Download Gynecologic Cancer Update 2010 - Scioto County Medical Society

Gynecologic Cancer Update 2010
Eric L. Eisenhauer, M.D.
Assistant Professor
Division of Gynecologic Oncology
James Cancer Hospital and Solove Research Institute
Ohio State University School of Medicine
Conflict of Interest
Objectives
• Review current guidelines for cervical cancer
treatment
• Discuss changes to 2009 FIGO staging
system for cervical and endometrial cancer
• Understand rationale for current surgical and
medical treatment of endometrial cancer
• Review recent data for the treatment of
primary and recurrent ovarian cancer
Cancer Statistics – 2010
Estimated New Cases
28%
Breast
14%
Estimated Deaths
26%
Lung and bronchus
Lung and bronchus
15%
Breast
10%
Colon and rectum
9%
Colon and rectum
6%
Uterine corpus
7%
Pancreas
5%
Thyroid
5%
Ovary
4%
Non-Hodgkin
lymphoma
4%
Non-Hodgkin
lymphoma
4%
Melanoma
3%
Leukemia
3%
Kidney
3%
Uterine corpus
3%
Ovary
2%
Liver
3%
Pancreas
2%
Brain
207,090
21,880
43,470
39,840
13,850
Jemal, A. et al. CA Cancer J Clin 2010; 60:277-300
7,950
Estimated New
Gynecologic Cancers: 2010
5%
3%
15%
51%
26%
Uterus
Ovary
Cervix
Vulva
Vagina & Other
Uterus
43,470
Vulva
3,900
Ovary
21,880
Vagina & Other
2,300
Cervix
12,200
Jemal, A. et al. CA Cancer J Clin 2010; 60:277-300
Estimated Gynecologic
Cancer Deaths: 2010
15%
3% 3%
29%
Uterus
Ovary
Cervix
Vulva
Vagina & Other
50%
Ovary
13,850
Vulva
920
Uterus
7,950
Vagina & Other
780
Cervix
4,210
Jemal, A. et al. CA Cancer J Clin 2010; 60:277-300
Cervical Cancer
Year
Cases
Deaths
%
2006
9,710
3,700
38
2007
11,150
3,670
33
2008
11,070
3,870
35
2009
11,270
4,070
36
2010
12,200
4,210
35
Jemal A, et al. CA Cancer J Clin 2006-2010
Cervical Cancer
•
•
•
•
Most common gyn cancer worldwide
Clinical rather than surgical staging
Correlation of FIGO to TNM is poor
Minor changes to 2009 FIGO staging
– Deletion of Stage 0
– Subdivision of Stage IIA
• IIA1: tumor ≤ 4 cm with involv. < 2/3 upper vag
• IIA2: tumor > 4 cm with involv. <2/3 upper vag
Cervical Carcinoma
Stage Distribution and Survival
Stage
I
Distribution
of Patients
62%
Five-year
Survival
85%
II
18%
60%
III
11%
35%
IV
9%
15%
Cervical Cancer
• Poor prognostic factors:
– Positive lymph nodes
– Parametrial involvement
– Positive resection margins
• 1999 NCI Clinical Alert
– Noted results of 5 randomized trials showing
benefit of chemoradiation (cisplatin) over radiation
alone
Cervical Cancer
• Since 1999, few frameshifts in thinking
about cervical cancer therapy
• Ongoing HPV vaccine trials
• Attempts at consolidation therapy
• Trials of targeted agents
• New combinations for advanced or
recurrent disease
Chemotherapy for Advanced or
Recurrent Cervical Cancer
• Combination chemotherapy
– GOG 76X; Cisplatin + paclitaxel, 46% RR (Rose et al, 1999)
– GOG 169; cisplatin + paclitaxel vs cisplatin; improved RR
not OS (Moore et al 2004)
– GOG 179; topotecan + cisplatin; improved OS (Long et al,
2005)
– GOG 204; topotecan, gemcitabine, vinorelbine, paclitaxel
• Interim analysis: so sig benefit; RR, PFS and OS favors
cisplatin + paclitaxel (Monk et al, 2009)
• Favored regimen: cisplatin + paclitaxel
• Role of carboplatin + paclitaxel?
Uterine Cancer
Year
Cases
Deaths
%
2006
41,200
7,350
18
2007
39,080
7,400
19
2008
40,100
7,470
19
2009
42,160
7,780
18
2010
43,470
7,950
18
Jemal A, et al. CA Cancer J Clin 2006-2010
Uterine Neoplasia
Hyperplasia
Adenocarcinoma
Sarcoma
Sporadic
Inherited
•Lynch syndrome (HNPCC)
•Cowden’s disease
•BRCA syndrome?
Type I
•Estrogen-dependent
•Endometrioid
•MMR/MSI
•PTEN, KRAS
Type II
•Estrogen-independent
•Serous, clear cell
•TP53, HER-2/neu, p16
Endometrial cancer incidence and
mortality by histologic type
Hamilton CA et al. Br J Cancer, 2006
Risk Factors
Characteristic
Late Menopause (age 52)
Increased Risk
2.4 x
Nulliparous
3x
Unopposed Estrogen
10 x
Obesity
>30 lbs
>50 lbs
3x
10 x
**INCREASED ESTROGEN:PROGESTERONE**
Hyperplasia-WHO Classification
Types of Hyperplasia
Simple
Progressing to
Cancer (%)
1
Complex
Simple with Atypia
3
8
Complex with Atypia
29
RECENT EVIDENCE CHALLENGES THESE RATES OF PROGRESSION
Kurman et al, Cancer 56:403,1985
Rates of progression HC
Lacey JV Jr. Absolute risk of endometrial carcinoma during 20-year follow-up among women with
endometrial hyperplasia. J Clin Oncol. 2010 Feb 10;28(5):788-92
If an endometrial biopsy shows complex
atypical hyperplasia, what is the risk that an
underlying endometrial cancer is present?
Concurrent Carcinoma with
Complex Atypical Hyperplasia
GOG 167
• Pre-op diagnosis of CAH on EMB
• 306 patients
• 43% had carcinoma on final pathology
– 16% high grade histologic cell types
• serous, clear cell, undifferentiated
– 30% had myometrial invasion
– 10% stage IC
CL Trimble, Concurrent endometrial carcinoma in women with biopsy of atypical
endometrial hyperplasia: A GOG study, Cancer. 106 (4): 812-819, Feb 2006
Complex atypical hyperplasia
– 48% found to have cancer
– Invasive disease in 27%
• 8% with deeply invasive and/or grade 3
disease
Suh-Burgmann E, et al. Complex atypical endometrial hyperplasia: the risk of unrecognized
adenocarcinoma and value of pre-operative dilation and curettage. Obstet Gynecol 2009;114:523-529.
Surgery for CAH
• At time of surgery, CONSIDER:
– Perform Pelvic Washings
– Intra-op Frozen Section
– Have capability to perform surgical
staging if needed
– Surgical staging (modified or not)
Revised FIGO staging
FIGO 1988
FIGO 2009
STAGE I
STAGE I
A. Invasion < half myometrium
B. Invasion ≥ half myometrium
A. Limited to the endometrium
B. Invasion to < half myometrium
C. Invasion ≥ half myometrium
STAGE II
A. Endocervical glandular involvement
B. Cervical stromal invasion
STAGE III
A. Invades serosa or adnexa or
positive cytology
B. Vaginal metastases
STAGE II
-Cervical stromal invasion
STAGE III
A. Invades serosa or adnexa
B. Vaginal or parametrial involvement
C1. Positive pelvic nodes
C2. Positive aortic nodes
C. Positive pelvic or aortic nodes
STAGE IV
A. Invades bladder or bowel mucosa
B. Distant metastases, including intraabdominal or inguinal
STAGE IV
A. Invades bladder or bowel mucosa
B. Distant metastases, including intraabdominal or inguinal
Stage I
New IA
New IB
Modified from Disaia, Clinical Gynecologic Oncology, sixth edition
Stage II
New II
Modified from Disaia, Clinical Gynecologic Oncology, sixth edition
Stage III
New IIIC1
Modified from Disaia, Clinical Gynecologic Oncology, sixth edition
New IIIC2
So What?????
Survival outcomes
Stage
Distribution (%)
5 year survival
Confined to uterus
69%
95.5%
Regional spread
(lymph nodes)
19%
67.5%
Distant
8%
17.1%
Unknown
(unstaged)
4%
55.5%
Treatment
• Surgical Staging
– Peritoneal Washings
– Hyst/BSO
– Pelvic and Paraaortic lymph nodes
• Not sampling….lymphadenectomy is required
– Option of minimally invasive surgery
• LS, Robotic
• Adjuvant Therapy
Who to Surgical Stage?
• Without Debate
– Grade ≥ 2 lesions
– Myometrial Invasion > ½
– Cervical extension
– Extra-uterine spread
– Serous, clear-cell, undifferentiated cell
types or squamous
– Enlarged lymph nodes
ACOG Practice Bulletin
• Who to surgically stage?
– Most women should be staged
– Exceptions “include young or
perimenopausal women with grade 1
endometrioid adenocarcinoma associated
with atypical hyperplasia and women at
increased risk of mortality secondary to
comorbidities.”
ACOG Practice Bulletin No. 65. Obstet Gynecol 2005
And Why?
Accuracy of pre-operative sampling
• Pre-operative grade 1 endometrial cancer
– The Ohio State experience
•
•
•
•
Histology upgraded in 19%
18% (32/181) had stage II or greater
Lymphatic metastases in 4%
Extra-uterine disease in 10.5%
Grade 1
– Overall 26% of patients were found to have high risk factors
– MSKCC experience
• Histology upgraded in 15% (+1.2% serous/clear cell)
• 14% (69/490) had stage II or greater
– Overall 18.5% of patients were found to have high risk
factors
– Affects ~ 20-25% of patients
Ben-Shacar I, et al. Surgical staging for patients presenting with grade 1 endometrial carcinoma. Obstet Gynecol 2005;105:487-493.
Leitao MM, et al. Accuracy of preoperative endometrial sampling diagnosis of FIGO grade 1 endometrial adenocarcinoma. Gynecol Oncol. 2008;111(2):244-8.
NCCN
National Comprehensive Cancer Network
• Current Recommendations
– Comprehensive surgical staging of all
tumors greater than Grade I, IA
– Consider comprehensive surgical staging
of Grade I, IA
•
© National Comprehensive Cancer Network, Inc. 2009/2010. NCCN and NATIONAL
COMPREHENSIVE CANCER NETWORK are registered trademarks of National
Comprehensive Cancer Network, Inc.
Minimally-invasive staging
• GOG LAP2
– 2616 women with early EMCA
– Randomized to laparoscopy vs laparotomy
– Early endpoints: QoL, complications,
staging
– Later endpoints: PFS, OS
Minimally-invasive staging
• GOG LAP2
– Lpsc conversion rate ~25%
– Lpsc may be safer
• 14% vs 21% mod-severe postop events (P<0.001)
– Lpsc is adequate for staging
• Same rate of detection of advanced disease
– Lpsc has lower pain scores
– Lpsc had shorter hosp stay and faster return to work
– Lpsc had overall improved QoL for first 6 mo
Walker JL et al. J Clin Oncol 2009, 27:5331.
Walker JL et al. J Clin Oncol 2009, 27:5337.
Limitations of Laparoscopy
• 2-D vision
• Counterintuitive
movements
• Limited manipulation
• Few degrees of
freedom
• Steep learning curve
Robotic Surgery for Endometrial
Cancer at OSU
• Began Spring 2006
– 97 patients with endometrial carcinoma
• 9% laparotomy required
• 91% completed robotically
–
–
–
–
84 with pelvic and aortic LND
4 without LND (BMI range = 47-60)
BMI = 34 kg/m2, LOS = 1 day
One severe intraoperative complication
– Robotic surgical staging for endometrial
cancer is feasible
Fowler JM et al. J Robotic Surg 2008
Endometrial Cancer
Robotic (n=105)
LS (n=76)
Room Time
305 min
336 min
Skin to Skin
242 min
287 min
Staging
86%
89%
77%
Conversion
10%
26%
23%
BMI (kg/m2)
34
29
27
BMI >30
60%
38%
BMI >40
26%
3%
LOS
1 day
2 days
3%
18%
Transfusion
LAP2
Seamon LG et al. Gynecol Oncol 2008
Robotics and Obesity
BMI
Conversion
40
15%
45
24%
50
34%
55
48%
Laparoscopy
Outcome
Robotic
BMI
Converted
40
Completed
34
Seamon LG et al. Obstet Gynecol 2008 and Gynecol Oncol 2009
Post Operative Treatment
Uterine Risk Factors and
Recurrence Rate
Uterine Factor
Recurrence Rate (%)
Grade 1, 2, 3
4%, 9%, 16%
Deep myometrial
invasion
Isthmus/cervix
involvement
Lympho/vascular space
involvement
15%
16%
27%
After surgical staging, which early stage
patients benefit from further therapy?
Intermediate risk
• GOG 99
– Phase III RCT
– 392 women
– Staging with or without post-op WPRT
– Defined “intermediate risk”
• Stage IB, IC, IIA/IIB (occult)
• 5 year recurrence rate of 20-25%
• Excluded serous and clear cell
Keys HM et al. Gynecol Oncol 2004
Adjuvant WPRT: GOG 99
No
Adjuvant Adjuvant
Treatment
WPRT
Progression
88%
96%
Free : 2 yrs
Survival:
3 yrs
89%
96%
P Value
0.004
0.09
Keys HM et al. Gynecol Oncol 2004
PORTEC-2
• Phase III RCT
• 427 women high-intermediate risk after
hysterectomy
• Randomized to WPRT vs vag brachy
• Defined high-intermediate risk:
1) >60 y.o. stage IC gr 1-2
2) >60 y.o. stage IB gr 3
3) any age, stage IIA
Nout RA et al. Lancet 2010
PORTEC-2
WPRT
1.6%
VBT
1.8%
P
0.74
Local recur
2.1%
5.1%
0.17
Distant mets
5.7%
8.3%
0.46
DFS (45 mo)
78%
83%
0.74
OS (45 mo)
80%
85%
0.57
Vaginal recur
Nout RA et al. Lancet 2010
So how to treat high-intermediate risk?
• GOG 249?
Eligible: Stage I-IIA endometrial carcinoma, with high-intermediate risk factors
Stage IIB (occult) endometrial carcinoma (any histology), with or without risk factors, and
Stage I-IIB (occult) serous or clear cell endometrial carcinoma, with or without other risk features
TREATMENT RANDOMIZATION
Regimen I: Pelvic Radiation Therapy (4500/25 fractions-5040 cGY/28 fractions) over 5-6 weeks
Optional Vaginal Cuff Boost ONLY for Stage II patients and Stage I patients with
papillary serous and clear cell carcinomas
OR
Regimen II: Vaginal Cuff Brachytherapy + 3 cycles of chemotherapy consisting of
Paclitaxel 175 mg/m2 (3hr) + Carboplatin AUC 6 q 21 days
chemotherapy to start within 3 weeks of initiating brachytherapy
Extra-Uterine Involvement
• Stage IIIA
• Stage IIIC
• Stage IV
Extra-uterine Risk Factors
for Recurrence (%)
Extra-uterine Factor
Recurrence Rate
Adnexal Metastasis
14
+ Peritoneal Cytology
19
+ Peritoneal Disease
25
Pelvic Nodal Metastases
28
Para-aortic Nodal
Metastases
40
Advanced Disease
• GOG 122
• RCT compared cis/adria (AP) vs WAI
– 5 yr PFS 50% vs 38% for chemo arm
– 5 yr OS 60% vs 43% for chemo arm
• Recurrence
Pelvic
Extrapelvic
WAI
AP
13%
38%
18%
32%
Remaining questions:
-Best systemic chemotherapy?
-Risk for local recurrence: role of combined chemoRT?
Marcus E. Randall, et al; Randomized Phase III Trial of Whole-Abdominal Irradiation Versus
Doxorubicin and Cisplatin Chemotherapy in Advanced Endometrial Carcinoma: A Gynecologic
Advanced Disease
•
•
•
•
•
•
GOG 184
Optimal stage III and IVA
All received volume-directed RT
cis/adria (AP) vs cis/adria/paclitaxel (TAP)
3 yr PFS 64% vs 62%
Recurrence
Local
Distant
8%
28%
Homesley H et al Gynecol Oncol 2009
Remaining questions
• Systemic chemotherapy better than WAI for a
systemic disease (GOG 122)
• Most recurrences are systemic, not locoregional
(GOG 122 and GOG 184)
• Best chemotherapy: TAP no better than AP (GOG
184)
• 16% of pts receiving volume-directed RT did not
make it to chemotherapy (GOG 184)
• TAP vs carbo/paclitaxel (GOG 209 – closed)
• Role of RT in combination with chemo
– GOG 258
– Carbo/paclitaxel (CT) x6 vs. RT + CT x4
Adjuvant Treatment Summary
Stage/ Grade
Low
Risk
Inter-mediate High Risk
Risk
IA G1/2
IA (G3)
IB (all grades)
IIA
IIB
Postoperative
(complete
surgical
staging)
None
Vaginal Cuff
Brachy Therapy
or Observation
(*exception is in
stage IIB)
Stage III
Stage IV
UPSC (all stages)
CCC (all stages)
Undiff (all stages)
Chemotherapy
consider RT (Vaginal
Cuff Brachy Therapy
vs. whole pelvic)
Endometrial Cancer: James Cancer Hospital
Treatment Recommendations
Stage I, A-B; any grade
No further therapy (NFT)
+/- vaginal brachytherapy
Stage II, any grade
Radical hyst w/LND then observation
Otherwise consider XRT
Stage IIIA
Individualized mgmt
Stage IIIB-IVA
Clinical trial
Chemotherapy +/- XRT
Stage IV B
Clinical trial or chemotherapy
Ovarian Cancer
Gradual Therapy Changes Improve Survival
SEER Cancer Statistics Review, 1975-2001
Ovarian Cancer
Year
Cases
Deaths
%
2006
20,180
15,310
76
2007
22,430
15,280
68
2008
21,650
15,520
71
2009
21,550
14,600
67
2010
21,880
13,850
63
Jemal A, et al. CA Cancer J Clin 2006-2010
Pathology
 Epithelial (65%)
Serous (80%) – Tubal
Mucinous (10%) – Intestinal
Clear cell – Endocervical
Endometrioid – Endometrial
Brenner – Transitional cell
 Benign = Cystadenoma
 Invasive = Cystadenocarcinoma
 Borderline = Tumor of LMP
Survival by Stage
Stage
Percent 5-year Survival
I
24%
90%
II
6%
80%
III
55%
15-50%
IV
15%
5-15%
What is My Risk of Ovarian Cancer?
Dx 61
61 yr
-Ovarian CA
Risk of Ovarian Cancer
 Baseline
1.5% risk
 2+ relatives
3% risk
 One 1o relative
5% risk
 Two 1o relatives
7% risk
 BRCA2 mutation
25% risk
 BRCA1 mutation
40% risk
Disease Volume
Interventions to  Mortality?
Current point of diagnosis
and initiation of treatment
Prevention
Screening
Time
Interventions to  Mortality?
 Prevention
– Pedigree Analysis
– Medical: Oral Contraceptives
– Surgical: Risk-Reducing Oophorectomy
 Screening
– Pelvic Examination
– Ultrasonography
– CA125 and other (OvaSure) Serum Testing
– Proteomics (OvaCheckTM)
Screening – US and CA 125
“…there is no evidence available yet
that the current screening modalities
of CA 125 and ultrasonography can
be effectively used for widespread
screening to reduce mortality from
ovarian cancer…”
NIH Consensus Development Panel, 1994
Screening - OvaCheck
TM
“In the opinion of SGO, more
research is needed to validate
the test’s effectiveness before
offering it to the public”
Society of Gynecologic Oncologists, 2004
Screening - OvaSure
TM
“In the opinion of SGO,
additional research is needed
to validate the test’s
effectiveness before offering it
to women”
Society of Gynecologic Oncologists, 2008
Ovarian Cancer Staging
 Stage I – Confined to the ovaries
 Stage II – Confined to the pelvis
 Stage III – Implants out of the pelvis or
positive lymph nodes
 Stage IV – Distant metastases
 Positive pleural effusion or intraparenchymal
liver disease
Cytoreductive Surgery
 Goal is elimination of all tumor
• No gross residual (microscopic)
• Optimal (<1 cm)
• Suboptimal (>1 cm)
 Operative Technique
• Resection of urinary or intestinal tract
 Surgical Outcomes
• Optimal in ~75% of cases
• Does it matter?
Does Cytoreduction Matter?
Optimal Suboptimal
Response Rate
Clinical CR
95%
75%
Pathologic CR
50%
25%
Progression free interval (mo)
34
13
Survival (mo)
50
36
10-yr survival
35%
15%
Stage IIIC Ovarian Cancer
 Microscopic – 40-75%
 Optimal – 30-40%
 Suboptimal – 5-10%
Practical Management of Advanced Cancer
Advanced (stage III or IV)
Ovarian Cancer
Surgical Candidate?
Debulkable disease
Medically fit
Yes
No
Optimal Cytoreduction? (<1cm)
Yes
Chemotherapy
No
3 cycles of chemotherapy, then
consider interval cytoreduction,
then complete chemotherapy
Neoadjuvant Chemotherapy
 GCIG Collaboration







14 European centers, 1998-2006
718 patients with stage IIIC-IV EOC
670 randomized
Primary surgery vs 3 cycles NACT
Non-inferiority trial
Primary endpoint: overall survival
Secondary: PFS, QoL, adverse events
Vergote I et al. New Engl J Med 2010; 363:943-55
Neoadjuvant Chemotherapy
 Results




Optimal cytoreduction: 42% vs 81%
Adverse events higher in primary surgery arm
NACT Hazard Ratio = 0.98 (P = 0.01 non-inf)
Complete resection of all macroscopic disease was
strongest predictor of overall survival
 Conclusion

NACT followed by interval cytoreduction was not
inferior to primary surgery
Vergote I et al. New Engl J Med 2010; 363:943-55
Neoadjuvant Chemotherapy
 Criticism





Primary cytoreduction rate only 42%
Survival lower than
Long enrollment period
GOG trials of suboptimal only patients
Median PFS was only 12 months
Median OS was only 29 months
Were second-line therapies available to these patients?
 Takeaway

Interesting, but unlikely to replace US standard
Vergote I et al. New Engl J Med 2010; 363:943-55
How did we arrive at the current
standard and what have we done
to improve it?
Primary Treatment of Ovarian Cancer
Cyclophosphamide +
Cisplatin
STANDARD OF CARE
1995
1997
GOG 172 confirms IP
therapy leads to a survival
advantage compared with IV
NEW STANDARD OF CARE?
GOG 158 shows Taxol-carboplatin = TaxolCDDP, with improved toxicity and QoL
1999
2001
GOG 111 establishes Taxol-CDDP
as standard 1st line
SWOG 8501 demonstrates improved
survival with IP therapy
2003
2005
2008
GOG 178 demonstrates improved DFS with
longer duration of maintenance Taxol – No
data on overall survival
GOG 182 demonstrates
no survival advantage
to triplet or sequential
doublet therapy
Advanced Ovarian Cancer
Median Survival: 1975 - 2005
80
57
52
months
60
20
(optimal)
(optimal)
37
40
66
24
12
14
0
1975
Alkeran
1983
1986
multi-drug
1996
1998
cisplatin
2003
paclitaxel
2005
IP therapy
GOG 158: Carboplatin vs. Cisplatin
Arm 1
• FIGO stage III
epithelial ovarian or
peritoneal cancer
• Optimal (<1 cm)
cytoreduction
R
A
N
D
O
M
I
Z
E
Paclitaxel 135 mg/m2 24 hr IV q21 d x6
Cisplatin 75 mg/m2 IV D2 q 21 d x6
Arm 2
Paclitaxel 175 mg/m2 3 hr IV q21 d x6
Carboplatin AUC 7.5 IV D1 q21 d x6
Ozols RF et al. J Clin Oncol 2004;21:3194-200
GOG 158: Carboplatin vs. Cisplatin
• Efficacy
Median recurrence-free
survival, mo
Negative SLS, %
• Toxicity
More frequent with
paclitaxel/cisplatin:
P + CDDP
21.7
P + Carbo
22.0
45.2
51.5
More frequent with
paclitaxel/carboplatin:
– Grade IV neutropenia
– Grade III/IV thrombocytopenia
– Grade III/IV gastrointestinal
– Grade I/II pain
– Fever
– Metabolic
SLS = second-look surgery.
Ozols RF et al. J Clin Oncol 2004;21:3194-200
Improvements in Primary Therapy
• Intraperitoneal Chemotherapy
• Weekly (dose-dense) taxanes ?
• Bevacizumab consolidation ?
Improvements in Primary Therapy:
Intraperitoneal Therapy
GOG 172
• FIGO stage III
epithelial ovarian or
peritoneal cancer
• Optimal (<1 cm)
cytoreduction
IV
R
A
N
D
O
M
I
Z
E
Paclitaxel 135 mg/m2 24 hr IV q21 d x6
Cisplatin 75 mg/m2 IV D2 q 21 d x6
IP
Paclitaxel 135 mg/m2 24 hr IV q21 d x6
Cisplatin 100 mg/m2 IP D2 q 21 d x6
Paclitaxel 60 mg/m2 IP D8 q 21 d x6
Armstrong DK. Proc Am Soc Clin Oncol 2002;21:201a.
GOG 172: Intraperitoneal Therapy
 Significantly increased toxicity with IP:
● Neutropenia, thrombocytopenia, GI, renal, infection,
fatigue, metabolic and pain
 Outcomes:
● RR recurrence 0.73 in IP arm compared with IV arm
(23 versus 18 months, P=0.05)
● Overall survival 65 versus 49.7 months (P=0.03)
● Confirmed findings of SWOG 8501 and GOG 114
(survival advantage with IP therapy)
Armstrong DK et al. N Engl J Med 2006
Intraperitoneal Therapy?
GOG Trial
Regimen
PFI
Median Survival
GOG 104
IV: CDDP/CTX
IP: CDDP/CTX
Not reported
Not reported
41 mo
49 mo
Alberts et al
Risk of Death Hazard Ratio = 0.76
GOG 114
Markman et al
IV: CDDP/Taxol
IP: CDDP then
IV Carbo/Taxol x2
22mo
28 mo
52 mo.
63 mo
Risk of Death Hazard Ratio = 0.81
GOG 172
Armstrong et al
IV: Taxol/CDDP
IP: Taxol/CDDP and
IV Taxol
18 mo
23 mo
50 mo
65 mo
Risk of Death Hazard Ratio = 0.73
Toxicity with IP chemotherapy
• Presence of an IP catheter
– Infection, fever
• IP administration of chemotherapy
– Abdominal pain, nausea, vomiting
• Chemotherapy
– Greater hematologic, metabolic, and
neurologic toxicity
Intravenous versus Intraperitoneal
Administration of Cisplatin
Pharmacokinetics
IV CDDP 100 mg/m2
100
80
80
60
60
40
Plasma
Peritoneal
fluid
AUC
AUC
100
IP CDDP 90 mg/m2
Peritoneal
fluid
40
20
20
0
0
Plasma
Improvements in Primary Therapy:
Weekly Taxane
JGOG
• FIGO stage II-IV
EOC
• Optimal or
suboptimal
• 1º endpoint = PFS
• N = 631
Arm 1
R
A
N
D
O
M
I
Z
E
Paclitaxel IV 180 mg/m2 q21 d x6
Carboplatin IV AUC 6 q 21 d x6
Arm 2
Paclitaxel IV 80 mg/m2 q7 d x18
Carboplatin IV AUC 6 q 21 d x6
Katsumata N et al. Lancet 2009;374:1331-1338
JGOG: Weekly Taxane
• Rationale:
– Duration of exposure is an important determinant of paclitaxel
cytotoxicity
– Preclinical evidence of anti-angiogenic effect
• Results:
– Median PFS longer in dose-dense (28 vs 17 mo)
– 3 yr OS higher in dose dense (HR=0.75, P=0.03)
– Heme and non-heme toxicities similar
• Conclusions:
– PFS and OS improved with dose-dense primary taxane therapy
– GOG has incorporated weekly taxane arms in several trials
Katsumata N et al. Lancet 2009;374:1331-1338
GOG 218
• FIGO stage III/IV
epithelial ovarian or
peritoneal cancer
• Optimal/Suboptimal
• 1º endpoint: PFS
• N = 1873
Arm 1
R
A
N
D
O
M
I
Z
E
Carboplatin IV AUC 6 (6 cycles)
Paclitaxel IV 175 mg/m2 (6 cycles)
Placebo IV (5 cycles)
+ maintenance placebo up to 15 mo
Arm 2
Carboplatin IV AUC 6 (6 cycles)
Paclitaxel IV 175 mg/m2 (6 cycles)
Bevacizumab IV 15 mg/kg (5 cycles)
+ maintenance placebo up to 15 mo
Arm 3
Carboplatin IV AUC 6 (6 cycles)
Paclitaxel IV 175 mg/m2 (6 cycles)
Bevacizumab IV 15 mg/kg (5 cycles)
+ maintenance bevacizumab up to 15 mo
Burger R et al, ASCO 2010
GOG 218 Results
 Results:
 Women in Arm 3 (T/C/B + B) had median PFS 14 months
compared to 10 months in Arm 1 (T/C); (HR = 0.72, P<0.0001)
 Women in Arm 2 (T/C/B) did not have significant increase in PFS
compared to Arm 1 (T/C)
 Adverse events consistent with previous trials of bevacizumab
 Criticism:
 Is bevacizumab necessary with primary treatment if Arms 1 and
2 are similar?
 OS data not yet mature
Burger R et al, ASCO 2010
ICON7
Arm 1
• FIGO stage II/IV
epithelial ovarian or
peritoneal cancer
• Optimal/Suboptimal
• 1º endpoint: PFS
• N = 1528
R
A
N
D
O
M
I
Z
E
Carboplatin IV AUC 6 (6 cycles)
Paclitaxel IV 175 mg/m2 (6 cycles)
Arm 2
Carboplatin IV AUC 6 (6 cycles)
Paclitaxel IV 175 mg/m2 (6 cycles)
Bevacizumab IV 15 mg/kg (5 cycles)
+ maintenance bevacizumab up to 15 mo
*10/11/2010 Press release: PFS reduced by 15% at 12 months
* Mature data will not be available for another 2 years
Perren T et al, ESMO 2010
Response to Chemotherapy
 Overall response rate = 75-80%
with chemotherapy
 66% of patients will recur and die
of their advanced ovarian cancer
Treatment Options for
Recurrent Ovarian Cancer
• Chemotherapy
– Cytotoxic
– Empiric versus assay-directed
– Non-cytotoxic (“targeted”) therapy
– High-dose with marrow transplant
• Surgery (2o cytoreduction)
• Immunotherapy
• Radiation therapy
Secondary Cytoreduction
Best Candidates
 Response to 1st line Rx
 DFI > 6-12 months
 Platinum sensitive
 Isolated recurrent disease
 Good performance status
 Further Rx options
 Previous optimal
cytoreduction
Poor Candidates
 Progressive disease
 Platinum resistant
 Short DFI
 Exhausted further Rx
 Poor surgical candidate
 Ascites
 Extensive disease
Treatment-free Interval
Response to Platinum Retreatment
10% RR
30% RR
50% RR
75% RR
About 50% of recurrences are >6 months
Platinum-Sensitive Recurrence
• Recurrence diagnosed > 6 months from
completion of primary therapy
• Generally retreat with platinum combination
• Evidence for both paclitaxel (ICON4) and
gemcitabine (AGO-OVAR) in combination
with carboplatin
• New evidence for carboplatin-PLD
Platinum-Sensitive Recurrence
• GCIG
–
–
–
–
–
–
European consortium
RCT non-inferiority trial
976 women with plat-sensitive recurrence
Carboplatin + PLD vs carboplatin + paclitaxel
Primary endpoint: PFS
Results:
• PFS superior in PLD arm (HR=0.82, P=0.005)
• Severe non-heme tox higher in paclitaxel arm
Pujade-Lauraine E et al. J Clin Oncol 2010;28:3323-3329
GOG 213: Doublets for Recurrence
RANDOMIZATION
•Epithelial ovarian cancer or
primary peritoneal cancer
•Recurrent disease
•Platinum sensitive
•+/- Cytoreduction
I
Paclitaxel Doublet
Carboplatin
Paclitaxel
II
Docetaxel Doublet
Carboplatin
Docetaxel
III
Doxil Doublet
Carboplatin
Doxil
IV
Gemcitabine Doublet
Carboplatin
Gemcitabine
V
Topotecan Doublet
Carboplatin
Topotecan
Sequential Doublet
VI
Carboplatin
Sequential Doublet
Paclitaxel
To treat or not to treat….
Early vs delayed treatment of
recurrent ovarian cancer
• MRC OV05/EORTC 55955
– 9 European centers
– RCT of 1442 women of EOC in complete remission
– Clinical exam and CA125 q 3 mo
– Pts/investigators blinded to these results
– If CA125 >2X ULN, pt randomized to early treatment (within
28 days) or delayed treatment (not until clinical or
symptomatic relapse)
– 529 women randomized: 265 early, 264 delayed
– Primary endpoint: overall survival
Rustin GJS et al. Lancet 2010;376:1155-1163
Early vs delayed treatment of
recurrent ovarian cancer
• Results
– No difference in overall survival (HR = 0.98)
• Conclusions
– Value of routine CA125 measurement not proven
• Criticism
– Long enrollment (1996-2005)
– Large number of early stage (20%) but overall survival poor (26-27
mo from randomization)
– Contemporary therapy for recurrence not available to many
patients
• Takeaway
– Provocative, but not likely to be uniformly adopted
Rustin GJS et al. Lancet 2010;376:1155-1163
The Future?
PARP inhibitors
Imatinib
TKIs