Protocol Summary RTOG 0938 – Hypofractionated Radiotherapy for Prostate Cancer

1. Protocol SummaryRTOG 0938 – Hypofractionated Radiotherapy for Prostate Cancer Jackson Lau Dos 741 Protocols & Studies 10/29/2012

2. Purpose • RTOG 0938 is a Phase II trial to assess quality of life outcomes of two hypofractionated radiotherapy regimens for prostate cancer as compared to standard radiotherapy treatment • Research strongly suggests that early stage prostate cancer can be effectively treated with hypofractionated radiotherapy • Deliver higher doses of radiation in fewer treatments • To obtain information on bowel, urinary and sexual side effects of the study treatment vs standard treatments

3. What is RTOG? • Radiation Therapy Oncology Group (RTOG) • National clinical cooperative multidisciplinary group consisting of physicians and researchers from over 300 academic and medical facilities in the US, Canada and internationally. • Mission – to increase the survival outcome and quality of life of adults with cancer through high quality clinical trials • Funded by the National Cancer Institute • Established in 1968 for the purpose of conducting radiation therapy research and clinical investigation • RTOG continues to provide an infrastructure for investigators to seek more effective treatments for cancer • Successful trials in this protocol will: • Fulfill RTOG’s mission of improving survival and quality of life for cancer patients • Increase awareness and participation by investigators and patients in subsequent phases and trials • Continued financial support from National Cancer Institute

4. Background • Majority of prostate cancer is diagnosed in the early stage • Have not spread to lymph nodes or other organs • Much research is focused on the best treatment strategy for these patients • Propose hypofractionated radiotherapy as an alternative to standard treatment • Common radiotherapy regimen • 5 days/wk, 39 to 41 treatment sessions for 7-8 weeks

5. Background (cont.) α/βratios of Human Tumors1 • Studies show prostate specific antigen (PSA) control is significantly affected by the dose fractionation used • Dose response of tumors and normal tissues to fractionated irradiation is described by the “α/βratio ” • Indication of the fractionation sensitively of a particular cell type • Clinical results suggest that the fractionation sensitivity of prostate tumors is very high • α/βratio for prostate tumor much lower than most other tumors

6. Background (cont.) α/βratio for prostate tumor and normal tissue1 • Radiosensitivity • Cells with high proliferation rates have little time to repair • High alpha-beta ratio (ieskin, mucosa and most tumors) • Not very sensitive to fraction size • Cells with slow proliferation rates have long cell cycle time allowing plenty of time for intracellular repair between successive fractions • Low alpha-beta ratio (ie connective tissues, muscles, prostate tumors) • Very sensitive to fraction size • The lower α/βratio for prostate tumors than the surrounding late responding normal tissues creates the potential for therapeutic gain

7. Background (cont.) Hypofractionated schedule1 • Most tumors have rapid proliferation rates: use large # of small doses while keeping damage to late reacting normal tissues low • However, prostate cancer have slow proliferation rates: use fewer and larger fractions • Decreasing the # of fractions • Increases the biochemical non-evidence of disease (bNED) - % of patients with 5 yr success rate • Biological Effective Dose (BED) remains the same with no increase in toxicity for normal tissues (ie rectum)

8. Background (cont.) • Hypofractionated regimens could be designed with fewer but larger doses, to maintain equivalent late reactions while yielding improved tumor control • Possible with highly conformal technologies (ie IMRT)

9. Study Proposal • A phase II randomized trial to assess quality of life outcomesof two different hypofractionatedregimens • Regimen #1 • 36.25 Gy in 5 fractions of 7.25 Gy 2x/wk over 2.5 weeks (15-17 days) • Regimen #2 • 51.6 Gy in 12 daily fractions of 4.3 Gy over 2.5 weeks (16-18 days) • Control Group • Prostate cancer patients receiving standard treatment

10. Benefits • Treatment • High potential for therapeutic gain • Potential to significantly affect the future treatment of early stage prostate cancer • Logistics • More convenient for patients by reducing the number of clinic visits for treatment • Economic • Fewer treatments leads to health care cost savings

11. Patient Selection • Sample size for this study = 174 patients • Conditions of eligibility • Diagnosis of adenocarcinoma of the prostate • History/physical examination with digital rectal examination of the prostate • Prostate biopsy with Gleason scores 2-6 • Clinical stage T1-2a • PSA < 10 ng/mL • Zubrod Performance Status 0-1 • Age ≥ 18 • Provide study specific informed consent • Willingness and ability to complete the Expanded Prostate Cancer Index Composite (EPIC) questionnaire • Assess patients urinary, bowel, sexual functions

12. Patient Selection (cont.) • Conditions for ineligibility • Prior or concurrent invasive malignancy • Evidence of distant metastases • Regional lymph node involvement • Previous radical surgery • Previous pelvic irradiation or prostate brachytherapy • Previous hormonal therapy • Previous or concurrent cytotoxic chemotherapy • Severe active co-morbidity • Hepatic insufficiency • Acquired Immune Deficiency Syndrome

13. Radiation Therapy Regimen • Regimen #1: • 7.25 Gy/fraction for 5 fractions of radiation • Total dose = 36.25 Gy • Delivered 2x a week • A minimum of 72 hours and a maximum of 96 hours between each treatment • No more than 2 fractions will be delivered per week • Total duration of treatment will be no shorter than 15 days and no longer than 17 days

14. Radiation Therapy Regimen (cont.) • Regimen #2: • 4.3 Gy/fraction for 12 daily fractions • Total dose = 51.6Gy • Treated 5 days a week • The total duration of treatment will be no shorter than 16 days and no longer than 18 days

15. Protocol Technical Requirements • Require the use of IMRT or related techniques (Tomotherapy, VMAT, Cyberknife) • Treatments are required to be performed with an image guided technique for target localization • A computerized method for image registration is required for determination of patient shift information • Recommended photon energies 6-10MV • Beams with higher energies are discouraged

16. Patient Setup, Localization and Tracking Guidelines Patients are positioned supine Minimum immobilization apparatus will be a pillow under the knees Use of rectal balloons are allowed by not required Degree of bladder fullness should be made to duplicate what is anticipated for daily treatment Acceptable IGRT techniques should be utilized for initial localization and tracking or periodic monitoring to ensure beam positioning is maintained throughout long treatments

17. Treatment Planning Protocol • Computed Tomography (CT) will be the primary image platform for treatment planning • Axial cuts of 2.5 mm or less will be acquired throughout the pelvis and prostate from the top of the iliac crests superiorly to the perineum inferiorly • Definition of volumes in accordance to ICRU report #50 and #62 • Planning target volume (PTV) is defined as the CTV plus a 3mm margin posteriorly and 5mm in all other dimensions • To meet dose constraints, the anterior margin can be reduced to 3mm • Isodose line used for the prescription dose should cover a minimum of 95% of the PTV • Minimum dose within the PTV to a point that is 0.03 cc in size must be ≥95% of the prescribed dose

18. Treatment Planning Protocol (cont.) • Static gantry IMRT beam arrangements will be designed with a minimum of 5 gantry angles • The use of non-coplanar beams is encouraged • The maximum dose within the PTV is 7% above the prescribed dose for a point that is 0.03cc in size • Must not occur outside of the PTV • Hotspots should be manipulated to avoid the prostate-rectal and prostate-bladder interfaces as defined by the CTV • Urethra dose shall not exceed 107% of the prescription dose

19. Treatment Planning Protocol (cont.) • Normal tissue volume to be contoured include: • bladder, rectum, bilateral femora, seminal vesicles, penile bulb, skin and urethra • The bladder should be contoured from its base to the dome • The rectum should be contoured from the anus for a length of 15cm or to the rectosigmoidflexure • The following table lists the maximum critical organ dose limits for both regimens • Treatment delivery that do not meet these limits will constitute either a variation (acceptable) or deviation (unacceptable protocol violation)

20. Critical Structure Constraints

21. Documentation & Compliance Requirements • Documentation • CTV, PTV and designated organs at risk, dosimetry and DVHs are reviewed for compliance with protocol • For IMRT, at least one port film from each orthogonal film along with the DRRs shall be included • Compliance Criteria • Minimum allowable dose within PTV is > 95% of the prescribed dose to a volume that is at least 0.03cc • The maximum dose volume of the PTV must not be shared by a normal critical structure • Dose to the prostate rectal interface and prostate bladder interface shall not exceed the dose constraint parameters from the previous slide

22. Potential Side Effects • Small bowel or rectal irritation • Abdominal cramping, diarrhea, rectal urgency, or proctitis • Bladder complications • Urinary frequency/urgency, dysuria, hematuria, urinary tract infection, and incontinence • Radiation dermatitis

23. Surveys • Expanded Prostate Index Composite (EPIC) questionnaire • Assess patients urinary, bowel, sexual functions • Optional EQ-5D questionnaire • A self assessment survey • Covers mobility, self care, usual activities, pain/discomfort, anxiety/depression and current overall health

24. References Thank You Fowler JF. The radiobiology of prostate cancer including new aspects of fractionated radiotherapy. ActaOncol. 2005;44:265-276.