
==== Front
Radiat Oncol
Radiat Oncol
Radiation Oncology (London, England)
1748-717X
BioMed Central London

39289692
2520
10.1186/s13014-024-02520-8
Research
Secondary solid malignancies in long-term survivors after total body irradiation
http://orcid.org/0000-0002-7435-9337
Gruber Isabella i.gruber@ukr.de

1
Wolff Daniel 2
Koelbl Oliver 1
1 https://ror.org/01226dv09 grid.411941.8 0000 0000 9194 7179 Department of Radiation Oncology, University Hospital Regensburg, Franz-Josef-Strauß Allee 11, Regensburg, Germany
2 https://ror.org/01226dv09 grid.411941.8 0000 0000 9194 7179 Department of Internal Medicine III, University Hospital Regensburg, Franz-Josef-Strauß Allee 11, Regensburg, Germany
17 9 2024
17 9 2024
2024
19 1221 5 2024
5 9 2024
© The Author(s) 2024
2024
https://creativecommons.org/licenses/by/4.0/ Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.
Background

Total body irradiation (TBI)-based allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a curative treatment for selected patients with acute myeloid leukemia (AML). Yet, secondary malignancies contribute to long-term morbidity and mortality with TBI potentially influencing these risks.

Methods

This retrospective study analyzed the cumulative incidences of secondary solid malignancies and precancerous lesions of 89 consecutive AML patients after TBI-based conditioning before 1st allo-HSCT between 2000 and 2016. TBI was performed with an average dose rate of 4 cGy/min and a twice-daily fractionation. Cause-specific hazard models analyzed risk factors for secondary malignancies/precancerous lesions and the competing risks of dying before developing secondary malignancies/precancerous lesions.

Results

The median patient age at TBI was 42.5 years (interquartile range, 32.5–51.2), while the median follow-up was 15.2 years (interquartile range, 13.0-18.2). Most patients received a myeloablative conditioning (MAC) containing 8 Gy (n = 47) and 12 Gy TBI (n = 11). Reduced-intensity regimens (RIC, 4 Gy TBI) were applied in 31 patients. Of note, patients receiving RIC were older than patients receiving MAC. The most common cancer types were non-squamous cell carcinomas (n = 14) after exclusion of a patient diagnosed with sarcoma within less than a year after TBI. The cumulative incidences of secondary malignancies and precancerous lesions were 8% (95%CI, 4–16), 14% (95%CI, 7–23), and 17% (95%CI, 9–27) at 10, 15 and 20 years, while the cumulative incidences of premature deaths were 59% (95%CI, 48–69), 59% (95%CI, 48–69), and 64% (95%CI, 49–76). In multivariate analyses, higher patient age at TBI was associated with lower rates of secondary malignancies/precancerous lesions, while higher patient age translated into a trend towards premature deaths (before patients could develop malignancies). Higher TBI doses, mainly applied in younger patients, translated into lower rates of secondary malignancies/precancerous lesions while lacking associations with mortality. Chronic GVHD requiring systemic immunosuppression was associated with premature deaths.

Conclusions

Although this study indicates an inverse relationship between TBI doses applied and treatment-related malignancies, confounding by competing risks is present. The age dependency may be explained by the fact that older patients had a lower life expectancy independent of malignancies, illustrating the pitfalls of competing risks.

Trial registration

The study was retrospectively registered.

Keywords

Total body irradiation
Low-dose radiotherapy
Secondary solid malignancies
Allogeneic hematopoietic stem cell transplantation
Carcinogenesis
Acute myeloid leukemia
Universitätsklinikum Regensburg (8921)Open Access funding enabled and organized by Projekt DEAL.

issue-copyright-statement© BioMed Central Ltd., part of Springer Nature 2024
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pmcBackground

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) applying TBI and non-TBI-based conditioning regimens is a curative treatment option for selected patients with acute myeloid leukemia (AML). Yet, secondary malignancies contribute to long-term morbidity and mortality with conditioning regimens potentially modulating these risks [1]. Myeloablative conditioning (MAC) containing higher doses of TBI (8–12 Gy) is usually applied in fit and young patients (< 50 years of age) [2, 3]. Reduced-intensity conditioning (RIC) combining lower doses of chemotherapy and/or TBI (doses ranging from ≥ 4 Gy to < 8 Gy) is used particularly in patients ineligible for myeloablative conditioning to reduce transplant-related complications while maintaining efficacy [2, 4]. Both recipients of TBI and non-TBI-based conditioning regimens are at risk of developing secondary malignancies after allo-HSCT [5, 6]. Literature indicates that TBI is associated with basal cell carcinomas, and breast, thyroid, and brain cancers occurring with a long delay after allo-HSCT [7–9]. In contrast, chronic graft-versus-host disease (cGVHD)-related squamous cell carcinomas (SCCs) of the skin and oropharynx seem to occur after shorter latency [5]. Cumulative incidences of secondary solid malignancies after allo-HSCT as reported in the literature vary depending on statistical methodologies, patient population, conditioning regimens, and cGVHD and are as high as 13.5% at 15 years [10] and 22% at 30 years [11]. Yet, data are sparse regarding incidences of secondary solid malignancies after allo-HSCT applying modern and uniform TBI techniques. In this retrospective study, we, therefore, estimated the cumulative incidences of secondary solid malignancies and precancerous lesions in the presence of the competing risks of premature mortality after applying a standardized fractionated TBI technique for AML patients and 1st allo-HSCT. Cause-specific hazard models analyzed associations between transplant characteristics and the rates of secondary solid malignancies/precancerous lesions including the competing risks of premature death before developing malignancies.

Methods

Data collection

We retrospectively analyzed the cumulative incidences of secondary solid malignancies and precancerous lesions in adult patients with primary or secondary AML receiving TBI as part of the conditioning regimen before 1st allo-HSCT at the Departments of Radiation Oncology and Hematology of the University Hospital Regensburg between 01/2000 and 10/2016. Patients conditioned with TBI after 10/2016 were not analyzed to ensure sufficient follow-up. As patients conditioned with non-TBI-based regimens were older, this study didn´t analyze non-TBI-based regimens to prevent an age bias [12]. Secondary solid malignancies were subdivided into squamous cell carcinomas (SCCs) and non-squamous cell carcinomas (non-SCCs). Clinical data were extracted from the medical charts of the Departments of Radiation Oncology and Hematology of the University Hospital Regensburg. Transplantation variables included patient age at the time of TBI, conditioning regimens (RIC, 4 Gy TBI; MAC, 8 Gy and 12 Gy TBI), sex, diagnosis, Karnofsky performance score (KPS), hematopoietic cell transplantation-comorbidity index (HCT-CI) [13], 2017 European LeukemiaNet (ELN) genetic risk stratification [14], disease status before TBI, stem cell source, recipient and donor characteristics and GVHD prophylaxis. Graft-versus-host disease prophylaxis and conditioning regimens were dependent on the patient´s age, comorbidities and disease risk. The use of antithymocyte globulin (ATG) as part of GVHD prophylaxis was standard in unrelated donor transplantation and at the discretion of the physicians in sibling donor transplantation. Variables related to outcome were the cumulative incidences of secondary solid malignancies and precancerous lesions, relapse, non-relapse mortality (NRM), cGVHD (requiring systemic immunosuppression) and grade II-IV aGVHD. All patients received screening examinations for cutaneous malignancies before TBI. The screening of secondary malignancies after allo-HSCT included annual physical examinations, which encompassed examinations of the thyroid glands, skin, oropharynx and oral cavity. Patients suffering from cGVHD and those at high risk for developing cancers of the oropharynx and oral cavity were examined every 6 months. Gynecological and urological screenings for secondary solid malignancies were performed annually. Data closing was in October 2023. The local Ethics Board of the University of Regensburg approved this study (approval number, 20-1810-101).

TBI

Details of our TBI technique were previously published [15, 16]. We used Siemens Primus linear accelerators (Siemens Medical Systems, Inc., Concord, CA) and linear accelerators of type Elekta Synergy ™ with an Agility ™ head (Elekta Ltd, Crawley, UK) during the study period. All patients received rotational arcs with 6 megavoltage (MV) photon beams. We used a twice-daily fractionation and a minimum of 6 h between fractions. The average dose rate to the body was 4 cGy/min. Two individual lung shields of MCP96 with calculated thickness were designed if doses exceeded 8 Gy to reduce the total dose to the center of the lung to 7 Gy. Areas of the chest wall shielded by the lung blocks were irradiated once a day with electron beams to achieve full doses to the thoracic walls [15].

Definitions and statistical endpoints

Competing risks are common in survival data describing an event (e.g. premature deaths in patients before they could develop secondary malignancies) that prevents the event of interest, e.g. development of secondary malignancies [17, 18]. We used, therefore, the cumulative incidence function (CIF) to describe the cumulative incidences of secondary solid malignancies and precancerous lesions accounting for the competing risks of premature deaths among patients who did not develop secondary solid malignancies/precancerous lesions. Cause-specific hazard models analyzed the impact of pre-transplantation variables on the rates of secondary malignancies/precancerous lesions and the competing risks of premature deaths. Risk factors evaluated were patient age at TBI, TBI dose, ATG as part of GVHD prophylaxis, and cGVHD requiring immunosuppressive therapy. Age at TBI and TBI doses were analyzed as continuous variables. The impact of cGVHD changing value throughout the observation period on the rates of secondary solid malignancies/precancerous lesions was analyzed by applying a counting process format [19], while patients entered the risk set at the age of TBI. Secondary solid malignancies included solid cancers of any site and histology after TBI while excluding post-transplant lymphoproliferative disorders. The study recorded the times to the first secondary malignancy for patients developing ≥ 2 secondary malignancies. Acute GVHD and cGVHD were defined according to described standard criteria [20, 21]. Acute GVHD was classified as clinically significant at grade II-IV aGVHD. For the cumulative incidences of cGVHD requiring systemic immunosuppressive therapy, relapse or death without prior cGVHD was counted as a competing event. We captured non-relapse mortality (NRM) and relapse of AML. NRM was defined as deaths from any cause in the absence of prior relapse of the initial AML, with relapse considered a competing event. Relapse was defined as manifest hematologic relapse requiring treatment.

Statistical analysis

This study presents continuous variables as median and interquartile range (IQR) and categorical variables as absolute and relative frequencies. We used the cumulative incidence function (CIF) to estimate cumulative incidences of secondary malignancies and precancerous lesions, relapse, NRM, and cGVHD in the presence of competing risks [18]. CIF were compared using Gray´s test. The effects of transplantation variables on the rates of secondary malignancies/precancerous lesions and the competing risks of premature deaths were estimated with cause-specific hazard (CSH) analyses treating all other events as censored. The proportional hazards assumption of the CSH model was tested using Schoenfeld residuals. Hazard Ratio (HR) and 95% confidence intervals (95% CI) were presented as effect estimates. Median follow-up time was estimated using the reverse Kaplan-Meier method. All P-values were two-sided, and P-values < 0.05 were considered significant. Statistical analysis was performed using R, version 4.3.2 (R Core Team. R: A language for statistical computing. 2014. The R Foundation for Statistical Computing, Vienna, Austria) and SPSS 26.0 (SPSS Inc., Chicago, IL, USA).

Results

Patient and transplantation characteristics

Eighty-nine patients received TBI-based conditioning before 1st allo-HSCT. Table 1 summarizes transplant characteristics. Median patient age at TBI was 42.5 years (IQR, 32.5–51.2). The median follow-up time was 15.2 years (IQR, 13.0-18.2).

Table 1 Patients characteristics (n = 89)

Characteristics	value	
Follow-up, years, median (IQR)	15.2 (13.0-18.2)	
Patient age, median (IQR)	42.5 (32.5–51.2)	
Sex, n (%)		
male

female

	56 (62.9%)

33 (37.1%)

	
Diagnosis, n (%)		
de novo acute myeloid leukemia

secondary acute myeloid leukemia

	68 (76.4%)

21 (23.6%)

	
Karnofsky performance score		
< 80

≥ 80

	8 (9.0%)

81 (91.0%)

	
Hematopoietic cell transplantation-comorbidity index (HCT-CI), n (%)		
0

1–2

≥ 3

	40 (44.9%)

34 (38.2%)

15 (16.9%)

	
2017 ELN genetic risk stratification, n (%)		
favorable

intermediate

adverse

	13 (14.6%)

36 (40.4%)

40 (44.9%)

	
Disease status at allo-HSCT, n (%)		
First complete remission, CR1

CR2, first partial remission, PR1

> CR2, refractory, active disease

	31 (34.8%)

32 (36.0%)

26 (29.2%)

	
Donor type, n (%)		
matched sibling donor

matched unrelated donor

mismatched unrelated donor

	32 (36.0%)

50 (56.2%)

7 (7.9%)

	
Stem cell source, n (%)		
peripheral blood

bone marrow

	82 (92.1%)

7 (7.9%)

	
Conditioning regimens, n (%)		
reduced intensity (4 Gy TBI)

myeloablative intensity (8 Gy TBI, 12 Gy TBI)

	31 (34.8%)

58 (65.2%)

	
Donor age, years, median (IQR)	38.0 (30.5–44.0)	
Female donors to male recipients, n (%)		
yes

no

	14 (15.7%)

75 (84.3%)

	
Graftversushost disease prophylaxis, n (%)		
Cyclosporine, MTX

Cyclosporine, MMF

Post-transplant Cyclophosphamide, Tacrolimus, MMF

	57 (64.0%)

30 (33.7%)

2 (2.2%)

	
Antithymocyte globulin (ATG) *, n (%)		
yes

no

	61 (68.5%)

28 (31.5%)

	
CMV, cytomegalovirus; ELN, European LeukemiaNet; * ATG was part of graft-versus-host disease prophylaxis; MTX, Methotrexate; MMF, Mycophenolate Mofetil

Most patients (n = 47) received a myeloablative conditioning (MAC) regimen containing 8 Gy TBI. Reduced-intensity conditioning (RIC) regimens comprising 4 Gy TBI were applied in 31 patients, while eleven patients received MAC with 12 Gy TBI (Table 2). The median age of patients receiving RIC (4 Gy) and MAC (8–12 Gy) was 50.7 years (IQR, 41.0–59.0) and 38.9 years (IQR, 29.7–45.1). This difference was statistically significant (P < 0.001). ELN genetic risk classification was similar between RIC and MAC groups (P = 0.443), while the distribution of disease status at allo-HSCT was different (P < 0.001). Fifteen patients receiving RIC were in > 2nd complete remission (including refractory AML), while 11 patients receiving MAC were in > 2nd complete remission (including refractory AML). Most patients receiving MAC were in first complete remission (n = 28), while only 3 patients receiving RIC were in first complete remission at allo-HSCT. PR1 and CR2 were present in 13 patients receiving RIC and 19 patients receiving MAC.

Table 2 Conditioning regimens before allo-HSCT (n = 89)

Regimens	n (%)	
TBI 8 Gy, Cyclophosphamide, Fludarabine (myeloablative conditioning)

8 Gy TBI (four 2 Gy doses on two consecutive days, d -8, d -7), Cyclophosphamide 2 × 60 mg/kg (d -4, d -3), Fludarabine 3 × 30 mg/m² (d -6, d -5, d -4)

	42 (47.2%)	
FLAMSA-RIC, TBI 4 Gy, Cyclophosphamide (reduced-intensity conditioning)

FLAMSA regimen (d -12 to d -9), Fludarabine 4 × 30 mg/m², HD-Ara-C 4 × 2000 mg/m², Amsacrine 4 × 100 mg/m². Reduced intensity conditioning regimen after 3 days of rest: 4 Gy TBI on d -5 (two 2 Gy doses), Cyclophosphamide (2 × 40 mg/kg for MRD or 2 × 60 mg/kg for MUD, MMRD or MMUD) on d -4 to d -3,

Antithymocyte globulin (ATG) 10 mg/kg for MRD or 20 mg/kg for MUD, MMRD, MMUD from d -4 to d -2,

prophylactic donor lymphocyte infusions at day + 120 or 30 days after discontinuation of immunosuppression, 1–5 × 106 CD3+cells/kg

	31 (34.8%)	
TBI 12 Gy, Cyclophosphamide (myeloablative conditioning)

12 Gy TBI (six 2 Gy doses, on three consecutive days, d -7 to d -5), Cyclophosphamide 2 × 60 mg/kg on 2 consecutive days (d -4, d -3)

	11 (12.4%)	
TBI 8 Gy, Fludarabine (myeloablative conditioning)

8 Gy TBI (four 2 Gy doses on 2 consecutive days, d -5 and d -4), Fludarabine 4 × 30 mg/m² (d -5 to d -2)

	5 (5.6%)	
MRD, matched related donor; MUD, matched unrelated donor; MMRD, mismatched related donor; MMUD, mismatched unrelated donor

Chronic graft-versus-host disease

Two-year and 5-year cumulative incidences of cGVHD requiring systemic immunosuppression were 33% (95%CI, 23–42) and 36% (95%CI, 26–46). Twenty-nine patients had a history of grade II-IV aGVHD without cGVHD (requiring systemic immunosuppression), while 26 patients had neither aGVHD nor cGVHD. Eighteen patients had a history of aGVHD and cGVHD, while 16 patients had a history of cGVHD without prior aGVHD. Severe cGVHD was the most frequent maximum grade of cGVHD (n = 17) while twelve patients had moderate cGVHD, and five patients had mild cGVHD. Most patients had three or more cGVHD organ sites (median 3, IQR, 2–4). The most common sites of cGVHD in patients suffering from cGVHD were the skin (n = 24), oral mucosa (n = 20), eyes (n = 14), and liver (n = 11). The cumulative incidences of cGVHD (requiring systemic immunosuppression) in patients receiving RIC and MAC were similar over the entire follow-up period (P = 0.91). Two-year and 5-year cumulative incidences of cGVHD were 35% (95%CI, 19–53) and 39% (95%CI, 21–56) in patients receiving RIC, while patients receiving MAC showed 2-year and 5-year cumulative incidences of cGVHD of 31% (95%CI, 20–43) and 34% (95%CI, 22–47), respectively.

Secondary malignancies

Table 3 shows details of all secondary solid malignancies and precancerous lesions in 89 patients. Patient no. 290 was diagnosed with a pleomorphic undifferentiated sarcoma which appeared within less than a year after TBI. It was assumed that the sarcoma was present at the time of allo-HSCT. Therefore, this patient was excluded from further analyses resulting in 88 patients.

Table 3 Secondary solid malignancies and precancerous lesions after total body irradiation-based conditioning (n = 89)

No.	Secondary malignancies (SMs), precancerous lesions	TBI dose	Years from TBI to SMs,
† death due to SMs	Age at TBI	Sex	Chronic GVHD requiring systemic
immunosuppression, organs of involvement	Smoker	
	Non-squamous cell carcinomas (non-SCCs) in 8 patients							
419	Mucoepidermoid cancer, lower lip, T1 G1 R0	TBI 4 Gy	11.69	26.2	male	yes, skin. liver, joints	no	
266	Medullary thyroid cancer, pT1a pN0 L0 V0 R0	TBI 4 Gy	5.33	40.2	male	yes, skin, oral mucosa, eyes	no	
266	Cutaneous basal cell carcinoma, face	TBI 4 Gy	5.33	40.2	male	yes, skin, oral mucosa, eyes	no	
19	Mucoepidermoid carcinoma, major salivary gland, pT2 pN1 cM0	TBI 8 Gy	9.63	22.8	male	yes, oral mucosa, eyes, gastrointestinal, liver	no	
240	Cutaneous basal cell carcinoma, neck	TBI 8 Gy	12.73	45.8	male	no	yes	
240	Cutaneous basal cell carcinoma, face	TBI 8 Gy	12.73	45.8	male	no	yes	
290	Pleomorphic undifferentiated sarcoma, pT3 pN1 cM0 R1 *	TBI 8 Gy	0.88, † death after 0.74 years	51.6	female	yes, gastrointestinal	no	
117	Papillary thyroid cancer, pT1a L0 V0 R0	TBI 4 Gy	6.02	19.4	male	yes, skin, eyes	no	
96	Prostate cancer, adenocarcinoma	TBI 4 Gy	12.45, † death after 3.55 years	60.2	male	no	no	
96	Cutaneous basal cell carcinoma, face	TBI 4 Gy	16.0	60.2	male	no	no	
307	Cutaneous basal cell carcinoma, face	TBI 8 Gy	14.5	38.6	female	yes, skin	no	
307	Cutaneous basal cell carcinoma, face	TBI 8 Gy	14.5	38.6	female	yes, skin	no	
307	Cutaneous basal cell carcinoma, face	TBI 8 Gy	15.2	38.6	female	yes, skin	no	
307	Cutaneous basal cell carcinoma, face	TBI 8 Gy	16.7	38.6	female	yes, skin	no	
307	Cutaneous eccine carcinoma, face	TBI 8 Gy	18.2	38.6	female	yes, skin	no	
	Squamous cell carcinomas (SCCs) in 3 patients							
428	Cutaneous squamous cell carcinoma, face	TBI 8 Gy	3.20	52.7	male	yes, skin	no	
428	Cutaneous squamous cell carcinoma, face	TBI 8 Gy	3.50	52.7	male	yes, skin	no	
432	Cutaneous squamous cell carcinoma, face	TBI 8 Gy	16.98	22.9	male	no	yes	
9	Squamous cell carcinoma, lip, pT1 cN0 cM0	TBI 8 Gy	9.40	20.3	male	yes, skin, oral mucosa, CNS, gastrointestinal	no	
	Precancerous lesions, carcinomas in situ in 3 patients							
33	Severe intraepithelial neoplasia of the vagina (VIN3)	TBI 8 Gy	7.41	25.1	female	yes, skin, oral mucosa, liver, CNS, eyes, vaginal	no	
307	Cutaneous carcinoma in situ, ear	TBI 8 Gy	18.22	38.6	female	yes, skin	no	
412	Cutaneous carcinoma in situ, skin	TBI 4 Gy	3.79	48.6	male	yes, skin, oral mucosa, lung, eyes	no	
* It was assumed that the pleomorphic undifferentiated sarcoma which appeared within less than a year after TBI was present at the time of allo-HSCT. Therefore, this patient was excluded from further analyses

The cumulative incidences of secondary solid malignancies and precancerous lesions were 8% (95%CI, 4–16), 14% (95%CI, 7–23) and 17% (95%CI, 9–27) at 10, 15 and 20 years, while the cumulative incidences of premature deaths were 59% (95%CI, 48–69), 59% (95%CI, 48–69), and 64% (95%CI, 49–76), respectively. Seven patients developed at least one non-SCC. The most common non-SCCs were cutaneous basal cell carcinomas of the face, while two male patients developed thyroid cancers. The mean time from allo-HSCT to the development of the first non-SCC was 10 years (95%CI, 7–14). Four secondary SCCs occurred in 3 patients. Cutaneous SCCs were the most frequent SCCs. The mean time from allo-HSCT to the first SCC was 10 years (95%CI, -7-27).

Figure 1 shows the estimates of the cumulative incidences of secondary solid malignancies with 95% confidence intervals treating premature deaths among patients who did not develop secondary solid malignancies as competing risks. The cumulative incidences of secondary solid malignancies were 6% (95%CI, 2–13), 12% (95%CI, 6–20), and 14% (95%CI, 7–24) at 10, 15 and 20 years.

Fig. 1 Estimates of the cumulative incidences of secondary solid malignancies with 95% confidence intervals (n = 88)

The cumulative incidences of invasive non-SCCs were 4% (95%CI, 1–9), 10% (95%CI, 4–18), and 9% (95%CI, 4–18) at 10, 15 and 20 years. The cumulative incidences of invasive SCCs were 2% (95%CI, 1–8), 2% (95%CI, 1–8), and 5% (95%CI, 1–14) at 10, 15 and 20 years, respectively.

The cumulative incidences of relapse at 5, 10 and 15 years were 43% (95%CI, 33–53), 44% (95%CI, 34–54) and 44% (95%CI, 34–54), while the cumulative incidences of non-relapse mortality (NRM) were 16% (95%CI, 9–24), 18% (95%CI, 11–27) and 18% (95%CI, 11–27), respectively.

Hazard models for secondary solid malignancies and precancerous lesions and the competing risks of premature deaths

Table 4 shows the cause-specific hazards (HR CS) for secondary solid malignancies and precancerous lesions and the competing risks of premature deaths. In the multivariate regression models, older age at TBI translated into lower rates of secondary malignancies/precancerous lesions (HR cs 0.95, 95% CI, 0.90-1.00; P = 0.043). The analysis of competing events revealed that older patients showed a trend towards premature deaths (deaths before they could develop secondary malignancies/precancerous lesions, HR cs 1.02, 95%CI, 1.00-1.05; P = 0.069). Higher TBI doses (mainly applied in younger patients) translated into reduced rates of secondary malignancies/precancerous lesions (HR cs 0.76, 95% CI, 0.59–0.98; P = 0.035) while lacking associations with premature deaths. Chronic GVHD translated into increased rates of deaths before patients could develop secondary malignancies/precancerous lesions (HR cs 8.04, 95%CI, 3.97–16.3; P < 0.001).

Table 4 Cause-specific hazards (HR CS) for secondary malignancies/precancerous lesions and the competing risks of premature deaths (n = 88)

	Cause-specific hazard model for
secondary malignancies *	Cause-specific hazard model for
premature deaths before the development of secondary malignancies *	
Univariate analysis	Multivariate analysis	Univariate analysis	Multivariate analysis	
HRCS	95%CI	Pvalue	HRCS	95%CI	Pvalue	HRCS	95%CI	Pvalue	HRCS	95%CI	Pvalue	
Patient age †	0.96	0.91–1.02	0.2	0.95	0.90-1.00	0.043	1.03	1.00-1.05	0.028	1.02	1.00-1.05	0.069	
TBI dose ◊	0.82	0.65–1.03	0.091	0.76	0.59–0.98	0.035	0.92	0.83–1.02	0.11	1.00	0.89–1.12	> 0.9	
Chronic GVHD #	1.86	0.50–6.91	0.4	1.31	0.31–5.59	0.7	7.85	3.91–15.8	< 0.001	8.04	3.97–16.3	< 0.001	
ATG ‡	0.89	0.27–2.96	0.8	0.67	0.19–2.37	0.5	1.00	0.57–1.77	> 0.9	1.34	0.74–2.42	0.3	
* secondary solid malignancies of any histology including precancerous lesions; † patients entered the risk set at the age of TBI; ◊ TBI dose was analyzed metrically; # Chronic graft-versus-host disease (GVHD) requiring systemic immunosuppression was analyzed as time-dependent variable; ‡ Antithymocyte globulin (ATG) was part of GVHD prophylaxis

Discussion

The present study analyzed the cumulative incidences of secondary solid malignancies and precancerous lesions in AML patients conditioned with TBI before 1st allo-HSCT over 16 years. The cumulative incidences of secondary solid malignancies of any histology including precancerous lesions were 14% and 17% at 15 and 20 years, respectively. We acknowledge a selection bias as RIC containing 4 Gy TBI was applied in older patients with advanced disease status, while younger patients received higher doses of TBI. Multivariate analyses revealed that higher patient age at TBI translated into lower rates of secondary malignancies. The age dependency may be explained by the confounding of competing risks. Older patients mainly receiving lower doses of TBI died more frequently before they could develop treatment-related secondary malignancies. Nevertheless, our results indicate that higher doses of TBI, mainly applied in young patients, were associated with lower rates of secondary malignancies while lacking associations with other causes of mortality. The results partly support radiobiological assumptions and theoretical predictions of carcinogenesis after ionizing radiotherapy suggesting, that the incidence of radiation-induced malignancies increases with increasing radiation dose until a peak is reached and then decreases rapidly [22–24]. Low-dose radiotherapy is not immediately lethal but induces sub-lethal DNA damages and mutations, increasing the risks of carcinogenesis over time. Contrarily, high doses of radiotherapy inducing direct cell death and apoptosis may prevent mutations, and thus carcinogenesis as cell kill becomes the predominant effect. However, the exact dose peak at which cell killing outweighs cell mutation is difficult to predict as molecular, cellular, and tissue-specific factors are integral [22, 23]. Boice et al. [24] analyzed the relationship between radiation doses and leukemia risk after radiotherapy for cancer of the cervix, supporting the radiobiological considerations of carcinogenesis after therapy showing an increased risk for radiation-induced leukemia up to doses of about 4 Gy and a decreased risk at higher doses. Regardless of these radiobiological considerations, we acknowledge the bias of competing risks and the small number of secondary malignancies as confounders in the present analysis.

A reason for making a comparison between studies focusing on the second cancer risk after TBI difficult is the fact that the literature on TBI shows variability in planning and treatment with TBI [25]. Although dose rates of 7.5 cGy/min or less and a twice-daily fractionation are recommended, dose rates and photon energy vary from 2.25 to 37.5 cGy/min and 6 to 25 MV, influencing the risks of secondary solid malignancies after TBI [25]. Furthermore, some studies provide no information about dose rates and the application of lung shielding, which contributes to different toxicity and organ damage after treatment.

Several studies examined the influence of pre-transplantation variables on the risks of second cancers after TBI- and non-TBI-based conditioning [11, 26, 27]. In summary, carcinogenesis after allo-HSCT remains multifactorial, while the number of pretransplant chemotherapy cycles [27], age at exposure, GVHD [12] and its treatment seem to be relevant. Environmental and genetic factors with variabilities in individual susceptibility to DNA-damaging therapies additionally influence the risks of secondary malignancies after allo-HSCT [22, 23]. Scott et al. [28] indicated that clinically photodamaged skin and a history of cutaneous SCC are important risk factors for non-melanoma skin cancer after allo-HSCT, factors not analyzed in the present study. However, the results of the present study are not entirely consistent with other recent studies, which excluded non-melanoma skin cancers or comprised different primary diagnoses. Leisenring et al. [7] analyzed skin and mucosal SCCs and BCCs after TBI- and non-TBI-based conditioning concluding that TBI increases the risks of BCCs but not of SCCs. Modern fractionation with fractionated doses < 13 Gy did not affect the hazards of BCCs in contrast to TBI applied as a single dose and fractionated doses ≥ 13 Gy. Both are no longer recommended as standard [7]. Chronic GVHD and its immunosuppressive therapy seem to increase the risks of SCCs of the skin and mucosa [5, 29], while associations of cGVHD with non-SCCs are less pronounced. The present analysis lacks an association of cGVHD with secondary malignancies (of any histology), which is most likely due to the small patient group. Yet, cGVHD, which represents a main cause of long-term morbidity and mortality, was associated with premature deaths before patients could develop secondary malignancies. Life-long surveillance for secondary malignancies is mandatory for all transplant survivors. Examinations include examinations of the thyroid glands, skin, genitals, and oropharynx [30]. With the help of yearly follow-up examinations, two thyroid cancers were diagnosed in 2 men suffering from cGVHD, which is a known additional risk factor for secondary thyroid cancers [8]. In summary, cutaneous non-melanocytic cancers (BCCs, SCCs) were the most frequent cancer types after TBI, which is in line with recent data demonstrating non-melanocytic skin cancers as the most common cancer types in Germany [31]. The retrospective design and the small number of patients conditioned with TBI limit this study. The study was not powered to analyze risk factors for secondary malignancies of specific anatomical sites and histological subtypes. Moreover, the small number of secondary malignancies apart from non-melanoma skin cancer reduced the generalizability of the results. In addition, the selection bias to treat young patients with TBI and older patients with non-TBI-based regimens, prohibited comparisons of TBI and non-TBI patients regarding secondary malignancies. Nevertheless, the primary strength of the present study is the consistent delivery of modern TBI over 16 years.

Conclusions

This study indicates a potential inverse relationship between the risk for secondary malignancies and TBI doses applied and is consistent with radiobiological considerations, which assume a decrease in secondary malignancies at high doses. Yet, confounding by competing risks remains a limitation. The use of lower TBI doses in older patients interferes with the age-related increased mortality not caused by secondary malignancies. Therefore, older patients appeared to have lower risks for secondary malignancies than younger patients. This study illustrates the pitfalls of not reporting and considering competing risks in survival data which is relevant in evaluation of newer technologies, such as total marrow irradiation (TMI) and volumetric modulated arc therapy (VMAT) and associated risk assessment for carcinogenesis.

Acknowledgements

Not applicable.

Author contributions

Material preparation, data collection and analysis were performed by GI. The manuscript was written by GI. WD provided patient samples and contributed to the conception and interpretation of the work. KO contributed to the interpretation of the work including the radiobiological considerations. All authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

Funding

GI and KO received no funding. WD received research support from Novartis and honoraria from Novartis, Sanofi, Incyte, Behring, Neovii, Takeda and Mallinckrodt.

Open Access funding enabled and organized by Projekt DEAL.

Data availability

The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.

Declarations

Ethics approval and consent to participate

The study was performed in line with the principles of the Declaration of Helsinki. Approval was granted by the Ethics Committee of University Regensburg (number, 20-1810-101, date, February 10, 2021). Informed consent was obtained from all individual participants included in the study.

Consent for publication

Not applicable.

Competing interests

Wolff Daniel received research support from Novartis and honoraria from Novartis, Sanofi, Incyte, Behring, Neovii, Takeda and Mallinckrodt.

Abbreviations

TBI Total body irradiation

allo-HSCT Allogeneic hematopoietic stem cell transplantation

AML Acute myeloid leukemia

SSM Secondary solid malignancy

IQR Interquartile range

NRM Non-relapse mortality

cGVHD Chronic graft-versus-host disease

MAC Myeloablative conditioning

RIC Reduced-intensity conditioning

SCCs Squamous cell carcinomas

KPS Karnofsky performance score

HCT-CI Hematopoietic cell transplantation-comorbidity index

ELN European LeukemiaNet

ATG Antithymocyte globulin

MV Megavoltage

CIF Cumulative incidence function

CSH Cause-specific hazard

HR Hazard ratio

CI Confidence interval

CR1 First complete remission

PR1 First partial remission

CR2 Second complete remission

FLAMSA Fludarabine, HD-Ara-C, Amsacrine

MRD Matched related donor

MUD Matched unrelated donor

MMRD Mismatched related donor

MMUD Mismatched unrelated donor

VIN Intraepithelial neoplasia of the vagina

CNS Central nervous system

TMI Total marrow irradiation

VMAT Volumetric modulated arc therapy

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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References

1. Kolb HJ Socié G Duell T Van Lint MT Tichelli A Apperley JF Malignant neoplasms in long-term survivors of bone marrow transplantation. Late effects Working Party of the European Cooperative Group for Blood and Marrow Transplantation and the European late Effect Project Group Ann Intern Med 1999 131 10 738 44 10.7326/0003-4819-131-10-199911160-00004 10577296
Kolb HJ, Socié G, Duell T, Van Lint MT, Tichelli A, Apperley JF, et al. Malignant neoplasms in long-term survivors of bone marrow transplantation. Late effects Working Party of the European Cooperative Group for Blood and Marrow Transplantation and the European late Effect Project Group. Ann Intern Med. 1999;131(10):738–44.10577296
2. Bacigalupo A Ballen K Rizzo D Giralt S Lazarus H Ho V Defining the intensity of conditioning regimens: working definitions Biol Blood Marrow Transpl 2009 15 12 1628 33 10.1016/j.bbmt.2009.07.004
Bacigalupo A, Ballen K, Rizzo D, Giralt S, Lazarus H, Ho V, et al. Defining the intensity of conditioning regimens: working definitions. Biol Blood Marrow Transpl. 2009;15(12):1628–33.
3. Scott BL Pasquini MC Logan BR Wu J Devine SM Porter DL Myeloablative Versus reduced-intensity hematopoietic cell transplantation for Acute myeloid leukemia and myelodysplastic syndromes J Clin Oncol off J Am Soc Clin Oncol 2017 35 11 1154 61 10.1200/JCO.2016.70.7091
Scott BL, Pasquini MC, Logan BR, Wu J, Devine SM, Porter DL, et al. Myeloablative Versus reduced-intensity hematopoietic cell transplantation for Acute myeloid leukemia and myelodysplastic syndromes. J Clin Oncol off J Am Soc Clin Oncol. 2017;35(11):1154–61.
4. Sengsayadeth S Savani BN Blaise D Malard F Nagler A Mohty M Reduced intensity conditioning allogeneic hematopoietic cell transplantation for adult acute myeloid leukemia in complete remission - a review from the Acute Leukemia Working Party of the EBMT Haematologica 2015 100 7 859 69 10.3324/haematol.2015.123331 26130513
Sengsayadeth S, Savani BN, Blaise D, Malard F, Nagler A, Mohty M. Reduced intensity conditioning allogeneic hematopoietic cell transplantation for adult acute myeloid leukemia in complete remission - a review from the Acute Leukemia Working Party of the EBMT. Haematologica. 2015;100(7):859–69.26130513
5. Rizzo JD Curtis RE Socié G Sobocinski KA Gilbert E Landgren O Solid cancers after allogeneic hematopoietic cell transplantation Blood 2009 113 5 1175 83 10.1182/blood-2008-05-158782 18971419
Rizzo JD, Curtis RE, Socié G, Sobocinski KA, Gilbert E, Landgren O, et al. Solid cancers after allogeneic hematopoietic cell transplantation. Blood. 2009;113(5):1175–83.18971419
6. Majhail NS Brazauskas R Rizzo JD Sobecks RM Wang Z Horowitz MM Secondary solid cancers after allogeneic hematopoietic cell transplantation using busulfan-cyclophosphamide conditioning Blood 2011 117 1 316 22 10.1182/blood-2010-07-294629 20926773
Majhail NS, Brazauskas R, Rizzo JD, Sobecks RM, Wang Z, Horowitz MM, et al. Secondary solid cancers after allogeneic hematopoietic cell transplantation using busulfan-cyclophosphamide conditioning. Blood. 2011;117(1):316–22.20926773
7. Leisenring W Friedman DL Flowers MED Schwartz JL Deeg HJ Nonmelanoma skin and mucosal cancers after hematopoietic cell transplantation J Clin Oncol 2006 24 7 1119 26 10.1200/JCO.2005.02.7052 16461782
Leisenring W, Friedman DL, Flowers MED, Schwartz JL, Deeg HJ. Nonmelanoma skin and mucosal cancers after hematopoietic cell transplantation. J Clin Oncol. 2006;24(7):1119–26.16461782
8. Cohen A Rovelli A Merlo DF Van Lint MT Lanino E Bresters D Risk for secondary thyroid carcinoma after hematopoietic stem-cell transplantation: an EBMT late effects working party study J Clin Oncol 2007 25 17 2449 54 10.1200/JCO.2006.08.9276 17557958
Cohen A, Rovelli A, Merlo DF, Van Lint MT, Lanino E, Bresters D, et al. Risk for secondary thyroid carcinoma after hematopoietic stem-cell transplantation: an EBMT late effects working party study. J Clin Oncol. 2007;25(17):2449–54.17557958
9. Friedman DL Rovo A Leisenring W Locasciulli A Flowers MED Tichelli A Increased risk of breast cancer among survivors of allogeneic hematopoietic cell transplantation: a report from the FHCRC and the EBMT-Late Effect Working Party Blood 2008 111 2 939 44 10.1182/blood-2007-07-099283 17911386
Friedman DL, Rovo A, Leisenring W, Locasciulli A, Flowers MED, Tichelli A, et al. Increased risk of breast cancer among survivors of allogeneic hematopoietic cell transplantation: a report from the FHCRC and the EBMT-Late Effect Working Party. Blood. 2008;111(2):939–44.17911386
10. Martelin E Volin L Itälä-Remes M Niittyvuopio R Lindström V Heiskanen J Incidence and risk factors of secondary cancers after allogeneic stem cell transplantation: analysis of a single centre cohort with a long follow-up Bone Marrow Transpl 2019 54 2 334 7 10.1038/s41409-018-0290-6
Martelin E, Volin L, Itälä-Remes M, Niittyvuopio R, Lindström V, Heiskanen J, et al. Incidence and risk factors of secondary cancers after allogeneic stem cell transplantation: analysis of a single centre cohort with a long follow-up. Bone Marrow Transpl. 2019;54(2):334–7.
11. Baker KS Leisenring WM Goodman PJ Ermoian RP Flowers ME Schoch G Total body irradiation dose and risk of subsequent neoplasms following allogeneic hematopoietic cell transplantation Blood 2019 133 26 2790 9 10.1182/blood.2018874115 30992266
Baker KS, Leisenring WM, Goodman PJ, Ermoian RP, Flowers ME, Schoch G, et al. Total body irradiation dose and risk of subsequent neoplasms following allogeneic hematopoietic cell transplantation. Blood. 2019;133(26):2790–9.30992266
12. Isabella G Katharina A Matthias E Oliver K Daniel W Secondary solid malignancies and precancerous lesions after allogeneic hematopoietic stem cell transplantation using non-total body irradiation-based conditioning in acute myeloid leukemia J Cancer Res Clin Oncol 2024 150 3 152 10.1007/s00432-024-05679-5 38517548
Isabella G, Katharina A, Matthias E, Oliver K, Daniel W. Secondary solid malignancies and precancerous lesions after allogeneic hematopoietic stem cell transplantation using non-total body irradiation-based conditioning in acute myeloid leukemia. J Cancer Res Clin Oncol. 2024;150(3):152.38517548
13. Sorror ML Maris MB Storb R Baron F Sandmaier BM Maloney DG Hematopoietic cell transplantation (HCT)-specific comorbidity index: a new tool for risk assessment before allogeneic HCT Blood 2005 106 8 2912 9 10.1182/blood-2005-05-2004 15994282
Sorror ML, Maris MB, Storb R, Baron F, Sandmaier BM, Maloney DG, et al. Hematopoietic cell transplantation (HCT)-specific comorbidity index: a new tool for risk assessment before allogeneic HCT. Blood. 2005;106(8):2912–9.15994282
14. Döhner H Estey E Grimwade D Amadori S Appelbaum FR Büchner T Diagnosis and management of AML in adults: 2017 ELN recommendations from an international expert panel Blood 2017 129 4 424 47 10.1182/blood-2016-08-733196 27895058
Döhner H, Estey E, Grimwade D, Amadori S, Appelbaum FR, Büchner T, et al. Diagnosis and management of AML in adults: 2017 ELN recommendations from an international expert panel. Blood. 2017;129(4):424–47.27895058
15. Gruber I Koelbl O Treutwein M Zeman F Herr W Holler E Analysis of long-term mortality after total body irradiation-based and melphalan-based chemotherapy conditioning for acute myeloid leukemia Ann Hematol 2023 102 8 2199 211 10.1007/s00277-023-05318-y 37347269
Gruber I, Koelbl O, Treutwein M, Zeman F, Herr W, Holler E, et al. Analysis of long-term mortality after total body irradiation-based and melphalan-based chemotherapy conditioning for acute myeloid leukemia. Ann Hematol. 2023;102(8):2199–211.37347269
16. Härtl PM Treutwein M Hautmann MG März M Pohl F Kölbl O Total body irradiation-an attachment free sweeping beam technique Radiat Oncol 2016 11 81 10.1186/s13014-016-0658-y 27287010
Härtl PM, Treutwein M, Hautmann MG, März M, Pohl F, Kölbl O, et al. Total body irradiation-an attachment free sweeping beam technique. Radiat Oncol. 2016;11:81.27287010
17. Lau B Cole SR Gange SJ Competing risk regression models for epidemiologic data Am J Epidemiol 2009 170 2 244 56 10.1093/aje/kwp107 19494242
Lau B, Cole SR, Gange SJ. Competing risk regression models for epidemiologic data. Am J Epidemiol. 2009;170(2):244–56.19494242
18. Austin PC Lee DS Fine JP Introduction to the Analysis of Survival Data in the Presence of competing risks Circulation 2016 133 6 601 9 10.1161/CIRCULATIONAHA.115.017719 26858290
Austin PC, Lee DS, Fine JP. Introduction to the Analysis of Survival Data in the Presence of competing risks. Circulation. 2016;133(6):601–9.26858290
19. Austin PC Latouche A Fine JP A review of the use of time-varying covariates in the Fine-Gray subdistribution hazard competing risk regression model Stat Med 2020 39 2 103 13 10.1002/sim.8399 31660633
Austin PC, Latouche A, Fine JP. A review of the use of time-varying covariates in the Fine-Gray subdistribution hazard competing risk regression model. Stat Med. 2020;39(2):103–13.31660633
20. Filipovich AH Weisdorf D Pavletic S Socie G Wingard JR Lee SJ National Institutes of Health Consensus Development Project on Criteria for clinical trials in chronic graft-versus-host disease: I. diagnosis and staging Working Group Report Biol Blood Marrow Transpl 2005 11 12 945 56 10.1016/j.bbmt.2005.09.004
Filipovich AH, Weisdorf D, Pavletic S, Socie G, Wingard JR, Lee SJ, et al. National Institutes of Health Consensus Development Project on Criteria for clinical trials in chronic graft-versus-host disease: I. diagnosis and staging Working Group Report. Biol Blood Marrow Transpl. 2005;11(12):945–56.
21. Jagasia MH Greinix HT Arora M Williams KM Wolff D Cowen EW National Institutes of Health Consensus Development Project on Criteria for clinical trials in chronic graft-versus-host disease: I. The 2014 diagnosis and staging Working Group Report Biol Blood Marrow Transpl 2015 21 3 389 e4011 10.1016/j.bbmt.2014.12.001
Jagasia MH, Greinix HT, Arora M, Williams KM, Wolff D, Cowen EW, et al. National Institutes of Health Consensus Development Project on Criteria for clinical trials in chronic graft-versus-host disease: I. The 2014 diagnosis and staging Working Group Report. Biol Blood Marrow Transpl. 2015;21(3):389–e4011.
22. Lindsay KA Wheldon EG Deehan C Wheldon TE Radiation carcinogenesis modelling for risk of treatment-related second tumours following radiotherapy Br J Radiol 2001 74 882 529 36 10.1259/bjr.74.882.740529 11459732
Lindsay KA, Wheldon EG, Deehan C, Wheldon TE. Radiation carcinogenesis modelling for risk of treatment-related second tumours following radiotherapy. Br J Radiol. 2001;74(882):529–36.11459732
23. Epstein R Hanham I Dale R Radiotherapy-induced second cancers: are we doing enough to protect young patients? Eur J Cancer 1997 33 4 526 30 10.1016/S0959-8049(97)00056-7 9274430
Epstein R, Hanham I, Dale R. Radiotherapy-induced second cancers: are we doing enough to protect young patients? Eur J Cancer. 1997;33(4):526–30.9274430
24. Boice JDJ Blettner M Kleinerman RA Stovall M Moloney WC Engholm G Radiation dose and leukemia risk in patients treated for cancer of the cervix J Natl Cancer Inst 1987 79 6 1295 311 3480381
Boice JDJ, Blettner M, Kleinerman RA, Stovall M, Moloney WC, Engholm G, et al. Radiation dose and leukemia risk in patients treated for cancer of the cervix. J Natl Cancer Inst. 1987;79(6):1295–311.3480381
25. Giebel S Miszczyk L Slosarek K Moukhtari L Ciceri F Esteve J Extreme heterogeneity of myeloablative total body irradiation techniques in clinical practice: a survey of the acute leukemia working party of the European group for blood and marrow transplantation Cancer 2014 120 17 2760 5 10.1002/cncr.28768 24804873
Giebel S, Miszczyk L, Slosarek K, Moukhtari L, Ciceri F, Esteve J, et al. Extreme heterogeneity of myeloablative total body irradiation techniques in clinical practice: a survey of the acute leukemia working party of the European group for blood and marrow transplantation. Cancer. 2014;120(17):2760–5.24804873
26. Sieker K Fleischmann M Trommel M Ramm U Licher J Bug G Twenty years of experience of a tertiary cancer center in total body irradiation with focus on oncological outcome and secondary malignancies Strahlentherapie Und Onkol 2022 198 6 547 57 10.1007/s00066-022-01914-5
Sieker K, Fleischmann M, Trommel M, Ramm U, Licher J, Bug G, et al. Twenty years of experience of a tertiary cancer center in total body irradiation with focus on oncological outcome and secondary malignancies. Strahlentherapie Und Onkol. 2022;198(6):547–57.
27. Nunez L Abedin T Naqvi S Shen H Chaudhry A Bellerby S Cumulative incidence of subsequent malignancy after allo-HCT conditioned with or without low-dose total body irradiation Blood Adv 2022 6 3 767 73 10.1182/bloodadvances.2020003910 34995342
Nunez L, Abedin T, Naqvi S, Shen H, Chaudhry A, Bellerby S, et al. Cumulative incidence of subsequent malignancy after allo-HCT conditioned with or without low-dose total body irradiation. Blood Adv. 2022;6(3):767–73.34995342
28. Scott JF Brough KR Grigoryan KV Muzic JG Kim GY Conic RRZ Risk factors for Keratinocyte Carcinoma in recipients of allogeneic hematopoietic cell transplants JAMA Dermatology 2020 156 6 631 9 10.1001/jamadermatol.2020.0559 32267479
Scott JF, Brough KR, Grigoryan KV, Muzic JG, Kim GY, Conic RRZ, et al. Risk factors for Keratinocyte Carcinoma in recipients of allogeneic hematopoietic cell transplants. JAMA Dermatology. 2020;156(6):631–9.32267479
29. Curtis RE Metayer C Rizzo JD Socié G Sobocinski KA Flowers MED Impact of chronic GVHD therapy on the development of squamous-cell cancers after hematopoietic stem-cell transplantation: an international case-control study Blood 2005 105 10 3802 11 10.1182/blood-2004-09-3411 15687239
Curtis RE, Metayer C, Rizzo JD, Socié G, Sobocinski KA, Flowers MED, et al. Impact of chronic GVHD therapy on the development of squamous-cell cancers after hematopoietic stem-cell transplantation: an international case-control study. Blood. 2005;105(10):3802–11.15687239
30. Socié G Rizzo JD Second solid tumors: screening and management guidelines in long-term survivors after allogeneic stem cell transplantation Semin Hematol 2012 49 1 4 9 10.1053/j.seminhematol.2011.10.013 22221779
Socié G, Rizzo JD. Second solid tumors: screening and management guidelines in long-term survivors after allogeneic stem cell transplantation. Semin Hematol. 2012;49(1):4–9.22221779
31. Nanz L Keim U Katalinic A Meyer T Garbe C Leiter U Epidemiology of keratinocyte skin Cancer with a focus on cutaneous squamous cell carcinoma Cancers (Basel) 2024 16 3 1 12 10.3390/cancers16030606
Nanz L, Keim U, Katalinic A, Meyer T, Garbe C, Leiter U. Epidemiology of keratinocyte skin Cancer with a focus on cutaneous squamous cell carcinoma. Cancers (Basel). 2024;16(3):1–12.
