Investigation of clinical gastrointestinal toxicity and underlying normal tissue damage associated with concurrent abdominal radiation therapy and tyrosine kinase inhibition
Tyrosine kinase inhibitors (TKIs) may be combined with radiation therapy (RT) to enhance tumor control due to their anticancer and antiangiogenic effects; however, clinical evidence has emerged which suggests the treatment combination of RT and TKI may result in higher incidence of normal tissue side effects, dependent on the organs at risk in the radiation treatment field, than would be expected for either modality alone. We evaluated the incidence of gastrointestinal (GI) toxicity in canine cancer patients receiving concurrent hypofractionated abdominal RT and the TKI toceranib and compared to those receiving abdominal RT alone, toceranib alone, or concurrent non-abdominal RT and toceranib. Medical records of canine cancer patients were retrospectively reviewed and identified dogs were included in the following treatment categories: dogs which received RT to a portion of the abdomen and concurrent TOC (n = 19), abdominal RT alone (n = 29), TOC alone (n = 20), or non-abdominal RT plus TOC (n = 9). Toxicities were graded using the Veterinary Cooperative Oncology Group - Common Terminology Criteria for Adverse Events criteria and compared to published data on TOC-associated GI toxicity. Patients receiving TOC while undergoing abdominal RT had significantly increased rates of any grade of diarrhea (p = 0.002), hyporexia (p = 0.0045), and vomiting (p = 0.003), as well as severe hyporexia (p = 0.003) when compared across the treatment groups. This retrospective study revealed significantly increased incidences of GI toxicity when abdominal RT was combined with TOC in canine patients. Following these findings, we investigated the morbidity and underlying histological changes associated with combined abdominal RT and the TKI sunitinib in a mouse model. Prior to the experimental study, we identified a dose of abdominal RT in CD1 outbred mice which would induce mild GI toxicity according to weight loss and histologic changes in GI tissues harvested 7 days after irradiation; 12 gray (Gy) was selected as the optimal dose for the subsequent experiment. Twenty-five mice were then assigned to control (n = 5), sunitinib alone (n = 7), RT alone (n = 6), or RT + sunitinib (n = 7) groups and were weighed daily. All mice received daily oral gavage of vehicle or sunitinib (40 mg/kg) in vehicle for the entire study. On day 7 mice received 12 Gy abdominal RT or sham irradiation. On day 14 mice were euthanized and their entire GI tract was harvested for histopathologic evaluation, semiquantitative scoring of inflammation, and immunohistochemical quantification of cells positive for CD31 (vascularity) and Ki67 (proliferation). Major findings of this study included that mice in the combined therapy group, RT + sunitinib, lost significantly more weight than sunitinib alone (p < 0.0001) or RT alone (p = 0.0258). Mice in the RT alone group had a significant increase in GI vascular density, as determined by CD31, when compared to the SUN group (p = 0.0252). The mice in the RT + sunitinib group did not mount the same GI vascular response as the RT treated mice. The RT + sunitinib group had more crypt abscessation when compared to groups not receiving RT (vs. Control, p = 0.0076; vs. sunitinib alone, p = 0.0023). And, while it did not reach statistical significance when compared to the RT alone group, the RT + sunitinib group had more abscessation than RT alone (p = 0.0862) which could indicate a trend of higher levels of crypt abscessation with this combined treatment modality. The results from our canine retrospective clinical study and the preclinical mouse model experiment suggest that abdominal RT + TKI increases morbidity and GI toxicity at the RT and TKI doses investigated. Continued investigation of the underlying normal tissue effects associated with concurrent TKI and abdominal RT are recommended in order to determine whether combining these therapies could be optimized for safety and efficacy, such that GI toxicity is minimalized while achieving optimal tumor control.
Includes bibliographical references.
Includes bibliographical references.