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An assessment of necrosis grading in childhood osteosarcoma: the effect of initial treatment on prognostic significance

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An assessment of necrosis grading in childhood osteosarcoma: the effect of initial treatment on prognostic significance

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Content AN ASSESSMENT OF NECROSIS GRADING IN CHILDHOOD OSTEOSARCOMA THE EFFECT OF INITIAL TREATMENT ON PROGNOSTIC SIGNIFICANCE i AN ASSESSMENT OF NECROSIS GRADING IN CHILDHOOD OSTEOSARCOMA: THE EFFECT OF INITIAL TREATMENT ON PROGNOSTIC SIGNIFICANCE BY YU-CHEN CHANG A Thesis Presented to the FACULTY OF THE USC GRADUATE SCHOOL UNIVERSITY OF SOUTHERN CALIFORNIA In Partial Fulfillment of the Requirements for the Degree MASTER OF SCIENCE (APPLIED BIOSTATISTICS AND EPIDEMIOLOGY) August 2014 Copyright 2014 YU-CHEN CHANG AN ASSESSMENT OF NECROSIS GRADING IN CHILDHOOD OSTEOSARCOMA THE EFFECT OF INITIAL TREATMENT ON PROGNOSTIC SIGNIFICANCE ii Dedication I dedicate my thesis to the various people who have influenced my life and supported me through my master degree. Thanks to my committee chair, Dr. Daniel Stram for guiding me through my graduate study. Thanks to my co-chair, Dr. Mark Krailo and my committee member, Dr. Wendy Mack for providing knowledge and advice though my completion of thesis. Thanks to my family and classmates for being supportive and encouraging. Especially, thanks to my mom for giving me the chance to study in the United States. AN ASSESSMENT OF NECROSIS GRADING IN CHILDHOOD OSTEOSARCOMA THE EFFECT OF INITIAL TREATMENT ON PROGNOSTIC SIGNIFICANCE iii Table of Contents Dedication ii List of Tables iv List of Figures v Abstract 1 Introduction 3 Patients and Methods 8 Results 20 Discussion 34 References 36 AN ASSESSMENT OF NECROSIS GRADING IN CHILDHOOD OSTEOSARCOMA THE EFFECT OF INITIAL TREATMENT ON PROGNOSTIC SIGNIFICANCE iv List of Tables Table 1. Necrosis Grading 9 Table 2. Univariate Analysis of Prognostic Factors 26 Table 3. Final Model 28 AN ASSESSMENT OF NECROSIS GRADING IN CHILDHOOD OSTEOSARCOMA THE EFFECT OF INITIAL TREATMENT ON PROGNOSTIC SIGNIFICANCE v List of Figures Figure 1. CCG-782, Induction Scheme 10 Figure 2. CCG-782, Maintenance B Schema for Grade III to IV Responders, 1 Cycle (repeat twice) 11 Figure 3. CCG-782, Maintenance A schema for Grade I to II Responders, 1 Cycle (repeat twice) 11 Figure 4. INT-0133, Protocol Road Map 13 Figure 5. Treatment Assignment and Necrosis Grading by Study 20 Figure 6. Kaplan-Meier Curve of Main Effects Model according to Necrosis Grading and Study 29 Figure 7. Kaplan-Meier Curve of Main Effects Model by specifying [0,10.93] Quartile Age Group and stratifying Necrosis Grading and Study 30 Figure 8. Kaplan-Meier Curve of Main Effects Model by specifying (10.93,13.37] Quartile Age Group and stratifying Necrosis Grading and Study 31 Figure 9. Kaplan-Meier Curve of Main Effects Model by Specifying (13.37,16] Quartile Age Group and stratifying Necrosis Grading and Study 32 Figure 10. Kaplan-Meier Curve of Main Effects Model by specifying (16,22) Quartile Age Group and stratifying Necrosis Grading and Study 33 AN ASSESSMENT OF NECROSIS GRADING IN CHILDHOOD OSTEOSARCOMA THE EFFECT OF INITIAL TREATMENT ON PROGNOSTIC SIGNIFICANCE 1 Abstract Purpose: The primary aim of this thesis is to determine whether the risk for treatment failure associated with necrosis grading changes according to the study (CCG-782 V.S. INT-0133) onto which a patient was enrolled. The secondary aim is to identify whether other factors identified at the time of study enrollment are significantly related to risk for treatment failure and whether such factors account for differences in outcome between the two studies. Patients and Methods: The study population consisted of 929 patients from two Children’s Cancer Group (CCG) studies of childhood osteosarcoma: 206 from CCG-782 and 723 from INT- 0133. The primary outcome measure for this analysis was event free survival (EFS). Non- parametric methods, including the log-rank test and the Kaplan-Meier estimator of EFS as a function of time since the definitive surgery and a semi-parametric method, Cox proportional hazard model, were implemented to determine the association between necrosis grading, study of enrollment, and the risk of EFS. Results: Overall, necrosis grading III-IV was associated with a reduced the risk of EFS-event, compared to necrosis grading I-II. Reduction in the risk of EFS differed between CCG-782 and INT-0133. After analyses of prognostic factors such as sex, age, tumor site, race, and treatment arrangement, age modeled in quartiles was the only prognostic factor that was significantly related to risk for treatment failure; this prognostic factor did not account for differences in outcome between the two studies and necrosis grading result. Conclusions: The difference of the risk of EFS between necrosis grading III-IV and I-II in CCG- 782 was larger than in INT-0133. The factors that caused such difference could be the different AN ASSESSMENT OF NECROSIS GRADING IN CHILDHOOD OSTEOSARCOMA THE EFFECT OF INITIAL TREATMENT ON PROGNOSTIC SIGNIFICANCE 2 time of definitive surgery, the difference of chemotherapy treatment, the recruitment of different individuals across time on these studies, or the extra institutions within study, INT-0133. Key words: Osteosarcoma, Children Cancer Group (CCG), Event Free Survival (EFS), Kaplan Meier Estimator, Cox Model, Necrosis Grading AN ASSESSMENT OF NECROSIS GRADING IN CHILDHOOD OSTEOSARCOMA THE EFFECT OF INITIAL TREATMENT ON PROGNOSTIC SIGNIFICANCE 3 Introduction Osteosarcoma originates from primitive bone-forming mesenchymal cells and is the most common primary bone malignancy (56% of bone cancer). 1 The incidence rate and 95% confidence interval of pediatric and adolescent osteosarcoma (aged 0-19 years) for all races and both sexes is 5.0 (4.6-5.6) per year per millions persons. 1 The overall 5-year survival rate for osteosarcoma is 68%, without significant differences between sexes. 1,2,3 Current therapy comprises preoperative chemotherapy followed by surgery and postoperative chemotherapy, which significantly improves the survival rates of patients with osteosarcoma 1 . According to M. Hudson et al, patients receiving preoperative chemotherapy, cisplatin (CDDP), and surgery have a 62% survival rate. 5 Patients receiving amputation and limb salvage surgery have 55% and 58% survival rate, respectively. 5 Without chemotherapy, only 15%-20% of patients with osteosarcoma of the extremity without metastases survive five years after diagnosis. 9 Evaluating the effect of chemotherapy depends on detection of tumor necrosis and a method to adequately quantify the necorsis. 6 Some investigators consider that tumor necrosis in response to initial chemotherapy should be used to select post-operative chemotherapy because they consider tumor necrosis a valid predictor of osteosarcoma that assesses or is sensitive to agents administered at the start of treatment. 6 From previous trials, researchers have demonstrated that different combinations of preoperative chemotherapy and postoperative chemotherapy greatly influence the survival outcome. 5,7-9 A number of factors are associated with the risk for treatment failure of osteosarcoma. These prognostic factors are described below. AN ASSESSMENT OF NECROSIS GRADING IN CHILDHOOD OSTEOSARCOMA THE EFFECT OF INITIAL TREATMENT ON PROGNOSTIC SIGNIFICANCE 4 Age There are large differences in the incidence rates of osteosarcoma by attained age. 4 Osteosarcoma has a bimodal age distribution. 1 The first peak is at 10-14-year-old age group corresponding to puberty. 1 The incidence rate is higher in older children than in younger children. Osteosarcoma frequently occurs in children and adolescents aged 10-20 years and seldom in children aged below 5 years. 1 Incidence rates gradually rise in children aged 5-10 years and steeply rise between 11 and 15 years. 1,3 The second peak in incidence occurs in adults older than 65 years of age. 1 According to the National Cancer Data Base Report, the relative 5- year survival rates are 60% for patients aged 30 years or less, 50% for patients aged 30-49 years, and 30% for patients aged 50 years or more. 1 Gender The incidence rate of osteosarcoma is higher in males than in females: 5.4 per year per million males vs. 4.0 per year per million females. 1,2 During 1973 to 2004, the Surveillance, Epidemiology, and End Results Program (SEER) reported 3482 cases of osteosarcoma and the data indicated that the relative 5-year survival rate was higher in females (65.8%) than in males (58.4%), respectively. 4 While the incidence rate is higher in males, survival rate of osteosarcoma is higher in females. AN ASSESSMENT OF NECROSIS GRADING IN CHILDHOOD OSTEOSARCOMA THE EFFECT OF INITIAL TREATMENT ON PROGNOSTIC SIGNIFICANCE 5 Ethnicity The incidence rate of pediatric and adolescent osteosarcoma is higher in blacks than in Hispanics and whites: blacks, 6.8 per year per million persons; Hispanics, 6.5 per year per million persons; and Whites, 4.6 per year per million persons. 1 According to SEER between 1992 to 2004, the relative 5-year survival rate is higher in “other races category” (66%, including American Indian/Alaska Native, Asian/Pacific Islander, Hispanic) than in whites (60.8%) and blacks (61%). 4 Site of Disease Osteosarcoma occurs in any bone and usually in areas near the metaphyseal growth plates of the long bones of the extremities such as the distal femur and proximal tibia. 1 The tumor occurs most commonly in the femur (42%, with 75% of the tumors in the distal femur), in the tibia (19%, with 80% of tumors in the proximal tibia), and in the humerus (10%, with 90% of tumors in the proximal humerus). 1 Other locations are the pelvis (8%), the skull or jaw (8%) and ribs (1.25%). 1 Survival rates also vary by tumor sites. 4 The highest survival rates are in the proximal tibia (78%) and the distal femur (73%) for patients with osteosarcoma and the lowest rates are in the lumbar spine and pelvis region (32%). 4 If the relative risk for EFS (Method) after definitive surgery associated with good necrosis grading (Table 1) were unaffected by initial treatment, a viable treatment option to effect a change in overall outcome for osteosarcoma patients would be to intensify treatment up to the time of definitive surgery. Such intensification comes at the risk of additional deaths attributed to AN ASSESSMENT OF NECROSIS GRADING IN CHILDHOOD OSTEOSARCOMA THE EFFECT OF INITIAL TREATMENT ON PROGNOSTIC SIGNIFICANCE 6 treatment toxicity. The results of this analysis do not favor early intensification, since such approach does not clearly improve the outcome by improving the number of patients who have good response while leaving the outcome associated with good response unchanged. The most recent international study, EURAMOS-1, randomized patients within groups define by necrosis grading after definitive surgery. Design parameters for such a randomization utilize historical data to establish baseline post-definitive-surgery EFS. The results of the analysis show that study planners must exercise caution when establishing an historical cohort, since historical results vary significantly across time. We are interested in assessing the risk of EFS (Method) associated with necrosis grading (Table 1) changes according to the study (CCG-782 vs. INT-0133) onto which a patient was enrolled. We also identify whether other factors measured at the time of study enrollment are significantly related to risk for treatment failure and whether such factors account for differences in outcome between the two studies. The Children’s Cancer Group (CCG) study CCG-782 used vincristine (VCR), high-dose methotrexate (HDMTX) and the combination of bleomycin, cyclophosphamide and dactinomycin (BCD) prior to surgery and the same agents plus doxorubicin (DOX) were used postoperatively, and then revised by using cisplatin (CCDP), DOX and BCD after surgery as the postoperative chemotherapy. 9 The study implemented a single arm trial of preoperative chemotherapy, basing the postoperative therapy on the necrosis grading after preoperative chemotherapy, evaluated the usage of necrosis grading of the primary tumor to decide the AN ASSESSMENT OF NECROSIS GRADING IN CHILDHOOD OSTEOSARCOMA THE EFFECT OF INITIAL TREATMENT ON PROGNOSTIC SIGNIFICANCE 7 chemotherapy regimen used after definitive surgery, and identified patient characteristics that influenced the risk of EFS. 9 The CCG and the Pediatric Oncology Group (POG) carried out the Intergroup Study INT-0133 (CCG-7921/POG-9351) which was a 2 by 2 factorial design. 7,8 The first factor was chemotherapy regimen as one of a three-drug chemotherapy regimen consisting of DOX, CCDP, and HDMTX, or a four-drug regimen using these agents with the addition of ifosfamide (IFOS). The second factor was the incorporation or not of the biological modifier liposomal MTP to a particular chemotherapeutic regimen. 7,8 These two studies provided 929 patients on which to test our research questions. AN ASSESSMENT OF NECROSIS GRADING IN CHILDHOOD OSTEOSARCOMA THE EFFECT OF INITIAL TREATMENT ON PROGNOSTIC SIGNIFICANCE 8 Patients and Methods Patients who were eligible for CCG-study CCG-782, had histologically confirmed, newly diagnosed non-metastatic osteosarcoma of an extremity, were aged 22 years or less at diagnosis, had not previously received any therapy. The extent of their disease prior to study entry was confirmed by total body radionuclide bone scan and either chest tomography or computerized chest tomography. Patients who were ineligible had parosteal, periosteal, multi-centric, and post- radiation osteosarcoma. 9 Patients who were eligible for CCG study INT-0133, were aged 30 years or less at diagnosis, had histologically confirmed, newly diagnosed high-grade osteosarcoma of bone and intramedullary osteosarcoma, had adequate organ function as defined by renal function (serum creatinine ≤ 1.5 × normal or creatinine clearance more than 40 mL/min/m 2 or more than 70 mL/min/1.73m 2 ), adequate hepatic function (bilirubin ≤ 1.5 × normal and AST or ALT ≤ 2.5 × normal), and adequate cardiac function (fractional shortening on echocardiogram ≥ 29% or ejection fraction by radionuclide angiography ≥ 50%). Patients with clinically detectable metastatic disease were eligible at CCG institutions but ineligible at POG institutions. 7,8 Some patients enrolled on INT-0133 were excluded because these individuals did not meet eligibility criteria of CCG-782. That is, the patients were 22 years or more, the tumor sites located in the pelvis, or other central skeletal locations. AN ASSESSMENT OF NECROSIS GRADING IN CHILDHOOD OSTEOSARCOMA THE EFFECT OF INITIAL TREATMENT ON PROGNOSTIC SIGNIFICANCE 9 Approval from the institutional review board (IRB) was required at every institution and every study before enrollment. Informed consent was obtained from all patients or their guardians, and the appropriate IRB-approved written informed consent was signed. 7-9 Necrosis Grading In each trial, the tumor specimen from definitive surgery was assessed for necrosis grading after implementation of preoperative chemotherapy. The necrosis grading system was based on the trial (CCG-782 and INT-0133). Necrosis grading Grading I No effect identified Grading II 5%-95% viable tumor remaining Grading III Scattered foci of viable tumor seen (<5% of the tumor) Grading IV No viable tumor seen in extensive sampling (at least a full cross section of the tumor) Table 1. Necrosis Grading 7-9 A grade I-II necrosis grading was considered a standard response. A grade III-IV necrosis grading was considered a good response. Global assessment of necrosis was made by the institutional pathologist. Necrosis was classified using the scoring system designed by Huvos, as modified by CCG to subdivide grade. For the analysis herein, necrosis grading was grouped into two categories: (1) standard response; and (2) good response. 7-9 AN ASSESSMENT OF NECROSIS GRADING IN CHILDHOOD OSTEOSARCOMA THE EFFECT OF INITIAL TREATMENT ON PROGNOSTIC SIGNIFICANCE 10 Treatment Assignment In CCG-782, all patients received four courses of vincristine (VCR) and HDMTX with leucovorin rescue; one course of dactinomycin (BCD) was given between the second and third MTX courses (Figure 1). 9 Surgery was scheduled for 7 to 10 days following completion of the fourth MTX course, approximately 9 weeks from the start of chemotherapy or at any point during induction if radiographically-confirmed tumor progression occurred. 9 After surgery, all patients without local tumor progression received consolidation chemotherapy, which comprised one course of BCD, four courses of vincristine and HDMTX with leucovorin rescue, and one course of doxorubicin (DOX). 9 After completion of chemotherapy, patients were assigned to one of two maintenance regimens that were based on the necrosis grading of the primary tumor induced by preoperative chemotherapy. 9 Patients who had a good response received three cycles of maintenance therapy with BCD, HDMTX with leucovorin rescue, VCR, and DOX (Figure 2). HDMTX was deleted after the first cycle of maintenance therapy. 9 Patients who had a standard response received three cycles of maintenance therapy with DOX, CDDP, and BCD (Figure 3). 9 Patients who underwent early definitive surgery because of radiographically-suspected local tumor progression received postoperative chemotherapy with BCD, CDDP, and DOX. 9 AN ASSESSMENT OF NECROSIS GRADING IN CHILDHOOD OSTEOSARCOMA THE EFFECT OF INITIAL TREATMENT ON PROGNOSTIC SIGNIFICANCE 11 Figure 1. CCG-782, Induction Scheme. HDMTX, high-dose MTX: 12 g/m 2 in patients ≤ 12 years (maximum, 18 g); 8 g/m 2 in patients > 12 years (maximum, 18gl; Citrovorum factor 15 mg orally every 6 hours 12 doses starting 24 hours after the beginning of MTX. VCR, Vincristine 1.5 mg/m 2 (maximum, 2.0 mg). BCD, (B) bleomycin 15 mg/m 2 /d × 2; (C) cyclophosphamide 600 mg/m 2 /d × 2; (D) dactinomycin 600 µg/m 2 /d × 2 (maximum, 1,250 µg). DOX, 30 mg/m 2 /d × 3 9 Figure 2. CCG-782, Maintenance B Schema for Grade III to IV Responders, 1 Cycle (repeat twice). Abbreviations as in Figure 1 9 AN ASSESSMENT OF NECROSIS GRADING IN CHILDHOOD OSTEOSARCOMA THE EFFECT OF INITIAL TREATMENT ON PROGNOSTIC SIGNIFICANCE 12 Figure 3. CCG-782, Maintenance A schema for Grade I to II Responders, 1 Cycle (repeat twice). CDDP, 120 mg/m 2 or 3 mg/kg. Other abbreviations as in Figure 1 9 In INT-0133, each individual was randomized at the time of study enrollment to one of four different chemotherapy regimens: Regimen A: without liposomal muramyltripeptide (L-MTP- PE), Regimen A: with L-MTP-PT, Regimen B: without L-MTP-PE, or Regimen B: with L-MTP- PE. Regimen A consisted of cisplatin (CCDP), doxorubicin (DOX), and high-dose methotrexate (HDMTX). Regimen B consisted of CCDP, DOX, HDMTX and ifosfamide (IFOS). 7,8 Even though MTP treatment did not begin until week 12 of protocol therapy, randomization of treatment assignment was completed at entry. 7,8 Definitive surgery of the primary tumor was planned 10 weeks after the start of the assigned chemotherapy. 7,8 The choice of surgical procedure was left to the institutional orthopedic surgeon. 7,8 Limb preservation was strongly encouraged whenever possible. 7,8 Maintenance therapy began at week 12 but could be delayed to accommodate for recovery from surgery. 7,8 Maintenance therapy ended at week 31 in regimen A and at week 38 in regimen B. 7,8 AN ASSESSMENT OF NECROSIS GRADING IN CHILDHOOD OSTEOSARCOMA THE EFFECT OF INITIAL TREATMENT ON PROGNOSTIC SIGNIFICANCE 13 Figure 4. INT-0133, Protocol Road Map. DOXO (=DOX), doxorubicin; CDDP, cisplatin; HDMTX, high-dose methotrexate; L-MTP-PE, liposomal muramyl tripeptide phosphatidylethandamine; IFOS, ifosfamide 7,8 The Cox proportional hazard model 13 was used to compare the risk of EFS (Statistical Analysis) among the randomized treatment assignments: Regimen A: without muramyltripeptide (MTP- PE), Regimen A: with MTP-PE, Regimen B: without MTP-PE, or Regimen B: with MTP-PE in INT-0133 and between the two studies: CCG-782 and INT-0133. AN ASSESSMENT OF NECROSIS GRADING IN CHILDHOOD OSTEOSARCOMA THE EFFECT OF INITIAL TREATMENT ON PROGNOSTIC SIGNIFICANCE 14 The prognostic factors were defined in our study as: 1. Age Age was calculated from the patient’s birthdate to their enrollment date in the study (CCG-782 or INT-0133), was recorded as whole years and excluded patients aged 22 years or more from INT-0133. The possible prognostic effect of age was modeled using three grouping methods (i) age as it related to putative age of puberty; (ii) quartiles in the analytic population; and (iii) risk- group age: age dichotomized into groups that resulted in maximally chi-squared log-rank test when considered as a single characteristic. (i) and (ii) were analyzed by Cox proportional hazard model. 13 (iii) was analyzed by maximally selected chi-squared model described below. 10,11 (i) Age as it related to putative age of puberty The study population was categorized by three age groups as: (1) 9 years or less – to identify patients who likely had not experienced puberty, (2) 10-17 years – to identify patients who were transitioning from pre-puberty to post-puberty and as such were experiencing rapid physiological changes, including growth; and (3) 18 or older – to characterize patients who likely were post pubertal. 12 (ii) Quartiles in the analytic population Corresponding to the age at 0%, 25%, 50%, 75%, and 100% quartiles, the study population was categorized into four age subgroups: [0,10.93], (10.93,13.37], (13.37,16], and (16,22). AN ASSESSMENT OF NECROSIS GRADING IN CHILDHOOD OSTEOSARCOMA THE EFFECT OF INITIAL TREATMENT ON PROGNOSTIC SIGNIFICANCE 15 (iii) Risk-group age The study population was divided into two groups: a high risk and a low risk groups based on age at enrollment using maximally selected chi-squared statistics. 10,11 Maximally selected chi-squared statistics was a method to select optimal cutpoint of a quantitative variable that may be predictive of increased risk for an event and to maximize a test statistic (in this case, the log-rank statistic) comparing the two groups defined by the cutpoint. 10,11 Since the cut point was selected by maximization of the log-rank test, the central chi-squared distribution was not the distribution of the test statistic under the null hypothesis of no relationship between age group and the risk of EFS. 10,11 The null distribution of the test statistic was estimated by randomly permuting age at enrollment amongst patients in the data set 1000 times, determining the maximal log-rank chi-squared test for each permutation and constructing the empirical distribution of the maximal value of the log-rank test thus calculated .10,11 The maximal log-rank chi-squared obtained from the original dataset was compared with the quartiles from the empirical distribution of maximal log-rank chi-squared values obtained by permutation. 10,11 2. Treatment Assignment Described above. AN ASSESSMENT OF NECROSIS GRADING IN CHILDHOOD OSTEOSARCOMA THE EFFECT OF INITIAL TREATMENT ON PROGNOSTIC SIGNIFICANCE 16 3. Gender The study population consisted of male and female patients from CCG-782 and INT-0133. 4. Ethnicity The study population consisted of whites, Hispanics, African Americans, Asians, Native Hawaiians, Native Americans, Indian Subcontinents, Filipino and other races from CCG-782 and INT-0133. We classified patients into three groups: whites, blacks, and others that included Asians, Native Hawaiians, Native Americans, Indian Subcontinents, Filipino and other races. 5. Tumor Site The study population consisted of appendicular skeletons (humerus, ulna, radius, femur, patella, tibia, fibula, fibular head, os calcis, hand, and foot) and excluded patients with tumors pelvis or other central skeletal locations from INT-0133. We classified into three groups: femur, humerus, and all other tumor sites. Statistical Analysis Primary Outcome Measures: Event-Free Survival (EFS) was defined as the time from the date of the definitive surgery until an adverse event or last patient contact, whichever came first. Adverse events included disease progression, diagnosis of second malignant neoplasm (SMN), or death before disease progression. Main effects model included necrosis grading, study of enrollment, and EFS and was implemented using Cox proportional hazard model, which AN ASSESSMENT OF NECROSIS GRADING IN CHILDHOOD OSTEOSARCOMA THE EFFECT OF INITIAL TREATMENT ON PROGNOSTIC SIGNIFICANCE 17 maximized the partial likelihood formed by event times and associated risk sets to model the likelihood that an individual alive and under follow-up at time experiences the event of interest in the next time period. 13 Univariate analyses for each prognostic factor such as age, tumor site, race, gender, and treatment assignment were also implemented using Cox proportional hazard model. After adjusting for significant prognostic factors, the association between necrosis grading, study of enrollment, and risk of EFS was estimated by using non-parametric methods, including the log-rank test and the Kaplan-Meier estimator 14 of EFS as a function of time since definitive surgery and a semi-parametric method, Cox proportional hazard model. Patients from INT-0133 who did not meet the eligibility criteria for CCG-782 were removed from the analyses. In Cox models, interaction terms between necrosis grading, study of enrollment, and prognostic candidates were also considered in these analyses. Randomization of treatment assignments and selection bias in INT-0133 were also considered into the analyses and was also implemented using Cox model. The hazard of an event was modeled as: 𝜆 𝑡 𝑅,𝑆 = 𝜆 ! (𝑡)𝑒 !!!!!!!!!!!∗! (1) 𝜆 𝑡 𝑝𝑟𝑜𝑔𝑛𝑜𝑠𝑡𝑖𝑐 𝑓𝑎𝑐𝑡𝑜𝑟 = 𝜆 ! 𝑡 𝑒 !" (2) X: prognostic factors 𝜆 𝑡 𝑅,𝑆,𝑅 ∗𝑆,𝑋 = 𝜆 ! (𝑡)𝑒 !!!!!!!!!!!∗!!!!! (3) 𝜆 𝑡 𝑇2,𝑇3,𝑇4 = 𝜆 ! 𝑡 𝑒 !!!!!!!!!!!!!! (4) 𝜆 𝑡 𝑅,𝑆,𝑅 ∗𝑆,𝑋,𝑅 ∗𝑋 = 𝜆 ! (𝑡)𝑒 !!!!!!!!!!!∗!!!!!!!!!∗! (5) 𝜆 𝑡 𝐺𝑃 = 𝜆 ! (𝑡)𝑒 !"# (6) AN ASSESSMENT OF NECROSIS GRADING IN CHILDHOOD OSTEOSARCOMA THE EFFECT OF INITIAL TREATMENT ON PROGNOSTIC SIGNIFICANCE 18 Briefly, the following terms were included in the regression model: (1) Main effects model to estimate the association between necrosis grading, enrollment of study, and EFS: R: necrosis grading, coded as 0 if necrosis grading=I-II (standard response) and 1 if necrosis grading=III-IV (good response). S: study, coded as 0 if the study trial was CCG-782 and 1 if the study trial was INT-0133. R*S: interaction term between necrosis grading and study of enrollment. (2) Univariate analyses to estimate the association between each prognostic candidate including categorical levels and EFS: B: blacks, coded as 1 if patients’ race were blacks and 0 otherwise. RO: other race, coded as 1 if patients’ race were neither whites nor blacks and 0 otherwise. H: humerus, coded as 1 if patients’ tumor site was humerus and 0 otherwise. TO: other tumor site, coded as 1 if patients’ tumor site was neither femur nor humerus and 0 otherwise. G: gender, coded as 1 if patients were females and 0 otherwise. (i) Age as it related to putative age of puberty. Ab2: the [10,17] age group as a reference group. Ab1: the [0,9] age group, coded as 1 and 0 otherwise. Ab3: the [18,22) age group, coded as 1 and 0 otherwise. (ii) Quartiles age group in the analytic population. Aq3: the (13.37,16] age group as a reference group. Aq1: the [0,10.93] age group, coded as 1 and 0 otherwise. Aq2: the (10.93,13.37] age group, coded as 1 and 0 otherwise. Aq4: the (16,22) age group, coded as 1 and 0 otherwise. A: age sixteen or more, coded as 1 and 0 otherwise; the [0,16) age group as a reference group. (3) Main effects model including other possible significant prognostic factor X separately to confirm the significant association between parameters from main effects model, prognostic factors, and EFS. AN ASSESSMENT OF NECROSIS GRADING IN CHILDHOOD OSTEOSARCOMA THE EFFECT OF INITIAL TREATMENT ON PROGNOSTIC SIGNIFICANCE 19 (4) Treatment Assignment model to test the randomization in INT-0133 influenced the risk of EFS or not: In INT-0133, Regimen A: without MTP-PE as a reference group; T2: Regimen A: with MTP-PE, coded as 1 and 0 otherwise; T3: Regimen B: without MTP- PE, coded as 1 and 0 otherwise; T4: Regimen B: with MTP-PE, coded as 1 and 0 otherwise. (5) Final model included interaction term: Interaction term was modeled multiplicatively with the covariates. X*R: significant prognostic factor*necrosis grading. (6) Examining the selection bias within the study, INT-0133, coded as 1 if patients were entered in CCG and 0 otherwise (POG). A P-value of 0.05 or less associated with the partial likelihood ratio test from the Cox proportional hazards regression model for the null hypothesis that the particular factor coding was not related to the risk for EFS was considered necessary to identify the particular factor as a significant prognostic candidate. AN ASSESSMENT OF NECROSIS GRADING IN CHILDHOOD OSTEOSARCOMA THE EFFECT OF INITIAL TREATMENT ON PROGNOSTIC SIGNIFICANCE 20 Result Patient Inclusion The study population consisted of 929 patients from two CCG studies of pediatric osteosarcoma: 206 from CCG-782 and 723 from INT-0133. Sixteen patients were determined to be ineligible after enrolling into the INT-0133 study. Forty-seven patients enrolled on INT-0133 were excluded because these individuals did not meet eligibility criteria of CCG-782. That is, the patients were 22 years or more, or the tumor sites located in the pelvis, or other central skeletal locations. Seven patients had at least one missing values of time points before the definitive surgery. The CONSORT diagram was displayed below. Figure 5. Treatment Assignment and Necrosis Grading by Study AN ASSESSMENT OF NECROSIS GRADING IN CHILDHOOD OSTEOSARCOMA THE EFFECT OF INITIAL TREATMENT ON PROGNOSTIC SIGNIFICANCE 21 Event Free Survival (EFS) Analysis Main Effects and Grad-by-Study Interaction Model: Evaluation of Differential Association of Necrosis Grading with Event Free Survival (EFS) in the Two Studies In, CCG-782, two hundred and six patients were assessed for necrosis grading. One hundred and forty-eight (71.8%) patients had a standard response and 58 (28.2%) patients had a good response. In INT-0133, six hundred and forty-one patients of the 723 evaluable patients were assessed for necrosis grading. Eighty-two patients did not receive definitive surgery as part of protocol therapy. Three hundred and fifty-four (55.2%) patients had a standard response and 287 (44.8%) patients had a good response (Table 2). After merging these two datasets, the results of Kaplan Meier curve indicated that, in order of increasing risk for EFS, patients enrolled on CCG- 782 with a good response (III-IV) had a reduced the risk of EFS when compared with similar patients enrolled on INT-0133 and patients enrolled on INT-0133 with a standard response (I-II) had a reduced the risk of EFS when compared with similar patients enrolled on CCG-782 (p<0.001, Figure 6). The results in Cox proportional hazard model indicated that, in CCG-782, patients with a standard response had a 4.2 times higher risk of EFS than those with a good response. However, in INT-0133, patients with a standard response had a 1.95 times higher risk of EFS than those with a good response. Shortly, the difference of the risk of EFS between a standard response and a good response was larger in CCG-782 than in INT-0133. There was a statistically significant interaction between necrosis grading and study of enrollment (p=0.035). AN ASSESSMENT OF NECROSIS GRADING IN CHILDHOOD OSTEOSARCOMA THE EFFECT OF INITIAL TREATMENT ON PROGNOSTIC SIGNIFICANCE 22 Prognostic Factors: Univariate Analysis From previous studies, the incidence rates for osteosarcoma varied by gender, age, ethnicity, and tumor sites of disease. Details of the patients’ univariate analysis was described in Table 2. There was no statistically significant association between patients’ sex (p=0.22), race (p=0.53) or tumor site (p=0.14) and the risk of EFS (Table 2). There was no significant association between age grouping based on (i) putative age at puberty or (iii) age as categorized according to the maximal log-rank statistics and the risk of EFS ((i) p=0.15; (iii) 0.1<p<0.25). When age was considered as (ii) quartiles, with the (13.37,16] age group as the reference category there was a statistically significant association between the quartile age and the risk of EFS (p=0.028). The [1.36,10.93] age group had a 1.087 times higher the risk of EFS than the (13.37,16] reference group. The (10.93, 13.37] age group had an almost the same risk of EFS when compared to the (13.37,16] reference group. The (16,22] age group had a 1.46 times higher risk of EFS than the (13.37,16] reference group. The results of univariate analyses, quartiles age was a significant prognostic factor and was included into the main effects model that assessed of the effect of necrosis grading and study of enrollment (Table 2). Main Effect Model including all Prognostic Factors After including age coded as quartiles into main effects model, the results of likelihood ratio test in Cox proportional hazard model indicated that there was a statistically significant association AN ASSESSMENT OF NECROSIS GRADING IN CHILDHOOD OSTEOSARCOMA THE EFFECT OF INITIAL TREATMENT ON PROGNOSTIC SIGNIFICANCE 23 between quartile age group and the risk of EFS (p<0.005). Quartile age was considered as a statistically significant prognostic factor and was included into the final model. Final Model including all Statistically Significant Prognostic Factors Having included age quartiles as a statistically significant prognostic factor (p<0.005), our final model included necrosis grading, two studies, quartile age and an interaction term between necrosis grading and study of enrollment. The results indicated that there was a statistically significant association between necrosis grading, study of enrollment, and risk of EFS after adjusting for quartile age (p=0.027) and indicated that patients with a standard response (I-II) had a 1.36 times higher risk of EFS in CCG-782 than in INT-0133 and patients with a good response (III-IV) had a 1.65 times higher risk of EFS in INT-0133 than in CCG-782 after adjusting for quartile age. On the other way, in CCG-782, patients with a standard response had a 4.3 times higher risk of EFS than those with a good response after adjusting for quartile age. However, in INT-0133, patients with a standard response had a 1.87 times higher risk of EFS than those with a good response after adjusting for quartile age (Table 3). After adjusting for quartile age, the order of Kaplan Meier curves retained the same relative order of risk associated with study of enrollment and necrosis grading for each of the age quartiles considered (Figure 7- 10). The Final Model including Interaction terms We considered the interaction between necrosis grading and different levels of quartiles age. There was no statistically significant interaction between necrosis grading and quartiles age AN ASSESSMENT OF NECROSIS GRADING IN CHILDHOOD OSTEOSARCOMA THE EFFECT OF INITIAL TREATMENT ON PROGNOSTIC SIGNIFICANCE 24 ([0,10.93] age group (p=0.86), (10.93,13.37] age group (p=0.97) and (16,22) age group (p=0.76), (13.37,16] age group was considered as the reference group). Comparing treatment assignments between two studies The Cox proportional hazard model indicated that there was no statistically significant difference among treatment assignments on the risk of EFS among the INT-0133 patients (p=0.0582) (Table 2). The identical results in Meyers et al indicated that the risk for EFS was not significantly associated with randomized treatment assignment. 8 Thus, stratifying the treatment assignments in INT-0133 was excluded from the analyses and study of enrolment remained indicator variable in our model (CCG-782=0, INT-0133=1). Eliminating the selection bias within study, INT-0133 Because patients in INT-0133 were recruited from both CCG and POG, more institutions participated in INT-0133 than were in CCG-782. The extra institutions could be entering patients with a fundamentally different prognosis. However, the result from the Cox proportional hazard model indicated that there was no statistically significant difference between these two institutions (CCG vs. POG) (p=0.579). In conclusion, the risk for treatment failure statistically significant associated with necrosis grading changes according to the study (CCG-782 V.S. INT-0133) onto which a patient was enrolled. When age was classified into quartiles in the analytic population, age was significantly AN ASSESSMENT OF NECROSIS GRADING IN CHILDHOOD OSTEOSARCOMA THE EFFECT OF INITIAL TREATMENT ON PROGNOSTIC SIGNIFICANCE 25 related to risk for treatment failure and such prognostic factor did not account for difference in outcome between the two studies. After adjusting for the single significant prognostic factor, quartile age, such association between necrosis grading, study of enrollment, and the risk EFS still remained. AN ASSESSMENT OF NECROSIS GRADING IN CHILDHOOD OSTEOSARCOMA THE EFFECT OF INITIAL TREATMENT ON PROGNOSTIC SIGNIFICANCE 26 Patient Feature Characteristic CCG-782 INT-0133 Overall Percent of Total (Percent of Non-Missing Values) Hazar d Rate Ratio P-value Necrosis Grading Standard response 148 (*71.8%) 354 (55.2%) 502 (54%) 91.2% (missing=82) 1 <0.0001 Good response 58 (28.2%) 287 (44.8%) 345 (37.1%) 0.24 Gender Male 110 (53.4%) 397 (54.9%) 507 (54.6%) 100% 1 0.22 Female 96 (46.6%) 326 (45.1%) 422 (45.4%) 100% 0.878 Age as it related to putative age of puberty 0-9 33 (16%) 98 (13.55%) 131 (14.1%) 100% 1.099 0.15 10-17 151 (73.3%) 519 (71.78%) 670 (72.12%) 100% 1 18-22 22 (10.7%) 106 (14.67%) 128 (13.77%) 100% 1.333 Age Quartiles 0-25% [0,10.93] 47 (22.8%) 184 (25.6%) 231 (25%) 100% 1.087 0.03 25%-50% (10.93,13.37] 63 (30.6%) 169 (23.4%) 232 (25%) 100% 1.004 50%-75% (13.37,16] 55 (26.7%) 191 (26.5%) 246 (26.5%) 100% 1 75%-100% (16,22] 41 (19.9%) 177 (24.5%) 218 (23.5%) 100% 1.46 Risk group age Age<16 150 (72.8%) 545 (75.4%) 695 (74.8%) 100% 1 ** 0.1<p<0 .25 Age>=16 56 (27.2%) 178 (24.6%) 234 (25.2%) 100% 1.403 Race White 148 (71.8%) 479 (66.3%) 627 (67.5%) 99.35% (missing=6) 1 0.53 Black 19 (9.2%) 101 (14%) 120 (12.9%) 1.041 AN ASSESSMENT OF NECROSIS GRADING IN CHILDHOOD OSTEOSARCOMA THE EFFECT OF INITIAL TREATMENT ON PROGNOSTIC SIGNIFICANCE 27 Other 33 (16%) 143 (19.7%) 176 (18.9%) 1.165 Primary tumor site Femur 110 (53.4%) 418 (57.8%) 528 (56.8%) 95.9% (missing=38) 1 0.14 Humerus 27 (13.1%) 175 (24.2%) 202 (21.7%) 0.795 Other 69 (33.5%) 92 (12.7%) 161 (17.3%) 0.819 Treatment Assignmen t CCG-782 206 (100%) 206 (22.2%) 100% 1 *** 0.08 Regimen A: without MTP- PE 0 177 (24.5%) 177 (19%) 100% 0.962 **** 0.06 Regimen A: with MTP-PE 0 183 (25.3%) 183 (19.7%) 0.899 Regimen B: without MTP- PE 0 177 (24.5%) 177 (19.1%) 1.096 Regimen B: with MTP-PE 0 186 (25.7%) 186 (20%) 0.695 *Percentage of the two studies was calculated within the study and overall percentage was calculated between two studies. **Analyzed using maximally selected chi-squared test with corrected p-value. ***The p-value was estimated from the model included CCG-782 and INT-0133 of each arm. ****The p-value was estimated from the model included INT-0133 of each arm. Statistical significant determined at p=0.05 Table 2. Univariate Analysis of Prognostic Factors AN ASSESSMENT OF NECROSIS GRADING IN CHILDHOOD OSTEOSARCOMA THE EFFECT OF INITIAL TREATMENT ON PROGNOSTIC SIGNIFICANCE 28 Parameter Hazard Ratio Pr>ChiSq Study 0.732 0.0262 Response (Necrosis Grading) 0.235 <0.0001 Study×Resp 2.242 0.027 *Ageq1 [0,10.93] 0.965 0.8251 Ageq2 (10.93,13.37] 0.885 0.4574 Ageq4 (16,22) 1.340 0.058 *Ageq3: (13.37,16] as a reference group Table 3. Final Model AN ASSESSMENT OF NECROSIS GRADING IN CHILDHOOD OSTEOSARCOMA THE EFFECT OF INITIAL TREATMENT ON PROGNOSTIC SIGNIFICANCE 29 Figure 6. Kaplan-Meier Curve of Main Effects Model according to Necrosis Grading and Study. AN ASSESSMENT OF NECROSIS GRADING IN CHILDHOOD OSTEOSARCOMA THE EFFECT OF INITIAL TREATMENT ON PROGNOSTIC SIGNIFICANCE 30 Figure 7. Kaplan-Meier Curve of Main Effects Model by specifying [0,10.93] Quartile Age Group and stratifying Necrosis Grading and Study AN ASSESSMENT OF NECROSIS GRADING IN CHILDHOOD OSTEOSARCOMA THE EFFECT OF INITIAL TREATMENT ON PROGNOSTIC SIGNIFICANCE 31 Figure 8. Kaplan-Meier Curve of Main Effects Model by specifying (10.93,13.37] Quartile Age Group and stratifying Necrosis Grading and Study AN ASSESSMENT OF NECROSIS GRADING IN CHILDHOOD OSTEOSARCOMA THE EFFECT OF INITIAL TREATMENT ON PROGNOSTIC SIGNIFICANCE 32 Figure 9. Kaplan-Meier Curve of Main Effects Model by specifying (13.37,16] Quartile Age Group and stratifying Necrosis Grading and Study AN ASSESSMENT OF NECROSIS GRADING IN CHILDHOOD OSTEOSARCOMA THE EFFECT OF INITIAL TREATMENT ON PROGNOSTIC SIGNIFICANCE 33 Figure 10. Kaplan-Meier Curve of Main Effects Model by specifying (16,22) Quartile Age Group and stratifying Necrosis Grading and Study AN ASSESSMENT OF NECROSIS GRADING IN CHILDHOOD OSTEOSARCOMA THE EFFECT OF INITIAL TREATMENT ON PROGNOSTIC SIGNIFICANCE 34 Discussion The study population consisted of two CCG studies, INT-0133 and CCG-782. Because of the different eligibility criteria, I derived an analytic dataset that consisted of patients who conformed to the most restrictive eligibility criteria on either study. The new study population with the same criteria demonstrated a significant association between necrosis grading, study of enrollment, and the risk of EFS. The significant association of necrosis grading with the risk of EFS significantly differed by studies. The difference of the risk of EFS between good response and standard response in CCG-782 was larger than in INT-0133. After adjusting for quartile age, the order of Kaplan Meier curves retained the same relative order of risk associated with study of enrollment and necrosis grading for each of the age quartiles considered. There were three factors that could cause this difference from our data. First, the time of the definitive surgery was different between two studies. In CCG-782, the definitive surgery occurred at week 7. However, in INT-0133, the definitive surgery occurred at week 10. The time interval of patients from CCG-782 that received treatments was shorter than in INT-0133. The time of the definitive surgery might explain the different survival function associated with necrosis grade between the two studies. Second, the content of treatment differed between the two studies. In CCG-782, patients received vincristine (VCR), high-dose methotrexate (HDMTX), dactinomycin (BCD), and doxorubicin (DOX). In INT-0133, patients received cisplatin (CCDP), doxorubicin (DOX), high-dose methotrexate (HDMTX), ifosfamide (IFOS) (only for Regimen B) and with or without liposomal AN ASSESSMENT OF NECROSIS GRADING IN CHILDHOOD OSTEOSARCOMA THE EFFECT OF INITIAL TREATMENT ON PROGNOSTIC SIGNIFICANCE 35 muramyltripeptide (L-MTP-PE). The different treatment assignments between these two studies were VCR and BCD in CCG-782, and CCDP, IFOS and L-MTP-PE in INT-0133. The timeline of treatment assignment between the two studies was also different. All of these treatment- related factors might influence necrosis grade association with the EFS risk. Third, selection bias might be a possible explanation because (1) different individuals were entered on studies across time or (2) more institutions were participants in INT-0133 than were in CCG-782. Regarding the first possibility, a different “kind” of patient might had been entered on CCG-782 than was on INT-0133. This could result from different mechanisms to determine extent of tumor and whether a patient was considered without metastases at diagnosis. The study of enrollment was confounded with epoch during which the patient was enrolled. (1980 vs. 1990s). Regarding the second aspect of selection bias, the extra institutions might have entered patients with a fundamentally different prognosis. However, the results of Cox proportional hazard model indicated that there was no statistically significant difference between CCG and POG among patients in INT-0133. These issues of bias cannot be readily addressed with this dataset. Future studies, however, could be designed to address these issues. First, we could fix the time of definitive surgery and randomize the chemotherapeutic approach. Alternatively, we could use the same treatment in the next trial but randomly assign the timing of surgery. AN ASSESSMENT OF NECROSIS GRADING IN CHILDHOOD OSTEOSARCOMA THE EFFECT OF INITIAL TREATMENT ON PROGNOSTIC SIGNIFICANCE 36 References 1. Giulia Ottaviani, Norman Jaffe. (2009). The epidemiology of osteosarcoma. Pediatric and adolescent osteosarcoma, 3-13 2. Elizabeth Ward, PhD; Carol DeSantis, MPH. (2014). Childhood and adolescent cancer statistics. CA: A Cancer Journal for Clinicians, 1-21 3. U.S. Cancer Statistics Working Group. United States Cancer Statistics: 1999–2010 Incidence and Mortality Web-based Report. Atlanta: U.S. Department of Health and Human Services, Centers for Disease Control and Prevention and National Cancer Institute; 2013. Available at: www.cdc.gov/uscs. 4. Lisa Mirabello, PhD, Rebecca J. Troisi, ScD. (2009). Osteosarcoma incidence and survival rates from 1973 to 2004. Cancer, 1531-43 5. Melissa Hudson, Mark Robert Jaffe, Norman Jaffe. (1990). Pediatric Osteosarcoma: therapeutic strategies, results, and prognostic factors derived from a 10-year experience. Journal of Clinical Oncology, Vol 8, No 12, 1988-1997 6. A. Kevin Raymond, Norman Jaffe. (2009). Osteosarcoma multidisciplinary approach to the management from the pathologist’s perspective. Pediatric and Adolescent Osteosarcoma. 63-84 7. Paul A. Meyers, MD, Cindy L. Schwartz, MD, Mark Krailo, PhD. (2008). Osteosarcoma: The addition of muramyl tripeptide to chemotherapy improves overall survival: A report from the Children’s Oncology Group. Journal of Clinical Oncology, 633-638. AN ASSESSMENT OF NECROSIS GRADING IN CHILDHOOD OSTEOSARCOMA THE EFFECT OF INITIAL TREATMENT ON PROGNOSTIC SIGNIFICANCE 37 8. Paul A. Meyers, MD, Cindy L. Schwartz, MD, Mark Krailo, PhD. (2005). Osteosarcoma: a randomized, prospective trial of the addition of ifosfamide and/or muramyl tripeptide to cisplatin, doxorubicin, and high-dose methotrexate. Journal of Clinical Oncology, 2004-2011. 9. Arthur J. Provisor, Lawrence J. Ettinger, James B. Nachman, Mark D. Krailo. (1997). Treatment of nonmetastatic osteosarcoma of the extremity with preoperative and postoperative chemotherapy: a report from the children’s cancer group. Journal of Clinical Oncology, 76-84. 10. Anne-Laure Boulesteix. (2006). Maximally selected chi-square statistics for ordinal variables. Biometrical Journal, 451-462. 11. Berthold Lausen, Martin Schumacher. (1996). Evaluating the effect of optimized cutoff values in the assessment of prognostic factors. Computational Statistics & Data Analysis, 307- 326. 12. Richard B. Womer, Daniel C. West, Mark D. Krailo. (2012). Randomized controlled trial of interval-compressed chemotherapy for the treatment of localized Ewing sarcoma: a report from the Children’s Oncology Group. Journal of Clinical Oncology, Vol. 30, No. 33, 4148-4154. 13. Cox, David R (1972). "Regression Models and Life-Tables". Journal of the Royal Statistical Society, Series B 34 (2): 187–220. JSTOR 2985181. MR 0341758 14. Kaplan, E. L.; Meier, P. (1958). “Nonparametric estimation from incomplete observations”. J. Amer. Statist. Assen. 53 (282); 457-481. JSTOR 2281868.

Abstract (if available)

Abstract Purpose: The primary aim of this thesis is to determine whether the risk for treatment failure associated with necrosis grading changes according to the study (CCG-782 V.S. INT‐0133) onto which a patient was enrolled. The secondary aim is to identify whether other factors identified at the time of study enrollment are significantly related to risk for treatment failure and whether such factors account for differences in outcome between the two studies. ❧ Patients and Methods: The study population consisted of 929 patients from two Children’s Cancer Group (CCG) studies of childhood osteosarcoma: 206 from CCG‐782 and 723 from INT‐0133. The primary outcome measure for this analysis was event free survival (EFS). Non‐parametric methods, including the log‐rank test and the Kaplan‐Meier estimator of EFS as a function of time since the definitive surgery and a semi‐parametric method, Cox proportional hazard model, were implemented to determine the association between necrosis grading, study of enrollment, and the risk of EFS. ❧ Results: Overall, necrosis grading III‐IV was associated with a reduced the risk of EFS‐event, compared to necrosis grading I‐II. Reduction in the risk of EFS differed between CCG‐782 and INT‐0133. After analyses of prognostic factors such as sex, age, tumor site, race, and treatment arrangement, age modeled in quartiles was the only prognostic factor that was significantly related to risk for treatment failure

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Asset Metadata

Creator Chang, Yu-chen (author)

Core Title An assessment of necrosis grading in childhood osteosarcoma: the effect of initial treatment on prognostic significance

School Keck School of Medicine

Degree Master of Science

Degree Program Applied Biostatistics and Epidemiology

Publication Date 08/05/2014

Defense Date 08/05/2014

Publisher University of Southern California (original), University of Southern California. Libraries (digital)

Tag Children's Cancer Group (CCG),Cox model,event free survival (EFS),Kaplan Meier estimator,necrosis grading,OAI-PMH Harvest,Osteosarcoma

Format application/pdf (imt)

Language English

Contributor Electronically uploaded by the author (provenance)

Advisor Krailo, Mark (committee chair), Stram, Daniel O. (committee chair), Mack, Wendy Jean (committee member)

Creator Email chan641@usc.edu,jemc36@gmail.com

Permanent Link (DOI) https://doi.org/10.25549/usctheses-c3-452085

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Legacy Identifier etd-ChangYuche-2761.pdf

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Document Type Thesis

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Access Conditions The author retains rights to his/her dissertation, thesis or other graduate work according to U.S. copyright law. Electronic access is being provided by the USC Libraries in agreement with the a...

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