1.Historical background
The fact that osteosarcoma is highly malignant and the chance of survival after destructive surgery such as amputation never exceeds 20% has prompted many scholars to search for effective anti-osteosarcoma drugs in an attempt to improve the prognosis of osteosarcoma patients through chemotherapy. 1961 Evans reported that 17 patients with stage III osteosarcoma (Enneking osteosarcoma staging system) responded with mitomycin C in 4 cases In 1963, Sullivan reported the efficacy of levulinic acid nitrogen mustard in osteosarcoma; subsequently, there were sporadic reports on the treatment of osteosarcoma with alkylating agents such as cyclophosphamide (CY), but the overall picture is that the efficacy of alkylating agents in the treatment of osteosarcoma is inconsistent and lacks clinical value. reviewed the literature and concluded that the effectiveness of alkylating agents in osteosarcoma was around 15%.
In 1972, Cortes et al. reported 13 cases of stage III osteosarcoma treated with adriamycin (ADM), of which 4 obtained a good response; in 1972, Jaffe et al. subjected Djerassi to high-dose methotrexate and tetrahydrofolate rescue (High-Dose Me-thotrexate with Citrovorum Factor “Rescue”, MTX+CFR) regimen for progressive leukemia and lung cancer, used HDMTX+CFR to treat 10 cases of stage III osteosarcoma, four of which achieved significant responses. Subsequently, in 1974 Rosen et al. reported the use of sequential therapy with HDMTX+CFR and ADM to treat 13 cases of stage III osteosarcoma, with significant results achieved in 7 cases. Based on the precise efficacy of HDMTX+CFR and ADM in osteosarcoma and the fact that more than 80% of patients with osteosarcoma develop pulmonary metastases after amputation, Rosen et al. and Jaffe et al. successively used these drugs alone or in combination as conventional adjuvant therapy after osteosarcoma surgery, which significantly improved the prognosis of osteosarcoma patients and wrote a new chapter in the treatment of osteosarcoma.
2.Adjuvant chemotherapy
In the practice of HDMTX+CFR for stage III osteosarcoma, Rosen et al. found that the edema of metastases was reduced, pain was relieved, and the abnormally elevated alkaline phosphatase (SAP) decreased to the normal range after the drug was administered. However, it was noted in clinical observations that in some cases, the normalized SAP would rebound within 2–3 weeks after administration, and that drug resistance could occur with HDMTX+CFR alone, lacking further evidence of efficacy. Based on this clinical phenomenon, Rosen et al. combined HDMTX+CFR and ADM for the treatment of osteosarcoma, giving MTX or ADM twice a month, respectively, and treated a total of 15 patients with stage III osteosarcoma successively, resulting in an extension of the mean survival of stage III osteosarcoma from 3 months in the control group to 15 months. Also, because metastasis and recurrence of osteosarcoma mostly occur 9 – 10 months after surgery and the total course of treatment takes about 1 year, the total amount of ADM would exceed 900 mg/m2 if calculated according to this regimen, which would produce irreversible damage to the heart, thus 1 CY was inserted between MTX and ADM each to reduce the amount of ADM by ：
(1) VCR 1.5mg/m2 and MTX 200mg/kg.
(2) CY 40–60mg/kg.
(3) ADM 45mg/m2.
This is the earliest chemotherapy regimen for osteosarcoma, RosenT4, which was administered alternately at 2-week intervals for 1 year. Subsequently, several adjuvant chemotherapy regimens for osteosarcoma have been reported. As clinical studies progressed, cisplatinum (CDP), etoposide (VP16), isocyclophosphamide (IFO), and bleomycin, cyclophosphamide, and actinomycin-D (Dactiomycin) were discovered. Dactiomycin) BCD, etc. They are effective in osteosarcoma in 26% – 80% of cases alone, and even more so in combination. Therefore, a series of multidrug combination regimens have been developed accordingly, such as Rosen et al. T7, T10, T12, Jaffe et al. and Bacci et al. osteosarcoma chemotherapy regimens. The main rationale is to combine drugs with different mechanisms of action and different toxicities that have definite effects on osteosarcoma according to certain rules to improve the effectiveness of chemotherapy]. However, when developing and implementing chemotherapy regimens, it is important to understand and pay attention not only to the merits of the drugs selected, but also to the concept of Dose Intensity. 100% Dose Intensity means that the patient receives the intended dose of a given chemotherapy regimen within a specified period of time, and that any reduction in dose or delay in dosing can affect the final outcome of chemotherapy. Bramwell et al. randomized 98 osteosarcoma cases into 2 groups, one group received ADM (25 mg/m2 for 3 d continuously) and CDP (100 mg/m2 given once) for 6 courses, while the other group received HDMTX for 8 d followed by ADM and CDP, the single doses of ADM and CDP were equal in both groups, and the total duration of chemotherapy was the same, as the second The 5-year survival rates were 64% and 51%, respectively, reflecting the close relationship between drug dose intensity and the effect of chemotherapy. impact than the addition of new drugs. In conclusion, without reducing the dose of a single drug per unit of time, the combination of drugs with different self-limiting toxicity and mechanism of action is beneficial to overcome the heterogeneity of tumor cells, reduce the generation of drug resistance and improve the effect of chemotherapy.
3.Neoadjuvant chemotherapy
In 1977, Jaffe reported that 13 cases of osteosarcoma (4 cases in stage IIB and 9 cases in stage III) were treated with HDMTX once a week, and one case of osteosarcoma of the upper humerus was treated with HDMTX for 4 weeks before surgery, followed by intra-arterial perfusion of ADM for 6 h. In combination with local radiotherapy, it was found that the tumor shrank significantly, and angiography showed a decrease in neovascularization and disappearance of tumor staining. Artificial joint transplantation was performed after tumor resection, and postoperative specimens were compared with biopsy specimens before chemotherapy with significant tumor cell necrosis, fibrous membrane formation around the tumor foci, and near-normal function of the reconstructed shoulder joint. rosen et al [12] used the interval when patients with osteosarcoma were waiting for special prosthesis to be made, and changed the T4 regimen from pure postoperative chemotherapy to preoperative start application, which achieved significant results and enabled some patients to have their limbs The concept of neoadjuvant chemotherapy has gradually been developed.
Neoadjuvant chemotherapy is a modification of the postoperative chemotherapy regimen that is applied preoperatively and guided by the degree of response of the primary tumor site to chemotherapy drugs, with the following specific reasons and advantages.
(1) The biological study of tumor shows that the sensitivity of micro metastases to chemotherapy is higher than that of relatively large metastases, and preoperative chemotherapy can enable patients to avoid the delay of lowering the immunity of the body to promote the rapid growth of tumor and time due to blood transfusion, etc., and play the role of killing metastases in the first time.
(2) To kill the primary tumor foci as much as possible to make them shrink, which is conducive to the limb-preserving surgery.
(3) Timely adjustment of individual chemotherapy regimen according to the response of the primary foci during chemotherapy.
(4) Screening out high-risk cases to receive intensive treatment before the tumor may recur or metastasize.
(5) Judging the prognosis, those with good preoperative chemotherapy effect and high tumor cell necrosis rate will continue to receive chemotherapy after surgery and have a relatively high chance of tumor-free survival.
The earliest neoadjuvant chemotherapy regimen was applied to the treatment of osteosarcoma by Rosen et al. in 1979, which consisted of HDMTX, ADM and BCD (T7 regimen), and achieved a survival rate of 70%, and after a longer follow-up, the results showed that the primary focus responded well to preoperative chemotherapy, and the prognosis of those with tumor cell necrosis rate greater than 90% was much better than those with less than 90%, and their survival rates were 91% and 38% respectively. The survival rates were 91% and 38%, respectively. Similarly, studies such as Bramwell et al. and Provisor et al. have confirmed the correlation between the degree of preoperative tumor response to chemotherapy and prognosis.
The adjustment of postoperative chemotherapy regimens according to the response of the primary tumor to chemotherapeutic agents is one of the studies of interest and was first attempted by Rosen et al. in 1982 with the development of the T10 regimen. The tumor cell necrosis rate was greater than 90% after surgery, and HDMTX was replaced by CDP in the regimen for tumor cell necrosis rate less than 90%. In the subsequent T12 regimen, the more toxic ADM and CDP in T10 were replaced by BCD, and if preoperative chemotherapy was not effective, ADM and CDP were applied for a longer period after surgery. However, Meyers et al. and Provisor et al. failed to find that adjusting the postoperative chemotherapy regimen significantly improved the survival of those who were not sensitive to preoperative chemotherapy. Bacci et al. did not achieve similar results to Rosen et al. until 1991 and 1993 when new drugs such as VP16 and IFO were added to postoperative chemotherapy.
4. Preoperative route of drug administration
Preoperative intra-arterial administration of tumor trophoblastic artery can achieve 1.5–4 times higher drug concentration than intravenous administration in the primary site, which enhances local chemotherapy effect and facilitates limb preservation, while systemic blood concentration is the same as intravenous administration without affecting the accompanying systemic chemotherapy effect.
In 1985, Jaffe et al. reported a randomized comparison of the efficacy of arterial administration of MTX and CDP, and found that the CDP group responded well, with a tumor cell necrosis rate greater than 90% in 27% of patients, compared with 60% in the CDP group. The results showed that 78% of patients in the intra-arterial CDP group responded well, while only 56% of patients in the other group responded well. The long-term survival rate was 67% in 66 cases (52%) with tumor cell necrosis rate >90%, significantly higher than 36% in those with tumor necrosis rate <90%. Uchida et al. followed 67 cases of osteosarcoma treated with neoadjuvant chemotherapy for more than 4 years and found that the survival rate in the group with a single intra-arterial administration of CDP as part of preoperative chemotherapy was significantly higher than that in the groups with only intravenous MTX and ADM, 69.5% and 40.6%, respectively. These results suggest that intra-arterial administration can obtain a higher tumor cell necrosis rate while still retaining the correlation between the degree of tumor cell necrosis and the prognosis of osteosarcoma, and that CDP is the preferred agent suitable for intra-arterial administration.
Hyperthermic Isolated Limb Perfusion (HILP) allows for higher local drug concentrations in the tumor and can be combined with high temperature to maximize the killing effect on the primary site with less systemic toxicities. The local CDP concentration during HILP was 10–20 times higher than that of systemic plasma CDP, and 5 times higher than that of arterial administration alone, and the higher concentration was maintained throughout the course of HILP. In 1991, I started to use HILP to treat osteosarcoma of the limb and obtained a high rate of tumor cell necrosis, and found that the local concentration of platinum was about 5 times higher than that of systemic chemotherapy by monitoring the blood platinum concentration. The effect of systemic chemotherapy is also taken into account. However, the local chemotherapy conditions are much better than those of systemic chemotherapy in HILP, so it remains to be seen whether the high necrosis rate means a high survival rate.