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Second Cancers
• The number of patients with second cancers is
growing rapidly
• Second cancers :
sequelae of treatment,
lifestyle factors
environmental exposures
host determinants
combinations of effects gene- environment and
gene -gene interactions
• Methods to Assess Second Cancer Risk
Cohort Studies
Case-Control Studies
• Carcinogenicity of Individual Treatment
Modalities
Radiation Therapy
Chemotherapy
Radiation Therapy
Elevated risks of second cancer have been
documented among patients treated with
radiation therapy (RT) for
HL,
testicular cancer,
cervix cancer,
breast cancer,
childhood cancer.
prostate cancer
cancer of the nasopharynx
low-dose radiation
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Japanese atomic bomb survivors,
occupational radiation exposure,
sizable amounts of diagnostic radiation
RT for nonmalignant diseases.
Consequently, the relationship between
radiation dose and cancer risk is better
understood for these low-dose exposures.
• For most solid tumors, there is an
approximately linear increase in risk with
increasing radiation dose up to about 5 Gy.
• leukemia :a linear increase in risk with dose up
to 1.5 to 2 Gy
• Increased cell killing with Tx results in lower
second cancer risks: not aloways
• For example: HL, the risk of breast cancer
• lung cancer, sarcoma, glioma and meningioma
(above 5 Gy).
• risk of radiation-induced solid cancer
increases with increasing dose well into the RT
dose range prescribed to treat many cancers.
• It is also apparent that there is variation in the
sensitivity of different tissues with regard to
cancer induction by radiation, with sites such
as the thyroid, female breast, and bone
marrow being most radiosensitive
IMRT
• More volume of tissue exposed to low- and
intermediate-dose radiation
1. More treatment fields
2. longer to deliver than conventional RT(more
leakage)
IMRT
• The additional low-dose exposure may
increase the risk of second cancers especially
in
high energy beams
young ages
RT+
• Hormonal factors
• other carcinogenic agents
• known genetic factors
Chemotherapy
• Leukemia (model disease)
• In contrast, the induction of solid tumors after
chemotherapy is less well understood
Two major types of treatment-related
leukemia
1. Alkylating agent-induced AML
2. Topoisomerase inhibitor-induced AML.
Alkylating agents with known or suspected
leukemogenic effects in humans
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mechlorethamine,
Chlorambucil
Cyclophosphamide
Melphalan
Semustine
Lomustine
Carmustine
Procarbazine
Prednimustine
Busulfan
Dihydroxybusulfan
platinating agents.
• The risk of alkylating agent-related AML has
been shown to increase with increasing
cumulative dose, duration of therapy, or dose
intensity
Topoisomerase II inhibitors
• etoposide and teniposide
• As compared with alkylating agent-induced
AML, epipodophyllotoxin-related AML has a
shorter induction period (median, 2 to 3
years) and generally presents without
preceding MDS, and its risk appears not to be
dose dependent.
susceptibility to chemotherapyinduced cancers.
1. host phenotype (e.g., age, gender)
2. host genotype (e.g., polymorphisms)
3. exposure-related variables (e.g.,
chemotherapy dose, regimen, co-treatment
with radiotherapy),
• Risk of Second Malignancy in Patients with
Selected Primary Cancers
Hodgkin's Lymphoma
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leukemia
(NHL),
connective tissue
bone,
thyroid cancer.
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12.
lung,
stomach,
esophagus
colon,
breast,
Cervix
, mouth and pharynx, and melanoma.
Time
• increased leukemia risk has its peak occurrence 3
to 9 years after chemotherapy,
• The RR of solid tumors is minimally elevated in
the 1- to 4-year follow-up period, and increases
steadily with increasing follow-up time from 5
years until at least 20 years since first treatment.
• For several tumor sites (breast, thyroid,
esophagus), the excess risk does not become
apparent until after 10 or even 15 years of
observation.
• Risk Factors for Leukemia and NHL after H L
‫رژیم کموتراپی‬
‫پیوند مغز استخوان‬
HL-Alkylating agent chemotherapy
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MOPP
escalated BEACOPP
MOPP-ABVD
COPP-ABVD
standard BEACOPP
ABVD
HL
• Taken together, the preponderance of
available data does not support the
hypothesis that the combination of
chemotherapy and RT confers a higher risk of
leukemia than chemotherapy alone
HL
• In some series, relatively high actuarial risks
(4% to 15% at 5 years) of AML/MDS have been
observed after autologous stem cell
transplantation for HL.
• The prognosis of AML/MDS after HL treatment
is extremely poor, with only 15% of patients
surviving more than 1 year and no apparent
survival benefit from allogenic stem cell
transplantation.
• The causes of the excess risk of NHL after HL
treatment are not well understood.
• Risk Factors for Solid Malignancies after
Treatment for Hodgkin's Lymphoma
Role of Chemotherapy
Effect of Age at Treatment
Role of Chemotherapy
• RT+MOPP chemotherapy ) lung cancer (
• chemotherapy alone?
• smoking and RT,
• smoking + chemotherapy.
• The inconsistent results with regard to the
influence of chemotherapy on solid tumor risk
may be due to the fact that most studies
considered all solid tumors combined,
whereas chemotherapy may differentially
affect the risk of tumors at disparate sites.
Effect of Age at Treatment
• Several studies have shown that the RR of
solid tumors increases strongly with younger
age at first treatment .The effect is most
notable for breast cancer
Conclusion-HL
• the occurrence of treatment-related second
cancers is a major problem in survivors of HL.
• The substantial increase in solid tumor risk
with greater follow-up time necessitates
careful, lifelong medical surveillance of all
patients.
• dissuade HL patients from smoking even
before treatment starts.
• screening for lung cancer ?
Women with HL
• regular breast examinations should be
emphasized
• From 8 years after irradiation (but not before
age 25), the follow-up program of these
survivors should include :
yearly breast palpation and breast imaging(MRI)
GI cancer -HL
• in patients who have received para-aortic and
pelvic radiation fields and thoroughly examine
any gastrointestinal complaints.
Modern chemotherapy
• Important questions to be answered in future
research are whether modern chemotherapy
regimens with lower doses of procarbazine
and mechlorethamine also contribute to the
risk of nonbreast solid tumors, and, if so,
which cytotoxic drugs are responsible for the
excess risk
Non-Hodgkin's Lymphoma
• second malignancies following NHL(etiologic factors?, possibly immune
related?)
malignant melanoma
Kaposi's sarcoma
AML
buccal cavity
salivary gland
Mouth
lung
Vagina
urinary bladder
kidney parenchyma
Bone
MDS/AML
• Additional work needs to be undertaken in
order to more fully delineate the roles of the
various types of prior therapy for lymphoma,
the preparative regimen for transplantation,
and other factors in the subsequent
development of MDS/AML.
summary
• survivors of NHL are at increased risk for a number of
second malignancies, although to a considerably smaller
degree than are HL patients.
• The excess risks of AML and bladder cancer have been
shown to be treatment related.
• The persistent increase in the risk of all second cancers for
more than 20 years after NHL treatment alerts clinicians to
the importance of long-term surveillance.
• smoking cessation.
• Health care providers should also be aware of the large risk
of bladder cancer among patients who had been treated
with the high-dose cyclophosphamide regimens of the past
Testicular Cancer
• Solid Tumor
standard infradiaphragmatic radiotherapy fields
ssupradiaphragmatic radiotherapy fields
Testicular Cancer
• chemotherapy alone is associated with
significantly increased risks of solid cancers,
• Platinum is retained in the human body for
prolonged durations after treatment and
causes both leukemia and solid tumors in
preclinical studies.(TC or ovarian cancer)
Leukemias IN TC survivors
• studies have described the role of both
radiotherapy and chemotherapy
Ovarian Cancer
• Most :acute leukemia
• breast, colon, rectum, small intestine, bladder,
renal pelvis, eye (ocular melanoma), and
intrahepatic bile ducts.
• Reproductive and genetic factors predisposing
to ovarian cancer may have contributed to the
elevated risk of breast, colorectal, and other
neoplasms.
Breast Cancer
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contralateral breast
Ovary
Lung
Esophagus
Colon
Connective tissue
Melanoma
Leukemia
• For :contralateral breast, ovary, and uterus, and
possibly melanoma, the excesses may be fully or
partly explained by a common etiology (e.g.,
genetic predisposition or hormonal risk factors).
• Other excess risks may be treatment related or
reflect the interaction of several factors. Adjuvant
CT, hormonal treatment, and RT, and
combinations of these modalities, are being
administered to a growing proportion of breast
cancer patients.
• It is unfortunate, that it has not yet been
examined whether RT as applied from the
1980s onward, especially postlumpectomy
radiation, affects the risk of contralateral
breast cancer
contralateral breast cancer
• How long :protective effect of tamoxifen
• adjuvant chemotherapy may reduce the risk
of contralateral breast cancer,
• AML :
use of dose-intensification strategies in
chemotherapy protocols for breast cancer?
granulocyte colony stimulating factor?
• Conclusive evidence has emerged that
tamoxifen is associated with a moderately
increased risk of endometrial cancer
( ‫)پاتولوژی های با پروگنوز بدتر‬
malignant mixed mesodermal tumors
uterine sarcoma
Conclusion(Breast)
• only part of the elevated risk of second
malignancies following breast cancer is due to
treatment.
• a contralateral tumor is unlikely to be
meaningfully affected by current RT for the initial
breast cancer, whereas tamoxifen reduces the
risk of contralateral disease.
• Conventional anthracycline-based chemotherapy
is associated with a low excess risk of leukemia.
• However, leukemia risk appears to increase with
larger cumulative doses of anthracyclines and
cyclophosphamide, and RT adds to this risk.
• The effectiveness of screening for endometrial
cancer has not been demonstrated.
Consequently, outside of research settings,
there is no basis for regular gynecologic
examinations in asymptomatic patients taking
tamoxifen.
stop smoking
• The risk of lung cancer is about a twofold
increase after postmastectomy RT, but not
after postlumpectomy radiation. There is
ample reason to advise breast cancer patients
to stop smoking, especially if they receive
radiation treatment
Pediatric Malignancies
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second primary bone tumors
soft tissue sarcoma
leukemia,
cancers of the brain, thyroid, and breast
breast ,skin,197 and other carcinomas
head and neck
adult-type carcinomas overall showed a four-fold
excess at an early age (median age at diagnosis:
27 years).
• Only a portion of the excess second cancer
risk in survivors of childhood cancer is related
to treatment
• Over the past decade, prophylactic cranial RT
has been largely replaced by intrathecal
methotrexate, but the number of these
injections has not been related to the
subsequent risk of brain tumors
conclusion
• The magnitude of new malignancies depends on treatment and the
type of initial malignancy, si
•
• It is therefore imperative that survivors of childhood cancer be
carefully monitored to assess the long-term risks of various types of
second cancers.
• Bone sarcoma is highest.
• The leukemogenic potential of epipodophyllotoxin-containing
regimens that vary in cumulative dose and schedule of
administration should continue to be rigorously assessed, as holds
true for other new chemotherapy regimens
• RT is the main risk factor although chemotherapy has recently
been shown to add substantially to the increased risk from
radiation.