Rainer Kotz

Primary Metastatic Osteosarcoma: Presentation and Outcome of Patients Treated on Neoadjuvant Cooperative Osteosarcoma Study Group Protocols

PURPOSE 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. PATIENTS AND METHODS 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. RESULTS 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. CONCLUSION 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 Relapse After Combined Modality Therapy: An Analysis of Unselected Patients in the Cooperative Osteosarcoma Study Group (COSS)

PURPOSE To evaluate the impact of patient, tumor, and treatment-related factors on outcome in unselected patients with recurrent osteosarcoma. PATIENTS AND METHODS 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). RESULTS 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. CONCLUSION 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.

Serum Cobalt Levels After Metal-on-Metal Total Hip Arthroplasty

BACKGROUND Systemic cobalt dissemination from the Metasul Co-28Cr-6Mo-0.2C metal-on-metal total hip prosthesis has been demonstrated in the first year after implantation. The aim of this prospective study was to monitor the serum cobalt concentrations in patients during the first five years after total hip arthroplasty with a metal-on-metal articulation. METHODS A total hip arthroplasty was performed without cement in 100 consecutive patients who had either unilateral osteoarthritis or unilateral osteonecrosis. Fifty patients were randomized to be treated with a metal-on-metal articulation, and fifty patients, with a ceramic-on-polyethylene bearing. The femoral stem was made of a Ti-6Al-7Nb alloy, and the threaded acetabular cup was made of commercially pure titanium. Blood samples were taken before the operation and at multiple time-points for five years after the operation. Serum cobalt concentrations were measured with use of atomic absorption spectrometry. RESULTS In the metal-on-metal group, the median serum cobalt concentration was 1 micro g/L at one year after surgery and 0.7 micro g/L at five years. The median of the serum cobalt concentrations measured from three to twelve months did not differ from the median of subsequent measurements, with the numbers available. The median serum cobalt level in the control group of patients treated with the ceramic-on-polyethylene articulation was below the detection limit at all time-points. CONCLUSIONS Systemic cobalt release from Metasul metal-on-metal articulations was demonstrated throughout the five-year study period. The median serum cobalt concentrations were found to be slightly above the detection limit and remained in a constant range. The serum cobalt concentrations did not reflect a so-called run-in wear period of the metal-on-metal articulations.

Prevalence of flat foot in preschool-aged children.

OBJECTIVES. Our aim with this study was to establish the prevalence of flat foot in a population of 3- to 6-year-old children to evaluate cofactors such as age, weight, and gender and to estimate the number of unnecessary treatments performed. METHODS. A total of 835 children (411 girls and 424 boys) were included in this study. The clinical diagnosis of flat foot was based on a valgus position of the heel and a poor formation of the arch. Feet of the children were scanned (while they were in a standing position) by using a laser surface scanner, and rearfoot angle was measured. Rearfoot angle was defined as the angle of the upper Achilles tendon and the distal extension of the rearfoot. RESULTS. Prevalence of flexible flat foot in the group of 3- to 6-year-old children was 44%. Prevalence of pathological flat foot was <1%. Ten percent of the children were wearing arch supports. The prevalence of flat foot decreases significantly with age: in the group of 3-year-old children 54% showed a flat foot, whereas in the group of 6-year-old children only 24% had a flat foot. Average rearfoot angle was 5.5° of valgus. Boys had a significant greater tendency for flat foot than girls: the prevalence of flat foot in boys was 52% and 36% in girls. Thirteen percent of the children were overweight or obese. Significant differences in prevalence of flat foot between overweight, obese, and normal-weight children were observed. CONCLUSIONS. This study is the first to use a three-dimensional laser surface scanner to measure the rearfoot valgus in preschool-aged children. The data demonstrate that the prevalence of flat foot is influenced by 3 factors: age, gender, and weight. In overweight children and in boys, a highly significant prevalence of flat foot was observed; in addition, a retarded development of the medial arch in the boys was discovered. At the time of the study, >90% of the treatments were unnecessary.

Tumor size and prognosis in aggressively treated osteosarcoma

PURPOSE The aim of this retrospective analysis was to investigate the prognostic significance and optimal measures of tumor size in osteosarcoma treated with intensive neoadjuvant chemotherapy. PATIENTS AND METHODS Initial anterior-posterior (AP) and lateral x-ray films of 128 patients treated within the trials Cooperative Osteosarcoma Study (COSS)-80, -82, and -86, were evaluated for the following three tumor diameters: length, width, and depth. Metastasis-free survival (MFS) analyses were performed in univariate and multivariate models with one, two, and three dimensions of the tumor as absolute or relative measures (tumor length, referred to bone length, plane and volume to body-surface area). RESULTS Univariate analyses of MFS showed a high prognostic significance of all absolute measures. Relative measures, at best, showed a comparable predictive value. Cox regression analysis indicated the high prognostic significance of absolute tumor volume (ATV; P < .0001) and histologic response (P < .0001). None of 19 patients with an ATV < or = 70 cm3 and only four of 53 with an ATV < or = 150 cm3 relapsed, while in patients with an ATV more than 150 cm3, the relapse rate remained 40% to 60%, irrespective of further increase in volume. CONCLUSION Initial tumor size is an important and easily obtainable prognostic factor in osteosarcoma and may serve as a basis for risk-adapted therapy. It is best represented by the absolute three-dimensional measure ATV. There is a cut-off point regarding the incidence of metastases at a tumor volume of approximately 150 cm3 as calculated from two-plane x-ray films.

Osteosarcoma of the Pelvis: Experience of the Cooperative Osteosarcoma Study Group

PURPOSE 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. PATIENTS AND METHODS 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. RESULTS 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. CONCLUSION 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.

Local therapy in localized Ewing tumors: results of 1058 patients treated in the CESS 81, CESS 86, and EICESS 92 trials.

PURPOSE The impact of different local therapy approaches on local control, event-free survival, and secondary malignancies in the CESS 81, CESS 86, and EICESS 92 trials was investigated. METHODS AND MATERIALS The data of 1058 patients with localized Ewing tumors were analyzed. Wherever feasible, a surgical local therapy approach was used. In patients with a poor histologic response or with intralesional and marginal resections, this was to be followed by radiotherapy (RT). In EICESS 92, preoperative RT was introduced for patients with expected close resection margins. Definitive RT was used in cases in which surgical resection seemed impossible. In CESS 81, vincristine, adriamycin, cyclophosphamide, and actinomycin D was used. In CESS 86, vincristine, adriamycin, ifosfamide, and actinomycin D was introduced for patients with central tumors or primaries >100 cm(3). In CESS 92, etoposide, vincristine, adriamycin, ifosfamide, and actinomycin D was randomized against vincristine, adriamycin, ifosfamide, and actinomycin D in patients with primaries >100 cm(3). RESULTS The rate of local failure was 7.5% after surgery with or without postoperative RT, and was 5.3% after preoperative and 26.3% after definitive RT (p = 0.001). Event-free survival was reduced after definitive RT (p = 0.0001). Irradiated patients represented a negatively selected population with unfavorable tumor sites. Definitive RT showed comparable local control to that of postoperative RT after intralesional resections. Patients with postoperative RT had improved local control after intralesional resections and in tumors with wide resection and poor histologic response compared with patients receiving surgery alone. Patients with marginal resections with or without postoperative radiotherapy showed comparable local control, yet the number of patients with good histologic response was higher in the latter treatment group (72.2% vs. 38.5%). CONCLUSION Patients with resectable tumors after initial chemotherapy had a low local failure rate. With preoperative RT, local control was comparable. RT is indicated to avoid intralesional resections. After intralesional or marginal resections and after a poor histologic response and wide resection, postoperative RT may improve local control.

Long-term followup of uncemented tumor endoprostheses for the lower extremity.

Between 1982 and 1989, 100 primary lower limb reconstructions were done using the Kotz Modular Femur Tibia Reconstruction System after resection of a malignant tumor. In 32 patients a proximal femur prosthesis was implanted, in 40 patients a distal femur prosthesis was implanted, in 19 patients a proximal tibia component was implanted, in four patients a total femur prosthesis was implanted, and in five patients a total knee prosthesis was implanted. The Kaplan-Meier estimate of the overall survival rate of the prostheses was 85% after 3 years, 79% after 5 years, and 71% after 10 years. The most common reason for implant failure was aseptic loosening in 27% of patients (11 patients; range, 10–121 months) after the initial operation. The other reasons for revision surgery were implant fracture (n 5 4) and infection (n 5 4). Early repair of prostheses-related minor complications, such as worn polyethylene bushings, resulted in a statistically significant reduction of implant failure. After a median followup of 127.5 months after the initial surgery, 51 patients had died and eight patients were lost to followup. Forty-one patients were evaluated clinically and radiologically using the Musculoskeletal Tumor Society score and the radiologic implant evaluation system of the International Symposium on Limb Salvage; these 41 patients had a mean of 80% (range, 40%–100%) of the normal functional capability.

Osteosarcoma: The COSS Experience

COSS, the interdisciplinary Cooperative German-Austrian-Swiss Osteosarcoma Study Group, was founded in 1977 and has since registered some 3,500 bone sarcoma patients from over 200 institutions. For the purpose of the Pediatric and Adolescent Osteosarcoma Conference in Houston, March 2008, the outcomes of 2,464 consecutive patients with high-grade central osteosarcoma, who had been diagnosed between 1980 and 2005 and had been treated on neoadjuvant COSS protocols, were reviewed. Intended treatment had included surgery and multidrug chemotherapy, with high-dose methotrexate, doxorubicin, cisplatin, and ifosfamide being used in most protocols. After a median follow-up of 7.31 years for 1,654 survivors, 5- and 10-year survival estimates were 0.748/0.695 for 2,017 patients with localized extremity tumors and 0.369/0.317 for 444 patients with axial tumors or/and primary metastases, respectively. Tumor response to preoperative chemotherapy was of independent prognostic significance. Over the years, there was a major shift from amputation towards limb-salvage. This development was least evident for patients below the age of 10. While survival expectancies improved from the first to the second half of the recruitment period, no further improvement was evident within the latter period. In the manuscript, the results described above are discussed based on the findings of the previous analyses of our group.

Limb salvage in periacetabular sarcomas : Review of 21 consecutive cases

The oncologic and functional outcome was reviewed in 21 consecutive patients who underwent limb salvaging surgery for periacetabular sarcoma using a new surgical approach and different types of reconstruction between 1972 and 1990. Histologic diagnosis in 86% showed osteosarcomas, chondrosarcomas, and Ewings tumors. Age ranged from 10.0 to 61.5 years (mean age, 32.9 years). The resection margin was wide in 15 patients but marginal in 2 patients and intralesional in 4 patients. All of the latter patients died of their disease. In all cases where 3-dimensional imaging was used, wide resection margins could be achieved, whereas this was possible only in 50% of the cases with conventional imaging techniques. Seven patients died of their disease 3 to 15 months after surgery, 2 died of chemotherapy induced sepsis, and 2 patients died perioperatively. At followup, 8 patients had no evidence of disease (mean, 57.6 months; range, 12-190 months), and 2 patients were alive with disease. Fourteen patients could be observed for at least 12 months (mean, 41.1 months) and were functionally evaluated according to Ennekings criteria. If extensive resection was necessary, the best results were found if the defect had been reconstructed with a custom made prosthesis. The results were only satisfactory after implantation of saddle prostheses and poor with allografts or when no reconstruction of the bone defect was done.