Radiation Oncology:Endometrium

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  • Creasman WT, Gyn Oncol 1976

Contents

Staging

There is also a clinical staging system developed by FIGO in 1971.

Surgical/pathologic staging (FIGO), AJCC 6th edition:

  • IA - Limited to endometrium
  • IB - < 1/2 of myometrium
  • IC - 1/2 or more of myometrium
  • II - invades cervix
    • IIA - glandular epithelium of endocervix
    • IIB - stroma of cervix
  • IIIA - involves serosa and/or adnexa (direct extension or mets) and/or ascites or positive peritoneal washings
  • IIIB - vaginal involvement (direct extension or mets)
  • IIIC - LN+
  • IVA - bladder or bowel
  • IVB - distant mets

Patterns of spread

Regional LNs include: obturator, internal iliac, external iliac, common iliac, para-aortic, presacral, parametrial

Surgical staging studies

  • Creasman, GOG (1977-83) - Abstract — "Surgical pathologic spread patterns of endometrial cancer. A Gynecologic Oncology Group Study." Creasman WT et al. Cancer. 1987 Oct 15;60(8 Suppl):2035-41.
    • 621 pts, 43 institutions. All pts had clinical Stage I. Underwent TAH/BSO, selective pelvis and para-aortic lymphadenectomy, peritoneal cytology, endocervical curettage prior to surgery to rule out occult Stage II disease. Evaluated site of tumor, grade, depth of invasion, capillary space involvement, adnexal metastasis.
    • Myometrial invasion (middle or deep) in 41%. Positive peritoneal cytology in 12%. Adnexal mets in 5%. Pelvic LN+ in 9%. PA LN+ in 6%. Extrauterine mets in 6%. CSI in 15%. With higher grade tumors, more likely to have middle or deep myometrial invasion (Grade 1, 22%; Grade 2, 44%; Grade 3, 58%). Pelvic LN+ correlated with grade (Grade 1, 3%; Grade 2, 9%; Grade 3, 18%), myometrial invasion (superficial, 5%; middle, 6%; deep, 25%), positive peritoneal cytology (7% vs 25%), involvement of lower uterine segment (double vs fundus only), adnexal mets (32% vs 8%), intraperitoneal spread (51% vs 7%), capillary space involvement (27% vs 7%). For para-aortic LN, similar findings, except histology also mattered (higher risk for "other" category, which included papillary and clear cell, 18% vs 5%). Depth of invasion matters more for LN risk than does grade.
      Low Risk: Grade 1, endometrium only, no intraperitoneal disease -- 0% pelvic LN, 0% PA
      Moderate Risk: inner or middle myometrial invasion, Grade 2 or 3, no intraperitoneal disease -- one factor only: 3% pelvic, 2% PA. two factors: 6% pelvic, 2% PA
      High Risk: deep myometrial invasion only (18% pelvic, 15% PA), intraperitoneal disease (33%, 8%), both (61%, 30%)
    • Positive nodes grossly enlarged only 10% of the time, thus dissection is needed, not just palpation alone.
  • GOG 33 (1977-1983) - Abstract — "Relationship between surgical-pathological risk factors and outcome in clinical stage I and II carcinoma of the endometrium: a Gynecologic Oncology Group study." Morrow CP et al. Gynecol Oncol. 1991 Jan;40(1):55-65.
    • 1180 pts, Stage I and II (occult). Risk of recurrence was highest in Grade 3 tumors. 47 of 48 pts with para-aortic LN had either 1) grossly positive pelvic LN, 2) grossly positive adnexal mets, or 3) outer 1/3 myometrial invasion. 5-year recurrence free rate: 92.7% (negative risk factors other than grade and myoinvasion), 69.8% (Stage II), 56% (positive peritoneal washings), 55% (vascular space invasion), 57.8% (LN+ or adnexal mets), 41.2% (PALN+).

Lymphadenectomy

  • Kilgore, Univ. of Alabama (1969-90) - Abstract Full Text — "Adenocarcinoma of the endometrium: survival comparisons of patients with and without pelvic node sampling." Kilgore LC et al. Gynecol Oncol. 1995 Jan;56(1):29-33.
    • Retrospective study. 649 pts. Compared multiple site pelvic node sampling (mean 11 nodes) vs limited site sampling (mean 4 nodes) vs no sampling. Improved overall survival for pts with multiple site sampling vs no sampling.
  • Duke, 2005 (1973-2002) - PMID 15738538 — "Retrospective analysis of selective lymphadenectomy in apparent early-stage endometrial cancer." Cragun JM et al. J Clin Oncol. 2005 Jun 1;23(16):3668-75.
    • Retrospective. 509 pts. Clinical stage I-IIA.
    • Pts with poorly differentiated tumors and more than 11 lymph nodes removed had improved survival and PFS compared with those with < 11 LN. Number of nodes removed was not predictive for grades 1-2.

Ongoing trials:

  • UK Medical Research Council-ASTEC trial - Randomized. Role of lymphadenectomy in intermediate to high-risk endometrial cancer

Postoperative radiotherapy

  • Norwegian Trial (1968-1974) - Abstract — "Postoperative external irradiation and prognostic parameters in stage I endometrial carcinoma: clinical and histopathologic study of 540 patients." Aalders J et al. Obstet Gynecol. 1980 Oct;56(4):419-27.
    • Stage I. All pts had TAH/BSO (no lymphadenectomy). All pts underwent postoperative brachytherapy, 60 Gy to the surface of the vagina.
    • 540 pts randomized to no further treatment vs pelvic XRT. 40 Gy with central shielding after 20 Gy.
    • OS 90% vs 87% (XRT) at 9 yrs. XRT decreased LR (6.9% vs 1.9%) but there were more distant mets (5.4% vs 10%, borderline SS). Similar recurrence rate in both groups, but more deaths in XRT group.


  • PORTEC Trial, The Netherlands (1990-1997) - Abstract Full Text — "Surgery and postoperative radiotherapy versus surgery alone for patients with stage-1 endometrial carcinoma: multicentre randomised trial. PORTEC Study Group. Post Operative Radiation Therapy in Endometrial Carcinoma." Creutzberg CL et al. Lancet. 2000 Apr 22;355(9213):1404-11.
    • Stage I pts with myometrial invasion. Stage IC grade 1 (deep myometrial invasion >50%), grade 2 with any invasion (IB-C grade 2), and grade 3 with superficial invasion (<50%) (IB grade 3). All pts had TAH/BSO with washings, not allowed to have lymphadenectomy. Allowed adenocarcinoma and variants (including papillary serous and clear cell).
    • 715 pts randomized to postoperative XRT vs no further therapy. Fields: superior border at L5/S1. Dose: 46 Gy.
    • 5-year LRF 4.2% vs 13.7%. Most recurrences in vagina, 73%. Distant mets unaffected (7.5%). Overall survival the same (81% vs 85% @5yrs). Most deaths due to other causes. Most local relapses were salvaged, which may explain why the survival is similar in both arms despite a difference in LR. 2-year and 3-year survival after vaginal relapse 79% and 69%, versus 21% and 13% for pelvic or distant relapse. Excess of secondary cancers of the GI tract, which is associated with endometrial cancer. Higher LRF (3-fold) for pts >60 yrs. Grade 3 predictive of cancer-related death. Grade 3 and deep myometrial invasion predictive of LR (but not statistically significant).
    • Abstract Full Text — "Survival after relapse in patients with endometrial cancer: results from a randomized trial." Creutzberg CL et al. Gynecol Oncol. 2003 May;89(2):201-9.
      • At 5 years, the survival after vaginal relapse was 65% in the control group compared to 43% in the RT group.
    • Abstract — "Outcome of high-risk stage IC, grade 3, compared with stage I endometrial carcinoma patients: the Postoperative Radiation Therapy in Endometrial Carcinoma Trial." Creutzberg CL et al. J Clin Oncol. 2004 Apr 1;22(7):1234-41.
      • 5-yrs distant metastases rates were 3% to 8% for grade 1 and 2 tumors; 20% for stage IB, grade 3 tumors; and 31% for stage IC, grade 3 tumors. OS was 83% to 85% for grades 1 and 2; 74% for stage IB, grade 3; and 58% for stage IC, grade 3 patients
  • GOG 99 (1987-1995) - Abstract Full Text — "A phase III trial of surgery with or without adjunctive external pelvic radiation therapy in intermediate risk endometrial adenocarcinoma: a Gynecologic Oncology Group study." Keys HM et al. Gynecol Oncol. 2004 Mar;92(3):744-51.
    • Originally included "intermediate risk" -- stages IB, IC, and II (occult), any grade, with negative LN. Revised during the course of study to enroll only "high intermediate risk" group: 1) >70 yrs old with only 1 other risk factor (Grade 2 or 3 tumor; lymphovascular invasion; outer third myometrial invasion), 2) >50 yrs old with 2 risk factors; 3) any age with 3 risk factors. All pts had TAH/BSO, selective bilateral pelvic and para-aortic lymphadenectomy.
    • 392 pts randomized to postoperative XRT vs no further therapy. Fields: superior border at L4/L5, lateral borders 1cm beyond pelvis, posterior border at posterior border of S3, ant border at symphysis pubis. Dose: 50.4 Gy.
    • 2-yr recurrence rate: 3% vs 12%. 2-yr LR 1.6% vs 7.4%. 4-year OS 92% vs 86% (NS). In HIR subgroup: 2-yr recurrence, 6% vs 26%.
    • Conclusion: limit RT to high intermediate risk group.

Vaginal brachytherapy

  • American Brachytherapy Society recommendations, 2000 - PMID 11020575 — "The American Brachytherapy Society recommendations for high-dose-rate brachytherapy for carcinoma of the endometrium." Nag S et al. Int J Radiat Oncol Biol Phys. 2000 Oct 1;48(3):779-90.

With pelvic radiotherapy:

  • Wake Forest, 1990 - PMID 2380095 — "Role of intracavitary cuff boost after adjuvant external irradiation in early endometrial carcinoma." Randall ME et al. Int J Radiat Oncol Biol Phys. 1990 Jul;19(1):49-54.
    • Retrospective. 157 pts. Treated with surgery + external beam RT. Compared pts with or without vaginal cuff boost of 30-50 Gy surface dose.
    • No difference in local control (but higher risk features in the group receiving brachy).
    • Conclusion: Adding vaginal cuff boost to EBRT does not improve local control

Brachytherapy alone:

  • Eltabbakh, Roswell Park - Abstract — "Excellent long-term survival and absence of vaginal recurrences in 332 patients with low-risk stage I endometrial adenocarcinoma treated with hysterectomy and vaginal brachytherapy without formal staging lymph node sampling: report of a prospective trial." Eltabbakh GH et al. Int J Radiat Oncol Biol Phys. 1997 May 1;38(2):373-80.
    • 303 pts. Stage 1B, Grades 1-2, treated with hysterectomy only without lymph node staging, then LDR brachytherapy to 30 Gy to 0.5cm depth. 10, 20, and 30-year DFS were >95% (median 8 yr f/u).

Whole abdominal irradiation

  • GOG 9001 (1990-92) - PMID 8946862, 1996 — "A phase I study of weekly cisplatin and whole abdominal radiation for the treatment of stage III and IV endometrial carcinoma: a Gynecologic Oncology Group pilot study." Reisinger SA et al. Gynecol Oncol. 1996 Dec;63(3):299-303.
    • Phase I. 10 pts. Stage III-IV, maximally debulked.
  • GOG 94(1986-94) - Whole abdominal radiotherapy in the adjuvant treatment of patients with stage III and IV endometrial cancer. Also included Stage I-II papillary serous or clear cell.
    • Phase II.
    • PMID 15913742, 2005 — "Whole abdominal radiotherapy in the adjuvant treatment of patients with stage III and IV endometrial cancer: a gynecologic oncology group study." Sutton G et al. Gynecol Oncol. 2005 Jun;97(3):755-63.
    • PMID 16213007, 2005 — "Adjuvant whole abdominal irradiation in clinical stages I and II papillary serous or clear cell carcinoma of the endometrium: A phase II study of the Gynecologic Oncology Group." Sutton G et al. Gynecol Oncol. 2006 Feb;100(2):349-54.


Chemotherapy vs Whole abdominal irradiation

  • GOG 122, 2006 (1992-2000) - Whole abdominal irradiation vs chemotherapy for advanced disease.
    • PMID not available yet — "Randomized Phase III Trial of Whole-Abdominal Irradiation Versus Doxorubicin and Cisplatin Chemotherapy in Advanced Endometrial Carcinoma: A Gynecologic Oncology Group Study." Randall ME et al. J Clin Oncol. 2006 Jan 1;24(1).
    • 388 pts. Stage III-IV, all histologies. Required TAH/BSO, surgical staging, and <2cm residual tumor. Para-aortic LN allowed but no mets to chest or SCLV. Randomized to WAI (30 Gy, 20 fx, AP/PA plus boost to pelvic +/- para-aortic LN 15 Gy in 8 fx) vs chemotherapy (AP; doxorubicin + cisplatin q3w x 8 cycles).
    • For WAI: recurrence in 54% (pelvic in 13%, abd in 16%, extraabdominal or liver 22%). For chemo: 50% recurrence (18%,14%,18%). Hazard ratio for chemo vs WAI was 0.71; predicted difference in PFS of 12% at 5 yrs. Improved OS for chemo arm: 55% vs 42% at 5 yrs.
    • Conclusion: chemotherapy improves PFS and OS for advanced disease, compared with WAI.