Wong Andrea L A, Sundar Raghav, Wang Ting-Ting, Ng Thian-C, Zhang Bo, Tan Sing-Huang, Soh Thomas I P, Pang Angela S L, Tan Chee-Seng, Ow Samuel G W, Wang Lingzhi, Mogro Jannet, Ho Jingshan, Jeyasekharan Anand D, Huang Yiqing, Thng Choon-Hua, Chan Ching-Wan, Hartman Mikael, Iau Philip, Buhari Shaik A, Goh Boon-Cher, Lee Soo-Chin
Department of Haematology-Oncology, National University Cancer Institute, National University Health System, Singapore.
Haematology Oncology Research Group, National University Cancer Institute, National University Health System, Singapore.
Oncotarget. 2016 Sep 27;7(39):64089-64099. doi: 10.18632/oncotarget.11596.
Prolonged anti-angiogenic therapy destroys tumor vasculature, whereas vascular-normalizing doses may enhance intra-tumoral drug delivery. We hypothesize that low-dose, short-course sunitinib normalizes vasculature, enhancing chemotherapy efficacy.
In phase Ib, treatment-naïve breast cancer patients received four cycles of pre-operative doxorubicin/cyclophosphamide, with sunitinib before each cycle. The optimal dose of sunitinib leading to tumor vessel normalization on immunohistochemistry was identified. In phase II, subjects were randomized to chemotherapy alone or chemotherapy plus sunitinib at the recommended phase II dose (RP2D). Primary endpoint was pathological complete response (pCR) rate. Tumor and functional imaging biomarkers were evaluated serially.
In phase Ib (n=9), sunitinib 12.5 mg daily for 7 days before each chemotherapy was established as RP2D. In phase II, patients receiving chemotherapy plus sunitinib (n=24) had similar pCR rates (5.0% versus 4.3%, p=1.00), but a higher incidence of chemotherapy dose delays (33.3% versus 8.7%, p=0.04), compared to those receiving chemotherapy alone (n=25). The addition of sunitinib to chemotherapy significantly increased vascular normalization index (VNI) and decreased lymphatic vessel density (D2-40) on immunohistochemistry [VNI:25.50±27.94% versus 49.29±31.84%, p=0.034; D2-40:3.29±2.70 versus 1.29±1.54, p=0.014, baseline versus post-cycle 1], and improved perfusion on DCE-MRI (Ktrans:12.6±9.6 mL/100 g/min versus 16.3±10.7 mL/100 g/min, baseline versus post-cycle 1, p=0.015). Conversely, immunohistochemical and DCE-MRI parameters were not significantly altered by chemotherapy alone.
Low-dose, short-course sunitinib prior to anthracycline-based chemotherapy in breast cancer patients did not improve pCR and increased chemotherapy dose delays. However, the addition of sunitinib induced compelling pharmacodynamic evidence of vascular normalization. Further studies with alternative cytotoxic regimens should be explored.
长期抗血管生成治疗会破坏肿瘤血管,而血管正常化剂量可能会增强肿瘤内药物递送。我们假设低剂量、短疗程的舒尼替尼可使血管正常化,提高化疗疗效。
在Ib期,初治乳腺癌患者接受四个周期的术前多柔比星/环磷酰胺治疗,每个周期前给予舒尼替尼。通过免疫组化确定导致肿瘤血管正常化的舒尼替尼最佳剂量。在II期,受试者被随机分为单纯化疗组或化疗加舒尼替尼组,舒尼替尼采用推荐的II期剂量(RP2D)。主要终点是病理完全缓解(pCR)率。对肿瘤和功能成像生物标志物进行连续评估。
在Ib期(n = 9),确定每个化疗周期前7天每日服用12.5 mg舒尼替尼为RP2D。在II期,与单纯接受化疗的患者(n = 25)相比,接受化疗加舒尼替尼的患者(n = 24)的pCR率相似(5.0%对4.3%,p = 1.00),但化疗剂量延迟的发生率更高(33.3%对8.7%,p = 0.04)。化疗加用舒尼替尼显著增加了免疫组化的血管正常化指数(VNI)并降低了淋巴管密度(D2 - 40)[VNI:25.50±27.94%对49.29±31.84%,p = 0.034;D2 - 40:3.29±2.70对1.29±1.54,p = 0.014,基线对第1周期后],并改善了DCE - MRI的灌注(Ktrans:12.6±9.6 mL/100 g/min对16.3±10.7 mL/100 g/min,基线对第1周期后,p = 0.015)。相反,单纯化疗未显著改变免疫组化和DCE - MRI参数。
乳腺癌患者在基于蒽环类化疗前使用低剂量、短疗程舒尼替尼并未提高pCR率,反而增加了化疗剂量延迟。然而,加用舒尼替尼诱导了令人信服的血管正常化药效学证据。应探索采用替代细胞毒性方案的进一步研究。