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© 2000 American Society for Clinical Oncology Long-Term Outcome for Patients With Nonmetastatic Osteosarcoma of the Extremity Treated at the Istituto Ortopedico Rizzoli According to the Istituto Ortopedico Rizzoli/Osteosarcoma-2 Protocol: An Updated ReportFrom the Service of Chemotherapy, Laboratory of Pathology, Fifth Service of Orthopedic Surgery, and Laboratory of Oncologic Research, Department of Musculoskeletal Oncology, I.F. Goidanich of the Istituto Ortopedico Rizzoli, Bologna, Italy. Address reprint requests to Gaetano Bacci, MD, Sezione di Chemioterapia, Istituto Ortopedico Rizzoli, Via Pupilli 1, 40136 Bologna, Italy; email gaetano.bacci{at}ior.it
PURPOSE: To provide an estimate of long-term prognosis for patients with osteosarcoma of the extremity treated in a single institution with neoadjuvant chemotherapy and observed for at least 10 years. PATIENTS AND METHODS: Patients with nonmetastatic osteosarcoma of the extremity were preoperatively treated with high-dose methotrexate, cisplatin, and doxorubicin (ADM). Postoperatively, good responders (90% or more tumor necrosis) received the same three drugs used before surgery, whereas poor responders (less than 90% tumor necrosis) received ifosfamide and etoposide in addition to those three drugs. RESULTS: For the 164 patients who entered the study between September 1986 and December 1989, surgery was a limb salvage in 136 cases (82%) and a good histologic response was observed in 117 patients (71%). At a follow-up ranging from 10 to 13 years (median, 11.5 years), 101 patients (61%) remained continuously free of disease, 61 relapsed, and two died of ADM-induced cardiotoxicity. There were no differences in prognosis between good and poor responding patients. ADM-induced cardiotoxicity (six patients), male infertility (10 of the 12 assessable patients), and second malignancies (seven patients) were the major complications of chemotherapy. Despite the large number of limb salvages performed, only four local recurrences (2.4%) were registered. CONCLUSION: With an aggressive neoadjuvant chemotherapy, it is possible to cure more than 60% of patients with nonmetastatic osteosarcoma of the extremity and amputation may be avoided in more than 80% of them. Because local or systemic relapses, myocardiopathies, and second malignancies are possible even 5 years or more after the beginning of treatment, a long-term follow-up is recommended for these patients.
TWO RANDOMIZED studies, and many uncontrolled ones, demonstrated that adjuvant and neoadjuvant chemotherapy dramatically improved the prognosis of patients with nonmetastatic osteosarcoma of the extremity, raising the survival rate from 10% to 20% to 60% to 70%.1-13 Simultaneously, the frequency of limb salvage surgery increased from 10% to 20% to 80% to 90%, with a corresponding decrease in the amputation rate. However, most of these studies reported their results in terms of the probability of event-free survival (EFS) up to 5 years, calculated on study populations whose minimum follow-up was often less than 3 years,1-6,10 and only in a few studies have these results been updated.7,14,15 Additionally, in most of these studies little is known about the postrelapse treatments and outcome of patients who develop metastases or local recurrence. A long-term follow-up for patients with osteosarcoma treated with adjuvant or neoadjuvant chemotherapy is of great importance for several reasons. First, in our experience,16 as well as in that of other authors,17 it seems that chemotherapy, besides improving the cure rate, can alter the natural history of this disease, delaying the time until disease recurrence in relapsing patients so that late relapses are not uncommon. Second, in patients observed for an adequate period of time, second malignant neoplasms have been reported by several authors.9,18-20 Third, late toxic effects of chemotherapy, such as doxorubicin (ADM)–induced cardiotoxicity2,4,11,21 and sterility,22 are also possible. Finally, in most patients treated with limb salvage, it is possible that the devices used for reconstructions do not last for a long time, and therefore, over a long period, the functional results deteriorate and new operations have to be performed. In 1993, we published the results achieved in 164 patients with osteosarcoma of the extremity treated at our institution between 1986 and 1989 according to the Rizzoli’s second neoadjuvant protocol (IOR/OS-2).23 At the time of this publication, the follow-up ranged between 3 and 6 years (median, 4 years). The aim of this article is to update these results and evaluate the EFS, postrelapse outcome of the relapsing patients, overall survival (OS), incidence of second tumors, late toxic effects of chemotherapy, and surgical complications, as well as functional results, in patients observed for at least 10 years.
Patient Selection and Pathology Patients were considered eligible for the trial if they met the following criteria: typical radiographic and histologic features of primary, high-grade, central osteosarcoma; tumor located in the extremity; no previous history of cancer and no prior treatments; age less than 40 years; no associated disease contraindicating chemotherapy; and no evidence of metastases at diagnosis. Of the 319 newly diagnosed cases of osteosarcoma observed at the authors’ institution between September 1986 and December 1989, 187 were eligible for the study. One hundred thirty-two patients were excluded: 39 with metastatic disease at presentation; 67 with osteosarcoma varieties (parosteal [n = 11], periosteal [n = 7], low-grade [n = 7], malignant fibrous histiocytoma [n = 26], radioinduced osteosarcomas [n = 6], osteosarcoma in Paget’s disease [n = 4], and dedifferentiated osteosarcoma [n = 6]), metastatic at presentation in 13 of them; 31 with tumor not located in the extremity, with metastases at presentation in five; nine older than 40 years, with one metastatic disease; and one with previous treatment. In 15 patients, there was more than one reason for exclusion. All the eligible patients were offered a new neoadjuvant treatment according to the IOR/OS-2 protocol after having been informed of the potential advantages and risks. Of the 187 eligible patients, 23 declined to enter the study and were treated with immediate surgery followed by adjuvant chemotherapy (20 cases) or moved to other institutions for treatment (three cases). The remaining 164 patients are the basis of this article, and their characteristics are reported in Table 1.
The diagnosis of osteosarcoma, established by clinical and radiologic findings, was always confirmed on histologic slides of tumor tissue obtained from an open or needle biopsy as well as from the resected specimen. Two pathologists (F.B. and M.C.) reviewed the slides and all agreed on diagnosis, subtype, and grade of malignancy. On the basis of predominant cell type and intercellular material, the tumor was classified as osteoblastic, fibroblastic, chondroblastic, or telangiectatic. This distinction, always made on surgical specimens, was possible in all but 13 cases that were defined as not classifiable.
Preoperative Evaluation and Preoperative Chemotherapy Preoperative chemotherapy consisted of methotrexate (MTX), ADM, and cisplatin (CDP), according to the schedule and doses reported in Fig 1. MTX (8 g/m2) was delivered intravenously in a 6-hour infusion with citrovorum factor rescue (15 mg every six hours for 11 times, starting 24 hours after the beginning of MTX). Hydration during and after MTX infusion was performed according to the guidelines suggested by Rosen et al.1 Starting on day 7, patients received CDP and ADM. CDP was delivered intra-arterially at the dose of 120 mg/m2 over a 72-hour continuous infusion, whereas ADM was given intravenously at the dose of 60 mg/m2 in a 8-hour infusion, starting 48 hours after the beginning of CDP infusion. Hematopoietic, renal, metabolic, and liver functions were checked before and after each chemotherapy administration. No dose reductions were considered in the protocol, and if the absolute granulocyte count was less than 1,000/mL (800 for MTX cycles) and/or the platelet count was less than 100,000/mL (80,000 for MTX cycles), chemotherapy was delayed until recovery. The blood count was monitored every 2 days starting a week after the end of the chemotherapy cycle, and patients received transfusions if the platelet count dropped below 10,000/mL or the hemoglobin level dropped below 6 g/dL.
Type of Surgery and Pathologic Evaluation Surgery was scheduled 3 weeks after the end of preoperative chemotherapy. Before surgery, the tumor was restaged to assess its extension after preoperative treatment. The type of surgery (amputation, rotation plasty, or limb salvage), as well as the type of reconstruction after resection (prosthesis, Kuntscher rod or plate and cement, vascularized fibula combined with allograft, allograft, or autograft) was chosen depending on the location and extension of the tumor, neurovascular structure involvement, skeletal maturity, desired lifestyle, and presence of complicating factors, such as displaced pathologic fractures or infected biopsy sites. In any case, for conservative surgery, it was mandatory that the preoperative staging assured the possibility of achieving wide surgical margins and preserving a limb that could at least be partially functional after reconstruction at the same time. After surgery, the surgeons and the pathologists reviewed the gross specimens to determine surgical margins that, following the classification of Enneking et al,24 we reported to be radical (abscission of the entire anatomic compartment containing the tumor), wide (tumor mass removed with a surrounding cuff of normal tissue), marginal (tumor removed with at least one area that was in contact with the reactive tissue zone, but without violation of the pseudocapsule of the mass), intralesional (tumor removed, yet at least one margin contained tumor cells), and contaminated (the tumor was removed, but at least one surgical margin had the presence of tumor cells, and therefore, intraoperatively, additional tissue was removed in an attempt to obtain a wide margin with violation). The margins were adequate if radical or wide and inadequate if marginal, intralesional, or contaminated. The histologic response to chemotherapy was evaluated according to the criteria previously reported25 and graded as good (90% or more tumor necrosis) or poor (less than 90% tumor necrosis). These two grades roughly correspond to grades III and IV and to grades I and II of the descriptive classification proposed by Rosen et al1 and generally followed by many authors.
Postoperative Chemotherapy and Follow-Up All the drugs were applied as single agents for each cycle, with the exception of etoposide and CDP, which were combined. The dose-intensity of the single drug received was calculated as mg/m2/wk by dividing the total amount of the drug by the duration of treatment in weeks, and it was expressed as the percentage of the protocol-planned single-drug dose-intensity. The received dose-intensity was expressed as the mean of the percentages of the received dose-intensities of all drugs included in the protocol.26 During postoperative chemotherapy, besides the clinical evaluation, patients were checked every 2 months with radiographs of the chest and of the operated limb. Additional investigations were performed only if there was a clinical and/or radiographic suspicion of relapse. After completion of chemotherapy, patients were observed in the outpatient clinic with radiographs every 2 months for 2 years, every 3 months in the third year, and then every 6 months.
Evaluation of Surgical Complications and Functional Results
Statistics
Treatment Compliance and Chemotherapy Dose-Intensity In 11 patients, chemotherapy was stopped early (after surgery in seven cases, and after the first postoperative cycle in four) because patients refused to continue treatment (eight cases) or because of infective surgical complications (three cases). In five patients who were poor responders, etoposide was omitted for persistent myelosuppression or slow recovery from myelosuppression. Finally, four patients with necrosis less than 90% were erroneously treated after surgery as good responders. In the remaining 144 patients, the mean dose-intensity of chemotherapy was 89.7% of the scheduled dose-intensity (range, 63% to 103%). In these patients, of the total 1,563 cycles of chemotherapy performed, 148 cycles (9%) were delayed from 8 to 25 days. The reasons for these delays were as follows: delayed bone marrow recovery (n = 99) or MTX clearance (n = 4), surgical complications (n = 15), other abnormal laboratory findings indicating a persistent hepato- or renal toxicity (n = 6), and extramedical or organizational problems (n = 24). The median cumulative delay in chemotherapy for these 144 patients was 24.6 days for good responders and 36.6 days for poor responders, corresponding to 11% and 14%, respectively, of the total scheduled time of treatment. Although the protocol did not call for dose reductions, these were performed in 29 cycles and ranged from 5% to 25% (mean, 13%) of the scheduled dose. Because of delays and dose reductions, only 17 patients (12%) received the treatment exactly as scheduled according to the protocol, 87 (60%) received between 90% and 99% of the scheduled dose-intensity, and the remaining 40 patients (28%) received a dose-intensity between 63% and 89%. The dose-intensity of chemotherapy was higher in good responders who had a shorter postoperative treatment compared with that of poor responders who had a longer treatment with two more drugs. The median dose-intensity in the two groups was respectively 91.9% and 81.9% of the scheduled dose-intensity (P < .0001).
Clinical and Radiologic Response to Preoperative Chemotherapy
The radiologic response in osteosarcoma consists of an increment of density of the lesion on plain radiographs associated with a decreased vascularity on angiograms. Moreover, a reduction of the mass of the tumor in soft tissues can be observed, because of a decrease of the inflammatory component surrounding the tumor.28 Radiologic responses were observed in 151 patients (92%), there were no significant changes in 11 (7%), and a radiographic progression of the tumor was observed in two (1%). A radiologic reduction in tumor size of more than one third of the tumor mass in the soft tissue was observed in 79 patients (48%), but a reduction
Surgery and Local Recurrence
In limb salvage procedures, reconstruction was prosthesis in 79 patients, Kuntscher rod or plate plus cement in 10, vascularized fibula combined with allograft in 11, allograft in 21, and autograft in eight. No reconstruction was necessary in seven patients with tumors located in the fibula. The surgical margins were adequate in 137 patients (84%) and inadequate in 27. In more detail, margins were as follows: in amputated patients, the surgical margins were radical in 14 (78%) and wide in four (22%); in patients treated with limb salvage, margins were wide in 110 cases (81%), marginal in 12 (9%), intralesional in seven (5%), and wide but contaminated in seven (5%); and in patients who had a rotationplasty, the margins were wide in nine (90%) and intralesional in one (10%). Although 27 patients (16%) had inadequate surgical margins, local relapse occurred in only four (2%) patients, 23, 28, 48, and 66 months from the beginning of treatment. In three cases, the local failures were without detectable metastasis at diagnosis, whereas in one case, it was associated with a simultaneous lung metastasis. All four of these patients had been treated with limb salvage, and the surgical margins had been adequate (wide) in one and inadequate in three (wide but contaminated in two and intralesional in one). Three primary tumors were located in the femur and one in the tibia. Two of the three patients whose local recurrences were without detectable metastasis at diagnosis were treated by an amputation, whereas the remaining patient underwent new limb salvage. Surgery was always followed by further chemotherapy with ifosfamide at conventional doses (2 g/m2/d for 5 days). All three of these patients successively developed lung metastases, associated with a new local recurrence in the patient who underwent resection, and all died of the tumor. The last patient with local recurrence associated with a solitary lung metastasis had contemporaneous operation on both sites (new limb salvage for the local recurrence and wedge resection for the pulmonary metastasis). Postoperatively, he received high doses of ifosfamide (15 g/m2 for a 5-day continuous infusion). Three years later, the patient had new lung metastases, and 1 year after this, he died of the tumor.
Histologic Response to Preoperative Chemotherapy
Survival
As illustrated in Table 1, at the univariate analysis, the EFS rate was not related to the patient’s sex or age, tumor volume or site, histologic subtype, serum lactate dehydrogenase or alkaline phosphatase level, or presence or absence of pathologic fracture. As listed in Table 3, EFS was also unrelated to MTX serum levels at the end of infusion and to type of surgery performed.
According to the grade of histologic response to chemotherapy, the EFS was 67% (SE, 0.045) for the 115 good responders and 51% (SE, 0.073) for the 47 poor responders. This difference is not statistically significant (P = .08). Moreover, if we do not consider the four poor responders who were erroneously treated after surgery as good responders, the difference between the two groups is even less: 67% (SE, 0.045) versus 56% (SE, 0.081). No significant differences in terms of EFS were found when the 22 patients with total necrosis were compared with the remaining patients: 68% (SE, 0.11) versus 57% (SE, 0.042), P = .144. The first signs of relapse were metastases in 57 patients, local recurrence in three, and metastases plus local recurrence in one. As reported before, the three patients who initially relapsed only locally also successively developed lung metastases. The first site of metastases was the lung in 56 patients (91.8%) and bone in five (8.2%). The average time to relapse was 28.8 months (range, 4 to 112 months), with no difference between good and poor responders (29.3 v 28.0 months).
Postrelapse Treatment and Outcome The postrelapse outcome of these 44 patients was as follows: 15 (34%) were alive and free of disease 38 to 121 months after the last treatment, 28 died of the tumor 9 to 76 months after relapse (mean, 39 months), and one was alive with uncontrolled disease 28 months after the last (third) relapse. In these 44 patients who underwent metastasectomy, the only prognostic factor for postrelapse EFS was the length of the free interval. The mean time to relapse was 44.8 months (range, 12 to 112 months) for the survivors and 23.3 months (range, 4 to 42 months) for patients who died. This difference is highly significant (P < .0005).
Toxicity Six patients (4%) experienced a clinically severe cardiotoxicity. In five patients, it developed 1 to 12 weeks after the last cycle of chemotherapy. Two of these patients, with no signs of metastases or local recurrence, died respectively 1 and 9 weeks after the appearance of the cardiopathy, two died of disseminated metastases, and one is alive and well 7 years after heart transplantation. In another patient, the myocardiopathy became clinically manifested during the last month of her first pregnancy, 8 years after the end of chemotherapy. This patient was alive and well 2 years after heart transplantation. Episodes of World Health Organization grade 1 or 2 renal toxicity were recorded after 11 chemotherapy cycles (0.6%). Lung tuberculosis controlled by medical treatment occurred in two patients, and one episode of transient ascites after the administration of the last cycle of MTX was observed.
Fertility There were 54 long-term women survivors. None of the 26 who had received chemotherapy after the time of puberty experienced permanent amenorrhea. Menarche occurred normally in the 28 patients who had received chemotherapy before puberty. All 12 of the women who sought a pregnancy succeeded (there were a total of 13 pregnancies, one of which ended with early spontaneous abortion and 12 of which ended with the delivering of healthy newborns).
Second Tumor
Surgical Complications and Functional Results One hundred thirty-four surgical complications (36 minor and 98 major) were observed in 94 patients, thus resulting in 57% of the patients having at least one complication. Thirty-six patients had more than one complication. No complications were observed in the 18 patients who underwent amputation, whereas three major complications were observed in the 10 patients treated with rotationplasty. Reported in Table 5 are major surgical complications in patients treated with limb salvage according to the type of reconstruction. Eighty-nine patients had to undergo new surgery for major surgical complications: 20 underwent reoperation twice, nine three times, and three had a total of four operations. The earliest major complication was observed 4 weeks, and the latest 6 years, after the first operation. Thirteen (13%) of the 98 major complications were diagnosed 3 years or more after the beginning of treatment.
The complications that required surgery were successfully managed without causing the loss of the involved limb or definitive removal of the reconstructive device, with the exception of a deep infection that required amputation and three prosthetic reconstructions in which it was necessary to remove the implant. It must be emphasized that the 98 major complications also included 25 cases of substitution of polyethylene bushings in Kotz Modular Femur and Tibia Reconstruction System prosthesis, which is a minor surgical procedure. Functional results were not assessable in 12 patients. In the 152 evaluated cases, all 10 of the patients treated with rotation plasties had good functional results, whereas among the 18 amputated patients, nine had good and nine poor functional results. For the 124 patients treated with a limb salvage, the functional results were excellent in eight (6%), good in 80 (65%), and poor in 36 (29%). In these patients, the most of unsatisfactory results resulted from major complications or were related to the lack of movement (in patients treated with an arthrodesis).
The updated results of our study indicate the achievement of a long-term EFS greater than 60% among patients with osteosarcoma of the extremity who were treated with neoadjuvant chemotherapy according to the IOR/OS-2 protocol and observed for at least 10 years. Furthermore, our results show that late relapses and late complications of treatment are not uncommon. The curves of EFS were characterized by an initial phase corresponding to the first 2 years after the beginning of treatment with a rapid decrease of probability of EFS followed by a second phase in which the EFS curve slowly decreased to a plateau, reached by year 8. The EFS at 2, 5, and 10 years was 80%, 65%, and 62%, respectively. This pattern is similar to the one observed in our first neoadjuvant study.15 For these patients, a long-term follow-up is recommended, and the possibility of a late relapse has to be considered in evaluating the early results of new chemotherapy regimens. In osteosarcoma, the histologic response to preoperative chemotherapy strongly predicts subsequent EFS and OS,1,2,4-7,9-11,15 and the idea of rescuing poor responders by changing chemotherapy in the postoperative phase remains controversial. Although in most studies this strategy failed,4,5,7,9,15 Benjamin et al,29 using postoperative salvage chemotherapy with high-dose MTX, ifosfamide, and ADM/dacarbazine, obtained a 5-year EFS among poor responder patients preoperatively treated with CDP and ADM that was not different from that of good responders. In the present study, from a statistical point of view, patients with good and poor histologic response had a similar prognosis. If we exclude the four poor responders who were erroneously treated as good responders, the 10-year EFS in good and poor responders was 67% and 56%, respectively. Because this difference is not statistically significant, it seems that the strategy of a salvage postoperative treatment for poor responders is effective. In fact, after surgery, whereas good responders were treated only with the three drugs (MTX, CDP, and ADM) used preoperatively, the poor responders also received postoperatively ifosfamide and etoposide. Nonetheless, it must be stressed that the lack of statistical significance between good and poor responders could be a result of the size of the sample, with the possibility of a type II statistical error. On the other hand, the only way to demonstrate the efficacy of a salvage chemotherapy is a randomized study for poor responders, which is difficult to perform because of the rarity of the tumor. For patients who relapse after neoadjuvant treatment despite following treatments, the prognosis is generally poor, with a 5-year postrelapse survival ranging between 13% and 25%.8,12,30-32 In the present series, 15 (24%) of the 61 relapsed patients were alive and free of disease from 3 to 10 years after the last treatment. As reported in other studies,8,31,32 no patients who relapsed with local recurrence and bone or unresectable pulmonary metastases survived, whereas 15 (34%) of the 44 patients whose lung metastases were surgically removed were long-term survivors. For this group of patients, the only prognostic factor was the length of the interval between the beginning of treatment and the time of relapse. Two major treatment-induced late complications observed in our study deserve attention because of their probable irreversibility: ADM cardiomyopathy and male infertility. The problem of ADM cardiotoxicity for patients with osteosarcoma treated by adjuvant and neoadjuvant chemotherapy has been outlined by many authors.2,4,9,11 The most impressive report on this topic is that of Geidel et al,21 who, evaluating 785 patients with osteosarcoma treated with combined chemotherapy in the Cooperative Osteosarcoma Study Group studies, reported that, in addition to 2% of patients experiencing congestive heart failure, more than 50% of patients had a subclinical heart disease at echocardiography and radionuclide ventriculography. In our study, in which the cumulative dose of ADM was 480 mg/m2, we had six cases of severe congestive heart failure (3.6%), which led to two deaths and two successful heart transplantations. Some authors reported that the frequency of clinical heart damage increases with time until the end of the anthracycline therapy33 and that, therefore, it is possible that the incidence of ADM cardiotoxicity increases with a longer follow-up. Of note, one of the myocardiopathies observed in our patients became suddenly manifest during a pregnancy 8 years after the end of chemotherapy. Infertility has been reported as a late effect in many long-term survivors treated with chemotherapy. According to the literature, males seem to be specifically prone to this complication, whereas females are less severely affected, and in a less predictable way.22,34,35 The results of our study seem to confirm these data. Ten of 12 of our male patients whose data are available lost fertility, whereas females showed no persistent alterations of the menses and all 11 of the patients who sought a pregnancy succeeded in having a baby. Our data on male patients are in contrast with the data reported by Nicholson et al,35 who, evaluating 82 long-term survivors of osteosarcoma, concluded that "deficit in marriage and fertility were not significant." Because, for most men, it seems that even a few doses of an alkylate agent may result in life-long azoospermia, all young males with osteosarcoma in the future should have the option for cryopreservation of semen before chemotherapy with regimens that cause infertility. Also, the occurrence of a second malignant neoplasm in successfully treated patients with osteosarcoma has become an area of increasing concerns.4,9,11,18-20 In the present study, five of 101 long-term survivors developed a second neoplasm. This rate is equal to the one reported by Nicholson et al,35 who documented four second malignancies in 82 survivors of osteosarcoma with an average follow-up of 17.5 years, and significantly higher than the rate reported by Pratt et al,20 who reported a cumulative incidence of second neoplasm at 10 years of only 2% in the analysis of a series of 334 patients observed for 0.1 to 31 years (mean, 2.7 years). Moreover, whereas in the series by Pratt et al eight of the nine patients with second malignancies had a family history of cancer, not one of our five patients with second malignancy had a history of familial cancer predisposition. Because second malignancies are usually late events (two of the five second neoplasms of our study were observed more than 10 years after the beginning of treatment), it is also possible that the incidence of a second neoplasm increases with a longer follow-up. The data reported by Beattie et al19 are alarming. These authors, analyzing the results of children with osteosarcoma who had a complete resection of pulmonary metastases after relapse and who were observed for up to 20 years, reported that three of six of the 10-year survivors developed a second primary cancer in the second decade of follow-up. The introduction of neoadjuvant chemotherapy brought about changes in the surgical treatment of osteosarcoma of the extremity, which today is mainly performed by resection and reconstruction instead of amputation. In our study, only 18 patients (11%) underwent amputation and 136 had limb salvage. Because the data from multi-institutional and single-center studies showed a local recurrence rate that is three to four times higher after limb-sparing resections as compared with amputation,36-39 some authors expressed concerns about this greater incidence of limb-salvage procedures.40,41 The increased number of resections could, in fact, lead to a general narrowing of surgical margins, increasing, as a consequence, the risk of local recurrence. In the present study, none of patients treated with limb salvage had radical margins, and 27 had marginal, contaminated, or intralesional surgery. Nevertheless, only four local recurrences were observed. In three of these patients, surgical margins were contaminated or marginal; the margins were wide in only one. For this reason, we believe that in osteosarcoma of the extremity treated with effective chemotherapy and by experienced surgeons, surgical margins can be safely diminished and wide resections may be acceptable. The rate of local recurrences observed in our patients treated with limb salvages is significantly lower than the rate (9% to 12.5%) reported by other authors38-40 and similar to the rate reported by Sluga et al.42 The increment of limb salvage procedures and the better long-term survival of patients with nonmetastatic osteosarcoma of the extremity result in a greater rate of immediate and delayed complications. In the present study, 86 (63%) of 136 patients treated with limb salvage had some major surgical complications and had to undergo reoperation one or more times. Lindner et al43 reported a similar rate of major surgical complications (52%) in 79 patients treated with limb salvage and neoadjuvant chemotherapy according to the Cooperative Osteosarcoma Study Group protocols. It is important to stress that 15% of the major complications seen in our patients occurred 3 years or more after surgery. Moreover, approximately one third of these patients had a functional result that was equal or worse than the functional results that generally follow amputation. Therefore, we believe that, in planning a limb salvage procedure for osteosarcoma of the extremity, concerns over complications and functional results, in addition to concerns regarding local recurrence, should be considered. In other words, for each patient, a rational solution must be found to obtain optimal functions with minimal risk of local recurrence and surgical complications. In conclusion, the updating of our study shows that patients with osteosarcoma of the extremity who are successfully treated must be carefully followed up for a long time to identify, at an early stage, late relapses, late treatment-related complications, and second neoplasms. In osteosarcoma, it is generally accepted that patients with no evidence of disease after 5 years from diagnosis are expected to live as long as someone without a history of cancer. According to our results, this cutoff should be increased to assure reliability. In fact, in our experience, being alive and free of disease 5 years after diagnosis did not assure prolonged survival, because nine of 122 (7.2%) of the 5-year survivors died of their primary disease or of a second malignancy. Moreover, some nonlethal side effects of chemotherapy, such as myocardiopathy and infertility, may become evident late. Therefore, because survivors of osteosarcoma are at high risk of late events, a protracted medical follow-up is of great importance for counseling and to find new treatments able to minimize late side effects in future groups of survivors.
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ABSTRACT
INTRODUCTION
2 test. Significance was set at P < .02. 
50% of the tumor mass was observed in only 20 patients (12%). In all the patients who had a poor radiologic response, the histologic response was poor, whereas in the patients with a radiographic response, all rates of necrosis were observed. 
