Kiyoo Furuse

Multiinstitutional phase II study of neoadjuvant chemotherapy for osteosarcoma (NECO study) in Japan: NECO-93J and NECO-95J

BackgroundOsteosarcoma is the most frequent primary malignant bone tumor. In Europe and the United States, its prognosis has been greatly improved by the use of multimodal treatment, including preoperative and postoperative chemotherapy as well as surgery. In Japan, however, only a few clinical studies on osteosarcoma have been carried out.MethodsTo evaluate the efficacy of neoadjuvant chemotherapy on nonmetastatic, operable osteosarcoma arising in the extremities, a prospective multiinstitutional phase II trial, the Neoadjuvant Chemotherapy for Osteosarcoma (NECO) study, was conducted. Preoperative chemotherapy included high-dose methotrexate (HD-MTX), cisplatin (CDDP), and adriamycin (ADR). If the induction therapy was assessed as not effective, high-dose ifosfamide (IFO) was added to the chemotherapy regimen. A total of 124 patients were enrolled in this trial, and ultimately 113 patients were eligible.ResultsThe 5-year overall survival (OAS) and event-free survival (EFS) rates in the NECO study were 77.9% and 65.5%, respectively. A good histological response to the induction chemotherapy resulted in favorable OAS (78.7%). The patients assessed as poor histological responders with progressive disease after the induction chemotherapy exhibited comparable outcomes (OAS 89.5%, EFS 68.2%). There were no significant differences between the OAS and EFS rates of the patients in terms of response to preoperative chemotherapy.ConclusionsWe analyzed the results of the intensive neoadjuvant chemotherapy and the effects of adding IFO on patients with osteosarcoma in Japan. The results suggest efficacy of the high-dose IFO addition to the standard three-drug chemotherapy regimen. However, a randomized clinical study is needed to establish the true impact of IFO on patients with osteosarcoma.

Chromosomal rearrangement t(11;22) in extraskeletal Ewing's sarcoma and primitive neuroectodermal tumour analysed by fluorescence in situ hybridization using paraffin-embedded tissue.

The clonal chromosomal rearrangement t(11;22) has been reported by karyotypic analysis to be specific for Ewings sarcoma of bone and soft tissue origin as well as primitive neuroectodermal tumour. In this report, immunohistological analysis of MIC 2 expression and fluorescence in situ hybridization (FISH) were performed using paraffin‐embedded tissues. We examined t(11;22) in the nuclei isolated from two Ewings sarcomas, four primitive neuroectodermal tumours, and three neuroblastomas, which served as negative controls by FISH with an α‐satellite DNA probe for chromosome 11, a chromosome 22 marker probe, and whole chromosome painting probes for both chromosomes 11 and 22. Both cases of Ewings sarcoma and the four primitive neuroectodermal tumour specimens were immunoreactive for MIC 2. Both Ewings sarcomas and three of the four primitive neuroectodermal tumours contained the tumour‐specific t(11;22), but the three neuroblastomas did not show this translocation. Based on the cytogenetic results and on the immunohistological investigation of MIC 2 expression, Ewings sarcoma is suggested to be related closely to primitive neuroectodermal tumour. FISH is a useful aid in determining the tumour type of Ewings sarcoma and putative related tumours.

Ultrastructural features of malignant fibrous histiocytoma of bone.

Five cases of malignant fibrous histiocytoma originating in the femur and tibia, sometimes with local recurrences, are reported. Histological and clinical characteristics of this lesion were similar to those in soft tissues with the same disease. The present histiocytomas were observed by electron microscopy and shown to consist of 5 types of neoplastic cells which were regarded as undifferentiated cells, histiocyte‐like cells, which were predominating, flbroblast‐like cells, multinucleated giant cells and xanthomatous cells. These findings led us to confirm the existence of malignant fibrous histiocytoma originating in bone as well as in soft tissues.

A Cooperative Study on Limb Salvage Treatment for Osteosarcoma

Between 1973 and 1986,225 patients with nonmetastatic primary osteosarcoma (OS) of the limbs were registered and treated. The cumulative survival rate was analyzed in several aspects. When classified into the limb salvaged group (72 patients), amputated or disarticulated group (153 patients), and total group (total patients), the 5-year (10-year) cumulative survival rate was 54.6% (49.3%), 51.3% (46.4%), and 62.1% (55.6%), respectively. When classified by the regimen of adjuvant chemotherapy to groups administered adriamycin alone (ADR) for 21 patients, ADR and high-dose methotrexate (MTX) for 108 patients, carcinostatics combined with cisplatin (+CDDP) for 62 patients, and 34 unclassifiable patients, the 5-year (8-year) cumulative survival rate was 15.1% (10.1%) for the ADR group, 62.4% (57.5%) for the ADR + MTX group, and 57.3% (57.3%) for the +CDDP group. The 10-year rate was 10.1% for the ADR group and 57.5% for the ADR + MTX group. The level was significantly lower in the ADR group than in other two groups (P < 0.001). Of 72 limb salvaged patients, 38 were involved with some complications. Of the 38 patients, secondary ablation was performed in 14 patients due to local recurrence (eight patients), infection (four patients), and circulatory disturbance (two patients). The serum alkaline phosphatase level, lactate dehydrogenase level, and pulmonary metastasis were studied as the prognostic factors.

Present Status of Patients with Metastatic Bone Tumor at National Yonago Hospital and Role of Orthopedists

We analyzed present status of patients (pts) with metastatic bone tumor (MBT) and discussed role of orthopedists for them. In 5 years between 1983 and 1987, 16pts with MBT first visited our orthopedic clinic, while 50pts with MBT, more than three times of the 16, were treated at our clinics in the same period. Of the 50, MTB was diagnosed in 8 (57.1%) of 14 prostatic cancers, 5 (20.0%) of 25 breast cancers treated with surgery, 31 (14.6%) of 212 lung cancers and 6 (3.0%) of 203 gastric cancers. Role of orthopedic surgeons is to advise other doctors of the diagnosis of MBT and have a quality of their lives improve by selecting more reasonable treatments and evaluating the therapeutic response for bony lesions.

Three Cases of Bone and Joint Tuberculosis

Over the past 7 years we have treated three cases of bone and joint tuberculosis. They were proved to be tuberculous infection of the 10th and 11th thoracic vertebrae, olecranon and ankle joint. Tuberculosis should be considered in the differential diagnosis of unexplained chronic arthritis and osteomyelitis. Therapy should include excision of involved bone and soft tissues and appropriate chemotherapy.

Limb Salvage Treatment for Osteosarcoma Based on Clinicopathological Studies of Preoperative Chemotherapy

The effects of preoperative adjuvant chemotherapy were assessed with the ratio of decrease in serum alkaline phosphatase (ALP), radiographic improvement level, and tumor necrotic ratio. The subjects were 16 patients with nonmetastatic typical primary osteosarcoma (OS) of the limbs treated between March 1975 and November 1986. The patients were divided by response to therapy into three groups of good response (+R, eight patients), poor response (-R, eight patients), and total patients. The cumulative survival rate was in the total patient group 56% at 145 months, in the +R group 67% at 112 months, and in the -R group 38% at 145 months, showing a significant difference (P< 0.005) between the +R and -R groups. When any one of the three indices was determined to be good, we could expect the preoperative adjuvant chemotherapy to be effective. Prognosis was consistent with the serum ALP decrease ratio in 77% of patients, with the radiographic improvement level in 75%, and with the tumor necrotic ratio in 56%. Histopathologically, when the necrotic level exceeded 50%, necrosis extended from the central to peripheral part of the tumor rapidly; however, viable tumor tissues persisted in the peripheral part. Tumors penetrated the cortex and growth plate easily and rarely reached the joint cavity or capsular structures. Comparing the relation between periosteal and medullary tumors in 11 patients, the former were located more proximally than the latter in two patients, the latter were more proximal than the former in six patients, and the periosteal and medullary levels were the same in three patients. The gap between the tips of the former and the latter ranged from 2 to 3 cm. Two patients were involved with microthrombi in the vein, but there were no skip metastases.

Osteosarcoma — Japanese Experience

The incidence of osteosarcoma (OS) is 1/100,000–200,000 in the Japanese population. About 200 patients with OS are registered at the National Cancer Center Hospital (NCCH) every year.(l) Of malignant primary bone tumors, OS carries the highest percentage in incidence (ca. 43%), and is most likely to occur between the ages of 10 and 30; 60% are young adults in their 20’s, with a slight predominance of males. Before 1970, therapeutic results of OS were very disappointing in Japan. Because of pulmonary metastases in more than 90% of patients within one year from ablative surgery, the 5-year survival rate was 5 to 15%, in spite of various treatment efforts.(2) In 1960, Miki (3) introduced a regional perfusion technique using anticancer agents before limb amputation, originally described by Creech et al.(4) in 1958. (Anticancer agents were circulated in the affected limb before amputation via an extra-corporeal circulation system.) Tateishi reported that the 5-year survival rate for 101 patients treated with this regimen was significantly increased to 35% from 17% over patients treated with ablative surgery alone.

Soft Tissue Sarcomas — Japanese Experience

Between 1971 and 1980, Kyushu University, Jikei University and the NCCH collected 1556 cases of STS, which were classified (in decreasing order) as: malignant fibrous histiocytoma (MFH) (305 cases, 19.6%); liposarcoma (LS) (220 cases, 14.1%); rhabdomyosarcoma (RMS) (210 cases, 13.5%); and leiomyosarcoma (LMS) (125 cases, 8.0%), unclassified STS (111 cases, 7.1%).(1) These tumors appeared as predominant in various age groups. MFH and LMS predominated in late adult life (mean age, 59 and 57.5 years, respectively); LS in middle adult life (mean age 48.5 years); and RMS, especially of the embryonal type, in childhood. Although many tumor types had a slight predilection for males, LMS, malignant schwannoma and alveolar soft part sarcoma were more frequent in females. The most common primary site for each tumor type in Japan does not differ with that in other countries. An organization of five orthopedic institutions (2) reported a study on 414 patients with STS treated between 1972 and 1983. (3) The 5-year cumulative survival rates were, in the order of whole STS’s, LS, MFH, LMS and RMS, 55.8%, 73.7%, 63.0%, 32.4% and 26.8%, respectively.