nci workshop on advanced technologies in radiation oncology: cervix december 1, 2006 david gaffney...
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NCI Workshop on Advanced Technologies in Radiation Oncology:
Cervix
December 1, 2006
David Gaffney MDPhDHuntsman Cancer Hospital
University of Utah
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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
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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
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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
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• 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
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Radiotherapy for Cervix Cancer: An
Important Paradigm • Dose Limiting toxicity
– Small Bowel: < 45 Gy– Rectum: < 75 Gy– Bladder: < 75 Gy
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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)
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Radiotherapy for Cervix Cancer: An Important Paradigm
• Imaging is better now: PET
Grigsby et al IJROBP 59(3):706, 2004
Pelvic Nodes Para-aortic nodes
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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.“
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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 Gy t1/2 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 cervixLin et al IJROBP 63:1494, 2005
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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
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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
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Cervix: Stereotactic RT
No Randomized Trials!
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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
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Cervix: Image Guided BrachytherapyRX 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
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Cervix: ProtonsNo 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.”
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Cervix: NeutronsYes! Randomized Trials!
Neutron therapy in cervical cancer: results of a phase III RTOG Study. Maor MH et al IJROBP 14:885, 1988
-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.
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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.
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Neutrons/Photons vs Photons
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Neutrons/Photons vs Photons
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Hyperthermia: Two Ongoing Randomized Trials
• Dutch Trial– RT and hyperthermia +/- chemo
• Ellen Jones MDPhD Duke PI– ChemoRT +/- hyperthermia (q week)
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Promising Technologies in Cervix Cancer
• Image Guided Brachy: MR-Based (RTOG 0417)– Point A was not designed for dose prescription
Dimoupoulos et al IJROBP66(1):83, 2006
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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)
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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?)
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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