In Japan, the development of treatments for osteosarcoma has been supported by the orthopedic surgeons with passion of the institutes engaged in multi-institutional studies. In addition, the bone tumor registry, which was started by Professor Amako (Kyushu University) in 1954, facilitated early advancements in the development of treatments for bone tumors. The bone tumor registry expanded to Japanese bone tumor registry after the decision at the annual meeting of the Japanese Orthopaedic Association in 1957. It has been managed in National Cancer Center since 1964 and paper registration forms have been substituted by digital media since 2006.

In 1960, osteosarcoma treatment was limited to amputation or disarticulation, and the survival rate of patients without metastases was 3–15 % [12]. Thereafter, in 1964, Miki et al. reported a treatment regimen of regional perfusion of anticancer drugs [13]. Subsequently, in 1966, Akahosi et al. and Masuda et al. reported the efficacy of continuous intra-arterial infusion [14]. For prevention of pulmonary metastases, Ohno et al. reported a method of continuous infusion of anticancer drugs into the bronchial artery [15]. As such, the primary methods of preoperative arterial infusion and regional perfusion were adopted. In 1971, Tateishi et al. reported a 5-year OS rate of 31.7 % in 64 patients who received regional perfusion therapy comprising 5-fluorouracil (5-FU), mitomycin C (MMC), and nitromin between 1960 and 1970 [16]. In addition, Akaboshi et al. reported a 5-year OS rate of 31.4 % in patients receiving intra-arterial infusion of 5-FU and MMC [17].

Thereafter, several multi-institutional studies of adjuvant therapy for treatment of osteosarcoma were started in 1975. First, the Japanese Orthopedic Oncology Group (JOOG) conducted a multicenter study of postoperative adjuvant chemotherapy with ADM [18]. During this study, osteosarcoma patients without metastasis and who underwent amputation or disarticulation during the period between 1973 and 1980 received ADM at 0.6–0.8 mg/kg for 3 days by intravenous infusion beginning on postoperative week 1 and received multiple doses until a total dose of 600 mg (500 mg/m²) was reached. However, in 1976, many investigators began to introduce combined therapy with ADM + HD-MTX, and the final report in 1988 was structured as a comparative study between ADM as monotherapy and combined therapy with ADM + HD-MTX. In addition, during this period, the decision of whether to administer preoperative therapy via intra-arterial infusion or regional perfusion therapy varied among studies. Among the accumulated cases, 59 were excluded, and 117 were included for analysis. The 5-year OS and DFS rates of all cases were 50.2 % and 39.4 %, respectively, whereas the 5-year OS and RFS rates of the 80 subjects in the ADM-only group were 44.4 % and 35.6 % compared with the rates of 63.1 % and 47.8 % in the combined treatment group, respectively, indicating more favorable outcomes, although these differences were not significant. When restricted to the 65 subjects who received a total ADM dose of ≥500 mg, the 5-year OSR was significantly greater in combined treatment group than in the 48 subjects in the ADM-only group (76.5 % vs. 52.1 %, respectively). They concluded that combined ADM and HD-MTX treatment was more appropriate as adjuvant chemotherapy for osteosarcoma. Furthermore, another analysis of the cases who developed pulmonary metastases after initial treatment was based on the 23 subjects who underwent resection of metastatic lesions compared with 43 who did not. The 5-year OS rate was significantly greater in the resection group than in the nonresection group (43.5 % vs. 2.6 %, respectively), suggesting that resection of pulmonary metastases was the more effective method to prolong survival.

In addition, a study conducted by the Ministry of Health and Welfare (MHW) during approximately the same period (1973–1981) reported the 5-year OS and DFS rates of 52.6 % and 37.0 %, respectively, in 1983 [19]. The 5-year OS and DFS rates in the ADM-only group were 32.7 % and 26.1 % compared with the rates of 59.5 % and 41.4 % in the MTX combination therapy group, respectively, again showing more favorable outcomes for combination therapy. Because these two multi-institutional studies included many of the same institutions, there is a high likelihood that patients were duplicated. However, even if this is the case, the efficacy of combination therapy was confirmed by both multicenter studies.

Preoperative adjuvant chemotherapy was first introduced in 1980. Between 1980 and 1981, the MTX osteosarcoma research group registered 35 patients who received VCR and HD-MTX preoperatively and VCR, HD-MTX, ADM, and CPM postoperatively and reported the 3-year OS and DFS rates of 58.2 % and 40 %, respectively [20]. The histological response to preoperative chemotherapy was determined, and although there was no statistically significant difference, the survival time tended to be longer in those with a favorable histological response.

In addition, during this period, CDDP and ifosfamide (IFO) were introduced as novel drugs to treat osteosarcoma in Japan. In 1984, CDDP was introduced into the market for the treatment of cancers of the testes, bladder, renal pelvis and ureters, prostate, and ovaries. In 1989, the therapeutic effects of CDDP monotherapy for primary and metastatic lesions in patients with osteosarcoma were reported [21]. Although the evaluation methods differed from those used today, this treatment was successful in 3 of 18 subjects. Ten years later, in December 1999, CDDP was approved for use for the additional indication of osteosarcoma. In addition, from July 1978 to September 1980, joint studies of IFO to treat malignant bone and soft tissue tumor reported effective outcomes in 12 of 22 subjects with osteosarcoma [22]. Although the use of IFO was covered by the national insurance program for this and other indications in 1985, hematuria and bladder dysfunction were observed as characteristic adverse drug reactions of IFO; thus, wide-scale use was delayed until the 1994 commercialization of mesna, a detoxifying agent that inhibits hemorrhagic cystitis induced by IFO.

Limb-preserving surgery became popular in the 1980s. From 1980 to 1985, 250 cases of osteosarcoma were accumulated retrospectively from 22 Japanese institutions and were reported in 1992 as the 10-year intergroup study [23]. All subjects who underwent limb-preserving surgery received adjuvant chemotherapy consisting mainly of MTX, ADM, and CDDP. This study reported that subjects who underwent amputation or disarticulation also usually received the same adjuvant chemotherapy regimen, but the details were not mentioned. The 5-year OS rate was 58 % in all 250 subjects, 70 % in the 107 subjects (42.8 %) who underwent limb-preserving surgery, and 49 % in the 143 subjects (57.2 %) who underwent amputation or disarticulation, indicating significantly better outcomes after limb-preserving surgery. Analysis of the resection margin was also performed, and resection with wide margin and marginal margin partially and resection with wide margin fully had the same outcome. The outcomes after limb-preserving surgery were favorable; thus, it was concluded that the optimal strategy was to perform limb-preserving surgery to achieve more favorable long-term limb function. It was also concluded that this strategy required more aggressive localized chemotherapy and radiotherapy to get higher rate of tumor necrosis and development of reconstructive surgery, involving joint replacement and bone grafts.

Outcomes of the T-10 and T-12 protocols reported by Rosen in the US during the mid-1980s had a major impact on strategies for osteosarcoma [10]. In both protocols, the postoperative treatment was changed based on the histologic necrosis rate of the tumor after resection, with preoperative treatment composed mainly of HD-MTX. Fundamentally, groups that achieved good results continued to receive HD-MTX treatment, and those with insufficient results received treatment with CDDP and ADM. Of 87 subjects who received treatment according to the T-10 protocol, DFS was reported in 67 subjects (77 %) and OS was reported in 71 subjects (81.6 %) after a follow-up period of 3–6 years. Of 51 subjects treated according to the T-12 protocol, DFS was reported in 38 subjects (75 %) and OS was reported in 39 (76 %) after a median short-term follow-up period of 2 years. Based on these results, Rosen concluded that it was possible to avoid administering drugs that could cause further adverse reactions to patients who had favorable results after preoperative treatment and to complete treatment early. As mentioned above, these results were later refuted by Meyers after long-term follow-up observations, but at that time, the outcome was very impressive, and several studies to verify this result were conducted in other countries.