Radiotherapy of Gynecological Malignancies

Transcription

1 Radiotherapy of Gynecological Malignancies Felipe A. Calvo Hospital General Universitario Gregorio Marañon Madrid, Spain ESO-ESMO Latin-American Masterclass Bogotá, Colombia April 2016

2 Radiotherapy of Gynecological Malignancies Cervix Endometrial Vaginal Vulvar A rare disease in Europe 2

3 Global Disease Over 500,000 cases worldwide 3 rd most common cause cause of yr new invasive cx ca in US Age-Standardized Incidence Rates of CervicalCancer per 100,000

4 79 squamous cell 24 adenoca From Mexico, Norway, US Nature Epub 25Dec 2013

5 HPV 18 greatest benefit from Ch-RT 327 patients St IIB-IVA CCRT DSS most In +HPV 18 and 58 HPV 18 HPV 58 HPV 16 HPV 33 Wang et al.ijrobp84(4): , 2012

6 Cervical Cancer NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines ) Version NCCN.org Continue Version ,11/25/15 National Comprehensive CancerNetwork,Inc. 2015, All rights reserved.the NCCN Guidelines and this illus tration may not be reproduced in anyform withoutthe ex press written permission of NCCN.

7 Printed by Eduardo Alvarado on 4/21/2016 9:46:08 AM. For personal use only. Not approved for distribution. Copyright 2016 National Comprehensive Cancer Network, Inc., All Rights Reserved. NCCN Guidelines Version Cervical Cancer NCCN Guidelines Index Cervical Cancer TOC Discussion CLINICAL STAGE BIOPSY RESULTS PRIMARY TREATMENT (NON-FERTILITY SPARING) Stage IA1 (no LVSI) Cone biopsy f Negative margins and inoperable Negative margins and operable Observe Extrafascial hysterectomy h See Surveillance (CERV-10) Positive margins for dysplasia or carcinoma Extrafascial or modified radical hysterectomy + pelvic lymph node dissection if margins positive for carcinoma h (category 2B for node dissection) (Consider SLN mapping [category 2B]) h or Consider repeat cone biopsy f to better evaluate depth of invasion See Surgical Findings (CERV-5) Stage IA1 (with LVSI) and Stage IA2 Modified radical hysterectomy + pelvic lymph node dissection h ± para-aortic lymph node sampling (category 2B) (Consider SLN mapping [category 2B]) h or Pelvic RT j,k + brachytherapy l,m See Surgical Findings (CERV-5) See Surveillance (CERV-10) f Cold knife conization (CKC) is the preferred method of diagnostic excision, but loop electrosurgical excision procedure (LEEP) is acceptable, provided adequate margins and proper orientation are obtained. h See Principles of Evaluation and Surgical Staging (CERV-A). j Radiation can be an option for medically inoperable patients or those who refuse surgery. ksee Principles of Radiation Therapy for Cervical Cancer (CERV-B). l These doses are recommended for most patients based on summation of conventional external-beam fractionation and low-dose rate (40 70 cgy/h) brachytherapy equivalents. Modify treatment based on normal tissue tolerance, fractionation, and size of target volume. (See Discussion) m The traditional dose would be Gy to total point A dose. Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged. Version ,11/25/15 National Comprehensive CancerNetwork,Inc. 2015, All rights reserved.the NCCN Guidelines and this illus tration may not be reproduced in anyform withoutthe ex press written permission of NCCN. CERV-3

8 Histology: Adeno vs. Squamous 1671 patients from 5 GOG prospective trials 11% had adeno- or adenosquamous histology Adenocarcinomas were more likely to be stage IB2 (27.5% vs 20.0%) and fewer were stage IIIB (21.4% vs 28.6%) Squamous carcinomas were larger, more poorly differentiated (46.2% vs 26.8%) RT Alone ChemoRT Gynecol Oncol. 2014;135:208 p=0.0499

9 FIGO Staging System Studies permitted by FIGO for staging: EUA, colposcopy, endocervical curettage, hysteroscopy, cystoscopy, proctoscopy, IVP, CXR, skeletalx-ray Studies not permitted but often obtained in the U.S.: CT, MRI pelvis If there is disagreement aboutparametrial invasion, the earlier stage should be chosen. No LN includedin FIGO staging

10 Nomograms for Cervical Cancer Histology, Ethnicity, PS, Tumor Size, Stage, Grade, Pelvic Nodes, Treatment Progression-Free Survival Overall Survival J Clin Oncol. 2015;33:2136 Stage IIA/IIB overlap PFS; IB/IIAin OS

11 Printed by Eduardo Alvarado on 4/21/2016 9:46:08 AM. For personal use only. Not approved for distribution. Copyright 2016 National Comprehensive Cancer Network, Inc., All Rights Reserved. NCCN Guidelines Version Cervical Cancer NCCN Guidelines Index Cervical Cancer TOC Discussion CLINICAL STAGE Stage IB1 and Stage IIA1 Stage IB2 and Stage IIA2 (also see CERV-6 for alternative recommendations for these patients) PRIMARY TREATMENT (NON-FERTILITY SPARING) Radical hysterectomy + pelvic lymph node dissection h (category 1) ± para-aortic lymph node sampling (category 2B) (Consider SLN mapping [category 2B]) h,i or Pelvic RT j,k + brachytherapy (total point A dose: Gy) l ± concurrent cisplatin-containing chemotherapy n Definitive pelvic RT k + concurrent cisplatin-containing chemotherapy n + brachytherapy (total point A dose 85 Gy) l (category 1 for primary chemoradiation) or Radical hysterectomy + pelvic lymph node dissection h ± para-aortic lymph node sampling (category 2B) or Pelvic RT k + concurrent cisplatin-containing chemotherapy n + brachytherapy l,o + adjuvant hysterectomy p (category 3) See Surgical Findings (CERV-5) See Surveillance (CERV-10) See Surveillance (CERV-10) See Surgical Findings (CERV-5) See Surveillance (CERV-10) h See Principles of Evaluation and Surgical Staging (CERV-A). i For SLN mapping (category 2B), the best detection rates and mapping results are in tumors <2 cm. j Radiation can be an option for medically inoperable patients or those who refuse surgery. k See Principles of Radiation Therapy for Cervical Cancer (CERV-B). l These doses are recommended for most patients based on summation of conventional external-beam fractionation and low-dose rate (40 70 cgy/h) brachytherapy equivalents. Modify treatment based on normal tissue tolerance, fractionation, and size of target volume. (See Discussion) n Concurrent cisplatin-based chemotherapy with RT utilizes cisplatin as a single agent or cisplatin plus 5-fluorouracil. o The traditional dose would be Gy to total point A dose. p This approach can be considered in patients whose extent of disease or uterine anatomy precludes adequate coverage by brachytherapy. Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged. Version ,11/25/15 National Comprehensive CancerNetwork,Inc. 2015, All rights reserved.the NCCN Guidelines and this illus tration may not be reproduced in anyform withoutthe ex press written permission of NCCN. CERV-4

12 PET at diagnosis: Detection of Nodal Metastases

13 Post-treatment PET predictive Schartz et al. JAMA 2007

14 Printed by Eduardo Alvarado on 4/21/2016 9:46:08 AM. For personal use only. Not approved for distribution. Copyright 2016 National Comprehensive Cancer Network, Inc., All Rights Reserved. NCCN Guidelines Version Cervical Cancer NCCN Guidelines Index Cervical Cancer TOC Discussion SURGICAL FINDINGS ADJUVANT TREATMENT Negative nodes, negative margins, negative parametrium Positive pelvic nodes and/or Positive surgical margin and/or Positive parametrium Observe or Pelvic RT k if combination of high-risk factors (ie, primary tumor size, stromal invasion, and/or LVSI that meet Sedlis criteria q [category 1]) ± concurrent cisplatin-based chemotherapy n (category 2B for chemotherapy) Pelvic RT k + concurrent cisplatin-containing chemotherapy n (category 1) ± vaginal brachytherapy k See Surveillance (CERV-10) Para-aortic lymph node positive by surgical staging Chest CT or PET-CT scan Negative for distant metastasis Positive for distant metastasis Consider biopsy of suspicious areas as indicated Negative Positive Para-aortic lymph node RT k + concurrent cisplatincontaining chemotherapy n + pelvic RT k ± brachytherapy k Systemic therapy r ± individualized RT k k See Principles of Radiation Therapy for Cervical Cancer (CERV-B). n Concurrent cisplatin-based chemotherapy with RT utilizes cisplatin as a single agent or cisplatin plus 5-fluorouracil. q Risk factors may not be limited to the Sedlis criteria. See Sedlis Criteria (CERV-C). r See Chemotherapy Regimens for Recurrent or Metastatic Cervical Cancer (CERV-D). Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged. Version ,11/25/15 National Comprehensive CancerNetwork,Inc. 2015, All rights reserved.the NCCN Guidelines and this illus tration may not be reproduced in anyform withoutthe ex press written permission of NCCN. See Surveillance (CERV-10) CERV-5

15 GOG 92 update IJROBP 65(1): , 2006 Median f/u 10 years 46% reduction in risk of recurrence (HR 0.54) 42% reductionin risk of progression/death Reductionin adenoca 8.8% vs. 44% 30% improvement in overall survival (p=0.07) Increases Grade 3/4 toxicity by 4.5% RT vs Obs

16 + LN + Margins + Parametria 4 yr PFS 63% vs. 80% (p=0.003) 4yr OS 71% vs. 81% (p=0.007) RTOG 0724 (adj Carbo/Taxol) Post-op Chemo-RT: SWOG 8797 High-risk patients Peters et al. JCO 2000

17 Predictive value of MRI Wang et al. Cancer 2010; 116(21): MRI at diagnosis,2-3 weeks into EBRT; after 45Gy, 1-2 mo post Tx Regression ratio predictive of recurrence Initial MR Volume 40 cc and ratio: post-eb vol/initial vol <20% significantly lower LC and DSS

18 Locally advanced cases MR: Sag and Axial T2-weighted Images: Imaging as a Biomarker?

19 Relative risk of failure Randomized trials of cisplatin-containing CT-RT leadingto NIH clinicalalert in April, 1999

20 Meta-Analysis CT +RT Green JA et al, Lancet 358: 781, Review of 19 randomized Trials of CT+RT for cervical cancer ( ) 4580 pts randomized, 3656 evaluable 16% absolute improvement in PFS (47% to 63%) Benefit on both local controland distant failures 12% absolute improvement in survival (40% to 52%) Greater benefit for cst IB-IIB Increased acute toxicity with CT+RT, but insufficient data with regard to late toxicity

21 Outback Chemotherapy Dueñas-González A et al. JCO 2011;29: A: Concurrent Gem/Cis plus outback Gem/Cis x 2 B: Concurrent Cis + RT (A) progression-free survival (PFS) and (B) overall survival 3 y PFS: 74.4% for arm A vs. 65.0% for arm B (P =.03)

22 Stage III-IVA greatest benefit CDDP/Gem Gyn Onc 126: , 2012

23 Locally Advanced Cervical Cancer A bit of RT techniques

24 Intact Cervix IMRT Cervix Wide margins Organ motion Para-aortic nodes Small bowel 5cc < 55 Gy (planning) 15 cc < 55 Gy (treatment)

25 Postop IMRT Atlas Include obturator nodes, ITV margins up to 3 cm on vagina

26 IMRT to Para-aortic Nodes IJROBP 85(4): IJROBP 87(2): PET identification Dose escalation Gy (median 63 Gy) Median LN 2.25cm (rg 1-7cm) F/U 3 years Nodal control 86% OS 68%, DFS 58% Anatomic distribution

27 PET/CT Fusion Nodal Contour Nodal boost Gy

28 Boost - Brachytherapy

29 Brachytherapy is Necessary Tumor control probability correlated with RT dose and cervix ca volume Fletcher, Shukovsky J Radiol Electrol 56: , 1975!!! External beam only External Beam + brachytherapy 4 y PC 4 y Survival Lanciano JROBP 20:95,1991 Local Control Montana Cancer 57:148, % 67% 19% 46% 40% 52%

30 Viswanathan ASTRO 10/03/11

31 Brachytherapy utilization rate (%) 100 SEER registries Stage IB IVA cervical cancer treatedbetween

32 Overall survival by cervical cancer brachytherapy use Brachytherapy P <.001 No Brachytherapy Years 25% reduction in brachytherapy; 13% reduction in survival SEER, Int J Radiat Oncol Biol Phys 2013;87:

33 NCDB analysis IMRT increase directly proportional to brachytherapy decrease Gill et al, IJROBP Dec 2014

34 Adjusted overall survival by cervical cancer brachytherapy use NCDB Gill et al., Int J Radiat Oncol Biol Phys, % reduction in brachytherapy; 14% reduction in survival

35 Utilization of HDR increased from 13% to 70% LDR HDR IJROBP 2005;63(4): IJROBP 2014;89(2):249-56

36 Printed by Eduardo Alvarado on 4/21/2016 9:46:08 AM. For personal use only. Not approved for distribution. Copyright 2016 National Comprehensive Cancer Network, Inc., All Rights Reserved. NCCN Guidelines Version Cervical Cancer NCCN Guidelines Index Cervical Cancer TOC Discussion CLINICAL STAGE ADDITIONAL WORKUP PRIMARY TREATMENT Negative adenopathy Pelvic RT k + concurrent cisplatin-containing chemotherapy n + brachytherapy k (category 1) Radiologic imaging only Positive adenopathy Consider needle biopsy See Imaging Results (CERV-7) Stage IB2, Stage IIA2 (See CERV-4 for alternative recommendations for these patients) Stage IIB, IIIA, IIIB, IVA or Surgical staging (category 2B): Extraperitoneal or laparoscopic lymph node dissection Negative Positive Pelvic RT k + concurrent cisplatin-containing chemotherapy n + brachytherapy k (category 1) See Node Status (CERV-8) k See Principles of Radiation Therapy for Cervical Cancer (CERV-B). n Concurrent cisplatin-based chemotherapy with RT utilizes cisplatin as a single agent or cisplatin plus 5-fluorouracil. Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged. Version ,11/25/15 National Comprehensive CancerNetwork,Inc. 2015, All rights reserved.the NCCN Guidelines and this illus tration may not be reproduced in anyform withoutthe ex press written permission of NCCN. See Surveillance (CERV-10) CERV-6

37 Printed by Eduardo Alvarado on 4/21/2016 9:46:08 AM. For personal use only. Not approved for distribution. Copyright 2016 National Comprehensive Cancer Network, Inc., All Rights Reserved. NCCN Guidelines Version Cervical Cancer NCCN Guidelines Index Cervical Cancer TOC Discussion Stage IB2, IIA2 Stage IIB, IIIA, IIIB, IVA IMAGING RESULTS PRIMARY TREATMENT Pelvic RT k + concurrent cisplatin-containing chemotherapy n + brachytherapy k (category 1) ± para-aortic lymph node RT k Pelvic node positive; Para-aortic lymph node negative or Extraperitoneal or laparoscopic lymph node dissection s Para-aortic negative Pelvic RT k + concurrent cisplatincontaining chemotherapy n + brachytherapy k (category 1) See Surveillance (CERV-10) Positive adenopathy by CT, MRI, and/or PET Pelvic node positive; Paraaortic lymph node positive Consider extraperitoneal or laparoscopic lymph node dissection s Para-aortic positive Extended-field RT k + concurrent cisplatin-containing chemotherapy n + brachytherapy k Distant metastases; with biopsy confirmation as clinically indicated Systemic therapy r ± individualized RT k k See Principles of Radiation Therapy for Cervical Cancer (CERV-B). n Concurrent cisplatin-based chemotherapy with RT utilizes cisplatin as a single agent or cisplatin plus 5-fluorouracil. r See Chemotherapy Regimens for Recurrent or Metastatic Cervical Cancer (CERV-D). s Consider postoperative imaging to confirm the adequacy of node removal. Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged. Version ,11/25/15 National Comprehensive CancerNetwork,Inc. 2015, All rights reserved.the NCCN Guidelines and this illus tration may not be reproduced in anyform withoutthe ex press written permission of NCCN. See Surveillance (CERV-10) CERV-7

38 Printed by Eduardo Alvarado on 4/21/2016 9:46:08 AM. For personal use only. Not approved for distribution. Copyright 2016 National Comprehensive Cancer Network, Inc., All Rights Reserved. NCCN Guidelines Version Cervical Cancer NCCN Guidelines Index Cervical Cancer TOC Discussion Stage IB2, IIA2; Stage IIB, IIIA, IIIB, IVA NODE STATUS PRIMARY TREATMENT Pelvic lymph node positive and para-aortic lymph node negative by surgical staging Pelvic RT k + concurrent cisplatin-containing chemotherapy n + brachytherapy k (category 1) Para-aortic lymph node positive by surgical staging Further radiologic workup as clinically indicated Negative for distant metastasis Positive for distant metastasis Consider biopsy of suspicious areas as indicated Negative Extended-field RT k + concurrent cisplatin-containing chemotherapy n + brachytherapy k Positive Systemic therapy r ± individualized RT k k See Principles of Radiation Therapy for Cervical Cancer (CERV-B). n Concurrent cisplatin-based chemotherapy with RT utilizes cisplatin as a single agent or cisplatin plus 5-fluorouracil. r See Chemotherapy Regimens for Recurrent or Metastatic Cervical Cancer (CERV-D). Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged. Version ,11/25/15 National Comprehensive CancerNetwork,Inc. 2015, All rights reserved.the NCCN Guidelines and this illus tration may not be reproduced in anyform withoutthe ex press written permission of NCCN. See Surveillance (CERV-10) CERV-8

39 Radiother Oncol Mar;114(3): Hanna TP 1 et al The population benefit of radiotherapy for cervical cancer: local control and survival estimates for optimally utilized radiotherapy and chemoradiation. 53% of all cervix patients had adjuvant or curative radiotherapy indications. 96% were for CRT. The estimated 5-year absolute benefits of optimally utilized radiotherapy alone were: LC: 31%, OS: 17%. These were over and above the contribution of other modalities to outcomes. The incremental 5-year absolute benefits of CRT were: LC 4%, OS 3%.

40 Brachytherapy Jul-Aug;14(4): Lee KK 1 et al High-dose-rate vs. low-dose-rate intracavitary brachytherapy for carcinoma of the uterine cervix: Systematic review and meta-analysis. outcome data for 18,937 patients, 10,807 patients HDR-ICBT 8,130 patients LDR-ICBT The treatment outcome equivalent in terms of survival, pelvic recurrence, and major complications.

41 Hysterectomy with radiotherapy or chemotherapy or CRT: locally advanced cervical cancer seven RCTs (1217 women) 3 multi-centre trials, 2 single-centre, 2? Histerectomy + RT = RT/CRT locally advanced cervical cancer (stages IB2 to III) hysterectomy (simple or radical) with radiotherapy (N = 194) versus radiotherapy alone (N = 180); hysterectomy (simple or radical) with chemoradiotherapy (N = 31) versus chemoradiotherapy alone (N = 30); hysterectomy (radical) with chemoradiotherapy (N = 111) versus internal radiotherapy with chemoradiotherapy (N = 100); hysterectomy (simple or radical) with upfront (neoadjuvant) chemotherapy (N = 298) versus radiotherapy alone (N = 273). Cochrane Database of Systematic Reviews 7 APR 2015 DOI: / CD pub2 Insufficient evidence that hysterectomy with radiotherapy, with or without chemotherapy, improves the survival of women with locally advanced cervical cancer who are treated with radiotherapy or chemoradiotherapy alone

42 Radiotherapywith concurent cisplatin-b ased doubletorwekly cisplatin for cervical cancer: A systematic review and meta-an alysis Fau sto P etreli Gynecologic Oncology, Gynecol Oncol Jul;134(1): Radiotherapy with concurrent cisplatin-based doublet or weekly cisplatin for cervical cancer: a systematic review and meta-a Petrelli F1, De Stefani A2, Raspagliesi F3, Lorusso D3, Barni S4 platinum-based doublet chemotherapy plus concurrent RT was associated with improvements in the OS and PFS of 35% and 30% patients, respectively, compared to RT plus weekly CDDP. Therefore, platinum-based combination therapy plus RT should be the preferred treatment over weekly CDDP plus RT for stage IB IVA CC.

43 Radiotherapy of Gynecological Malignancies Cervix Endometrial Vaginal Vulvar A common disease in Europe 43

44 Biologic Classification Type I and Type II Endometrial Carcinomas: A Historical perspective Type I Estrogen-related Obesity, tamoxifen Type 2 Unrelated to estrogen exposure Atrophic background Associated with EIN Low grade endometrioid (Grade 1) Favorable outcome Postmenopausal High grade histotypes (serous, clear cell) Poor clinical outcomes

45 Uterine Neoplasms NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines ) Version NCCN.org Continue Version ,11/20/15 National Comprehensive CancerNetwork,Inc. 2015, All rights reserved.the NCCN Guidelines and this illus tration may not be reproduced in anyform withoutthe ex press written permission of NCCN.

46 Printed by Eduardo Alvarado on 4/21/2016 9:45:46 AM. For personal use only. Not approved for distribution. Copyright 2016 National Comprehensive Cancer Network, Inc., All Rights Reserved. NCCN Guidelines Version Endometrial Carcinoma NCCN Guidelines Index Uterine Neoplasms TOC Discussion INITIALCLINICAL FINDINGS PRIMARY TREATMENT Total hysterectomy and bilateral salpingo-oophorectomy (TH/BSO) b,c and surgical staging d Adjuvant treatment for surgically staged: d Stage I (See ENDO-4) Stage II (See ENDO-5) Stage IIIA(See ENDO-5) Stage IIIB-IV (See ENDO-6) Medically operable Incompletely staged See (ENDO-7) Disease limited to the uterus (endometrioid histology) a Patient desires fertilitysparing options See (ENDO-8) Not suitable for primary surgery Tumor-directed RT e or Consider hormone therapy in select patients f,g See Surveillance (ENDO-9) a See (UN-1) for clarification of uterine neoplasms. b See Hysterectomy and Pathologic Evaluation (ENDO-A). c Endometrial carcinoma should be removed en bloc to optimize outcomes; morcellation should be avoided. d The degree of surgical staging to assess disease status depends on preoperative and intraoperative findings. Multidisciplinary expertise is recommended. See Principles of Evaluation and Surgical Staging (ENDO-B). e See Principles of Radiation Therapy for Uterine Neoplasms (UN-A). f Patients should be closely monitored. Consider endometrial biopsies every 3 to 6 months. g See Systemic Therapy for Recurrent, Metastatic, or High-Risk Disease (ENDO-C). Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged. Version ,11/20/15 National Comprehensive CancerNetwork,Inc. 2015, All rights reserved.the NCCN Guidelines and this illus tration may not be reproduced in anyform withoutthe ex press written permission of NCCN. ENDO-1

47 Low and Intermediate Risk No therapy Vaginal brachytherapy alone Safe and effective Selected stage I endo ca patients after lymph node dissection Lymph node assessment Diagnostic: not stage I but stage III

48 Early-stage Disease Regions at risk: LN and Vaginal cuff

49 Significant differences in dose distribution No treatment of lymphatic tissue

50 Clinical Guidelines ASTRO Guidelines Practical Rad Oncology 2014; 4(3): Multidisciplinary effort SGO, ASCO authors 5 key questions generated from panel Committee voted on strength of recommendation and literature ESMO-ESGO-ESTRO Consensus Statement (Ann Oncol 2016)

51 Arguments for RT after LND in high risk patients LVI, Grade 3 Lymph nodes left behind Lymphangiogram after lymph node dissection Obturator space close to nerves and vessels Common iliac nodes near blood vessels Lymphatic vessels left behind Connect uterus to lymph nodes Lymph node sectioning by pathologist may miss micrometastasis (or entire node)

52 Pelvic RT decreases LR Trial Year # Stage LND LR Norwegian (1980) 540 IA-IIA PORTEC (2000) 715 IB, IC (not IC3) GOG 99 (2004) 392 IB, IC, occult II ASTEC (2007) 906 I, IIA +/- +++

53 Intensity-Modulated Radiation:? ê Toxicity and é Local Control

54 Quality of Life 7 year update 2009 Jul EBRT VB P value Fecal leakage 10.6% 1.8% 0.03 Diarrhea 8.4% 0.9% 0.04 Limitations Bowel 10.5% 1.8% Bowel Urgency 23.3% 6.6% <0.001 Urinary Urgency 39.3% 25.5% 0.05 IJROBP 2015;93(4):

55 Loco-regional recurrence for stage I endometrial carcinoma patients external beam radiotherapy (EBRT) vs no EBRT treatment. Anthony Kong et al. JNCI J Natl Cancer Inst 2012;104: The Author Published by Oxford University Press. All rights reserved. For Permissions, please journals.permissions@oup.com.

56 overall survival (OS) for stage I endometrial carcinoma external beam radiotherapy (EBRT) vs no EBRT Anthony Kong et al. JNCI J Natl Cancer Inst 2012;104: The Author Published by Oxford University Press. All rights reserved. For Permissions, please journals.permissions@oup.com.

57 overall survival (OS) high-risk stage I Anthony Kong et al. JNCI J Natl Cancer Inst 2012;104: The Author Published by Oxford University Press. All rights reserved. For Permissions, please journals.permissions@oup.com.

58 Indications for pelvic EBRT High risk features Stage III positive nodes, adnexal mets, or serosa Stage I (no LND) LVI risk to remaining lymphatics Grade (2), 3 Age (>60), >70 MMI (>66%) Inadequate surgery LN not assessed Unilateral LN Low number nodes Supracervical hysterectomy benign Stage II Extrafascial hysterectomy

59 After LND, LVI negative: VB +/- EBRT Grade I Grade II Grade III IA /- VB IB /- VB VB IC VB VB VB +/- EB II MMI, LVI, size VB +/-EB VB +/- EB EB +/- VB

60 Printed by Eduardo Alvarado on 4/21/2016 9:45:46 AM. For personal use only. Not approved for distribution. Copyright 2016 National Comprehensive Cancer Network, Inc., All Rights Reserved. NCCN Guidelines Version Endometrial Carcinoma NCCN Guidelines Index Uterine Neoplasms TOC Discussion INITIAL CLINICAL FINDINGS ADDITIONAL WORKUP Negative result PRIMARY TREATMENT TH/BSO b,c and surgical staging d Adjuvant treatment for surgically staged: d Stage I (See ENDO-4) Stage II (See ENDO-5) Stage IIIA(See ENDO-5) Stage IIIB-IV (See ENDO-6) Suspected or gross cervical involvement (endometrioid histology) a Consider cervical biopsy or MRI h Medically operable Radical hysterectomy and bilateral salpingo oophorectomy (RH/BSO) b,c and surgical staging d or Incompletely staged See (ENDO-7) Positive result i or gross involvement Not suitable for primary surgery g See Systemic Therapy for Recurrent, Metastatic, or High-Risk Disease (ENDO-C). h MRI performed with contrast unless contraindicated. i Clear demonstration of cervical stromal involvement. j Based on summation of conventional external-beam fractionation and low-dosea See (UN-1) for clarification of uterine neoplasms. b See Hysterectomy and Pathologic Evaluation (ENDO-A). c Endometrial carcinoma should be removed en bloc to optimize outcomes; morcellation should be avoided. d The degree of surgical staging to assess disease status depends on preoperative and intraoperative findings. Multidisciplinary expertise is recommended. See Principles of Evaluation and Surgical Staging (ENDO-B). e See Principles of Radiation Therapy for Uterine Neoplasms (UN-A). RT: Gy to point A/ paracervical dose j (category 2B) TH/BSO b,c and surgical staging d Tumor-directed RT e ± Chemotherapy g Surgical resection, if rendered operable or Chemotherapy (category 2B) g Surgical resection if rendered operable (tumordirected RT if still inoperable) rate brachytherapy equivalent. See Surveillance (ENDO-9) Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged. Version ,11/20/15 National Comprehensive CancerNetwork,Inc. 2015, All rights reserved.the NCCN Guidelines and this illus tration may not be reproduced in anyform withoutthe ex press written permission of NCCN. ENDO-2

61 Printed by Eduardo Alvarado on 4/21/2016 9:45:46 AM. For personal use only. Not approved for distribution. Copyright 2016 National Comprehensive Cancer Network, Inc., All Rights Reserved. NCCN Guidelines Version Endometrial Carcinoma NCCN Guidelines Index Uterine Neoplasms TOC Discussion INITIAL CLINICAL FINDINGS ADDITIONAL WORKUP None PRIMARY TREATMENT See Primary Treatment (disease limited to uterus) (ENDO-1) Suspected extrauterine disease (endometrioid histology) a CA-125 (optional) MRI/CT/PET, as clinically indicated k Intra-abdominal: Ascites Omentum Nodal Ovarian Peritoneal Initially unresectable extrauterine pelvic disease: Vaginal Bladder Bowel/rectum Parametrial TH/BSO b,c + surgical staging d /debulking l (may consider preoperative chemotherapy g ) RT e + brachytherapy ± chemotherapy g or Chemotherapy Chemotherapy g and/or RT e and/or Extra-abdominal/liver Hormone therapy g May consider a See (UN-1) for clarification of uterine neoplasms. palliative TH/BSO c b See Hysterectomy and Pathologic Evaluation (ENDO-A). c Endometrial carcinoma should be removed en bloc to optimize outcomes; morcellation should be avoided. d The degree of surgical staging to assess disease status depends on intraoperative findings. Multidisciplinary expertise is recommended. See Principles of Evaluation and Surgical Staging (ENDO-B). e See Principles of Radiation Therapy for Uterine Neoplasms (UN-A). g See Systemic Therapy for Recurrent, Metastatic, or High-Risk Disease (ENDO-C). k CT and MRI performed with contrast throughout the guidelines unless contraindicated. Contrast not required for screening chest CT. Adjuvant treatment for surgically staged: d Stage IIIA(See ENDO-5) Stage IIIB-IV (See ENDO-6) See Surveillance (ENDO-9) Re-evaluate for surgical resection and/ or RT based on response See Surveillance (ENDO-9) See Surveillance (ENDO-9) l The surgical goal is to have no measurable residual disease. Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged. Version ,11/20/15 National Comprehensive CancerNetwork,Inc. 2015, All rights reserved.the NCCN Guidelines and this illus tration may not be reproduced in anyform withoutthe ex press written permission of NCCN. ENDO-3

62 Printed by Eduardo Alvarado on 4/21/2016 9:45:46 AM. For personal use only. Not approved for distribution. Copyright 2016 National Comprehensive Cancer Network, Inc., All Rights Reserved. NCCN Guidelines Version Endometrial Carcinoma NCCN Guidelines Index Uterine Neoplasms TOC Discussion All staging in guideline is based on updated 2010 FIGO staging. (See ST-1) CLINICAL FINDINGS ADVERSE RISK HISTOLOGIC GRADE/ADJUVANT TREATMENT e,n,o Surgically staged: Stage I d Stage IA (<50% myometrial invasion) Stage IB ( 50% myometrial invasion) FACTORS m G1 G2 Adverse risk factors not present Adverse risk factors present Adverse risk factors not present Adverse risk factors present Observe Obse rve or Vaginal brachytherapy Obse rve or Vaginal brachytherapy Observe or Vaginal brachytherapy and/or external beam radiation Obse rve or Vaginal brachytherapy Observe or Vaginal brachytherapy and/or EBRT (category 2B for EBRT) Obse rve or Vaginal brachytherapy Observe or Vaginal brachytherapy and/or EBRT d therapy (EBRT) The degree of surgical staging to assess disease status depends on intraoperative findings. Multidisciplinary expertise is recommended. See Principles of Evaluation and Surgical Staging (ENDO-B). e See Principles of Radiation Therapy for Uterine Neoplasms (UN-A). g See Systemic Therapy for Recurrent, Metastatic, or High-Risk Disease (ENDO-C). m See Discussion for information on adverse risk factors. n Adjuvant therapy determinations are made on the basis of pathologic findings. o Initiate RT as soon as the vaginal cuff is healed, preferably no later than 12 weeks after surgery. p The role of adjuvant chemotherapy in invasive, high-grade, uterine-confined disease is the subject of current studies. (Hogberg T, Signorelli M, de Oliveira CF, et al. Sequential adjuvant chemotherapy and radiotherapy in endometrial cancer--results from two randomised studies. Eur J Cancer 2010;46: ) Hormonal therapy is not used for high-grade disease. Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged. Version ,11/20/15 National Comprehensive CancerNetwork,Inc. 2015, All rights reserved.the NCCN Guidelines and this illus tration may not be reproduced in anyform withoutthe ex press written permission of NCCN. G3 Obs erve or Vaginal brachytherapy Observe or Vaginal brachytherapy and/or EBRT Vaginal brachytherapy and/or EBRT or Obser ve (category 2B for observation) EBRT and/or Vaginal brachytherapy ± chemotherapy g,p (category 2B for chemotherapy) See Surveillance (ENDO-9) ENDO-4

63 Printed by Eduardo Alvarado on 4/21/2016 9:45:46 AM. For personal use only. Not approved for distribution. Copyright 2016 National Comprehensive Cancer Network, Inc., All Rights Reserved. NCCN Guidelines Version Endometrial Carcinoma NCCN Guidelines Index Uterine Neoplasms TOC Discussion All staging in guideline is based on updated 2010 FIGO staging. (See ST-1) CLINICAL FINDINGS HISTOLOGIC GRADE/ADJUVANT TREATMENT e,g,n,o G1 G2 G3 Surgically staged: d Stage II q,r Vaginal brachytherapy and/or EBRT Vaginal brachytherapy and/or EBRT EBRT ± vaginal brachytherapy p (category ± chemotherapy 2B for chemotherapy) Surgically staged: d Stage IIIA Chemotherapy ± RT or Tumor-directed RT ± chemotherapy or EBRT ± vaginal brachytherapy Chemotherapy ± RT or Tumor-directed RT ± chemotherapy or EBRT ± vaginal brachytherapy Chemotherapy ± RT or Tumor-directed RT ± chemotherapy or EBRT ± vaginal brachytherapy d The degree of surgical staging to assess disease status depends on intraoperative findings. Multidisciplinary expertise is recommended. See Principles of Evaluation and Surgical Staging (ENDO-B). e See Principles of Radiation Therapy for Uterine Neoplasms (UN-A). g See Systemic Therapy for Recurrent, Metastatic, or High-Risk Disease (ENDO-C). n Adjuvant therapy determinations are made on the basis of pathologic findings. o Initiate RT as soon as the vaginal cuff is healed, no later than 12 weeks after surgery. p The role of adjuvant chemotherapy in invasive high-grade uterine confined disease is the subject of current studies. (Hogberg T, Signorelli M, de Oliveira CF, et al. Sequential adjuvant chemotherapy and radiotherapy in endometrial cancer--results from two randomised studies. Eur J Cancer 2010;46: ) Hormonal therapy is not used for high-grade disease. q Observation or vaginal brachytherapy is also an option for patients with stage II disease who have had a radical hysterectomy with negative surgical margins and no evidence of extrauterine disease. r The adverse fundal risk factors influencing therapy decisions for stage I disease (see ENDO-4) may also impact the choice of adjuvant therapy for stage II disease. Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged. Version ,11/20/15 National Comprehensive CancerNetwork,Inc. 2015, All rights reserved.the NCCN Guidelines and this illus tration may not be reproduced in anyform withoutthe ex press written permission of NCCN. See Surveillance (ENDO-9) ENDO-5

64 J Clin Oncol May 20;33(15): Wiltink LM 1 et al No Increased Risk of Second Cancer After Radiotherapy in Patients Treated for Rectal or Endometrial Cancer in the Randomized TME, PORTEC-1, and PORTEC-2 Trials.

65 Ongoing Trials EB effective to reducerisk of pelvic relapse Carboplatin/taxol reduces distant relapse risk Future trials withnew agents (ex. anti-vegftherapy) may further reduce early metastates GOG 0258 St 3/4 Cisplatin + RT (concurrent) à Carbo/Taxol vs. Carbo/Taxol alone PORTEC 3 Pelvic RT vs. Cisplatin+ RT (concurrent) àcarbo/taxol

66 Radiotherapy of Gynecological Malignancies Cervix Endometrial Vaginal Vulvar An enigmatic disease in Europe and Latin-America 66

67 2.517 pts EBRT EBRT + BT Median OS 3,6 y 6,1 y

68 Gynecol Oncol Orton A et al Brachytherapy improves survival in primary vaginal cancer.

69 Radiotherapy of Gynecological Malignancies Cervix Endometrial Vaginal Vulvar external internal A difficult disease to treat 69

70 Pre-treatment evaluation of distal vaginal and vulvar cancers Tomographic scanning of the pelvis Will detect large nodes that are not palpable Guides RT planning Dose Need for LND Field arrangement Electron energy 5.5 cm

71 Patterns of Spread n Direct extension: vagina, urethra, anus, pelvic bones n Superficial and Deep Inguinal Nodes: - Depth of Invasion: <1 mm= <5% 1-3 mm= 5-15% >3 mm= 25% >5 mm= 40% Tumors >2 cm in size have a >20% inguinal metastasis rate n Pelvic Nodes Gunderson and Tepper, 2007

72 LN drainage from vulva Lymphatics: 1st echelon: Superficial inguinofemoral 2nd echelon: Deep inguinofemoral Femoral 3rd echelon: External iliac/pelvic nodes

73 Pelvic lymph node status vs. survival FIGO 2009 Staging 0 Carcinoma in situ IA 2 cm and stromal invasion 1 mm IB II IIIA IIIB > 2 cm, or stromal invasion > 1 mm Extension to adjacent perineal structures 1-2 LN each <5 mm or 1 LN 5 mm 3+ LN <5 mm, or 2+ LN 5 mm IIIC IVA LN with ECE Fixed/ulcerated LN, extension to upper 2/3 urethra/vagina, bladder/rectal mucosa or fixed to pelvic bone IVB Distant metastases, including pelvic lymph node metastasis

74 Survival by stage FIGO stage Survival, Survival, Survival, 1 year 2 years 5 years I (n=286) 96% 90% 78% II (n=266) 88% 73% 59% III (n=216) 75% 54% 43% IV (n=71) 35% 17% 13% Beller U, et al. Carcinoma of the Vulva Int J Gynaecol Obstet 2006; 95:S7

75 Homesley trial (GOG 36) 114 pts tx d with radical vulvectomy and bilateral inguinal LND If positive inguinal nodes, pts randomized to: Pelvic LN dissection vs. Post-op RT to pelvic and inguinal nodes Outcomes: Groin Recurrence: RT 5% vs. surgery 24% (SS) OS: RT 68% vs. surgery 54%

76 Radiation therapy vs pelvic node resection for carcinoma of the vulva with positive groin nodes Homesley et al. Obstet Gynecol 68:733 (1986) Radiation therapy DSS50 Pelvic node dissection 25 0 P = Time (months)

77 Pelvic lymph node status vs. survival Poor prognosis of pelvic N+ led to M1 designation Graph shows arms from the surgery alone arm 23% OS at 2 yrs. for + pelvic nodes Homesley et al. Obstet Gynecol 68:733 (1986) surgery alone Pelvic nodes DSS Pelvic nodes Time (months)

78 Changing the FIGO 2009 Staging Stage IIIA Stage IIIB Stage IIIC Stage IV Years after surgery Adapted from Tabbaa et al. Gynecol Oncol

79 Changing the FIGO 2009 Staging PLN+ Stage IIIA Stage IIIB Stage IIIC Stage IV Years after surgery Adapted from Tabbaa et al. Gynecol Oncol

80 N+ Positive pelvic nodes should be treated with curative intent Consideration should be made with next FIGO staging meeting to remove pelvic nodes from stage IVB

81 Management of Vulvar SCC Yes Resectable? No Surgery per stage RT +/- chemo Stage 1A Stage > 1A WLE only WLE+ Inguinal LN dissection Preop ChemoRT Definitive Post-op radiation as indicated

82 IMRT 3DCRT + e- 82

83 36 pts <24 months / R1 / fragmentation compensated 5 y 49%

84 Extended = maximal effort surgery 5y 42% EBRT Fragmentation R0 for local control

85 Radiotherapy of Gynecological Malignancies Cervix: bio(crt)-techno(dose-escalation) intensification Endometrial: optimize pelvic EBRT delivery + agents Vaginal: brachytherapy a decisive component of radicality Vulvar: N+ are not M1 survivors 85