Lung cancer is a focus of radioimmunotherapy research and development. There are currently at least 8 phase 1 and phase 2 clinical trials evaluating radiotherapy or chemoradiation plus a PD-1/PD-L1 immune checkpoint blockade agent, pembrolizumab or nivolumab, in patients with NSCLC.12
Educating patients about the possible risks and toxic symptoms associated with radioimmunotherapy regimens will fall largely to oncology nurses, as will monitoring patients against the emergence of adverse events, which in some cases must be detected and managed quickly to avoid potentially life-threatening events.
A 2017 systematic review of data from 49 clinical studies of concurrent stereotactic radiotherapy (SRT) and targeted therapies or immunotherapies, including 8 retrospective studies and case reports of ipilimumab radioimmunotherapy, found that the available evidence base suggests these treatments are well tolerated when deployed against brain metastases.4 However, it should be emphasized that most of the studies in this review described results for patients with brain metastases.4 The 6 retrospective studies of SRT plus concurrent CTLA-4 checkpoint blockade with ipilimumab in patients with melanoma brain metastases found that at median doses ranging from 14 to 60 Gy in 1 to 5 radiation fractions, SRT plus ipilimumab did not increase toxicity risks over ipilimumab immunotherapy alone.4 Grade 3 toxicities included pruritus, hepatitis, diarrhea, pyrexia, nausea, fatigue, anorexia, skin reactions, endocrine reactions, and GI toxicities; one patient suffered grade 4 cardiopulmonary toxicity.4 Among reported toxicities were also grade 3 seizures and CNS hemorrhages attributable to SRT itself, rather than the combined radioimmunotherapy.4
Less is currently known about PD-1/PD-L1 immune checkpoint blockade plus radiotherapy, although several clinical trials are now under way.4,10,12 Studies representing 27 patients receiving nivolumab plus SRT reported 2 cases of grade 3 cerebral edema and 1 case of grade 4 cerebral edema.4 As mentioned above, there are at least 8 phase 1 and 2 clinical trials under way for PD-1/PD-L1-blockade radioimmunotherapy in patients with NSCLC.12 Findings from those studies, once reported, should cast much-needed new light on toxicity risks.
The authors of the 2017 systematic review cautioned that even as concurrent SRT immunotherapy and targeted therapies become more widely used, little is yet known about the safety profiles of these combination regimens.4 They called for prospective registry databases to standardize and improve reporting of toxicities. 4
1. Demaria S, Coleman CN, Formenti SC. Radiotherapy: changing the game in immunotherapy. Trends Cancer. 2016;2(6):286-294.
2. Van Limbergen EJ, De Ruysscher DK, Olivo Pimentel V, et al. Combining radiotherapy with immunotherapy: the past, the present and the future. Br J Radiol. 2017;90(1076):20170157.
3. Chajon E, Castelli J, Marsiglia H, De Crevoisier R. The synergistic effect of radiotherapy and immunotherapy: a promising but not simple partnership. Crit Rev Oncol Hematol. 2017;111:124-132.
4. Kroeze SG, Fritz C, Hoyer M, et al. Toxicity of concurrent stereotactic radiotherapy and targeted therapy or immunotherapy: a systematic review. Cancer Treat Rev. 2017;53:25-37.
5. Weichselbaum RR, Liang H, Deng L, Fu YX. Radiotherapy and immunotherapy: a beneficial liaison? Nat Rev Clin Oncol. 2017;14(6):365-379.
6. Janiak MK, Wincenciak M, Cheda A, Nowosielska EM, Calabrese EJ. Cancer immunotherapy: how low-level ionizing radiation can play a key role. Cancer Immunol Immunother. 2017;66(7):819-832.
7. Martin D, Rödel F, Balermpas P, Rödel C, Fokas E. The immune microenvironment and HPV in anal cancer: rationale to complement chemoradiation with immunotherapy. Biochim Biophys Acta. 2017;1868(1):221-230.
8. Postow MA, Callahan MK, Barker CA, et al. Immunologic correlates of the abscopal effect in a patient with melanoma. N Engl J Med. 2012;366(10):925-931.
9. Hiniker SM, Chen DS, Reddy S, et al. A systemic complete response of metastatic melanoma to local radiation and immunotherapy. Transl Oncol. 2012;5(6):404-407.
10. Marcrom S, De Los Santos JF, Conry RM. Complete response of mediastinal clear cell sarcoma to pembrolizumab with radiotherapy. Clin Sarcoma Res. 2017;7:14.
11. Seung SK, Curti B, Crittenden M, et al. Phase 1 study of stereotactic body radiotherapy and interleukin-2–tumor and immunological responses. Sci Transl Med. 2012;4(137):137ra74.
12. Hanna GG, Illidge T. Radiotherapy and immunotherapy combinations in non-small cell lung cancer: a promising future? Clin Oncol. 2016;28(11):726-731.
13. Baues C, Trommer-Nestler M, Jablonska K, et al. Short review of potential synergies of immune checkpoint inhibition and radiotherapy with a focus on Hodgkin lymphoma: radio-immunotherapy opens new doors. Immunotherapy. 2017;9(5):434-433.
14. Ahmed KA, Grass GD, Creeland B, et al. Tolerability and safety of thoracic radiation and immune checkpoint inhibitors among patients with lung cancer. Paper presented at: 2017 Multidisciplinary Thoracic Cancers Symposium; March 16-18, 2017; San Francisco, CA.
15. Hanna GG, Coyle VM, Prise KM. Immune modulation in advanced radiotherapies: targeting out-of-field effects. Cancer Lett. 2015;368(2):246-251.
16. Dovedi SJ, Adlard AL, Lipowska-Bhalla G, et al. Acquired resistance to fractionated radiotherapy can be overcome by concurrent PD-L1 blockade. Cancer Res. 2014;74(19):5458-5468.
17. Green M, Feng FY, Mehra R, Spratt DE. Convergence of immunotherapy, radiotherapy and prostate cancer: challenges and opportunities [published online August 3, 2017]. Future Med. doi: 10.2217/imt-2017-0059
18. Franceschini D, Franzese C, Navarria P, et al. Radiotherapy and immunotherapy: can this combination change the prognosis of patients with melanoma brain metastases? Cancer Treat Rev. 2016;50:1-8.
19. Reznik E, Smith AW, Taube S, et al. Radiation and immunotherapy in high-grade gliomas: where do we stand? [published online September 12, 2017]. Am J Clin Oncol. doi: 10.1097/COC.0000000000000406
20. Hiniker SM, Reddy SA, Maecker HT, et al. A prospective clinical trial combining radiation therapy with systemic immunotherapy in metastatic melanoma. Int J Radiat Oncol Biol Phys. 2016;96(3):578-588.
21. Herskind C, Wenz F, Giordano FA. Immunotherapy combined with large fractions of radiotherapy: stereotactic radiosurgery for brain metastases — implications for intraoperative radiotherapy after resection. Front Oncol. 2017;7:147.