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© 2002 American Society for Clinical Oncology Effect of Timing of Pulmonary Metastases Identification on Prognosis of Patients With Osteosarcoma: The Japanese Musculoskeletal Oncology Group StudyByFrom the Department of Orthopaedic Surgery, School of Medicine, Kanazawa University, Kanazawa; Department of Orthopaedic Surgery, School of Medicine, Teikyo University, Tokyo; Division of Orthopaedic Surgery, Sapporo National Hospital, Sapporo; and Department of Orthopaedic Surgery, School of Medicine, Hiroshima University, Hiroshima, Japan. Address reprint requests to Hiroyuki Tsuchiya, MD, PhD, Department of Orthopaedic Surgery, School of Medicine, Kanazawa University, 13-1 Takara-machi, Kanazawa 920-8641, Japan; email: tsuchi{at}med .kanazawa-u.ac.jp.
PURPOSE: The prognostic value of the time of identification of lung metastasis was investigated in 280 patients with metastatic lung osteosarcoma as a multi-institutional study of the Japanese Musculoskeletal Oncology Group. PATIENTS AND METHODS: The 280 patients with lung metastasis were divided into four groups: group 1, patients with lung metastasis identified at initial presentation; group 2, those with lung metastasis identified during preoperative chemotherapy; group 3, those with lung metastasis identified during postoperative chemotherapy, and group 4, those with lung metastasis identified after completion of treatment. Survivals of the four groups were compared. Additionally, the effects of number of metastatic nodules, metastasectomy, and the effect of chemotherapy on the primary tumor on survival of the four groups were analyzed. RESULTS: There were 46 patients in group 1, 30 in group 2, 94 in group 3, and 110 in group 4. The overall 2-year survival rates from the time of identification of lung metastasis were 33%, 31%, 24%, and 40% for groups 1, 2, 3, and 4, respectively, whereas the 5-year survival rates were 18%, 0%, 6%, and 31%, respectively. Patients in group 4 thus demonstrated significantly better prognosis than any of the other patients (P < .0001). CONCLUSION: Time of identification of lung metastasis is an important prognostic factor. In terms of clinical behavior, groups 2 and 3 are completely different than group 4. These data ensure the need to stratify stage III osteosarcomas into subgroups according to the time of diagnosis of lung metastases. To improve the survival of osteosarcoma patients, new treatment modalities should be introduced into the treatment armamentarium for lung metastasis from osteosarcoma, especially in groups 1, 2, and 3.
THE LUNG IS THE most common site for osteosarcoma metastasis. In approximately 15% to 20% of patients with osteosarcoma, lung metastasis is clinically detectable at initial presentation,1,2 whereas approximately 50% of patients with nonmetastatic osteosarcoma at initial presentation develop metastatic lung disease later.3,4 Lung metastasis has a major impact on prognosis for patients with osteosarcoma. The purpose of this study was to investigate prognostic value of the time of identification of lung metastasis in patients with osteosarcoma. This is a multi-institutional study of the Japanese Musculoskeletal Oncology Group.
The retrospective study comprised 280 patients of osteosarcoma with lung metastases. The patients were 195 males and 85 females with a mean age of 17.9 years (range, 4 to 82 years). The primary tumor was located in the femur of 165 patients, the tibia of 67, the humerus of 25, and in other locations for 23 patients. The mean follow-up was 38 months (range, 3 to 258 months). Multiagent chemotherapy was performed for 279 patients, with the chemotherapy basis in these patients being neoadjuvant chemotherapy (pre- and postoperative) for 273 patients and adjuvant (only postoperative) chemotherapy for six. Out of 273 patients who underwent neoadjuvant chemotherapy, 33 patients received preoperative intra-arterial chemotherapy, whereas the remaining received intravenous preoperative chemotherapy. One patient underwent no chemotherapy. Diagnosis of metastatic nodules in the lung was made by x-rays and computed axial tomographic scans. During metastasectomy operation (if the patient had surgical excision of their pulmonary metastases), all the visible and palpable nodules were excised and subjected to histopathologic study for confirmation of the diagnosis of metastases. Patients were divided into the following four groups: group 1, patients with lung metastasis identified at initial presentation; group 2, those with lung metastasis identified during preoperative chemotherapy; group 3, those with lung metastasis identified during postoperative chemotherapy; and group 4, those with lung metastasis identified after completion of treatment (Fig 1). Survivals of the patients in the four groups were compared. The Rosen and Huvos system was used for evaluation of the histologic response to preoperative chemotherapy.5 This system is formed of the following four grades: grade 4, no viable cells; grade 3, only scattered foci of viable cells; grade 2, some areas of viable cells; grade 1, little or no effect.
In addition to the time of identification of lung metastasis, we investigated the value of three prognostic factors: the effect of chemotherapy on the primary tumor, the number of pulmonary metastatic nodules, and the treatment for lung metastasis. For evaluation of the effect of number of metastatic lung nodules on patient’s survival, patients were further subdivided into two groups, patients in the numerous group had four or more nodules, and those in the few group had three or fewer nodules. The Kaplan-Meier method was used to analyze the survival probability curve. Significant differences were evaluated with the log-rank test. Chi-square test was used for evaluation of the intergroup differences with regards to method of treatment, incidence of local recurrence, extrapulmonary metastases, and response to chemotherapy. P values of less than .05 were considered significant.
Characteristics of patients of every group are listed in Table 1. There were 46 patients in group 1, 30 in group 2, 94 in group 3, and 110 in group 4. There were no statistically significant intergroup differences in the method of treatment of the primary tumor or in the incidence of local recurrence (P = .3318) (Table 2). The intergroup difference as regards the incidence of use of intra-arterial chemotherapy was statistically insignificant (P = .7326). During the course of the disease, 84 patients (18 in group 1, 11 in group 2, 29 in group 3, and 26 in group 4) developed extrapulmonary metastases. The intergroup difference as regards the incidence of extrapulmonary metastases was statistically insignificant (P = .2270).
When survival curves were measured from the time of diagnosis of osteosarcoma, the overall 2-year survival rates were 33% for group 1, 31% for group 2, 32% for group 3, and 78% for group 4. The corresponding overall 5-year survival rates were 18%, 10%, 6%, and 37% (Fig 2). A comparison of the survival period from the time of identification of lung metastasis showed that the overall 2-year survival rates were 33% for group 1, 31% for group 2, 24% for group 3, and 40% for group 4, whereas the 5-year survival rates were 18% for group 1, 0% for group 2, 6% for group 3, and 31% for group 4 (Fig 3). Patients in group 4 thus demonstrated significantly better prognosis than any of the other patients (P < .0001).
Table 2 lists the histologic response to chemotherapy in the 4 groups. No statistically significant difference between the responses to chemotherapy could be detected between the four groups (P = .1399) or between group 4 in one hand and groups 2 and 3 in the other hand (P = .4754). The overall 2-year survival rates from the time of identification of lung metastases were 71% for the grade 4 response group, 37% for the grade 3 response group, 29% for the grade 2 response group, and 17% for the grade 1 response group. The corresponding 5-year survival rates were 45%, 24%, 16%, and 5%. Patients with a grade 4 response in group 1 and those with grade 3 or 4 response in group 4 showed significantly better prognosis than other patients (P < .0001) (Fig 4).
Number of lung metastatic nodules (Table 3) was recognized as a prognostic factor. The survival rate of the few group was significantly better than that of the numerous group (P < .0001). In the few group, the overall 2-year survival rates from the time of identification of lung metastases were 45% for group 1, 48% for group 2, 33% for group 3, and 50% for group 4, and the corresponding 5-year survival rates were 19%, 0%, 10%, and 40%. In the numerous group, the overall 2-year survival rates were 19% for group 1, 8% for group 2, 8% for group 3, and 12% for group 4, and the corresponding 5-year survival rates were 13% for group 1 and 0% for groups 2 and 3. Patients with less than three nodules in group 4 showed significantly better prognosis than other patients (P = .0005) (Fig 5).
With regard to treatment for lung metastasis, 248 patients underwent metastasectomy and/or chemotherapy, whereas 15 patients did not receive any treatment (because of widespread military metastases or bad performance status). Patients in every group who were treated with metastasectomy with or without chemotherapy demonstrated significantly better prognosis (P < .0001). The overall 5-year survival rates of the patients who underwent metastasectomy from the time of identification of lung metastases were 31% for group 1, 19% for group 2, 10% for group 3, and 48% for group 4. The patients in groups 1 and 4 showed significantly better survival rates than those in groups 2 and 3 (P = .0120 and < .0001, respectively). On the other hand, the overall survival rates of the patients who did not undergo metastasectomy from the time of identification of lung metastases did not show significant intergroup differences, with 5% for group 1, 0% for group 2, 5% for group 3, and 8% for group 4 (Fig 6).
The long-term survival of patients with osteosarcoma has dramatically improved over the last two decades because of the advent of aggressive chemotherapy regimens.6-8 Neoadjuvant and adjuvant chemotherapy has drastically reduced the metastatic death rate, but 30% to 50% of patients still die of pulmonary metastases.6,8,9 Previous reports have advocated surgical removal of lung metastases of osteosarcoma with good results.10-28 The best results reported have followed the combination of pulmonary resection and adjuvant chemotherapy.9,14,16,21,27,29 Many factors have been investigated for correlation with survival after pulmonary metastasectomy, including age, sex, primary tumor location, disease-free interval, tumor-doubling time, bilaterality, resectability, and number of pulmonary nodules.9,10,12,14-19,21,23-28 This study was conducted to compare clinical behaviors of osteosarcomas having lung metastases at initial presentation, those that develop metastases during chemotherapy treatment, and those that develop metastases after the completion of treatment regimen. Although the effect of timing of pulmonary metastases on survival of osteosarcoma patients was not previously studied, controversy existed in the literature about the prognosis of patients having metastasis at initial presentation. Some authors reported poor prognosis for those patients, however, others reported that this group does not always have a dismal prognosis.13,30 In this study, only a few patients in group 1, who had lung metastasis of osteosarcoma identified at presentation, had the potential to survive for a long time. This subgroup includes the patients who have tumors with complete response to chemotherapy. Those tumors behave almost similar to tumors of group 4. However, the rest of the tumors in group 1 had the same clinical behavior of tumors in groups 2 and 3. Approximately 30% of patients in group 4, who developed lung metastasis after completion of the first standard treatment consisting of chemotherapy and surgery, had good prognosis. The best prognosis in this group was observed in those who received metastasectomy for their lung metastases. Contrary to good biologic behavior in group 4, patients in groups 2 and 3 who developed lung metastasis during treatment had little or no possibility of survival even though the response of the primary tumor to preoperative chemotherapy was good and the number of lung metastatic nodule is fewer than three. Enneking designated low-grade, high-grade, and metastatic sarcomas by the Roman numerals I, II, and III, respectively.31 These three stages of sarcomas were further stratified into A or B depending on whether the lesion is anatomically intracompartmental (A) or extracompartmental (B). The data presented in the current work ensure the need for stratification of osteosarcomas in stage III. We would propose stratification of stage III into stages III A1 or B1, III A2 or B2, III A3 or B3, and III A4 or B4, depending on the time of identification of lung metastases. Stages IIIA1 and IIIB1 denote the group of patients who have lung metastases at time of presentation; stages IIIA2 and IIIB2 denote those who have lung metastases identified during preoperative chemotherapy; stages IIIA3 and IIIB3 denote those have lung metastases identified during postoperative chemotherapy; and stages IIIA4 and IIIB4 denote those have lung metastases identified after completion of treatment. This stratification would help comparison of the results in research works. Unfortunately, currently, no tools are available for the detection of micrometastasis or to predict development of lung metastasis during treatment by chemotherapy. Also it is very important to understand the mechanism of metastatic disease of osteosarcoma.32-35 This study further ensures the good prognostic effect of metastasectomy on patients’ survival. Metastasectomy was found to be the most effective treatment, at present, for lung metastasis of osteosarcoma. The 163 patients who had undergone metastasectomy showed better prognosis than the patients who had not. Although patients in groups 2 and 3 had bad prognosis, generally, patients who received metastasectomy still show better prognosis than patients who did not receive this line of treatment in the same group. Also, although the patients in group 4 showed the highest survival rate, patients in this group who did not receive metastasectomy had a poor prognosis. As for chemotherapeutic response to the primary tumor, good response was observed in 24% to 46% of each group. There was a positive correlation between chemotherapy response and survival rate. In group 1, only patients with complete response had chance to survive longer. However, on the other hand, the prognostic effect of response to chemotherapy is not so evident in group 4 because patients with poor chemotherapeutic response in group 4 still showed a 5-year survival rate of 20% to 40% when pulmonary metastases were treated with metastasectomy. It is still unclear why most patients with metastasis identified at the initial presentation or during treatment had a probability of survival that is inferior to patients who had metastasis after completion of chemotherapeutic regimen. Is this simply the result of greater tumor burden, or are there are biologic differences? Identification of the underlying factors responsible for bad prognosis in patients of groups 1, 2, and 3 would help to develop a therapeutic strategy against these factors. The discordance between the response of the primary tumor and the metastases to chemotherapy was striking in some cases. In 12 patients with localized osteosarcoma (stage II) (one in group 2, five in group 3, and six in group 4), pulmonary metastases were identified during or after completion of their chemotherapy despite the fact that the primary cancer was totally necrotic. This discordance could not be attributed to route of administration of chemotherapy because half of these patients received intra-arterial (localized to the limb) chemotherapy and the other half received intravenous (systemic) ones. Similar cases of discordance behavior of the primary tumor and pulmonary metastases would present good candidates for biologic screening to identify a difference that determine the behavior of lung metastases and treatment results. In conclusion, the time of identification of lung metastasis could be a very important prognostic factor. Patients in groups 2 and 3 had the poorest prognosis. In group 1, only patients with complete response to preoperative chemotherapy had a chance to survive. Patients in group 4 treated with metastasectomy demonstrated a significantly better prognosis. Depending on these data, a new system for stratification of stage III osteosarcomas was proposed. To improve the survival rate for osteosarcoma patients, new treatment modalities should be introduced into the treatment armamentarium for patients with lung metastasis from osteosarcoma, especially in groups 1, 2, and 3. Lung perfusion of anticancer drugs, immunotherapy, allogenic peripheral-blood stem-cell transplantation, gene therapy, pharmacogenomics, and pulmonary transplantation offer future possibilities as more effective treatment modalities.36-40
The appendix listing doctors who participated in the study is available online at www.jco.org. The following doctors participated in the study: K. Kusuzaki, MD, Kyoto Prefectural University of Medicine; T. Otsuka, MD, Nagoya City University; K. Tanaka, MD, and Y. Iwamoto, MD, Kyusyu University; T. Minamizaki, MD, Tottori University; K. Sakayama, MD, Ehime University; K. Yonemura, MD, Kumamoto University; H. Kakizaki, MD, National Hirosaki Hospital; S. Nagoya, MD, Sapporo Medical University; S. Yoshida, MD, Oita Medical University; Y. Miyauchi, MD, Nara Medical University; K. Kushida, MD, Kanagawa Cancer Center; S. Yokokura, MD, Tokyo University; Y. Yazawa, MD, Tochigi Cancer Center; K. Mochizuki, MD, Kyorin University; A. Kawai, MD, Okayama University; T. Umeda, MD, National Cancer Center; H. Futani, MD, Hyogo College of Medicine; O. Inoue, MD, Ryukyu University; K. Ihara, MD, Yamaguchi University; Y. Nishimoto, MD, Gifu University; K. Saotome, MD, Dokkyo University; H. Isaki, MD, National Defense Medical College; H. Sugiura, MD, Nagoya University; E. Sato, MD, Yamanashi Medical University; S. Osaka, MD, Nihon University, Nerima Hikarigaoka Hospital; H. Watanabe, MD, Gunma University; S. Nishioka, MD, Kinki University; and Y. Hino, MD, Kawasaki Medical University, Japan.
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Copyright © 2002 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
