of osteosarcoma, one to each typeteleangiectatic, chondroblastic, small-cell and sclerosing (Table1). Age distribution of patients is shown in Figure 1.
All of diagnosed patients were enrolled to regimen with mifamurtide including one with relapsed locoregional disease. Mifamurtide was administrated intravenously as 1 hour infusion in dose of 2mg/m2(maximum 4 mg single dose). Total of 48 doses were given to each patient, 24 doses twice a week and 24 doses once a week during 36 weeks. As premedication we routinely used paracetamol in dose of 500-1000mg.
Sample characteristic was given in summary tables. Outcome of the patients was analyzed using survival analysis. Results were shown as Kaplan-Meier curves and summarized as estimates for 3-and 5-year survivals. White blood cell counts recovery was shown as cumulative incidence. Analyses were done using R software 3.5.1 (5).

Results
After neoadjuvant treatment, 9 of 16 (56%) achieved good response defined as necrosis ≥90% and 4 of 16 (25%) had poor response on treatment. Three out of 16 patients (18%) underwent surgical resection before administration of chemotherapy thus their histologic response was not evaluable. Only one out of four poor responders later died of progressive metastatic disease.
We observed some of known side effects during administrations of mifamurtide. These were fever and chills in majority of patients ( Table 2) Table 3 and Figure 3.

Discussion
To our knowledge we report herein the best event and progression free survival results of treatment of locoregional osteosarcoma published. Our study has some limitations. First of all, the sample size is small. Second, sample size needs one and half more year for robust 5-year survival estimates to conclude that 3-year estimate survivals will be maintained.
Locoregional control with no any progressive disease describes well experienced team of orthopedic surgeons. Pediatric oncologists, orthopedic surgeons, pathologist and radiologists in our center have set a multidisciplinary board with regular meetings. All specialists discuss the disease management issues for each patient -about timing and type of surgery and coordination with chemotherapy or adjuvant radiotherapy-to minimalize treatment protocol deviations. Both chemotherapy and mifamurtide schedules were kept. Long lasting chemotherapy has adverse effect to bone recovery. Leukocyte recovery with median 2,6 weeks is expected and not compromised by mifamurtide.
Recent analysis of Euramos-1 study which was conducted worldwide and included 2260 patients demonstrated the 3-year and 5-year event free survival 59 and 54%, and overall survival 79 and 71%respectively. This study confirmed previously reported results of other cooperative groups or institutional series. (6) For evaluation of mifamurtide efficacy is better to use 3-year and 5-year metastatic free survival. We report herein progression free survival 92,3% (CI 78,9-100%) and 92,3% (CI 78,9-100%), respectively, which is equivalent to metastatic free progression.
Also another small size study confirms better treatment result with mifamurtide as 3-year overall and event free survival 87,5 and 75,6%, respectively. (7) Compared to our small sample size, the large French study reports in 126 patients survival benefit of mifamurtide as 18% improvement in 3-year event free survival (52 vs.70%, HR 0,55), even worse than in our analysis and comparable to Euramos results without mifamurtide. (8) For patients with metastatic disease, the published results show trend to longer overall and event free survival after addition of mifamurtide, but phase III sample size was small and improvement did not achieved conventional statistical significance. Results of an expanded access trial suggest a decreased risk of subsequent recurrence and death with the inclusion of mifamurtide in the treatment strategy for metastatic high-risk patients also. (9)

Conclusions
We conclude that combination of chemotherapy, surgery and mifamurtide in adjuvant setting is the best treatment option for young patients with osteosarcoma. Experienced multidisciplinary advisory task board is essential in each center which cares of osteosarcoma patients. The expert team should give every effort at all times to avoid protocol deviations and keep treatment schedules as recommended. The treatment described in this study consisted of "on-label" drugs and prospective data collection has been approved by institutional ethics committee of University Hospital Brno.
All research described herein was conducted according to the Declaration of Helsinki. The written parental or participant (in patients over age of 18 years, according to national regulations) consent with therapy was obtained.

Not Applicable
Availability of data and material The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.

Authors´ contributions
All authors have read and approved the manuscript.   Mifamurtide adverse events