I. Rosen’s T protocol
In 1973 Rosen used a combination of preoperative VCR, HD-MTX-CF and ADM chemotherapy (T5 regimen) in patients who were prepared for large tumor resection and artificial joint replacement, and postoperative chemotherapy regimen was determined according to the degree of necrosis of the tumor tissue after surgery. For cases with grade III-IV response, the T5 regimen was continued postoperatively, and for patients with grade I-II response, the postoperative regimen was switched to T4, i.e., the addition of CTX, which was the earliest application of neoadjuvant chemotherapy. Rosen then added BCD to the T regimen based on its effectiveness in osteosarcoma, resulting in the T7 regimen, which was characterized by an increase in the number of drugs administered and a longer duration. In 1978, Rosen designed the T10 regimen, which focused on adding cisplatin to patients with a grade I-II response to preoperative chemotherapy, especially for those with pulmonary metastases, and improved survival with the addition of DDP after surgery. Rosen’s study showed that the T10 regimen was superior to the T7 regimen, with a five-year relapse-free survival rate of 54%-68% and an overall survival rate of 64%-80%, but the CCSG (Children’s Cancer Study Group) and COSS-82 re-examined the T10 regimen clinically, with results that were contrary to those of Rosen. The results of the Rizzoli Study Center also showed that the T10 regimen did not improve patient survival, and it concluded over a long follow-up period that there was no significant difference in survival between the T10 and T7 regimens. Although it is difficult to make comparisons across studies, there is no doubt that Rosen’s T10 regimen is an effective, but complex and side-effective regimen that may not be as effective as expected in the small number of cases treated at some centers, and in his observations of the efficacy of T7 and T10 chemotherapy regimens, almost all patients with 100% histological necrosis survived. The T12 regimen was designed to reduce unnecessary chemotherapeutic side effects by giving only one dose of BCD and two doses of HD-MTX to patients who had received adequate preoperative chemotherapy. In addition, preoperative chemotherapy was subtracted from ADM, which has cardiotoxic effects, and the results showed no significant difference from the results of the T10 regimen (CR+PR). the follow-up results of the T12 regimen showed a five-year survival rate of about 80%. in 1991, Rosen added IFO, which is currently considered effective for osteosarcoma, to the T12 regimen to form the T19 regimen to improve the preoperative chemotherapy efficacy (Table 31-5-1).
Table 31-5-1 T19 regimen
A. Methotrexate
12000 mg/m2 i.v. Week 1 and 2
B. Isocyclophosphamide
2000mg/m2/d i.v. day one to day six
C. Methotrexate
12000mg/m2 i.v. for two consecutive weeks, after two weeks from B
D. Isocyclophosphamide
2000mg/m2/d i.v. day one to day six, three weeks from B
E. Methotrexate
or cisplatin
Adriamycin
12,000mg/m2 i.v. for two weeks, after two weeks of D
120mg/m2 i.v. day one, two weeks after D
60mg/m2 i.v. day one, two weeks from D
F. Surgical excision
Note: If the preoperative evaluation and specimen necrosis rate reaches CR+PR, the preoperative chemotherapy regimen will be extended starting two weeks after surgery.
If CR+PR was not achieved, postoperative chemotherapy was changed from E to cisplatin + adriamycin in the preoperative regimen.
Coss study protocol
Coss is the abbreviation of the German-Austrian Collaborative Study Group on Osteosarcoma Chemotherapy. Since 1977, a series of chemotherapy regimens have been studied, including Coss-77, Coss-80 , Coss-82, and Coss-86. Coss-86 (Table 31-5-2) further intensifies the chemotherapy regimen based on Coss-80 to further improve survival of patients with poor prognosis. Unlike Coss-80, cisplatin was no longer administered as a single agent, but in combination with IFO. another study of Coss-86 aimed to further improve limb preservation by enhancing the effect of local chemotherapy through arterial administration of DDP, but its results showed that tumor necrosis due to preoperative chemotherapy was not higher than the effect of systemic chemotherapy. The results of the study also determined the extent of post-chemotherapy tumor necrosis by histopathology and measured the amount of platinum within the specimen, with the end result of reducing the rate of local tumor recurrence and improving survival.
III. Jeffe’s TIOS (treatment and investigation of osteosarcoma) chemotherapy protocol
In the early 1980s, Jeffe designed TIOS-Ⅰ (early 80s-85) and TIOS-Ⅲ (85-89) to compare the efficacy of preoperative chemotherapy with MTX and DDP by transarterial administration. It was concluded that preoperative chemotherapy with DDP administered transarterially was significantly more effective than MTX; that the efficacy was related to the number of courses and the cumulative amount of DDP; that intensive postoperative chemotherapy could improve the survival rate of patients with poor preoperative chemotherapy response; that the improvement of chemotherapy efficacy could increase the limb preservation rate, and that the future development of chemotherapy would be to identify patients with poor efficacy and give chemotherapy at the appropriate dose intensity to improve the survival rate.
IV. Chemotherapy at the Rizzoli Institute (Bacci)
The Rizzoli Institute in Italy is a well-known bone tumor center, which has been conducting research on chemotherapy for osteosarcoma since 1972 and has been applying neoadjuvant chemotherapy since 1983, constantly updating its protocols, mainly exploring the significance of adjuvant chemotherapy, the safety of limb preservation, the efficacy of MTX high dose compared with medium dose and the efficacy of neoadjuvant chemotherapy dual route of arteriovenous administration regimen. In 1991, Bacci applied MTX, DDP and ADM to 125 cases of osteosarcoma, of which 74% were grade III and IV, with a 2-year survival rate of 87%. 87%; in another group of 127 patients treated with MTX and DDP, grade III and IV accounted for 52%, with a 2-year survival rate of 59%. At present, the Institute uses neoadjuvant chemotherapy for the treatment of osteosarcoma by a dual pathway, with a sustained tumor-free survival rate of 87%, a local recurrence rate of only 8%, and a limb preservation rate of 92% at one to three years of follow-up.
V. US CCG program
In 1991, Miser et al. reported on the Mayo Clinic study of the application of IFO (isocyclophosphamide) for the treatment of osteosarcoma. They used a combination of IFO, HD-MTX and Doxorubincin, and the results showed a grade III-IV histologic response of 85%. This is the best result achieved so far with osteosarcoma chemotherapy. As a result, the CCG (Children’s Cancer Group) designed the CCG7921 study protocol in 1993 with the aim of repeating the effects of IFO for replication. This protocol is still under study.
In 1991, Leinerman reported preliminary results of the application of MTP-PE (Muramyl Tripeptide-Phosphatidyl Ethanolamine) in the treatment of recurrent osteosarcoma, finding that the tumor tissue was surrounded by fibrous tissue, infiltrated by inflammatory cells, and most of the tumor cells died.The mechanism of MTP-PE treatment of tumors is through the activation of the mononuclear macrophage system, which turns into toxic megalophages that kill tumors. Many subclinical and clinical studies have confirmed the efficacy of MTP-PE, thus the study of MTP-PE was included in the CCG7921 protocol. 10 weeks of preoperative chemotherapy was designed in the CCG7921 protocol and patients were randomized into two groups, group A with ADM, HD-MTX and IFO and group B with CDP instead of IFO, to observe the difference in efficacy between the two groups to determine the effectiveness of IFO. MTP-PE was also randomized in both groups of patients postoperatively (Table 31-5-3). The phase III CCG-POG93-51 trial, now underway, will show whether immunologic therapy in the CCG regimen can improve survival in patients with osteosarcoma.
Table 31-5-3 CCG7921 regimen
Preoperative chemotherapy
Postoperative chemotherapy
Group A
Adriamycin
Cisplatin
High-dose methotrexate
Adriamycin
Cisplatin
High dose methotrexate
Biopsy
Random grouping
Group A + MTP-PE (tripeptide phosphatidylethanolamine)
Adriamycin
Cisplatin
High-dose methotrexate
Chemotherapy evaluation
Surgery
Adriamycin
Cisplatin
High dose methotrexate
MTP-PE
Group B
Adriamycin
Isocyclophosphamide
High-dose methotrexate
Adriamycin
Isocyclophosphamide
High dose methotrexate
Group B + MTP-PE (tripeptide phosphatidylethanolamine)
Adriamycin
Isocyclophosphamide
High-dose methotrexate
Adriamycin
Cisplatin
High dose methotrexate
MTP-PE