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