Continuing Education Activity

Cervical cancer is the fourth most common cancer among women worldwide. Primary prevention and screening are by far the most effective modalities for decreasing the healthcare burden and mortality attributable to cervical cancer. In the United States and other developing countries, most screening and diagnostic efforts are directed towards early identification of high-risk human papillomavirus (HPV) lesions through HPV testing and pap smears. Interprofessional team members must recognize that cervical cancer is a preventable disease. It is largely preventable even in women who are sexually active if they receive early human papillomavirus (HPV) vaccination. The potential opportunity for prevention of cervical cancer via early HPV vaccination is one that interprofessional team members and their patients cannot afford to miss. Since 2006, HPV vaccination has been available for the prevention of cervical cancer. Interprofessional team members have a moral obligation to educate their young female patients about this the opportunity to prevent cervical cancer. The potential opportunity for prevention of cervical cancer via early HPV vaccination is one that interprofessional team members and their patients cannot afford to miss. This activity reviews the evaluation and management of cervical cancer and highlights the role of the interprofessional team in providing HPV vaccination to women of childbearing age so that these women will not develop what currently stands as the 4th most common cancer in females worldwide.

Objectives:

• Describe the risk factors for developing cervical cancer.
• Explain the pathophysiology of cervical cancer.
• Describe the evaluation of a patient with cervical cancer.
• Explain the importance of improving coordination amongst the interprofessional team to encourage prevention and enhance care and improve outcomes for patients affected by cervical cancer.

Introduction

Cervical cancer continues to be listed among the top gynecologic cancers worldwide. According to current data, it is ranked fourteenth among all cancers and fourth-ranked cancer among women worldwide.[1] Cervical cancer intervention focuses on primary and secondary prevention. [2] Primary prevention and screening is the best method to decrease the burden of cervical cancer and to decrease mortality. In the United States and other developing countries, most screening and diagnostic efforts are directed toward early identification of high-risk human papillomavirus (HPV) lesions through HPV testing and Pap smears. Although HPV testing is not recommended in women younger than 30 years of age, low-risk younger women should begin screening with Pap tests at age 21 and continue until age 65, according to the United States Preventive Services Task Force recommendations. Newer recommendations offer 3 to 5-year intervals between screening based on prior results and the use of pap and HPV co-testing. [3][4] Since cervical cancer is a sexually transmitted infection, it is a preventable disease. Targeted education, screening, and intervention can reduce the burden of disease.

Like many diseases and cancers, disparities exist in screening rates, early diagnosis, and timely treatment. Screening rates tend to be less in low socioeconomic and low-resource areas with ethnic and age variations. Studies show that women with obesity and chronic disease may also have lower rates of cervical and breast cancer screening. A study on ethnic minority women in the United Kingdom reports several barriers to screening including lack of awareness, fear, embarrassment, and shame, and low perceived risk.[5] One study reviewing the barriers for Haitian women revealed socioeconomic barriers, language barriers, and a limited understanding of health and disease. [6]  In the United States, cervical cancer mortality is disproportionately higher for African American women. Since 2006, vaccination has been available for the prevention of cervical cancer. Vaccination can improve cancer death rates in underdeveloped countries where resources may not be available for routine screening and in populations with higher mortality rates.

Etiology

Current literature reports that Human papillomavirus (HPV) is found in the majority of sexually active people at some point during their life. There are more than 130 types of known HPV with 20 HPV types identified as cancer-related. HPV-related cervical dysplasia rates are only known in women since men are not screened outside of research protocols. HPV 16 and 18 are the most commonly found HPV in invasive cervical cancer. Population-based HPV prevalence studies show that the greatest prevalence of high-risk HPV occurs in the young adult period before 25 years of life and cervical cancer death peaks in the middle age period of 40 to 50 years of life. Studies have shown that HPV-related cervical disease in women younger than 25 years old is largely self-limiting. However, those with co-infection may be less likely to have spontaneous clearance and progress to cancer. Risks factors for HPV and cervical cancer include age at first intercourse, multiple sexual partners, smoking, herpes simplex, HIV, co-infection with other genital infections, and oral contraceptive use. HPV is transmitted by skin to skin contact including during sexual intercourse, hand to genital organ contact, and oral sex.[7][8]

Epidemiology

Globally, there are more than 500,000 new cases of cervical cancer annually. Approximately 250,000 women die of cervical cancer annually.  In the United States, about 4000 women die from cervical cancer annually with African Americans, Hispanics, and women in low-resource areas having higher disparities in evidenced-based care and a much higher mortality rate.[9][10]HPV, the causative agent is a sexually transmitted viral infection. Cervical cancer mortality is higher among women who have not been screened in the last five years and those women without consistent follow-up post identification of a precancerous lesion. Trends continue to show that women with the highest risk of mortality may be less likely to receive a vaccination that could potentially prevent cervical cancer.

Pathophysiology

HPV is the causative agent in cervical cancer. More than 75 percent of cases are due to high-risk HPV 16 and 18.[11] Although there are more than a half-million cases of HPV identified annually, most are low-grade infections and will spontaneously resolve within two years. Progression of high-grade lesions and cancer are seen in the presence of other carcinogenic factors such as listed above.

History and Physical

Patients with cervical cancer is usually asymptomatic in the early stages. The history and physical must include sexual history including the age of first sexual encounter. Sexual history includes questions about postcoital bleeding and pain during intercourse. The history includes questioning about previous sexually transmitted infections, the number of lifetime partners, previous history of HPV infection, history of human immunodeficiency virus, use of tobacco, and whether the patient has had a previous vaccination against HPV. Women should be asked about menstrual patterns and any abnormal bleeding, persistent vaginal discharges, irritations, or known cervical lesions. The physical exam must include a full evaluation of the external and internal genitalia. In women with cervical cancer, the exam findings might include a friable cervix, lesions, erosions, or bleeding with examination and fixed adnexa.

Evaluation

According to the United States Preventative Services Task Force (USPTF), Pap screening is recommended beginning at age 21 years of age. HPV testing begins at age 30 in conjunction with Pap smear cytology. Screening is recommended every three years for women with continued normal screening and those low risk for cervical cancer. For women over 30 years of age, cytology can be every five years with HPV testing. Level A recommendation for women with low-risk status and consistent normal screenings can discontinue cervical cancer cytology and HPV testing at age 65. Women who have had a total abdominal hysterectomy including removal of the cervix for benign disease do not require further screening.[4]

Patients that have been diagnosed with invasive disease require a comprehensive staging workup. The International Federation of Gynecology and Obstetrics (FIGO) staging system allows for several methods to stage a patient. Classically, this was based on the local extent of the tumor which could be determined with a combination of pelvic examination, cystoscopy, proctoscopy, chest x-ray, and/or intravenous urography in addition to basic labs (CBC, CMP, etc). More recently, advanced imaging modalities were allowed for staging such as MRI and PET scans. A pelvic MRI is excellent for detecting local tumor extension. It can also be used for gauging tumor response. PET scans are more sensitive than CT for the detection of nodal and visceral metastasis. This is critical as the presence of nodal disease can greatly influence the prognosis.

Treatment / Management

Precancerous lesions are managed conservatively for those women younger than 25 years. The majority of abnormal findings in women younger than 25 are low-risk cervical dysplasia and will resolve spontaneously. Colposcopy evaluates persistent, abnormal cytology or lesions suspected to be greater than low risk. These are managed according to findings. Low-risk lesions may be watched and reevaluated more frequently, and high-risk lesions are treated based on size, location, and staging. Cryotherapy or excision is done to manage pre-cancerous lesions that are limited in size and depth. Conization, laser, or Loop Electrosurgical Excision Procedure (LEEP) are used in managing those lesions that include the endocervical canal and are more extensive. LEEP may provide better visualization of the squamocolumnar junction and provide the benefit of less bleeding in the outpatient setting. [12]

If invasive cancer is diagnosed, the next step in management is staging to determine further treatment. Staging is based on findings and results from examination, tissue findings, imaging, and reported signs and symptoms. Grading is based on the size and depth of cancer and signs of spread to other organs. Treatment of early-stage disease is typically surgical resection which can range from a conization to a modified radical hysterectomy. However, women with high risk features post-resection may require adjuvant treatment with chemotherapy and radiation. For women who desire pregnancy with early-stage disease, conization or trachelectomy may be an option. For more advanced disease, concurrent chemoradiation is the standard of care.

Differential Diagnosis

Evaluating visible cervical lesions for cervical cancer is important. However, most cervical cancer will not present with an overt mass in early stages and as discussed above is asymptomatic. Other possible causes of cervical lesions or abnormal bleeding include sexually transmitted infections, cervical fibroids, endometriosis, and cervical polyps. Diagnosis may require further testing and evaluation of symptoms to determine whether the disease is related to cervical cancer. In some cases, diagnostic biopsy is needed to finalize the diagnosis. Rarely, metastatic cancer may be identified on the uterine cervix during a routine pap smear.[13]

Surgical Oncology

Surgery – Cervical Cancer

Surgical resection is typically offered to patients with early-stage disease that is confined to the cervix. It can range from relatively noninvasive techniques such as cervical conization to radical hysterectomy. Surgery is the preferred treatment modality for early-stage cervical cancers, especially in younger patients where preservation of ovarian function and/or fertility is desired.

Types of Surgery

Cervical Conization

Cervical conization is typically indicated in patients with carcinoma in situ (CIS) disease or Stage IA1 invasive cervical cancer. It can be accomplished with a cold knife cone (CKC) which removes the transformation zone and a portion of the cervix with at least a 3mm margin. A scalpel or laser may be used for this procedure. Pathologic evaluation of the margins and the presence of lymphovascular invasion (LVI) is critical. If either of these features are present, then additional re-excision or more invasive surgical treatment may be required. If no LVI exists on the specimen, lymph node involvement is exceedingly rare, and therefore nodal evaluation is unnecessary. Patients without any adverse pathologic findings may be observed. Recurrence rates are typically <10% but they must be followed closely with periodic colposcopy and cytology. Five-year survival rates exceed 95%. Complications include hemorrhage, infection, infertility, cervical incompetence, and stenosis. The rate of complication ranges from 2-12%.[14][15]

Radical Trachelectomy

Patients that are not candidates for conization due to adverse pathological features or more advanced disease but who desire fertility preservation can undergo a radical trachelectomy. The procedure consists of the removal of the majority of the cervix, resection of the parametria, and mobilization of the ureters, bladder, and rectum. A 5mm section of the cervix is preserved to allow for the placement of a cerclage to allow for future pregnancy. A lymph node evaluation with either a sentinel node biopsy or pelvic lymphadenectomy typically accompanies a radical trachelectomy due to the increased risk of nodal involvement. Adverse pathologic features such as positive margins, parametria involvement, and/or lymph node involvement or meeting Sedlis criteria would necessitate adjuvant treatment with radiotherapy with or without chemotherapy. A vaginal approach or laparotomy can be used but there is a lack of data on minimally invasive techniques. The 5-year recurrence rate is approximately 5% and an overall survival rate of 97%.[16] The pregnancy rate post-procedure is 24% with a live birth occurring in 75% of patients.[16] Complications include cervical sutures problems, dysmenorrhea, isthmic stenosis, and vaginal discharge.

Extrafascial hysterectomy

Extrafascial hysterectomies, also known as Type A radical hysterectomies, have a narrow range of clinical indications.[17] Typically it is offered to patients with Stage IA1 disease who are not interested in fertility preservation. It involves the removal of the entire cervix and uterus. Ovarian function can be preserved as their removal is optional with this procedure. The parametria are not resected. A vaginal approach or laparotomy may be used.  Lymph node evaluations are typically not performed unless adverse pathologic features are discovered post-operatively. If patients are found to have adverse pathologic features, they may require a completion parametrectomy or external beam radiotherapy with or without chemotherapy.

Radical Hysterectomy

A Radical hysterectomy may be considered in almost all cases of early-stage cervical cancer when fertility preservation is not a priority. The older Piver-Rutledge-Smith classification has been replaced by the Querleu-Morrow system, which simplified the classification process based solely on the extent of lateral parametria resection.[18] Four types of radical hysterectomy are described from Type A – D. Type A represents only a minimal parametrial resection while Type D represents resections of the paracervix to the pelvic sidewall. The most commonly performed radical hysterectomies fall in the Type B and C categories which differ in the transection of the paracervix at the level of the ureter or internal iliac vessels respectively.[18] Minimally invasive approaches have been shown to provide inferior oncologic outcomes compared to more established open approaches in terms of disease-free (91.2% vs 97.1%) and overall survival (93.8 vs 99%) with the majority of patients having Stage IB1 disease.[19] Complications include hemorrhage, infection, venous thromboembolism, pulmonary embolus, small bowel obstruction, vesicovaginal fistula, hydronephrosis, ureteral injury, stress incontinence, and lower extremity edema.

Lymph node evaluation

The detection of lymph node involvement is essential as it yields important prognostic information and guides therapeutic decision-making. The decision to evaluate the lymph nodes should be guided by the risk of nodal involvement which is a function of the stage ( See Table Below). PA nodal risk is typically ½ the pelvic nodal risk by stage. While pelvic lymphadenectomies are considered the gold standard, sentinel node biopsies may also be pursued for selected early Stage I cervical cancer. Sentinel node biopsies are safe and feasible. They have been investigated in Stage IA1-IIA1 patients with a sensitivity of 92% and a 98.2% negative predictive value with less lymphatic morbidity and no differences in recurrence-free survival.[20][21] The sentinel node biopsy approach continues to be investigated in large-scale international trials in SENTICOL III (NCT03386734).

Recurrent Disease

Pelvic Exenteration

Pelvic exenteration is the most radical surgical procedure for cervical cancer. Indications are confined to patients with central pelvic recurrence after radiotherapy or Stage IVA patients that cannot receive radiotherapy. Classically, a total pelvic exenteration includes the removal of the uterus, fallopian tubes, ovaries, vagina, bladder, urethra, and rectum. Reconstruction consists of a double-barrel wet colostomy, ilial conduit, or continent diversion for the urinary system and a double-barrel wet colostomy or end colostomy for the GI system. Formation of a neovagina can be accomplished with a myocutaneuous flap or split-thickness skin graft with an omental J-flap. Variations of this technique include anterior and posterior exenteration which spare the rectum or the bladder respectively. Exenteration can be further classified into supra and infralevator depending on whether the urogenital diaphragm and levator muscles are removed. The posterior supralevator exenteration approach allows for the possibility of maintaining not only urinary function but fecal continence if a colonic anastomosis can be formed. The five-year survival rate for patients treated with exenteration range from 40-50% in the recurrent setting.[22][23] Local recurrence rates at 3 and 5 years are 84% and 75% respectively.[22] Survival is not impacted by the type of exenteration performed.[24] Mortality from the operation has fallen dramatically over the last 70 years to less than 5% but with surgical morbidity greater than 50%.[22] Early complications include abscess formation, fistulas, urinary leakage, peritonitis, stoma necrosis, flap necrosis, and stump dehiscence. Late complications include stoma stenosis, incontinence, hydronephrosis, stone formation, and abdominal wall hernia.

Cervical Cancer in Pregnancy

Cervical cancer is one of the most common malignancies discovered in pregnancy. The treatment of cervical cancer in pregnant patients has unique challenges in terms of staging and treatment. Regardless of their decision, patients should be evaluated by a maternal-fetal medicine specialist to aid discussion of risks to the fetus and potential pregnancy loss. Women must weigh the risk of delaying treatment until delivery or proceeding immediately.

The determination of gestational age is crucial. Minimum fetal viability is approximately 24 weeks gestation but there is a significant risk of neonatal death and long-term disability in those that survive. Disability-free survival at 25 years increases substantially with more advanced gestational age with 4% of infants born at 22 weeks versus 78% for those born at 28 weeks gestation.[25] For reference, full-term infants have a disability-free survival of 97%.[25]

While the radiation delivered during a PET/CT scan remains far below the threshold for the development of birth defects and loss of pregnancy, the use of ionizing radiation in imaging studies should be kept to a minimum in this population.[26] When appropriate, other imaging modalities such as ultrasound and MRI are preferred to determine local tumor extent and distant metastatic involvement. However, MRI and ultrasound have a low sensitivity for small nodal metastasis.

More invasive staging techniques may need to be employed. In patients with a high risk of nodal metastasis, laparoscopic pelvic lymphadenectomy may be used in select patients to establish the stage. [27] The safety of this procedure has only been studied in limited case series but can be performed in any trimester however earlier gestational age would be preferred. These techniques may still be employed in some circumstances where advanced imaging is not available or is contraindicated. In addition, the FIGO staging system continues to allow the use of proctosigmoidoscopy and cystoscopy for local staging of cervical cancer (FIGO System).

Treatment strategies must be individualized and discussed in a multidisciplinary fashion with medical oncology, radiation oncology, OB-GYN, maternal-fetal medicine, and gynecologic oncology. In patients that wish to preserve their pregnancy and be treated, both the gestational age and the stage should first be established. In general, radiotherapy is contraindicated as the dose of ionizing radiation received will invariably lead to fetal demise or severe birth defects. While treatment approaches may vary, in general, those with gestational ages <22 weeks and Stage IA1 disease can be treated with conization but this carries a 15% risk of significant bleeding and spontaneous abortion. Gestational ages >22 weeks may be able to delay treatment until delivery if they have early-stage disease. Patients with more advanced disease (>IB1) may receive platinum-based neoadjuvant chemotherapy (cisplatin/paclitaxel) until delivery followed by surgical resection. Limited data suggests this is a safe regimen for both mother and fetus.[28] Small series indicate approximately a 75% tumor response rate with 15% of patients experiencing a local recurrence. The risk of fetal toxicity with these regimens is unknown but may include respiratory distress syndrome, malformations, and childhood malignancies.[28]  

Immediate treatment is recommended in cases of documented lymph node metastasis, progression of the disease, or if the patient decides to terminate the pregnancy.

If the patient decides to terminate the pregnancy before treatment, then definitive treatment recommendations are the same as those of a non-pregnant patient.

Radiation Oncology

Introduction

Radiotherapy remains a crucial component in the treatment of cervical cancer. Randomized evidence from the 1990’s and early 2000’s has established radiotherapy in almost every facet of treatment. It may be utilized as a definitive or adjuvant treatment with or without platinum-based chemotherapy.

Definitive Radiotherapy

Early Stage Cervical Cancer

Radiotherapy may be utilized as the sole modality of treatment in early-stage cervical cancer IA1-IIA1. External beam radiotherapy with a brachytherapy boost has equivalent 5yr and 20-year overall survival (83% and 75% respectively) compared to radical hysterectomy with less morbidity.[29][30] However, adjuvant hysterectomy may be considered in patients with bulky tumors >4 cm.[31]

Advanced Cervical Cancer

Locally aggressive and/or node-positive disease is usually treated with definitive concurrent platinum-based chemoradiotherapy followed by a brachytherapy boost. The addition of chemotherapy to definitive radiotherapy has resulted in considerable improvements in overall survival compared to radiotherapy alone with 8-year overall survival of 41% versus 67%.[32] Improvements in local recurrence and distant metastasis have also been noted.[32]

Post-operative Radiotherapy

In the post-operative setting, radiotherapy with or without chemotherapy is recommended when specific surgical pathologic findings are present. These factors are thought to represent an increased risk of recurrence.

Conventionally, the Sedlis criteria provided guidance in the use of adjuvant radiotherapy without chemotherapy in post-radical hysterectomy patients with at least 2 of the following 3 features: >4cm tumor size, LVSI, or >1/3 stromal invasion.[33] These criteria were meant to identify patients with at least a 30% risk of relapse at 3 years.[34] Patients who met these criteria and were treated with pelvic radiotherapy were noted to have an improvement in progression-free survival (78% vs 65%) and local recurrence (21% vs 14%).[33] More recently, there have been concerns that these criteria may be overlooking women who might benefit from adjuvant radiotherapy due to such a high threshold.[34] A nomogram has been developed incorporating the original Sedlis criteria as well as tumor histology to provide a more linear and continuous risk assessment rather than a simple threshold.[34]

Classically, the addition of chemotherapy to radiotherapy was guided by the Peters trial which randomized patients with positive nodes, involved parametria, or positive surgical margins to radiotherapy alone or with concurrent platinum-based chemotherapy. The addition of chemo resulted in a 10% improvement in overall survival at 4 years and almost a 20% improvement in progression-free survival over the same time frame.[35] More contemporary studies such as the STARS trial have sought to expand the use of chemotherapy in the adjuvant setting in patients meeting either the original Sedlis or Peters criteria.[36]

Delivery Techniques

The two major delivery methods include external beam radiotherapy, directed at the primary and pelvic lymphatics, and brachytherapy, where a sealed radiation source is placed in close proximity to the tumor.

External Beam Radiotherapy (EBRT)

External beam radiotherapy techniques include 3D conformal or intensity-modulated radiotherapy (IMRT). Intact cervical cancer patients’ plan can be employed. A reduction in gastrointestinal and hematological side effects has been documented with the use of IMRT in both the adjuvant and definitive setting.[37][38][37]

Brachytherapy (BT)

Brachytherapy can be used alone in early-stage diseases or as a boost after external beam radiotherapy in more advanced diseases. This treatment technique is highly conformal and dose delivery is controlled by adjusting the dwell times within the delivery device. This technique will be discussed further in the Brachytherapy section.

Simulation

Patients undergoing external beam treatments can be placed in the supine position. Accounting for cervical motion is especially important when using IMRT. This is accomplished by taking two separate scans of the patients with full and empty bladder. Prone positioning may also be performed using a belly board however if there are large daily fraction shifts then IMRT may not be reproducible. Prone positioning may allow for a reduction in small bowel dose when using IMRT.[39]

Target Delineation

Traditionally, pelvic fields were drawn on 2D x-ray consisting of AP/PA and opposed lateral fields which made up the four-field box. The superior edge of the field was the bottom of L4 and inferiorly drawn to the bottom of the obturator foramen or at least 3cm below the lowest extent of disease. The lateral fields have the same superior/inferior borders with the anterior border is the anterior pubic symphysis and the posterior border is the sacral hollow including S2.

In the era of CT-based planning, PET/CT fusions, and IMRT, more precise delineation of the gross disease and elective volumes can be accomplished. A GTV would consist of gross disease seen on CT scan, PET, and physical examination. An internal target volume (ITV) would account for variation in bladder filling can also be employed but this would require the patient to have two CT simulations (empty and full bladder). The CTV1 expansion would include the entire cervix and uterus (if intact). PTV1 on primary disease is typically 1.5cm. The CTV2 would include the parametrial tissue, paravaginal tissues, and at least the 1/2 upper vagina. If there is vaginal involvement, then consideration of covering the entire vagina should be given. This PTV2 expansion should be 1.0 cm. The elective nodal volumes in the CTV3 should include obturator nodes, external iliac nodes internal iliac nodes, and presacral nodes. Consideration should be given to coverage of the inguinal nodes should be given if there is lower vaginal involvement. PTV expansion on the elective nodes is typically 0.7 cm.

Coverage of the paraaortic nodes may be needed in cases where there is evidence of disease in the nodal chain or the patient has a positive pelvic node and will not be receiving systemic therapy. At which point, the superior boundary would then become the T12/L1 interspace w with the nodal strip ending at the top of the pelvic field L5/S1.

Dosing and Dose Constraints

The standard whole pelvic dose is 45-50.4Gy in 1.8 – 2.0Gy per fraction. Any gross nodal disease may be boosted to 60Gy if possible given OAR constraints are not exceeded.

External beam radiation therapy has greatly improved with the adoption of Intensity Modulated Radiotherapy (IMRT) resulting in a reduction in acute toxicity while maintaining oncologic outcomes. Typical organs at risk include the rectum, bladder, bowel, femoral heads, and bone marrow. QUANTEC dose constraints can be an excellent guide. Typically, with external beam therapy alone doses of 45-50Gy alone will not lead to significant rates of bladder or bowel acute toxicity. Trial protocols typically allow for V40<80% for the rectum and V45<35% for the bladder.[38] If brachytherapy is planned, then minimizing these doses during the external beam phase of treatment will allow for higher doses to be delivered during the boost phase of treatment (Brachytherapy Dose constraints will be covered in the Brachytherapy Section). Bone marrow suppression resulting in Grade ≥3 neutropenia has been demonstrable lower (8.6% vs 27.1%) with the use of Image-guided radiotherapy and IMRT.[37] The most common constraints for bone marrow in the pelvis are V10<90% V20<75% and V40<37%.[37][38] For Small bowel, QUANTEC lists V45<195cc while more modern protocols specify V40<30%.[38][40][38]    

Brachytherapy

Brachytherapy is typically employed as a boost technique in Stage IB2-IVA cervical cancer. It allows for highly conformal dose delivery to the tumor while minimizing exposure of normal tissues. High dose rate (HDR) brachytherapy (>12Gy/hr) is the most commonly used technique however it requires a radioactive source usually Iridium-192.

Procedure

Typically, brachytherapy is either started at the conclusion of the external beam portion of the treatment or interdigitated with EBRT in the last week of treatment. EBRT and brachytherapy should not be administered on the same day. Total treatment time (EBRT and Brachytherapy) should not exceed 8 weeks. Excessive treatment times can result in a 1%/day decline in local control and overall survival.

Pre-implant 

Prior to undergoing brachytherapy, a review of the patient’s history, pathology, imaging, and physical exam should be performed. A complete blood and metabolic panel should be obtained within a week of the procedure. Metabolic derangements should be investigated and corrected prior to the procedure. Patients with Absolute Neutrophil Counts (ANC) less than 500 mm should not undergo the procedure until counts have recovered. Review of medications especially anticoagulants should be done and PT/INR obtained. Careful consideration should be given to holding anticoagulant medications prior to the procedure. Inpatients that are confined to bed should be given thrombopropylaxis while in house as well as calf compression devices. Bowel preparation should also be reviewed with the patient prior to the procedure.

Applicators

Several applicators exist which may be used for various clinical scenarios. The ring and tandem is the most common device used for intact cervical cancer. The tandem is placed in the cervical canal while the ring is placed inside the vaginal fornices. Tandem and ovoids are utilized in a similar way but are preferred in patients with a barrel shaped cervix. Interstitial applicators such as the Syed template can be used in patients with extensive parametria involvement, pelvic side wall involvement, lower vaginal involvement, or vaginal cuff recurrence. Tandem and cylinder applicators can be used in cases of vaginal stenosis, inability to place a ring or ovoid, or lower vaginal involvement <5mm thick. Modifications to the Tandem and Ring or Vaginal cylinder can be made to also accommodate interstitial needles.[41][42]

Anesthesia

Patient discomfort experienced during the procedure can lead to suboptimal placement of the applicator, longer procedure times, and distress for the patient. An anesthetic is typically required to help optimize patient comfort and procedure mechanics. The types of anesthesia administered varies but can include general anesthesia, spinal anesthesia, epidural anesthesia, intravenous conscious sedation, and oral pain medication.

Placement of an Intracavitary Applicator for an Intact Cervix

The patient is placed in the dorsal lithotomy position in stirrups. After adequate sterile preparation of the area, a Foley catheter is inserted and the balloon inflated with dilute contrast to allow for detecting on CT. A speculum is then inserted to visualize the cervix and a uterine sound is then used to determine the length of the cavity. This will aid in determined the length and angle of the tandem. A Smitt sleeve is occasionally used to maintain the patency of the cervical os but if not present then serial dilations may be required. Once this is complete, the tandem is inserted followed by the ring or ovoid. Fiducial markers may also be placed at the time of procedure to outline the extent of disease or the opening of the cervical os so it is visible on CT. These applicators can be locked in place so that their relative positions do not change.

Displacement of the bladder and rectum are critical to reduce excess dose and limit toxicity. The packing material can consist of gauze soaked in a radiopaque solution. Applicators fitted with inflatable balloons or separate rectal blades are also available. Anterior packing displaces the bladder while posterior packing displaces the rectum. It is very important to ensure no packing is placed in front of the ring or ovoids as this will significantly reduce the dose.

Once complete, the patient will undergo a CT simulation for 3D brachytherapy planning. Three dimensional CT based planning has been shown to have improved overall survival (65% vs 74%) and lower rates of Grade 3-4 toxicity (23% vs 3%) compared to 2D planning.[43] A 1-5mm slice thickness is recommended. [41][42] More recently MRI guided brachytherapy has been incorporated into planning to allow for improved tissue delineation which is best seen on the T2 weighted fat-suppressed sequences (T2-FSE) imaging.[44] Paraxial and Para coronal images should be obtained with respect to the cervix-uteri as well as sagittal images.[45] It can also allow for assessment of response to chemoradiation. Technically, low and high intensity magnetic field MRI machines can be utilized.  Patients can be given glucagon prior to MRI to reduce bowel motion. A pelvic coil is recommended to increase the signal-to-noise ratio. Ideally a 3mm slice thickness should be the obtained which helps improve detection of parametrial involvement, but <5mm is acceptable. The disadvantage of this approach is the increased costs, longer procedure times, and need for strict MR compatibility of the materials being used.

Proper placement of the applicator should be confirmed. This can be accomplished with plain radiography or more advanced imaging such as CT or MRI. Adequate placement includes the tandem bisecting the ring/ovoids on AP and lateral imaging, tandem 1/3-1/2 the distance between the sacral promontory and the pubic symphysis, the tip of tandem below the sacral promontory, no packing superior to the ring/ovoids, and no inferior displacement of the ring/ovoids relative to the flange. 

Target Delineation

As part of 3D based planning, contouring of the targets is essential. GEC-ESTRO has established standardized terminology regarding target delineation.[45] The high-risk clinical target volume (HR-CTV) consists of the entire cervix and all gross disease at the beginning of brachytherapy treatment, intermediate-risk clinical target volume (IR-CTV) incorporates the HR-CTV and gross disease prior to any treatment, and the low-risk clinical target volume (LR-CTV) which includes the IR-CTV as well as the entire uterus, upper vagina, entire parametria, and spaces between the bladder and rectum.[46]

Normal organs at risk (OARs) should be contoured to include the bladder, rectum, sigmoid colon, and vagina.

Dose and Dose Constraints

Ensuring adequate dose to the target is critical and has been shown to lead to improved local control and survival. Dose and fractionation schemes may vary by institutional preference but they must result in a total equivalent dose in 2 gray fractions (EQD2) of 85Gy or higher assuming 45Gy was originally delivered to the pelvis. There are several calculators that exist that allow for the EQD2 to be determined. The EQD2 spreadsheet utilized by the EMBRACE trial group colloquially known as the “Vienna Spreadsheet” allows for EQD2 calculations to the target structures as well as the organs at risk. The most common dose fractionation schemes include 4 X 7Gy, 5 X 6Gy, and 6 X 5Gy which have EQD2 of approximately 90.1, 88.6, and 83.7Gy respectively.

For 3D-based planning, the critical dosimetric parameter is the D90≥90%. The goal is for 90% of the HR-CTV to be covered by at least 90% of the prescription dose. The EQD2 should be calculated to ensure the total dose received is approximately 85Gy or higher. There are instances where it is acceptable for the EQD2 to be slightly lower. In cases of a complete response prior to brachytherapy or partial response with <4cm in residual disease then EQD2>80Gy may be used while those with >4cm residual disease >85Gy is recommended.[41][42]

Despite the transition to 3D-based volumetric planning and the continued evolution of brachytherapy treatment, 2D dosimetric reporting systems persist and should be understood. Point A, where the uterine artery crosses the ureter, is located 2cm up the tandem and 2cm normal to the tandem and was originally part of the Manchester system. This point was traditionally where the prescription dose was prescribed, but more recently has become a starting point where dose coverage can be further manipulated in 3D to ensure coverage of the HR-CTV. Point B, also part of the original Manchester system, is located 2 cm up the tandem and 5cm from the patient’s midline. This represents the pelvic side wall lymphatics and typically received 1/3 of the prescription dose. It has fallen out of favor and is no longer reported. The isodose lines for typical tandem and ring/ovoid implant should appear pear-shaped. In addition, the ICRU 38 specified a bladder and rectal point. The bladder point is located posterior to the foley balloon that has been pulled down to the neck of the bladder. The rectal point is 5mm posterior to the vaginal wall.

Doses to OARs must also be carefully documented. Again, it is the cumulative dose EQD2 that is critical. The dosimetric parameter D, which represents the highest dose received by 2 cubic centimeters of tissue, is commonly used for evaluating a brachytherapy plan. The ABS guidelines allow for the D2cc of the bladder to receive ≤ 90Gy EQD2 while the Dof the rectum and sigmoid should be ≤ 75Gy EQD2. However, recent data suggest that late rectal morbidity may be substantially lower even using a D2cc ≤ 65Gy.[47]

Complications

Long-term toxicity is a concern with any patient that receives radiation therapy. The most frequent complications are bowel/rectal and urinary. There does not appear to be a difference in the frequency or severity of complications with respect to age. The greatest risk of late sequelae is typically within three years of treatment.

Proctitis

Radiation proctitis can result in tenesmus and intermittent bleeding with bowel movements. Treatment is the same with acute proctitis that can occur during radiation. It typically occurs at 3 months post-treatment at the earliest but may take years to develop. Treatments can include Mesalamine or steroid-based suppositories with the goal of relieving pain and stopping any bleeding. Randomized trials have suggested that mesalamine may be slightly more efficacious than steroid-based suppositories.[48] Other treatments can include 4% formaldehyde application to control rectal bleeding. In refractory cases, argon plasma laser coagulation may be performed on the offending vessels.

Cystitis

Radiation cystitis can lead to dysuria, urinary frequency, and in some cases hematuria. It can occur acutely within 2-3 weeks of starting radiotherapy up to 3 years post-treatment.

For acute cystitis, a urinary tract infection must be ruled out therefore a urinalysis is an appropriate first time. For dysuria relief, a short course of pyridium can be used although the urine color change may be alarming for some patients and they should be counseled ahead of time. Urinary frequency can be treated with anticholinergic drugs such as oxybutynin or mirabegron although caution is advised when used in elderly patients.

Chronic cystitis has an incidence of 5-10%.[49] These patients are more likely to experience hematuria in addition to frequency and dysuria. The severity can range from mild to severe and life-threatening. Mildly symptomatic patients may be managed conservatively. Any antiplatelet or anticoagulation medications that the patient is taking should be reviewed and their necessity questioned. In more severe cases, a cystoscopy with clot evacuation and irrigation is necessary. During a cystoscopy, instillation of formalin

In refractory cases, hyperbaric oxygen therapy (HBOT) has been utilized and has been shown to provide relief and control bleeding in 92% of cases however recurrences may occur.[50] There is also the risk of barotrauma associated with this procedure.

Secondary Malignancy

Radiation-induced cancers tend to appear several decades after treatment. The overall risk of secondary malignancy is increased with the use of pelvic radiotherapy compared to those treated with surgery alone. Women treated under the age of 50 had a 40 year cumulative risk of 22% vs 16% for those treated over 50.[51] The excess cancers tended to be confined to rectum, bladder, lung, and genitals. Other retrospective studies have shown an increase in the risk of leukemia which peaks around 5-10 years post-treatment.[52] Limiting OAR doses may help to reduce the risk. 

Hormone Deficiency

Radiation-induced ovarian failure typically occurs within 6-12 months post-radiation. Minimum doses for ovarian failure are inversely related to age ranging from 20.3Gy at birth to 14.3Gy at the age of 30.[53] The doses used for cervical cancer can easily precipitate ovarian failure. Pre-menopausal patients have several options for preserving ovarian function namely definitive surgery or ovarian transposition. Laparoscopic ovarian transpositions allow for the ovaries to be placed outside of the radiation field usually 3.0 cm away. This procedure is also useful for fertility preservation. Functional preservation rate is around 80%. Ovarian cryopreservation is another technique that can be utilized. Exogenous hormonal supplementation with estrogen should be considered for the prevention of osteoporosis, osteopenia, and maintaining libido.

Vaginal Stenosis

Vaginal stenosis and canal shortening can develop over months to years post-treatment. Stenosis can make it difficult for intercourse and to obtain gynecological exams. Consistent use of a vaginal dilator is typically recommended however compliance is highly variable. Sexual dysfunction is quite common ranging from a lack of desire for sexual activity to a lack of adequate vaginal lubrication.

Bone Fracture

Pelvic radiotherapy can increase the risk of pelvic fractures with most fractures occurring at dose levels of 45-63Gy. Bone health is another concern in patients that undergo radiation to the pelvis. Approximately 10% of patients radiated for cervical cancer experienced a pelvic fracture. The most common site of fracture is the sacrum with the majority occurring within 2 years after treatment. Bone mineral density scans and appropriate intervention to maintain bone health may help to reduce this risk.

Uterine Perforation

Uterine perforations is a complication related to brachytherapy applicator insertion resulting in excessive doses to normal tissues, poor target coverage, bleeding, and infection. Rates of perforation range from 2-18%.[54][55][56] Management is controversial ranging from postponement to allow for healing to outright abandonment of the procedure. However, treatment delays are known to adversely affect the outcome. Management of the perforation is typically expectant as the risk of vascular and organ injury is low when the perforation is caused by a blunt instrument. Stable patients without signs of infection may be discharged and observed. Prophylactic antibiotics may be dispensed. Signs of hemodynamic instability and infection warrant more aggressive approaches with IV fluids, antibiotics, and surgical exploration.

Medical Oncology

Definitive

The RTOG trials established the utility of platinum-based chemotherapy regimens. There is consistent overall survival, disease-free survival, and local control advantages compared to radiotherapy alone.[32] It is postulated that chemotherapy acts as a radiosensitizer. The most common agent used is weekly cisplatin 40mg/m. Single-agent platinum-based regimens had the best progression-free survival and overall survival compared to non-platinum-based regimens and a better toxicity profile compared to combinations of platinum-based regimens such as Cis/5-FU/hydroxyurea.[57] Carboplatin may also be used in cases where cisplatin would not be tolerated. Some practices continue to use a combination of cisplatin/5-FU. This regimen is delivered concurrently with radiotherapy.

Adjuvant Chemoradiotherapy may be added after surgical resection should the patient have high-risk features (Please see the radiation oncology section for more details). An overall survival benefit and a progression-free survival benefit have been demonstrated with the addition of chemotherapy to radiotherapy in certain high-risk post-operative patients.[35]

The use of adjuvant chemotherapy after definitive chemoradiation continues to be investigated in clinical trials. The results have been mixed. The addition of adjuvant carboplatin/taxol to chemoradiation for locally advanced cervical cancer resulted in higher rates of grade 3-5 toxicity and no difference in overall survival or progression-free survival. Another trial using concurrent and adjuvant cisplatin/gemcitabine demonstrated improved 3-year progression-free survival but markedly higher rates of grade 3-4 toxicity and hospitalizations.[58] RTOG 0724 is an ongoing trial investigating the use of adjuvant cisplatin/paclitaxel after definitive chemoradiation in high-risk post-operative patients (NCT00980954).

Recurrence and Metastasis

In the recurrent and metastatic setting, patients that are not candidates for exenterative surgery or radiotherapy may receive systemic therapy alone. Many of these patients have received single-agent cisplatin-based therapy and therefore multidrug regimens are typically used. Cisplatin/paclitaxel has been shown to improve progression-free survival in patients with recurrent cervical cancer but no difference in median overall survival.[59] While other drug combinations such as cisplatin/topotecan, cisplatin/gemcitabine, and cisplatin/vinorelbine are potential options, GOG 204 suggested that these regimens are not superior to cisplatin/paclitaxel.[60] The incorporation of biologic agents such as VEGF receptor antagonists such as bevacizumab into common chemotherapeutic regimens has shown improvement in overall survival. [61] Immunotherapy with PD-1 inhibition has also been incorporated into chemotherapeutic regimens and is recommended for patients with a Combined Positive Score of >=1. Single-agent pembrolizumab has an objective response rate of 12-14% in patients with recurrent or metastatic cervical cancer.[62] Keynote 826 demonstrated that the addition of pembrolizumab to multidrug chemotherapy led to an improvement in overall survival and progression-free survival.[63]

Complications

The most commonly used platinum drugs are cisplatin and carboplatin. Common side effects include neutropenia, thrombocytopenia, anemia, febrile, neutropenia, nephrotoxicity, neurotoxicity, and infection. While cisplatin is the drug of choice, carboplatin can be used in patients that may not tolerate cisplatin particularly if they already have underlying renal disease. Although thought to have lower efficacy, prospective data suggest non-inferiority in terms of efficacy and a statistically significant lower incidence of febrile neutropenia, neutropenia, and creatinine elevation ([64]).

Bevacizumab carried the risk of hypertension, hemorrhage, thromboembolic events (5% arterial and 11% venous), renal injury, and ovarian failure in pre-menopausal women. Pembrolizumab is known for precipitating autoimmune phenomena such as pneumonitis, colitis, hepatitis, nephritis, and endocrinopathies.

Staging

The International Federation of Gynecology and Obstetrics (FIGO) staging system was recently updated in 2018 and remains the dominant staging methodology. The AJCC 8 addition also has a TNM classification system where the T stages correspond to the FIGO stage however it is not regularly used. Classically, the FIGO staging would rely on clinical examination as well as cystoscopy, proctoscopy, hysteroscopy, urography, and plain film X-ray. These relatively basic tests were allowed so that developing countries with fewer healthcare resources could adequately stage patients. More recently, advanced imaging techniques such as MRI and PET became part of the staging workup. MRI is preferred for establishing the T stage given superior tissue delineation compared to CT with contrast. FIGO stage I disease is strictly confined to the cervix with the A/B designation indicating the depth of invasion ≤5mm or >5mm. FIGO stage II represents disease that invades beyond the uterus but has not extended into the lower vagina. This stage also has an A/B designation based on the involvement of the parametria. FIGO stage III indicates disease that has extended to the lower third of the vagina (IIIA) or extension to the pelvic side wall and/or hydronephrosis (IIIB). Classically, nodal disease did not influence the FIGO staging system, however, it has been shown that nodal disease is one of the most important prognostic indicators for reduced 5-year overall survival.[65] As a result, new stages IIIC1 and IIIC2 were added to reflect the involvement of pelvic nodes or para-aortic nodes respectively. FIGO Stage IVA disease indicates locally aggressive disease with the involvement of adjacent organs such as the bladder, rectum, or tumor extension beyond the true pelvis. FIGO stage IVB disease indicates spread to other solid organs or non-regional nodal disease.

Prognosis

The estimated effectiveness of HPV vaccination is 90 percent. [66] Inconsistent screening is an independent risk factor for the late diagnosis of cervical cancer. [67] The five-year survival rate for cervical cancer can approach 92 percent. The higher stage at presentation decreases survival and increases the chance of recurrence. African American women tend to have the highest mortality and lowest survival rate. The survival rate may be less than 50 percent. Contributing factors to differences in outcomes may include differences in the delivery of evidence-based care, later stage of diagnosis, lymph node spreading, age, and size and invasion of the tumor at the time of diagnosis. [10][68]

Complications

Complications of advanced disease and associated treatments are similar to other cancers. Complications may include renal failure, hydronephrosis, pain, lymphedema, bleeding disorder, and fistulas. [69] For more details regarding specific complications of the various interventions, please refer to each treatment modality section. 

Deterrence and Patient Education

Both traditional methods of patient education and innovative methods can increase awareness of cervical cancer and the need for prevention and early screening. [70][71] The literature shows that doctors may not be recommending or discussing HPV vaccination with patients. Women and parents also have vaccination fears. In high-risk populations, additional education to physicians may increase awareness, prevention, and screening among those women at risk for the highest mortality.[72]  Although, a patient may prefer health system education from the provider. Additional education including culturally sensitive information, appropriate language to reach low health literacy populations, and targeted efforts to women not yet sexually active are needed to expand patient education and awareness of cervical cancer prevention and screening beyond the clinical setting through community outreach. [73][74]

Pearls and Other Issues

Primary prevention includes vaccination to prevent cervical cancer. There is a quadrivalent vaccine that prevents not only cervical cancer but also prevents genital warts. The recommended age for vaccination is from 9 to 45 years old for females. It is approved for females ages 9 to 45 and is also recommended for males. Health promotion aimed at vaccination can have a major impact on cervical cancer mortality in women in low resource areas and those who are in high-risk ethnic groups. A vaccine that only covers HPV 16 and 18 is no longer marketed in the United States. However, its use may continue in other areas outside of the United States.

Enhancing Healthcare Team Outcomes

The interprofessional team care in the prevention, screening, treatment, and management of cervical cancer can improve awareness, screening, and management of cervical cancer. The use of public education can increase awareness about cervical cancer prevention and screening and the importance of identifying precancerous lesions. [75][76][77] Primary care providers performing cervical cancer screening, colposcopies, and LEEP procedures, must have ongoing dialogues with gynecology about findings, suspicious lesions, outcomes, and management and treatment. Organized protocols and guidelines across the system can lead to better outcomes in increasing awareness, screening, management and treatment, and follow-up. Developing a culturally sensitive system directed at increasing patient-centered education will also require the input of diverse staff and providers with language skills, cultural competency, lab, and nursing.

The interprofessional team can optimize the treatment of patients through communication and coordination of care. Primary care physicians, gynecologists, radiation oncologists, and nurse practitioners provide diagnoses and care plans. Specialty care ambulatory care and oncology nurses should work with the team for coordination of care and are involved in patient education. They should provide feedback to the rest of the team. Pharmacists should evaluate vaccinations, medications prescribed, recognize drug-drug interactions, provide patient education, and monitor compliance. The team can thus improve outcomes for patients with cervical cancer. [level 5]