Managing Grade 1 Endometrial Adenocarcinoma and Complex Atypical Endometrial Hyperplasia: Is fertility-sparing progestin treatment an option?

Transcription

1 Managing Grade 1 Endometrial Adenocarcinoma and Complex Atypical Endometrial Hyperplasia: Is fertility-sparing progestin treatment an option? Kristine Penner, MD, MPH, MS 71 st Annual Ob Gyn Assembly of Southern California 5/7/2016

2 Disclaimers I have no disclaimers or conflicts of interest

3 Outline Endometrial cancer Premenopausal women Treatment CAH & Grade 1 EA Progestin therapy Sampling and imaging Mode and Dose Efficacy Fertility Predictors of resolution with progestin therapy Treatment decisions Summary Questions

4 Outline Endometrial cancer Premenopausal women Treatment CAH & Grade 1 EA Progestin therapy Sampling and imaging Mode and Dose Efficacy Fertility Predictors of resolution with progestin therapy Treatment decisions Summary Questions

5 Endometrial Cancer Most common gynecologic malignancy in developed countries. Incidence in the US: 60,050 in 2016 Peak incidence: 60yo 25% Premenopausal 5-10% < 40yo Yearly Mortality: 10,470 Siegel, Cancer Statistics 2016.

6 Type I vs. Type II Endometrial Cancer Type I: 90% of cases Estrogen related Associated with atypical hyperplasia Low grade endometrioid adenocarcinoma Clinical risk factors: endogenous or exogenous estrogen excess, obesity, nulliparity, diabetes mellitus, hypertension. Key, Br J Cancer, 1988; Kaaks, Cancer Epidemiol Biomarkers Prev, 2002.

7 Type I vs. Type II Endometrial Cancer Type II: 10% of cases Unrelated to estrogen or hyperplasia Present as high grade tumors. High grade endometrial adenocarcinoma OR Alternate histology: Papillary serous, Clear cell carcinoma Clinical risk factors: Age, African-American Key, Br J Cancer, 1988; Kaaks, Cancer Epidemiol Biomarkers Prev, 2002.

8 Background Type I Endometrial Cancer Type I Endometrial Cancer in Premenopausal Women Excess androgens Chronic anovulation Decreased progesterone synthesis -> Progesterone deficiency Increased period of proliferation Key, Br J Cancer, 1988; Kaaks, Cancer Epidemiol Biomarkers Prev, 2002.

9 Progesterone deficiency in premenopausal women leads to increased endometrial proliferation

10 Endometrial Cancer Staging Stage I Stage II Stage III Tumor confined to corpus uteri IA IB Tumor limited to endometrium or invades <50% of the myometrium Tumor invades > 50% of the myometrium Tumor invades cervical stroma but does not extend beyond uterus Local and/or regional spread IIIA IIIB IIIC1 IIIC2 Tumor involves uterine serosa and/or adnexa Vaginal or parametrial involvement Metastasis to the pelvic lymph nodes Metastasis to the para-aortic lymph nodes Stage IV IVA Tumor invades bladder mucosa and/or bowel mucosa IVB Distant metastasis FIGO Committee on Gynecologic Oncology, IJGO 2009.

11 Endometrial Cancer Treatment and Prognosis Traditional Treatment Surgical hysterectomy, bilateral salpingooophorectomy, lymph node sampling. Radiation and/or Chemotherapy as indicated Prognosis for Stage 1 A, Grade 1 EA 95% five-year survival following Hysterectomy/BSO alone.

12 Outline Endometrial cancer Premenopausal women Treatment CAH & Grade 1 EA Progestin therapy Sampling and imaging Mode and Dose Efficacy Fertility Predictors of resolution with progestin therapy Treatment decisions Summary Questions Why include Complex Atypical Hyperplasia?

13 Progression from Endometrial Hyperplasia to Adenocarcinoma Kurman et al, Cancer, women with hyperplasia followed untreated for mean 13 years. Progression to carcinoma: Simple Hyperplasia: 1% Complex Hyperplasia: 3% Simple Atypical Hyperplasia: 8% Complex Atypical Hyperplasia: 29% Lacey et al, JCO, women with hyperplasia; cumulative risk for progression to carcinoma: 4 years 9 years 19 years Hyperplasia no atypia 1.2% 1.9% 4.6% Atypical Hyperplasia 8.2% 12.4% 27.5%

14 Differentiating CAH and Grade 1 EA Inclusion criteria: Community hospital pathology diagnosis of atypical endometrial hyperplasia Hysterectomy within 12 weeks of enrollment No interval treatment. Methods: Trimble et al, Cancer, 2006 Pathology rereveiw of biopsy and hysterectomy specimens by three expert pathologists Consensus = 2 of 3 agree

15 Differentiating CAH and Grade 1 EA Results: Trimble et al, Cancer, 2006 On rereview of index biopsy: 25% had less than atypical hyperplasia 40% had atypical hyperplasia 29% had endometrial carcinoma. 6% with no consensus. At least 54% discordance from community diagnosis.

16 Differentiating CAH and Grade 1 EA Results: Trimble et al, Cancer, 2006 On review of hysterectomy specimen: 42% of all subjects had endometrial carcinoma Subjects where rereview showed atypical hyperplasia or less on biopsy: 31% had a diagnosis of endometrial carcinoma on hysterectomy Subjects with no consensus on biopsy dx: 63% had endometrial carcinoma on hysterectomy Majority Grade 1 Eight subjects with Grade 2 and Grade 3 disease No stage greater than (new) Stage IB (outer 50% myometrial invasion)

17 Outline Endometrial cancer Premenopausal women Treatment CAH & Grade 1 EA Progestin therapy Sampling and imaging Mode and Dose Efficacy Fertility Predictors of resolution with progestin therapy Treatment decisions Summary Questions

18 Who can be considered for treatment solely with progestin? ACOG supports the option for patients with atypical hyperplasia or Grade 1 EA. ACOG Practice Bulletin No. 149, April Subjects with ultrasound evidence of adnexal mass should be evaluated for mass removal prior to initiating treatment, given 10-30% chance of synchronous primary. Walsh et al, Ob Gyn, 2005.

19 What additional evaluation needs to be done before starting progestin treatment? D&C vs. office endometrial biopsy: No difference in accuracy of diagnosis. Stovall et al, Ob Gyn, 1989; Silver et al, Ob Gyn, 1991; Lipscomb et al, AJOG, Still consider D&C Daniel et al, Ob Gyn, 1988; Larson et al, Ob Gyn, 1995.

20 What additional evaluation needs to be done before starting progestin treatment? D&C vs. office endometrial biopsy: No difference in accuracy of diagnosis. Stovall et al, Ob Gyn, 1989; Silver et al, Ob Gyn, 1991; Lipscomb et al, AJOG, Still consider D&C Daniel et al, Ob Gyn, 1988; Larson et al, Ob Gyn, To evaluate for myometrial invasion: Because the pretest probability of invasion is low for Grade 1 disease, all studies are less accurate Of MRI, Ultrasound and CT: MRI is most accurate» Accuracy of MRI for deep invasion 87-90%» PPV: 50%» NPV: 90-95% Kinkel, Radiology, Shin, Acta Rad, 2011.

21 Oral: What form of progestin? Megesterol Acetate (Megace) Medroxyprogesterone (Provera) Progesterone (Prometrium) Norethindrone acetate (Aygestin) Intrauterine: Levonorgestrel-releasing intrauterine system (Mirena)

22 What dose of progestin? Megesterol 80 mg PO BID (160mg/day) is often starting dose. Unclear if there is a dose-response relationship. Unclear if cyclic or continuous therapy associated with better response. Bottom line: No one knows

23 Endometrial cancer Premenopausal women Treatment CAH & Grade 1 EA Progestin therapy Sampling and imaging Mode and Dose Efficacy Outline Predictors of resolution with progestin therapy Treatment decisions Summary Questions Fertility How effective is treatment of Grade 1 Endometrial Adenocarcinoma with progestins?

24 Progestin Therapy for Grade 1 EA Author Year N Age (years) Duration of Tx Resolution (%) Time to resolution Followup Recurrence (%, of those resolved) Bokhman % na Kim % % Randall % % Saegusa na 77% Na na Na Imai % % Kaku % % Duska na 83% na na 30% Wang % % Gotlieb % % Niwa % % Ota % % Yang na 67% % Wheeler na 33% na % Minaguchi % na 45 33% Yamazawa % % Ushijima % % Eftekhar % % Hahn na 63% % Signorelli % % Yu na 63% % Mao na 67% % Cade na 67% % Mazzon % % Laurelli % na 43 7% Minig na 57% % Perri na 89% % Kim na 80% % Park % % Penner % na Wang % % Summary % %

25 Progestin Therapy for Grade 1 EA Author Year N Age (years) Duration of Tx Resolution (%) Time to resolution Followup Recurrence (%, of those resolved) Bokhman % na Kim % % Randall % % Saegusa na 77% Na na Na Imai % % Kaku % % Duska na 83% na na 30% Wang % % Gotlieb % % Niwa % % Ota % % Yang na 67% % Wheeler na 33% na % Minaguchi % na 45 33% Yamazawa % % Ushijima % % Eftekhar % % Hahn na 63% % Signorelli % % Yu na 63% % Mao na 67% % Cade na 67% % Mazzon % % Laurelli % na 43 7% Minig na 57% % Perri na 89% % Kim na 80% % Park % % Penner % na Wang % % Summary % %

26 Progestin Therapy for Grade 1 EA Author Year N Age (years) Duration of Tx Resolution (%) Time to resolution Followup Recurrence (%, of those resolved) Bokhman % na Kim % % Randall % % Saegusa na 77% Na na Na Imai % % Kaku % % Duska na 83% na na 30% Wang % % Gotlieb % % Niwa % % Ota % % Yang na 67% % Wheeler na 33% na % Minaguchi % na 45 33% Yamazawa % % Ushijima % % Eftekhar % % Hahn na 63% % Signorelli % % Yu na 63% % Mao na 67% % Cade na 67% % Mazzon % % Laurelli % na 43 7% Minig na 57% % Perri na 89% % Kim na 80% % Park % % Penner % na Wang % % Summary % %

27 Progestin Therapy for Grade 1 EA Author Year N Age (years) Duration of Tx Resolution (%) Time to resolution Followup Recurrence (%, of those resolved) Bokhman % na Kim % % Randall % % Saegusa na 77% Na na Na Imai % % Kaku % % Duska na 83% na na 30% Wang % % Gotlieb % % Niwa % % Ota % % Yang na 67% % Wheeler na 33% na % Minaguchi % na 45 33% Yamazawa % % Ushijima % % Eftekhar % % Hahn na 63% % Signorelli % % Yu na 63% % Mao na 67% % Cade na 67% % Mazzon % % Laurelli % na 43 7% Minig na 57% % Perri na 89% % Kim na 80% % Park % % Penner % na Wang % % Summary % %

28 Progestin Therapy for Grade 1 EA Author Year N Age (years) Duration of Tx Resolution (%) Time to resolution Followup Recurrence (%, of those resolved) Bokhman % na Kim % % Randall % % Saegusa na 77% Na na Na Imai % % Kaku % % Duska na 83% na na 30% Wang % % Gotlieb % % Niwa % % Ota % % Yang na 67% % Wheeler na 33% na % Minaguchi % na 45 33% Yamazawa % % Ushijima % % Eftekhar % % Hahn na 63% % Signorelli % % Yu na 63% % Mao na 67% % Cade na 67% % Mazzon % % Laurelli % na 43 7% Minig na 57% % Perri na 89% % Kim na 80% % Park % % Penner % na Wang % % Summary % %

29 What has improved the resolution Prospective studies rate? Hysteroscopic resection of tumor initially and hysteroscopic evaluation (+/- resection) at set intervals Multi-modality treatment Intrauterine levonorgestrel + oral progestin Mazzon, Fertility & Sterility, 2010; Laurelli, Gyn Onc, 2011; Kim, IJGC, 2011; Park, Arch Gyn Ob, 2011; Wang, Int J Clin Exp Med, 2015.

30 Progestin Therapy for Grade 1 EA Author Year N Age (years) Duration of Tx Resolution (%) Time to resolution Followup Recurrence (%, of those resolved) Bokhman % na Kim % % Randall % % Saegusa na 77% Na na Na Imai % % Kaku % % Duska na 83% na na 30% Wang % % Gotlieb % % Niwa % % Ota % % Yang na 67% % Wheeler na 33% na % Minaguchi % na 45 33% Yamazawa % % Ushijima % % Eftekhar % % Hahn na 63% % Signorelli % % Yu na 63% % Mao na 67% % Cade na 67% % Mazzon % % Laurelli % na 43 7% Minig na 57% % Perri na 89% % Kim na 80% % Park % % Penner % na Wang % % 100% Summary % %

31 Progestin Therapy for Grade 1 EA Author Year N Age (years) Duration of Tx Resolution (%) Time to resolution Followup Recurrence (%, of those resolved) Bokhman % na Kim % % Randall % % Saegusa na 77% Na na Na Imai % % Kaku % % Duska na 83% na na 30% Wang % % Gotlieb % % Niwa % % Ota % % Yang na 67% % Wheeler na 33% na % Minaguchi % na 45 33% Yamazawa % % Ushijima % % Eftekhar % % Hahn na 63% % Signorelli % % Yu na 63% % Mao na 67% % Cade na 67% % Mazzon % % Laurelli % na 43 7% Minig na 57% % Perri na 89% % Kim na 80% % Park % % Penner % na Wang % % Summary % %

32 Progestin Therapy for Grade 1 EA Author Year N Age (years) Duration of Tx Resolution (%) Time to resolution Followup Recurrence (%, of those resolved) Bokhman % na Kim % % Randall % % Saegusa na 77% Na na Na Imai % % Kaku % % Duska na 83% na na 30% Wang % % Gotlieb % % Niwa % % Ota % % Yang na 67% % Wheeler na 33% na % Minaguchi % na 45 33% Yamazawa % % Ushijima % % Eftekhar % % Hahn na 63% % Signorelli % % Yu na 63% % Mao na 67% % Cade na 67% % Mazzon % % Laurelli % na 43 7% Minig na 57% % Perri na 89% % Kim na 80% % Park % % Penner % na Wang % % Summary % %

33 Progestin Therapy for Grade 1 EA Author Year N Age (years) Duration of Tx Resolution (%) Time to resolution Followup Recurrence (%, of those resolved) Bokhman % na Kim % % Randall % % Saegusa na 77% Na na Na Imai % % Kaku % % Duska na 83% na na 30% Wang % % Gotlieb % % Niwa % % Ota % % Yang na 67% % Wheeler na 33% na % Minaguchi % na 45 33% Yamazawa % % Ushijima % % Eftekhar % % Hahn na 63% % Signorelli % % Yu na 63% % Mao na 67% % Cade na 67% % Mazzon % % Laurelli % na 43 7% Minig na 57% % Perri na 89% % Kim na 80% % Park % % Penner % na Wang % % 89% Summary % %

34 Progestin Therapy for CAH Author Year N Age (years) Duration of Tx Resolution (%) Time to resolution Followup Recurrence (%, of those resolved) Randall % % Kaku % % Jobo % % Wang % na na na Wheeler na 50.0% % Minaguchi % na % Milam % na na na Ushijima % % Signorelli % % Yu na 82.4% % Minnig na 95% % Penner % na Summary % %

35 Progestin Therapy for CAH Author Year N Age (years) Duration of Tx Resolution (%) Time to resolution Followup Recurrence (%, of those resolved) Randall % % Kaku % % Jobo % % Wang % na na na Wheeler na 50.0% % Minaguchi % na % Milam % na na na Ushijima % % Signorelli % % Yu na 82.4% % Minnig na 95% % Penner % na Summary % %

36 Progestin Therapy for CAH Author Year N Age (years) Duration of Tx Resolution (%) Time to resolution Followup Recurrence (%, of those resolved) Randall % % Kaku % % Jobo % % Wang % na na na Wheeler na 50.0% % Minaguchi % na % Milam % na na na Ushijima % % Signorelli % % Yu na 82.4% % Minnig na 95% % Penner % na Summary % %

37 Progestin Therapy for CAH Author Year N Age (years) Duration of Tx Resolution (%) Time to resolution Followup Recurrence (%, of those resolved) Randall % % Kaku % % Jobo % % Wang % na na na Wheeler na 50.0% % Minaguchi % na % Milam % na na na Ushijima % % Signorelli % % Yu na 82.4% % Minnig na 95% % Penner % na Summary % %

38 Levonorgestrel IUS CAH: Case series: pre- & post-menopausal patients 90% regression Grade 1 EA: Case series: pre- & post-menopausal patients 76% regression Varma et al, EJOG, 2006.

39 Outline Endometrial cancer Premenopausal women Treatment CAH & Grade 1 EA Progestin therapy Sampling and imaging Mode and Dose Efficacy Fertility Predictors of resolution with progestin therapy Treatment decisions Summary Questions

40 Fertility after successful progestin treatment CAH: 39% patients achieved pregnancy Grade 1 EA: 30% patients achieved pregnancy 115 live births

41 Outline Endometrial cancer Premenopausal women Treatment CAH & Grade 1 EA Progestin therapy Sampling and imaging Mode and Dose Efficacy Fertility Predictors of resolution with progestin therapy Treatment decisions Summary Questions

42 Objective What are demographic, clinical and pathologic predictors of resolution of CAH or G1 EA when treated with progestins?

43 Methods: Study Design Inclusion Criteria: Premenopausal women with CAH or Grade 1 EA Progestin therapy for a minimum of eight weeks Retrospective chart review for clinical, epidemiological, and treatment data. Pathologic rereview for histopathological festures.

44 Methods: Outcome Resolution: No evidence of hyperplasia or malignancy in hysterectomy specimen or at least two sequential samples. Persistence or Progression Hyperplasia or malignancy in spite of treatment.

45 Results Patient Characteristics (N = 40) Median Age 36 yo (23-48) Median BMI 35 (19-68) Obese (BMI 30kg/m 2 ) 73% Nulliparous 80% Initial Diagnosis CAH 65% Grade 1 EA 35% Time to 1 st Follow up 3.8 months ( ) Dose Megesterol 160mg 40% Length of Treatment 9 months (2-59) Resolution 51%

46 Results: Predictors of Resolution at Diagnosis Study Population N = months: 43% 18 months: 63% Architecture of Pretreatment Specimen Less Abnormal ( 2 features) Group 1 More abnormal ( 3 features) N = 11 SRR = months: 31% 18 months: 31% Group 2 BMI 35 N = 13 SRR = months: 33% 18 months: 66% BMI Group 3 BMI < 35 N = 16 SRR = months: 59% 18 months: 75%

47 Results: Predictors of Resolution at First Follow Up Study Population N = months: 43% 18 months: 63% Diagnosis at First Follow up Specimen Complexity, Atypia or Carcinoma Group 1 Benign or SH N = 16 SRR = months: 67% 18 months: 84% Group 2 Yes N = 15 SRR = months: 10% 18 months: 38% Stromal Decidualizaion Group 3 No N = 9 SRR = months: 46% 18 months: 64%

48 Stromal decidualization?

49 Results: Predictors of Resolution at First Follow Up Study Population N = months: 43% 18 months: 63% Diagnosis at First Follow up Specimen Complexity, Atypia or Carcinoma Group 1 Benign or SH N = 16 SRR = months: 67% 18 months: 84% Group 2 Yes N = 15 SRR = months: 10% 18 months: 38% Stromal Decidualizaion Group 3 No N = 9 SRR = months: 46% 18 months: 64%

50 Outline Endometrial cancer Premenopausal women Treatment CAH & Grade 1 EA Progestin therapy Sampling and imaging Mode and Dose Efficacy Fertility Predictors of resolution with progestin therapy Treatment decisions Summary Questions

51 How long do you wait for a response? Patient should be sampled every 3-6 months Most patients who are going to respond will have significant evidence of improvement by 6-9 months. Response times as long as EIGHTEEN months have been seen in other studies, In my case series, 3 years was the longest time to resolution.

52 Who is likely to have persistent disease? More architectural abnormalities Higher BMI Minimal response at first biopsy, especially if there is evidence of progestin effect on the tissue

53 Predictors of Resolution: Progesterone Receptor Rich expression of PR associated with increased resolution Resolution at: 12 mos 18 mos PRA Rich 77% 89% PRA Non Rich 36% 58% Resolution at: 12 mos 18 mos PRB Rich 80% 90% PRB Non Rich 34% 57%

54 Who is likely to have persistent disease? More architectural abnormalities Higher BMI Minimal response at first biopsy, especially if there is evidence of progestin effect on the tissue Tissue with low expression of the progesterone receptor

55 Dosing: Cyclic vs Continuous? PRA and PRB expression drops after treatment

56 Outline Endometrial cancer Premenopausal women Treatment CAH & Grade 1 EA Progestin therapy Sampling and imaging Mode and Dose Efficacy Fertility Predictors of resolution with progestin therapy Treatment decisions Summary Questions

57 Summary Progestin is a reasonable treatment for Grade 1 EA and CAH Resolution rate of 60-70%. No definitive recommendations for Specific dosing Form of progestin Reasonable to begin with Megesterol 80mg PO BID or Mirena IUS (or BOTH!) Add second modality if no response at 3 months. Rediscuss plan after each biopsy, based on findings, including stromal decidualization

58 Summary Consider MRI to evaluate for myometrial invasion Consider hysteroscopic resection prior to initiation of treatment Patients should be followed with repeated endometrial sampling every 3-6 months +/- hysteroscopic evaluation and biopsies Once disease resolved, patient should pursue fertility immediately, ideally with the help of REI. If not planning to pursue fertility immediately: maintenance with either OCP or levonorgestrel IUS. Once childbearing is completed, patients should consider definitive treatment with at least TAH/BSO, given recurrence rates of 20-40% Consider referral for bariatric surgery if obese

59 References 1. American Cancer Society, Cancer Facts & Figures , Atlanta: American Cancer Society. 2. Gallup, D.G. and R.J. Stock, Adenocarcinoma of the endometrium in women 40 years of age or younger. Obstet Gynecol, (3): p Reed, S.D., et al., Incidence of endometrial hyperplasia. Am J Obstet Gynecol, (6): p. 678 e Bokhman, J.V., et al., Can primary endometrial carcinoma stage I be cured without surgery and radiation therapy? Gynecol Oncol, (2): p Duska, L.R., et al., Endometrial cancer in women 40 years old or younger. Gynecol Oncol, (2): p Gotlieb, W.H., et al., Outcome of fertility-sparing treatment with progestins in young patients with endometrial cancer. Obstet Gynecol, (4): p Imai, M., et al., Medroxyprogesterone acetate therapy for patients with adenocarcinoma of the endometrium who wish to preserve the uterus-usefulness and limitations. 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60 Outline Endometrial cancer Premenopausal women Treatment CAH & Grade 1 EA Progestin therapy Sampling and imaging Mode and Dose Efficacy Predictors of resolution with progestin therapy Treatment decisions Summary Questions

61 Managing Grade 1 Endometrial Adenocarcinoma and Complex Atypical Endometrial Hyperplasia: Is fertility-sparing progestin treatment an option? Kristine Penner, Yes!! MD, MPH, MS UCI Ob/Gyn Grand Rounds (with 3/22/2013 some caveats )