Abstract
The pattern of relapse, treatment and final outcome of 235 patients with osteosarcoma of the extremity who relapsed after neoadjuvant treatments performed between 1986 and 1998 at a single institution is reported. The 235 relapses were treated by surgery, surgery plus second line chemotherapy, and only second line chemotherapy or radiotherapy. The 5-year post-relapse-event-free-survival (PREFS) was 27.6% and the post-relapse-overall-survival (PROS) 28.7%. All 69 patients who are presently alive and free of disease were treated by surgery, alone or combined with chemotherapy. None of patients treated only by chemotherapy or radiotherapy survived. We conclude that it is possible to obtain prolonged survival and cure in about 1/4 of relapsing osteosarcoma patients with aggressive treatments. The complete removal of the recurrence is essential for outcome, while the role of the association of second-line chemotherapy remains to be defined.
The addition of multiagent chemotherapy to surgery has dramatically improved the outcome of patients with osteosarcoma (OS) of the extremity Citation[1–4]. About 30 – 35% of these patients however still had local or systemic relapse, with the lung being the most common site of disease recurrence. There are many studies which report the outcome of patients who relapse, but their results are contrasting. In fact the overall post recurrence survival (OPRS) rate for patients with osteosarcoma initially treated by combined treatment ranges between 13% Citation[5] and 61% Citation[6] and the event free post recurrence survival (EFPRS), reported in only a few series, between 6% Citation[6] and 27% Citation[7]. These discrepancies can be explained by the lack of homogeneity of these series and the small number of patients these reports are based on. The present investigation is a retrospective analysis of 235 patients who developed recurrence from extremity non-metastatic high-grade OS treated with neoadjuvant chemotherapy, with particular focus on pattern of relapse, therapies used to treat recurrences, and factors that could influence the disease-free and the overall post-relapse survival.
Patients and methods
Treatment and outcome at the initial diagnosis
Between September 1985 and December 1998, 620 patients with non-metastatic OS of the extremity were treated at our institution according to four different neoadjuvant protocols of chemotherapy activated successively. These protocols have been reported in detail in previous papers Citation[8–12]. The diagnosis of osteosarcoma, established by clinical and radiological findings, was always confirmed on histologic slides of tumour tissue obtained from an open or trocar closed biopsy, as well as the resected specimen.
A complete medical history was obtained for all patients, who also underwent a thorough physical examination and several chemical laboratory tests. The primary tumor was evaluated on standard radiographs, and Technetium 99-MDP bone scans. CT was performed only in the 620 patients treated after 1985. MRI was also performed in about half of patients. Bone metastases were investigated by total body scans, whereas chest radiographs and CT scans of the chest were used to exclude lung metastases. Surgery consisted of amputation in 49 (7.9%) patients, limb salvage in 541 (87.3%), and rotationplasty in 30 (4.8%). The histologic response to chemotherapy, evaluated following the criteria previously reported Citation[13] was good in 407 patients (65.6%) and poor in 213 (34.3%).
During postoperative chemotherapy, besides the clinical evaluation, patients were checked every two months with CT scans of the chest and treated limb. Additional investigations were performed only if there was a clinical and/or radiographic suspicion of relapse. After completion of chemotherapy, patients were followed in the outpatient clinic with CT every two months for two years, every three months in the 3rd year and then every six months. At a follow-up ranging between seven and 22 years (mean 13.5 years), of the 620 patients who entered the cited studies 379 (61.1%) remained continuously event free, six died of chemotherapy toxicity, and 235 relapsed.
Patient selection after relapse to enter this review
All patients who relapsed from the cited four neoadjuvant studies were eligible for this report since it was possible to collect information on date, type of treatment, and final outcome of all the recurrences. After relapse, 188 (80%) were treated at our institution and 47 (20%) in other hospitals. The characteristics of the 235 patients evaluated are reported in .
Table I. Patients’ features at the initial diagnosis, type of initial treatment and 5-year post relapse event-free survival (PREFS) rate.
Because the pattern of relapse of osteosarcoma is heterogeneous, the strategies of treatment were individualized according to type, site and the extension of the relapse, as well as the relapse-free interval (RFI) from the start of treatment or from the last relapse. Nevertheless, the cornerstone of treatment was the complete surgical removal of the recurrence whenever possible. A second round of chemotherapy was usually performed only when it was not possible to achieve complete surgical remission of the relapse or when the recurrence pattern suggested a particularly aggressive behaviour (more than 2 metastases or short RFI). This second-line chemotherapy up to 1991 was usually performed with drugs not used in the first-line neoadjuvant treatment. Since 1991, all patients treated at our Institute, have been receiving four cycles of high-dose Ifosfamide (15 g/m2 over 5 days of continuous infusion), regardless of the drugs used in the previous neoadjuvant treatment.
Statistics
The aim of this study was to evaluate treatment and the outcome of the patients who relapsed, and to try to identify factors that could influence the post relapse survival (PRS). Remission after relapse was defined as removal of all evident disease, with no tumor tissue at the resected margins on the histologic examination. Post-relapse-event free survival (PREFS) and post-relapse-overall survival (PRS) were calculated from the date of recurrence until death or last follow-up. The following parameters were investigated: (1) relapse-free-interval (RFI), i.e., time surgical removal of primary tumor and date of onset of the subsequent relapse; (2) pattern of relapse (lung metastases, bone metastases, metastases in other sites, metastases in more than one site, isolated local recurrence, local recurrence associated with metastases); (3) in the case of lung metastases, at first relapse, it was also evaluated if metastases were monolateral or bilateral, and the number of pulmonary nodules, evaluated in the resected specimen in patients treated with thoracotomy or on CT in patients not surgically treated. The Statview 4.5 statistical package was used for statistical analysis. The evaluation of PRES and PRS was performed using the Kaplan-Meyer method for calculating survival curves. Differences between the groups were compared by means of the χ2 test and t test.
Results
Pattern of recurrence
There was a total of 411 relapses, that are summarized in . Fifty-nine patients had only one recurrence, 64 two recurrences, 24 three, 4 four and 6 five. The median interval from the start of treatment to the first recurrence was 25.4 months (range: 3 – 135), 24.2 for poor responders and 26.2 months for good responders (p < 0.04). The median interval between the first and the second recurrence was 12.7 months, between the second and the third 11.8 months, between the third and the fourth 15.2 months, and between the fourth and the fifth 4 months.
Table II. Number of patients according to type of relapse.
First Relapse
The first relapses were isolated lung metastases in 188 patients (80%), isolated distant bone metastases in 21 (8.6%), isolated metastases in other sites in two (kidney, heart), more-than-one-site metastases in two, isolated local recurrence in eight (7.6%), local recurrence associated with lung metastases in 14. It is interesting to note that in 13 of the 14 patients who first relapsed with contemporary local recurrence and distant metastases, the metastases were located in the bone in seven patients, and in the lung in six. In other words, in the 28 patients who relapsed with bone metastases there were seven contemporary local recurrences (20.5%), while in the 196 who relapsed with lung metastases, the contemporary local recurrences were only seven (3.1%). This difference is highly significant (p < 0.0001). The mean interval from the start of treatment and the first relapse was longer for patients who relapsed with isolated metastases (29.4 months) than for patients who relapsed with isolated local recurrence (24 months). Treatments of relapses are reported in . The treatment of the first relapse was only surgery in 141 patients (60%), surgery combined with second-line chemotherapy in 32 (13.6%), only chemotherapy in 22 (9.3%) and only radiotherapy in three. The remaining 37 patients (15.7%) received no treatment, or only palliative therapy. As a result of treatment of the first relapse, 173 patients (73.6%) achieved remission while the remaining 62 patients were never freed of their recurrence. All of these 62 patients died at a mean interval of 10.7 month (range: 2 – 117) from the relapse. The likelihood of achieving remission was unrelated to gender, protocol of chemotherapy initially applied, site of primary tumor, its volume, or the type of surgery used to treat the tumor. It was instead significantly correlated with the age of patients (71% for patients 14 years old or younger vs 56.4% for older patients, p < 0.006), histologic response to preoperative neoadjuvant chemotherapy (72.2% for good responders vs 53.6% for poor responders, p < 0.0007), serum level of alkaline phosphatase at the beginning of neoadjuvant treatment (70.4% for pts with normal values vs 56.7% for patients with high values), and site of first metastases (68.0% for patients with lung metastases vs 25.9% for patients with metastases in other sites; p < 0.0001). In patients with isolated lung metastases the rate of remission was significantly correlated with the number of metastatic nodules (89.2% for patients with only one or two nodules vs 46.9% for patients with more than two nodules, p < 0.0001), and with the site of pulmonary lesions (88.1% for the 160 patients with monolateral lesions vs 30.0% for the 90 patients with bilateral lesions, p < 0.0001). According to the type of treatment, none of the patients treated with radiotherapy or only second-line chemotherapy was rendered free of disease. For patients treated by surgery alone (141 cases) or surgery combined with second-line chemotherapy (32 cases) the rate of remissions was respectively 95.3% and 81.4% (p < 0.005). For patients treated only by chemotherapy the mean number of lung metastases was six. In addition, the rate of patients who relapsed after two years was 45.0% for the group treated only by surgery and 25.1% for the group that received other forms of treatment (p < 0.02). Among the 188 patients with isolated lung metastases, 68 of the 106 (64%) treated by surgery were freed of disease. The rate of remission was 100% for patients with five or less nodules, and only 30% for patients with more than five nodules.
Table III. Treatment according to relapse.
Of the 173 patients who reached remission, 53 (30.6%) remained continuously free of disease at 6 – 156 months (x = 84.9 months) from the treatment performed after the relapse, while 120 had a second relapse after 2 – 117 months (x = 11.6 months).
2nd, 3rd, 4th and 5th relapses
The second relapse of these 120 patients consisted of isolated lung metastases in 80 cases (66.6%), isolated metastases in other bones in 19 (15.8%), isolated metastases in other sites in three, metastases in more than one site in 10 (8.3%), isolated local recurrence in 6 (5%), local recurrence and lung metastases in one, and local recurrence and bone metastases in one. The treatment was surgery only in 40 patients (33.3%), surgery combined with chemotherapy in 25 (20.8%), chemotherapy only in 17 (14.2%), and radiotherapy only in one. In the remaining 37 (30.8%) patients no treatments or only palliative therapies were performed. The result of treatment of the 120 patients who had a second relapse, after remission was the following: 54 (45%) achieved remission and 66 (55%) did not. Sixty-six patients who were not freed of disease died of the tumor three to 65 months after the last relapse (mean = 11 months). Of the 54 patients who entered in second remission, 14 (25.9%) are presently alive and free of disease 3 – 179 months (mean 33.9 months) from the last treatment, while the remaining 40 had a third relapse.
The sites of the 3rd relapses were isolated in the lung in 20 patients, isolated in other bones in seven, isolated in another site in two, in two or more sites in nine, isolated local recurrence in one and a local recurrence combined with lung metastases in the last case. The treatment of these patients was surgery in 12 cases (30%), surgery combined with chemotherapy in four (10%), and only chemotherapy in nine. The remaining 15 patients (37.5%) had only palliative treatments. The results of treatment of the 3rd relapse were the following: 12 patients (30%) had complete remission and 28 were not completely freed of their recurrence. All the latter 28 patients died of the tumor at a mean time, from the last relapse, of 15.3 months (range: 4 – 76). Of the 12 patients who reached remission, two are alive and free of disease 4 – 76 months from the last treatment, and ten had a new relapse. The site of the 4th relapse was in the lung in six patients, other bones in one, the heart in one, and in more than one site in two.
The treatment of the 4th relapse was surgery in four cases, surgery plus chemotherapy in one, and chemotherapy only in one. The remaining four patients had only palliative treatments. Of these ten patients, six achieved remission and four did not. These last four patients died of the tumor (time: 7 months, range: 2 – 12). All six patients who had entered remission had a 5th relapse, four in the lung and two outside lung and bone. The treatment of these patients was surgery in three cases, while the other three patients had only palliative therapy. While all three patients treated with palliative intent died in a few months, the three patients treated by surgery are alive and free of disease 12, 22 and 36 months after the last treatment.
Comparison between the first and the following relapses
The rate of patients who achieved remission decreased from first to last relapse (73.6% to 33%, p < 0.02). The rate of patients who had only lung metastases decreased (48.8% to 32.1%, p < 0.02). The number of patients who relapsed with metastases localized in different sites increased (1.2% to 12.5%, p < 0.01). According to the type of treatment in the relapses following the first, the rate of patients treated by surgery decreased (73.6% to 33.3%, p < 0.02), while the rate of patients who had only a palliative treatments increased (15.7% to 66.6%, p < 0.002)
Type of surgery used to treat recurrences
Thirty of the 35 local recurrences were treated with surgery that consisted of amputation in 18 and new limb salvage in 17. The other five local recurrences received only palliative treatment. The isolated lung metastases were surgically treated in the 54.7% of cases globally (59.6% at first relapse vs. 41.4% at following relapses). Thoracotomy resulted in a complete removal of all the disease in 94.5% of patients, while in the remaining cases, due to the unexpected diffusion of metastases, it was only an exploratory operation. Pulmonary surgery was a wedge resection in the 84.8% of patients, lobectomy in 13.0%, and a pneumonectomy in 2.3% of cases. Also 16 of the 48 isolated bone metastases, all located in extremity bones, were surgically treated (amputation in 12 cases and limb salvage in four). In all cases, the removal of metastatic lesion was complete.
Summary of the outcome of all patients and prognostic factors
At the last follow-up of the 235 considered patients, 69 were alive and free of disease (29.7%) from 0.5 to 13 years (mean 6.2 years) after the last treatment, five were alive with uncontrolled disease, 159 were dead.
For patients who died of the tumor the mean survival time from the last relapse was 11.3 months (1 – 132 months). More precisely, 80.6% of patients died in the first year, 13.7% in the second, 2.4% in the third, 2.3% in the fourth and 0.8% after 5 years. No patients died between the 4th and the 5th year. Of the 69 patients presently alive and free of disease, 53 (76.8%) relapsed only once, 6 (8.4%) two times, 7 (9.8%) three times, 0 four times, and 3 (4.2%) five times. None of the patients who never reached remission survived 5 years. The 5-year PREFS after the last treatment is 27.7% and the PROS is 28.8%. As reported in , at the univariate analysis, the PREFS rate was significantly correlated with the time of first relapse (19.8% for patients who relapsed in the first two years vs 41.5% for patients who relapsed after two years, p < 0.0007). For patients in whom the first relapses were lung metastases, the 5-year PREFS was significantly correlated also with the number of lung metastases (22.3% for patients who relapsed with more than two nodules and/or with pleural effusion vs 44.1% for patients who first relapsed with one or two lung nodules, p < 0.0001). It is important to stress that there is a significant correlation between time-to-metastases in the first relapse and number of metastatic nodules. In fact, for patients who in the first relapse had only one or two lung metastases the mean time to recurrence was 29.8 months, while for patients with three or more metastases the mean time was 19.4 months (p < 0.0001). On the other hand, only 25.7% of patients with more than two nodules relapsed in the first two years vs 49.6% of patients who first relapsed with only one or two lung metastases (p < 0.0001). The final outcome was also correlated with the hospital in which patients were treated after the first relapse. The 5-year EFS after the last relapse was in fact 38.2% for the 195 patients treated at our institution and 12.5% for the 33 patients treated at other hospitals. The final outcome was instead not correlated with the type of neoadjuvant protocols in the primary treatment. In particular, the PREFS was the same regardless of the use of salvage chemotherapy for poor responders, and therefore having more effective drugs for the post-relapse treatment of good responders is required. As reported before, the age of patients, type of histological response to chemotherapy after the primary neoadjuvant treatment, and initial serum level of alkaline phosphatase were all correlated with the complete remission after treatment of first relapse, but they were not correlated with the final outcome.
Table IV. Prognostic factors of 5-year post-relapse event free survival (PREFS) according several variables at first relapse.
Discussion
In patients with non-metastatic osteosarcoma who relapse after a primary treatment, multiple retrospective series have shown the curative potential of pulmonary metastectomy, alone or combined with second-line chemotherapy, often repeated several times. The data concerning the real benefit of this therapeutic approach are however contrasting, with a survival rate after recurrence that ranges between 13% Citation[5] and 61% Citation[8]. This discrepancy probably reflects the fact that several factors complicate the analysis of the published literature regarding the post-relapse survival. In fact, as noted by Hawkins and Arndt Citation[6]: (1) some series represent selected cohorts of patients amenable to surgical excision thereby excluding patients with unresectable, and therefore unfavorable outcome Citation[5], Citation[14–16]; (2) some series included patients who had not received adjuvant or neoadjuvant chemotherapy as part of their primary osteosarcoma therapy Citation[5], Citation[17–20]; (3) most series reported only survival rates, often at different times, and only few series reported DFS or EFS rates after disease recurrences Citation[1], Citation[21], Citation[22]. However, the data concerning the post-relapse event-free survival are also really contrasting, and range between 7% Citation[1] and 27% Citation[21]. Small study populations of many series, changing radiographic evaluation, or differences in surgical approaches for recurrent OS might have a role in the cited discrepancies in different series.
In our analysis, performed on the largest series reported in the literature to our knowledge, we have considered a homogeneous group of patients with osteosarcoma in the extremity, who relapsed after complete surgery and neoadjuvant chemotherapy performed in a single institution. In addition to the homogeneity of patients evaluated, the main strength of our study is that more than 80% of these patients had also been treated at the same institution by the same team of doctors after the relapse, and those who survived had been followed here for a mean of 30 months from the last relapse.
The main shortcoming is that we elaborated results concerning patients who were treated over a 22-year period. During this long time new drugs, new radiological techniques, and new surgical reconstruction procedures for bone lesions have been introduced and not all of our patients have been able to take advantage of these innovations.
The pattern of relapse observed in our study was similar to that reported in previous studies Citation[18], Citation[19], Citation[21], Citation[23]. Also the reduction in the number of pulmonary nodules at the initial disease recurrence reported in other studies Citation[21], Citation[24], Citation[25] for patients treated with adjuvant or neoadjuvant chemotherapy in comparison with patients treated in the historical series only by surgery of the primary tumor was confirmed by our study. In fact, at least at the first recurrence about half of patients who relapsed with isolated lung lesions had only one or two lung nodules and the rate of bilateral pulmonary recurrence at first relapse was relatively low (36.0%). The 5-year PREFS from the last relapse was 27.6% and the PROS 27.8%. The 5-years PREFS was significantly better in patients that at first relapse have a long relapse-free interval (RFI), metastases located only in the lung and, in the last group of patients in those with less than three metastatic nodules. These findings are not surprising and could indicate a different biological behavior of the tumor that seems to be confirmed by the fact that in our series patients, who at first relapse had contemporary local and systemic recurrence, had metastases more frequently located in the bone than in the lung. The prognosis was also better for the patients treated at our Institute than for those treated elsewhere. It is impossible however to determine whether this difference was due to the reduced experience in treating this tumor at the other institutions or to the fact that we treated selected patients with a better prognosis (in itself). It must be stressed however that in our group there was a significantly higher rate of patients who relapsed after two years (39.4% vs 19.2%, p < 0.008), with less than three pulmonary nodules (51.1% vs 30.9%, p < 0.025), but this differences lost significance at multivariate analysis.
From our study we were not able to demonstrate the usefulness of the association of second-line chemotherapy to surgery in relapsed patients. In fact, the outcome of patients treated only by surgery or by surgery combined with second-line chemotherapy was almost the same. It must be considered, however, that patients treated only by surgery had significantly less extensive metastatic disease and relapsed later in comparison with patients treated with a combination of surgery and chemotherapy.
Our results seem to be confirmed by a recent study by Kempf-Bielack et al. Citation[26] who reported a 23% of 5-year post relapse survival, and found surgery to be an essential element of the second-line cure. So, it is possible to state that today, the role of second-line chemotherapy treatment combined with surgery in the management of relapsing osteosarcoma patients is not established yet, and no controlled studies are available on this topic. On the other hand, the rarity of the tumor and the heterogeneous pattern of relapse of osteosarcoma makes it almost impossible to carry out randomized studies. According to the number of successive recurrences, the rate of patients who achieved remission was significantly higher after the first relapse in comparison with the following relapses (63.5% vs 38.8%, p < 0.0001).
However, is interesting to note that three of six patients treated after the 5th relapse reached remission. In addition, also the interval between the last relapse and death in patients who did not achieve remission differed from patient to patient. In fact, some patients died in few months, while others lived more than five years. More exactly, 32% of patients died in six months but five patients survived more than five years. If one considers that the patients who died after the last relapse had no further treatments or only palliative treatment, also these data seem to confirm heterogeneity in the biological behavior of osteosarcoma from patient to patient.
In conclusion, the current study seems to demonstrate that in patients with osteosarcoma of the extremities who relapse after neoadjuvant chemotherapy, although at the cost of repeated surgical procedures, prolonged survival, and probably also cure, are possible in about 1/4 of cases and that this rate is higher in particular subgroups of patients.
Related Research Data
References
- Fuchs N, Bielack SS, Epler D, et al. Long-term results of the co-operative German-Austrian-Swiss osteosarcoma study group's protocol COSS-86 of intensive multidrug chemotherapy and surgery for osteosarcoma of the limbs. Ann Oncol 1998; 9: 893–9
- Bacci G, Ferrari S, Bertoni F, et al. Long-term outcome for patients with nonmetastatic osteosarcoma of the extremity treated at Istituto Ortopedico Rizzoli according to the IOR/OS-2 protocol: an updated report. J Clin Oncol 2000; 18: 4016–27
- Goorin AM, Schwartzentruber DJ, Devidas M, et al. Presurgical chemotherapy compared with immediate surgery and adjuvant chemotherapy for nonmetastatic osteosarcoma: Pediatric Oncology Group Study POG-8651. J Clin Oncol 2003; 21: 1574–80
- Smeland S, Muller C, Alvegard T, et al. Scandinavian Sarcoma Group Osteosarcoma Study SSG VIII: prognostic factors for outcome and the role of replacement salvage chemotherapy for poor histological responders. Eur J Cancer 2003; 39: 488–94
- Martini N, Huvos AG, Mike V, Marcove RC, Beattie EJ. Multiple pulmonary resection for metastatic osteogenic sarcoma. J Bone Joint Surg (Am) 1971; 12: 271–80
- Hawkins DS, Arndt CA. Pattern of disease recurrence and prognostic factors in patients with osteosarcoma treated with contemporary chemotherapy. Cancer 2003; 98: 2447–56
- Antunes M, Bernardo J, Salete M, Prieto D, Eugenio L, Tavares P. Excision of pulmonary metastases of osteogenic sarcoma of the limb. Eur J Cardiothorac Surg 1999; 15: 592–6
- Picci P, Ruggieri P, Mercuri M, et al. Primary chemotherapy and delayed surgery (neoadjuvant chemotherapy) for osteosarcoma of the extremities. The Istituto Rizzoli experience in 127 patients treated peroperatively with intravenous methotrexate (high versus moderate doses) and intraarterial cisplatin. Cancer 1990; 65: 2539–53
- 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 1993; 72: 3227–38
- Ferrari S, Mercuri M, Picci P, et al. Nonmetastatic osteosarcoma of the extremity: results of a neoadjuvant chemotherapy protocol (IOR/OS-3) with high-dose methotrexate, intraarterial or intravenous cisplatin, doxorubicin, and salvage chemotherapy based on histologic response. Tumori 1999; 85: 458–64
- Bacci G, Briccoli A, Ferrari S, et al. Neoadjuvant chemotherapy for osteosarcoma of the extremity: long-term results of the Rizzoli's 4th protocol. Eur J Cancer 2001; 37: 2030–9
- Bacci G, Ferrari S, Longhi A, et al. High-dose ifosfamide in combination with high-dose methotrexate, doxorubicin and cisplatin in the neoadjuvant treatment of extremity osteosarcoma: preliminary results of an Italian Sarcoma Group/Scandinavian Sarcoma Group pilot study. J Chemother 2002; 14: 198–206
- Picci P, Bacci G, Campanacci M, et al. Histologic evaluation of necrosis in osteosarcoma induced by chemotherapy. Cancer 1985; 56: 1515–21
- Spanos PK, Payne WS, Ivins JC, Pritchard DJ. Pulmonary resection for metastatic osteogenic sarcoma. J Bone Joint Surg (Am) 1976; 58: 624–8
- Heij HA, Vos A, de Kraker J, Voute PA. Prognostic factors in surgery for pulmonary metastases in children. Surgery 1994; 115: 687–93
- Schaller RT, Haas J, Schaller J, Morgan A, Bleyer A. Improved survival in children with osteosarcoma following resection of pulmonary metastases. J Pediatr Surg 1982; 17: 546–50
- Pastorino U, Gasparini M, Tavecchio L, et al. The contribution of salvage surgery to the management of childhood osteosarcoma. J Clin Oncol 1991; 9: 1357–62
- Ward WG, Mikaelian K, Dorey F, et al. Pulmonary metastases of stage IIB extremity osteosarcoma and subsequent pulmonary metastases. J Clin Oncol 1994; 12: 1849–58
- Saeter G, Hoie J, Stenwig AE, Johansson AK, Hannisdal E, Solheim O. Systemic relapse of patients with osteogenic sarcoma: prognostic factors in long term survival. Cancer 1995; 75: 1084–93
- Temek BK, Wexler LH, Steinberg SM, McClure LL, Horowitz M, Pass HI. Metastasectomy for sarcomatous pediatric histologies: results and prognostic factors. Ann Thorac Surg 1995; 59: 1385–90
- Goorin AM, Shuster JJ, Baker A, Horowitz ME, Meyer WH, Link MP. Changing patterns of pulmonary metastases with adjuvant chemotherapy in patients with osteosarcoma: results from the Multiinstitutional Osteosarcoma Study. J Clin Oncol 1991; 9: 600–5
- Tabone MD, Kalifa C, Rodary C, Raquin M, Valteau-Couranet D, Lemerle J. Osteosarcoma recurrences in pediatric patients previously treated with intensive chemotherapy. J Clin Oncol 1994; 12: 2614–20
- Huth JF, Eilber FR. Patterns of recurrence after resection of osteosarcoma of the extremity: strategies for treatment of metastases. Arch Surg 1989; 124: 122–6
- Jaffe N, Smith E, Abelson HT, Frei E. Osteogenic sarcoma: alterations in the pattern of pulmonary metastases with adjuvant chemotherapy. J Clin Oncol 1983; 1: 251–4
- Bacci G, Ferrari S, Longhi A, et al. Pattern of relapse in patients with osteosarcoma of the extremities treated with neoadjuvant chemotherapy. Eur J Cancer 2001; 37: 32–8
- Kempf-Bielack B, Bielack SS, Jurgens H, et al. Osteosarcoma relapse after combined modality therapy: and analysis of unselected patients in the Cooperative Osteosarcoma Study Group. J Clin Oncol 2005; 23: 559–68