Concurrent Chemo-radiotherapy

Dr.Moufida Ibrahim Elmabrouk

Radiation Oncologist
 HISTORY OF CHEMORADIATION
• Radiation therapy has been the mainstay of nonsurgical
treatment of cancer for over a century, while the classic
chemotherapy drugs such as cisplatin and 5-fluorouracil (5-
FU) have been in clinical use for almost 50 years.
• The combination of these modalities is a more recent event
and the optimal combinations and scheduling continue to
evolve.
• Despite gaps in knowledge, the combination of radiation
and chemotherapy has become the standard of care for
most patients with solid tumors based on improvements in
locoregional disease control and survival
 PRINCIPLES OF COMBINING ANTICANCER
AGENTS WITH RADIATION THERAPY
• Combining chemotherapy with radiation therapy has
produced important improvements in treatment
outcome.
• Randomized clinical trials show improved local
control and survival through the use of concurrent
chemotherapy and radiation therapy for patients
with:
• high-grade gliomas and locally advanced cancers of
the head and neck, cervix , lung, esophagus,
stomach, rectum, prostate, and anus.
 PRINCIPLES GUIDING THE INTEGRATION OF
CHEMORADIATION
• Synergism
• Additive
• Subadditive
• Interference
• Antagonism
Rationale for Combination Therapy
Rationale for Combination Therapy
• There are least two proposed reasons why
chemo-radiotherapy might be successful
• The first is radio-sensitization.
• A second proposed realize the benefit of
improved local control radiation along with
the systemic effect of chemotherapy(concept
called spatial additively ).
Schematic example of an isobologram depicting the combination
of radiation and a systemic agent
 Mechanisms of interaction
• Mechanisms of interaction between drugs and
radiation can be evaluated at the cellular level on the
basis of radiation survival curves prepared with or
without the drug. Drugs can influence the survival
curve in three ways:
• (a) Displacement of curve;
• (b) loss of shoulder, indicating the effects of drug on
the repair of sub-lethal damage;
• (c) change in the slope of the curve indicating
sensitization or protection.
Mechanisms of interaction
 Mechanisms of interaction
• DNA is thought to be the same prime target for the
lethal effects of both radiation and drugs, resulting
in destruction of the proliferative capacity of
malignant "stem" cells
• Considering DNA as the sole target may be a
misleading generalization; other cellular organelles
and molecules may be damaged and there are also
data to show that radiation induced lipid
peroxidation in cellular membranes can also result
in cell death.
 Mechanisms of interaction
Anti-turmor Drugs May Interact with Radiation By
• Affecting the molecular pharmacology of X-rays (e.g.,
stabilization of free radicals).
• Changing the nature of the receptor site for X-rays
• Interfering with repair of X-ray damage either by a
physical change in the DNA or via enzyme inhibition.
• Inducing cell cycle progression delays that influence
subsequent responses to radiation.
• Altering the proportion of hypoxic/oxic cells in a tumor
cell population.
 Mechanisms of interaction
Radiation May Interact with Antitumor Drugs By
• Altering the blood supply to a tumor and hence
affecting drug transport and distribution.
• Reducing or enhancing drug metabolism .
• "Sensitizing" the target to subsequent drug
damage.
• Competing for or blocking damage repair
processes .
• Influencing the rate and extent of re-oxygenation.
 FACTORS INFLUENCING THE EFFECTS OF
DRUG-RADIATION INTERACTIONS
A. TUMOR AND NORMAL TISSUE TYPE
 For example, cyclophosphamide exacerbates
radiation toxicity in the lung and bladder, but not in
the small intestine or esophagus
B. DRUG TYPE
 Drugs which are cell cycle or phase dependent, such
as methotrexate, vincristine, 5-fluorouracil, and
hydroxyruea, are the most likely to interact with
radiation effects on rapidly proliferating tissues.
C. DRUG DOSE AND SCHEDULE
 For some chemotherapeutic agents, enhanced cytotoxicity may be
seen only with a prolonged drug infusion rather than a bolus
injection, even if the drug alone is more active when administered
by bolus.
D. TIME SEQUENCE
E. RADIATION DOSE AND FRACTIONATION
F. RADIATION DOSE RATE
G. ENDPOINTS OF CYTOTOXIC EFFECT
 cell cycle delay, reproductive ability, and the induction of mutations
and neoplastic transformation suggested as possible end point.
 Quantification of the Chemotherapy and Radiation
Interaction: The Therapeutic Ratio

How the addition of a second cytotoxic agent to radiation treatment may

influence the therapeutic ratio
 Type of interaction
• four different interactions between
radiotherapy and chemotherapy which could
be clinically advantageous:
• (1) spatial cooperation.
• (2) toxicity independence.
• (3) enhancement of tumor response.
• (4) protection of normal tissues.
 Precautions !
• Gemcitabine, a most potent sensitizer to irradiation, must
be used at fractional doses with irradiation.
• chemotherapy-radiotherapy combinations presents special
problems because of the synergistic therapeutic, and toxic,
effects of the two therapies on both normal and malignant
tissue.
• The normal tissue of greatest concern is the bone marrow,
although intestinal epithelium, heart, lungs, brain and any
other organ in the path of the beam may be affected.
 Precautions !
• This can severely compromise the ability to
deliver myelo-toxic chemotherapy, even
months or years after the radiation.
• Conformal irradiation narrows the irradiation
field and preserves a greater portion of the
marrow-bearing tissue
Radiation treatment plans: Comparison of two methods. A 64-year-old former smoker
presented with stage IIIA non–small-cell lung cancer, with disease in the right lower
lobe, hilum, and mediastinal station R4. Concurrent chemoradiation was
recommended.
 CLASSIFICATION OF CHEMOTHERAPEUTIC
AGENTS

• PHASE-SPECIFIC CHEMOTHERAPY
These drugs, such as methotrexate and vinca alkaloids, kill proliferating cells only
during a specific part or parts of the cell cycle.
Antimetabolites, such as methotrexate, are more active against S-phase cells
(inhibiting DNA synthesis) whereas vinca alkaloids are more M-phase specific
(inhibiting spindle formation and alignment of chromosomes).
• CELL CYCLE-SPECIFIC CHEMOTHERAPY
Most chemotherapy agents are cell cycle-specific, meaning that they act
predominantly on cells that are actively dividing.
• CELL CYCLE-NONSPECIFIC CHEMOTHERAPY
These drugs, for example alkylating agents and platinum derivatives, have an
equal effect on tumour and normal cells whether they are in the proliferating or
resting phase
The figure illustrates the different phases of the
growth cycle of tumor cells
 Classes of chemotherapy
• Alkylating agents
• Platinating agents
• Antimetabolites
• Topoisomerase inhibitors
• Anti-microtubular agents
• Miscellaneous
DEFINITIONS OF RADIOSENSITIZATION
• Suppression of intracellular-SH [thiols] or other
endogenous radio-protective substances .
• Radiation-induced formation of cytotoxic substances
from the radiolysis of the sensitizer.
• Inhibitors of post-irradiation cellular repair processes
• Sensitization by structural incorporation of thymine
analogues into intracellular DNA .
• Oxygen-mimetic sensitizers, for example, the electron
affinic nitroimidazoles.
Mechanisms of Benefit from Radiation–Drug
Therapy
• Cytotoxic Enhancement
• Exacerbation of DNA Damage
• Inhibition of DNA Repair
• Cell Cycle Effects
• Enhanced Apoptosis
Traditional ways of thinking about radio-sensitization
 Definition of Targeted Radiosensitizers

• The term targeted is currently used to refer to

a variety of drugs, such as therapeutic
antibodies that target specific molecules.
Examples of targeted drugs include tyrosine
kinase inhibitors, PARP inhibitors, and mTOR
inhibitors.
• The endpoint here is that the growth of the
whole tumor is slowed and the cells targeted
are not necessarily the malignant cells only.
Several biological mechanisms that have potential to
alter sensitization strategies
Targeting the Hypoxic Subpopulation
• Combining radiation with bio-reductive drugs,
such as tirapazamine or mitomycin C,
selectively targets hypoxic tumor cells while
the oxic population is targeted by radiation.
Targeting Nontumor Cells
• vascular targeting agents such as combrestatin
or dimethylxanthenone acetic acid, which
cause a shutdown of the tumor vasculature
leading to tumor cell death via hemorrhagic
necrosis
Targeting Drug-Resistant Cells with Radiation
• Combined treatment with radiation and drugs
may lead to improvement in therapeutic index
if one modality can target a subpopulation
resistant to the other .
Targeting Repopulation
• Greater specificity would be expected from
agents that specifically inhibit tumor cell
proliferation such as hormonal agents
tamoxifen and antiandrogens, which are used
concurrently with radiation for the treatment
of breast or prostate cancer, and
antiproliferative agents such as cisplatin in
non-hormonal-dependent tumors.
Temporal Modulation
• The classic radiobiological framework for
discussing dose fractionation effects, the four
R’s of radiotherapy: repair, repopulation,
reoxygenation, and redistribution refer to the
four biological processes that take place in the
time interval between radiation dose fractions
Spatial Cooperation
• The term spatial cooperation is used to
describe the scenario whereby radiotherapy
acts locoregionally, and chemotherapy acts
against distant micrometastases, without
interaction between the agents.
Normal Tissue Protection
• compounds that can sensitize targeted areas
to radiotherapy while limiting bystander and
systemic toxicity
Thank you
(A) For linear dose-response curves, the expected additive response is represented by
the dashed line. (B) Recommended terminology for interactions between two agents,
based upon an isobologram.