Collection of Recorded Radiotherapy Seminars

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1 IAEA Human Health Campus Collection of Recorded Radiotherapy Seminars

2 High Dose Rate Brachytherapy in Cervix Cancer Luis Souhami, MD Professor Department of Radiation Oncology McGill University, Montreal, Canada McGill University

3 Radiotherapy of Cervix Cancer External Beam Radiation Therapy Gy Brachytherapy LDR HDR

4 Variations in Treatment Regimens Low Dose Rate 1 or 2 applications 20 to 40 Gy/fraction High Dose Rate More than 50 treatment regimens* 1 to 16 fractions 3 to 17 Gy/fraction *Orton et at IJROBP 1991

5 Why Fractionate? Low Dose Rate High Dose Rate Allow tumor regression Better pelvic geometry Radiobiology (toxicity) Allow tumor regression Better pelvic geometry Financial stimulus

6 Pioneers in HDRB for Cervix Cancer O Connel, Joslin et al. Cardiff 1965: 4 x 10 Gy Arai et al. Japan 1968: various fractionation Akine et al. Japan 1972: 4 x 5 Gy Shigematsu et al. Japan 1973: 3 x 10 Gy Inoue et al. Japan 1978: 3-6 x 7.5 Gy Chen et al. Taiwan 1980: 3 x Gy Roman et al. Montreal 1984: 3 x 8 Gy Choi et al. Hong Kong 1984: 3 x 7-8 Gy Patel et al. Chandigarh 1986: 2-4 x Gy

7 Textbook of Radiotherapy Gilbert H. Fletcher 3 rd Edition 1980 With remote control applicators, thousands of rads are given in a few minutes. The predominance of single hit events, which has the biologic advantage of continuous low dose rate irradiation, is lost and extrapolation from past experience is impossible.

8 Converting LDR to HDR Liversage - Br J Radiol 1969 N = µt/2{1-[1-exp(-µt)]/µt} N = # fractions; T = time; µ = recovery constant Dale Br J Radiol 1990 BED tum = Nd x [1 + d/(α/β) tum ] BED late = fnd x [1 + fd/(α/β) late ] f = known fraction of the true tumor dose BED tum = RT x [1+ 2R/{µ tum (α/β) tum }] BED late = frt x [1+ 2R/{µ late (α/β) late }] R = dose rate HDR LDR

9 Fractionation in HDR Dale 1985 HDR equivalent to LDR if 17 fractions of 3.5 Gy given Orton to 12 fractions will do it Brenner and Hall 5 to 12 fractions for early effects

10 McGill Experience First Selectron in N. America First treatment in 1984 Micro Selectron installed in 1988 Implant always done under spinal anesthesia Home made planning system Roman, Souhami et al: IJROBP 1991 Souhami et al: Gynecol Oncol 2005 McGill University

11 Patient Characteristics 282 pacients ( ) Median age: 62 years (25 95) Stage: IB IIA IIB IIIA IIIB 22 patients 49 patients 116 patients 7 patients 77 patients 8% 17.5% 41% 2.5% 27% McGill University

12 Technical Parameters EBRT Median Dose : 46 Gy ( Gy) HDRB Median Dose : 24 Gy ( Gy) Median nºfxs : 3 (1 3) McGill University

13 Results Median follow-up: 50.1 months Median follow-up patients at risk: 86.6 months McGill University

14 Overall survival 1.0 Overall Survival Survival % 5 52% 5 47% Time (y) McGill University

15 Survival by Stage Survival by Stage IB IIA IIB IIIA IIIB IVA Survival p < Time (y) McGill University

16 Overall Survival Stage 5 years (%) 10 years (%) 15 years (%) IB IIA IIB IIIA IIIB Overall McGill University

17 Patterns of Failure Local only 43 patients 15% Distant only 33 patients 12% Local & distant 25 patients 9% McGill University

18 Local Failure by Stage Local Failure by Stage p < fail IB fail IIA fail IIB fail IIIA fail IIIB fail IVA Failure McGill University Time (y)

19 McGill Experience Local Failure by Treatment Duration 1.0 Local Failure by Treatment Duration p = Rx duration > 47d Rx duration < 47d IIB Failure McGill University Time (y)

20 Cervix Cancer Duration of RT vs Local Control Author # Pts Pelvic Control Fyles 830 1% day/30 days Lanciano % day/55 days Petereit % day/55 days Perez % day/49 days Girinsky % day/52 days McGill University

21 McGill University

22 Late Toxicity GI GU Overall 15.3% 8.1% Grade % 3.5% McGill University

23 Complication Probability vs BED BED at ICRU Rectal Point (Gy3) Complications No Complications Complication Probability BED (Gy 3 ) Clark, Souhami et al IJROBP 1997 McGill University

24 HDRB: Regimens Stages IIB-IIIB Author # Pts Year Median FU (mos) EBRT (Gy) HDR #fxs/gy Mosalaei /10 Souhami /8 Lorvidhaya /6-7.5 Han /3.86 Ferrigno /6 Pötter /7 Patel /9 Int J Gyn Cancer 2006; Gynecol Oncol 2005; IJROBP 2000; Gynecol Oncol 1996; IJROBP 2001; Cancer Radioth 2000; IJROBP 2005

25 HDRB: Regimens Stages IIB-IIIB Author Local Control Rectal Toxicity ( Grade III) Mosalaei IIB = 96%; IIIB = 87% 11% Souhami IIB = 80%; IIIB = 61% 6% Lordidhaya IIB = 80%; IIIB = 61% 10% Han 80% (overall) 3.5% Ferrigno 62% (overall) 3% Pötter IIB = 87%; IIIB = 69% 6% Patel IIB = 80%; IIIB = 67% 0% Int J Gyn Cancer 2006; Gynecol Oncol 2005; IJROBP 2000; Gynecol Oncol 1996; IJROBP 2001; Cancer Radioth 2000; IJROBP 2005

26 Making it really complicated Han et al: Gynecol Oncol 1995

27 Linear Quadratic Effective Doses Tumor Control Late Effects GOG Patel Potter Ferrigno Souhami Mosaleia Lorvidhaya GOG: 45 Gy + 5fxs/6 Gy Patel: 45 Gy + 2fxs/9 Gy Potter: 45 Gy + 4fxs/7 Gy Ferrigno: 45 Gy + 4fxs/6 Gy Souhami: 45 Gy + 3fxs/8 Gy Mosalaei: 50 Gy + 3fxs/10 Gy Lorvidhaya: 50 Gy + 4fxs/6 Gy

28 Stage IIIB: Pelvic Control and Survival vs Point A Gy Pelvic control Survival r= r= Petereit, Pearcey IJROBP 1999

29 All Complications vs Point A Gy r=-0.04 Complications Complication Probability BED (Gy 3 ) Petereit, Pearcey IJROBP Pt A

30 Randomized Trials Trial 1 Trial 2 Trial 3 LC LDR LC HDR Tox LDR Tox HDR 1- Lertsanguansinchai et al IJROBP Hareyama et al Cancer Patel et al IJROBP 1994

31 Dr. S.K.. Shrivastava Trial supported by IAEA CRP N E33016 Presented at ASTRO 2006

Authors conclusions This review showed no significant differences between HDR- and LDR-ICBT when considering OS, DSS, RFS, local control rate, recurrence, metastasis and treatment related

41 Authors conclusions This review showed no significant differences between HDR- and LDR-ICBT when considering OS, DSS, RFS, local control rate, recurrence, metastasis and treatment related complications for women with cervical carcinoma. Due to some potential advantages of HDR-ICBT (rigid immobilization, outpatient treatment, patient convenience, accuracy of source and applicator positioning, individualized treatment) we recommend the use of HDR-ICBT for all clinical stages of cervix cancer.

42 What is the optimal HDRB fractionation? McGill

43 Randomized Trial: 3 vs 5 Gy fractions Nam, Ahn: J Korean Med Sci 2004 Korean study: only 56 pts studied EBRT 45 Gy HDRB: 3 Gy (3 times/week) X 10 vs 5 Gy (twice/week) X 5 Late toxicity: 24% (group A) vs 9% (Group B) Disease Specific Survival Pelvic Control Rate

44 ABS - Recommendations for HDRB Nag et al. IJROBP 2000 It must be emphasized that the dose recommendations are intended to serve only as a guide; it should be noted that these schedules have not been thoroughly tested McGill

45 HDR Cervix: UK Jones et al: Br J Radiol 1999 McGill

46 HDR: Australian Protocols MacLeod et al Austral Radiol 2001 McGill

47 IAEA Study - E33026 Treatment Scheme Stage IIB-IIIB R A N D O M I Z E EBRT + HDRB 7 Gy/4 fxs plus CDDP weekly EBRT + HDRB 7 Gy/4 fxs - no CDDP EBRT + HDRB 9 Gy/2 fxs plus CDDP weekly EBRT + HDRB 9 Gy/2 fxs - no CDDP EBRT = 46 Gy/23 fxs CDDP = 40 mg/m 2

48 IAEA Study E33026 Rationale Common disease in developing countries. Locally advanced disease is norm and curative therapy is radiation-based No prior RCT comparing HDRB fractionations. Results with fewer fractions stimulating 2-fraction HDR with no-chemo would spare resources and may reduce toxicities Chemotherapy has yielded mixed results from RCTs. No study has compared different HDRB fractionations with chemo for any interaction effect

49 IAEA Study - E33026 Eligibility Biopsy-confirmed cervix cancer Stages IIB and IIIB Biopsy can be up to 120 d prior to date of randomization Age > 18.0 yr and KPS > 40 Life expectancy (>6m) with good general condition and no contraindications (medical, psychiatric, oncological) Not pregnant, breast-feeding, HIV+, etc. Imaging (CT recommended, optional other tests) Investigations done < 31 d prior to date of randomization: Appropriate bone marrow reserve Normal renal function Other blood tests (electrolytes; Calcium; LFTs) Para-aortic nodes benign, no bilateral hydronephrosis Written consent and likely compliant to follow-up

50 IAEA Study - E33026 Objectives Confirm there is no interaction between HDR fractionation and chemotherapy for survival and toxicity Determine efficacy and toxicity of 4x vs. 2x HDRB That 4x is not clinically superior to 2x Determine benefit and toxicity of chemo vs. no chemo Improves local control and survival without significant increase in high-grade toxicity Directly compare 2xHDRB no-chemo with 4xHDRB + chemo

51 IAEA Study - E33026 Objectives Detect patterns of molecular markers and determine one or more that predict for treatment success Determine whether E6 and E7 viral protein expressions predict for treatment resistance Compare staff documentation and patient self-reporting of toxicities in a subset of patients

52 IAEA Study - E33026 Trial Time-Line First patient accrued in September 2005 Last patient accrued in May 2010 Expect first outcomes analysis in Accrual CDF Sept May 2010 Total accruals by centre proportion of 601 cases Sep-05 Oct-05 Nov-05 Dec-05 Jan-06 Feb-06 Mar-06 Apr-06 May-06 Jun-06 Jul-06 Aug-06 Sep-06 Oct-06 Nov-06 Dec-06 Jan-07 Feb-07 Mar-07 Apr-07 May-07 Jun-07 Jul-07 Aug-07 Sep-07 Oct-07 Nov-07 Dec-07 Jan-08 Feb-08 Mar-08 Apr-08 May-08 Jun-08 Jul-08 Aug-08 Sep-08 Oct-08 Nov-08 Dec-08 Jan-09 Feb-09 Mar-09 Apr-09 May-09 Jun-09 Jul-09 Aug-09 Sep-09 Oct-09 Nov-09 Dec-09 Jan-10 Feb-10 Mar-10 Apr-10 May-10 Total accrual of 601 cases calendar month Total accrual = 601 Macedonia Morocco Pakistan Brazil South Africa Peru India

53 HDRB Recent Developments Potter et al. pioneered the integration 3D imaging with 3D treatment planning using MRI The Gyn GEC-ESTRO Working Group developed concepts and terms for 3D imaging and planning McGill

54 GEC-ESTRO Working Group Definitions GTV GTV defined by imaging plus visible and palpable disease GTV D at time of diagnosis GTV B1, GTV B2, GTV B3... at brachytherapy McGill

55 GEC-ESTRO Working Group Definitions CTV based in tumor load High Risk CTV major risk for local recurrence. Includes the GTV at time of brachytherapy and the entire cervix Intermediate Risk CTV major risk of recurrence (HR CTV) plus a margin ( cm) Low Risk CTV potential microscopic spread McGill

56 Target volume based on cancer cell density Haie-Meder, Potter et al. Radioth Oncol 2005

57 GEC-ESTRO Working Group Rectum Bladder Definitions Organs at Risk defined by MR ICRU points to be documented DVH of bladder and rectum To report minimum dose by maximally irradiated contiguous of organ at: 1 cm 3, 2 cm 3 and 5 cm 3 McGill

58 HDRB in Cervix Cancer Lessons Learned More convenient for staff and patient Outpatient Short administration time Outcomes similar to LDRB Cost-effective Fewer fractions equally effective and safe

59 Conclusions Optimal fractionation regimen not established Small number of fractions (<5) is well tolerated without apparent tumor control compromise Results comparable to HDRB using larger number of fractions Results comparable to LDR McGill

60 Conclusions ICRU rectal point dose should be kept below 125 Gy 3 Treatment duration should be kept short 3D imaging and planning replacing classical standard prescription at Point A McGill

Locally advanced disease & challenges in management

Gynecologic Cancer InterGroup Cervix Cancer Research Network Cervix Cancer Education Symposium, February 2018 Locally advanced disease & challenges in management Carien Creutzberg Radiation Oncology, Leiden