NCI Workshop on Advanced Technologies in Radiation Oncology: Cervix

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NCI Workshop on Advanced Technologies in
Radiation Oncology Cervix

• December 1, 2006
• David Gaffney MDPhD
• Huntsman 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
  20061611061111.

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 lt 45 Gy
• Rectum lt 75 Gy
• Bladder lt 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 LNs failed.
1/33 with PET PA LNs failed.
Lymph node recurrence as the only site of
failure occurred in lt2 of our patientsTo 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

Sequential FDG-PET brachytherapy treatment
planning in carcinoma of the cervix Lin et al
IJROBP 631494, 2005
Rapid involution and mobility of carcinoma of
the cervix, Lee et al IJROBP 58(2)625, 2004
SUV t1/2 20 days or 25 Gy
t1/2 21 days or 31 Gy
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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
toxicity2. Prospective RTOG phase II trial 0418
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Cervix Image Guided BrachytherapyRX to HR-CTV
by MR, not point ANo 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 6879-83, 1991.
• N15, 1983 to 1987
• Particle Radiation Medical Science Center
• Local Control 14/15.
• Radiation-induced proctitis (n2, neither of
  which required surgical treatment) were the only
  complications despite a dose gt 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
  14885, 1988
• -n156 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 lt 0.01).
• -Tumor clearance was 52 and 72 for mixed beam
  and photons, respectively (plt0.03).
• -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 (plt0.13). 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 179377,
  2003
• N227, 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, plt0.003

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 IJROBP 66(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