Osteosarcoma in Patients Younger Than 12 Years Old Without Metastases Have Similar Prognosis as Adolescent and Young Adults

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1 Pediatr Blood Cancer 2015;62: Osteosarcoma in Patients Younger Than 12 Years Old Without Metastases Have Similar Prognosis as Adolescent and Young Adults Sabrina Jeane Prates Eleutério, MD, 1 Andreza Almeida Senerchia, MD, 1 * Maria Teresa Almeida, MD, 2 Cecilia Maria Da Costa, MD, 3 Daniel Lustosa, MD, 4 Luiz Mario Calheiros, MD, 5 Jose Henrique Silva Barreto, MD, 6 Algemir Lunardi Brunetto, MD, PhD, 7 Carla Renata Pacheco Donato Macedo, MD, 1 and Antonio Sergio Petrilli, MD, PhD 1 Background. Childhood cancer is relatively rare and tends to present specific age distribution, as a prognostic factor for some of these diseases. Information on how young age affects prognosis, response to chemotherapy, and local control options in children versus AYA with osteosarcoma (OST) is minimal. Methods. In order to identify the main differences in clinicalpathologic features, surgical approaches and survival rates of primary high grade OST of the extremity between children (n ¼ 156; <12 years old) and AYA (n ¼ 397; years old), the institutional database with 553 patients treated by BOTG studies over 15 years were reviewed. Results. There were no differences in metastasess at diagnosis, tumor size, and grade of necrosis between the two age groups. The rate of amputation was 30% higher in the children group (P ¼ 0.018). The rate of limb salvage surgery using reconstruction with allograft or autograft was 70% higher in the children group (P ¼ 0.018) while endoprosthesis rate was 40% higher in the AYA group (P ¼ 0.018). The log rank test revealed that survival is similar between the two age groups for non-metastatic patients (P ¼ for OS and P ¼ for EFS). Metastatic patients of both ages group had higher risk of dying compared to non-metastatic (HR % CI ; P < 0.001). Children with metastases at diagnosis had less OS time (P ¼ 0.049) and EFS time (P ¼ 0.032) than adolescents. Conclusion. Non-metastatic OST in preadolescent patients does not appear to be significantly differentfrom those seen in AYA patients, but has local control challenges. Children presenting with metastases should be considered an ultra-high-risk group. Pediatr Blood Cancer 2015;62: # 2015 Wiley Periodicals, Inc. Key words: adolescent; amputation; children; childhood bone cancer ; chemotherapy ; osteosarcoma; young adult INTRODUCTION Osteosarcoma (OST) is the most common primary malignancy in children and adolescents. The incidence of OST peaks in adolescence and young adult and is much lower in preadolescence, a feature that suggests a relationship between rapid bone growth and the development of this tumor [1,2]. Among possible prognostic factors, the presence of metastatic disease at the time of diagnosis, large tumor volume, and poor response to preoperative chemotherapy have been consistently shown to confer a poor prognosis [3]. Age at diagnosis as a significant prognostic factor for patients with OST is however controversial. While some authors have described a lack of association between age and prognosis [4 10], others have reported a worse prognosis for children [11,12], and still others have reported children fared better than adolescents and adults [13,14]. Long-term survival for patients with localized OST has improved to approximately 70% due to the introduced multi-agent chemotherapy together with gradually-improved surgical techniques in the past three decades [15 18]. Limb-salvage surgeries have become more common during this period, and in many centers they are offered to 80% or more of the patients presenting with OST [19] with no difference in the long-term survival rate between patients treated with amputation and those treated with limb-salvage surgeries [20]. We analyzed the differences in clinical pathologic features, surgical approaches, and survival rates of primary high grade OST of the extremity between children younger than 12 years old and those older children and young adults treated by three consecutive studies for the treatment of OST carried out in Brazil over 15 years. MATERIALS AND METHODS Patients The records of 553 patients, including 156 less than 12 years old, who participated on the Brazilian Osteosarcoma Treatment C 2015 Wiley Periodicals, Inc. DOI /pbc Published online 8 March 2015 in Wiley Online Library (wileyonlinelibrary.com). Group (BOTG) studies between 1991 and 2005, were analyzed. Inclusion criteria for enrollment in these protocols were: patients with typical imaging and histological features of primary, highgrade OST, tumor located in the extremity and age under 30 years. Complete medical history and physical examination, complete blood count, serum biochemistry, plain radiograph of the chest and primary tumor site, computed tomography (CT) of the chest, radioisotope bone scan and a CT scan or magnetic resonance imaging (MRI) of the primary site were performed at diagnosis. These assessments were repeated just prior to surgery and at regular intervals thereafter, during and after the completion of therapy, for at least 5 years. All studies were approved by the IRB at each of the 25 participating institutions and informed consent was obtained from the patients or their legal representatives. 1 Institutode Oncologia Pediatrica/GRAACC Universidade Federal de Sao Paulo, Sao Paulo, Brazil; 2 Instituto da Crianca Universidade de Sao Paulo, Sao Paulo, Brazil; 3 Hospital do Cancer A. C. Camargo, Sao Paulo, Brazil; 4 Hospital do Cancer do Ceara, Ceara, Brazil; 5 Sociedade Pernambucana de Combate ao Cancer, Pernambuco, Brazil; 6 Sociedade de Oncologia da Bahia, Bahia, Brazil; 7 Hospital de Clınicas de Porto Alegre, Porto Alegre, Brazil Conflict of interest: The authors certify that they have no affiliations with or involvement in any organization or entity with any financial or non-financial interest in the subject matter or materials discussed in this manuscript. Correspondence to: Andreza A. Senerchia, Department of Clinical Research, Instituto de Oncologia Pediatrica/GRAACC Universidade Federal de Sao Paulo, Rua Botucatu, , Sao Paulo, Brazil. andrezasenerchia@hotmail.com Received 13 June 2014; Accepted 8 January 2015

2 1210 Eleutério et al. Treatment Protocol Chemotherapy. Patients were treated by three different protocols of neoadjuvant chemotherapy. These protocols, activated in successive periods were reported in detail in previous articles [8,21], are presented in Figure 1. In summary, study III used pairs of drugs (epirubicin, carboplatin, and ifosfamide) rotating throughout the standard risk arm. Patients presenting with tumors larger than 12 cm and those requiring immediate or early amputation were considered to be at high risk of treatment failure. They were treated additionally with high-dose methotrexate. Study IV intensified therapy with platinum compounds (carboplatin and cisplatin) and in study V we added high-dose ifosfamide to the standard cisplatin/ doxorubicin regimen. Surgery and pathology. Definitive surgery was performed at week 9 for studies III and IV and week 12 for study V. The institutional orthopedic surgeon in collaboration with the pediatric oncology team chose the appropriate procedure for each case. Limb preservation was encouraged whenever possible using a variety of techniques such as nonconventional endoprosthesis, resection of expendable bones, plaques, and bone graft fixation (autograft or allograft). After primary tumor removal, the histological response to preoperative chemotherapy was defined by the institutional pathologist using the scoring system designed by Huvos (grade IV 100%, grade III 90 99%, grade II 50 89%, grade I < 50%) [22]. All pulmonary metastases were surgically removed, as soon as possible, after resection of the primary tumor. Patients with nonmetastatic disease were considered to be in complete remission on the date of the primary tumor resection, whereas patients with Figure 1. Protocol design for Studies III, IV, and V.

3 Osteosarcoma in Children and AYA 1211 metastatic tumors were considered to be in complete remission on the date of the pulmonary metastases complete resection. Statistics. The following variables were evaluated: gender, age, time from the onset of symptoms to diagnosis, primary tumor site, presence of metastases at diagnosis, tumor size ( 12 cm or > 12 cm), type of surgery (limb-sparing or amputation), treatment protocol, and histological response and assessed according to their association with survival. Age was analyzed as a categorical variable using the categories: <12 (children) and 12 years (AYA) according the definition of the Brazilian Child and Adolescent Statute, that considered child as a person who has not yet completed 12 years of age and the adolescent as that between 12 and 18 years of age. Categorical data were summarized as absolute and relative frequencies; quantitative data were described as median and interquartile range. Comparisons between groups (<12 years and 12 years) were performed by Pearsons x 2 or Fisher exact test for categorical data and by Mann Whitney test for numerical data. The overall survival (OS) and event free survival (EFS) curves were estimated using the Kaplan Meier method. OS was defined as the time interval between the date of enrollment onto the study and death from any cause or the most recent follow-up contact. EFS was defined as the time interval between enrollment onto the study and disease relapse, death from any cause, or the most recent follow-up contact. The log rank test and Cox proportional hazards model were used to analyze the effect of age and other variables on OS and EFS. A P-value of <0.05 was considered to indicate significance. Data were analyzed using SPSS statistical software, release 20.0 for Windows. RESULTS Clinical-Pathologic Variables In our review of all 553 patients treated by BOTG studies over 15 years, lung alone was the most common metastatic site, followed by bone alone, in the two age groups. In comparison with children, older patients had a higher male: female ratio (1:1 vs. 1.4:1; P ¼ 0.048). From presentation to diagnosis, the median duration was higher in AYA group (120 days) than in children group (81 days) (P < 0.001) with no relationship to the tumor size. There were no differences in metastases at diagnosis, tumor size, and grade of necrosis between the two age groups. The distribution of baseline clinical and treatment variables is shown in Table I. In the children group, 96 patients underwent limb-salvage surgeries, there were 57 cases of amputation, and three patients did not undergo definitive surgery. The rate of amputation was 30% higher in the children group 30.1% versus 23.7% (P ¼ 0.018), respectively. The rate of limb-salvage surgery using reconstruction with allograft or autograft was 70% higher in the children group (19.6% vs. 11.2% [P ¼ 0.018]) while the endoprosthesis rate was 40% higher in the AYA group (54.3% vs. 39.9% [P ¼ 0.018]). The incidence of poor responders (Huvos I and II) was higher in children with tumor size equal or larger than 12 cm (P ¼ 0.001). Survival The 5 year overall survival of metastatic and non-metastatic children and AYA was 11.9% versus 25.1% and 57.4% versus 60.3%, respectively (Fig. 2A). The 5-year EFS for each group was 6.8% versus 19.9% and 47.8% versus 50.6%, respectively (Fig. 2B). The log rank test revealed that survival is similar between the two TABLE I. Comparison of Patient s Characteristics Between Children and AYA age groups for non-metastatic patients (P ¼ for OS and P ¼ for EFS). Metastatic patients of both ages group had higher risk of dying compared to non-metastatic (HR % CI ; P < 0.001) Children with metastases at diagnosis had less OS time (P ¼ 0.049) and EFS time (P ¼ 0.032) than AYA. There was no statistically significant relationship between tumor size and survival. Relapse and Outcomes The AYA group showed a 40.2% rate of relapse and a 9.3% rate of local recurrence. There were 66 cases of relapse (42.6%) in the children group and a 7.8% rate of local recurrence. There was a statistically significant relationship between limb-salvage surgery and local recurrence for children (P ¼ 0.005) and AYA (P < 0.003) and also between grade of necrosis and recurrence for AYA (P ¼ 0.019). No statistically significant relationship was seen between type of conservative surgery and recurrence between the two age groups (P ¼ for children and P ¼ for AYA). DISCUSSION Children (n ¼ 156) AYA (n ¼ 397) P-value Male:female ratio 1:1 1.4: Lag time * median 81 (50 120) 120 (75 180) Primary tumor site Femur 103 (66) 204 (51,4) Tibia 35 (22,4) 120 (30,2) Humerus 12 (7,7) 45 (11,3) Others 6 (3,8) 28 (7,1) Metastasis at diagnosis Yes 40 (25,6) 120 (30,2) No 116 (74,4) 277 (69,8) Tumor size <12 cm 68 (58,6) 158 (53,7) 12 cm 48 (41,4) 136 (46,3) Protocol Study III 30 (19.2) 66 (16.6) Study IV 32 (20.5) 81 (20.4) Study V 94 (60.3) 250 (63) Surgical Procedure Amputation 57 (37,3) 118 (31,4) Limb-salvage surgery 96 (62,7) 258 (68,6) Tumor Necrosis GI/GII 80 (69) 184 (65,9) GIII/GIV 36 (31) 95 (34,1) Relapse Yes 66 (42,6) 159 (40,2) No 89 (57,4) 237 (59,8) * Mann Whitney test. Primary high-grade OST of the extremities in children aged 12 years or under is uncommon. Of the 553 patients registered into three consecutive studies over a roughly 15-year period 28% were under 12 years of age. Age was not a relevant prognostic factor for survival for non-metastatic. However, children with metastatic disease at diagnosis have disappointing low-survival rates. Results

4 1212 Eleutério et al. Figure 2. Comparison of overall survival (OS; panel A) and event free survival (EFS; panel B) of osteosarcoma children (<12 years old) and adolescents (12 18 years old) without and with metastases after chemotherapy, and local control surgery. Non-metastatic: Top (green): adolescents versus Top (blue): children. Metastatic: Bottom (red): adolescents versus Bottom (gold): children. Non-metastatic OS and EFS adolescents versus children P ¼ and P ¼ 0.393; Metastatic OS and EFS adolescents versus children P ¼ 0.49 and In both age groups the risk of death was much greater in those with metastatic disease at diagnosis (P < 0.001). showed by previous studies in the treatment of this group of patients are controversial. An important consideration is the exclusion of metastatic patients in some studies [10 12] such as the manner in which age has been converted to a categorical variable. Some authors have evaluated children as the person who has not yet completed 12 years of age [8,9,11], while others have defined children as all under 10 years of age [6,9,22] and still others have used a cut-off set at 14-year old [12,14]. The present institutional review of OST in children and AYA did not reveal any significant prognostic factor among the following variables: metastases at diagnosis, tumor size, and grade of necrosis, except between symptom onset and diagnosis that might be due the high level of parental monitoring for younger children. However, we could not demonstrate a correlation between the delay in diagnosis and tumor size. Different workgroups stated that a longer treatment delay does not cause a lower survival rate [8,24,25]. With regard to limb-salvage surgery, as previously reported by others, this procedure was higher than amputation for all age groups. Bacci reported 68% of patients treated by limb-salvage surgery and Ferrari found this procedure in 83% of the patients. In other two studies, limb salvage procedure was possible in up to 90% of patients [6,7,9,11]. The rate of amputation in children was higher than that for the AYA and the type of reconstruction after resection of load-bearing bones (endoprosthesis and bone graft surgery) between the age groups differed statistically. Bone graft surgery was more often an option in children (19.6% vs. 11.2% [P ¼ 0.018]) and endoprothesis in AYA (54.3% vs. 39.9% [P ¼ 0.018]). This difference may be due by the fact limb-salvage surgery is challenging for children because of skeletally immature growth which results in unacceptable leg discrepancy in the future, lack of suitable, extendable, endoprosthetic replacement for. Despite the high relapse rate among patients who underwent limb-salvage surgery, local recurrence was not the main cause of relapse. Although this study was a retrospective analysis with potential limitations, it is a relatively large cohort. In conclusion, nonmetastatic OST in preadolescent patients is not much different from those seen in AYA patients, but has local control challenges which seemed to be adequately addressed in our cohort. Children presenting with metastases should be considered an ultra-highrisk group. Biological approaches may provide future options to consider for this ultra-high-risk group. REFERENCES 1. Bleyer A, O Leary M, Barr R, Ries LAG, editors. Cancer epidemiology in older adolescents and young adults 15 to 29 years of age, including SEER incidence and survival Bethesda, MD: National Cancer Institute.; Bleyer A, Barr R, Hayes-Lattin B, Thomas D, Ellis C, Anderson B. Biology and Clinical Trials Subgroups of the US National Cancer Institute Progress Review Group in Adolescent and Young Adult Oncology. The distinctive biology of cancer in adolescents and young adults. 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