Radiation Oncology Trials Alone in Multimodality Settings

1. Radiation Oncology Trials Alone & in Multimodality Settings Stephen M. Hahn University of Pennsylvania School of Medicine Philadelphia, PA USA

3. The Evolution of Radiation Therapy Key points to make: Completely new carriage and leaf design to Other improvements made: Reduced Head Diameter by 10 cm from previous �Standard� MLC Key points to make: Completely new carriage and leaf design to Other improvements made: Reduced Head Diameter by 10 cm from previous �Standard� MLC

4. Effect of underdosage and overdosage This means,an increase in tumour dose necessitates a decrease in toxicity in order to increase tumour control. This is expressed as an increase of the therapeutic ratio.This means,an increase in tumour dose necessitates a decrease in toxicity in order to increase tumour control. This is expressed as an increase of the therapeutic ratio.

6. Trials of Radiation Therapy Alone Target Volume Organs at Risk Quality Assurance Dose Volume Time Assessment of Toxicities

8. Interpretation of radiotherapy trials:Radiotherapy outcomes are dependent upon technical factors 

10. Quality Control-Radiation Standard dose and fractionation schedules Specify fields or target volumes � be precise Specify doses to target volumes IMRT vs. 3-D conformal radiotherapy CT-based vs. conventional simulation Field verification Dose inhomogeneity

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12. Multi-Modality Radiation Trials

13. Translation to the Clinic -Potential Problems Baseline response rate Baseline cure rate Baseline toxicity Interdependence of one modality on the other for therapeutic effect Competing risks for end-point of interest

14. Factors Affecting Radiation Sensitivity Intrinsic Factors Ras mutational status EGFR DNA repair capabilities DNA methylation Extrinsic Factors Tumor microenvironment � hypoxia pH Tumor vasculature � �normalization�

17. Chemoradiotherapy An improved therapeutic index should be the goal Effect of chemoradiotherapy on the tumor compared to the effect of chemoradiotherapy on normal tissue toxicity Classically there are 4 ways to define the interaction spatial cooperation toxicity independence radioprotectors radiation sensitizers Steel & Peckham IJROBP 5:85, 1979

18. Therapeutic Gain This means,an increase in tumour dose necessitates a decrease in toxicity in order to increase tumour control. This is expressed as an increase of the therapeutic ratio.This means,an increase in tumour dose necessitates a decrease in toxicity in order to increase tumour control. This is expressed as an increase of the therapeutic ratio.

20. Preclinical Studies-Rationale Combining chemotherapy with radiation requires a rationale preferably grounded in supporting preclinical data There should be convincing preclinical data that indicates that the combination is either Efficacious (radiation sensitization) No overlapping toxicities (toxicity independence)

21. Preclinical Studies-Rationale Demonstrate in vitro radiosensitization in human tumor cell lines Demonstrate in vivo radiosensitization in human tumor models Demonstrate the lack of sensitization of normal tissues Preclinical studies should use clinically relevant doses and schedules of agents & XRT

22. Question # 1

23. Question # 2

24. Phase I Studies of Drugs and Radiation

25. Phase I studies-Endpoints The goals of combined modality Phase I studies are similar to single agent studies However, the design and application often differs The primary endpoint is usually an assessment of toxicity with the goal of identifying a recommended Phase II dose

26. Phase I studies The definition of the recommended Phase II dose: the doses and schedules of both the drug and radiation when used in combination It is NOT the same as the maximally tolerated dose although MTD can be used to identify the recommended Phase II dose The schedule and dose of radiation may be very different from that used with each agent alone

27. Phase I studies Data helpful for the design of the study Single agent pharmacokinetic data from the relevant scheduling regimen Continuous dosing during XRT vs. once a week dosing Single agent pharmacodynamic data Agent�s affect on a molecular target that is relevant to the interaction between XRT and radiation Single agent safety data

28. Phase I studies-Design Issues Patient selection What tumor sites? The answer to this question impacts greatly upon the assessment of toxicity. The selection of tumor site may also be impacted by the agent being used in combination with XRT (think C225 and HNC) Curative or palliative radiotherapy? This will affect total radiation dose and fractionation This will affect the patient population and perhaps the ability to tolerate combined modality therapy In general, Phase I data are generated from studies that are cancer-specific and/or site-specific.

29. Phase I studies-Design Issues What doses and schedules of the agent should be selected? If the goal is radiosensitization, then delivery of the agent during as many fractions of radiation is desirable The schedule and dose may also be impacted by the known characteristics and target of the agent What doses of radiation should be selected? A typical approach especially in the curative setting is to start with a standard radiation dose; however escalation of the radiation dose may be desirable in certain clinical situations

30. Phase I studies-Design Issues A limited dose-escalation design is typical for these studies Dose-limiting toxicity rules Grade IV hematological toxicity Grade III non-hematological toxicity Exceptions should be considered � Grade III diarrhea in the setting of upper abdominal XRT Breaks during XRT

31. Phase I studies-Design Issues Dose escalation rules Standard Phase I dose escalation rules are acceptable especially if multiple agents are being used (including conventional chemotherapy) Consider using a toxicity assessment in association with clinical or biological endpoints Particularly with targeted agents, defining the �optimal biologic dose� might be appropriate Be careful because the biological endpoint is a surrogate for clinical efficacy and this may not be known during the Phase I development period

32. Phase I studies-Endpoints Toxicity criteria Consider XRT or combined modality-specific criteria (RTOG) Toxicity assessment is typically during the entire radiation course and some defined period of time after XRT, e.g. 30 days How do we assess late effects? There are practical and time limitations Bevacizumab and thoracic radiation

33. Phase I studies-Design Issues Think about the next step in development What is the standard therapy for the tumor site being treated? What is the role of conventional chemotherapy? How should surgery (if appropriate) be integrated? How should chemotherapy be integrated?

34. Anti-Angiogenic Therapy Hypothesis: Can anti-angiogenic therapy augment the effect of radiation therapy and chemotherapy on rectal cancer? Immature and inefficient blood vessels could be pruned by eliminating excess endothelial cells --> �Normalized Vasculature� --> Improved delivery of nutrients and therapeutics

37. Antiangiogenic therapy: Conclusions from Preliminary In- vivo Data The addition of antiangiogenic agents to chemoradiation programs: increases tumor perfusion/reduces hypoxia increases tumor radioresponse does not appear to increase (skin) toxicity increases chemoresponse

38. Phase I Study

39. Rectal Cancer: Phase I Study (Schema) Bevacizumab 5-10 mg/kg, 2 weeks prior to XRT Level Bev (q2wk) 5-FU (mg/m2/d) RT (Gy) 1 5 mg/kg 225 50.4 2 10 mg/kg 225 50.4 Bevacizumab: 4 Infusions After determination of MTD, 20 additional pts to be treated Willett et al. Nature Medicine, 2004

40. Study Endpoints / Correlates MTD of Bevacizumab with EBRT and 5-FU Preliminary Data: pCR, LC, PFS, S Correlative studies Functional imaging (PET, CT perfusion studies) Interstitial Pressure Measurement Circulating Endothelial Cells and Precursors Tissue Serum and Urine

42. Phase II studies The decision to proceed with a combined modality Phase II study is dependent upon the safety and early efficacy results from the Phase I trial The primary goals of a Phase II combined modality study is efficacy

43. Phase II trials-Endpoints Response rates are often not helpful for selecting efficacious regimens Delayed time to response with XRT Residual unevaluable masses vs. scarring Progressive disease outside of the XRT field Underlying high local response rates to XRT

44. Phase II trials-Endpoints Consider other efficacy endpoints Complete response rate Pathological complete response rate Local or locoregional control rates Time to progression Survival The endpoint selected will depend upon the tumor & the current standard therapy

45. Phase II trials-Endpoints Additional toxicity data both acute and late toxicity are essential components Collection of late toxicity data in the larger group of patients that constitutes a Phase II study will be helpful as the Phase III study is designed

46. Phase II trials-Design Early stopping rules for toxicity (most likely acute toxicity) should be considered Early stopping rules for low response rates compared to historical controls may also be a useful design consideration Usually dramatic differences in response must be seen for early stopping rules to be implemented

47. Phase III Study Generally a major interdependence of modalities Quality control of each modality can be of enormous importance in defining whether a therapy should be used Produces an interaction which can effect the study outcome

48. Special Considerations in trials that include surgical therapy The surgeon as a prognostic factor Adherence to surgical technique Quality control Experience of the surgeon The pathologist as a variable Quality control

49. COMBINED MODALITY THERAPY One must consider multiple issues in study design Biologic interaction between modalities Patient selection Quality control Base line data- response, toxicity, survival The same issues as in other studies,but approached differently