1. NCI Workshop on Advanced Technologies in Radiation Oncology: Cervix December 1, 2006 David Gaffney MDPhD Huntsman Cancer Hospital University of Utah

2. Radiotherapy for Cervix Cancer: An Important Paradigm Cure very large tumors with RT alone –Local control correlates with survival Brachytherapy permits very high dose to tumor –Requisite component of successful treatment Morbidity is high (dose to bladder and rectum) Concurrent Chemotherapy improves LC and DMFS Modern Imaging (MRI and PET ) provides superior pre-Tx evaluation and treatment

3. Radiotherapy for Cervix Cancer: An Important Paradigm Cure very large tumors with RT alone –Eifel PJ, et al Time course and outcome of central recurrence after radiation therapy for carcinoma of the cervix. Int J Gynecol Cancer 2006;16:1106–1111. 5% of patients received chemotherapy

4. Radiotherapy for Cervix Cancer: An Important Paradigm Local control remains a clinical problem (ASTRO 2006) –RTOG 0128: 2 yr DFS is 69% –2 yr Local Regional Failure is 26% –55% of first sites of recurrence included a local-regional component

5. Brachytherapy permits very high dose to tumor, and minimized complications –FIGO IIIB squamous cell carcinoma of the cervix: an analysis of prognostic factors emphasizing the balance between external beam and intracavitary radiation therapy Logsdon and Eifel IJROBP 43(4):763, 1999. Pt A 85 Gy, VSD 110 Gy, Cervical os 150-200 Gy

6. Radiotherapy for Cervix Cancer: An Important Paradigm Dose Limiting toxicity –Small Bowel: < 45 Gy –Rectum: < 75 Gy –Bladder: < 75 Gy

7. Chemo? Chemotherapy improves DMFS and LC! Neoadjuvant chemo has not worked in multiple randomised trials NCI 1999: 5 randomised trials –All improved local control –2 improved DMFS Other chemo showed same benefit as CDDP (IPD Meta-analysis Tierney IGCS 2006) Extended adjuvant chemo may have benefit (IPD Meta-analysis Tierney IGCS 2006)

8. Radiotherapy for Cervix Cancer: An Important Paradigm Imaging is better now: PET Grigsby et al IJROBP 59(3):706, 2004 Pelvic NodesPara-aortic nodes

9. Imaging is better now: PET 5/132 with PET + Pelvic LN’s failed. 1/33 with PET + PA LN’s failed. “ Lymph node recurrence as the only site of failure occurred in <2% of our patients…To resect or not to resect enlarged lymph nodes or to increase the irradiation dose to toxic levels in all patients is not the clinically relevant issue.“

10. Radiotherapy for Cervix Cancer: An Important Paradigm Tumors regress rapidly: shrinking GTV, poorly defined CTV- --effect of endometrial extension is not clear SUV t1/2 20 days or 25 Gyt1/2 21 days or 31 Gy Rapid involution and mobility of carcinoma of the cervix, Lee et al IJROBP 58(2):625, 2004 Sequential FDG-PET brachytherapy treatment planning in carcinoma of the cervix Lin et al IJROBP 63:1494, 2005

11. Radiotherapy for Cervix Cancer: An Important Paradigm FDG-PET imaging for the assessment of physiologic volume response during radiotherapy in cervix cancer Lin et al IJROBP 65(1):177, 2006 RFS by PET

12. Cervix Cancer Cervix/Vagina is mobile Variable filling of bowel and bladder ITV used in post hysterectomy setting in RTOG 0418 Lee et al IJROBP 2004

13. Cervix: Stereotactic RT No Randomized Trials!

14. Cervix: IMRT/IGRT No Randomized Trials! 1. Promising Single Institutional Data -AJ Mundt MD U of Chicago/UCSD -bone marrow sparing -less GI and hemetologic toxicity 2. Prospective RTOG phase II trial: 0418

15. Cervix: Image Guided Brachytherapy RX to HR-CTV by MR, not point A No Randomized Trials! Single Institution Experience: Univ of Vienna RTOG 0417 -secondary endpoint: develop dose volume library to correlate with toxicity

16. Cervix: Protons No Randomized Trials! –High-energy proton beam radiation therapy for gynecologic malignancies. Potential of proton beam as an alternative to brachytherapy. Arimoto et al Cancer 68:79-83, 1991. –N=15, 1983 to 1987 –Particle Radiation Medical Science Center –Local Control 14/15. –Radiation-induced proctitis (n=2, neither of which required surgical treatment) were the only complications despite a dose > 80 Gy in most cases. –“The results suggest that sharply localized, high-dose proton beam RT can produce an antitumor effect equivalent to that of conventional brachytherapy.”

17. Cervix: Neutrons Yes! Randomized Trials! Neutron therapy in cervical cancer: results of a phase III RTOG Study. Maor MH et al IJROBP 14:885, 1988 Maor MH -n=156 patients -(50 Gy in 25 fractions over 5 weeks plus intracavitary applications or external-beam boost) or mixed-beam radiotherapy (2 fractions a week of neutrons, 3 fractions a week of photons to a total RBE-adjusted dose of 50 Gy plus intracavitary applications or external mixed- beam boost). -The % of patients undergoing intracavitary applications was 50% on mixed beam and 75% on photons (p < 0.01). -Tumor clearance was 52% and 72% for mixed beam and photons, respectively (p<0.03). -Median survivals were 1.9 years on mixed beam and 2.3 years on photons. -Severe complications occurred in 19% and 11% in mixed beam and photons respectively (p<0.13). The inferior outcome with neutron therapy in this study may have resulted from the use of horizontal neutron beams of varying energy and penetration.

18. Neutrons: Randomized Brachy Trial 252Cf vs conventional gamma radiation in the brachytherapy of advanced cervical carcinoma long-term treatment results of a randomized study. Tacev et al Strahlenther Onkol 179:377, 2003 –N=227, 40 Gy-eq via brachy in first week, 16 Gy photon brachy week 5, ext beam 40 Gy/20 fractions, pt A 85 Gy –19% increase in OS and LC for 252Cf, p<0.003 Promising phase II experience at Univ of Kentucky by Maruyama et al. Sources now at Tufts.

19. Neutrons/Photons vs Photons

22. Hyperthermia: Two Ongoing Randomized Trials Dutch Trial –RT and hyperthermia +/- chemo Ellen Jones MDPhD Duke PI –ChemoRT +/- hyperthermia (q week)

23. Promising Technologies in Cervix Cancer Image Guided Brachy: MR-Based (RTOG 0417) –Point A was not designed for dose prescription Dimoupoulos et al IJROBP 66(1):83, 2006

24. Promising Technologies in Cervix Cancer Improved imaging (ACRIN/GOG study: Correlate surgical findings with MR and PET) Improved imaging (ACRIN/RTOG proposed study: MR and PET; Correlate imaging with response, pre, during and post Tx, identify poor responders) GOG/RTOG have performed trials previously in Cervix and Endometrium successfully +/- RT: GOG 92 and 99 (Reminiscent of success of RTOG 0413/NSABP B39) IMRT (RTOG 0418) Stratification factor in GOG trials Image Guided Brachytherapy (MRI)

25. Promising Technologies in Cervix Cancer Better Radiosensitizers: In Meta-analysis: other chemo had same survival benefit as CDDP (Tierney et al IGCS 2006) Extended Adjuvant chemo in LN + patients Personalized Tx eg microarray gene expression analysis (permit dose escalation, choice of chemo?)

26. Promising Technologies in Cervix Cancer Hyperthermia (mult adv may make this more attractive) High LET Brachytherapy program –Positive trial with Cf252 –Limited institution Proton beam –For Intact Cervix: Adaptive RT and IGRT required –Lymph node boosts –Recurrent disease –Poorly responding advanced stage disease