Cancer Studies and Molecular Medicine

Open journal

ISSN 2377-1518

Dosimetric Characterization of an Abscopal Response in a Patient With Oligometastatic Melanoma Undergoing Concurrent Treatment With Pembrolizumab and Stereotactic Body Radiotherapy (SBRT)

Jennifer Sims-Mourtada*, Serguei Casteneda, David Huang, John McGlade, Sunjay Shah, Lindsay Romak, Adam Raben and Firas Mourtada

Jennifer Sims-Mourtada, PhD

Senior Clinical Scientist, Center for Translational Cancer Research, Helen F. Graham Cancer Center, Christiana Care Health Services, Newark, DE, USA; E-mail:


Stereotactic Body Radiotherapy (SBRT) is a sophisticated form of radiation that allows high dose, conformal radiation delivery to solid tumors. In addition to providing local control, reports of abscopal (or out-of-field) effects indicate a possible systemic effect of SBRT.1,2 Although, clinical reports of abscopal immune responses induced by SBRT are relatively rare,2 recent advances in immunotherapy and the potential benefits of the combination of immunotherapy and SBRT have driven interest in radiationinduced anti-tumor immune responses. Several clinical studies are currently underway to determine the effects of combined radiationand check-point inhibition.3 Although, results of clinical trials combining PD-1 inhibition and radiation are still forthcoming, clinical reports demonstrate that combination radio-immunotherapy may yield therapeutic advantage.4,5 While reports suggest that hypofractionated regimens used in SBRT may induce superior immune priming, the optimal dose, and fractionation regimens are still to be determined.


Patient History and Treatment

Here we report a dosimetric characterization of a possible abscopal response in a 57-year-old female with oligometastatic melanoma. Patient data was obtained during a retrospective chart review under a protocol approved by the Institutional Review Board (IRB) of Christiana Care Health Services, Inc., Newark, DE, USA. Previously, the patient received intensity modulated radiation therapy treatment in the management of her metastatic melanoma to the left orbit. She underwent surgical resection followed by post-operative radiation therapy to the orbit. She completed a dose of 375 Gy in 15 fractions at 25 Gy per fraction. She was also diagnosed at that time with right lateral temporal metastasis and underwent radiosurgery. The patient received a dose of 20 Gy to the single right temporal metastasis. The patient was placed on maintenance pembrolizumab with good response but had a single-site progression one year later evidenced by increase in size to a right lower lobe centrally located oligo-metastasis for which she received palliative CyberKnife® (AccurayInc, Sunnyvale, CA, USA) SBRT. She received a dose of 50 Gy in 5 fractions prescribed to the 74% isodose line, determined using a Monte Carlo dose calculation (Figure 1). At this time, the patient also presented with a rapidly enlarging palpable right supraclavicallymph node which demonstrated asymmetry with focal hypermetabolic activity on positron emission tomography/computed tomography (PET/CT).

Figure 1. Lung Cyberknife case (50 Gy in 5 fractions) with suboptimal tumor coverage with (8 o’clock) clinical intent to spare the adjacent ribs to reduce risk of bone fracture. PTV: blue line


Patient Response

A partial response was noted, approximately 3 months after CyberKnife® treatment, in the irradiated lesion, identified decreased hypermetabolic activity and a 50% reduction in size by PET/CT. The patient also developed a systemic response in the previously enlarged cervical lymph node which was located out of the radiation field. The patient reported resolution of the palpable cervical lymph node shortly after radiation treatment. This node was no longer clinically palpable when the patient presented for staging three months after treatment. A radiological response was also noted. By PET/CT, there was no evidence of lymphadenopathy with the previously enlarged hypermetabolic lymph node now showing a reduction in size and no 18F fluorodeoxyglucose (FDG) activity.

Dosimetric Characterization

Upon review of the CyberKnife® SBRT plan dosimetric parameters, we realized that the dose of 50 Gy in 5 fractions is slightly lower than the standard dose for lung lesions of 55 Gy in 5 fractions. Additionally, the planning target volume (PTV) was atypically colder (89.9% of PTV covered by the 100% prescription dose) with the clinical intent to decrease chances of bone fracture in the ribs. There was also a relatively high value of gross tumor volume (GTV) and a homogeneity index (HI) of 1.35. HI, defined as max dose/prescribed dose, is a factor to indicate the degree of uniformity of dose within the target. These findings suggest that higher HI may be associated with enhanced immunologic effects of SBRT.


Meta-analysis of preclinical studies has shown that the probability of an abscopal immune response intensifies with increasing biological effective doses. Furthermore, preclinical studies have suggested that ablative or hypofractionated radiation is superior to conventional fractionation schemes for release of immunostimulatory cytokines such as interferon gamma, upregulation of MHC and the activation of effector CD8+ T-cells.8,9,10,11,12,13 However, hypofractionated regimens may also have immunosuppressive effects. Hydrofluoric acid (HF) induces severe damage to vasculature and is associated with increased hypoxia. Hypoxia not only decreases the biological effects of radiation, but may also promote immunosuppression through alterations of cytokine gradients, recruitment of tumor-associated macrophages (TAMS) and increased functions of Tregs.14,15,16 Likewise, radiation has been shown to induce changes in macrophage polarity. While conventional fractionation regimens have been shown to promote anti-tumor M1 macrophage polarity, HF may result in immunosuppressive M2 differentiation.15,17,18 Additionally, there is concern that high doses used in HF may have a detrimental effect on existing or infiltrating T-cells as a reduction in TILs has been observed following single doses higher than 7-10 Gy.16,19,20,21,22 Thus, although SBRT may promote enhanced CD8+ T-cell responses, efficacy may be diminished by the death of infiltrating lymphocytes and other microenvironmental changes that increase immunosuppression. In contrast, conventional doses of ≤2 Gy per fraction may preserve endogenous and infiltrating tumor reactive T-cells. While conventional fractionation schedules may overcome some of the drawbacks of HF, doses may not be high enough to induce a robust immuneresponse.

Although, current planning objectives strive for PTV coverage over 95% of the dose prescription with HI <1.2, this case study suggests that abscopal effects may be enhanced in patients treated SBRT with sub-optimal PTV dose coverage and undergoing concurrent immunotherapy. The inherent high dose gradient of CyberKnife® beam profile (due to the steep dose gradient from beam center to edge) might be an important contributing factor to the possible response observed here and may contribute to the advantage of CyberKnife® SBRT over standard radiation therapy in combination with immunotherapy. The effects of dose heterogeneity on biological attributes such as hypoxia and the immune response are unknown. Moreover, the optimal dose and fractionation schedule for synergistic effects of CyberKnife® with immunotherapy are not yet well-defined. In our case, it is unclear if the slight decrease in dose (50 Gy vs. 55 Gy) had an impact on immunological response patterns. However, the lower dose combined with supoptimal tumor coverage may have helped limit hypoxia and promote immune responses leading to an abscobal effect in this case. Further investigation on the impact of heterogeneous dose delivery on activation of anti-tumor immune responses is needed. Dosimetric characterization of radiotherapy may help to provide information about optimal radiation doses for interactions with immunotherapeutics.


The authors report no conflicts of interest with this work.

1. Marconi R, Strolin S, Bossi G, Strigari L. A meta-analysis of the abscopal effect in preclinical models: Is the biologically effective dose a relevant physical trigger? PLoS One. 2017; 12(2): e0171559. doi: 10.1371/journal.pone.0171559

2. Reynders K, Illidge T, Siva S, Chang JY, De Ruysscher D. The abscopal effect of local radiotherapy: Using immunotherapy to make a rare event clinically relevant. Cancer Treat Rev. 2015; 41(6): 503-510. doi: 10.1016/j.ctrv.2015.03.011

3. Crittenden M, Kohrt H, Levy R, et al. Current clinical trials testing combinations of immunotherapy and radiation. Semin Radiat Oncol. 2015; 25(1): 54-64. doi: 10.1016/j.semradonc.2014.07.003

4. Sharabi A, Kim SS, Kato S, et al. Exceptional response to nivolumab and stereotactic body radiation therapy (SBRT) in neuroendocrine cervical carcinoma with high tumor mutational burden: Management considerations from the center for personalized cancer therapy at UC San Diego Moores Cancer Center. Oncologist. 2017; 22(6): 631-637. doi: 10.1634/theoncologist.2016-0517

5. Haymaker CL, Kim D, Uemura M, et al. Metastatic melanoma patient had a complete response with clonal expansion after whole brain radiation and PD-1 blockade. Cancer Immunol Res. 2017; 5(2): 100-105. doi: 10.1158/2326-6066.CIR-16-0223

6. Dewan MZ, Galloway AE, Kawashima N, et al. Fractionated but not single-dose radiotherapy induces an immune-mediated abscopal effect when combined with anti-CTLA-4 antibody. Clin Cancer Res. 2009; 15(17): 5379-5388. doi: 10.1158/1078-0432.CCR09-0265

7. Lugade AA, Moran JP, Gerber SA, Rose RC, Frelinger JG, Lord EM. Local radiation therapy of B16 melanoma tumors increases the generation of tumor antigen-specific effector cells that traffic to the tumor. J Immunol. 2005; 174(12): 7516-7523. doi: 10.4049/ jimmunol.174.12.7516

8. Lee Y, Auh SL, Wang Y, et al. Therapeutic effects of ablative radiation on local tumor require CD8+ T cells: Changing strategies for cancer treatment. Blood. 2009; 114(3): 589-595. doi: 10.1182/ blood-2009-02-206870

9. Klein B, Loven D, Lurie H, et al. The effect of irradiation on expression of HLA class I antigens in human brain tumors in culture. J Neurosurg. 1994; 80(6): 1074-1077. doi: 10.3171/jns.1994.80.6.1074

10. Santin AD, Hiserodt JC, Fruehauf J, DiSaia PJ, Pecorelli S, Granger GA. Effects of irradiation on the expression of surface antigens in human ovarian cancer. Gynecol Oncol. 1996; 60(3): 468- 474.doi: 10.1006/gyno.1996.0075

11. Santin AD, Hermonat PL, Hiserodt JC, et al. Effects of irradiation on the expression of major histocompatibility complex class I antigen and adhesion costimulation molecules ICAM-1 in human cervical cancer. Int J Radiat Oncol Biol Phys. 1997; 39(3): 737-742. doi: 10.1006/gyno.1996.0075

12. Ceradini DJ, Kulkarni AR, Callaghan MJ, et al. Progenitor cell trafficking is regulated by hypoxic gradients through HIF-1 induction of SDF-1. Nat Med. 2004; 10(8): 858-864. doi: 10.1038/ nm1075

13. Kioi M, Vogel H, Schultz G, Hoffman RM, Harsh GR, Brown JM. Inhibition of vasculogenesis, but not angiogenesis, prevents the recurrence of glioblastoma after irradiation in mice. J Clin Invest. 2010; 120(3): 694-705. doi: 10.1172/JCI40283

14. Westendorf AM, Skibbe K, Adamczyk A, et al. Hypoxia enhances immunosuppression by inhibiting CD4+ effector T cell function and promoting treg activity. Cell Physiol Biochem. 2017; 41(4): 1271-1284. doi: 10.1159/000464429

15. Prakash H, Klug F, Nadella V, Mazumdar V, Schmitz-Winnenthal H, Umansky L. Low doses of gamma irradiation potentially modifies immunosuppressive tumor microenvironment by retuning tumor-associated macrophages: Lesson from insulinoma. Carcinogenesis. 2016; 37(3): 301-313. doi: 10.1093/carcin/bgw007

16. Klug F, Prakash H, Huber PE, et al. Low-dose irradiation programs macrophage differentiation to an iNOS(+)/M1 phenotype that orchestrates effective T cell immunotherapy. Cancer Cell. 2013; 24(5): 589-602. doi: 10.1016/j.ccr.2013.09.014

17. Dovedi SJ, Cheadle EJ, Popple A, et al. Fractionated radiation therapy stimulates anti-tumor immunity mediated by both resident and infiltrating polyclonal T-cell populations when combined with PD1 blockade. Clin Cancer Res. 2017; 23(18): 5514-5526. doi: 10.1158/1078-0432.CCR-16-1673

18. Schaue D, Ratikan JA, Iwamoto KS, McBride WH. Maximizing tumor immunity with fractionated radiation. Int J Radiat Oncol Biol Phys. 2012; 83(4): 1306-1310. doi: 10.1016/j.ijrobp.2011.09.049

19. Qu Y, Jin S, Zhang A, et al. Gamma-ray resistance of regulatory CD4+CD25+Foxp3+ T cells in mice. Radiat Res. 2010; 173(2): 148-157. doi: 10.1667/RR0978.1

20. Schaue D, Ratikan JA, Iwamoto KS, McBride WH. Maximizing tumor immunity with fractionated radiation. Int J Radiat Oncol Biol Phys. 83(4): 1306-1310. doi: 10.1016/j.ijrobp.2011.09.049

21. Greenberg RA. Complex responses to DNA damage. Paper presented at: Epigenetics in Cancer; April 25, 2017; Philadelphia, PA, USA: The Wistar Institute.

22. Dovedi SJ, Cheadle EJ, Popple A, et al. Fractionated radiation therapy stimulates anti-tumor immunity mediated by both resident and infiltrating polyclonal T-cell populations when combined with PD1 blockade. Clin Cancer Res. 2017; 23(18): 5514-5526. doi: 10.1158/1078-0432.CCR-16-1673


Practical Pointers for Drug Development and Medical Affairs

Gerald L. Klein*, Roger E. Morgan, Shabnam Vaezzadeh, Burak Pakkal and Pavle Vukojevic



Prevalence and Risk Factors of Subclinical Mastitis of Goats in Banadir Region, Somalia

Omar M. Salah*, Yasin H. Sh-Hassan, Moktar O. S. Mohamed, Mohamed A. Yusuf and Abas S. A. Jimale


Use of Black Soldier Fly (Hermetia illucens) Prepupae Reared on Organic Waste

Maggot Debridement Therapy: A Natural Solution for Wound Healing

Isayas A. Kebede*, Haben F. Gebremeskel and Gelan D. Dahesa,


Figure 11. Risk Map for the Introduction of Ruminant Diseases at Borders

Ovine Network in Morocco: Epizootics Spread Prevention and Identification of the At-Risk Areas for “Peste des Petits Ruminants” and “Foot and Mouth Disease”

Yassir Lezaar*, Mehdi Boumalik, Youssef Lhor, Moha El-Ayachi, Abelilah Araba and Mohammed Bouslikhane



The Impact of Family Dynamics on Palliative Care at the End-of-Life

Neil A. Nijhawan*, Rasha Mustafa and Aqeela Sheikh


Long-Term Follow-Up After Laparoscopic Radical Prostatectomy for Localized and Locally Advanced Prostate Cancer

Shrenik J. Shah*, Abhishek Jha, Chirag Davara, Rushi Mistry and Kapil Kachhadiya




Pie Chart Showing Overall Proportions of Diagnostic Category of FNAC, JUMC

Retrospective Study

2024 Apr

Abel Tefera*, Lemlem Terefe and Kitesa Biresa
Prevalence (%) of Types of Anthropometric Failure among Previous and Present Studied Tribal Children

Original Research, peer reviewed

2024 Apr

Biswajit Mahapatra and Kaushik Bose*


2024 Apr

Gerald L. Klein*, Roger E. Morgan, Shabnam Vaezzadeh, Burak Pakkal and Pavle Vukojevic