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Radiotherapy in high risk early endometrial cancer

Radiotherapy in high risk early endometrial cancer. Wui-Jin Koh, MD Department of Radiation Oncology University of Washington, Seattle, WA. Endometrial cancer case. 64 yo, diet-controlled DM, BMI=35 PMB  EMB = Gr2 endometriod adenocarcinoma

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Radiotherapy in high risk early endometrial cancer

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  1. Radiotherapy in high riskearly endometrial cancer Wui-Jin Koh, MD Department of Radiation Oncology University of Washington, Seattle, WA

  2. Endometrial cancer case • 64 yo, diet-controlled DM, BMI=35 • PMB  EMB = Gr2 endometriod adenocarcinoma • CXR neg, CBC/BMP WNL, pt deemed surgical candidate • Vaginal hysterectomy + BSO • Path • 3 cm tumor, LVSI+, 75% myoinvasion • Cul-de-sac washings negative Case from 3/07 Int Gynecologic Cancer Society tumor board, submitted by Dr Karl Podratz www.igcs.org

  3. Endometrial cancer case(64 yo, Gr 2, LVSI+, 75% invasion) • Would you consider the patient cancer to be • Low risk? • Intermediate risk? • High risk?

  4. Endometrial cancer case(64 yo, Gr 2, LVSI+, 75% invasion) • What further therapy would you recommend? • Observation • Vaginal brachytherapy • External radiation +/- brachytherapy • Chemotherapy • Chemotherapy and radiation • Surgical staging including retroperitoneal LND www.igcs.org

  5. Endometrial cancer case(64 yo, Gr 2, LVSI+, 75% invasion) • Systematic pelvic and PALN dissection to renal vessels • No intraabdominal disease noted • Path: 34 pelvic and 16 PALN harvested • All lymph nodes histologically negative • Repeat peritoneal cytology negative www.igcs.org

  6. Endometrial cancer case(64 yo, Gr 2, LVSI+, 75% invasion, 50/50 LN-) • Would you now consider the patient cancer to be • Low risk? • Intermediate risk? • High risk?

  7. Endometrial cancer case(64 yo, Gr 2, LVSI+, 75% invasion, 50/50 LN-) • What further therapy would you recommend? • Observation • Vaginal brachytherapy • External radiation +/- brachytherapy • Chemotherapy • Chemotherapy and radiation www.igcs.org

  8. Radiotherapy in high-risk early endometrial cancer • Complex, controversial and confusing • “At least Professor Vergote (IGCS president) did not ask you to talk on radiotherapy in early stage ovarian cancer” • Ted Trimble, IGCS president-elect

  9. Radiotherapy in high-risk early endometrial cancer - definitions • Adjuvant RT following primary surgery • RT alone has curative potential in medically inoperable patients • Early = Uterine confined (stage I/II) • Adenocarcinoma, endometriod histology • Uterine papillary serous carcinoma as a distinct entity

  10. Proposed definition of ‘risk’ in EC • High risk - extrauterine disease • (ie – not early stage) • Implies that treatment is needed • Low risk - Stage IA all grades, IBG1, IBG2, IIA? • Intermediate risk • IBG3 • All stage IC’s • Cervical stromal involvement

  11. Endometrial cancer – general observations • Role of adjuvant RT in early disease • Historically overused • Current decreased trend is a good thing! • No randomized trial (n=3) has shown overall survival benefit • improvement in pelvic control, ?PFI • Role of chemotherapy increasing in extrauterine disease, but unproven in early disease

  12. Adjuvant RT for Uterine-confined EC • Issues • Prognostic factors and definitions of risk • Extent of surgical staging • Patterns of failure after surgery • Toxicity of adjuvant therapy

  13. Intrauterine pathologic prognostic factors • Grade • DMI • LVSI • Cervical stromal invasion • Cell type - papillary serous / clear cell • Lower uterine segment involvement? • Tumor bulk • Biomolecular markers (PTEN, Her2/neu, p53…)

  14. Does surgical extent alter risk in EC? • Therapeutic benefit? • Kilgore (Gynecol Oncol 1995); ASTEC 2006 • Alters individual assessment and classification of risk • 1988 FIGO surgicopathologic staging • Risk assessment of clinical vs pathologic uterine-confined EC (Zaino, Cancer 1996) • The harder you look for it, the greater the sensitivity

  15. Surgical-Pathological staging considerations • Without LNS, prognosis primarily based on grade and depth of myometrial invasion (DMI) • Grade & DMI predicts for LN+ • Patients with LN+ now upstaged to IIIC • Stage migration • 92.7% 5-yr survival for pathological Stage I cancer with no adverse risk features other than grade and myoinvasion (Morrow, Gynecol Oncol 1991)

  16. Endometrial cancer case(64 yo, Gr 2, LVSI+, 75% invasion, 3/3 LN-) • Would you now consider the patient cancer to be • Low risk? • Intermediate risk? • High risk? • High intermediate risk?

  17. Role of RT in non-surgically staged EChistorical analysis • Aalders, Obstet Gynecol, 1980 • 540 St I pts, all received ICBT, 6000 rads • Randomized to no vs 4000 rads pelvic RT • No difference in overall survival or overall relapse • Pelvic RT decreased pelvic failure, but altered pattern of failure • ? benefit in patients with grade 3 and > 50% DMI

  18. Efficacy of RT in non-surgically staged EChistorical analysis • Kucera, Gynecol Oncol 1990 • Selective addition of pelvic RT to patients with high risk intrauterine features ‘equalized’ outcome to good prognostic group. • Carey, Gynecol Oncol 1995 • Selective use of pelvic RT in high risk patients achieved good overall outcome.

  19. Role of RT in non-formally staged EC?Contemporary analysis • PORTEC (Creutzberg Lancet 2000, Sholten IJROBP 2005) • 714 patients, ICG1, IBG2, ICG2, IBG3 • ICG3 specifically NOT included • Randomized to NAT vs 46 Gy pelvic RT • No brachytherapy • RT decreases LRF, but has no impact on survival • RT not indicated in IBG2, < 60 yo • RT increases morbidity

  20. Role of RT in non-formally staged EC? • PORTEC (Scholten IJROBP 2005) • Centralized path review – 134 cases ‘excluded’ based on stage IB Gr1 ‘downstaging’ – did not affect outcome • 10 yr LR failure rate: S – 14%, S+RT – 5% (p < 0.001) • 73% of LRF’s were isolated vaginal • Risk factors – age ≥ 60, Gr 3, ≥ 50% myoinvasion • If at least 2 of 3 risk factors present • 10 yr LRF rate: S- 23.1%, S+RT – 4.6% • Late toxicity - 5 yr actuarial rates (Creutzberg, IJROBP 2001) • All grades: S – 4%, S+RT – 26% (p < 0.0001) • Grade 1: S- 4%, S+RT – 17% • Grade 3-4: S+RT – 3%

  21. Role of RT in non-formally staged EC? “In view of the significant locoregional control benefit, radiotherapy remains indicated in Stage I endometrial carcinoma patients with high-risk features for locoregional relapse.” PORTEC –Scholton, IJROBP 2005

  22. Role of RT in surgically staged EC?Contemporary analysis • GOG 99 (Roberts, SGO 1998 abst) • 392 pathologic stage IB/IC/occult II patients, all grades • Randomized to NAT vs 50 Gy pelvic RT • No brachytherapy • Significant decrease in pelvic failures • “Use of adjunctive RT in women with intermediate risk EC decreases the risk of recurrences but has an inappreciable effect on overall survival”

  23. Role of RT in surgically staged EC?GOG 99(Keys, Gynecol Oncol 2004) Overall survival: HR 0.86 (90% CI 0.57-1.29, p=0.56), median f/u 69 m

  24. Benefit of RT in HIR subset of GOG 99?(Keys, Gynecol Oncol 2004) • “High Intermediate Risk” • Gr 2 or 3, LVSI, outer third myometrial invasion • Age > 50 and 2 of above • Age > 70 and 1 of above “Adjuvant RT in early stage intermediate risk endometrial carcinoma decreases the risk of recurrence, but should be limited to patients whose risk factors fit a high intermediate risk definition.”

  25. Role of RT in surgically staged EC?GOG 99(Keys, Gynecol Oncol 2004) S (n=202) 88% 18 13 1 S+RT (n=190) 97% (p=0.007) 3* 2* 8 2-yr recur-free Confined pelvic/ vaginal failure Isolated vaginal Failure GI comp ≥ Gr 3 * 2 of these patients refused radiotherapy

  26. Patterns of failure in early endometrial cancer undergoing surgery only– implications for treatment • The majority of pelvic failures in both PORTEC and GOG 99 were isolated vaginal • Are non-radiated isolated vaginal failures curable? • PORTEC – 5 yr survival 65% • GOG 99 – 5/13 DOD on preliminary evaluation • Predictors of vaginal relapse • Gr 3 histology, LVSI+ (Mariani, Gyn Oncol 2005) • Can adjuvant vaginal brachytherapy address potential vaginal failures, and improve the therapeutic index?

  27. IVBT as adjuvant for uterine-confined EC- intermediate risk • Chadha et al, Gynecol Oncol 1999 • 38 pathologic stage I EC, full surgical staging • IB/G3 - 12, IC/G1 - 14, IC/G2 - 9, IC/G3 - 3 • IVBT 7 Gy x 3 @ 0.5 cm • 5 yr DFS 87%, 5 yr OS 93% • No vaginal/pelvic failure, 3 failed in upper abd • No significant late morbidity

  28. IVBT as adjuvant for uterine-confined EC- intermediate risk • Ng et al, Gynecol Oncol 2000 • 77 pathologic stage I EC, full surgical staging • IBG3 - 17, ICG1 - 10, ICG2 - 33, ICG3 - 17 • IVBT 60 Gy LDReq to upper 2 cm mucosa • 5 yr DFS = 82%, 5 yr OS = 94% • 11 recurrences • 3 distant, 1 pelvis • 7 vagina (5 lower 2/3) • No significant late complications

  29. IVBT as adjuvant for uterine-confined EC- intermediate risk • Ng et al, Gynecol Oncol 2001 • 15 pathologic stage II(occ) EC, surgically staged • IIA - 5, IIB - 10 (G1 - 5, Gr 2 - 8, Gr 3 - 2) • IVBT 60 Gy LDReq to upper 2 cm mucosa • Median f/u = 36 months • No recurrences • No significant complications

  30. Cost of therapy • IVBT less costly than external beam RT • Patient convenience • Ancillary costs • Time to recovery • Time away from employment

  31. IVBT as adjuvant for uterine-confined EC • Vaginal failures occur in 8 - 15% (with identifiable risk factors) • Despite surgery! • IVBT addresses primary site of preventable failure • Especially in surgically staged patients • PORTEC 2 – ext RT vs IVBT

  32. IVBT as adjuvant for uterine-confined EC • Effective in preventing vaginal relapse • When applied appropriately • Prevention is better than salvage • Well-tolerated • If disease volume at risk is beyond the ‘reach’ of IVBT, local-regional therapy alone may be insufficient (!?)

  33. Role of external RT in EC? • Documented extrauterine disease • High risk of extrauterine disease • Incompletely staged cases with significant intrauterine risk factors • ‘greatest-risk’ subset of early EC, independent of surgical staging • IC Gr3, IIB

  34. Contemporary imaging tools in RT planning CT with digital subtraction RA IMA AB CIB Circ iliac

  35. Contemporary RT imaging/planning tools CT reconstruction PET Rose, 1997 Mundt, U Chicago

  36. 100% 100% PTV PTV 70% 70% RT isodose distribution IMRT 4-field pelvic ‘box’ Courtesy: Arno Mundt, MD

  37. Dose-volume histogram analysis Conv IMRT Courtesy: Arno Mundt, MD

  38. Incompletely staged EC • 70+% of endometrial cancer cases in the US are NOT operated on by Gyn Oncologists • Radiologic Imaging • Consider surgical staging • If you agree that you would not give pelvic RT if no LN involvement is found

  39. Numerator fractional depth of invasion is defined as follows: Endometrium only = 0; inner 1/3 = 1; 1/3 to 2/3 = 2; greater than 2/3 = 3. Tumor grade expressed as 1, 2, or 3. Koh et al, 2001 (based on data from Creasman et al, 1987)

  40. Incompletely staged EC - Adjuvant RT? • Likelihood of LN+ • LN+% = 3 x Grade X DMI (in fractional thirds) • analysis from Creasman, Cancer 1987 • Cure for pathologic stage III EC with PRT ~ 65% • Greven, Cancer 1993 • Complication rate for RT s/p TAH ~ 5% • 0.65 x LN+% > 5% ---> LN+% > 8% to justify PRT?

  41. Grade 1 2 3 St IA IB IC IIA IIB 1999 NCCN guidelines for surgically staged EC - adjuvant RT Obs / ICBT / PRT +/- ICBT Obs Obs Obs / ICBT / PRT +/- ICBT ICBT / PRT +/- ICBT Obs Obs / ICBT / PRT +/- ICBT PRT +/- ICBT PRT +/- ICBT Obs / ICBT* ICBT* PRT + ICBT PRT + ICBT PRT + ICBT PRT + ICBT * if DMI ≤ 50% www.nccn.org

  42. Grade 1 2 3 St IA IB IC IIA IIB 2001 NCCN guidelines for surgically staged early EC - adjuvant RT Obs / ICBT / PRT +/- ICBT Obs Obs Obs / ICBT / PRT +/- ICBT Obs / ICBT / PRT +/- ICBT Obs / ICBT Obs / ICBT / PRT +/- ICBT Obs /ICBT / PRT +/- ICBT PRT +/- ICBT Obs / ICBT* Obs / ICBT* PRT + ICBT PRT + ICBT PRT + ICBT PRT + ICBT * if DMI ≤ 50% www.nccn.org

  43. 2006 NCCN guidelines for surgically staged EC - adjuvant RT • A 3-dimensional table!! • Incorporates traditional grade and depth of invasion • Adds consideration of patient age, LVSI, tumor size

  44. Grade 1 2 3 St IA IB IC IIA IIB 2006 NCCN guidelines for surgically staged early EC - adjuvant RT Obs / ICBT / PRT +/- ICBT Obs Obs Obs / ICBT / PRT +/- ICBT Obs / ICBT / PRT +/- ICBT Obs / ICBT Obs / ICBT / PRT +/- ICBT Obs / ICBT / PRT +/- ICBT ICBT / PRT +/- ICBT Obs / ICBT PRT +/- ICBT Obs / ICBT PRT +/- ICBT ICBT/ PRT +/- ICBT PRT + ICBT PRT + ICBT PRT + ICBT www.nccn.org

  45. Adjuvant RT for early endometrial cancer – metaanalysis and systematic reviews • Cochrane Review(Kong et al, Ann Oncol 2007) • Pelvic RT leads to a 72% RR reduction in locoregional relapses • Trend towards benefit in survival for patients with multiple risk factors (eg Gr3 and stage IC) • Inherent risk of added toxicity • Ontario program in evidence-based care – Gyn Cancer Disease Site Group practice guidelines March 2006 (Lukka et al -www.cancercare.on.ca/pdf/pebc4-10f.pdf) • Regardless of surgical staging, external adjuvant RT • Is recommended for ICG3 • Is NOT recommended for IA/IB G1G2 • Is a reasonable option for IC G1G2, IA/IB G3

  46. Grade 1 2 3 St IA IB IC IIA IIB Adjuvant ext pelvic RT for EC - circa 1984 University of Washington, Seattle

  47. Grade 1 2 3 St IA IB IC IIA IIB Adjuvant ext pelvic RT for EC - circa 1990surgically staged University of Washington, Seattle

  48. Grade 1 2 3 St IA IB IC IIA IIB Adjuvant RT for EC - Y2KSurgically staged ICBT ICBT? ICBT ICBT ICBT ICBT University of Washington, Seattle

  49. Grade 1 2 3 St IA IB IC IIA IIB Adjuvant RT for EC - 2007Surgically staged ICBT ICBT ICBT? ICBT ICBT ICBT ICBT University of Washington, Seattle

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