# Radiation Oncology/TBI

* Front Page: Radiation Oncology | RTOG Trials | Randomized Trials

## 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