Principles of concurrent chemoradiotherapy by Dr. Rejil Rajan, DNB RADIATION ONCOLOGY, DM MEDICAL ONCOLOGY RESIDENT

1. Principles of
Chemoradiotherapy with
few clinical examples
REJIL RAJAN

2. Definition
 Concomitant or Concurrent chemo-radiation
refers to administering chemotherapy during a
course of radiation.

4. GOALS
 The goals of combining chemotherapeutic drugs with
radiation therapy are to increase patient survival by
improving locoregional tumor control, decrease or
eliminate distant metastases, or both, while preserving
organ and tissue integrity and function

5. Rationale
 Initially given by Steel and Peckham in 1979
 Spatial cooperation
 Independent toxicity
 Enhancement of tumor response
 Protection of normal tissues

6. Spatial Cooperation
 Initial rationale for combining chemotherapy with radiation therapy
 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
 Example: Radiotherapy local regional control & chemotherapy 
prevent distant failure

8. Radiotherapy response
enhancement
 Sensitization of the cells to effects of radiation
 Additive: Amount of cytotoxic activity equal to summation of 2
modalities
 Supraadditive : cytotoxicity is more than simple sum
 Infra-additive drugs possess radio protective properties that
lessen the cytotoxic effect of radiation on the tumor and/or
normal tissue.

9. Toxicity Independence
Normal-tissue toxicity is the main dose-limiting factor for both
chemotherapy and radiation therapy. Therefore, combinations of
radiation and drugs would be better tolerated if drugs were selected
such that toxicities to specific cell types and tissues do not overlap
with,
or minimally add to, radiation-induced toxicities.

10. Normal tissue protection
 Clinical aim is to reduce the incidence, severity or
duration of early and/or late side-effects
 To protect normal tissues so that higher doses of
radiation can be delivered to the tumor. This can be
achieved through technical improvements in
radiation delivery or administration of chemical or
biologic agents that selectively or preferentially
protect normal tissues against the damage by
radiation or drugs
 E.g Amifostine

11. Biological cooperation
 Targeting distinct cell populations or using different
mechanisms of cell killing or inducing tumor regrowth
delays.
 E.g. Mitomycin C to target specifically hypoxic tumor
cells.

12. Temporal modulation
 Exploits the radiobiological principles of fractionation.
 Radiation & drugs used concomitantly or in a rapidly
alternating schedule.
 combining EGFR blockade with fractionated radiation
could reduce cell proliferation during therapy and
might possibly reduce the accelerated cell proliferation
induced by radiation

13. Pictorial Representation

14. Timing of drug administration relative to fractionated radiation therapy
for the five exploitable mechanisms in combining drugs and radiation.
Timing

15. Therapeutic ratio

16. Drug Radiation Interactions

17. Assessment of Drug Radiation
Interaction

18.  Isobologram-
 Additivity envelope model was developed to
describe the log-linear cell survival relationship
observed in radiation studies
an isoeffect plot for the dose response to
the combination of two agents

20. Isobologram
 Points that fall below the
envelope between mode 1
& 2 curves indicate supra-
additivity
 Points occurring within the
envelope (between the two
curves) indicate additivity
 Points above the envelope
indicate infra-additivity.

21. Cell-cycle schematic and respective
sensitivity to chemotherapeutic agents.
Schematic Representation

22. MECHANISM

28. Molecular Targeting Possibilities in
Combination with Chemoradiation
Epidermal growth factor receptor inhibitors
Altering chromatin architecture
DNA repair inhibitors
Farnesyltransferase inhibitors
Angiogenesis inhibitors
Cyclooxygenase-2 inhibitors
Proteosome inhibitors
Apoptosis inducers
Gene or siRNA transfer

29. EGFR-targeted therapies and
chemoradiotherapy
 Studies show enhanced radiosensitivity leading to
supraadditive efficacy both in vitro and in vivo
 Mechanisms
 Inhibition of cell proliferation
 Impairment of DNA damage repair
 Attenuation of tumor neoangiogenesis,
 Promotion of radiation-induced apoptosis

30. Anti angiogenesis
 Target the VEGR ligand, such as bevacizumab
 Transient normalization of the abnormal structure in
tumour  reoxygenation
 antiangiogenic destruction of tumor vessels leads to
hypoxia

31. Dilemmas of Concurrent
chemoradiation
 Increases acute toxicities
 Cost issues
 Identify proper subset of patient who will benefit most
 Long term toxicities with newer agents awaited
 Absolute benefit in overall survival

33. Cervical cancer

34. EORTC/NCIC (Stupp et al.) – phase III: 573 patients with newly diagnosed
glioblastoma (16% biopsy only, 40% GTR, 44% STR) randomized to RT alone vs.
RT + concurrent and adjuvant temozolomide. RT was 60 Gy/30 fx.
Temozolomide was concurrent daily (75 mg/m2/day) and adjuvant (150–200
mg/m2/day × 5 days) q4 weeks × 6 month. Concurrent and adjuvant
temozolomide significantly improved MS (14.6 vs. 12.1 month) and 5-year OS
(9.8 vs. 1.9%). MGMT gene promoter methylation was the strongest predictor
for outcome and benefit from temozolomide
Glioblastoma Multiforme

35. EORTC 22931 (Bernier et al. 2004): 334 patients with
operable stage III/IV oral cavity, oropharynx, larynx, and
hypopharynx cancer randomized to post-op RT (2/66 Gy) vs.
post-op chemoRT (2/66 Gy and cisplatin 100 mg/m2 on days 1,
22, 43). Chemo-RT improved 3/5-year DFS (41/36→59/47%),
3/5-year OS (49/40→65/53%), and 5-year LRC (69→82%), but
increased grade 3–4 toxicity (21→41%).
Head And Neck Cancers

36. RTOG 95–01 (Cooper et al. 2004): 459 patients with operable cancer of
the oral cavity, oropharynx, larynx, or hypopharynx who had ³2 involved
lymph nodes, nodal extracapsular extension, or a +margin randomized
to post-op RT (2/60–66 Gy) vs. post-op chemo-RT (2/60–66 Gy and
cisplatin ×3c Chemo-RT improved 2-year DFS (43→54%), LRC
(72→82%), and had a trend for improved OS (57→63%), but increased
grade 3–4 toxicity (34→77%).

37. MACH-NC metaanalysis (Pignon et al. 2009): 87 phase III trials and
16,485 patients. 4.5% OS benefit at 5 years when chemotherapy was
added to RT, with greater benefit for concurrent chemo-RT vs. induction
chemo followed by RT (6.5% OS benefit with concurrent chemo-RT).
Similar results in trials with post-op RT, conventional, and altered
fractionation. No difference between mono or
polychemotherapy regimens, but increased benefit with
platinum-based compounds. Decreasing benefit with increasing age,
with no benefit observed if ³71 years.

38. Esophageal cancer
 RTOG 85-01 study established chemoradiotherapy
without surgery as a curative option for patients who
did not have evidence of distant metastasis of their
esophageal cancer and confirmed that radiotherapy
alone was not curative.
 Radiotherapy (64 Gy in 6·4 weeks) along with
radiotherapy (50 Gy in 5 weeks) combined with four
cycles of chemotherapy (fl uorouracil 1000 mg/m2 on
days 1–4) and cisplatin (75 mg/m2 on day 1 of weeks
1, 5, 8, and 11) in 121 patients

39. RTOG 85-01 study

Overall
survival
Local
recurrence/
Residual
disease
RT 0% 37
CT+RT 26% 26%

40. Anal cancer
 Randomized, controlled studies have demonstrated that
concurrent chemoradiotherapy with 5-fluorouracil (5FU),
mitomycin and radiotherapy is superior to radiotherapy alone
 Concurrent chemoradiotherapy allows approximately two
thirds of patients to be cured with sphincter preservation

41. Results from the UKCCCR randomised trial of radiotherapy alone versus radiotherapy, 5-fluorouracil,
and mitomycin. UKCCCRAnal Cancer Trial Working Party.UKCo-ordinating Committee on Cancer
Research. Lancet 1996;348:1049 –1054.
3 yr local failure
(significant)
O.S
(non-significant)
CT+RT 39% 65%
RT 61% 58%

42. Rectal cancer French FFCD 9203 (Gerard 2006): 733 eligible patients with T3-
4N0 resectable adenoca rectum randomized to pre-op RT (1.8/45 Gy) vs. pre-op
concurrent RT + bolus 5FU and LV d1-5 weeks 1 and 5. All patients had
adjuvant 4c of FU-LV chemo. Pre-op chemoRT increased pCR (4 to11%) and LC
(83 to 92%), but also grade 3–4 toxicity (3 to15%). No difference in sphincter
saving surgery (52%), EFS, or OS (67%).
Rectal Cancer

43. EORTC 22921 (Bosset et al. 2006; JCO 2007): 1,011 patients with
resectable rectal CA randomized to pre-op RT, pre-op chemoRT, pre-op RT +
post-op chemo, or pre-op chemoRT + post-op chemo. RT consisted of 45 Gy
and chemo consisted of 5-FU and leucovorin (pre-op chemo × 2 cycles,
post-op chemo × 4cycles). No difference in 5-year OS between pre-op and
post-op chemo groups (64.8% vs. 65.8%). Five-year LRR improved for
chemoRT groups (8.7, 9.6, and 7.6%) compared to RT alone group (17.1%),
and chemoRT increased the pCR rate (5 to14%).

44. Thank You