Tsuchiya H, Tomita K, Mori Y, Asada N, Morinaga T, Kitano S, Yamamoto N
Department of Orthopaedic Surgery, School of Medicine, Kanazawa University, Japan.
Anticancer Res. 1998 Jan-Feb;18(1B):657-66.
Osteosarcoma is usually treated with intensive preoperative and postoperative chemotherapy and wide tumor resection, resulting in a 60% to 70% 5-year survival rate. Caffeine has a DNA-repair inhibiting effect. We therefore investigated the impact of caffeine given in conjunction with chemotherapy and limb-sparing surgery on survival and local tumor control in patients with nonmetastatic, high-grade osteosarcoma. Twenty-two patients were given 3 to 5 preoperative courses of intra-arterial cisplatin (120 mg/m2, 1 to 2 hours) and caffeine (1.5 g/m2/day x 3 days) with or without doxorubicin (30 mg/m2/day x 2 days). Following this treatment, limb-sparing surgery was performed by means of intentional marginal excision aiming at preservation of important structures such as major neurovascular bundles, tendons, ligaments and the epiphysis. Three courses of cisplatin and doxorubicin combined with caffeine, and high-dose methotrexate with vincristine and citrovorum factor rescue were given intravenously as postoperative chemotherapy for 21 patients and three courses of high-dose methotrexate and combination of ifosfamide, etoposide and methotrexate for 1 patient. Following the preoperative chemotherapy, there were no viable tumor cells in 19 patients, only scattered foci of viable cells in 2 patients, and some areas of viable tumor cells in 1. The 21 patients with a good chemotherapeutic response on radiographs underwent minimized marginal excision. Functional evaluation of the affected limbs was excellent for 17 patients, good for 3, fair for 1, and poor for 1. No local tumor recurrence was seen in this series. Eighteen patients remain disease-free with a mean follow-up of 61 months. Two patients died of metastatic disease, 1 died of chemotherapy-related complications, and 1 died of unknown causes. The overall 5-year cumulative survival rate was 90%, and the 5-year event-free survival rate was 75%. Chemotherapeutic caffeine enhanced tumor necrosis and improved the success rate of limb-sparing surgery using marginal procedure without any adverse impact on survival. The results of our limited clinical trial appear to justify further prospective, multicenter randomized trials of the benefits of caffeine combined with chemotherapy for nonmetastatic osteosarcoma and other malignant neoplasms.
骨肉瘤通常采用强化的术前和术后化疗以及广泛的肿瘤切除进行治疗，5年生存率为60%至70%。咖啡因具有抑制DNA修复的作用。因此，我们研究了咖啡因联合化疗和保肢手术对非转移性、高级别骨肉瘤患者生存率和局部肿瘤控制的影响。22例患者接受了3至5个术前疗程的动脉内顺铂（120mg/m²，1至2小时）和咖啡因（1.5g/m²/天×3天）治疗，部分患者联合或不联合阿霉素（30mg/m²/天×2天）。经过该治疗后，通过有意的边缘切除进行保肢手术，旨在保留重要结构，如主要神经血管束、肌腱、韧带和骨骺。21例患者术后化疗静脉给予3个疗程的顺铂和阿霉素联合咖啡因，以及大剂量甲氨蝶呤联合长春新碱和亚叶酸钙解救；1例患者术后化疗给予3个疗程的大剂量甲氨蝶呤以及异环磷酰胺、依托泊苷和甲氨蝶呤联合治疗。术前化疗后，19例患者无存活肿瘤细胞，2例患者仅有散在的存活细胞灶，1例患者有部分存活肿瘤细胞区域。21例影像学化疗反应良好的患者接受了最小化边缘切除。17例患者患侧肢体功能评估为优，3例为良，1例为中，1例为差。该系列中未见局部肿瘤复发。18例患者无疾病生存，平均随访61个月。2例患者死于转移性疾病，1例死于化疗相关并发症，1例死于不明原因。总体5年累积生存率为90%，5年无事件生存率为75%。化疗用咖啡因可增强肿瘤坏死，并提高采用边缘手术的保肢手术成功率，且对生存率无任何不利影响。我们有限的临床试验结果似乎证明有必要进一步开展关于咖啡因联合化疗对非转移性骨肉瘤和其他恶性肿瘤益处的前瞻性、多中心随机试验。
