Is Osteosarcoma between the Two Peak Ages Different?

Background: Unlike two known peak age groups (10 14 and older than 65 years of age), there was relatively scant attention in osteosarcoma patients between them, and previous reports had analyzed other than Asians. Therefore we conducted this study with Korean patients and focused on 20 40 years of age, then investigated age-specific or race-specific meaningful outcomes. Materials and Methods: 379 patients who were newly diagnosed as osteosarcoma in two Korean major cancer hospitals from September 1986 to July 2015 with more than 2-year follow-up were retrospectively studied. There were 290 patients with 20 40 years of age, 60 patients aged 19 or younger, and 29 patients aged 41 or older. Age at diagnosis, gender, location of primary lesion, metastasis at diagnosis, histologic subtypes, histologic response were analyzed as prognostic factors by overall survival (OS) and event-free survival (EFS) rates. Results: Primary pelvic lesion and poor histologic response were significantly unfavorable prognostic factors, but not age-specific. However, proportion of metastasis at diagnosis was significantly highest in 20 40 years of age group. For the age at diagnosis, older patients presented poorer 5-year OS and EFS rates, but for 10-year, 20 40 years of age group showed unusually better prognosis than younger age’s, with statistic significance in OS rates but not in EFS rates. Conclusion: Osteosarcoma patients with 20 40 years of age in Korea presented relatively better prognosis after longer-term 10-year despite their late diagnosis causing more metastasis at diagnosis, which emphasized expedite diagnosis and appropriate treatment to expect much better prognosis than peak age groups.


Introduction
Osteosarcoma has a bimodal age distribution; the first peak is in the 10 -14 years of age group which coincides with pubertal growth spurts, and the second peak is in adults older than 65 years of age who are more likely to represent a second malignancy, commonly related to Paget's disease [1].Between these two peaks of age, 20 -40 years of age group is generally considered as "young adults" [2].
Although cancer is the second most cause of death next to suicide in the young adult group, relatively less attention has caused its consequent relatively little improvement of survival rate in this group [3] [4].Differences of pathogenesis and biology of cancers including osteosarcoma in this group, compared to younger and older peak groups, have emphasized importance of distinctly different approaches in early diagnosis, treatment and follow-up in these patients' group.Janeway et al. [5] have reported outcome of osteosarcoma in adolescent and young adult (AYA) patients, based on 1054 patients from Children's Oncology Group in North America.However, in this article, more than 90% of the patients were other than Asians (66% of white, 14% of black, and 12% of Hispanic races).Therefore, we analyzed and reported the outcomes of osteosarcoma in 20 -40 years of age group from the data in Kosin University Gospel Hospital and Korea Cancer Center Hospital.The most osteosarcoma patients of the two tertiary medical centers are enrolled in Korea, to compare the results with North America's and Europe's which would be helpful for awareness of their characteristics and decision of appropriate treatment modalities based on considerable risk factors in East Asians.

Materials and Methods
From September 1986 to July 2015, a total of 379 patients (220 males and 159 females) who were newly diagnosed as osteosarcoma in Kosin University Gospel Hospital and Korea Cancer Center Hospital, the two of the major Korean cancer hospitals with most osteosarcoma patients, were retrospectively enrolled in this study.All the patients had undergone an open biopsy, neoadjuvant chemotherapy, surgery, and adjuvant chemotherapy as a scheduled treatment protocols widely accepted based on the results of multi-institutional prospective trials [6] [7] [8], then were followed up for more than 2 years to be included in this study.
Any patients with follow-up loss in less than 2 years or not completed the treatment protocols were excluded.Bone scan and chest CT were performed in every patient to check out distant metastasis, and positron emission tomography (PET) was also performed in recent cases.
The patients were divided into 3 groups according to their age at diagnosis.Group A included the patients aged 19 years or younger, and there were 60 patients (33 males and 27 females) in this group.Group B, mainly focused group in this study, included the patients aged 20 to 40 years, and there were 290 patients (174 males and 116 females) in this group.Group C included the patients aged For gender, in the whole 220 males, 5-and 10-year OS rates were 65.5% and 36.4% and 5-and 10-year EFS rates were 58.2% and 33.6%.In the whole 159 females, 5-and 10-year OS rates were 67.3% and 43.4% and 5-and 10-year EFS rates were 61.6% and 40.3%.They did not show statistical significance in 5-and 10-year OS and EFS rates by gender (p = 0.792, p = 0.236, p = 0.569, p = 0.225).

Discussion
Osteosarcoma is the most common childhood malignancy of the bone [10], and occurs eighth in general incidence among all childhood cancers, accounts for 2.4%, and death rates for osteosarcoma have been decreasing by approximately 1.3% per year.The 5-year survival rate using a multidisciplinary approach varies from 60% to 70% [7] [11].
For the outcomes of osteosarcoma, many published articles mainly focused on two peak age groups, 10 -14 years of age (early adolescence) and older than 65 years of age (elderly populations).However, there had not been many reports about outcomes of the age group between the two peak age groups, except for the massive study by Janeway et al. [5] about outcomes of osteosarcoma in the patients aged 18 to 30 years in North America.Between the age of 15 and 65, we authors focused on the patients aged 20 to 40 years on Korean social background.OS*: overall survival, EFS † : event-free survival, Good ‡ : Necrosis ≥ 90%, Poor § : Necrosi < 90%.[18] reported that 5-year OS and progression-free survival rates were 27% and 19% based on 76 patients with high-grade pelvic osteosarcoma registered in the Cooperative Osteosarcoma Study Group (COSS).Parry et al. [19]  For the proportion of histologic subtypes, Hauben et al. [23] analyzed 568 patients for whom subtype was available then reported 404 (71%) were of the conventional subtype, 54 (10%) were chondroblastic, 53 (9%) had fibroblastic tumors and the remainder consisted of rare subtypes.Our data also presented similar proportion, not only in the whole group but also in the group B. For the relationship of histologic subtypes and their prognosis, there seem to be controversial in the opinions among the previous studies.Parry et al. [19] reported that best 5-year disease-specific survival rate was among osteoblastic subtypes at 35.2%, followed by chondroblastic of 24.3%, and non-defined at 23.6%.Hauben et al. [23] reported that there were a higher proportion of good responders in the fibroblastic group and a lower proportion of good responders in the chondroblastic group in comparison with the conventional subtype, and concluded that chondroblastic subtype experienced better survival.In contrast, Bacci et al. [24] reported that 5-year OS rate was significantly higher in fibroblastic (83%) tumors than in osteoblastic (62%) and chondroblastic (60%) tumors, and 5-year OS rate was significantly higher in good responders than in poor responders in all subtypes except the chondroblastic subtype.In our study, slightly different patterns of prognosis were found among the subtypes accord-ing to OS and EFS rates.Chondroblastic subtype showed relatively better prognosis with 10-year OS and EFS rates of 61.9% and 42.9%, and fibroblastic subtype showed relatively poorer prognosis with 10-year OS and EFS rates of 18.5% and 16.7%.However, these were not statistically significant (p < 0.001, p = 0.024).Therefore we think that more studies should be performed to establish the exact relationship between the histologic subtypes and their prognosis.
In determination of histologic response to chemotherapy, evaluation was performed by comparing necrosis of resected tumor with the biopsy specimen.For cutoff point in assessment of chemotherapeutic effect, many studies use 90% necrosis as standard [25] [26] [27], therefore we authors also used this point as a cutoff value determination whether histological responses were good or poor.
Although there was one recent article stating that histological necrosis after chemotherapy did not significantly influence survival [28], histological response seems to be one of the generally-accepted significant prognostic factors in osteosarcoma [29] [30].In our study, the patients with poor histologic response presented much more unfavorable survival rates than those with good histologic response, regardless of the age, and these results were statistically significant (p = 0.018).This tendency means that histologic response is also a significant unfavorable prognostic factor not only in the young adult but also for the whole osteosarcoma patients.
In this retrospective, two-center study we found that presence of metastasis at diagnosis, primary lesion at pelvis, and poor histologic response were significant unfavorable prognostic factors in the patients with osteosarcoma.These findings are also generally supported by many other reports [5] [7] [11] [13], not just for specific age group but for all the osteosarcoma patients.However, the proportion of metastasis at diagnosis was significantly higher in 20 -40 years of age group in our study.We assume that this is due to late timing of diagnosis caused from their relatively late visit to hospital when suspicious symptoms or pain were presented, which may arise from their unstable socioeconomic status in Korea, therefore more extensive research about this phenomenon should be performed in the near future.

Conclusion
Upon multivariate analysis, primary lesion at pelvis and poor histologic response maintained significant poor prognostic values on the outcome of osteosarcoma in 20 -40 years of age group, but these factors were not age-specific characteristics.However, metastasis at diagnosis was significantly more found at the 20 -40 years of aged group.But for 10-year OS and EFS rates, these patients presented relatively good prognosis, in spite of significantly higher proportion of metastasis at diagnosis compared to the other age groups.This relative overtake of longer-term survival rates in these patients aged 20 -40 years is an unique finding in our study; therefore more studies will be needed to find out whether this tendency is race-specific or not.In conclusion, if expeditious workups to prevent T. Kim et al.

Table 1 .
Characteristic of the study population and association of parameters age at diagnosis.

Table 2 .
Parameters and their association with overall survival by univariate analysis.

Table 3 .
Location of primary lesions by age group.

Table 6 .
Histologic response by age group.