Uterine Cancer

1. Uterine Cancer Dr Khalid Akkour MD FRCSC Assistant professor & consultant Gynecologic Onclogy college of medicine King Saud University

2. Endometrial Cancer • The most common gyne malignancy in the U.S. • 6% of all cancers in women • Generally high rate of survival due to early diagnosis (90% stage 1)

3. Risk factors… Epidemiologic diffences: Risk related to hormonal stimulation or unrelated to estrogen at all. Estrogen-related endometrial cancer (Type I) tends to be a lower grade histologically. Endometrial cancers unrelated to hormones (Type II) tend to be a higher grade and stage eg. Papillary serous or clear cell tumors.

4. How endometrial hyperplasia is associated with endometrial cancer Endometrial hyperplasia is a continuum… Simple hyperplasiacomplex hyperplasia without atypiacomplex hyperplasia w/ atypia endometrial cancer (well differentiated adenocarcinoma)

5. How endometrial hyperplasia is associated with endometrial cancer Simple hyperplasia without atypia– 1% progress to endometrial cancer Simple hyperplasia with atypia 9% Complex hyperplasia without atypia– 3% Complex hyperplasia with atypia—28% (30-40% of endometrial cancers are found in a background of atypical hyperplasia). Overall, these tend to be lower grade tumors.

6. Risk factors for endometrial cancer These risk factors are only helpful in identifying women at risk for type I disease.

7. For type I disease, what would be some common exogenous estrogen sources? Unopposed estrogen in HRT Tamoxifen

8. What would be endogenous sources of estrogen as a risk factor for endometrial cancer? Obesity. Anovulatory cycles. Estrogen secreting tumors

9. Endometrial cancer NOT assoc. w/ estrogen(Type II) Papillary serous Clear cell tumors Usually these affect multiparous, but generally healthy, older patients.

10. For type I disease, what would be some common exogenous estrogen sources? Unopposed estrogen in HRT Tamoxifen

11. The Benefits and Risks of Estrogen in HRT Benefits: helps relieve hot flashes, vaginal dryness, and preventing osteoporosis. Unopposed estrogen increases the risk of endometrial hyperplasia and endometrial cancer. With unopposed estrogen 20-50% of women will develop endometrial hyperplasia after 1 year. Risk of endometrial cancer is related BOTH to dose and duration of treatment, the incidence of endometrial cancer goes from 1/1000 to 42/1000.

12. Tamoxifen Tamoxifen– a competitive inhibitor of estrogen binding to estrogen receptors that also has partial agonist activity (tamoxifen is a weak estrogen) - used in pts. w/ early stage breast ca - as treatment of recurrent disease - risk reduction in high risk women

13. Tamoxifen Unfortunately while it suppresses breast tissue growth, it stimulates endometrial lining. Probably a 2 to 3 fold risk of endometrial cancer w/tamoxifen. Especially in women older than 50

14. Tamoxifen What did ACOG say about tamoxifen?... Even though tamoxifen is associated with endometrial cancer, the benefits in treating women with breast ca. outweigh the risks…but… -women need a yearly gyne exam -women should monitor themselves for abnormal vaginal sx., e.g . Bleeding, discharge, etc -screening such as pelvic U.S. is NOT recommended (too many false positives) -Limit tamoxifen use to 5 years -if there is atypical endometrial hyperplasia, treat and reassess tamoxifen (ie. Consider hysterectomy)

15. Other risk factors for endometrial cancer Obesity obese women have high levels of endogenous estrogen probably from the conversion of androstenedione to estrone and the aromatization of androgens to estrogen both of which occur in the adipose tissue

16. Other risk factors for endometrial cancer Diabetes and HTN a risk factor because these conditions are often associated with obesity, and also because of the effects of hyperinsulinemia and insulin-like growth factors.

17. Other risk factors for endometrial cancer Chronic anovulation women with chronic anovulation have unopposed or mildly opposed estrogen. PCOS as an example

18. Other risk factors for endometrial cancer Familial predisposition Lynch syndrome (up to 43% of women of affected families will develop ovarian cancer)

19. Other risk factors for endometrial cancer Parity Nulliparity itself is not a risk factor as much as the anovulatory cycles that are associated with infertility.

20. Other risk factors for endometrial cancer Diet– especially high fat Menarche/Menopause: early menarche and late menopause Prolonged estrogen exposure

21. Protective Factors Oral contraceptives: decreases both the risk of ovarian and endometrial cancer (RR = 0.6 if used for one year…effect lasts for 15 years!) Protective effect probably due to progesterone.

22. Protective Factors Physical activity Smoking

23. Histopathology Most common types of endometrial cancer: Endometriod adenocarcinoma (70-80%) Clear cell and serous tumors are more aggressive and probably present at a more advanced age. (together 5-10%) Mucinous and squamous about 2%

24. Clinical presentation The “classic symptom” is abnormal uterine bleeding 20-30% of women with post-menopausal bleeding will have uterine cancer. ( the risk is higher the farther they are away from menopause)

25. Clinical presentation Abnormal pap smear not a reliable way of picking up endometrial ca. The presence of endometrial cells on a pap smear in women > 40 is an indication for bx. Hyperplasia in 36% Adenoca in 11%

26. Diagnosis Easy to do with office EMB Hysteroscopy w/ D & C (gold standard) Detection rates of endometrial ca. by pipelle was between 91 and 99% Detection of hyperplasia was 81% Recommendation: EMB as initial test; Hysteroscopy/D&C if EMB inconclusive or high suspicion

27. Transvaginal ultrasound In postmenopausal women, an endometrial thickness of 4-5 mm or less is reassuring. (only 1-2% will have endometrial ca. if nl endometrial thickness) ?? If nl TVS do you need an EMB w/abnl bleeding. A thicker endometrium requires EMB, hysteroscopy/D&C overall TVS is not recommended as a screening tool.

28. Transvaginal ultrasound It is recommended to do an EMB rather than rely on TVS results in evaluating abnormal uterine bleeding

29. Cancer Staging Staging is always done surgically Requires a total hysterectomy, BSO, PLND, +/- PaoLND & omentectomy.

30. Cancer Staging Patterns of metastatic spread: Pelvic and paraaortic lymph nodes, lung, inguinal and supraclavicular nodes, liver, peritoneal cavity, bone, brain, and vagina

31. Cancer Staging Pre-op imaging CXR CT (not necessary unless you think there’s extra pelvic disease– it doesn’t alter tx and doesn’t really let you know of depth of invasion etc.– MRI would be better in assessing invasion)

32. Cancer Staging Labs CA-125 ?

33. HNPCC and Screening • Since 40-60% of patients with this develop endometrial ca., do an EMB at age 35 -women with HNPCC-associated mutations -women with a family member with this mutation -Doing an ultra sound is not enough!

34. Summary of Recommendations Ql: Which patients with endometrioid endometrial cancer require no additional therapy after hysterectomy? • Following total abdominal hysterectomy with or without node dissection, no radiation therapy is a reasonable option for patients without residual disease in the hysterectomy specimen despite positive biopsy (despite a positive pre-hysterectomy biopsy of any grade) • Following total abdominal hysterectomy with or without node dissection, no radiation therapy is a reasonable option for patients with grade 1 or 2 cancers with either no invasion or <50% myometrial invasion. • Vaginal cuff brachytherapy may be considered in patients with negative node dissection with grade 3 tumor without myometrial invasion.  • Vaginal cuff brachytherapy may be considered in patients with negative node dissection with grade 1 or 2 tumors with <50% myometrial invasion and higher-risk features, such as age >60 and/or LVSI.

35. Summary of Recommendations Q2: Which patients with endometrioid endometrial cancer should receive vaginal cuff radiation? • Vaginal cuff brachytherapy is as effective as pelvic radiation therapy at preventing vaginal recurrence for patients with: (1) grade 1 or 2 tumors with ~50% myometrial invasion or (2) grade 3 tumors with <50% myometrial invasion. • Vaginal cuff brachytherapy is preferred to pelvic radiation in patients with the above risk factors particularly in patients who have had comprehensive nodal assessment.

36. Summary of Recommendations Q3: Which women should receive postoperative external beam radiation? • To date, there is no documented improvement in overall survival for women with endometrial cancer treated with EBRl; and long-term complications including bowel and bladder dysfunction or secondary cancers have been reported. • Patients with grade 3 cancer with ~50% myometrial invasion or cervical stroma invasion may benefit from pelvic radiation to reduce the risk of pelvic recurrence. • Patients with grade 1 or 2 tumors with ~50% myometrial invasion may also benefit from pelvic radiation to reduce pelvic recurrence if other risk factors are present, such as age >60 years and/or LVSI.Vaginal brachytherapy may be a better option for patients with these features, especially if surgical staging was adequate and nodes were negative.

37. Summary of Recommendations Q3: Which women should receive postoperative external beam radiation? • The best available evidence at this time suggests that reasonable options for adjuvant treatment of patients with positive nodes, or involved uterine serosa, ovaries/fallopian tubes, vagina, bladder, or rectum includes external beam radiation therapy, as well as adjuvant chemotherapy. The best evidence for this population supports the use of chemotherapy, but consideration of external beam radiation is reasonable. • Chemotherapy without external beam radiation may be considered for some patients with positive nodes, or involved uterine serosa, ovaries/fallopian tubes, vagina, bladder, or rectum based on pathologic risk factors for pelvic recurrence. • Radiation therapy without chemotherapy may be considered for some patients with positive nodes, or involved uterine serosa, ovaries/fallopian tubes, vagina, bladder, or rectum based on pathologic risk factors for pelvic recurrence. Patients receiving chemotherapy appear to have improved survival compared with radiation alone, unless the patient is not a candidate for chemotherapy.

38. Summary of Recommendations Q4: When should brachytherapy be used in addition to external beam radiation? • Prospective data is lacking to validate the use of vaginal brachytherapy after pelvic radiation and most retrospective studies show no evidence of a benefit, albeit with small patient numbers. Use of vaginal brachytherapy in patients also undergoing pelvic external beam radiation is not generally warranted, unless risk factors for vaginal recurrence are present.

39. Summary of Recommendations Q5: How should radiation therapy and chemotherapy be integrated in the management of stage I-III endometrioid endometrial cancer? • The best available evidence suggests that concurrent chemoradiation followed by adjuvant chemotherapy is indicated for patients with positive nodes or involved uterine serosa, ovaries/fallopian tubes, vagina, bladder, or rectum. Evidence regarding concurrent chemoradiation is limited at this time, and this recommendation is based on expert opinion; we anticipate level 1 evidence from upcoming prospective randomized clinicaltrials (GOG 0258 and PORTEC-3).Chemotherapy may also be considered in certain high-riskearly stage endometrial cancer patients, and clinical trials of this question are underway. • Alternative sequencing strategies with external beam radiation and chemotherapy are also acceptable. Small, prospective trials have examined sequential radiation followed by chemotherapy. "SandwichN-type therapy currently has only limited, non-randomized evidence.

40. LEIOMYOSARCOMA

41. Introduction ULMS incidence is 0.7-1.0/100,000 Most ULMS are high grade sarcomas with high risk of recurrence & progression. Overall survival is dependant on the stage , 5y survival for - stage 1 = 76% , stage 2 = 60%, stage 3 = 45% stage 4 = 29%. Metastatic disease usually in the 5th decade or before in a women with a good performance status. Response rate for chemotherapy in the metastatic setting is reported to bé 15-54%.

42. Diagnosis Some small studies showed that MRI can distinguish benign from malignant lesions Intrauterine tumors increasing in size after menopause should rise the suspecion for malignancy. In most patients, the diagnosis of LMS is made at the time of myomectomy or hysterectomy for persumed benign disease.

43. Staging - FIGO 2009

44. Initial Treatment • Surgery : • for patients whose disease is limited to the uterus, hysterectomy is recommended. • if malignancy is suspected preoperatively , no mocellation US-FDA issued a safety alert 2014 against power morcellators . • routine LN dissection is not recommended , only large or suspecious nodes have to bé removed. • BSO is reasonable in perimenopausal & postmenopausal women . No survival benefits. • 40-70% of ULMS are ER &/or PR positive • PATIENTS < 50 Y with disease limited to uterus , no difference whether BSO is done or not.

45. Initial Treatment If the disease is locally advanced but potentially completely resectable, an attempt to resect it is reasonable, optimal cytoreduction increased both PFS & OS. For multisite metastasis or unresectable disease >> no role for hysterectomy ( only palliative e.g severe uterine bleeding ) Laparoscopic re-evaluation after morecellation hysterectomy should bé considered to evaluate for & resect any residual disease. Resection of the cervix & doing BSO if not yet done is reasonable for those had only supracervical hysterectomy.

46. Post-resection management of uterus-limited disease Although the risk of recurrent disease is >50%, no adjuvant intervention has been shown to improve PFS or OS. The standard management is observation. 30% of patients found to have ULMS at the time of surgery will have metastatic disease. CT , PET/CT or MRI is recommended postoperatively to r/o distant mets. Adjuvant radiation did not show any survival benefit (local recurrence was the same for the radiation & the control group).

47. Post-resection management of uterus-limited disease Adjuvant chemotherapy with doxyrubicin did not show a survival benefit. Adjuvant docetaxel + Gemcitabine followed by doxyrubicin improved 2y PFS to 78% but failed to improve OS. An International randomized phase III trial of observation versus Gemcitabine/docetaxel for 4 cycles followed by doxyrubicine 4 cycles is ongoing - GOG 277)

48. Post-resection management of locally advanced disease No consensus Observation, Chemo , radiation or hormone blockade therapy are acceptable options.

49. Metastatic disease If complete resection of the metastatic disease is possible >> survival benefit. No consensus for the adjuvant treatment

50. Systemic treatment options for unresectable or metastatic disease No established superior 1st line chemotherapy. Reasonable regimens to consider : - doxyrubicin , 19% RR - doxyrubicin/ifosfamide 30% RR - gemcitabine 20% RR - gemcitabine/docetaxel 27% RR - ifosfamide 17% RR Other chmotherapeutic agents used as 2nd line are : pazopanib 6% RR, trabectudine 10-16% , decarbazine or temzolomide. Hormonal therapy such as aromatase inhibitors should bé considered when hormone receptors are positive >>10% survival benefit in a small burden/indolent disease.