Download INDICATIONS FOR RADIATION THERAPY FOR CERVICAL AND

INDICATIONS FOR RADIATION THERAPY FOR
CERVICAL AND ENDOMETRIAL CANCERS
Ludwig Plasswilm
Department of Radiation Oncology
Kantonsspital St Gallen
ENDOMETRIAL CANCER
Adjuvant radiotherapy ?
G1
IA
IB
IA
Keine*
IB
<60a: Keine
>60a: BT
BT**
BT**
XRT + BT
IC
IIA <50%
IIA >50%
G2
Keine*
G3
BT
<60a: Keine
>60a: BT
XRT
BT**
XRT + BT
BT**
XRT
XRT + BT
XRT + BT
IIB
XRT + BT
XRT + BT
XRT + BT
IIIA
XRT
XRT
XRT
IIIB
XRT + BT
XRT + BT
XRT + BT
IIIC (N+)
XRT +/- BT
XRT +/- BT
XRT +/- BT
Additional risk factors (?): histological type, lymphovascular invasion, age, ….
Endometrial Cancer Stage I
Adjuvant Radiotherapy?
Trial
No. patients
and eligibility
Surgery
Randomization
Age
(mean)
TAH-BSO*
Brachytherapy vs.
brachy and pelvic RT
60
Norwegian
1968-1974
540
Stage I
PORTEC
1990-1997
714
TAH-BSO
IB grad 2-3
IC grade 1-2
NAT** vs. pelvic RT
66
GOG-99
1987-1995
392
TAH-BSO and
St IB, IC
lymphadenectomy
St II (occult)
NAT vs. pelvic RT
61
*TAH; total abdominal hysterectomy
BSO; bilateral salpingo-oophorectomy
** NAT; no additional treatment
Comparison of the randomized trials of adjuvant radiotherapy in stage I
endometrial carcinoma
Trial
Locoregional
recurrence
Survival
Severe
complications
Norwegian
1968-1974
7% vs. 2%
at 5 years
P <0.01
89% vs. 91%
at 5 years
p = NS
no data
PORTEC
1990-1997
14% vs. 4%
at 5 years
P <0.001
85% vs. 81%
at 5 years
P = 0.31
3% GI at
5 years
GOG-99
1987-1995
12% vs. 3%
at 2 years
P <0.01
86% vs. 92%
at 4 years
P = 0.56
8% GI at
2 years
Post Operative Radiation Therapy
in Endometrial Carcinoma ?
715 Pat.: TAH / BSO;
no lymphadenectomy
•
IB, G2 oder G3;
IC, G1 oder G2
•
RT 46 Gy pelvin vs.
no IC G3
Locoregional relapse
Surgery And Postoperative Radiotherapy Versus Surgery Alone For Patients With
Stage-1 Endometrial Carcinoma: Multicentre Randomised Trial. PORTEC Study Group
14%
P < 0.001
4%
no adj. RT
(G1/2:
90%)
OS !
Creutzberg 2000
Postoperative Radiotherapy For Stage 1 Endometrial Carcinoma: Long-term
Outcome Of The Randomized PORTEC Trial With Central Pathology Review
Locoregional relapse
14%
5%
Scholten 2005
Locoregional relapse according to grade
grade3
risk
18%
!
11%
7%
Locoregional relapse according
to age group
!
13%
11%
age
risk
4%
Scholten 2005
Adjuvant External Beam Radiotherapy In The Treatment Of
Endometrial Cancer (MRC ASTEC And NCIC CTG EN.5 Randomised
Trials): Pooled Trial Results, Systematic Review, And Meta-analysis
July, 1996 - March, 2005; 905 (789 ASTEC, 116 EN.5) women with intermediate-risk or high-risk earlystage disease from 112 centres in seven countries (UK, Canada, Poland, Norway, New Zealand,
Australia, USA) were randomly assigned after surgery to observation (453) or to external beam
radiotherapy (452).
RT: 40–46 Gy in 20–25 daily fractions to the pelvis, treating five times a week.
2009
Adjuvant External Beam Radiotherapy In The Treatment Of
Endometrial Cancer (MRC ASTEC And NCIC CTG EN.5 Randomised
Trials): Pooled Trial Results, Systematic Review, And Meta-analysis
2009
Adjuvant External Beam Radiotherapy In The Treatment Of
Endometrial Cancer (MRC ASTEC And NCIC CTG EN.5 Randomised
Trials): Pooled Trial Results, Systematic Review, And Meta-analysis
Overall survival
2009
Adjuvant External Beam Radiotherapy In The Treatment Of
Endometrial Cancer (MRC ASTEC And NCIC CTG EN.5 Randomised
Trials): Pooled Trial Results, Systematic Review, And Meta-analysis
Isolated vaginal or pelvic initial recurrence
With brachytherapy used in 53% of women in ASTEC/EN.5, the local recurrence
rate in the observation group at 5 years was 6.1%
2009
EXTERNAL BEAM RADIOTHERAPY
vs.
BRACHYTHERAPY
Vaginal Brachytherapy Versus Pelvic External Beam Radiotherapy For
Patients With Endometrial Cancer Of High-intermediate Risk
(PORTEC-2): An Open-label, Non-inferiority, Randomised Trial
427 patients with stage I or IIA endometrial
carcinoma with features of high-intermediate;
(1) age greater than 60 years and
stage 1C grade 1 or 2 disease, or
stage 1B grade 3 disease;
(2) stage 2A disease, any age.
!
Recurrence (all patients),
after a median follow-up of 45 months
Kaplan-Meier survival curve for overall survival
Nout 2010
External Pelvic And Vaginal Irradiation Versus Vaginal Irradiation
Alone As Postoperative Therapy In Medium-risk Endometrial
Carcinoma - A Prospective Randomized Study
Five Swedish cancer centers, from January 1997 through February 2008;
n = 562 patients, median follow-up: 62 months
Patient and tumor characteristics
Sorbe 2012
External Pelvic And Vaginal Irradiation Versus Vaginal Irradiation
Alone As Postoperative Therapy In Medium-risk Endometrial
Carcinoma - A Prospective Randomized Study
The definition of medium-risk carcinomas was as
follows: 1) FIGO Stage I (surgical staging);
2) Endometrioid histological type; 3) presence of one of
the following risk factors: FIGO Grade 3 (poorly
differentiated), deep (>50%) myometrial infiltration, or
DNA aneuploidy;
Cumulative proportion of locoregional
recurrences versus type of postoperative
treatment.
Overall survival rate versus type of
postoperative treatment.
Sorbe 2012
External Pelvic And Vaginal Irradiation Versus Vaginal Irradiation
Alone As Postoperative Therapy In Medium-risk Endometrial
Carcinoma - A Prospective Randomized Study
Late side effects vs. type of treatment
Abbreviations: Arm A = EBRT plus VBT; Arm B = VBT alone. Late tissue reactions (based on RTOG/EORTC
toxicity criteria) were recorded more then 3 months after radiotherapy.
Sorbe 2012
Adjuvant Radiotherapy for Stage I Endometrial Cancer:
An Updated Cochrane Systematic Review and Meta-analysis
Forest plot of hazard ratios (HRs) comparing the locoregional recurrence for stage I
endometrial carcinoma patients who received external beam radiotherapy (EBRT)
treatment vs those who received no EBRT treatment.
Kong 2012
Endometrial Cancer – early stage
Indications for radiation therapy
Stage
Grade 1
Grade 2
Grade 3
IA
(Endometrium)
IA
no adj treatment
adj BT
IB
(Myometr. Invasion < 50%)
IB IC
adj BT
(Myometr. Invasion > 50%)
adj EBRT
?
Additional risk factors:
histological type, lymphovascular invasion, age, ….
BT
EBRT ?!
Low-risk
Intermediate-risk
High-risk
Endometrial Cancer – advanced stage
Indications for radiation therapy
IIA <50%
G1
G2
BT
BT
G3
XRT + BT
IIA >50%
XRT + BT
XRT + BT
XRT + BT
IIB
XRT + BT
XRT + BT
XRT + BT
IIIA
XRT
XRT
XRT
IIIB
XRT + BT
XRT + BT
XRT + BT
IIIC (N+)
XRT +/- BT
XRT +/- BT
XRT +/- BT
BT = Brachytherapy
XRT = external beam Radiotherapy
two institutions,
1990 to 2003
608 eligible women
RT was delivered to
133 women
Survival
all pts.
stage IA - IIA
non random !
Survival
according to stage grouping
stage IC, IIA
plus Chemo?
S + RT
65%
S
10 y;
40%
Macdonald 2006
PORTEC 3:
Randomized Trial of Radiation Therapy With or Without
Chemotherapy for Endometrial Cancer
1.
2.
3.
4.
5.
stage IA with invasion, grade 3 with documented LVSI
stage IB grade 3
stage II
stage IIIA or IIIC; or IIIB if parametrial invasion only
stage IA (with invasion), IB, II, or III with serous or clear cell histology
External beam pelvic radiotherapy (48.6 Gy in 1.8 Gy fractions)
Vaginal brachytherapy boost in case of cervical involvement
cisplatin 50 mg/m2 i.v., 2 cycles during radiotherapy, 3 wks interval
carboplatin AUC 5, 4 cycles after completion of radiotherapy, 3 wks interval
paclitaxel 175 mg/m2, 4 cycles after completion of radiotherapy, 3 wks interval
Indications for radiation therapy
for cervical cancers
Primary Radio (Chemo)- therapy
Adjuvant Radio (Chemo)- therapy
Randomised Study Of Radical Surgery Versus Radiotherapy
For Stage Ib-IIa Cervical Cancer
September, 1986, - December, 1991, 343 eligible patients were randomised:
172 to surgery and 171 to radical radiotherapy
Adjuvant radiotherapy was delivered after surgery for women with surgical stage
pT2b or greater, less than 3 mm of safe cervical stroma, cut-through, or positive
nodes
62 of 114 women with cervical diameters of 4 cm or smaller and 46 of 55 with
diameters larger than 4 cm received adjuvant therapy
5-year overall and disease-free survival were identical in the surgery and
radiotherapy groups (83% and 74%, respectively, for both groups, median
follow-up of 87 months)
Recurrent disease: 25% in the surgery group and 26% in the radiotherapy
group.
28% surgery-group patients had severe morbidity compared with 12%
radiotherapy-group patients (p = 0.0004)
Landoni 1997
Concurrent Cisplatin-based Radiotherapy And Chemotherapy For
Locally Advanced Cervical Cancer
Randomized trial of radiotherapy in combination with three concurrent chemotherapy regimens
— cisplatin alone; cisplatin, fluorouracil, and hydroxyurea; and hydroxyurea alone
Women with primary untreated invasive squamous-cell carcinoma, adenosquamous
carcinoma, or adenocarcinoma of the cervix of stage IIB, III, or IVA, without involvement of the
para-aortic lymph nodes; n= 526
Kaplan–Meier Estimates of Overall Survival
The overall survival rate was significantly higher among patients in the group given radiotherapy combined
with cisplatin therapy (117 of 176, P=0.004) and among patients in the group given radiotherapy combined
with treatment with cisplatin, fluorouracil, and hydroxyurea (116 of 173, P=0.002) than among patients in
the group given radiotherapy combined with hydroxyurea therapy (88 of 177).
Rose 1999
Phase III Trial Comparing Radical Radiotherapy With and Without
Cisplatin Chemotherapy in Patients With Advanced Squamous Cell
Cancer of the Cervix (National Cancer Institute of Canada)
Patient Characteristics
stage IB to IVA squamous cell cervical
cancer with central disease > 5 cm or
histologically confirmed pelvic
lymph node involvement
randomized to receive
RT (EBRT plus brachytherapy) plus
weekly CDDP chemotherapy (40
mg/m2) (arm 1) or
the same RT without chemotherapy
(arm 2).
Pearcey 2002
Phase III Trial Comparing Radical Radiotherapy With and Without
Cisplatin Chemotherapy in Patients With Advanced Squamous Cell
Cancer of the Cervix
Progression-free survival
Solid line, CDDP and RT; dotted line, RT alone.
Overall survival
Solid line, CDDP and RT; dotted line, RT alone.
Pearcey 2002
Phase III, Open-Label, Randomized Study Comparing Concurrent
Gemcitabine Plus Cisplatin and Radiation Followed by Adjuvant
Gemcitabine and Cisplatin Versus Concurrent Cisplatin and Radiation
in Patients With Stage IIB to IVA Carcinoma of the Cervix
All patients received EBRT, 28 fractions of 1.8 Gy per day, 5 days per week, over the 6 weeks.
All patients were scheduled to receive 30 to 35 Gy of brachytherapy (BCT) in week 7.
Arm A treatment consisted of gemcitabine plus cisplatin chemoradiotherapy for 6 weeks.
After BCT and a subsequent 2-week rest period, patients randomly assigned to arm A received adjuvant
chemotherapy (cisplatin 50 mg/m2 on day 1 plus gemcitabine 1,000 mg/m2 on days 1 and 8,
every 3 weeks for two cycles).
Arm B treatment consisted of cisplatin chemoradiotherapy for 6 weeks.
Duenas-Gonzales 2011
Phase III, Open-Label, Randomized Study Comparing Concurrent
Gemcitabine Plus Cisplatin and Radiation Followed by Adjuvant
Gemcitabine and Cisplatin Versus Concurrent Cisplatin and Radiation
in Patients With Stage IIB to IVA Carcinoma of the Cervix
Kaplan-Meier estimates of progression-free survival and overall survival for patients who were
randomly assigned to arm A or arm B. PFS at 3 years is shown by the dotted black lines and
was 74.4% for arm A and 65.0% for arm B (P = .029). HR, hazard ratio.
Duenas-Gonzales 2011
Results of the GYNECO 02 Study, a Phase III Trial
Comparing Hysterectomy with No Hysterectomy in Patients with a
(Clinical and Radiological) Complete Response After Chemoradiation
Therapy for Stage IB2 or II Cervical Cancer
stage IB2 or II cervical cancer without extrapelvic disease on conventional imaging;
pelvic external radiation
therapy (45 Gy with or without parametrial or nodal boost) with
Characteristics of patients in both arms
concomitant cisplatin chemotherapy (40 mg/m2 per week) followed by uterovaginal
brachytherapy (15 Gy to the intermediate risk clinical target volume); and (c) complete
clinical and radiological response 6 – 8 weeks after brachytherapy. Patients were
randomized between HT (arm A) and no HT (arm B).
PDPF survival, OS, and DFS are shown for patients treated with definitive radiotherapy
using HDR-ICBT with a low cumulative dose schedule (BED 62 Gy10 at point A).
Morice 2012
Results of the GYNECO 02 Study, a Phase III Trial
Comparing Hysterectomy with No Hysterectomy in Patients with a
(Clinical and Radiological) Complete Response After Chemoradiation
Therapy for Stage IB2 or II Cervical Cancer
Kaplan–Meier estimates of the overall survival
rate for patients in arm A (hysterectomy) and
arm B (no hysterectomy).
Kaplan–Meier estimates of the event-free
survival rate for patients in arm A (hysterectomy)
and arm B (no hysterectomy).
Morice 2012
Adjuvant Radio (Chemo)- therapy
A Phase III Randomized Trial Of Postoperative Pelvic Irradiation In
Stage Ib Cervical Carcinoma With Poor Prognostic Features: Followup Of A Gynecologic Oncology Group Study
Stage IB cervical cancer with negative lymph nodes but with 2 or more of the following
Patient
and tumor
characteristics
features: more than one third
(deep)
stromal
invasion, capillary lymphatic space
involvement, and tumor diameter of 4 cm or more.
EBRT: planned pelvic dose was from 46 Gy in 23 fractions to 50.4 Gy in 28 fractions.
Rotman 2006
A Phase III Randomized Trial Of Postoperative Pelvic Irradiation In
Stage Ib Cervical Carcinoma With Poor Prognostic Features: Followup Of A Gynecologic Oncology Group Study
RT
OBS
OBS
RT
Cumulative risk of recurrences by treatment group:
24 RT patients and 43 OBS patients recurred.
RT significantly reduced recurrence risk (p=0.007).
OBS=observation; RT=irradiation.
Progression-free survival by treatment group:
30 RT patients and 49 OBS patients recurred or
died. RT significantly increased progression-free
survival (p=0.009).
OBS=observation; RT= irradiation.
OS; n.s.
Rotman 2006
Concurrent Chemotherapy and Pelvic Radiation Therapy Compared
With Pelvic Radiation Therapy Alone as Adjuvant Therapy After
Radical Surgery in High-Risk Early-Stage Cancer of the Cervix
Patient Characteristics
Patients had undergone a radical
hysterectomy with pelvic
lymphadenectomy.
xx
Clinical stage IA2, IB, and IIA
and who had
- positive pelvic lymph nodes
and/or
- positive margins
and/or
- microscopic involvement of the
parametrium
x
Peters 2000
Concurrent Chemotherapy and Pelvic Radiation Therapy Compared
With Pelvic Radiation Therapy Alone as Adjuvant Therapy After
Radical Surgery in High-Risk Early-Stage Cancer of the Cervix
RT: 49.3 GY RT in 29 fractions to a standard pelvic field.
Chemotherapy: consisted of bolus cisplatin 70 mg/m2 and a 96-hour infusion of fluorouracil
1,000 mg/m2/d every 3 weeks for four cycles, with the first and second cycles given
concurrent to RT.
P = .003
P = .007
Progression-free survival for 127 patients
Overall survival for 127 patients
randomized to receive CT + RT and for
116 patients randomized to receive RT alone.
randomized to receive CT + RT and for
116 patients randomized to receive RT alone.
Peters 2000
Pelvic Irradiation With Concurrent Chemotherapy Versus Pelvic and
Para-Aortic Irradiation for High-Risk Cervical Cancer: An Update of
Radiation Therapy Oncology Group Trial (RTOG) 90-01
stage IIB to IVA disease,
stage IB to
IIA disease
with a tumor diameter 5 cm, or
Pretreatment
Tumor
Characteristics
positive pelvic lymph nodes. Patients were stratified by stage (study was not designed to
detect differences in outcome within the subgroups).
!
Eifel 2004
Pelvic Irradiation With Concurrent Chemotherapy Versus Pelvic and
Para-Aortic Irradiation for High-Risk Cervical Cancer: An Update of
Radiation Therapy Oncology Group Trial (RTOG) 90-01
Chemotherapy: consisted of an IV infusion of cisplatin 75 mg/m2 of body-surface area over
a 4-hour period followed by an IV infusion of fluorouracil 4,000 mg/m2 over a 96-hour
period. Two additional cycles of chemotherapy were scheduled at 3-week intervals.
Kaplan-Meier estimates of overall
survival for patients who received
extended-field radiotherapy (EFRT)
or concurrent chemotherapy and
radiotherapy (CT-RT; P < .0001).
Kaplan-Meier estimates of overall survival for
patients who received extended-field radiotherapy
(EFRT) or concurrent chemotherapy and
radiotherapy (CT-RT) in subgroups stratified by
International Federation of Gynecology and
Obstetrics stage.
Eifel 2004
Pelvic Irradiation With Concurrent Chemotherapy Versus Pelvic and
Para-Aortic Irradiation for High-Risk Cervical Cancer: An Update of
Radiation Therapy Oncology Group Trial (RTOG) 90-01
Estimated 5-Year Survival and Local Recurrence Rates in Stratified Stage Groups
Abbreviations: RT, radiotherapy; FIGO, International Federation of Gynecology and obstetrics.
A value less than 1 indicates an advantage for pelvic RT and chemotherapy.
†Failure is death as a result of treated cancer, complications of protocol treatment, or unknown causes.
Eifel 2004
Cervical Cancer
Indications for radiation therapy (RT / RCT)
definitive radio- / radiochemotherapy accepted as one
of the treatment options for early-stage cervical cancer
postoperative treatment when
nodes or margins are positive or
parametrial extension is noted pathologically
locally advanced disease
chemotherapy / optimal chemotherapy regimen?