Tumor Necrosis in Pediatric Osteosarcoma: Impact of Modern Therapies

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1 DOCTYPE = ARTICLE Tumor Necrosis in Pediatric Osteosarcoma: Impact of Modern Therapies Eleanor Hendershot, MN, RN, ACNP Alberto Pappo, MD David Malkin, MD Lillian Sung, MD Tumor necrosis following preoperative chemotherapy in patients with osteosarcoma is a predictor of overall survival. With modern therapies, 45% of patients are expected to achieve more than 90% tumor necrosis. Investigators at the authors center, however, increasingly noted that patients were experiencing inferior necrosis responses. A retrospective study of treated patients at the center was undertaken to examine this. The purpose of this study was to determine (1) whether the number of patients with favorable histological responses had changed over time and (2) whether the percentage of patients with favorable responses was similar to published outcomes. Chart reviews were performed on patients treated from 1993 to 2003 according to the Pediatric Oncology Group 9351, regimen A protocol. Twenty-one patients met all eligibility requirements; 52% of patients had more than 90% necrosis. No correlation existed between degree of necrosis and year of treatment (r = 0.06; P =.8). Patients with osteosarcoma treated at the authors institution have comparable tumor necrosis responses to published outcomes, and no change occurred over time. This study stresses the importance of rigorous retrospective reviews before implementing treatment changes. Key words: osteosarcoma, tumor necrosis, prognostic factors, chemotherapy, survival 2006 by Association of Pediatric Oncology Nurses DOI: / Osteosarcoma is the most common primary malignant bone tumor in children and adolescents. It arises from mesenchymal bone-forming cells and most commonly affects the metaphyseal growth plate of long bones. It affects 5.6 per million children younger than 15 years annually, with a peak incidence occurring in the second decade of life (Hartford et al., 2006). Osteosarcoma occurs more often in African Americans compared with whites and in males compared with females (Link, Gebhardt, & Meyers, 2002). The cause of osteosarcoma is unknown; however, several risk factors have been identified including ionizing radiation and periods of rapid bone growth. Prior diagnosis of retinoblastoma, bone dysplasias, Li-Fraumeni syndrome, Paget s disease, Eleanor Hendershot, MN, RN, ACNP, works in the outpatient hematology/ oncology clinic at the Hospital for Sick Children in Toronto, Ontario, Canada, as the nurse practitioner in the Solid Tumor Program. She is a lecturer in the Faculty of Nursing at the University of Toronto. Alberto Pappo, MD, is a staff oncologist in the Division of Hematology/Oncology at the Hospital for Sick Children. He is the head of the Solid Tumor Section and a professor of pediatrics at the University of Toronto. David Malkin, MD, is a staff oncologist and clinician-scientist in the Division of Hematology/ Oncology at the Hospital for Sick Children. He is a professor of pediatrics and medical biophysics, University of Toronto. Lillian Sung, MD, PhD, is a clinician-scientist in the Division of Hematology/Oncology at the Hospital for Sick Children in Toronto, Ontario. She is an assistant professor in the Department of Pediatrics and the Department of Health Policy Management and Evaluation at the University of Toronto. Address for correspondence: Eleanor Hendershot, MN, RN, ACNP, Division of Hematology/Oncology, Hospital for Sick Children, 555 University Avenue, Toronto, Ontario, Canada M5G 1X8; eleanor.hendershot@ sickkids.ca. 176 Journal of Pediatric Oncology Nursing, Vol 23, No 4 (July-August), 2006: pp

2 Tumor Necrosis in Pediatric Osteosarcoma and Rothmund-Thompson syndrome have also been associated with an increased risk for developing osteosarcoma (Link et al., 2002). Osteosarcoma most commonly occurs in the distal femur, proximal tibia, and proximal humerus and most often metastasizes to lung and bone. Gross metastatic disease is evident at diagnosis in less than 20% of patients (Kager et al., 2003). However, micrometastatic disease is likely almost always present at the time of diagnosis. Patients with osteosarcoma often present with signs and symptoms that may have been present for weeks to months. The most common presenting symptom is a visible or palpable mass in the affected area. Pain is usually a presenting complaint that is often aggravated by physical activity. A history of trauma is not uncommon, although its clinical relevance is unclear. Constitutional symptoms such as fever, weight loss, or night sweats are rare. Radiographs of the affected area will confirm the presence of a destructive bony lesion that can be lytic, sclerotic, or mixed. The presence of a Codman s triangle is characteristic on plain films and represents a periosteal reaction (Ragland, Bell, Lopez, & Siegal, 2002). A sunburst pattern is also occasionally seen on plain radiographs and represents ossification in the soft tissues (Marina, Gebhardt, Teot, & Gorlick, 2004) (Figure 1). Once a tumor is identified, magnetic resonance imaging of the entire affected bone and adjacent soft tissues area should be performed to evaluate the extent of tumor, vascular supply, its proximity to joints and the neurovascular bundle, and skip lesions representing proximal or distal regional metastatic bony disease (Figure 2). The metastatic workup involves imaging of the chest with computed tomography scan to identify any pulmonary nodules. A whole-body bone scan is performed to determine if there are bone metastases. There are no specific blood tests diagnostic of osteosarcoma; however, lactic acid dehydrogenase and alkaline phosphatase levels are elevated in 30% and 50% of patients, respectively (Link et al., 2002). These enzymes reflect osteoclast and osteoblast activity within the bone and may suggest a high tumor burden. A biopsy is performed to confirm the diagnosis of osteosarcoma. Osteosarcoma cells are spindle shaped and are characterized by the production of malignant osteoid (Jurgens, Winkler, & Gobel, 1997). There are various histological subtypes of osteosarcoma, the most common of which is osteoblastic, which is seen in 78% of patients (Pinkerton, 1999). Other histologies Figure 1. Figure 2. Plain Radiograph: Osteosarcoma of Tibia With Visible Sunburst Periosteal Reaction Magnetic Resonance Imaging Showing Osteosarcoma of the Proximal Tibia include chondroblastic and fibroblastic and then, with decreasing frequency, malignant fibrous histiocytomalike, giant cell-rich, telangiectatic, low-grade intraosseous, small cell, and juxtacortical. Tumor staging evaluated using the Enneking staging system is based on the presence of intracompartmental and extracompartmental extension of the tumor as well as tumor grade and the presence of metastases. Journal of Pediatric Oncology Nursing 23(4);

3 Hendershot et al. Tumors are divided into low and high grade depending on the aggressive nature of the tumor and its potential to metastasize (Davis, Bell, & Goodwin, 1994). Osteosarcoma is treated with combined modality therapy that includes surgery and chemotherapy. Both are vital for long-term survival. Osteosarcoma originally treated with surgery alone yielded survival rates of only 15% to 20%, providing compelling evidence that even in the absence of overt metastases at diagnosis, micrometastases are likely present and cause disease recurrence (Marina et al., 2004). Local control must always be in the form of surgical resection because osteosarcoma is not generally a radiosensitive tumor. The use of adjuvant chemotherapy over the past 20 years has dramatically improved the outcome of these patients. The concept of preoperative chemotherapy was pioneered at Memorial-Sloan Kettering Cancer Center (Rosen et al., 1979). The goals of preoperative chemotherapy are 3-fold: the immediate treatment of micrometastatic disease, limb preservation, and assessment of response to chemotherapy. The most commonly used chemotherapeutic agents include doxorubicin, cisplatin, and high-dose methotrexate (Zalupski et al., 2004). Some investigators have also advocated the use of etoposide and ifosfamide, especially in the presence of metastatic disease. Several cycles of chemotherapy are given, followed by surgical resection of the tumor. This is then followed by maintenance chemotherapy using the same agents. The 3-year disease-free survival in localized osteosarcoma is in the range of 60% to 70% (Bacci et al., 2002). Those who respond well to preoperative chemotherapy, as evidenced by a high degree of tumor necrosis, have 5-year overall survival (OS) rates of 75% to 80%; those who respond poorly to preoperative chemotherapy have 5-year OS rates of 45% to 55% (Bielack et al., 2002). Those who present with metastatic disease have long-term OS rates in the range of 10% to 40% (Goorin et al., 2002). Background Histological response to preoperative chemotherapy is strongly associated with survival in pediatric osteosarcoma. At the time of local control, this response is estimated by measuring the percentage of tumor necrosis in the resected specimen. The percentage of tumor necrosis correlates with chemosensitivity and clinical outcome (Eilber et al., 2001). The point at which degree of necrosis is determined to be significant has been somewhat controversial. Most groups now define a good histological response as having less than 10% viable tumor at the time of surgery. A poor response is defined as the presence of more than 10% viable tumor cells (Link et al., 2002; Marina et al., 2004). Results of the Pediatric Oncology Group (POG) protocol for localized osteosarcoma, termed POG 9351, or Children s Cancer Group (CCG) 7921, found that 45% of patients had favorable responses (>90% necrosis) following preoperative chemotherapy (Meyers et al., 2005). At our center, however, some clinicians questioned the tumor necrosis results in our patients. The POG 9351/CCG 7921 regimen A protocol is currently the protocol used at our center as the standard of care for patients with localized high-grade osteosarcoma in the absence of an open clinical trial. The primary objective of this study was to determine whether there had been an overall change in tumor necrosis over the past 10 years in patients treated for localized osteosarcoma of the extremity on the POG 9351/CCG 7921 protocol. Secondary objectives were (1) to qualitatively describe the proportion of patients with a good response to preoperative chemotherapy (>90% necrosis) to examine whether our institutional outcomes were similar to those reported in the literature and (2) to evaluate the relationship between tumor necrosis with clinical outcome. Patients and Methods A retrospective chart review was performed, after having obtained institutional research ethics board approval. Patients with localized osteosarcoma of the extremity were identified from 1993, the year in which the POG 9351/CCG 7921 protocol was opened, through 2003, the year this study closed. A list of patients was generated through the hospital s database of oncology diagnoses. All patients with localized, high-grade osteosarcoma of the extremity were identified, and those treated on or as per the POG 9351/CCG 7921 regimen A were included in the study. Preoperative chemotherapy included 2 full cycles of chemotherapy. Each cycle included 1 course of cisplatin and doxorubicin and 2 courses of high-dose methotrexate (Table 1). Patients with secondary osteosarcomas were excluded from the study because of their prior exposure to chemotherapy agents. 178 Journal of Pediatric Oncology Nursing 23(4); 2006

4 Tumor Necrosis in Pediatric Osteosarcoma Table 1. Chemotherapy Agents and Doses Used Before Local Control (2 Cycles) 12 Drug Dose Day Cisplatin 120 mg/m 2 1 Doxorubicin 25 mg/m (72-hour continuous infusion) Methotrexate 12 g/m 2 21 Methotrexate 12 g/m 2 28 Number of Patients Information regarding age, date of diagnosis, date of surgery, tumor location, and type of surgery was collected. Statistical Analysis For the primary objective, we examined whether there was an association between percentage tumor necrosis and year of diagnosis using Spearman s correlation coefficient. To examine whether the percentage of tumor necrosis was associated with patient outcomes including OS, the Cox proportional hazards model was used. 2 0 Figure 3. >90% 70-79% 50-59% 30-39% 10-19% Degree of Tumor Necrosis (%) Patients With Various Degrees of Histological Response Following Preoperative Chemotherapy Results From January 1993 to November 2003, 24 patients were treated according to the POG 9351/CCG/7921 regimen A protocol at our institution. Two had secondary osteosarcomas and 1 had a complete resection before receiving chemotherapy and were excluded, leaving 21 patients who were included in our study. The median age at diagnosis was 13.1 years (range, years). The median degree of tumor necrosis was 90% (range, 10%-99%). The 3-year OS was 71% ± 11%. Fifty-two percent (11) of children showed a good histological response, defined as more than 90% necrosis (Figure 3). There was no relationship between necrosis and year of surgery (r = 0.06, P =.8) (Figure 4). There was no relationship between percentage necrosis and OS (hazard ratio 0.98, P =.2). There was almost no power to look at this though because there were only 5 deaths out of the 21 patients. Discussion We found that despite our clinical suspicion, there was no change in the percentage necrosis over the 10-year Figure 4. No Correlation Between Percentage Necrosis and Year of Treatment period of our study, and the proportion of patients at our institution with a good response to preoperative chemotherapy was similar to that reported in the literature. One limitation of our study is that we only included those patients receiving 1 particular chemotherapy regimen. Nonetheless, because it was patients following this regimen who contributed to the recent observations of inferior necrosis rates who prompted this review, examination of just those patients following the POG 9351/CCG 7921 regimen A protocol was justifiable. Journal of Pediatric Oncology Nursing 23(4);

5 Hendershot et al. The results of this review were reassuring in that they reinforced for us that tumor necrosis responses to preoperative chemotherapy at our institution are similar to rates reported by Meyers and colleagues (2005) for the entire study group. Our initial concern was raised because we had 3 consecutive patients in 8 months who experienced inferior necrosis rates in 2003, prompting this review (Figure 4). The phenomenon of regression to the mean is a possible explanation for our recent results with poor tumor necrosis at our institution. This statistical phenomenon can make normal variations in repetitive data look like an actual change or trend (Barnett, van der Pols, & Dobson, 2005). When extreme observations are observed, on average, the next observation will be closer to the mean value. Regression to the mean can make effects attributable to chance look like real change (Morton & Torgerson, 2003). This type of situation can have serious implications in health care. If action is taken based on 1 abnormal result and a treatment is prescribed, then the intervention may look as though it was successful because the successive measurement is closer to the mean. Regression to the mean, however, would predict that the repeated measurements without the intervention would likely have been closer to the mean regardless. We had hypothesized that delays in chemotherapy administration, medication administration methods, medication timing, and drug resistance as well as changing tumor biology could potentially account for changes in response to preoperative chemotherapy in patients with osteosarcoma at our institution. However, the results that we obtained were important to alleviate concerns that institutional practices were contributing to our patients having perceived worse outcomes than those reported in the literature. Conclusions There was no change in histological response to preoperative chemotherapy in patients with highgrade osteosarcoma of the extremity over the past 10 years treated at our institution on the POG 9351/CCG 7921 regimen A protocol. Our results were congruent with those reported in the literature. These results and this study do, however, highlight 2 very important points. The first is the importance of recognizing limitations and dangers of basing medical decisions and practice on anecdotal evidence and case reports. The second point stresses the value of rigorous analyses using retrospective reviews. Natural variation in data may appear significant when in fact successive measurements will likely show that they are closer to the mean. These findings highlight the importance of performing rigorous data analyses using retrospective reviews before implementing treatment changes. Acknowledgments We thank Carol Winter, RN, data manager at the Hospital for Sick Children, for her assistance in obtaining a list of patients from the hematology/oncology database. References Bacci, G., Ferrari, S., Longhi, A., Forni, C., Zavatta, M., Versare, M., et al. (2002). High-grade osteosarcoma of the extremity: Differences between localized and metastatic tumors at presentation. Journal of Pediatric Hematology Oncology, 24, Barnett, A. G., van der Pols, J., & Dobson, A. J. (2005). Regression to the mean: What it is and how to deal with it. International Journal of Epidemiology, 34, Bielack, S. S., Kempf-Bielack, B., Delling, G., Exner, G. U., Fledge, S., Helmke, K., et al. (2002). Prognostic factors in high-grade osteosarcoma of the extremities or trunk: An analysis of 1,702 patients treated on neoadjuvant cooperative osteosarcoma study group protocols. Journal of Clinical Oncology, 20, Davis, A. M., Bell, R. S., & Goodwin, P. J. (1994). Prognostic factors in osteosarcoma: A critical review. Journal of Clinical Oncology, 12, Eilber, F. C., Rosen, G., Eckardt, J., Forscher, C., Nelson, S. D., Selch, M., et al. (2001). Treatment-induced pathologic necrosis: A predictor of local recurrence and survival in patients receiving neoadjuvant therapy for high-grade extremity soft tissue sarcomas. Journal of Clinical Oncology, 19, Goorin, A. M., Harris, M. B., Bernstein, M., Ferguson, W., Devidas, M., Siegal, G. P., et al. (2002). Phase II/III trial of etoposide and high-dose ifosfamide in newly diagnosed metastatic osteosarcoma: A pediatric oncology group trial. Journal of Clinical Oncology, 20(2) Hartford, C. M., Wodowski, K. S., Rao, B. N., Khoury, J. D., Neel, M. D., & Daw, N. C. (2006). Osteosarcoma among children aged 5 years or younger: The St. Jude children s research hospital experience. Journal of Pediatric Hematology Oncology, 28, Jurgens, H., Winkler, K., & Gobel, U. (1997). Bone tumours. In C. R. Pinkerton & P. N. Plowman (Eds.), Paediatric oncology (2nd ed., pp ). London: Chapman & Hall. Kager, L., Zoubek, A., Potschger, U., Kastner, U., Flege, S., Kempf- Bielack, B., et al. (2003). Primary metastatic osteosarcoma: 180 Journal of Pediatric Oncology Nursing 23(4); 2006

6 Tumor Necrosis in Pediatric Osteosarcoma Presentation and outcome of patients treated on neoadjuvant cooperative osteosarcoma study group protocols. Journal of Clinical Oncology, 21, Link, M. P., Gebhardt, M. C., & Meyers, P. A. (2002). Osteosarcoma. In P. A. Pizzo & D. G. Poplack (Eds.), Principles and practice of pediatric oncology (4th ed., pp ). Philadelphia: Lippincott Williams & Wilkins. Marina, N., Gebhardt, M., Teot, L., & Gorlick, R. (2004). Biology and therapeutic advances for pediatric osteosarcoma. Oncologist, 9, Meyers, P. A., Schwartz, C. L., Krailo, M., Kleinerman, E., Betcher, D., Bernstein, M. L., et al. (2005). Osteosarcoma: A randomized, prospective trial of the addition of the ifosfamide and/or muramyl tripeptide to cisplatin, doxorubicin, and high-dose methotrexate. Journal of Clinical Oncology, 23, Morton, V., & Torgerson, D. J. (2003). Effect of regression to the mean on decision making in health care. British Medical Journal, 326, Pinkerton, C. R. (1999). Osteogenic sarcoma. In C. R. Pinkerton, A. J. Michalski, & P. A. Veys (Eds.), Clinical challenges in paediatric oncology (pp ). Oxford, UK: ISIS Medical Medial. Ragland, B. D., Bell, W. C., Lopez, R. R., & Siegal, G. P. (2002). Cytogenetic and molecular biology of osteosarcoma. Laboratory Investigation, 82, Rosen, G., Marcove, R. C., Caparros, B., Nirenberg, A., Kosloff, C., & Huvos, A. G. (1979). Primary osteogenic sarcoma. The rational for pre-operative chemotherapy and delayed surgery. Cancer, 43, Zalupski, M. M., Rankin, C., Ryan, J. R., Lucas, D. R., Muler, J., Lanier, K. S., et al. (2004). Adjuvant therapy of osteosarcoma A phase II trial. Cancer, 100, Continuing Education Credit The Journal of Pediatric Oncology Nursing is pleased to offer the opportunity to earn pediatric hematology/oncology nursing continuing education credit for this article online. Go to and select Continuing Education. There you can read the article again or go directly to the posttest assessment. The cost is $15 for each article. You will be asked for a credit card or online payment service number. The posttest consists of 10 questions based on the article, plus several assessment questions (e.g., how long did it take you to read the article and complete the posttest?). A passing score of 80% (8 of 10 questions correct) on the posttest and completion of the assessment questions yields one hour of continuing education in pediatric hematology/oncology nursing for each article. Journal of Pediatric Oncology Nursing 23(4);