Cooperative Osteosarcoma Study Group Research Articles

Second and Subsequent Recurrences of Osteosarcoma: Presentation, Treatment, and Outcomes of 249 Consecutive Cooperative Osteosarcoma Study Group Patients

Second and Subsequent Recurrences of Osteosarcoma: Presentation, Treatment, and Outcomes of 249 Consecutive Cooperative Osteosarcoma Study Group Patients

Second and Subsequent Recurrences of Osteosarcoma: Presentation, Treatment, and Outcomes of 249 Consecutive Cooperative Osteosarcoma Study Group Patients

To evaluate patient and tumor characteristics, treatment, and outcomes in a large cohort of unselected patients with second and subsequent recurrences of osteosarcoma. Two hundred forty-nine consecutive patients who had originally received combined-modality therapy on neoadjuvant Cooperative Osteosarcoma Study Group protocols and went on to develop a total of 409 second and subsequent osteosarcoma recurrences were analyzed for patient-, tumor-, and treatment-related factors and outcomes. Five-year overall and event-free survival rates were 16% and 9% for 249 second, 14% and 0% for 93 third, 13% and 6% for 38 fourth, and 18% and 0% for 14 fifth recurrences, respectively. The proportion of recurrences confined to the lungs decreased and the proportion of those with chest wall involvement increased with increasing numbers of recurrences. The duration of relapse-free intervals and the number of lesions at recurrence correlated with outcomes. While only one of 205 patients with rerecurrence survived past 5 years without surgical remission, 5-year overall and event-free survival rates were 32% and 18% for 119 second, 26% and 0% for 45 third, 28% and 13% for 20 fourth, and 53% and 0% for five fifth recurrences, respectively, in which a renewed surgical remission was achieved. The use of chemotherapy correlated with longer survival in patients without surgical remissions. To our knowledge, this is the first report of survival estimates derived from large cohorts of unselected patients with second and subsequent osteosarcoma recurrences. It confirms the overwhelming importance of surgical clearance. Prognostic indicators after rerecurrences resemble those known from first recurrence. The exact role of re-treatment with chemotherapy, particularly in the adjuvant situation, remains to be defined.

Pediatric extraskeletal osteosarcoma

Sir, Beall et al. [1] are to be commended for reminding clinicians and radiologists about the entity of extraskeletal osteosarcoma, which is rare in adults and exceedingly rare in children. However, their final conclusion that “treatment is often palliative but can improve survival greatly in children and may even be curative in low-grade cancers” requires clarification and comment. With appropriate multidisciplinary care consisting of surgery with wide, uncontaminated margins as well as intensive, multidrug chemotherapy, there is a reasonable likelihood of achieving long-term, recurrence-free survival not only in low-grade cancers, but in high-grade tumors as well, in children as well as in adults. Using such a combined modality approach, for example, our Cooperative Osteosarcoma Study (COSS) group has achieved an event-free survival estimate of 56% at 5 years for 17 patients (including four in the pediatric age group) with high-grade extraskeletal osteosarcoma who received treatment as for conventional osteosarcoma of bone. The corresponding percentage for those 14 patients among the 17 who achieved a complete surgical remission as part of combined modality therapy was 69% [2]. Also, Ahmad et al. [3] have reported a 5-year disease-specific survival of 46% in a group of 38 patients with localized disease, of whom 24 had some form of chemotherapy [3]. Therefore, curative treatment attempts should not be limited to patients with low-grade variants of extraskeletal osteosarcoma, which are much rarer even than their very rare high-grade counterparts, but should be offered to most affected patients!

Interdisciplinary combined treatment of craniofacial osteosarcoma with neoadjuvant and adjuvant chemotherapy and excision of the tumour: a retrospective study

Osteosarcomas are highly malignant tumours of bone, and are rare in the craniofacial area. They account for only 1% of all head and neck malignancies. In this study we describe the treatment of 12 patients who were diagnosed with osteosarcoma of the mandible or maxilla between 1990 and 2004. These patients were given interdisciplinary treatments, either with a combination of neoadjuvant and adjuvant high-dose chemotherapy following the protocol of the cooperative osteosarcoma study group (COSS) with radical excision of the tumour ( n = 7), with a combination of radiation and radical excision ( n = 2), or with radical excision alone of the tumour ( n = 3). The 5-year survival of the group treated only by excision was 1 of 3, whereas that of the group treated by combination of chemotherapy and surgical removal was 7 of 7. The two patients treated with radiation and excision also lived 5 years after the end of the treatment, but had side-effects of radiation, whereas those treated with chemotherapy had no serious side-effects. We therefore conclude that combined interdisciplinary treatment of radical resection of the tumour with high-dose chemotherapy according to standard protocols is the most effective treatment for craniofacial osteosarcomas.

International collaboration is feasible in trials for rare conditions: The EURAMOS experience

20501 Background: Osteosarcoma is rare and the outcome for patients has plateaued following the introduction of multi-agent chemotherapy. To demonstrate further improvements would likely require large numbers of patients, only achievable in this setting via International collaboration. Therefore, in October 2001, 4 multinational groups - Children's Oncology Group (COG), Cooperative Osteosarcoma Study Group (COSS), European Osteosarcoma Intergroup (EOI) and Scandinavian Sarcoma Group (SSG) - agreed on the merits of collaboration to determine whether altering post-operative therapy based on histological response improved outcome. Following a number of practical and regulatory hurdles the trial opened to accrual in April 2005. Methods: Eligibility criteria include: new diagnosis with resectable osteosarcoma; age <40 years; normal organ function. Standard therapy includes 29 weeks of cisplatin, doxorubicin and high-dose methotrexate (MAP). Following two cycles of cisplatin/doxorubicin and 2–6 cycles of high-dose methotrexate, patients undergo resection. Post-operative therapy is dependent on histological response. Good histological responders (>90% necrosis) are randomized to continuing MAP or MAP with maintenance pegylated interferon. Poor histological responders are randomized to MAP or MAP plus ifosfamide and etoposide. Results: All groups are recruiting and accrual is ahead of schedule: 373 patients have been enrolled (159 COG, 108 COSS, 83 EOI, 23 SSG) and 160 patients randomized: 87 (54%) good responders (46 MAP), 73 (46%) poor responders (39 MAP). Conclusions: International collaboration is feasible and results in rapid accrual of large number of patients. The implementation of such trials is difficult and time consuming due to the complexity of multinational regulatory issues. However, the effort is worthwhile to potentially improve outcomes for patients with rare diseases. No significant financial relationships to disclose.

Osteosarcoma in children aged less than five years at diagnosis: Experience of the Cooperative Osteosarcoma Study Group

9554 Background: The incidence of osteosarcoma considerably varies with age and preschool children are reported to be extremely rarely affected. This study was conducted to investigate presentation, treatment, and outcome in very young children with osteosarcoma. Patients and Methods: The authors retrospectively analyzed the collected data of 2,706 consecutive patients with newly diagnosed high-grade osteosacroma of bone registered in the COSS studies between 1976 and 2005; and identified 28 patients (1%) aged less than five years at diagnosis. Demographic, diagnostic, tumor, and treatment related variables; response and survival data of these 28 patients were analyzed. Results: Of the 28 (male, N = 16; female, N = 12) identified toddlers (two years, N = 4; three years, N = 10; four years, N = 14), 27 presented with a high-grade central osteosarcoma of an extremity (femur, N = 12; humerus, N = 10; tibia, N = 5) and one with a secondary osteosarcoma of the orbit. The size of the primary extremity tumor was large in 74% of patients. Primary metastases were detected in 4/28 children. All 28 patients received multiagent chemotherapy, and 13 of the 21 analyzed tumors responded well to neoadjuvant chemotherapy (>90% necrosis). Limb sparing surgery was feasible in 11 children, whereas ablative procedures were performed in 14 patients. A macroscopically complete surgical remission of all clinically detectable tumors was achieved in 24/28 patients during front line therapy. With a median follow-up of 1.7 years (4.2 years for survivors), 15/28 patients were alive. Outcome was poorer for the 28 toddlers compared to the 2,678 older patients (5-year event free survival 43% ± 10% vs. 56% ± 1%)(P = 0.02). Conclusion: Osteosarcoma is extremely rare in preschool children. These young patients often have large tumors which may require mutilating resections. Despite the high rate of ablative surgery, the prognosis, however, may be poorer compared to older patients. No significant financial relationships to disclose.

Epidermal Growth Factor Receptor Expression in High-Grade Osteosarcomas Is Associated with a Good Clinical Outcome

The expression of the epidermal growth factor receptor (EGFR) in osteosarcomas has repeatedly been described. With the introduction of anti-EGFR-targeted therapies in clinical practice, these findings regain increased attention. Experience with anti-EGFR-targeted therapies in other cancers has made clear that besides the expression status of EGFR, a detailed knowledge about gene mutations is of major predictive power. We therefore aimed to explore the EGFR expression and gene mutation status in high-grade osteosarcomas. We investigated tumor samples of osteosarcoma patients of all age groups by means of immunohistochemistry (n=111) and egfr fluorescence in situ hybridization (n=39). Sixty-three patients were treated according to the Cooperative Osteosarcoma Study Group protocols and complete clinical follow-up was available in these cases. Ninety-one of 111 (81%) of osteosarcomas revealed an expression of EGFR. EGFR expression showed a dose-response relation with improved event-free and overall survival. This was independent of the degree of tumor regression due to neoadjuvant chemotherapy. Nine of 39 (23%) osteosarcomas showed egfr amplifications by means of fluorescence in situ hybridization. All these cases expressed EGFR. When comparing EGFR expression between primary biopsy and resection specimen (n=19), viable residual tumor cells in resection specimens revealed a lower EGFR expression and a tendency toward membranous staining compared with the initial biopsy. In conclusion, expression and amplification of EGFR are frequently observed in high-grade osteosarcomas and are associated with improved prognosis in a dose-responsive way. This implies that low EGFR expression possibly predicts lack of response to conventional treatment in high-grade osteosarcomas and may warrant a more intensive therapeutic approach, although not based on EGFR targeting.

Skip Metastases in Osteosarcoma: Experience of the Cooperative Osteosarcoma Study Group

The outlook for patients with osteosarcoma who present with synchronous regional bone metastases (skip metastases), either in the primary bone site or transarticular, is considered to be extremely poor. This study was conducted to further investigate the prognostic implication of skip metastases in osteosarcoma. The authors retrospectively analyzed the collected data of 1,765 consecutive patients with newly diagnosed high-grade osteosarcoma of bone who were registered in the neoadjuvant Cooperative Osteosarcoma Study Group studies and identified 24 patients (1.4%) with unequivocally proven skip metastases. All 24 patients were treated by an aggressive surgical approach coupled with polychemotherapy. Demographic, diagnostic, tumor, and treatment-related variables and response and survival data were analyzed. Skip metastases were identified preoperatively in 11 of 24 patients by bone scan, eight of 22 patients by plain x-ray, 15 of 18 patients by magnetic resonance imaging, and five of 10 patients by computed tomography. A complete surgical remission (CSR) of all clinically detectable tumor sites was achieved in 22 of 24 patients during front-line therapy. With a median follow-up time of 4.4 years (8 years for survivors) from diagnosis, 12 patients were alive, all of whom were in continuous CSR. Survival did correlate with location of skip metastases and histologic response to neoadjuvant chemotherapy. Synchronous regional bone metastases are rare in osteosarcoma, and preoperative detection relies on appropriate diagnostic imaging. Aggressive multimodal therapy holds the promise to achieve prolonged survival, especially in patients in whom these metastases occur within the same bone as the primary lesion and whose tumors respond well to chemotherapy.

Dose intensity of chemotherapy for osteosarcoma and outcome in the Cooperative Osteosarcoma Study Group (COSS) trials

The prognostic relevance of dose intensity in the treatment of osteosarcoma is still under discussion. The aim of this study was to investigate whether higher dose intensities of chemotherapy correlated with better outcomes. This study contains 917 consecutive Cooperative Osteosarcoma Study Group (COSS) patients <40 years with primary, high-grade central, nonmetastatic osteosarcoma of the extremities, who were in complete remission at least until day 200 after the start of chemotherapy. All COSS-protocols were based on a uniform treatment concept of aggressive polychemotherapy and definitive surgery. Chemotherapy dose intensity in the first 200 days of treatment (DI200) and possible correlations to overall and event-free survival were investigated. The study focused on methotrexate, doxorubicin, cisplatin, and ifosfamide, which are considered to be the most active drugs against osteosarcoma. Multivariate analyses including well-known prognostic factors were added to complete this investigation. Until day 200, patients received 80.7 +/- 26.1 g/m2 methotrexate (MTX); 242 +/- 69 mg/m2 doxorubicin (DOX); 324 +/- 133 mg/m2 cisplatin (DDP); and 13.9 +/- 9.8 g/m2 ifosfamide (IFO) (mean +/- SD). Median follow-up from day 200 was 6.6 (0.02-22.1) years. There was no correlation between a higher DI200 of any one drug and better outcomes in uni- or multi-variate analyses. Total treatment intensity did not show such correlations either. In an overall setting of intensive multidrug treatment of osteosarcoma, we could not prove that higher dose intensities correlate with better outcomes.

Osteosarcoma of the Hand and Forearm: Experience of the Cooperative Osteosarcoma Study Group

Osteosarcoma is extremely rare in the hand and forearm. Therefore, only limited data are available for planning treatment or predicting the outcome and prognosis of osteosarcoma in the peripheral upper extremity. Epidemiological, clinical, and histopathologic data were analyzed in 39 patients with osteosarcoma of the forearm or hand who were enrolled in studies of the Cooperative German-Austrian-Swiss Osteosarcoma Study Group from 1977 to December 2000. In patients with high-grade osteosarcoma, the treatment entailed surgical resection in combination with chemotherapy, whereas patients with low-grade osteosarcoma underwent only surgery. The 5-year overall survival rate among the 33 patients with high-grade central osteosarcoma of the distal upper extremity was 86.2% +/- 6.4%. The 5-year event-free survival rate was 65.4% +/- 9.6%. Five of the eight patients with secondary metastases were in remission at the time of analysis. Four patients died of their disease, and two patients died of chemotherapy-related complications. The mean overall survival rate was 88.0% +/- 6.5% in patients treated by wide or radical tumor resection and was 75.0% +/- 21.7% in patients with nonwide margins of resection. Whether amputation or local resection was performed had no significant influence on the prognosis. All six patients whose osteosarcoma was not classified as high-grade central osteosarcoma were in remission at the time of analysis. The results demonstrate a remarkably high survival rate for patients with high-grade osteosarcoma of the hand and forearm and confirm that multiagent chemotherapy in combination with wide excision is a highly effective treatment for this malignant tumor.

Osteosarcoma Relapse After Combined Modality Therapy: An Analysis of Unselected Patients in the Cooperative Osteosarcoma Study Group (COSS)

To evaluate the impact of patient, tumor, and treatment-related factors on outcome in unselected patients with recurrent osteosarcoma. Five hundred seventy-six consecutive patients who had achieved a first complete surgical remission (CR) during combined-modality therapy on neoadjuvant Cooperative Osteosarcoma Study Group (COSS) protocols and then developed recurrent osteosarcoma were analyzed (median time from biopsy to relapse, 1.6 years; range, 0.1 to 14.3 years). There were 501 patients with metastases, 44 with local recurrences, and 31 with both. Metastases involved lungs (469 patients), bones (90 patients), and/or other sites (54 patients). After a median follow-up of 1.2 years for all patients and 4.2 years for survivors, actuarial overall survival (OS) rates at 2, 5, and 10 years were 0.38, 0.23, and 0.18, respectively. Five-year OS was 0.39 for 339 patients with and 0.00 for 229 patients without a second surgical CR (P < .0001). A long time to relapse, a solitary lesion, and, in the case of pulmonary metastases, unilateral disease and the absence of pleural disruption, were of positive prognostic value in uni- and multivariate analyses, as were a second surgical CR and the use of second-line chemotherapy. Radiotherapy was associated with moderately prolonged survival in patients without a second CR. The very limited prognostic differences associated with the use of second-line chemotherapy appeared to be more pronounced with polychemotherapy. Time to relapse and tumor burden correlate with postrelapse outcome in osteosarcoma. Complete surgery is an essential component of curative second-line therapy. Chemotherapy, particularly chemotherapy with more than one agent, may contribute to limited improvements in outcome.

Prognostic Relevance of Increased Angiogenesis in Osteosarcoma

The purpose of this work was to evaluate the prognostic relevance of microvessel density (MVD) for response to chemotherapy and long-term outcome in osteosarcoma. Pretherapeutic tumor biopsies of 60 patients with high-grade central osteosarcoma, who were treated according to multimodal neoadjuvant protocols of the German-Austrian-Swiss Cooperative Osteosarcoma Study Group, were evaluated for intratumoral MVD. MVD was correlated with demographic and tumor-related variables, response, and survival. The median intratumoral MVD was 52 microvessels per 0.26-mm2 field area (interquartile range, 31-77 microvessels per 0.26-mm2 field area). At a median follow-up period of 3.5 years, patients with a high (>median) MVD had significantly higher 5- and 10-year overall survival rates (84%) than patients with low (< or =median) MVD (49%; P = 0.0029). Furthermore, increased relapse-free survival for patients with high MVD (P = 0.0064) was observed. In a subgroup analysis of 44 patients with primary high-grade central osteosarcoma of the extremities without primary metastases and good surgical remission, high MVD was associated with 5- and 10-year overall survival rates of 91% compared with 58% for low MVD (P = 0.034). Cox regression analysis revealed that MVD was an independent prognostic factor for survival. A good response to chemotherapy (histologic grading scale of Salzer-Kuntschik) correlated significantly with a high MVD (P = 0.006). Increased angiogenesis is a prognostic indicator for higher survival and response rates to chemotherapy in patients with osteosarcoma. Thus, measurement of MVD might be useful in decisions selecting patients for future neoadjuvant treatment.

Tumors of the Hand

Because the hand, like the face, is the first encounter of a patient by any clinician, a basic knowledge of hand tumours is relevant to all clinical practice. Tumours can arise from any of the six main tissues of the hand. Most tumours of the hand are not true neoplasms but the result of classic disease states—trauma, infection, inflammatory disease, metabolic disorder, degenerative disorder, congenital anomaly. The clinician then needs to know which tumours should be investigated and referred on to a specialist. Egloff's book, published in association with the Federation of Societies for Surgery of the Hand, provides a near-comprehensive review. Tumours of the hand and upper extremity were the subject of an issue of Hand Clinics this year (2004; 20: No. 2) but no book has been devoted solely to the subject since the 1988 Tumours of the Hand by Glicenstein, Ohana and Leclercq (Springer Verlag). Two omissions are noteworthy. First, 90% of hand tumours are ganglia, and Egloff and his team decided to exclude these because they are not true tumours and their treatment is to be found in all textbooks. In our opinion, ganglia deserved a place because they come into the different diagnosis of tumours; a ganglion can be hard to distinguish from a giant cell tumour of tendon sheath, which is the second commonest tumour. Second, skin tumours, except for melanomas, are excluded. Otherwise the book offers comprehensive coverage of tumours both benign and malignant, with important and useful information on clinical and radiological diagnosis (including ultrasound and MRI). Advances in MRI have helped not only in diagnosis but also in follow-up to detect recurrences and extensions. For malignant tumours the authors emphasize the need for investigation and treatment in specialist centres where hand surgeons, pathologists, oncologists and radiologists work as a team. Peripheral nerve sheath tumours and vascular tumours, which can be difficult to diagnose and manage, are well discussed, and an excellent section on soft tissue tumours ends with a chapter describing the 25-year experience of the Cooperative Osteosarcoma Study Group. All the chapters are well referenced. Many kinds of surgeon—general, orthopaedic, plastic, neuro—will value the advice provided here on diagnosis and management. Trainee and specialist hand surgeons will find it particularly useful.

Ziele und Ergebnisse der COSS-Studien

Osteosarcoma is the most common primary malignant tumor of bone (annual incidence: 2 - 3/Mio). Ever since 25 years ago, affected children, adolescents, and adults from Germany, Austria, and Switzerland receive their therapy within trials of the Cooperative Osteosarcoma Study Group (COSS). Approximately 60 % of all patients ever entered into COSS-trials could be cured with an interdisciplinary treatment approach consisting of complete surgical removal of the primary tumor plus intensive pre- and postoperative chemotherapy. The COSS-group's database now includes information on more than 3,000 osteosarcoma patients treated with such a multimodal approach, the largest series worldwide. The present paper is intended to detail the experience gathered from this cohort.

Comparisons of the Skeletal Locations of Putative Plutonium-Induced Osteosarcomas in Humans with those in Beagle Dogs and with Naturally Occurring Tumors in both Species

Osteosarcomas occur from exposures to bone-seeking, alpha-particle-emitting isotopes, particularly plutonium. The skeletal distribution of putative 239Pu-induced osteosarcomas reported in Mayak Metallurgical and Radiochemical Plutonium Plant workers is compared with those observed in canine studies, and these are compared with distributions of naturally occurring osteosarcomas in both species. In the Mayak workers, 29% and 71% of the osteosarcomas were in the peripheral and central skeleton, respectively, with the spine having the most tumors (36%). An almost identical distribution of plutonium-induced osteosarcomas was reported for dogs injected with 239Pu as young adults. This distribution of osteosarcomas is quite different from the distributions of naturally occurring osteosarcomas for both species. In the Cooperative Osteosarcoma Study Group in humans (1,736 osteosarcomas from all ages), over 91% of the tumors occurred in the peripheral skeleton. In the Mayo Clinic group of older individuals (>40 years old), over 60% of the osteosarcomas appeared in the peripheral skeleton. The distribution of naturally occurring osteosarcomas in the canine is similar to that in the adult human. The similarities of the distributions of plutonium-associated osteosarcomas in the Mayak workers with those found in experimental studies suggest that many of the reported osteosarcomas may have been associated with plutonium exposures. These results also support the experimental paradigm that plutonium osteosarcomas have a preference for well vascularized cancellous bone sites. These sites have a greater initial deposition of plutonium, but also greater turnover due to elevated bone remodeling rates.

Primary metastatic osteosarcoma: presentation and outcome of patients treated on neoadjuvant Cooperative Osteosarcoma Study Group protocols.

To determine demographic data and define prognostic factors for long-term outcome in patients presenting with high-grade osteosarcoma of bone with clinically detectable metastases at initial presentation. Of 1,765 patients with newly diagnosed, previously untreated high-grade osteosarcomas of bone registered in the neoadjuvant Cooperative Osteosarcoma Study Group studies before 1999, 202 patients (11.4%) had proven metastases at diagnosis and therefore were enrolled onto an analysis of demographic-, tumor-, and treatment-related variables, response, and survival. The intended therapeutic strategy included pre- and postoperative multiagent chemotherapy as well as aggressive surgery of all resectable lesions. With a median follow-up of 1.9 years (5.5 years for survivors), 60 patients were alive, 37 of whom were in continuously complete surgical remission. Actuarial overall survival rates at 5 and 10 (same value for 15) years were 29% (SE = 3%) and 24% (SE = 4%), respectively. In univariate analysis, survival was significantly correlated with patient age, site of the primary tumor, number and location of metastases, number of involved organ systems, histologic response of the primary tumor to preoperative chemotherapy, and completeness and time point of surgical resection of all tumor sites. However, after multivariate Cox regression analysis, only multiple metastases at diagnosis (relative hazard rate [RHR] = 2.3) and macroscopically incomplete surgical resection (RHR = 2.4) remained significantly associated with inferior outcomes. The number of metastases at diagnosis and the completeness of surgical resection of all clinically detected tumor sites are of independent prognostic value in patients with proven primary metastatic osteosarcoma.

Osteosarcoma after allogeneic bone marrow transplantation. A report of four cases from the Cooperative Osteosarcoma Study Group (COSS).

Osteosarcoma, one of the most frequent secondary malignancies after the treatment of young patients with cancer, has only very rarely been observed in association with hematopoietic stem cell transplantation (HSCT). We report four patients who were identified by searching the database of the Cooperative Osteosarcoma Study Group (COSS) for patients whose osteosarcoma arose following HSCT. Transplant indications had been acute lymphoblastic leukemia (3). and sickle cell disease (1). and the stem cell source was bone marrow in all cases (three allogeneic, one syngeneic). All four had received chemotherapy with alkylators as part of their conditioning regimen and/or first line therapy. The conditioning regimen included total body irradiation in three patients. The osteosarcomas arose at the age (adolescence) and sites (around the knee) typical for the disease. All four patients received chemotherapy as part of multimodal osteosarcoma treatment, and all four are currently alive, three in continuous remission at 5 7/12, 2 11/12, and 0 6/12 years and one with relapsed osteosarcoma at 4 1/12 years. One of the osteosarcoma-free survivors suffered a third malignancy, myelodysplastic syndrome. Osteosarcoma should be included among the secondary malignancies that can arise following HSCT. Multi-modal therapy according to guidelines for de novo osteosarcoma can lead to long-term survival in selected patients.

Bone mineral density in long-term survivors of highly malignant osteosarcoma.

We studied the bone mineral density (BMD) of 48 long-term survivors of highly malignant osteosarcoma who had been treated according to the chemotherapy protocols of the German- Swiss-Austrian Co-operative Osteosarcoma Study Group which include high-dose methotrexate. The mean age of the patients was 31 +/- 4.2 years and the mean follow-up 16 +/- 2.2 years. The BMD of the lumbar spine and of the proximal femur of the non-operated side was measured by dual-energy x-ray absorptiometry. A questionnaire was given to determine life-style factors, medical history and medication. Ten patients were osteoporotic, 21 osteopenic and 17 normal according to the WHO definition. Eighteen patients suffered fractures after receiving chemotherapy and all had significantly lower levels of BMD for all the sites measured.

Osteosarcoma of the pelvis: experience of the Cooperative Osteosarcoma Study Group.

To define patients and tumor characteristics as well as therapy results, patients with pelvic osteosarcoma who were registered in the Cooperative Osteosarcoma Study Group (COSS) were analyzed. Sixty-seven patients with a high-grade pelvic osteosarcoma were eligible for this analysis. Fifteen patients had primary metastases. All patients received chemotherapy according to COSS protocols. Thirty-eight patients underwent limb-sparing surgery, 12 patients underwent hemipelvectomy, and 17 patients did not undergo definitive surgery. Eleven patients received irradiation to the primary tumor site: four postoperatively and seven as the only form of local therapy. Local failure occurred in 47 of all 67 patients (70%) and in 31 of 50 patients (62%) who underwent definitive surgery. Five-year overall survival (OS) and progression-free survival rates were 27% and 19%, respectively. Large tumor size (P =.0137), primary metastases (P =.0001), and no or intralesional surgery (P <.0001) were poor prognostic factors. In 30 patients with no or intralesional surgery, 11 patients with radiotherapy had better OS than 19 patients without radiotherapy (P =.0033). Among the variables, primary metastasis, large tumor, no or intralesional surgery, no radiotherapy, existence of primary metastasis (relative risk [RR] = 3.456; P =.0009), surgical margin (intralesional or no surgical excision; RR = 5.619; P <.0001), and no radiotherapy (RR = 4.196; P =.0059) were independent poor prognostic factors. An operative approach with wide or marginal margins improves local control and OS. If the surgical margin is intralesional or excision is impossible, additional radiotherapy has a positive influence on prognosis.

Osteosarcoma of the spine

Due to the low incidence rate, the optimal strategy for the treatment of patients with spinal osteosarcoma is unknown. Twenty-two patients with osteosarcoma of the spine (15 with tumors of the sacrum and 7 with tumors at other sites) who received chemotherapy according to the Cooperative Osteosarcoma Study Group protocol were analyzed. Six patients presented with metastasis, and 16 patients had no evidence of metastasis at the time of entry into the protocol. Of 12 patients who underwent excision of their tumors, 2 patients underwent wide excision, 3 patients underwent marginal excision, and 7 patients underwent intralesional excision. Eight patients received irradiation: Six patients received conventional radiotherapy only, one patient received neutron beam therapy, and one patient received samarium-153-ethylene diamine tetramethylene phosphonate therapy. Follow-up ranged between 24 months and 105 months (median, 47 months). The median survival was 23 months, and three patients have survived without disease for > 6 years. Patients with primary metastases (P = 0.004), large tumors (P = 0.010), and sacral tumors (P = 0.048) had lower overall survival compared with patients who had no metastasis, small tumors, and nonsacral tumors, respectively. There was a significant difference in overall survival between 5 patients who underwent either wide or marginal surgery and 17 patients who underwent either intralesional surgery or no surgery (P = 0.033). Among 17 patients who underwent no surgery or intralesional surgery, overall survival tended to be better in 7 patients who received irradiation compared with the overall survival in 10 patients who did not receive irradiation (P = 0.059). Patients with metastases, a large tumors, and sacral tumors had a poor prognosis in the current study with small numbers of patients. Wide or marginal excision of the tumor improved survival. Patients with osteosarcoma of the spine should be treated with a combination of chemotherapy and at least marginal excision for those with surgically accessible tumors. Postoperative radiotherapy may be beneficial.