Radiation Therapy in the
Treatment of Cervical Cancer
Marc I. Botnick, M.D.
Valley Radiotherapy Associates
Goals

Familiarity with the different forms of
radiation treatment used in the care of
cervix cancer patients
Indications for adjuvant therapy post
radical hysterectomy
Results of definitive XRT and chemo/XRT
for cervical cancer
Epidemiology

11,070 new cases expected to be
diagnosed in the U.S. in 2008
Second leading cause of cancer death
after breast cancer for women ages 20-39
Incidence in Latina women is 2x that of
white Americans
Death rates in the U.S. have been
declining since the 1930’s
Etiology

HPV infection

>90% of cervical cancers have HPV DNA identified
Types 6, 11, 16, 18

Cigarette Smoking
Multiple sexual partners
Early age first coitus

Prolonged oral contraceptive use - adenocarcinoma

DES exposure – clear cell histology
HIV infection
Histology

Squamous Cell Carcinoma (80-90%)

Grade and subtype does not predict prognosis
Variants: Verrucous, papillary, sarcomatoid, small cell
Adenocarcinoma

Suggestion for increasing incidence
May reflect better path recognition
80% are endocervical
Usually moderately differentiated
Variants: adenosquamous, villoglandular, glassy cell,
adenoid basal, adenoid cystic
Natural History

Most arise at the squamocolumnar junction

Greatest risk for neoplastic transformation coincides
with periods of great metaplastic activity
Develop as exophytic growths protruding from
the cervix or as endocervical lesions that expand
the cervix without an obvious mucosal lesion
Natural History

Inferior Vaginal extension
Lateral extension into the parametria by
way of broad or utero-sacral ligaments
Bladder/Rectal involvement is rare (<5%)
Rare to have detectable hematogenous
dissemination at initial diagnosis
LN Involvement

Orderly pattern of metastatic progression initial to
primary echelon nods in the pelvis, then to PA nodes,
and then distant sites
Lateral cervix:

Upper branches – upper hypogastric nodes
Middle branches – deep hypogastic (obturator) nodes
Low branches – common iliac, presacral and subaortic nodes

Posterior cervix – superior rectal, subaortic nodes

Anterior branches – internal iliac nodes
LN Involvement

Correlates with stage, T size, histologic subtype,
depth of invasion, LVSI.
Reported incidences vary widely due to
differences in extent of lymphadenectomy and
surgical selection criteria
Stage I
Stage IB2
Stage IIB
Stage IIIB
PA LN
<5%
6%
19%
29%
Presentation

Abnormal vaginal bleeding
Vaginal discharge
Pelvic pain
Dyspareunia
Flank pain – due to hydronephrosis
Constipation
Sciatica
Work Up

PAP Test

10-15% false negative in women with invasive cancer
Poor at diagnosing gross lesions – must biopsy

Colposcopy and directed biopsies

Endocervical curettage

If PAP abnormal and colpo negative
Pelvic Exam/EUA
Work Up

FIGO

Colposcopy, ECC, hysteroscopy
CXR
IVP
Cystoscopy/proctoscopy for advanced lesions

35% sensitivity to detect +PA nodes
Cannot distinguish metastatic vs. reactive LNs
MRI

Plain films of bones
CT a/p

Must confirm by biopsy, bullous edema insufficient
Better assessment of tumor location and depth of invasion
Poor judge of parametrial extent
PET
Prognostic Features –
Tumor Variables

LN involvement

# nodes involved, largest node, pelvic vs. PA
Parametrial extension

Tumor size
LVSI
Deep stromal Invasion (>2/3, 10mm)

Grade

Controversial relationship between grade and squamous histology
Clear correlation between grade and adenocarcioma behavior
Histology

Adenocarcinomas may have higher pelvic relapse rate after surgery or
XRT alone; and may have higher rates of DM
GOG 49

645 pts with stage I cervix CA treated with RH +
PA/pelvic lymphadenectomy.

Recurrence correlated with:

microscopically positive pelvic LN (3-yr DFS 74.4% vs 85.6%)
depth of invasion (94% vs 84% vs 74% by thirds)
tumor size (94% occult, 85% <3cm, 68% >3cm)
LVSI (88% vs 77%)
grade (90% vs 86% vs 76%)
parametrial involvement (85% vs 70%)
margin status, 84.3% vs 69.1% but N.S.
Gyn Onc 1990;38:352-7.
Prognostic Features –
Treatment Variables

Hemoglobin

PMH (1978) – increased pelvic relapse if Hb < 12.5
XRT less efficacious in hypoxic environment
Mixed data regarding raising Hb with EPO
Treatment Time

Wash U: Stage IB, the cause specific survival was 86%
for 7 wks or less, 78% (7-9 wks), and 55% (>9wks).
Loss of control 1%/day beyond 7 weeks
Predominately in Stage III, IV
GOG 191

Phase III trial to evaluate the efficacy of maintaining Hb
above 12.0 g/dL with weekly EPO vs above 10.0 g/dL
without EPO for stage IIB-IVA cervical cancer patients
undergoing combined therapy

Closed prematurely due to concerns about thromboembolic
events. 109 patients accrued (<25% planned)
Outcome:

PFS
65% vs. EPO 58%
OS
75% vs. 61% (insufficient numbers)
Thromboembolism: control 8% vs. EPO 19% (ns)
Gyn Onc 2008;108(2):317-25.

Stage IIB-IVA cervical cancer received
radiochemotherapy and were randomized to EPO 3x
weekly or standard care for up to 12 wks

Median Hb increased by 1.3 g/dL with EPO, but
decreased by 0.7 g/dL in the control group (P < 0.0001)

No significant correlation between Hb increase and
treatment failure was demonstrated

Relapse-free survival (29% vs 32%), CR (53% vs 58%)
Int J Gyn Cancer. 2008;18:515-24.
FIGO Staging (1994)
Stage IA
Stage IB1
Stage IB2
Stage IIA
Stage IIB
Stage IIIA
Stage IIIB
Stage IVA
Stromal invasion <5mm depth and <7mm width
T <4cm or preclinical lesion > IA
T > 4cm
Upper vagina
Parametria
Pelvic sidewall, hydronephrosis
Lower third of the vagina
Bladder or rectal mucosa
Outcome
FIVE YR SURVIVAL RATES
Stage I 80%
Stage II 65%
Stage III 30%
Stage IV 15%
Outcome
Stage
IB, LNIB, LN+
5yr survival
85-90%
45-55%
75-80%
Rx
RH +/- XRT
RH +/- XRT
RH + C/XRT
Treatment Options

Radical Hysterectomy

Definitive Radiotherapy

Adjuvant XRT +/- chemotherapy
External Beam + Brachytherapy
Combined Chemotherapy and Radiotherapy

Cisplatin vs. other agents
Radiation Therapy
Linear Accelerator
How Radiation Works

Radiation is administered in the form of photons
or particles

When photons/particles interact with biologic material
they result in ionizations that can either interact directly
with subcellular structures or with water to then
generate free radicals
Ionizing radiation: photons (x-rays and gamma rays),
particle radiation (electrons, protons)
Direct effects of radiation are the consequence
of DNA damage

The key target for cell inactivation is a double stranded
DNA break
Normal cells are usually able to recover, but cancer cells
are less able
Lose their ability to divide and multiply
How Radiation Works

Radiation usually works best on cells
that are actively dividing.

Doesn't work as well on cells that are resting
(G0) or are dividing slowly.
G2-M phase is the most radiosensitive
Cancer cells usually divide more often than
most normal cells so the radiation can kill
more of them.
The differences in sensitivity throughout the
cell cycle are exploited by fractionated
radiotherapy due to the concept of
reassortment
Simulation
Supine v. prone
Immobilization
Rectal/bladder contrast
Vaginal marker/seeds
Conventional Simulation
CT Simulation
Contouring Planning CT Scan
Contouring Planning CT scan
Digitally Reconstructed
Radiographs
Conventional Field Borders
Superior: L4/5 or L5/S1
Inferior: inf edge of ischial tuberosity
Anterior: anterior to symphysis pubis
Posterior: post edge sacrum
Lateral: 2cm lateral to bony pelvis
Conventional Treatment Plan
Intensity Modulated Radiation Therapy
(IMRT)

IMRT provides the most effective means to produce tightly conformal dose
distributions in complex treatment situations

IMRT planning emphasizes an image based virtual simulation approach in defining
tumor and critical structure volumes

Requires detailed specification of the dose prescription including dose and
dose/volume constraints for all targets and critical structures

Improved computer optimization of radiation beam fluence

Benefit:

Improved normal tissue sparing Æ “less toxicity”
toxicity”
Better target coverage and conformity
Can create dose concavities and wrap around structures
Drawbacks

Minimal long term control data
More sensitive to clinical and geometric uncertainties than conventional
conventional XRT because of
sharper dose gradients
Intact Cervix IMRT Treatment Plan
Post-Op Pelvis Plan
Extended Field Plan
Helical Tomotherapy
Helical Tomotherapy
Integrated CT guidance
Ring gantry design for helical delivery
A superior binary multi-leaf collimator
for beam shaping and modulation
delivers intensity-modulated radiation therapy
with a helical (spiral) delivery pattern
Helical Tomotherapy
Brachytherapy
High Dose Rate (HDR) vs.
Low Dose Rate (LDR)

Remote after-loading with Iridium-192 source

No radiation precautions to personnel or family

Outpatient regimen, but more insertions

Optimize dwell times and dwell positions
Intracavitary Brachytherapy
Devices
Intracavitary Brachytherapy

Dosimetry

80 to 85 Gy for small IB-IIA
85 to 90 Gy for larger tumors >4cm and IIB+
Pelvic Sidewall - 50-55 Gy (early stage) or 55-60 Gy
(adv stage)
HDR

6Gy x 4 fx = 32Gy LDR
6Gy x 5 fx = 40Gy LDR
Manchester Planning System
Point A

Corresponds to the paracervical triangle in the medial edge of the broad
ligament where the uterine vessels cross the ureter
2 cm above the external cervical os and 2 cm lateral to midline
Point B

5 cm lateral from the midline at the same level as Point A
Dose to pelvic sidewall
Weakness: wide variation in Point A in respect to the ovoids. Point A
often occurs in a high-gradient region of the isodose distribution.
Therefore, minor differences in position can result in large
differences in dose.
Intracavitary Brachytherapy
Planning

ICRU dose points

Bladder point - surface of a Foley balloon filled with contrast; located at center of
balloon on AP film, posterior surface of the balloon on a line through midballoon
on lateral film

Rectum point - 5 mm posterior to the posterior vaginal wall (packing) at the level
of the bisection of the T&O.

Vaginal mucosa - at surface of ovoids

Sigmoid point: half distance from tandem to sacral promontory
Tolerance doses –

Bladder -limit 75-80 Gy
Rectum -limit 70-75 Gy
Vaginal surface dose – limit 120-140 Gy
Optimized Applicator Placement

The ovoids should fill the
vaginal fornices; level of
flange
Tandem midline,
unrotated, bisect the
ovoids
Keel (flange) in close
proximity to gold seed
markers
Optimized Applicator Placement

Tandem

1/3 between S1/2 and the
symphysis pubis
Midway between the bladder
and S1/2
Bisect the ovoids
Ovoids should be against
the cervix (marker seeds)
The bladder and rectum
should be packed away
from the implant w/o going
above
Interstitial Brachytherapy

Cervix CA Indications:

distal vaginal involvement
Poor geometry - narrow vagina not allowing the use of appropriate
intracavitary applicators
prior hysterectomy with the impossibility of a tandem placement
recurrence inside an area previously irradiated restricting the use of
further external irradiation
Primary vaginal tumors, interstitial brachytherapy has been reported
when paravaginal extension is not correctly encompassed with
standard intracavitary brachytherapy (>5mm)
Vaginal recurrences, especially from endometrial cancer
Interstitial Brachytherapy

Perineal templates

Martinez Universal Perineal Interstitial Template (MUPIT)
Syed-Neblett template
The template has arrays of holes used as guides for the needles.

15 or 17 gauge

Central hole in the template allows a plastic vaginal cylinder with a
central opening which accepts the conventional uterine tandem

Guide holes are designed to allow the inserted trocars lie in parallel
horizontal planes, insuring an adequate geometry of the application.

The planes are spaced one cm apart in concentric circles.
Treating with HDR
Brachytherapy
Definitive XRT

High success rate for early lesions
Increased failure rate for advanced
disease
Stage IIB ~20-50%
Stage III 50-75%

Definitive Radiotherapy Guidelines

Conventional XRT

4 field approach, 15MV photons
Target the cervix/uterus, pelvic nodes
4500cGy followed by reduced pelvic field with
midline block to 5040-5400cGy; 60Gy to bulky
nodes if possible
Brachytherapy

Low dose rate (Cs-137, half life 30yrs)

1-2 implants of tandem and ovoid intracavitary
applicator
30-45Gy to point A over 3-4d.
3 sources in tandem and 1 in each ovoid
High dose rate (Ir-192, half life 90d)

5 insertions once a week to deliver 30Gy to point A
Start at 3600cGy
Surgery vs. XRT

No survival or DFS difference
Advantages to surgery: preserve ovarian function, avoid
shortening/fibrosis of vagina, assess LN status
Advantages to RT: easy to deliver if poor surgical
candidate, lower risk of complications
Combined surgery + RT highest rate of complications
Landoni et al.

Randomized 343 patients with Stage IB-IIA to radical hysterectomy vs.
radical RT.

Adjuvant RT allowed for stage IIB or greater, <3mm of safe cervical stroma,
positive margins, or positive LN (62/114 IB1, 46/55 IB2).

5-year outcome: no difference

Non-bulky:

AdenoCA: better outcome with surgery

OS surgery 87% vs. RT 90%
DFS surgery 80% vs. 82%
OS (70% vs. 59%)
DFS (66% vs. 47%)
Complications (Grade 2-3): Surgery 28% vs RT 12%
Leg edema surgery 0%, RT 1%, surgery + RT 9%
Post-op XRT

Many Stage IB pts may benefit from XRT increased risk
for local/regional failures

Intermediate risk factors (need 2):

LVI
deep stromal invasion (middle or deep third)
Size > 4 cm
High risk factors

Positive nodes
Positive parametria
Positive margins
GOG 92

277 pts Stage IB, node negative, s/p radical
hysterectomy and lymphadenectomy randomized to +/adjuvant pelvic XRT 50.4 Gy.

Included pts with: 1) LVSI, deep 1/3 stromal invasion, any size;
2) LVSI involved, middle 1/3 invasion, size >= 2cm; 3) LVSI
involved, superficial 1/3 invasion, >= 5 cm; or 4) LVSI not
involved, deep or middle 1/3 invasion, >= 4 cm.
Results

Recurrences
2-year recurrence free rate
Grade 3/4 adverse effects
Distant mets
15% vs 28%
88% vs 79%
6% vs 2%
2% vs 7%
Gyn Onc. 1999;73:177-83.
GOG 92

Significant 46% reduction in risk of recurrence

Significant reduction in risk of progression or death

local recurrence 14% (RT) vs 20.7% (no RT)
distant 3% vs 8.6%.
Improved PFS by 42%.
Decreased death rate by 30% (28.6% vs 20%) but not S.S.
(p=0.07)
9% of patients with adenosquamous/carcinoma tumors
recurred vs. 44.0% in OBS.
Int J Rad Onc. 2006;65:169-76
Acute Toxicity

Hematologic: Anemia, neutropenia
GI: diarrhea, proctitis
GU: frequency, urgency, dysuria
Fatigue
Low fiber diet, Imodium, hydrocortisone
Hold citrus, caffeine; Pyridium; Anti-chol.
Late Toxicity

Retrospective. 1784 pts, FIGO stage IB.
Grade 3 or higher complications occurred in 7%
at 3 yrs and 9% at 10 yrs.
After 10 yrs, 0.34% per yr (20 yrs, ~14% risk)
Risk of rectal complications was the greatest,
more than urinary complications.
Red J. 1995;32:1289-300.
Late Grade 3 Complications

Small Bowel 4.2%

Rectum
3.3%

Bladder
3.0%

Sigmoid
0.2%
Definitive XRT

Long-term Outcome after Radiotherapy for 91 patients
with FIGO Stage IIIB and IVA Carcinoma of the Cervix

Outcome:

Failures:

5-year LC 53%, RFS 30%, OS 29%
10-year LC 53%, RFS 26%, OS 21%
90% within 2 years; 60% local, 29% regional
17% para-aortic with pelvic XRT
Toxicity: Grade 3-5 rate 13%
Red J. 2007;67:1445-50.
RTOG 90-01

403 pts with stage IIB-IVA, or Stage IB-IIA with >5cm tumor, or
LN+ cervix cancer.

Randomized to:

45Gy to pelvis + PA nodes
45Gy to pelvis plus 3 cycles 5-FU and cisplatin and 5-FU q3w.
Results

5yr DFS
5yr OS
40% vs 67%
58% vs 73%
Decreased DM and LR in chemo+RT arm.
Toxicity: comparable, higher reversible hematologic in CRT
NEJM 1999;340:1137-43
RTOG 90-01

8yr overall survival rate for patients treated with CT+RT was significantly
greater (67% v 41%; P <.0001)

Overall reduction in the risk of disease recurrence of 51% (36% to 66%)
for patients who received CTRT

Patients with stage IB-IIB disease who received CTRT had better overall
and disease-free survival than those treated with EFRT

Patients with stage III-IVA disease had better DFS (P =.05) and a trend
toward better overall survival (P =.07)

The rate of serious late complications of treatment was similar for the two
treatment arms. .
JCO 2004;22:p872-80
GOG 123

Randomized 369 pts with Stage IB2 cervix cancer to XRT +/- chemo
-> extrafascial hysterectomy

Results

45 Gy EBRT followed by brachytherapy to 75 Gy to point A.
Cisplatin weekly 40 mg/m2 x 6 doses.
Extrafascial hysterectomy 6-8 weeks after RT.
3-yr OS 74% vs 83% (RT+chemo)
Recurrence rate 37% vs 21%
Authors felt that improved LC led to improved OS due to addition of
cisplatin, and that adding hysterectomy did not impact OS
NEJM 1999;340:1154-61
GOG 123

At 72 months

71% of patients receiving CT/RT were alive and disease free
compared with 60% of those receiving RT alone.
78% of CT plus RT patients were alive, compared with 64% of RT
patients.

Increased acute hematologic and GI toxicity with CT+RT.

No difference in the frequency of late adverse events.
Am J Obst Gyn 2007 Nov;197:503.e1-6.
GOG 109

268 patients with clinical stage IA2-IIA cervical cancer
s/p radical hysterectomy and pelvic lymphadenectomy,
with high risk features randomized to RT vs RT+CT.
Cisplatin 70 mg/m2 and a 5FU 1,000 mg/m2/d every 3
weeks x four cycles (1st and 2nd cycles concurrent with
RT).
Eligible:

Positive pelvic nodes, parametrial involvement, or surgical margins
Results

4-year OS 71% vs 81%
4-year PFS 63% vs 80%
JCO 2000 Apr;18:1606-13
GOG 109 update

243 women were evaluable in a univariate analysis
Improvement in 5yr survival for adjuvant CT in patients
with tumors < 2 cm was only 5% (77% versus 82%),
while for tumors >2 cm it was 19% (58% versus 77%).
5yr survival benefit was less evident among patients
with one nodal metastasis (79% versus 83%) than when
at least two nodes were positive (55% versus 75%).
Gyn Onc 2005 Mar;96:721-8
GOG 85

Randomized 368 pts with Stage IIB-IVA to hydroxyurea
(80 mg/kg twice weekly) vs. cisplatin/5FU wks 1, 5

Outcome:

All pts had PA lymphadenectomy. Pelvic lymphadenectomy not
required.
PFS
CF 57% vs. HU 47%
OS
CF 55% vs. HU 43%
Toxicity: leukopenia CF 4% vs. HU 24%
Conclusion: cisplatin/5-FU better PFS, OS, and less toxic
than hydroxyurea
JCO 1999;17(5):1339-48.
GOG 120

Randomized 526 pts FIGO stage IIB-IVA to XRT + concurrent
chemotherapy with:

2-yr outcome:

cisplatin (40 mg/m2, weekly x 6),
cisplatin / 5-FU / hydroxyurea wks 1, 5
hydroxyurea (3 g/m2 po twice weekly, weeks 1-6).
Improved PFS and OS in groups receiving cisplatin vs those only
receiving hydroxyurea.
Decreased local failures as well as distant mets.
Conclusion: cisplatin regimens improve overall survival and
progression free survival for locally advanced cervical ca.
NEJM
1999;340:1144-53
GOG 120

10-years update

LF
PFS:
OS
Arm 1 22% vs. Arm 2 21% vs. Arm 3 34%
46% vs. 43% vs. 26%
53% vs. 53% vs. 34%
JCO 2007;25:2804-10
GOG 165

Protracted infusion 5FU 5d/wk vs. weekly cisplatin
40mg/m2 and concurrent radiation therapy (RT) for
stage IIB-IVA cervical cancer with clinically negative PA
nodes.
Closed prematurely when a planned interim analysis
indicated that 5FU/RT had a higher treatment failure
rate (35%) and mortality rate
No difference in pelvic treatment failure, but there was
an increase in the rate of DM in the 5FU arm.
JCO 2005;23:8289-95
Kim et al.

158 patients stages IIB-IVA without PA lymph nodes were
randomized to receive 3 monthly cycles of 5FU plus cisplatin (20
mg/m2) x 5 days or 6 cycles of weekly cisplatin (30 mg/m2)

Full chemoradiotherapy was delivered to 60% and 71% patients in
groups I and II

Acute grade 3/4 hematologic toxicity was 43% and 26%

The complete response rate of each group was 91%

4yr overall and progression-free survival rates were 70% and 67%
in group I and 67% and 66% in group II
Gyn Onc 2008;108:195-200.
Conclusions

Adjuvant XRT alone is indicated for….
Adjuvant chemo+XRT is indicated for…
Addition of chemo to XRT in the definitive
setting is beneficial for……
Cisplatin is foundation for
radiosensitization in setting of chemo/XRT
EORTC: Prophylactic PA XRT

Randomized 441 pts with stage IB-IIB with
positive pelvic LN; or Stage IIB with distal
vaginal or para-aortic involvement; or any Stage
III to pelvic RT +/- PA RT

Clinically involved PA nodes not allowed.
No difference in LC, DFS, or DM, but decreased
PA metastases.
Conclusion: Routine PA RT is not indicated
Prophylactic PA XRT

RTOG 79-20 (1979-86)
Randomized 335 pts with bulky Stage IB - IIA or Stage IIB (73%)
to: pelvic RT alone (40-50 Gy) or pelvic + PA RT (44-45 Gy).
1990 Int J Radiat Oncol Biol Phys. 1990 Sep;19(3):513-21.

2-yr OS 72% vs 81%
5-yr OS 55% vs 66% (SS). No difference in LRC or DM
Toxicity: Grade 4/5 P-RT 4% vs. PA-RT 8% (primarily in patients with
prior surgery 11% vs. 2%)
1995 JAMA. 1995 Aug 2;274(5):387-93.

10-yr OS 44% vs 55%. No difference in DFS.
Conclusion: benefit for elective paraaortic radiation.