Cervical Cancer: Current Perspectives on Pathophysiology, Diagnosis, Prevention, and Therapeutic Advances

Aarti Malkapure, Prajakta Shingote, Ajay Bhagwat, Prasad Jadhav, Akshada Thorat,

doi:10.5281/zenodo.17432542

Review Paper | Open Access
Volume 03 | Issue 10 | Article Id IJPS/250310362

Cervical Cancer: Current Perspectives on Pathophysiology, Diagnosis, Prevention, and Therapeutic Advances
Aarti Malkapure* Prajakta Shingote Ajay Bhagwat Prasad Jadhav Akshada Thorat
Samarth College of Pharmacy, Belhe, Pune, Maharashtra, India, 412410

Abstract

Cervical cancer is 4th most common cancer among women globally with around 6,60,000 new cases and around 3,50,000 deaths in 2022. Most cervical cancers are caused by Human Papillomavirus (HPV), a sexually transmitted infection. HPV spreads through sexual contact (anal, oral or vaginal) and can lead to cancer. Only certain types of HPV cause cervical cancer. The two types that most commonly cause cancer are HPV-16 and HPV-18. Signs and symptoms of cervical cancer include abnormal vaginal bleeding, such as bleeding after vaginal sex, bleeding after menopause, bleeding and spotting between periods, or having (menstrual) periods that are longer or heavier than usual, bleeding after douching may also occur, an unusual discharge from the vagina which may contain some blood and/or occur between your periods or after menopause, pain during sex, pain in the pelvic region. The four main treatments are surgery, radiation therapy, chemotherapy, targeted therapy.

Keywords

Cervical cancer, Human Papillomavirus (HPV), HPV-16 and HPV-18, Symptoms, Treatment.

Introduction

One of the most common gynaecologic diseases in the world is still cervical cancer. Based on available statistics, it is the fourth most prevalent cancer in women globally and ranks 14th overall. Cervical cells are where cervical cancer begins. The lower, narrow end of the uterus, or womb, is called the cervix. The uterus and vagina (birth canal) are connected by the cervix. Typically, cervical cancer progresses gradually over time. Cervical cells undergo a process called dysplasia, in which aberrant cells start to show up in the cervical tissue, prior to cancer developing in the cervix. The aberrant cells may eventually develop into cancer cells and begin to proliferate and spread farther into the cervix and surrounding regions if they are not eliminated or eliminated. Primary and secondary prevention are the main goals of cervical cancer intervention. The most effective ways to reduce the incidence and mortality of cervical cancer are through primary prevention and screening.[1] With racial, ethnic, and age differences, screening rates are lower in low-socioeconomic and low-resource locations. According to studies, women who are obese and suffer from chronic illnesses may be less likely to get screened for breast and cervical cancer. Cervical cancer is avoidable because it is a STI, and by focusing on education, screening, and prevention, the incidence of cervical cancer can be decreased worldwide. Cervical cancer preventative vaccinations have been available since 2006. When the World Health Organization (WHO) called for the universal eradication of cervical cancer in May 2018, almost 70 nations and international academic bodies responded right once. Subsequently, on November 17, 2020, the World Health Organization unveiled the global strategy to expedite the eradication of cervical cancer as a public health issue in order to illuminate the path for future cervical cancer prevention and control. This means that 194 nations have committed to working together to eradicate cervical cancer for the first time.[2]

2. BIOLOGY OF CERVICAL CANCER

The mucus-secreting columnar epithelium and stratified squamous epithelium that envelop the cervix are especially susceptible to viral neoplastic transformation at the squamocolumnar junction. Adenocarcinomas are more prevalent in endocervix tumors, but squamous cell carcinomas are the most prevalent kind. The majority of cervical cancer cases are caused by HPV infection, which is responsible for 95% of malignant lesions. It may take years or decades for dysplasia to develop into aggressive cancer.

EPIDEMIOLOGY

Over 99 percent of cervical malignancies are caused by a persistent HPV infection. Worldwide, there are over 250,000 cervical cancer-related fatalities and over 500,000 new cases of the disease each year. Developing nations account for 80% of instances. About 4,000 women in the US lose their lives to cervical cancer each year. Low-resource communities have a far higher death rate and more disparities in evidence-based care for women, Black people, and Hispanic people. Women who have not been screened in the previous five years and those who do not have regular follow-up when a precancerous cervical lesion is discovered have a higher mortality rate. According to trends, women who are most at risk for mortality might be less likely to get vaccinated against HPV.[3]

SYMPTOMS OF CERVICAL CANCER [4]

Symptoms of Cervical Cancer: Early cervical cancer commonly has no symptoms, which is why screening is necessary to detect it. The most common actual symptoms are:

Vaginal bleeding: Because of the cervix's extremely delicate surface, tumours leak readily. In reality, a woman's overall risk of developing cervical cancer is around 30% if she experiences fresh vaginal bleeding after menopause. Women with premenstrual syndrome are frequently at risk for bleeding throughout their periods, strong menstrual flow, spotting bleeding during periods, or after sexual activity.

Vaginal discharge: White or often yellowish foul-smelling discharge that may occur with particularly advanced or necrotic cancer.

Cervical pain: When inserting a tampon or finger rather than the vagina, cervical pain is felt. This cervical motion pain raises the possibility of an infection or malignancy upon physical examination. Pelvic pain may be widespread in cases of more severe disease.

Urinary symptoms: As the tumour spreads into the vagina and eventually blocks the kidneys' ability to drain urine, urinary symptoms appear as the disease progresses. The most frequent cause of cervical cancer-related deaths is uraemia.

Signs of spread to other areas of the body include: lymph gland enlargement in the groin or collar bone are or the left armpit. Advanced spread may give bone, liver, lung, bowel or brain abnormalities.

The late symptoms: can be weight loss, anaemia and body lethargy.

Complications:

Haemorrhage.
Pyelitis, Pyelonephritis, and Hydronephrosis
Frequency of Urination

DIAGNOSTIC EVALUATION [4]

Pap smear test: The most used Pap smear test, the Papanicolaou test, is used to check for cervical cancer. In order to identify high-risk women, the test looks for abnormal changes in the cervix's cells that can point to cervical cancer or a precancerous disease. The age at which cervical screening should begin is 21 years old.
Biopsy: A small piece of tissue will be taken. This patient will be anesthetized for this.
Colposcopy: The gynecologist uses a colposcope, a lighted magnifying device made especially for inspecting the tissue of the vagina and the cervix, to view the cervix while holding the vagina open with a speculum.
Cone biopsy: A small cone shaped section of the abnormal tissue is taken from the cervix for examination under a microscope.
LLETZ: A diathermy bis used to remove abnormal tissue. The tissue is sent to lab to be checked
Blood test: (Number of Blood cells).
Computerised tomography scan: A three-dimensional cross-sectional image of the bodily part is displayed on the screen. The patient must first consume a barium drink. On the scan, the barium appears white. Barium liquid may be injected into the rectum and a tampon may be inserted into the vagina just prior to the scan. The entire scan process takes ten to thirty minutes.
MRI: Magnetic Resonance Imaging scan (By using the high MRI with a special vaginal coil, a technique to measure the movement of water within the tissue, the researchers may be able to identify cervical cancer in its early stages.)
Pelvic ultra sound: This technology employs high-frequency sound waves to project an image of the target area onto a monitor. To ensure that the bladder is full and a clear image can be seen, the patient will be asked to consume a lot of fluids before the test. One option is to replace the external equipment adjacent to the stomach or introduce a transvaginal ultrasound device into the vagina.

CAUSES OF CERVICAL CANCER

Primary Cause:
1. Human Papillomavirus (HPV) infection (accounts for 99% of cervical cancer cases)

1. Risk Factors

Persistent HPV infection
Early age at first intercourse (<16 years)
Multiple sexual partners
History of sexually transmitted infections (STIs)
Smoking and tobacco use
Immunodeficiency (e.g., HIV/AIDS)
Family history of cervical cancer
Obesity
Long-term use of oral contraceptives (>5 years)
Exposure to diethylstilbestrol (DES) in utero
1. Other Factors

Poor cervical screening history
Lack of HPV vaccination
Inadequate nutrition (low intake of fruits, vegetables, and antioxidants)
Genetic predisposition (e.g., mutations in TP53, BRCA1/2)

ETIOLOGY OF CERVICAL CANCER

Human Papillomavirus (HPV) infection: 99% of cervical cancer cases Most cervical cancer cases are caused by the sexually transmitted human papillomavirus (HPV). This is the same virus that causes genital warts. There are about 100 different strains of HPV. Only certain types cause cervical cancer. The two types that most commonly cause cancer are HPV-16 and HPV-18.[5]

MECHANISM OF HPV-INDUCED CARCINOGENESIS [6,7]

HPV virus infects cervical epithelial cells
Viral DNA integrates into host genome
E6 and E7 oncogenes disrupt cell cycle regulation
p53 and Rb tumor suppressor proteins inactivated
Uncontrolled cell proliferation and malignant transformation

CO-FACTORS

Immunosuppression (HIV/AIDS, organ transplantation). [8]
Smoking and tobacco use. [9]
Hormonal factors (oral contraceptives, hormone replacement therapy). [10]
Genetic predisposition (mutations in TP53, BRCA1/2)
1. Other potential etiologic factors:-

Chlamydia trachomatis infection. [11]
Herpes simplex virus type 2 infection. [12]
Dietary factors (low antioxidant intake). [13]
Environmental exposures (radiation, chemicals)

10. STAGES OF CERVICAL CANCER [14]

A cancer?stage describes the extent of cancer in the body, especially whether the cancer has spread from where it first formed to other parts of the body. It is important to know the stage of cervical cancer in order to plan the best treatment.

Stage I cervical cancer
Stage II cervical cancer
Stage III cervical cancer
Stage IV cervical cancer
Recurrent cervical cancer

Stage I: cervical cancer?has formed and is found in the?cervix?only. It is divided into stages IA and IB, based on the size of the tumor?and the deepest point of tumor invasion.

Stage IA is subdivided based on the deepest point of tumor invasion.
Stage IA1: A very small amount of cancer that can only be seen with a?microscope?is found in the tissues?of the cervix. The deepest point of tumor invasion is 3?millimeters?or less.
Stage IA2: A very small amount of cancer that can only be seen with a microscope is found in the tissues of the cervix. The deepest point of tumor invasion is more than 3 millimeters but not more than 5 millimeters.
Stage IB is subdivided based on the size of the tumor and the deepest point of tumor invasion.
Stage IB1: The tumor is 2?centimeters?or smaller and the deepest point of tumor invasion is more than 5 millimeters.
Stage IB2: The tumor is larger than 2 centimeters but not larger than 4 centimeters.
Stage IB3: The tumor is larger than 4 centimeters.

Stage II cervical cancer:

In stage II, cervical cancer?has spread to the upper two-thirds of the?vagina?or to the tissue?around the?uterus.

Stage II is subdivided based on how far the cancer has spread.

Stage IIA: Cancer has spread from the?cervix?to the upper two-thirds of the vagina but has not spread to the tissue around the uterus. Stage IIA is further divided based on the size of the?tumor:
Stage IIA1: The tumor is 4?centimeters?or smaller.
Stage IIA2: The tumor is larger than 4 centimeters.
Stage IIB: Cancer has spread from the cervix to the tissue around the uterus.

Stage III cervical cancer:

In stage III, cervical?cancer?has spread to the lower third of the?vagina and/ or to the pelvic wall, and/ or has caused kidney problems, and/ or involves lymph nodes.

Stage III is subdivided based on how far the cancer has spread.

Stage IIIA: Cancer has spread to the lower third of the vagina but has not spread to the pelvic wall.
Stage IIIB: Cancer has spread to the pelvic wall; and/or the tumor?has become large enough to block one or both?ureters?or has caused one or both kidneys to get bigger or stop working.
Stage IIIC: Stage IIIC is divided into stages IIIC1 and IIIC2, based on the spread of cancer to the lymph nodes.

Stage IV cervical cancer:

In stage IV, cervical cancer?has spread beyond the?pelvis, or has spread to the lining of the bladder or rectum, or has spread to other parts of the body.

Stage IV is subdivided into stages IVA and IVB, based on where the cancer has spread.

Stage IVA: Cancer has spread to nearby?pelvic organs, such as the bladder or rectum.
Stage IVB: Cancer has spread to other parts of the body, such as the?liver, lungs, bones, or distant?lymph nodes.

11. RECURRENT CERVICAL CANCER

Recurrent cervical cancer is cancer that has recurred (come back) after it has been treated. The cancer may come back in the cervix or as metastatic tumors in other parts of the body.?Tests will be done to help determine where the cancer has returned in your body, if it has spread, and how far.?The type of treatment that you have for recurrent?cervical?cancer will depend on how far it has spread.

Fig.2 Staging of Cervix Cancer

12. PATHOPHYSIOLOGY OF CERVICAL CANCER

Step 1: HPV Infection

Human Papillomavirus (HPV) infects cervical epithelial cells through micro-abrasions or sexual transmission. [15]
HPV virus attaches to cell surface receptors (e.g., heparan sulfate).[16]

Step 2: Viral Replication

1. HPV DNA enters the cell nucleus and replicates. [17]
2. Viral E1 and E2 proteins regulate replication. [18]

Step 3: Integration and Oncogenesis

HPV DNA integrates into host genome, disrupting cell cycle regulation. [7]
E6 and E7 oncogenes inactivate p53 and Rb tumor suppressor proteins. [19]
Uncontrolled cell proliferation and malignant transformation. [20]

Step 4: Immune Evasion

HPV-infected cells invade immune surveillance through immune suppression. [6]
Downregulation of MHC class I and II molecules. [21]

Step 5: Angiogenesis and Metastasis

Tumor cells induce angiogenesis, promoting blood vessel formation. [22]
Tumor cells invade surrounding tissue and metastasize to distant sites. [23]

Key Molecular Alterations
1. p53 mutation/inactivation
2. Rb mutation/inactivation
3. PI3K/AKT pathway activation
4. VEGF overexpression Types of Cervical Cancer

Fig.1 Key Molecular Alteration

13.TYPES OF CERVICAL CANCER

1. Squamous Cell Carcinoma (SCC): 70-80% of cervical cancer cases

Originates from squamous epithelial cells
Subtypes: keratinizing and non-keratinizing

2. Adenocarcinoma (AC): 10-20% of cervical cancer cases

Originates from glandular epithelial cells
Subtypes: endocervical, intestinal, and signet-ring cell

3. Adenosquamous Carcinoma (ASC): 3-5% of cervical cancer cases

Mixed squamous and glandular components

4. Small Cell Carcinoma (SCC): 1-2% of cervical cancer cases

Aggressive, neuroendocrine-type tumor

5. Large Cell Carcinoma (LCC): rare

Undifferentiated, pleomorphic cells

6. Glassy Cell Carcinoma (GCC): rare

Clear cytoplasm, distinctive morphology

7. Mucoepidermoid Carcinoma (MEC): rare

Mixed mucinous and squamous components

8. Serous Carcinoma (SC): rare

Papillary, glandular architecture

Rare and Unusual Types

Neuroendocrine Tumors (NETs): <1%
Melanoma: <1%
Lymphoma: <1%
Sarcoma: <1%

14. MECHANISM OF HPV 16 INDUCED CANCER

Step 1: Viral Entry

HPV16 infects the cervical cells through sexual contact or skin-to-skin contact.[15]
The virus enters the cells through microabrasions or tiny wounds in the cervical epithelium.[16]

Step 2: Viral Replication

HPV16 replicates in the cervical cells, producing viral DNA and proteins.[17]
The viral protein E2 regulates viral replication and transcription.[18]

Step 3: Expression of Oncoproteins

HPV16 encodes two major oncoproteins, E6 and E7, which are essential for cervical cancer development [19].

Step 4: Inhibition of Tumor Suppressor Proteins [19,20,7]

E6 binds to and degrades p53 (a tumor suppressor protein), preventing it from regulating cell growth and division.
E7 binds to and inhibits pRb (a tumor suppressor protein), leading to uncontrolled cell growth and division.

Step 5: Disruption of Cell Cycle Regulation[24]

Inhibition of p53 and pRb leads to:
Uncontrolled cell growth and division
Increased genetic instability
Accumulation of mutations

Step 6: Epigenetic Changes [25,26]

HPV16-induced epigenetic changes, such as DNA methylation and histone modification, silence tumor suppressor genes and activate oncogenes.

Step 7: Cervical Cancer Development [6]

The combination of genetic and epigenetic changes leads to the development of cervical cancer.
HPV16-positive cervical cancer cells exhibit high levels of E6 and E7 oncoproteins.

Step 8: Progression to Invasive Cancer [23]

If left undetected and untreated, HPV16-positive cervical cancer cells can invade nearby tissues and spread to other parts of the body.

15. TREATMENT

The treatment of cervical cancer depends on several factors, including the stage of cancer, the patient’s overall health, and whether the cancer has spread to other areas. Treatment options are typically grouped into the following categories:

1. Surgery [27,28]

Surgery is often the primary treatment for early-stage cervical cancer and can also be used in combination with other therapies for more advanced stages. Surgical options include:

Conization (Cone biopsy): A procedure to remove a cone-shaped piece of tissue from the cervix, used in early-stage cancers or precancerous changes (CIN).
Hysterectomy: The removal of the uterus, which may include:
Simple hysterectomy: Removal of the uterus and cervix.
Radical hysterectomy: Removal of the uterus, cervix, surrounding tissues, part of the vagina, and possibly lymph nodes in the pelvis.
Trachelectomy: A fertility-sparing surgery where the cervix is removed, but the uterus is preserved, suitable for women with early-stage cancer who wish to maintain fertility.
Pelvic lymph node dissection: Removal of lymph nodes in the pelvic area to check for cancer spread.
1. Radiation Therapy [29]

Radiation therapy uses high-energy radiation to kill cancer cells or shrink tumors. It is often used for patients with more advanced stages of cervical cancer or as part of adjuvant therapy (after surgery). There are two types of radiation used in cervical cancer treatment:

External beam radiation therapy (EBRT): Radiation is directed at the pelvic area from outside the body. It is often used for cancers that have spread beyond the cervix.
Internal radiation therapy (Brachytherapy): Radioactive material is placed directly inside or near the tumor, typically in the cervix or vaginal canal. This is often used in conjunction with external radiation for advanced cervical cancer.
1. Chemotherapy [30]

Chemotherapy involves the use of drugs that kill cancer cells or prevent their growth. It is commonly used for more advanced cervical cancers, cancers that have spread (metastasized), or recurrent cancer. Chemotherapy is often given in combination with radiation therapy (chemoradiation) to enhance treatment efficacy.

Common chemotherapy drugs for cervical cancer:

Cisplatin (often used in combination with radiation)
Carboplatin
Paclitaxel
Gemcitabine

Neoadjuvant chemotherapy: Given before surgery to shrink tumors.
Adjuvant chemotherapy: Given after surgery or radiation to reduce the risk of recurrence.
1. Immunotherapy

Immunotherapy is a newer treatment approach that enhances the body's immune system to recognize and fight cancer cells. It is often used for advanced or recurrent cervical cancer.

Checkpoint inhibitors: These drugs block proteins (like PD-1 or PD-L1) that cancer cells use to hide from the immune system. Examples include:

Pembrolizumab (Keytruda)
Cemiplimab (Libtayo)
Atezolizumab (Tecentriq)

Cancer vaccines: While HPV vaccines are primarily used for prevention, therapeutic vaccines are being researched to treat existing cervical cancer by stimulating the immune system to target cancer cells.
1. Targeted Therapy

Targeted therapies are drugs that specifically target molecules involved in the growth and spread of cancer. These therapies are designed to affect cancer cells more precisely while sparing healthy cells. Some examples include:

Bevacizumab (Avastin): A targeted drug that inhibits VEGF (vascular endothelial growth factor), preventing the formation of blood vessels that tumors need to grow. It is used in combination with chemotherapy for recurrent cervical cancer.
PARP inhibitors: Drugs like niraparib (Zejula), which target DNA repair mechanisms, are being investigated for treating cancers with specific genetic mutations (e.g., BRCA mutations).
1. Hormone Therapy

Hormone therapy is not typically used for cervical cancer since it is not hormone-driven like other cancers (e.g., breast or prostate cancer). However, in some rare cases where cervical cancer has spread or recurred, hormonal therapy might be considered if there are estrogen receptors on the cancer cells.

1. Fertility-Sparing Treatment

For young women diagnosed with early-stage cervical cancer who wish to preserve their fertility, there are fertility-sparing options, including:

Trachelectomy (removal of the cervix, while preserving the uterus).
Cone biopsy for early-stage cancers or precancerous lesions.
In some cases, radiation therapy or chemotherapy may be modified to preserve fertility, though this is less common.
1. Palliative Care

For patients with advanced or metastatic cervical cancer, palliative care focuses on alleviating symptoms and improving quality of life. It may include:

Pain management
Managing side effects of treatments (nausea, vomiting, etc.)
Supportive care to address psychological, social, and emotional concerns.

16. RECENTLY APPROVED VACCINE

for the prevention of cervical cancer. If given before sexual maturity, these vaccines can provide up to 90% protection against cervical cancer. These vaccines are:

Gardasil™ (marketed by Merck)
Cervarix™ (marketed by Glaxo Smith Kline)
Cervavac

a. Gardasil [32]

In December 2014, the FDA approved Gardasil 9, which protects against nine strains of HPV.

Gardasil is available as Gardasil which protects against 4 types of HPV (6, 11, 16, 18) and Gardasil 9 which protects against an additional 5 types (31, 33, 45, 52, 58).

Gardasil™ is given at 0, 2, and 6 months. This means after you take the first dose, the next dose needs to be taken after two months and thereafter 6 months.

GARDASIL 9 should be administered intramuscularly in the deltoid region of the upper arm or in the higher anterolateral area of the thigh.

The safety of GARDASIL 9 was evaluated in six clinical studies that included more than 13,000 individuals & it is used in both males and females.

1. 1. Cervarix: [33]

Cervarix™ is given at 0, 1, and 6 months. This means after you take the first dose, the next dose needs to be taken after a month and thereafter 6 months.

Immunization with Cervarix consists of 3 doses of 0.5-mL each, by intramuscular injection according to the following schedule: 0, 1, and 6 months. The preferred site of administration is the deltoid region of the upper arm. Cervarix is available in 0.5-mL single-dose vials and prefilled TIP-LOK syringes. Cervarix is used only in female.

The most common local adverse reactions in patients were pain, redness, fatigue, headache, muscle pain, gastrointestinal symptoms, and joint pain and swelling at the injection site.

Cervarix was voluntarily taken off of the market in the US in 2016 due to low demand.

1. 1. Cervavac :

India's first indigenously developed vaccine to prevent cervical cancer, CERVAVAC, is all set to be available later this year, costing between ?200-400 a shot. CERVAVAC will be effective against at least four variants of Human Papilloma Virus (HPV). While the vaccines must be given to both young boys and girls, chances of getting this cancer are more among women.

Several brands of HPV vaccines are available in India, including Gardasil 9, a nonavalent vaccine priced at approximately Rs 10,000 per dose, Gardasil 4 (quadrivalent) at around Rs 4,000 per dose, and Cervavac, an indigenous quadrivalent vaccine by the Serum Institute of India, priced at about Rs 2,000 per dose. All of these vaccines are safe, with no major side effects reported so far.

RECENTLY APPROVED DRUGS FOR CERVICAL CANCER

The FDA has approved several treatments for cervical cancer in recent years, particularly focusing on immune checkpoint inhibitors and targeted therapies. These treatments are typically used for advanced or recurrent cervical cancer, especially after chemotherapy has failed.

1. 1. Cemiplimab (Libtayo)[34]
FDA Approval Year: 2021
Approval Indication: Cemiplimab is an immune checkpoint inhibitor that targets the PD-1 receptor, a protein on immune cells that cancer cells can use to avoid detection. By blocking PD-1, cemiplimab helps the immune system recognize and attack the cancer cells
Indication: Cemiplimab was approved for the treatment of recurrent or metastatic cervical cancer that has progressed after chemotherapy. It was specifically approved for patients whose tumors express PD-L1, a protein that can be targeted by the drug.

B. Atezolizumab (Tecentriq) [35]

FDA Approval Year: 2020
Approval Indication: Atezolizumab, like cemiplimab, is an immune checkpoint inhibitor targeting PD-L1. It was approved for use in combination with chemotherapy for the treatment of metastatic cervical cancer.
Indication: It is used in patients with PD-L1-positive cervical cancer and is often administered with carboplatin and paclitaxel chemotherapy.

C. Niraparib (Zejula) [36]

FDA Approval Year: 2020
Approval Indication: Niraparib is a PARP inhibitor, which works by blocking a repair mechanism in cancer cells. It is used in patients with recurrent cervical cancer who have certain genetic mutations, like BRCA mutations.
Indication: Niraparib is approved for patients with recurrent cervical cancer who have been previously treated with chemotherapy.

18. CURRENT RESEARCH AREAS FOR THE TREATMENT OF CERVICAL CANCER [37]

a. Immunotherapy

Immunotherapy continues to be a promising area of research for cervical cancer treatment, especially for advanced or recurrent cases. Several immune checkpoint inhibitors, such as pembrolizumab (Keytruda), nivolumab (Opdivo), and cemiplimab (Libtayo), are already in use for treating advanced cervical cancer. Current research is focused on:

Combination therapies: Clinical trials are exploring the combination of immunotherapy with chemotherapy or targeted therapies to enhance the immune response and improve patient outcomes.
Biomarker identification: Studies aim to identify biomarkers that can predict which patients will benefit most from immune checkpoint inhibitors, particularly PD-L1 expression in tumors.

b. Targeted Therapy

Research in targeted therapies is focused on drugs that block specific molecules or pathways driving cervical cancer. Key areas include:

PARP inhibitors: These are being investigated in cervical cancers with specific genetic mutations, such as those in the BRCA genes. Niraparib (Zejula) and other PARP inhibitors may help treat tumors with DNA repair deficiencies.
Angiogenesis inhibitors: These drugs, which block the formation of new blood vessels that tumors need to grow, are being tested in combination with other therapies for advanced cervical cancer. For example, bevacizumab (Avastin) is already approved for use in cervical cancer, and ongoing research is looking at its potential in combination with immunotherapy or chemotherapy.

c. Personalised and Precision Medicine

Advances in genomic profiling are helping to develop more personalized treatment plans. By analyzing the genetic makeup of cervical cancer cells, researchers hope to identify specific mutations that can be targeted with drugs or other therapies. Liquid biopsy technologies, which analyze tumor DNA from blood samples, are also being studied to monitor disease progression and tailor treatments to individual patients.

d. Therapeutic Vaccines

While HPV vaccines are primarily used for prevention, therapeutic vaccines are in development to treat existing cervical cancer. These vaccines aim to stimulate the immune system to recognize and attack HPV-infected cells that have progressed to cancer. Some of these therapeutic vaccines are designed to target specific viral proteins (like E6 and E7) that are present in HPV-driven cancers.

e. Adoptive Cell Therapy (ACT)

Adoptive T-cell therapy, including CAR-T cell therapy, is being explored for cervical cancer. This involves extracting and modifying a patient's immune cells to enhance their ability to target and destroy cancer cells. Although CAR-T therapy has shown success in blood cancers, research is ongoing to adapt this approach for solid tumors like cervical cancer.

Improved Radiotherapy

Advances in radiation techniques are providing more targeted and effective treatments with fewer side effects. Proton therapy and stereotactic body radiation therapy (SBRT) are being researched for cervical cancer, offering the possibility of delivering higher doses of radiation to tumors while minimizing damage to surrounding healthy tissue.

g. HPV Vaccine Development

Researchers are working on new HPV vaccines that target additional strains of the virus, further improving protection against cervical cancer. These vaccines could help reduce the incidence of cervical cancer globally by preventing HPV infection, especially in populations where vaccine uptake is lower.

h. Combination Therapy Approaches

Combinations of chemotherapy, radiotherapy, immunotherapy, and targeted therapies are being explored to improve efficacy. Research is focused on finding the best combinations to treat cervical cancer while minimizing side effects and resistance.[38-42]

CONCLUSION

Cervical cancer remains a significant global health concern, with human papillomavirus (HPV) as the primary cause. While prevention through vaccination has substantially reduced the incidence of cervical cancer, early detection and effective treatment remain crucial for managing the disease, particularly in advanced stages. Recent advancements in cervical cancer treatment, including the approval of novel drugs and vaccines, alongside ongoing research, offer renewed hope for patients and clinicians alike.

In recent years, the approval of immunotherapies such as cemiplimab (Libtayo) and atezolizumab (Tecentriq) marks a significant shift toward immune checkpoint inhibitors as a cornerstone of treatment for advanced, recurrent, or metastatic cervical cancer. These therapies enhance the immune system's ability to target and eliminate cancer cells, especially in tumors expressing PD-L1. Such therapies, either alone or in combination with chemotherapy, have shown promising results, extending survival and improving quality of life for many patients.

The HPV vaccine has revolutionized prevention, significantly reducing the incidence of cervical cancer by targeting the HPV types responsible for the majority of cases. Newer HPV vaccine formulations and expanded coverage to additional strains continue to evolve, offering greater protection and potentially lowering cervical cancer rates globally. Therapeutic vaccines are also under investigation, aiming to treat existing HPV-related cancers by stimulating the immune system to target infected cells, further advancing the promise of personalized cancer immunotherapy.

Ongoing research into targeted therapies, including PARP inhibitors and angiogenesis inhibitors, is providing hope for patients with specific genetic mutations or metastatic disease. These therapies are being explored in combination with other treatments to overcome resistance and increase efficacy. Additionally, the use of genomic profiling and liquid biopsy technologies to personalize treatment is likely to further improve outcomes by identifying patients most likely to respond to particular therapies.

REFERENCES

Arbyn, M., Weider pass, E., Bruni, L., de Sanjos’, S., Saraiya, M., Farley, J., & Bray, F. (2020). Estimates of incidence and mortality of cervical cancer in 2018: a worldwide analysis. The Lancet Global Health, 8(2), e191–e203.https://doi.org/10.1016/S2214-109X(19)30482-6
Bray, F., Ferlay, J., Soerjomataram, I., Siegel, R. L., Torre, L. A., & Jemal, A. (2018). Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries.CA: A Cancer Journal for Clinicians, 68(6), 394–424.https://doi.org/10.3322/caac.21492
Perkins, R. B., Wentzensen, N., Guido, R. S., Schiffman, M., et al. Cervical Cancer Screening: A Review. JAMA, 2023;330(6):547-558.
https://www.researchgate.net/publication/352131920_CERVICAL_CANCER_-An_Overview
Walboomers, J. M. M., Jacobs, M. V., Manos, M. M., et al. (1999). Human papillomavirus is a necessary cause of invasive cervical cancer worldwide. Journal of Pathology, 189(1), 12–19.
Doorbar, J., Egawa, N., Griffin, H., Kranjec, C., & Murakami, I. (2015). Human papillomavirus molecular biology and disease association. Reviews in Medical Virology, 25(S1), 2–23.
Moody, C. A., & Laimins, L. A. (2010). Human papillomavirus oncoproteins: Pathways to transformation. Nature Reviews Cancer, 10(8), 550–560.
Palefsky, J. M. (2003). Human papillomavirus-related disease in people with HIV. Current Opinion in Oncology, 15(5), 386–391.
Moreno, V., Bosch, F. X., Muñoz, N., et al. (2002). Effect of oral contraceptives on risk of cervical cancer in women with human papillomavirus infection: the IARC multicentric case–control study. The Lancet, 359(9312), 1085–1092.
Calleja-Agius, J., Brincat, M. P., & Borg, M. (2014). Genetic susceptibility to cervical cancer. European Journal of Gynaecological Oncology, 35(4), 354–358.
Smith, J. S., Bosetti, C., Muñoz, N., Herrero, R., Bosch, F. X., Eluf-Neto, J., ... & Franceschi, S. (2004). Chlamydia trachomatis and invasive cervical cancer: a pooled analysis of the IARC multicentric case–control study. International Journal of Cancer, 111(3), 431–439.
Garcia-Closas, R., Castellsagué, X., Bosch, X., & González, C. A. (2005). The role of diet and nutrition in cervical carcinogenesis: a review of recent evidence. International Journal of Cancer, 117(4), 629–637.
Zhao, F. H., Lewkowitz, A. K., Hu, S. Y., Chen, F., Li, L. Y., Zhang, Q., ... & Qiao, Y. L. (2012). Risk factors associated with cervical cancer in China: a multicenter case-control study. International Journal of Gynecologic Cancer, 22(5), 830–838.
https://www.cancer.gov/types/cervical/stages
Stanley, M. A. (2012). Epithelial cell responses to infection with human papillomavirus. Clinical Microbiology Reviews, 25(2), 215–222.
Johnson, K. M., Kines, R. C., Roberts, J. N., Lowy, D. R., Schiller, J. T., & Day, P. M. (2009). Role of heparan sulfate in attachment to and infection of the genital mucosa by human papillomaviruses. Journal of Virology, 83(5), 2067–2074.
McBride, A. A. (2013). The papillomavirus E2 proteins. Virology, 445(1-2), 57–79.
Wilson, R., Fehrmann, F., & Laimins, L. A. (2005). Role of the E1^E4 protein in the HPV life cycle. Journal of Virology, 79(10), 6528–6537.
Scheffner, M., Werness, B. A., Huibregtse, J. M., Levine, A. J., & Howley, P. M. (1990). The E6 oncoprotein encoded by human papillomavirus types 16 and 18 promotes the degradation of p53. Cell, 63(6), 1129–1136.
Dyson, N., Howley, P. M., Münger, K., & Harlow, E. (1989). The human papilloma virus-16 E7 oncoprotein is able to bind to the retinoblastoma gene product. Science, 243(4893), 934–937.
Ashrafi, G. H., Haghshenas, M. R., Marchetti, B., O'Brien, P. M., & Campo, M. S. (2005). E5 protein of human papillomavirus type 16 downregulates HLA class I expression and inhibits antigen presentation. Virology, 333(1), 1–7.
Lopez-Beltran, A., Luque, R. J., Quintero, A., Requena, M. J., Montironi, R., & Cheng, L. (2006). Angiogenesis in cervical intraepithelial neoplasia and invasive carcinoma: Correlation with VEGF expression. Histology and Histopathology, 21(8), 867–874.
Bermudez, A., Bhatla, N., & Leung, A. N. (2016). Cervical cancer: Pathology, staging, and imaging considerations. Seminars in Roentgenology, 51(4), 306–315.
Münger, K., & Howley, P. M. (2002). Human papillomavirus immortalization and transformation functions. Virus Research, 89(2), 213–228.
Badal, V., Ghosh, I., Satterwhite, D. J., & Evander, M. (2003). Epigenetic alterations in cervical carcinogenesis. Cancer Letters, 200(1), 1–8. https://doi.org/10.1016/S0304-3835(03)00444-9
Clarke, M. A., Koutsky, L. A., & Wentzensen, N. (2019). DNA methylation as a biomarker for cervical precancer and cancer. International Journal of Cancer, 144(5), 1075–1086.
Li H, Pang Y, Cheng X. Surgery of primary sites for stage IVB cervical cancer patients receiving chemoradiotherapy: a population-based study. J Gynecol Oncol. 2020 Jan;31(1):e8. doi: 10.3802/jgo.2020.31.e8. Epub 2019 Aug 2. PMID: 31788998; PMCID: PMC6918894.
Gupta S, Kumar P, Das BC. HPV: Molecular pathways and targets. Curr Probl Cancer. 2018 Mar-Apr;42(2):161-174. doi: 10.1016/j.currproblcancer.2018.03.003. Epub 2018 Apr 5. PMID: 29706467.
Cohen PA, Jhingran A, Oaknin A, Denny L. Cervical cancer. Lancet. 2019 Jan 12;393(10167):169-182. doi: 10.1016/S0140-6736(18)32470-X. PMID: 30638582.
Johnson CA, James D, Marzan A, Armaos M. Cervical Cancer: An Overview of Pathophysiology and Management. Semin Oncol Nurs. 2019 Apr;35(2):166-174. doi: 10.1016/j.soncn.2019.02.003. Epub 2019 Mar 14. PMID: 30878194.
Mock C, Adjei S, Acheampong F, Deroo L, Simpson K. Occupational injuries in Ghana. Int J Occup Environ Health. 2005 Jul-Sep;11(3):238-45. doi: 10.1179/107735205800246028. PMID: 16130964.
Petrosky, E., Bocchini, J. A., Hariri, S., Chesson, H., Curtis, C. R., Saraiya, M., ... & Markowitz, L. E. (2015). Use of 9-valent human papillomavirus (HPV) vaccine: Updated HPV vaccination recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR. Morbidity and Mortality Weekly Report, 64(11), 300–304.
https://www.sciencedirect.com/science/article/pii/S2666679022000040?via%3Dihub
Harper, D. M., Franco, E. L., Wheeler, C. M., Moscicki, A. B., Romanowski, B., Roteli-Martins, C. M., ... & Dubin, G. (2006). Efficacy of a bivalent L1 virus-like particle vaccine in prevention of infection with human papillomavirus types 16 and 18 in young women: A randomized controlled trial. The Lancet, 364(9447), 1757–1765.
https://www.tandfonline.com/doi/full/10.1080/14712598.2024.2373320#d1e146
https://pmc.ncbi.nlm.nih.gov/articles/PMC11200956/
https://www.sciencedirect.com/science/article/pii/S2666679022000040?via%3Dihub
Badhe, N., Maniyar, S., Kadale, P., Kale, R., Bhagwat, A. and Doke, R.R., Advancements in nanotechnology for glaucoma detection and treatment: A focus on biosensors, IOP monitoring, and nano-drug delivery systems.
Gandhi, B., Bhagwat, A., Matkar, S., Kuchik, A., Wale, T., Kokane, O. and Rode, N., 2025. Formulation and Evaluation of Bilayer Tablets of Atenolol and Amlodipine for the Treatment of Hypertension. Research Journal of Pharmacy and Technology, 18(5), pp.2037-2042.
Bhagwat A, Lokhande A, Pingat M, Doke R, Ghule S. Strategies and Mechanisms for Enhancing Drug Bioavailability through Co-Amorphous Mixtures-A Comprehensive Review. Research Journal of Pharmacy and Technology. 2025;18(1):409-14.
Bhagwat A, Tambe P, Vare P, More S, Nagare S, Shinde A, Doke R. Advances in neurotransmitter detection and modulation: Implications for neurological disorders. IP Int J Comprehensive Adv Pharmacol. 2024;9(4):236-47.
BHAGWAT, Ajay, et al. Development of Nanoparticles for the Novel Anticancer Therapeutic Agents for Acute Myeloid Leukemia. Int J Pharm Sci Nanotechnol, 2023, 16.4: 6894-906.