Clinical session  Gynecological cancers  Cervical and endometrial cancers Prof. C. Sessa IOSI - Bellinzona 10° ESO-ESMO MA...
<ul><li>The most common gy cancer in Western countries </li></ul><ul><li>Incidence 15/100’000 women/yr Europe </li></ul><u...
Endometrial cancer Pathology and biology * Include also: adenocantoma, adenosquamous, undiff., squamous, mucinous Type II ...
Endometrial cancer Diagnosis <ul><li>Bimanual P/V examination </li></ul><ul><li>TVU: endometrial thickness, dilation and c...
Endometrial cancer The FIGO staging is surgical and pathological Old FIGO staging New FIGO staging Pathological assessment...
Endometrial cancer Treatment * if  controindications to surgery, RT and/or VBT Surgery Palliative histerectomy IV III I St...
MRC ASTEC study: efficacy of pelvic lymphadenectomy Lancet,2009
Endometrial cancer Treatment Adjuvant radiotherapy Background <ul><li>Two types of RT  </li></ul><ul><li>pelvic external b...
Endometrial cancer Treatment Adjuvant radiotherapy VBT is the treatment of choice for intermediate high risk patients NAT ...
Endometrial cancer Treatment Adjuvant Concurrent CT-RT vs RT *  risk factors: gr3,  >50% M ** CT: TP, AP, TEP, TAP before ...
Endometrial cancer <ul><li>Different use of different regimens in heterogeneous groups of pts </li></ul><ul><li>Consider f...
Endometrial cancer <ul><li>Evaluated in combination with RT (PORTEC 3) </li></ul><ul><li>Preferred regimen carbo/paclitaxe...
Endometrial cancer Treatment Advanced disease (stages III-IV) Ongoing studies for endometrioid stage III for non endometri...
Growth Factors and the mTOR Pathway Protein Production 4E-BP1 PTEN S6 elF-4E Growth Factors IGF-1, EGF, TGF α , VEGF, etc ...
mTOR inhibitors in endometrial cancer Colombo et al.
mTOR Inhibition May Enhance the Antitumor Effects of Other Therapies  mTOR Inhibition Chemotherapy Radiation EGFR Inhibito...
Endometrial cancer <ul><li>Role and extent of para-aortic lymphadenectomy </li></ul><ul><li>Treatment of  high risk locali...
Conclusions Outside clinical trials Endometrial cancer Surgery  lymphadenectomy in selected high risk pts  (grade, M, tumo...
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MON 2011 - Slide 11 - C. Sessa - Cervical and endometrial cancers (part I)

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  • Growth-stimulating signals originating from within and outside the cell are integrated through mTOR into processes that maintain cell viability and stimulate cell growth, cell division, and angiogenesis. mTOR is a sensor that acts as a biochemical switch, ensuring that supplies of energy and nutrients in the cell are sufficient to support these processes 1,2 In cancer cells, one or more of the proteins shown upstream of mTOR may be deregulated, and this loss of regulation contributes to, and in some cases drives, the malignancy. These include overproduction of hormones, cytokines, and growth factors and aberrant expression of growth factor receptors and signaling molecules, such as PI3-K, PTEN, Akt, and TSC1/2 (and LKB1, which is not shown). Aberrant signaling in parallel signaling pathways also affects signaling through mTOR because these pathways are connected to the mTOR pathway. These connections are referred to as “cross-talk” and involve the Ras/Raf/MAPK pathway and Abl signaling 2-5 References Bjornsti and Houghton. Nat Rev Cancer . 2004;4:335-348. Crespo and Hall. Microbiol Mol Biol Rev . 2002;66:579-591. Huang et al. Cancer Biol Ther . 2003;2:222-232. Mita et al. Clin Breast Cancer. 2003;4:126-137. Wullschleger et al. Cell. 2006;124:471-484.
  • Cancer therapy with mTOR inhibition may potentially be used with other approaches to cancer monotherapy or multimodality therapy. Several multiagent combinations are being investigated in clinical trials. The figure shows combinations for which a rationale has been developed in preclinical studies
  • MON 2011 - Slide 11 - C. Sessa - Cervical and endometrial cancers (part I)

    1. 1. Clinical session Gynecological cancers Cervical and endometrial cancers Prof. C. Sessa IOSI - Bellinzona 10° ESO-ESMO MASTERCLASS IN CLINICAL ONCOLOGY Ermatingen, 4.4.2011
    2. 2. <ul><li>The most common gy cancer in Western countries </li></ul><ul><li>Incidence 15/100’000 women/yr Europe </li></ul><ul><li>Mortality 4-5/100’000 women/yr </li></ul><ul><li>80-90% post menopausal; 5% in <40 yrs old </li></ul><ul><li>Peak incidence 60 yrs </li></ul><ul><li>Aetiological factors: unopposed / excessive oestrogen exposure </li></ul><ul><li>Predisposing factors: nulliparity, early menarche/late menopause </li></ul><ul><li>obesity, diabetes, hypertension </li></ul><ul><li>treatment with tamoxifen </li></ul><ul><li>Genetic susceptibility: Lynch type II syndrome </li></ul>Endometrial cancer Epidemiology
    3. 3. Endometrial cancer Pathology and biology * Include also: adenocantoma, adenosquamous, undiff., squamous, mucinous Type II (10-20%) Type I (70-80%)* 43% 85% 5 yr survival p53 mut (90%) HER2 overexpress. (45%) amplific. (70%) MSI with MMR defects (20%) PTEN deletion (80%) KRAS, β caterin mut (40%) PI3K mut (39%) Molecular alterations abdominal, lymphatic local Recurrence aggressive favourable Behaviour advanced 60% early 70% Initial stage high low Grading no yes Hormone sensitivity endometrial CIN atypical hyperplasia Precursor lesions papillary serous; clear cell endometrioid adenoca. Histotype
    4. 4. Endometrial cancer Diagnosis <ul><li>Bimanual P/V examination </li></ul><ul><li>TVU: endometrial thickness, dilation and currettage </li></ul><ul><li>MRI: depth myometrial invasion (M), cervical involvement </li></ul><ul><li>MRI/CT: metastatic lymphnodes </li></ul><ul><li>Histeroscopy (gas): site, volume of tumor, cervical involvement, guided biopsy </li></ul><ul><li>Surgical biopsy: grading, M </li></ul>
    5. 5. Endometrial cancer The FIGO staging is surgical and pathological Old FIGO staging New FIGO staging Pathological assessment includes: M, cervical involvement, tumor size and location, extension to fallopian tubes and ovaries, grade and hystological subpypes, lymphovascular space invasion (LVSI), nodal status 75% stage I
    6. 6. Endometrial cancer Treatment * if controindications to surgery, RT and/or VBT Surgery Palliative histerectomy IV III I Stage Maximal surgical debulking no randomized studies, prognostic not therapeutic para aortic lymphadenectomy no evidence of benefit in DFS, OS (ASTEC) pelvic lymphadenectomy Comparable DFS/OS better short term outcome with lps Laparotomy/laparoscopy TAHBSO (I,A)* Abdominal inspection/washing Comments Issue Recommended
    7. 7. MRC ASTEC study: efficacy of pelvic lymphadenectomy Lancet,2009
    8. 8. Endometrial cancer Treatment Adjuvant radiotherapy Background <ul><li>Two types of RT </li></ul><ul><li>pelvic external beam radiotherapy (EBRT) for local/regional control </li></ul><ul><li>VBT for vaginal vault control </li></ul><ul><li>Risk factors for node invasion: stage, age, histotype, grade, M, LSVI </li></ul><ul><li>Risk categories </li></ul><ul><li>Low risk (55%): IA, endometrioid, gr 1-2 </li></ul><ul><li>Intermediate risk (30%): IB gr 1-2, IA gr 3, endometrioid, no LSVI </li></ul><ul><li>High risk (15%): IB gr 3, II-III, nonendometrioid any stage </li></ul><ul><li>In stage I ↓pelvic recurrence but not ↑OS after adjuvant EBRT </li></ul>
    9. 9. Endometrial cancer Treatment Adjuvant radiotherapy VBT is the treatment of choice for intermediate high risk patients NAT vs EBRT EBRT vs VBT NAT vs EBRT 4% vs 7% (p=o.039) 2% vs 5% Locoregional recurrence 4% vs 14% (P <0.001) 84 % vs 84% 80% vs 85% Survival 81% vs 85% ASTEC/EN5 PORTEC 2 (high risk-intermediate) PORTEC 1 (intermediate) 3% vs 7% gr 3-4 TAHBSO ± lymphadenect. I AB gr 3 IC II, serous, CC acute GI 13% vs 54% TAHBSO IB gr 3 IC gr 1-2 IIA Severe complications 3% GI at 5 yrs TAHBSO IBgr2-3 ICgr1-2
    10. 10. Endometrial cancer Treatment Adjuvant Concurrent CT-RT vs RT * risk factors: gr3, >50% M ** CT: TP, AP, TEP, TAP before or after RT ongoing EBRT plus DDP x 2 ->TP x4 vs TP x 6 III-IVA GOG 258 ongoing ongoing OFS 7% PFS 78% vs 69% GOG 249 PORTEC 3 NSGO-EORTC-9501/ EORTC5591 EBRT vs VBT TP x3 I-II high risk I-II serous, CC EBRT vs EBRT plus DDP ->TP x 4 IB-C gr3, IIA gr3, serous IB-III IIIA, IIIC EBRT (VBT) + CT ** vs EBRT ( ± VBT) I-IIIa, IIIC*
    11. 11. Endometrial cancer <ul><li>Different use of different regimens in heterogeneous groups of pts </li></ul><ul><li>Consider for HR patients and /or with nodal metastases </li></ul><ul><li>HR patients: stage, gr3 endometrioid, >50% M, Serous CC </li></ul><ul><li>Preferred regimen carbo/paclitaxel (GOG209) </li></ul><ul><li>No advantage of CAP over EBRT in high risk pts (IC gr3, II gr3 M>50%, III) </li></ul>Treatment Adjuvant chemotherapy Background
    12. 12. Endometrial cancer <ul><li>Evaluated in combination with RT (PORTEC 3) </li></ul><ul><li>Preferred regimen carbo/paclitaxel (GOG 249) </li></ul><ul><li>Retrospective data of efficacy in clear cell, serous papillary </li></ul><ul><li>Comparable to TAP in terms of PFS, OS in bulky disease </li></ul>Treatment Adjuvant chemotherapy Current issues <ul><li>Role of concurrent CT/RT in locally advanced /metastatic disease </li></ul>
    13. 13. Endometrial cancer Treatment Advanced disease (stages III-IV) Ongoing studies for endometrioid stage III for non endometrioid stage III CT/surgery/RT CT Individualized treatment IIIA only Observation GOG 209: TAP vs TP TAP more toxic AP vs TAP CT E dipendent tumors only Hormones Ridaforolimus vs Progestins mTOR inhibitors PI3K inhibitors HER2 inhibitors in serous New agents
    14. 14. Growth Factors and the mTOR Pathway Protein Production 4E-BP1 PTEN S6 elF-4E Growth Factors IGF-1, EGF, TGF α , VEGF, etc Cell Growth and Proliferation Angiogenesis mTOR Oxygen, energy, and nutrients <ul><li>mTOR </li></ul><ul><ul><li>Intracellular protein </li></ul></ul><ul><ul><li>Central controller of cell growth and proliferation </li></ul></ul><ul><li>mTOR signaling is often deregulated in cancer </li></ul><ul><li>Downstream inhibition of mTOR has potential for </li></ul><ul><ul><li>Antiproliferative effects on tumor cells </li></ul></ul><ul><ul><li>Angiogenesis inhibition </li></ul></ul><ul><ul><li>Enhancement of the effects of chemotherapy </li></ul></ul>TSC2 TSC1 Akt/PKB PI3-K S6K1 Ras/Raf Abl ER Ras/Raf pathway kinases
    15. 15. mTOR inhibitors in endometrial cancer Colombo et al.
    16. 16. mTOR Inhibition May Enhance the Antitumor Effects of Other Therapies mTOR Inhibition Chemotherapy Radiation EGFR Inhibitors Antiestrogens Antiangiogenics
    17. 17. Endometrial cancer <ul><li>Role and extent of para-aortic lymphadenectomy </li></ul><ul><li>Treatment of high risk localized disease </li></ul><ul><li>Role of PET to assess nodal status </li></ul><ul><li>Optimum systemic therapy for advanced disease </li></ul><ul><li>Individualized treatment of recurrent disease (combined approach, systemic treatment, palliative RT) </li></ul>Treatment Pending issues
    18. 18. Conclusions Outside clinical trials Endometrial cancer Surgery lymphadenectomy in selected high risk pts (grade, M, tumor size) to define need and type of adjuvant therapy Radiotherapy EBRT: no survival benefit but less recurrence in high risk. The indication for adjuvant RT should take into account the risk of vaginal recurrence (age, grade) and the benefit shown in stage IA VBT is indicated in IC gr1-2, IB gr1-2, IIA gr1-2, IIA gr3 < 50%, IA gr3, IB gr3 Medical treatment TP almost standard regimen No indication for adjuvant CT but concurrent with EBRT Promising new molecule targeted agents

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