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Originally published as JCO Early Release 10.1200/JCO.2007.14.9104 on September 22 2008 © 2008 American Society of Clinical Oncology. Osteosarcoma in Patients Older Than 65 Years
From the Department of Musculoskeletal Oncology, Istituto Ortopedico Rizzoli, Bologna, Italy Corresponding author: Alessandra Longhi, MD, Sezione Chemioterapia, Istituto Ortopedico Rizzoli, Via Pupilli 1, 40136 Bologna, Italy; e-mail: alessandra.longhi{at}ior.it
Purpose We reviewed the outcome of osteosarcoma patients older than 65 years, an age group usually excluded from protocols, to determine the different clinical features and prognostic factors in this age group compared with younger patients. Patients and Methods Patients treated at our institute who had high-grade osteosarcoma and were older than 65 years were observed. Results Forty-three patients were eligible to be enrolled onto this study; of these, 22 were male and 21 were female. The median age of this group was 69 years (range, 65 to 80 years). Of the 43 patients, 29 patients had localized disease, and 14 patients had metastatic disease. Localizations were appendicular in 33 patients, and axial in 10 patients. Twenty-nine patients had a primary osteosarcoma, 13 patients (30%) had a sarcoma in Paget's disease, and one patient had postradiotherapy (RT) osteosarcoma. The median interval from onset of symptoms to diagnosis was 4 months (range, 0 to 73 months).Thirty-two of 43 patients received surgery for a primary tumor. Of these, 18 patients had limb salvage, 13 patients had an amputation, and one patient had palliative surgery; the remaining 11 patients received palliative RT. Fourteen patients received chemotherapy; two deaths related to chemotherapy were observed. Median overall survival (OS) for all 43 patients was 19 months (range, 3 to 229 months); 5-year OS was 22% (SE = 3%) for the whole group, and 45% OS for those patients with localized primary osteosarcoma. Multivariate analysis demonstrated that stage, volume, and surgery were significant prognostic factors. Insignificant prognostic factors were sex, type of surgery, chemotherapy, and Paget's disease. Conclusion Patients older than 65 years with osteosarcoma have a worse prognosis compared with younger patients. This older age group is characterized by a longer time lapse from the onset of symptoms to diagnosis, more metastatic cases at diagnosis, less use of limb salvage, fewer patients receiving chemotherapy, and more patients excluded from clinical trials than a younger age group.
Due to prolonged life expectancy, interest is growing in geriatric oncology. It has been estimated that by 2050, 80% of cancers will occur in patients older than age 60 years.1 In Italy, 20% of the population is currently older than age 60 years.2 In the last decade, few studies have been published about breast, lung, colon, and ovary cancer in the elderly population. A need for an alternative evaluation system of an older individual's functional status, together with the need to identify markers of frailty, has emerged to identify the elderly who can benefit from aggressive cancer treatment.3 Osteosarcoma is a malignant bone tumor. Most cases occur between 10 and 20 years of age, peaking during the adolescent growth spurt and in the seventh and eighth decades of life. Before the 1970s, the prognosis for patients with high-grade osteosarcoma was poor, with long-term survival rates of less than 20%.4 Advances in adjuvant and neoadjuvant chemotherapy have improved the 5-year disease-free survival to more than 60%,4 and improved surgical techniques have changed the proportion of amputation versus limb salvage; the current rate of limb salvage is 71% to 90%.5,6 However,these data are not applicable to adult patients older than age 40 years because all trials are tailored for a younger population. Few studies have evaluated the treatment and outcome of patients older than age 40 years. In a previous study, we compared the survival of 29 patients, age 40 to 60 years, with localized osteosarcoma of the extremities who were treated with neoadjuvant chemotherapy and surgery. At 8 years, overall survival (OS) was 62%, which was similar to that of younger patients (age < 40 years) treated at our institute.7 In a European Musculo-Skeletal Oncology Society retrospective review, the outcome of 481 patients older than age 40 years from 12 centers was reported by Griemer.8 The 5-year OS was 46% for the entire group, but was only 30% for patients older than age 60 years. This subgroup of patients showed some peculiarities, such as less limb salvage (only 49% in patients > 60 years compared with 64% in patients age 40 to 60 years). In general, the prognosis in the older population is poorer compared with children and adolescents.9,10 Conventionally, the poor prognosis is attributable to the fact that the tumor is usually a secondary lesion and more axial in localization, and the elderly patient's tolerance to high-dose chemotherapy is reduced.10,11 When osteosarcoma occurs in patients older than 65 years, it is sometimes in the setting of a pre-existing condition, such as Paget's disease, irradiated bone, chondrosarcoma, bone infarct, and occasionally osteogenesis imperfecta.10 The clinical features and prognostic indicators are well known for young patients but not for older patients. The aim of this retrospective study was to determine whether osteosarcoma in patients older than 65 years had different clinical features and a different prognosis compared with younger patients.
We reviewed our database retrospectively; 2,806 patients with high-grade osteosarcoma were admitted to our institute between 1961 and 2006. Of these, 64 patients were age 65 years or older (2.1%). We included in our study only 43 of 64 patients who had complete clinical, radiologic, and pathologic records, and appropriate follow-up.
The inclusion criteria for enrollment onto the study were high-grade osteosarcoma of the bone, age An osteosarcoma diagnosis was always confirmed on histology slides of tumor tissue obtained from a biopsy as well as resected specimens. Osteosarcoma was classified as classic, telangiectatic, and small cell. On the basis of predominant intercellular material, classic osteosarcoma was subclassified as osteoblastic, fibroblastic, and chondroblastic. The choice of cutoff at age 65 years was because our protocols enroll only patients younger than age 65 years. More recently, we have established a new protocol (European Bone Over 40 Sarcoma Study), which was conceived for patients older than age 40 years but younger than age 65 years. This protocol is aimed at patients who cannot be included in other conventional protocols that include patients from age 0 to 40 years. We obtained information from the patients’ medical charts about tumor stage, site, comorbidity, type of surgery, chemotherapy assigned, cardiac and renal function (ECG, blood urea nitrogen, and creatinine in all patients), and creatinine clearance (urine creatinine x minute corrected volume/serum creatinine/) in those who received chemotherapy. All patients had an adequate follow-up. The end point of the study was a 5-year OS, which was estimated from the day of diagnosis until death or last follow-up. We evaluated age, sex, location, stage, time interval from onset of symptoms to diagnosis, tumor volume, treatment, and complications as prognostic factors. Demographic details and treatment variables are reported by descriptive statistics. OS was calculated using the Kaplan-Meier survival test. Survival times were calculated from the time of diagnosis to death or last follow-up. Multivariate analysis was performed using the Cox proportional hazard regression method. Statistical analysis was performed using SSPS software (SSPS Inc, Chicago, IL; Tables 1 and 2).
Clinical Features Forty-three patients with high-grade bone osteosarcoma fulfilled the inclusion criteria for enrollment onto the study; of these, 22 were male, and 21 were female. The age of the patients at the time of diagnosis ranged from age 65 to 80 years (median, 69 years). The median time interval from the onset of symptoms to diagnosis (biopsy) was 4 months (range, 0 to 73 months). The lesion was located in a limb in 33 patients, and in the axial skeleton in 10 patients. There was a predominance of osteolytic lesions and a frequent absence of a periosteal reaction. Median Eastern Cooperative Oncology Group performance status was grade 1 to grade 2. At diagnosis, the disease was localized in 29 patients (67.4%), and metastatic in 14 patients (32.5%); metastases involved only the lungs in 12 patients, only the bones in one patient, and the bones and lungs in one patient. Twenty-nine patients had a primary osteosarcoma (67.4%), and 13 patients (30.2%) had an osteosarcoma in Paget's disease; one patient had post-radiation therapy (RT) osteosarcoma of the left scapula that occurred 5 years after RT for a soft tissue sarcoma of the shoulder area.
Site
Histologic Features
Sex
Paget's Disease Thirteen patients had Paget's disease. Four patients were metastatic at diagnosis. The median age, median tumor volume, and OS of the patients was not statistically different from that of the other patients without Paget's disease (Fig 2).
Tumor Volume In 40 patients, it was possible to calculate tumor volume on the pathologic specimen or, for those who did not receive surgery, on computed tomography and magnetic resonance or x-ray imaging. The median volume was 272 cm3 (range, 5 to 4,212 cm3), calculated using the ellipsoid formula.13 In three patients, we could not calculate the volume because radiologic imaging was not available (withdrawn by the patients). Fifteen patients had a volume of less than 150 cm3, while 25 patients had a volume of more than 150 cm3. Median and mean tumor volume in patients who had limb salvage was 145 and 275 cm3, respectively (range, 5 to 1,750 cm3), while the median and mean tumor volume in patients who underwent amputation was almost double (304 and 753 cm3, respectively; range, 78 to 4,212 cm3). Median tumor volume in patients who did not undergo surgery but only received palliative RT was even greater (467 cm3; range, 64 to 3,005 cm3; Fig 3).
Large volume tumors more than 150 cm3 were present in 70% of males, but were present in only 30% of females. OS was related to tumor volume, with an OS of 40 months (95% CI, 9.4 to 70.6 months) in patients with tumor volume less than 150 cm3, versus an OS of 15 months (95% CI, 7.2 to 22.8 months) for a tumor volume more than 150 cm3. None of the patients with a tumor volume more than 300 cm3 survived. Patients with Paget's disease had a nonstatistical difference in tumor volume (P = .43).
Surgery
Furthermore, median tumor volume was smaller in patients who underwent resection compared with patients who underwent amputation. Nine patients underwent surgery for the primary tumor despite having metastases at diagnosis (eight patients had only lung metastases, and one patient had lung and bone metastases); two of the surgeries were for amputations and seven operations were for limb salvages. The OS of this group was 15 months, twice that of metastatic patients who did not receive surgery for the primary tumor (Fig 5).
Chemotherapy Fourteen patients (32.5%) received chemotherapy; six of these patients had localized disease and eight patients had metastatic disease. Ten of these patients received surgery and chemotherapy (four patients with amputations, and six patients with resections), whereas four patients received only chemotherapy without surgery as palliative treatment. Chemotherapy was administered preoperatively as neoadjuvant only in two patients. Of 14 patients, two deaths related to toxicity of chemotherapy—one death due to septic shock and another death after a febrile neutropenia—were observed. Chemotherapy was administered at our institute in three patients, and in other hospitals in 11 patients. The drugs administered were doxurubicin, epirubicin, cisplatin, ifosfamide, and dacarbazine for a median of six cycles.2-9 No patient received methotrexate due to its high nephrotoxicity. All patients received ifosfamide and an anthracycline; eight patients also received cisplatin in a continuous intravenous infusion. All drugs were delivered at doses reduced by 20% compared with standard protocols, and for a reduced number of cycles (six to seven cycles compared with nine to 14 cycles in European Bone Over 40 Sarcoma Study protocols for patients age 40 to 60 years). Twenty-nine patients did not receive chemotherapy. Ten patients were excluded because of impaired cardiac function (eight patients) or renal function (two patients). Of the eight patients with abnormal cardiac function, one patient had a myocardial infarct but was asymptomatic, and seven patients had asymptomatic ischemic cardiomyopathy on medical treatment. Of the two patients with abnormal renal function, one patient had a previous nephrectomy (renal tuberculosis at an early age) and another patient had mild creatinine elevation (probably because of nephroangiosclerosis).Four patients refused treatment; for the remaining 15 patients, the physician decided not to prescribe chemotherapy due the patients’ age, which was outside the protocols limits, even if performance status and general medical conditions were similar to the conditions of patients accrued at a later time. All patients who received chemotherapy had their renal function measured by creatinine clearance (UCr x VBM/SCr) before therapy; the creatinine clearance was in the normal range.Median survival for those who received chemotherapy was 15 months (range, 3 to 203 months) v 19 months (range, 0 to 229 months) for those who did not receive chemotherapy. Only three of 14 patients are alive and disease free. None of the patients who experienced relapse received a second-line therapy.
Outcome Median OS for all 43 patients was 19 months, with a mean of 35 months (range, 3 to 229 months). Five-year OS (using the Kaplan-Meier method) for the whole group was 22% (SE = 3%), but OS was 33% for patients with localized disease, and 0% for those with metastatic disease. Five-year OS for those patients who received surgery was 30% v 0% for those patients who had no surgery. Only 21 patients reached a disease-free status after surgery, and their median disease-free survival was 14 months (range, 5 to 229 months). Multivariate analysis (Cox proportional hazards regression with Wald's method) demonstrated that volume (P = .05), stage (local v metastatic; P = .005), and surgery (yes or no; P < .00005) were significant prognostic factors. Other variables, such as site, sex, Paget's disease, and type of treatment (chemotherapy, type of surgery) were not statistically significant. Five-year OS in the subgroup of patients with primary, localized osteosarcoma who received surgery (16 patients overall) was 45% (SE = 13.2%) as opposed to 60% to 65% in younger patients (in our previous study with patients age 40 to 60 years, 5-year OS was 62%).5 If we exclude the three patients with axial localization, the 5-year OS of the remaining 13 patients who had localized primary osteosarcoma of the extremity was 47.6% (SE = 15%). Due to the small number of patients in this subgroup, these data should be used cautiously and be confirmed by larger studies. However, the OS trend seems to be worse in the elderly population.
Most patients with osteosarcoma are adolescents between age 10 and 20 years, but the rate of osteosarcoma in older patients is increasing14 due to longer life expectancy.There is little in the literature concerning osteosarcoma in patients older than 65 years; information related to the clinical outcome of older patients with osteosarcoma reveals a dismal prognosis because osteosarcoma in older patients is often a secondary lesion from a sarcomatous transformation of Paget's disease,15 and metastatic at diagnosis.16 In this retrospective analysis of osteosarcoma in elderly patients older than 65 years seen at a single institution during a 45-year period, we provide some clinically relevant findings despite the small number of patients. We observed in this study, as in other series,7,8,12 a predilection for axial localization in elderly as opposed to osteosarcoma in adolescents, where the limbs are mainly involved. In our study, only four patients (9.3%) of 43 had a primary tumor in the knee area, while the knee is affected in approximately 62% of adolescents.17 Many studies have revealed that patients with axial lesions have a poorer prognosis. Due to this characteristic site distribution, surgical treatment in the elderly population is technically more difficult, and incomplete surgical resection is more common.18-20 The median time lapse from onset of symptoms to diagnosis was 4 months, while in one of our studies in the younger population, the median time lapse was 10 weeks.21 The delayed diagnosis in older patients may be because of the coexistence of other benign bone pathologies that confound or probably reflect a different attitude of patients and their physicians to underestimate the first symptoms. Stage at diagnosis also was worse in our group; 13 patients had metastatic disease (30.2%) and 30 patients (69.8%) had localized disease with a statistically significant difference in OS (P < .005). The conventional treatment for osteosarcoma is surgery and chemotherapy. In our study, only 32 patients received surgery for a primary tumor (74.4%). Surgery consisted of limb salvage only in 18 patients (56%), while the incidence of limb salvage in the younger population is approximately 90%.6 We found a significantly longer OS (P < .00005) in patients who received surgery. Only 14 patients in our study received chemotherapy, which was adjuvant in all except two patients. Despite dose reduction, hematologic toxicity was more severe in older patients compared with younger patients. In our series, chemotherapy was administrated in patients older than 65 years only after the year 2000. Before that time, none of the elderly patients received chemotherapy. Treating elderly patients with chemotherapy probably reflects a change in the physicians’ attitude. After 2000, we began to treat patients older than 65 years with a good performance status outside the protocol, and now we have a protocol tailored for patients older than 65 years. To date, we have no results to report. The effectiveness of chemotherapy in the elderly population is difficult to determine from previously published series.7,8,12 Grimer et al,8 in a review of 481 patients older than age 40 years found that chemotherapy significantly improved survival. Patients treated with chemotherapy had a 5-year OS of 51% compared with 39% in those patients who underwent surgery alone, but this series was composed of a more heterogeneous population (age 40 to 90 years). In another one of our studies on 29 patients, age 40 to 60 years with localized high-grade osteosarcoma of the extremity and treated from 1986 to 1993 with neoadjuvant chemotherapy, the overall 8-year survival rate was 62%.7Comparative studies show that hematologic toxicity and cardiotoxicity may be more severe in older patients.22 We conclude that osteosarcoma in this subgroup of elderly patients older than 65 years has a worse prognosis compared with that of the younger population (for localized disease, 33% v 62%). In older patients, there is a slight delay in diagnosis, more metastatic cases (30%), more axial locations, and much less limb salvage. Osteosarcoma is frequently associated with Paget's disease, but Paget's disease did not worsen the prognosis in our series. We need to improve our multidisciplinary treatment strategy to increase the survival rate of elderly patients. It is not the calendar age but the biologic age that makes the difference in tolerance to aggressive treatment. Surgery is still a mainstay of treatment, and an effort should be made whenever possible to try and preserve function in patients who can have other disabilities related to age. It is also important to tailor chemotherapy protocols for the patients with decreased bone marrow tolerance, and decreased renal and cardiac function. Protocols of chemotherapy for the elderly with osteosarcoma might enhance the relative effectiveness of multimodality treatment in this group of patients.
The author(s) indicated no potential conflicts of interest.
Conception and design: Alessandra Longhi, Costantino Errani Administrative support: Costantino Errani, Cristina Ferrari Provision of study materials or patients: Alessandra Longhi, Costantino Errani, Daniel Gonzales-Arabio, Cristina Ferrari Collection and assembly of data: Alessandra Longhi, Costantino Errani, Daniel Gonzales-Arabio, Cristina Ferrari Data analysis and interpretation: Alessandra Longhi, Costantino Errani, Daniel Gonzales-Arabio Manuscript writing: Alessandra Longhi, Costantino Errani, Daniel Gonzales-Arabio Final approval of manuscript: Alessandra Longhi, Costantino Errani, Daniel Gonzales-Arabio, Mario Mercuri
published online ahead of print at www.jco.org on September 22, 2008 Authors’ disclosures of potential conflicts of interest and author contributions are found at the end of this article.
1. Balducci L: Epidemiology of cancer and aging. J Oncol Manage 14:47-50, 2005[Medline] 2. Italian Statistic (ISTAT) report from 1 January 2006. www.istat.it 3. Lichtman SM, Balducci L, Aapro M: Geriatric oncology a field coming of age. J Clin Oncol 25:1821-1823, 2007 4. Bacci G, Picci P, Ferrari S, et al: Primary chemotherapy and delayed surgery for nonmetastatic osteosarcoma of the extremities: Results in 164 patients preoperatively treated with high doses of methotrexate followed by cisplatin and doxorubicin. Cancer 72:3227-3230, 1993[CrossRef][Medline] 5. Bacci G, Longhi A, Fagioli F, et al: Adjuvant and neoadjuvant chemotherapy for osteosarcoma of the extremities: 27-year experience at Rizzoli Institute, Italy. Eur J Cancer 41:2836-2845, 2005[CrossRef][Medline] 6. Ferrari S, Smeland S, Mercuri M, et al: Italian and Scandinavian Sarcoma Groups neoadjuvant chemotherapy with high-dose ifosfamide, high-dose methotrexate, cisplatin, and doxorubicin for patients with localized osteosarcoma of the extremity: A joint study by the Italian and Scandinavian Sarcoma Groups. J Clin Oncol 23:8845-8852, 2005 7. Bacci G, Ferrari S, Donati D, et al: Neoadjuvant chemotherapy for osteosarcoma of the extremity in patients in the fourth and fifth decade of life. Oncol Rep 5:1259-1263, 1998[Medline] 8. Grimer RJ, Cannon SR, Taminiau AM, et al: Osteosarcoma over the age of forty. Eur J Cancer 39:157-163, 2003[CrossRef][Medline] 9. Jeon DG, Lee SY, Cho WH, et al: Primary osteosarcoma in patients older than 40 years of age. J Korean Med Sci 21:715-718, 2006[Medline] 10. Huvos AG: Osteogenic sarcoma of bones and soft tissues in older persons: A clinicopathologic analysis of 117 patients older than 60 years. Cancer 57:1442-1449, 1986[CrossRef][Medline] 11. Carsi B, Rock MG: Primary osteosarcoma in adults older than 40 years. Clin Orthop Relat Res 397:53-61, 2002 12. Ek ET, Ojaimi J, Kitagawa Y, et al: Outcome of patients with osteosarcoma over 40 years of age: Is angiogenesis a marker of survival? Int Semin Surg Oncol 21:3-7, 2006 13. Bieling P, Rehan N, Winkler P, et al: Tumor size and prognosis in aggressively treated osteosarcoma. J Clin Oncol 14:848-858, 1996 14. Stark A, Kreicbergs A, Nilsonne U, et al: The age of osteosarcoma patients is increasing: An epidemiological study of osteosarcoma in Sweden 1971 to 1984. J Bone Joint Surg Br 72:89-93, 1990[Medline] 15. Siegel RD, Ryan LM, Antman KH: Osteosarcoma in adults: One institution's experience. Clin Orthop Relat Res 240:261-269, 1989 16. Mankin HJ, Hornicek FJ: Paget's sarcoma: A historical and outcome review. Clin Orthop Relat Res 438:97-102, 2005[Medline] 17. Campanacci M: Bone Tumors (ed 2). Lippincott-Verlag, 1999, pp 1418-1468 18. Glasser D, Lane J, Huvos A, et al: Survival, prognosis, and therapeutic response in osteogenic sarcoma. Cancer 69:698-708, 1992[CrossRef][Medline] 19. Okada K, Hasegava T, Nishida J, et al: osteosarcoma after the age of 50: clinicopathologic study of 64 cases, an experience in northern Japan. New York, NY, Springer-Verlag Wien, 1999, pp 1618-1658 20. Brooks S, Starkie CM, Clarke NM: Osteosarcoma after the fourth decade: A clinical-pathological review. Arch Orthop Trauma Surg 104:100-105, 1985[Medline] 21. Bacci GS, Ferrari A, Longhi D, et al: Delay in diagnosis of high-grade osteosarcoma of the extremities: Has it any effect on the stage of disease? Tumori 86:204-206, 2000[Medline] 22. Kimmick GG, Fleming R, Muss HB, et al: Cancer chemotherapy in older adults: A tolerability perspective. Drugs Aging 10:34-49, 1997[Medline] Submitted October 19, 2007; accepted April 8, 2008.
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Copyright © 2008 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
65 years, and metastatic or localized, primitive, or secondary osteosarcoma. We excluded patients with other types of bone sarcoma, such as malignant fibrous histiocytoma, fibrosarcoma, spindle cell sarcoma, and dedifferentiated chondrosarcoma. 
