Page 1685 - Hematology_ Basic Principles and Practice ( PDFDrive )

Chapter 93 Late Complications of Hematologic Diseases and Their Therapies 1503

Abnormalities involving chromosomes 5 (-5/del[5q]) and 7 (-7/ invasive breast SMN at 30 years after diagnosis is 18.3%, with no
del[7q]) are frequently seen. AML secondary to topoisomerase II apparent plateau in incidence within the cohort at this time. 242
inhibitors presents as overt leukemia, without a preceding myelodys- With extended follow-up of cohorts of young HL survivors,
plastic phase. The latency is brief, ranging from 6 months to 5 years, increased risks for common adult carcinomas, including colorectal,
and is associated with balanced translocations involving chromosome lung, and stomach, have emerged, and these cancers are being diag-
237
bands 11q23 or 21q22. nosed at younger ages than observed in the general population. In
a large population-based study of solid tumor risk among 18,862
Subsequent Malignancies Among Survivors of 5-year survivors reported to 13 registries, breast, lung, and gastro-
intestinal cancers accounted for almost two-thirds of the estimated
Acute Lymphoblastic Leukemia excess number of cases. 251
Evaluation of large cohorts of patients with childhood ALL entered
on Children’s Oncology Group therapeutic trials have shown that the Subsequent Breast Cancer
cumulative incidence of second and subsequent malignancies
approaches 4% at 15 years from diagnosis of ALL. 229–231 CNS tumors, Breast cancer is the most common solid SMN after HL, largely due
the most common subsequent malignancy observed among survivors to chest radiation for treatment of HL. The risk of radiation-related
of childhood ALL, are predominantly associated with exposure to breast cancer among female HL survivors ranges from 25-fold to
232
cranial irradiation. Histologically, radiation-related late-occurring 55-fold that of the general population.* For female HL patients
neoplasms include high-grade gliomas (glioblastomas and malignant treated with chest radiation at less than 16 years of age, the cumula-
astrocytomas), peripheral neuroectodermal tumors, ependymomas tive incidence of breast cancer approaches 20% by age 45 years. 237,242
and meningiomas, and basal cell carcinomas (BCCs). 229,230,233,234 The latency after chest radiation ranges from 7 to 10 years, and
Other commonly reported subsequent malignancies among ALL the risk of breast cancer increases in a linear fashion with radiation
survivors include thyroid cancer and t-MDS/AML. Secondary dose, with an estimated RR of 6.4 at a dose of 20 Gy and 11.8 at a
thyroid malignancies are generally associated with radiation exposure dose of 40 Gy. 242,258 Moreover, 40% of identified cases were found to
to the thyroid gland as part of CNS irradiation, either prophylactic have developed contralateral disease. Among women treated for
or for treatment of CNS leukemia. Thyroid malignancy has been childhood cancer with chest RT, those treated with whole-lung
reported to represent between 6% and 17% of secondary cancers irradiation have a greater risk of breast cancer than previously recog-
259
among large cohorts of ALL survivors 229,230,232 and typically develops nized, demonstrating the importance of radiation volume. There
10 or more years from treatment. The risk of t-MDS/AML after appears to be a protective effect of early menopause either because of
therapy for ALL is generally low, except among those patients treated alkylating agents or radiation dose above 5 Gy to the ovaries, sug-
with epipodophyllotoxin therapy, where a cumulative risk of 3.8% at gesting that ovarian hormones play an important role in promoting
235
6 years has been reported. Therapy-related AML associated with tumorigenesis once an initiating event has been produced by radia-
topoisomerase II inhibitors is characterized typically by a shorter tion. 257,258,260 The 25-year cumulative incidence of breast cancer is
261
latency period (3–5 years from therapeutic exposure) than that seen reported to be 11% after allogeneic HCT. Allogeneic HCT survi-
for t-MDS/AML after alkylating agents, lack of a myelodysplastic vors are at a 2.2-fold increased risk for developing breast cancer when
phase, and the presence of 11q23 rearrangements with mutations in compared with an age and sex-matched general population. The
the mixed-lineage leukemia (MLL) gene. Epipodophyllotoxin- median latency from HCT to diagnosis of breast cancer is 12.5 years.
associated secondary AML depends more on the schedule of drug The incidence is higher among those exposed to TBI (17%) than
administration than total cumulative dose. 236 among those who did not receive TBI (3%). The risk is increased
among those exposed to TBI at a younger age. The substantially
Subsequent Malignancies Among Survivors of increased RRs of breast cancer observed at 10–20 years postdiagnosis
are not sustained into ages at which the risk of breast cancer in the
Hodgkin Lymphoma general population becomes substantial; among women who survived
to an age of at least 50 years, there is currently no evidence of an
Survivors of HL demonstrate the highest risk for subsequent malig- increased risk of breast cancer compared with the general popula-
262
nancies. This is particularly true for patients treated in the earlier eras tion. Importantly, mortality associated with breast cancer after
with predominantly radiation-based therapies; these patients are at childhood cancer is substantial; breast cancer–specific mortality at 5
237
10-fold increased risk when compared with the general population. and 10 years was 12% and 19%, respectively. 259
263
A number of studies, with cohorts ranging from 499 to 5925 HL Travis et al developed estimates of cumulative absolute risk for
patients, have reported the cumulative incidence of second malignan- use in counseling patients. For example, the cumulative absolute risks
cies to range from 7.6% at 20 years to 18.0% at 30 years. 232,238–242 for an HL survivor who was treated at age 25 years with a chest
The sex difference in a 30-year cumulative incidence of any SMN of radiation dose of 40 Gy or more without alkylating agents were
10.9% among males and 26.1% in females (p < .001) is driven by estimated to be 1.4% after 10 years, 11% after 20 years, and 29%
the incidence of invasive breast cancer. 242 after 30 years.
Early studies of HL identified the increased risk for t-MDS/AML
among patients treated with MOPP-based therapy, which included
mechlorethamine and cyclophosphamide. 243,244 These alkylating Subsequent Thyroid Cancer
agent-associated t-MDS/AMLs are characterized by a relatively short
latency period, presence of chromosomal abnormalities involving Thyroid cancer is observed after neck radiation for HL, ALL, and
chromosomes 5 and/or 7, and are often preceded by a phase of brain tumors, and after TBI for HCT. 219,232,264 The risk of thyroid
myelodysplasia. The risk for t-MDS/AML usually does not extend cancer has been reported to be 18-fold that of the general popula-
95
beyond the first 10–15 years after therapeutic exposure. Extended tion. RT at a young age is the major risk factor for the development
follow-up studies of early cohorts have already reported excess risks of thyroid cancer. A linear dose–response relationship between
for lung and gastrointestinal cancers. 237,245–248 More recent studies, thyroid cancer and radiation is observed up to 20 Gy, with a decline
with longer follow-up of cohorts, demonstrate that the most fre- in the OR at higher doses, demonstrating evidence for a cell kill
quently observed solid second malignancies include breast cancer, effect. 265,266 Female sex, younger age at exposure, and longer time
thyroid cancer, and bone/soft tissue sarcomas. 237,248–250 Compared since exposure are significant modifiers of the radiation-related risk
with the general US population, SIRs are highest for bone cancer
22.3 (95% CI: 10.0–49.6), thyroid cancer 17.6, and breast cancer
17.0 per 10,000 person-years, respectively. Cumulative incidence of *References 219, 232, 237, 238, 248, 249, 252–257.