Management of histologically confirmed cervical cancer SLCOG Guideline

Ultimate goal of treating a cancer patient is to cure the disease where possible and to have control of primary disease and delay the recurrences in patients in whom complete cure is not possible. Patients beyond above levels should receive appropriate symptom relieving treatment. Pre-operative staging, individualized treatment planning and appropriate adjuvant treatment and risk based follow up are corner stones in managing these patients.

The purpose of this guideline is to describe the management of histologically proven cervical cancer and provide currently available best evidence to health care professionals to provide optimal care for these patients. This guideline also reviews their management options depending on the resources available in the local setting.
Ultimate goal of treating a cancer patient is to cure the disease where possible and to have control of primary disease and delay the recurrences in patients in whom complete cure is not possible. Patients beyond above levels should receive appropriate symptom relieving treatment. Pre-operative staging, individualized treatment planning and appropriate adjuvant treatment and risk based follow up are corner stones in managing these patients.

Summary of key recommendations 2.1 Patient assessment:
All patients should undergo speculum and per vaginal examination.
All the patients beyond FIGO stage IA1 should undergo examination under anesthesia before planning curative surgery. This should be performed by a senior clinician (Consultant, Senior Registrar) with prior experience in cervical cancer clinical staging As a minimum, chest X ray and ultrasound of the abdomen (when a cross sectional imaging is not available) should be performed in all patients to assess for distant solid organ involvement and renal tract obstruction.
MRI is the gold standard imaging to assess local tissues when available without delay, CECT (Contrast Enhanced Computerized Tomography) scan of the chest, abdomen and pelvis should be considered in every patient before radical treatment Full blood count, renal functions, liver functions etc should be performed to assess the fitness for surgery. All the patients who are diagnosed to have cervical cancers are better to be discussed in a multi-disciplinary setting before the surgical/ medical intervention -if the facilities are available.

Treatment of Stage IA1 disease
Post cervical cone biopsy/LLETZ biopsy or a hysterectomy specimen histology with stage IA1 cervical cancer should be assessed by a Consultant Gynaecologist or Gynaecological Oncologist.

SLCOG Guideline
When planning treatment, patient's fertility wishes and prognostic histological features should be accounted.
LVSI is a well-recognized risk factor for lymphatic metastasis, it should be considered for further necessity of surgery.
When cervical cone excision is done, specimen should be not fragmented and correctly oriented with a mark (Eg: Stitch). Repeat cone excision is required if the cancer is < 3mm away from the resection margins or margins are difficult to assess.
Involved resection margin would upgrade the disease to IB1 and patient would require radical surgery.

Treatment of Stage IA2 disease
Post cervical cone biopsy/LLETZ biopsy or a hysterectomy specimen histology with stage IA2 cervical cancer should be assessed by a Consultant Gynaecologist or Gynaecological Oncologist.
For high risk IA2 disease (Grade 3, Positive LVSI), open radical hysterectomy with bilateral salpingectomy + bilateral pelvic lymphadenectomy is preferred. Risk of ovarian metastasis is low in this group (including adenocarcinoma of the cervix) and decision for oophorectomy should be individualized according to risk factors and patient wishes.
Piver-Rutledge type ll/ Querleu-Morrow type B hysterectomy is preferred for stage IA2 disease.
Minimal access surgery is contraindicated in these patients.
Radical trachelectomy or simple trachelectomy can be done if fertility preservation is considered.

2.3b Post hysterectomy
If stage IA2 disease is diagnosed in a post hysterectomy specimen, bilateral pelvic lymphadenectomy should be performed.

Stage IB1, IB2 disease
Standard treatment for IB1 and IB2 disease is open radical hysterectomy with bilateral salpingectomy + bilateral pelvic lymphadenectomy.
Piver-Rutledge type III / Querleu-Morrow type C1 radical hysterectomy is recommended in this group.
External iliac lymph nodes: Nodes from the bifurcation of common iliac artery to the deep circumflex iliac vein.
Internal iliac lymph nodes: Nodes around the internal iliac vessels.
Obturator lymph nodes: Nodes from the obturator fossa down to the level of the obturator nerve.

2.4a Fertility sparing treatment for Stage IB disease
Abdominal or vaginal radical trachelectomy with bilateral pelvic lymphadenectomy can be considered when maximum tumour diameter is < 20mm and not involving the uterine corpus.
All patients should undergo MRI scan of the pelvis and PET CT scan to assess suitability for fertility sparing surgery.
These patients require inputs from Gynaecological Oncologist, clinical oncology and reproductive medicine specialists before planning surgery.

Primary radio therapy in stage IA and IB disease:
Primary radical chemo radiotherapy should be reserved for patients who are not fit enough for surgery.

Stage IB3, IIA disease
Primary radiotherapy is preferred in this group.
If primary surgery is offered, it should be done only after case-based risk assessment (tumour grade, LVSI, size of tumour, length of vaginal involvement, anticipated technical difficulties).

2.7
Above procedures should be performed in a setting with adequate facilities, staff and surgical expertise.
In absence of facilities and expertise, these patients should be referred to a center with such facilities. Surgery should be done by a Consultant Gynaecologcial Oncologist or a Gynaecologist with experience in performing radical hysterectomy.

Stage IIB and above
These patients should be referred to a clinical oncologist for further management.

Follow up after primary treatment
A follow up based on appropriate history and examination is recommended.

Re-malignant HPV infection.
Follow up frequency should be dictated by risk of recurrence of the cancer.

Recurrent cervical cancer
Suspected patients with recurrent disease should be referred to a gynaecological cancer centre.
Inputs from the clinical oncologist and radiologist is required before planning treatment in all patients.
All patients should receive clinical pelvic assessment by an experienced Gynaecologist/Gynaecological Oncologist and histological confirmation when lesion is accessible for biopsy. CE CT scan of the chest, abdomen and pelvis should be performed to exclude distant recurrence.
MRI is the best investigation to assess the local tumor extent, especially in relation to pelvic side wall.
An examination under anaesthesia should be performed in patients with central disease.
Recurrence within short period of primary treatment or multi focal disease is not suitable for radical surgery or radiotherapy. Surgery, radiotherapy or chemotherapy should be given only in palliative intent.
Single recurrent lesion who had no previous radical radiotherapy in a medically fit patient with a prolonged disease free interval can be managed by radical radiotherapy. Need for surgical debulking should be individually assessed in case-based manner.
Central, isolated pelvic recurrence who had radiotherapy with prolonged disease-free interval can be radically excised by pelvic exenteration or radical hysterectomy (depending on exact site of recurrence) as these patients are not suitable for further radio therapy.
CT scan or Positron Emission Tomography (PET) scan to exclude any distance metastasis should be done in all patients before selecting for exenterative procedures.

Introduction
Cervical cancer is the commonest gynaecological malignancy in Sri Lanka and developing world 1,2 . Screening for pre-malignant disease has shown great success worldwide, especially in the developed countries. While radical surgery or radical radiotherapy can achieve high levels of cure, it is vital to avoid dual modality radical treatment to minimize complications. This guideline discusses the management of biopsy proven cervical cancer.

Patient assessment
All patients should undergo speculum and per vaginal examination.
All the patients beyond FIGO stage IA1 should undergo examination under anaesthesia before planning curative surgery. This should be performed by a senior clinician (consultant, senior registrar) with prior experience in cervical cancer clinical staging As a minimum, chest X ray and ultrasound of the abdomen (when a cross sectional imaging is not available) should be performed in all patients to assess for distant solid organ involvement and renal tract obstruction.

SLCOG Guideline
MRI is the gold standard imaging to assess local tissues when available without delay, CECT (Contrast Enhanced Computerized Tomography) scan of the chest, abdomen and pelvis should be considered in every patient before radical treatment.
Full blood count, renal functions, liver functions etc should be performed to assess the fitness for surgery.
All the patients who are diagnosed to have cervical cancers are better to be discussed in a multi-disciplinary setting before the surgical/ medical intervention if the facilities are available.
Aim of this evaluation is to clinically stage the patient to assess suitability for curative surgery. This should include combined recto vaginal examination +/-cystoscopy / rigid sigmoidoscopy in presence of clinical features suggestive of bladder and rectal involvement.
In instance where a stage beyond IIA is evident on vaginal assessment, examination under anaesthesia can be exempted if a histology report is available.
If available without delay, an MRI scan can provide more details about parametrial involvement, size of the tumor and pelvic lymph node enlargement. MRI is considered as the best mode of assessment for local invasion in tumours larger than 10 mm 3,4 and it has an important role in selecting patients for fertility sparing radial surgery (trachelectomy).
CECT (Contrast Enhanced Computerized Tomography) scan of the chest, abdomen and pelvis can give more details about solid organ involvement, ureteric obstruction as well as pelvic and para-aortic lymph node enlargement. It should be mentioned that, with availability of pre-operative medical imaging, in 2018 FIGO made provisions for inclusion of pelvic and para-aortic lymph node metastasis in cervical cancer staging.

Treatment of Stage IA1 disease
Post cervical cone biopsy/LLETZ biopsy or a hysterectomy specimen histology with stage IA1cervical cancer should be assessed by a Consultant Gynaecologist or Gynaecological Oncologist.
When planning treatment, patient's fertility wishes and prognostic histological features should be accounted.
LVSI is a well-recognized risk factor for lymphatic metastasis, it should be considered for further necessity of surgery When cervical cone excision is done, specimen should be not fragmented and correctly oriented with a mark. (E.g.: Stitch). Repeat cone excision is required if the cancer is < 3mm away from the resection margins or margins are difficult to assess 5 .
Involved resection margin would upgrade the disease to IB1 and patient would require radical surgery.
Stage 1A1 disease is almost always diagnosed on a post cervical cone biopsy/LLETZ biopsy or a hysterectomy specimen. Depending on the margin status and lympho-vascular space invasion (LVSI), some patients would require further interventions as stated in the table below. LVSI is a well-recognized risk factor for lymphatic metastasis.

Treatment of Stage IA2 disease
Post cervical cone biopsy/LLETZ biopsy or a hysterectomy specimen histology with stage IA2 cervical cancer should be assessed by a Consultant Gynaecologist or Gynaecological Oncologist. Similar to IA1 disease, Stage IA2 is almost always diagnosed on a cervical cone biopsy/LLETZ biopsy or a hysterectomy specimen. However due to higher risk of metastatic disease and recurrence, more radical approach is recommended.

4.3a Post cone biopsy/ loop excision -stage 1A2
Simple open hysterectomy + bilateral salpingectomy with bilateral pelvic lymphadenectomy is recommended in patients with low risk histology features (Grade 1/2, Negative LVSI).
For high risk IA2 disease (Grade 3, Positive LVSI), open radical hysterectomy with bilateral salpingectomy + bilateral pelvic lymphadenectomy is preferred. Risk of ovarian metastasis is low in this group 6 (including adenocarcinoma of the cervix) and decision for oophorectomy should be individualized according to risk factors and patient wishes.
Minimal access surgery is contraindicated in these patients.

Radical trachelectomy or simple trachelectomy can be done if fertility preservation is considered.
Both Piver-Rutledge type ll/ Querleu-Morrow type B and Piver-Rutledge type III/ Querleu-Morrow type C1 radical hysterectomy are associated with similar oncological outcomes in this group. Therefore less invasive Piver-Rutledge type ll/ Querleu-Morrow type B2 hysterectomy is preferred for stage IA2 disease 7 .
Pelvic lymphadenectomy is recommended for all the patients due to 5% to 10% risk of lymphatic metastasis 8 .
Minimal access surgery should not be performed in these patients due to 4-fold increase of deaths when compared to open route 9 .
Fertility sparing treatment -Abdominal or vaginal radical trachelectomy with bilateral pelvic lymphadenectomy can be done where fertility preservation is wished. Simple trachelectomy can be considered in patients with low-risk histology features (Grade 1/2, Negative LVSI). However, this decision should be individualized.
Refer to next section for more details on trachelectomy.

4.3b Post hysterectomy
If stage IA2 disease is diagnosed in a post hysterectomy specimen, bilateral pelvic lymphadenectomy should be performed.

Stage IB1, IB2 disease
Standard treatment for IB1 and IB2 disease is open radical hysterectomy with bilateral salpingectomy + bilateral pelvic lymphadenectomy.
Piver-Rutledge type III /Querleu-Morrow type C1 radical hysterectomy is recommended in this group.
External iliac lymph nodes: Nodes from the bifurcation of common iliac artery to the deep circumflex iliac vein.
Internal iliac lymph nodes: Nodes around the internal iliac vessels.
Obturator lymph nodes: Nodes from the obturator fossa down to the level of the obturator nerve.
Risk of ovarian metastasis in Stage IB adenocarcinoma is around 4% 10 . Therefore patients preference and risk factors for ovarian cancer should be considered when planning bilateral oophorectomy in pre-menopausal women. When performing radical hysterectomy, autonomic nerve sparing would reduce long term complications. Refer the appendix for technical details of radical hysterectomy classification.

4.4a Fertility sparing treatment for Stage IB disease
Abdominal or vaginal radical trachelectomy with bilateral pelvic lymphadenectomy can be considered when maximum tumour diameter is < 20mm and not involving the uterine corpus 11 .

SLCOG Guideline
All patients should undergo MRI scan of the pelvis and PET CT scan to assess suitability for fertility sparing surgery.
These patients require inputs from gynaecological oncologist, clinical oncology and reproductive medicine specialists before planning surgery.
Risk of recurrence in this group is around 5% and radical tachylectomy would have similar oncological outcome to a radical hysterectomy. However, MRI scan and PET scan should be done to select patients suitable for this conservative surgery. Live birth rate after radical trachelectomy is around 25% to 50% 5 .

Primary radio therapy in stage IA and IB disease:
Primary radical chemo radiotherapy should be reserved for patients who are not fit enough for surgery.
Primary radical chemo radiotherapy is associated with similar survival outcomes compared to radical surgery. However radical radiotherapy is associated with more long-term complications compared to radical surgery (sexual dysfunction, bladder symptoms, bowel symptoms, chronic pelvic pain, premature menopause, lymph oedema). Therefore, radical surgery is preferred over radical chemo radiotherapy in this group.

Stage IB3, IIA disease
Primary radiotherapy is preferred in this group.
If primary surgery is offered, it should be done only after case-based risk assessment. (tumour grade, LVSI, size of tumour, length of vaginal involvement, anticipated technical difficulties).
Stage IB3 and IIA are associated with higher incidences of lymph node involvement, positive surgical resection margins, parametrium involvement and cancer recurrence. Therefore, primary radiotherapy is preferred in this group 12,13 . Place of neo adjuvant chemotherapy in this category is still under investigation.

4.7.
Above procedures should be performed in a setting with adequate facilities, staff and surgical expertise. In absence of facilities and expertise, these patients should be referred to a center with such facilities. Surgery should be done by a Consultant Gynaecologcial Oncologist or a Gynaecologist with experience in performing radical hysterectomy.

Stage IIB and above
These patients should be referred to a clinical oncologist for further management.
Mode of treatment is either chemo radiotherapy or chemo therapy. There are 2 risk groups in which post-operative radiotherapy is indicated 14 .

Post-operative radiotherapy
1. High risk -positive or close (less than 5mm) surgical margins 15 or lymph node metastases or parametrial spread.

Recurrent cervical cancer
Suspected patients with recurrent disease should be referred to a gynaecological cancer centre.
Inputs from the clinical oncologist and radiologist is required before planning treatment in all patients.
All patients should receive clinical pelvic assessment by an experienced Gynaecologist/Gynaecological Oncologist and histological confirmation when lesion is accessible for biopsy.
CE CT scan of the chest, abdomen and pelvis should be performed to exclude distant recurrence.
MRI is the best investigation to assess the local tumor extent, especially in relation to pelvic side wall.
An examination under anaesthesia should be performed in patients with central disease.
Recurrence within short period of primary treatment or multi focal disease is not suitable for radical surgery or radiotherapy. Surgery, radiotherapy or chemotherapy should be given only in palliative intent.
Single recurrent lesion who had no previous radical radiotherapy in a medically fit patient with a prolonged disease free interval can be managed by radical radiotherapy. Need for surgical debulking should be individually assessed in case-based manner.
Patients with central, isolated pelvic recurrence who had previous radiotherapy with prolonged disease-free interval can be radically excised by pelvic exenteration or radical hysterectomy (depending on exact site of recurrence) as these patients are not suitable for further radio therapy.
CT scan or Positron Emission Tomography (PET) scan to exclude any distance metastasis should be done in all patients before selecting for exonerative procedures.
Behavior of cervical cancer is more complex in the recurrent disease compared to primary. Therefore inputs from the oncologist and radiologist is required before planning treatment in these patients. Remission period from the primary treatment, anatomical distribution of the disease, previous radio therapy as well as physical fitness/performance status are important variables to consider when managing these patients.
Recurrence within 1 year of the primary treatment and multi-focal disease are considered as features of poor prognosis. Previous radical irradiation of the pelvis is associated with cellular changes that prevents the possibility of re-irradiation due to extremely high incidence of organ toxicity (urinary fistula, faecal fistula, skin ulceration, bowel stricture formation, ureteric stricture formation etc).
Therefore, pelvic exenteration is the only curative option for resectable recurrent disease in patients who had previous radical radio therapy.

Clinical governance
Patient presenting with post coital bleeding or any other symptom suggestive of cervical cancer should be referred to a specialist gynaecological service within 14 days.
The definitive treatment of a histologically confirmed case of cervical cancer, should be aimed to occur within 6 weeks from the date of biopsy. Patients should be promptly referred to specialist centers to achieve this target.