阿霉素仍为转移性软组织肉瘤一线标准治疗

维也纳——在欧洲肿瘤内科学会(ESMO)年会上报告的一项Ⅲ期临床试验结果表明，与作为晚期软组织肉瘤一线化疗的阿霉素单药治疗相比，更为积极的阿霉素+异环磷酰胺联合治疗方案未显示出总生存方面的明显优势。

欧洲癌症研究与治疗组织(EORTC)62012研究的结果显示，联合治疗与阿霉素单药治疗的主要终点指标——中位总生存期分别为14.3个月和12.8个月[危险比(HR)为0.83，P=0.076]，1年生存率分别为60%和 51%。

Winette van der Graaf博士

荷兰内梅亨大学医学中心的Winette van der Graaf博士代表主要作者、英国皇家马斯登医院的Ian Judson博士在报告中指出，正如此前观察到的那样，阿霉素+异环磷酰胺联合治疗可提高患者的应答率和无进展生存期，但要以更大的毒性为代价，“标准治疗仍是阿霉素单药。”她认为，如果预见手术治疗对象是不可切除肿瘤或是可治性转移灶切除，可考虑联合用药方案，该方案也可作为无共病的严重症状患者的治疗选择，尽管需要与患者讨论其利弊。有了上述结果，估计与患者的讨论会变得更容易。

EORTC软组织和骨肉瘤小组设计这项研究，旨在回答长期以来有关阿霉素单药与阿霉素联合异环磷酰胺中究竟哪一种是转移性软组织肉瘤最佳一线治疗方案的疑问。此前EORTC的Ⅲ期试验(J. Clin. Oncol. 1995;13:1537-45)探索了小剂量异环磷酰胺联合用药情况，而最新Ⅱ期试验结果表明高剂量异环磷酰胺可提高应答率和无进展生存期。

在EORTC 62012试验中，来自9个国家38个中心的研究者将455例年龄18~60岁的局部晚期不可切除或转移性软组织肉瘤患者随机分为2组：单药组第1天或72 h连续静注75 mg/m²阿霉素，联合治疗组第1~3天静注25 mg/m²阿霉素+第1~4天静注2.5 g/m²异环磷酰胺+第5天皮下注射6 mg聚乙二醇非格司亭。按照患者年龄、身体状态、肝转移情况以及组织学分级分层，晚期患者此前未接受化疗。

结果显示，中位随访56个月后，单药组和联合治疗中位无进展生存期分别为4.6个月和7.4个月(HR=0.74，P=0.003)，后者延长明显。亚组分析显示，40~49岁患者组无进展生存期延长明显，但对所有50岁以下患者进行汇总分析后，无进展生存期延长不再显著。所有亚组均未见总生存率方面的明显优势。完全应答率非常低，单药组和联合治疗组分别为0.4%和1.8%。值得关注的是，联合治疗组的部分应答率提高1倍(24.7% vs. 13.2%)，但总应答率(26.5% vs. 13.6%)远远低于基于Ⅱ期试验结果(66% vs. 52%)的预期。

波士顿Dana-Farber癌症研究所肉瘤和骨瘤中心主任George Demetri博士讨论认为，表面看来，联合治疗的无病生存期差异似乎并不重要，但对于中位生存期通常仅为1年的转移性软组织肉瘤患者，这一差异就意味着他们的无病生存时间延长20%。鉴于联合化疗具有相当大的毒性，对于医生而言，最关键的是能否确定真正的受益患者。

 
George Demetri博士

Demetri博士指出，有更多的联合治疗组患者因为毒性问题而停药(40例vs. 6 例)。最常见的≥3级不良事件分别为发热性中性粒细胞减少症(46% vs. 13.5%)、贫血(35% vs. 4.6%)和血小板减少症(33.5% vs. 0.4%)。

他警告称，不应将该结果盲目外推至临床实践中，因为受试者比典型临床患者更为年轻和健康。然而，这些可靠的数据可用于患者知情选择。他认为，如果患者属于常见的无症状型转移性肉瘤，选择阿霉素单药治疗或许足矣，也更为有益和人性化。如果患者属于症状型或因肿瘤疼痛而需要通过缩小肿瘤改善生活质量，那么选择联合治疗或许受益更大，尽管毒性也较大。

该项试验由EORTC资助。van der Graaf 博士和Judson博士均报告无利益冲突。Demetri博士报告与多家制药公司存在经济利益。

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By: PATRICE WENDLING, Oncology Practice

VIENNA – A more aggressive combination of doxorubicin and ifosfamide provided no significant overall survival advantage over single-agent doxorubicin as first-line chemotherapy in advanced soft-tissue sarcoma in a phase III trial.

The European Organisation for Research and Treatment of Cancer (EORTC) 62012 study’s primary end point of median overall survival reached 14.3 months with the combination and 12.8 months with doxorubicin alone (hazard ratio, 0.83; P = .076). One-year survival rates were 60% and 51%, respectively.

As previously observed, the combination of doxorubicin (Adriamycin) and ifosfamide (Ifex) increased response rates and progression-free survival, but at a cost of considerably more toxicity. "The standard treatment remains single-agent doxorubicin," Dr. Winette van der Graaf said during a Presidential Symposium at the European Society for Medical Oncology Congress.

Combination therapy, she added, can be considered if surgery for unresectable tumors or curative metastasectomy is foreseen, and may be an option for highly symptomatic patients without comorbidity, although the pros and cons should be discussed with the patient.

"The advantage of having the results of this study is that it’s easier now to have this discussion with the patient," said Dr. van der Graaf, of Radboud University Nijmegen (Netherlands) Medical Centre.

The EORTC Soft Tissue and Bone Sarcoma Group designed the trial to answer the long-standing question of whether single-agent doxorubicin or doxorubicin plus ifosfamide is the best first-line treatment for metastatic soft-tissue sarcomas. An earlier EORTC phase III trial (J. Clin. Oncol. 1995;13:1537-45) explored the combination at a lower dose of ifosfamide than is used today, with more recent phase II trials suggesting that a higher dose could increase response rates and progression-free survival.

EORTC 62012 investigators at 38 centers in nine countries randomly assigned 455 patients, aged 18-60 years, with locally advanced unresectable or metastatic soft-tissue sarcoma to receive doxorubicin 75 mg/m2 bolus on day 1 or as a 72-hour continuous IV infusion or doxorubicin 25 mg/m2 on days 1-3 plus ifosfamide 2.5 g/m2 on days 1-4 and pegfilgrastim 6 mg subcutaneous on day 5.

Patients were stratified by age, performance status (0 vs. 1), liver metastases, and histological grade. No prior chemotherapy was allowed for advanced disease.

After a median follow-up of 56 months, median progression-free survival increased significantly from 4.6 months with single-agent doxorubicin to 7.4 months with the addition of ifosfamide (HR 0.74, P = .003), Dr. van der Graaf reported on behalf of lead author Dr. Ian Judson of the Royal Marsden Hospital, London.

Subgroup analyses revealed significantly longer progression-free survival among patients aged 40-49 years, but this significance disappeared when all patients under age 50 were included in the analysis. No subgroups had significantly better overall survival.

The complete response rate was very low, at 0.4% in the doxorubicin arm and 1.8% in the combination arm. Remarkably, partial responses doubled with combination therapy from 13.2% to 24.7%, but overall response rates (13.6% vs. 26.5%) were far less than expected from phase II trials, where they ranged from 52% to 66%, she observed.

At first blush, the difference in progression-free survival with combination therapy may not appear that important, but from the perspective of patients with metastatic soft-tissue sarcoma, who typically have a median survival of only 1 year, this means that they’ll spend about 20% of their lifetime longer with disease control, said discussant Dr. George Demetri, director of the Center for Sarcoma and Bone Oncology at the Dana-Farber Cancer Institute in Boston.

"The question for us as clinicians is can we target patients who truly would get more benefit from this kind of doubling of tumor response and control, despite the sizable toxicities of the more toxic combination chemotherapy," he said.

Dr. Demetri pointed out that significantly more patients discontinued combination therapy than single-agent doxorubicin due to toxicity (40 patients vs. 6 patients). The most common grade 3 or higher adverse events in the combination and doxorubicin arms were febrile neutropenia (46% vs. 13.5%), anemia (35% vs. 4.6%) and thrombocytopenia.

Dr. Demetri cautioned that the results should not be blindly extrapolated to clinical practice because patients in the trial were younger and healthier than those typically seen in practice. However, the solid data can be used to make informed choices, he said.

If a patient is asymptomatic, as many metastatic sarcoma patients are, then single-agent doxorubicin, which he described as a strong, aggressive, "truck" of a therapy, "may be sufficient" and "more kind, more humane" to the patient, he said. If the patient is symptomatic or tumor shrinkage is required to improve quality of life because of tumor-related pain, "then perhaps combination therapy, although more toxic, may be more beneficial," he added.

The EORTC sponsored the trial. Dr. van der Graaf and Dr. Judson reported no conflicts of interest. Dr. Demetri reported financial relationships with several pharmaceutical companies.