Histologic response of high-grade nonmetastatic osteosarcoma of the extremity to chemotherapy,.

In 510 patients with osteosarcoma of the extremity treated at the authors' institute between March 1983 and June 1995 with different regimens of neoadjuvant chemotherapy, factors that influenced the histologic response were investigated. The rate of total necrosis was not related to the patients' gender, age, site, size of tumor, serum of alkaline phosphatase values, or route of cisplatin administration. The histologic response significantly and independently correlated with the number of drugs administered before surgery and with the histologic subtype of the tumor. According to the number of drugs used, the percentage of total necrosis was 31% for a four-drug regimen, 18% for a three-drug regimen, and only 1.5% for a two-drug regimen. According to the histologic type, the rates of total necrosis were 41% for telangiectatic tumors, 36% for fibroblastic tumors, 15% for osteoblastic tumors, and 3% for chondroblastic tumors. The authors concluded that in neoadjuvant therapy of osteosarcoma, the histologic response to preoperative treatment, which correlates with prognosis, depends on the effectiveness of the chemotherapy regimen and on some features intrinsically inherent to the tumor. These data should be considered when selecting the type of treatment (adjuvant or neoadjuvant) and the combinations of drugs to be used in preoperative treatment of patients with osteosarcoma.

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 report.

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.

Extraabdominal desmoid tumor. A study of 83 cases.

One hundred three patients with extraabdominal desmoid tumor were treated between 1970 and 1996 at the authors' institution. Among these, 15 patients were lost to followup and five were excluded because they had less than 1-year followup. The remaining 83 patients were followed up for a mean of 11.2 years. Thirty-seven (44.6%) patients experienced local recurrence on average 1.8 years after treatment. There was no difference in the incidence of recurrence between the two groups treated with surgery only (45.3%) or with adjuvant radiation therapy administered after inadequate surgical resection of the tumor margins (41.2%). Recurrence was not related to age, gender, and site. None of the 83 patients died of the disease. For recurrent but stable lesions, clinical observation alone may be considered.

P-glycoprotein expression in osteosarcoma: a basis for risk-adapted adjuvant chemotherapy.

Previous reports on osteosarcomas treated with multi-agent chemotherapy have shown that P-glycoprotein expression is a reliable prognostic indicator. The current thinking is that, of the several agents used for the treatment of osteosarcoma, only doxorubicin is involved in drug resistance mediated by P-glycoprotein. This study examines the relationship of P-glycoprotein expression to clinical outcome in osteosarcomas, treated only with doxorubicin in addition to surgery, to determine if the prognostic significance of P-glycoprotein expression reflects the ability of osteosarcoma to respond to this drug. The expression of P-glycoprotein in tumor specimens was assessed by immunohistochemistry in 37 nonmetastatic, operable osteosarcomas treated at a single institution with doxorubicin as a single adjuvant drug. The P-glycoprotein status was analysed in relation to the length of event-free survival. A widespread pattern of P-glycoprotein expression in tumor cells at diagnosis was significantly associated with a higher rate of systemic relapse (p < 0.001). On comparison of this group of patients with a similar series of 92 patients, all treated with multi-agent chemotherapy plus surgery of the primary lesion and previously analysed for P-glycoprotein status, only P-glycoprotein-positive, doxorubicin-resistant tumors consistently benefited from the addition of drugs other than doxorubicin (p < 0.001). Osteosarcomas with different abilities to respond to adjuvant chemotherapy can be identified by the expression of P-glycoprotein in tumor cells at the clinical onset. P-glycoprotein status may serve as a basis for risk-adapted, individualized therapeutic regimens. Standard programs are sufficient for P-glycoprotein-negative osteosarcomas, whereas P-glycoprotein-positive tumors may benefit from the use of more intensive therapeutic approaches.

Osteoid osteoma. Direct visual identification and intralesional excision of the nidus with minimal removal of bone.

We describe 100 consecutive patients with osteoid osteoma. Of the 97 who had operations, 89 were treated by intralesional excision and eight by wide resection. The three remaining patients were not operated on because the osteoid osteoma was almost painless, or was found in the pedicle of the 12th thoracic vertebra at the site of entrance of the artery of Adamkjewicz. The diagnosis was confirmed histologically in all specimens. No local recurrences were observed at a minimum follow-up of one year. All except one patient were mobilised two to four days after surgery. A precise preoperative diagnosis of the lesion is mandatory, based on clinical findings, standard radiographs, thin-section CT and a bone scan. We compared our operative technique with 247 cases in which the percutaneous technique of removal or coagulation of the nidus had been performed. The latter procedure has a less constant rate of primary cure (83% v 100%). Its principal indication appears to be for osteoid osteomas in the proximal femur and the pelvis.

Italian Cooperative Study for the treatment of children and young adults with localized Ewing sarcoma of bone: a preliminary report of 6 years of experience.

BACKGROUND: In 1991, the Italian Association for Pediatric Hematology-Oncology and the National Council of Research (CNR) initiated an Italian Cooperative Study (SE 91-CNR Protocol) with the main objective of improving the overall survival (SUR) and the event free survival (EFS) of children and young adults with localized Ewing sarcoma and primitive neuroectodermal tumors of bone compared with a previous study (IOR/Ew2 Protocol). METHODS: Between November 1991 and November 1997, 165 patients were enrolled in this study, 160 of whom were evaluable. The patients were treated with a multimodal approach characterized by intensified chemotherapy, hyperfractionated and accelerated radiation therapy, and the addition of ifosfamide and etoposide to standard chemotherapy with vincristine, actinomycin-D, doxorubicin, and cyclophosphamide. RESULTS: After a median follow-up of 37 months, 126 of the 160 evaluable patients remained free of disease recurrence. Thirty-one patients developed a disease recurrence (20 with disseminated disease). CONCLUSIONS: The 3-year SUR and EFS rates found in the current study (83.6% and 77.8%, respectively) may be considered satisfactory. Only age at diagnosis < or =14 years and a good histologic response appeared to affect the outcome of patients with localized Ewing sarcoma positively. These results appear to demonstrate the efficacy of the addition of ifosfamide in induction chemotherapy to four-drug standard combination chemotherapy, as confirmed by the improved outcome in terms of 3-year EFS reported in the SE 91-CNR Protocol compared with the IOR/Ew2 Protocol (77.8% vs. 60.7%). In addition, the better outcome also could be explained by the change in treatment strategy with a trend toward the use of more surgery than radiation therapy compared with the authors' previous protocol.

The expression of P-glycoprotein is causally related to a less aggressive phenotype in human osteosarcoma cells.

The relationship between P-glycoprotein expression and malignancy is controversial. We have recently found that, in osteosarcoma, multidrug resistance (MDR) is associated with a less aggressive behavior, both in vitro and in clinical settings. In this study, we evaluated whether P-glycoprotein overexpression has a cause-effect relationship with the reduced metastatic potential of MDR cells, or rather reflects a more complex phenotype. MDR1 gene-transfected osteosarcoma cell clones, showing different levels of P-glycoprotein expression, were analysed for their in vitro characteristics and their tumorigenic and metastatic ability in athymic mice. Apart from the different levels of P-glycoprotein, no significant change in the expression of surface antigens or in the differentiative features were observed in the MDR1 gene transfectants compared to the parental cell lines or control clones, obtained by transfection with neo gene alone. In contrast to controls, however, MDR1 transfectants showed a significantly lower ability to grow in semi-solid medium and were completely unable to grow and give lung metastases in athymic mice. These findings indicate that P-glycoprotein overexpression is causally associated with a low malignant potential of osteosarcoma cells, and open new insights on the role and functions of P-glycoprotein activity.

Intraepiphyseal resection of the proximal tibia and its impact on lower limb growth.

From 1989 through 1996, 10 children affected by high grade bone tumors of the proximal tibia underwent an intraepiphyseal intercalary resection. The residual epiphyseal bone segment measured less than 2 cm in thickness in all cases and reconstruction always was performed using the combination of a vascularized fibular autograft and a massive bone allograft. The proximal epiphyseal osteosynthesis was fixed by small fragment screws. The aim of this study was to report the growth pattern of the residual proximal tibial epiphysis and to evaluate any possible lower limb discrepancy and/or deformity after the end of skeletal maturity. At current followup six patients were available for the final evaluation. Radiographic documentation included computed tomography scan of both knees before surgery, a panoramic radiographic view and a computed tomography scan of both lower limbs after the end of skeletal growth. The length of both femurs and tibias, the size of the tibial plateau and of the opposite distal femur, and any possible deformity of femur or tibia were measured and compared with the preoperative data. No patient had a limb length discrepancy greater than 3.5 cm. In all cases the ipsilateral femur had a valgus deformity of the hip develop. In two patients this deformity was associated with an elongation of the femur, partially compensating for the shortening of the tibia. The tibial plateau close to reconstruction grew less than the contralateral one (range 2%-8%) but maintained its normal relationship with the distal femur. None of these patients reported any restriction in recreational activities. They could walk, run, and jump. Their functional result according the International Society of Limb Salvage functional grading system was satisfactory in all cases.

[Local recurrence after surgical or surgical-chemotherapeutic treatment of osteosarcoma of the limbs. Incidence, risk factors and prognosis]. / Le recidive locali dopo trattamento chirurgico o chirurgico-chemioterapico dell'osteosarcoma delle estremità. Incidenza, fattori di rischio e prognosi.

METHODS: Local recidivation (incidence, risk factors an prognosis) was analysed retrospectively in 765 patients with non-metastatic osteosarcoma of the extremities treated between 1972 and 1992 either with surgery alone (78 cases) or with surgery and associated adjuvant (258 cases) and neoadjuvant chemotherapy (429 cases). RESULTS: The local recurrence of the disease, which was documented in 26 patients (3.4%), was significantly related to the type of surgery performed (1.1% in 344 amputated patients vs 5.2% in 422 patients treated with resection; p < 0.003) and with surgical margins (0.6% in 700 radical or extensive operations vs 22.7% in 66 marginal or intralesional interventions; p = 0.0001). In patients treated with neoadjuvant chemotherapy, the incidence of local recidivation was also correlated with the type of histological response to chemotherapy (2.9% in 274 cases with a "good" response vs 8.4% in 154 cases with a "poor" response; p < 0.021). In all 26 patients local recidivation was associated with metastases occurring before (16 cases), after (3 cases) or in concomitance (7 cases) with the local recurrence of neoplasia. In spite of treatment performed at the start of recidivation, 25 patients (96.1%) died from the tumour whereas the mortality rate in those patients with metastases but no local recidivation was only 72.1% (261 out of 362 cases). This difference was also statistically significant (p < 0.01). CONCLUSIONS: The results obtained appear to justify the current trend of minimising demolitive surgery in osteosarcoma of the extremities. Surgery should only be performed in these patients by centres able to make an adequate evaluation of surgical margins and the histological response to preoperative chemotherapy. In view of the fatal prognosis linked to recidivation and the high probability of its onset in cases with inadequate surgical margins and a poor response to chemotherapy, the authors propose that subsequent amputation should be performed immediately in those patients undergoing resection who present both these conditions.

Predictive factors for local recurrence in osteosarcoma: 540 patients with extremity tumors followed for minimum 2.5 years after neoadjuvant chemotherapy.

We investigated predictive factors for local recurrence in 540 patients with non-metastatic osteosarcoma of the extremity treated with surgery and neoadjuvant chemotherapy, between March 1983 and October 1994. The median follow-up was 7.5 (2.5-15) years. Local recurrences developed in 31 (6%) patients after a median time of 2 (0.5-7) years. Local recurrence did not correlate with patients' age and sex, histologic subtype, site and tumor volume, presence of pathologic fracture, chemotherapy regimen and type of surgery. Local recurrence-free survival (LRFS) correlated with the quality of surgical margins and response to chemotherapy: the 7-year LRFS was 97% after adequate surgical margins and 71% after inadequate surgical margins (p < 0.0001), and was 95% in good responders and 90% in poor responders (p = 0.001). Only 1 of 31 patients with local recurrence was free of disease 15 months after the last treatment, 3 were alive with uncontrolled disease and 27 died. This post-relapse outcome is significantly worse than in patients who relapsed with metastases only (25% free of disease, 0.5-9 years after the last treatment). We conclude that, in osteosarcoma of the extremity, limb-salvage procedures should be planned only when the preoperative staging indicates that it is possible to achieve adequate surgical margins. If the pathologic examination of the surgical specimen shows inadequate surgical margins, an immediate amputation should be considered, especially if the histologic response to preoperative chemotherapy was poor.

Radiotherapy in vertebral tumors. Indications and limits: a report on 28 cases of Ewing's sarcoma of the spine.

After brief notes on techniques used to radiate the spine, its indications and the limits of doses required by its adjacency to the spinal cord, our experience in the treatment of 28 patients with a diagnosis of Ewing's sarcoma localized in the spine, not metastatic at onset, that came to our observation between 1980 and 1994 is reported. All of the patients were treated by chemotherapy. As for local treatment radiotherapy was performed in all of the cases, in 50% of cases it was associated with surgery (6 laminectomies, 6 excisions, and 2 vertebrectomies). Five-year survival rate was 43.5%. The prognosis of this group of patients was intermediate among forms localized in the limbs and those localized in the pelvis. There is a greater frequency of cerebral (20%) and skeletal metastases (55%) as compared to the disease that occurred in other sites where secondary pulmonary localizations generally prevailed. Local control was similar for disease occurring in other sites despite the need to deliver doses that were lower than those typically used for this pathology in regions above the cauda.

The value of imaging in the diagnosis and treatment of bone tumors.

The authors report their experience in the diagnosis of bone tumors at the Rizzoli Institute of Bologna. The main imaging techniques used to this purpose are conventional radiography, CT, MRI, and isotope bone scan. Angiography is rarely used. Conventional radiography is the examination of choice and is sufficient in several benign lesions not requiring treatment. Supplementary imaging studies are usually needed when radiographic findings are questionable and/or the lesion requires treatment. When a biopsy is required, it should be carried out after a complete imaging work-up, which sometimes allows a correct prebiopsy diagnosis, indicates the biopsy modality, approach and site, and is also mandatory to stage the tumor, plan the surgical approach and technique, and show in the finest details the occult tumor spread. CT best shows mineralized tissues and pulmonary metastases. It is also frequently used as a guide for needle biopsies. MRI beautifully shows the different tissues and compartments and it is particularly sensitive in depicting fat. Moreover, it can be repeated many times, even in pregnant women, because it needs no ionizing radiations and iodinated contrast; it is also free of artifacts in the patients with orthopedic devices which are usually nonferromagnetic. However, the execution of an adequate MRI requires experience and knowledge of bone pathologic conditions. Bone scan helps in detecting any 'active' area in the bone. It can be thus useful to depict lesion quiescence or activity and to stage any tumor which can metastasize to the skeleton. Bone scan is also helpful to show bone lesions when they are not visible on plain radiographs and indicates the tumor response to preoperative chemotherapy. Angiography is helpful when a preoperative selective embolization is needed, or when complex vertebral surgery or vascular surgery are planned. The bad outcome of bone tumors often depends on incomplete, inadequate or misinterpretated imaging findings.

Neoadjuvant chemotherapy for osteosarcoma of the extremity in patients in the fourth and fifth decade of life.

From January 1986 to March 1993, 29 patients aged between 40 and 60 years with primary high grade osteosarcoma of the extremity were treated at Rizzoli Institute with neoadjuvant chemotherapy. Before surgery patients received cisplatin and adriamycin. Postoperatively, patients with a good histologic response received the same two drugs preoperatively used, while in case of poor response ifosfamide and etoposide were added to cisplatin and adriamycin. Twenty-five patients (86%) were surgically treated with a limb salvage, whereas 4 patients (14%) were amputated. With a median follow-up of 8 years (5-12), the 8-year event-free survival was 57% and the 8-year overall survival was 62%. No chemotherapy-related deaths were recorded and toxicity was manageable. These results are significantly better than those achieved in 24 patients of the same age, treated at Rizzoli Institute between 1975 and 1985 only with surgery (87% of amputation and 17% of 8-year event-free and overall survival) and indicate an advantage for the use of neo-adjuvant chemotherapy also in patients with high grade osteosarcoma of the extremity older than 40 years.

Follow-up protocols in orthopedic oncology.

Little has been written about the specific timing and elements Involved in the follow-up of orthopedic oncology patients. The experience with bone tumor treatment at the First Clinic of the Istituto Rizzoli started 30 years ago and more than 15,000 patients have been treated to date. The increment of limb salvage surgery is linked with the improvements in imaging and surgical skills and with the availability of new reconstructive techniques. For this purpose it is mandatory to carry out meticulous monitoring of the patients. A large number of patients are still followed up to evaluate the results in terms of oncological and functional status. Based on this experience we developed a time schedule to better respond to the need for adequate patient evaluation.

Osteosarcoma of the extremities with synchronous lung metastases: long-term results in 44 patients treated with neoadjuvant chemotherapy.

Between September 1986 and September 1991, 44 patients with lung metastases originating from an osteosarcoma of an extremity were treated with: primary chemotherapy, simultaneous resection of primary and metastatic lesions (when feasible), and then further chemotherapy. After primary chemotherapy, lung metastases disappeared in 5 patients, whereas in 11 patients they remained surgically unresectable. All 16 patients received local treatment of the primary tumor only. In the remaining 28 patients simultaneous surgical treatment of the primary and the metastatic tumor was performed. The removal of metastatic lesions was complete in 25 and incomplete in 3 patients. With a median follow-up of 8 years (5.5-10.8) all 14 patients who never achieved a tumor-free status died. Of the 30 patients who achieved remission 5 (17%) remained continuously free of disease and 25 developed new metastases, associated with local recurrence in 4 cases. The 5-year overall survival for all 44 patients of the study was 14%, and the 5-year disease-free survival for the 30 patients who reached remission was 17%. These results are significantly worse than those achieved with the same chemotherapy protocol in 144 contemporary patients with localized disease at presentation (73% disease-free and 79% overall survival). We conclude that, despite aggressive chemotherapy which is successful in patients with localized disease, the prognosis remains very poor for patients with osteosarcoma of the extremities with lung metastases at presentation, and justifies the use of novel therapies.

Predictive factors of histologic response to primary chemotherapy in osteosarcoma of the extremity: study of 272 patients preoperatively treated with high-dose methotrexate, doxorubicin, and cisplatin.

PURPOSE: In osteosarcoma of the extremity, a strong correlation between chemotherapy-induced necrosis and prognosis has been reported. The aim of this study was to investigate the possible factors that influence histologic response to primary chemotherapy. PATIENTS AND METHODS: In 272 patients with high-grade osteosarcoma of the extremity preoperatively treated with high-dose methotrexate (HDMTX), cisplatin (CDP), and doxorubicin (ADM), the histologic response to chemotherapy was evaluated and graded as complete (no viable tumor cells) or incomplete (persistence of viable tumor cells). Several factors, such as metastatic disease to the lung at diagnosis, sex, age, site and tumor volume, histologic subtype, serum alkaline phosphatase, lactate dehydrogenase (LDH), and methotrexate (MTX) pharmacokinetics were investigated to test their predictive significance on histologic response. RESULTS: Fifty-one patients with localized disease (20.6%) and none of the 25 patients with metastatic disease at presentation had a complete histologic response (P = .006). After multivariate analysis, performed on patients with localized disease only, MTX serum peak (> or = 700 micromol/L) and histologic subtype were proven to be significant predictive factors of histologic response. A complete response was seen in 28.8% of patients with 700 micromol/L or greater MTX serum levels and in 9.9% of those patients with lower levels (P = .001). The chondroblastic subtype was less responsive (6.1% of complete response), compared with the osteoblastic (16.3%), fibroblastic (33.3%), and telangiectatic (42.3%). CONCLUSION: Patients with metastatic osteosarcoma and localized chondroblastic osteosarcoma have a reduced chemosensitivity to primary chemotherapy with MTX, CDP, and ADM. MTX serum peak significantly influences tumor necrosis. A dose adaptation of MTX is recommended to obtain a serum peak of 700 micromol/L or greater when MTX is infused in 6 hours.

Risk factors for local recurrences after limb-salvage surgery for high-grade osteosarcoma of the extremities.

BACKGROUND: Improvements in preoperative staging as well as in chemotherapeutic regimens have made limb-salvage surgery a reliable modality of treatment for high-grade osteosarcomas of the extremities, with local recurrences in most series of less than 10% after this type of surgery. The quality of surgical margins and local response to preoperative chemotherapy are known to be the most significant factors in recurrence [1, 8-10, 12], and complications related to the biopsy procedure may also be a significant factor. The study reported here comprised a histopathological analysis of our recurrent cases as part of an effort to identify the impact of each of the factors cited above. MATERIALS AND METHODS: Five hundred fourteen cases of high-grade, non-multicentric osteosarcoma of the extremities were treated at the Istituto Ortopedico Rizzoli between March 1983 and August 1991. In this study we analyzed 23 cases of local recurrence in patients with classic osteosarcoma who underwent limb-salvage procedures. RESULTS: In 15 cases we found correlation between the site of local recurrence and the site where the margins were less than wide. In five cases the recurrence was secondary to complications of the biopsy procedure (hematoma, delayed healing). In one case we suspect a previously undetected skip lesion. In the remaining two cases no clear explanation was found for the recurrence. There was also a statistically significant difference in the time of appearance of recurrences related to the tumor response to chemotherapy. CONCLUSIONS: For only two cases of recurrence was there no clear explanation. In one we suspect an undetected skip metastasis, and in the other there were certain factors which may have increased its risk of recurrence (non diagnostic trochar biopsy followed by an incisional biopsy, fair tumor necrosis, recurrence in a 'problem' anatomical site, i.e., the popliteal space). In the remaining cases the following factors were found to be directly related to the development of a local recurrence: a) the quality of the surgical margins, b) site of the biopsy as well as complications related to the biopsy procedure, c) local response to preoperative chemotherapy.