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Cancer Treatment Reviews 53 (2017) 47–52

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Cancer Treatment Reviews
journal homepage: www.elsevierhealth.com/journals/ctrv

General and Supportive Care

Splenic irradiation for splenomegaly: A systematic review
Nicholas G. Zaorsky a,⇑,1, Graeme R. Williams a,1, Stefan K. Barta b, Nestor F. Esnaola c, Patricia L. Kropf b,
Shelly B. Hayes a, Joshua E. Meyer a,⇑
a
Department of Radiation Oncology, Fox Chase Cancer Center, Philadelphia, PA, USA
b
Department of Medical Oncology, Fox Chase Cancer Center, Philadelphia, PA, USA
c
Department of Surgical Oncology, Fox Chase Cancer Center, Philadelphia, PA, USA

a r t i c l e i n f o a b s t r a c t

Article history: Splenic irradiation (SI) is a palliative treatment option for symptomatic splenomegaly (i.e. for pain, early
Received 10 October 2016 satiety, pancytopenia from sequestration) secondary to hematologic malignancies and disorders. The
Received in revised form 19 November 2016 purpose of the current article is to review the literature on SI for hematologic malignancies and disorders,
Accepted 29 November 2016
including: (1) patient selection and optimal technique; (2) efficacy of SI; and (3) toxicities of SI. PICOS/
PRISMA methods are used to select 27 articles including 766 courses of SI for 486 patients from 1960
to 2016. The most common cancers treated included chronic lymphocytic leukemia and myeloprolifera-
Keywords:
tive disorders; the most common regimen was 10 Gy in 1 Gy fractions over two weeks, and 27% of
Leukemia
Lymphoma
patients received retreatment. A partial or complete response (for symptoms, lab abnormalities) was
Meta-analysis obtained in 85–90% of treated patients, and 30% were retreated within 6–12 months. There was no cor-
Myelofibrosis relation between biologically equivalent dose of radiation therapy and response duration, pain relief,
Splenomegaly spleen reduction, or cytopenia improvement (r2 all <0.4); therefore, lower doses (e.g. 5 Gy in 5 fractions)
Radiotherapy may be as effective as higher doses. Grade 3–4 toxicity (typically leukopenia, infection) was noted in 22%
Radiation oncology of courses, with grade 5 toxicity in 0.7% of courses. All grade 5 toxicities were due to either thrombocy-
Palliation topenia with hemorrhage or leukopenia with sepsis (or a combination of both); they were sequelae of
Cancer
cancer and not directly caused by SI. In summary, SI is generally a safe and efficacious method for treating
Toxicity
patients with symptomatic splenomegaly.
Ó 2016 Elsevier Ltd. All rights reserved.

Introduction with splenomegaly is treatment of the underlying disorder (e.g.
chemotherapy or allogenic stem cell transplantation).
Symptomatic splenomegaly is a debilitating complication com- In spite of primary treatment, many of these patients require
monly observed in hematologic malignancies and disorders, palliation of their splenomegaly. Palliative approaches are gener-
including chronic lymphocytic leukemia (CLL), myelofibrosis ally targeted at the underlying disorder (e.g. alkylating agents,
(MF), myeloid metaplasia, lymphoma, prolymphocytic leukemia immunomodulatory agents), but are often poorly tolerated and/
(PLL), and hairy cell leukemia (HCL). In the US, splenomegaly due or minimally effective [3]. Approaches directly targeting the spleen
to these conditions represents up to 27% of all splenomegaly cases, include splenectomy or splenic irradiation (SI). Although splenec-
while common benign causes include liver disease, infection, and tomy is efficacious (and sometimes recommended for diagnosis
congestive splenomegaly [1]. Manifestations of symptomatic sple- and therapy) for select patients, 36% of those undergoing splenec-
nomegaly include mechanical discomfort, tenderness in the left tomy experience significant complications, and 6% experience
upper quadrant, early satiety, gastric compression, abdominal post-operative mortality [4].
bloating, abdominal pain, dyspnea, fatigue, cachexia, and cytopenia First performed in 1903, SI is well-recognized among radiation
secondary to sequestration [2]. First-line therapy for most patients oncologists as an alternative to splenectomy [5], though non-
radiation oncologists may be unaware of its efficacy [6,7]. SI may
be an ideal treatment for patients who have a poor response to sys-
⇑ Corresponding authors at: Department of Radiation Oncology, Fox Chase Cancer
temic therapy and/or are not surgical candidates due to advanced
Center, 333 Cottman Avenue, Philadelphia, PA 19111-2497, USA. Fax: +1 215 214
4038.
age or poor performance status [8]. The purpose of the current arti-
E-mail addresses: nicholaszaorsky@gmail.com (N.G. Zaorsky), joshua. cle is to review the literature SI for hematologic malignancies and
meyer@fccc.edu (J.E. Meyer). disorders, including: (1) patient selection, treatment regimen, and
1
The authors contributed equally to this work.

http://dx.doi.org/10.1016/j.ctrv.2016.11.016
0305-7372/Ó 2016 Elsevier Ltd. All rights reserved.

the addition of these patients is relatively Paulino [18] MF. 27 studies were included in the entire or reduction of splenomegaly – was provided. total courses received chemotherapy) or from disease progression. PLL: prolymphocytic leukemia. and toxicities according to Radiation Therapy Oncology nias were considered to be a result of progressive disease rather Group (RTOG) toxicity grade.8%) [11. identified predictors of poor response across the various disorders.16–21]. includ- the biologically equivalent dose (BED). Notably. HCL 32 52 sis). ing the indication for SI. we included Soldic [20] NHL. and (3) toxicities of SI. as per Supplementary for SI. we abstracted the rate of complete those already listed such as polycythemia vera. CML: chronic myeloid (myelogenous) leukemia. CLL. Among all studies included. One study alone reported 122 patients and 246 courses [11]. 1. Additionally. PV. In some cases.12. lymphoma. Compiling all studies in our review.” ‘‘radiotherapy. cirrho. symptoms after therapy). With respect to tox- meta-analysis.G. a total of 486 pura. CML. 0. Zaorsky et al. ferent fractionation schedules: most of whom were between 50 and 70 years old (median BED ¼ ðnd½1 þ d=ða=bÞÞ age = 60. indication Radiation Therapy Oncology Group (RTOG). 122 246 for exclusively non-malignant conditions (e. MPD (n = 82. and non-Hodgkin’s lym- SI was prescribed (e. we were unable to discern the etiology of the various With respect to indications for SI and patient setup.g. All treatment courses were ally. CLL.g. AML. we available for all patients (particularly those taken from larger series). With respect to doses. (2) efficacy of SI. SI. and acute toxicities.0%). Symptomatic splenomegaly was the indication for In this equation. IMF. We reported toxicities per definitions of the ing factors were obtained from the studies: patient age. cytopenias). NHL. dose Patient and treatment factors per fraction. sickle cell disease. icity. we excluded any (1) where the full Parmentier [31] MPD 9 12 manuscript could not be obtained. Finally. patients were most commonly schemes [13. HCL (n = 5. re-treatments) y Included n = 1 patient for ITP. additionally. ITPy. Study Design (PICOS) Dunn [49] HCL 1 2 approach [9]. and multidisci. NHL 8 8 (3) with insufficient data on outcomes or toxicities.7%). AML. dose per RT course (with the median dose used. Pistevoi-Gombaki [33] MPD 20 30 Ishibashi [16] IMF. 23. We used the a/b ratio value of 10 (i. we dis. HCL. which helps to compare dif. pain. possible if the patient had recurrence of symptoms or a poor response. NHL.4%). including With respect to outcomes. spleno- Data abstraction and analysis megaly. PLL our calculation because this approximates responses for cancer (n = 2. the duration of the response – defined as clinical pain relief palliative by intent. hairy cell approaches with respect to outcomes.10]. unfortu- nately. Control. sepsis senting with splenic pain or CBC irregularities. outcomes. and this was not coded as toxicity. and toxicities. Lavrenkov [17] MPD. (2) not authored in English. The underlying disorders of these patients.g. the rate of any RTOG grade 1–5 toxicity was calculated based on each study. MM pathic thrombocytopenic purpura [ITP]. with further courses (i. Altogether. leukemia. techniques. IMF 11 16 several case reports (per Table 1) in order to most comprehensively Wagner [21] CML. Outcome. Sharp [51] HCL 1 2 Analyses (PRISMA) literature selection process [9.” Mod [54] MPD 1 1 After identifying studies. NHL: non- Hodgkin’s lymphoma. prior treatment (e. splenomegaly.9%).14]. n is the number of radiation fractions and d is the treatment among nearly all studies. MPD: myeloproliferative disorder. CLL. BED10) in treated for the following diseases: CLL/CML (n = 115. multiple myeloma.12]. SI beam arrange. The most common indications were pain or . Two studies include one fraction size. MPD. 16.12]. CML.” and Greenberger [53] MPD 14 21 ‘‘splenic irradiation. or (4) on SI Kriz [11] CML. IMF 17 24 characterize treatment technique. CLL. We conducted a systematic search using the Pre. IMF: idiopathic myelofibrosis. defined as a prescribed regimen of SI with the intent to improve * Included n = 4 patients for ITP. reported cytopenias. Finally. Individual patient data were not than SI toxicity. PV 25 25 Schratter-Sehn [19] CLL. OMF. HIV-associated idio. OMF: osteomyelofibrosis. AML 17 26 ITP (n = 4 and n = 1).e. Reference Indication Patients Courses Aabo [29] CLL 23 31 Byhardt [36] CLL 14 23 Literature selection Guiney [15] CLL 22 32 Nazmy [45] CLL/CML 18 22 Evidence acquisition Roncandin [34] CLL 38 32 Muncunill [46] PLL 1 1 We defined inclusion criteria for literature search using the Yamamoto [47] PLL 1 2 Al-Moundhri [48] HCL 1 2 Population. ITP: idiopathic thrombocytopenic pur- plinary care. An a/b ratio is used to estimate the effects of radiation patient each who received SI in the absence of splenomegaly on various tissues and compare various dose and fractionation [15. if a range was provided). secondary to leukopenia) may be from the treatment (e. We included two studies that included patients treated for McFarland [12] CML. percent of patients pre. We searched Weitberg [52] HCL 1 2 Bouabdallah [30] MPD 15 17 the medical literature from 1960 through 2016 in MEDLINE and Elliott [32] MPD 23 50 PubMed using the terms ‘‘splenomegaly. CLL. ITP*. patients were treated with 766 individual courses of SI (‘‘course” PV: polycythemia vera. response (CR) or partial response (PR) of the symptom for which idiopathic thrombocytopenic purpura. including patient setups. Intervention. There were 766 SI courses to 486 patients. prior ment median dose per fraction and course. Addition. the follow. AML 49 85 negligible for the entire series [11. Table 1 cuss the future direction of SI using novel radiotherapeutic Overview of disorders causing splenomegaly with associated studies and case reports.g. 57. some studies treated patients for various etiologies. MM: multiple myeloma. Nishii [50] HCL 1 1 ferred Reporting Items for Systematic Reviews and Meta. Davda [35] Waldenstrom’s macroglobulinemia 1 1 We further grouped the retrospective series and case reports by Abbreviations: AML: acute myeloid (or myelogenous) leukemia. chemotherapy). / Cancer Treatment Reviews 53 (2017) 47–52 technique.5 years). CLL: chronic lym- the decade published to provide perspectives on the evolution of SI phocytic leukemia. toxicities. certain toxicities per the RTOG scale (e. PV.g. The a/b ratio is used in the calculation of Table 1 summarizes the studies included in this review. phoma (n = 281.48 N. Table 1. cytope- per patient. and SI may all cause leukopenia and anemia.e. we present radiation therapy (RT) regi- mens as reported in the studies. OMF.

For papers that reported separate outcomes for splenomegaly.3 Gy) per course with retreatment as needed for than 40% to 100%. common symp- received. CLL/CML. 1. Zaorsky et al. offered data on duration of therapeutic benefit and overall survival. and improved cytopenias. indicated disease (e. and cyclophosphamide (n = 13). Outcomes anemia. RT was used alone in all other studies.5 Gy) and the total dose (range: improvement of cytopenias. hydroxyurea (n = 48). there was no apparent correlation with delivered by linear accelerator photon units. There was variability in both the courses resulted in splenic pain relief. 3 times/week). MPD.15]. 16% (n = 51) by improvement in symptoms of doses of 5 Gy vs. and CBC responses.32–34]. range 1–9. thrombocytopenia. The response is determined by directly reporting from paper abstracts or calculating a response rate based on data provided in the paper. Efficacy of SI was assessed based on pain palliation. The BED10 of stereotactic body RT for lung cancer and HCL. Per Fig. 72% of courses reduced the size of the spleen.30. reduction. / Cancer Treatment Reviews 53 (2017) 47–52 49 discomfort (n = 469. Fig. totaling to about studies on myeloproliferative disease. Partial response rates of SI in different cancers.30]. Commonly cited therapies were prednisone or PR). Fractionation was most often daily or every which aspects of cytopenias responded best to SI. 58% (n = 280) of patients received treatment for spleno. pain.31]. and 78% resulted in dose per fraction (range: 0. 93% (n = 497) were deliv. For studies of RT for multiple indications and for CLL/ cancer are typically 80–90 Gy [22]. treatment to <5 Gy [18. >2–4 units [29. yet some patients Supplementary Table 2 lists factors associated with poor received in excess of 24 Gy by the conclusion of all treatments response. PR among all studies was greater than 60%. HCL. 2. and/or improvement in cytopenias (documented as a CR megaly prior to RT. An study [35]. busulfan galy response.15.5 Gy). Other common fractionation regimens for SI significantly fewer patients. 2. Legend: The rate of partial or complete response from each study is plotted vs. For studies that listed separate response rates for splenome- (n = 56). Several studies because of no response with the first course.g.5 Gy per fraction. Studies also other day (i. Age and RT field size ered via AP/PA fields and 6% (n = 30) via single anterior field. other malignancies. had worse response to SI retreatment [36. The most varied results occurred in used even lower doses. Studies lacked sufficient data to determine symptomatic control. Systemic therapy was average was calculated using the number of courses for each result. partial responses were 100% but these studies included is 100 Gy [26–28]. a weighted average was calculated based on the number of courses. PLL.15]. 61%). reduced pain.g. delivered Cobalt-60 teletherapy units. average RT dose per course was around 9–10 Gy. listed factors was considered a PR with respect to the overall effi- Data on number of courses delivered was available for 64% cacy of SI. 1 displays partial responses in individual 11 Gy. On average. or studies that included multiple cancers). or recurrence of reported long-term relief of symptoms. 10 Gy. The size of the circle corresponds to the number of patients included (inset). Fig.. There was no apparent outlier hematologic malignancy that markedly different response rates to SI vs. or lymphocytosis. CML. For both PLL apy [14. Patients who previously failed chemotherapy also 534 courses with field setup information. 97%) from splenomegaly and cytopenias (e.e. including high transfusion requirements (e. Of 309 patients who could be analyzed for number of courses and these results are included in Fig. were not associated with response [20]. administered concurrently with RT to 4 patients in one study Additionally. the median PR rate for 0. Of in 1 Gy fractions. N.G. In juxtaposition.16. n = 298. mentary Table 3 presents a comprehensive review of outcomes able for 42% (324/766) of all courses delivered: 77% (n = 250) were and toxicities. the BED10s of external beam RT for prostate studies. often 0. improvement in any one or a combination of the [21]. the median number of courses was 1. either tom relief duration was 6–12 months [30.23–25].. high-grade lymphoma [17]. while the mean per fraction. Supple- Details about linear accelerators and patient setup were avail. 59% of all (435/766) of all courses given. 27% (n = 83) received multiple courses of RT (i.g. including 18 years in one symptoms).1–2. and >120 Gy with brachyther. chlorambucil (n = 29). a weighted (n = 18). . splenic size Overall. (309/486) of all patients included in the study representing 57% Overall. Additionally. where PR ranged from less 6 Gy (BED10 of 6. In general these studies cited symptoms refrac. prior use of chemotherapy [36. The most common fractionation regimen was 1 Gy relief of any symptom among all studies was 88%. to a total of 10 Gy. diagnosis of tory to therapy as the reason for higher doses and multiple courses.e. per month) [30]. and 7% (n = 23) with electrons. which corresponds to a BED10 of PR rate was 85%.15–30. leukopenia.

(B) The response rate (with PR or CR) for individual symptom alleviation vs. which corresponds to a BED10 of 11 Gy (vertical line coplotted). ease sites where RT results in excellent local control. there is no improvement in symptoms with increasing dose. The rate of any toxicity was between 5 and 60% among most studies. With respect to outcomes. BED is plotted. There was no apparent outlier in poor outcomes based on year of study Toxicities publication. 2. There the plateau of the sigmoidal dose-response curve seen in other dis- was no relationship between BED10 response duration or the pro. 60–100% had a reduction in spleen size. 1 are included. (C) The toxicity rate (grade 3–5) vs. and a/b is 10. / Cancer Treatment Reviews 53 (2017) 47–52 Fig. or CBC improvement. BED is plotted. there was no clear rela. reduced lung cancer [38]. The most common regimen was 10 Gy in 1 Gy frac- tions over two weeks.01  0. consti- diseases (e. The median response duration was 11 months (range 2–216). There is no association in symptoms with increasing dose (r2 = 0.e.22. tionship between BED10 and toxicity (i..g.g.05). The dose of radiation is calculated by using BED = (nd[1 + d/(a/b)]). BED10. The size of the circle corresponds to the number of patients included (inset). BED is plotted. Efficacy and toxicity vs. The most common fractionation regimen was 1 Gy per fraction. These findings are consistent with tuting 82. including T1 portion of courses in each study displaying pain relief.27]. Similarly. However.34).4). dose of radiation among all studies. Zaorsky et al.39]. The most common toxicities were grade 3 and 4. n is the number of radiation fractions and d is the fraction size. Legend: The efficacy and toxicity are plotted vs. sialorrhea) [37]. and prostate cancer [14. Table 2 lists data on SI toxicity according to RTOG criteria. ation [26. to a total of 10 Gy.G. 65–100% of patients experienced pain relief. (A) The response rate (with PR or CR) for any symptom alleviation vs. metastatic disease treated with stereotactic radi- spleen size. All cancers from Fig.5% (n = 142/172) of all reported toxicities. . no studies reported long-term dose of RT is similar to that used the treatment of certain benign toxicity.02  0. and the data suggest that lower doses (e. Only 5 Gy in 5 fractions) may be as effective as higher doses.50 N. There is no improvement in symptoms with increasing dose (r2 = 0. BED for all cancers. 2 shows plots of outcomes and toxicities vs. Fig. The size of the circle corresponds to the number of patients included (inset). This low acute toxicities were calculated. while the number with CBC improvement was variable. all r2 values <0.

the toxic effects of SI are similar to the All authors have seen an approved of the final version of this sequelae of hematologic malignancies. behind recurrence (e. pain.5% (n = 142/766) of all SI experienced RTOG-grade toxicities due to progressive disease ver- courses. Additionally. Field size reduc. Symptom n Grade 1 or 2 Grade 3 or 4 Grade 5 Low grade% (1 or 2)/high grade% (3–5) Nausea/vomiting/abdominal cramps 9 8 1 0 89%/11% Leukopenia/neutropenia and/or thrombocytopenia 114 5 104 5 4%/96% Anemia 48 12 36 0 25%/75% Cardiovascular (myocardial infarction) 1 0 1 0 0%/100% Totals 172 25 142 5 15%/85% Toxicity-free courses N = 594 (77%) The bold values represent the totals. and certain deaths may be due to the cancer itself rather 94% of documented toxicities). commercial.5%) doses (e.g. with heterogeneous indications This research did not receive any specific grant from funding for treatment (e.7% of stroma/vasculature (e. Author agreement/declaration particularly the larger studies. two studies agencies in the public.7%).G. did not include patient-level data for analysis. necroptosis) [41]. thrombocytopenia. GI upset. Limitations Funding sources There are several limitations to our analysis. we included a heterogeneous group of patients. sus RT. or tables in reduced fields. cellular death due to different modes course resulted in non-lethal myocardial infarction resulting from surrounding mitotic catastrophe (e. apoptosis. (2) leukopenia with sepsis [15]. over the coming All authors have read and approved the manuscript. Notably. Lower itor blood counts. First. One imens (e. clinicians should therapy if a prescribed cutoff is reached. [32]. 3%). including isolated neutropenia than non-cancer causes (e. 4%). In our analysis of toxicity manuscript.g.20]. hematologic system may respond dramatically due to intracellular death pathways not typically found in carcinomas (e. 28%).e. these effects following SI. or not-for-profit sectors. 8%). Supplementary Fig. dose regimen is 10 Gy in 1 Gy fractions over two weeks. Further. there were 5 cases (0. pericytes) [43]. were limited [29. We are not using any copyrighted informa- prior to each fraction) may play a larger role in SI. the spleen) may decrease in volume dramatically between fractions. cytopenias). No text. this splenomegaly from hematologic malignancies. <2 Gy). figures. 3C). and anemia.g. cancers of the the patients for infection. certain patients SI directly caused by SI. a non-malignant cause of splenomegaly [11.g. although this may be due to underreporting. it was usually not possible to discern which patients account for adverse effects in only 18. effects on radiation induced anemia [12]. follow these patients closely and have a low threshold for treating Following RT of relatively small doses (i.e. Approval/disclosures necroptosis) [41]. the ria).g. identifiers. anterior-posterior fields were the preferred technique (54. The most common toxicities were hematologic (n = 162. a combination of leukopenia and characterize extremely hyperfractionated or hypofractionated reg- thrombocytopenia (n = 7. when compared to the total sample population. 3 offers a reasonable treatment schema that is consistent with the results of our literature survey. and anemia requiring trans. text boxes. the grade toxicities. Commonly reported toxicities were asymptomatic pancytopenia. the reduction of RT field size financial disclosures. though details party. information in this paper. using Conclusion 10 Gy in 1 Gy fractions [40]. Several of the studies included in this review this article have been previously published or owned by another reduced field size during the course of treatment.g. We have no decades. or other protected health tions may reduce toxicity while being equally effective as non. Conflicts of interest ment (Supplementary Fig. Finally. Future studies may explore this tech- nique more using adaptive planning with inter-fraction assess. SI is a safe and efficacious method for treating symptomatic fusion. included patients who were treated for ITP. N. patient photographs. thrombocytopenia (n = 52. anemia (n = 48. The other documented toxicity was nausea can have significant toxicity.3%) and photons were the most frequently used source (94. first session of SI. Additionally. and anemia. tion. Moreover. many of the papers included.g. or (3) a combination of both how the dose is prescribed (e. low hemoglobin causing myocardial (n = 6. with a majority of the polled oncologists (89.g.19. This article represents original work that has not been . Thus. Finally.30. clinicians should follow Our study findings are consistent with a published 2004 poll of these patients closely and have a low threshold for treating the radiation oncologists in the United Kingdom. the use of adaptive RT (i. in which parallel patients for infection. Given regularly monitoring complete blood counts and discontinuing the limited hematologic reserve of these patients.g. isodose line). 5 Gy in 5 fractions) may be equally efficacious. >8 Gy/fraction). Zaorsky et al. to a volume vs. the grade 5 toxicities were sequelae of cancer and not This review also reveals that while effective. Given the limited hematologic reserve of these patients. thrombocytopenia. Our analysis of toxicity reveals that which was either self-limited or treated with anti-emetics. the BED equation may not adequately or leukopenia (n = 36. The most common study discussed a few options providers employ to regularly mon. infarction) [42]. 21%). A potential Future directions option would be to deliver 5 Gy in 5 fractions.e. or molecular pathways all courses) that resulted in death (grade 5 toxicity per RTOG crite. None. / Cancer Treatment Reviews 53 (2017) 47–52 51 Table 2 RTOG grade toxicities after SI. vasculogenesis) [44]. all were due to either (1) thrombocytopenia with hemorrhage BED does not take into account the volume of irradiated tissue or [12]. and pancytopenia (n = 13. 30%). The treated organ (i. Thus. There grade 3 and 4 toxicities are more commonly reported than low- was no apparent different in toxicities after retreatment vs.12]. which are findings consistent with our review.

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