Endometrial Cancer
Transcription
Endometrial Cancer
Endometrial Cancer William Small Jr., MD Professor of Radiation Oncology The Robert H. Lurie Comprehensive Cancer Center of Northwestern University Learning Objectives: •Discuss the role of radiation therapy in early stage and advanced stage endometrial cancer. •Review controversies in Radiation Techniques. Explain the role of surgery and surgical staging in the management of endometrial cancer. •Review the role of chemotherapy in the management of early and advanced stage endometrial cancer. When utilizing IMRT in the post-operative treatment of endometrial cancer the MOST important aspect of treatment is? 1. Daily image guidance. 2. Asking the patient to have a full bladder on a daily basis. 3. Assuring that bone and bowel are excluded from the CTV. 4. Carful attention to an ITV. Who will win the Super Bowl this Year ? 1. The Chicago Bears. 2. The NFL team from Chicago. 3. I don’t care as long as the Packers are not in the Super Bowl. Endometrial Cancer Estimated New Cancer Cases and Deaths by Sex, 2012 Men Women Incidence Deaths Incidence Deaths All 848,170 301,820 All 790,740 275,370 Prostate 241,740 28,170 Breast 226,870 39,510 Lung 116,470 87,750 Lung 109,690 75,590 Colon/Rectum 73,420 26,470 Colon/Rectum 70,040 25,220 Bladder 55,600 10,510 Uterine 47,130 8,010 American Cancer Society, Surveillance Research, 2012 “The reports of my death have been greatly exaggerated.” -Mark Twain “There are three kinds of lies: Lies, Damned Lies, and Statistics.” -Benjamin Disraeli -Mark Twain FIGO 1988 Surgical staging System Early stage disease • Stage I IA Limited to the endometrium IB < half of the endometrium IC > half of the endometrium • Stage II Corpus and cervix IIA Endocervical glands only IIB Endocervical stromal invasion FIGO 1988 Surgical staging System Late stage disease • Stage III IIIA Tumor Involves the serosa and/or adenexa (direct extension or metastasis) and/or cancer cells in ascites or peritoneal washings IIIB Vaginal Involvement III C Metastasis to Pelvic or Para-aortic Lymph Nodes • Stage IV IVA Tumor Involves the bladder or bowel mucosa IVB Distant Metastasis FIGO 2009 Surgical staging System Early stage disease • Stage I IA No or < half of the endometrium IB = or > half of the endometrium • Stage II Corpus and cervix Endocervical stromal invasion Int J Obs Gyn, May 2009, FIGO 2009 Surgical staging System Late stage disease • Stage III IIIA Tumor Involves the serosa and/or adenexa (direct extension or metastasis) IIIB Vaginal and/or parametrial Involvement III C1 Metastasis to Pelvic Lymph Nodes IIIC2 Metastasis to Para-aortic +/- pelvic Lymph Nodes • Stage IV IVA Tumor Involves the bladder or bowel mucosa IVB Distant Metastasis and/or inguinal metastasis Post Operative Radiotherapy Early Stage Disease Very contentious Disease All Patients Receive Adjuvant RT Even Low Grade Minimally Invasive Tumors No Patients Receive adjuvant RT Even High Grade Deeply Invasive Tumors Center A Center B In intermediate risk endometrial cancer, the risk of recurrence with and without pelvic RT is approximately? 1. 2. 3. 4. 3% vs. 12 %. 3% vs. 20% 1% vs. 5% 10% vs. 30%. Postoperative RT Rationale • Early stage patient with adverse pathologic features are at risk for extra uterine disease and recurrence • Most commonly cited pathologic factors -Myometrial Invasion (MI) -Tumor Grade -Cervical involvement - Age - LVSI • Importance demonstrated in GOG33 GOG 33 • Surgical Pathologic study of 621 stage I pts Positive Pelvic LNs Positive PA LNs Grade 1 3% 2% 2 9% 5% 3 18% None 1% 1% Superficial 5% 3% Middle 6% 1% Deep 25% P<0.0001 11% P<0.0001 MI P<0.0001 17% P<0.0001 More useful to combine grade & MI Positive Pelvic LNs Positive PA LNs Invasion G1 G2 G3 Invasion G1 G2 G3 None 0% 3% 0% None 0% 3% 0% Inner 3% 5% 9% Inner 1% 4% 4% Middle 0% 9% 4% Middle 5% 0% 0% Creasman WT et al, Cancer 1987;60:2035 Deep 11% 19% 34% Deep 6% 14% 23% Cervical involvement and also CSI are correlated with Positive LNs Positive Pelvic LNs Positive PA LNs Site Fundus 8% Isthmus cervix 16% Negative 7% Positive 27% 4% P = 0.01 14% P= 0.0001 Capillary Space involvement 4% P=0.0001 19% P= 0.0001 Rationale also provided by the correlation between adverse pathologic factors and vaginal failure • Price 1965 41 clinical stage I patients undergoing surgery alone Vaginal Recurrence All Patients 14% Grade 1 4.4 2 5.7 3 13.6 None 3.7 < half 4.7 > half 15.1 MI Unfortunately Grade and Myometrial invasion not combined in the analysis Price et al. Am J Obstet Gynecol 1965; 91:1060 What evidence supports the use of Adjuvant Radiation Therapy is Stage I & II Endometrial Carcinoma ? Retrospective studies also suggest benefit of Adjuvant RT in patients with adverse pathologic factors Pelvic Recurrence with RT Pelvic Recurrence without RT Carey 1995 High Risk pts Deep MI, G3, +Cx, Adenos. 3.9% 14.3% Pitson 2002 Stage II (55% IIA) 5.6% 22.2% Carey et al, Gynecol Oncol 1995; 57:138 Piston et al, Int J Radiation Oncol Bio Phys 2002; 53:862 Retrospective studies also suggest benefit of Adjuvant RT in patients with adverse pathologic factors • In a retrospective review of 927 patients Stage I&II pts Vaginal Recurrence with RT – either Vault or Total Vagina Vaginal Recurrence without RT Stage I Low Risk G 1 – 2, <1/3 MI 1% 3.2% Stage I High Risk G3 &/Or >1/3 MI 1.3% 11.7% Stage II 5.2 % 12.8% Elliot at al., Int J Gyne cancer 1994; 4 : 84 Post operative RT Stage I & II Disease • Five prospective randomized trials have been conducted to evaluate post operative radiotherapy in early stage disease – – – – – Norwegian Trial PORTEC 1 GOG 99 ASTEC/EN 5 PORTEC 2 Norwegian Trial • Clinical Stage I • 540 Patients • TAH + BSO without LN Sampling • No assessment of peritoneal cytology Vaginal Brachytherapy LDR 60 Gy @vaginal surface Arm 1 Arm 2 Pelvic RT 40 Gy Midline block after 20 Gy No further therapy Aalders et al, Obstet Gynecol 1980; 56(4);419 Norwegian Trial • Pelvic RT reduces vaginal / pelvic failures in patients with high risk features (deep MI & G3 Tumors) Vaginal/Pelvic recurrence Grade 1 – < ½ MI 2 Tumors > ½ MI No RT 4% 9.8% With RT 2.3% 9.4% Grade 3 Tumors 5.6% 19.6% 2.1% 4.5 % < ½ MI > ½ MI Aalders et al, Obstet Gynecol 1980; 56(4);419 Norwegian Trial • No Overall survival benefit with Radiotherapy 5 Years Survival Rate Pelvic RT 89% No Pelvic RT 91% Only in Patients with deeply invasive Grade 3 Tumors Death from Cancer Pelvic RT 18.2% No Pelvic RT 27.5% Aalders et al, Obstet Gynecol 1980; 56(4);419 LVSI LVSI was evaluated in the last 151 patients on trial. Vessel invasion seen in 19.9 % of the patients. Local recurrence 21 % in the no Pelvic RT group versus none in the Pelvic RT group. Aadlers Trial: Conclusions • Grade 3> 50 % invasion – pelvic RT. • All patients with LVSI receive pelvic RT • All other patients with invasion receive VBT. PORTEC Trial Post Operative Radiation Therapy in Endometrial Carcinoma • Selected Clinical Stage I Grade 1 > ½ MI Grade 2 any MI Grade 3 < ½ MI • 715 Patients • TAH + BSO without LN Sampling • All histologies • Regimen 1 Pelvic radiotheraoy 46 Gy / 23 Fractions No Vaginal Brachytherapy • Regimen 2 No further Treatment • • • • HIR Definition – Recent Publication Age > 60 Grade 3 Invasion >50% HIR defined as: 2 of those 3 factors present (except for grade 3 with deep invasion = high risk, eligible for PORTEC3) Fig. 3 Source: International Journal of Radiation Oncology * Biology * Physics (DOI:10.1016/j.ijrobp.2011.04.013 ) Copyright © Elsevier Inc. Terms and Conditions PORTEC – 10-year outcome with PA review Locoregional recurrence (actuarial rates) All pts 5-yr 10-yr p RT No RT 3% 13% 5% 14% <0.001 Exclusion of IB grade 1 (n=134): RT No RT 4% 15% 5% 17% <0.001 Creutzberg, Lancet 2000; Scholten, IJROBP 2005 PORTEC – 15-year outcome ( Median f/u: 13.3 Years) • Locoregional recurrence (actuarial rates) – 5.8 % in the Radiotherapy Arm – 15.5 % in the NAT Arm Nout et al; JCO, 2011 Site of Loco-regional Recurrences • 74% of the locoregional recurrences were isolated vaginal recurrences. Nout et al; JCO, 2011 GOG 99 Trial • Stage IB - II (Occult) • Regimen 1 • Pap/Serous-Clear Pelvic radiotheraoy Cell Excluded 50.4 Gy / 1.8 Gy/ Fraction • 392 Patients No Vaginal Brachytherapy • TAH + BSO with • Regimen 2 selective Bilateral Pelvic & Para- aortic No further Treatment lymphadenectomy Keys et al. Gynecol Oncol 2004; 92;744 • Assessment of peritoneal cytology Overall Results • Median follow-up of surviving patients – 68 months. • The 24-month cumulative incidence of recurrence (CIR) rate was 3% in the RT group and 12 % in the no additional therapy group. • 13 of the 18 loco-regional recurrences in the NAT arm were in the vaginal vault (72%) Overall Results • CIR at 24 months of isolated local (vagina or pelvic) 1.6% versus 7.4% • 48 month Kaplan-Meier estimates for survival – 86% in the NAT group, 92 % in RT group (p=0.55). • The GI, GU, Cutaneous and Hematological side effects were significantly higher in the RT group. HIR group (GOG-99) Prognostic factors: › advanced age › high grade (2 or 3) › outer 33% myometrial invasion › lymph-vascular space invasion (LVI) HIR (high intermediate risk): • at least 70 yr with any other risk factor • at least 50 yr with any 2 other risk factor • any age with all 3 other factors Keys, Gynecol Oncol 2004 GOG-99: recurrence HIR, NAT: 27% HIE, RT: 13% Relative hazard RT: 0.42 (58% hazard reduction) HIR: 33% of patients, 67% of recurrences Keys, Gynecol Oncol 2004 GOG 99: Survival LIR: 92 - 94% HIR, RT: 88% HIR, no RT: 74% Relative hazard for RT: 0.86 (ns); HIR: 0.73 Keys, Gynecol Oncol 2004 MRC ASTEC Radiotherapy and NCIC EN.5 Trial Adjuvant external beam radiotherapy (EBRT) in the treatment of endometrial cancer: results of the randomized MRC ASTEC and NCIC CTG EN.5 trials ASTEC ISRCTN 16571884 EN.5 clinicaltrials.gov NCT 00002807 Presented by Jane Orton On behalf of all ASTEC and EN.5 Collaborators Trial Design Surgery High risk pathology and no macroscopic disease RANDOMIZE No external beam RT External beam RT Inclusion Criteria ASTEC and EN.5 FIGO Stage Grade 1 Grade 2 Grade 3 Papillary Serous/cle ar cell IA 1 (<1%) 1 (<1%) 8 (1%) 15 (2%) IB 1 (<1%) 5 (1%) 99 (11%) 48 (5%) IC 213 (24%) 337 (37%) 100 (11%) 27 (3%) IIA 9 (1%) 19 (2%) 6 (1%) 3 (<1%) IIB 2 (<1%) 0 0 1 (<1%) Eligibility Criteria • Brachytherapy allowed if – centre policy – stated before randomisation – used in both arms • Positive para-aortic nodes an exclusion • Positive pelvic lymph nodes – Eligible for ASTEC – Ineligible for EN.5 Brachytherapy In the ASTEC trial HDR: Two fractions of 4 Gy at 0.5 cm from the vaginal mucosa over 3-7 days or LDR: 15 Gy – upper third of the vagina. In the EN-5: Given in accordance with local practice. Trial Profile 905 Randomized 453 No EBRT 452 EBRT 98% No EBRT 2% received EBRT 92% received EBRT 8% No EBRT 51% Brachytherapy 52% Brachytherapy 453 assessed for primary outcome measure 452 assessed for primary outcome measure Patient Characteristics Baseline characteristics balanced between treatment groups • median age 65 years • 98 % performance status 0-1 • 83% endometrioid histology • 25% lymphovascular space invasion • 4% positive peritoneal cytology • Surgery received – 71% TAH/BSO – 29% TAH/BSO plus lymphadenectomy • 4% of patients (with nodes harvested) had positive pelvic nodes Radiotherapy Details EBRT N=452 2 45 25 34 Percentage (%) 40 60 24 (5%) 80 Distribution of EBRT dose used 0 Median: Total Dose (Gy) Fractions Duration in days 416 (92%) 10 (3%) 20 EBRT +/brachytherapy Brachytherapy alone None Missing 5 Treatment compliance (% of patients who received total dose of 40-46 Gy in 20-25 fractions) 82% 10 15 20 25 30 35 40 45 Total dose (Grays) 50 55 60 65 70 Acute and Late Toxicity Acute toxicity (post surgery and radiotherapy) Worst score Mild Moderate Severe/Life threatening Late Toxicity Severe/Life threatening No EBRT N=453 EBRT N=452 121 (27%) 258 (57%) 77 (17%) 38 (8%) 3 (<1%) 143 (32%) 100 (22%) 14 (3%) 3% 8% Isolated Vaginal or Pelvic Initial Recurrence (ASCO Presentation) 1.0 Events 28 14 No EBRT EBRT 0.9 Totals 453 452 0.8 Cumulative incidence 0.7 3% difference in 5 year cumulative incidence rate (4% in EBRT to 7% in no EBRT) 0.6 HR=0.53, 95% CI=0.29-0.97, p=0.038 0.5 0.4 Only includes 42/123 total recurrences 0.3 0.2 0.1 0.0 0 PATIENTS at Risk No EBRT EBRT 1 2 3 4 5 6 7 81 78 35 32 Years from randomisation 453 452 425 420 366 376 282 281 211 212 142 142 Isolated Vaginal or Pelvic Initial Recurrence • 5-year cumulative incidence 6.1 % versus 3.2 % (p=0.02) Overall Survival: by centre brachytherapy policy (ASCO Presentation) [no. events/no. entered] EBRT No EBRT O-E Variance Hazard Ratio (Fixed) Brachytherapy Yes 23/196 29/190 -3.99 12.98 0.74 (0.43-1.27) p=0.268 No 30/181 25/184 3.96 13.69 1.34 (0.79-2.27) p=0.284 0 0.5 EBRT Better Interaction Test: chi-square=2.37, df=1, p=0.123 1 2 5 No EBRT Better Recurrence-Free Survival: by centre brachytherapy policy (ASCO Presentation) Meta-analysis: overall survival Study EBRT n/N No EBRT n/N Peto OR (IPD) 95% CI PORTEC GOG ASTEC + EN5 57/354 30/190 65/452 48/360 36/202 66/453 714 392 905 1.22 [0.83, 1.79] 0.86 [0.57, 1.29] 1.00 [0.71, 1.41] Total (95% CI) 152/996 150/1015 2011 1.02 [0.82, 1.27] N Peto OR (IPD) 95% CI Test for heterogeneity: Chi² = 1.51, df = 2 (P = 0.47), I² = 0% Test for overall effect: Z = 0.20 (P = 0.84) 0.1 0.2 0.5 Favours EBRT 1 2 5 10 Favours No EBRTl 0.2% difference in 5-year OS (87.8% in EBRT and 88% in no EBRT) 95% CI of difference = -2.0% to 3.0% What is the most common outcome after a vaginal cuff relapse when no previous radiotherapy has been delivered? 1. Patients are salvaged without complications 2. Patients are salvaged with complications 3. No patients are salvage The “Myth” that Isolated Vaginal Recurrences are Easily Salvageable • Accompanying editorial to GOG 99 by Michael Berman noted: “Yet vaginal recurrences usually are treated successfully with radiotherapy in patient not previously treated with adjunctive radiation” • The data from GOG 99 noted that 12 of 13 patients in the NAT arm were treated with salvage radiotherapy – crude observations noted 5 of these thirteen died of endometrial cancer. Immediate versus delayed RT • Salvage rate may not be as high as those commonly quoted. • > 70% results are typically quoted. • Most studies do not support this even in isolated vaginal recurrences. • Survival typically range around 40 – 50 %. • Poorer outcomes in non-vaginal pelvic recurrences. Salvage RT Series Locally Recurrent Endometrial Cancer Author Number Local Control 5 Years Survival Kuten (1989) 51 35% 18% Jereczek(2000) 73 48% 25% Curran (1988) 47 48% 31% Jhingran (2003) 91 75% 43% Hoekstra (1993) 26 84% 44% Sears (1994) 45 54% 44% Hart (1998) 26 65% 53% Wylie (2000) 58 65% 53% Lin (2005) 50 74% 53% Creutzberg (2003) 35 77% 66% Salvage treatment with high-dose-rate brachytherapy for isolated vaginal endometrial cancer recurrence • • • • • • And the risk of toxicity should NOT be ignored 22 isolated vaginal recurrences 18 EBRT + HDR, 4 HDR alone Median follow-up 32 month 18% grade 3-4 GI toxicity 50% grade 3 vaginal sequelae Petignat et al. Gynecol Oncol 2006; 101:445 Population Based Data SEER analysis: efficacy of RT • SEER program (NCI), 10% US population • 21.249 patients, 1988-2001 • 19% of patients had RT (82% EBRT) • 43% had surgical node sampling Lee et al, JAMA 295, 389-97, 2006 Multivariate Analysis Table 2. Cox regression analysis with relative survival endpoint Covariates Stage 1A, Grade I Stage 1B, Grade I Stage 1C, Grade I Stage 1A, Grade II Stage 1B, Grade II Stage 1C, Grade II Stage 1A, Grade III/IV Stage 1B, Grade III/IV Stage 1C, Grade III/IV Race/ethnicity=Black Pathologic Node Negative at TAH-BSO Age at Diagnosis (per decade, base age 65) Radiation + Stage 1A, Grade I Radiation + Stage 1B, Grade I Radiation + Stage 1C, Grade I Radiation + Stage 1A, Grade II Radiation + Stage 1B, Grade II Radiation + Stage 1C, Grade II Radiation + Stage 1A, Grade III/IV Radiation + Stage 1B, Grade III/IV Radiation + Stage 1C, Grade III/IV HR (95% CI) 1.000 1.13 (0.97-1.31) 2.06 (1.63-2.61) 1.38 (1.14-1.67) 1.47 (1.27-1.72) 2.04 (1.64-2.54) 2.47 (1.97-3.11) 2.64 (2.21-3.16) 5.09 (4.09-6.32) 0.54 (0.46-0.63) 0.90 (0.83-0.98) 1.79 (1.73-1.86) 0.85 (0.40-1.80) 0.91 (0.64-1.29) 0.45 (0.32-0.64) 1.37 (0.82-2.28) 1.00 (0.81-1.24) 0.96 (0.76-1.21) 1.02 (0.66-1.57) 0.98 (0.80-1.19) 0.74 (0.58-0.93) *Baseline reference group= no radiation, stage 1A, grade 1 cohort. p value reference .13 <.001 <.001 <.001 <.001 <.001 <.001 <.001 <.001 <.001 <.001 .67 .59 <.001 .23 .97 .75 .93 .82 .009 What is the “best” RT • It is clear that radiotherapy is indicated in high risk early stage endometrial cancer. • Can VBT replace external beam for the majority of these patients? An American Brachytherapy Society Survey Regarding the Practice Patterns of PostOperative Irradiation for Endometrial Cancer William Small Jr., M.D. Beth Erickson, M.D. Francis Kwakwa, M.A. Has there been an increasing trend for referrals for vaginal brachytherapy? YES 54.2 NO 31.8 NO OPINOIN 12.8 PORTEC - 2 trial (2002-2006) Stage I-IIA endometrial carcinoma • age > 60 and IC grade 1-2, or IB grade 3 • stage 2A (except grade 3 > 1/2) • surgery: TAH-BSO Groningen Waddenzee Friesland Noord Holland pelvic radiotherapy Flevoland R Zuid Holland vaginal brachytherapy Drenthe Ijsselmeer Overijssel Gelderland Utrecht Noord Brabant Zeeland Limburg PORTEC-2 Randomized Between: Pelvic Radiotherapy – 46 Gy in 23 fractions VS Vaginal Brachytherapy – 21 Gy HDR or 30 Gy LDR PORTEC-2 Author Conclusions • “Despite the slightly but significantly increased pelvic failure rate in the VBT arm, DM, RFS and OS were similar. As patient reported quality of life after VBT was…better, VBT should be the treatment of choice for patients with high-intermediate risk endometrial cancer” PORTEC-4 • HIR endometrial carcinoma • Vaginal brachytherapy vs no further treatment • 21 Gy in 3 fractions vs 15 Gy in 3 fractions 2 R 1 1 VBT 3 x 7 Gy at 5 mm 1 VBT 3 x 5 Gy at 5 mm No further treatment Close FU; EBRT/VBT for vaginal relapse 4 How should you treat – so called – intermediate risk patients? • The data on unselected patients consistently shows a reduction in vaginal recurrences. • I believe the “best” technique is to look at all the risk factors before deciding on an individual patient. Departments of Radiation Oncology, Preventive Medicine, and Obstetrics and Gynecology, Division of Gynecologic Oncology, Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL. Int J Radiol Oncol Biol Phys,. Volume 84, Number 2 (2012) 415-419. Patient and tumor characteristics (n = 252) Characteristic Patients (n) Follow-up (mo) Median Range Age (y) Median Range Type of surgery TAH/BSO without LN biopsy TAH/BSO with LN biopsy Pelvic LNs removed Median Range Para-aortic LNs removed (n) Median Range VBT 169 NAT p 83 <0001 104 1-330 61 0-328 .71 61 29-89 60 33-85 28 (16.6) 18 (21.7) .39 141 (83.4) 66 (79.5) .49 .03 10 0-36 8 0-32 .002 3 0-19 2 0-12 Patient and tumor characteristics (n = 252) Characteristic Tumor histologic grade 1 2 3 Depth of invasion (cm) Median Range Lymphatic or vascular space invasion Interval from surgery to RT (d) Median Range VBT NAT p .01 96 (56.8) 64 (37.9) 9 (5.3) 63 (75.9) 17 (20.5) 3 (3.6) .0006 0.30 0.072.40 0.22 0.020.90 19/153 (12.4) 4/72 (5.6) 41 8.257 NA .16 Patient outcomes data Variable Disease status (all patients) Alive without disease Dead of another cause Alive with disease Dead of disease Recurrence Interval from surgery to recurrence (mo) Median Range Recurrence location* Vagina Pelvis Para-aortic Upper abdomen Lung Status after recurrence Alive without disease Died of another cause Alive with disease Died of disease VBT (n = 169) NAT (n = 83) p .07 145 (85.8) 18 (10.7) 1 (0.6) 5 (3.0) 8 (4.7) 40 9-102 78 (94.0) 2 (2.4) 1 (1.2) 2 (2.4) 6 (7.2) 19 2-49 1 4 1 3 3 3 2 0 1 0 3 (37.5) 1 (12.5) 1 (12.5) 3 (37.5) 3 (50) 0 (0) 1 (16.7) 2 (33.3) Abbreviations: NAT – no adjuvant therapy; VBT = vaginal brachytherapy Data in parentheses are percentages *Several patients had multiple sites of recurrence NS NS Vaginal Brachytherapy Techniques When delivering Vaginal Brachytherapy in a patient with endometroid histology – what is your typical target? 1. 2. 3. 4. 5. Upper 2 cm of the vaginal. Upper 3 cm of the vaginal Upper one third of the vagina. Upper one half of the vagina. The entire vagina. When delivering Vaginal Brachytherapy in a patient with endometroid histology – what is your typical dose? 1. 6 Gy times 5 to the vaginal mucosa. 2. 4 Gy times 6 to the vaginal mucosa. 3. 7 Gy times 3 to 0.5 cm from the vaginal mucosa. 4. 5.5 Gy times 4 to 0.5 cm from the vaginal mucosa. 5. Other. American Brachytherapy Society consensus guidelines for adjuvant vaginal cuff brachytherapy after hysterectomy. William Small, Jr., M.D.,1*, Sushil Beriwal, M.D., 2 D. Jeffrey Demanes, M.D.,3 Kathryn E. Dusenbery, M.D., 4 Patricia Eifel, M.D.,5 Beth Erickson, M.D., 6 Ellen Jones, M.D., 7 Jason J. Rownd, M.D.,8 Jennifer F. De Los Santos, M.D., 9Akila N. Viswanathan, M.D.,10 and David Gaffney, M.D.11 Brachytherapy 11(2012) 58-47. Pay particular attention to healing – especially on the current proliferation of robotic surgery. Choose the applicator that is correct for the clinical situation. Cylinders most common which range in size from 2 – 4 cm. Placement of a radio-opaque seed or clip(s) at the vaginal apex should be considered. Place the largest cylinder that fits comfortably. Minimize movement from placement, planning and treatment. 7 Gy X 3 to 0.5 cm is the most commonly prescribed fractionation scheme. Many sites use different fractionation schemes. I use 5.5 Gy X 4 to 0.5 cm. Diameter Size (cm) Vaginal Surface @ 5 mm 2 100% 60% 3 100% 68% 4 100% 71% Intensity Modulated Radiation Therapy • IMRT may decreases the risk of severe sequelae • Dosimetric studies demonstrate significant sparing of small bowel, bladder and rectum • Preliminary outcome studies have noted low toxicity rates and excellent Pelvic Control. Atlas Update In Progress • Utilize patterns of recurrence data from RTOG 0418. • Better define obturator nodal region. • Eliminate all reference to boney landmarks. • Give recommendations regarding rectal distention. • Included recommendations for common iliacs and para-aortic CTV. Dosimetric Studies • IMRT versus conventional Pelvic RT Small Bowel Bladder Rectum Decreases the volume receiving the prescription dose by Roeske 50% 23% 23% Heron 51% 31% 66% Chen 70% NS NS Ahamad 40 – 63% NS NS Wong 95% NS NS Clinical outcome studies Adjuvant IMRT in Endometrial Cancer Number Follow up DFS Pelvic Chronic Control Toxicity Knab 31 24m 84% 100% Beriwal 47 20m 100% No ≥ Grade 2 2.1% at 3 years ≥ Grade 2 Knab et al, Int J Radiat Oncol Biol Phys 2004 ; 60:303 Beriwal et al, Int J Radiat Oncol Biol Phys 2006 ; 66:S41 Efficacy and safety of IMRT after surgery in patients with endometrial cancer: RTOG 0418 phase II study Anuja Jhingran, Kathryn Winter, Lorraine Portelance, Brigitte Miller, Mohammad Salehpour, Rakesh Gaur, Louis Souhami, William Small, and David Gaffney Supported by RTOG U10 CA21661, CCOP U10 CA37422, and ATC U24 CA 81647 NCI grants. 89 RTOG 0418 • Objectives: – Primary – to determine the transportability of pelvic IMRT for patients with endometrial carcinoma to a multi-institutional setting. – Secondary • To assess adverse events related to this regimen. • To test the hypothesis that there is a reduction in short-term bowel injury with this regimen compared to standard treatments. • To estimate the rates of local-regional control, distant metastasis, disease-free and overall survival. 90 RTOG 0418 – Endometrial Arm Protocol • Chemotherapy was not allowed in the endometrial arm. • Guidelines for contouring were detailed in protocol as well as a web-base atlas. • Dose/volume constraints for targets and normal tissue were outlined. • Patients were simulated with a both empty and full bladder scan and a vaginal ITV was contoured encompassing contours from both scans. Pts. were treated on full bladder scan. • Dose to nodal PTV and vaginal PTV (ITV with margin) was 50.4 Gy in 28 fractions. • Vaginal brachytherapy was allowed at the discretion of the physician. 91 RTOG 0418 – Endometrial Arm Protocol • Central quality assurance was performed – the first case from each institution was reviewed by one of the two PIs prior to treatment and the second case could be reviewed at the discretion of the PIs. • Adverse events (AEs) were assessed using the CTCAE v. 3.0. • Primary endpoint - if <5 of 42 treatments delivered 50.4 Gy to the nodal PTV and to vaginal PTV, then the protocol is considered reproducible. 92 RTOG 0418 – Endometrial Arm GI Toxicity (n=40) Overall Grade 0/1 Grade 2+ n % n % 29 73 11 28 Adverse Event # days from start Grade A Enteritis 38 2 B Diarrhea 37 2 C Diarrhea 41 2 Enteritis 41 2 D Enteritis 40 2 E Enteritis 55 2 F Stricture 139 2 Diarrhea 35 2 Enteritis 35 2 Proctitis 35 2 G Diarrhea 24 3 H Diarrhea 41 2 I Diarrhea 35 2 J Diarrhea 51 2 K Diarrhea 23 3 RTOG 0418 Purpose – Secondary Endpoints • To estimate the rates: – Local-regional recurrence – Distant recurrence – Disease-free survival – Overall survival • Assess adverse events 94 RTOG 0418 – Endometrial Arm • • • • • Study period – March 2006 – June 2007 58 patients enrolled, 43 eligible patients Median age – 57 (min-max: 36-73) Median FU – 3.5 years (min-max: 1.0-4.4) OS and DFS rates estimated using the KaplanMeier method. • Local-regional and distant recurrence rates estimated with the cumulative incidence method. 95 RTOG 0418 – Endometrial Arm Tumor Stage and Grade IB, G2-3 IIIC IIB IC, G1-3 IIA 96 RTOG 0418 – Endometrial Arm Outcomes Endpoint Number of Failures Overall Survival 4 Disease-Free Survival Local-Regional Failure Para-aortic nodes Distant (excluding paraaortic nodes) 5 3 2 3 Estimated 2-Year Rate (95% CI) 95.2% (82.3, 98.8) 90.6% (76.8, 96.4) 7.0% (0, 14.8) 4.8% (0, 11.3) 7.1% (0, 14.9) Estimated 3-Year Rate (95% CI) 92.4% (78.0, 97.5) 90.6% (76.8, 96.4) 7.0% (0, 14.8) 4.8% (0, 11.3) 7.1% (0, 14.9) 97 RTOG 0418 – Endometrial Arm Cause of Death Cause of Death n (%) Treated Cancer Intracranial hemorrhage 2 (50%) 1 (25%) Unknown Total 1 (25%) 4 (100%) 98 RTOG 0418 – Endometrial Arm Conclusions • IMRT in the post-operative setting is feasible across multiple institutions using a detailed protocol and centralized Q/A and may be used in phase III protocols. • G2 and higher small bowel toxicity was reduced from 40% in traditional XRT to 28% with IMRT (p = 0.13) – not powered to detect a 12% decrease. • Contouring of OARs were all within minor deviations except for small bowel which needs a better definition. • Contouring of nodal and vaginal tissue had some major deviations and will need continued monitoring with good Q/A in a protocol setting. RTOG 0418 – Endometrial Arm RTOG 0418 – Endometrial Arm RTOG 0418 – Endometrial Arm RTOG 0418 – Endometrial Arm RTOG 0418 – Endometrial Arm CASE STUDY • The patient was treated with pelvic IMRT on RTOG 0418 with concurrent weekly cisplatin. • An ITV was accomplished to determine the CTV. • The consensus contouring guidelines were utilized to draw the CTV. Full and Empty Bladder Full and Empty Bladder Full and Empty Bladder The Practice of Post Operative Pelvic IMRT in Gynecological Malignancies 1) The CTV needs to be as accurate as possible. 2) Internal target motion MUST be accounted for simple daily cone beam CT’s are inadequate because the nodal volumes will follow boney landmarks – whereas the vaginal volumes are influenced by bladder and rectal filling. 3) Therefore a ITV is critical unless daily bladder and rectal volume is regulated. Should IMRT be A Standard Therapy In the Postoperative Treatment of Endometrial Cancer A RANDOMIZED PHASE III STUDY OF STANDARD VS. IMRT PELVIC RADIATION FOR POST-OPERATIVE TREATMENT OF ENDOMETRIAL AND CERVICAL CANCER (TIME-C) CO-PIS ANN KLOPP MD, PHD ANAMARIA YEUNG MD PRO AND QOL CO-CHAIR LARI WENZEL, PH.D. KAREN GIL, PH.D. COST ANALYSIS CO-CHAIR ANDRE KONSKI, MD, MBA, MA, FACR STATISTICIAN STEPHANIE SHOOK TIME-C: Objectives Primary Objective: oTo determine if acute gastrointestinal toxicity is reduced with IMRT using patient reported measure of toxicity Secondary Objective: oTo determine if acute grade 2 gastrointestinal toxicity (CTCAE v. 3.0) is reduced with IMRT compared to conventional WPRT. oTo determine if acute grade 3+ hematologic toxicity (CTCAE v. 3.0) is reduced with IMRT compared to conventional WPRT. oTo determine if acute urinary toxicity is reduced with IMRT using a patient reported measure of toxicity. oTo assess the impact of pelvic IMRT on quality of life using patient reported outcomes. Schema Eligibility Women with endometrial or cervical cancer P postrequiring operative pelvic radiation or chemoradiation Stratification factors XRT dose • 45 Gy • 50.4 Gy Chemotherapy P • No Chemotherapy • 5 cycles of weekly cisplatin at 40mg/m2 Disease Site •Endometrial •Cervix R A N D O P M I Z E IMRT pelvic radiation P treatment 4-field pelvic radiation P treatment Post-Treatment Complications PORTEC 1 : Long Term QOL SF-36 Scores EBRT NAT Remain close to the toilet related to urinary control 26 10 Urinary Incontinence 30 16 Limitations of daily activity related to bowel symptoms 26 15 Nout et al; JCO, 2011 PORTEC 1: EBRT Technique • 52% Four Field (5-year comp rate 21%) • 18 % Three Field (5-year comp rate 36%) • 30 % AP/PA (5-year comp rate 30%) – 5 Yr actuarial rate of toxicity 26 % vs. 4 % – Grade 3 or 4: 3 % vs 0 % - 67 % of complications Grade 1, Grade 2: 7 % vs 1%. – P=0.06 for technique and complication rate. Creutzberg, In J Rad Oncol Biol Phys, 2001 Vaginal Length after Vaginal Brachytherapy for Endometrial Cancer William Small Jr., MD Professor The Robert H. Lurie Comprehensive Cancer Center of Northwestern University Vaginal Length after Intracavitary Radiotherapy Looked at 90 patients with intracavitary RT after treatment for cervical or endometrial CA (48). Measurements were taken at 6 and 12 months and then yearly. The vaginal dilator compliance rate was 68 % of using 1 o more times per week. Bruner et al, Int J Radiol Bilo Phys, 1993 Objective Feasibility study to assess changes in vaginal length from pre- to post- vaginal brachytherapy for endometrial cancer in women prescribed vaginal dilators. Methods Patients randomized to standard vs enhanced education: Standard: Enhanced: • Given smooth plastic vaginal dilator • Dilatation began 2-4 wks post completion of VBT • Written instructions on dilator use Encouraged to engage in sexual intercourse with vaginal penetration as per institution standard • Attention control telephone calls at weeks 1, 4, 12, and 18 • Standard + intensive, theory driven education and counseling Endpoint – Change in Vaginal Length Metric – Vaginal Sound Modified plastic vaginal dilator Calibrated in centimeters 15 cms long X 2.85 cms in diameter Inter-rater reliability tested by GOG during two training sessions with live models - 88 MDs and RNs from over 45 institutions attended a 1/2 hr didactic session followed by a 1- hr clinical practicum - Measurements taken by instructor and student at each insertion Inter-rater reliability was high with intraclass correlation coefficients of 0.88 among instructors and 0.76 among trainees For purposes of this study – each individual physician underwent a training session with the study PI and a the investigators ability to reliably measure was confirmed on a patient. Bruner et al Int J Gynecol Cancer.;16(5):1749-55, 2006 Results Preliminary findings of the first 23/50 women with VL data pre and 6 mo post VBT: PreVBT VL 8.7cm (SD + 1.51) PostVBT VL 8.8cm (SD + 1.58) Dilator compliance was variable at 6mos: • 22% using the dilator <1 time/week • 22% using the dilator 1 time/week • 56% using the dilator 2-3 times/week Conclusions No difference in VL from before to 6 mos after VBT for the treatment of endometrial cancer Increased dilator use may be beneficial in preventing loss of vaginal length post VBT but requires further study Second Primaries Treatment delivered Observed/Expected No Radiation 0.92 Brachytherapy Alone 0.97 EBRT Alone 1.1 EBRT and Brachy 1.22 Any Radiation 1.09 Brown et al., Int J Radiol Biol Phys, 2010. Colon Cancer Source: International Journal of Radiation Oncology * Biology * Physics 2010; 78:127-135 (DOI:10.1016/j.ijrobp.2009.07.1692 ) Copyright © 2010 Elsevier Inc. Terms and Conditions Vaginal Cancer Source: International Journal of Radiation Oncology * Biology * Physics 2010; 78:127-135 (DOI:10.1016/j.ijrobp.2009.07.1692 ) Copyright © 2010 Elsevier Inc. Terms and Conditions Cumulative Risk of Bladder Cancer Bladder Cancer Risk PORTEC 1 • At a median follow-up of 13.3 years 19% of the patients had a second primary. • 22% in the EBRT group, • 16% in the no additional treatment group • P=0.10 Creutzberg, Int J Radiol Biol Phys, In Press Locally Advanced Disease • In general, most reports have used “involved field” radiotherapy for patients with Stage III disease. Whole Abdominal Radiotherapy • GOG 122 noted a significant worse outcome in advanced patients with WAR (38% 5-year survival) as compared to chemotherapy. • GOG 122 delivered 30 Gy to the whole abdomen and 15 Gy to the pelvis – 25 % of patients with stage IV. • Our series of WAR patients noted a 86 % 5-year survival, Smith et al noted a 77 % 3-year survival. Pelvic Recurrence Advanced Disease Author Stage Radiotherap y Chemotherap Observatio y n Patel et al, 2007 III 13% - 33% - 77 % non Vag Vault Mundt et al, 2001 I-IV - 39.5 % – 53% non Vag - Small et al, 2000 I-IV 10 % - - Randall et al, III-IV 2008 13% (Initial) 18% (Initial) Hoekstra et al, 2009 0% IIIC EBRT and outcome Pelvic relapse Disease-specific survival Overall survival Klopp et al Gyn Oncology 2009 SEER DATA • Schmid et al (Gyn Onc, 2009) reviewed the SEER data base from 1988 – 2001 • 5-year disease specific survival (DSS) with RT 67.9% vs 53.4% without RT (p<0.001). • Single lymph node DSS 74.3 vs. 54.4 % (p<0.001), 2-5 lymph nodes DSS 59.7 vs. 52.7 % (p=0.089). SEER DATA • • • • Endometroid 73.7 vs 61.9% (p=0.007) Clear Cell 77.1 vs. 39.2% (p=0.046) Papillary Serous 44 vs. 45.5 % (p=0.48) Sarcoma 44.9 vs 46.3 % (p=0.51) – The data remained significant on multivariate analysis My Current General Treatment Approach Stage I Patients Limited*/No Lymph Node Surgery Given PORTEC/ASTEC Results – Becoming Increasingly Similar to Dissected Patients Grade I Grade II 1 1 IA (Inv) VB2,3 VB2,3 VB 3 IB VB4 VB4 Pelvic +/VBT IA (No Inv) Grade III VB • *<10 nodes, limited number of sites (arbitrary definition ) – Radiographic Imaging for all but Stage 1A Grade1 and 2 • 1 Low risk of vaginal recurrence and nodal involvement • 2 Consider observation for minimal invasion – no high risk features. • 3 Consider pelvic RT instead if +LVI and close to ½ MI +/- advanced age • 4 Consider pelvic RT instead if +LVI, deep invasion, advanced age In surgically staged patients, VB alone is becoming the preferred adjuvant RT approach • Stage I Patients Surgically Staged* Grade 1 Grade 2 Grade 3 IA ( No Inv) -- -- VB IA (Inv) -- 1 VB 2 VB 2 IB VB 3 VB 3 Pelvic +/- VB4 • *>10 nodes, multiple sites (arbitrary cut off) • 1 Consider VB depending on other high-risk features. • 2 Consider observation depending on other high-risk features. • 3 Consider Pelvic Radiotherapy if with high-risk features • 4 Consider VBT if limited invasion and minimal high-risk features. Stage II Patients • In general, I deliver pelvic radiotherapy followed by a VBT boost – depends on the surgery that is accomplished. Stage III Patients • I generally deliver tumor directed radiotherapy. What About Lymph Node Dissection GOG 33- Creasman A surgical/pathologic study of 621 patients with clinically stage I endometrial cancer Percent of patients with positive pelvic LN’s Invasion Grade 1 Grade 2 Grade 3 None 0 3 0 Inner 3 5 9 Middle 0 9 4 Deep 11 19 34 Efficacy of systematic pelvic lymphadenectomy in endometrial cancer (MRC ASTEC trial): a randomised trial . • 85 Centres, 4 Countries, 1408 women • Hysterectomy and BSO +/- pelvic lymphadenectomy In GOG 33 LN’s • Intermediate or high risk early stage disease% positive 5-9% – FIGO (1988) IA or IB with high grade pathology – FIGO (1988) IC or IIA 10-34% • Controversial point: “To control for post-surgical treatment…randomized (independent of lymph node status) into the ASTEC radiotherapy trial Lancet 2009; 373: p125-36 ASTEC Tx Randomization • Because women were randomized to adjuvant radiotherapy without regard to the results of the pelvic lymph node dissection: – This is a study of the surgical benefit to removing lymph nodes. – It does not answer the question of whether detecting occult nodal metastasis in low and intermediate risk patients better directs adjuvant tx and thus improves survival. ASTEC Survival and sites of recurrence Cause Of Death No LN LN’s removed Total 88 13% 103 15% Disease 65% 63% Treatment related 5% 7% Disease & Treatment 0 2% Not Disease 30% 28% What About Chemotherapy? Is it the next step to improving overall survival? GOG 122 Schema GOG 122 Dox/CDDP WART p=.01 Adjuvant chemotherapy versus radiotherapy in highrisk endometrial carcinoma: result of a randomised trial Stage IC G3 STAGE II G3 >50% MI Stage III Regimen 1: Pelvic RT (45-50 gy) Regimen 2: CDDP, Adriamycin, Cytoxan 5 cycles R Maggi et al, BJC,2006;95:266 Adjuvant chemotherapy versus radiotherapy in highrisk endometrial carcinoma: result of a randomised trial • Median follow up 95.5 months • No difference in 5 Year DFS or OS • RT • locoregional initial recurrence: 7 %, • Distant: 21 %, • Both:5 • Chemotherapy • locoregional initial recurrence: 11%, • Distant: 16 %, • Both:5 % • RT reduced local recurrence, chemotherapy reduced distant failure R Maggi et al, BJC,2006;95:266 Chemotherapy • Such results suggest that a more prudent approach would be to combine chemotherapy and RT • Published trials, however, have reported mixed results GOG 34 • Chemotherapy did not improve outcome 3 Years Survival Extra-Pelvic Failure RT Alone 75% 22.5% RT + Adriamycin 68% 16.3% P = NS P = NS • Moreover, 12 (7%) of these surgically staged patients developed a SBO after pelvic +/- PART • Maybe adriamycin alone is not enough To test a more aggressive regimen, the RTOG launched RTOG 9708 Stage I – III TAH – BSO +/- Nodal Surgery Grade 2-3 > ½ MI + cervical stroma Extra-uterine (Pelvic only) disease + washings Pelvic RT 45 Gy +VB CDDP 50 mg/m2 Days 1,28 Four cycles Chemo CDDP 50 mg/m2 + Paclitaxel 175 mg/m2 Kathryn Greven et al., Gynecol Oncol 2006;103:155 Concurrent and adjuvant chemotherapy Phase II trial RTOG (46 pts): • stage I-II high risk or stage III (66%) Concurrent: cisplatin 50 mg/m2 days 1, 28 Adjuvant: 4x cisplatin 50 mg/m2 and paclitaxel 175 mg/m2 • 4-yr locoregional relapse 4%, distant 19% • 4-yr DFS 81%, OS 85% (stage III: 77 and 72%) • No recurrences in stage IC, IIA, IIB promising data, phase III needed – attempted in RTOG 9901 – closed for lack of accrual. Only high-risk early stage in that trial related to competing Phase III GOG randomized trial for Stage III patients, Greven et al, Gynecol Oncol 2006 NSGO EC-9501/EORTC-55991 May 1996 to January 2007 Randomization n=382 RT ≥ 44 Gy XRT ± n=196 optional VBT (39%) Radical surgery TAH+BSO (+PLA) RT+CT Surgical stage I, II, IIIA (positive peritoneal fluid cytology only), or IIIC (positive pelvic lymph nodes only) with high risk for micro-metastatic disease Patients with serous, clear cell, or anaplastic carcinomas were eligible regardless of other risk factors OR (VBT 44%) n=186 CT+RT CT : intially AP Later AP, TcP, TAP, TEcP Primary endpoint Progression-free survival (PFS) Thomas Hogberg, Lund Univ Hosp Oct 2009 NSGO EC-9501/EORTC-55991 PFS progression-free survival (PFS) 0.79 0.75 Chemo/RT 0.50 RT alone 0.72 0.25 HR 0.63 (95 % CI 0.41 - 0.98) p = 0.04 0.00 probability of survival 1.00 PFS NSGO-EC-9501/EORTC-5591 0 1 2 3 4 5 123 143 110 119 84 82 years Number at risk random = 0 191 random = 1 186 170 175 149 158 random = 0 random = 1 Thomas Hogberg, Lund Univ Hosp Oct 2009 Combined Modality Trials • Several new combined modality trials are underway or in the planning stages • GOG 249 compares pelvic RT versus VB + chemotherapy in intermediate risk Stage I and IIa patients • PORTEC-3 comparing pelvic RT versus pelvic RT + chemotherapy in high risk pts • GOG 258 compares chemotherapy alone versus chemotherapy plus volume directed RT in advanced stage patients. When utilizing IMRT in the post-operative treatment of endometrial cancer the MOST important aspect of treatment is? 1. Daily image guidance. 2. Asking the patient to have a full bladder on a daily basis. 3. Assuring that bone and bowel are excluded from the CTV. 4. Carful attention to an ITV. Conclusions • RT continues to play an important role in endometrial cancer • Its optimal role is still evolving • Attention turning to combined modality approaches in high risk patients following surgery • Novel approaches, notably IMRT and in the future IGRT, should help improve the quality and delivery of RT in these women.