Caffeine-assisted chemotherapy and minimized tumor excision for nonmetastatic osteosarcoma

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.