Jaffe Norman, Carrasco Humberto, Raymond Kevin, Ayala Alberto, Eftekhari Farzin
Division of Pediatrics, University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, USA.
Cancer. 2002 Nov 15;95(10):2202-10. doi: 10.1002/cncr.10944.
Contemporary therapy for osteosarcoma is comprised of initial treatment with chemotherapy and surgical extirpation of the primary tumor in the affected bone. In view of the major advances forged by chemotherapy in the treatment of the primary tumor, an attempt was made to destroy the tumor exclusively with this therapeutic modality and abrogate surgery.
Thirty-one consecutive patients were treated. All had localized disease (absence of metastases) at the time of diagnosis. Initial treatment with chemotherapy was comprised of high-dose methotrexate and leucovorin rescue (MTX-LF) in 3 patients and intraarterial cisplatin in 28 patients. Clinical, radiologic, angiographic, radionuclide, and histologic investigations were utilized to assess the efficacy of treatment. After a response at 3 months, entry into the study was permitted and treatment was maintained for a total of 18-21 months with a combination of agents comprised of MTX-LF, intraarterial cisplatin, and doxorubicin. Patients were monitored closely for disease recurrence with the investigations outlined earlier. Two informed consents were required: one at the time of diagnosis and another at 3 months after the initial response had been attained.
Only 3 of 31 patients were cured with the administration of chemotherapy alone. Local recurrence and pulmonary metastases were not reported to develop in these 3 patients during a follow-up period of 204+ to 225+ months. Four other patients also possibly were cured with chemotherapy alone. At their request, several months after the cessation of chemotherapy, they underwent surgical extirpation of the tumor. No evidence of viable tumor was found. These patients remained free of disease for 192+ to 216+ months. Thus, only seven patients did not develop local recurrence and/or pulmonary metastases. Among the remaining 24 patients, 9 developed local recurrences without pulmonary metastases 14-74 months (median, 30 months) after the initial response. Eight of the nine patients were rendered tumor free by extirpation of the local recurrence. Two of these eight patients subsequently died, one of the acquired immunodeficiency syndrome (AIDS) and the other of varicella septicemia. The ninth patient refused amputation and died of metabolic complications. Three other patients developed local recurrences 20-69 months and pulmonary metastases 10-98 months after achievement of the initial response. These patients were rendered tumor free by extirpation of the local recurrence and metastasectomy. One of these patients also later died of AIDS. In the remaining 12 patients, local recurrences developed 5-29 months (median, 14 months) after the initial response was achieved. The patients also developed pulmonary metastases 11-60 months after the initial response. In eight patients the local recurrences were extirpated and metastasectomy was performed; however, these patients later died of recurrent pulmonary metastases. The remaining four patients refused to undergo extirpation of the local recurrence. The pulmonary metastases were not resected. They failed to respond to alternate therapy. Thus, the tumor-free survival rate was 23% (7 of 31 patients): 3 patients who were treated with chemotherapy only and 4 patients who were treated with chemotherapy plus surgery. The overall survival rate (patients who remained free of disease and those who underwent resection for local recurrence and metastasectomy) was 48% (15 of 31 patients). Prior to the deaths from AIDS and varicella septicemia, the overall survival was 58% (18 of 31 patients).
Utilizing the regimen employed in the current study, only 3 of 31 patients with osteosarcoma (10%) were cured exclusively with chemotherapy. Four additional patients who underwent extirpation of the primary tumor without disease recurrence and in whom no viable tumor was found in the resected specimens possibly could increase the number of patients who potentially were cured with chemotherapy to 7 (23%). With an overall expected cure rate of 50-65% with "conventional" sin whom no viable tumor was found in the resected specimens possibly could increase the number of patients who potentially were cured with chemotherapy to 7 (23%). With an overall expected cure rate of 50-65% with "conventional" strategies, the results of the current study do not justify the adoption of current forms of chemotherapy as exclusive treatments for osteosarcoma.
骨肉瘤的现代治疗包括先用化疗进行初始治疗，然后对患骨的原发性肿瘤进行手术切除。鉴于化疗在原发性肿瘤治疗方面取得的重大进展，有人尝试仅用这种治疗方式来摧毁肿瘤并取消手术。
连续治疗了31例患者。所有患者在诊断时均为局限性疾病（无转移）。初始化疗治疗包括3例患者采用大剂量甲氨蝶呤和亚叶酸解救（MTX - LF），28例患者采用动脉内顺铂。利用临床、放射学、血管造影、放射性核素和组织学检查来评估治疗效果。在3个月出现反应后，允许进入研究，并使用MTX - LF、动脉内顺铂和阿霉素联合用药维持治疗共18 - 21个月。采用上述检查对患者进行密切监测以观察疾病复发情况。需要两份知情同意书：一份在诊断时签署，另一份在初始反应达到后3个月签署。
31例患者中仅3例单纯通过化疗治愈。在204 +至225 +个月的随访期内，这3例患者未报告发生局部复发和肺转移。另外4例患者也可能单纯通过化疗治愈。应他们的要求，在化疗停止数月后，他们接受了肿瘤的手术切除。未发现有存活肿瘤的证据。这些患者在192 +至216 +个月内无疾病复发。因此，只有7例患者未发生局部复发和/或肺转移。在其余24例患者中，9例在初始反应后14 - 74个月（中位数为30个月）出现无肺转移的局部复发。9例患者中有8例通过切除局部复发灶而达到无瘤状态。这8例患者中有2例随后死亡，1例死于获得性免疫缺陷综合征（AIDS），另1例死于水痘败血症。第9例患者拒绝截肢，死于代谢并发症。另外3例患者在初始反应后20 - 69个月出现局部复发，10 - 98个月出现肺转移。通过切除局部复发灶和转移灶切除术，这些患者达到无瘤状态。其中1例患者后来也死于AIDS。在其余12例患者中，在初始反应后5 - 29个月（中位数为14个月）出现局部复发。这些患者在初始反应后11 - 60个月也出现肺转移。8例患者切除了局部复发灶并进行了转移灶切除术；然而，这些患者后来死于复发性肺转移。其余4例患者拒绝切除局部复发灶。未切除肺转移灶。他们对替代治疗无反应。因此，无瘤生存率为23%（31例患者中的7例）：3例仅接受化疗的患者和4例接受化疗加手术的患者。总生存率（无疾病复发的患者以及接受局部复发切除和转移灶切除术的患者）为48%（31例患者中的15例）。在死于AIDS和水痘败血症之前，总生存率为58%（31例患者中的18例）。
采用本研究中使用的方案，31例骨肉瘤患者中仅3例（10%）单纯通过化疗治愈。另外4例患者在切除原发性肿瘤后未出现疾病复发，且在切除标本中未发现存活肿瘤，这可能使潜在通过化疗治愈的患者数量增加到7例（23%）。“传统”策略的总体预期治愈率为50 - 65%，本研究结果并不支持采用目前形式的化疗作为骨肉瘤的唯一治疗方法。
