Efecte endocrine tardive ale [630555]

Efecte endocrine tardive ale
terapiei cancerului
Monica Gheorghiu
Sef lucrari UMF Carol Davila
Institutul National de Endocrinologie C.I.
Parhon

Improvement in Cure Rate of
Childhood Cancer
◼Prior to 1970 most
patients did not
survive
◼Over the last 30
years the cure rate
has steadily
increased (80%)
80.480.4
1.4 % / Year1.4 % / YearIncrease in Cure Rate (Survival Plateau)
has been Steady and Linear
606070708080
19751975 19851985 19951995%%
CureCure
5050C C GC C G
BleyerBleyer
Jemal A et al, Cancer statistics, 2006. CA: A Cancer Journal for Clinicians 2006

Improvement in Cure Rate of
childhood cancer
◼Due to intensive combinations of
treatment, including
◼Surgery
◼Chemotherapy
◼Radiation
◼Bone Marrow Transplant
◼Immune modulation
◼Supportive Care

Cost of Survival
◼At least 60 -70% of long term survivors of childhood cancer will
have at least one late effect of the cancer or its treatment
◼25-30% will have severe or life threatening late effects
◼Late effects may be obvious or subtle
◼Can occur at any time after treatment from early childhood to
late adulthood
◼Late effects may be exacerbated or precipitated by other health
problems later in life
◼Late effects impact quality of life and quantity of life
Oeffinger KC et al. Chronic health conditions in adult survivors of childhood cancer. NEJM 2006; 355 Estimation: currently 1 in 640 adults aged 20 –39 years (USA),
1 in 715 young adults (UK) by 2010 will be a survivor of childhood cancer

Long Term Challenges
Survivors of > 5 years = 10.8 x excess in overall mortality
(67% of deaths = recurrence of the original tumor)
◼Second Malignancy –SMR 19.4 (standardized mortality rates) 1
◼Cardiac (SMR 8.2)
◼Lungs (SMR 9.2)
◼Neurocognitive (all other causes SMR 3.3)
◼Psychosocial
◼Endocrine (43% including fertility, growth, bone compos)2
◼Fertility
◼Growth, Bone composition
◼Immunologic
1. Mertens AC et al, Childhood Cancer Survivors Study (CCSS) .J Clin Oncol 2001; 19: 3163 -3172
2. Gurney JG et al, Cancer 2003; 97: 663 -673

Second Malignancy
◼Cumulative incidence of 3 -10% at 20 years post
treatment, = 5 -10x increased
◼Breast cancer
◼Cumulative incidence of 35% at 20 -25 years post mantle XRT
◼Median incidence at 15 years post XRT
◼Median age 31
◼Thyroid,Salivary gland, Skin, Brain, Bone cancer 20to XRT
◼Leukemia 20 to alkylating agents and topoisomerase II inhibitors
◼Genetic predisposition to cancer
◼Awareness of risk and early detection will improve
survival

Endocrine dysfunction
◼Affects 20 -50%
◼Thyroid dysfunction
◼Growth hormone deficiency
◼Sex hormones
◼Fertility
◼Adrenal insufficiency
◼Obesity

Prevalence of endocrine disorders in 310 adults,
survivors of childhood cancer, followed for a median time
of 16.0 years after the first cancer diagnosis (2013)
-At the last follow -up visit available, 48.46% of females and62.78% of
males were affected by at least one endocrine disease
-The most common disorders were gonadal dysfunction, primary
hypothyroidism, and GH deficiency (GHD).
-The main risk factors for endocrine disease were:
-male sex (hazard ratio (HR)=1.45, (95% CI 1.05 –1.99)
-radiotherapy (HR=1.91, 95% CI 1.28 –2.84)
-hematopoietic stem cells transplantation (HR=3.11, 95% CI 2.23 –4.34)
-older age at cancer diagnosis (HR=1.89, 95% CI 1.25 –2.85).
E Brignardello, F Felicetti, A Castiglione, P Chiabotto, A Corrias, F Fagioli, G Ciccone and G Boccuzzi,
European Journal of Endocrinology (2013) 168 465 –472 (Torino)

Prevalence of endocrine disorders at the last
follow -up visit, by gender
E Brignardello et al, European Journal of Endocrinology (2013)

◼Cranial or craniospinal irradiation for intracranial or
hematological malignancies
◼Reduced height velocity and final height
◼CCSS survivors with brain tumors: 40% have a final height <
10thpercentile
◼Growth velocity impaired at the dg and during trt (acute illness,
poor nutrition, XRT -induced hypothyroidism, cancer trt)
◼Catch -up growth is frequent after trt completion and remission
is achieved. Primary effects of multi -modality cancer
therapy on growth
Gurney JG et al, Cancer 2003; 97: 663 -673

Primary effects of multi -modality cancer
therapy on growth
GHGrowth
XRT=radiotherapy Murray RD, Clinical Endocrine Oncology,
Blackwell Publishing, 2008

◼Variables : dose, fractionation, duration, age
◼Low XRT doses (9 –24 Gy) GH neurosecretory dysfunction (normal
stimulated GH, subnormal 24h secretion) attenuated pubertal
growth spurt
◼TBI (9 –15.5 Gy) as preconditioning for bone marrow transplant in
ALL results in GHD in children, but rarely in adults evaluated 4 years
later
◼Doses < 50 Gyaffect primarily the hypothalamus (vascular or
neuronal damage?), > 50 Gyaffect also the pituitary
◼Y90 implants in pituitary adenomas (500 –1500 Gy) induce fewer h.
deficits vs conventional XRT (37,5 –42,5 Gy): spare the hypothalamus
◼Fluxul sg hipotalamic scade cu durata de la iradiere , darraportul
hipotal /occipital blood flow nu s -a modif intre6 lunisi5 anide la irad,
desi deficitele au fostprogresive . Primary effects of multi -modality cancer
therapy on growth

Primary effects of multi -modality cancer
therapy on hypothalamo -pituitary axis
XRT=radiotherapy Murray RD, Clinical Endocrine Oncology,
Blackwell Publishing, 2008(in 60% of cases; exceptions: ACTH deficiency before LH/FSH)
Posterior pituitary dysfunction following irradiation is not described

Gonadotropin
(30-60% at 5 yr)ACTH (20 –40% at
5 yr)
TSH (5 –25% at 5 yr)Pituitary insufficiency after cranial radiotherapy
GH (60 -100% at 5 yr)
at approx 40 Gy

◼Annual check -up of GH, IGF1 (with GH stimulation tests)
◼Treatment initiation in children with no tumor recurrence: 2 years
after the tumor treatment, in those with reduced peak GH response
(±reduced height velocity)
◼The final height is not as good as in children with idiopathic GHD
(delay of trt?).
◼After craniospinal irradiation, GH replacement treatment may amplify
the disproportion by increasing the growth of the long bones, while
spine is more resistant
◼In these children growth should be monitored by leg length velocity.Treatment with GH

Effects of multi -modality cancer therapy
on male reproductive system
◼Damage may occur to either or both germ cells or Leydig cells
(+/-FSL/LH deficit)
◼Effects related to age & pubertal status
◼May be caused by radiation therapy and/or chemotherapy
(for gonadal tumors or testicular relapses of hematological
malignancies)
◼Manifestations:
◼decreased or absent sperm count; infertility
◼delayed puberty, gynecomastia

Male Germ Cells
CHEMOTHERAPY
◼Dose & drug dependent
◼cyclophosphamide
◼mechlorethane
◼chlorambucil
◼procarbazine
◼nitrosourea, vincristine,
vinblastina, cisplatin
◼Pubertal status not important
◼May be reversibleRADIATION
◼Increased effect with higher
dose and increased fractionation
◼Sensitivity is higher in the more
immature cells (spermatogonia)
◼Pubertal status not important
◼Unlikely to be reversible
◼(threshold for permanent
testicular damage at 1.2 –1.4
Gy)

Male Leydig cells
CHEMOTHERAPY
◼Slower growing than germ
cells, so less likely affected
◼Effects related to age: more
likely to occur after pubertyRADIATION
◼Less radiosensitive
◼Damage is dose -dependent
(20 –30 Gy), inversely related
to age at Rx
◼May have normal pubertal
maturation but marginal
function

Effects on male reproductive system
TBI –total body irradiation; XRT -radiotherapyMurray RD, Clinical Endocrine Oncology,
Blackwell Publishing, 2008
ChemotherapyLocal XRT, spinal XRT ,
total body TBI

Effects of multi -modality cancer therapy
on female reproductive system
◼Germ cell failure and loss of ovarian endocrine function usually occur
together (6.3% ovarian failure within 5 yr, 54% of them had >10 Gy)
◼Age & dose dependent
◼pre-pubertal ovaries relatively resistant to injury
◼Caused by radiation and/or chemotherapy (for pelvic tumors,
lymphoma, craniospinal i, TBI for BMT)
◼Manifestations:
◼delayed puberty, amenorrhea, premature menopause, ovarian
failure, infertility
◼teratogenic effects on pregnancy (if Rx while pregnant)
◼prematurity, low birth weight of offspring
Chemaitilly W et al, JCEM, 2006;91:1723 -1728

Effects on female reproductive system:
OVARY
TBI –total body irradiation; XRT -radiotherapyMurray RD, Clinical Endocrine Oncology,
Blackwell Publishing, 2008
Local XRT, spinal XRT , TBI
Chemotherapy

Effects on female reproductive system:
UTERUS
TBI –total body irradiation; XRT -radiotherapyMurray RD, Clinical Endocrine Oncology,
Blackwell Publishing, 2008
Pelvic XRT

Prevention of reproductive damage
◼Use of treatment regimens with less gonadal toxicity
◼Suppression of the gonadal axis with GnRH analogs before
cancer therapy –gonadal protection in animals, not convincing
in humans.
◼Males: -sperm frozen
◼Females: -oocytes and embryos frozen (successful
implantation in 10% and 20 –25% of cycles)
-cryopreservation of ovarian strips that are later
grafted at the original site or elsewhere
-oophoropexy and shielding before irradiation
(reduces amenorrhea by 50%)
Sex steroid replacement : in women under 50 with gonadal
failure; rarely needed in men

Effects on thyroid gland
◼External beam irradiation for lymphomas, head and neck
tumors, spinal irradiation in brain tumors and hematological
malignancies
◼Direct relationship with thyroid cancer
◼80% are well -differentiated papillary carcinomas, most of
the rest follicular neoplasms

Effects on thyroid gland: NODULES
Neck XRT or total body TBI
Murray RD, Clinical Endocrine Oncology,
Blackwell Publishing, 2008No association between chemotherapy and thyroid cancervs 1-5% in general population

Effects on thyroid gland: Thyroid cancer
OR for TK following 10 -20 Gy:
-16.3
-2.9

Effects on thyroid gland: FUNCTION
Murray RD, Clinical Endocrine Oncology,
Blackwell Publishing, 2008
Neck XRT or total body TBI

Follow -up and treatment for thyroid
complications following irradiation of the
neck for cancer
◼Annual examination of the neck and thyroid (controversy
between ultrasound and palpation only)
◼Thyroxine therapy aimed at TSH suppression
-after surgery for thyroid benign nodules –lowers the high
risk for recurrence of benign radiation -induced nodules
-after dg of hypothyroidism

Effects on parathyroid gland: FUNCTION
Murray RD, Clinical Endocrine Oncology,
Blackwell Publishing, 2008
No special recommendations for follow -up , prevention or treatment

Why Should Patients be Followed?
◼For the patient
◼Prevention, Detection and Treatment of late effects
◼Advice and counselling
◼Security of knowing that their status is understood
◼For the health care team
◼Research into late effects and translation into improvements
in current treatment
◼Job satisfaction
◼Avoid litigation!
◼For Society
◼?Cost benefit of prevention and early detection of disease
◼Surveillance of offspring of survivors

Who should be Followed?
◼Contact should be maintained with all
patients for life
◼Level of contact should be variable
dependent on the likelihood of late effects
◼Annual visits
◼Letter, phone, e mail follow up with possibility of
attending clinic

Where should they be followed?
◼Multidisciplinary team:
oncologist, endocrinologist, surgeon/ neurosurgeon, GP
◼< 18 years: Pediatric subspecialists
◼> 18 years: referral to adult specialist clinics
◼Counselling, rehabilitation services

Conclusion
◼Endocrine late effects in survivors of cancer can
lead to abnormalities in all endocrine axes.
◼Both chemotherapy and radiology play a role in
the etiology of the adverse sequalae.
◼Vigilance for the late effects (decades –long-life)
◼They can be treated or modified for the benefit of
the child / young adult