CCRT

Dr swathi R Krishna
 The combined use of radiation therapy and chemotherapy in cancer
treatment has already proven to be beneficial for several malignancies.
 chemotherapy given during a course of radiation therapy, it is referred to as
concurrent chemotherapy.

,
biologic rationale.
 reduce the number of cells in tumors undergoing radiation therapy by their
independent cytotoxic action
 rendering tumor cells more susceptible to killing by ionizing radiation.
 may also act on metastatic disease by virtue of their systemic activity
The goals of combining chemotherapeutic drugs with radiation therapy
are
 improving locoregional tumor control with out increase in toxicity and thus
preserving organ and tissue integrity and function
 decrease or eliminate distant metastases
Therapeutic index

 Both radiation and chemotherapeutic drugs are cytotoxic to tumor and normal
tissue cells
 the antitumor effectiveness and the severity of normal tissue damage
produced by either radiation or drugs are increased as their dose is increased.
 This dose–effect relationship is sigmoidal and enables estimation of the
therapeutic index (ratio), which is defined as the ratio between the doses
(radiation, drug) that produce the same level (probability) of antitumor
efficacy and normal tissue damage.
 To be therapeutically beneficial, the therapeutic ratio must be positive (>1);
that is, individual agents or their combination must be more effective against
tumors than normal tissues.
Schematic dose–response curves for tumor and normal tissue damage with radiation. The offset between the
two curves indicates the therapeutic range. Chemoradiotherapy leads to a shift of both curves to the left,
ideally with a stronger shift of the tumor curve (as indicated by the longer arrow), increasing overall efficacy
of treatment
Strategies by which CCRT improve
Therapeutic Index
 classified into four groups by Steel and Peckham
 A)Spatial cooperation
 B)Independent toxicity
 C)Enhancement of tumor response
 D)Protection of normal tissues
A) Spatial cooperation
  Action of RT and CT drugs directed towards different anatomical sites
  No interaction between the two modalities
  the cooperation between radiation and chemotherapy is achieved through the
Independent action of the two agents
  Localized tumors would be the domain of radiation therapy because large doses of
radiation can be given and chemotherapeutic drugs are likely to be more effective in
eliminating disseminated micrometastases
 Forms basis for adjuvant chemoradiation therapy and treatment of hematologic
malignancies that have spread to “sanctuary” sites, such as the brain.
(These sites are poorly accessible to chemotherapeutic agents, and thus, they are more
appropriately treated with radiation therapy)
B) Independent toxicity
 increased toxicity is the most imp dose limiting factor for both CT and RT
Combinations drugs were selected such that toxicities do not overlap with,
radiation-induced toxicities treatment would be better tolerated with out
affecting the tumor control
thus getting higher control without increased toxicity
C)Enhancement of tumor radio
response
 Interaction between drugs and radiation
at the molecular, cellular, or
pathophysiologic (micro-environmental,
metabolic) level
result in an antitumor effect greater than
would be expected on the basis of additive
actions.
D) Protection of normal tissues
 This can be achieved through
 Technical improvements in radiation delivery.
 Administration of chemical or biologic agents that selectively or preferentially
protect normal tissues against the damage by radiation or drugs.
Amifostine(WR-2721) has been used in several clinical trials and has recently
been used in a chemoradiation setting.
Cyclophosphamide, Cyt Arab, Chlorambucil, Methotrexate are effective
radioprotective agents.
Analyzing Drug-Radiation Interactions

 Drugs considered for use in combination with radiation therapy needs to

undergo preclinical evaluation for its interaction with radiation both in in
vitro cell culture systems and in vivo, for assessing antitumor activity and
normal tissue toxicity.
 in vitro assessment : interaction between two agents is more easily
defined and quantified because complete cell survival curves are readily
obtained.
 The in vitro cell survival assay measures the ability of cells to produce
colonies of a defined minimum size.
 Survival curves - plots of the surviving fraction of cells on a logarithmic scale
and the dose of radiation or drugs on a linear scale
 To assess the effect of the drug on cell radiosensitivity, the combined drug–
radiation curve is commonly plotted after the cytotoxicity produced by the drug
alone is excluded
 additive effect :
 the cytotoxicity of the drug contributes only to the overall cell killing does not
influence cell radiosensitivity
 The radiation cell survival curve is not changed
 supra-additive :
 Chemotherapeutic agents may interact with radiation by altering cell
radiosensitivity
 the cell killing is greater than the sum of cell killings produced by individual agents.
 Such drugs may eliminate the shoulder on the
radiation survival curve, implying that drugs can
inhibit cell repair from radiation damage
 or they may change the slope of the exponential
portion of the survival curve- A steeper slope
indicates increased sensitization to radiation
 subadditive effect:
 cell killing is smaller than the sum of cell killings
produced by individual agents
 a shallower slope indicates protection.
 the effects of the combined treatment are best assessed using the
“isobologram,” - an isoeffect plot for the dose response to the combination of
two agents’
 Dose–response curves are determined for each agent to generate an
“envelope of additivity” for evaluating the interaction of two treatments
 mode 1 curve that assumes that
both agents have completely
independent mechanisms of
action
 mode 2 curve that assumes that
the two agents have exactly the
same mechanism of action
 envelope of additivity, denotes
expected additive response over a
range of doses of the agents used.
When combination therapy data points are plotted on
the isobologram, they may fall
 between mode 1 and mode 2 (additive interaction;
within the envelope)
 above mode 1 (infra-additive interaction)
 below mode 2 (supra-additive, or synergistic
interaction)
 in vivo assessment:
 This is essential for determination of therapeutic gain
 Syngeneic animal tumors or human tumor xenografts in nude mice are most
often used for this purpose.
 The efficacy of the treatment is determined by the extent of tumor growth
delay or the rate of tumor cure.
 In normal tissues, the effect of chemotherapeutic drugs on radiation response
can be assessed using.
 A) clonogenic assays- the endpoint depends directly on the reproductive
integrity of individual cells.eg: the jejunal crypt assay
 B) based on functional endpoints (such as breathing rate in lung damage and
paralysis in spinal cord damage):
 These endpoints tend to reflect the minimum number of functional cells
remaining in tissues or organs and not the proportion of cells retaining
reproductive integrity
 Enhancement Ratios
Sensitizer enhancement ratio (SER):- Magnitude of the sensitizing effect of a drug
for a given effect is given by the sensitizer enhancement ratio (SER):
 The Dose Modification Factor(DMF):- of a drug, is defined as the dose of
radiation required to produce an effect without and with a drug
 If DMF = 1 No drug effect
< 1 Protection
> 1 Enhancement
Mechanisms of Drug–Radiation
Interactions
 1.Increasing Initial Radiation Damage
 2. Inhibition of Cellular Repair
 3. Cell Cycle Redistribution
 4. Counteracting Hypoxia-Associated Tumor Radioresistance
 5. Inhibition of Tumor Cell Repopulation
 6. inhibition of pro survival and poor prognostic factors
 7. inhibition of immunosuppressive effect of RT
1.Increasing Initial Radiation Damage
Radiation induces many lesions (like SSBs, DSB, base damage, DNA–DNA and DNA–
protein cross-links etc) in the DNA molecule leading to cell death.
 So drugs that incorporate into DNA and make it susceptible radiation damage
can be used concurrently with Radiation.
 Eg.- halogenated pyrimidines, cisplatin
2.Inhibition of Cellular Repair
 There are two types of repair after DNA get damaged
 SLDR (sublethal damage repair)- increase in cell survival when the radiation
dose is split into two fractions of radiation separated by a time interval.
 PLDR(potentially lethal damage repair)-increase in cell survival as the result of
post irradiation environmental conditions,
which prevent cells from dividing for several hours  allows the completion of
repair of DNA lesions that would have been lethal if the DNA had undergone
replication within several hours after irradiation
 Hence,drugs that interact with cellular repair mechanisms and inhibit repair
can be used in CTRT, that may enhance cell or tissue response to radiation.
 Eg-
halogenated pyrimidines
Nucleoside analogs, such as gemcitabine
Platinum compounds
3.Cell Cycle Redistribution
 the sensitivity of the cell response to radiation vary depending on which phase
of the cell cycle the cells are in at the time of irradiation
 Cells in the G2 and M phases are approximately three times more sensitive to
Radiation than cells in the S phase.
 can be therapeutically exploited in chemoradiation therapy
 a. The drugs that can block transition of cells through mitosis, with the result
that cells accumulate in the radiosensitive G2 and M phases of the cell cycle
 Radiation delivered at the time of significant accumulation of cells in both the
G2 and M phases results in enhanced radioresponse of cells
 Eg- Taxanes
 b. Elimination of the radioresistant S-phase cells by the chemotherapeutic
agents.
 These agents become incorporated into S-phase cells and eliminate them by
inducing apoptosis
 induce the surviving cells to undergo parasynchronous movement to
accumulate in the G2 and M phases of the cell cycle between 1 and 2 days
after drug administration
 Eg- Nucleoside analogs, such as fludarabine or gemcitabine
4. Counteracting Hypoxia-Associated Tumor Radioresistance
 Hypoxic cells are 2.5 to 3 times more resistant to radiation than well-
oxygenated cells
 combining chemotherapeutic agents with radiation therapy can reduce or
eliminate hypoxia or its negative influence on tumor radio response
 A) tumor shrinkage:
 CT preferentially kill proliferating cells, primarily found in well-oxygenated
regions of the tumor agents.
 Destruction of tumor cells in these areas leads to an increased oxygen supply
to hypoxic regions and hence reoxygenates hypoxic tumor cells.
 Massive loss of cells after chemotherapy lowers the interstitial pressure,
which then allows the reopening of previously closed capillaries and the re-
establishment of blood supply
 Eg- Taxanes
 B) Bioreductive drugs-
 these drugs undergo reductive activation in a hypoxic milieu, rendering them
cytotoxic.
 selectively kills hypoxic cells
  Eg- Tirapazaminea.
 C) hypoxic radiosensitize
 selectively radiosensitize hypoxic cells to reduce their negative impact has
been considered and tested in clinical trials
 eg: nimorazole
5. Inhibition of Tumor Cell Repopulation
 The constant balance between cell production and cell loss maintains the
integrity of normal tissues.
 When this balance is perturbed by cytotoxic action of chemotherapeutic drugs
or radiation, the integrity of tissues is re-established by an increased rate of
cell production.
 tumors also respond to radiation- or drug-induced cell loss with a
compensatory regenerative response
 The cell loss after each fraction of radiation during radiation therapy induces
compensatory cell regeneration (repopulation)
 It has been shown that the rate of cell proliferation in tumors treated by
radiation or chemotherapeutic drugs is higher than that in untreated tumors
 This increased rate of treatment induced cell proliferation is commonly
termed “accelerated repopulation”.
 Chemotherapeutic drugs, because of their cytotoxic or cytostatic activity, can
reduce the rate of proliferation when given concurrently with radiation
therapy, and hence increase the effectiveness of the treatment
Newer strategies

 Inhibition of pro survival and poor prognostic factors

Targeting Molecular Signaling Path ways That May Be Responsible for
Radioresistance
 Eg- Cetuximab- EGFRinhibitor
 Targeting the Tumor Microenvironment
 Eg- Antiangiogenic agents
 immune Checkpoint inhibition
o method for inhibiting immunosuppressing mechanisms
o checkpoint inhibitor class are- inhibit cytotoxic T lymphocyte antigen-4
(CTLA-4) and programmed death 1 (PD1)
 Targeting cancer stem cells
 Cancer stem cells are defined - cells within a tumor that possess the capacity
to self-renew and generate the heterogeneous lineages of cancer cells that
make up the tumor.
 Cancer stem cells as a source of radiation resistance for solid tumors has been
noted in some in vitro studies
 Drugs aiming molecular pathways that could influence cancer stem cell
radiosensitivity may be used
Improving Systemic Therapy Outcome by Cytoreduction
of Gross Metastases with Local SBRT

 This mechanism suggests that stereotactic body radiotherapy technique

(SBRT) could be used to cytoreduce gross disease in patients with limited
number of metastatic sites, at the onset of initiation of systemic therapy.
 based on studies in patients with non–small cell lung cancer- This study
demonstrated a remarkable PFS and OS after SBRT given with erlotinib , in
patients with 6 or less metastatic site, as compared to historical patients.
TIMING OF DRUG ADMINISTRATION IN
RELATION TO RADIATION THERAPY
 the selection of optimal timing of drug administration must be based on
o mechanisms of tumor radio enhancement by a given drug
o the drug’s normal tissue toxicity
o the conditions under which the highest enhancement is achieved.
o For eg:
 tumors sensitive to taxanes-A major mechanism for tumor radio enhancement was
reoxygenation of hypoxic cells,so the best effect is achieved if drug treatment
precedes radiation by 1 to 3 days-bolus of a taxane given once or twice weekly
 tumors resistant to taxanes- radioenhancement is by accumulation of
radiosensitive G2- and M-phase cells 6 to 12 hours after drug administration-daily
administration
 If the objective is to counteract rapid repopulation of tumor cell clonogens
induced by radiation, then administration of cell cycle–specific
chemotherapeutic agents during the second half of radiation therapy, when
accelerated repopulation is more expressed, is more effective
ADVANTAGES AND DISADVANTAGES
CCRT
 Advantages:
 Shorter treatment time
 Radiation enhancement
 Both local treatment and treatment of distant micro metastases therapy
delivered up front
 Disadvantages
 Compromised systemic therapy
 Increased toxicity- may lead to delay in completing RT
 No cytoreduction of tumor prior to RT
Drugs for Chemo-radiation
drugs have been chosen for combination with radiation therapy based on
their known clinical activity in particular disease sites.
Alternatively, agents that are effective in overcoming resistance
mechanisms associated with radiation therapy could be chosen
 Mitomycin-C
 Mitomycin-C is a quinone
 mechanisms of action include inhibition of DNA and RNA synthesis
 Radiation enhancement is due to its ability to target hypoxic cells that are
known to be relatively radiation resistant & prevention of repopulation
 Hypoxic Sensitizers: Tirapazamine, Nimorazole
 hypoxic cell cytotoxin
 Shows differential toxicity between hypoxic and well oxygenated cells.
CHEMORADIATION THERAPY AS STANDARD OF
CARE BY SELECTED DISEASE SITES

 Upper Aerodigestive tract cancer

 Gastrointestinal malignancies
 Gynecological and genito-urinary cancers
Clinical Trials in Head and Neck cancer

EORTC -22931 & RTOG-9501

The addition of concomitant cisplatin to postoperative radiotherapy improves
outcome in patients with locally advanced head and neck cancers (oral cavity,
oropharynx, larynx or hypopharynx), with risk factors- extracapsular extension
(ECE) and/or microscopically involved surgical margins
INTERGROUP STUDY 0099
Chemoradiotherapy versus radiotherapy in patients with locally advanced
nasopharyngeal cancer- addition of CT to RT improved OS & PFS
 GORTEC 94-01 trial-
 most favourable outcomes where seen with conventional
concurrent chemoRT
 MACH-NC meta analysis
This meta-analysis demonstrated a clear advantage of CT-RT
rather than induction or adjuvant chemo.
Benefit of addition of Chemo is consistent in all tumor locations
of HNSCC
Clinical Trials in Anal canal
Clinical Trials in ca cervix
 THANKYOU