Radiation-Induced Second Primary Cancer

“Second Primary Cancer and Familial Cancer Syndromes”

Prof. L. Livi

Mediterranean School of Oncology

Rome- January 27, 2012

Ionizing Radiation

• Ionizing radiation is produced by unstable atoms. Unstable atoms differ from stable atoms because they have an excess of energy or mass or both.

• Unstable atoms are said to be radioactive. In order to reach stability, these atoms give off, or emit, the excess energy or mass. These emissions are called radiation.

• Ionizing radiation is produced by unstable atoms. Unstable atoms differ from stable atoms because they have an excess of energy or mass or both.

• Unstable atoms are said to be radioactive. In order to reach stability, these atoms give off, or emit, the excess energy or mass. These emissions are called radiation.

Ionization

negative ion (electron)

positive ion: atom with 3 protons, 2 electrons

+ ++

Process that leads formation of a pair of ions by removal of electron from an orbital.

Types or Products of Ionizing Radiation

Types or Products of Ionizing Radiation

or X-

rayneutron

Ionizing Radiation

•Electromagnetic radiation•Corpuscular radiation

•Directly ionizing (corpuscolar radiation, charged particles: electrons, protons,α particles, heavy ions): directly destroy the atomic structure of the crossing vehicle

•Indirectly ionizing (X-rays and γ-rays, neutral particles): when they are absorbed in the through material, they transfer energy producing charged particles that move faster and ionize matter.

Penetration capacity of radiation: 1) physical characteristics of the medium 2) characteristics radiation

Corpuscolar radiation: inversely proportional to the mass; Directly proportional to kinetic energy;Electromagnetic radiation: penetration depends on the wavelength dalla lunghezza d’onda

Expelled electron

1- Compton effect

Incident X-ray

The incident radiation strikes an external electron and ejects it(ionization ). Lthe incident radiation loses some of its energy and continues deflected in a different direction (scattering)

Positive charghed atom

Deflected x-ray with lower energy

Compton effect : the photon interacts with lower energy electron; photon yelds some of its energy to the electron as kinetic energy.Photon is deflected compared to the initial direction.

2- Photoelectric effect

The incident radiation strikes an external electron and ejects. Radiation loses all its energy and stop (absorption)

Expelled electron

Positive charged atom

Photoelectron effect photon interacts with electrons bound and gives all his energyto the electron.

The place left vacant is filled by the electron ejected from an outer electron in an orbital or a free electron outside the atom. The passage of an electron from an outer orbital to internal results in the energy emission (photon)

Absorbtion of neutron

Neutrons are uncharged particles and so are highly penetrating ; they are indirectly ionizing and are absorbed by elastic or inelastic scattering.

They interacts with nuclei of atoms and set in motion fast recoil protons, α-particles and heavier nuclear fragments.

Ionizing Radiation at the Cellular Level

• Causes breaks in one or both DNA strands or;

• Causes Free Radical formation

Part 3, lecture 1: Radiation protection 11

The target in the cell: DNAThe target in the cell: DNA

DNA strand breaks

DNA is the principal target for the biologic

effect of radiation,.

Deoxyribonucleic acid (DNA) is a large molecule

with double helix structure, two strand of sugar, phospate group

and bases held together by hydrogen bonds.

Radiation Induced Chromosome Damage• Chromosomes are composed of DNA.

• Radiation effects range from complete breaks of the nucleotide chains of DNA, to point mutations which are essentially radiation-induced chemical changes in the nucleotides which may not affect the integrity of the basic structure

THE TYPES OF DAMAGE TO THE DNA INCLUDE:

• DNA Single Strand Breaks• DNA Double Strand Breaks• Sugar Damage• Base Damage• Local Denaturation• DNA-DNA Cross-links• DNA-Protein Cross-links

DNA double strand breaksIs the most lethal form ofionizing radiation-induceddamage

DNA DSBDNA DSB

chromosome instability,mutations

chromosome instability,mutations

cancercancerproliferation

arrest or cell death

proliferation arrest

or cell death

cell cycle check-points

DSB mis-repairDSB mis-repair

repair systems

correct DSB repaircorrect DSB repair

DNA double-strand breaks

Cell Results

Damage is repairedCell DeathInhibition of Cell DivisionInactivation of EnzymesAlteration of Membrane PermeabilityChromosome Aberrations

Cell Death• For differentiated cells that do not proliferate, such as nerve,

muscle or secretory cells, death can be defined as the loss of specific function

• For proliferating cells, such as stem cells in the hematopoietic system or the intestinal epitelium, death can be defined as loss of the capacity for sustained proliferation: that is REPRODUCTIVE DEATH

Cell Survival Curves

• A cell survival curve describes the relationship between the radiation dose and the proportion of cells that survive.

The shape of the survival curveThe fraction of cells surviving is plotted on a logarithmic scale against dose on a linear scale.

Significative improvements in cancer treatment in last few decades.

The use of radiation in the treatment of cancer is widespread and is increasing with up to 40 % of patients with cancer

receiving radiotherapy as part of their management.

The number of cancer survivors in the United States has tripled since 1971 and is growing by 2% each year.

National Cancer Institute published data in 2006 reporting that “Cancer survivors constitute 3.5% of the U.S. population”

One of the most severe side effects following successful cancer therapy is the diagnosis of a second primary

cancer.

Second primary malignancies among the group of Cancer Survivors now account for 16% of all cancer

incidence

Second primary cancer is defined as a new cancer that is distinct from the original disease and presents an independent picture of malignancy, and for which the possibility of it being a metastatic tumor has been ruled out.

Many studies have shown association between radiotherapy and the risk of developing

second cancer,

it is not known what proportion of second it is not known what proportion of second cancers might be related to cancers might be related to radiotherapyradiotherapy

There are several historical published reports identifying criteria for diagnosing radiation-induced

second malignancies:

• History of previous irradiation

• The new cancer should arise within the previously irradiated field

• The second neoplasm should be histologically different from the first

• Relatively long latent period between the tumors.

Latent period is the time scale between completion

of radiotherapy and the development of a second malignancy.

• It can vary widely from as little as 14 months to over 50 years.

• It can vary according to histological type; radiation-induced squamous cell carcinomas are thought to

develop after a longer latent period than radiation-induced sarcomas (45 years compared with 20 years)

Radiotherapy induces solid tumors, with increased risksreported at numerous sites.

Organs that are particularly sensitive to the carcinogenic effects of radiation include breast and thyroid.

Lois B. Travis, Cancer Epidemiol Biomarkers Prev 2006;

Alice J. Sigurdson et al, Nature (2003)

Breast cancer after HD

• The advent of effective chemo-radiotherapy has made Hodgkin Disease (HD) a highly curable malignancy

• The great improvement in survival rates allowed the observation in long-term survivors of several treatment complications

Noordijk EM et al. J Clin Oncol 2006Van Leeuwen FE et al. J Clin Oncol 2000Matasar MJ et al. Radiol Clin North Am 2008

• Treatment-related toxicity surpasses HD as the greatest contributor to overall mortality

• Secondary malignancies are the most serious complications characterized by important morbidity and mortality

Aleman BM et alJ Clin Oncol 2003

• Many studies have demonstrated a significant increasing risk of secondary acute non-lymphocytic leukaemia, non-Hodgkin's lymphoma and solid tumours among HD patients

• Breast cancer remains the most common SM among female survivors, especially in those treated at young ages with supradiaphragmatic RT

Biti G et al. Int J Radiat Oncol Biol Phys 1994Parker RG. Int J Radiat Oncol Biol Phys 1990Swerdlow AJ et al. J Clin Oncol 2000

Cutuli B et al. Radiother Oncol 2001Aisenberg AC et al. Cancer 1997

Breast cancer after HD

MATERIALS AND METHODS

Distribution of 1 538 cases of HD according to selected clinical and pathologic characteristics :

• 47,1% female, < 30 years• Most common histological type was nodular sclerosis (50,6%), stage II

(54,6%), localization in the mediastinum (63,4%)

• 54,3% of the patients received only RT, 37,2% of the patients received RT-CMT.

Supradiaphragmatic alone or with subdiaphragmatic complementary extended field radiotherapy (EFRT) was delivered to 82.7% of patients

(36-40 Gy)

Supradiaphragmatic involved field radiotherapy (IFRT) was delivered to 10.7% of patients

(max dose to the involved nodal regions 30 Gy)

RESULTS

• BC occurred in 39 patients with an overall incidence of 5.4% (female group)

• Mean interval after HD treatment: 19.5 years (SD±9.0) • Median age of HD diagnosis: 31.2 years (SD14.5) and the median age of

BC diagnosis : 50.8 years (SD±13.3)• 48.8% of the patients developed BC after >20 years from HD diagnosis • 37/39 women received mediastinal RT, all, except one, with EFRT

At a median follow up of 15.6 years (range 0.5-48 years), 1 141 patients had no evidence of HD

Supradiaphragmatic nodal region RT is one of the most important risk factor for BC among

women treated for HDHorwich A et al, Br J Cancer 2004Cutuli B et al, Eur J Cancer 1997Cutuli B et al, Radiother Oncol 2001Aisenberg AC et al, Cancer 1997Foss Abrahamsen A et al, Ann Oncol 2002Travis LB et al, J Natl Cancer Inst 2005 van Leeuwen FE et al, J Clin Oncol 1989

DISCUSSION

We observed a clear decreasing trend of the secondary BC incidence with increasing age of HD treatment (ns)

The largest excesses of BC are observed among women diagnosed with HD at age 30 or youngerage 30 or younger, especially those younger than 20younger than 20

Horwich A et al. Br J Cancer 2004Travis LB et al. N Engl J Med 1996Bhatia S et al. N Engl J Med 1996

““It is important to minimise dose and limit volume of It is important to minimise dose and limit volume of breast tissue in the field for those women requiring breast tissue in the field for those women requiring

supradiaphragmatic radiotherapy at ages less than 30 supradiaphragmatic radiotherapy at ages less than 30 yearsyears””

There is no significant increase of BC risk, compared to general There is no significant increase of BC risk, compared to general population, in women treated after 35 years of agepopulation, in women treated after 35 years of age

A pattern that is consistent with the radiosensitivity of the A pattern that is consistent with the radiosensitivity of the breast at young agesbreast at young ages

DISCUSSION