carcinoma cervix -update

carcinoma cervix, incidence, pathogenesis preinvasive stages, histology, ajcc 8, stage, examination, management, surgery,radiotherapy, nccn guideline,update,

1. Management of CARCINOMA CERVIX – A Review Dr. MUNEER . A DNB Radiotherapy

2. INTRODUCTION Cervical cancer is the fourth most common cancer in women. Most common gynaecological cancer in the world. More than 85% of Global burden occurs in developing countries, where cervical cancer is the leading cause of death in women.

3. india most common cancer in Indian women cervical cancer had increased from 0.11 million in 2000 to 0.16 million in 2010 Over 80% of the cervical cancer present at a fairly advanced stage and annually around 80,000 deaths are reported in India. India, the second most populous country in the world, accounts for 27% (77,100) of the total cervical cancer deaths6

4. PRE DISPOSING FACTORS coitus before the age of 18 years. multiple sexual partners. Delivery of the first baby before the age of 20 years. multiparity with poor birth spacing between pregnancies. History of smoking

5. poor personal hygiene. poor socioeconomic status. women with- HPV (16,18,31,33) HIV HSV 2 infection condylomata , have an increased risk.

6. women with pre invasive lesion immunocompromised women(following transplant). women on combined oral contraceptives and progesterone have doubled the risk of ADENOCARCINOMA ENDOCERVIX 5% of women who received diethylstilbestrol in utero developed cancer of vagina and cervix. withdrawal of this hormone has reduced the incidence.

7. HPV and Ca Cervix Persistent HPV infection - most important cause. Incidence of Cervical Ca is related to prevelance of HPV in population. In countries with high incidence of Ca Cervix, prevlence of HPV is 10-20%. In countries with low incidence of Ca Cervix , prevlence of HPV is 5-10%. Immunization against HPV will prevent persistent infection with HPV and thus carcinoma. In developed countries , the substantial decline in incidence and mortality of Squamous cell carcinoma is presumed due to result of effective screening. NCCN 2017

8. Avoidance of Human Papillomavirus Infection (abstinence, or condoms (lower risk by 60%) HPV16/18 vaccination will lower the risk by 92% Screening (pap smear) will lower incidence and mortality by 80% Smoking cessation (smoking cigarettes increases the risk in HPV+ women by 2 to 3 times)

9. CERVICAL SCREENING PROTOCOL joint recommendations of the American Cancer Society (ACS), the American Society for Colposcopy and Cervical Pathology (ASCCP) and the American Society for Clinical Pathology (ASCP) in 2012, and later accepted and promoted by the American Congress of Obstetricians and Gynecologists (ACOG) Starting women age 21 Women ages 21-29 Screen with cytology every 3 years Women Ages 30-65 Screen with cytology cotesting with HPV every 5 years. OR cytology alone every 3 year Women<21 Do not screen Women>65, had adequate prior screening and are not at high risk Do not screen Women after hysterectomy with removal of cervix ,no h/o high grade precancer or cervical cancer Do not screen Women<30yrs Do not screen with HPV testing

10. Clinical Presentation Asymptomatic - Most common presentation in western countries due high rate of screening ( Intraepithelial or early invasive carcinoma of the cervix may be detected by cytological smears before symptoms appear ) Abnormal vaginal bleeding – >80 % earliest symptom of invasive cervical cancer ( most commonly post coital bleeding ) Spotting Menorrhagia – Heavier than usual flow Fowl smelling discharge – May or may not be mixed with blood Exophytic / ulceroproliferative mass visible on examination

11. Symptoms of Advanced Carcinoma Cervix Anemia,Fatigue – Due to chronic blood loss Anuria -- Renal failure – due to pressure effect on ureter leading to back pressure on kidney Rectal bleeding- venous engorgement due to pressure effect Constipation Dysuria Hematuria

12. Contd… Triad Sciatic pain (from lumbosacral plexus involvement / compression by tumor / PID) Lower extremity edema (from extensive pelvic lymph node involvement / lymphatic obstruction) Hydronephrosis ( ureteral obstruction)

13. Contd… Ascites- Due to peritoneal deposits Dribbling of urine per vaginum –Due to vesico vaginal fistula formation Fecal matter per vaginum- Rectovaginal fistula Metastasis as Cervical Malignancy Metastasis of distant tumors to the uterine cervix is rare ( about 4% of all tumors ) and should be considered in the differential diagnosis. Metastases to the cervix from the breast, ovary, and kidney have been reported.

14. Histologic Subtypes Squamous-Cell Carcinoma (>90%) Large cell-Keratinizing or Nonkeratinizing or small cell carcinomas Verrucous- very well differentiated scc , tendency to recur locally but not metastasize Papillary transitional Lymphoepithelioma -like Adenocarcinoma (7-10%) (arises from the cylindrical mucosa of the endocervix or the mucus secreting endocervical glands Mucinous Endometrioid - MC Endocervical adeno ca Clear Cell Serous Mesonephric Well differentiated villoglandular Minimal deviation (adenoma malignum )- associated with Peutz-Jeghers,ominous natural history Other epithelial Adenosquamous Glassy Cell Carcinoid Tumor Neuroendocrine Small-cell Undifferentiated Basaloid Ca Primary Sarcoma of cervix

15. STAGING

16. FIGO STAGING International Federation of Gynecology and Obstetrics has put forth a staging system that depends mainly on clinical examination It includes– Inspection Palpation Colposcopy Endo cervical curettage , conization Hysteroscopy Cystoscopy Proctoscopy Intravenous urography , barium enema X ray to rule out lung and bone mets

17. STAGING Clinical rather than surgical staging This allows staging to occur in low resource setting Stage should be assigned before any definitive therapy is administered. The clinical stage should never be changed on the basis of subsequent findings. When the stage to which a particular case should be allotted is in doubt, the case should be assigned to the lesser stage Not included in the FIGO Staging are- Lymphangiography , FNAC or Biopsy of LN , MRI,CT,PET , Laparoscopy & Laparotomy

18. UPDATE ( AJCC 8 TH EDN)

19. AJCC 8 FIGO Tx primary tumour cannot be assesed T0 No evidence of primary tumour T1 I CERVICAL CARCINOMA CONFINED TO UTERUS T1 a IA Invasive carcinoma diagnosed only by microscopy. T1 a1 IA1 Measured stromal invasion 3 mm or less in depth and 7mm or less in horizontal spread. T1 a2 IA2 Measured stromal invasion more than 3 mm and <5mm, and 7mm in horizontal spread.

20. AJCC 8 FIGO T1 b I B Clinically visible lesion confined to cervix or microscopic disease greater than IA1,2 T1 b1 I B1 Clinically visible lesion <= 4cm in greatest dimension T1 b2 I B2 Clinically visible lesion > 4cm in greatest dimension

21. AJCC 8 FIGO II Cervical carcinoma invade beyond the uterus but not to the pelvic sidewall or lower third of vagina T1 b II A Cervical lesion w/o parametrial involvement T1 b1 I I a1 Clinically visible lesion <= 4cm in greatest dimension T1 b2 II a2 Clinically visible lesion > 4cm in greatest dimension II B Cervical lesion with parametrial involvment but not upto LPW

22. AJCC 8 FIGO T 3a III A Tumor involving lower third of vagina, no extension to LPW T 3b III B Tumor extending to LPW and/or causing hydronephrosis or nonfunctioning kidney Pelvic side wall is defined as the muscle, fascia, neurovascular structure, and skeletal portions of the bony pelvis. On rectal examination there is no cancer free space between the tumour and pelvic side wall

23. AJCC 8 FIGO N x Regional lymphnode cannot be assessed N No Regional lymph node metastasis N 0 ( i +) Isolated tumour cell in regional lymphnode (s) . No greater than 0.2 cm N 1 Regional lymphnode metastasis Regional lymphnode REGIONAL LYMPHNODES Para- metrial , obturator , internal iliac ( hypogastric ), external iliac, sacral , presacral , commmon iliac , para- aortic

24. AJCC 8 FIGO IV A Tumor invades mucosa of bladder or rectum and/or extends beyond true pelvis (bullous edema is not sufficient to classify a tumour as T4

25. AJCC 8 FIGO M No distant metastasis M 1 IV B Distant metastasis ( including peritoneal spread or involvement of supraclavicular ,mediastinal , or distant lymph node : lung ; liver ; or bone. Distant Metastasis

26. Patterns of Spread Local Invasion Lymphatic Risk relates to depth of invasion Pelvic nodes before paraaortic or supraclavicular Hematogenous More likely in adenocarcinoma, neuroendocrine or small cell tumors Intraperitoneal Unknown incidence Poor prognosis

27. Patterns of spread Direct Invasion Corpus 10-30% Urinary Bladder Cervical Epithelium Cervical Stroma Parametrium Vagina Rectum

28. LYMPH NODE METASTASIS Perez CA,dIsAIA pj,Knapp RC,et al.Gynecologic tumors.In:Devita VT Jr,Hellman S,Rosenberg SA,eds.Cancer:Principles and Practice of Oncology,2 nd edition Philadelphia:jb Lippincott,1985;1013-1041. STAGE PELVIC LN(%) PARA-AORTIC LN(%) IA1 0.5 IA2 4.8 <1 IB 15.9 2.2 IIA 24.5 11 IIB 31.4 19 III 44.8 30 IVA 55 40

29. CARCINOMA OF THE UTERINE CERVIX (MALLINCKRODT INSTITUTE OF RADIOLOGY 1959–1986): ANATOMIC SITE OF FIRST METASTASIS

30. Prognosis TUMOR - size , depth of invasion , LN status , histology ,vascularity , oncogenes , receptors PATIENT - Age, S/E condition ,immune status MEDICAL CONDITION - anemia, hypertension and the t/t factors TREATMENT RELATED FACTORS -dose, no of intra- cavitary

31. Lymph node metastasis is one of the most important predictors of prognosis. Survival rates for patients treated with radical hysterectomy with or without postoperative radiotherapy for stage IB disease were usually reported as 85% to 95% for patients with negative nodes and 45% to 55% for those with lymph node metastases. {“ Averette HE, Lichtinger M, Sevin BU, et al. Pelvic exenteration : a 150-year experience in a general hospital. Am J Obstet Gynecol 1970;150:179. Delgado G, Bundy B, Zaino R, et al. Prospective surgical-pathological study of disease-free interval in patients with stage IB squamous cell carcinoma of the cervix: a Gynecologic Oncology Group study. Gynecol Oncol 1990;38:352”}

32. Roman et al reported a correlation between the percentage of histopathologic sections containing LVSI and the incidence of lymph node metastases. Uterine-body involvement has been associated with an increased rate of distant metastases[ Noguchi H, Shiozawa I, Kitahara T, et al. Uterine body invasion of carcinoma of the uterine cervix as seen from surgical specimens. Gynecol Oncol 1988;30:173 .] Most investigators have concluded that adenocarcinomas confer a poorer prognosis [ Shingleton HM, Bell MC, Fremgen A, et al. Is there really a difference in survival of women with squamous cell carcinoma, adenocarcinoma, and adenosquamous cell carcinoma of the cervix? Cancer 1995;76:1948. ]

33. DIAGNOSTIC AND METASTATIC WORK UP HISTORY AND PHYSICAL EXAMINATION: Pelvic and recto v aginal examination: Tumor extension SCF LN PROCEDURES: Colposcopy Pap smear if no bleeding 4 Quadrant punch biopsy Cold knife conization if no gross lesion visible or microscopic carcinoma suspected LAB Cbc Blood chemistries Urinalalysis RADIOLOGY Chest xray CT or MRI of abdomen and pelvis PET/PET-CT

34. Examination There are three steps : The External Genital Exam The Speculum Exam The Bimanual Exam Prerequisites : Patient must be counselled properly regarding the procedures to be done. A female attendant should be present by the side(nurse/or relative). A light source should be available. Sterile gloves,swabs,speculum,sponge holding forceps required. 1.Shaws’s Gynaecology,The gynaecology examination 2.Dutta’s Textbook of Gyanecology5th edition

35. Step 1. The External Genital Exam Visually examine the soft folds of the vulva and the opening of the vagina to check for signs of irritation, discharge, cysts, genital warts, or other conditions. Note character of visible vaginal discharge if any. Elicit the signs of Stress incontinence and Genital prolapse. Look for hemorrhoids,any other palpable pathology over the area.

36. Step 2. The Speculum Exam Speculum examination should preferably be done prior to bimanual examination. Advantages : Cervical scrape cytology and endocervical sampling can be taken as screening in the same sitting. Discharge P/V can be sent for examination if need be Cervical lesion may bleed during bimanual examination which makes the lesion difficult to visualise Anterior vaginal wall is to be visualized by Sim’s speculum

37. Step 2. The Speculum Exam Insert a speculum into the vagina usually in lithotomy position . When opened, it separates the anterior and posterior lip of the vagina, which normally are closed and touch each other, so that the cervix can be seen. Patient may feel some degree of pressure or mild discomfort when the speculum is inserted and opened. so it is essential that patient must be advised to relax

38. Contd.. The position of the cervix or uterus may affect the comfort as well. May feel the chill of the metal, if a metal speculum is used Lubricate the speculum and warm it to body temperature for more comfort. PER SPECULUM

39. BIMANUAL DIGITAL EXAMINATION 1 ) Assessing the cervix : Vaginal fingers locate the cervix and the external cervical os : - Determine whether it is open or closed Directed posteriorly when the uterus is anteverted Consistency usually firm when normal, but hard due to fibrosis or carcinoma, soft in pregnancy Note any mass its size, shape, consistency, position, mobility , extension

40. BIMANUAL DIGITAL EXAMINATION 2 Assessing the anae: The vaginal fingers are now moved into one of the lateral fornices with the abdominal hand moving to the corresponding iliac fossa. Assess for any adnexal masses (ovaries and fallopian tubes) on both sides - size, shape, tenderness , etc.

41. BIMANUAL DIGITAL EXAMINATION 3 Assessing the Pouch of Douglas (recto-uterine pouch): -The vaginal fingers now placed into the posterior fornix of the vagina and its shape is assessed (normally concave away from the fingers, but may be convex towards the fingers if there is a mass in the Pouch of Douglas).

42. Combined PR and PV Examination It is done with one finger inserted per vaginally and the second finger of same hand per rectally Aim of the examination is to evaluate the extension of tumor up to lateral pelvic wall Both the fingers are moved towards lateral pelvic wall If tumor extends to pelvic wall the 2 fingers do not converge

43. PAP Smear Insert the spatula with the endocervical tip ( the longest part), into the endocervical canal and turn 360 degrees. Apply the smear onto the slide – 2 strokes. The Craigbrush is superior to the spatula if the transition zone is high and you cannot see it. Turn it gently in five complete circles and apply the smear to the slide in gentle strokes. Within 20 seconds of taking it, apply the smear onto the glass slide with a light sweeping motions. Spray immediately with one spray of fixative , Conventional Liquid based cytology

44. Liquid Based Cytology: Taken using plasctic spatula Rinsed in a buffered methanol solution Sepatrated by centrifugation Advantages : avoids false positive,false negative reduces number of unstaisfactory smears

45. Pap tests can detect The presence of abnormal cells in the cervix Infections and inflammations of the cervix Symptoms of STDs (With the exception of trichomoniasis , Pap tests cannot identify specific STDs, )

46. Categories for Pap test results: Normal results: If no abnormal cells are seen, then the test result is normal. If only benign changes are seen, usually resulting from inflammation or irritation, then the test result is normal. Abnormal results: Atypical cells of undetermined significance (ASCUS, AGUS). Low-grade squamous intraepithelial lesions (LSIL) or cervical intraepithelial neoplasia (CIN) 1. These are mild, subtle cell changes, and most go away without treatment. High-grade squamous intraepithelial lesions (HSIL) or CIN 2 or 3. Moderate and severe cell changes which require further testing or treatment. Carcinoma.

47. Pap test performance: Sensitivity = 51% for CIN I or higher Range of 37% to 84% Specificity = 98% for CIN I or higher Range of 86% to 100% meta-analyses of cross-sectional studies (AHCPR 1999). Historical success in developed countries. High specificity, meaning women with no cervical abnormalities are correctly identified by the test with normal test results. be cost-effective in middle-income countries. Strengths of cytology :

48. Limitations of cytology: Moderate to low sensitivity: High rate of false-negative test results Women must be screened frequently Results are not immediately available Requires multiple visits Likely to be less accurate among post-menopausal women ACCP. Pap smears: An important but imperfect method . Cervical Cancer Prevention Fact Sheet. (October 2002).

49. ENDOCERVICAL CURETTAGE: scraping of mucus membrane by endocervical brush or curettage.

50. Punch Biopsy Multiple punch biopsy of the grossly visible lesion should be adequate to diagnose invasive carcinoma It is advised that the specimen be taken from all the four quadrant Important thing is to obtain specimen from periphery of lesion with some normal tissue Biopsy specimen from central area of necrosis or ulceration may not be sufficient for diagnosis Dilatation and curettage

51. Colposcopy

52. COLPOSCOPY Binocular stereoscope giving 10-20 times magnification To study cervix when pap smear detect abnormal cells To locate the abnormal areas and take biopsy Conservative surgery under colposcopic guidence Follow up Visual inspection of acetowhite areas; Applying 5% acetic acid Acid coagulates protein of nucleus and cytoplasm and makes the protein opaque and white Dull white plaque with faint border: LSIL Thick plaque with sharp border: HSIL

53. CT CT provides diagnostic information about the presence of metastases, enlarged lymph nodes, and the primary tumor. On a CT scan, cervical tumor seen as an enlarged, irregular, hypoechoic mass with ill-defined margins. Parametrial regions appear dense when involved, and uterosacral involvement may be seen. Lymph nodes appear enlarged, with most >1 cm on axial dimension considered pathologic. The overall accuracy of CT scanning in staging cervical cancer ranges from 63% to 88%. 50 , 52 Sensitivity - 44% Specificity - 93%. 53

54. MRI MRI is frequently used for the initial assessment of the cervical tumor and of extracervical tumor extension T1W: isointense T2W: hyperintense CE-T1W: hyperintense

55. MRI is significantly better than clinical examination or CT for detecting uterine-body involvement or measuring tumor size , but no method was accurate at evaluating the cervical stroma. MRI was significantly better at detecting the tumor and parametrial involvement. MRI also increased detection of involved lymph nodes . The tumor is less likely to be as visible on MRI for adenocarcinoma cases, compared to squamous cell cancer. Perez &Brady,6 th edition

56. CT vs MRI $ Sensitivity Specificity Accuracy * CT MRI CT MRI CT MRI Parametrial invasion 55% [44-66 %] 74% [68-79 %] - - 76% 94% Lymph nodes 43% [37-57 %] 60% [52-68 %] - - 86% 86% Bladder invasion - - 73% [52-87 %] 91% [83-95 %] - - Bladder and rectal invasion 71% 75% - - - - Stromal invasion - - - - 78% 88% Staging - - - - 65% 90% $ Bipat S, et al, Gynecol Oncol. 2003 Oct;91(1):59-66 * Obs&Gyn,1995;86(1):43-5

57. Positron Emission Tomography PET scanning is increasingly used in the evaluation of patients with invasive cervical cancer, using 2-[ 18 F]-fluoro-2-deoxy-D-glucose (FDG). Rose et al. observed uptake in 91% of the primary tumors in 32 patients with locally advanced carcinoma of the cervix. Compared with surgical staging, PET scanning has a sensitivity of 75% & specificity of 92% in detecting para-aortic metastasis. PET-CT – highly accurate localization of focal radiotracer uptake significantly improved diagnostic accuracy when compared with PET or CT alone. The most significant prognostic factor for progression-free survival was the presence of positive para-aortic lymph nodes on PET imaging. Grisby et al, JCO 2001

58. Maximum standardized uptake value (SUV max) is an independent predictor of death from cervical cancer and is associated with persistent disease . The SUV of the pelvic node predicts pelvic disease recurrence. Squamous cell carcinoma is more often FDG avid than is adenocarcinoma. Perez & Brady,6 th edition

59. Therapeutic Modalities

60. Principles of treatment Both the primary lesion and the potential sites of spread should be evaluated and treated Optimal therapy consists of radiation or surgery ALONE - Morbidity is higher when both are combined

61. PRE INVASIVE CIN part or the full thickness of the stratified squamous epithelium is replaced by cells showing varying degree of dysplasia , but the BASEMENT MEMBRANE IS INTACT. These pre invasive lesions end up as invasive lesions over a period of time. 4% - at the end of first year 11%- by the end of 3 years 22%- by 5 years 30%- by 10 years

62. DYSPLASIA Dysplasia in term literally means disordered growth.It is characterised by a constellation of changes that include a loss of uniformity of the individual cells as well as a loss in their architectural orientation. dysplasia is graded as mild (CIN I) moderate (CIN II) severe (CIN III) tadpole cells as seen in invasive cancer

63. MILD DYSPLASIA(CIN I) - undifferentiated cells are confined to lower third of epithelium. aka low grade squamous intraepithelial neoplasia(LSIL)[ Bethseda classification]. MODERATE DYSPLASIA(CIN II) - undifferentiated cells occupy lower 50-75% of thickness. SEVERE DYSPLASIA(CIN III) - entire thickness of epithelium is filled with abnormal cells. basement membrane is still intact. CIN II and CIN III are together considered as high grade squamous intra-epithelial lesion HSIL.

64. Conization Removes the cervical lesion, the transformation zone & the endocervical canal in the shape of a cone along with endocervical curettage Indications: both diagnostic & therapeutic To assess correctly the depth and the linear extent when microinvasion suspected Inconclusive colposcopy TZ not fully visualized A visible lesion extending to endocx canal Dysplastic fragments in ECC Discordance of >1 grade among the diagnostic evaluation Treatment of Stage Ia1

65. Types of surgeries in CARCINOMA CERVIX

66. Surgical procedures in Carcinoma Cervix Fertility sparing surgeries Conization Trachelectomy Radical hysterectomy Laparoscopic assisted radical vaginal hysterectomy LEER Lymphadenectomy &Staging lymphadenectomy Exentration Oophoropexy

67. Conization Removes the cervical lesion, the transformation zone & the endocervical canal in the SHAPE OF A CONE along with endocervical curettage Is both diagnostic & therapeutic

68. Radical trachelectomy Tricky and difficult to master: the surgeon removes the CERVIX, PARAMETRIUM, SURROUNDING LYMPH NODES, AND UPPER 2 CM OF THE VAGINA . The uterus is then attached to the remaining vagina. A cerclage is placed where the Neocervix used to be to allow the patient to carry a pregnancy Transvaginally / transabdominally /laparoscopic with lymphadenectomy Selection criteria Lesion size < 2 cm Absence of overt LN metastases Absence of LVSI.

69. SIMPLE RADICAL INDICATION HSIL , 1A 1 IA2 & IB1 ,IF <2 cm , SQUAMOUS Intent CURATIVE, FERTILITY PRESERVED CURATIVE, FERTILITY PRESERVED Uterus SPARED SPARED Ovaries SPARED SPARED Cervix REMOVED REMOVED Vaginal margin NONE UPPER ¼ TO 1/3 Ureters NOT MOBILIZED TUNNELED THROUGH BROAD LIGAMENT Cardinal l RESECTED AT CERVICAL BORDER DIVIDED AT PELVIC SIDEWALL Utero sacral l DIVIDED AT CERVICAL BORDER DIVIDED NEAR SACRAL ORGIN Surgical approach VAGINAL VAGINAL/LAP/ROBOTIC LAPROSCOPY

70. RVT is a safe and feasible procedure to perform in women with small cervical carcinomas who wish to preserve fertility Complications : cervical stenosis , vaginal discharge, or dysmenorrhea and reduced fertility , 2 nd trimester miscarriage or premature delivery, deep dyspareunia and recurrent candidiasis Lesion size >2 cm is probably the most important risk factor in terms of tumor recurrence Pregnancy rates following RVT range between 41% -79%, and term delivery ( 37 weeks) is reached in 38% of the pregnancies In-appropriate in gastric type adeno carcinoma and adenoma malignum For 1B 1 ART is considered than VRT , because it provide broader resection of parametrium However miscarriage and pre term labour rates were elevated among women who underwent radical trachelectomy

71. Type I hysterectomy(simple ) type A Extrafascial hysterectomy-The fascia of the CERVIX AND LOWER UTERINE SEGMENT, which is rich in lymphatic, is removed with the uterus No pelvic LND

72. Type II radical hysterectomy( wertheim’s ) type B The uterine artery is ligated where it crosses over the ureter and the uterosacral and cardinal ligaments are divided midway towards their attachment to the sacrum and pelvic sidewall, respectively. The upper one-third of the vagina is resected. Less extensive Selective removal of enlarged LNs UTERINE ARTERY URETER

73. Type III radical hysterectomy ( Meig’s ) type C The uterine artery is ligated at its origin from the superior vesical or internal iliac artery. Uterosacral and cardinal ligaments are resected at their attachments to the sacrum and pelvic sidewall. The upper one-half of the vagina is resected. Pelvic LND

74. Types OF hysterectomies

75. Extended radical hysterectomy TYPE IV - The ureter is completely dissected from the vesicouterine ligament, the superior vesical artery is sacrificed, and three-fourths of the vagina is resected TYPE V - There is additional resection of a portion of the bladder or distal ureter with ureteral reimplantation into the bladder. Rarely used

76. Type-II Vs Type III -Hysterectomy The therapeutic efficacy of a type II comparable to that of a type III but with lower morbidity THE TYPE II OPERATION WAS ASSOCIATED WITH Shorter mean operative time Less late urologic morbidity Similar recurrence rates & Cause-specific mortality 5year OS & DFS Type II procedure appears preferable as long as appropriate tumor clearance can be achieved

77. Laparoscopy-assisted radical vaginal hysterectomy (LARVH) Procedure : laparoscopic visualization of the abdominal cavity to exclude macroscopic disease Laparoscopic lymphadenectomy Radical vaginal hysterectomy (type II or III) Advantages : Less blood loss Better cosmetic results Faster recovery, shorter hospitalization Complications Similar to those seen with abdominal surgery

78. Staging lymphadenectomy Aim- To discovers positive lymph nodes as clinical staging is imprecise Clinical stage fails to identify para-aortic involvement Stage IIa - 10 % Stage IIb -20% Pelvic LN dissection PA LN dissection- Bulky cx ca Grossly positive LNs For whom frozen section evaluation will be performed

79. Staging lymphadenectomy Arguments in favor Surgical staging is the most accurate method of determining lymph node involvement. Therapeutic survival benefit of resecting bulky lymph nodes prior to chemo radiation Arguments against Delay in the institution of primary CRT Increased risk of morbidity (especially late bowel obstructions) with the combined modality approach. Methods Transperitoneal approach-radiotherapy induced bowel complications – 30% Extraperitoneal dissection- postradiotherapy bowel complications-<5% Laparoscopic lymphadenectomy

80. LEER, LATERALLY EXTENDED ENDOPELVIC RESECTION For recurrent disease involving pelvic side walls Extended lateral resection plane Internal iliac vessels, endopelvic part of obturaror internus , coccygeus , iliococcygeus , pubococcygeus are removed

81. EXENTERATION An ultraradical surgical procedure consisting of an en bloc resection of the FEMALE REPRODUCTIVE ORGANS, LOWER URINARY TRACT, AND A PORTION OF THE RECTOSIGMOID . Indications Recurrent or advanced gynecologic cancer Extensive central pelvic disease that cannot be resected with a lesser procedure Has received Radiation before Contraindications Presence of distant metastasis - 50% Unresectable or extrapelvic disease - 30-50% Disease extending to pelvic side walls

82. OOPHOROPEXY Aim: To shield the normal premenopausal ovary from the damaging effects of radiation PROCEDURE: The ovaries and their vascular supply are brought out of the pelvis and sutured lateral and above the psoas muscle Ovarian failure can result despite oophoropexy because of scatter radiation and surgically induced changes in ovarian blood supply& innervation

83. CRITERIA FOR CONSERVATIVE PROCEDURE The entire area must be visible within the squamocolumnar junction. No evidence of macro or micro metastasis as proven by histopathological study. No evidence of endocervical involvement. Young women desirous of child bearing.

84. Hysterectomy is desirable in- old and parous women, when a women cannot comply with followup . if uterus is associated with fibroids/DUB/prolapse. if micro invasion exists. if recurrence occurs following conservative therapy or persistence of lesion.

85. SURGERY Best role, only option : Preinvasive disease Definite role, alternate option : Early invasive disease Controversial role : Bulky disease Some role, only option : recurrent disease (RT failure)

86. STAGE & MANAGEMENT

87. FERTILITY SPARING IA 1, IA2, IB1 CLINICAL STAGE PRIMARY TREATMENT I A 1 ( No LVSI ) CONE BIOPSY with negative margin ( preferably a non fragmented specimen with 3 mm - ve margin) If +VE margin >> repeat CONE BIOPSY/TRACHELECTOMY I A 1 ( With LVSI) I A 2 CONE BIOPSY with negative margin ( preferably a non fragmented specimen with 3 mm - ve margin) If +VE margin >> repeat CONE BIOPSY/TRACHELECTOMY + PELVIC LYMPH NODE DISSECTION +/- Para-aortic ln sampling OR RADICAL TRACHELECTOMY+ PLND +/- Para-aortic ln sampling I B 1 RADICAL TRACHELECTOMY+ PLND +/- Para-aortic ln sampling NCCN 2017

88. NON FERTILITY SPARING IA 1, IA2, CLINICAL STAGE PRIMARY TREATMENT I A 1 (No LVSI ) I A 1 ( With LVSI) I A 2 MODIFIED RADICAL HYSTERECTOMY + PELVIC LYMPH NODE DISSECTION +/- Para-aortic ln sampling OR PELVIC EBRT+ BRACHYTHERAPY NCCN 2017 OBSERVE TYPE1/II HYSTERECTOMY TYPE 1-HYSTERECTOMY

89. IB 1 , IIA 1 , CLINICAL STAGE PRIMARY TREATMENT I B 1 II A 1 MODIFIED RADICAL HYSTERECTOMY + PELVIC LYMPH NODE DISSECTION +/- Para-aortic ln sampling OR PELVIC EBRT+ BRACHYTHERAPY +/-CONCURRENT CISPLATIN CONTAINING CHEMOTHERAPY NCCN 2017

90. IB 2 , IIA 2 , CLINICAL STAGE PRIMARY TREATMENT I B 2 II A 2 DEFINITIVE PELVIC EBRT+ CONCURRENT CISPLATIN CONTAINING CHEMOTHERAPY + BRACHYTHERAPY (Cat 1) OR RADICAL HYSTERECTOMY+ PLND +/-PA LN(cat 2) OR PELVIC EBRT+CONCURRENT CISPLATIN CONTAINING CHEMOTHERAPY + BRACHYTHERAPY+ Adj HYSTERECTOMY ( Cat 3) NCCN 2017

91. Stage IIB, III, and IVA Disease Radiotherapy (EBRT+CC+BT) is the primary treatment for locoregionally advanced cervical carcinoma. The success of radiotherapy depends on a careful balance between external-beam radiotherapy and brachytherapy, optimizing the dose to tumor and normal tissues and the overall duration of treatment.

92. Randomized study of radical surgery v/s radiotherapy for stage Ib-IIa cervical cancer: Lancet 1997 Only prospective trial comparing radical surgery with radiotherapy Design Surgery EBRT+ICR pT2b , <3 mm margins, positive margins, positive pelvic node, parametrial extn. Post op RT IB and IIA 343

93. Results Median follow-up of 87 months Worse morbidity seen in combined modality Treatment modality 5-year overall and disease-free survival Toxicity Surgery 83% & 74 % 25% 28% Radiotherapy 83 % & 74% 26% 12% Local recurrence P=0.004

94. For patients treated with radiotherapy alone for stage IIB, IIIB, and IV disease, 5-year survival rates of 65% to 75%, 35 % to 50%, and 15% to 20%, respectively , have been reported. “ Benedet J, Odicino F, Maisonneuve P, et al. Carcinoma of the cervix uteri. J Epidemiol Biostat 1998;3:5. Logsdon MD, Eifel PJ. FIGO IIIB squamous cell carcinoma of the cervix: an analysis of prognostic factors emphasizing the balance between external beam and intracavitary radiation therapy. Int J Radiat Oncol Biol Phys 1999;43:763.”

95. FAILURE RATE FOLLOWING RADICAL RADIATION IN CARCINOMA CERVIX STAGE PELVIC FAILURE DISTANT METS IB 10% 16% IIA 17% 30% II B 23% 28% III 42% 45% IVA 74% 65% Mallinckrotd Institute of Radiology, 1959-89

96. Therefore, there is need to use some additional modality of treatment with radiation to improve results of locally advanced carcinoma cervix.

97. CHEMORADIATION IN CARCINOMA CERVIX ?????

98. NATIONAL CANCER INSTITUTE CLINICAL ANNOUNCEMENT Concurrent chemoradiation for cervical cancer FEBRUARY 1999

99. 106 improve survival by 1. Increasing control of the primary cervical tumor ( Radiosensitization ) Additivity : increased killing, Synergism inhibition of repair of RT induced damage, promoting cells into radio sensitive phase, intiate proliferation in non-proliferating cells., reducing fraction of hypoxic cells 2. Decreasing the rate of distant metastases STEEL PARADIGM

100. 107 Major Trials Author Trial No. Investigational Arm Control Arm Tumor Comment Keys 1999 GOG 123 369 RT+ Cisplatin Surgery RT alone Surgery Stage IB (≥ 4cm) Combined with Surgery Peters 2000 SWOG 8797 243 Surgery RT+Cisplatin+5FU Surgery RT alone IA2, IB, IIA (with postop high risk) Combined with Surgery Morris & Eifel 1999 &.2004 RTOG 9001 388 RT+Cisplatin+5FU Extended -field RT IB or IIA (≥5cmorPLN+) IIB, III, IVA Surgical staging for PALN Whitney 1999 GOG 85 368 RT+Cisplatin+5FU RT+ Hydroxyurea IIB, III, IVA Surgical staging for PALN Rose 1999 GOG 120 526 RT+Cisplatin RT+Cisplatin + 5FU +Hydroxyurea RT+ Hydroxyurea IIB, III, IVA Surgical staging for PALN Pearcey 2002 NCIC 253 RT+Cisplatin RT alone IB2, IIA(≥5cm), IIB, III, IVA No surgical staging for PALN

101. 109 Randomized controlled trials of concurrent chemotherapy

102. GOG 80 GOG 120 GOG 123 RTOG 9001 SWOG 8757

103. 111 Reduction in the risk of death by cisplatin-based CRT: 6 major trials

104. 112 Locally advanced cervix cancer Concurrent chemoradiation: Results of RCTs Significant reduction (43-46%) in the risk of recurrence & death. Reduction in relative risk of recurrence & death remarkably similar in all studies. Compelling evidence of survival benefit (10-15%) with concurrent cisplat chemo.

105. 113 Concurrent Chemoradiation Results of Meta-analyses 19 RCTs between 1981 and 2000 : 4580 randomized patients Increase in OAS by 12% & RFS by 16% (absolute benefit) (p=0.0001) Greater benefit in patients in stages IB2 and IIB Decrease in local and systemic recurrence (p=0.0001) Cochrane Collaborative Group (19 Trials) (4580 patients) Green JA et al Lancet 358;781 (Sept. 2001) “Grade A” Update in July 2005: 21 trials and 4921 pts Similar findings (absolute benefit: 10%) Test for Heterogeneity : Positive No data on late toxicities Cochrane Database Syst Rev. 2005 Jul 20;(3):CD002225.

106. Breaks during or between external-beam and intracavitary therapy should be discouraged, and every effort should be made to complete the entire radiation treatment in less than 7 to 8 weeks. Several studies have suggested that treatment courses longer than 8 weeks are associated with decreased pelvic disease control and survival rates. “Fyles A, Keane TJ, Barton M, et al. The effect of treatment duration in the local control of cervix cancer. Radiother Oncol 1992;25:273. Perez CA, Grigsby PW, Castro-Vita H, et al. Carcinoma of the uterine cervix. I. Impact of prolongation of overall treatment time and timing of brachytherapy on outcome of radiation therapy. Int J Radiat Oncol Biol Phys 1995;32:1275. Petereit DG, Sarkaria JN, Chappell R, et al. The adverse effect of treatment prolongation in cervical carcinoma. Int J Radiat Oncol Biol Phys 1995;32:1301.”

107. 115 Impact of RT delay on survival (GOG 120&165) (Monk BJ, et al: J Clin Oncol 2007) P=0.012

108. 116 Optimal timing of intervention for acute toxicity ( Ohno T. et al, Gynecol. Oncol. 2006)

109. 117 Criteria for modification of chemotherapy Cisplatin is suspended in -Grade 2 hematological toxicities (WBC < 3000, Plt < 75000) - Fever > 38ºC -PS 3-4 -Grade >3 non-hematological toxicities (e.g. diarrhea, loss of appetite, fatigue) -Serum creatinine > 2.0 mg/dl -Cases that are judged to be difficult to administer cisplatin by responsible physician. Cisplatin is resumed when the hematological and nonhematological toxicities are recovered to grade 1.

110. FIGO GUIDELINE IN 2000 For Advanced Cervical cancer (Stage IIb , III, IVA) Benedet et al Int J of Gynecol Oncol 2000 Addition of concurrent cisplatin-containing chemotherapy to standard radiotherapy reduces the risk of disease recurrence by as much as 50%.

111. NEOADJUVANT CHEMOTHERAPY NEO ADJUVANT CT followed by surgery has been used in areas where RT is not available , data suggest NO IMPROVEMENT in survival when compared with surgery alone for early –stage cervical cancer or locally advanced cervical cancer. A meta analysis of data on pts with stage IB1 to IIA cervical cancer found that NACT may reduce the need of adj RT by decreasing tumour size and metastases , but indicated no OS benefit. Second meta analysis suggested that response to NACT was a strong prognostic factor for PFS and OS

112. Indications for adjuvant therapy High-risk disease Positive or close resection margins Positive lymph nodes positive parametrial involvement Intermediate-risk disease Lymphovascular space invasion Large tumor size (>4 cm ) Deep cervical stromal invasion (to the middle or deep one-third) low-risk disease Negative margins Negative lymph nodes Negative parametrial involvement

113. Adjuvant RT/ RT+CT

114. POSITIVE ADENOPATHY IB2, IIA2,IIIA,IIIB,IV A

115. POSITIVE ADENOPATHY IB2, IIA2,IIIA,IIIB,IV A Work up for metastasis

116. RECURRENCE

117. SURVEILLANCE(NCCN Guidelines 2017) Interval H& P 3-6 monthly 2yrs 6-12 monthly 3-5 yrs >5 yrs annually Cervical and vaginal cytology as indicated for lower genital tract neoplasia Annual Imaging as indicated CT, PET ,MRI Lab Assessment as indicated CBC ,BUN, Creatinine Patient education Symptoms of potential recurrence Lifestyle Obesity Exercise Nutrition Sexual health and vaginal dilator use.

118. OVERALL SURVIVAL BY STAGE SURVIVAL(5YR) Last Revised: 02/26/2015 IA 93% IB1 83% IB2 80% IIA 63% IIB 38% IIIA 35% IIIB 32% IVA 16% IVB 15% The rates below were published in 2010 in the 7 th  edition of the AJCC staging manual. They are based on data collected by the National Cancer Data Base from people diagnosed between 2000 and 2002. These are the most recent statistics available for survival by the current staging system

119. Targets for EBRT Entire cervix Uterus and tubes Upper third of vagina Entire vagina in selected cases Parametrial tissues (cardinal, uterosacral and pubocervical ligaments) Pelvic nodes (external and internal iliac, in selected cases up to common iliac) Inguinal nodes in selected cases. Para-aortic nodes in selected cases.

120. Principles of radiotherapy volume : Gross disease, parametria , us ligaments, sufficient vaginal margin ( atleast 3mm), Presacral and other Nodes at risk Nodes at risk - Negative node on surgical or radiology ( EIL,IIL,O) ; H igh risk/suspected node – cover common iliac also ; CIL /para aortic – EX EBRT( upto the level of renal vessels or even more according to the nodal station)

121. Dose For coverage of microscopic/ nodal disease 45-50 GY (1.8 to 2 gy /#) BOOST : 10-15 gy for gross unresected adenopathy

122. Brachytherapy Critical component of definitive therapy Usually performed using an intracavitory approach When combined with EBRT , BT intiated towards the latter part of traetment . In highly selected very early disease (STAGE I A2) BT alone may be an option.

123. THANK YOU