Tumor hypoxia detected by positron emission tomography with 60Cu-ATSM as a predictor of response and survival in patients undergoing Neoadjuvant chemoradiotherapy for rectal carcinoma: a pilot study.
Tumor hypoxia detected by positron emission tomography with 60Cu-ATSM as a predictor of response and survival in patients undergoing Neoadjuvant chemoradiotherapy for rectal carcinoma: a pilot study.
复制标题
DOI：
10.1007/s10350-008-9420-3
复制
发表时间：
2008-11
影响因子：
3.9
通讯作者：
Siegel BA
中科院分区：
文献类型：
--
作者：
Dietz DW;Dehdashti F;Grigsby PW;Malyapa RS;Myerson RJ;Picus J;Ritter J;Lewis JS;Welch MJ;Siegel BA
直肠癌对新辅助放化疗的反应是可变的。肿瘤缺氧降低了放疗和化疗的有效性，是肿瘤放射抵抗的一个众所周知的危险因素。我们假设使用新型低氧检测剂60cu -二乙酰-双（n4 -甲基硫代氨基脲）（60Cu-ATSM）进行成像，可以预测直肠癌对新辅助放化疗的反应和预后。60Cu-ATSM先前在宫颈癌和肺癌中得到验证。局部侵袭性（T2-4）原发性或淋巴结阳性直肠癌患者位于肛门边缘<12厘米处，被招募参加这项初步研究。经直肠内超声、CT及磁共振检查确定肿瘤大小及分期。11名患者还接受了临床正电子发射断层扫描18f -氟脱氧葡萄糖在治疗的临床医生的决定。原发肿瘤采用60Cu-ATSM正电子发射断层成像，通过测定肿瘤与肌肉活动比半定量测量示踪剂的积累。然后给予新辅助放化疗（60cu - atsm -正电子发射断层扫描2周内），45 Gy分25次给予骨盆，持续静脉输注5-氟尿嘧啶（225 mg/m2/天）。在新辅助放化疗后6至8周行直肠切除术，并将肿瘤提交病理进行大小测量和分期。将肿瘤-肌肉活动比与肿瘤18f -氟脱氧葡萄糖摄取、肿瘤对新辅助放化疗的反应以及患者生存进行比较。19例患者入组研究，其中2例被排除在最终分析之外（1例在新辅助放化疗期间死亡，1例在新辅助放化疗期间肿瘤穿孔需要紧急手术）。在剩下的17例患者中，14例肿瘤缩小，13例下降。肿瘤与肌肉活动比值中位数为2.6，可区分预后较差和预后较好的患者。低氧肿瘤（肿瘤与肌肉活动比>2.6）的总生存率和无进展生存率均低于非低氧肿瘤（肿瘤与肌肉活动比≤2.6，P均<0.05）。此外，3个大小不变的肿瘤中有2个肿瘤与肌肉活动比为>2.6（阳性预测值66%），而14个大小减小的肿瘤中有6个肿瘤与肌肉活动比为>2.6（阴性预测值57%）。4个未降级的肿瘤中有3个肿瘤与肌肉的活动比为>2.6（阳性预测值为75%），而13个降级肿瘤中有5个肿瘤与肌肉的活动比为>2.6（阴性预测值为62%）。低分期肿瘤的平均肿瘤-肌肉活动比（2.2）显著低于非低分期肿瘤的平均肿瘤-肌肉活动比（3.3）（P=0.03）。缩小肿瘤（2.3）与非缩小肿瘤（2.9）的平均肿瘤-肌肉活动比差异无统计学意义（P=0.36）。肿瘤18f -氟脱氧葡萄糖摄取（n=11）与60Cu-ATSM摄取无相关性（r=0.4； P=0.9），低氧肿瘤患者与常氧肿瘤患者平均18f -氟脱氧葡萄糖摄取无显著差异（P=0.3）。这项小型试点研究的结果表明，60Cu-ATSM-PET可能预测直肠癌患者的生存，并可能预测肿瘤对新辅助放化疗的反应。需要更大规模的II期研究来验证这些结果。
The response of rectal cancers to neoadjuvant chemoradiotherapy is variable. Tumor hypoxia reduces the effectiveness of both radiation therapy and chemotherapy and is a well-known risk factor for tumor radioresistence. We hypothesized that imaging with the novel hypoxia-detecting agent, 60Cu-diacetyl-bis (N4-methylthiosemicarbazone) (60Cu-ATSM), previously validated in cervical and lung cancers, would predict the response of rectal cancers to neoadjuvant chemoradiotherapy and prognosis. Patients with locally invasive (T2–4) primary or node-positive rectal cancer located <12 cm from the anal verge were recruited for this pilot study. Pretreatment tumor size and stage were determined by endorectal ultrasonography, CT, and magnetic resonance imaging. Eleven patients also underwent clinical positron emission tomography with 18F-fluorodeoxyglucose at the discretion of the treating clinician. The primary tumor was imaged by positron emission tomography with 60Cu-ATSM, and accumulation of the tracer was measured semiquantitatively by determining the tumor-to-muscle activity ratio. Neoadjuvant chemoradiotherapy was then administered (within 2 weeks of 60Cu-ATSM-positron emission tomography) and consisted of 45 Gy given in 25 fractions to the pelvis with continuous intravenous infusion of 5-fluorouracil (225 mg/m2/day). Proctectomy was performed six to eight weeks after neoadjuvant chemoradiotherapy and the tumor submitted to pathology for size measurement and staging. Tumor-to-muscle activity ratios were compared with tumor 18F-fluorodeoxyglucose uptake, tumor response to neoadjuvant chemoradiotherapy, and with patient survival. Nineteen patients were enrolled in the study, two of whom were excluded from final analysis (1 death during neoadjuvant chemoradiotherapy and 1 tumor perforation during neoadjuvant chemoradiotherapy requiring emergent surgery). Of the 17 remaining patients, 14 had a reduction in tumor size and 13 were downstaged. The median tumor-to-muscle activity ratio of 2.6 discriminated those with worse prognosis from those with better prognosis. Both overall and progression-free survivals were worse with hypoxic tumors (tumor-to-muscle activity ratio >2.6) than with nonhypoxic tumors (tumor-to-muscle activity ratio ≤2.6; both P<0.05). In addition, 2 of the 3 tumors with no change in size had tumor-to-muscle activity ratios >2.6 (positive predictive value 66 percent), whereas 6 of 14 with decreased size had tumor-to-muscle activity ratios >2.6 (negative predictive value 57 percent). Three of the 4 tumors not downstaged had tumor-to-muscle activity ratios >2.6 (positive predictive value 75 percent), whereas 5 of 13 downstaged tumors had tumor-to-muscle activity ratios >2.6 (negative predictive value 62 percent). The mean tumor-to-muscle activity ratio for downstaged tumors (2.2) was significantly lower than that of nondownstaged tumors (3.3) (P=0.03). The difference in mean tumor-to-muscle activity ratio between downsized (2.3) and nondownsized (2.9) tumors did not reach statistical significance (P=0.36). Tumor 18F-fluorodeoxyglucose uptake (n=11) did not correlate with 60Cu-ATSM uptake (r=0.4; P=0.9) and there was no significant difference in mean tumor 18F-fluorodeoxyglucose uptake between patients with hypoxic tumors and those with normoxic tumors (P=0.3). The results of this small pilot study suggest that 60Cu-ATSM-PET may be predictive of survival and, possibly, tumor response to neoadjuvant chemoradiotherapy in patients with rectal cancer. A larger Phase II study is warranted to validate these results.