novel therapeutics in gynecological malignancies tamar safra, md tel aviv sourasky medical center,...
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Novel Therapeutics in Gynecological Malignancies
Novel Therapeutics in Gynecological Malignancies
Tamar Safra, MD
Tel Aviv Sourasky Medical Center, Tel Aviv
Tamar Safra, MD
Tel Aviv Sourasky Medical Center, Tel Aviv
Ovarian Cancer- New Treatments
Uterine Cancer – Evolving Treatment
Ovarian Cancer- New Treatments
Uterine Cancer – Evolving Treatment
Ovarian CancerOvarian Cancer
• The most lethal of gynecologic malignancies
• Future goals – Early detection– Development of novel
agents
• The most lethal of gynecologic malignancies
• Future goals – Early detection– Development of novel
agents
Ovarian CancerOvarian Cancer
• New drugs and analogs of old drugs
• New schedules for old drugs
• Methods to overcome drug resistance
• Biological agents
• Combination of chemotherapy with biological therapy
• Hormonal therapy
• New drugs and analogs of old drugs
• New schedules for old drugs
• Methods to overcome drug resistance
• Biological agents
• Combination of chemotherapy with biological therapy
• Hormonal therapy
Mitotic Spindle Inhibitors
Mitotic Spindle Inhibitors
New TaxanesNew Taxanes
• Taxanes and epothilones - under active clinical development– Overcome drug resistance– Enhance tumor delivery– Reduced neuropathy– Reduced alopecia
• Xyotax, a polyglutamate conjugated to paclitaxel - activity without alopecia
• Abraxane - nanoparticle paclitaxel forumulation is under investigation
• Taxanes and epothilones - under active clinical development– Overcome drug resistance– Enhance tumor delivery– Reduced neuropathy– Reduced alopecia
• Xyotax, a polyglutamate conjugated to paclitaxel - activity without alopecia
• Abraxane - nanoparticle paclitaxel forumulation is under investigation
Paclitaxel Poliglumex (PPX)
Paclitaxel Poliglumex (PPX)
• Conjugate of paclitaxel with poly-L-glutamic acid
• Enhances distribution in tumor• Prolonged release of free paclitaxel• Greater activity• Active in tumors with MDR (Multi-
Drug Resistance) gene• Shorter administration
• Conjugate of paclitaxel with poly-L-glutamic acid
• Enhances distribution in tumor• Prolonged release of free paclitaxel• Greater activity• Active in tumors with MDR (Multi-
Drug Resistance) gene• Shorter administration
GOG 212 Phase III Study : Maintenance Chemotherapy
for EOC
GOG 212 Phase III Study : Maintenance Chemotherapy
for EOC
Paclitaxel 175 mg/m2
q 28 days x 12Paclitaxel 175 mg/m2
q 28 days x 12
PPX 175mg/m2
q 28 days x 12PPX 175mg/m2
q 28 days x 12
ObservationObservation
EOC with CR after 6 cycles of chemotherapy
EOC with CR after 6 cycles of chemotherapy
Different Schedules of old
drugs
Different Schedules of old
drugs
TopotecanTopotecan
• An S-phase specific drug
• Activity and toxicity are schedule dependent
• Investigated methods• Daily administration – 5 days q 3 weeks • Low‑dose continuous infusion (CI)• Weekly schedule
• An S-phase specific drug
• Activity and toxicity are schedule dependent
• Investigated methods• Daily administration – 5 days q 3 weeks • Low‑dose continuous infusion (CI)• Weekly schedule
Topotecan Mechanism of Action
Topotecan Mechanism of Action
Topoisomerase I creates DNA
breaks for repair and replication
Topoisomerase I creates DNA
breaks for repair and replication
Topotecan binds to topoisomerase I
creating DNA breaks
Topotecan binds to topoisomerase I
creating DNA breaks
Damage toDNA causes
cell death
Damage toDNA causes
cell death
Topotecan Daily
Topotecan Daily
Study DesignStudy Design
TopotecanTopotecan
1.5 mg/m1.5 mg/m22/d D1-5 /d D1-5 Q21dQ21d30-minute infusion30-minute infusion
TopotecanTopotecan
1.5 mg/m1.5 mg/m22/d D1-5 /d D1-5 Q21dQ21d30-minute infusion30-minute infusion
Ten Bokkel Huinink. J Clin Oncol 1997;15:2183-93
Multicenter, prospective, randomizedMulticenter, prospective, randomized phase-III studyphase-III study
Stratification by age, ascites and previous response to Stratification by age, ascites and previous response to platinum-based therapyplatinum-based therapy
PaclitaxelPaclitaxel
175 mg/m175 mg/m22 D1 D1
Q21dQ21dover 3 hoursover 3 hours
PaclitaxelPaclitaxel
175 mg/m175 mg/m22 D1 D1
Q21dQ21dover 3 hoursover 3 hours
Time to ProgressionTime to ProgressionTime to ProgressionTime to Progression
Time (weeks)
topotecan(n=112)
Paclitaxel (n=114)
1.0
0.2
0.4
0.6
0.8
0.0
0 4 8 12 16 20 24 28 32 36 40 44 48 52 56 60 64 68 72 76 80
Pro
po
rtio
n
P =.072
Ten Bokkel Huinink. Ann Onc. 2004;15:100-3
Median TTP
19.8w
14.7w
Median TTP
19.8w
14.7w
Hematological Side Hematological Side EffectsEffects
Hematological Side Hematological Side EffectsEffects
Topotecan (n = 111)
Paclitaxel (n = 112)
Neutropenia (grade 4) 79.3% 23.2%
Febrile neutropenia 5.4% 0.9%
Grade 4 neutropenia with > grade 2 infection
19.6%
3.5%
G-CSF administration treatment/ prophylaxis
20.5%/34.8%
0.9%/0.9%
Thrombocytopenia (grade 4) 25.2% 1.8%
Sepsis 5.4% 1.8%
Deaths 1.8% 0%
Topotecan (n = 111)
Paclitaxel (n = 112)
Neutropenia (grade 4) 79.3% 23.2%
Febrile neutropenia 5.4% 0.9%
Grade 4 neutropenia with > grade 2 infection
19.6%
3.5%
G-CSF administration treatment/ prophylaxis
20.5%/34.8%
0.9%/0.9%
Thrombocytopenia (grade 4) 25.2% 1.8%
Sepsis 5.4% 1.8%
Deaths 1.8% 0%
Ten Bokkel Huinink. J Clin Oncol 1997;15:2183-93Ten Bokkel Huinink. J Clin Oncol 1997;15:2183-93
Topotecan Continuous Infusion
(CI)
Topotecan Continuous Infusion
(CI)
Continuous Infusion Phase-II
Continuous Infusion Phase-II
Response
• RR - 35% (95% CI, 15% to 54%)
• TTP - 26 weeks
Response
• RR - 35% (95% CI, 15% to 54%)
• TTP - 26 weeks
Hochster H. J Clin Oncol. 1999;17:2553-61Hochster H. J Clin Oncol. 1999;17:2553-61
0.4 mg/m2/24h, D1-21 Q28d N=24
0.4 mg/m2/24h, D1-21 Q28d N=24
Grade III-IV toxicity• 31% neutropenia• 52% anemia
requiring transfusion
• 4% thrombocytopenia
Grade III-IV toxicity• 31% neutropenia• 52% anemia
requiring transfusion
• 4% thrombocytopenia
Topotecan Weekly
Topotecan Weekly
Weekly Topotecan in Patients with Recurrent or
Persistent Epithelial Ovarian Cancer
Phase-II Study
Weekly Topotecan in Patients with Recurrent or
Persistent Epithelial Ovarian Cancer
Phase-II Study
Safra T, Inbar M, Levy T et alSafra T, Inbar M, Levy T et al
Objectives Objectives
To investigate the safety and efficacy
of weekly topotecan in relapsed and
persistant EOC
To investigate the safety and efficacy
of weekly topotecan in relapsed and
persistant EOC
Safra T, Inbar M, Levy T et al
Treatment RegimenTreatment Regimen
4 mg/m² topotecan D1,8,15 Q28d
4 mg/m² topotecan D1,8,15 Q28d
Safra T, Inbar M, Levy T et alSafra T, Inbar M, Levy T et al
Patients CharacteristicsPatients Characteristics
• N=45
• Age – median 64y (range 42-87)
• Stage – Ic-IIc in 4 (9%) patients III-IV in 41 (91%) patients
• Platinum status – Sensitive 56%
Resistant 44%
• Previous chemotherapy – median 1(range 1-5)
• N=45
• Age – median 64y (range 42-87)
• Stage – Ic-IIc in 4 (9%) patients III-IV in 41 (91%) patients
• Platinum status – Sensitive 56%
Resistant 44%
• Previous chemotherapy – median 1(range 1-5)
Safra T, Inbar M, Levy Taet alSafra T, Inbar M, Levy Taet al
RESULTSResponse Rates
RESULTSResponse Rates
Total patients , n 45
CR, (n) % (4) 8.9
PR, (n) % (12) 26.6
RR, (n) % (16) 35.5
SD, (n) % (21) 48.8
Total patients , n 45
CR, (n) % (4) 8.9
PR, (n) % (12) 26.6
RR, (n) % (16) 35.5
SD, (n) % (21) 48.8
Safra T, Inbar M, Levy T et alSafra T, Inbar M, Levy T et al
Time to Progression Time to Progression
Safra T, Inbar M, Levy T et alSafra T, Inbar M, Levy T et al
Median TTP 4.43m
(95%CI, 3.64-5.23)
Overall SurvivalOverall Survival
1Y OS - 76%
2Y OS - 50%
OS – median 11.6+ m (0.57-31)
1Y OS - 76%
2Y OS - 50%
OS – median 11.6+ m (0.57-31)
Safra T, Inbar M, Levy T et alSafra T, Inbar M, Levy T et al
ToxicityToxicity
(2 )Hochster H. J Clin Oncol. 1999;17:2553-61 (2 )Hochster H. J Clin Oncol. 1999;17:2553-61(1 )Ten Bokkel Huinink. Ann Onc. 2004;15:100-3 (1 )Ten Bokkel Huinink. Ann Onc. 2004;15:100-3
Ten Bokkel et al., 2004
(1)
Hochster H et al.,
1999(2)
Safra T et al.
Total patients, n 226 24 45
Dose Intensity, mg/m /wk 2.5 2.8 3
RR, (% )
23%
35%
35.5%
Median TTP, week
19 26 19
Hematologic Toxicity:
Grade 3/ 4-
Neutropenia
Thrombocytopenia
Anemia
79%
25%
40%
31%
4%
52%
2.3%
8.8%
23%(G2)
Nonhematologic Toxicity:
Alopecia
Nausea
Fatigue
76%
68%
54%
0%
4.6%
16%
Ten Bokkel et al., 2004
(1)
Hochster H et al.,
1999(2)
Safra T et al.
Total patients, n 226 24 45
Dose Intensity, mg/m /wk 2.5 2.8 3
RR, (% )
23%
35%
35.5%
Median TTP, week
19 26 19
Hematologic Toxicity:
Grade 3/ 4-
Neutropenia
Thrombocytopenia
Anemia
79%
25%
40%
31%
4%
52%
2.3%
8.8%
23%(G2)
Nonhematologic Toxicity:
Alopecia
Nausea
Fatigue
76%
68%
54%
0%
4.6%
16%
Conclusions Conclusions
• Weekly topotecan is efficacious in relapsed and persistent EOC
• Weekly topotecan is very feasible
- Low rate of grade III-IV hematological toxicity
- Mild non-hematological toxicity with no alopecia
• Weekly topotecan is efficacious in relapsed and persistent EOC
• Weekly topotecan is very feasible
- Low rate of grade III-IV hematological toxicity
- Mild non-hematological toxicity with no alopecia
Safra T, Inbar M, Levy T et alSafra T, Inbar M, Levy T et al
Multiple Drug Resistance (MDR)
Multiple Drug Resistance (MDR)
Using Erlotinib To Overcome ABCG2-
Mediated Chemoresistance To
Topotecan
Using Erlotinib To Overcome ABCG2-
Mediated Chemoresistance To
TopotecanRebecca Kosloff, MDRebecca Kosloff, MD
ABCG2ABCG2
– ABCG2 is one of the MDR genes
– Half-transporter structure causing efflux of the drug to the extracellular material
– Higher affinity for TKIs then other MDR1
– ABCG2 is one of the MDR genes
– Half-transporter structure causing efflux of the drug to the extracellular material
– Higher affinity for TKIs then other MDR1
– Examples of TKI’s: • Erlotinib • Gefitinib• Imatinib
– Examples of TKI’s: • Erlotinib • Gefitinib• Imatinib
HypothesisHypothesis
Erlotinib to reverse ABCG2-mediated resistance to topotecan in ovarian cancer
Topotecan Topotecan
Intracellular extracellular
Erlotinib to reverse ABCG2-mediated resistance to topotecan in ovarian cancer
Topotecan Topotecan
Intracellular extracellular
ABCG2
ErlotinibErlotinib
Phase I and II and pharmacokinetics are
on the way
Phase I and II and pharmacokinetics are
on the way
Biologics/targeted drug therapy
Biologics/targeted drug therapy
Epidermal Growth Factor Receptor
(EGFR)
Epidermal Growth Factor Receptor
(EGFR)
Effects of HER1/EGFR Activation
Proliferation, invasion, metastasis, angiogenesis, and inhibition of apoptosis
Src PLCGAPGrb2 Shc Nck Vav Grb7 Crk
PKC Ras
JNK AblPI3K Akt
Extracellular
Intracellular Transactivation
MAPK
P P
EGFR targeted therapy
Anti-HER1/EGFR-blocking antibodies
Anti-ligand-blocking
antibodies
TKIs Ligand–toxin
conjugatesAntibody–
toxinconjugates
PP P
P
Noonberg SB, Benz CC. Drugs 2000;59:753–67
12
34
5
Anti-HER monoclonal antibodiesAnti-HER monoclonal antibodies
• Inhibit cell-cycle progression; potentiate apoptosis• Decrease production of angiogenic factors• Recruit natural killer cells to tumours• Enhance receptor internalisation
• Inhibit cell-cycle progression; potentiate apoptosis• Decrease production of angiogenic factors• Recruit natural killer cells to tumours• Enhance receptor internalisation
Agus D, et al. Cancer Cell 2002;2:127–37Baselga J. Cancer Cell 2002;2:93–95
Agus D, et al. Cancer Cell 2002;2:127–37Baselga J. Cancer Cell 2002;2:93–95
Cell membraneCell membrane
HER1/EGFRHER1/EGFR HER2HER2
ErbituxErbitux HerceptinHerceptin
Tyrosine-kinase domain
Tyrosine-kinase domain
ErlotinibErlotinib
Anti-EGFR studies have been initiated – most are not yet
published
Anti-EGFR studies have been initiated – most are not yet
published • Anecdotal responses noted in phase I studies, encouraging
phase II studies – Cetuximab (Erbitux) – Trastuzumab (Herceptin) - RR only 7.3%*– EMD72000
• GOG - a phase II study of cetuximab • EMD72000 - a phase II trial , completed but not yet reported
• Combinations with chemotherapy are being studied in small scale
• Anecdotal responses noted in phase I studies, encouraging phase II studies – Cetuximab (Erbitux) – Trastuzumab (Herceptin) - RR only 7.3%*– EMD72000
• GOG - a phase II study of cetuximab • EMD72000 - a phase II trial , completed but not yet reported
• Combinations with chemotherapy are being studied in small scale
* Bookman et al. J Clin Oncol. 21(2):283-90, 2003* Bookman et al. J Clin Oncol. 21(2):283-90, 2003
Small Molecules – TKI’s (Tyrosine Kinase
Inhibitors)
Small Molecules – TKI’s (Tyrosine Kinase
Inhibitors)
Erlotinib (Tarceva)Erlotinib (Tarceva)
• TKI –EGFR indicated in metastatic disease of pancreas and NSCLC
• Inhibitor of ABCG2– Preclinical data with topotecan
• Some response as a single agent in ovarian cancer *– N=34 pts , heavily pretreated
• RR 6%• SD 44%• Median OS 8 m
• Erlotinib in combination with docetaxel and carboplatin as first line treatment for ovarian cancer shown some response **
• TKI –EGFR indicated in metastatic disease of pancreas and NSCLC
• Inhibitor of ABCG2– Preclinical data with topotecan
• Some response as a single agent in ovarian cancer *– N=34 pts , heavily pretreated
• RR 6%• SD 44%• Median OS 8 m
• Erlotinib in combination with docetaxel and carboplatin as first line treatment for ovarian cancer shown some response **
* Gordon et al, Int J Gynecol Cancer 2005;15:785–792**Finkler et al., ASCO Ann Meeting Proc 2001; 20:208a (abstr 831)
Anti-angiogenic therapies
Anti-angiogenic therapies
The angiogenic switch in tumor developmentThe angiogenic switch in tumor development
Adapted from Bergers G, et al. Nature 2002;3:401–10
Angiogenic switchResults in over-expressionof pro-angiogenic signals,such as VEGF
Small tumor (1–2mm)• Avascular• Dormant
Small tumor (1–2mm)• Avascular• Dormant
Larger tumor• Vascular• Metastatic potential
Larger tumor• Vascular• Metastatic potential
Anti-VEGF antibodyAnti-VEGF antibody
• Bevacizumab (Avastin) - a monoclonal antibody
• Prevents interaction VEGF with its receptors
• Prevents activation of downstream signalling pathways
• Vascular regression
• Bevacizumab (Avastin) - a monoclonal antibody
• Prevents interaction VEGF with its receptors
• Prevents activation of downstream signalling pathways
• Vascular regression
Bevacizumab
Bevacizumab
– P– P– P– P
P– P– P– P–
VEGFVEGF
XX
Growth
Proliferation
Migration
Survival
Growth
Proliferation
Migration
Survival
XX
ShrinkingtumourShrinkingtumour
Regressing vasculatureRegressing vasculature
Jain RK. Nat Med 2001;7:987–9Jain RK. Nat Med 2001;7:987–9
Blocking VEGF may cause existing tumour blood vessels to regress and lead to tumour
shrinkage
Blocking VEGF may cause existing tumour blood vessels to regress and lead to tumour
shrinkage
Carboplatin and Paclitaxel With or Without
Bevacizumab in Treating Patients With Stage III or
Stage IV Ovarian Epithelial or Primary Peritoneal
Cancer
Carboplatin and Paclitaxel With or Without
Bevacizumab in Treating Patients With Stage III or
Stage IV Ovarian Epithelial or Primary Peritoneal
Cancer
GOG 218: Bevacizumab Plus Standard Chemotherapy
GOG 218: Bevacizumab Plus Standard Chemotherapy
Carboplatin plusPaclitaxel q 21 d x 6
Carboplatin plusPaclitaxel q 21 d x 6
Carboplatin plusPaclitaxel q 21 d x 6plus Bevacizumab
15 mg/kg cycles 2-6
Carboplatin plusPaclitaxel q 21 d x 6plus Bevacizumab
15 mg/kg cycles 2-6
Carboplatin plusPaclitaxel q 21 d x 6plus Bevacizumab
15 mg/kg cycles 2-6
Carboplatin plusPaclitaxel q 21 d x 6plus Bevacizumab
15 mg/kg cycles 2-6
Placeboq 21 d x 15 mo
Placeboq 21 d x 15 mo
Placeboq 21 d x 15 mo
Placeboq 21 d x 15 mo
Bevacizumabq 21 d x 15 mo
Bevacizumabq 21 d x 15 mo
Patients with previously untreated suboptimal advanced stage epithelial ovarian cancer or primary peritoneal cancer(N =2000)
Patients with previously untreated suboptimal advanced stage epithelial ovarian cancer or primary peritoneal cancer(N =2000)
RandomizationRandomization
Endocrine TherapyEndocrine Therapy
TamoxifenTamoxifen
• Several positive phase II studies using tamoxifen – RR=17%*– 2 patients having greater than a 5 year
response*
• GOG-0198 - Phase III trial of tamoxifen compared with thalidomide in EOC
• Several positive phase II studies using tamoxifen – RR=17%*– 2 patients having greater than a 5 year
response*
• GOG-0198 - Phase III trial of tamoxifen compared with thalidomide in EOC
* Ahlgren, et al. Journal of Clinical Oncology 1993, 11:1957-68.
Aromatase inhibitorsAromatase inhibitors• A phase II study of Letrozole (Femara) 2.5 mg/d
in 50 patients showed: – Ten patients with SD on CT for at least 12 weeks* – Response correlated with - higher estrogen receptors,
lower erbB2, and higher EGFR*
• Another phase II study ** of letrozole 2.5 mg/d with 27 patients showed:– RR of 15%– No correlation was found between response and
estrogen/progesterone receptor expression
• Aromatase inhibitors - need to be examined in Phase III studies and in combination with cytotoxic agents.
• A phase II study of Letrozole (Femara) 2.5 mg/d in 50 patients showed: – Ten patients with SD on CT for at least 12 weeks* – Response correlated with - higher estrogen receptors,
lower erbB2, and higher EGFR*
• Another phase II study ** of letrozole 2.5 mg/d with 27 patients showed:– RR of 15%– No correlation was found between response and
estrogen/progesterone receptor expression
• Aromatase inhibitors - need to be examined in Phase III studies and in combination with cytotoxic agents.
* Bowman, et al. Clinical Cancer Research 2002, 8:2233-9.** Papadimitriou, et al. Oncology 2004, 66(2):112-7.
* Bowman, et al. Clinical Cancer Research 2002, 8:2233-9.** Papadimitriou, et al. Oncology 2004, 66(2):112-7.
Locally Advanced Endometrial cancer
Chemotherapy Radiotherapy
or Combination
Locally Advanced Endometrial cancer
Chemotherapy Radiotherapy
or Combination
GOG #122GOG #122
396 patients 396 patients
208 patientswhole abdomen RT
208 patientswhole abdomen RT
194 patientsadriamicin and cisplatin
194 patientsadriamicin and cisplatin
Randomized
Disease Free Survival
Disease Free Survival
P=0.007
Overall SurvivalOverall Survival
P=0.004
GOG#122Sites of Relapse (%)
GOG#122Sites of Relapse (%)
WAI AP
Overall 54 50
Pelvic 13 18
Abdominal 16 14
Extra-abdomianl 22 18
WAI AP P
Un-adjusted 38% 42% ?
Stage-adjusted* 38% 50% 0.007
GOG#1225-year Diseases-free Survival
GOG#1225-year Diseases-free Survival
* More unfavorable stages in AP arm
Randall M JCO, 2006
Grade 3-4 WAI (%) AP (%)
WBC 4 62
ANC <1 85
GI 13 20
Hepatic 3 1
Cardiac 0 15
Neurologic <1 7
Tx-related deaths N=4 N=8
Feasibility of GOG#122
Adverse Treatment Effects
Feasibility of GOG#122
Adverse Treatment Effects
How to Improve Treatment in Uterine
Adenocarcinoma
How to Improve Treatment in Uterine
Adenocarcinoma
• Adjuvant Chemotherapy (CT) is at least as good as radiotherapy (RT)
• Should we omit pelvic RT?
• How best to combine RT and CT?
• What is the best CT?
• Adjuvant Chemotherapy (CT) is at least as good as radiotherapy (RT)
• Should we omit pelvic RT?
• How best to combine RT and CT?
• What is the best CT?
What is the best chemotherapy Regimen ?
What is the best chemotherapy Regimen ?
• Adriamycin
• Cisplatin
• Carboplatin
• Paclitaxel
• Adriamycin
• Cisplatin
• Carboplatin
• Paclitaxel
Combination improves RR with limited improvements in PFS and OS in patients with advanced/recurrent disease.
The GOG has conducted several phase III trials comparing Adria to Adria/Cis (GOG 107), AC to AT (GOG 163), AC to TAP (GOG 177)
Combination improves RR with limited improvements in PFS and OS in patients with advanced/recurrent disease.
The GOG has conducted several phase III trials comparing Adria to Adria/Cis (GOG 107), AC to AT (GOG 163), AC to TAP (GOG 177)
Phase II studies have identified several active agents:Phase II studies have identified several active agents:
Endometrial CancerFront-line Randomized Trials
Advanced/Recurrent
Endometrial CancerFront-line Randomized Trials
Advanced/Recurrent
RRMedian OS
(mos)
GOG 163
Doxorubicin/Cisplatin 40% 12.4
Doxorubicin/Paclitaxel 44% 13.6
GOG 163
Doxorubicin/Cisplatin 34% 12.1
Doxorubicin/Paclitaxel/Cisplatin/G-CSF
57% 15.3
ConclusionConclusion
• Adjuvant CT should be used in most pts with advanced endometrial cancer
• That shouldn’t be done at the expense of adjuvant RT
• New strategies to combine CT and RT are needed
• IMRT may provide a venue to combine CT and RT concurrently
• Adjuvant CT should be used in most pts with advanced endometrial cancer
• That shouldn’t be done at the expense of adjuvant RT
• New strategies to combine CT and RT are needed
• IMRT may provide a venue to combine CT and RT concurrently
Tel-Aviv Medical Center, Tel-Aviv, ISRAEL
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