Uterine Cervix

Disclaimer

This manual is not a substitute for consultation with an appropriate specialist.
The contents of this manual have been developed through consensus of a Provincial Tumour Group. Please note the various update dates for each section as some of the content of the manual may not be up to date.

1. Predisposing Factors//Risk Factors

Updated December 2021

Cancer of the uterine cervix is the 13th most common cancer in Canadian women, with an estimated 1500 new diagnoses in 2016. About 400 women will die from the disease per year. The most common histologic types of cervical cancer are squamous cell carcinomas, which arise in the ectocervix (70%), and adenocarcinomas or adenosquamous carcinomas arising in the endocervical canal (25%).

Known Risk Factors

Human papillomavirus (HPV): HPV is the most common sexually transmitted disease and is the major factor causally associated with cervical cancer. HPV is a group of more than 100 different types of viruses, of which at least 13 types are known carcinogens. HPV-16 and -18 cause 70% of the cervical cancers and precancerous cervical lesions⁴. High-risk groups include women who have less access to Pap tests or women who have never participated in screening programs.

Smoking: women who smoke are at increased risk of developing cervical cancer. Tobacco by-products may contribute to cervical cancer by either local DNA damage or local immunosuppression and reduced immune response to HPV infection⁵.

Human immunodeficiency virus (HIV): HIV infection in women appears to elevate risk of cervical cancer due to immunosuppression⁶.

Diethylstilbestrol (DES): this is a form of estrogen that was used from 1940 to 1971 for treatment of certain conditions during pregnancy such as miscarriages. Daughters of women who took this medication during their pregnancy are at higher risk of developing clear cell carcinoma of cervix or vagina. DES daughters may also be at increased risk of cervical squamous cell carcinoma development if they had exposure to HPV.

Possible Risk Factors

Sexually transmitted infections: some studies demonstrated higher risk of cervical squamous cell cancer with past or current chlamydia or herpes simplex virus type 2 infections⁸. More research is required to clarify the role of these infections for cervical cancer.

Family history of cervical cancer: there is some evidence that women with family history of cervical cancer have higher chance of cervical cancer diagnosis compared to women without a family history⁹. However, more studies are required to clarify whether this is due to genetics or having higher motivation for screening and health protective behaviours.

Obesity: observational studies reported no association between cervical cancer and being overweight. But obesity was weakly associated with an increased risk of cervical cancer¹⁰. More research is required to provide conclusive evidence in this regard.

Prevention

HPV vaccines: these vaccines are powerful tools to diminish the rate of HPV-associated cancers including cervical, oropharyngeal, anal, vulvar, vaginal and penile malignancies. Three HPV vaccines have been developed and approved for use by Health Canada:

Cervarix® (HPV2)
[against HPV types 16 and 18]
Gardasil® (HPV4)
[Human Papillomavirus quadrivalent (against HPV types 6, 11, 16, 18)]
Gardasil®9 (HPV9)
[Human Papillomavirus nonavalent (against HPV types 6, 11, 16, 18, 31, 33, 45, 52 and 58)].

All 3 vaccines protect against the 2 types of HPV that cause about 70% of cases of cervical cancer. The HPV9 vaccine protects against 5 additional types of HPV that cause about 15% to 20% of cervical cancers. The HPV4 and HPV9 vaccines also protect against 2 types of HPV that cause about 90% of cases of genital warts.

Vaccination is recommended for girls and women between the ages of 9 and 45 years before they come in contact with HPV. The vaccine may also benefit women who are sexually active and have not yet been infected with HPV.

In British Columbia, the HPV9 vaccine is recommended and provided free to girls in grade 6. In September 2016, the HPV9 vaccine replaced the HPV4 vaccine which was previously provided as part of the school-based immunization program. The HPV9 vaccine is also provided free to females who are 9 to 26 years of age or infected with HIV. Since September 2017, BC's publicly funded immunization program includes the HPV9 vaccine for grade 6 boys. Therefore, all grade 6 students in BC, both female and male, are offered the HPV9 vaccine series for free as part of the regular school-based immunization program. For more information please refer to the Ministry of Health announcement: B.C. extends free HPV coverage to boys.

The HPV4 vaccine is recommended and provided free to girls and young women born in 1994 to 2004 who have not received the vaccine. Girls and young women in this age group who missed getting the HPV4 vaccine can contact their health care provider to get immunized at no cost.

The HPV4 vaccine is also free for males who are at an increased risk for HPV infection. This includes males who are:

9 to 26 years of age (inclusive) and have sex with men (or who are not yet sexually active but questioning their sexual orientation), are street involved, or are HIV positive.
9 to 18 years of age in the care of the Ministry of Children and Family Development.
In youth custody services centres.

For more information on eligibility for free HPV vaccine, please visit ImmunizeBC.

Those who are not eligible for free HPV vaccine can purchase it at most pharmacies, travel clinics, and some sexual health clinics.

Vaccination prevents HPV infection but does not get rid of it once the infection occurs. Individuals who have received the HPV vaccine still require cervical cancer screening. The vaccine does not protect against all types of HPV that can cause cancer and it also does not prevent other sexually transmitted infections.

Vaccination is safe, very effective, and has few side effects. For more information, please call your local Public Health Unit or speak to your family physician.

References

Canadian Cancer Society (http://www.cancer.ca/en/cancer-information/cancer-type/cervical/statistics/?region=on#ixzz4dJJSN4Fw new cases in 2016)
http://www.bccancer.bc.ca/about/news-stories/news/2016/british-columbia-adopts-new-cervical-cancer-screening-policy (link)
Kelsey J, Whittemore AS. Epidemiology and primary prevention of cancers of the breast, endometrium and ovary: a brief overview. Ann Epidemiology 1994;4:89-95.
WHO report- http://www.who.int/mediacentre/factsheets/fs380/en/
Fonseca-Mourinho et al. Smoking and Cervical Cancer. ISRN Obst and Gyne, vol 2011
NCI report- https://www.cancer.gov/about-cancer/causes-prevention/risk/infectious-agents/hiv-fact-sheet.
IARC working Group on the Evaluation of Carcinogenic Risk of Combined Estrogen-Progestogen Contraceptives to Humans. Vol 91: 1-528, 2007.
Madeleine et al. Risk of Cervical Cancer Associated with Chlamydia trachomatis Antibodies by Histology, HPV type , and HPV Cofactors. Int J Cancer 2007; 120(3):650-655.
Bellinger et al. The Role of Family History of Cancer on Cervical Cancer Screening Behavior in a Population-Based Survey of Women in the Southeastern United States. Women's Health Issues; 2003;23(4): e197-e204.
Poorolajal et al. The association between BMI and cervical cancer risk: a meta-analysis. Eur J Cancer Prev. 2016 May;25(3):232-8.

2. Screening/Early Detection

The early detection of precancerous lesions, through the Papanicolaou (Pap) smear, can prevent invasive squamous cell carcinoma of the cervix. This test was introduced in Canada in the mid-1960s and is widely used in British Columbia. Since June 2016, BC Cancer has adopted a new cervical cancer screening policy, which recommends screening women aged 25-69 every three years. Changes to British Columbia’s cervical cancer screening policy are based on recommendations from two BC-based expert reviews. Regular Pap smear screening continues to be the most effective method to diagnose lesions which are in a pre-clinical and pre-invasive state where the opportunity for cure is uniformly high.

Cervical Cancer Screening Program

Average risk screening start age

Cervical cancer screening should begin at age 25.

Average risk screening interval

Average risk women between the ages of 25-69 should be screened every three years.

Average risk screening stop age

Screening can stop at age 69 if results have always been normal.

Higher than average risk screening recommendations

Immunocompromised individuals and those previously treated for dysplasia are considered at high risk of developing cervical cancer and should be screened annually.

For more information on British Columbia's Cervical Cancer Screening Policy, please click here.

3. Diagnosis

3.1 Investigation of Abnormal Pap Smears

Cervical Pap smears remain the most effective method of identifying the patient with possible preinvasive or preclinical cervical neoplasia. Pap smears taken in the presence of bleeding, spotting or discharge are often difficult to interpret and may be unreliable. It is recommended that women aged 25-69 be screened every 3 years. Women who have a history of prior abnormal smears (CIN) should continue with annual smears. Refer to section 2 above for Pap smear guidelines.

The optimum time for taking smears in the pre-menopausal women is in mid-cycle. However, for practical purposes this is not always possible, but if there is difficulty in obtaining good smears in these individuals then repeat smears should be scheduled for this interval. There is no single sampling device which is adequate for all cases, but in the vast majority of individuals the standard wooden Ayres spatula is satisfactory. Individuals who are post-menopausal or in whom the squamocolumnar junction may be placed within the endocervical canal because of previous surgery or other factors, may require sampling with an endocervical Cytobrush or other devices to obtain specimens from this area. If a Cytobrush is used immediate fixation with Cytospray is required. Conversely, individuals who have a large area of columnar epithelium on the ectocervical surface need to have sampling from the peripheral margins of this transformation zone. If an endocervical specimen is taken as well as the standard scrape both specimens should be placed on the same slide using the opposite half of the glass slide.

Simple lack of endocervical cells in the Pap smear report does not necessarily mean that the smear in itself is inadequate. In older individuals where difficulties may be present in obtaining good quality smear, particularly in the post-menopausal women or women who have undergone radiation treatments to the pelvis, often a short course of topical or oral estrogen therapy will thicken the epithelium and produce a much better quality smear for evaluation.

It should be emphasized that an office punch biopsy should be taken of any clinically suspicious or so-called "target lesion" noted at the time of pelvic examination. The biopsy would take place in the colposcopy clinic if the GP didn’t have cervix biopsy equipment in their clinic.

3.2 Indications for Colposcopy

The recommended method of investigation of patients with abnormal Pap smears where no target lesion exists is with colposcopy. Regional colposcopy clinics have been established throughout the province for this purpose and their locations are listed in Appendix V. It is to be noted that patients are referred to the regional clinics for assessment, not to the individual performing colposcopy at these locations. Patients are then returned to the original physician for decision as to further management and disposition based on the results and findings of the colposcopic examination. Private practice office colposcopy is not part of the BC Cancer Provincial Colposcopy Program and as such is not subject to BC Cancer's Quality Control Program.

To find the colposcopy guidelines, please click here.

See the list of regional colposcopy clinics.

3.3 Histologic classification of invasive carcinomas

WHO histological classification of tumours of the uterine cervix – 2017

Epithelial tumours

Squamous tumours

Squamous cell carcinoma, not otherwise specified

Keratinizing
Non-keratinizing
Basaloid
Verrucous
Warty
Papillary
Lymphoepithelioma-like
Squamotransitional

Early invasive (microinvasive) squamous cell carcinoma

Glandular tumours

Adenocarcinoma

Mucinous adenocarcinoma

Endocervical
Interstinal
Signet-ring cell
Minimal deviation
Villoglandular

Endometrioid adenocarcinoma
Clear cell adenocarcinoma
Serous adenocarcinoma
Mesonephric adenocarcinoma
Early invasive (microinvasive) squamous cell carcinoma

Other epithelial tumours

Adenosquamous carcinoma
Glassy cell carcinoma variant
Adenoid cystic carcinoma
Adenoid basal carcinoma
Neuroendocrine tumours

Carcinoid
Atypical carcinoid
Small cell carcinoma
Large cell neuroendocrine carcinoma

Undifferentiated carcinoma

3.4 Microscopic description for cervical tumours should include the following features:

Histologic type
Histologic grade (1-3 or well, moderately well and poorly differentiated)
Presence or absence of lymphatic, vascular or neural involvement
Presence or absence of parametrial involvement
Presence or absence of associated lesion
Depth of stromal invasion measured from the base of the epithelium and horizontal spread

4. Staging

4.1 The FIGO (Fédération International de Gynécologie et Obstétrique) system is the preferred staging for uterine cervix.

TNM Categories	FIGO Stages
TX		Primary tumour cannot be assessed
T0		No evidence of primary tumour
Tis^٭		Carcinoma in situ (preinvasive carcinoma)
T1	I	Cervical carcinoma confined to uterus (extension to corpus should be disregarded)
T1a^٭٭	IA	Invasive carcinoma diagnosed only by microscopy. Stromal invasion with a maximum depth of 5 mm measured from the base of the epithelium and a horizontal spread of 7 mm or less. Vascular space involvement, venous or lymphatic, does not affect classification.
T1a1	IA1	Measured stromal invasion of 3.0mm or less in depth and 7.0mm or less in horizontal spread
T1a2	IA2	Measured stromal invasion of more than 3.0 mm and not more than 5.0 mm with a horizontal spread 7.0 mm or less
T1b	IB	Clinically visible lesions confined to the cervix or microscopic lesion greater than T1a/IA2. Includes all macroscopically visible lesions, even those with superficial invasion.
T1b1	IB1	Clinically visible lesion 4.0 cm or less in greatest dimension
T1b2	IB2	Clinically visible lesion more than 4.0 cm in greatest dimension
T2	II	Cervical carcinoma invading beyond the uterus but not to the pelvic wall or to lower third of the vagina
T2a	IIA	Tumour without parametrial invasion
T2a1	IIA1	Clinically visible lesion 4.0 cm or less in greatest dimension
T2a2	IIA2	Clinically visible lesion more than 4.0 cm in greatest dimension
T2b	IIB	Tumour with parametrial invasion
T3	III	Tumour extending to pelvic sidewall* and/or involving lower third of vagina and/or causing hydronephrosis or non-functioning kidney ^*Pelvic sidewall is defined as the muscle, fascia, neurovascular structures and skeletal portions of the bony pelvis. On rectal examination there is no cancer free space between the tumour and the pelvic sidewall
T3a	IIIA	Tumour involving lower third of vagina but not extending to pelvic wall
T3b	IIIB	Tumour extending to pelvic wall and/or causing hydronephrosis or non-functioning kidney
T4	IVA	Tumour invading mucosa of bladder or rectum and/or extending beyond true pelvis Note: the presence of bullous edema is not sufficient to classify a tumour as T4

TNM Categories	FIGO Stages
NX		Regional lymph nodes cannot be assessed
N0		No regional lymph node metastasis
N0(i+)		Isolated tumour cells in regional lymph nodes no greater than 0.2 mm
N1	IIIB	Regional lymph node metastasis
M0		No distant metastasis
M1	IVB	Distant metastasis (including peritoneal spread, involvement of supraclavicular, mediastinal, or paraaortic lymph nodes, lung, liver, or bone)

^*FIGO no longer includes stage 0 (Tis)

^٭٭All macroscopically visible lesions—even with superficial invasion—are T1b/IB.

Anatomic stage/prognostic groups (FIGO 2008)
Stage 0^*	Tis	N0	M0
Stage I	T1	N0	M0
Stage IA	T1a	N0	M0
Stage IA1	T1a1	N0	M0
Stage IA2	T1a2	N0	M0
Stage IB	T1b	N0	M0
Stage IB1	T1b1	N0	M0
Stage IB2	T1b2	N0	M0
Stage II	T2	N0	M0
Stage IIA	T2a	N0	M0
Stage IIA1	T2a1	N0	M0
Stage IIA2	T2a2	N0	M0
Stage IIB	T2b	N0	M0
Stage III	T3	N0	M0
Stage IIIA	T3a	N0	M0
Stage IIIB	T3b	Any N	M0
	T1-3	N1	M0
Stage IVA	T4	Any N	M0
Stage IVB	Any T	Any N	M0

4.2 Staging Diagram

View a larger version of the Cervix Staging Diagram.

4.3 Investigations for Staging

Following biopsy confirmation of carcinoma of the cervix, history and physical examination and the following staging investigations should be done:

Lab studies: CBC, differential, BUN and creatinine, liver function tests and β-HCG in pre-menopausal patients, as indicated.
Radiological studies: MRI pelvis and PET-CT scan for select patients with early stage cervical cancer (Management Algorithm - click on image below to enlarge). CT scan of the chest-abdomen-pelvis can be done if PET scan is not available. PET-scan and MRI of the pelvis are standard of care before starting radiotherapy (for staging and planning purposes)
Examination under anesthesia (EUA), if necessary, to assess primary tumour volume and extent.

5. Management

5.2 CIN (Cervical Intraepithelial Neoplasia)
5.3 Invasive Squamous Cell Carcinoma & Adenocarcinoma
5.4 Invasive Small Cell Neuroendocrine Carcinoma
5.5 Local or Regional Recurrence
5.6 Carcinoma of the Cervix in Pregnancy

5.1 HPV Infection

Koilocytosis on a Pap smear is evidence of an HPV infection, but does not mean that a patient needs routine colposcopic assessment. Often this change will be in conjunction with mildly dyskaryotic cells. If the problem persists then colposcopic examination is recommended. If evidence of a clinical HPV lesion (condyloma is noted on the cervix or upper vagina) is noted, then colposcopic examination may help the assessment of the severity and location of lesions.

5.2 CIN (Cervical Intraepithelial Neoplasia)

Please click here to see the current BC Cancer Colposcopy Program guidelines.

5.3 Invasive Squamous Cell Carcinoma & Adenocarcinoma

5.3.1 Stage IA

The treatment of these lesions will be based on a thorough histologic examination of a properly obtained cone biopsy specimen. It is strongly recommended that all these patients have their slides reviewed at BC Cancer and that the patient is presented to the multidisciplinary conference for a treatment recommendation.

a. Stage IA1 without LVI

If margins are negative, conservative treatment with simple hysterectomy is recommended. If margins are positive, simple or modified radical hysterectomy with sentinel lymph node biopsy +/- pelvic lymph node dissection is recommended. Occasionally, for very early disease removed with a satisfactory margin, cold knife conization or LEEP may be considered adequate therapy, if fertility preservation is an issue.

b. Stage IA1 with LVI and stage IA2

Radical treatment will be required. This will usually be surgical, including modified radical hysterectomy with pelvic lymph node dissection (or sentinel lymph node biopsy). If fertility preservation is desired, radical trachelectomy with pelvic lymph node dissection (or sentinel lymph node biopsy) could be considered. If the patient is not a surgical candidate, then radical radiotherapy would be used with a combination of external beam treatment plus intracavitary/interstitial brachytherapy.

Role of Sentinel Lymph Node Biopsy for Stage IA1 with LVSI to IB1

Sentinel lymph node mapping can increase the detection of metastatic lymph nodes over conventional lymphadenectomy, as mapping studies have shown that up to 10% of sentinel nodes are found in areas not captured in a standard pelvic lymph node dissection. In addition, diagnostic accuracy is increased with the use of pathological ultrastaging for the sentinel node.

Appropriate candidates for sentinel lymph node biopsies in lieu of pelvic lymphadenectomy include patients who meet all of the following criteria:

Tumor diameter less than 4cm
No suspicious lymph nodes seen on pre-operative imaging or during surgery
Bilateral sentinel lymph node detected intra operatively

If a sentinel lymph node is not identified intraoperatively, a full pelvic lymph node dissection should be performed in that hemipelvis. Patients who do not meet the above mentioned criteria for sentinel lymph node biopsy should have a full bilateral pelvic lymphadenectomy.

When used appropriately, the sensitivity of a sentinel node biopsy has been reported to be 99.6% with a negative predictive value of 99.9%.

References

Tax C, Rovers MM, de Graaf C, Zusterzeel PL, Bekkers RL. The sentinel node procedure in early stage cervical cancer, taking the next step; a diagnostic review. Gynecol Oncol. 2015;139(3):559-67

Adjuvant Radiotherapy

Adjuvant pelvic radiotherapy is recommended when simple hysterectomy is inadvertently performed where modified radical hysterectomy and pelvic lymph node dissection (or sentinel lymph node biopsy) was needed for treatment of the invasive disease. Completion of radical hysterectomy is not routinely recommended but can be discussed in multidisciplinary rounds.

Postoperative radiotherapy will also be recommended following radical hysterectomy in the face of poor prognostic factors (see below).

5.3.2 Stage IB1 and IIA1

We recommend either radical surgery or primary radiochemotherapy.

Radical surgery may be considered as primary therapy in the following situations:

Absence of a highly aggressive histology
Contraindications to primary radiation therapy
Suitable surgical and anesthetic risk

Patients not fulfilling these criteria will be treated with primary radiotherapy.

Adjuvant Radiotherapy

Adjuvant pelvic radiotherapy is recommended if 2 or more of the following features exist:

LVI
Deep stromal invasion
Tumor ≥4 cm

Adjuvant Concurrent Radiochemotherapy

Adjuvant pelvic radiotherapy +/- vaginal vault brachytherapy with concurrent chemotherapy is recommended if any of the following is identified on pathology:

Positive pelvic lymph node
Positive parametrial involvement
Positive margin

5.3.3 Stage IB2, IIA2, IIB, III or IV

Concurrent radiochemotherapy with pelvic external beam radiation treatment followed by intracavitary +/-interstitial brachytherapy is recommended (see radiotherapy section below). If there is evidence of residual disease at 3 months after completion of radiotherapy, salvage hysterectomy may be considered. These cases should be presented at multidisciplinary conference.

Radiotherapy can be used for palliation and local-regional control in the metastatic setting. Palliative chemotherapy can be considered (see below).

5.4 Invasive Small Cell Neuroendocrine Carcinoma

This is an uncommon variant of cervical carcinoma which, like lung small cell, is usually systemic in spread and has lower 5-year survival. All patients need urgent chemotherapy +/- radiotherapy to the pelvis +/- para-aortic regions to try to improve both local and systemic control. Definitive surgery is not recommended, and urgent referral is advised.

Prophylactic cranial irradiation is not recommended for small cell carcinoma of cervix.

5.5 Local or Regional Recurrence

Management of these patients is highly individualized and should be discussed at the multidisciplinary conference. Salvage radiotherapy +/- chemotherapy, salvage surgery, palliative chemotherapy or clinical trials could be considered.

5.6 Carcinoma of the Cervix in Pregnancy

Disease in the pregnant woman is generally managed as in the non-pregnant woman. The treatment policies must be individualized as to the stage and extent of disease, gestational age and, in particular, the wishes of the patient by the multidisciplinary team.

In the case of a high risk Pap smear, colposcopy should be performed. Colposcopic guided biopsy of suspicious areas is recommended only if there is clinical suspicion of malignancy. An ECC should not be performed during pregnancy. If there is no clinical suspicion for malignancy, colposcopy should be repeated every trimester and again 2-3 months post- partum.

Should invasive carcinoma be discovered in early pregnancy and thought to be unsuitable for primary surgical therapy, termination of the pregnancy is usually carried out with the method depending on the gestational age and is followed by radiotherapy +/- chemotherapy. Patients with suspected clinical stage IA1 disease may be treated primarily with a cone biopsy. This should be performed after the first trimester to minimize complications and risks to the pregnancy.

If more advanced disease is suspected, options for management include radical hysterectomy with fetus in situ and pelvic lymphadenectomy, or delay of definitive treatment to allow for fetal maturity. In the latter situation, neoadjuvant chemotherapy during the pregnancy should be considered. For those patients diagnosed in the latter stage of pregnancy with a viable fetus, delivery by caesarean section is usually recommended although studies have not shown that vaginal delivery has produced a higher morbidity or decreased survival in patients delivered this way.

Radiotherapy

Primary Radiotherapy

Pelvic +/- para-aortic radiotherapy to a dose of 45-50 Gy in 1.8-2 Gy per fraction is recommended. Gross pelvic or para-aortic lymph nodes (or PET positive nodes) should receive a dose boost, using simultaneous integrated boost or sequential technique. Pelvic radiotherapy only is recommended in cases with negative nodes. Para-aortic irradiation is recommended in cases with positive para-aortic nodes and can be considered in cases of positive pelvic nodes.

External beam radiotherapy must be followed by intracavitary +/- interstitial brachytherapy unless contraindicated for medical reasons. Interstitial technique to augment intracavitary brachytherapy must be considered in cases of large tumours, asymmetrical tumours, significant lateral extension and unfavourable anatomy. CT-guided brachytherapy planning must be done. MRI-guided brachytherapy planning should be considered for all cases, having shown increased local control and decreased toxicity in large cohort studies. The MRI should be done for at least one fraction, usually at the first insertion, with applicators in place. Target volumes and organs at risk, including bladder, rectum, sigmoid and bowels, should be contoured and volumetric dose prescription must be done.

In cases of extensive persistent disease at the time of brachytherapy, an additional external beam boost can be considered.

The overall treatment time (OTT) defined as the time from beginning to the end of (chemo) radiotherapy (including external beam and brachytherapy) for definitive treatment of intact cervical cancer should not be longer than 7 weeks, with the following conditions:

External beam radiotherapy start date should not be delayed in order to meet the OTT of 7 weeks.
Shorter OTT needs to be balanced against proper and safe brachytherapy implantation and treatment.
Brachytherapy over 3 fractions instead of 4 is allowed to help shorten the OTT if clinically advisable.

Adjuvant Radiotherapy

Pelvic radiotherapy to a dose of 45-50Gy in 1.8-2Gy per fraction is recommended, with or without brachytherapy boost.

Chemotherapy

Primary Concurrent Chemo-Radiation

Results from each of five randomized phase III trials show an average overall survival advantage for cisplatin-based therapy given concurrently with radiation therapy. Although the trials vary somewhat in terms of stage of disease, dose of radiation, and schedule of cisplatin and radiation, they all demonstrate significant survival benefit for this combined approach. The protocol designation for this therapy is GOCXCRT. It consists of weekly cisplatin at 40 mg/m2 weekly for five weeks during external beam radiation therapy.

Advanced or Recurrent Disease

Palliative treatment may be offered in the form of standard chemotherapy or as part of investigatory protocols. In the first-line setting, our current standard is carboplatin, paclitaxel, and bevacizumab (GOCXCATB). Palliative chemotherapy incorporating bevacizumab has been shown to improve overall survival.

There is no evidence that treatment in the second- or later-line setting improves overall survival, compared with best supportive care alone.

For more information on chemotherapy protocols, please click here.

References

Tang J, et al. Chemoradiation and adjuvant chemotherapy in advanced cervical adenocarcinoma. Gynecol Oncol 2012;125:297-302.
Tewari K, et al. Improved survival with bevacizumab in advanced cervical cancer. N Engl J Med 2014;370:734-43.

Estrogen Replacement Therapy

No data exists to show a contraindication for hormone replacement in cervical or vaginal cancer. Many of these patients are young and at high risk for estrogen deprivation related morbidity. It is common practice to encourage such patients to take estrogen replacement therapy. There are a multitude of choices but in the presence of a uterus, it is recommended to use continuous estrogen and progesterone with the estrogen at a moderate dose (Estradiol 2mg po daily or Estradot patch 50mcg change twice a week) and the progesterone at a low dose (2.5 mg Provera). Histologic studies have shown that continuous therapy with combined estrogen and progesterone induces an atrophic bland endometrium. This regime may result in some initial bleeding for the first one to two months but in general the women are amenorrheic.

An alternative regime would be to use cyclical estrogen and progesterone. This has the disadvantage of inducing a withdrawal bleed in some patients who have not had total ablation of the endometrium. Hematometra may develop if there is cervical stenosis present leading to abdominal pain or a mass.

Transdermal estrogen replacement therapy is associated with a lower risk of thromboembolism, stroke and hypertriglyceridemia compared to oral estrogen preparations. However, an oral preparation is a reasonable option for women with low risk of thromboembolic events.

Recommendation: Continuous estrogen and progesterone, e.g.:

Micronized 17-beta estradiol 1-2mg taken daily, 50mcg of transdermal estradiol (Estradot Patch) to be changed twice a week (eg Monday and Thursday) or Conjugated Estrogen (Premarin) 0.625-1.25mg taken daily

Provera 2.5 mg daily

(note: these small doses of Provera do not seem to have the same deleterious effects on serum lipids as the higher doses.)

In the absence of a uterus estrogen alone in usual doses is recommended.

6. Follow-up

Surveillance after primary curative therapy for cervical cancer is recommended, although its effectiveness is not well studied.

To determine the patient's immediate response to the treatment employed
Early recognition and prompt management of treatment related complications
Early detection of persistent or recurrent disease
Collection of meaningful data regarding the efficacy of existing treatment policies and their complications so that any appropriate modifications can be instituted

In 2016, consensus-based surveillance recommendations were updated by the Program in Evidence-Based Care of Cancer Care Ontario Cervical Cancer Follow-up Guideline Working Group, following review and analysis of the literature. A reasonable surveillance strategy involves clinic visits at the following intervals:

Years 1-2	every 3-4 months
Years 3-5	every 6-12 months
Years 5+	annually

Follow-up visits should include history and complete physical examination. Physical examination should include bimanual, pelvic and rectal examination as well as speculum examination.

If vaginal vault cytology is used to detect new precancerous conditions of the vagina, it should be performed no more frequently than once annually. An abnormal cytology result that suggests the possibility of neoplasia warrants colposcopic evaluation and directed biopsy. It is important to note that the accuracy of cervicovaginal cytology is compromised by the anatomic and tissues changes resulting from pelvic radiation. Cytology follow-up is not recommended for patients who have been treated with radiotherapy.

In the absence of concerning symptoms or signs, other investigations such as imaging and blood work, including tumour markers, are not advocated.

Repeat PET-scan could be considered at 3-6 months after completion of the treatment. The validity of PET-scan after completion of radiochemotherapy is still being evaluated. Some of the indications for PET-scan include:

Evaluation of possible residual disease on clinical examination
Evaluation of residual abnormal signal on post-treatment MRI
Evaluation of progressive disease amenable to salvage treatments

Initial follow-up is performed by BC Cancer medical staff but when appropriate, arrangements will be made for surveillance by the referring or family physician.

References

Elit L, et al. Follow-up for cervical cancer: a Program in Evidence-Based Care systematic review and clinical practice guideline update. Curr Oncol 2016;23(2):109-118.