SAMO MASTERCLASS Bern, Prof. C. Sessa IOSI - Bellinzona

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1 SAMO MASTERCLASS Bern, Gynecological cancers Prof. C. Sessa IOSI - Bellinzona

2 Epithelial ovarian cancer Epidemiology Fourth most common cause of female mortality Incidence 13/ woman/yr Europe Mortality 7.6/ women/yr Europe Peak incidence > 50yrs Predisposing factors Nulliparity, early menarche and late menopause ( Continuous ovulation ) Family history and BRCAness (up to 50% of high grade serous) -BRCA1 mut 15-45% life time risk -BRCA2 mut10-20 % lifetime risk BRCA ness: phenotype of some sporadic tumors similar to familial BRCA cancers with homologous recombination dysfunction due to genetic BRCA and canc epigenetic mechanism

3 Epithelial ovarian cancer Pathology WHO classification: 8 subtypes and 1-3 grading system Kurman classification Subtypes Mutations (%) BRAF KRAS PTEN PIK3CA BRCA1/2 TP53 Precursor histotype Type I (LMP) Serous, mucinous, endometrioid, clear cell (serous) (mucinous) 20 (clear cell/endom.) Rare Rare Borderline serous/mucinous Type II (HNP) High-grade serous, NMT, undifferentiated Rare Rare Rare Rare (serous) Serous de novo Endometriosis Clear cell/endometrioid Sensitivity to chemotherapy Low High Endometrioid

4 Epithelial ovarian cancer

5 Epithelial ovarian cancer Diagnosis and staging Aspecific symptoms (pain, GI) mainly in advanced disease Pelvic examination and TVU, CA125 not specific CT scan to aid in surgical planning A histological diagnosis should be obtained if possible

6 Epithelial ovarian cancer FIGO staging of cancer of the ovary (2006) Stage I IA IB IC Stage II IIA IIB IIC Stage III IIIA IIIB IIIC Stage IV Growth limited to the ovaries Growth limited to one ovary Growth limited to both ovaries Tumor either stage Ia or Ib, but with tumor on surface, or with capsule ruptured, or with ascites with malignant cells, or with positive peritoneal washings. Growth involving one or both ovaries with pelvic extension. Extension and/or metastases to the uterus and/or tubes. Extension to other pelvic tissues. Tumor either stage IIa or IIb, but with tumor on surface, or with capsule(s) ruptured, or with ascites with malignant cells, or with positive peritoneal washings. Tumor involving one or both ovaries with histologically confirmed peritoneal implants outside the pelvis and/or positive regional lymph nodes. Tumor grossly limited to the true pelvis, with negative nodes, but with histologically confirmed microscopic seeding of abdominal peritoneal surfaces. Tumor of one or both ovaries with histologically confirmed peritoneal implants, < 2 cm in diameter. Peritoneal metastasis beyond the pelvis >2 cm in diameter and/or positive regional lymph nodes. Distant metastases. Pleural effusion with positive cytology FIGO staging is the most important prognostic factor

7 Epithelial ovarian cancer

8 Epithelial ovarian cancer

9 Epithelial ovarian cancer

10 Epithelial ovarian cancer Primary treatment in advanced stages Surgery Aim: to achieve an optimal cytoreduction, associated with significantly OS and PFS Interval surgery after primary chemotherapy might be considered in selected patients (low PS, extensive disease) 2nd look laparoscopy or laparotomy obsolete

11 Epithelial ovarian cancer Primary treatment in advanced stages Front-line chemotherapy Recommended for all FIGO stage II-IV post surgery Standard regimen: Paclitaxel and Carboplatin q3 wks x 6 Weekly schedule (dose-dense, MITO 7) as option Addition of bevacizumab in higher risk patients for 1 yr treatment duration (ICON 7)

12 Epithelial ovarian cancer Schema FIGO stage I IIA (clear cell or grade 3) or FIGO stage IIB IV Surgically debulked histologically confirmed OC n=1528 Dec 2006 to Feb :1 R Carboplatin AUC 5 or 6 Paclitaxel 175 mg/m 2 Carboplatin AUC 5 or 6 Paclitaxel 175 mg/m 2 Bevacizumab 7.5 mg/kg q3w 18 cycles (12 months) Stratification variables: Stage & extent of debulking (I III debulked 1cm vs I III debulked >1 cm vs IV and inoperable stage III) Timing of intended treatment start ( 4 vs >4 weeks after surgery) GCIG group OC = epithelial ovarian, primary peritoneal or fallopian tube cancer

13 Epithelial ovarian cancer Final OS: High-risk (n=502) Proportion alive Stage III suboptimally debulked, any stage IV or no debulking surgery Stage III Control Research Total Non-proportionality test: Deaths (%) (66) p= Restricted mean, months Median, months Log-rank test p=0.03 HR (95% CI) 0.78 ( ) BEV exposure Time (months) Number at risk Control Research

14 Epithelial ovarian cancer Treatment of recurrence ~75% patients with advanced ovarian cancer develop recurrent or progressive disease Aims of treatment Select the best timing to initiate chemotherapy Balance of efficacy and toxicity In asymptomatic patients, quality of life needs to be maintained; in those with symptoms it needs to be improved Control symptoms and extend survival Chemotherapy is the principal modality Surgery according to clinical course

15 Epithelial ovarian cancer Recurrent ovarian cancer: population characteristics Response to platinum Time to recurrence Response to further platinum Platinum-sensitive >12 mo 30 60% Platinum-partially sensitive 6 12 mo 25 30% Platinum-resistant <6 mo <10% Platinum-refractory No initial response N/A

16 Epithelial ovarian cancer Regimens of proven value in recurrent disease Patients Time to recurrence Regimens Level of evidence Platinum-sensitive >12 mo > 6 mo Carboplatin-doublet Carboplatin-doublet (Carbo-GEM, Carbo-PLD) I,A I,B Platinum-partially sensitive Carboplatin-doublet + Beva (OCEANS) 6-12 mo Carboplatin-doublet Non platinum-doublet Platinum-resistant <6 mo Weekly paclitaxel + Bevacizumab (Aurelia) I,A I,B I,B* I,B *INOVATYON study

17 Epithelial ovarian cancer

18 Epithelial ovarian cancer AURELIA trial design Platinum-resistant OC a 2 prior anticancer regimens Chemotherapy Treat to PD/toxicity Optional BEV monotherapy d No history of bowel obstruction/abdominal fistula or clinical/ radiological evidence of rectosigmoid involvement R b 1:1 BEV 15 mg/kg q3w c + chemotherapy Treat to PD/toxicity Investigator s choice (without BEV) Primary endpoint: PFS (RECIST v1.0) Secondary endpoints: ORR OS (after OS events in 70%) Quality of life Safety and tolerability Chemotherapy options (investigator s choice): Paclitaxel 80 mg/m 2 days 1, 8, 15, & 22 q4w Topotecan 4 mg/m 2 days 1, 8, & 15 q4w (or 1.25 mg/m 2, days 1 5 q3w) PLD 40 mg/m 2 day 1 q4w ORR = objective response rate; PD = progressive disease; PFS = progression-free survival; a Epithelial ovarian, primary peritoneal or fallopian tube cancer b Stratification factors: selected chemotherapy; prior anti-angiogenic therapy; platinum-free interval (<3 vs 3 6 months) c Or 10 mg/kg q2w. d 15 mg/kg q3w, permitted on clear evidence of PD

19 Epithelial ovarian cancer OV 05/EORTC Ovarian cancer in complete remission after first-line platinum-based chemotherapy and a normal CA125 REGISTER Blinded CA125 measured every 3 months CA125 >2 x upper limit of normal RANDOMIZED Early treatment Clinician and patient informed Delayed treatment Clinician not informed,, treatment delayed until clinically indicated Rustin G, et al Lancet 2010; 376: 1155 (2010)

20 Epithelial ovarian cancer Key Conclusions OV05/EORTC In early treatment arm based on rise in CA125: Second-line chemotherapy started a median of 4.8 months earlier Third-line chemotherapy started a median of 4.6 months earlier This early treatment did not improve overall survival HR=0.98;( 95% CI ); p=0.85 Absolute difference at 2 years 0.7% (95% CI 7.6, 4.5%) Early chemotherapy does not improve quality of life Role of surgical resection of recurrence still to be proven

21 Cervical Cancer Epidemiology Third most common cause of female mortality Incidence 13.2/ women/yr Europe Mortality 5.9/ /yr Incidence and mortality higher in developing countries (85% of cases, 90% of deaths) Aetiological factors Predisposing factors High risk (16/18) HPV persistent infection Early age first intercourse Early pregnancies Squamous 80% Adenocarcinoma 10-20%

22 Cervical Cancer HPV and cervical cancer Vaccination WHO recommendation: HPV immunization of girls at age 9-to-12 Bivalent or quadrivalent HPV vaccines against HPV16 and HPV18 can prevent 70% of cervical cancer Screening WHO recommendation: screening in woman 30 yrs with HPV tests and treat with criotherapy (or loop electrosurgical excision procedure)

Cancer of the cervix uteri FIGO staging (2009) Stage IA T1a FIGO Only

3 mm depth Stage IB T1b FIGO FIGO Clinical visible lesion IB1 4 cm greatest

up to 2/3 IIB obvious parametrial involvement Stage III T3 FIGO FIGO IIIA

23 Cancer of the cervix uteri FIGO staging (2009) Stage IA T1a FIGO Only histologically diagnosed IA1 stroma invasion 3 mm depth IA2 stroma invasion > 3 mm depth Stage IB T1b FIGO FIGO Clinical visible lesion IB1 4 cm greatest diameter IB1 > 4 cm greatest diameter Stage II T2 FIGO FIGO IIA Involvement up to 2/3 IIB obvious parametrial involvement Stage III T3 FIGO FIGO IIIA involvement of the lower vagina IIIB extension onto the pelvic sidewall, or hydronephrosis

24 Cancer of the cervix uteri FIGO staging (2009) Stage IV T4 IVA Spread to adjacent pelvic organs IVB Spread to distant organs Regional nodes

25 Cervical Cancer Staging Staging is determined at the time of the primary diagnosis and cannot be altered Clinical staging (FIGO) to select and evaluate therapy Pathological staging (TNM) to estimate prognosis and evaluate results

26 Cervical Cancer Diagnosis and biology Bimanual P/V examination, colposcopy, biopsy and/or endocervical currettage (ECC) MRI pelvis/abdomen CT (PET/CT if possible): local extension and nodal systemic metastases Chest x-ray if grossly invasive disease Cystoscopy, rectoscopy (IIB-IV) Prognostic factors: stage, > 4 cm tumor size, outer 1/3 stromal invasion, nodal involvement, limphovascular space invasion (LVS), histotype and differentiation.

27 Cervical Cancer Survival by FIGO stage

28 Cervical Cancer Treatment Stage Recomended Issue IA1 IA2 IB1, IIA Hysterectomy + PLND* if LVSI Hysterectomy Radical hysterectomy + PLND or EBRT Conservative surgery Complementary concurrent CT/RT if risk factors (LVSI, G 3, positive parametria, (I, A) positive resection margins, multiple nodes) IB2 Combination CT/RT with Cisplatin (I, A) IIB-IV Combination CT/RT** with cisplatin (I, B) *PLND: pelvic lymphadenectomy **RT: External beam radiotherapy (EBRT) + brachytherapy (BRT) ± lombo-aortic EBRT

29 Locally advanced cervical cancer 2/22/99: NCI issues clinical announcement on cervical cancer The results of 5 large studies have shown that women with invasive cervical cancer have better survival when they receive chemotherapy which includes the drug cisplatin along with radiation therapy.

30 Cervical Cancer Pending issues Adjuvant CT after combined CT/RT Optimal CT for combination with EBRT+BRT Neoadjuvant CT: EORTC (IB2-IIA-IIB) (NACT and surgery vs combination CT/RT)

31 Cervical Cancer Stage IVB Palliative systemic therapy Recurrence not suitable for local treatment (pelvic and extrapelvic) Chemotherapy CTplatinum based with PFS OS gr3 PLT (mos) (mos) (%) Topotecan Paclitaxel Gemcitabine Vinorelbine Targeted agents Cetuximab Bevacizumab Monk, JCO, 2009

32 Cervical Cancer GOG 240: Schema Carcinoma of the cervix Primary stage IVB Recurrent/persistent Measureable disease GOG PS 0 1 No prior chemotherapy for recurrence (N=452) Stratification factors: Stage IVB vs recurrent/persistent disease Performance status Prior cisplatin Rx as radiationsensitizer Activated: 4/6/09 Closed to accrual: 1/3/12 R A N D O M I Z E 1:1:1:1 I II III IV Paclitaxel 135 or 175 mg/m 2 IV Cisplatin 50 mg/m 2 IV Paclitaxel 135 or 175 mg/m 2 IV Cisplatin 50 mg/m 2 IV Bevacizumab 15 mg/kg IV Paclitaxel 175 mg/m 2 IV Topotecan 0.75 mg/m 2 d1-3 Paclitaxel 175 mg/m 2 IV Topotecan 0.75 mg/m 2 d1-3 Bevacizumab 15 mg/kg IV Chemo alone Q21d Rx to PD, toxicity, CR Chemo + Bev KS Tewari (study chair). Identifier: NCT Presented by: Krishnansu S. Tewari, MD, FACOG, FACS 32

33 Cervical Cancer GOG 240: Demographics & Baseline Characteristics Characteristic Chemo Alone (n=225), % Chemo + Bev (n=227), % Median age, years (range) 46 (20 83) 48 (22 85) Histology, % Squamous AdenoCa, unspec. Race, % White African American Asian Pacific Islander Stage of disease, % Recurrent Persistent Advanced Performance status, % 0 1 Prior platinum, % Pelvic disease, % Presented by: Krishnansu S. Tewari, MD, FACOG, FACS 33

34 Cervical Cancer GOG 240: OS for Chemo vs Chemo + Bev Proportion Surviving Chemotherapy (n=225) Events, n (%) 140 (62) Median OS, mos 13.3 Chemotherapy + Bev (n=227) 131 (58) 17.0 HR=0.71 (97% CI, ) P= Median follow-up 20.8 mos Months on Study Presented by: Krishnansu S. Tewari, MD, FACOG, FACS 34

35 Cervical Cancer GOG 240: Conclusions Bev + CT significantly improves OS in stage IVB, recurrent or persistent cervical carcinoma Nearly 4-month improvement in OS Increase in median PFS and ORR Cisplatin + paclitaxel arm is current standard of care and did not underperform Benefit seen even in irradiated pelvis Bev treatment is associated with a higher rate of AEs 3 8% rate of known bev-related AEs The improvement in OS with bev treatment was not accompanied by a decrease in HRQoL Presented by: Krishnansu S. Tewari, MD, FACOG, FACS 35

Treatment of recurrent disease Extrapelvic recurrence Pelvic recurrence Previous treatments Pts condition No previous radiation Options include: CT / RT NACT BSC Previous radiation

include: Resection of isolated disease BSC if surgery is not feasible: RT Recommended follow-up Every 3 months for two years or more often if clinically indicated.

36 Treatment of recurrent disease Extrapelvic recurrence Pelvic recurrence Previous treatments Pts condition No previous radiation Options include: CT / RT NACT BSC Previous radiation Central pelvic recurrence Options include Radical H (if tumor <2 cm) exenteration NACT + surgery Sidewall pelvic recurrence Site Systemic CT CT/RT Resection in selected cases Options include: Resection of isolated disease BSC if surgery is not feasible: RT Recommended follow-up Every 3 months for two years or more often if clinically indicated. Every 4-6 months thereafter. Annually afterwards. Investigations in addition to gynaecological examination should be performed depending on symptoms, local findings and general condition of the patient

37 Cervical Cancer Incurable recurrent disease Individualized treatment of symptoms Pelvic pain Neurological symptoms (pain, motor and/or sensitivity dysfunction) Ureteric obstruction with renal failure Hemorrhage, malodours discharge Lymphedema Fistula

38 Endometrial cancer Epidemiology The most common gy cancer in Western countries Incidence 13/ women/yr Europe Mortality 2-3/ women/yr 80-90% post menopausal; 5% in <40 yrs old Peak incidence 60 yrs Aetiological factors: unopposed / excessive oestrogen exposure Predisposing factors: nulliparity, early menarche/late menopause BMI>30, diabetes, hypertension treatment with tamoxifen Genetic susceptibility: Lynch type II syndrome (5%)

39 Endometrial cancer Pathology and biology Type I (70-80%)* Type II (10-20%) Histotype endometrioid adenoca. papillary serous; clear cell Precursor lesions atypical hyperplasia endometrial CIN Hormone sensitivity yes no Grading low high Initial stage early 70% advanced 60% Behaviour favourable aggressive Recurrence local abdominal, lymphatic Molecular alterations MSI with MMR defects (20%) PTEN deletion (80%) KRAS, βcatenin mut (40%) PI3K mut (39%) p53 mut (90%) HER2 overexpress. (45%) amplific. (20%) 5 yr survival 85% 43% * Include also: adenocantoma, adenosquamous, undiff., squamous, * mucinous Include a

40 Endometrial cancer Diagnosis Main symptom: post menopausal bleeding Bimanual P/V examination TVU: endometrial thickness, dilation and currettage Histeroscopy (gas): site, volume of tumor, cervical involvement, guided biopsy Staging MRI: depth myometrial invasion (M), cervical involvement MRI/CT: metastatic lymphnodes Surgical biopsy: grading, M

Cancer of corpus uteri FIGO staging (2009) Stage I Confined to

50% Stage II Invasion of cervical stroma Stage III Local

Invasion serosa uteri and/or adnexae IIIB Vagina and/or

41 Cancer of corpus uteri FIGO staging (2009) Stage I Confined to corpus FIGO IA FIGO IB Myometrium invasion IA no or < 50% IB > 50% Stage II Invasion of cervical stroma Stage III Local and/or regional spread of the tumor FIGO IIIB FIGO IIIA IIIA Invasion serosa uteri and/or adnexae IIIB Vagina and/or parametrial involvment IIIC Nodal involvement IIIC1 Pelvic IIIC2 Para-ortic

Cancer of the corpus uteri FIGO staging (2009) Stage IV Local and/or distant metastases IVA Invasion of bladder and/or bowel micosa IVB distant metastases (intraabdominal and/or inguinal

42 Cancer of the corpus uteri FIGO staging (2009) Stage IV Local and/or distant metastases IVA Invasion of bladder and/or bowel micosa IVB distant metastases (intraabdominal and/or inguinal nodes) Regional nodes Histopathologic criteria for high-risk Grade 3 histology Non endometrioid histology 50% myometrial invasion Limphovascular space invasion (LVSI) Stage I in 75% of patients

43 Endometrial cancer Prognosis FIGO Stage 5yr survival (%) IA 89.6 IB 77.6 IIIC1 57 IIIC2 49 Histological subtype Endometrioid 83 Clear-cell 62 Papillary 53

44 Endometrial cancer Treatment Surgery Stage Recommended Comments Laparoscopic/robotic surgery Comparable DFS/OS better short term outcome with lps I Pelvic lymphadenectomy (IAG3, IB) No evidence of benefit in DFS, OS (ASTEC) II Para aortic lymphadenectomy No randomized studies, prognostic not therapeutic I III IV TAHBSO Abdominal inspection/washing Issue Maximal surgical debulking Palliative hysterectomy

45 Endometrial cancer Treatment Adjuvant radiotherapy Background Two types of RT pelvic external beam radiotherapy (EBRT) for local/regional control VBT for vaginal vault control Risk factors for node invasion: stage, age, histotype, grade, M, LSVI Radiotherapy not indicated Grade 1-2 and < 50% myometrial invasion or only 1 risk factor VBT is indicated 2 risk factors EBRT and/or CT is indicated 3 risk factors, stages II and III

46 Endometrial cancer Treatment Adjuvant radiotherapy PORTEC 1 IB G2-3 (intermediate) IC G1-2 PORTEC 2 (high riskintermediate) IB IIA TAHBSO TAHBSO NAT vs EBRT EBRT vs VBT Locoregional recurrence 4% vs 14% (P <0.001) Survival 2% vs 5% 85% vs 80% 81% vs 85% Severe complications 3% GI at 5 yrs acute GI 54% vs 13% VBT is the treatment of choice for intermediate high risk patients

47 Endometrial cancer Treatment in highhigh-risk Adjuvant Concurrent CT CT--RT vs RT NSGO-9501/EORTC5591 I-IIA*; IIIC MANGO ILIADE Any histology PORTEC 3 IG3 II-III Serous / clear cell * risk factors: G3, >50% M ** CT: TP, AP, TEP, TAP before or after RT EBRT (VBT) + CT ** vs EBRT (± VBT) 5yr PFS 78% - 69% (p 0.009) OS 82%-75% (p 0.07) EBRT vs EBRT plus DDP TP x 4 ongoing

48 Endometrial cancer Treatment Advanced disease (stages IIIIII-IV) Individualized treatment Treatment Comments CT/surgery/RT CT For endometrioid stage III For non endometrioid stage III Observation IIIA only (cytology) CT TAP too toxic Carboplatin Paclitaxel Hormones Progestogens, AI Endometrioid histology only New agents mtor inhibitors PI3K inhibitors FGFR inhibitors

49 Endometrial cancer Conclusions Treatment outside outside clinical trials 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) Medical treatment TP standard regimen No indication for adjuvant CT but concurrent with EBRT Promising new molecule targeted agents

17 th ESO-ESMO Masterclass in clinical Oncology

17 th ESO-ESMO Masterclass in clinical Oncology Cervical and endometrial Cancer Cristiana Sessa IOSI Bellinzona, Switzerland Berlin, March 28 th, 2018 Presenter Disclosures None Cervical Cancer Estimated