Il parere dell esperto. Giovanni Scambia Polo Scienze della Salute della Donna e del Bambino

Transcription

1 Il parere dell esperto Giovanni Scambia Polo Scienze della Salute della Donna e del Bambino

2 Ovarian cancer in the Era of Personalized Medicine Tailored Surgery for Ovarian Cancer Cervical cancer

3 Menagin Ovarian Cancer in the Era of Personalized Oncology

4

5 OC is not one disease Outcome depends on histotype

6

7 PARP inhibitors in ovarian cancer: current status and future promise OLAPARIB (Lynparza ) FDA approved: mantainance therapy in platinum sensitive relapse high grade ovarian cancer + Deleterious BRCA mutation associated with advanced ovarian cancer EMA approved: mantainance therapy in BRCA + platinum sensitive relapse high grade ovarian cancer NIRAPARIB (Zejula ) FDA + EMA approved: mantainance therapy in platinum sensitive relapse high grade ovarian cancer RUCAPARIB (Rubraca ) FDA approved: Deleterious BRCA mutation associated with advanced ovarian cancer VELIPARIB TALAZOPARIB

8

9

10

11

12

13

14

15

16

17

18

19

20 Quality of Life?

21 ITEMS NACT RATIONALE in ONCOLOGY NACT in ADVANCED OVARIAN CANCER Clinical evidences supporting NACT Potential risks of NACT Catholic University management NACT PERSPECTIVES Tailored treatment

22 Neoadjuvant ChemoTherapy: PRINCIPLES COLO-RECTAL CANCER LUNG CANCER PROSTATE CANCER BREAST CANCER To shrink the tumor in patients who were not candidates for primary surgery, and to allow organ preservation reduction of mortality rate 1990s-2010s 1982 New strategy to increase resectability ( to downstage the patient) on head and neck cancer Cancer statistics, 2017

23 RESIDUAL DISEASE SURGICAL EFFORT NACT vs PDS: RCTs A.Fagotti et al. (EJC ) Single institution Phase III Randomised clinical trial 110 eligible women, 55 assigned to arm A (PDS) and 55 to arm B (NACT+IDS) PATIENTS SELECTION AEOC supposed resectable women with PI > 8 or < 12 Gynecologic Oncology (considered as HTL) were included 2 arms: A) PDS followed by systemic adjuvant chemotherapy ; B) NACT followed by IDS EARLY (<30days) COMPLICATIONS High and uniform SCS 2 Co-primary outcomes: post-operative complications Procedures endowed with high SCS (score =2-3) were & PFS required in 100% versus 48.1%, in PDSarm versus LATE 1-6 months from surgery) COMPLICATIONS NACT/IDS arm, respectively (p = ) - NACT /IDS is better than PDS in patients with HTL (PI >8 and < 12) in abdomen, as assessed by s-lps, in terms of perioperative morbidity - No differences in QoL measurements at the end of treatment between the 2 arms.

24 MIS approaches may be useful when evaluating whether maximum cytoreduction can be achieved in newly diagnosed and recurrent OC 109,122,123,135,136 Level of evidence: IIB

25 Variation in NACT at high volume hospitals Gynecologic Oncology pts with FIGO stage IIIC IV of OC. 78.4% received PDS, while 21.6% treated with NACT/IDS. Utilization of NACT to treat stage IIIC and IV OC varies widely among high volume hospitals. Receipt of care at a hospital with an average or high NACT use rate was associated with a decreased rate of death compared to care at a low utilization hospitals. All woman treated at 55 high volume hospitals (>20 cases/year), classified in: Low utilization of NACT (14) Average utilization of NACT (31) High utilization of NACT (10) It is plausible that low utilization of NACT is associated with increased suboptimal primary cytoreductive surgery rates and increased major postoperative complications with adjuvant treatment delays, both leading to decresed survival. Further research is needed.

26 Potential risks of NACT Annals of Surgical Oncology, 2013 NACT+IDS pts showed more frequently carcinomatosis, and platinum-resistant disease at recurrence compared with PDS Patients treated with NACT+IDS showed a shorter Post-Relapse survival compared with PDS (3-yrs PRS, PDS=58% vs NACT-IDS=18% ) NACT-IDS negatively influences the pattern and timing of recurrence, probably favoring the selection of chemoresistant clones

27 Potential risks of NACT Incorporation of Bevacizumab into upfront regimens prolongs PFI in AOC patients, but is associated with a more aggressive behaviour of recurrent disease: 1) Wider presentation of relapse ( p 0.035) 2) Lower percentage of patients suitable for SCS ( p 0.016) Gynecologic Oncology 3) Shorter TTP to second line chemotherapy in women with platinum-sensitive disease (p-value ( p-value 0.041)

28 CATHOLIC UNIVERSITY MANAGEMENT OF AOC OVARIAN CANCER SURGERY GUIDELINES ALGORITHM FOR EPITHELIAL OVARIAN CANCER SURGERY (2) - ASSESSMENT FORM - Vizzielli score S-LPS S-LPS Do you feel that this algorithm is clinically relevant? Do you feel that this algorithm is usable in your practice? Strongly disagree Indecision Strongly agr ò ò ò Open commentary - Elements supporting your position (e.g. clinical arguments, bibliographic data, etc.) MANDATORY if at least one score is < 7 (optional in other situations) Vizzielli score

29

30

31 31

32 MINIMALLY INVASIVE SURGERY after NACT Am J Obstet Gynecol 2016 Multicentric phase II Clinical Trial Of 184 advanced EOC patients considered eligible for IDS, finally 30 woman received the planned treatment of MI-IDS. Minimally Invasive-IDS in patients with clinically complete response to NACT seems to be feasible and safe in terms of perioperative outcomes, psycho-oncological impact, and survival rate. A high level of satisfaction was informally recorded for our patients, in line with the fact that a scarless surgery may help to avoid an unnecessary mark of a difficult history, and reduce postoperative pain.

33 MINIMALLY INVASIVE SURGERY after NACT Gyn Oncology Retrospective case-control study 30 AEOC pts treated with MI- IDS; 65 submitted to LPT-IDS Small sample size Short duration of median FU Women treated with MI-IDS showed a 6 months longer PFS compared to Controls Minimally invasive approach could represent an advantageous alternative surgical way to perform interval debulking surgery in this specific subset of patients. MIS is superior to standard laparotomy in terms of EBL, discharge time and TTC. MI approach determines a higher percentage of women with positive well-being compared to pts treated with the conventional approach. Retrospective cohort study pts with AOC, who underwent NACT and IDS 47.5% LPS vs 52.5% LPT Relatively short FU (3 ys) Lack of random allocation Inability to verify registry data No difference in survival between women who underwent laparoscopic IDS and those underwent laparotomy. Short postoperative hospitalization after laparoscopic surgery and no difference in risk of unplanned readmission or perioperative death. In well-selected pts, such as those who have a complete response to NACT, laparoscopic IDS may be a safe and effective alternative to laparotomy.

34 MOLECULAR CHARACTERIZATION FOR NACT Progression-free survival (%) AOC pts with BRCAmut are highly responsive to P-based chemotherapy, with also prolonged PFS after NACT, compared with BRCA naïve. Gorodnova TV, et al. Cancer Letter, 2015; Mahdi H, et al. Gynecol Oncol 2015 BRCAwt BRCAmut PDS p=0.05 PDS p=ns NACT NACT Median PFS Median PFS PDS NACT 26 months 18 months PDS NACT 28 months 24 months Submitted

35 Neoadjuvant ChemoTherapy: PRINCIPLES LUNG CANCER COLO-RECTAL CANCER LUNG CANCER COLO-RECTAL CANCER PROSTATE CANCER BREAST CANCER BREAST CANCER To shrink the tumor Ann Surg in Oncol patients (2012 who ) were not candidates for primary surgery, and to allow organ Achiving preservation a complete pathologic reduction response of seems mortality to correlate rate to the best prognosis ever achieved 2017 To test the activity of a therapeutic approach or the potential importance of biological factors in determining disease outcome 1990s-2010s J Clin Oncol 30: , New strategy to increase resectability ( to downstage the patient) on head and neck cancer Cancer statistics, 2017

36 Neoadjuvant ChemoTherapy: PERSPECTIVES AJOG (2014) OS PFS cpr is an uncommon event in AOC patients receiving NACT and is associated with a longer PFS and OS compared with women showing no cpr cpr, rather than only an estimation of disease extension after NACT, clearly emerges as a marker of extreme sensitivity to platinum-based chemotherapy. PATHOLOGICAL RESPONSE TO NACT cpr: cases with no residual neoplastic cells in all the surgical specimens, including the adnexa micropr: microscopic foci (maximum diameter 3 mm) macropr: persistent macroscopic site of disease after NACT

37 Neoadjuvant ChemoTherapy: PERSPECTIVES Olaparib with weekly JM8 and TAX as NACT in BRCA mut advanced HGSOC women: a PHASE II multicentric study PRIMARY AIM: Pathological complete response after 3 cycles of NACT including OLAPARIB and weekly JM8-TAX in BRCAmut advanced HGSOC SECONDARY AIMS: Complete cytoreduction rate at IDS, response rate (RECIST criteria), surgical assessment of response with a laparoscopic standardized score (Fagotti score), toxicity Profile, PFS,OS. BRCA1=27%

38 Catholic University Integrated Algorithm for Personalized Treatment in HGSOC Suspicious AEOC : GYO + imaging + S-LPS TUMOUR LOAD & peri-op risk LTL/ITL<8 Low peri-op risk 75% TISSUE ACQUISITION Histology & molecular analysis PDS HTL 8-12 High peri-op risk 20-25% Unresectable CHEMOSENSITIVE (High grade; BRCA mut; TGF-beta pathway) CHEMORESISTANT (LGSOC; mucinous; BRCA wt) <5% NACT with target treatment Discuss with the pt PDS or NACT Offer exp. treatment NACT

39 CONCLUSIONS... We are moving from generalized guidelines, where PDS is still against NACT, to tailored approaches where PDS and NACT are both first-line available treatments that we need to carefully choose for EACH patient DON T MAKE IT LOOK GOOD ON YOU BUT MAKE IT GOOD FOR YOU

40 KEY POINTS CARATTERIZZAZIONE MOLECOLARE CHIRURGIA TRATTAMENTO MEDICO where are we going?

41 News in cervical cancer? Unanswered questions Int J Gynecol Cancer Jan;26(1): Early stage and fertility sparing tratments Sentinel node Adjuvant treatment Local Adavenced disease (Prognostic groups) What is the appropriate endpoint? Should we do phase II or phase III studies? Proposed primary endpoints included overall survival (OS), progression free survival (PFS), and response rates (ORR). Secondary endpoints included PFS, quality of life (QOL), patient reported outcomes (PRO), and safety Neoadjuvant chemotherapy Metastatic cervical cancer Target Therapy

42

43 CTRT: CONSIDERED THE WORLD STANDARD TREATMENT for LACC Feb-1999: NCI issues clinical announcement on cervical cancer EXTERNAL BEAM pelvic radiation(40 to 60 Gy) BRACHYTHERAPY (8,000 to 8,500 cgy to Point A) I.V. CISPLATIN CHEMOTHERAPY Cisplatin 40mg/m2 (Max dose 70mg) IV q wk during RT (6wks) 1.reduction in risk of death (HR 0.69, 95% CI ) 2.reduction in risk of local recurrence (OR 0.59, 95% CI ) 3.trend in reduction of distant metastasis (OR 0.81, 95% CI )

44

45

46

47 OTHER OPTIONS Chemo/radiation Chemo/radiation followed by surgery Neoadjuvant chemotherapy followed by surgery followed by chemo/radiation

48 Trial closed for poor accrual No difference OS between surgery vs no surgery after CTRT This study failed to demonstrate that RH after EBRT-CT is superior to standard BCT

49 Accrual: 103 pts Eligibility Cervix carcinoma stage IB2-IVA Age<80y Adequate bone marrow function Adequate renal function Normal liver function T Clinical Response -CR 36 pt(34.9%) -PR 63 pt(61.2%) -SD 2 pt(1.9%) -PD 2 pt(1.9%) RT 39.6 GY(PELVIC LYMPH NODE DRAINAGE, BULKY TUMOR,PARAMETRIA) GY(PRIMARY TUMOR,PARAMETRIA) CT CISPLATIN 20 MG/M2 P1Q25+CAPECITABINE 1300 MG/M2 DAILY DFS 73% OS 86.1% 3 years TOXICITY -Leukopenia -Gastrointestinal -Genitourinary 19.4% G1 19.4% G2 32% G1 9.7% G2 11.6% G1 2.9% G2 RELAPSE 25 pt(24.3%) DEATH 10 pt(9.7%) RADICAL HYSYTER ECTOMY Ferrandina et al. Int J Radiat Oncol Biol Phys 2014

50 OTHER OPTIONS Chemo/radiation Chemo/radiation followed by surgery Neoadjuvant chemotherapy followed by surgery followed by chemo/radiation

51 NACT: AIMS DEBULKING EFFECT AND TUMOR SIZE REDUCTION IMPROVING SURGICAL OUTCOMES BETTER ACTIVITY AGAINST MICROMETASTASIS PERMIT CONSERVATIVE SURGERY LESS TOXICITY EASIER MANAGEMENT OF SALVAGE THERAPY

52 OTHER OPTIONS Chemo/radiation Chemo/radiation followed by surgery Chemo/radiation-chemotherapy Neoadjuvant chemotherapy followed by surgery followed by chemo/radiation

53

54 IB2 to III stages

55 NACT & RS vs RT 5 randomized trials 872 pts (97% of total) Stage: IB 35% II 38% III 26% Tierney et al. Eur J Cancer 2003

56 EORTC (started 1999!!!) INCLUSION CRITERIA FIGO IB2, IIA, IIB PS 0-2 Age Squamous Adenocarcinoma Adenosquamous STRATIFICATION FIGO Institution Age vs Histology: Squamous vs Adenocarcinoma vs Adenosquamous ENDPOINTS Primary: OS Secondary: PFS Toxicity QoL R A N D O M Cisplatin based chemotherapy: Min. total dose of 225 mg/mq 25 mg/mq per week Final dose no later than 8 week Chemo-radiotherapy CDDP 40 mg/mq (6 week) + EBRT Gy Radical hysterectomy

57

58 OTHER OPTIONS Chemo/radiation Chemo/radiation followed by surgery Chemo/radiation-chemotherapy Neoadjuvant chemotherapy followed by surgery followed by chemo/radiation

59

60 TREATMENTS IN LACC Chemo/radiation Chemo/radiation followed by surgery Neoadjuvant chemotherapy followed by chemo/radiation Neoadjuvant chemotherapy followed by surgery CHEMOTHERAPY IS MANDATORY! But how can we choose???

61 KEY QUESTIONS WHICH Platinum doublet? Carboplatin or cisplatin? Which role for TARGET THERAPY in CC?

62

63 +3,5 m +2,2 m

64 CECILIA (MO29594): trial design A MULTICENTRE OPEN-LABEL SINGLE-ARM PHASE II STUDY EVALUATING THE SAFETY AND EFFICACY OF Bevacizumab IN COMBINATION WITH CARBOPLATIN AND PACLITAXEL IN PATIENTS WITH METASTATIC, RECURRENT OR PERSISTENT CERVICAL CANCER Metastatic, recurrent or persistent cervical cancer patients not amenable to curative treatment with surgery and/or radiation therapy n=150 Carboplatin AUC5 q3w* Paclitaxel 175mg/m 2 q3w* Bevacizumab 15mg/kg q3w Until disease progression, unacceptable toxicity or withdrawal of consent AUC, area under the concentration curve; q3w, every 3 weeks *Minimum of 6 cycles, unless toxicity necessitates discontinuation of one or both chemotherapy agents, in which case non-implicated drug(s) and Bevacizumab can be continued alone MO29594 Adapted from

65 NINTENANIB Ongoing Trial: Phase II, randomized, double bind and placebo controlled trial Figo IVB/recurent disease Randomize Carboplatin AUC5 + Paclitaxel 175mg/m 2 + Nintenanib 200 mg Bid Weeks 1-6 Carboplatin AUC5 + Paclitaxel 175mg/m 2 + Placebo Bid Weeks 1-6 Nintenanib until progression Placebo until progression Primary End-point: PFS Secondary End-point: OS, Toxicity, Patient Health status

66 Advanced cervical carcinoma (FIGO stage IIB-IIIB or IB- IIA with pelvic node metastasis and/or tumour size 5 cm n=57 RT/BRT 45 Gy (over 5 ws in 25 once daily fractions) Bevacizumab 10 mg/kg Iv q2 weeks (days 1, 15 and 29, total 3 doses) during chemoradiation, before cisplatin and on the same day as cisplatin Phase II, single arm trial Primary endpoints: treatment-related serious adverse events rates and adverse events rates within the first 90 days Secondary endpoints: treatment-related serious adverse events rates and adverse events rates at any time, DFS, OS, angiogenic markers Schefter et al IJR Oncol Biol Phys. 2012,2014

67

68

69

70 The Catholic University GYO Network Dpt. Oncology Centre for Research, Campobasso Gyn Onc Unit University of Piemonte Orientale Novara Abano Terme Chieti Campobasso Gyn Onc Unit Miulli Hospital, Acquaviva delle Fonti Dpt. Ob/GYN Gemelli Hospital, Rome Palermo Acquaviva delle Fonti Gyn Onc Unit University of Chieti Gyn Onc Unit University of Palermo

71

72 Criteria for suboptimal debulking surgery in AOC SITE Essen criteria Leuven criteria Abdominal metastases Extra-abdominal metastases Pts characteristics Multiple parenchymatous liver metastases Infiltration of large parts of the pancreas (not only tail) and/or the duodenum Infiltration of the porta hepatis or truncus coeliacus Deep infiltration of the radix mesenterii Diffuse and confluent carcinomatosis of the stomach and/or small bowel Involvement of the SMA Not completely resectable metastases Poor PS-ECOG Intraephatic metastases Infiltration of the duodenum and/or pancreas and/or the large vessels of the porta hepatis or truncus coeliacus All, excluding: resectable inguinal lymph nodes, solitary retrocrual or paracardial nodes, Pleural fluid cytologically malignant cells without presence of pleural tumors Vergote I and Du Bois A, 2012

73 Sensitivity Sensitivity Predictive performances 5 of CT scan in AEOC PI Table 6 Performance of Approach A (Model 2) in defining the rate of patients unnecessarily explored or inappropriately unexplored PIV Unnecessarily explored (1 NPV) (%) Model 2 Inappropriately unexplored (1 PPV) (%) Ferrandina G, BJC, 2009 dings confirm previously reported results (Bristow et al, 2000; i et al, 2000; Cooper et al, 2002; Saygili et al, 2002; Memarzadeh al, 2003), and definitively recognise the extent of the impact yed by ECOG-PS in the preoperative prediction of ovarian cer primary resectability (Aletti et al, 2007). The models based diagnostic performance and on results from multivariate Borley J, BJOG, 2014 Model 3 Model Specificity ur e 2 Distribution of predictive index values (A) and ROC curves in Model 3 and Model 4. ish Journal of Cancer (2009) 101(7), AUC3= 0.78 AUC4= Suidan RS, Gyn Onc, 2014 analysis showed the same accuracy in predicting the chance of optimal cytoreduction, although they included slightly different CT-based features; in particular, involvement of bowel mesentery, AUC= omentum, liver, and diaphragm were shown to fulfil all the required criteria (Bristow 0.0 et 0.2al, 2000) 0.4in Approach 0.6 A, 0.8 whereas 1.0 in multivariate analysis the involvement 1-Specificity of peritoneum and suprarenal aortic lymph nodes, besides bowel/mesentery and diaphragm disease, were independently associated with suboptimal cytoreduction. The divergence between the two approaches remains Ferrandina (model B) AUC difficult to explain, although the strict and, to a certain extent, unpredictable associations among the variables might more likely have an impact on multivariate analysis. In any case, 0.82 our findings support the relevance of the assessment of the status of bowel mesentery and diaphragm Reader involvement, 1 recognised 0.55 among the most important features determining the feasibility of ovarian Reader Reader & 2009 Cancer Research UK Rutten IJGC, IJGC, 2016

74 ITEMS NACT RATIONALE in ONCOLOGY NACT in ADVANCED OVARIAN CANCER Clinical evidences supporting NACT Potential risks of NACT Catholic University management NACT PERSPECTIVES Tailored treatment

75 NACT vs PDS: RCTs Multicentric RCT (87 hospitals in the UK and New Zealand) 550 women with FIGO stage III or IV of OC randomized 276 PDS vs 274 NACT/IDS Median FU: 52m CHORUS TRIAL Kehoe et al, Lancet 2015 EORTC TRIAL Vergote et al, NEJM, 2010 Multicentric RCT (59 institutions) 718 pts enrolled, 670 women with biopsyproven FIGO stage IIIC or IV OC randomized 336 PDS vs 334 NACT/IDS Median FU: 55m mos = 30 m (IDS) vs 29 m (PDS) Although these trials show non inferior results of NACT with lower morbidity, they have not neglegible bias in terms of PATIENTS SELECTION and SURGICAL EFFORT mos= 24,6m (IDS) vs 22,6 m (PDS) PFS = 12m (IDS) vs 10,7 m (PDS) Selection bias in recruitment of patiens believed to be inoperable with high tumor load (Fotopolou at al. JCO-2017) Low survival rates due to: 1) patients selection; 2) surgery was substandard compared with that in other trials; (S.Chi at al. is the easy way ever the better way? JCO- 2011)

76 ITEMS NACT RATIONALE in ONCOLOGY NACT in ADVANCED OVARIAN CANCER Clinical evidences supporting NACT Potential risks of NACT Catholic University management NACT PERSPECTIVES Tailored treatment