During residency through 2003, I learned about the historical role of radiation treating the spleen on the lymphoma service, including use of low-dose radiation as palliative treatment with potential significant toxicity (1). But when treating gastrointestinal malignancies, there was no research at the time indicating concern about the potential effects of splenic irradiation. As radiation therapy has evolved over the past two decades, our ability to accurately shape high dose radiation fields has improved substantially.
In the era of intensity modulated radiation therapy (IMRT) and stereotactic body radiotherapy (SBRT), we have mostly ignored the spleen until recently. The time has come to contour it, so that treatment planning systems include splenic dose in plan optimization because of its potential to help or harm our patients.
Spleen as Innocent Bystander
As IMRT use increased, the question became meaningful enough that I reviewed a small number of patients receiving abdominal radiation at my hospital 2007-8 and found a Dmean of 19 Gy and V20Gy of 82% for distal esophageal cancer patients (2). We didn't have enough patients to look at clinical outcomes but that seemed like a meaningful dose particularly for immune cells and spleen function. Reviewing the literature, I learned that Drs. C. Norman Coleman and Henry Kaplan identified splenic atrophy with radiation therapy in 1980 (3), subsequently demonstrating organ injury and a risk of sepsis (4, 5). There are well-documented risks of sepsis after splenectomy (6), and I didn't want the radiation to contribute to that risk. Since 2011, I have recommended pneumococcal vaccinations for my patients with upper abdominal malignancies before receiving chemoradiation on first principles, initially in the absence of any good data. Recent research confirms an association with higher splenic doses and risk of infection in pediatric cancer survivors that only increases with time, suggesting immunization has value (7).
Over the past decade, QUANTEC provided no guidance at all (8). RTOG consensus contouring guidelines show it in the figures but don't mention any detail (9). If the physician or dosimetrist doesn't contour and place constraints on the spleen, treatment planning system software will consider the spleen a safe part of the body to push dose to avoid other important intra-abdominal organs.
Now, there are increasing data emerging suggesting that we should care about potential negative effects of splenic radiation with solid malignancies. In gastric cancer, a small study showed chemoradiation had a splenic Dmean of 40 Gy with mean 37% volume loss and a high risk of pneumonia (10). For esophageal cancer chemoradiation, higher spleen dose is associated with a higher risk of lymphopenia in one study and lower toxicity in another (11, 12). Distal esophageal cancers and larger irradiated volumes are more likely to have severe lymphopenia, suggesting lower dose to normal tissue may matter (13, 14). Lymphopenia is also associated with lower survival (13). Similar data are emerging in pancreatic cancer chemoradiation (15–18), with lower rates of lymphopenia using stereotactic body techniques (19, 20). Splenic dose may also be clinically relevant in hepatoma (21).
Lung cancer research has mostly ignored potential splenic radiation toxicity. One study suggests decreased spleen volume with chemoradiation for non-small cell lung cancer but did not look at spleen dose or location of the primary tumor (22). Some interest in bone marrow toxicity has focused upon the vertebral bodies without evaluating splenic dose (23, 24). Cardiac dose and lung also has been associated with hematologic toxicity but did not assess the spleen or primary tumor location (25, 26). It is possible that the association of lymphopenia with higher cardiac dose occurs in left lower lobe primary tumors, where the spleen may also receive higher doses. Without including the spleen in treatment planning, any potential detrimental effects for lung cancer patients will remain unknown.
A Role in Cancer Control?
The spleen also may play an important role in effective cancer treatment, especially in the immunotherapy era (27). Treatment-related lymphopenia is associated with worse disease progression and survival in esophageal, pancreatic, and lung cancer (13, 16, 28–30). The spleen is an important source of tumor-associated macrophages and neutrophils (31), which may contribute to tumor progression and death via decreased immune surveillance or pro-inflammatory stimulation for tumor growth (32–37). Radiation can also induce regulatory T cells (38), which may alter peripheral blood immunophenotype in a tissue-specific fashion (39).
Based upon the currently published literature, I can't predict what low doses of splenic radiation may do to worsen or improve cancer control. But it seems the spleen deserves more attention if it could help lessen treatment toxicity and may factor into efficacy.
Our treatment planning systems will not consider the spleen of any clinical value unless we do. The time has come to seriously evaluate splenic dose in solid malignancies. We have ample opportunity for more retrospective and prospective studies so we can learn how to better address the immunologic health of our patients receiving radiation therapy.
Statements
Author contributions
The author confirms being the sole contributor of this work and has approved it for publication.
Conflict of interest
The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
References
1.
WeinmannMBeckerGEinseleHBambergM. Clinical indications and biological mechanisms of splenic irradiation in chronic leukaemias and myeloproliferative disorders. Radiother Oncol. (2001) 58:235–46. 10.1016/S0167-81400000316-9
2.
KatzMMcKeeABMacDonaldBASiroisLGagneFMKnabBR. Splenic Dose With Abdominal Radiation Therapy: A Quantitative Dosimetric Study. (2011). Slideshare.com. Available online at: https://www.slideshare.net/subatomicdoc/splenic-dose-with-abdominal-radiation-therapy
3.
DaileyMOColemanCNKaplanHS. Radiation-induced splenic atrophy in patients with Hodgkin's disease and non-Hodgkin's lymphomas. N Engl J Med. (1980) 302:215–7. 10.1056/NEJM198001243020406
4.
DaileyMOColemanCNFajardoLF. Splenic injury caused by therapeutic radiation. Am J Surg Pathol. (1981) 5:325–31. 10.1097/00000478-198106000-00002
5.
ColemanCNMcDougallIRDaileyMOAgerPBushSKaplanHS. Functional hyposplenia after splenic irradiation for Hodgkin's disease. Ann Intern Med. (1982) 96:44–7. 10.7326/0003-4819-96-1-44
6.
RamSLewisLARicePA. Infections of people with complement deficiencies and patients who have undergone splenectomy. Clin Microbiol Rev. (2010) 23:740–80. 10.1128/CMR.00048-09
7.
WeilBRMadenciALLiuQHowellRMGibsonTMYasuiYet al. Late infection-related mortality in asplenic survivors of childhood cancer: a report from the Childhood Cancer Survivor Study. J Clin Oncol. (2018) 36:1571–8. 10.1200/JCO.2017.76.1643
8.
MarksLBTen HakenRKMartelMK. Guest editor's introduction to QUANTEC: a user's guide. Int J Radiat Oncol Biol Phys. (2010) 76(3 Suppl.):S1–2. 10.1016/j.ijrobp.2009.08.075
9.
TripAKSikorskaKvan SandickJWHeegMCatsABootHet al. Radiation-induced dose-dependent changes of the spleen following postoperative chemoradiotherapy for gastric cancer. Radiother Oncol. (2015) 116:239–44. 10.1016/j.radonc.2015.07.036
10.
JabbourSKHashemSABoschWKimTKFinkelsteinSEAndersonBMet al. Upper abdominal normal organ contouring guidelines and atlas: a Radiation Therapy Oncology Group consensus. Pract Radiat Oncol. (2014) 4:82–9. 10.1016/j.prro.2013.06.004
11.
SaitoTToyaRYoshidaNShonoTMatsuyamaTNinomuraSet al. Spleen dose-volume parameters as a predictor of treatment-related lymphopenia during definitive chemoradiotherapy for esophageal cancer. In Vivo. (2018) 32:1519–25. 10.21873/invivo.11409
12.
ChinALAggarwalSPradhanPBushKvon EybenRKoongACet al. The role of bone marrow and spleen irradiation in the development of acute hematologic toxicity during chemoradiation for esophageal cancer. Adv Radiat Oncol. (2018) 3:297–304. 10.1016/j.adro.2018.02.005
13.
van RossumPSNDengWRoutmanDMLiuAYXuCShiraishiYet al. Prediction of severe lymphopenia during chemoradiation therapy for esophageal cancer: development and validation of a pretreatment nomogram. Pract Radiat Oncol. (2019) 10:e16–26. 10.1016/j.prro.2019.07.010
14.
DavuluriRJiangWFangPXuCKomakiRGomezDRet al. Lymphocyte nadir and esophageal cancer survival outcomes after chemoradiation therapy. Int J Radiat Oncol Biol Phys. (2017) 99:128–35. 10.1016/j.ijrobp.2017.05.037
15.
ChadhaASLiuGChenHCDasPMinskyBDMahmoodUet al. Does unintentional splenic radiation predict outcomes after pancreatic cancer radiation therapy?Int J Radiat Oncol Biol Phys. (2017) 97:323–32. 10.1016/j.ijrobp.2016.10.046
16.
ZschaeckSBlümkeBWustPKaulDBahraMRiessHet al. Dose-escalated radiotherapy for unresectable or locally recurrent pancreatic cancer: dose volume analysis, toxicity and outcome of 28 patients. PLoS ONE. (2017) 12:e0186341. 10.1371/journal.pone.0186341
17.
BalmanoukianAYeXHermanJLaheruDGrossmanSA. The association between treatment-related lymphopenia and survival in newly diagnosed patients with resected adenocarcinoma of the pancreas. Cancer Invest. (2012) 30:571–6. 10.3109/07357907.2012.700987
18.
WildATYeXEllsworthSGSmithJANarangAKGargTet al. The association between chemoradiation–related lymphopenia and clinical outcomes in patients with locally advanced pancreatic adenocarcinoma. Am J Clin Oncol. (2015) 38:259–65. 10.1097/COC.0b013e3182940ff9
19.
WildATHermanJMDholakiaASMoningiSLuYRosatiLMet al. Lymphocyte-sparing effect of stereotactic body radiation therapy in patients with unresectable pancreatic cancer. Int J Radiat Oncol Biol Phys. (2016) 94:571–9. 10.1016/j.ijrobp.2015.11.026
20.
WuGBaineMJZhaoNLiSLiXLinC. Lymphocyte-sparing effect of stereotactic body radiation therapy compared to conventional fractionated radiation therapy in patients with locally advanced pancreatic cancer. BMC Cancer. (2019) 19:977. 10.1186/s12885-019-6220-1
21.
LiuJZhaoQDengWLuJXuXWangRet al. Radiation-related lymphopenia is associated with spleen irradiation dose during radiotherapy in patients with hepatocellular carcinoma. Radiat Oncol. (2017) 12:90. 10.1186/s13014-017-0824-x
22.
WenSWEverittSJBedoJChabrotMBallDLSolomonBet al. Spleen volume variation in patients with locally advanced non-small cell lung cancer receiving platinum-based chemo-radiotherapy. PLoS ONE. (2015) 10:e142608. 10.1371/journal.pone.0142608
23.
DeekMPBenenatiBKimSChenTAhmedIZouWet al. Thoracic vertebral body irradiation contributes to acute hematologic toxicity during chemoradiation therapy for non-small cell lung cancer. Int J Radiat Oncol Biol Phys. (2016) 94:147–54. 10.1016/j.ijrobp.2015.09.022
24.
BarneyCLScovilleNAllanEAyanADiCostanzoDHaglundKEet al. Radiation dose to the thoracic vertebral bodies is associated with acute hematologic toxicities in patients receiving concurrent chemoradiation for lung cancer: results of a single-center retrospective analysis. Int J Radiat Oncol Biol Phys. (2018) 100:748–55. 10.1016/j.ijrobp.2017.11.025
25.
ContrerasJALinAJWeinerASpeirsCSamsonPMullenDet al. Cardiac dose is associated with immunosuppression and poor survival in locally advanced non-small cell lung cancer. Radiother Oncol. (2018) 128:498–504. 10.1016/j.radonc.2018.05.017
26.
TangCLiaoZGomezDLevyLZhuangYGebremichaelRAet al. Lymphopenia association with gross tumor volume and lung V5 and its effects on non-small cell lung cancer patient outcomes. Int J Radiat Oncol Biol Phys. (2014) 89:1084–91. 10.1016/j.ijrobp.2014.04.025
27.
AntoniaSJVillegasADanielDVicenteDMurakamiSHuiRet al. Overall survival with durvalumab after chemoradiotherapy in Stage III NSCLC. N Engl J Med. (2018) 379:2342–50. 10.1056/NEJMoa1809697
28.
ZhouXLZhuWGZhuZJWangWWDengXTaoWJet al. Lymphopenia is esophageal squamous cell carcinoma: relationship to malnutrition, various disease parameters, and response to concurrent chemoradiotherapy. Oncologist. (2019) 24:e677–86. 10.1634/theoncologist.2018-0723
29.
LadburyCJRusthovenCGCamidgeDRKavanaghBDNathSK. Impact of radiation dose to the host immune system on tumor control and survival for Stage III non-small cell lung cancer treated with definitive radiation therapy. Int J Radiat Oncol Biol Phys. (2019) 105:346–55. 10.1016/j.ijrobp.2019.05.064
30.
ChoOOhYTChunMNohOKLeeHW. Radiation-related lymphopenia as a new prognostic factor in limited-stage small cell lung cancer. Tumour Biol. (2016) 37:971–8. 10.1007/s13277-015-3888-y
31.
Cortez-RetamozoVEtzrodtMNewtonARauchPJChudnovskiyABergerCet al. Origins of tumor-associated macrophages and neutrophils. Proc Natl Acad Sci USA. (2012) 109:2491–6. 10.1073/pnas.1113744109
32.
WisdomAJHongCSLinAJXiangYCooperDEZhangJet al. Neutrophils promote tumor resistance to radiation therapy. Proc Natl Acad Sci USA. (2019) 116:18584–9. 10.1073/pnas.1901562116
33.
CoxSHurtCGrenaderTMukherjeeSBridgewaterJCrosbyT. The prognostic value of derived neutrophil to lymphocyte ratio in oesophageal cancer treated with definitive chemoradiotherapy. Radiother Oncol. (2017) 125:154–9. 10.1016/j.radonc.2017.08.023
34.
ScillaKABentzenSMLamVKMohindraPNicholsEMVyfhuisMAet al. Neutrophil-lymphocyte ratio is a prognostic marker in patients with locally advanced (Stage IIIA and IIIB) non-small cell lung cancer treated with combined modality therapy. Oncologist. (2017) 22:737–42. 10.1634/theoncologist.2016-0443
35.
PikeLRGBangAMahalBATaylorAKrishnanMSpektorAet al. The impact of radiation therapy on lymphocyte count and survival in metastatic cancer patients receiving PD-1 immune checkpoint inhibitors. Int J Radiat Oncol Biol Phys. (2019) 103:142–51. 10.1016/j.ijrobp.2018.09.010
36.
SebastianNWuTBazanJDriscollEWillersHYegya-RamanNet al. Pre-treatment neutrophil-lymphocyte ratio is associated with overall mortality in localized non-small cell lung cancer treated with stereotactic body radiotherapy. Radiother Oncol. (2019) 134:151–7. 10.1016/j.radonc.2019.01.032
37.
RakaeeMBusundLRJamalySPaulsenEERichardsenEAndersenSet al. Prognostic value of macrophage phenotypes in resectable non-small cell lung cancer assessed by multiplex immunohistochemistry. Neoplasia. (2019) 21:282–93. 10.1016/j.neo.2019.01.005
38.
WirsdörferFCappucciniFNiazmanMde LeveSWestendorfAMLüdemannLet al. Thorax irradiation triggers a local and systemic accumulation of immunosuppressive CD4+ FoxP3+ regulatory T cells. Radiat Oncol. (2014) 9:98. 10.1186/1748-717X-9-98
39.
McGeeHMDalyMEAzghadiSStewartSLOesterichLSchlomJet al. Stereotactic ablative radiation therapy induces systemic differences in peripheral blood immunophenotype dependent upon irradiated site. Int J Radiat Oncol Biol Phys. (2018) 101:1259–70. 10.1016/j.ijrobp.2018.04.038
Summary
Keywords
spleen, radiation therapy, lymphopenia, esophageal cancer, lung cancer, pancreatic cancer, gastric cancer, vaccination
Citation
Katz MS (2020) Bystander Effects and Unintended Consequences: Time to Include the Spleen in Radiation Therapy Planning. Front. Oncol. 10:1171. doi: 10.3389/fonc.2020.01171
Received
10 January 2020
Accepted
09 June 2020
Published
16 July 2020
Volume
10 - 2020
Edited by
Charles A. Kunos, National Cancer Institute (NIH), United States
Reviewed by
Jeff Buchsbaum, National Institutes of Health (NIH), United States; James M. Brindle, Rhode Island Hospital, United States
Updates
Copyright
© 2020 Katz.
This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Matthew S. Katz Matthew.Katz@lowellgeneral.org
This article was submitted to Radiation Oncology, a section of the journal Frontiers in Oncology
Disclaimer
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.