Sarcomas of Bone

p53-ARF-MDM2 Pathway

In conjunction with the CDK4/6 inhibitor p16INK4A, mutations of the TP53 gene are the most recurrent genetic alterations associated with cancer. The TP53 gene encodes the well-known tumor suppressor p53, which plays an important role in various regulatory processes involved with cell cycle progression. Most important, p53 acts as an important negative regulator, facilitating growth arrest, senescence, and/or apoptosis when cells are exposed to genotoxic, cytotoxic, and/or physiologic stresses. A transcription factor, p53 possesses two transcriptional activation domains and a DNA-binding domain that recognizes specific sequences. After exposure to cellular stress, p53 activates expression of CDKN1A, which encodes the cyclin-dependent inhibitor p21CIP1. It is through the expression of p21 that p53 negatively regulates the cell cycle.

The expression level and activity of p53 is regulated by two different proteins: MDM2 and p14ARF. MDM2 is an E3 ubiquitin ligase, which facilitates the degradation of p53 in a ubiquitin- and proteasome-dependent manner. Interesting to note, MDM2 is a transcriptional target of p53, whose expression is increased in concert with increased levels of p53. In addition to promoting degradation, MDM2 can also inhibit p53 function through a direct protein-protein interaction, suppressing its transcriptional activity, in addition to translation of the messenger RNA transcript itself. To combat these negative regulatory effects, p14ARF is able to positively regulate p53, in part through the negative regulation of MDM2. p14ARF can actually be found at the same gene locus as CDKN2A, which encodes the CKI p16. The two gene sequences do overlap but possess alternate reading frames and are independently regulated. ARF binds MDM2, preventing it from interacting with p53. Consequently, p53 becomes stabilized and its overall activity increases within the cell.

CIP/KIP Family of Cyclin-Dependent Kinase Inhibitors

The CIP/KIP family of proteins is the second group of cyclin-dependent kinase inhibitors (CKIs). There are three different members: p21CIP1, p27KIP1, and p57KIP2. Similar to the INK4 family of CKIs, CIP/KIP proteins inhibit the kinase activity of cyclin-dependent kinases (CDKs) by preventing their association with cyclin subunits and adenosine triphosphate molecules, both of which are required for the phosphorylation of target substrates. Unlike the INK4 family, however, CIP/KIP proteins are able to functionally inhibit multiple CDKs. For instance, both p27 and p57 can inhibit the kinase activity of CDK4/6 and CDK2, whereas p21 acts to control the function of both CDK2 and CDK1. Of the three family members, p21 is the most diverse, performing a variety of functions in addition to controlling CDK activity. For example, it was previously mentioned that p21 is a transcriptional target of p53. After exposure to various stresses, p53 activates the expression of p21, thus inducing a DNA damage response. In addition, p21 has been shown to localize to the cytoplasm, where it acts to inhibit the induction of apoptosis by interacting with proteins involved in mediating this process.

Other Important Players

The last two cell cycle regulators that are discussed are C-MYC and Ki-67. Both of these proteins play crucial roles during cell proliferation but do so in very different ways. C-MYC influences several processes involved in cell cycle regulation via its function as a transcription factor. For example, C-MYC, when bound to its partner MAX, has been shown to induce the expression of cyclins D1 and D2 and of CDK4, subsequently promoting G ₁ phase progression. The MYC-MAX heterodimer can also support continued cell cycle progression through the repression of multiple CKIs, including p15, p18, p21, and p27. Furthermore, C-MYC can increase the expression of E2F2 and cyclin A2, both of which affect the S phase of cell cycles and contribute to overall proliferation. Similar to C-MYC, Ki-67 has been shown to be vital for cell proliferation. Ki-67 is a cell proliferation–associated nuclear antigen that is thought to contribute to cell cycle progression via its involvement in ribosomal RNA and ribosome synthesis. Interesting to note, Ki-67 is expressed in all of the phases of cell cycle (excluding G ₀ ), but whether or not it participates in other such related processes is currently unknown.

A small subset of osteosarcomas are hereditary. Osteosarcoma in siblings occurs in fewer than 1 in 1000 to 3000 osteosarcoma patients. Observation of two or more affected siblings in a family indicates an underlying genetic predisposition. When siblings in multiple generations are affected, an autosomal dominant disorder is most likely responsible. One example would be the hereditary form of retinoblastoma (RB). Individuals with hereditary RB (germline RB gene mutation) have a 2000-fold risk for osteosarcoma in the second decade of life when compared with the general population.

The gene for RB has been localized to the long arm of chromosome 13 (13q14). The RB gene is recognized as the prototype of a tumor suppressor gene and has been implicated in the pathogenesis of a number of human neoplasms. A tumor suppressor gene normally functions by restraining cell (tumor) growth, so loss of function or inactivation of a tumor suppressor gene results in tumor growth. Loss of 13q14 (the RB gene) is thought to be responsible for the development of RB. A two-hit kinetic model for this class of genes was proposed by Knudson. For hereditary RB, the primary mutation in one RB locus occurs in germinal cells; for sporadically occurring RB, the primary mutation exists in somatic cells. The second step, responsible for malignant transformation, is the loss of function of the remaining normal homologue in somatic cells by some chromosomal rearrangement or mutation identified as loss of heterozygosity for markers in or around the RB gene. Molecular analyses of both sporadic osteosarcomas and osteosarcomas from patients with RB have revealed homozygous loss of RB gene function in a high percentage of cases. Assessment of loss of heterozygosity at the RB gene in a study by Feugeas and colleagues revealed that RB gene locus loss of heterozygosity could be an early predictive feature for osteosarcomas with a potentially unfavorable outcome. Osteosarcoma develops in 12% of patients with bilateral RB, yet as many as 70% of osteosarcomas have a dysfunctional RB gene product. Thus other oncogenes are likely implicated in the oncogenesis of osteosarcoma.

Several investigators have demonstrated that the mutational profiles of the RB gene in osteosarcoma are basically the same as those for RB and that mutation of the RB gene plays an essential role in the development of osteosarcoma. Besides loss of gene function at the locus on chromosome 13, however, loss of heterozygosity for other chromosomal loci, such as 3q, 17p, and 18q, has been implicated.

Adjuvant Chemotherapy

The use of adjuvant chemotherapy for osteosarcoma was introduced in the 1970s, and after initial concern relative to its efficacy, a randomized trial confirmed its benefit. It is now established as an essential part of the treatment of osteosarcoma. Initially used as an adjuvant after amputation or resection of a tumor, chemotherapy is now used in the neoadjuvant setting, although no clear survival benefit to that approach has been documented. The use of neoadjuvant chemotherapy does allow the assessment of histologic response to the chemotherapy, which has prognostic implications, allows time for planning of limb salvage operations, and makes those resections easier and probably safer.

A number of single-institution and multiinstitution studies have reported the results of treatment protocols, including multiagent neoadjuvant chemotherapy and limb-sparing surgery. The specific drugs and their methods of administration are important. Delépine and colleagues published a meta-analysis of the relationship of total dose and dose intensity of methotrexate from nine single-institution and nine multiinstitution randomized trials. They concluded that both methotrexate dose and dose intensity had major prognostic value. Intravenous administration of chemotherapy appears to be as effective as the intraarterial route of administration. A meta-analysis of 16 regimens published by a group from the National Cancer Institute found that dose intensity was the most important determinant of a favorable outcome, defined as a good histopathologic response to neoadjuvant chemotherapy. Other studies likewise have supported the importance of doxorubicin treatment in patients with osteosarcoma.

The use of preoperative chemotherapy was extended to selected patients in an attempt to contain growth of the primary tumor while awaiting construction of a custom prosthesis (usually 12 to 16 weeks). The sequence of several courses of primary chemotherapy and subsequent surgery afforded the opportunity to examine and histopathologically grade the tumor tissue response to multiple chemotherapy agents. Patients with greater than 90% tumor necrosis (good) were shown to have a better disease-free survival than those with a poor (<90%) response to chemotherapy. Goorin and associates completed a study of 106 patients admitted to Pediatric Oncology Group Study 8651 who were randomly assigned to immediate surgery or to preoperative chemotherapy with high-dose methotrexate, doxorubicin, and cisplatin for two cycles (10 weeks). Six patients were excluded from analysis. Of the remaining 100 patients, 45 were randomly assigned to immediate chemotherapy, and 55 were randomly assigned to immediate surgery. At 5-years follow-up, 67 patients remained disease free. At 5 years, the projected EFS rate was 65% for immediate surgery and 61% for presurgical chemotherapy. There was no apparent advantage for the group that received preoperative chemotherapy. This was a difficult study to complete because at the time there was a surgical bias toward neoadjuvant chemotherapy for limb salvage patients, making accrual slow. The number of limb-preserving procedures was nearly equal in both groups (55% with immediate surgery and 50% with presurgical chemotherapy). Although the percentage of patients in the two groups was similar, the overall percentage of patients receiving limb-sparing procedures was much lower than the usual 60% to 90% limb-preserving procedures reported. Only one local recurrence was reported among all 100 patients.

Surgical resection of the primary tumor is usually planned for 10 to 12 weeks after induction chemotherapy. Limb preservation is elected if the tumor responds favorably—that is, there is evidence of a clinically favorable response, including diminished local pain; radiographic evidence of mineralization of the previously unmineralized soft tissue portion of the tumor on radiographs; and MRI evidence of retention of a normal fatty tissue plane between vascular and neural structures and the tumor. However, if the lesion enlarges and the vessels become involved secondarily (poor response), ablative surgery is recommended. Once the operative wound heals (usually within 2 to 3 weeks), adjuvant chemotherapy is initiated and is maintained for approximately 40 weeks, depending on the particular study. Wilkins and colleagues described their results at two institutions with a dose-intensified neoadjuvant protocol using intravenous doxorubicin and intraarterial cisplatin administered until a maximum angiographic response was observed (usually four courses). Despite showing results similar to others previously reported, it requires extraordinary resources, making it unlikely that a similar study could be carried out in an extensive cooperative manner.

Long-term outcomes were studied by Bacci and coauthors, who reported the results of treatment of 164 patients with nonmetastatic extremity osteosarcoma who were followed for a minimum of 10 years. Preoperative chemotherapy consisted of high-dose methotrexate, cisplatin, and doxorubicin. Postoperatively, good responders (≥90% tumor necrosis) received the same three drugs, whereas poor responders (<90% tumor necrosis) received ifosfamide and etoposide in addition to the three-drug chemotherapy regimen. Follow-up showed that 101 patients (62%) remained continuously free of disease, 61 had experienced relapse, and two had died of doxorubicin-related cardiotoxicity. There were no differences in outcome between good and poor responders.

Limb-preserving surgery was performed in 136 of the patients (83%) in the Bacci study, and 117 (71%) had a good histologic response. Despite the large percentage of patients with limb-sparing procedures, only four local recurrences developed (2.4%). The complications of chemotherapy included doxorubicin-induced cardiotoxicity (six patients) and secondary malignancies (seven patients) at a median follow-up of 11.5 years.

In 1997, Bramwell conducted a review to provide answers to important questions about the role of chemotherapy in the management of patients with nonmetastatic osteosarcoma of the extremities. Many studies were analyzed, including a study by Link and coworkers that clearly demonstrated the role of adjuvant chemotherapy in the treatment of patients with conventional osteosarcoma. The role of adjuvant chemotherapy was also confirmed by another study that provided additional objective evidence for the efficacy of multiagent chemotherapy in preventing and/or delaying relapse. The five studies that were reviewed by Bramwell approached the results of Rosen and associates ; three were multicenter studies and two were reports from a single institution. Bramwell concluded that although the Rosen T10 regimen is complex and toxic, it can be given in a multicenter setting without apparent major compromise in efficacy.

Bramwell concluded that outcomes with multiagent chemotherapy were similar to those of regimens containing the most active drugs (doxorubicin and cisplatin) that were used in two consecutive European Osteosarcoma Intergroup protocols when compared with results from multicenter studies using the T10 regimen.

It is apparent that histopathologic response to neoadjuvant chemotherapy correlates with improved survival. The reports by Picci and colleagues (Bologna, 355 patients), Kempf-Bielack and coworkers (Cooperative Osteosarcoma Study Group, 504 patients), and Delépine and associates (Paris, 112 patients) all demonstrated that a good response to neoadjuvant chemotherapy was an independent prognostic factor. Meyers and colleagues reported the relationship between duration of preoperative chemotherapy and histopathologic response. In univariate analysis, the duration of preoperative chemotherapy did not correlate with relapse-free survival. With longer preoperative treatment, a greater proportion of patients had a favorable histopathologic response to therapy, but the correlation of the response with outcome decreased. Bramwell postulated that with prolonged preoperative chemotherapy, a good response to chemotherapy might lose its prognostic significance. The CCG-782 study published by Provisor and coworkers involving 268 patients with nonmetastatic osteosarcoma of the extremity used the resected tumor histologic response to neoadjuvant chemotherapy to determine postoperative chemotherapy. In 206 patients, the tumor was morphometrically assessed for residual viable tumor; 28% displayed a good (<5% viable tumor) histologic response, whereas the remaining patients were judged to have a poor histologic response (>5% residual viable tumor). The patients who had a good response had an 8-year postoperative EFS rate of 81% and a survival rate of 81%. Patients with a poor histologic response had an 8-year postoperative EFS rate of 46% and an overall survival rate of 52%. The researchers concluded that EFS and overall survival appeared to be related directly to histologic response to neoadjuvant chemotherapy. If that is true, then increasing the percentage of necrosis by intensifying chemotherapy should improve outcome even further. A study compared standard chemotherapy with an intensified arm to assess this contention. Conventional treatment consisted of six 3-week cycles of cisplatin (100 mg/m ² by 24-hour infusion) and doxorubicin (25 mg/m ² per day by 4-hour infusion for 3 days). Intensified therapy was treatment with identical total doses of cisplatin and doxorubicin, planned as six 2-week cycles supported by granulocyte colony-stimulating factor. In this study, 497 eligible patients were evaluated, and good histologic response (>90% tumor necrosis) was observed in 36% of standard arm and 50% of the intensified arm. However, there was no evidence of a difference in overall survival between the two treatment regimens. The study found that intensification of chemotherapy could increase the percentage of necrosis but not progression-free survival or overall survival. Another study looked at increasing the dose of chemotherapy with the same drugs in 196 osteosarcoma patients. The authors failed to find a difference in percentage of necrosis, 5-year EFS, or overall survival, suggesting that response to chemotherapy is related to the specific drugs used but that increasing the intensity is of little benefit. The tumors either respond or do not, suggesting biologic differences in the tumors.

Currently, there are no strong data showing that changing drugs in the poor histologic responders improves the survival of those patients. A retrospective study reported by Benjamin and associates compared outcomes from three consecutive cohorts of patients receiving intraarterial cisplatin and intravenous doxorubicin between 1980 and 1992. In cohort 1 (37 patients), the postoperative chemotherapy was the same. In cohort 2 (59 patients), the postoperative chemotherapy for poor responders consisted of high-dose methotrexate, bleomycin, cyclophosphamide, and dactinomycin alternating between doxorubicin and dacarbazine. In cohort 3 (28 patients between 1988 and 1992), poor responders were managed with three alternating regimens of high-dose methotrexate, ifosfamide, and alternating doxorubicin and dacarbazine. The significant 5-year relapse-free survival rate for poor responders for the three cohorts was 13%, 34%, and 67%. Bramwell believes that although the results appear significant, they could also be explained on the basis of small sample size, increasing dose intensity, total dose, and increased duration of preoperative chemotherapy.

A meta-analysis of North American and European studies of nonmetastatic osteosarcoma showed that three-drug regimens had better EFS and overall survival rates than two-drug regimens (EFS, 48% and 58%; and overall survival, 62% and 70%, respectively). Adding a fourth drug (e.g., ifosfamide) did not improve outcome further, but dose intensification improved histologic response to chemotherapy. There was no benefit to intraarterial chemotherapy.

A randomized multiinstitutional study of patients from North America and Europe, EURAMOS-1, is attempting to address this question more definitively by randomly assigning poor responders, defined as showing at least 10% viable cells after preoperative methotrexate, doxorubicin, and cisplatin (MAP) chemotherapy, to continued MAP therapy or an intensified arm in which ifosfamide and etoposide were added to the MAP: MAPIE. A total of 618 patients were randomized, and at a median follow-up of 5 years, the EFS did not differ between the treatment groups, although the MAPIE regimen was associated with more grade 4 toxicity. The researchers concluded that intensified therapy with this regimen did not improve the outcome of patients with a poor response to neoadjuvant therapy. This study also looked at the good responders, randomly assigning them to continued MAP or MAP with the addition of interferon-α. There was no observed benefit of adding interferon-α in this study, although because a considerable portion of patients never received interferon-α, longer-term follow-up continues.

The issue of whether other agents incorporated into intensive multiagent regimens will improve survival further is less clear. Preliminary trials incorporating ifosfamide into multiagent chemotherapy appeared promising, but a recent study of the Children's Oncology Group patients who were randomly assigned to multiagent regimens that either contained or did not contain ifosfamide shed some doubt on this. In this study, 677 nonmetastatic osteosarcoma patients were treated with one of four prospectively randomized treatments. All patients received identical cumulative doses of cisplatin, doxorubicin, and high-dose methotrexate and underwent definitive surgical resection of the primary tumor. They were randomly assigned to receive or not to receive ifosfamide and/or muramyl tripeptide (MTP), a pulmonary macrophage stimulant. The addition of ifosfamide in this dose schedule to standard chemotherapy did not enhance EFS. The addition of MTP to the ifosfamide arm appeared to add further benefit, but the study was not designed to test this, and this question remains uncertain but intriguing. Whether MTP should be included in standard treatment protocols remains a topic of debate at this time. There was a suggestion in a small cohort of patients with metastatic osteosarcoma that addition of liposomal muramyl tripeptide phosphatidylethanolamine (L-MTP-PE) may enhance EFS and overall survival, but this study was not of sufficient size to be definitive.

To test whether intensified ifosfamide therapy might be of benefit, a study of 182 patients treated with two cycles of high-dose ifosfamide (15 g/m ² ), methotrexate (12 g/m ² ), cisplatin (120 mg/m ² ), and doxorubicin (75 mg/m ² ) was conducted. Postoperatively, patients received two cycles of doxorubicin (90 mg/m ² ) and three cycles each of high-dose ifosfamide, methotrexate, and cisplatin (120–150 mg/m ² ). Granulocyte colony-stimulating factor support was mandatory after the high-dose ifosfamide-cisplatin-doxorubicin combination. No disease progression was recorded during primary chemotherapy. With a median follow-up of 55 months, the 5-year probability of EFS was 64%, and the overall survival rate was 77%. The addition of high-dose ifosfamide to methotrexate, cisplatin, and doxorubicin in the neoadjuvant setting was found to be feasible but associated with major renal and hematologic toxicities. Survival rates were similar to those obtained with four-drug regimens including just standard-dose ifosfamide. Growth factors do appear to offer a benefit in increasing dose intensity. In a pilot study, the European Osteosarcoma Intergroup demonstrated that the use of granulocyte colony-stimulating factor supported increased dose intensity, making chemotherapy every 2 weeks feasible. Thrombocytopenia remained dose limiting, and whether attainable dose intensification improves survival remains uncertain.

The histologic subtypes of osteosarcoma also appear to influence response rates. Bacci and colleagues at the Rizzoli Institute in Bologna correlated the histopathologic response to preoperative chemotherapy in 1058 patients with conventional osteosarcoma of the extremity. They classified the tumors as osteoblastic (70%), chondroblastic (13%), fibroblastic (9%), and telangiectatic (6%). At diagnosis, 911 patients had localized disease and 147 had resectable pulmonary metastases. The response to preoperative chemotherapy was good (≥90% tumor necrosis) in 59% of patients and poor (<90% tumor necrosis) in 41%. Notably, the rate of good responders was significantly higher ( P = .0001) in patients with fibroblastic (83%) and telangiectatic tumors (80%) than in those with osteoblastic (62%) and chondroblastic (60%) tumors. In all subtypes (excepting the chondroblastic), the 5-year overall survival rate was significantly higher ( P = .0001) in good responders (68%) than in poor responders (52%).

Essential to the improvement in survival in osteosarcoma is the combination of effective surgical resection along with the use of chemotherapy. Jaffe and colleagues in the Department of Pediatrics at the University of Texas MD Anderson Cancer Center attempted the cure of 31 patients with nonmetastatic osteosarcoma. Their protocol for selection included initial treatment with chemotherapy consisting of high-dose methotrexate and leucovorin rescue (MTX-LF) in three patients and intraarterial cisplatin in 28 patients. After response at 3 months, entry into the study was permitted, and chemotherapy treatment was maintained for a total of 18 to 21 months with a combination of MTX-LF, intraarterial cisplatin, and doxorubicin. Only 3 of 31 patients (10%) were cured exclusively with chemotherapy. Four additional patients requested surgical extirpation of the tumor after the cessation of chemotherapy. Histopathologic examination revealed no evidence of viable tumor. Adding these patients to the three mentioned previously yielded a total of seven patients (23%) who had a cure from chemotherapy alone. Because the expected cure rate with conventional strategies is 50% to 65%, the authors concluded that their results do not justify the option of current forms of chemotherapy as exclusive treatments for osteosarcoma.

In summary, although great improvements have been made since the 1970s in the outcome of patients with nonmetastatic osteosarcoma, it seems that a plateau has been reached with little new improvement in outcome in recent years. It is likely that future progress will result from novel treatments capitalizing on knowledge of the molecular biology of osteosarcoma and the development of new, targeted agents to specific molecular targets. Many have been proposed, but none are in routine clinical use, nor have they been successfully studied in clinical trials. This remains an area of intense interest and research.

Morphometric analysis of pathologic specimens was instituted after it was recognized that chemotherapy-induced necrosis correlated with clinical outcome. Picci and coauthors described their methodology in 50 patients. Necrosis was divided into three categories: good (100% to 80% necrosis), fair (80% to 50% necrosis), and poor (<50% necrosis). Other authors have used different classifications. Depending on the system that is used, tumor necrosis ranging from 60% to 95% is common. The information gained has prognostic significance. Winkler and associates were early to report that patients with unfavorable pathologic responses to preoperative chemotherapy experienced a poorer (49%) disease-free survival than did patients with a favorable pathologic response (87%; P = .005). Glasser and coworkers later reviewed 279 consecutive patients with stage II osteosarcoma of the appendicular skeleton who were treated between 1976 and 1986. Continuous disease-free survival for the overall group was 70% at 5 years and 69% at 10 years. The only independent predictor of a favorable outcome was found to be the histopathologic response to chemotherapy as defined by pathologic review of the surgical specimen.

A literature review by Davis and colleagues attempted to identify prognostic factors that could influence survival in patients with nonmetastatic high-grade osteosarcoma of the extremities. Eight previously reported large series of patients included sufficient data to evaluate the numerous identified variables. Only two variables proved significant to univariate analysis: tumor size and chemotherapy-induced tumor necrosis after primary chemotherapy. Only tumor necrosis remained significant after multivariate analysis, however. Other large series have demonstrated similar prognostic responses to neoadjuvant chemotherapy.

E-Table 89.1 summarizes recent data regarding treatments for nonmetastatic osteosarcoma reported by 10 internationally recognized institutions. The table suggests that results have improved owing to management by multiagent neoadjuvant chemotherapy combined with adequate local surgery performed by experienced musculoskeletal surgeons. Several conclusions can be drawn from these studies:

• Patients who request limb-sparing operations do not appear to be at greater risk for development of local or distant relapse than patients who have transmedullary amputations.

• The administration of sequential multiagent adjuvant chemotherapy has significantly improved disease-free survival for patients without metastasis.

• The risk of local recurrence appears to be no greater in patients who complete limb-preserving procedures than for those who have an amputation, although this never has and likely never will be proven in a randomized study for obvious reasons.

Relationship of Surgical Margins, Neoadjuvant Chemotherapy, and Local Recurrence

The role of neoadjuvant chemotherapy in facilitating limb preservation appears to be well established. The relationship among margins, chemotherapy, and local recurrence is not as straightforward. Although, in general, local recurrence is higher in patients with inadequate margins, some patients who are so treated do not have recurrence, whereas in some patients with wide or radical margins, disease does recur or persist locally. The effect of neoadjuvant chemotherapy in this regard is suspected to be beneficial, but only retrospective data are available. Four of the institutions reporting data shown in E-Table 89.1 also provided data on the pathologic margins achieved at surgery and correlated the surgical margins with locally recurrent disease. Of the 271 margins reported by Memorial Sloan-Kettering, 266 were adequate (261 wide and 5 radical), and five were inadequate (three marginal and two intralesional). Of the 18 locally persistent tumors, however, all developed in patients who were thought to have wide margins. There were no locally recurrent tumors from the five known inadequate surgical margins. The University of Vienna group reported 61 margins as wide, with 12 inadequate (nine marginal and three intralesional) margins. Only two local recurrences developed, one in a patient having an intralesional amputation and the other with a marginal resection and reconstruction.

A similar review from Birmingham, England, revealed 23 marginal and 15 intralesional margins in 99 patients, with a 4.5% recurrence rate. Investigators in a French study reported 100 patients with nonmetastatic osteosarcoma managed by neoadjuvant chemotherapy and surgery with “numerous” marginal margins but no intralesional margins. These researchers reported one local recurrence. A Rizzoli Institute study, examining 125 patients retrospectively, identified 15 patients with inadequate margins. Only one patient had a local recurrence.

Investigators from the Rizzoli Institute in Bologna have shown by multivariate analysis that the incidence of local recurrence in 355 patients was related closely to surgical margins ( P < .0001) and response to preoperative chemotherapy ( P < .0001). There were 28 patients who experienced local recurrence (7%), three of whom survived (11%). Six of 10 patients who did not receive preoperative chemotherapy had local recurrence. In the other limb salvage procedures, 110 patients had wide margins, 12 were marginal, seven had intralesional margins, and seven had wide contaminated margins. Although 27 patients had inadequate margins, only three developed local recurrence, all within the first 2 years after diagnosis.

To better illustrate the relationship between surgical margins and local recurrence, Picci and colleagues reported on a single-institution study retrospectively reviewing 355 patients with nonmetastatic high-grade osteosarcoma of the pelvis and extremities. The average length of follow-up was 65 months for surviving patients.

Pathologic review demonstrated less-than-wide margins in 65 of the 355 patients. The most common anatomic site for inadequate margins was the popliteal region near the vascular and neural structures, where 20 of 140 patients were found to have inadequate margins (either marginal or intralesional). Only 7 of the 20 patients had local recurrence, however. Locally persistent disease developed in only 3 of 15 patients with inadequate margins associated with lesions around major joints locally persistent disease. The intramedullary canal was the site of inadequate margins in 20 of 237 patients, and local recurrence developed in 6 patients. It is of interest that 7 of the 11 patients with intralesional surgical margins and 16 of the 21 with contaminated margins did not have local recurrence. These findings could not be explained on the basis of poor survival or early death. The observation is believed to be related to the effectiveness of preoperative chemotherapy at producing tumor necrosis and the development of a “mature” capsule surrounding the tumor where satellite tumor nodule formation had been suppressed.

An analysis of a more recent group, 164 patients with nonmetastatic osteosarcoma of the extremities, also came from the Rizzoli Institute. Limb-sparing procedures were performed in 136 patients (83%), 18 patients (11%) had amputation, and 10 (6%) had rotationplasty. The surgical margins were reviewed. In amputations, 18 margins were wide or greater; in rotationplasty, nine were wide and one was intralesional. In the limb salvage procedures, 110 patients had wide margins, 12 were marginal, seven had intralesional margins, and seven had wide contaminated margins. Although 27 patients had inadequate margins, only three experienced local recurrence, all within the first 2 years after diagnosis.

The unanswered question is whether the poor correlation with margin and recurrence relates to neoadjuvant chemotherapy or the underlying tumor biology or some combination of the two. It may also relate to the ability of the surgeon in conjunction with the pathologist to accurately determine whether margins are truly wide because the soft tissues around the tumor move about during the operation and after the specimen has been removed, making it difficult to accurately determine whether a margin is wide, marginal, or intralesional even when the specimen is inked. Adequate surgical resection is certainly a worthwhile goal, but the causes of local recurrences are probably more complex than adequacy of margin.

Rotationplasty

Rotationplasty for tumors around the knee and hip is a very functional alternative to amputation ( Fig. 89.4A–E ), but carries a cosmetic disadvantage. For skeletally immature patients, patients with a pathologic fracture, or patients with large tumors, especially of the distal femur, a rotationplasty should be considered. A similar procedure of hip rotationplasty has been described and may be used at times for proximal femoral tumors.

Tibial rotationplasty was first described by Borggreve in 1930 for management of a limb that was markedly shortened by tuberculous involvement of the knee. In 1950, van Nes and others extended the use of the procedure to treat congenital femoral focal limb deficiencies. The first tibial rotationplasty used for reconstruction after a radical resection of the distal femur for osteosarcoma was performed by Dr. Martin Salzer and coworkers in Vienna in 1974 and reported in 1981.

The largest collective experience, reported in 1991, involved 70 patients with sarcoma of bone who were managed with rotationplasty. Forty-seven patients had stage IIB osteosarcoma; other conditions included MFH of bone, parosteal osteosarcoma, chondrosarcoma, Ewing sarcoma, giant cell tumor of bone, periosteal osteosarcoma, and undifferentiated sarcoma of bone. Sixty-two of the lesions originated in the distal femur, six involved the diaphysis, and two originated in the tibia. At a mean follow-up of 4.3 years, Kaplan-Meier analysis revealed a 70% probability of survival and a 58% probability of disease-free survival.

The surgical oncology principles of tibial rotationplasty yield surgical margins that are comparable to those of a transmedullary amputation. In patient selection, the only absolute requirement is the absence of tumor involvement of the sciatic nerve and a previously untraumatized, essentially normally functioning foot and ankle (see Fig. 89.4F–N ). The procedure is applicable for lesions that involve the distal half of the femur and the proximal third of the tibia that spare both the peroneal and tibial divisions of the nerve. Large, locally invasive lesions of the distal femur, even with knee joint involvement, are often amenable to tibial rotationplasty.

The procedure is ideally used in young, skeletally immature patients in whom the anticipated adult limb length inequality (associated with the loss of the distal femoral and proximal tibial epiphyses) would be substantial if other reconstructions were used. The desired final effect is to have the axis of rotation of the rotated ankle joint slightly proximal to the axis of rotation of the normal knee at skeletal maturity. A recent study from Italy showed that the QoL in survivors as assessed with the 36-item Short Form (SF-36) was very similar to, and sometimes better than, that in the general Italian population, although the study stressed the importance of support from family and others.

A recent study looked at 25 patients who survived osteosarcoma and underwent rotationplasty at 15 years from treatment. They noted generally good MSTS functional scores, but that when the rotationplasty “knees” were distal to the normal knee, there were gait and cosmetic issues. They also noted early osteoarthritis of the foot and ankle joints.

Resection and Distraction Osteogenesis

Borrowing from techniques of the pediatric orthopedic surgeon, distraction osteogenesis has been used by some for limb salvage in children. This technique involves slowly transporting a segment of vascularized bone with an external fixation device to fill the gap that tumor resection creates. It requires the ability to preserve the articular cartilage, and the potential risks include close margins and infection from the percutaneous pins in patients receiving chemotherapy. The results of treating patients who have undergone a local resection for tumor of bone and treatment with bone transport (10 patients), shortening-distraction (three patients), and distraction osteogenesis (six patients) have been reported, but distraction osteogenesis has not had widespread acceptance in the United States.

Canadell and colleagues described an innovative physeal-sparing procedure in skeletally immature patients in whom the primary tumor was limited to the metaphysis. During the neoadjuvant chemotherapy phase, distraction forces were applied to the epiphysis, “pulling” the tumor away from the epiphysis and providing new, widened uninvolved metaphyseal bone for a margin of resection without sacrificing the adjacent joint. The procedure was used in 20 patients with a mean follow-up of 54 months without evidence of local recurrence ( E-Fig. 89.1 ).

Expandable Prostheses

Limb length is an issue to be considered in a skeletally immature patient with a tumor of the lower extremity. In general, patients younger than 8 years are probably best treated with amputation or, when possible, rotationplasty. Girls aged 8 to 10 years and boys aged 12 years have significant growth remaining, such that resection of a physis about the joint will lead to significant limb length discrepancy. One alternative for managing this issue in children is to use standard allografts or endoprostheses and rely on techniques of epiphysiodesis or subsequent limb lengthening to equalize the extremities. Another alternative is to use expandable prostheses to deal with limb length. There are several on the market, some of which require operations to expand the prostheses and others of which can be lengthened with use of electromagnetic devices in a radiology suite ( E-Fig. 89.2 ). One prosthesis allows noninvasive extension of the limb, which can be performed in the clinic as the child grows. The data on the use of this prosthesis are early but encouraging. One report of 34 children with femoral and tibial sarcomas, 27 of whom remained alive at a mean follow-up of 44 months, showed mean MSTS scores of 85% and a mean extension of 32 mm (range, 4 to 80 mm). Deep infection developed in six patients, and five patients eventually underwent amputation. The early reports of these prostheses are encouraging, especially to parents, but the long-term outcomes are unknown. They are very expensive and complex prostheses, and few data are available with respect to two key issues: whether a very young child can reach skeletal maturity with equal limb lengths and good function, and whether the results of the required revision to an adult prosthesis at skeletal maturity will be successful. Early reports show that lengthening can be achieved and that the complication rates are likely higher than in skeletally mature patients treated with nonexpandable endoprostheses. A higher rate of flexion contractures had been noted, because young children are not as cooperative with physical therapy, and loosening and failure of the implant also can occur in these complex prostheses. The optimal method of fixation of the stems to the host bone remains controversial. It is also unclear whether sufficient bone stock will remain when the patient needs to be converted to an adult prosthesis, because of stress shielding of the stem in these immature bones. A study has shown that children treated with an expandable prosthesis have high emotional acceptance as assessed with the Pediatric Outcomes Data Collection Instrument, although only 12 of 26 potential families completed the assessment.

Amputation

Ablation or primary amputation may be considered for patients with pathologic fracture and for patients who are younger than 9 years in whom lower extremity limb length inequality would be considerable. Also, stage IIB lesions that arise below the knee and below the elbow may be best treated with primary amputation. It should be recognized, however, that selected patients with favorable lesions that arise below the knee and elbow might also be candidates for limb-sparing procedures. Also, some pathologic fractures have been shown to heal during intensive neoadjuvant chemotherapy. We have become so accustomed to salvaging limbs that amputations are probably not being used enough. It is wise to remember that with modern prosthetics for the lower extremity, function and QoL can be quite good, and perhaps equivalent to or better than that after limb salvage for tumors of the distal femur and below. Improvements such as bony ingrowth mechanisms for attachment of the prosthesis directly to bone are being evaluated clinically. Amputation should not be viewed as a failure or sign of defeat until we develop better methods for limb reconstruction.

Surgical Options for Limb Salvage Reconstruction

Endoprostheses

Early experience with metallic reconstructions for limb salvage of tumors required custom-made implants, which took time to manufacture and had design features that limited longevity. Now there are modular prostheses for most anatomic sites of the upper and lower extremities that allow the surgeon to reconstruct individual defects at the time of the resection without custom implants ( Fig. 89.5 ). Design improvements in rotating knee hinges and cementless stem options will likely lead to increased longevity of these implants. The advantages of endoprostheses include their relative ease of use, a lower reported infection rate, and a more rapid return to function because there is no waiting for union as in bone allografts. The main drawbacks include the concern for longevity of the implants and their fixation to the host bone. The complications and functional outcomes of these implants have been included in several articles. A multicenter study classified a large group of endoprosthetic complications into five categories: soft tissue complications, aseptic loosening, structural failures, infection, and tumor failure, with infection being the most common complication.

A stem design that uses constant compression forces and a cementless fixation system that is purported to induce bone hypertrophy and lessen stress shielding has been reported, but only in preliminary form. Long-term reports with sound comparisons to other types of stems are lacking in the literature. A study of 22 patients treated with an osseointegration compressive device for stem fixation reported outcomes in 18 survivors at 5 years. Aseptic mechanical implant survivorship was 16 of 18 and overall survivorship was 12 of 18. Most of the failures occurred early—that is, within the first 30 months—which indicated to the authors that there is a transient period of implant stabilization. In young children, it is unreasonable to expect a complex implant to last the patient's lifetime if the patient survives the disease, and multiple revisions are to be expected. Advances in fixation of implants to the host and design improvements in the joints will likely improve the longevity and usefulness of these implants.

Bone allografts

Bone allografts are another alternative to limb salvage for sarcomas. They offer the potential advantage of incorporation by the host and greater longevity but are technically more demanding than prostheses. Availability of a bone bank with a variety of shapes and sizes of allografts is a prerequisite, although several large commercial bone banks that are accredited by the American Association of Tissue Banks are now available. Younger patients are more suitable because the recovery period is longer because of the need to protect the osteosynthesis site until it heals. Allografts can be used as osteoarticular grafts ( Fig. 89.6 ), replacing one side of a joint, or can be combined with a standard prosthesis to create allograft-prosthetic composites ( Fig. 89.7 ). Intercalary defects are particularly suited to allografts, because the joint on either end of the diaphyseal defect is intact ( Fig. 89.8 ). An arthrodesis of a shoulder, knee, or hip can also be created with allografts. The main drawbacks are the potential for disease transmission and the relatively high reported complication rates compared with endoprostheses.

The experience with large-bone allografts for reconstruction in high-grade osteosarcoma at the Rizzoli Institute in Bologna has been reviewed by Donati and colleagues. Between 1986 and 1994, 112 large-bone allograft reconstructions were performed. Forty-one were used for arthrodesis of the knee, and three were used in the ankle. Thirty-nine were used as intercalary grafts (see Fig. 89.8 ), and 22 were used as osteoarticular allografts ( E-Fig. 89.3 ) (3 humeral, 6 in the distal femur, and 13 in the proximal tibia). Seven composite constructs were reported: two were in the proximal and distal humerus, one in the proximal femur (as in Fig. 89.9 ), and four in the proximal tibia. Complications included delayed union (>1 year without radiographic union) in 49% of patients and fracture in 30%. There were no deep infections. With the modification of the Mankin scale by Gebhardt and coworkers, good to excellent functional results were reported in 74% of the 92 patients who were available for review. Details of the options and functional results of these reconstructions at various sites are beyond the scope of this chapter. Articles that address these reconstructions include Gilbert and colleagues, Aponte-Tinao and colleagues, Abdeen and colleagues, Muscolo and colleagues, and Bianchi and colleagues.

Local Recurrence

Two studies have indicated that local recurrence within 18 to 24 months of surgery has a substantial negative influence on long-term survival. Ferrari and colleagues, from three Italian institutions, reviewed the data on patients who were treated for nonmetastatic osteosarcoma of the extremities between October 1986 and June 1995; they found 162 patients with recurrence or relapse. The main prognostic factors for postrelapse survival were the relapse-free interval, site of metastasis, and number of pulmonary nodules. Complete surgical resection of the recurrence was found to be pivotal in the strategy of treatment. When the risk factors were combined, patients with a relapse-free interval longer than 24 months and with only one or two pulmonary nodules had a postrelapse survival rate of 72%. Patients with a short relapse-free interval and three or more lung pulmonary nodules had a poor postrelapse survival rate of 5%. Patients with unresectable recurrence did receive benefit from second-line chemotherapy, but the authors’ data did not support the generalized use of chemotherapy after complete surgical resection of the first recurrence.

Weeden and colleagues reported the effect of local recurrence on survival of 559 patients entered into two randomized controlled trials of the European Osteosarcoma Intergroup in which preoperative chemotherapy was used, but there was no survival benefit between chemotherapy arms. A landmark analysis allowed the assessment of 440 patients at 18 months, and 22 patients (5%) had experienced a local recurrence. Patients with a local recurrence had a fourfold greater risk of death during the 18 months after surgery. Similar analyses were conducted with landmark time points at 1 and 2 years. With a multivariate proportional hazards model, 368 patients were assessed to investigate the relative prognostic importance of histologic response and local recurrence. It appears clear that histologic response to chemotherapy and local recurrence had a significant effect on survival. A study from St. Jude's Research Hospital analyzed prognostic factors for survival in 26 patients with a local recurrence of osteosarcoma who were treated between 1970 and 2000. The initial surgical procedure was amputation in 20 patients (76.9%) and limb salvage in six patients (23.1%). Eleven patients (42.3%) developed an isolated local recurrence, and 15 patients (57.7%) developed local and distant recurrence. The 5-year estimate of postrecurrence survival (PRS) for the 26 patients was 19.2%. The factors that affected survival after recurrence were as follows:

• Recurrence 2 or more years from the time of diagnosis (5-year PRS of 50.0% ± 20.4% compared with earlier recurrence (10.0% ± 5.5%) ( P = .037).

• Patients with negative margins after initial surgery were found to have improved survival (5-year PRS of 33.3% ± 13.6%) compared with patients with positive margins (7.1% ± 4.9%) ( P = .015).

• Patients who underwent complete surgical resection at the time of recurrence were found to have a better PRS (5-year PRS of 41.7% ± 14.2%) compared with patients who did not undergo surgery (0% ± 0%) ( P < .001).

This demonstrated that the prognosis for patients after local recurrence of osteosarcoma is poor, but attempts at salvage should be made. Complete surgical resection at the time of recurrence is essential for survival.

A study from the European Osteosarcoma Intergroup of 202 patients assessed the primary surgical treatment alternatives. Three centers differed in the rates of limb salvage, and all local recurrences arose in limbs with attempted limb salvage. Local recurrence was closely related to the adequacy of the margins of excision and to the chemotherapeutic response. Interesting to note, patients who had undergone limb salvage surgery and who experienced local recurrence still had a better survival rate than did patients who underwent primary amputation (37% versus 31% survival at 5 years), suggesting that they had a less-aggressive tumor. Of patients who experienced relapse, 31% of those with local recurrence alone were cured with further treatment, compared with only 10% of those with metastases.

A retrospective analysis of the management and outcome of 44 patients who experienced local recurrence from 1983 to 1999 after neoadjuvant chemotherapy of osteosarcoma of the extremities was performed in a single institution. In 24 patients (54.5%), local recurrence was the first sign of recurrence; in eight patients (18.2%), local recurrence followed systemic recurrence, and in 12 patients (27.3%) the two events were concurrent. The only prognostic factor that was identified for disease-free survival of patients after local recurrence was the presence of systemic recurrence at the time of diagnosis of the local recurrence or before. The 5-year postrecurrence EFS rate was 29.1% for patients without metastases at the time of local recurrence versus 0% for those with metastases ( P = .02). The analysis confirmed that patients with osteosarcoma of the extremities who experience local recurrence are at a significantly high risk for metastatic disease and dying of the tumor despite the use of effective neoadjuvant chemotherapy. Another study looked at 407 patients and found 23 patients with resectable local recurrence. Median time to local recurrence was 13 months. All patients were treated with chemotherapy after recurrence. The 5-year and 10-year survival rates in the recurrent cases were 29% and 10%, respectively. Increased risk of local recurrence ( P < .0001) was strongly correlated with positive margins of resection. The strongest correlates with poor survival were local recurrence within the first year after primary resection ( P = .001) and, as in the Bacci study, metastasis at the time of first local recurrence ( P = .04). Failure to achieve clinical remission after disease recurrence ( P = .04) was also a poor prognostic factor.

To determine whether inappropriate surgical procedures based on an initial misdiagnosis affected recurrence and survival rates, one group retrospectively reviewed the surgical treatment and results of 117 patients with high-grade osteosarcomas. Nine patients had intralesional curettage performed at other institutions based on an erroneous diagnosis of a benign lesion. Two of the nine patients underwent amputations, and seven patients underwent limb salvage procedures. Of the 108 patients who were not misdiagnosed, six patients underwent amputations and 102 patients underwent limb salvage procedures. All patients received neoadjuvant therapy. Fifteen of the 117 patients had local recurrences. Patients who had inappropriate surgical procedures at diagnosis had an increased risk of local recurrence and lower 10-year survival rates.

A study assessed the prognostic factors for survival in 449 patients with extremity osteosarcoma without metastatic disease at initial diagnosis and treatment (38 with local recurrence, 411 without local recurrence). They compared the survival difference between patients with local recurrence ( n = 38) and without local recurrence (control; n = 76) matched for age, location, initial tumor volume, and tumor volume change after chemotherapy, and assessed prognostic factors in this subgroup. In a cohort study, multivariate analysis revealed that initial tumor volume, tumor enlargement, inadequate margin, and local recurrence predicted poor survival. In the case-control study, the 10-year metastasis-free survival rates of two groups were 13.1% ± 10.7% and 19.3% ± 9%, respectively. Tumor enlargement and initial tumor volume showed multivariate significance. The investigators concluded that local recurrence has a small impact on survival in patients with high-risk osteosarcoma.

Metachronous Osteosarcoma

Aung and colleagues described a single-institution assessment of patients who experienced metachronous skeletal osteosarcoma from 1973 to May 2000. A retrospective review of records from 426 patients with nonmetastatic high-grade and primary osteosarcoma revealed 23 patients, with a median age of 18.7 years, who experienced metachronous osteosarcoma. Initial therapy included combination chemotherapy and surgery. Treatment of the metachronous relapse consisted of chemotherapy or radiation alone or surgery with or without additional individualized chemotherapy.

The median time to the diagnosis of a metachronous lesion was 1.4 years, with a range of 0.2 to 11.3 years. Patients who experienced late metachronous osteosarcoma experienced significantly longer postmetachronous osteosarcoma survival compared with those whose metachronous disease developed early. For the former group, the 2- and 5-year postmetachronous osteosarcoma survival rates were 72.7% and 61%, respectively. In contrast, all five patients who experienced metachronous disease between 12 and 24 months of their original presentation died within 1.5 years of follow-up. Among patients who experienced late metachronous disease, further analysis based on type of therapy suggested that those who were treated with a combined modality (including surgery and aggressive chemotherapy) for their metachronous disease fared better than did those who received monotherapy. The authors also concluded that local therapy with surgery directed at the bulky primary tumor is the only effective method for local control.

Rodriguez and associates described the treatment of five patients in whom primary osteosarcoma had been treated effectively with chemotherapy and resection of the primary tumor and in whom another osteosarcoma developed at another site but without pulmonary metastases. The interval between management of the primary tumor and the subsequent development of another, apparently unrelated metachronous osteosarcoma ranged from 99 to 150 months. All patients remained otherwise free of disease 24 to 96 months after treatment of the metachronous lesion, except for one patient who experienced acute myelogenous leukemia, most likely as a late effect from chemotherapy. Fitzgerald and colleagues reported that among 800 patients, 12 experienced metachronous osteosarcoma, and none experienced pulmonary metastases, a quite different response from that of patients who were reported with primary metastatic osteosarcoma. Others have observed that aggressive treatment of metachronous osteosarcoma is indicated and suggested that the etiology in some might be related to hereditary RB or Li-Fraumeni syndrome.

Second Malignant Neoplasms

Aung and associates retrospectively reviewed the experience of the Memorial Sloan-Kettering Cancer Center with long-term survivors of osteosarcoma and the subsequent development of secondary malignancies. The patients were treated between February 1973 and March 2000, and all had received chemotherapy and/or surgery. Chemotherapy consisted of a combination of agents that included high-dose methotrexate, doxorubicin, bleomycin, cyclophosphamide, dactinomycin, vincristine, cisplatin, and ifosfamide. Of 509 patients, 14 were identified with secondary malignant neoplasms. The time interval from diagnosis of the primary osteosarcoma to development of the secondary malignant neoplasm ranged from 1.3 years to 13.1 years (median, 5.5 years). The second neoplasms occurred in the central nervous system in four patients. There were two cases of acute myeloid leukemia and one case each of myelodysplastic syndrome, non-Hodgkin lymphoma, high-grade pleomorphic sarcoma, leiomyosarcoma, fibrosarcoma, carcinoma of the breast, and mucoepidermoid carcinoma. The standard incidence was 4.6% when patients with a history of RB or Rothmund-Thompson syndrome were excluded.