Jinekolojik Tümörler. Dr. Cem Önal Başkent Üniversitesi Tıp Fakültesi Radyasyon Onkolojisi AD

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1 Jinekolojik Tümörler Dr. Cem Önal Başkent Üniversitesi Tıp Fakültesi Radyasyon Onkolojisi AD

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3 Konu başlıkları Serviks kanseri Eş zamanlı KRT alan hastalarda kemik iliği koruyucu IMRT Postoperatif RT alan hastalarda vajen dozunun geç toksisite ile ilikisi IMRT uygulamasında CTV tanımında konsensus Serviks kanserinde NLR/PLR nin prognostik önemi Endometrium kanseri Postop cisp+bev+imrt carbo+paklitaksel faz II çalışma

5 Phase II Multi-Center Clinical Trial of Bone Marrow-Sparing Intensity Modulated Radiation Therapy with Concurrent Cisplatin for Stage IB-IVA Cervical Cancer Department of Radiation Medicine and Applied Sciences University of California, San Diego Loren K. Mell, M.D.

6 Toksisite Hematolojik toksisite KRT uygulunmasını etkileyebilir IMRT nin katkısı?? Teknik değişiklikleri Organ ve hedef hareketleri Kompleks yöntem Maliyet Katkı tam değil

7 Study Aims & Design Single-Arm Multi-Center Phase II Clinical Trial Primary Endpoint: Acute Clinically Significant Grade 2 GI Toxicity (Diphenoxylate/Atropine) Grade 3 Neutropenia Secondary Endpoint: Determine optimal bone marrow sparing technique

8 18FLT-PET for Functional Bone Marrow Imaging Otosegmentasyon Compare IG-BMS-IMRT vs. CT-based BMS-IMRT Quantify Outcomes, Late Toxicity, QOL (EORTC) Test Feasibility and Plan Quality

9 Aim Goal: Determine if signal to advance to Phase III N = 83 Patients 90% Power, Type I error = 5% H 0 : p=40% vs. 1-tailed H A : p < 40% NCI Quick Trial (R21) Registered with ClinicalTrials.Gov (NCT )

10 Methods Stage IB-IVA cervical cancer, postop (13%) or intact (87%) Pelvic RT Gy / fractions SIB to gross nodes Gy allowed Cisplatin 40 mg/m 2 weekly x 5 cycles no adj ChT Brachy: Gy in 4-5 fractions w/hdr Daily kv/kv and/or CBCT Toxicity Measured from baseline to 1 mo. post ChemoRT

11 Treatment Details & Compliance 74% -- Had PET/CT and/or MRI 42% -- IG-BMS-IMRT 58% -- CT-based BMS-IMRT 82% -- Received All 5 cycles of Cisplatin 98% -- Completed all treatment Median duration of chemort = 50 days (~7 weeks)

12 Results (vs. Published Data) P=0.012* P<0.001* P=0.27

13 Results - CT-BMS-IMRT vs. IG-BMS-IMRT P=0.25 P=0.035*

14 Dosimetric comparison Pelvic Bone Marrow Bowel CT-BMS-IMRT IG-BMS-IMRT IG-BMS- IMRT V10 V20 V30 Mean V40 CT-BMS-IMRT IG-BMS-IMRT 0 CT-BMS-IMRT V30 CT-BMS-IMRT IG-BMS-IMRT V45 Cumulative Late Grade 3 Toxicity: 7.6%

15 Outcomes PROGRESSION-FREE SURVIVAL OVERALL SURVIVAL 2-Year PFS: 78.6% 2-Year OS: 90.8%

16 Outcomes Median Follow-Up: 26.0 months LOCOREGIONAL FAILURE DISTANT FAILURE 2-Year LRF: 9.5% 2-Year DF: 12.4%

17 Conclusions/Comments Acute toxicity (Mainly GI) reduced relative to reports from trials using standard techniques IG-BMS-IMRT may be new indication for IMRT Phase III INTERTECC Trial (IG-BMS-IMRT vs. non-marrow sparing RT w/concurrent cisplatin x 6 cycles) NRG-GY006 Trial (RT/cis vs. RT/cis/triapine, IG-BMS-IMRT optional with credentialing) will help assess feasability.

18 Liang Y et al., IJROBP, 85 (2), , 2013

21 McGuire SM et al., IJROBP, 96 (1), , 2016

22 4 6 Gy McGuire SM et al., IJROBP, 96 (1), , 2016

24 Impact of cumulative radiation doses to vagina on late toxicity and sexual quality of life in patients treated with post-operative adjuvant radiation therapy for cervical cancer Roshni Singh, Supriya Chopra, Reena Engineer, Sadhana Kannan, Siji Paul, Sarthak Mohanty, Jamema Swamidas, Umesh Mahantshetty, Jaya Ghosh, Amita Maheshwari, Rajendra Kerkar, Sudeep Gupta, Shyam Shrivastava Advanced Centre for Treatment Research and Education in Cancer (ACTREC) Tata Memorial Centre, Mumbai, India

25 Background Radical or adjuvant RT associated with late vaginal morbidity Significant impact on sexual quality of life Till date 3 studies (EMBRACE and PGI, India) have reported on vaginal dose correlation with late toxicity Heterogeneous: Vaginal dose points and results Dose Effect Relationship confounded Presence of residual disease Irregular interfraction vaginal packing Varying interfraction dose gradients to vaginal walls

26 Aims Hypothesis There is dose effect relationship for late vaginal morbidity Primary To investigate relationship of dose with clinically significant vaginal morbidity (vaginal shortening and telangiectasia) Secondary To evaluate the impact of vaginal toxicity on sexual quality of life no residual disease and uniform dose postop pelvic RT+ cylinder Brachy

27 Methods Jan, Dec,2014 Age > 18 years, Histologically proven cases of cervical cancer Recruited on ongoing postoperative trials and consent for vaginal photography Patients treated with EBRT and Vaginal BT +/- concurrent chemotherapy

28 Methods Estimation of Vaginal EBRT and BT Dose to Predefined Dose Points and Corresponding EQD2 (Gy 3 ) Grading of Vaginal Stenosis in Reference to Baseline and Telangiectasia + Sexual Quality of Life ROC Analysis: Highest Specificity for Vaginal Morbidity Univariate and Multivariate Analysis Correlation of Toxicity with Sexual QOL

29 Baseline Vaginal Length and Diameter Vaginal Length Vaginal diameter Vaginal Length Baseline Vaginal Length - Slice thickness x No of slices from vault to introitus Baseline Vaginal Diameter - Distance between the lateral cylinder surfaces

30 Definition of Vaginal Dose Points Vaginal Surface Dose 5mm from vaginal surface 5mm from vaginal surface 2cm 5mm from vaginal surface Vaginal Apex At 2cm from apex Circumferential and Longitudinal Vaginal Dose Points 4 dose points at vaginal apex, 2 cm, 4 cm from apex. 4 dose points at 5 mm depth at vaginal apex, 2 cm and 4 cm from apex.

31 Vaginal Morbidity Grade I Grade II Grade III Vaginal Stenosis (More than 25% or Less than 25%): Telangiectasia (CTCAE Version 3:0; Yes or No)

32 Results Total patient 92 Follow up (months) 36 (18-60) Age (year) 49 (32-71) Type III Hysterectomy CTRT 35% 88% Mean Length Shortening 19% (0-60%) Vaginal Shortening 25% 40% Telangiectasia (Total/Grade I/II/III) 77% 30%/28%/20% Vaginal Apex Surface Dose (V s ) (Apical Surface Dose Point) Vaginal apex dose at 5mm from surface (Apical Rectovaginal Dose Point, V 5mm ) Gy 3 ( ) 87.6 Gy 3 ( ) (95.7Gy 10 ) (75.2Gy 10 ) ROC Analysis V s 142 Gy 3 RV (V 5 mm ) 88 Gy 3

33 Prognostic factors Univariate analyses: Stenosis Vaginal surface dose 142Gy 3 (p=0.004) Dose received at 5mm from surface of apex (recto-vaginal point) 88 Gy 3 (p=0.04) Multivariate analysis: Stenosis Vaginal surface dose 142Gy 3 (p=0.004) No Dose Effect Relationship for Telangiectasia

34 Dose Volume Correlation 27 out of 92 patients- vaginal apex dose 142Gy 3 Volume of vagina receiving greater than 142Gy 3 determined Mean volume - 3.2cc (range cc) No correlation between Dose and Volume

35 Proba bility of >25% va ginal stenosis Predictive Probability of Vaginal Stenosis Dose_5mm Recto-vaginal Point Dose (Apex) EQD2 Gy 3 Pr(toxicity) plb pub Incremental Probablity of 5% with every 10 Gyincrease in RV dose from Gy

36 Sexual Quality of Life Improvement in vaginal function was significant at 1 year compared to 6 months (p=0.04) Significant increase in worry that sex would be painful (p=0.02) No correlation between vaginal length shortening and sexual QOL

37 Conclusions Doses received at vaginal apical surface and surrogate RV point independently predict for vaginal stenosis No dose relationship for telangiectasia No volume effect for stenosis or telangiectasia No dose correlation between vaginal toxicity and sexual quality of life

38 Vajinal doz tanımı??? Westerveld H et al., Radiotherapy and Oncology 107 (2013)

42 Computed Tomography and MRI Consensus CTV Contouring for IMRT in Intact Cervical Carcinoma Yashar C, Petersen I, Bosch W, Albuquerque K, Beriwal S, Chino J, Erickson B, Feddock J, Gaffney D, Iyer, R, Kamrava M, Klopp A, Kunos C, Mayadev J, Mell L, Portelance L, Viswanathan A, Wolfson A, Jhingran A Catheryn Yashar MD, FACRO University of California San Diego cyashar@ucsd.edu

43 Purpose Target definition is crucial for treatment with IMRT. Consensus CTV guidelines have been published for MRI (Lim K IJROBP 79:2011) MRI is not as available as CT in some locations and image fusion carries inherent uncertainties and if not done with the same bladder/bowel filling can be difficult This study evaluated the variability in CTV definition amongst physicians experienced in IMRT for the definitive treatment of cervical cancer for both CT and MRI

44 Methods Contours were done by a consensus work group (n=17) experienced in IMRT and gynecologic radiation therapy Two cases (early and locoregionally advanced) were chosen that had both CT and MRI images Initial contouring was done on CT, blind to the MRI The contouring was then repeated on MRI Contours included a CTV1 uterus and cervix and CTV2 parametrial and vagina Nodal contours were excluded as consensus guidelines exist for nodal volumes

45 Methods CTV contours were analyzed for consistency and clarity of target delineation on both the CT and MRI using an expectation-maximization algorithm for simultaneous truth and performance level estimation (STAPLE, CERR) Value Level of Agreement -1 <= Kappa <= 0 Poor 0 < Kappa <= 0.2 Slight 0.2 < Kappa <= 0.4 Fair 0.4 < Kappa <= 0.6 Moderate 0.6 < Kappa <= 0.8 Substantial 0.8 < Kappa <= 1 Almost Perfect

46 Case 1 IB2 all contours - CT CTV almost perfect CTV moderate 40 yo with Stage IB2 cervical carcinoma

47 CT Case 1 IB2 95% consensus

48 Case 1 IB2 all contours - MRI CTV almost perfect CTV moderate

49 MRI Case 1 95% consensus contour

50 Case 2 IIIB all contours - CT CTV almost perfect CTV substantial 36 yo with Stage IIIB disease. The tumor was 5-6cm with right pelvic wall involvement

51 CT Case 2 IIIB 95% consensus

52 MRI Case 2 - IIIB CTV almost perfect CTV substantial

53 MRI Case 2 95% consensus contour

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55 Vaginal variability Case 1 IB2 Case 2 - IIIB

56 CT vs MRI Case CTV Structure CT volume (cc) MR volume (cc) Intersection (CT,MR) (cc) Dice Coefficient (CT,MR) 1 Uterus + Cervix Vagina + Parametria Uterus + Cervix Rectum and bladder filling 2 Vagina + Parametria Case 1 - Volumes of CT and MR structures are comparable Case 2 Uterus/Cervix, which is much larger in CT than the MR

57 CT vs MRI Case 1 - IB2 Case 2- IIIB CTV1 CTV2 CTV1 CTV2 Kappa CT Kappa MRI

58 Conclusions Data suggests that the measure of agreement between observers has improved with experience Measure of agreement near perfect for uterus and cervix in both MRI and CT Measure of agreement substantial for parametria in MRI and moderate on CT The largest differences were the amount of vagina included in the CTV and the amount of perirectal tissue included

59 Interobserver variability Eminowicz GE et al., Radiotherapy and Oncology 117 (2015)

60 Daha iyi delineasyon Fonksiyonel görüntüler PET-BT, DW-MRI, perfüzyon MR Kılavuz ve atlas Eğitim

61 MR > JM > BT Mitchell DG et al., J Clin Oncol 24: , 2006

62 Han K et al., Radiotherapy and Oncology 120 (2016)

63 Eminowicz G et al., Practical Radiation Oncology (2016) 6, e203-e213

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67 Updated 4-Year Results For NRG Oncology/RTOG 0921: A Phase II Study Of Postoperative Intensity Modulated Radiation Therapy With Concurrent Cisplatin And Bevacizumab Followed By Carboplatin And Paclitaxel For Patients With Endometrial Cancer Akila N. Viswanathan, MD, MPH, Kathryn Winter, MS, Brigitte E. Miller, MD, Ying Xiao, PhD, Anuja Jhingran, MD, Lorraine Portelance, MD, Walter Bosch, DSc, Ursula Matulonis, MD, Neil Horowitz, MD, Robert S. Mannel, MD, Luis Souhami, MD, Beth Erickson, MD, William Small, Jr., MD, David Gaffney, MD, PhD ASTRO September 25, 2016

68 Concurrent chemoradiation in uterine cancer Phase II: RTOG 9708, St I IVA, concurrent cisplatin with RT followed by carboplatin/taxol* Phase III (accrued, in follow up): NRG/GOG 258 (n=810): Stage III-IV uterine cancer concurrent cisplatin with RT (3D conformal) followed by carboplatin/paclitaxel x 4 cycles vs. Carbo/Taxol alone x 6 cycles PORTEC 3 (n=686): Phase III clinical trial in Stage III-IV uterine cancer concurrent cisplatin with RT (3D conformal) followed by carboplatin/paclitaxel x 4 cycles vs. Carbo/Taxol alone x 6 cycles

69 RTOG Phase II Uterine Ca Clinical Trial PELVIC IMRT (45 Gy/25 fx) with OPTIONAL BOOST + CONCURRENT CISPLATIN (50 mg/m 2, d1 and d29) BEVACIZUMAB (5mg/kg, d1, d15 and d29) ADJUVANT CARBOPLATIN (AUC 5, every 21 days x 4) PACLITAXEL (135 mg/m 2, every 21 days x 4)

70 RTOG Eligibility Patients had a hysterectomy and 1 of the following highrisk factors: Grade 3 carcinoma with >50% myometrial invasion Grade 2 or 3 disease with any cervical stromal invasion Known extrauterine extension confined to the pelvis

71 RTOG Goals To report 4-year outcome results including late adverse events (AEs) >1 year from treatment start overall survival (OS), para-aortic failure (PaF), distant failure (DF), and diseasefree survival (DFS) To evaluate results relative to RTOG 9708 Survival, with the addition of bevacizumab Toxicity, with the use of IMRT

72 RTOG Patient and Tumor Characteristics

73 RTOG Toxicities With a median follow up of 3.92 years (min-max: ), 5 patients with reported grade 3 or 4 AEs > 1 year from treatment start: grade 3 diarrhea/ vomiting/low lymphocyte count/dyspnea/ acute kidney injury grade 3 hematuria grade 3 vaginismus grade 3 skin/pelvic infection grade 4 low lymphocyte/neutrophil count

74 RTOG 0921 and 9708

75 Outcome Results: RTOG 0921 and 9708

76 RTOG Conclusions The addition of bevacizumab did not increase long-term toxicities High overall survival rates with no pelvic recurrences at 4 years Sadece vajen cuff BRT??

78 Prognostic utility of pretreatment hematologic parameters in patients receiving definitive chemoradiotherapy for cervical cancer Cem Onal, Ozan C. Guler, Berna A. Yildirim Baskent University, Adana Dr Turgut Noyan Research and Treatment Center Department of Radiation Oncology Adana, TURKIYE

79 Introduction Inflammation is critical in cancer initiation and development. Tumor progression and metastasis interactive cascades involving tumor and the host-derived stromal microenvironment inflammation and angiogenesis. The prognostic use of systemic inflammatory markers, neutrophil-to-lymphocyte ratio (NLR) and platelet-tolymphocyte ratio (PLR) recently demonstrated in other malignancies, has yet to be shown in cervical cancer.

80 Purpose Inflammatory cells are capable of triggering proliferative signals inducing resistance to apoptosis continuing DNA mutations Platelets tumor angiogenesis via release of vascular endothelial growth factor and other proangiogenic factors, including urokinase plasminogen activator Neutrophilia confer an environment favorable for development and progression of tumors. Circulating tumor cells may activate encountered platelets generating microplatelets that promote tumor invasion.

81 Materials and methods Electronically stored clinical data cervical cancer patients treated at the Department of Radiation Oncology, Baskent University School of Medicine between October 2006 and September 2014 were retrospectively reviewed Of the 276 study candidates initially identified, 24 patients concurrent infectious disease 17 patients lacked complete blood cell counts before treatment 235 patients qualified for analysis

82 Materials and methods All patients received ChT concurrently with RT for a median of 6 cycles (range, 1-6) At least 4 cycles of concurrent ChT were completed in 88% of patients. External RT 50.4 Gy (range, Gy) BRT doses 28 Gy (range, Gy). Characteristics Number of patients Percentage Age, median (range), yrs 57 (21 86) Tumor size (mean±sd), 5.4±1.9 cm Histopathology SCC Adenocarcinoma 17 7 Stage IB IIA 9 4 IIB IIIA 17 7 IIIB IVA 10 4 Pelvic lymph node metastasis None Pelvic Pelvic + para-aortic 35 15

83 Materials and methods Median NLR = 3.03 (range, ) 118 patients (50.2%) low NLR 117 patients (49.8%) high NLR Median PLR = (range, ) 114 patients (48.5%) low PLR 121 patients (51.5%) high PLR Cut-off values redefined using ROC analysis

84 Results - NLR Variables NLR < 3.03 NLR 3.03 p n (%) n (%) Age (median±sd, years) 58.5± ± Pathology SCC 112 (51.4) 106 (48.6) 0.15 Adenocarcinoma 6 (35.3) 11 (64.7) FIGO Stage < IIB 17 (54.8) 14 (45.2) 0.36 IIB 101 (49.5) 103 (50.5) Tumor size < 4 cm 99 (58.2) 71 (41.8) < cm 18 (27.7) 47 (72.3) Lymph node metastasis Absent 68 (59.6) 46 (40.4) Present 49 (40.5) 72 (59.5) Treatment response CR 95 (70.4) 40 (29.6) <0.001 Non-CR 23 (23.0) 77 (77.0) p< ± ± ±2.85

85 Results - PLR Variables PLR < PLR p n (%) n (%) Age (median±sd, years) 59.1± ± Pathology SCC 108 (49.5) 110 (50.5) 0.19 Adenocarcinoma 6 (35.3) 11 (64.7) FIGO Stage < IIB 19 (61.3) 12 (38.7) 0.09 IIB 95 (46.6) 109 (53.4) Tumor size < 4 cm 102 (60.0) 68 (40.0) < cm 19 (29.2) 46 (70.8) Lymph node metastasis Absent 70 (57.9) 51 (42.1) Present 44 (38.6) 70 (61.4) Treatment response CR 86 (63.7.4) 49 (36.3) <0.001 Non-CR 28 (28.0) 72 (72.0) P= ± ± ±108.26

86 Results Univariate analysis Univariate analysis OS NLR (p<0.001) PLR (p<0.001) FIGO stage (p=0.002) Tumor size (p=0.004) Lymph node metastasis (p=0.001) Univariate analysis PFS NLR (p<0.001) PLR (p<0.001) FIGO stage (p = 0.004) Tumor size (p = 0.001) Lymph node metastasis (p=0.001)

87 Results Multivariate analysis Variables Risk factors HR (95%CI) p Overall survival Age ( ) 0.02 Stage <IIB vs. IIB ( ) 0.06 Tumor size <4 cm vs. 4 cm ( ) 0.43 Lymph node metastasis negative vs. positive ( ) <0.001 Pretreatment NLR <3.03 vs ( ) <0.001 Pretreatment PLR < vs ( ) 0.78 Progression-free survival Age ( ) 0.05 Stage <IIB vs. IIB ( ) 0.07 Tumor size <4 cm vs. 4 cm ( ) 0.35 Lymph node metastasis negative vs. positive ( ) <0.001 Pretreatment NLR <3.03 vs ( ) <0.001 Pretreatment PLR < vs ( ) 0.97

88 Results NLR Cut point = 3.11 AUC = 0.796; 95% CI, ; p< 0.001) Sensitivity 73.0% and specificity 73.3%. PLR Cut point = AUC = 0.727; 95% CI, ; p<0.001) Sensitivity 66.0% and specificity 65.2%.

89 Discussion

90 Limitations Retrospective study CRP level (as an inflammatory marker) were not routinely done. HPV screening not routine Impact on the prognosis of cervical cancer could not be assessed. The immune status of these patients may differ in the presence or absence of HPV. Median NLR and PLR cut points were preferred Definitive cut points were not set.

91 Conclusion Pretreatment NLR and PLR were associated with pathologic characteristics. High NLR and PLR is linked with larger tumors, lymph node metastasis, and poorer therapeutic response. NLR reflects a balance in host antitumor immunity Pretreatment NLR and lymph node metastasis proved independently predictive of both OS and PFS.

92 Conclusion NLR may be a suitable biomarker, serving to guide systemic therapy and predict patient outcomes. The patients with elevated NLR and lymph node metastasis had higher risk of disease recurrence with worse survival, warranting additional adjuvant treatment strategies.

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96 Eve giderken...

97 Konu başlıkları Serviks kanseri GIS tokisitesini yok Faz III çalışma Özellikle Eş zamanlı KRT alanazaltmakta, hastalardahematolojik kemik iliğitoksisiteye koruyucuetkisi IMRT Postoperatif alan stenoz hastalarda vajen dozunun geç toksisite ilevar ilikisi SadeceRT vajinal ile vajen apeks dozu arasında korelasyon IMRT uygulamasında CTV tanımında konsensus Deneyim ile fark azalmakta, BT ile MR da konsensu mevcut, PRM MR üstün Serviks kanserinde prognostik NLRNLR/PLR yüksekliğinin kötü prognoz önemi immüm yanıt Endometrium kanseri riskli hastalara IMRT ile zamanlı cisp+bev carbo Yüksek Postop cisp+bev+imrt eşcarbo+paklitaksel faz +IIpaklitaksel çalışma ile toksisitede artış olmadan yüksek sağkalım ve çok iyi lokal kontrol

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