# Radiation Oncology/Cervix/Overview

* Front Page: Radiation Oncology | RTOG Trials | Randomized Trials
* Cervix: Main Page |
* Overview |
* Micro-invasive |
* Early Stage Non-Bulky |
* Early Stage Bulky |
* Locally Advanced |
* Brachytherapy |
* Cervix Randomized |
* GOG Trials |
* RTOG Cervix

## Epidemiology

* 3rd most common gynecologic malignancy in US. 10,370 cases/yr and 3,710 deaths/yr in US (in 2005).
* Worldwide, is the second most common cancer and second leading cause of cancer mortality in women.
* Was the most common cause of cancer deaths in US women in the 1930s, but due to improved screening incidence decreased from 32.6/100,000 in 1940's to 8.3/100,000 in 1980's
* Increased risk: HPV 16/18, HSV2, early age at initiation of sexual activity, tobacco, DES, lower socioeconomic status, current use of oral contraceptives
* Presence of cervical Ca in the setting of HIV denotes AIDS status
Oral contraceptives
* Meta-analysis; 2007 PMID 17993361 -- "Cervical cancer and hormonal contraceptives: collaborative reanalysis of individual data for 16,573 women with cervical cancer and 35,509 women without cervical cancer from 24 epidemiological studies." (Appleby P, Lancet. 2007 Nov 10;370(9599):1609-21.)
** Central review of 16,573 women with cervical CA compared with 35,509 women without
** Outcome: current users had 1.9x risk compared to never use. Risk declined after stopping, and returned to baseline by 10 years

## Prevention

HPV Vaccine
* Stanford, 2007 PMID 17617529 -- "Impact of the human papilloma vaccine on cervical cancer." (Chan JK, J Clin Oncol. 2007 Jul 10;25(20):2975-82.)
** Review

## Anatomy

* Inferior portion of the uterus. Has supravaginal (endocervix) and vaginal (ectocervix) portions
* Barrel-shaped; measures 2.5-3 cm in adult multigravida female
* Composed of:
** Ectocervix - intravaginal portion
** External os - opening of the cervix into the vagina
** Endocervix - cervical canal, which connects external os with the internal os
** Internal os - opening of the cervix into the uterine cavity
Lymphatic Drainage
* Cervix (3 separate routes)
** Laterally, along uterine artery to external iliac LNs
** Posterolaterally, behind ureters to internal iliac LNs
** Posteriorly, into common illac and lateral sacral LNs
* Fundus of uterus
** Mainly to internal iliac LNs via broad ligament
** Some to para-aortics via ovarian vessels
** Some to external iliac and inguinal LNs via round ligament
* Upper third vagina
** Laterally to both internal and external iliac LNs
* Middle third vagina
** Internal iliac LNs alone
* Lower third vagina
** Merge with vulva into superficial inguinal
* Perez, Principles and Practice of GYN ONC (1st Ed), 1992
** Likelihood of PA LN+
*** IB2: 6%
*** IIB: 19%
*** IIIB: 29%

## Histology

* Ectocervix (vaginal cervix) is typically squamous cell (nonkeratinizing, stratified)
* Endocervix (endocervical canal) is typically adeno (columnar epithelium, mucin-secreting)
* Transformation zone (ectropion) is where the tall columnar cells are transformed into flat squamous cells. This is the site of origin for squamous cell dysplasia and carcinoma, and may be located outside the os or within the canal

## Screening

On exam, a barrel-shaped cervix is defined as an expanded cervix > 4 cm diameter and indicates an endocervical tumor.
Screening test (Pap):
* 2001 Bethesda System:
** PMID 11966386 — "The 2001 Bethesda System: terminology for reporting results of cervical cytology." Solomon D et al. JAMA. 2002 Apr 24;287(16):2114-9.
*** Epithelial abnormalities:
**** Atypical squamous cells (ASC) - divided into ASC-US ("of undetermined significance") and ASC-H ("cannot exclude high-grade squamous intraepithelial lesion")
**** LSIL - low-grade squamous intraepithelial lesion (includes HPV, mild dysplasia, CIN 1)
**** HSIL - high-grade squamous intraepithelial lesion (includes moderate and severe dysplasia, carcinoma in situ, CIN 2 and CIN 3)
**** Squamous cell carcinoma
*** Glandular abnormalities:
**** Atypical glandular cells (AGC)
**** Endocervical adenocarcinoma in situ (AIS)
**** Adenocarcinoma
Management of an abnormal pap result:
* 2001 Consensus Guidelines (ASCCP)
** Guidelines (PDF) - Algorithm from the ASCCP
** PMID 11966387 Full text — "2001 Consensus Guidelines for the management of women with cervical cytological abnormalities." Wright TC Jr et al. JAMA. 2002 Apr 24;287(16):2120-9.
*** Management of biopsy-confirmed CIN1 and CIN2-3.
Management of abnormal histology:
* 2001 Consensus Guidelines (ASCCP)
** Guidelines (PDF) - Algorithm from the ASCCP
** PMID 12861176 Full text — "2001 consensus guidelines for the management of women with cervical intraepithelial neoplasia." Wright TC Jr et al. Am J Obstet Gynecol. 2003 Jul;189(1):295-304.

### HPV testing vs Pap smear

* Finland (2003-2005) -- HPV DNA screen vs conventional cytology
** 2010 PMID 20423964 Full Text -- "Rate of cervical cancer, severe intraepithelial neoplasia, and adenocarcinoma in situ in primary HPV DNA screening with cytology triage: randomised study within organised screening programme" (Anttila A, BMJ 2010;340:c1804)
** Randomized. 58,076 women, age 30-60, routine population-based screening program. Arm 1) HPV DNA test vs Arm 2) conventional cytological screening. Primary outcome cervical cancer, CIN-III and carcinoma in situ (both reported as CIN-III+)
*** Outcome: CIN-III+ HPV 76 cases (6 cervical CA) vs cytology 53 cases (8 cervical CA)
*** Conclusion: Primary HPV screening more sensitive than conventional cytology in detecting CIN-III+ lesions; number cervical cancer small

## Surgical staging

* GOG 49, 1990 (1981-84)
** 732 pts, Stage I and > 3 mm invasion (currently IA2), of which 645 pts were treated with radical hyst + paraaortic and pelvic lymphadenectomy. Pts with paraaortic mets were excluded.
** 1990 PMID 2227547 — "Prospective surgical-pathological study of disease-free interval in patients with stage IB squamous cell carcinoma of the cervix: a Gynecologic Oncology Group study." Delgado G et al. Gynecol Oncol. 1990 Sep;38(3):352-7.
*** Worse DFS for pts with microscopically positive pelvic LN (3-yr DFI 74.4% vs 85.6%) but no difference in OS. DFI correlated with depth of invasion (94% vs 84% vs 74% by thirds), tumor size (94% occult, 85% <3cm, 68% >3cm), capillary-lymphatic invasion (88% vs 77%), grade (90% vs 86% vs 76%), parametrial involvement (85% vs 70%). For margin status, 84.3% vs 69.1% but N.S. Pelvic LN+ is not prognostic.
*** Conclusion: Tumor size, depth of invasion, and CLS invasion (LVI) were independent factors for DFS
** 1989 PMID 2599466 — "A prospective surgical pathological study of stage I squamous carcinoma of the cervix: a Gynecologic Oncology Group Study." Delgado G et al. Gynecol Oncol. 1989 Dec;35(3):314-20.
*** Risk factors for pelvic LN+: capillary-lymphatic space involvement, depth of invasion, parametrial involvement, age.
** Comment: prognostic factors allow patients to be classified as low, intermediate, or high risk. Led to the risk factors used in Sedlis's paper. See below.
Para-aortic nodes:
* GOG 19, 1980 (1973-76)
** PMID 7353805 (no abstract) — "Results and complications of operative staging in cervical cancer: experience of the Gynecologic Oncology Group." Lagasse LD et al. Gynecol Oncol. 1980 Feb;9(1):90-8.
** 290 pts, Stage IB-IVB. Underwent surgical exploration with sampling of bilateral paraaortic lymph nodes either in conjunction with radical hystectomy (IB) or a separate procedure (II-IV).
** Squamous (89%), adenosquamous (6%), adenocarcinoma (4%). About half were Stage IB. 36% of pts were upstaged by surgical exploration.
** Positive para-aortic nodes in: Stage IB (5.6%), Stage II-IV (29.3%). Grade was not predictive of number with +PA LN. For adenocarcinoma, 33% had +PA (even though most had Stage IB).
** Conclusion: implication for pts who have disease outside of standard RT field. Importance of surgical staging.

### Use of PET in staging

* Chang Gung University, Taiwan (2002-2006) -- pretreatment PET vs no PET
** Randomized. 129 patients, Stage I-IVA cervical cancer, positive pelvic but negative PALN by MRI. Arm 1) pretreatment PET vs Arm 2) no PET. Treated with chemo-RT, standard pelvic fields. If PET+, extended to include PALN
** 2010 PMID 19464824 -- "A prospective randomized trial to study the impact of pretreatment FDG-PET for cervical cancer patients with MRI-detected positive pelvic but negative para-aortic lymphadenopathy." (Tsai CS, Int J Radiat Oncol Biol Phys. 2010 Feb 1;76(2):477-84. Epub 2009 May 21.)
*** Outcome: PET identified 11% extra-pelvic mets; of these 57% remained disease free after modified fields. 4-year DFS PET+ 75% vs. PET- 77% (NS); 4-year OS 79% vs 85% (NS)
*** Conclusion: Pretreatment PET can improve detection of pelvic mets, but may not translate into survival benefit
* Washington University
** 2001 PMID 11533097 — "Lymph node staging by positron emission tomography in patients with carcinoma of the cervix." Grigsby PW et al. J Clin Oncol. 2001 Sep 1;19(17):3745-9.
*** Retrospective, 101 patients. Pts underwent CT and PET. +pelvic LN in 20% (CT) vs 67% (PET), +para-aortic LN in 7% vs 21%. 2-yr progression free status in (CT-/PET-): 64%, (CT-/PET+):18%, (CT+/PET+):14%.
*** Conclusion: PET is better at detecting abnormal lymph nodes than CT and is a better predictor for survival.
** SUV; 2010 (2003-2008) PMID 20108309 -- "Pelvic lymph node F-18 fluorodeoxyglucose uptake as a prognostic biomarker in newly diagnosed patients with locally advanced cervical cancer." (Kidd EA, Cancer. 2010 Mar 15;116(6):1469-75.)
*** Retrospective. 83 patients, Stage IB1 to IIIB cervical cancer. Average SVU cervix 14.0 (3.2-38.4), average SUV PLN 5.9 (2.1-33), average PLN size 2.1 cm (0.6-7.9)
*** Outcome: SUV PLN correlated with increased risk of persistent disease (SS), pelvic recurrence (SS), DSS (SS) and OS (SS)
*** Conclusion: SUV of pelvic LNs is predicts for outcome
** 2010 (2000-2009) PMID 20308664 -- "Lymph node staging by positron emission tomography in cervical cancer: relationship to prognosis." (Kidd EA, J Clin Oncol. 2010 Apr 20;28(12):2108-13. Epub 2010 Mar 22.)
*** Retrospective. 560 patients, Stage IA1-IVB, pretreatment PET staging.
*** Outcome: LN+ 47%, increasing with stage. Recurrence stratified by none, pelvic+ (HR 2.4), para-aortic+ (HR 5.9), or SCV+ (HR 30.3). If P+, 35% PA+, and 12% SCV+. All patients with PA+ had P+, all patients with SCV+ had PA+
*** Conclusion: Nodal involvement by PET stratified patient recurrence and survival
| FIGO | # Patients | Negative | Pelvic+ | Para-aortic+ | SCV+ |
| IA1 | 1 | 100% | 0% | 0% | 0% |
| IA2 | 11 | 91% | 9% | 0% | 0% |
| IB1 | 146 | 81% | 19% | 2% | 0% |
| IB2 | 81 | 49% | 51% | 9% | 1% |
| IIA | 14 | 50% | 50% | 21% | 7% |
| IIB | 161 | 46% | 54% | 17% | 4% |
| IIIA | 4 | 50% | 50% | 25% | 25% |
| IIIB | 111 | 32% | 68% | 33% | 11% |
| IVA | 11 | 45% | 55% | 27% | 0% |
| IVB | 20 | 15% | 85% | 60% | 50% |
| All | 560 | 34% | 47% | 17% | 6% |

## Prognostic Molecular Markers

* PMID 15936552 -- Coexpression of cyclooxygenase-2 and thymidine phosphorylase as a prognostic indicator in patients with FIGO stage IIB squamous cell carcinoma of uterine cervix treated with radiotherapy and concurrent chemotherapy. (Pyo H, Int J Radiat Oncol Biol Phys. 2005)
** Conclusion: "Thymidine phosphorylase expression or COX-2/TP coexpression may be used as a molecular prognostic marker for squamous cell carcinoma of the uterine cervix. TP appears to be an important downstream molecule of COX-2 during angiogenesis and may be a new target for the treatment of uterine cervical cancer."

## Surgical treatment

* Radical trachelectomy - removes all cancer with margin, but leave internal os. This is stitched closed, leaving a small opening for menses to escape. This arrangement can support a pregnancy, with baby born via C-section
Classes of hysterectomy:
* Piver classification, 1974 - PMID 4417035 — "Five classes of extended hysterectomy for women with cervical cancer." Piver MS et al. Obstet Gynecol. 1974 Aug;44(2):265-72.
** All classes (I-V) extend beyond the excision boundaries of a standard hysterectomy, such that all cervical tissue is removed
** Class I - Simple Extrafascial Hysterectomy - removes just the uterus and a small rim of vaginal cuff.
** Class II - Modified Radical Hysterectomy - removes uterus, a 1-2 cm cuff of vagina, wide excision of parametrial and paravaginal tissues (median half of cardinal and uterosacral ligaments). The ureters and uterine arteries and only partially mobilized (as in Class III). Ligates uterine artery at ureter. (Limited to cervical cancers with invasion up to 5 mm).
** Class III - Radical Hysterectomy (Wertheim-Meigs procedure) - classic operation. Removes uterus and upper 2/3 of vagina. Dissection of paravaginal and parametrial tissues to the pelvic sidewalls. Ligates uterine artery at its origin at the internal iliac A. Pelvic lymphadenectomy.
** Class IV - Extended Radical Hysterectomy - same as Class III but adds full mobilization of the ureters past the bladder (which is the point to which they are mobilized in the Class II and Ill procedures). Removes more paracervical tissue medial to the uteter.
** Class V - Pelvic Exenteration - Anterior exenteration removes uterus, tubes, ovaries, vagina, and bladder. Posterior exenteration removes uterus, tubes, ovaries, and rectosigmoid. Total exenteration removes all pelvic organs.

### Treatment of the pregnant patient and fertility-sparing treatment

* Abstract Full Text — Dargent et al. "Laparoscopic vaginal radical trachelectomy: A treatment to preserve the fertility of cervical carcinoma patients" Cancer. 2000 Apr 15;88(8):1877-82.
    Trachelectomy is a conservative surgery that is designed to spare the function of the organ. Uses laparascopic (for LN dissection) and transvaginal approaches. Used on patients < 40 yrs old who have Stage Ia lesions with low risk of LN involvement or small volume Stage IB1-IIA lesions
* Abstract Full Text (Case Report) — Ben-Arie et al. "Conservative treatment of stage IA2 squamous cell carcinoma of the cervix during pregnancy." Obstet Gynecol. 2004 Nov;104(5 Pt 2):1129-31.

## Non-surgical treatment
### Benefit of chemotherapy

* Meta-analysis shows benefit
Meta-Analysis
* MRC UK PMID 19001332 -- "Reducing uncertainties about the effects of chemoradiotherapy for cervical cancer: a systematic review and meta-analysis of individual patient data from 18 randomized trials." (Vale C, J Clin Oncol. 2008 Dec 10;26(35):5802-12. Epub 2008 Nov 10.)
** Individual patient data analysis. 15 trials with 3,452 patients
** 2 chemo-RT + chemo vs RT trials: 5-year OS 79% vs. 60% (HR 0.46, SS): 19% absolute improvement
** 13 chemo-RT vs. RT trials: 5-year OS 66% vs. 60% (HR 0.81, SS): 6% absolute improvement
** No difference between platinum-based (HR 0.83) and non-platinum-based (HR 0.77) chemo. Benefit by stage I-IIA 10%, IIB 7%, III-IVA 3%
** Conclusion: There is a survival benefit for chemo-RT over RT alone
* Canada, 2002 - PMID 12109823 — "Concurrent cisplatin-based chemotherapy plus radiotherapy for cervical cancer--a meta-analysis." Lukka H et al. Clin Oncol (R Coll Radiol). 2002 Jun;14(3):203-12.
** Relative risk of death for chemotherapy, 0.74; 0.78, for advanced stage; 0.56, for high-risk early stage disease.
* Liverpool, 2001 (UK) - PMID 11564482 — "Survival and recurrence after concomitant chemotherapy and radiotherapy for cancer of the uterine cervix: a systematic review and meta-analysis." Green JA et al. Lancet. 2001 Sep 8;358(9284):781-6.
** 4580 pts from randomized studies.
** Pts most likely to benefit from concurrent chemotherapy are those with: positive pelvic lymph nodes, large cervical lesions. Concurrent chemotherapy reduced incidence of distant mets
Population Study
* Ontario, 2007 (1992-2001) PMID 17557951 -- "Impact of adoption of chemoradiotherapy on the outcome of cervical cancer in Ontario: results of a population-based cohort study." (Pearcey R, J Clin Oncol. 2007 Jun 10;25(17):2383-8.)
** Retrospective. 4069 women. Primary RT used for 42% patients. In 1992-1998 <10% concurrent RT, in 1999-2001 >60% concurrent RT
** 3-year OS: RT alone 59% vs. CRT 70% (SS); no change over time in those with surgery only
** Conclusion: Adoption of CRT significant improvement in OS at the population level, consistent with results from randomized trials

### Patterns of failure

For RT alone:
* PMID 1129485 (1964-69) - "Analysis of sites and causes of failures of irradiation in invasive squamous cell carcinoma of the intact uterine cervix."
    94% of failures in first 3 years. Stage I-IIA: 6% LRF, Stage IIB: 18%, Stage III: 33%. Main predictor of failure is massive disease.
Prognostic factors:
* PMID 2025841, 1991 - "Carcinoma of the cervix treated with radiation therapy. I. A multi-variate analysis of prognostic variables in the Gynecologic Oncology Group." Cancer. 1991 Jun 1;67(11):2776-85.

## Patterns of Care

ACR Patterns of Care studies:
* Patterns of Care study (1978):
** PMID 2249184, 1990 — "The Patterns of Care Outcome Study for cancer of the uterine cervix. Results of the Second National Practice Survey." Coia L et al. Cancer. 1990 Dec 15;66(12):2451-6.
* Patterns of Care study (1988-89), 1996
** PMID 12118541, 1996 — "Treatment planning for carcinoma of the cervix: a patterns of care study report." Ling CC et al. Int J Radiat Oncol Biol Phys. 1996 Jan 1;34(1):13-9.
** Recorded treatment planning information.
* Patterns of Care study (1992-94), 1999
** PMID 10030261, 1999 — "Patterns of radiotherapy practice for patients with squamous carcinoma of the uterine cervix: patterns of care study." Eifel PJ et al. Int J Radiat Oncol Biol Phys. 1999 Jan 15;43(2):351-8.
* Patterns of Care study (1996-1999), 2004
** PMID 15519786, 2004 — "Patterns of radiotherapy practice for patients with carcinoma of the uterine cervix: a patterns of care study." Eifel PJ et al. Int J Radiat Oncol Biol Phys. 2004 Nov 15;60(4):1144-53.
** PMID 16099599, 2005 — "Patterns of brachytherapy practice for patients with carcinoma of the cervix (1996-1999): a patterns of care study." Erickson B et al. Int J Radiat Oncol Biol Phys. 2005 Nov 15;63(4):1083-92.
Combined analyses:
* Patterns of care 1973 and 1978
** PMID 2004942, 1991 — "Pretreatment and treatment factors associated with improved outcome in squamous cell carcinoma of the uterine cervix: a final report of the 1973 and 1978 patterns of care studies." Lanciano RM et al. Int J Radiat Oncol Biol Phys. 1991 Apr;20(4):667-76.
* Patterns of care 1973, 1978, and 1983
** PMID 7860414, 1995 — "Long-term results of treatment of cervical carcinoma in the United States in 1973, 1978, and 1983: Patterns of Care Study (PCS)." Komaki R et al. Int J Radiat Oncol Biol Phys. 1995 Feb 15;31(4):973-82.

## Adenocarcinoma

Treatment results:
* MDACC, 1990 (1965-85) - PMID 2337867 — "Adenocarcinoma of the uterine cervix. Prognosis and patterns of failure in 367 cases." Eifel PJ et al. Cancer. 1990 Jun 1;65(11):2507-14.
** RT or RT + surgery. 367 pts.
** 5-yr RFS 73% - Stage I, 32% - Stage II. No significant difference for primary RT vs RT + extrafascial hysterectomy.
** Conclusion: Survival of Stage II adenocarcinoma is lower than that for squamous.

## Outcome Nomograms

* GOG/NRG data; 2015 PMID 25732170 -- "Nomograms Predicting Progression-Free Survival, Overall Survival, and Pelvic Recurrence in Locally Advanced Cervical Cancer Developed From an Analysis of Identifiable Prognostic Factors in Patients From NRG Oncology/Gynecologic Oncology Group Randomized Trials of Chemoradiotherapy. (Rose, PG, J Clin Oncol. 2015 Jul 1;33(19):2136-42. doi: 10.1200/JCO.2014.57.7122. Epub 2015 Mar 2.)
** Retrospective. 2,042 patient with locally advanced cervical cancer, enrolled on GOG clinical trials
** Nomogram developed. Variables: histology, race, PS, tumor size, tumor grade, FIGO stage, LN status, treatment with concurrent cisplatin
** Conclusion: Nomogram can be used to better estimate individual outcomes

## Radiation Use By Stage

* Kingston, 2005 (Canada) PMID 15936156 -- "An evidence-based estimate of the appropriate rate of utilization of radiotherapy for cancer of the cervix." (Usmani N, Int J Radiat Oncol Biol Phys. 2005 Nov 1;63(3):812-27. Epub 2005 Jun 2.)
** Review of literature for appropriateness of RT in cervical cancer
** North American population: RT indication in 65% of cervical CA cases at some point; 63% as initial management, 2% for progressive/recurrent disease
*** Stage IA: 11%
*** Stage IB: 75%
*** Stage II/III: 100%
*** Stage IV: 97%

## Other Resources

* eContouring Webinar - Gynecological Cancers with Arno Mundt III, M.D.
* ASTRO/ARRO Journal Club Webinar 2012 - "Image-guided brachytherapy for cervical cancer" with Beth Erickson, MD, FACR
* ASTRO/ARRO Journal Club Webinar 2011 - "Chemoradiation for cervical cancer" with Patricia J. Eifel, MD