Nt [84]. Preclinical data show an inhibition of vascular growth when combining everolimus with radiation, however a direct radio-sensitizing effect could not be consistently shown [85,86]. A recent study [87]Data on available studies combining radiotherapy and lenalidomide or thalidomide GSK343MedChemExpress GSK343 treatment are shown in Table 4. Thalidomide was initially used and approved as sedative drug until the early 1960s when it became clear that the intake of “Contergan” during pregnancy could lead to severe deformities. It was only in the late 1990s that thalidomide was rediscovered for its anti-angiogenic properties in cancer therapy [89]. Thalidomide is clinically used in the treatment of multiple myeloma; other areas of possible clinical use and ongoing clinical trials include leprosy, erythema nodosum leprosum and myelodysplastic syndrome. The most common side effects of thalidomide-besides somnolence-are thromboembolic events as well as peripheral polyneuropathy. In vitro studies with cells of squamous cell carcinoma and of multiple myeloma showed no evidence for any radio-sensitizing quality of thalidomide. However, a radio-sensitizing effect has been observed in normal hematopoietic bone marrow [90]. Experiments in mice showed thalidomide induced tumour re-oxygenation pointing to a possible radio-sensitizing effect in vivo [91]. Experiments in rats indicate that thalidomide might be protective against radiation-induced proctitis when given 7 days after a single-RT [92]. In humans, thalidomide has been tested in combination with radiotherapy in phase I-III studies. Most data exist for radiation of the CNS combined with the administration of thalidomide. The largest study so far was conducted by Knisely and co-workers [93]. In this phase III study 183 patients with multiple cerebral metastases were randomized for palliative WBRT (37,5 Gy in 15 fx) vs. WBRT (sameNiyazi et al. Radiation Oncology 2011, 6:177 http://www.ro-journal.com/content/6/1/Page 9 ofTable 3 Studies on small molecules.Substance PubMed ID:https://www.ncbi.nlm.nih.gov/pubmed/28914615 Author(s) Sunitinib Chi et al. [153] St ler et al. [154] Year Study type 2010 Phase II N tumour RT dose/ChTx/technique 52.5 (15 Fx) IMRT/3D-CT Toxicity 9 grade III upper GI bleeding, 4 hepatitis grade III/4 grade III pancreatitis, 26 grade III + IV thrombopenia, 4 grade III leukopenia 5 grade IV hypertension, 14 grade III + IV nausea 62 grade III + IV lymphopenia, 19 grade III neutropenia, 14 grade III + IV thrombopenia, 5 grade III rectal bleeding 23 HCC2010 Prospective, nonrandomized22 RCC (all sites)Median 40 Gy (median 8 Fx)Kao et al. [80] 2009 Phase I21 Oligometastases 40-50 Gy (10 Fx)Hui et al. [155] sorafenib lapatinib Peters et al. [77]2010 Phase II 2008 Case study13 Nasopharyngeal carcinoma 1 RCCSunitinib after RT (60-70 Gy) 15 fatal hemorrhages, 31 Grade IV and multiple Chx hemorrhages, (among other toxicities) 8 Gy single dose 66-70 Gy + CisPt Grade V bowel perforation (stopped two days before, three days later recommenced) 35 grade III mucositis, 19 grade III dermatitis, 13 grade III + IV lymphopenia, 6 grade III neutropenia 29 grade III + IV neutropenia, 86 grade III + IV mucositis, 33 grade III + IV dermatitis, 3 grade V infections, 17 grade III + IV infections, 4 grade III rash, 3 grade III neurotoxicity Grade III+IV: lymphopenia (21 ), neutropenia (2 ), GI (12 ), infection (7 ), n, pulmonary (5 ), renal, skin (2 ), metabolic (2 ), intratumoral hemorrhage: 7 . 20 grade III + IV GI toxicity, 15 grade III + IV skin toxic.
