Estimated 13,960 women werevdiagnosed with cervical carcinoma in 2o23 with 4310 expected deaths.
The incidence rate of cervical cancer in the US is 11.5 per hundred thousand women age 15 to 75 years.
Overall, cervical cancer rates are decreasing in the US, although the incidence remains high in Hispanic, Black, and Asian populations.
Incidence of cervical cancer in Black women is 16.8 per hundred thousand, and Hispanic women, 15.8 per 100,000, and in white women 6.8 per hundred thousand and five year survival is lower for black women at 55.8% than for white women at 63%.
Individuals with immunosuppression or DES exposure, have higher risks of cervical cancer.
Worldwide 311,000 women died of cervical cancer in 2021.
Fourth most common cancer in women worldwide, with 600,000 new cases diagnosed annually.
85% of cases occur in developing countries, where cervical cancer is a leading cause of cancer, death in individuals born as female.
The annual cost of cervical cancer care in the US is $1.6 billion
It is the second most common cancer and second most common cause of death from cancer in women of reproductive age worldwide.
Among the most preventable human malignancies.
squamous cell cancer cancer, approximately 80% of all cervical cancers and adenocarcinoma accounts for approximately 20%.
Adenocancers and adenosquamous cancers of the cervix have increased over the past decades, because cervical cytologic screening methods, are less effective for this types of cervical cancer as they are located deeper in the ectopic cervix.
Most of the sexually active population is estimated to be infected with HPV during their lifetimes, and a positive HPV test is considered a marker of sexual activity.
Cancer develops in people with persistence of an HPV infection not controlled by the immune system.
The incidence of cervical cancer appears to be related to the prevalence of HPV in the population.
Virtually all cervical cancers contain, at least one of 13 carcinogenic HPV genotypes.
Only 5% of cervical cancers are HPV independent.
Carcinogenic HPV genotypes are linked in a single branch of the alpha genus: alpha 9, -7, -5, and -6 species contain HPV genotypes that are carcinogenic.
HPV 16 is the most carcinogenic associated with more than 60% of cervical squamous cancers, and adenocarcinomas and oropharyngeal and other anogenital cancers.
When a carcinogenic HPV infection persists, infected cells, may undergo neoplastic transformation, indicating a change in replication to a clonal growth of transformed cells.
In pre-cancers, HPV viral oncoproteins, activate the cell cycle, and inhibit apoptosis, the process of programmed cell death, essential for renewing the squamous epithelium and protecting against neoplasia.
The cancerous cells stop proliferating when in contact with the basement membrane, and the epithelium grows away from the basement membrane, allowing earlier detection of abnormal growth.
Pre-cancer cells may enlarge circumferentially without invasion for years, allowing for the success of screening.
The risk of pre-cancer can be estimated by identifying the HPV genotype and using cytology and P 16/KI 67 dual staining to understand whether the HPV infection is replicating or abortive and transforming and more likely pre-cancerous.
Methylation of host DNA and viral markers are increased with transition from replicating HPV Infection to oncogenic transformation.
It is estimated that 80% of cervical cancer mortality can be reduced by screening: yet, there has been a 14 year decline in screening in the US.
It has the highest incidence and mortality rates in countries with the lowest values in the human development Index and correlates with a high prevalence of infection with HIV.
In developing countries it remains the number one cause of cancer related deaths among women, with nearly 500,000 women diagnosed annually worldwide.
It has a worldwide incidence of 600,000 with 311,000
In the United States the average age of patients is 47 years.
More than 80% of cases occur in poor resource countries.
It is largely preventable through both vaccination and screening for precursor lesions, with appropriate follow up and treatment.
Almost 9 out of 10 cervical cancer deaths occurred in the less developed regions of the world.
Second or third most common cancer in most low and middle income countries.
The leading cancer in sub-Saharan Africa.
More than 85% of all cervical cancers and cervical cancer related deaths occur in developing countries.
Fourth most common gynecologic malignancy in U.S.
Most common cancer in pregnancy.
Most cases occur among women who have not been adequately screened.
Worldwide the incidence and mortality from cervical cancer is second to breast cancer, and in parts of the developing world it is the major cause of death of women of reproductive age.
Rare before age 20, and the incidence starts to rise at the age of 25 or 30 years.
High risk include women without access health care and to those who have immigrated to the US where cervical cancer screening is not routinely performed.
Squamous cell carcinomas account for approximately 75% of all cervical cancers and adenocarcinoma cancers approximately 20%.
5 year survival rates for early stage, locally advanced, and metastatic cervical cancers are 91%, 57%, and 16%, respectively (SEER).
Just more than half of invasive cervical cancer cases involve regional or distant metastasis at diagnosis.
No evidence of cervical cancer screening in adolescents has decreased incidence of cervical cancer.
Incidence 1.5-14.9 per 100,000 in women aged 20-49 years of age.
Incidence 1.3 per 100,000 in women aged 20-24 years and 14.8 per 100,000 in women older than 50 years.
A 70% decline in mortality has occurred since introduction of Pap cytologic screening.
Despite an increase in the incidence of carcinoma in situ, invasive cervical cancer rates have been steadily declining because of early detection and treatment of pre-invasive disease.
The decrease in incidence has leveled off.
Frequent retesting with Pap smear is required for screening because of its low sensitivity.
Young age at first intercourse, high number of sexual partners, high parity, cigarette smoking, race and low socioeconomic status are significant risk factors.
Almost half of the cases are diagnosed while still confined to the cervix (stage I) where the cure rate is 85-90%.
Most patients present with early stage disease.
Most cases detected by screening are early-stage and largely curable.
Patients with locally advanced cervical cancer are likely to present with symptoms, such as, irregular vaginal bleeding, postcoital bleeding, and vaginal discharge.
Pelvic pain, bone pain, and back pain because of hydronephrosis, another urinary or bowel symptoms and presentation or associated with advanced and metastatic disease
Folate deficiency is the only dietary factor that has been shown to play a role in early cervical carcinogenesis.
The vinegar test for cervical cancer was studied over a 15-year period in India in more than 150,000 women and it reduced cervical cancer mortality by 31% and could potentially prevent 72,000 deaths in low-resource countries annually.
Between 1988 and 2003 only 8% of women were diagnosed with metastatic disease at the time of presentation (SEER).
Clinical staging is accurate approximately 60% of the time and undiagnosed involvement of lymph nodes is common.
Evaluation of invasive cervical cancer is made of tumor size, parametrial spread, lymph node involvement, and distant metastasis.
MRI is found to be superior to measurement of tumor size and determination of uterine body involvement.
Ultrasound imaging is comparable and could be use when MRI is not available.
Lymph node involvement by noninvasive evaluation with CT, MRI and PET/CT all play a role in staging.
Sensitivity to detect lymph node involvement is poor and tumor involvement of para-aortic nodes may be found on surgical evaluation.
Evaluation for distant metastasis by PET/CT or contrast CT of the chest abdomen and pelvis are indicated.
Lymph node resection before radiation improves survival in patients with macroscopic pelvic and paraaortic disease, but routine pretreatment surgical staging is not recommended.
Status of regional lymph nodes is an important prognostic factor.
In 1B cervical cancer the three-year disease-free survival was 74% for women with positive lymph nodes versus 86% for those with negative lymph nodes (Delgado G et al).
Lymphadenectomy can detect metastatic disease and survival benefit has been noted among node-negative patients who undergo more extensive lymph node dissection.
The rate of periaortic metastases in locally advanced cervical cancer is 15-20%, and the prognosis of patients with such spread have an overall survival rate of only 17%.
Imaging studies are able to detect fewer than 30% of paraortic node positive patients.
In women stage IA2–IIa disease the extent of lymphadenectomy influence survival especially among node negative women, and survival is improved on the grade and number of lymph nodes are removed: Among women with positive lymph nodes a more extensive lymphadenectomy had no effect on survival (Shah M et al).
The most common sites for hematogenous spread are to the lungs, bone ansd liver.
Bone metastases occur occasionally and is associated with bad prognosis advanced disease.
MRI and PET scan have a high sensitivity for detecting bone marrow or bone metastases.
Transition from precancer to cancer occurs on the average of 10 years.
Radical hysterectomy provides a 85% chance of 5-year survival.
After radical surgery, patients with pathological high risk factors such as parametria invasion, positive surgical margins, and lymph node metastases should receive adjuvant radiotherapy with concurrent cis-platinum based chemotherapy:about 30% of such patients will relapse.
In patients with low risk, cervical cancer (IA2,IB1), simple hysterectomy was not inferior to radical hysterectomy in respect to a three-year incidence of pelvic recurrence, and was associated with the lower risk of urinary incontinence or retention.
For patients with intermediate risk factors such as large tumor size, deep stromal invasion, or lymphatic vascular space involvement there is no current consensus on the role of chemotherapy in addition to aduvant radiotherapy.
In trials comparing open radical hysterectomy with minimally invasive laparoscopic or robotic radical hysterectomy: at 4 1/2 years, only 86% of patients with minimally invasive groups were cancer free compared with 96.5% of the patients with open surgery.
All patients with locally advanced cervical cancer are potential candidates for primary chemoradiation.
Weekly cisplatinum concurrent with radiation is the primary treatment of choice.
For stage IIA1 disease, surgical management with lymphadenectomy can be considered instead of primary chemo radiation.
In stage IIB through IVA disease surgery alone is unlikely to be curative and surgery followed by radiation has higher rates of complications compared with primary chemoradiation.
Carboplatinum is a non-inferior agent in patients that cannot tolerate cisplatinum.
In locally advanced cervical cancer recommended treatment includes external beam radiotherapy plus brachytherapy boost.
External beam radiotherapy to the pelvis is the most common initial therapy and should cover sites of disease to include periodic nodes.
Of women who develop cervical cancer 50% have never had a Pap smear and another 10% have not had a Pap smear within 5 years of their diagnosis.
Inappropriate triage and follow-up account for 10% of women who develop cervical cancer.
30% of cervical cancers result from errors in sampling and interpretation of Pap smears.
Standard prevention requires 3 visits: one for screening, one for colposcopically guided biopsy and one for treatment of precancerous condition.
Single cytologic analysis is insensitive for adequate screening.
About 25% of patients diagnosed with cervical cancer present with locally advanced disease.
Standard treatment for locally advanced cervical cancer is radiation therapy that includes stages IIB through stage IV and bulky stage IB lesions, however, concurrent cisplatin-based chemotherapy with radiation has emerged as the new standard.
Regardless of cancer subtype and HPV infection status primary treatment with curative intent for patients with cervical cancer consists of surgery, chemotherapy, or a combination of these treatments, with options varying by cancer stage.
Use of concurrent chemoradiation increases survival for locally advanced cervical cancer improving 5 year survival from 50-58%.
In a phase 3 randomized clinical trial of patients with early cervical cancer treated with sequential chemo radiation versus concurrent chemoradiation or radiation alone: found that the sequential chemo radiation therapy improved three-year disease free survival and distant disease free survival with comparable toxic affects.
There was no substantial improvement in survival among patients receiving concurrent chemo radiation compared with radiation alone (Huang H).
For bulky or locally advanced cervical cancer, radiation alone fails to control the disease and 35 to 90% of patients.
Bulky stage I (stage IBI2) and locally advanced stages II-IVA are treated with concurrent radiation and chemotherapy.
Randomized trials demonstrate that platinum-based chemotherapy given concurrently with radiation therapy prolongs survival in women who have locally advanced cervical cancer.
Intensity-modulated radiation therapy (IMRT) to the pelvis after surgery provides disease control similar to that seen with a distended external beam therapy, but with lower bowel toxicity: RTOG 0418 showed that the combination of the IMRT for patient’s with stage Ia, IB, IIA, and IIB disease with Cis-platinum was associated with an estimated disease-free survival of 86.9% utilizing 50.4 Gy and weekly cisplastin.
A meta-analysis of 4921 patients in 24 randomized trials revealed, improves overall survival and progression free survival when concomitant chemo-radiation was used for women with locally advanced disease (Green J.)
The most commonly used regimen during chemo-radiation is Cisplatin 40 mg per meter squared weekly for six weeks during radiation treatment.
In combination with radiation survival advantage noted to be present with a number of drugs including epirubicin, mitomicin, 5FU, Capecitabine.
Neoadjuvant chemotherapy before radiotherapy has not been shown to have a survival benefit compared with radiation therapy alone.
Neoadjuvant Chemotherapy for Locally Advanced Cervical Meta–analysis Collaboration Group suggested a survival advantage with higher doses of Cisplatin.
Most important contributing factor is Human papilloma virus (HPV).
Persistent HPV precedes cytopathologic changes.
HPV infection is usually cleared before causing disease.
Viral load of HPV 16 determines a woman’s risk of developing cervical cancer in situ many years in advance of the event.
Approximately 70% of cervical cancers are caused by persistent infections with high risk HPV type 16 or 18.
Persistence of other oncogenic HPV types 31, 33, 45, 52, and 58 also confer increased risk.
Largely a preventable disease with a known causative agent: HPV.
HPV accounts for an estimated 70% of all cervical cancers worldwide, with a slightly higher fraction in developed countries than in less developed ones.
99% of cervical cancers contain the genes of HPV’s, most commonly 16, 18, 3, 33,35, 39, 45, 51, 52, 56, 58, 59 and 68.
Carcinogenic HPV belong to the alphapapillomavirus genus.
HPV 16 most common carcinogenic type, accounting for half of cervical cancer cases.
HPV 18 implicated in endocervical adenocarcinoma, accounting for 15% of cervical cancers.
Adenocarcinomas, are caused almost exclusively by HPV 16, 18, and 45.
Adenocarcinomas may be missed by screening and colposcopy studies and screening programs are less effective than for squamous cell cancers.
Cervical adenocarcinomas have a worse prognosis than squamous cell carcinoma of the cervix.
PD-L1 expression in adenocarcinoma is much less than in squamous cell carcinoma.
Persistent infection with 1 of approximately 15 types of HPV causes almost all cases of cervix cancer.
Approximately 5% of cervical cancers may be unrelated to HPV.
HIV positive women have a higher risk of acquiring oncogenic HPV and are also susceptible to persistent and reactivated HPV infection.
HIV infected women are substantially more likely to develop cervical pre-cancer then HIV-uninfected women.
Cigarette smoking is the most important nonsexual risk behavior increasing the risk 2-4 fold.
Cigarette smoking increases the risk of cervical cancer in women infected with HPV.
Obese women with cervical cancer have a higher mortality rate.
For early-stage disease, surgery and radiation are probably equally efficacious.
About half of all deaths occur in the first year, 25% occur in the second year, and 15% occur in the third year, for a total of approximately 90% by the end of the third year.
Late recurrences of invasive cancer occurs in 2.5% of patients.
Cone biopsy is recommended if cervical biopsy is inadequate to define invasiveness or if accurate assessment of microinvasive disease is required.
Only excisional techniques (cold knife conization, large loop excision of the transitional zone, laser conization) are adequate to diagnose or rule out early invasion.
The average cervical cancer patient who dies loses approximately 25 years of life.
Black and Hispanic women have cervical cancer incidence rates 39% and 85% higher than white women, respectively.
Younger black women with cervical cancer are at risk for presenting with higher stage disease and have worse overall survival.
Infection with oncogenic types of human papilloma virus (mainly HPV16 and HPV18) is the initiating event in all cervical cancers.
Patients with HPV-31 have favorable prognosis.
When detected early the 5-year survival rate is more than 90%.
It is reasonable to lengthen the screening Pap smear test to three years in women of low risk and with three negative tests.
HPV18 related cervical carcinomas are associated with a poor prognosis.
Recurrent cancer seen in approximately 10-15% of patients with stage I-IIA and in 30-50% patients with stage IIB-III disease.
Mortality increases with increasing poverty and decreasing education level.
TREATMENT
Surgery the mainstay of treatment for microinvasive disease stages IA1-IA2 and early stage IB1-IIA.
Early-stage disease, IA-IB2 can be cured and most patients with radical hysterectomy and lymphadenectomy plus tailored adjuvant therapy.
With locally advanced carcinoma, IB3-IVA treated with chemoradiotherapy plus high dose rate intracavity brachytherapy..
For patients diagnosed with locally advanced disease, single agent cisplatinum based therapy concurrent with radiation remains the mainstay of treatment:IB3, II,III,and IVA.
do use of concurrent chemo radiation results in a 30 to 50% decrease in the risk of death compared with radiotherapy alone.
Cisplatin made the preferred radiosensitizing agent in the primary treatment patience with localization cervical cancer when use concurrently with external RT.
Stage IV makes up about 15% of cervical cancers with metastases generally occurring via lymphatic spread to the pelvic and periotic nodes will hematogenous spread to the lungs, bones, liver, and other distant organs.
Oligometastatic disease amenable to local treatment may be treated with definitive radiotherapy to or resection of metastasis and systemic therapy.
For patients with recurrent or persistent disease confined to the pelvis after prior radiation treatments cure may be possible with pelvic exenteration.
For patients with metastatic, progressive and recurrent disease, treatment consists of combination chemotherapy and incorporation of bevacizumab, and the addition of upfront immunotherapy and women whose cancer expresses programmed death ligand–1.
Cervical cancer is a good target for immunotherapy because its presence indicates impaired immune system function with a failure of the immune system to clear HPV.
The second rationale for its using immunotherapy is that most of the patients express program death ligand 1 (PD-L1), which is an optimal target for immune checkpoint inhibition.
Normal cervical epithelial cells do not express PD-L1 expression is noted in cells affected by HPV in both cervical intraepithelial neoplasia and cervical cancer.
PD-1 expression is found in 95% of cases of CIN and 80% of cases of cervical squamous cell carcinoma.
Cervical cancer demonstrates a number of aspects that make it a good candidate for tumor immunotherapy including: viral pathogenesis with HPV antigens, high tumor mutational burden (TMB), frequent neo antigen formation, high-grade tumor infiltration particularly with CD8 positive cytotoxic T lymphocytes and macrophages, and amplification of multiple checkpoint controlling targets, including PD-L1..
Cisplatin based treatment standard care for locally advanced disease.
Cisplatin 50 mg/m2 q 3 weeks for advanced or recurrent disease has a 50% response rate in chemotherapy naive patients and a 17% response rate in patients who have received prior chemotherapy.
Cisplatin at 100 mg/m2 given every three weeks for advanced or recurrent disease the overall response rate was better than the 50 mg/m2 dose group but the median progression free survival time was similar, 7.1 vs. 7 months.
For locally advanced cervical cancer cisplatin based concurrent radiation is the standard of care.
Cisplatin considered the most active and effective agent for metastatic disease.
Combination platinum-based regimens preferred over single agents in metastatic setting and include: Cis-platinum/paclitaxel/bevacizumab, cis-platinum/paclitaxel/Toprol.
Chemoradiotherapy using weekly cisPlatinum results in significantly better disease-free survival and overall survival compared with radiation therapy in women with Stage IIIB squamous cell carcinoma of the uterine cervix.
Despite achieving a four-year progression free survival a 51% and overall survival of 55%, standard treatment with chemo and radiation therapy does not cure patience with stage III or IV disease.
Patient with periotic lymph node metastases continue to have a poor prognosis, with a three-year progressive free survival rate of 34% and overall survival rate of 39%.
Cisplatin 50 mg/m2 plus topotecan 0.75 mg/m2 days 1-3 standard treatment for recurrent cancer or stage IVB.
In a phase III randomized study of the addition of gemcitabine to concurrent cisplatin chemoradiotherapy in locally advanced cervical cancer: 515 treatment naive stage IIB to IVA disease patients-3 year PFS significantly improved in gemcitabine arm, as was time to progression, and overall survival (Duenas-Gonzalez et al).
GOG240 compared paclitaxel and cisplatin or Topotecan with or without bevacizumab in patients with stage IV-B, recurrent or persistent cervical cancer: Revealed patients randomized to the bevacizumab arms lived a median of 17 months and those in the regimen without this drug lived a median of 13 months.
The phase III Gynecology Oncology Group (GOG) 240 trial showed addition of bevacizumab (Avastin) to standard chemotherapy improved overall survival (OS) by nearly 4 months in women with advanced or relapsed cervical cancer (Krishnansu S. Tewari et al).
Administering bevacizumab with chemotherapy also yielded a 12% improvement in tumor response rate compared with chemotherapy alone.
The addition of bevacizumab to multi agent chemotherapy increase the risk for a fistula formation, typically in patients who had received prior radiotherapy.
Median progression-free survival (PFS) and overall response rate were also notably improved, and benefit with the addition of bevacizumab to treatment was seen even in women who had received pelvic irradiation.
The response rate in patients treated with chemotherapy alone was 36%, compared with a 48% response rate in patients treated with chemotherapy plus bevacizumab.
Completion hysterectomy has no therapeutic impact in patients with clinical and radiologic complete response after chemo/radiation therapy (Morice P et al).
Adenocarcinoma of the cervix and its precursor lesion, adenocarcinoma in situ follow a less predictable clinical course than does its squamous cell equivalent.
For stage IV disease or recurrent disease with multiple sites of metastasis treatment is palliative intent and long-term survival is rare.
For stage IV disease combination platinum based chemotherapy ( topotecan, gemcitabine, paclitaxel) with bevacizumab significantly increases overall survival, progression free survival, and objective response rate compared with chemotherapy alone.
Ability to detect glandular carcinoma of the cervix is more difficult to detect on Pap smears than are squamous lesions.
Anti-PD-1 therapy for the treatment of patients with recurrent or metastatic cervical cancer on or after chemotherapy whose tumors express PD-L1.
Pembrolizumab is now the first anti-PD-1 therapy approved for the treatment of advanced cervical cancer, providing an important new second-line option.
In the phase 3 randomized, double-blind, placebo-controlled KEYNOTE-826 trial investigators assessed the use of pembrolizumab, paclitaxel and cisplatin or carboplatin, with or without bevacizumab in patients with first-line metastatic persistent recurrent cervical cancer who had not received treatment with chemotherapy.
The overall response rates for the pembrolizumab and placebo regimens were 68% and 50% in both arms, respectively, with a median duration of response of 18.0 months and 10.4 months in each respective group.
This approval is based on the KEYNOTE-158 trial.
In the KEYNOTE-158 trial, 98 patients with advanced cervical cancer were evaluated and nearly 84% were PD-L1 positive: The objective response rate to pembrolozumab to pretreated patients was nearly 15% with three complete and 9 partial responses..
For the patients whose tumors expressed PD-L1 the objective response rate was 14.3 percent with a complete response rate of 2.6 percent and partial response rate of 11.7 percent.
Pembrolozumab is also approved the second time therapy for MSI-H/dMMR cervical tumors.
Pembrolizumab’s cancer indication, for stage 3-4a cervical cancer in combination with chemoradiation therapy.
KEYNOTE-826 randomized clinical trial found that affine pembrolizumab to chemotherapy with or without Bevacizumab improved overall survival across sub groups of patients with persistent, recurrent, or metastatic cervical cancer.
Mismatch repair deficiency and microsattelite instability are reported in about 25% of cases of cervical cancer.
The FDA has approved the use of pembrolizumab plus chemotherapy with or without bevacizumab in patients with persistent, recurrent, or metastatic cervical cancer who have PD-L1 expression identified via an FDA-approved test.
Balstilimab is a PD-1 inhibitor and zalifrelimab is a CTLA-4 inhibitor.
The data demonstrated 26.5% objective response rates (ORR) which are durable in an all-comer, non-biomarker selected population of patients with refractory cervical cancer who have failed prior platinum chemotherapy with or without bevacizumab.
Cemplimab compared to single-agent chemotherapy among patients with recurrent cervical cancer after first line platinum containing chemotherapy significantly prolonged survival.
HPV tumor infiltrating lymphocyte therapy is selective and requires a large tumor biopsy specimen to obtain tumor specific TILs and it takes time to expand the TILs in vitro of approximately 22 days.
Patients with locally advanced or metastatic disease are at high risk for recurrence, with the majority occurring in the first two years: follow up should be every three months in the first two years, every six months for three years, and annually there after.
Sequelae of patients treated for locally advanced cervical cancer treatments stem from irradiation of the pelvis and include bowel, bladder, and sexual organ dysfunction.
Bowel dysfunction is common after pelvic radiation with a higher incidence than in patients who receive surgery alone with up to half of patients reporting decreased quality of life from bowel issues over a 20 year period.
Bowel dysfunction can cause nausea, vomiting, diarrhea, constipation and fecal urge and incontinence leading to social isolation and depression.
Bladder dysfunction with urgency or neurogenic bladder may be chronic for years after treatment has ended.
Patients treated with surgery and especially lymph node dissection often have chronic lymphedema.
Sexual dysfunction in survivors is prevalent and more pronounced in younger patients and often related to treatment related menopause and direct treatment effects on sexual organs.