Enhanced toxicity to chemoradiation in a patient with Anti-Jo-1-antisynthetase syndrome

Appropriate counseling of patients with autoimmune connective tissue disorders (ACTDs) is often challenging for radiation oncologists, especially regarding anticipated side-effects of radiation treatment. These patients can have highly variable and unpredictable sequelae from radiation therapy, and the uncertainty builds when radiation is convoluted by the addition of concurrent chemotherapy. While many patients may experience a mild intensification of toxicity above what is expected, some patients experience much more severe toxicity. These patients become critical learning cases, enabling a better understanding of the delicate and complex ways in which radiation response is altered in the context of ACTDs while allowing other patients with similar ACTD profiles to benefit from past experience. Our report makes an important contribution to this space by describing a particularly severe case of toxicity that manifested in such a patient and the ensuing clinical decision-making. Comprehensive genotyping of classic pharmacokinetic and pharmacodynamic pathway genes (including mutations in DPD and CDA) did not reveal any signatures that might explain her enhanced toxicity and we demonstrate that severe toxicity can still manifest in the era of modern conformal radiation treatments for rectal cancer. We urge caution in the treatment of patients with rare ACTDs, but also emphasize that curative treatment should not be withheld in such patients. We conclude by advocating for the development and maintenance of a prospective multiinstitutional database of patients with ACTDs to help inform and improve future practice.