Radiation Oncology/Spleen

Spleen

Overview

• Hematopoietic organ
• Several functions
  • Lymphoid: cellular and humoral immunity
  • Filtration: irreversible trapping of particulate matter (e.g. bacteria)
  • Surveillance: Removal of damaged/senescent RBCs
  • Platelet sequestration
    • Typically 1/3 of platelet number but can be significantly more in splenomegaly
    • Appears to be a passive process, whereby platelets are trapped by adhesion to reticular meshwork of the splenic cords
    • Can be released with epinephrine, so if normal platerel production is normal, no bleeding
  • Extramedullary hematopoiesis
    • Initially during embryonic development
    • Resumption of function possible with severe anemia or myelofibrosis
• Normal spleen in adults measures 8-13 cm and is typically not palpable. Weight 150-250 g
• Splenomegaly
  • Multiple causes: inflammation/infection (increase in white pulp), congestive expansion (increase in red pulp), increased blood pool, increased macrophage activity, proliferative cellular infiltration, extramedullary hematopoiesis, storage diseases, cysts, solid tumors (primary rare, solitary met from colorectal, ovarian)
  • Etiology varies: West - leukemia, lymphoma, myeloproliferative disorders, hemolytic anemia and portal hypertension. Tropics - infectious diseases

RT Indications

• Symptomatic LUQ pain, mechanical discomfort related to large spleen, early satiety due to stomach compression
• RT used in patients with indications for splenectomy, who are high risk surgical candidates or who decline surgery
• Mechanism of splenomegaly important for RT
  • Proliferative cell infiltration: chronic lymphocytic leukaemia (CLL), prolymphocytic leukaemia (PLL), acute myelogenous leukemia (AML), hairy cell leukaemia (HCL), splenic marginal zone lymphoma (SLVL)
  • Bone marrow myelofibrosis resulting in extramedullary hematopoiesis: primary myeloid metaplasia; or secondary to CML, polycythemia vera, or essential thrombocythemia
  • Immune thrombocytopnia (ITP)
  • Hypersplenism: typically seen as cytopenia caused by splenomegaly (e.g. portal hypertension)
• Disease-associated side effects (wt. loss, night sweats, low grade fever) often improve, but generally not primary indications
• Not likely to be effective in improving disease-related cytopenias (may in fact exacerbate them)

RT Effects

• Direct effect on radiosensitive extramedullary hematopoietic tissue or infiltrating lymphocytes
• Destruction of hematopoietic precursors residing or traversing the spleen
• Early and marked reduction in colony-forming granulocyte marcophages, persisting >1 month
• A systemic effect and sometimes peripheral blood and bone marrow complete remissions (CRs) observed in several clinical situations
  • Mechanism is not clear, but could involve direct RT-induced killing of splenic neoplastic clls, immune modulation via proportional changes in lymphocytes subsets and increased anti-tumor activity, RT-induced release of cytokines (e.g. TNFalpha, IL-2), and bystander/abscopal effect
• Also, compared to splenectomy, a marked and persistent cytopenias (which may lead to significant complications)

RT Overview

• No prospective or randomized trials
• No firm RT schedules, but low dose (<=1Gy) intermittent (2-3 fx/week), to total <=10 Gy recommended. One report suggests conventional 2 Gy/fx may be equally well tolerated. Consider dosing as follows (PMID 11230883 below):
  • Lymphoproliferative: 4-10 Gy total in 1 Gy/fx
  • Myelofibrosis: 1-9 Gy total, with 0.25-0.5 Gy/fx
  • Hypersplenism: RT typically not useful, but for example see PMID 18301984
• Patients should be continuously monitored, and fields adjusted with shrinking spleen
• RT should be stopped when therapeutic goal is achieved, rather than when prescription is reached
• Complications are primarily myelosuppression, and need to be monitored daily (CBC, exam)
  • Toxicity tolerable in lymphoid disorders, higher in myeloproliferative disorders
  • Decline in hemoglobin - can lead to MI
  • Thrombocytopenia - can result in significant bleeding
  • Retreatment as necessary, with consideration of renal dose

Literature

• Scotland; 2008 (2003-2004) PMID 18477126 -- "Low-dose palliative splenic irradiation in haematolymphoid malignancy." (Shrimali RK, J Med Imaging Radiat Oncol. 2008 Jun;52(3):297-302.)
  • Retrospective. 22 courses for 19 patients. Total dose 1.5 - 8.0 Gy (median 4.5 Gy), fractional dose 0.25 - 1 Gy delivered weekly or twice weekly. AP/PA. Median field reduction 25%
  • Outcome: 85% successful in symptom palliation, but only 25% produced hematologic response
  • Conclusion: splenic irradiation effective and well-tolerated palliative treatment option

• Vienna, 2003 (Austria) PMID 12624513 -- "Short-time splenic irradiation for splenomegaly." (Schratter-Sehn AU, Onkologie. 2003 Feb;26(1):21-4.)
  • Retrospective. 49 patients (CLL 6, CML 14, NHL 6, MPD 16, OMF 6, AML 1) treated with 85 courses with A) low dose <1 Gy/fx prolonged vs. B) conventional 2Gy/fx. Spleen pretreatment doses 3-70 Gy (mean 21 Gy)
  • Outcomes: spleen reduction 55/85 patients (Group A 47/72, Group B 8/13), clinical improvement 62/85 (Group A 57/72, Group B 5/13). Rapid response in 23 patients, with field reduction during treatment
  • Conclusion: Conventional short treatment showed rapid response, no difference in toxicity

• Naval Medical Center, San Diego, 2003 (1990-2001) PMID 12714892 -- "Palliative irradiation of the spleen." (McFarland JT, Am J Clin Oncol. 2003 Apr;26(2):178-83.)
  • Retrospective. 17 patients (5 CML, 4 CLL, 4 Myelofibrosis, 2 PCV, 1 ITP, 1 AML). Symptomatic splenomegaly
  • RT schedule: Week 1 - 0.5 Gy x2 fx, Week 2 - 0.75 Gy x2 fx, Week 3 - 1 Gy x2 fx
  • Outcome: 22/25 treatments resulted in decreased pain and symptoms. 5 patients retreated, 1 patient 5 treatments
  • Conclusion: Effective palliation. Retreatment possible. Less effective for ITP or leukocytosis

• Mayo, 1998 PMID 9827926 -- "Splenic irradiation for symptomatic splenomegaly associated with myelofibrosis with myeloid metaplasia." (Elliott MA, Br J Haematol. 1998 Nov;103(2):505-11.)
  • Retrospective. 23 patients with MMM treated with 50 courses of SI. RT: Median total dose 2.8 Gy, given in median 7.5 fractions.
  • Outcomes: 94% reduction in spleen size. 8/23 received multiple courses, 9/23 underwent splenectomy
  • Toxicity: 43% significant cytopenia, 26% life-threatening cytopenia after a single course, 13% fatal sepsis or hemorrhage
  • Conclusion: Good symptomatic relief, but high risk. Should not be offered to good surgical candidates for splenectomy

• Melbourne, 1989 (Australia) PMID 2912945 -- "A study of splenic irradiation in chronic lymphocytic leukemia." (Guiney MJ, Int J Radiat Oncol Biol Phys. 1989 Jan;16(1):225-9.)
  • Retrospective. 22 patients with 32 courses of SI. RT 0.25 - 0.5 Gy/fx, fields AP/PA and decreased with response, treatment halted with response
  • Outcomes: Splenomegaly 19/31 response; Splenic pain 4/10 response; Anemia 4/16 response; Thrombocytopenia 2/14 response (and 9/14 worsening thrombocytopenia). Median duration of response 14 months (3-116)
  • Toxicity: leucopenia, thrombocytopenia. No correlation with fraction size

• 1986 (1973-1982) PMID 2427184 -- "Splenic irradiation in the treatment of patients with chronic myelogenous leukemia or myelofibrosis with myeloid metaplasia. Results of daily and intermittent fractionation with and without concomitant hydroxyurea." (Wagner H, Cancer. 1986 Sep 15;58(6):1204-7.)
  • Retrospective. 17 patients with CML or MMM treated with 24 courses.
  • RT initially 1Gy to 15-20 Gy over 1 month, later 0.15-0.5 Gy/fx, total 0.15-6.5 Gy, given in 2-3 fx/week
  • Outcomes: 71% improvement for splenic pain, 50% improvement for splenomegaly

• 1977 PMID 74374 -- "Irradiation for control of hypersplenism and painful splenomegaly in myeloid metaplasia." (Greenberger JS, Int J Radiat Oncol Biol Phys. 1977 Nov-Dec;2(11-12):1083-90.)
  • Cumulative total doses 5-10 Gy, well tolerated
  • No correlation between dose and spleen reduction and toxicity

Review

• Harvard; 2008 PMID 19092156 -- "Case records of the Massachusetts General Hospital. Case 39-2008. A 51-year-old woman with splenomegaly and anemia." (Abramson JS, N Engl J Med. 2008 Dec 18;359(25):2707-18.)

• Tubingen, 2001 (Germany) PMID 11230883 -- "Clinical indications and biological mechanisms of splenic irradiation in chronic leukaemias and myeloproliferative disorders." (Weinmann M, Radiother Oncol. 2001 Mar;58(3):235-46.)