Cervical Cancer

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Epidemiology -Age -Socioeconomic class -Geography: Epidemiology
-Age
--47% < 35 years old at dx
--10% > 65 years old at dx
-Socioeconomic class
--Affects lower class women
--Poor access to healthcare
-Geography
--Relatively uncommon in US
--Most common cancer in middle-aged women
--Also leading cause of death
List risk factors: HPV exposure (50% HPV-16)
Age of onset sexual activity
Multiple sexual partners
History of genital warts
Cigarette smoking
Oral contraceptives
Immunocompromise
Etiology - HPV -Principal cause of what two diseases -HPV types and infection rate -HPV-16 presence: Etiology - HPV
-Principal cause
--Invasive cervical cancer
--Cervical intraepithelial neoplasia (CIN)
-More than 80 HPV types
-40 infect genital tract
HPV-16 present in
-50% cervical cancers
-50% high-grade CINs
Age of onset of sexual activity: During menarche, transformation zone is more susceptible to oncogenic agents
Higher risk of cancer
-Onset sexual activity < 16 years
-Onset sexual activity within one year of menarche
Relative risk of cervical carcinoma: Age at coitarche Years from menarche to coitarche: Age at coitarche
< 16 -- RR 16
16-19 -- 3
> 19 -- 1
Years from menarche to coitarche
< 1 -- RR 26
1-5 -- 7
6-10 -- 3
> 10 -- 1
Relative risk of cervical carcinoma: Total number of sexual partners Number of partners before age 20 Genital warts Smoked > 5 cigarettes daily: Total number of partners
> 4 vs no/1 parnter RR 3.6
Number of partners before age 20
> 1 partners vs no partner RR 7
Genital warts (any) RR 3.2
Smoked > 5 cigarettes/day > 20 years -- RR 4
Cigarette smoking-cancer connection: 1 Diminished immune function secondary to system effects
2 Local effect of tobacco-specific carcinogens found in cervical mucus
3 Independent risk factor for invasive and preinvasive disease
Oral contraceptive connection: Possible confounding factor
-Most women who use OCPs are more sexually active
-Exception may be for adenocarcinoma
Immunocompromise: Women with HIV have increased rates
Same for immunosuppressive rx
Due to suppression of normal immune response to HPV
88% recurrence rate in women with HIV (Maiman Obstet Gyn 1997)
Common Symptoms: Intermentrual bleeding in premenopausal patient
Menorrhagia
Metrorrhagia
Staging: Clinical or Surgical?: Clinical -- FIGO staging
-Based on histology for earlier stage I cancers and tumor sizes
-Based on extension of disease to pelvis for more advanced tumors
Imaging allowed under FIGO for cervical cancer?: CXR
Barium enema
IVP
Recent FIGO modification?: Original 1929 by League of Nations Health Organization
1950: preinvasive lesions moved from stage I to new stage 0
1976: hydronephrosis added as stage III
1994
- Current definitions of microinvasion (IA1 and IA2) added
- Subdivided IB according to cervical diameter

Better differentiation between stage IA1 and IA2
Stages patients with lesions that are clinically confined to the cervix based on size of the primary tumor
Surgical staging better than clinical?: Controversial
Clinical staging frequently inaccurate in predicting locoregional spread
FIGO and AJCC suggest method for using TNM categories for staging
Causes confusion when clinicall staged patients are mixed with others who have been classified based on pathologic stage
Most common surgical staging method: Sampling of pelvic and aortic lymph nodes
Advantages of surgical staging: Minimizes risk of subsequent radiation injury to small bowel due to surgical adhesions
-Allows for individualized treatment planning
Work-up for advanced disease in non-surgical candidate: CT abdomen and pelvis with renal and GI contrast
If aortic LN mets
--> FNA of nodes
If positive nodes
--> consider extended-field XRT
Scalene lymph node impact: 1 Negative on clinical exam and positive aortic LN
--> scalene LN biopsy
2 If positive
--> chemotherapy indicated
3 If negative or no aortic LN involvement on CT
--> consider surgical staging
Laparoscopic staging?: Still investigational
Work-up for early stage cancer: CXR PA & lat
Stage IA - no CT prior TAH
Stage IB1 - no CT abd/pelvis
Prognostic factors: Clinical stage
General medical status
Nutritional status
Immune status
Effect of anemia: 605 patients in Canada
Treated with XRT for cervical cancer
Average weekly hgb nadir was significant prognostic factor
Second only to stage
Hgb >= 12 mg/dL improved
1 XRT success
2 Disease-free survival
(1986 Bush Int J Rad Onc Bio Phys)
List six important studies: GOG 85
GOG 120 Cisplatin
GOG 120 Cis/5FU/H
GOG 123
SWOG 8797
RTOG 9001
Laparoscopic staging study: 98 patients
Lap extraperitoneal approach
Mean nodes 18
23 pts with positive LN
5 required 2nd procedure
2 with complications
Identified patients who might benefit from extended-field XRT with minimal adhesion-related toxicities
Explain the genomic iimpact of oncogenic HPV.: HPV DNA causes persistent transcription of E6 and E7 genes
-Disrupts the cell cycle control mechanisms
-Through functional inactivation of the tumor suppressor genes
-E6 --> p53
-E7 --> Rb
HPV strains 1 Cervical cancer 2 Gential warts: 1: 16, 18, 31, 33
2: 6 and 11
Is cervical cancer an AIDS-defining illness?: Yes. Added in 1993.
Define parametrium.: A layer of visceral pelvic fascia exterior to the smooth muscle of the uterine body and cervix that surrounds the corpus
What ligaments support the uterus and how are they formed?: Cardinal or transverse
-Bands of dense fibroconnective tissue at the base of the broad ligaments
-Connect the fascia of the lateral cervix and upper vagina with the fibrous tissue that surrounds the lateral pelvic vessels
Uterosacral
-Lie within rectouterine peritoneal folds
-Extend posteriorly from the supravaginal cervix around either side of the rectum
Pubocervical
Where does cervical cancer metastasize?: Primarily: lung
Secondarily
1 Para-aortic nodes
2 Liver
3 Bone
Histology of cervical cancer: Squamous carcinoma - 75%
Adenocarcinoma
-Mucinous (endocervical)
-Adenosquamous
Undiff small cell
-Aggressive, poorly diff
-Neuroendocrine features
-Similar to anaplastic small cell of the lung
-Freq widespread mets to bone, liver, skin, and brain
The risk of lymph node mets increases with increasing depth of invasion: 1 FIGO Stage IA1 2 FIGO Stage IA2: 1 FIGO Stage IA1: 0.6%
2 FIGO Stage IA2: 7%
The risk of paraaortic nodal involvement increases as the local disease extent increases: 1 FIGO stage IB 2 FIGO stage IIA 3 FIGO stage IIB 4 FIGO stage IIIA 5 FIGO stage IIIB 6 FIGO stage IVA: 1 FIGO stage IB: 8%
2 FIGO stage IIA: 12%
3 FIBO stage IIB: 29%
4 FIGO stage IIIA: 17%
5 FIGO stage IIIB: 27%
6 FIGO stage IVA: 47%
Most common sites for hematogenous spread: 1 2 3: 1 Lungs
2 Liver
3 Bone

Less common: bowel, adrenals, spleen, and brain

Rare: ovarian
In a woman being further evaluated or treated with conization, which modality is preferred?: Cold knife cone because there is no thermal artifact to obscure interpretation of the margins.

This may be adequate treatment of stage IA1 disease.
Differential diagnosis of cervical lesion.: 1 Nabothian cysts
2 Glandular hyperplasia
3 Mesoephric remnants or hyperplasia
4 Reactive glandular changes from inflammation
5 Endometriosis
Define Point A based on RTOG 0116.: Measure 2 cm along the intrauterine tandem from the cervical os or flange of the tandem and 2 cm laterally in the plane of the intracavitary system.
Point where ureter crosses uterine vessels
Define Point B based on RTOG 0116.: Measure 5 cm lateral from a point 2 cm vertically superior to the cervical os or flange of the central tandem along the patientsâ€™ midline.
Point of lateral parametrium.
Point for calculation of bladder dose.: Calculated at the center (in the superior-inferior plane) of a contrast-filled balloon of a Foley catheter and closest to the applicator system on a lateral view, as defined by ICRU 38.
Point for calculation of rectal dose.: Calculate the dose at a point 0.5 cm posterior to the vaginal ovoid or vaginal packing in the lateral projection, defined by ICRU 38.
Point for calculation of vaginal surface dose.: Calculated at the vaginal surface lateral to the midpoint at the surface of the ovoid
Per RTOG 0116 what are the max doses for the following normal structures: 1 Spinal cord 2 Bladder 3 Rectum: 1 Spinal cord: 45 Gy
2 Bladder: 80 Gy
3 Rectum: 75 Gy
Per RTOG 0116 what are the max doses for the following normal structures: 4 Vaginal surface 5 Kidney 6 Small bowel 7 10 x 10 area: 4 Vaginal surface: 135 Gy
5 Kidney: 18 Gy
6 Small bowel: 60 Gy
7 10 x 10 area: 45 Gy
Cervical cancer T staging: Cervical cancer T staging
T1/I - Confined to uterus
T2/II
- Invades beyond uterus
- Not to pelvic wall or lower 1/3 of vagina
T3/III
- Extend to pelvis wall +/- lower 1/3 vagina
- Causes hydronephrosis
T4/IV
- Invades bladder or rectal mucosa
- Extends beyond true pelvis
Cervical cancer FIGO IA: Cervical cancer FIGO IA

Confined to the uterus

IA1 - Stromal â‰¤ 3mm; horiz â‰¤ 7mm
IA2 - Stromal 3-5mm; horiz â‰¤ 7mm
Cervical cancer FIGO IB: Cervical cancer FIGO IB

Visible lesion continued to cervix or lesion > IA2

IB1 Lesion â‰¤ 4cm

IB2 Lesion > 4 cm
Cervical cancer FIGO II: Cervical cancer FIGO II

Invades beyond uterus but not pelvic wall or lower 1/3 vagina

IIA No parametrial invasion

IIB Parametrial invasion
Cervical cancer FIGO III: Cervical cancer FIGO III

Extends to pelvic wall or lower 1/3 vagin or hydro

IIIA Involves lower 1/3 vagina

IIIB Pelvic wall +/- hyddro
Cervical cancer FIGO IV: Cervical cancer FIGO IV

IVA
- Invades rectal or bladder
mucosa
- Extends beyond true pelvis
IVB
- Distant metastasis
In early-stage cervical cancer, which risk factors indicate adj RT after rad hyst and lymphadenectomy? What are the risk factors?: GOG 92 - Sedlis & Rotman

Adj RT for stage IB1 if 2 or more risk factors
- LVSI
- > 1/3 stroma invasion
- Tumor >= 4cm
In early-stage cervical cancer, which risk factors indicate adj CRRT after rad hyst and lymphadenectomy? What are the risk factors?: Intergroup 0107 - Peters

Adj CCRT if any feature
1 Positive nodes
2 Positive margins
3 Parametrial involvement
What did the Landoni study show?: For stage IB and IIA cervial cancer, either surgery or RT was effective.
No difference in PFS, LRR, or OS
More morbidity with surgery +RT (28 v 12%)
Does adjuvant hysterectomy after EBRT and brachytherapy for patients with cervical tumors > 4 cm improve PFS and OS?: GOG 71 - Keys

No difference in OS
Trend toward decrease LR
No difference in toxicity
Does prophylactic extended field RT improve LRC or OS in patients with IIB cervical cancer with no clinical or radiographic evidence of PAN involvement?: RTOG 79-20 - Rotman

WPRT 45 or EFRT 45

Improved 10yr OS (55 v 44%)
No difference in LRC or DM
Increased toxicity with EFRT (8 v 4%)
Cervical cancer - Tx by stage IA: Cervical cancer - Tx by stage IA

IA1
- Simple hysterectomy
- Cone biopsy with negative margins for fertility preservation
IA2: Rad hyst
Brachy alone (7 Gy x 5-6 Fx)
If high-risk features, treat like IB
Cervical cancer - Tx by stage IB1: Cervical cancer - Tx by stage IB1

Rad hyst with pelvic LND
Def RT
- EBRT WP 45
- Brachy (6Gy x 5 Fx)
Cervical cancer - Tx by stage IB2-IIA: Cervical cancer - Tx by stage IB2-IIA

CCRT with cisplatin
- EBRT WP 45
- ICBT HDR 6 Gy x 5 Fx
Cervical cancer - Tx by stage IIB: Cervical cancer - Tx by stage IIB

CCRT with cisplatin
- EBRT WP 45-50.4
- ICBT HDR 6 Gy x 5 Fx
Cervical cancer - Tx by stage IIIA: Cervical cancer - Tx by stage IIIA

CCRT with cisplatin
- EBRT WP, vagina, and inguinal nodes 50-54
- ICBT 6 Gy x 5 Fx
- If node+, add PAN IMRT (45-60 Gy)
Cervical cancer tx by stage: IIIB-IVA: Cervical cancer tx by stage: IIIB-IVA

CCRT with cisplatin
- EBRT WP 50-54 Gy
- ICBT 6 Gy x 5 Fx
- If LN+, add PAN IMRT (45-60 Gy)
For IIB-IVa, IB-IIA >= 5cm, OR LN+ cervical cancer, is EFRT + ICBT better than WP RT with ICBT and cisplatin/5FU?: RTOG 90-01 - Morris & Eifel

CCRT
- Improved OS (67 v 41%)
- DFS (61 v 46%)
- LRF (18 v 35%)
For IIB-IVA surgically staged/node-negative cervical cancer, is WP + ICBT with 1 weekly cisplatin 2 cis/5FU/hydroxyurea 3 hydroxyurea alone better?: GOG 120 - Rose

Cisplatin arms
- Improved 4yr OS (65 v 47%)
- Decreased recurrence (34 v 54%)
- Less toxicity with single agents.
For IA, IIA > 5cm, and IIB cervical cancers, is WP + ICBT better than WP + ICBT with cisplatin?: NCIC - Pearcey

No differences in 3/5yr OS.

Criticized because required only CT staging of nodes and small sample size (353).
For IB2 cervical cancer, is WP + ICBT followed by adj simple hysterectomy better than WP + ICBT with weekly cisplatin?: GOG 123 - Keys

CCRT
- Improved 3 yr OS (83 v 74%)
- Decreased LR (21 v 37%)
- Increased pCR (52 v 41%)

Felt that improved LC led to increased OS due to cisplatin and adding hysterectomy did not improve OS.
According to the Intergroup 0107 trial, patients with IA2, IB, or IIA cervix ca did NOT show benefit after adj pelvic RT and 5FU/cisplatin chemo if they had which of the following pathologic findings? A Positive parametria B Positive surgical m: According to the Intergroup 0107 trial, patients with IA2, IB, or IIA cervix ca did NOT show benefit after adj pelvic RT and 5FU/cisplatin chemo if they had which of the following pathologic findings?

D Positive LVSI
RTOG 90-01 studied CCRT versus EFRT in high-risk cervical patients. What percentage overall reduction in risk of recurrence was associated with CCRT at median f/u 6.6 years? A 15% B 25% C 50% D 80%: RTOG 90-01 studied CCRT versus EFRT in high-risk cervical patients. What percentage overall reduction in risk of recurrence was associated with CCRT at median f/u 6.6 years?

C 50% (18 v 35% LRF)
Which is FALSE about survival with regard to hemoglobin levels in patients with cervical ca treated with CCRT? A Pretx hgb predicts survival. B End-of-tx hgb is most predictive of survival. C Mean hgb during tx is predictive of dz progress: Which is FALSE about survival with regard to hemoglobin levels in patients with cervical ca treated with CCRT?

Not scored (GOG 0191)
Which is true based on Landoni? A Both arms had identical OS. B Surgery arm did not receive RT if postive margins. C Surgical arm pts received adj 5FU if positive nodes. D Morbidity from urologic cx was identical for both arms.: Which is true based on Landoni?

A Both arms had identical OS.
GOG 123: Optimal mgt of bulky IB cervical cancer? A Rad hyst and opstop pelvic RT B Rad hyst and postop CCRT pelvic C CCRT + ICBT D CCRT + ICBT with adj hyst: GOG 123: Optimal mgt of bulky IB cervical cancer?

D CCRT + ICBT with adj hyst (in-service answer!)
GOG 92: Which is FALSE? A Addition of pelvic RT improved OS by 20% B Addition of pelvic RT resulted in more grade 3 and 4 adverse events C Addition of pelvic RT reduced risk of local recurrences by 47% D Eligible patients had at least: GOG 92: Which is FALSE?

A Addition of pelvic RT improved OS by 20%
42yo s/p rad hyst/PLND for IB2 sqcca cervix: 5cm tumor, deep stromal invasion, +LVSI, all nodes neg. GOG 92: next tx? A No further therapy B Pelvic RT alone C Pelvic RT plus vaginal brachy D CCRT: 42yo s/p rad hyst/PLND for IB2 sqcca cervix: 5cm tumor, deep stromal invasion, +LVSI, all nodes neg. GOG 92: next tx?

D CCRT
ICRU 38 rectal dose point is how many cm posterior to the vaginal wall on lateral radiograph? A 0.1 cm B 0.5 cm C 1.0 cm D 1.5 cm: ICRU 38 rectal dose point is how many cm posterior to the vaginal wall on lateral radiograph?

B 0.5 cm
RTOG 79-20 (Rotman): which at 10 years is most likely with prophylactic EFRT with IIB and bulky IB and IIA cervix ca? A Diff in OS but not DFS B Survival after first failure was higher in pelvic RT only arm C Higher % of local failures wer: RTOG 79-20 (Rotman): which at 10 years is most likely with prophylactic EFRT with IIB and bulky IB and IIA cervix ca?

A Diff in OS but not DFS
GOG 92 (Sedlis): Which is true about adding adj RT in patients with poor px features? A No benefit in pts with adenoca B No improvement in PFS C Benefits if deep third of stroma or LVSI D Reduced risk of recurrence by 80%: GOG 92 (Sedlis): Which is true about adding adj RT in patients with poor px features?

C Benefits if deep third of stroma or LVSI
GOG 85/SWOG 8695 Intergroup (Whitney): RT with various CT A Severe leukopenia more common 5FU/Cis group B 5FU/Cis group with better OS and PFS C +PAN had best OS rates D Hydroxyurea arm had fewer pelvic recurrences: GOG 85/SWOG 8695 Intergroup (Whitney): RT with various CT

B 5FU/Cis group with better OS and PFS
GOG 120 (Rose): RT with 3 different chemo regimens A IB1 treated with Cis/5FU/HU had better local control B Three-drug regimen had lowest grade 3 and 4 side effects C Cisplatin-based CT improved OS and PRS rates D OS was highest with: GOG 120 (Rose): RT with 3 different chemo regimens

C Cisplatin-based CT improved OS and PRS rates
GOG surg-path (Delgado): 3-yr DF interval after rad hyst in pIB sqcca cx with deep third stromal invasion? A 94% B 85% C 74% D 53%: GOG surg-path (Delgado): 3-yr DF interval after rad hyst in pIB sqcca cx with deep third stromal invasion?

C 74%
GOG 123 (Keys): relative risk of progression with preop CCRT versus preop RT alone for bulky IB cervix ca? A 0.26 B 0.35 C 0.51 D 0.99: GOG 123 (Keys): relative risk of progression with preop CCRT versus preop RT alone for bulky IB cervix ca?

C 0.51
GOG 8797 (Peters): which path finding after rad hys/PLND is indication for adj CCRT? A Tumor > 5 cm B LVSI C Deep third stroma invasion D Microscopic parametrial involvement: GOG 8797 (Peters): which path finding after rad hys/PLND is indication for adj CCRT?

D Microscopic parametrial involvement
Which molecular mechanism is implicationed in cervical cancer with prior HPV infection? A E7 inactivates p53 B E7 inhibits Rb C E6 suppresses G2-M cell cycle arrest D E6 activates c-myc: Which molecular mechanism is implicationed in cervical cancer with prior HPV infection?

B E7 inhibits Rb

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