CERVICAL CANCER Updated Apr 2017 by: Dr. Jenny Ko (Medical Oncologist, Abbotsford Cancer Centre)

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1 1 CERVICAL CANCER Updated Apr 2017 by: Dr. Jenny K (Medical Onclgist, Abbtsfrd Cancer Centre) Surce: UpTDate 2017, ASCO/CCO/Alberta prvincial guidelines, NCCN Reviewed by: Dr. Sarah Glaze (Gyneclgic Onclgist, University f Calgary), Dr. Aalk Kumar (Gyneclgic Onclgist, UBC), Dr. Stephanie Lhereux (Gyneclgic Onclgist, University f Trnt) DISCLAIMER: The fllwing are study ntes cmpiled by the abve PGY-5 medical nclgy residents and reviewed by a staff medical nclgist. They reflect what we feel is relevant knwledge fr graduating medical nclgy residents preparing fr their final examinatin. The infrmatin has nt been surveyed r ratified by the Ryal Cllege. A) PUBLIC HEALTH EPIDEMIOLOGY - Incidence: 500,000/year - Mrtality: 288,000 deaths/year, usually at a yung age - Mst prevalent and imprtant cancer in wmen in several develping cuntries RISK FACTORS - HPV main risk factr - early nset f sexual activity, multiple sexual partners, a high-risk sexual partner (e.g. prmiscuus sexual activity, sexual expsure t a partner with human papillmavirus infectin), histry f sexually transmitted diseases (eg, Chlamydia trachmatis, herpes simplex virus) Ø Caused by high-risk sertypes: HPV 16: 50%, HPV-18: 20% - Other risk factrs - Smking, high parity, immunsuppressin, lw sciecnmic status, prlnged use f ral cntraceptives, and previus histry f vulvar r vaginal squamus dysplasia Ø Cigarette smking is nt assciated with an increased risk f adencarcinma f the cervix cmpared t nnsmkers - Adencarcinmas have been rising in incidence since the 1970s, especially in wmen yunger than 35 years f age. VACCINATION - L1 particle expressed by human papillmavirus Ø L1 prtein assembles int a virus-like particle (VLP) Ø VLPs are recgnized as antigens and induce humeral immunity All papillmaviruses share a cmmn genetic structure: they have a duble-stranded circular DNA genme encdes apprximately eight pen-reading frames (ORFs) and a nn-envelped capsid. The papillmavirus genme is divided int an early regin (E), encding six (E1, E2, E4, E5, E6, and E7) pen reading frames (ORF) that are expressed immediately after initial infectin f a hst cell, and a late regin (L) encding a majr capsid prtein L1 and a minr capsid prtein L2. The papillmavirus life cycle is tightly linked t the differentiatin prgram f the infected epithelium. One f the key events f HPVinduced carcingenesis is the integratin f the HPV genme int a hst chrmsme. Cells that express E6/E7 frm integrated HPV sequences have a selective grwth advantage. In cancer develpment, HPV- 16 early prteins E6 and E7 are ften believed t act as the ncprteins as bth are crucial fr hst cell immrtalizatin and transfrmatin. Particularly, E6 targets p53 tumr suppressr directly and enhances p53 degradatin via the actin f ubiquitin PREVENTION & SCREENING (CCO and Alberta guidelines) PREVENTION - HPV Vaccine

2 2 1) Gardasil: Quadrivalent HPV-16/18/6/11 L1 VLP vaccine, intramuscular injectin in a three-dse immunizatin prtcl at 0, 1 and 6 mnths, recmmended fr all wmen <45Y and men up t 26Y fr preventin f HPV related cancers and genital warts - Gardasil 9 just released in Canada HPV types 6, 11, 16, 18, 31, 33, 45, 52 and 58. 2) Cervarix: HPV-16/18 vaccine nly. Apprved fr use in females aged 10 t 25. At this time Cervarix has nt been apprved fr use in males in Canada. SCREENING Screening Initiatin Cervical cytlgy screening shuld be initiated after three years f first vaginal sexual activity (i.e., vaginal intercurse, vaginal/ral and/r vaginal/digital sexual activity) r age 21, whichever is later Screening Interval Screening shuld be dne annually until there are three cnsecutive negative Pap tests. Screening shuld cntinue every three years after three annual negative Pap tests. Screening at a three-year interval is recmmended, supprted by an adequate recall mechanism. Wmen wh have nt been screened in mre than five years shuld be screened annually until there are three cnsecutive negative Pap tests. Screening Cessatin Screening may be discntinued after the age f 69 if there is an adequate negative screening histry in the previus 10 years (i.e. 3-4 negative tests). Screening Wmen with Special Circumstances Immuncmprmised r HIV-psitive wmen shuld receive annual screening. Screening can be discntinued in wmen wh have undergne ttal hysterectmy fr benign causes with n histry f cervical dysplasia Wmen wh have undergne subttal hysterectmy (with an intact cervix) shuld cntinue screening accrding t the guidelines. Indicatins fr screening frequency fr pregnant wmen shuld be the same as wmen wh are nt pregnant. Wmen wh have sex with wmen shuld fllw the same cervical screening regimen as wmen wh have sex with men. Recmmended Management fr Wmen with Abnrmal Cytlgy (differs by prvince belw is Alberta specific) ASCUS (Atypical squamus cells f uncertain significance) HPV DNA testing with cytlgy is recmmended fr wmen aged 30 r lder with ASCUS. If the HPV DNA test is psitive, wmen shuld be referred fr clpscpy. If the HPV DNA test is negative, wmen shuld have repeat cytlgy in 12 mnths. Once a wman has had tw negative cytlgy test results, she shuld return t rutine screening. In the absence f HPV DNA testing, a repeat Pap test in six mnths is acceptable. If the Pap test is abnrmal, wmen shuld be referred fr clpscpy. If the Pap test is negative, wmen shuld have repeat cytlgy in anther six mnths. Once a wman has had tw negative Pap tests results, she shuld return t rutine screening. In wmen under the age f 30, a repeat Pap test in six mnths is recmmended. If the Pap test is abnrmal, wmen shuld be referred fr clpscpy. If the Pap test is negative, wmen shuld have repeat cytlgy in anther six mnths. Once a wman has had tw negative Pap tests results, she shuld return t rutine screening. ASC-H (Atypical squamus cells: cannt exclude high grade squamus) Clpscpy is recmmended fr wmen with ASC-H. LSIL (Lw-grade squamus intraepithelial lesin) Either clpscpy r repeat cytlgy in six mnths is recmmended fr wmen with LSIL.

3 3 If repeat cytlgy is used and the Pap test is abnrmal, wmen shuld be referred fr clpscpy. If the Pap test is negative, wmen shuld have repeat cytlgy in anther six mnths. Once a wman has had tw negative Pap test results, she shuld return t rutine screening. There is limited evidence t supprt the use f intravaginal estrgen t reverse the cytlgic changes in pstmenpausal wmen with LSIL. A curse f intravaginal estrgen fllwed by repeat cytlgy apprximately a week after cmpleting the regimen is acceptable fr wmen with LSIL wh have clinical r cytlgical evidence f atrphy and n cntraindicatins t using intravaginal estrgen. Referral fr clpscpy is recmmended if a result f ASC-US r greater is btained. HSIL (High-grade squamus intraepithelial lesin), Clpscpy is recmmended fr wmen with HSIL. Annual screening thereafter is recmmended (Alberta). AGC (Atypical glandular cells) Clpscpy is recmmended fr wmen with AGC. Wmen with AGC shuld als receive endcervical and endmetrial sampling 6% chance f malignancy mst endmetrial B) PRESENTATION & DIAGNOSIS SYMPTOMS & SIGNS - Early cervical cancer is frequently asymptmatic - Cmmn symptms:abnrmal vaginal bleeding, pstcital bleeding, vaginal discharge that may be watery, mucid, r purulent and maldrus - Pelvic r lwer back pain, which may radiate alng the psterir side f the lwer extremities, can ccur with advanced disease. - Bwel r urinary symptms, such as pressure-related cmplaints, hematuria, hematchezia, r vaginal passage f urine r stl, are uncmmn and suggest advanced disease INVESTIGATIONS - Visible: Punch bipsy f the lesin - Nn visible: clpscpy with directed bipsy Ø An adequate clpscpy requires that the entire squamclumnar junctin and all lesins be cmpletely visualized and that bipsies f the lesins explain the abnrmal cytlgy Ø If a pap smear is perfrmed n a frankly invasive cervicaltumur 50% will be nrmal (b/c f necrtic cells clse t surface). ALWAYS bipsy abnrmal appearing cervix - If clpscpy is inadequate r fr diagnsis f micrinvasive disease (stage IA, n clinically visible lesin): cnizatin, because maximum depth f invasin can nly be determined by examinatin f the entire lesin - Any cervix that is unusually firm r expanded shuld be sampled by punch bipsy and endcervical curettage, even if the cervical cytlgy smear des nt shw evidence f neplasia - Histlgic cnfirmatin f invasive cervical cancer is fllwed by a careful staging evaluatin that shuld include a thrugh physical examinatin. The cervix and entire vagina shuld be carefully inspected and palpated t identify vert tumr r subepithelial vaginal extensin. Rectvaginal examinatin permits the best assessment f tumr size and parametrialinvlvement. Palpatin f the liver and inguinal and supraclavicular lymph ndes is imprtant t screen fr metastatic disease - The cmpletin f the initial staging evaluatin requires chest radigraph, intravenus pyelgram (IVP), cmplete bld cunt, renal and liver functin tests, and, in suspected advanced disease, cystscpy and/r prctsigmidscpy (typically dne in the OR staging pelvic examinatin under anaesthesia). CT scan, MRI and nly in selected cases PET-CT are used t define the cancer clinical stage and plan the best treatment ptin fr

4 4 the patient. MRI has an imprtant rle in the evaluatin f strmal invasin, vaginal infiltratin, rectal r bladder invasin, presence f ndal lcalizatin and fr fertility-spare surgery. Thrax-abdmen CT scan is imprtant in the advanced stage disease t exclude distant metastasis. - Cervical cancer is clinically staged with this prcedure. FIGO Stage never changes, despite surgical findings (ie psitive ndes d nt change stage) PATHOLOGY & MOLECULAR BIOLOGY - Cmmn Histlgy: Ø Squamus cell carcinmas (SCCs) accunt fr apprximately 70 percent f cervical cancers, adencarcinmas 25 percent, and adensquamus carcinmas 3 t 5 percent Ø Neurendcrine r small cell carcinmas can riginate in the cervix, but are infrequent (pr prgnsis). Primary cervical lymphma and cervical sarcma are als rare - Cmmn Metastatic Sites:Lcal cntiguus, then lymphatic (lcal r distant, high incidence f supraclavicular psitive ndes)/hematgenus spread Ø Direct extensin may invlve the uterine crpus, vagina, parametria, peritneal cavity, bladder, r rectum. Ovarian invlvement by direct extensin f cervical cancer is rare; varian metastases ccur Ø The mst cmmn sites fr hematgenus spread are the lungs, liver, and bne; the bwel, adrenal glands, spleen, and brain are less frequent sites. STAGING (TNM vs FIGO) Primary tumr (T) T1 I Cervical carcinma cnfined t uterus (extensin t crpus shuld be disregarded) T1a IA Invasive carcinma diagnsed nly by micrscpy. All macrscpically visible lesins - even with superficial invasin - are T1b/1B. Strmal invasin with amaximal depth f 5.0 mm measured frm the base f the epithelium and a hrizntal spread f 7.0 mm r less. Vascular space invlvement, venus r lymphatic, des nt affect classificatin T1a1 IA1 Measured strmal invasin 3 mm r less in depth and 7 mm r less in lateral spread T1a2 IA2 Measured strmal invasin mre than 3.0 mm and nt mre than 5.0 mm with a hrizntal spread 7.0 mm r less T1b IB Clinically visible lesin cnfined t the cervix r micrscpic lesin greater than IA2 T1b1 IB1 Clinically visible lesin 4.0 cm r less in greatest dimensin IB2 Clinically visible lesin mre than 4.0 cm T2 II Cervical carcinma invades beynd uterus but nt t pelvic wall r t the lwer third f vagina T2a IIA Tumr withut parametrial invasin T2b IIB Tumr with parametrial invasin T3 III Tumr extends t the pelvic wall, and/r invlves the lwer third f the vagina, and/r causes hydrnephrsis r nnfunctining kidney T3a IIIA Tumr invlves lwer third f the vagina, n extensin t pelvic wall T3b IIIB Tumr extends t pelvic wall and/r causes hydrnephrsis r nnfunctining kidney IV Cervical carcinma has extended beynd the true pelvis r has invlved (bipsy prven) the bladder mucsa r rectal mucsa. Bullus edema des nt qualify as a criteria fr stage IV disease. T4 IVA Spread t adjacent rgans (bladder, rectum, r bth) M1 IVB Distant metastasis Reginal lymph ndes (N), AJCC staging nly Include paracervical, parametrial, hypgastric (bturatr), cmmn, internal and external iliac, presacral and sacral

5 5 N1 Reginal lymph nde metastasis AJCC stage gruping Stage 0 Tis N0 M0 Stage IA1 T1a1 N0 M0 Stage IA2 T1a2 N0 M0 Stage IB1 T1b1 N0 M0 Stage IB2 T1b2 N0 M0 Stage IIA T2a N0 M0 Stage IIB T2b N0 M0 Stage IIIA T3a N0 M0 T1 N1 M0 Stage IIIB T2 N1 M0 T3a N1 M0 T3b Any N M0 Stage IVA T4 Any N C) TREATMENT EALRY STAGE - Definitin f Early Stage: Stage IA Cervical cancer diagnsed n micrscpic examinatin with evidence f strmal invasin spanning 7 mm in the hrizntal dimensin and extending either 3 mm (stage IA1) r between 3 and 5 mm (stage IA2) in depth Stage IB1 a clinically visible lesin cnfined t the cervix measuring less than 4 cm r a micrscpic lesin with strmal invasin greater than in a stage IA lesin - Mst cmmn treatment (up t IB1): mdified radical hysterectmy with pelvic lymphadenectmy rather than primary chemrt - N cnsensus abut sentinel nde mapping - Primary RT nt adequate Rx fr cervical cancer cmpared t primary surgery - Retrspective study >4000 wmen with early stage cervical cancer identified in the SEER registry Primary surgery resulted in 59% reductin in the risk f death cmpared w primary RT (HR0.41) EARLY STAGE, INTERMEDIATE RISK - Definitin: in general, 2/3 f a) deep 1/3 invlvement b) >4cm c) LVSI LVSI plus deep ne-third cervical strmal invasin and tumr f any size LVSI plus middle ne-third strmal invasin and tumr size >2 cm LVSI plus superficial ne-third strmal invasin and tumr size >5cm N LVSI but deep r middle ne-third strmal invasin and tumr size >5 cm The risks f recurrence and death in the presence f these factrs are up t 30% fllwing surgery alne - Suggested treatment: adjuvant RT r chemrt t decrease risk f recurrence (cntrversial re: adjuvant RT r chemrt in early stage intermediate risk, chemrt preferred) EARLY STAGE, HIGH RISK - Definitin Psitive surgical margins OR Pathlgically cnfirmed invlvement f the pelvic lymph ndes OR Micrscpic invlvement f the parametrium Fr wmen with high-risk factrs, the recurrence risk is ~40% and the risk f death is up t 50% fllwing surgery alne - Recmmendatin: Adjuvant chemrt

6 6 - Discussin and trials nging t define the rle f adjuvant standard chem fllwing chemrads GOG92: A randmized trial f pelvic radiatin therapy versus n further therapy in selected patients with stage IB carcinma f the cervix after radical hysterectmy and pelvic lymphadenectmy: A Gyneclgic Onclgy Grup Study. (Sedlis 1999 GynecOncl) Regimen Radical hysterectmy and lymphadenectmy randmized t +/- adjuvant pelvic XRT Gy. Primary Endpint DFS Inclusin/Exclusin Stage IB, nde negative, but with high estimated risk f recurrence (frm GOG 49) Size (N) 277 Results Recurrences 15 vs 28%, 2Y recurrence free rate 88 vs 79% (significant) Distant mets 2% (RT) vs 7% (n RT). Imprved PFS by 42%. Decreased death rate by 30% (28.6% vs 19.7%) but nt statistically significant (p=0.07). Txicity Grade 3/4 adverse effects were 6% vs 2.1% Cnclusin Adjuvant pelvic XRT reduces recurrences and imprves PFS but nt OS in IB patients Other Cmments RT has imprved benefit fr adencarcinma r adensquamushistlgies (8.8% vs 44% recurrence). GOG109: Cncurrent chemtherapy and pelvic radiatin therapy cmpared with pelvic radiatin therapy alne as adjuvant therapy after radical surgery in high-risk early-stage cancer f the cervix. (Peters 2000 JCO) Regimen RT vs. RT + CT Pts in each grup received 49.3 GY RT in 29 fractins t a standard pelvic field Chem cnsisted f blus cisplatin 70 mg/m 2 and a 96 hur infusin f flururacil 1000 mg/m 2 /d every 3 weeks fr fur cycles, with the 1 st and 2 nd cycles given cncurrent t RT Primary Endpint DFS Inclusin/Exclusin Pts with clinical stage IA(2), IB, and IIA carcinma f the cervix, initially treated with radical hysterectmy and pelvic lymphadenectmy, and wh had psitive pelvic lymph ndes and/r psitive margins and/r micrscpic invlvement f the parametrium Size (N) 243 Results PFS significantly imprved in terms f HR (p=0.003) Prjected PFS at 4 years is 63% with RT and 80% with RT + CT OS significantly imprved in terms f HR (p=0.007) The prjected OS at 4 years is 71% with RT and 81% with RT + CT Txicity (e.g. cmmn txicities verall, cmmn grade 3/4 txicities) Cnclusin Adjuvant chemrt imprves PFS and OS (10% at 4 years) cmpared with RT alne in patients with early stage and high risk disease. Management f Lcally Advanced Cervical Cancer (Stage IB2 t IVA) - Definitin Cnfined t the cervix with a clinically visible tumr >4cm Invades beynd uterus but nt t pelvic wall r t lwer third f vagina (stage II)

7 7 Extends t the pelvic sidewall and/r invlves the lwer third f vagina and/r causes hydrnephrsis r a nnfunctining kidney (stage III) Invades the mucsa f the bladder r rectum r extends beynd the true pelvis (stage IVA) - Treatment: primary chemrt with weekly cisplatin 40mg/m 2 during 5 weeks f RT fllwed by brachytherapy - In sme advanced stage, hydrnephrsis is described and required ureteral stent r nephrdtmy befre starting treatment GOG120: Cncurrent cisplatin-based raditherapy and chemtherapy fr lcally advanced cervical cancer. (Rse 1999 NEJM) Regimen All patients received external-beam raditherapy accrding t a strict prtcl. Patients were randmly assigned t receive ne f three chemtherapy regimens: - 40 mg f cisplatin per square meter f bdy-surface area per week fr six weeks (grup 1); - 50 mg f cisplatin per square meter n days 1 and 29, fllwed by 4 g f flururacil per square meter given as a 96-hur infusin n days 1 and 29, and 2 g f ral hydrxyurea per square meter twice weekly fr six weeks (grup 2); - Or 3 g f ral hydrxyurea per square meter twice weekly fr six weeks (grup 3). Primary Endpint OS and DFS Inclusin/Exclusin Wmen with primary untreated invasive squamus-cell carcinma, adensquamus carcinma, r adencarcinma f the cervix f stage IIB, III, r IVA, withut invlvement f the para-artic lymph ndes Size (N) 526 Results Bth grups that received cisplatin had a higher rate f prgressin-free survival than the grup that received hydrxyurea alne (P<0.001 fr bth cmparisns) The relative risks f prgressin f disease r death were 0.57 (95 percent cnfidence interval, 0.42 t 0.78) in grup 1 and 0.55 (95 percent cnfidence interval, 0.40 t 0.75) in grup 2, as cmpared with grup 3. The verall survival rate was significantly higher in grups 1 and 2 than in grup 3, with relative risks f death f 0.61 (95 percent cnfidence interval, 0.44 t 0.85) and 0.58 (95 percent cnfidence interval, 0.41 t 0.81), respectively. Txicity The frequencies f bth grade 3 and grade 4 leukpenia in the grup given raditherapy cmbined with treatment with cisplatin, flururacil, and hydrxyurea were mre than duble in the ther tw grups (P<0.001). The frequencies f ther hematlgic effects f bth grade 3 and grade 4 predminantly granulcytpenia in the grup given raditherapy cmbined with cisplatin, flururacil, and hydrxyurea therapy were apprximately duble in the ther tw grups (P<0.001). Cnclusin Regimens f raditherapy and chemtherapy that cntain cisplatin imprve the rates f survival and prgressin-free survival amng wmen with lcally advanced cervical cancer. CCCMAC (2010 Cchrane database systemic review)

8 8 Regimen Raditherapy (with r withut surgery) versus cncmitant chemraditherapy (with r withut surgery) Primary Endpint OS Inclusin/Exclusin 15 randmized cntrlled trials (RCTs) t assess the effect f chemraditherapy n all utcmes Results 6% imprvement in 5-year survival with chemraditherapy (hazard rati (HR) = 0.81, P < 0.001). Fr wmen w stage IB t IIA, IIB, and III and IVA cervical cancer, the 5 year survival benefit was 10,7, and 3%, respectively (p=0.017) Chemraditherapy als reduced lcal and distant recurrence and prgressin and imprved disease-free survival (DFS). There was a significant survival benefit fr bth the grup f trials that used platinum-based (HR = 0.83, P = 0.017) and nn-platinum based (HR = 0.77, P = 0.009) chemraditherapy, but n evidence f a difference in the size f the benefit by raditherapy r chemtherapy dse r scheduling was seen. Txicity Acute haematlgical and gastr-intestinal txicity were increased with chemraditherapy, but data were t sparse fr an analysis f late txicity. Cnclusin These results demnstrate a benefit f nn-platinum based chemraditherapy. Furthermre, althugh these results suggest an additinal benefit frm adjuvant chemtherapy this requires testing in RCTs. Pelvic radiatin with cncurrent chemtherapy cmpared with pelvic and para-artic radiatin fr high-risk cervical cancer Mrris NEJM Regimen All patients received external-beam raditherapy accrding t a strict prtcl. Patients were randmly assigned t receive either 45 Gy f radiatin t the pelvis and para-artic lymph ndes r 45 Gy f radiatin t the pelvis alne plus tw cycles f flururacil and cisplatin (days 1 thrugh 5 and days 22 thrugh 26 f radiatin). Patients were then t receive ne r tw applicatins f lw-dse-rate intracavitary radiatin, with a third cycle f chemtherapy planned fr the secnd intracavitary prcedure in the cmbined-therapy grup. Primary Endpint OS Inclusin/Exclusin Wmen with advanced cervical cancer cnfined t the pelvis (stages IIB thrugh IVA r stage IB r IIa with a tumr diameter f at least 5 cm r invlvement f pelvic lymph ndes) Size (N) 403 Results 5Y DFS 67 vs 40% (significant) The rates f bth distant metastases (P<0.001) and lcreginal recurrences (P<0.001) were significantly higher amng patients treated with raditherapy alne. 5YS 73 vs 58% (significant) Txicity The seriusness f side effects was similar in the tw grups, with a higher rate f reversible hematlgic effects in the cmbined-therapy grup. Cnclusin The additin f chemtherapy with flururacil and cisplatin t treatment with external-beam and intracavitary radiatin significantly imprved survival amng wmen with lcally advanced cervical cancer. Rle f Brachytherapy - Three techniques f brachytherapy: Intracavitary brachytherapy Interstitial brachytherapy

9 9 Pulse dse rate brachytherapy uses Iridium-192 surce Treatment f para-artic ndes - Wmen with evidence f para-artic invlvement have a pr prgnsis with a 5 year survival rate f ~40% - Despite lw quality data, it is rutine practice t treat these patients with extended field RT. - N trials that cmpared chemrt using extended field RT (t cver the para-artic regin) vs pelvic RT, but given their high risk f disease prgressin and death, preference t treat with extended field RT w cncurrent cisplatin. - Imprtance f time t cmpletin f chemrt: treatment shuld be cmpleted within 8 weeks. There are limited data thugh n the imprtance f time t cmpletin fr wmen underging chemrt - Ptential Rle f systemic chem after chemrt Trials n ging - Neadjuvant chem limited evidence 2 meta-analysis - the first ne (Cchrane 2012) shwed a benefit in OS and PFS with NACT but the evidence was based nly n small trials. The secnd meta-analysis (Kim 2013) did nt shw any benefit in OS with NACT. MANAGEMENT OF RECURRENT OR METASTATIC DISEASE - Metastatic disease will develp in 15-61% wmen with cervical cancer, usually within the first 2 years f cmpleting treatment. Management f Lcal Recurrence - Treatment directed t the site f recurrence can be perfrmed with curative intent - Optins: hysterectmy, pelvic exenteratin, r RT the chice depends n the patient s prir treatment - Patients wh have previusly been treated with RT and thse wh are nt candidates fr surgical resectin shuld be ffered chem. - Candidates fr surgical resectin: Thse w lcal recurrences shuld be ffered surgical resectin with curative intent. Cmmnly emplyed criteria t identify thse wmen mst likely t benefit frm surgery: A central pelvic recurrence withut side wall fixatin r assciated hydrnephrsis Lng disease free interval Tumr size f the recurrence less than 3 cm in diameter - Nn-surgical ptins Candidates fr RT Wmen wh have nt been previusly treated w RT Wmen w perable disease wh pt nt t prceed with pelvic exenteratin Mst experts prefer chemrt fr these patients Candidates fr chem: if nt candidates fr surgical resectin r primary RT, chem is the ptin but this is a palliative intent. Management f Metastatic Disease - Management f metastatic cervical cancer depends n the extent f disease at presentatin. Fr patients with limited metastatic disease (ie. Disease in the para-artic ndes r slitary lung mets), treatment can be directed twards recurrence using radiatin therapy r a surgical apprach. Hwever, fr wmen w mre extensive disease, chem is the treatment ptin. - The fllwing factrs were assciated with a higher likelihd f a pr respnse t cisplatinbased cmbinatin chem (Mre Gynecl Oncl Jan;116(1):44-9): Black race vs nn black OR 0.49 fr pr respnse PS 1 r 2 OR 0.60 Pelvic disease vs nn-pelvic lcatin OR 0.58 Prir treatment with cisplatin as part f chemradiatin (vs nne) - RR 0.52 Recurrence within ne year f diagnsis (vs lnger) OR 0.61

10 10 This mdel suggests that chem-naive patients have a higher respnse rate than wmen wh received prir chem, including g as part f chemradiatin Cmbinatin Chemtherapy - Standard: platinum based chemtherapy cmbinatin, and recently apprved bevacizumab. - Cmbinatin > single agent (preferred = cis/paclitaxel) - Carbplatin is a suitable alternative.(cisplatin is preferred if n cntre indicatin particularly if patient did nt have prir cisplatin expsure) A randmized, phase III trial f paclitaxel plus carbplatin (TC) versus paclitaxel plus cisplatin (TP) in stage IVb, persistent r recurrent cervical cancer: Japan Clinical Onclgy Grup study (JCOG0505). (Kitagawa ASCO 2012) Regimen Randmly assigned treatment with cisplatin 50mg/m 2 plus paclitaxel 135 mg/m2 r carbplatin (AUC 5) plus paclitaxel 175 mg/m 2, administered every three weeks fr 6 cycles. Primary Endpint OS Inclusin/Exclusin Stage IVB, persistent r recurrent cervical cancer Size (N) 253 Results Cmpared with cisplatin/paclitaxel, treatment with carbplatin paclitaxel resulted in: Similar ORR (63 vs 60%) n difference in OS (HR fr mrtality 0.99) althugh a difference nted in the fllwing subgrups: amng wmen nt previusly treated with cisplatin, carbplatin plus paclitaxel resulted in a lwer median OS cmpared w cisplatin plus paclitaxel (13 vs 23 m, HR 1.57) amng wmen previusly treated with cisplatin, carbplatin plus paclitaxel resulted in a higher OS 19 vs 16 mnths, HR 0.69) Txicity Significantly less grade 4 neutrpenic events (45 vs 75%, p<0.0001). There were als less serius (gd ¾) incidences f renal insufficiency (-0 vs 2.4 %) N/V(3 vs 7%). Hwever carbplatin/paclitaxel resulted in mre neurpathic events (7 vs 1%) - Chem plus Bevacizumab as 1 st line treatment GOG240: Imprved Survival with Bevacizumab in Advanced Cervical Cancer (2014 Tewari NEJM) Regimen 2 by 2 factrial design. Chemtherapy with r withut bevacizumab at a dse f 15 mg/kg Chemtherapy cnsisted f cisplatin at a dse f 50 mg/m 2 plus paclitaxel at a dse f 135 r 175 mg 2 r tptecan at a dse f 0.75 mg/m 2 n days 1 t 3, plus paclitaxel at a dse f 175 mg/m 2 n day 1. Primary Endpint OS Inclusin/Exclusin Wmen with advanced cervical cancer - recurrent persistent, r metastatic cervical cancer Size (N) 452 Results Adding bevacizumab t chem was assciated with increased OS (17.0 vs 13.3m, HR fr death 0.71, p=0.004 in a ne-sided test)

11 11 Txicity Adding Bevacizumab prduced higher RR (48 vs 36%, p=0.008). Bevacizumab assciated with an increased incidence f hypertensin f grade 2 r higher (25% vs 2%), thrmbemblic events f grade 3 r higher (8% vs 1%), and GI fistula f grade 3 r higher (3 vs 0%) Cnclusin The additin f bevacizumab t cmbinatin chem in pts w recurrent, persistent, r metastatic cervical cancer was assciated with an imprvement f 3.7 mnths in mos 2 nd line therapy - UTD suggests single agent chem. Hwever there is n evidence that treatment in the secnd r later line imprves OS cmpared with BSC in this ppulatin. Management f acutely symptmatic pts: - Fr wmen w pelvic pain r bleeding frm lcally advanced disease, and fr pts w symptmatic metastatic disease, single-dse r shrt-curse external beam RT may be useful. Hwever, treatment planning is critical fr wmen wh have previusly been treated w RT due t the risks f excessive txicity t nrmal tissue. A typical regimen cnsists f twice daily fractinatins f external beam RT (3.7Gy per Summary f treatment ptins fr early stage cervical cancer: Fr wmen with stage IA, IB1 and nnbulky IIA cervical squamus cell cancers (SCCs), cure is pssible with either radical hysterectmy r definitive RT. We generally prefer surgery, particularly fr premenpausal wmen, fr the fllwing reasns: A desire t preserve varian functin in yung wmen The greater pssibility f a mre functinal vagina fllwing surgery as cmpared t RT The therapeutic value f resecting bulky lymph nde metastases Staging lymphadenectmy enables individualizatin f the RT field if RT is indicated If definitive RT is chsen ver radical hysterectmy, cncmitant cisplatin-based chemtherapy shuld be administered. Fr wmen with stage IB2 and abve, definitive chemradiatin therapy with cnsideratin t brachytherapy is preferred. Fr wmen with recurrent r metastatic disease, lcal symptm cntrl with radiatin if feasible and chemtherapy (e.g. cisplatin r carbplatin + paclitaxel, with bevacizumab additin recently apprved) can be cnsidered. PROGNOSIS Overall survival, percent FIGO stage Number f patients 1 year 2 years 5 years IA IA IB IB IIA IIB IIIA IIIB IVA IVB Cmpared t HPV 16, HPV 18 + was assciated with a significantly higher verall and causespecific mrtality. This effect was mst prnunced fr FIGO stage IB and IIA tumrs (hazard rati [HR] 3.1)

12 12 - Smking may als increase the likelihd f late treatment-related cmplicatins. In a retrspective review f 3,489 wmen treated with radiatin therapy fr cervical cancer at the MD Andersn Cancer Center, heavy smking was independently crrelated with the develpment f small bwel cmplicatins. Smking may als increase the risk f develpment f vesicvaginal fistula after treatment f Stage IVA disease. An adverse influence f smking n survival fllwing treatment f lcally advanced cervical cancer has been nted in sme studies, but nt thers FOLLOW-UP Recmmendatins f expert grups the ptimal surveillance strategy has nt been established. Guidelines frm the Natinal Cmprehensive Cancer Netwrk (NCCN) suggest the fllwing: - Clinical evaluatin: every 3-6 mnths years in the first 2 years, every 6-12 mnths years in 3-5 years then annually - Imaging evaluatin (xr, CT scan, MRI, PET) nly if clinically indicated (signs r symptms f relapse) Ø Clinical evaluatin cnsists f a review f systems and physical examinatin with particular attentin t the supraclavicular and inguinal lymph ndes, as well as rectvaginal and abdminal examinatins. CERVICAL CANCER IN PREGNANCY - Cervical cancer is ne f the mst cmmn malignancies in pregnancy, with an estimated incidence f 0.8 t 1.5 cases per 10,000 birthsè specialized/experienced team - Evaluatin Ø Clpscpic evaluatin f the cervix in pregnancy with bipsies shuld be perfrmed by clpscpists with experience in pregnancy-related changes in cervical appearance. Endcervical curettage shuld nt be perfrmed Ø Diagnstic cnizatin is nly indicated during pregnancy if cnfirmatin f invasive disease will alter the timing r mde f delivery; therwise, cnizatin is pstpned until the pstpartum perid t avid ptentially disrupting the pregnancy Ø A chest x-ray (with abdminal shielding) is perfrmed fr evaluatin f pulmnary metastatic disease in all patients with mre than micrscpic cervical cancer. Fr stage IA and micrscpic/very small stage IB (<1 cm) cervical cancer in which extracervical disease is unlikely, rutine radigraphic imaging f the urinary tract may be mitted. Fr all ther patients, the urinary tract shuld be imaged with ultrasngraphy r magnetic resnance t rule ut stage IIIB disease. Magnetic resnance imaging has the added advantage f prviding infrmatin n tumr size, parametrial disease, and lymph nde status. - Prgnsis: The curse f disease and prgnsis f cervical ca in pregnant wmen are similar t nn-pregnant patients - Treatment: A multidisciplinary team apprach is crucial t address the cmplex care issues cnfrnting a pregnant patient with cervical cancer, such as terminatin versus cntinuatin f pregnancy, delay f definitive treatment, mde f therapy during pregnancy, r timing and rute f delivery. EARLY STAGE Ø Wmen with high-grade pre-invasive disease and stage IA1 disease are fllwed with clinical examinatins and clpscpy each trimester thrughut pregnancy. If pstpartum evaluatin shws n residual disease, we suggest mnitring wmen wh desire future childbearing fr pssible recurrence and ffering extrafascial hysterectmy t wmen with stage IA1 disease wh have cmpleted childbearing Ø Planned delay f treatment t avid expsing the fetus t cancer therapy r preterm birth prbably des nt significantly increase maternal risk in wmen with early-stage (stage IA t IB1) disease presenting in the late secnd and early third trimester f pregnancy. Ø If the fetus is at r near term, the preferred apprach t invasive dz is immediate delivery and definitive rx f the mther. At early gestatinal ages, terminatin f the preg and

13 13 definitive rx f the mther is an ptin. If the mther chses t cntinue the preg, decisins regarding timing f rx and delivery require careful cnsideratin f the stage f disease and the trimester in which the diagnsis is made. Ø Neadjuvant chemtherapy may be an ptin fr patients with stage IB2, IIA, and early IIB disease if the patient is apprpriately cunseled, agrees t neadjuvant chemtherapy (cisplatin fr 2-7 cycles), and strngly desires t cntinue the pregnancy. Ø In wmen with early stage invasive disease (IB-IIA) wh d nt plan future childbearing, we suggest radical caesarean hysterectmy LOCALLY ADVANCED/METASTATIC DISEASE Ø Lcally advanced disease: immediate, definitive treatment fr patients with lcally advanced disease, dcumented lymph nde metastases, prgressin f disease during the pregnancy, and fr thse patients wh wish t underg immediate therapy Ø Patients with stage IVB disease r any ther stage disease with prven systemic metastases are candidates fr primary systemic chemtherapy, which may be initiated during pregnancy. Ø Vaginal delivery is acceptable fr wmen with micrscpic (stage IA) cervical cancer. Ø Caesarean delivery shuld be perfrmed fr wmen with macrscpic invasive dz (>=stage IB)