Cervical cancer

- Executive Summary

- Recommendations

➡️Diagnostic and Staging Work up

·  Diagnostic and staging work up should include history and physical examination, complete blood count, as well as liver function and renal function studies.

➡️Good practice statement

· We recommend cervical cytology or Papanicolaou (Pap) smears and cervical biopsies for diagnosis.

➡️Strong recommendation, high grade evidence, (4).

· We recommend cone biopsy (i.e., conization) if the cervical biopsy is inadequate to define invasiveness or if accurate assessment of microinvasive disease is required.

➡️Strong recommendation, high grade evidence, (5).

· Recommended radiologic imaging includes pelvic MRI, and FDG-PET/CT

➡️Strong recommendation, high grade evidence, (6,7).

· Consider examination under anesthesia (EUA) cystoscopy/proctoscopy for cases having ≥ stage IB.

➡️Good practice statement

·  Consider options for fertility sparing

➡️ Conditional recommendation, high grade evidence, (8).

➡️Staging and risk assessment

· Tumor risk assessment should include tumor size, stage, depth of tumor invasion, lymph node status, LVSI and histological subtype.

➡️Strong recommendation, high grade evidence, (Table 4, appendix).

➡️Management of local/locoregional disease

➡️Surgery

·  Surgical therapy in cervical cancer should be adapted to the stage of disease according to FIGO and TNM classification (Appendix).

➡️Good practice statement

· Surgery should only be considered in patients with earlier stages of cervical cancer (up to FIGO IIA) without risk factors necessitating adjuvant therapy, which results in a multimodal therapy without improvement of survival but increased toxicity.

➡️Strong recommendation, high grade evidence (9).

· Microinvasive cervical cancer (stage IA1) without LVSI should be managed with conisation or simple trachelectomy to preserve fertility, and simple hysterectomy is recommended if the patient does not wish to preserve fertility.

➡️Strong recommendations, high grade evidence (8).

· In stage IA1 with LVSI, surgical assessment of pelvic lymph nodes is recommende

➡️Strong recommendation, moderate grade evidence (10).

· In patients with FIGO stage IA2, IB and IIA, radical hysterectomy with bilateral lymph node dissection (with or without SLN) is standard treatment, if the patient does not wish to preserve fertility.

➡️ Strong recommendation, high grade evidence, (9,11).

Adjuvant/neoadjuvant treatment

·  Consider NACT with surgery as this may reduce the need for adjuvant RT.

➡️Conditional recommendation, high grade evidence, (12,13).

· Intermediate-risk surgicopathologic findings, frequently referred to as Sedlis criteria, are defined by a combination of lymphovascular space involvement, depth of stromal invasion, and tumor size (Table 5, appendix), and they should be treated by whole pelvic RT delivered to a total dose of 4500 to 5040 cGy, in 180 Gy per fraction or 4000 to 4400 Gy in 200 Gy per fraction.

 ➡️Strong recommendation, strong grade evidence, (14-16).

·  Adjuvant CRT is recommended in high-risk patients (one or more negative prognostic factors such as positive or close surgical margins, positive lymph nodes or microscopic parametrial involvement). For these patients, whole pelvic RT should be delivered to a total dose of 4500 to 5040 cGy, in   180 cGy fractions, with concurrent weekly cisplatin (40mg/m2).

➡️ Strong recommendation, high grade evidence, (14,17).

Chemoradiotherapy in locally advanced cervical cancer

· We recommend CRT  for patients with bulky IB2–IVA disease, and the most commonly used regimen is weekly cisplatin 40 mg/m2;

➡️ Strong recommendation, high grade evidence, (18-23).

· Patients not eligible to cisplatin may receive carboplatin or gemcitabine.

 ➡️Strong recommendation, very low grade evidence (24,25).

· Brachytherapy is needed to obtain a sufficiently high dose to ensure a high rate of local control in advanced cases.

➡️Good practice statement

Management of advanced/metastatic disease

· Palliative chemotherapy with the aim of relieving symptoms and improving quality of life is recommended if the patient has a PS< 2 and no formal contraindications.

➡️Strong recommendation, high grade evidence, (26,27).

· Cisplatin-based doublets with paclitaxel or topotecan have demonstrated superiority to cisplatin monotherapy and should be used.

➡️Strong recommendation, high grade evidence (26,27).

·  Paclitaxel and cisplatin combined with bevacizumab is recommended as the preferred first-line regimen in metastatic or recurrent cervical cancer based on the balance between efficacy and toxicity profile.

➡️ Strong recommendation, high grade evidence, (28-30).

· The combination of paclitaxel and carboplatin is recommended as an alternative for patients that are not candidates for cisplatin.

➡️Strong recommendation, moderate grade evidence, (31).

 ➡️Strong recommendation, moderate grade evidence, (32).

· Some patients develop small lung metastases only, which do not rapidly progress and can be managed with stereotactic RT and/or a watchful waiting policy, frequently delaying systemic chemotherapy for a significant period of time.

➡️Conditional recommendation, low grade evidence, (33).

Local recurrence of cervical cancer following radical surger

· Higher doses of RT can be delivered with brachytherapy and increase the likelihood of local control for patients with small volume central recurrences.

➡️Strong recommendation, high grade evidence (34).

➡️Clinical indicators

· Follow-up visits with a complete physical examination including a pelvic–rectal exam and a patient history should be conducted by a physician experienced in the surveillance of cancer patients.

➡️Good practice statement

· CT or PET/CT scan should be carried out as clinically indicated. A reasonable follow-up schedule involves follow-up visits every 3–6 months in the first 2 years and every 6–12 months in years 3–5.

➡️Good practice statement

· Patients should return to annual population-based general physical and pelvic examinations after 5 years of recurrence-free follow-up.

➡️Good practice statement

- Acknowledgments

• We would like to acknowledge the Oncology Committee of the Egyptian Health Council (EHC) Guidelines, for adapting these Guidelines. 
• Chair of the Oncology Committee of Egyptian Health Council Guidelines: Prof Hussein Khaled. 
• The Oncology Committee Members: Emad Hamada, Samir Shehata, Hesham Elghazaly, Hesham Tawfik, Fouad Abuotaleb, Ebtesam Saad Eldin, Ihab Khalil, Khaled Abdelkarim, Lobna EZZ Elarab, Mary Gamal, Mohamed Abdel Mooti, Mohamed Gamil, Nervana Hussein, Ola Khorshid, Omar Sherif Omar, Rasha Fahmi, Rasha Shaltout, Yousri Wasef & Yousri Rostom.

- Abbreviations

- Introduction

In Egypt, there was an estimated 1302 new cases of cervical cancer with an ASIR of 2.8/100 000 normal population and ranks the 13^th most common cancer among females. There were 820 (ASMR: 1.8/100 000 normal population) deaths occurred because of this disease based on GLOBOCAN 2022.

- Purpose and scope

These guidelines are developed to improve the quality of care for cervical cancer via providing a uniform standard of care across the country to help in early diagnosis, treatment and follow up for cervical cancer so more optimal treatment options and improved clinical outcomes. 

- Target audience

Clinicians who are involved in the care and treatment of patients with cervical cancer, include medical oncologists, radiation oncologists, clinical oncologist, gynecologists, surgeons, radiologists, pathologists, and palliative care specialists. 

- Methodology

A comprehensive search for guidelines was undertaken to identify the most relevant guidelines to consider for adaptation.   inclusion/exclusion criteria followed in the search and retrieval of guidelines to be adapted: 

-  Selecting only evidence-based guidelines (guidelines must include a report on systematic literature searches and explicit links between individual recommendations and their supporting evidence). - Selecting only national and/or international guidelines. 

-  Specific range of dates for publication (using Guidelines published or updated 2015 and later). 

-  Selecting peer reviewed publications only.

-  Selecting guidelines written in English language.

-  Excluding guidelines written by a single author not on behalf of an organization to be valid and comprehensive, a guideline ideally requires multidisciplinary input. 

-  Excluding guidelines published without references as the panel needs to know whether a thorough literature review was conducted and whether current evidence was used in the preparation of the recommendations. 

 All retrieved Guidelines were screened and appraised using AGREE II instrument (www.agreetrust.org) by at least two members. the panel decided a cutoff point or rank the guidelines (any guideline scoring above 50% on the rigor dimension was retained) 

The NCCN, ESMO, NICE guidelines are the main sources used while formulating the national guidelines for cervical cancer.

➡️  Evidence assessment 

 According to WHO handbook for Guidelines we used the GRADE (Grading of Recommendations, Assessment, Development and Evaluation) approach to assess the quality of a body of evidence, develop and report recommendations. GRADE methods are used by WHO because these represent internationally agreed standards for making transparent recommendations. Detailed information on GRADE is available through the on the following sites: 

. GRADE working group: https://www.gradeworkinggroup.org/

 . GRADE online training modules:http://cebgrade.mcmaster.ca/

Table 1: Quality of evidence in GRADE  

Table 2: Significance of the four levels of evidence

Table 3: Factors that determine How to upgrade or downgrade the quality of evidence  

➡️  The strength of the recommendation 

The strength of a recommendation communicates the importance of adherence to the recommendation: 

➡️Strong recommendations: With strong recommendations, the guideline communicates the message that the desirable effects of adherence to the recommendation outweigh the undesirable effects. This means that in most situations the recommendation can be adopted as policy. 

➡️Conditional recommendations: These are made when there is greater uncertainty about the four factors above (Table 2) or if local adaptation must account for a greater variety in values and preferences, or when resource use makes the intervention suitable for some, but not for other locations. This means that there is a need for substantial debate and involvement of stakeholders before this recommendation can be adopted as policy. 

When not to make recommendations; when there is lack of evidence on the effectiveness of an intervention, it may be appropriate not to make a recommendation.

- Update of this guideline

This guideline will be updated whenever there is new evidence. 

- Research gaps

▪️  Systematic inclusion of cost-benefit analyses in clinical trials with collection of health economic analysis such as incremental cost effectiveness ratio in order to facilitate clinical decision-making. 

▪️  Predictive biomarkers: response to specific systemic targeted therapies and immunotherapy. 

▪️  Improve models for pre-clinical testing of novel drugs. 

▪️  Search for tools to assess quality of life and in clinical trials.

▪️  Dietary supplements, nutritional counselling, physical activity recommendations and psychological support as part of an integrative healthcare approach to care for people with ovarian cancer. 

- References

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- Annexes

Table 5. Intermediate Risk-factors for Cervical Cancer (2).