Total recall of radiotherapy with mTOR inhibitors: a novel and potentially frequent side-effect?
Authors: C. Bourgier, C. Massard, C. Moldovan, J.-C. Soria, E. Deutsch
Journal: Annals of Oncology (2011)

Radiation recall syndrome (RRS) characterized by an inflammatory reaction within a previously irradiated volume has been reported after chemotherapy administration, few reports being made after administration of cetuximab and bevacizumab [1.Law A.B. Junor E.J. Chemotherapy-induced recall of cetuximab and radiation skin reaction.Clin Oncol (R Coll Radiol). 2009; 21: 77-78Abstract Full Text Full Text PDF PubMed Scopus (8) Google Scholar, 2.Azria D. Magne N. Zouhair A. et al.Radiation recall: a well recognized but neglected phenomenon.Cancer Treat Rev. 2005; 31: 555-570Abstract Full Text Full Text PDF PubMed Scopus (154) Google Scholar]. Here, we report RRS occurring during mTOR (mammalian target of rapamycin) kinase inhibitors administration. Known common toxic effects of these targeted therapies are rash, stomatitis, fatigue, and metabolic disorders. A 67-year-old woman had previously been treated for negative hormonal receptors and Her2-overexpressing left breast cancer by primary anthracycline-based chemotherapy, surgery, and adjuvant radiotherapy. Irradiation targeted the whole breast followed by a boost to the tumor bed [total dose (TD) = 45 + 15 Gy/29 fractions] and the internal mammary chain (TD = 45 Gy/20 fractions) in December 2004. Then, owing to liver metastases, the patient had received several metastatic chemotherapy regimens (docetaxel, trastuzumab, vinorelbine, capecitabine) and a palliative irradiation to bone metastases from the 12th dorsal vertebra to the 3rd lumbar vertebra (TD = 30 Gy/10 fractions) in January 2008. Paclitaxel, trastuzumab, and everolimus (10 mg daily) combination was initiated for metastatic progression in March 2008. Sixteen weeks after the initiation of everolimus, grade 3 gastric hemorrhage and grade 2 anemia occurred. Comparison of endoscopic findings and radiotherapy portals were consistent with 'in-radiation-field' mucosal reaction as well as gastritis histological characteristics (gastric inflammation, ulcers; Figure 1). A 66-year-old man had a history of prostate cancer treated by exclusive radiotherapy (TD = 70 Gy/35 fractions) in December 2006. Fourteen months after radiotherapy completion, the patient developed a liver-metastatic pancreatic cancer and was treated by gemcitabine–erlotinib and then by a pan-Her inhibitor—humanized anti-insulin-like growth factor-I receptor monoclonal antibody. In February 2010, a phase I trial was initiated for metastatic progression, which combined a pan-Her inhibitor with temsirolimus (15 mg weekly). Two weeks after the start of experimental treatment, the patient presented with grade 2 colitis, grade 3 bladder stenosis, and grade 3 thrombocytopenia (Figure 2). Lower rectal telangiectasia and chronic ulceration of the anterior anorectal junction were observed on rectosigmoidoscopy. Obstructed bladder was also noticed at cystoscopy. Review of radiotherapy portals confirmed that the lesions were within the irradiated area. A 53-year-old woman with repetitive locoregional relapse history of ovary carcinoma was enrolled in a trial assessing a pan-Her inhibitor and temsirolimus combination in February 2010. She was previously treated with pelvic surgery, multiple lines of chemotherapy (paclitaxel–carboplatin, oxaliplatin–bevacizumab, Caelyx, gemcitabine), and pelvic radiotherapy in September 2007 (TD = 45 + 15 Gy/31 fractions, delivered to the rectal wall and tumor bed for pelvic relapse). Four weeks after the start of temsirolimus (75 mg weekly), she presented with a subocclusive syndrome associated with grade 2 colitis. Thickening of right colonic wall without any sign of peritoneal carcinosis was observed on the computed tomography scan (Figure 3). All patient conditions improved as the treatment was stopped. These three overreaction cases of normal tissue after exposure to mTOR kinase inhibitors within pre-irradiated areas occurring months after radiotherapy are highly suggestive of RRS. In this setting, careful and long-term examination of all side-effects may yield higher-than-anticipated RRS rates [3.Lordick F. Geinitz H. Theisen J. et al.Increased risk of ischemic bowel complications during treatment with bevacizumab after pelvic irradiation: report of three cases.Int J Radiat Oncol Biol Phys. 2006; 64: 1295-1298Abstract Full Text Full Text PDF PubMed Scopus (119) Google Scholar, 4.Peters N.A. Richel D.J. Verhoeff J.J. Stalpers L.J. Bowel perforation after radiotherapy in a patient receiving sorafenib.J Clin Oncol. 2008; 26: 2405-2406Crossref PubMed Scopus (78) Google Scholar]. J-CS has received honoraria from Wyeth.