[Evaluation of adjuvant chemotherapy of osteosarcoma with special reference to adriamycin (final report)].

Adjuvant chemotherapy mainly with ADR performed in 117 patients (pts) with primary osteosarcoma of the extremity for the purpose of preventing pulmonary metastasis after radical ablative surgery. The mean follow-up period for 117 pts was 51.7 months (range: 3 to 137), for 53 survivors, 90.1 months (range: 60 to 137) and for 64 decreased, 20.5 months (range: 3 to 73). ADR was administered intravenously with 0.6-0.8 mg/kg/day for 3 consecutive days at monthly intervals after surgery until reaching 600 or 500 mg/m2 of the total cumulative dose. Five-year overall and disease-free survival rate of all pts was 50.2% and 39.4%, respectively. Thirty-seven pts (multi-drug group) with the combination of ADR and HDMTX had a higher survival rate (63.1% in 5-year overall survival rate and 47.8% in 5-year disease-free survival rate) than that of 80 pts with ADR alone (ADR group) (44.4% in 5-year overall survival rate and 35.6% in 5-year disease-free survival rate). Five-year survival rate for 65 pts administered the greater than 500 mg of ADR was 59.3% compared to 36.9% for 52 pts the less than 500 mg (p less than 0.05). In 65 pts administered the greater than 500 mg of ADR, 5-year survival rate (76.5%) of the multidrug group (17 pts) showed superiority to that 52.1%) of the ADR group (48 pts) (p less than 0.01). Even in the multi-drug group, 5-year survival rate (76.5%) of 17 pts administered the greater than 500 mg of ADR was higher than that (41.3%) of 20 pts given the less than 500 mg (p less than 0.01). Distant metastases were recognized at lung in 52 pts (lung group), lung + extrapulmonary organs in 14 (+ extragroup), and only extrapulmonary organs in 3 (extra group). Five-year survival rate of 66 pts with pulmonary metastasis was 17.1% and 21.2% in the lung group compared with 0% of the extra group (P less than 0.01). Five-year survival rate for 23 pts treated with thoracotomy was 43.5% compared to 2.6% for 43 without it (p less than 0.01).

[Rationale of preoperative chemotherapy of osteosarcoma].

The rationale of preoperative chemotherapy for osteosarcoma requires: eradication of microscopic metastatic foci which have already occurred in many patients with osteosarcoma, determination of a more effective form of postoperative adjuvant chemotherapy and easier and safer limb-salvage procedures through clearer marginal definition with reduction of primary lesions. In this paper, chemotherapeutic effects on the 5-year survival rate were analyzed for 49 patients with primary non-metastatic osteosarcoma of the extremities treated with radical surgery. The efficacy of preoperative chemotherapy was assessed in 11 cases of osteosarcomas treated with systemic chemotherapy as a preliminary study. As to the 5-year cumulative survival rate, the systemic group (20 cases) showed a level of 56.7%, which was significantly higher (p less than 0.05) than the figure of 13.8% in a historical retrospective group (29 cases). In assessing the effective tumor response to preoperative chemotherapy, a close correlation between the tumor necrotic ratio and the ratio of decrease of serum alkaline phosphatase was revealed. Seven (63.6%) of 11 cases showed correlation of the tumor necrotic ratio with the ratio of decrease of serum alkaline phosphatase. The tumor necrotic ratios calculated were relatively definite (50-60%) in the CDDP group (3 cases), varied (10-70%) in the HDMTX group (4 cases), and low (less than 40%) in the ADR group (4 cases), regarded as a control group in further studies.

[Osteoporotic changes in rheumatoid arthritis].

Bone mineral density (BMD) in the distal 1/6 and 1/3 sites of the radius was measured by single photon absorptiometry in 58 female patients with rheumatoid arthritis, not treated with corticosteroids. Half of the patients showed lower values of BMD than those (mean--1SD) of age-matched controls. BMD decreased more significantly with advancement of destructive changes of radiocarpal joint in postmenopausal patients. There was a significant inverse correlation between BMD and duration of the disease. Decreasing rate of BMD was much higher in postmenopausal patients than in premenopausal patients. These results indicated rheumatoid arthritis was not universally associated with osteoporosis. Osteoporosis occurred much more frequently in postmenopausal patients with a long duration of the disease showing marked joint destruction. In premenopausal patients, bone loss was most common in the region of affected joints. But, bone loss in postmenopausal patients occurred not only in the periarticular bone but in the diaphyseal bone.

[Preoperative adjuvant chemotherapy of skeletal and soft tissue sarcomas].

Preoperative adjuvant chemotherapy for skeletal and soft tissue sarcomas requires: (1) correct identification of the effective postoperative adjuvant chemotherapy, (2) eradication of any of the micrometastatic foci that may have already occurred in many of the patients with these sarcomas, (3) easier and safer limb-salvage procedure, being clearly defined, with shrinkage of the primary lesion. For this purpose, a preoperative adjuvant chemotherapy regimen making practical use of intra-arterial CDDP (cis-dichlorodiammineplatinum II) infusion is desired in multi-drug combined chemotherapeutic treatment, including HDMTX (high-dose methotrexate), ADR (adriamycin) and CDDP. In this paper, the clinical application of preoperative adjuvant chemotherapy to skeletal and soft tissue sarcomas with combination of HDMTX and CDDP is presented in the light of the observations of tumor response to these anticancer agents, and the possibility of to establishing a new preoperative adjuvant protocol is discussed.

[Adjuvant chemotherapy for osteosarcoma in Japan--past, present and future].

The therapeutic results for osteosarcoma were very discouraging before 1970 in Japan despite many modes of treatment. In 1960, Miki introduced the regional perfusion technique into the treatment of osteosarcoma, and in 1963, Akaboshi pioneered the intraarterial infusion technique. By these methods, a five-year survival rate about 30% was achieved during the period from 1971 to 1976. In Japan, the five-year disease-free survival rate will soon exceed 50% thanks to intensive multi-drug adjuvant chemotherapy, considering the therapeutic results of 117 cases of JOOG treated during 6 years from 1975 to 1980 and 114 cases included in the Group Study of Osteosarcoma treated during 8 years from 1973 to 1981. In most cases, ablative surgery must still be considered the standard method of treatment. However, the importance of preoperative adjuvant chemotherapy is emphasized because limb-saving operations have become an increasingly common feature in the management of osteosarcoma as a result of the recent advances achieved by intensive multi-drug adjuvant chemotherapy.

[Functional treatment of malignant bone tumors].

In treating malignant bone tumors of the limbs, what might be accepted as a reasonable therapy is preserving the functions of the affected limb, with controlling tumor both locally and systemically. Concerning giant cell tumor of bone (low malignancy), malignant fibrous histiocytoma of bone and primary or secondary chondrosarcoma (moderate malignancy) and osteosarcoma (high malignancy), surgical treatments to preserve the affected limb and to maintain it's function are going to be introduced with their actual applications mainly through clinical cases. In the treatment for osteosarcoma of the child, even after succeed in preserving the affected limb, there are some problems of the development of the limb, disorders of the local skin and soft tissue, and troubles concerning artificial materials.

Bone tumors in Japan.

The author organized the Japanese Registry of Bone Tumors; 27,665 bone tumors of various types were registered during the period from 1964 to 1980. The results of treatment by adjuvant multidrug chemotherapy for osteosarcoma in Japan were recorded; the five-year cumulative survival rate after treatment by multidrug chemotherapy is almost 70%. Among 82 patients with malignant fibrous histiocytoma, investigated with respect to treatment and prognosis, the five-year cumulative survival rate was 50.3%.

Suppressive effect of elcatonin, an eel calcitonin analogue, on excessive urinary hydroxyproline excretion in polyostotic fibrous dysplasia (McCune-Albright's syndrome).

A 12-year-old Japanese girl with polyostotic fibrous dysplasia and endocrine concomitants, was treated with elcatonin, a synthetic eel calcitonin analogue, 10 MRC unit/twice a week given by intramuscular injection. Significant decreases in 24 hr urinary content of hydroxyproline and other amino acids from bone collagen were observed during the course of treatment over 5 months. This biochemical result suggests that the synthetic eel calcitonin analogue exhibits the therapeutic effect in patients with polyostotic fibrous dysplasia by inhibiting bone resorption.

Enzyme histochemical study on bone tumors.

A total of 19 cases with bone tumors, including six osteosarcomas. three giant cell tumors of bone, one malignant fibrous histiocytoma, four nonossifying fibromas, four chondromas and one chondrosarcoma, were examined as to enzyme histochemistry; the enzymes consisted of alkaline phosphatase (ALPase), acid phosphatase (ACPase), nonspecific esterase (NSE), adenosine triphosphatase (ATPase), 5'-nucleotidase (5'-Nucl) and beta-glucuronidase (beta-Gl). Osteosarcoma was strongly positive for ALPase followed by 5'-Nucl. Giant cell tumor, malignant fibrous histiocytoma and nonossifying fibroma showed enzyme histochemistry similar to each other: multinucleated giant cells and round cells in these tumors were strongly positive for ACPase, NSE, ATPase and 5'-Nucl simulating osteoclasts and histiocytes, whereas spindle cells were positive for ATPase and 5'-Nucl in their cytoplasm and weakly positive for ACPase. Chondroma and chondrosarcoma were focally positive for ACPase and NSE; the ACPase was sensitive to tartaric acid treatment. These observations showed that ALPase activity is very characteristic to osteosarcoma, and is useful for its diagnosis. From enzyme histochemistry, giant cell tumor, malignant fibrous histiocytoma and nonossifying fibroma can be regarded as a histiocyte-derived tumor of bone in contrast to osteosarcoma and cartilaginous tumors.

Characterization of human B lymphocyte specific antigens.

Anti-human B cell serum (ABS) was developed by sequentially absorbing a rabbit anti-human tonsil serum (AHTS) with human red cells, liver, serum, and thymocytes. AHTS was also absorbed quantitatively with tissues and cells from different sources. ABS was nontoxic for thymocytes but lysed the majority of chronic lymphocytic leukemia (CLL) cells. This also killed a number of tonsil and blood lymphocytes which bound erythrocyte-antibody-complement complexes but not sheep erythrocytes. In further studies, it was shown that phytohemagglutin-responsibility of peripheral blood lymphocytes was not affected by treating them with ABS and complement. Anti-B cell activity of AHTS was not changed by absorption with thymus, liver, kidney, and brain tissues but absorbed with tonsil and CLL cells. These data confirm the B cell specificity of ABS. Indirect immunofluorescence was carried out on tissue sections of human tonsils and lymph nodes, which indicated that ABS-reactive cells were concentrated in lymphoid follicles including germinal centers, while plasma cells and cells located in the thymus-dependent area were essentially devoid of immunofluorescence.