EXPERIMENTAL AND CLINICAL TRANSPLANTATION

Objectives: We aimed to evaluate the safety of total body irradiation before bone marrow transplant.

Materials and Methods: We analyzed 110 patients (65 male, 45 female) who underwent total body irradiation for hematopoietic stem cell transplant between May 1998 and March 2013. Median age at total body irradiation was 17 years (range, 1-62 y). Median observation time was 777 days (range, 31-5494 d). Initial diagnoses were acute lymphoblastic leukemia (24 patients), acute myeloid leukemia (26 patients), chronic myeloid leukemia (7 patients), myelodysplastic syndrome (8 patients), malignant lymphoma (13 patients), mucopolysaccharidosis (12 patients), neuroblastoma (10 patients), and other diseases (10 patients). The total fractionated dose used for total body irradiation was 12 Gy in 69 patients and 6.0-10.8 Gy in 29 patients. Single-dose total body irradiation was administered to 12 patients. Most patients (63 of 110) received chemotherapy consisting of cyclophosphamide alone.

Results: Ocular complications were observed in 29.5% of the patients. Hypothyroidism, interstitial pneumonia, obliterative bronchiolitis, and veno-occlusive disease developed in 8.2%, 1.8%, 0.9%, and 2.7% of patients. Growth abnormality was observed in 10 (20%) of the 50 pediatric patients. The use of a lower dose (< 12 Gy vs 12 Gy) of fractionated total body irradiation did not decrease the incidence of adverse events; however, nonmyeloablative conditioning with low-dose single-fraction total body irradiation reduced the incidence of adverse events. Three patients who underwent total body irradiation as reirradiation therapy achieved long-term survival without adverse events.

Conclusions: Fractionated total body irradiation given at a lower dose (<12 Gy vs 12 Gy) did not decrease the incidence of adverse events.

Key words : Bone marrow transplantation, Japan, Long-term adverse effects, Safety

Although total body irradiation (TBI) is increasingly being used for preconditioning before hematopoietic stem cell transplant (HCT), the combination of busulfan and cyclophosphamide has also been used for preconditioning without TBI.¹ A national survey conducted by Inoue and associates in Japan demonstrated that patients who were treated using a TBI-containing regimen had better outcomes in terms of survival rate and relapse-free rate than patients who were treated using a preconditioning regimen without TBI.² Hartman and associates conducted a meta-analysis that included recent randomized controlled trials. They found that TBI-containing regimens tended to be superior, in terms of survival rates, than busulfan and cyclophosphamide regimens without TBI.³

The dual purposes of preconditioning for HCT are to suppress the patient’s immune system to prevent rejection of grafted hematopoietic stem cells and to eradicate malignant cells systemically. The advantages of TBI over chemotherapy include the following: (1) no sparing of sanctuary sites such as the testicles and the central nervous system; (2) high, homogeneous radiation doses that can be delivered to the whole body; (3) less possibility of cross-resistance with other antineoplastic agents; (4) no problems with excretion or detoxification; and (5) dose distribution that can be tailored by using shielding.⁴

The preparation regimens for bone marrow transplant (BMT) and TBI vary among different facilities; presently, there is no consensus on the most suitable regimen.2 To standardize the use of TBI, it is first necessary to evaluate its use in different facilities and patient outcomes. Here, our aim was to evaluate the use of TBI at varying doses in combination with various chemotherapy regimens at our hospital and to compare the long-term outcomes, including adverse events.

Materials and Methods

Study design and patients
The present study was a retrospective observational study of 110 patients (65 male, 45 female) who underwent preconditioning regimens that included TBI for HCT at our hospital between May 1998 and March 2013. The patients’ characteristics and treatment regimens are shown in Table 1. All procedures were performed in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Declaration of Helsinki and its later amendments or comparable ethical standards.

Conditioning chemotherapy regimens
A number of chemotherapy protocols were administered before or after TBI but prior to HCT.

Type of hematopoietic stem cell transplant
Allogeneic BMT was performed in most patients. Autologous BMT was performed in only 2 patients. Other patients underwent peripheral blood stem cell transplant and umbilical cord blood transplant (CBT).

Human leukocyte antigen mismatching
The number of patients with 0, 1, 2, 4, and unknown HLA mismatches according to HLA type were 37 (34%), 14 (13%), 9 (8.2%), 2 (2%), and 57 (52%).

Total body irradiation
Total body irradiation was delivered at a long-source axis distance using a linear accelerator (LINAC, Siemens Primus and Mevatron; Siemens AG, Munich, Germany). The 2 opposed-field technique was used. The uniformity of body thickness was adjusted by placing rice bags around the patient’s body, which was verified using radiographs. Shielding was considered only when the patient’s family requested its use, when reirradiation was performed, or after prophylactic cranial irradiation. The TBI regimens are summarized in Table 2. In all patients, the dose rate used was 10 cGy/min.

Statistical analyses
Statistical analyses were performed with SPSS software (SPSS: An IBM Company, version 21.0, IBM Corporation, Armonk, NY, USA) along with the Mann-Whitney test. Patients were divided into 3 groups: those who received a myeloablative TBI dose of 12 Gy, those who received < 12 Gy, and those who received a single dose. Incidences of adverse events after HCT were compared between patients treated with TBI at a total dose of 12 Gy and those who received a total dose of < 12 Gy. No comparisons were made with the group that received single-dose TBI because single-dose TBI was administered to only 12 patients; this sample size was considered too small to determine statistically significant differences.

The adverse events observed after HCT are summarized in Table 3.

Graft failure
Graft failure occurred in 7 patients (6.3%) among those who underwent any type of HCT. Three of these 7 patients had undergone umbilical CBT. Five patients underwent transplant from an unrelated donor, all of whom underwent CBT.

Cataracts
Cataracts developed in 9 patients (8.2%), with corneal ulcers in 2. Among the 9 patients with cataracts, 3 patients were ≥ 23 years of age and 4 had a history of steroid treatment. Four patients underwent transplant from an unrelated donor.

Hypothyroidism
Hypothyroidism, with diagnoses based on laboratory findings such as decreased serum free thyroxine and/or free triiodothyronine levels or elevated serum thyroid-stimulating hormone levels, developed in 9 patients (8.2%), among whom all but 1 were children. Two patients underwent transplant from an unrelated donor.

Pulmonary complications
Interstitial pneumonia (IP) developed in 2 patients (1.8%), both of whom had been treated with TBI at 12 Gy. One patient received cyclophosphamide alone, and the other received a busulfan-containing regimen. One patient underwent transplant from an unrelated donor. Obliterative bronchiolitis developed in 1 patient (0.9%).

Veno-occlusive disease
Veno-occlusive disease affecting the liver occurred in 3 patients (2.7%). None of these patients underwent transplant from an unrelated donor.

Growth abnormalities
Altogether, 10 (20%) of the 50 pediatric patients (defined as boys < 16 y and girls < 14 y old) presented with short stature (defined as a height > 2 standard deviation scores below the mean). Neuroblastoma was diagnosed in 5 of the 10 patients, making it the most common diagnosis.

Chronic graft-versus-host disease
A total of 31 patients (28.2%) experienced chronic graft-versus-host disease (cGVHD). Twenty patients underwent transplant from an unrelated donor. Of the 21 patients who underwent CBT, 5 patients (24%) presented with cGVHD.

Total body irradiation for reirradiation therapy
We evaluated 3 patients with a history of prior irradiation who had achieved long-term survival after TBI. One patient who had previously received TBI underwent a second round. This patient had mucopolysaccharidosis and, at 3 years of age, underwent conditioning with cyclophosphamide and TBI (2 Gy twice daily for 3 days delivered in 5 fractions to a total dose of 10 Gy) followed by CBT. Graft failure resulted in this patient. At 4 years of age, this patient underwent conditioning with cyclophosphamide and repeat TBI (2 Gy twice daily for 3 days delivered in 5 fractions to a total dose of 10 Gy) with lung and liver shielding during the single anterior field irradiation. This was followed by allogeneic BMT. The graft survived, and no adverse events associated with TBI have occurred to date. Three patients with a history of prior prophylactic cranial irradiation underwent TBI. Two of these patients were treated without cranial shielding and have experienced no adverse events associated with TBI. One female patient with acute lymphoblastic leukemia underwent prophylactic cranial irradiation (18 Gy/12 fractions) at 11 years of age. At 13 years, this patient underwent allogeneic BMT after TBI (3 Gy once daily for 4 days to a total of 12 Gy) with ovarian shielding. Subsequently, this patient achieved spontaneous delivery of a healthy infant at full-term.⁵

Thomas reported that the 2-year disease-free survival rate with fractionated TBI (12 Gy in 6 fractions) was superior to that achieved using single-dose TBI (10 Gy in a single fraction) in patients with acute myeloid leukemia.⁶ At present, a single, reduced dose of TBI is used for nonmyeloablative HCT in older patients or those with a poor performance status, indicating that they are not candidates for standard myeloablative HCT. Single-dose TBI at a dose of approximately 3 Gy has been used in patients with aplastic anemia and those who had previously undergone irradiation at our hospital. Scarpati and associates reported that patients with acute myeloid leukemia and chronic myelogenous leukemia who received TBI at a dose exceeding 9.9 Gy had significantly lower relapse rates than those receiving TBI at 9.9 Gy/3 fractions or at lower dose levels.⁷ Gopal and associates compared 2 TBI fractionation regimens (10.2 Gy/6 fractions/3 days and 12 Gy/4 fractions/4 days) and reported that the relapse-free survival rate at 3 years was higher in the group receiving 12 Gy/4 fractions/4 days.⁸ Soejima and associates compared a regimen of 12 Gy/6 fractions/3 days with a regimen of 12 Gy/4 fractions/4 days and found no differences in survival rates between these 2 groups.⁹ In our patients, the most common regimen was 12 Gy/4 fractions/4 days followed by a regimen consisting of 10 Gy/5 fractions/3 days.

Graft failure after HCT is a rare but significant complication. An analysis of data from the National Marrow Donor Program revealed an incidence of primary graft failure of 6% in unrelated-donor BMT cases.¹⁰ A survey conducted by the Japan Society for Hematopoietic Cell Transplantation demonstrated that rates of graft failure varied among different types of BMT. The rates were 4% for related-donor BMT, 7% for unrelated-donor BMT, and 27% for CBT, indicating a relatively high incidence in patients undergoing CBT.¹¹ Overall, 7 patients (6.3%) of the 110 in our study who were treated with any type of HCT experienced graft failure, with 3 of the 23 CBT patients (13%) experiencing graft failure.

Pulmonary complications, including IP, are prognostically important and have been reported in a number of studies. A recent study involving BMT with a TBI dose of 13.5 Gy/9 fractions/twice a day found that the incidence of grades 3 to 5 pulmonary toxicity was 33%.¹² Sampath and associates reviewed previous studies and reported that the lung dose, cyclophosphamide doses, and addition of busulfan were significantly associated with an increased incidence of IP. They also reported that lung shielding reduced the incidence of IP from 11.0% to 2.3%.¹³ Their results indicated that the TBI dose rate was not a significant factor determining the incidence of IP, although it was a risk factor for IP in patients undergoing single-dose irradiation.¹³ Gopal and associates found no differences in pulmonary function between patient groups receiving 10.2 Gy/6 fractions/3 days with no lung shielding versus those receiving 12 Gy/4 fractions/4 days with lung shielding.¹⁴ Della Volpe and associates reported that, following fractionated TBI (10 Gy/3 fractions/3 days, 5.5 cGy/min), the mean dose to the lung was a factor contributing to pulmonary complications.¹⁵ Only 2 of our patients (1.8%) experienced IP, an incidence that was lower than that reported previously. Both patients had received a chemotherapy regimen combined with TBI at a total dose of 12 Gy. One was administered cyclophosphamide alone and the other a busulfan-containing regimen. The reason for the lower incidence of IP of our patients is unclear; however, the adjustment of the uniformity of body thickness with rice bags around the body may have reduced the total lung dose. Other pulmonary complications included restrictive lung disorders, which may develop in as many as 20% of long-term survivors after HCT. One of these restrictive lung disorders is obliterative bronchiolitis, which reportedly develops in 2% to 14% of patients with cGVHD after HCT.¹⁶ Only 1 of our patients (0.9%) experienced cGVHD-associated obliterative bronchiolitis.

Ocular complications associated with TBI are common. Cataracts and corneal xerosis occurred in 15% and 13% of BMT patients in one study.¹⁷ The incidence of cataracts was reported to be significantly increased in patients ≥ 23 years of age, those who underwent TBI at a dose exceeding 4 cGy/min, those who underwent nonautologous BMT, and patients treated with steroids.¹⁸ Nine of our patients (8.2%) developed cataracts, among whom 3 were ≥ 23 years of age and 4 had a history of steroid treatment. In the present study, the number of patients who developed cataracts was the same among those who underwent autologous and nonautologous BMT (2 patients each).

Veno-occlusive disease, a hepatic disorder recognized after TBI, is caused not only by TBI but also by chemotherapy. A previous meta-analysis demonstrated that veno-occlusive disease occurred more frequently in patients given a busulfan + cyclophosphamide-based regimen without TBI than in patients undergoing a TBI-containing regimen in which the incidence was only 3.0%.³ Three of our patients (2.7%) experienced veno-occlusive disease, an incidence similar to that reported in earlier studies.

Hypothyroidism is also a typical complication, with the reported incidence ranging from 6.5% to 14.0%.^16,17 Nine of our patients (8.2%) developed hypothyroidism, with all but 1 being children. Similar findings have been previously described.

Endocrine disorders caused by hypopituitarism and bone growth disorders caused by growth plate dysfunction are major factors associated with growth abnormalities related to TBI. Patients with neuroblastoma often undergo BMT at a young age and are reportedly at a high risk of developing growth disorders.^19,20 Cranial radiotherapy, which is performed before TBI, has been reported as a high risk factor for growth disorders.²¹ The incidence of short stature after TBI is reported to be 25% to 31%.^21,22 In the present study, 9 of the 50 children enrolled (18%) had short stature. Five of these 9 children had a neuroblastoma. Three patients who achieved long-term survival with TBI after undergoing cranial radiotherapy did not have short stature.

The incidence of cGVHD after HCT varies among the types of HCT. The reported incidence of cGVHD was 27% to 50% for sibling-matched related-donor HCT, 42% to 72% for unrelated-donor HCT, and 54% to 57% for peripheral blood stem cell transplant.²³ Only a few studies have assessed the incidence of cGVHD in patients treated with CBT because CBT was introduced into clinical practice recently. Two recent studies found that the incidences of cGVHD after CBT were 11.6% and 18.0%.^24,25 In our study, cGVHD occurred in 5 of the 21 CBT patients (24%).

The incidences of the aforementioned complications after HCT were compared between patients treated with TBI at a dose of 12 Gy and < 12 Gy. The use of a lower dose (< 12 Gy vs 12 Gy) of fractionated TBI did not decrease the incidence of adverse events. However, the number of each adverse event was relatively small and the type of TBI and conditioning chemotherapy regimen varied; therefore, these differences were statistically underpowered. There have been no previous reports, to our knowledge, describing the use of TBI as reirradiation therapy. Consequently, we evaluated patients who achieved long-term survival after TBI used as reirradiation therapy. One patient with a history of prior 10-Gy TBI underwent repeat 10-Gy TBI and achieved engraftment. This patient has, to date, experienced no adverse events related to TBI. To date, 3 patients with a history of prior prophylactic cranial irradiation who underwent TBI have not experienced adverse events associated with TBI.

The present study has some limitations. The main limitation is the small sample size. A prospective study with a larger sample size is warranted to confirm our findings. Second, the generalizability of the present study results is limited to the Japanese population. Third, when TBI is used in combination with chemotherapy, it is difficult to distinguish whether an adverse event is attributed to one treatment modality or another. More longer term follow-up is needed, especially in pediatric patients.

We compared the long-term outcomes of patients who underwent TBI at our hospital with data from the relevant literature. Regarding the incidence of adverse events, the incidence of pulmonary complications was slightly lower than, or similar to, the incidences reported in the literature. Fractionated TBI given at a lower dose (< 12 Gy vs 12 Gy) did not decrease the incidence of adverse events.

Volume: 14 Issue: 6 December 2016

FULL TEXT