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© 2003 American Society for Clinical Oncology Metachronous Skeletal Osteosarcoma in Patients Treated with Adjuvant and Neoadjuvant Chemotherapy for Nonmetastatic OsteosarcomaFrom the Department of Pediatrics, Department of Surgery, Department of Biostatistics, and Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, NY. Address reprint requests to Paul A. Meyers, MD, Memorial Sloan-Kettering Cancer Center, Department of Pediatrics, PO Box 139, 1275 York Avenue, New York, NY 10021; email: meyersp{at}mskcc.org.
Purpose: The prognosis for patients who develop metachronous skeletal osteosarcoma (OS) has been considered grave compared with that for patients with relapse limited to the lungs. We investigated the incidence and outcome of metachronous skeletal OS after initial treatment of the primary tumor. Patients and Methods: Twenty-three (median age 18.7 years) of 426 patients with nonmetastatic, high-grade primary OS treated at Memorial Sloan-Kettering Cancer Center (New York, NY) between February 1973 and May 2000 developed metachronous skeletal OS. Initial therapy included combination chemotherapy and surgery. Treatment of subsequent relapses consisted of chemotherapy or radiation alone or surgery with or without additional individualized chemotherapy. Results: The median time from the diagnosis of primary OS to the development of metachronous OS was 1.4 years (range, 0.2 to 11.3 years). Median survival was 1.5 years (95% confidence interval [CI], 0.8 to 6.9 years). Two- and 5-year postmetachronous overall survival was 43.5% (95% CI, 23.2% to 63.7%) and 33% (95% CI, 13% to 53%), respectively. At last follow-up (range, 0.1 to 12.8 years), five (30.4%) patients were alive with no evidence of disease (range, 1.7 to 12.8 years; median, 4.4 years). For 11 patients who developed metachronous OS 24 months or more from initial diagnosis, 5-year postmetachronous survival rate for patients receiving combined modality versus monotherapy was 83% (95% CI, 54% to 100%) and 40% (95% CI, 0% to 83%), respectively. Conclusion: In a small subset of patients who developed late metachronous OS, combined-modality therapy with surgery and aggressive chemotherapy may result in long-term postmetachronous survival. This implies that principles used in treatment of primary OS may be applied to patients with late metachronous skeletal OS.
BEFORE TRIALS of adjuvant chemotherapy for osteosarcoma (OS) were conducted in the 1970s and 1980s, more than half of the patients treated primarily by surgery alone developed metastases within 6 months of diagnosis, and more than 80% developed recurrent disease within 2 years of diagnosis.1–9 Most developed multiple bilateral pulmonary metastases, and more than 95% of the patients who died of metastatic disease had lung involvement at the time of death, as indicated by autopsy.1,10 Complete surgical resection of all overt pulmonary metastatic disease in addition to adjuvant chemotherapy is a prerequisite for long-term salvage after relapse.11–13 Metastasis to bones of the skeleton occurs in 15% to 30% of the patients. In extremely rare instances, patients with OS present with synchronous or multifocal tumors in the absence of pulmonary metastasis on roentgenography. Their median survival is poor at 7 months.14–21 Skip metastases (considered to be metastatic lesions), although rare, are an ominous sign, and the use of adjuvant chemotherapy does not markedly improve the prognosis for this group of patients.22 On the basis of several individual descriptive case reports,21,23–29 the prognosis is considered poor for patients who develop metachronous skeletal OS. However, we are not aware of any published reports from a large, single-institution series reporting outcomes for these patients when treated with a combined-modality treatment approach. We report here the clinical features and outcome of patients treated at the Memorial Sloan-Kettering Cancer Center (MSKCC) for nonmetastatic primary OS with adjuvant chemotherapy and surgery who subsequently developed metachronous, metastatic skeletal OS.
A comprehensive list of patients who presented to MSKCC with newly diagnosed, high-grade OS was generated. The medical records and the histopathology of each patient were reviewed. Inclusion was restricted to patients first seen at MSKCC between February 1973 and May 2000. The former date was chosen arbitrarily as a date by which OS treatment strategy was accepted to include aggressive multiagent chemotherapy, preferably before and after definitive surgery with wide en bloc resection of primary disease. The latter date was chosen to allow adequate time for follow-up after completion of adjuvant chemotherapy. We defined metachronous, metastatic skeletal OS as an involvement of a distant bone by an apparent new tumor after the initial diagnosis and initiation of chemotherapy. We divided this cohort into early metachronous OS, which occurred less than 24 months from the diagnosis of the primary, and late metachronous OS, which occurred at least 24 months after the diagnosis of the primary OS.
During the study period, six different chemotherapy protocols were used in the treatment of primary OS: T4, T5, T7, T10, T12, and the CCG-7921/POG-9351 intergroup protocol (Table 1
Among the 512 patients with primary OS seen and treated at MSKCC during the study period, 426 patients (83%) presented with primary OS without any detectable pulmonary metastasis on imaging by chest x-ray or computerized tomography (CT). All patients had a radionuclide bone scan at initial presentation, which excluded bony metastasis. Of these 426 patients with nonmetastatic OS, 23 patients (5.4%) developed metachronous OS of the skeleton. Twelve patients developed early metachronous OS less than 24 months from the diagnosis of the primary (Table 2  ). The patient and tumor characteristics of the remainder of the patients (n = 11) who developed late ( 24 months) metachronous OS are shown in Table 3. Biopsies of the metachronous lesions in 16 of the 23 patients were performed at outside institutions or at MSKCC. All were reviewed and confirmed to be OS at MSKCC. In the seven patients who did not have a biopsy (because of location or hematologic instability), presence of the new tumor was detected by positive radionuclide bone scans. Three of the 23 patients had synchronous pulmonary metastasis at the time they were found to have metachronous OS of the skeleton. These three patients were included in the study to describe their clinical features and prognosis when compared with those with isolated metachronous skeletal OS. Twenty-three patients who developed a local recurrence after the diagnosis of the primary tumor were excluded from this analysis.
Statistical Analysis The time interval for developing metachronous skeletal OS was calculated from the date of diagnosis of primary OS to the date of diagnosis of metachronous OS of the skeleton. Postmetachronous survival interval was calculated from the date of diagnosis of metachronous skeletal OS until the date of death or last follow-up. Survival proportions were computed using the Kaplan-Meier method.35 Comparison of postmetachronous survival curves was performed using a log-rank test. A two-sided P < 0.05 was considered statistically significant. All statistical analyses were performed using the SAS software (SAS Institute, Cary, NC), version 8.0.
Of the 23 patients (median age, 15.5 years; range, 4.6 to 41.9 years) at diagnosis of primary OS who developed metachronous skeletal OS, seven patients (30%) were female and 16 (70%) were male. The median age at which metachronous OS occurred was 18.7 years (range, 5.9 to 42.2 years). The distributions of the initial site of OS were as follows: femur in 10 patients, humerus in seven patients, pelvis in four patients, and tibia and axial skeleton in one patient each (Table 2  ). The sites of metachronous OS were as follows: pelvis in seven patients, multiple bones in six patients, head and neck in three patients, axial skeleton in three patients, femur in two patients, and humerus and ulna in one patient each. Synchronous pulmonary metastases were detected by CT scans in three of the 12 early metachronous OS patients at 0.4, 1.1, and 1.4 years, respectively, from the diagnosis of the primary tumor. The time from diagnosis of the primary tumor to the time of development of the metachronous metastatic skeletal OS for the entire cohort ranged from 0.2 to 11.3 years (median, 1.4 years). Seven (30.2%) of the 23 patients were alive at the time of last follow-up, five (21.7%) were alive and free of disease (A-NED), and two were alive with disease (AWD). Of the 11 late metachronous OS patients, the median time to the diagnosis of metachronous OS was 5.4 years (range, 2.0 to 11.3 years). At last follow-up, five of the 11 patients were A-NED, and one was AWD. For the five patients who were A-NED, the interval from diagnosis of the primary to the time of development of the metachronous OS varied from 2.0 to 6.2 years, (median, 4.8 years). For the two patients who were AWD, the time from diagnosis of the primary tumor and the time of development of the metachronous skeletal OS were 0.5 and 4.8 years, respectively. Only one of the 12 patients with early metachronous OS was AWD at the time of last follow-up (10.8 years). Fifteen of the 23 patients were dead of disease (DOD), and one patient died from an unrelated cause with no evidence of disease (D-NED). The exact cause of death for this patient was not available. None of the patients who were alive at the time of last follow-up received chemotherapy alone for the treatment of their metachronous OS. Of the seven patients who were alive, treatment for the metachronous skeletal OS consisted of surgery only (patient 14), continuation of chemotherapy with radiation (patient 4), or combined surgery and chemotherapy (patients 15, 16, 17, 19, and 20). The treatment of the primary tumor for all patients consisted of combined-modality therapy with chemotherapy and surgery. Surgery in all patients consisted of en bloc (n = 11), amputation (n = 8), Van Nes rotationplasty (n = 1), hemipelvectomy (n = 2), and partial resection (n = 1). Three patients developed pulmonary metastases at the same time as they developed metachronous OS (patients 3, 12, and 19). The first two patients had bilateral thoracotomies after chemotherapy for the metachronous skeletal OS. The latter patient succumbed to progressive OS before thoracotomy.
With a median follow-up for this cohort of patients of 1.5 years (range, 0.1 to 12.8 years), five patients were A-NED (range, 1.7 to 12.8 years; median, 4.4 years), and two were alive with pulmonary disease at 9.0 and 10.8 years, respectively, from the time of development of the metachronous skeletal lesion (Tables 2
Patients who developed late metachronous OS experienced significantly longer postmetachronous OS survival compared with those who had early metachronous OS (P = .003; Fig 2 ). The 2- and 5-year postmetachronous OS survival for the former group was 72.7% (95% CI, 46% to 99%) and 61% (95% CI, 30% to 91%), respectively, and for the latter group, it was 16.7% (95% CI, 0% to 38%) and 8% (95% CI, 0% to 24%), respectively. All five patients who developed metachronous OS between 12 and 24 months died within 1.5 years of follow-up. The median survival rates for patients in the early and late groups were 0.6 years (95% CI, 0.4 to 1.3 years) and 6.9 years (95% CI, 1.5 to not reached), respectively. Among patients who developed late metachronous OS, further analysis based on therapy revealed a trend. Patients who were treated with a combined-modality approach (n = 6) with surgery and aggressive chemotherapy for their metachronous OS fared better with postmetachronous metastasis compared with those who received monotherapy (n = 5; P = .10; Fig 3). The 5-year survival rates for the two subgroups were 83% (95% CI, 54% to 100%) and 40% (95% CI, 0% to 83%), respectively. The median survival for the former group was not reached; median survival for the latter group was 2.6 years (95% CI, 0.8 to not reached). Among patients who developed early metachronous OS, there was no difference in subsequent survival between those who received combined therapy (n = 3) and those who received monotherapy (n = 9; Fig 4).
Historically, the development of metachronous skeletal OS after the completion of therapy has been believed to be lethal. To the best of our knowledge, there is little information available on the experience and outcomes of metachronous metastatic skeletal OS. A review of the English-language literature revealed several individual case reports on the subject.21,23–29 Marcove et al,27 from MSKCC, reported three patients who developed OS in a second bone. All of them achieved moderate to long-term NED (6.2, 13.0, and 16.0 years, respectively, from primary OS) at the time of analysis. Huth et al28 reported only one long-term (at 17 months) disease-free survival out of 225 patients, 10 of whom had developed metastasis to bone. In this first large, single-institution series, the results we obtained demonstrate that a significant proportion of patients with metachronous metastatic skeletal OS may achieve long-term disease-free survival when combined-modality therapy with surgery and chemotherapy is applied. We chose to restrict our analysis to the patients with nonmetastatic primary OS who developed an apparent new metastatic skeletal OS after the initial diagnosis and the initiation of therapy. On rare occasions, patients with OS present with multiple tumors, but these tumors may represent a larger primary tumor with multiple lesions. At present, there are no tools that exist to evaluate clonality in OS. Lesions may arise in the bone distant from the primary site during initial therapy and following completion of therapy. Among the 23 patients who developed metachronous metastatic skeletal OS, the median age was 15.5 years, and 70% of the patients were male. The most common presentation for metachronous OS was the involvement of the pelvis with a total of six patients (30%). Multiple bones were involved in 26% of the patients. The rate of occurrence in the extremities was 16% (n = 4). Although it is well known that the primary OS is most common in the metaphyses of long bones, metachronous skeletal OS, at least in our cohort of patients, appeared to be more common in the trunk, with a rate of 43% (n = 10). This coincides with other reports of secondary OS arising in the trunk more often than does primary OS.3,36–38 The probability of recurrence of OS at any site is highest in the first 3 years from initial diagnosis, with the lungs being the most common site of first relapse.1–10 In our cohort of patients, the median latency interval between the diagnosis of the primary and the metachronous OS was 1.5 years, similar to the median interval for the development of pulmonary metastasis. Of the five patients who were alive and disease free at the time of last follow-up, the median time to development of the metachronous OS was 4.8 years from the time of primary tumor. Only one of the patients who developed metachronous OS earlier than 1 year from the initial diagnosis survived. This patient was alive with pulmonary disease at last follow-up. It appears from this subgroup that a longer time interval from diagnosis of the primary to the metachronous OS correlates with prognosis. Local therapy with surgery directed at the bulky primary tumor is the only effective therapy for local control. Because almost all patients with OS have microscopic metastatic disease, systemic chemotherapy is required to achieve long-term disease-free survivals. Agents, including HD-MTX,39 doxorubicin,40 cisplatin,33 ifosfamide,41 and carboplatin42 have been incorporated into highly effective treatment regimens for metastatic or nonmetastatic OS. In addition, neoadjuvant chemotherapy before definitive surgical resection is currently the widely accepted treatment for OS. For patients who develop recurrence, the treatment must be tailored specifically for each circumstance depending on the therapy received for their primary tumor. Marcove et al27 previously reported our own institution’s experience on three patients with OS in which a second bone involvement occurred. Two of the patients received combined chemotherapy and surgery for their metachronous OS, whereas the third underwent wide resection of the tumor. All three were alive at 6.2, 16.0, and 13.0 years, respectively. Huth et al28 reported the patterns of recurrence after resection of OS in 255 patients. Of 107 patients with metastatic disease, 77 had isolated metastasis to the lungs, 17 had simultaneous metastasis to the lung and elsewhere, and 13 had other sites (10 were to the bone). The latter two groups of patients had the worst prognosis, with only one patient with metastasis to the bone remaining alive at 17 months after diagnosis and after receiving chemotherapy. In our analysis, nine of 23 patients (40%) with metachronous skeletal OS were treated with a combined-modality approach for their metachronous OS. Therapy for patients with early metachronous OS consisted of continuation of their initial OS therapy to completion in four patients, modified chemotherapy in five patients, and combined surgery and chemotherapy in three patients. The standard of therapy for relapsed patients with OS at MSKCC has been further chemotherapy with ifosfamide or high-dose ifosfamide (for patients who had already received conventional dose ifosfamide) in addition to surgical resection. Four of the nine patients (44.4%) who received combined-modality therapy were alive and free of disease at the time of last follow-up. Many studies have confirmed the value of the histological necrosis of the tumor following neoadjuvant or induction chemotherapy or Huvos grading in determining patient prognosis.5,43,44 Patients with an inferior response (Huvos grades 1 to 2) to initial chemotherapy have a higher probability of developing subsequent metastasis. Huvos grading was available for 15 (83%) of the 18 patients who received neoadjuvant chemotherapy for their primary tumor. Of these, 12 patients (80%) who developed subsequent metachronous OS had Huvos grades of 1 to 2. Only one patient with a Huvos grade 4 for the primary tumor located in the humerus developed a metachronous OS involving the sacrum. Huvos grading (grades 1, 2, and 4) was available for three of the six patients who were alive and who received neoadjuvant chemotherapy for their metachronous OS. The numbers are too small to determine the differences and correlations between the histological response and prognosis in metachronous OS.
The overall prognosis of patients with OS has been improving because of the development and use of intensive and effective aggressive therapy with surgery and neoadjuvant and adjuvant chemotherapy. Patients with an early metachronous skeletal OS or those with synchronous pulmonary involvement at the time of metachronous skeletal OS have far more advanced disease with the most unfavorable prognosis. The site of the primary, whether a wide surgical resection of all clinically detectable tumor is possible, the Huvos histological grade, the time it takes from diagnosis of the primary to the development of metachronous OS, the involvement of a synchronous pulmonary OS, and the therapy received are all important factors contributing to subsequent survival. However, a subset of patients in our cohort treated with aggressive therapy with surgery and chemotherapy had a prolonged survival beyond what has been previously reported. This implies that the principles used in the treatment of primary OS, when applied to patients presenting with late (
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Copyright © 2003 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
