Cristiana Sessa
IOSI Bellinzona, Switzerland
6th ESO-ESMO Eastern Europeand Balkan Region
Masterclass in Medical Oncology
Systemic management of cervical and endometrial cancer
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Presenter Disclosures
None
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Cervical Cancer
Estimated Incidence, Mortality and Prevalence Worldwide in 2012
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Cervical Cancer
Epidemiology
• In female in less developed countries
second most commonly diagnosed
third leading cause of cancer death
• Third most common cause of female mortality
• In 2012 worldwide
527’600 new cases
265’700 deaths
• In 2012 in Europe
58’000 new cases
24’000 cancer deaths
• Incidence and mortality higher in developing countries
(85% of cases, 90% of deaths)
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Cervical Cancer
Diagnosis and staging
• Bimanual P/V examination, colposcopy, biopsy and/or endocervicalcurrettage (ECC)
• MRI : to determine tumor size, degree of stromal penetration,vaginal and corpus extension.
• CT: to detect pathologic lymphnodes
• Chest xray
• Cystoscopy, rectoscopy (stages IIB-IV)
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FIGO Staging is based on the extent of tumor lesion
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Cervical Cancer
Survival by FIGO stage
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Cervical Cancer
Histopathological assessment
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Cervical Cancer
ESMO algorithm for cervical cancer – Early stage
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Radical hysterectomy vs radiotherapy in patients with stage I B, II A cervical cancer
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Concurrent chemotherapy + pelvic radiation therapy vs pelvic radiation therapy alone
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Cervical Cancer
ESMO algorithm for cervical cancer
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Cervical Cancer
2/22/99: NCI alert on cervical cancer
The results of 5 large studies have shown that women with bulky IB2-IVA cervical
cancer have better survival when they receive chemotherapy which includes the
drug cisplatin along with radiation therapy.
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Cervical Cancer
Concurrent chemoradiotherapy for cervical cancer: a meta-analysis of 18 randomized trials
• Greater effect for stage IB2-IIA/IIB with10% survival improvement,
3% for stage III / IVA
• Better results for platinum based therapy (40mg / m2 / wk)
• Greater benefit in overall survival with additional adjuvant CT
(to be confirmed in ongoing studies: INTERLACE)
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Cisplatin chemoradiotherapy vs radiotherapy in FIGO stage IIIB squamous cell carcinomA of the uterine cervix
A randomized clinical trial
Shrivstava S. et al
Jama Oncol, 2018ES
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Conclusions
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Cervical Cancer
ESMO algorithm for cervical cancer
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Cervical Cancer
Phase III trial four cisplatin-containing doublet combinationsin stage IVB, recurrent or persistent cervical carcinoma
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Cervical Cancer
GOG 240 : final protocol-specified Overall survivalCisplatin-Paclitaxel versus Cisplatin-Paclitaxel-Bevacizumab
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Adverse Event, n (%) Chemo Alone (n=220)
Chemo + Bev (n=220)
Treatment cycles, median (range) 6 7
Grade 5 AE(s) 3 (1.3) 7 (3.2)
GI events, non-fistula (grade ≥2) 97 (44) 115 (53)
GI fistula (grade ≥2) 1 (0.5) 11 (5)
GI perforation (grade ≥3) 0 (0) 5 (2.3)
GU fistula (grade ≥2) 1 (0.5) 8 (3.6)
Hypertension (grade ≥2) 4 (1.8) 55 (25)
Proteinuria (grade ≥3) 0 (0) 5 (2.3)
Pain (grade ≥2) 63 (29) 72 (33)
Neutropenia (grade ≥4) 58 (26) 80 (36)
Febrile neutropenia (grade >3) 12 (5.5) 12 (5.5)
Thromboembolism (grade ≥3) 4 (1.8) 18 (8.2)
Bleeding CNS (any grade) 0 (0) 0 (0)
GI (grade ≥3) 1 (0.5) 4 (1.8)
GU (grade ≥3) 1 (0.5) 6 (2.7)
bev, bevacizumab; chemo, chemotherapy; CNS, central nervous system; GI, gastrointestinal; GU, genitourinary.
Bevacizumab in advanced cervical cancer
Updated Toxicity
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Cervical Cancer
Randomised trial comparing cisplatin/paclitaxel with carboplatin /paclitaxel: a non inferiority study (JCOG 0505)
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Cisplatin / paclitaxel versus carboplatin/paclitaxel
in metastatic or recurrent cervical cancer
Overall survival
Kitagawa et al, JCO, 2015
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Cisplatin / paclitaxel versus carboplatin/paclitaxel
in metastatic or recurrent cervical cancer
Subgroups analysis of overall survival
Kitagawa et al, JCO, 2015
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Immunotherapy for cervical cancer
Several T cell based immunotherapy approaches in early clinical trials
Checkpoint inhibitors / immune modulators
Therapeutic vaccines
Bacterial vector
Viral vector
Peptide / protein based
Adoptive T cell therapy
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Emerging strategies in recurrent cervical caimmune checkpoint inhibitors
Pembrolizumab in patients with advanced cervical CaPhase 1b Keynote-028 study
Frenel, JCO, 2017
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Pembrolizumab in advanced cervical cancer
Frenel, JCO, 2017
KEY NOTE 028 results
Patients treated (%)
(n=24)Antitumor activity (%) Grade 3 TRAE (%)
Metastatic disease 100 ORR 17 Any 75
Prior RT 92 PR 17 Rash 21
Prior lines CT (≥3) 38 SD 13 Colitis 4
Prior Bev 42 PD 67 Guillain Barrè 4
Median response:
Median OS:
duration: 5.4 mo (4.1-7.5)
duration: 11 mo (95% CI: 4-15)
Median follow up: 11 mo (1.3-32.2)ESO-
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Pembrolizumab in advanced cervical cancer
Phase II KEY NOTE 158 results
Patients treated (%)
(n=82)
Antitumor activity
(pts number)
PD-L1+
(%)
OR 10 10
CR 3 3
PR 7 7
SD 17 14
PD 44 37
Pembrolizumab granted FDA approval for PD-L1 + Cervical Cancer 12 June 2018
ASCO, 2017
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Pembrolizumab in advanced cervical cancer
FDA approved DAKO PD–L1 IHC 22C3 pharmDx assay
as companion diagnostic test 12 June 2018
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Endometrial Cancer
Epidemiology The most common gy cancer in Western countries
Incidence 13/100’000 women/yr Europe
Mortality 2-3/100’000 women/yr
80-90% post menopausal; 5% in
*estimated from the literature Calle, Nat Rev Can 2004
Obesity-related cancers
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Murali R, Lancet Oncol, 2014
Endometrial Cancer
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Murali R, Lancet Oncol, 2014
Endometrial Cancer
7% 28% 39% 26%
Cancer Genome Atlas Research NetworkComprehensive genomic and transcriptomic analysis of endometrial cancer
Four genomic classes
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PORTEC 3
Phase III trial comparing concurrent chemo radiation (CTRT) and
adjuvant CT with pelvic RT alone in high-risk and advanced stage
endometrial carcinoma (EC) S. de Boer et al.
QuestionIs the combination of RT and CT better than RT alone in
improving PFS and OS in high-risk EC patients?
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PORTEC 3
Trial design
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PORTEC 3
Inclusion criteria
• Endometrial carcinoma
• Stage I grade 3, with deep invasion or LVSI+
• Stage II-III
• Stage I-III serous or clear cell cancers (>25%)
• WHO PS 0-2
• No residual macroscopic tumor after surgery
• Pathology review before randomisation
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PORTEC 3
Survival (OS and FFS)
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PORTEC 3
Conclusions
• Risk reduction of 7% (FFS) and 5% (OS)
• Significant 11% FFS benefit with CTRT for stage III Recommended
• Significant more toxicity with CTRT in the first 12 mos
• Good pelvic control with RT alone
• OS analysis may need a longer follow up
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Endometrial Cancer
Adjuvant treatment algorithm stage II-III high-risk pts
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PORTEC 3 Final results
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Endometrial Cancer
Advanced / recurrent disease treatment algorithms
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Primary endpoints: PFS at 6mo and ORR
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Conclusions
• Avelumab did not meet prespecified criteria to move to 2nd stage in the MSS cohort
• All 5 PFS6 and 3 PRs in MSI/POLE cohort pts with ≥ 3 prior lines of cytotoxic therapy
• This is consistent with the FDA approval of pembrolizumab in MSI/MMR deficient tumors
• Pembrolizumab in endometrial MSI: ORR in 5 of 14 (36%), DOR (4.2+ months, 17.6+ months)
• Correlative work (TILs, PD-L1, MMR by PCR, mutational load and signature) is ongoing
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Thank you!
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Molecular testing for Lynch Syndrome
• autosomal dominant familiar cancer risk syndrome
• due to a germline mutation in one of MMR genes in the tumor (MLH1,
MSH2, PMS2, MSH6)
• 42-54 % risk of endometrial and 6 – 12 % risk of OvCa
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