The combined use of radiation therapy and chemotherapy in cancer treatment is a logical and reasonable approach that has already proven beneficial for several malignancies.

1. Dr. Abani Kanta Nanda
2nd year PG Student
Dept. of Radiatherapy
AH Regional Cancer Centre

2. Introduction
 Despite advances and refinements in cancer treatment and an
emphasis toward early detection, the vast majority of human
malignancies are not effectively treated.
 Knowledge of the complex nature of human cancer is increasing
exponentially as modern molecular biology and genetics reveal
potential targets to combat and perhaps some day prevent this dreadful
disease.
 Yet, there is still a need to fully develop and optimize combined-
modality cancer treatment to help patients who will not have the
opportunity to benefit from the molecular biology revolution.

3.  The combined use of radiation therapy and chemotherapy in cancer
treatment is a logical and reasonable approach that has already proven
beneficial for several malignancies.
 Local control of the primary tumor mass (which can often be achieved
by high-dose radiation), combined with systemic chemotherapy to
control metastatic disease, should provide effective means to combat
such a highly complex disease.
 Moreover, the finding that many chemotherapy drugs enhance the
effects of radiation provides even more impetus to integrate both
modalities.

4. History
 In 1950 investigators began searching for chemical agents that might
enhance the effects of radiation.
 In 1958 Heidelberger et al obtained “potentiation of activity”by combining
fluorouracil with radiation in a preclinical study
 in which they treated transplanted murine tumors with fluorouracil
20 mg/kg/day for 7 days and radiation doses of either 15 or 20 Gy.
 In 1970s the results obtained with chemoradiotherapy at the Mayo Clinic
on gastrointestinal cancers.
 In 1970 Nigro and colleagues used a combination of fluorouracil and
mitomycin concurrent with radiation as neoadjuvant treatment in patients
with cancer of the anal canal.

5. Biologic Considerations
 Therapeutic benefit requires differential properties on tumor and
normal tissues.
 These include
1. genetic instability of tumors compared with normal tissues
2. differences in cell proliferation (particularly cell repopulation during
fractionated radiation therapy)
3. environmental factors such as hypoxia and acidity(which usually are
confined to tumors).

6. Biological basis of Chemo-radiation
1. Chemotherapy drugs reduces number of
tumor cells by their cytotoxic activity.
2. Renders tumor cells more susceptible to
radiation therapy – Radio sensitization
effect.
3. By virtue of systemic activity of
chemotherapy drugs, may act on distant
metastasis.
4. Chemo-radiation enhances radiation
response which gives better control of local
disease
Enhancement Example
Synergism 2+1=4
Additive 2+1=3
Subadditive 2+1=2.5
Interference 2+1=1.5
Antagonism 2+1=05
Nature of Radiation Enhancement

7. Chemotherapy may be given
1. Neo-adjuvant/Induction CT
2. Concurrent/Concomitant
3. Adjuvant
Used concurrently
Advantage:
Neither modality delayed
Shorter treatment time
Radiation enhancement
Disadvantage:
risk of increased toxicity
Biological basis of Chemo-radiation

8. Goals in Combining CT with RT
Increase patient survival by:
 Improving local-regional tumour control
 Decreasing or eliminating distant metastases
 Preserving organ or tissue integrity and function
 To have independent toxicity.
 To enhance tumour radio response.

9. Therapeutic Index or Therapeutic Ratio
 Is the ratio of the probability of tumor control to
the probability of normal tissue toxicity.
 Typically, the ratio is calculated based on the
50% control rate of tumor tissue versus the 50%
rate of normal tissue toxicity.
 These sigmoid-shaped curves determine
estimated efficacy versus toxicity of treatment.
 The therapeutic index takes careful treatment
planning to achieve
 maximal tumor cell destruction
 also spare normal tissue in hopes of preserving
function.
 “The greater the separation of these two curves,
the greater the therapeutic index.”

10. Four Strategies to improve Therapeutic
Index
Steel and Peckham classified into four groups: -
 A)Spatial cooperation
 B)Independent toxicity
 C)Enhancement of tumor response
 D)Protection of normal tissues

11. A) Spatial cooperation
On the other hand, chemotherapeutic drugs are
likely to be more effective in eliminating
disseminated micrometastases
 Action of RT and CT drugs directed
towards different anatomical sites
 No interaction between the two modalities
 Independent action of the two agents
 Eg- Localized tumors would be the
domain of radiation therapy because large
doses of radiation can be given.
RT
CT

12. B) Independent toxicity
 Combinations of radiation and drugs would be better tolerated if drugs
were selected such that toxicities do not overlap with, or minimally add
to, radiation-induced toxicities.
 Two modalities can both be given at full dose.

13. C) Enhancement of tumor response
 Interaction between drugs and radiation at the molecular, cellular, or
pathophysiologic (micro-environmental, metabolic) level, resulting in
an antitumor effect greater than would be expected on the basis of
additive actions.

14. 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.
 Another new class of radioprotective agents, the nitroxides, are
currently being studied preclinically.

15.  Cyclophosphamide, Cyt Arab., Chlorambucil, Methotrexate are
effective radioprotective agents.
 Cyt Arab in morrow
 do not modify stem cell radiosensitivity
 Stimulate enhanced repopulation by surviving stem cells

16. Ideal Radio Sensitiser
 Acts selectively in tumors as opposed to normal tissues.
 “Gets” to tumor in adequate concentration to elicit radiation
modification.
 Makes a radiation more effective to tumor by:
 Increasing radiation induced damage
 Increasing cytotoxic pathways(apoptosis)
 Inhibiting radiation repair
 Altering cell-cycle distribution to a radiosensitive phase
 Knowledge of appropriate timing of drug delivery and radiation
treatment for maximal enhancement.
 Preferentially noncytotoxic; however, if cytotoxic, exibits antitumor
activity alone(primary and metastatic).

17. Ideal Radiation Protector
 Acts selectively in normal tissues as opposed to tumor.
 “Gets” to normal tissues in adequate concentration to elicit radiation
modification.
 Is nontoxic.
 Makes a radiation dose less effective to normal tissues by:
 Decreasing radiation induced damage
 Scavenging free radicals
 Chemically repairing radicals induced by radiation
 Enhancing enzymatic radiation repair pathways
 Knowledge of appropriate timing of drug delivery and radiation
treatment for maximal protection.

18. Mechanistic Considerations in
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. Other Potential Interactions

19. 1.Increasing Initial Radiation Damage
 Radiation induces many different lesions in the DNA molecule, which
is the critical target for radiation damage which causes cell death.
 The lesions consist of
 single-strand breaks (SSBs)
 double-strand breaks (DSBs) PRINCIPAL DAMAGE
 base damage
 DNA–DNA and DNA–protein cross-links etc.

20.  So drugs that make DNA more susceptible radiation damage can be
used concorently with Radiation.
 Eg.- halogenated pyrimidines
{Iododeoxyuridine(IdUrd) in large unresectable sarcoma}

21. 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.
This time between two radiation fractions allows
radiation-induced DSBs in DNA to rejoin and repair.
 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.
Preventing cells from division allows the completion of
repair of DNA lesions that would have been lethal had DNA undergone
replication within several hours after irradiation

22.  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

23. 3.Cell Cycle Redistribution
 Cells in the G2 and M cell cycle phases were approximately three times
more sensitive to Radiation than cells in the S phase.
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
 Eg- Taxanes
b. Elimination of the radioresistant S-phase cells by the
chemotherapeutic agents.
 Eg- Nucleoside analogs, such as fludarabine or gemcitabine

24. 4.Counteracting Hypoxia-Associated Tumor
Radioresistance
 Hypoxic cells are 2.5 to 3 times more resistant to radiation than well-oxygenated
cells
a. Hypoxic cell radiosensitiser-
 Destruction of tumor cells in well oxygenated 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 reestablishment of
blood supply.
 It also causes tumor shrinkage so that previously hypoxic areas are closer to
capillaries and thus accessible to oxygen.
 By eliminating oxygenated cells, more oxygen becomes available to cells that
survived chemotherapy.

25.  Eg- Taxanes
b. Bioreductive drugs- these drugs accumulate in acidic environment,
that is due to anaerobic metabolism in the hypoxic cells, lead to cell
killing
 Eg- Tirapazamine

26. 5.Inhibition of Tumor Cell Repopulation
 The cell loss after each fraction of radiation during radiation therapy
induces compensatory cell regeneration (repopulation).
 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

27. 6.Other Potential Interactions
 Molecular Signaling Path ways:-
 Eg- Cetuximab, a EGFR inhibitor
 Targeting the Tumor Microenvironment:-
 Eg- Antiangiogenic agents
 Targeting cancer stem cells

28. Analyzing Drug-Radiation Interactions
A. Clonogenic survival assay:-
 Measures all forms of cell death as well as prolonged or irreversible
cell cycle arrest.
 Is the most encompassing method of measuring radiation
cytotoxicity in vitro.
 Survival curves are generated by plating known quantities of cells,
treating them with various doses of radiation and/or drug, and
plotting the surviving fraction of colonies formed in a
semilogarithmic fashion.

29.  Modification in radiosensitization, therefore, is demonstrated in
clonogenic survival curve data in which
Dose of Radiation
SurvivingFraction
a downward or leftward shift
implies a radiosensitizing
interaction.
an upward or rightward shift
implies a radioprotective
interaction

30. B) Steel and Peckham method:-
 Describes the construction of an “envelope of additivity” for evaluating
the interaction of two treatments using isobologram analysis.
 This envelope of additivity is constructed from cytotoxicity data by
calculating
 a mode 1 curve that assumes that both agents have completely
independent mechanisms of action
 as well as a mode 2 curve that assumes that the two agents
have exactly the same mechanism of action

31.  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).
Graph of an isobologram for examining the interaction of radiation
(RT) and a drug. Isoeffective doses of A (RT) and B (Drug) are indicated
on the axes

32. 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):
Radiation dose without sensitizer
Radiation dose with sensitizer
TheDose 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
SER=
DMF=
Dose(radiation)
Dose(Radiation + drug)

33. Drugs for Chemo-radiation
1. Platinum based drugs:
a)Cisplatin
b)Carboplatin
2. Antimicrotubules:
a)Paclitaxel
b)Docetaxel
3. Antimetabolites:
a)5 –Flurouracil
b)Methotrexate
c)Gemcitabine
d)Capecitabine
e)Pemetrexed
4. Topoisomerase I inhibitors:
a)Irinotecan
b)Topotecan
5. Alkylating agents
a)Temozolamide
6. Other
a)Mitomycin
b)Tirapazamine

34. Cell cycle specific anticancer drugs
G2 phase-
 Bleomycin
 Etoposide
 Teniposide
M phase-
 Vinorelbine
 Vincristin
 Vinblastin
 Paclitaxel
 Docetaxel
G1 phase-
 Steroids
 Asparaginase
S phase-
 Antimetabolites
 Methotrexaate
 Flurouracil
 Cytarabine
 Fludarabine
 Cladribine
 Gemcitabine

35. Cell cycle nonspecific anticancer drugs
Alkylating agents
 Chlorambucil
 Cyclophosphamide
 Busulfan
 Ifosfamide
 Mephelan
 Thiotepa
Anthracycline antibiotics
 Doxorubicin
 Daunorubicin
 Idarubicin
Other antibiotics
 Dactinomycin
 Mitomycin
 Mitoxantron
Nitrosourea
 Carmustin
 Lomustin
 streptozocin
Mislaneous Alkylator
like agents
Altretamine
Caroplatin
Cisplatin
Dacarbazine
Procarbazine

36. Mechanism of anticancer drugs
Cisplatin, Carboplatin. Oxaliplatin-
 Cell cycle–nonspecific agent. Reacts with two different sites on DNA to
produce cross-links (Covalently binds to DNA with preferential
binding to the N-7 position of guanine and adenine)
 Inhibition of DNA synthesis and transcription.
Cetuximab-
 Recombinant chimeric IgG1 monoclonal antibody directed against the
epidermal growth factor receptor (EGFR).
 Inhibition of critical mitogenic and anti-apoptotic signals involved in
proliferation, growth, invasion/metastasis, angiogenesis.

37. 5 Flurouracil-
 Cell cycle–specific with activity in the S-phase.
 Inhibition of the target enzyme thymidylate synthase by the 5-FU
metabolite, FdUMP which then gets misincorporated into DNA in the
form of dUTP → inhibition of DNA synthesis and function.
Paclitaxel, Docetaxel-
 Cell cycle–specific ( mitosis (M) phase ).
 High-affinity binding to microtubules enhances tubulin
polymerization.
 Dynamic process of microtubule is inhibited → inhibition of mitosis
and cell division.

38. Temozolamide-
 Nonclassic alkylating agent
 Cell cycle–nonspecific agent.
 Metabolic activation to the reactive compound MTIC is required for
antitumor activity.
 Methylates guanine residues in DNA and inhibits DNA, RNA, and protein
synthesis.
Mitomycin C-
 Antitumor antibiotic
 Alkylating agent to cross-link DNA → inhibition of DNA synthesis and
function.
 Bioreductive activation by NADPH cytochrome P450 reductase, and DT-
diaphorase to oxygen free radical forms → inhibit DNA synthesis and
function.
 Preferential activation in hypoxic tumor cells

39. Methotrexate-
 Cell cycle–specific antifolate analog ( S-phase) .
 Inhibition of dihydrofolate reductase (DHFR) resulting in depletion of
critical reduced folates.
 Inhibition of de novo thymidylate synthesis and purine synthesis.
Bevacizumab-
 Recombinant humanized monoclonal antibody directed against the
vascular endothelial growth factor (VEGF).
 Binds to all isoforms of VEGF-α
 Inhibits formation of new blood vessels in primary tumor and
metastatic tumors.

40. Vinorelbine, Vinblastin –
 Cell cycle–specific with activity in mitosis (M) phase.
 Inhibits tubulin polymerization, disrupting formation of microtubule
assembly
 Capecitabine –
 Antimetabolite
 Fluoropyrimidine carbamate prodrug form of 5-fluorouracil (5-FU).
 Capecitabine itself is inactive.

42. Indications for Chemo-radiation
1. Head & Neck cancer
2. Lung cancer-SCLC & NSCLC
3. Carcinoma Cervix
4. Carcinoma urinary bladder
5. Carcinoma Anal Canal
6. Carcinoma Esophagus
7. Carcinoma Rectum
8. Glioblastoma Multiforme
9. Sarcoma

43. Over view of disease entities and indications in
which concomitant Chemoradiotherapy is used:-
Disease
entities
Indication and
treatment
Commonly used
agents
benefit
Head and
Neck cancer
LAHNC- primary and
adjuvant treatment
Cisplatin, 5-FU, FHX (5-
FU, Hydroxyurea, Radiation),
Cetuximab
Improved organ preservation
and survival compared with
radiation alone
Non Small Cell
Lung Cancer
Stage IIIB, non-operable
non-metastatic disease
Cisplatin,
Cisplatin/Etoposide,
carboplatin/Paclitaxel,
Curative approach in poor
surgical candidate or IIIB
disease
Small Cell
Lung Cancer
Limited stage disease Cisplatin/Etoposide Curative in 20% patients
Esophageal
Cancer
Locally advanced
disease
Cisplatin/5-FU Survival benefit, Increase cure
rate, Organ preservation
Upper Aerodigestive track cancer:-

44. continued:-
Disease entities Indication and
treatment
Commonly used
agents
benefit
Rectal cancer Neoadjuvant 5-FU Improved sphincter preservation,
Decrease in local and distal failure
Anal cancer Mainstay of curative
treatment
5-FU, Mitomycin C Improved organ preservation
Gastric cancer Adjuvant Cisplatin, 5-FU Some data indicate survival benefit
Pancreatic cancer Adjuvant, Unresectable
locoregionally advanced
cancer
5-FU Improved locoregional control,
Possibly a survival benefit
cholangiocarcinoma Adjuvant, Unresectable
locoregionally advanced
cancer
5-FU Some data indicate survival benefit
Gastrointestinal malignancies:-

45. Continued:-
Disease entities Indication and
treatment
Commonly used
agents
benefit
Cervical cancer Primary modality Cisplatin, 5-FU,
Hydroxyurea
Improved local and distal
control, Organ preservation
Bladder cancer Primary modality Cisplatin Improved local control
Disease entities Indication and treatment Commonly used agents benefit
Glioblastoma Adjuvant Temozolamide Survival benefit
Sarcoma Neoadjuvant Doxorubicin Downstaging, Improved
organ preservation
Gynecological and genito-urinary cancers:-
Other cancers:-

46. Head and Neck cancer:-
 Chemoradiotherapy versus radiotherapy in patients with locally
advanced nasopharyngeal cancer: phase III randomized
 147 patients
 Concurrent chemo-Rt: Cisplatin (100mg/m²) on day 1, 22,43 {3
weekly} in + RT (70Gy/35#) followed by
 Adjuvant chemotherapy: Cisplatin (80mg/m²) on day1 and
5FU(1gm/m²)on day1-4 {3 weekly}
 3-year survival rate for patients randomized to radiotherapy was 46%,
and for the chemo-Rt group was 76% (P < .001)
 5year overal survival-37 vs 67%
INTERGROUP STUDY 0099

47. EORTC -22931 & RTOG-9501
 for the postoperative adjuvant treatment of patients with selected high-
risk locally advanced head and neck cancers (oral cavity, oropharynx,
larynx or hypopharynx).
 Both studies compared the addition of concomitant relatively high
doses of cisplatin 100mg/m² on d₁(on days 1, 22, and 43) {3weekly} to
radiotherapy vs radiotherapy alone .
 Extracapsular extension (ECE) and/or microscopically involved
surgical margins were the only risk factors for which the impact of
CCRT was significant in both trials.
 The addition of concomitant cisplatin to postoperative radiotherapy
improves outcome in patients with one or both of these risk factors.

48. EORTC RTOG
MARGIN +
ECE
2 POSITIVE
NODESSTAGE III-IV
PNI+
LVSI+
LEVEL 4 or 5 in OC,OP
ELEGIBILITY CRITERIA

49. Study by Chan et al.
 In the Intergroup 0099 trial-
 Only 63% completed all three cycles of concurrent chemotherapy
 Only 55% were able to receive all three courses of adjuvant therapy.
 As a result, weekly CDDP has been adopted by many institutions,
especially for patients with poor nutritional status.
 In a phase III trial comparing CRT versus RT alone in 350 patients with
locally advanced disease, Chan et al. Demonstrated good efficacy and
tolerability for a regimen consisting of weekly CDDP (40 mg/m2).
 70% of patients in the CRT arm received at least four cycles of CDDP,
and CRT was associated with a statistically significant survival benefit
after adjusting for age and disease stage.

50. GORTEC 94-01 trial
226 patient
Phase III multicenter, randomized trial comparing
radiotherapy alone
 Arm A- 70 Gy in 35 fractions
 Arm B- concomitant radiochemotherapy (70 Gy in 35
fractions with three cycles of a 4-day regimen containing
carboplatin and 5-fluorouracil).
The 5-year overall survival rate- 22% in Arm B and 16% in
Arm A (p = 0.05).
The 5-year locoregional control rate- 48% in Arm B and
25% in Arm A (p = 0.002).

51. Clinical Trials in ca cervix

52. NCI Clinical alert February 23, 1999
“based on significant improvement in both progression free
survival and overall survival when cisplatin-based
chemotherapy was given concurrently with radiotherapy”
Strong consideration should be given to the incorporation
of concurrent cisplatin based chemotherapy with radiation
therapy in women who require radiation therapy for
treatment of cervical cancer.”

53. Clinical Trials in Anal canal

54. Clinical Trials in Esophagus

55. summary
 CCRT increases patient survival by:
Improving local-regional tumour control
Decreasing or eliminating distant metastases
Preserving organ or tissue integrity and function
To have independent toxicity.
To enhance tumour radio response
 Amifostin is the only radioprotector clinically proved to use with
radiotherapy.
 A number of cell cycle specific and nonspecific chemotherapeutic drugs
are there, whose mechanism of action should be well understood, so that
there timing of administration with radiation could be determined to give
maximum result.