Osteosarcoma is a rare disease in adults and is the most common primary bone malignancy in children and young adolescents.[
In the pediatric population, localized osteosarcoma treatment consists of multi-agent chemotherapy with usually includes high doses of methotrexate, doxorubicin, and cisplatin.[
In this single-center retrospective cohort, adult patients with high-grade osteosarcoma who received treatment at a Brazilian tertiary public cancer center (Instituto do Câncer do Estado de São Paulo, Sao Paulo, Brazil) between 2007 and 2018 were evaluated. Electronic medical records were reviewed to collect patients' data, including clinical and demographical characteristics, treatment received, and outcomes.
Patients were included in the analysis if they presented with histologically confirmed localized high-grade osteosarcoma and received neoadjuvant, adjuvant, or perioperative treatment with a chemotherapy regimen that did not include methotrexate. Additionally, patients should be at least 16 years old. Exclusion criteria were the presence of distant metastasis, a localized disease not amenable to curative surgery at diagnosis, head and neck osteosarcoma, and diagnosis of a secondary malignant neoplasm in the past 5 years (except for nonmelanoma skin cancer).
Local ethics committees approved the present study.
Systemic treatment consisted of neoadjuvant or adjuvant chemotherapy with regimens based on combinations of cisplatin, doxorubicin, ifosfamide, and/or etoposide. Perioperative chemotherapy with chemotherapy cycles both pre- and post-surgery was also acceptable. The timing of chemotherapy in relation to surgery was defined by physicians' discretion.
All patients had curative surgery planned as part of their oncologic treatment. The planned surgery was not performed only in case of patients' refusal, disease progression during neoadjuvant chemotherapy, or other complication that contraindicated surgery.
Patients and treatment characteristics were summarized using descriptive statistics. Median and range were used to summarize continuous variables. Categorical variables were presented using their absolute and relative frequencies.
The outcomes evaluated were overall survival (OS) and recurrence-free survival (RFS). OS was defined as the time from diagnosis until death from any cause. RFS was the time from diagnosis until disease recurrence or death, whichever occurred first. Patients without these events were censored at the time of last follow-up.
Survival analyses were performed using the KaplanMeier method, with the log-rank test to compare the difference between survival curves when appropriate. Factors associated with OS were investigated using univariate Cox proportional hazards model. Factors included in the univariate analysis were: age (=40y vs. <40y), ECOG-performance status (=2 vs. 0-1), Huvos criteria after neoadjuvant chemotherapy (3-4 vs. 1-2), number of cisplatin cycles (=6 vs. <6 cycles), cumulative dose of doxorubicin (=375mg/m2 vs. <375mg/m2 ), the occurrence of grade 3-4 toxicities (yes vs. no), and type of surgery (amputation vs. preservation) The Huvos classification is a grading system from I-IV of the pathological response after chemotherapy, with higher grades being associated with better treatment response.[
For statistical significance, we considered p-values less than 0.05. Statistical analyses were performed using Stata software, version 15.1 (StataCorp, Texas, USA).
A total of 97 adult patients with osteosarcoma were treated at ICESP from 2007 to 2018. Sixty-one patients had localized resectable disease at diagnosis, and 48 of them (78.7%) received neoadjuvant or adjuvant chemotherapy without methotrexate, composing the study population. The protocol consisted of cisplatin 60mg/m2 day 1 and 2 with doxorubicin 37,5mg/m2 day 1 and day 2 with filgrastim support from day 3 until day 12.
Median age was 27 years (range 16.8-66.7) and the majority of patients (93.7%) presented primary tumor site at extremities. The most common histologic subtype was osteoblastic (43.7%). Patients' clinical and demographical characteristics are summarized in
| No of patients (n=48) | % | |
|---|---|---|
| Age, years | ||
| Median (range) | 27 (16.8-66.7) | |
| Gender | ||
| Male | 28 | 58.3 |
| Female | 20 | 41.7 |
| ECOG-PS | ||
| 0 | 6 | 12.5 |
| 1 | 29 | 60.4 |
| 2 | 12 | 25 |
| 3 | 1 | 2.1 |
| Primary tumor site | ||
| Extremity | 45 | 93.7 |
| Axial | 3 | 6.2 |
| Initial TNM stage | ||
| I | 3 | 6.2 |
| II | 34 | 70.8 |
| III | 9 | 18.7 |
| NA | 2 | 4.2 |
| Histologic type | ||
| Osteoblastic | 21 | 43.7 |
| Condroblastic | 4 | 8.3 |
| Mixed | 8 | 16.7 |
| Pleomorphic sarcoma | 3 | 6.2 |
| Others | 10 | 20.8 |
| NA | 2 | 4.2 |
| Chemotherapy timing | ||
| Neoadjuvant | 10 | 20.8 |
| Adjuvant | 10 | 20.8 |
| Perioperative (neoadjuvant + adjuvant) | 28 | 58.4 |
| Huvos | ||
| I | 15 | 39.5 |
| II | 9 | 23.6 |
| III | 7 | 18.4 |
| IV | 1 | 2.6 |
| NA | 6 | 15.8 |
| Surgery type | ||
| Limb preservation | 29 | 60.4 |
| Amputation | 19 | 39.6 |
ECOG-PS: Eastern Cooperative Oncology Group performance status; TNM: Tumor, node, metastasis; NA: Not available;
Huvos criteria for patients who were submitted to neoadjuvant chemotherapy (n=38).
The chemotherapy regimen received by most of the patients was a combination of cisplatin and doxorubicin (n=42; 87.5%). The other six patients received cisplatin, doxorubicin, ifosfamide, and etoposide (n=6; 12.5%), an institutional study evaluating the role of adding ifosfamide and etoposide in the adjuvant treatment. The median number of cisplatin/doxorubicin cycles was 6 (range 3-8), and the median cumulative dose of doxorubicin was 375mg/m2 (range 225-495mg/m2 ).
The most common second-line and third-line treatments were ifosfamide and etoposide (22 patients) and gemcitabine and docetaxel (8 patients), respectively.
Patients were followed for a median time of 29.2 months. During the follow-up period, 27 patients had disease recurrence or death. Median RFS was 29.9 months (95% CI: 11.3-NR months). Five-year RFS rate was 35.1% (95% CI: 20.3-50.2%). Ten of the 48 patients died, with the median OS not reached. Fiveyear OS rate was 71.6% (95% CI: 52.3-84.2%). KaplanMeier survival curves are shown in
Figure 1 A. Kaplan-Meier curves for recurrencefree survival; B. Overall survival. Of adult patients with localized high-grade osteosarcoma treated with chemotherapy without methotrexate.
In the univariate analysis, higher cumulative doses of doxorubicin (=375mg/m2 ) were associated with improved OS in comparison with lower doses (<375mg/m2 ) (HR 0.26, 95% CI: 0.07-0.94, p=0.041). Patients who received a cumulative doxorubicin dose more or equal to 375mg/m2 had a 5-year OS rate of 79.5% compared to 45% among those who received lower doses (p log-rank=0.029). Another factor that tended to be associated with OS was the number of cisplatin/doxorubicin cycles (neoadjuvant and adjuvant) (HR 0.30, 95% CI: 0.08-1.09, p=0.069). The results of the univariate analysis of factors associated with overall survival are presented in
| Variable | HR (95% CI) | p-value |
|---|---|---|
| Age (= 40y vs. < 40y) | 1.01 (0.21-4.81) | 0.980 |
| ECOG-PS (= 2 vs. 0-1) | 0.76 (0.16-3.61) | 0.732 |
| Huvos (3-4 vs. 1-2) | 1.44 (0.27-7.54) | 0.661 |
| No. of CT cycles (=6 vs. <6 cycles)
| 0.30 (0.08-1.09) | 0.069 |
| Cumulative doxorubicin dose (=375 vs. <375mg/m2) | 0.26 (0.07-0.94) | 0.041 |
| Grade 3-4 toxicities (yes vs. no)
| 1.37 (0.38-4.88) | 0.627 |
| Type of surgery (amputation vs preservation) | 2.30 (0.64-8.2) | 0.198 |
HR: Hazard ratio; CI: Confidence interval; No: Number; CT: Chemotherapy.
Figure 2 Kaplan-Meier curves for overall survival of adult patients with localized high-grade osteosarcoma treated with chemotherapy without methotrexate, according to cumulative dose of doxorubicin received (neoadjuvant, adjuvant or perioperative).
The main reasons for receiving less than six cycles were grade 3-4 toxicities (n=11/19, 57.9%) and disease progression during chemotherapy (n=6/19, 31.6%). In the overall study population, 17 patients (35.4%) had grade 3-4 toxicities. The most important grade 3-4 toxicities were hematologic, including neutropenia, asthenia, and gastrointestinal.
In the present study, adult patients with localized osteosarcoma treated with chemotherapy regimens without high-dose methotrexate had unfavorable outcomes, with only 35% disease-free and 71.5% alive in 5 years. The only factor associated with overall survival was the chemotherapy dose received, with a cumulative doxorubicin dose greater than 375mg/ m2 and the number of cisplatin/doxorubicin cycles greater than 6. Similarly, in the non-metastatic cohort of the largest Brazilian pediatric study with a median follow up of 92 months, the 5-year overall survival and relapse-free survival rates were 59% and 48%, respectively.[
In a study by Souhami et al. (1997),[
Another recent study by Wippel B et al. (2019)[
Besides, a recent Brazilian study from our group performed a retrospective study of 10 patients aged 16-23 years who received high-dose methotrexate. Two of them died of therapy-related causes.[
In our center, the clearance delay of methotrexate, the high toxicity in the adult population, and the loss of dose intensity of cisplatin and doxorubicin contributed to exclude the drug from our treatment protocol in adult osteosarcoma. In face of this, another treatment strategy we studied was the addition of ifosfamide and etoposide to the adjuvant treatment. We included six patients in a phase II study evaluating the addition of 6 cycles of ifosfamide and etoposide (IE) after surgery for patients who have already received up to 6 cycles of cisplatin and doxorubicin preoperatively.[
Our study's most important limitations include the small number of patients, the single-center, and the retrospective nature. Adult osteosarcoma remains a challenging disease with most treatments based on pediatric studies. In the present study, patients with localized osteosarcoma treated with chemotherapy without methotrexate at a public reference cancer center in Brazil had unfavorable outcomes compared to the worldwide pediatric population but similar to the Brazilian pediatric population. In developing countries, patients arrive to reference centers with locally advanced disease, which justifies the bad outcomes in both pediatric and adult populations. However, our institution is a reference center, and publishing articles and reviewing the literature on rare diseases is of utmost importance to help develop treatment guidelines in a developing country like Brazil.
In conclusion, the use of high-dose methotrexate (12g/m2 ) remains controversial in adult osteosarcoma and, in our opinion, should be used only inside clinical trial protocols. The clearance delay of methotrexate may contribute to postponing the subsequent cycles of the main drugs cisplatin and doxorubicin, interfering directly in the outcome. Our study found that the number of cisplatin and doxorubicin cycles and the cumulative doxorubicin dose were associated with better survival. However, 35% of the patients had a dose reduction because of grade 3 or 4 toxicity even without methotrexate. The most important guidelines like NCCN and ESMO guidelines still include methotrexate in the treatment of osteosarcoma in patients with less than 40 years old inside reference centers to manage the subsequent toxicities correctly.[
Lorem ipsum dolor sit amet, consectetur adipiscing elit. Ut elit tellus, luctus nec ullamcorper mattis, pulvinar dapibus leo.
Journal: Brazilian Journal of Oncology
DOI: 10.1055/s-00059887
e-issn: 2526-8732
Publisher: Thieme Revinter Publicações Ltda.
Publisher address: Rua do Matoso 170, Rio de Janeiro, RJ, CEP 20270-135, Brazil
No citations found for this article.
No references with the required fields found.
Dados de acesso insuficientes para visualização no mapa.