Radiation Oncology/TBI

Overview Goals of TBI: Immunosuppression - lymphocyte elimination to allow grafting of donor bone marrow Eradication of malignant cells - leukemia, lymphoma, rarely solid tumors Eradication of cells with genetic disorders - Fanconi's anemia, thalassemia major, Wiskott-Aldritch syndrome Benefit over chemo: No "sanctuary" sites (e.g. testes, brain) Delivered dose is independent of blood supply Delivered dose is independent of renal and hepatic function No cross-resistance with other agents Dose can be homogeneous, and tailored to "boost" areas at risk and "spare" more sensitive organs TBI dose required for adequate immunosuppression is high, so typically a combined chemo-TBI approach is used Cyclophosphamide has been used commonly; Etoposide has been used increasingly in ALL There is no randomized data, but fractionated TBI is typically given after cyclophosphamide There have been efforts to eliminate TBI from the conditioning regimen, because TBI was seen as one of the major causes of transplant-related mortality. Also, the risk of long-term toxicity such as secondary malignancies, pneumonitis, impaired growth, and endocrine dysfunction was worrisome. A meta-analysis suggested that survival was comparable between CY-TBI and BU-CY regimens, with better toxicity profile for the cyclophosphamide-TBI strategy Acute effects of whole-body irradiation are also important to understand from a radiation protection perspective TBI vs. Chemo-ablation only For patients undergoing allogeneic bone marrow transplant, cyclophosphamide 120 mg/kg + TBI has been the standard of care since 1970's In effort to decrease some of the long-term complications of TBI, efforts were made to replace it with chemotherapy only. Cyclophosphamide + busulfan was the typical combination 5 trials in 1980's randomized patients to CY-TBI (or Etoposide-TBI) vs. BU-CY. In one meta-analysis, TBI-based regimens were as good for survival as BU-CY, with lower incidence of veno-occlusive disease. In the other meta-analysis, focusing on myeloid leukemia patients only, the long-term survival and toxicity was comparable, with perhaps small survival benefit to CY-TBI A reasonable fractionation schedule would be 12 Gy in 6 fractions daily, at 10 cGy/min Meta-analysis Meta-analysis, 2001 PMID 11739158 -- "Busulfan plus cyclophosphamide compared with total-body irradiation plus cyclophosphamide before marrow transplantation for myeloid leukemia: long-term follow-up of 4 randomized studies." (Socie G, Blood. 2001 Dec 15;98(13):3569-74.) 4 trials (GEGMO, Nordic, SFGM, Fred Hutchinson), subset AML/CML patients (488) analyzed. Mean F/U 7 years CML: no difference between BUCY and CY-TBI. Projected 10-year OS 65% vs. 63% AML: Projected 10-year OS 51% vs. 63% (NS) Toxicity: CML: CY-TBI increased risk of cataracts, BUCY increased risk of irreversible alopecia, otherwise comparable. Long-term complications mostly result of chronic GVHD Conclusion: Comparable long-term outcomes, with some (NS) benefit for CY-TBI in AML Meta-analysis, 1998 PMID 9733266 -- "Survival, disease-free survival and adverse effects of conditioning for allogeneic bone marrow transplantation with busulfan/cyclophosphamide vs total body irradiation: a meta-analysis." (Hartman AR, Bone Marrow Transplant. 1998 Sep;22(5):439-43.) 5 trials. Outcome: OS and DFS better with TBI, but NS (p=0.09) Toxicity: More veno-occlusive disease with BUCY (HR 2.5, SS), otherwise no difference Conclusion: TBI-based regimens at least as good for survival, and less BVOD Randomized FORUM Trial (2013 - 2018) Randomized. Multinational. 417 patients. ALL, <=18, CR pre-stem cell allogeneic transplant. Arm 1) TBI 12 Gy (2 Gy x 6 fractions over 3 days, lung block at 10 Gy) plus Etoposide or Fludarabine/Thoirtepa and Treosulfa/Busulfan vs Arm 2) chemotherapy only 2 years; stopped early PMID 33332189 -- "Total Body Irradiation or Chemotherapy Conditioning in Childhood ALL: A Multinational, Randomized, Noninferiority Phase III Study" (Peters C, J Clin Oncol. 2021 Feb 1;39(4):295-307. doi: 10.1200/JCO.20.02529. Epub 2020 Dec 17.) Outcome: 2 year OS TBI 91% vs chemo only 75% (SS). Toxicity: 2 year treatment mortality 2% vs 9% (SS) Conclusion: Improved OS and lower relapse following TBI with etoposide compared to chemotherapy only. Recommend for patients >4 years with high risk ALL undergoing allogeneic HSCT Fred Hutchinson (1988-1992) -- CML; CY-TBI vs. BU-CY Randomized. 142 patients with CML in chronic phase, treated with cyclophosphamide 120 mg/kg + TBI 12/6 vs. busulphan 64 mg/kg + cyclophosphamide 120 mg/kg 9-years, 1999 PMID 10627126 -- "Long-term follow-up of a randomized study comparing cyclophosphamide and total body irradiation with busulfan and cyclophosphamide for patients receiving allogenic marrow transplants during chronic phase of chronic myeloid leukemia." (Clift RA, Blood. 1999 Dec 1;94(11):3960-2.). Median F/U 7.7 years 9-year outcome: OS: BUCY 73% vs. CY-TBI 65% (NS); relapse 19% vs. 22% (NS) Non-relapse mortality: 20% vs. 25% (NS) Conclusion: BU-CY better tolerated, and comparable efficacy 3-years, 1994 PMID 8081005 -- "Marrow transplantation for chronic myeloid leukemia: a randomized study comparing cyclophosphamide and total body irradiation with busulfan and cyclophosphamide." (Clift RA, Blood. 1994 Sep 15;84(6):2036-43. 3-year outcome: No difference in OS (80%), relapse (13%) or EFS (CY-TBI 68% vs. BUCY 71%) Toxicity: No difference in VOD; more creatining elevations and acute GVHD in CY-TBI group Conclusion: BU-CY better tolerated, similar OS and relapse SFGM (French)(1988-1991) -- CML; CY-TBI vs. BU-CY Randomized. 19 centers. 120 patients with CML, in first chronic phase. Treated with cyclophosphamide 120 mg/gk + TBI vs. busulfan 16 mg/kg + cyclophosphamide 120 mg/kg. RT: 13 patients single 10 Gy dose, 42 patients fractionated (mostly 12/6 BID over 3 days). Median dose rate 8 cGy/min; median lung dose 10 Gy. 5-years, 1995 PMID 7718899 -- "Allogeneic bone marrow transplantation for chronic myeloid leukemia in first chronic phase: a randomized trial of busulfan-cytoxan versus cytoxan-total body irradiation as preparative regimen: a report from the French Society of Bone Marrow Graft (SFGM)." (Devergie A, Blood. 1995 Apr 15;85(8):2263-8.) Median F/U 3.5 years 5-year outcome: OS CY-TBI 66% vs. BUCY 61% (NS); DFS 51% vs. 59% (NS) Transplant mortality: 29% vs. 38% (NS) Conclusion: BU-CY acceptable alternative to CY-TBI in CML patients Nordic BMTG (1988-1992) -- AML/ALL/CML; CY-TBI vs. BU-CY Randomized. 167 patients with leukemia. Treated with cyclophosphamide 120 mg/kg + TBI vs. busulfan 16 mg/kg + cyclophosphamide 120 mg/kg. RT: 10/1 or 11.3-12 Gy in 3-7 fxs at 4-12.7 cGy/min 7-years, 1999 PMID 10090927 -- "Increased risk of chronic graft-versus-host disease, obstructive bronchiolitis, and alopecia with busulfan versus total body irradiation: long-term results of a randomized trial in allogeneic marrow recipients with leukemia. Nordic Bone Marrow Transplantation Group." (Ringden O, Blood. 1999 Apr 1;93(7):2196-201.) 7-year outcome: DFS early disease 68% vs. 66% (NS); DFS advanced disease 17% vs. 49% (SS); OS early disease 72% vs. 67% (NS; OS advanced disease 17% vs. 49% (SS) Toxicity: VOD of liver: BUCY 12% vs. TBI 1% (SS); hemorrhagic cystitis 32% vs. 10% (SS); acute GVHD comparable but chronic GVHD 59% vs. 47% (SS). GVHD death 22% vs. 3% (SS). Obstructive bronchiolitis 26% vs. 5% (SS). Cataracts 6% vs. 20% (SS). Transplant mortality: early disease 21% vs. 12%; advanced disease 64% vs. 22% (SS) Conclusion: BUCY associated with more severe late toxicity. In advanced stage worse DFS and OS, in early stage disease comparable 3-years, 1994 PMID 8167351 -- "A randomized trial comparing busulfan with total body irradiation as conditioning in allogeneic marrow transplant recipients with leukemia: a report from the Nordic Bone Marrow Transplantation Group." (Ringden O, Blood. 1994 May 1;83(9):2723-30.) 3-year outcome: OS BUCY 62% vs. TBI 76% (SS); relapse similar Toxicity: VOD of liver: BUCY 12% vs. TBI 1% (SS); hemorrhagic cystitis 24% vs. 8% (SS); seizures 6% vs. 0% (SS). GVHD death 17% vs. 2% (SS). In advanced patients, transplant mortality 62% vs. 12% (SS) Conclusion: TBI is treatment of choice, especially in advanced disease; BUCY acceptable in early disease GEGMO (1987-1990) -- AML; CY-TBI vs. BU-CY Randomized. 101 patients with AML in first remission, >14 years. Preparation for transplant via 1) Cytoxan (120 mg/kg) + TBI vs. 2) Cytoxan + busulfan (16 mg/kg). Transplant from HLA-identical sibling. RT: 7 patients single 10 Gy dose, 34 patients 12/6 BID over 3 days, others also fractionated. Median dose rate 5 cGy/min; lung shielding to between 6-10 Gy 10-years, 2001 PMID 11392326 -- "Long-term follow-up of a randomized trial comparing the combination of cyclophosphamide with total body irradiation or busulfan as conditioning regimen for patients receiving HLA-identical marrow grafts for acute myeloblastic leukemia in first complete remission." (Blaise D, Blood. 2001 Jun 1;97(11):3669-71.) 10-year outcome: OS: CY-TBI 59% vs 43% (SS); DFS 55% vs. 35% (SS) Relapse: CY-TBI 25% vs. BUCY 37% (NS); trend toward early relapse in BUCY group (1-year 10% vs. 25%, p=0.05) Second cancers: 2 in each group (4%) 2-years, 1992 PMID 1586710 -- "Allogeneic bone marrow transplantation for acute myeloid leukemia in first remission: a randomized trial of a busulfan-Cytoxan versus Cytoxan-total body irradiation as preparative regimen: a report from the Group d'Etudes de la Greffe de Moelle Osseuse." (Blaise D, Blood. 1992 May 15;79(10):2578-82.). Median F/U 2 years 2-year outcomes: DFS CY-TBI 72% vs. BUCY 47% (SS), OS 75% vs. 51% (SS) Transplant mortality: CY-TBI 8% vs. 27% (p=0.06) Conclusion: Busulfan limited in this setting SWOG 8612 (1987-1991) -- leukemia; TBI/VP-16 vs. BU-CY 3-years, 1993 PMID 8471778 -- "A prospective randomized comparison of total body irradiation-etoposide versus busulfan-cyclophosphamide as preparatory regimens for bone marrow transplantation in patients with leukemia who were not in first remission: a Southwest Oncology Group study." (Blume KG, Blood. 1993 Apr 15;81(8):2187-93.) Randomized. 122 patients with advanced leukemia who failed first line. Treated with TBI/VP-16 vs. BU-CY. RT: 13.2/11 at 1.2 Gy/fx TID. Median F/U 2.6 years Outcome: No difference in DFS or OS. Toxicity: well tolerated Conclusion: Two regimens are equivalent RT Dose Fred Hutchinson -- CML Randomized. CML in chronic phase. Cyclophosphamide 120 mg/kg, then randomized TBI 12/6 daily vs. 15.75/7 daily 4-years, 1991 PMID 2015394 -- "Allogeneic marrow transplantation in patients with chronic myeloid leukemia in the chronic phase: a randomized trial of two irradiation regimens." (Clift RA, Blood. 1991 Apr 15;77(8):1660-5.) 4-year outcome: RFS 12 Gy 58% vs. 15.75 Gy 66% (NS). OS 60% vs. 66% (NS). Transplant mortality: 24% vs. 34% (NS) Conclusion: Higher RFS with higher dose, but no difference in OS due to higher mortality from other causes Fred Hutchinson (1985-1988) -- AML Randomized. 71 patients with AML in first remission. Cyclophosphamide 120 mg/kg, then randomized TBI 12/6 daily vs. 17.75/7 daily 11-years, 1998 PMID 9694737 -- "Long-term follow-Up of a randomized trial of two irradiation regimens for patients receiving allogeneic marrow transplants during first remission of acute myeloid leukemia." (Clift RA, Blood. 1998 Aug 15;92(4):1455-6.) Min F/U 7.5 years 11-year outcome: OS 51% in both arms (NS); cumulative relapse 12 Gy 39% vs. 17.75 Gy 14% (p=0.06); cumulative non-relapse mortality 19% vs. 38% (p=0.05) Conclusion: OS similar, higher mortality in higher dose arm during first 6 months 3-years, 1990 PMID 2224134 -- "Allogeneic marrow transplantation in patients with acute myeloid leukemia in first remission: a randomized trial of two irradiation regimens." (Clift RA, Blood. 1990 Nov 1;76(9):1867-71.) 3-year outcome: RFS 12 Gy 58% vs. 17.75 Gy 59% (NS); OS 65% vs. 59% (NS); cumulative relapse 35% vs. 12% (p=0.06) Transplant mortality: 12 Gy 12% vs. 17.75 Gy 32% (SS); moderate/severe GVGH 21% vs. 48% (SS) Conclusion: Higher TBI dose reduced probability of relapse but did not improve survival; significantly higher toxicity with higher dose Cranial boost U. Michigan (1994-2003) - PMID 15978741, 2005 — "Utility of cranial boost in addition to total body irradiation in the treatment of high risk acute lymphoblastic leukemia." Alexander BM et al. Int J Radiat Oncol Biol Phys. 2005 Nov 15;63(4):1191-6. Purpose: Evaluate role of cranial boost. Retrospective. 67 pts. High-risk pts treated with or without a cranial boost in addition to TBI prior to BMT. All received chemotherapy for conditioning. TBI was most commonly 2 Gy BID to 12 Gy or 2.5 Gy qd to 10 Gy. Cranial boost given in 39% of pts, median dose 11 Gy Conclusion: cranial boost not associated with lower CNS relapse rate. Toxicity Gustave Roussy, 1993 (France) PMID 8449718 -- "Prospective study of the clinical symptoms of therapeutic whole body irradiation." (Chaillet MP, Health Phys. 1993 Apr;64(4):370-4.) Prospective. 31 patients receiving 10 Gy in 4 hours TBI, prior to high dose cyclophosphamide for BMT. Acute side effects: 90% nausea (despite ondansetron), 80% vomiting, 42% headaches, early (during TBI) xerostomia 61%, temperature peak to 40.8C during first 6 hours, parotitis 74% during first 24 hours Acute Parotitis Please see the Acute Parotitis Toxicity section for more information Rapid destruction of serous cells by apoptosis; cell membrane damage as early as 2 hours after RT Increase in serum amylase even after 0.5 Gy; typically dose-dependent. Peak (up to 50x) 1-2 days after RT. Return to normal in 5-6 days. Frequently with associated parotid gland swelling, dry mouth, and loss of taste Radiation Protection Effects related to whole body irradiation, typically as a result of nuclear accidents or nuclear warfare. Please see Radiation Event Medical Management webpage at the U.S. Department of Health & Human Services Prodromal Syndrome Threshold 1 Gy Increasing dose leads to increased severity and decreased latency (time-to-onset) Marker 1-2 Gy 2-4 Gy 4-6 Gy 6-8 Gy >8 Gy Lymphocytes 0.8-1.5 d 0.5-0.8 d 0.3-0.5 d 0.1-0.3 d 0-0.1 d Diarrhea none none rare 6-9 days 4-5 days Epilation none start 15 d start 11 d done 11 d done 10 d Latency 4 weeks 2-4 weeks 1-2 weeks 5-7 days immediate Medical Response none consider hospital inpatient inpatient symptoms only Three main syndromes depending on dose Mean whole body lethal dose ~4 Gy Survival unlikely >8 Gy Hematopoietic syndrome (3-8 Gy) Gastrointestinal syndrome (10-50 Gy) CNS syndrome (>50 Gy) Hematopoietic syndrome Depression of blood components (leukocytes drop -> granulocytes spike then drop -> platelets drop) in 2-3 weeks; death in 1-2 months Symptoms: chills, fatigue, petechial hemorrhages, mouth ulceration, epilation Treatment Careful nursing, prophylactic antibiotics if ANC <0.5, cytokines/bone marrow growth factors Bone marrow transplant somewhat controversial at 8-10 Gy; only 1 BMT successful in saving a life. BMT >10 Gy resulted in death anyway by GI syndrome GI syndrome Death of intestinal stem cells -> latency of 4-5 days before replacement for mature cells not available; death in 3-10 days Symptoms: nausea, vomiting, diarrhea, fatigue, dehydration Mean survival time independent of dose CNS syndrome Symptoms: Severe nausea/vomiting/diarrhea in minutes, disorientation, respiratory distress, visual symptoms, seizures, coma Mean survival time dependent on dose