Cervical Cancer

Abstract

Cervical cancer is a worldwide public health problem. The leading cause of cervical cancer is persistent infection with high-risk human papillomavirus (HPV). Vaccines exist that protect against high-risk HPV types, and screening programs can detect signs of disease at an early stage, allowing for effective treatment and management of the condition. While being one of the most preventable and treatable forms of cancer, the mortality rate is high, especially in low- and middle-income countries. Early diagnoses, proper staging, and a multidisciplinary approach is the cornerstone of disease management. Surgical treatment, radiation therapy, chemotherapy, immune therapy, and supportive and palliative care are all essential parts of the complex treatment. A simple hysterectomy or brachytherapy for early-stage cervical cancer results in a 5-year OS of more than 98%. For selected patients, radical trachelectomy represents a fertility-sparing treatment option. Radiotherapy (RT), with or without cisplatin-based concurrent chemotherapy after radical or modified radical hysterectomy, is recommended for patients with intermediate- or high-risk features. RT, including brachytherapy plus concurrent chemotherapy, is the treatment of choice for patients with locally advanced disease. Irradiation often provides excellent short-term relief of pain and bleeding, particularly in patients with no history of prior RT.

1. Introduction

According to WHO, in 2020, an estimated 604,000 females were diagnosed with cervical cancer worldwide, and about 342,000 females died from the disease [1]. Every year in the United States, about 13,000 new cases of cervical cancer are diagnosed, and about 4000 women die of cervix cancer. Hispanic females have the highest rates of developing cervical cancer, and Black females have the highest rates of dying from cervical cancer [2]. The highest incidences occur in populations with a high prevalence of human papillomavirus (HPV) infection and inadequate screening rates. The mortality rates for cervical cancer range from less than 2 per 100,000 in western Asia, Western Europe, and Australia to more than 20 per 100,000 in central America, Melanesia, and the majority of Africa due to these factors, plus variances in access to effective therapies [3]. Most covariables traditionally associated with an increased risk of cervical cancer appear to be surrogates for sexually transmitted HPV infection. The results of tumor DNA analysis show that practically all squamous or adenocarcinoma of the cervix cases integrate DNA from at least one of multiple high-risk HPV subtypes. HPV16, HPV18, HPV31, HPV33, and HPV45 are high-risk subtypes; the most prevalent are HPV16 and HPV18, which account for around 70% of cervical malignancies. Risk factors for cervix cancer and its intraepithelial precursors include early coitus, multiple sexual partners, and a history of other sexually transmitted infections [4]. Although some researchers have observed a link between cervical cancer with continued oral contraceptive usage, various confounding risk factors and changes in diagnostic criteria make it challenging to demonstrate a causal relationship [5].

2. Anatomy and pathology

The cervix is the lower portion of the uterus that joins the corpus to the vagina (from the Latin collar, “neck”). The exocervix, also referred to as the ectocervix, protrudes into the top vagina and is protected with squamous epithelium. The canal that connects to the endometrial hollow space is the endocervix. It has a single layer of mucinous columnar cells and longitudinal mucosal ridges consisting of fibrovascular cores. The macroscopic intersection of the exocervix and endocervix is known as the external os. The microscopic connection of the mucous and squamous, columnar epithelia is called the squamocolumnar junction. The isthmus also referred to as the decreased uterine phase, is the area between the endocervix and the endometrial hollow space [6].

The transformation sector is the region among the most distal squamocolumnar juncture and the external os. This quarter’s immature squamous epithelium exhibits progressive nuclear maturation and increases the glycogen-loose cytoplasm closer to the surface. Colposcopy has a thin white membrane that thickens and turns white as the squamous epithelium grows. As cells collect glycogen, they become indistinguishable from the typical exocervical squamous epithelium. The transformation zone is where cervical squamous cancers mainly develop [6]. The classification of cervical epithelial alterations according to their histological characteristics differentiates groups of women based on the state of cellular maturation, and the thickness of the affected area in the squamous epithelium is presented in Table 1.

Specimen adequacy; Satisfactory for evaluation (note presence/absence of endocervical/transformation zone component); Unsatisfactory for evaluation … (specify reason). Specimen rejected/not processed (specify reason); Specimen processed and examined, but unsatisfactory for evaluation of epithelial abnormality because of (specify reason); General categorization (optional); Negative for intraepithelial lesion or malignancy epithelial cell abnormality; Other; Interpretation/result; Negative for intraepithelial lesion or malignancy; Organisms; Trichomonas vaginalis; Fungal organisms morphologically consistent with Candida species shift in flora suggestive of bacterial vaginosis; Bacteria morphologically consistent with Actinomyces species cellular changes consistent with herpes simplex virus; Other non-neoplastic findings (optional to report; list not comprehensive); Reactive cellular changes associated with inflammation (includes typical repair) radiation; Intrauterine contraceptive device glandular cells status post hysterectomy atrophy; Epithelial cell abnormalities; Squamous cell; Atypical squamous cells (ASC) of undetermined significance (ASC-US) cannot exclude HSIL (ASC-H); Low-grade squamous intraepithelial lesion (LSIL) encompassing: human papillomavirus/mild dysplasia/cervical intraepithelial neoplasia (CIN) 1; High-grade squamous intraepithelial lesion (HSIL) encompassing: moderate and severe dysplasia, carcinoma in situ; CIN 2 and CIN 3; Squamous cell carcinoma glandular cell; Atypical glandular cells (AGC) (specify endocervical, endometrial, or not otherwise specified); Atypical glandular cells, favor neoplastic (specify endocervical or not otherwise specified); Endocervical adenocarcinoma in situ (AIS) adenocarcinoma; Other (List not comprehensive); Endometrial cells in a woman S40 years of age

Table 1.

The 2001 Bethesda System (Abridged).

The Bethesda system divides cytological specimens into two main groups, low-grade squamous intraepithelial lesions (LSILs) and high-grade squamous intraepithelial lesions (HSILs) [7]. LSILs are characterized by modifications in mature squamous cells (superficial or intermediate) because of HPV, and the morphological modifications are identical to slight dysplasia or low-grade intraepithelial lesion (NIC1). The possibility of growing a high-grade intraepithelial lesion or most cancers over 5 years is 18% [8]. HSILs are characterized by losing the nucleus-to-cytoplasm ratio in the tiniest, maximum juvenile squamous cells (para-basal). This is the primary indicator of the pathology. The presence of NIC2, NIC3, and in situ most cancers in the histological section is all additives of an HSIL analysis in cytology. A NIC2 or NIC3 biopsy is carried out on most patients who have been diagnosed with HSIL [9]. Squamous cell carcinoma is an epithelial invasive tumor constructed from differentiated squamous cells. The Bethesda system does not subdivide squamous cell carcinoma in the same manner as the WHO category system. Keratinizing, non-keratinizing, papillary, basaloid, warty, squamous-transitional, and lymphoepithelial are the classifications used by the WHO (Table 2). This is because morphological developments cannot be outstanding through cytology information. Atypical glandular cells (AHCs) refer to abnormalities in the glandular epithelium that go beyond reactive changes but are insufficient to classify them as adenocarcinoma. The morphological entities that advise this prognosis may be benign or malignant. The benign conditions include endocervical and endometrial polyps, endometriosis, endocervical microcystic hyperplasia, adenosis, lively and lower uterine phase brushings, tubal metaplasia, and Arias-Stella phenomenon. Malignant situations include high-grade intraepithelial lesions with glandular penetration, in situ adenocarcinoma, and invasive adenocarcinoma [10].

Squamous epithelial tumors; Mimics of squamous precursor lesions Squamous metaplasia Atrophy of the uterine cervix Squamous cell tumors and precursors Condyloma acuminatum Squamous intraepithelial lesions of the uterine cervix Squamous cell carcinoma, HPV associated, of the uterine cervix Squamous cell carcinoma, HPV independent, of the uterine cervix Squamous cell carcinoma, NOS of the uterine cervix Glandular tumors and precursors; Benign glandular lesions Endocervical polyp Müllerian papilloma of the uterine cervix Nabothian cyst Tunnel clusters Microglandular hyperplasia Lobular endocervical glandular hyperplasia Diffuse laminar endocervical hyperplasia Mesonephric remnants and hyperplasia Arias Stella reaction of the uterine cervix Endocervicosis of the uterine cervix Tuboendometrioid metaplasia Ectopic prostate tissue Adenocarcinomas Adenocarcinoma in situ, HPV associated, of the uterine cervix Adenocarcinoma, HPV associated, of the uterine cervix Adenocarcinoma in situ, HPV independent, of the uterine cervix Adenocarcinoma, HPV independent, gastric type, of the uterine cervix Adenocarcinoma, HPV independent, clear cell type, of the uterine cervix Adenocarcinoma, HPV independent, mesonephric type, of the uterine cervix Other adenocarcinomas of the uterine cervix Other epithelial tumors Carcinosarcoma of the uterine cervix Adenosquamous and mucoepidermoid carcinomas of the uterine cervix Adenoid basal carcinoma of the uterine cervix Carcinoma of the uterine cervix, unclassifiable Mixed epithelial and mesenchymal tumors Adenomyoma of the uterine cervix Adenosarcoma of the uterine cervix Germ cell tumors Germ cell tumors of the uterine cervix

Table 2.

The World Health Organization classification of tumors cervix, 5th edition (2020).

Other pathological types of cervical cancer include endometrioid adenocarcinoma, clear cell adenocarcinoma, adenosquamous carcinoma, adenoid cystic carcinoma, adenoid basal cell carcinoma, small cell carcinoma, neuroendocrine carcinoma, and undifferentiated carcinoma.

Squamous cell carcinomas arise between 80 and 90% of all cervical cancers. Those designations no longer correspond correctly with analysis, despite the reality that squamous neoplasms are often sub-classified as large-cell keratinizing, huge-cellular no keratinizing, or small-cellular carcinomas [11]. It is estimated that between 10 and 20% of women may develop primary cervical adenocarcinoma throughout their lifetimes, although the incidence of this cancer appears to be on the rise, particularly in younger females [12].

3. Pathways of spread

Most cervical cancers start where the epithelium of the endocervix, frequently columnar, meets the epithelium of the ectocervix, which is especially squamous. As soon as a tumor has broken through the basement membrane, it can either move straight into the cervical stroma or use blood vessels to reach it. Invasive tumors can start as exophytic growths that stick out of the cervix into the vagina or endocervical lesions, which could purpose the cervix to grow very massive, although the ectocervix seems regular. From the cervix, the tumor can spread to the lower part of the uterus, the vagina, the extensive ligaments in which it could block the ureter, or the uterosacral ligaments, also causing blockage of the ureter. During a pelvic exam, massive tumors may additionally seem fixed. However, an actual invasion of the muscle tissues of the pelvic wall is uncommon. Even though there may be a thin layer of fascia and cell connective tissue between the cervix and the bladder, giant bladder involvement is uncommon in less than 5% of instances. The tumor may additionally spread back to the rectum. However, rectal mucosal involvement at the time of diagnosis is rare. The mucosal, muscular, and serosal layers of the cervix are well-drained by three anastomosing plexuses of lymphatics [13]. The cardinal ligament has a supra-ureteral pathway, and the uterosacral ligament has a dorsal pathway toward the rectal pillars. The vesicouterine ligament drains the upper vagina and bladder and has no lymphatic drainage from the cervix [14]. Three major lymphatic collecting trunks leave the uterine isthmus laterally. The upper branches follow the uterine artery from the anterior and lateral cervix, the intermediate branches drain to the deeper hypogastric (obturator) nodes, and the lowest branches drain posteriorly to the inferior and superior gluteal, common iliac, presacral, and subaortic lymph nodes.

Tumor stage, tumor size, histologic subtype, depth of invasion (DOI), and the existence of lymph vascular space invasion (LVSI) are all associated with the risk of pelvic and para-aortic node involvement. Almost all data on regional nodal metastases come from subjects that had lymphadenectomy as part of radical surgeries earlier than radiation therapy, and those numbers can range significantly. Studies have reported a 15–20% positivity rate for pelvic nodes and 1–5% for para-aortic nodes of patients with stage I disease who underwent radical hysterectomy for their treatment. Depending on many factors, including a physical exam and risk factors, the proportion of patients with positive nodes may be higher than 50% in those with more advanced diseases [15].

Hematogenous metastases are infrequent at diagnosis, and two-thirds of relapsed patients had pelvic disease. Relapses often involve distant metastases. Fagundes et al. found 10-year actuarial rates for distant metastases of 16%, 31%, 26%, and 39% for FIGO stages IB, IIA, IIB, and III radiotherapy (RT) patients, respectively [16]. If pelvic sickness is the first website of relapse, a systematic radiological assessment might not be executed, underestimating these. Lung metastases were the most commonplace extra pelvic region. Although the lumbar spine is a not unusual supply of skeletal metastasis, computed tomography (CT) indicates that women who appear to have isolated metastases may additionally rather have direct tumor extension from PA nodal disease [17].

4. Staging

The cervix was the first organ for which The International Federation of Gynecology and Obstetrics (FIGO) established a system for only clinical staging in 1958. Thereafter, to document the presence or absence of nodes and distant metastases, a pathological TNM staging system was developed and implemented. The FIGO Committee of Gynecological Oncology updated the staging system in 2018 so that clinical, radiological, or pathological evidence may be used to designate the stage (Table 3).

Stage	Description
I	The carcinoma is strictly confined to the cervix (extension to the uterine corpus should be disregarded)
IA	Invasive carcinoma that can be diagnosed only by microscopy, with maximum depth of invasion ≤5 mma
IA1	Measured stromal invasion ≤3 mm in depth
IA2	Measured stromal invasion >3 and ≤5 mm in depth
IB	Invasive carcinoma with measured deepest invasion >5 mm (greater than Stage IA); lesion limited to the cervix uteri with size measured by maximum tumor diameterb
IB1	Invasive carcinoma >5 mm depth of stromal invasion and ≤2 cm in greatest dimension
IB2	Invasive carcinoma >2 and ≤4 cm in greatest dimension
IB3	Invasive carcinoma >4 cm in greatest dimension
II	The carcinoma invades beyond the uterus, but has not extended onto the lower third of the vagina or to the pelvic wall
IIA	Involvement limited to the upper two-thirds of the vagina without parametrial involvement
IIA1	Invasive carcinoma ≤4 cm in greatest dimension
IIA2	Invasive carcinoma >4 cm in greatest dimension
IIB	With parametrial involvement but not up to the pelvic wall
III	The carcinoma involves the lower third of the vagina and/or extends to the pelvic wall and/or causes hydronephrosis or nonfunctioning kidney and/or involves pelvic and/or para-aortic lymph nodes
IIIA	The carcinoma involves the lower third of the vagina, with no extension to the pelvic wall
IIIB	Extension to the pelvic wall and/or hydronephrosis or nonfunctioning kidney (unless known to be due to another cause)
IIIC	Involvement of pelvic and/or para-aortic lymph nodes (including micrometastases)c, irrespective of tumor size and extent (with r and p notations)d
IIIC1	Pelvic lymph node metastasis only
IIIC2	Para-aortic lymph node metastasis
IV	The carcinoma has extended beyond the true pelvis or has involved (biopsy proven) the mucosa of the bladder or rectum. A bullous edema, as such, does not permit a case to be allotted to Stage IV
IVA	Spread of the growth to adjacent pelvic organs
IVB	Spread to distant organs

Table 3.

FIGO staging of cancer of the cervix uteri (2018).

^a

Imaging and pathology can be used, where available, to supplement clinical findings with respect to tumor size and extent, in all stages. Pathological findings supersede imaging and clinical findings.

^b

The involvement of vascular/lymphatic spaces should not change the staging. The lateral extent of the lesion is no longer considered.

^c

Isolated tumor cells do not change the stage but their presence should be recorded.

^d

Adding notation of r (imaging) and p (pathology) to indicate the findings that are used to allocate the case to Stage IIIC. For example, if imaging indicates pelvic lymph node metastasis, the stage allocation would be Stage IIIC1r; if confirmed by pathological findings, it would be Stage IIIC1p. The type of imaging modality or pathology technique used should always be documented. When in doubt, the lower staging should be assigned.

Clinical examination and physical evaluation initiate staging. FIGO 2018 staging allows ultrasonography, CT, MRI, and PET to offer further information about tumor size, nodal status, and local or systemic metastasis [18]. MRI is helpful for primary cancers beyond 10 mm. In experienced hands, ultrasonography provides high diagnostic preciseness. For future evaluation, note the staging modality. Imaging can provide new prognostic indicators to assist in choosing the best therapy. PET-CT is more accurate than CT and MRI (4–15% false-negative results) at detecting nodal metastases above 10 mm.

5. Work up

History and physical: Presentation may include postcoital bleeding, irregular or heavy vaginal bleeding, vaginal discharge, and lower back or pelvic pain. It may be asymptomatic and detected during the routine gynecologic examination.

Conduct complete pelvic examination, including bimanual examination and placement of fiducial markers at the caudal extent of vaginal disease. The patient should be positioned in a dorsal lithotomy during the examination. The rectovaginal exam gives information about parametrial extension and infiltration.

Labs: CBC, CMP, and LFTs. Consider HIV testing and pregnancy test.

Procedures/biopsy: Cervical biopsy and cone biopsy as indicated. For advanced stages (stage ≥IB2), consider examination under anesthesia, cystoscopy, and/or proctoscopy as indicated.

Pathology reports should always include information about a stromal invasion, lymph vascular space invasion (LVSI), sizes of the primary tumor, characteristics of margins and distance from the margins, parametrial invasion, number of dissected nodes, and number of positive nodes. The location of positive nodes is also essential, especially when an extranodal extension (ENE) is present.

Imaging: PET/CT. Pelvic MRI with intravaginal water-based gel. Chest imaging with a chest X-ray or CT chest.

6. Treatment

As a result of the fact that those with cervical cancer typically present with a mass that is clinically limited to the pelvis, achieving locoregional disease control is the fundamental obstacle that must be overcome throughout therapy [19]. Patients with an illness limited to a specific area see unprecedented rates of cure after receiving individualized treatment depending on the features of their tumors (Table 4).

Stage (FIGO 2009)	Treatment	5-year OS
IA1 (no lymphovascular space invasion [LVSI])	Extra fascial hysterectomy or modified radical hysterectomy (RH) ➔ evaluate risk factors that may require adjuvant treatment; If fertility-sparing: Conization with negative margins	>98%
IA1 (LVSI+) and IA2	Modified RH + pelvic lymph node dissection (PLND) ➔ evaluate risk factors that may require adjuvant treatment; OR; Pelvic RT + brachytherapy; If fertility sparing: Cone biopsy or radical trachelectomy + PLND	≥95%
IB1/smaller IIA1	RH + PLND ± para-aortic sampling ➔ evaluate risk factors that may require adjuvant treatment; OR pelvic RT + brachytherapy; OR chemoRT (pelvic RT + cisplatin) + brachytherapy; If fertility sparing is desired: Radical trachelectomy + PLND may be considered for IB1	∼90%
IB2/larger IIA1/IIA2	ChemoRT (pelvic RT + cisplatin) + brachytherapy	80–85%
IIB		70–75%
III		∼50%
IVA	ChemoRT (pelvic RT + cisplatin) + brachytherapy; exenteration in selected cases	15–25%
IVB, limited (oligometastatic disease)	ChemoRT (pelvic RT + cisplatin) + brachytherapy ± metastasectomy ±SBRT/SRT/SRS	5–15%
IVB	Chemotherapy; palliative radiotherapy	∼0%

Table 4.

Primary therapy and survival by disease extenta.

Microinvasive cancers invading less than 3 mm (stage IA1) are treated with conservative surgery, including excisional conization or extra fascial hysterectomy. Early-stage invasive tumors, meaning stage IA2 and IB1 and some small stage IIA1, are treated with radical or modified radical hysterectomy, radical trachelectomy (when fertility preservation is needed/desired), or RT. Selected patients with centrally recurring illness following radical dose RT may have radical pelvic exenteration; isolated pelvic recurrence after hysterectomy is often treated with RT.

The standard of care for stage IA1 patients is usually cervical conization or total (Type I) hysterectomy. Because less aggressive tumors have less than a 1% chance of developing pelvic lymph node metastases, pelvic lymph node dissection is often not recommended for patients with these tumors. Lymph node metastases are possible in 5% of patients whose tumors extend 3–5 mm into the stroma (FIGO stage IA2) [20]. For such patients, a modified radical (type II) hysterectomy should be performed along with bilateral pelvic lymphadenectomy. The modified radical hysterectomy is a less invasive surgery than the traditional radical hysterectomy (type III). Patients with stages IA2 to IB1 cervical cancer who have low-risk factors are being considered for potential fertility-sparing surgery. Women treated with radical hysterectomy or radical trachelectomy tend to have comparable outcomes, and a considerable percentage of patients treated with radical trachelectomy report successful pregnancies [21]. Although surgery is the treatment of choice for in situ and microinvasive cancer, people with significant medical conditions or other contraindications to surgery can be effectively treated with radiation therapy. Depending on the depth of invasion, these early lesions are treated with brachytherapy or brachytherapy combined with external RT, with cure rates over 95% [22].

Early-stage IB and IIA cervical carcinomas may be efficaciously handled with a combination of external-beam radiation therapy (EBRT) and brachytherapy or with radical hysterectomy and bilateral pelvic lymphadenectomy. Patients undergoing radical hysterectomy high-risk disease may gain from postoperative RT or chemoradiation [23]. Overall, disease-specific survival rates for individuals with stage IB cervical cancer treated with surgery or radiation are typically in the 80–90% range. The decision of therapy for patients with stage IB1 squamous carcinomas depends primarily on patient desire, risks associated with general anesthesia and surgery, physician preference, and an awareness of the nature and occurrence of problems with hysterectomy and radiation. Some surgeons have also advocated radical hysterectomy as the first line of therapy for individuals with stage IB2 tumors [24, 25]. Then again, patients with tumors larger than 4 cm in diameter usually have enough risk factors to necessitate adjuvant EBRT or chemoradiation, increasing the treatment time and adverse events [23, 26]. As a result, many gynecologic and radiation oncologists claim that patients with stage IB2 carcinomas benefit from chemoradiation, although these two therapies have never been directly compared in a prospective trial.

Radiation therapy is the recommended main local therapy for the vast majority of patients with advanced locoregional cervical cancer. The effectiveness of radiation therapy depends on establishing a delicate balance between external beam radiation therapy and brachytherapy, as well as maximizing the distribution of the radiation dose to both malignant and healthy tissue while decreasing the overall treatment duration. Patients treated with radiation therapy alone for stages IIB, IIIB, and IVA had 5-year survival rates of 65–75%, 35–50%, and 5–15%, respectively [27, 28]. This first treatment can increase the efficacy of later intracavitary brachytherapy by lowering the size of the tumor and bringing it back within the dose distribution of brachytherapy. External irradiation is always combined with concomitant chemotherapy to offer a consistent initial dosage to both the primary cervical cancer and any regional spread locations. The objective underlying brachytherapy, a crucial component of definitive radiation therapy, is to follow the inverse square rule in order to provide a higher dose to the cervix and paracervical regions while limiting damage to nearby normal tissue. If you wish to complete radiation therapy in less than 7–8 weeks, avoiding delays between an external beam surgery and an intracavitary procedure is one of the most crucial things to bear in mind [29].

For the majority of patients with an isolated pelvic recurrence after the first therapy with radical hysterectomy alone, definitive radiation is the preferred treatment. Vaginal recurrence is routinely treated with EBRT and brachytherapy, following the same techniques as for patients with vaginal cancer. Recurrences of pelvic wall cancer are frequently treated with EBRT. Certain patients may benefit from surgery combined with intraoperative radiation for local management. A vaginal recurrence is associated with a more favorable prognosis than a pelvic wall recurrence [30]. An isolated central recurrence of the subsequent radiation can be treated surgically in individuals. Due to the difficulty in assessing the extent of pathology following high-dose radiation and the significant risk of major urinary tract complications associated with pelvic surgery, surgical salvage treatment typically requires a pelvic exenteration, most commonly an anterior or complete exenteration [31, 32]. Less invasive procedures, including radical hysterectomy, are reserved for women with cervical cancer or tumors that do not spread into the rectum. In all situations, pelvic exenteration preparation must include a comprehensive medical and radiological evaluation and meticulous counseling of the patient and family regarding the extent of the treatment and postoperative difficulties. PET/CT scans should be performed to rule out the presence of severe pelvic sidewall involvement or extra pelvic metastases. Cancerous infiltration of the pelvic sidewall is a contraindication to exenteration; however, this may be difficult to determine if there is considerable radiation fibrosis.

Patients with unresectable recurrent cervical cancer who have undergone final radiation therapy have few therapeutic options available to them. However, chemotherapy is administered to the majority of patients with unresectable pelvic recurrences following radiation therapy. This results in relatively low response rates and large death rates.

Patients who present symptoms or experience relapses related to sickness in distant organs typically cannot be cured. The treatment for these individuals should focus on reducing their symptoms as much as possible by using effective painkillers and local RT. Tumors can be treated, although the results of treatment are typically very temporary. Metastases can produce pain in various locations, including the bone, brain, lymph nodes, and other areas. Localized RT can successfully treat this discomfort. Individuals who are toward the end of their lives and have an extended disease may find relief from pelvic pain and bleeding by undergoing a course of palliative pelvic radiation [33].

7. Radiation therapy treatment techniques

For external-beam RT, the use of CT-based treatment planning and conformal blocking is considered the standard of care (EBRT). MRI is the best imaging modality for patients with advanced malignancies for evaluating soft tissue and parametrial involvement. PET imaging is effective in individuals who have not been surgically staged to assist in defining the nodal volume of coverage and may be helpful postoperatively to confirm the excision of suspicious nodes.

To reduce treatment setup errors, CT simulation should be performed with the patient in a supine position and a specialized immobilization device. Patients with cancer covering the distal one-half of the vagina (or vaginal primary) should get bilateral inguinal RT, with CT simulation conducted in the “frog-leg” posture to avoid skin fold toxicity. Scans with a slice thickness of ≤3 mm should be acquired. The bladder and rectal filling level seen during simulation should ideally match that found with daily treatments. Consider two scans for the bladder full and empty to create an internal target volume (ITV). Fuse with MRI/PET imaging (if available) to define tumor extent. Treatment with a full bladder can shift the bowel from the treatment field and enhance bowel dosimetry; however, treatment with an empty bladder may be more repeatable and minimizes the absolute fluctuation in bladder volume. To simulate an empty rectum, bowel preparation with an enema might be employed. Because the patient’s pelvic vasculature acts as a reference for lymph node placement, intravenous contrast simulation is advised unless medically contraindicated. Implantation of fiducial markers prior to CT simulation or placement of radiopaque markers in the vaginal apex and introitus during simulation are two techniques for increasing target volume identification. Using PO contrast could also help delineate a bowel bag. Consider marking the lower portion of pathology if there is a vaginal extension.

In all settings, effort must be taken to encompass all pelvis regions at risk for pathology. EBRT is delivered using multiple conformal fields or intensity-modulated volumetric techniques, such as IMRT/volumetric-modulated arc therapy (VMAT)/tomotherapy. Typically, IMRT is used for most post-operative whole pelvis irradiation or extended field RT when inguinal and/or para-aortal nods are treated. Most ongoing clinical trials only utilize IMRT as the standard of EBRT.

For conformal RT, particularly IMRT, the gross target volume (GTV), clinical target volume (CTV), planning target volume (PTV), organs at risk (OARs), internal organ motion, and dose-volume histogram (DVH) have been established. The volume of EBRT should include the gross disease (if present), the parametria, the uterosacral ligaments, a sufficient vaginal margin from the gross disease (at least 3 cm), the presacral lymph nodes, and any additional at-risk nodal volumes. For patients with negative surgical or radiologic imaging of the lymph nodes, the radiation volume should encompass the whole external iliac, internal iliac, obturator, and presacral nodal basins. For individuals thought to be at a greater risk of lymph node involvement (e.g., bulkier tumors; suspected or confirmed lymph nodes localized to the low true pelvis), the radiation dose should be raised to include the common iliacs. In individuals with common iliac and/or para-aortic nodal involvement, pelvic and para-aortic radiation up to the level of the renal vessels is indicated (or even more cephalad as directed by involved nodal distribution). Patients with below one-third vaginal involvement should also have bilateral groins covered. There have been published international consensus guidelines for target volume contouring [34]. The multi-institutional cooperative group phase III NRG-GY006 clinical trial contouring recommendations derived by Nancy lee and colleagues are presented in Table 5 [35].

Target name	Details
GTV	All visible gross disease as assessed by clinical information, physical examination, radiographic studies, endoscopic examination, and biopsy results
CTV 1	GTV + cervix + uterus
CTV 2	Parametria and upper third of the vagina (or upper half if the vagina is clinically involved)
CTV 3	Common, external iliac, internal iliac, and presacral lymph nodes. The upper border should start the aortic bifurcation (approximately L4–L5 interspace). Presacral nodes should be included to the S2–S3 interspace; below this point this nodal volume can be separated into two structures. External iliac nodes should be included to the top of the femoral heads. If there is distal vaginal involvement, the inguinal nodes should be included (from the external iliac nodes to 2 cm caudal to the saphenous/femoral junction). If para-aortic nodes are involved, an extended field should be used, extending the superior border to the L1/L2 interspace or 3 cm cranial to gross disease. CTV3 should be obtained by placing a 7 mm margin around the vessels with inclusion of any adjacent visible lymph nodes, lymphoceles, or surgical clips. This volume should be modified to exclude bone, muscle, and bowel, and should not extend inferior to the ischial tuberosities
CTV-Boost	Gross pelvic lymph nodes. If the patient will receive a parametrial boost, this area should be included
ITV	If an ITV approach is to be used, CTV1 should be delineated on both the full and empty bladder scans and combined to generate the ITV
CTV_4500 or CTV_4760	CTV1 + CTV2 + CTV3 + ITV
PTV1	CTV1 + 15 mm uniform expansion
PTV2	CTV2 + 10 mm uniform expansion
PTV3	CTV3 + 5 mm uniform expansion
PTV4	ITV + 7 mm uniform expansion
PTV_boost	CTV_boost +5 mm uniform expansion
PTV_4500 or PTV_4760	PTV1 + PTV2 + PTV3 + PTV4 + PTV_boost.; This should be trimmed up to 3 mm from the skin surface, if necessary, to spare skin. The CTV should be fully encompassed by the PTV

Table 5.

Target delineation for cervical cancer (per NRG-GY006 protocol).

For patients with primary cervical cancer who are not candidates for surgery, brachytherapy is a key component of the ultimate treatment plan that they will follow. In this case, either an intracavitary or an interstitial approach will do the trick. GEC-ESTRO recommendations are available for volume-based brachytherapy contouring, and they recommend utilizing CT or MRI to delineate treatment targets [36]. A high-risk MRI-based CTV is defined as the whole cervix in addition to any parametrial or vaginal extension (gray zones). CT-based CTV (high-risk): all central tissue at the level of ring or ovoids, superiorly to internal os, then 1 cm “cone” along tandem above cervix; laterally, include any parametrial extension (gray/white) or clinical vaginal involvement. CT-based CTV (low-risk): all central tissue at the level of ring or ovoids, superiorly to internal os. There are two-point definitions for point-based dosage in brachytherapy: ICRU 38 and 2011 ABS point. Point A is located at the point where the tandem meets the line that connects the peaks of the ovoids or the ring; it is situated 2 cms above and 2 cms to the side of the tandem (point B 5 cm lateral to the tandem). The bladder point is the posterior position of the midfoley balloon after it has been inflated with 7 ml of fluid. The rectal point is located 5 mm posterior to the vaginal wall at the lower intrauterine source. The surface of ovoids or cylinders that make up the vaginal cavity.

In patients with an intact cervix, the original tumor and susceptible regional lymphatics are routinely treated with 45 Gy of definitive EBRT (40–50 Gy). The dose of EBRT would be proportional to the nodal status as assessed by surgery or imaging. The primary cervical tumor is then boosted employing brachytherapy with an additional 30–40 Gy using image guidance (preferred) or to point A (in low dose-rate [LDR] equivalent dose), for a total point A dose of 80 Gy for small-volume cervical tumors or 85 Gy for larger-volume cervical tumors. For highly tiny tumors (clinically inoperable IA1 or IA2), 75–80 Gy EQD2 D90 dosages may be explored. Grossly affected, unresected lymph nodes may be boosted with an additional 10–15 Gy of highly conformal EBRT. When employing imaging guidance for EBRT, care must be made to exclude or severely restrict the amount of normal tissue inside the high-dose zones (Tables 6–8).

Source	External beam organ	Type	Volume/dose
QUANTEC	Bowel bag	Vol (mL)	≤195 cc above 45 Gy
Institutional Series	Duodenum	Vol (mL)	<5–15 cc above 55 Gy
RTOG	Femoral heads	Vol (%)	<15% above 30 Gy; <50% above 30 Gy
GEC-ESTRO	Femoral heads	Dose max	50 Gy

Table 6.

GYN tissue tolerances.

Source	External beam organ	Type	Volume/dose
TIME-C	Bowel bag	Vol (%)	Goal <30% above 40 Gy
TIME-C	Bladder	Vol (%)	Goal <35% above 45 Gy
TIME-C	Bone marrow	Vol (%)	Goal <90% receives 10 Gy
TIME-C	Bone marrow	Vol (%)	Goal <37% receives 40 Gy
TIME-C	Rectum	Vol (%)	Goal <80% above 40 Gy

Table 7.

Post-hysterectomy dose constraints.

Source	Organ	Type	Volume/dose
GEC-ESTRO	Rectum	Vol (mL)	<2 cc above 65 Gy total EQD23 (limit 75 Gy)
GEC-ESTRO	Sigmoid	Vol (mL)	<2 cc above 70 Gy total EQD23 (limit 75 Gy)
GEC-ESTRO	Bladder	Vol (mL)	<2 cc above 80 Gy total EQD23 (limit 90 Gy)
GEC-ESTRO	Bowel	Vol (mL)	<2 cc above 70 Gy total EQD23 (limit 75 Gy)
GEC-ESTRO	Recto-vaginal point	Vol (mL)	<2 cc above 65 Gy total EQD23 (limit 75 Gy)
GECESTRO (vaginal cancer)	Vaginal surface	Dose max	<130 Gy total EQD23 (limit 140 Gy)

Table 8.

Brachytherapy for cervical cancer dose constraints.

The presence of one or more pathologic risk factors following a prior hysterectomy may justify the use of adjuvant RT. The following should be covered at a minimum: the top 3–4 cms of the vaginal cuff, the parametria, and surrounding nodal regions (such as the external and internal iliac, obturator, and presacral nodes). The radiation field’s superior edge should be increased accordingly for confirmed nodal metastases. In general, 45–50 Gy in conventional fractionation is advised for IMRT. Four grossly affected, unresected lymph nodes may be considered for boosting with an extra 10–20 Gy of highly conformal EBRT.

In exceptional cases, patients whose anatomy or tumor geometry makes intracavitary brachytherapy impossible may be effectively treated with an interstitial approach; however, such interstitial brachytherapy should be accomplished only by individuals and institutions with the required knowledge and training, and early referral for prompt use of own knowledge and experience is essential. In certain post-hysterectomy patients (particularly those with positive or near vaginal mucosal surgical margins), vaginal cylinder brachytherapy may be utilized as an adjunct to external beam radiation treatment (EBRT). Typically, the prescription is applied to the vaginal surface or 5 mm below it. Typical fractionation strategies include 5.5 Gy 2 fractions at 5 mm or 6 Gy 3 fractions at the vaginal surface.

SBRT is the most certain technique among all EBRT modalities in terms of its ability to simulate a brachytherapy dose distribution with a steep dose gradient and, as a result, achieve the same treatment outcomes as ICB, at least theoretically. Although being under investigation and recommended by few retrospective reviews, SBRT is not regarded as a reasonable alternative to brachytherapy for routine use.

8. Post-radiation toxicity and complications

In the scientific literature, the terms “acute toxicity” and “late toxicity” are defined in a variety of ways. In certain contexts, the term “acute toxicity” refers to the development of unfavorable consequences that take place both during the course of treatment and up to 42, 60, or 90 days following the completion of radiation therapy. Late toxicity is when an impact does not show up for 90 days or even years after it has been exposed to something. Although complications are reported to be slightly higher (10–15%) in patients with the locally progressed disease, the incidence of late sequelae in individuals with early-stage cervical cancer treated with RT is approximately 3.5%. However, complications are reported to be slightly higher in patients with more advanced diseases. The logic for this variance is straightforward: as the clinical stage of a patient continues to advance, the total dosage to central structures has a tendency to increase (e.g., 85–90 Gy are administered to the cervix in clinical stage III and IV patients). We can conclude that the risk of problems is related to the clinical stage, the volume of tissue being treated, the patient’s anatomy, and the total dosage supplied to certain tissues [37].

Mild tiredness and mild to moderate diarrhea are common side effects of pelvic radiation but may be managed with antidiarrheal drugs. Some patients may also have mild bladder discomfort, which can be a sign of a urinary tract infection. Patients receiving treatment with extended fields may experience nausea, stomach discomfort, and a reduction in peripheral blood cell counts. Concurrent chemotherapy considerably increases the risk of hematologic and gastrointestinal problems. The most prevalent sexual problems after irradiation are ovarian insufficiency in premenopausal women and vaginal stenosis in vaginal radiation patients. Vaginal stenosis is a tightening or narrowing of the vaginal canal that can interfere with a physical exam or sexual function. Its prevalence ranges from 20 to 88% [38]. Ovarian failure occurs in all premenopausal individuals treated with pelvic radiation unless the ovaries have been transferred. Uterine perforation, fever, and the common complications associated with anesthesia are all possible side effects of intracavitary brachytherapy. Thromboembolic events are uncommon.

Estimates of the risk of late sequelae from radical radiation vary depending on the grading system, length of follow-up, calculation method, treatment approach, and prevalence of risk variables in the study group. Complication rates in individuals with extremely locally advanced pathologies may be greater due in part to tissue loss induced by infiltrative malignancy. Rectal complications are most frequent in the first 3 years after therapy and include bleeding, stricture, ulceration, and fistula. Small intestinal obstruction is a rare consequence of conventional radiation in patients with no additional risk factors. Patients with open transperitoneal lymph node dissection have a considerably higher risk of small intestinal blockage. A history of pelvic inflammatory disease or peritonitis, thin body habitus, heavy smoking, and the use of high doses or large volumes for external-beam irradiation, particularly with low-energy treatment beams and large daily fraction sizes, can all increase the risk of small bowel complications in patients treated for cervical cancer [37].

High doses of radiation can produce persistent myelosuppressive effects and a lower tolerance to the effects of chemotherapy. These effects are caused when the microenvironment of the bone marrow is altered. Prospective analyses indicated a 25% prevalence of hematological damage >G3 when cisplatin-based chemoradiotherapy was utilized. Irradiating an expanded field that encompasses the para-aortic lymph node covering leads to greater irradiation of total bone marrow and, as a result, a higher incidence of hematological damage. This outcome must be examined and managed since it predisposes patients to infections, repeated hospitalizations, multiple transfusions, and delays in obtaining therapy [39, 40]. Loren K Mell reported about bone marrow-sparing IMRT in 2008. The report concluded that BMS-IMRT reduced the irradiation of pelvic bone marrow compared with the four-field box technique [41]. In order to find the most effective method to lessen the hematological toxicity associated with concurrent chemoradiotherapy (cCRT) for cervical cancer, De-Yang Yu and his colleagues set out to investigate the dosimetric characteristics of a variety of bone marrow-sparing strategies and radiation technologies in 2020. Their ultimate goal was to identify the most effective method. The scientists came to the conclusion that the IMRT plan that achieved the best sparing while still giving enough coverage of the target volume was the one that excluded the bone marrow from the radiation treatment and treated the pelvic bones with discrete dose-volume limitations. In addition, among all of the more recent radiation treatment systems, the VMAT has shown itself to be the most successful in terms of preserving bone marrow while still providing overall efficacy. Patients with cervical cancer might benefit from this treatment technique since it can potentially lessen the hematological toxicity they experience. By using this method, we are able to increase the effectiveness of radiation and reduce the need for expensive functional imaging of active bone marrow [42].

9. Ongoing clinical trials and future perspectives

On October 2021, the highly anticipated KEYNOTE-826 trial confirmed that there was a survival benefit of adding immunotherapy in the form of a drug called Pembrolizumab to chemotherapy for patients with persistent, recurrent, or metastatic cancer. The KEYNOTE-A18 trial is an ENGOT (European Network for Gynecological Oncological Trial groups) and GOG partners collaboration. It is a randomized phase 3 trial with chemoradiotherapy with or without pembrolizumab for high-risk locally advanced cervical cancer. And 980 patients are anticipated to receive pembrolizumab on day 1 of a 3-week cycle for 5 cycles, followed by pembrolizumab on day 1 of a 6-week cycle for 15 cycles. The primary outcome is progression-free survival (PFS) and overall survival (OS) [43]. Dr. Tewari is researching high-risk individuals, patients with stage IIIB or IIIC positive lymph nodes, or even aortic nodes, and has randomized them to chemotherapy, radiation, placebo versus durvalumab, added both in the radiation phase and the maintenance phase for up to 24 months. This study is known as CALLA, and it is enrolled. There are 714 subjects listed on clinicaltrials.gov, and the trial has been closed since December 2020 [44].

In addition, the currently approved therapies for cervical cancer are accompanied by debilitating side effects and tumor drug resistance. This is the case despite significant breakthroughs in the utilization of combination medicines. To increase the efficacy of single-agent therapies for cervical cancer, there is a pressing need to discover new and better medications. Immunotherapy, targeted therapy, and genetic methods such as CRISPR/Cas9 and RNAi are among the various cervical cancer therapies now under investigation. These are only a few instances of the treatment options available. Chemotherapy and radiation therapy are other treatment choices to explore. The majority of these therapies are still in the research phase, and the alternatives they provide are more costly. Identification of non-cancer medicines that target host factors that, in conjunction with HPV oncoproteins, notably E6 and E7, promote cervical cancer progression is one method that may lead to timely medication development at an acceptable and cheap price. This strategy, which combines a targeted approach with medication redirection, is appealing because it should find pharmaceuticals with far fewer adverse effects than conventional cancer therapies. This makes the idea more appealing. Due to the extensive study of their safety profiles, it is anticipated that they will enter clinical trials quickly [45].

Acknowledgments

I want to thank the people working at EVEX hospitals-Krystyna Kiel Oncology Center for their encouragement and advice that led to the completion of this paper. I also thank my friends for their encouragement and words of advice. Special thanks to my mentor—Krystyna Kiel. Finally, if not for my family, who supports me all the time, I would never be able to work on this extraordinary project.

Conflict of interest

The author declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article. This research did not receive a specific grant from funding agencies in the public, commercial, or not-for-profit sectors.