Approach Considerations
Intravaginal application of 5% 5-fluorouracil (5-FU) was found to be an effective treatment for cervical intraepithelial neoplasia (CIN) 2 in a prospective, nonblinded, randomized controlled study of 60 women. [64, 65] At 6-month follow-up, disease regression was observed in 26 of 28 women (93%) who were treated with 5-FU and in 15 of 27 women (56%) in an observation-only group. Normal cervical biopsy, a normal Pap smear, and a negative human papillomavirus (HPV) test were seen in 14 of the 28 patients in the treatment group at 6-month follow-up, compared with 6 of the 17 patients in the observation group. [64, 65] Topical 5-FU was well tolerated.
The treatment of cervical cancer varies with the stage of the disease (see Cervical Cancer Staging). For early invasive cancer, surgery is the treatment of choice. In more advanced cases, radiation combined with chemotherapy is the current standard of care. In patients with disseminated disease, chemotherapy or radiation provides symptom palliation. (See also Cervical Cancer Treatment Protocols.)
The treatment of cervical cancer frequently requires a multidisciplinary approach. Involvement of a gynecologic oncologist, radiation oncologist, and medical oncologist may be necessary.
Stage-Based Therapy
Stage 0 cancer
Carcinoma in situ (stage 0) is treated with local ablative or excisional measures such as cryosurgery, laser ablation, and loop excision. Surgical removal is preferred in that it allows further pathologic evaluation to rule out microinvasive disease. After treatment, these patients require lifelong surveillance.
Stage IA1 cancer
The treatment of choice for stage IA1 disease is surgery. Total hysterectomy, radical hysterectomy, and conization are accepted procedures. Lymph node dissection is not required if the depth of invasion is less than 3 mm and no lymphovascular invasion is noted.
Selected patients with stage IA1 disease but no lymphovascular space invasion who desire to maintain fertility may undergo therapeutic conization with close follow-up, including cytology, colposcopy, and endocervical curettage. Patients with comorbid medical conditions who are not surgical candidates can be successfully treated with radiation.
According to National Comprehensive Cancer Network (NCCN) guidelines, pelvic radiation therapy is currently a category 1 recommendation for women with stage IA disease and negative lymph nodes after surgery who have high-risk factors (eg, a large primary tumor, deep stromal invasion, or lymphovascular space invasion). [6]
Stage IA2, IB, or IIA cancer
For patients with stage IB or IIA disease, there are 2 treatment options:
-
Combined external beam radiation with brachytherapy
-
Radical hysterectomy with bilateral pelvic lymphadenectomy
Radical vaginal trachelectomy with pelvic lymph node dissection is appropriate for fertility preservation in women with stage IA2 disease and those with stage IB1 disease whose lesions are 2 cm or smaller. [6] The principal problems with pregnancy after trachelectomy are premature labor and the need to undergo cesarean section for delivery. [66]
In a retrospective review of 62 patients with stage IB1 cervical carcinoma who underwent attempted radical trachelectomy and underwent preoperative magnetic resonance imaging (MRI), Lakhman et al found that pretrachelectomy MRI helped identify high-risk patients who were likely to need radical hysterectomy and helped confirm the absence of residual tumor after a cone biopsy with negative margins. [67] A tumor size of 2 cm or larger and deep cervical stromal invasion on MRI were associated with an increased chance of radical hysterectomy.
Most retrospective studies have shown equivalent survival rates for trachelectomy and hysterectomy, though such studies usually are flawed because of patient selection bias and other compounding factors. However, a 2008 study showed identical overall and disease-free survival rates for the 2 procedures. [68]
Current surgical guidelines for stage IA2 to IIA cervical cancers allow for minimally invasive techniques, such as traditional laparoscopic and robotically assisted laparoscopic techniques, in the surgical management of these tumors. Indeed, it has been shown that these less morbid procedures are equally effective in achieving adequate surgical margins and lymph node dissection while possessing the added advantage of shorter postoperative recovery times. [69, 70, 71]
An analysis of women from the Surveillance, Epidemiology, and End Results (SEER) database who underwent radical hysterectomy with lymphadenectomy revealed that patients with node-negative early-stage cervical cancer who underwent a more extensive lymphadenectomy had improved survival. [72] Compared with patients who had fewer than 10 nodes removed, patients who had 21-30 nodes removed were 24% less likely to die of their tumors, and those who had more than 30 nodes removed were 37% less likely to die.
Postoperative irradiation of the pelvis reduces the risk of local recurrence in patients with high-risk factors (ie, positive pelvic nodes, positive surgical margins, and residual parametrial disease). [73] A randomized trial showed that patients with parametrial involvement, positive pelvic nodes, or positive surgical margins benefit from a postoperative combination of cisplatin-containing chemotherapy and pelvic irradiation. [74]
Postoperative radiation therapy is also recommended in patients who have at least 2 intermediate risk factors (including tumor size greater than 2 cm, deep stromal invasion, or lymphovascular space invasion). For patients with IB2 or IIA cancer and tumors larger than 4 cm, radiation and chemotherapy is selected in most cases. Risks are associated with combined therapy, but many of these patients will meet either intermediate- or high-risk criteria after radical hysterectomy and therefore are strong candidates for this approach.
Stage IIB, III, or IVA cancer
For locally advanced cervical carcinoma (stages IIB, III, and IVA), radiation therapy was the treatment of choice for many years. Radiation therapy begins with a course of external beam radiation to reduce tumor mass and thereby enable subsequent intracavitary application. Brachytherapy is delivered by means of afterloading applicators that are placed in the uterine cavity and vagina.
Additionally, the results from large, well-conducted, prospective randomized clinical trials have demonstrated a dramatic improvement in survival when chemotherapy is combined with radiation therapy. [75, 76, 77] Consequently, the use of cisplatin-based chemotherapy in combination with radiation has become the standard of care for primary management of patients with locally advanced cervical cancer. [6]
Stage IVB and recurrent cancer
Individualized therapy is used on a palliative basis. Radiation therapy is used alone for control of bleeding and pain, whereas systemic chemotherapy is used for disseminated disease. [6] For recurrent disease, the choice of therapy is influenced by the treatments previously employed.
Treatment of pelvic recurrences after primary surgical management should include single-agent chemotherapy and radiation, and treatment for recurrences elsewhere should include combination chemotherapy. [78, 79, 80] For central pelvic recurrence after radiation therapy, modified radical hysterectomy (if the recurrence is smaller than 2 cm) or pelvic exenteration should be undertaken. [81, 82]
For disease recurring after chemotherapy and radiation therapy, a disease-free interval of more than 16 months is considered to designate the tumor as platinum-sensitive. [83] The standard of care in these cases is chemotherapy with a platinum-based doublet of paclitaxel and cisplatin. [79, 80, 84, 85]
The NCCN also recommends docetaxel, gemcitabine, ifosfamide, 5-fluorouracil, mitomycin, irinotecan, and topotecan as possible candidates for second-line therapy (category 2B recommendation), as well as pemetrexed and vinorelbine (category 3 recommendation). In addition, bevacizumab as single-agent therapy is also acceptable. [6]
Treatment with bevacizumab plus cisplatin and paclitaxel or topotecan and paclitaxel was approved by the FDA in August 2014 for persistent, recurrent, or metastatic cervical cancer. [86, 87] A statistically significant improvement in overall survival (OS) and an increase in the rate of tumor shrinkage was shown in women treated with bevacizumab plus chemotherapy compared with chemotherapy alone. [86, 88] However, hypertension, thromboembolic events, and GI fistulas were higher in the bevacizumab group. [88] Bevacizumab/paclitaxel/cisplatin or topotecan is considered a first-line regimen for recurrent or metastatic cervical cancer. [6]
In a randomized study of 452 women with advanced cervical cancer (recurrent, persistent, or metastatic disease), Tewari et al reported that adding bevacizumab to combination chemotherapy prolonged survival in these women by about 3.7 months compared with chemotherapy alone (topotecan plus paclitaxel; cisplatin plus paclitaxel). [88, 89, 90, 91] Because topotecan-paclitaxel was not superior to cisplatin-paclitaxel, the data from the groups treated with these combination regimens were combined. [88, 89]
Median overall survival was 17.0 months with bevacizumab and chemotherapy, whereas it was 13.3 months with chemotherapy alone. [88, 89, 90, 91] At a median follow-up of 20.8 months, 60% of the patients died. [89] Progression-free survival was 8.2 months with bevacizumab plus chemotherapy but 5.9 months with chemotherapy alone. The response rate was 48% with bevacizumab and chemotherapy compared with 36% in the group receiving chemotherapy alone. [88, 89, 90, 91] However, the addition bevacizumab also led to an increased incidence of adverse effects such as hypertension of grade 2 or higher (25% vs 2%), thromboembolic events of grade 3 or higher (8% vs 1%), and gastrointestinal fistulas of grade 3 or higher (3% vs 0%) compared with chemotherapy alone. [88, 89]
Recurrences arising in a previously irradiated field or after a disease-free interval of less than 16 months are less likely to respond to subsequent therapies. Consequently, patients with such recurrences should be strongly encouraged to participate in clinical trials. Special efforts should be made to ensure that they receive comprehensive palliative care, including adequate pain control.
In June 2018, the FDA approved pembrolizumab for treatment of recurrent or metastatic cervical cancer with disease progression on or after chemotherapy in patients whose tumors express PD-L1 (CPS 1 or greater) as determined by an FDA-approved test. Approval was based on the KEYNOTE-158 clinical trial (n=98). For the 77 patients whose tumors expressed PD-L1 with a complete response rate (CRR) of 1 or greater, the overall response rate (ORR) was 14.3%, with a CRR of 2.6% and partial response rate of 11.7%. Among the 11 responding patients, median duration of response (DoR) was not yet reached (range, 4.1 to 18.6+ months), and 91% experienced a DoR of 6 months or longer. The median follow-up time was 11.7 months (range, 0.6 to 22.7 months). [92]
Pembrolizumab was also granted accelerated approval for unresectable or metastatic tumor mutational burden-high (TMB-H) [≥10 mutations/megabase (mut/Mb)] solid tumors in patients that have progressed following prior treatment and who have no alternative treatment options.
Approval was based on results in a prospectively-planned retrospective analysis of 10 cohorts of previously treated patients with various unresectable or metastatic TMB-H solid tumors enrolled in a multicenter, nonrandomized, open-label trial, KEYNOTE-158. Among the 13% of patients identified as TMB-H, defined as TMB ≥10 mut/Mb, the ORR for these patients was 29%, with a 4% CRR and 25% partial response rate. The median DoR was not reached, with 57% of patients having response durations ≥12 months and 50% of patients having response durations ≥24 months. [93]
Complications of Therapy
Radiation-related complications
During the acute phase of pelvic radiation therapy, the surrounding normal tissues (eg, intestines, bladder, and perineal skin) often are affected. Acute adverse gastrointestinal (GI) effects include diarrhea, abdominal cramping, rectal discomfort, and bleeding. Diarrhea can usually be controlled by giving either loperamide or atropine sulfate. Small steroid-containing enemas are prescribed to alleviate symptoms from proctitis.
Cystourethritis also can occur, leading to dysuria, frequency, and nocturia. Antispasmodics often are helpful for symptom relief. Urine should be examined for possible infection. If urinary tract infection (UTI) is diagnosed, therapy should be instituted without delay.
Proper skin hygiene should be maintained for the perineum. Topical lotion should be used if erythema or desquamation occurs.
Late sequelae of radiation therapy usually appear 1-4 years after treatment. The major sequelae include rectal or vaginal stenosis, small bowel obstruction, malabsorption, radiation enteritis, and chronic cystitis.
Surgical complications
The most frequent complication of radical hysterectomy is urinary dysfunction resulting from partial denervation of the detrusor muscle. Other complications include foreshortened vagina, ureterovaginal fistula, hemorrhage, infection, bowel obstruction, stricture and fibrosis of the intestine or rectosigmoid colon, and bladder and rectovaginal fistulas. Invasive procedures (eg, nephrostomy or diverting colostomy) sometimes are performed in this group of patients to improve their quality of life.
Nutrition
Proper nutrition is important for patients with cervical cancer. Every attempt should be made to encourage and provide adequate oral food intake.
Nutritional supplements (eg, Ensure [Abbott Nutrition, Columbus, OH] or Boost [Nestlé HealthCare Nutrition, Fremont, MI]) are used when patients have had significant weight loss or cannot tolerate regular food because of nausea caused by radiation or chemotherapy. In patients with severe anorexia, appetite stimulants such as megestrol can be prescribed.
For patients who are unable to tolerate any oral intake, percutaneous endoscopic gastrostomy tubes are placed for nutritional supplementation. In patients with extensive bowel obstruction as a result of metastatic cancer, hyperalimentation sometimes is used.
Prevention of Human Papillomavirus Infection
Human papillomavirus (HPV) infection is usually transmitted sexually, though rare cases have been reported in virgins. [94] Condom use may not prevent transmission. [94, 95] A study in a mouse model by Roberts et al found that a widely used vaginal spermicide, nonoxynol-9, greatly increased susceptibility to HPV infection, whereas carrageenan, a polysaccharide present in some vaginal lubricants, prevented infection. [96]
Evidence suggests that HPV vaccines prevent HPV infection. [97] PATRICIA (PApilloma TRIal against Cancer In young Adults) found HPV 16/18 vaccine to be efficacious against cervical intraepithelial neoplasia (CIN) grade 2 or 3 and adenocarcinoma in situ, irrespective of the HPV type in the lesion. [98] Cross-protective efficacy was demonstrated against 4 oncogenic HPV types not included in the vaccine. [99] Use of an HPV 6/11/16/18 vaccine reduced the risk of any high-grade cervical lesions by 19.0% overall, irrespective of causal HPV type. [96]
One HPV vaccine is available in the United States. A nine-valent HPV vaccine (Gardasil 9, 9vHPV) is indicated for females aged 9 through 45 years to prevent cervical cancer (and also genital warts and anal cancer); in addition to coverage of HPV types 6, 11, 16, and 18, it covers HPV types 31, 33, 45, 52, and 58. [100] Other HPV vaccines (2vHPV [Cervarix], 4vHPV [Gardasil]) are no longer available in the United States.
The 9vHPV vaccine is approved by the FDA for routine HPV vaccination of females and males aged 9 through 45 years. [101] The vaccination series can be started as young as age 9 years. Catch-up vaccination is recommended for females aged 13-26 years who have not been previously vaccinated or who have not completed the full series. [102] The 9vHPV vaccine may be offered as a 2-dose series for children and young adolescents aged 9-14 years. [103]
In the Costa Rica Vaccine Trial, researchers documented durable antibody responses after 1 dose (as opposed to the standard 3 doses) of the bivalent human papillomavirus (HPV) 16/18 L1 viruslike particle vaccine Cervarix. [104, 105] The investigators evaluated 78 women who received 1 dose of the vaccine, 192 who received 2 doses, and 120 who received all 3 doses. These women were compared with 113 women who did not receive vaccine but had antibodies against the viruses. All subjects in the 3 vaccine groups had antibodies against HPV 16 and 18 for as long as 4 years. [105] Although antibody titers in women who received 1 dose were lower than those in women who received 3 doses, they remained stable over 4 years.
Screening for cervical cancer should continue in vaccinated women, following the same guidelines as in unvaccinated women. [3] These vaccines do not provide complete protection against cervical cancer; oncogenic HPV types other than 16 and 18 account for about 30% of cases, and cross-protection may be only partial. In addition, not all vaccinated patients may mount an effective response to the vaccine, particularly if they do not receive all 3 doses or if they get the doses at time intervals that are not associated with efficacy.
Finally, the duration of protection with these vaccines has not yet been determined. The available evidence suggests that immunity from infection with the HPV types covered by these vaccines will persist for at least 6-8 years, [106] but continuing follow-up will be required to determine whether revaccination will be necessary.
The safety of HPV vaccines is a deeply controversial topic. Follow-up of large patient populations who participated in phase 3 clinical trials has documented that both FDA-approved HPV vaccines are extremely safe. Articles in the popular media, however, have detailed cases of young women with devastating illness attributed to the vaccines.
In post licensure safety surveillance for the quadrivalent HPV vaccine, 6.2% of all reports to the Vaccine Adverse Event Reporting System (VAERS) described serious adverse events, including neurologic injury (eg, Guillain-Barré syndrome) and 32 reports of death. In comparison with other vaccines, rates of most of these adverse events were no greater than the background rates, but there was disproportional reporting of syncope and venous thromboembolic events. [107]
-
Cervical carcinoma with adnexa.
-
Squamous cell cervical carcinoma.
-
Cervical intraepithelial neoplasia grade I.
-
Cervical intraepithelial neoplasia grade III.
-
CT scan of cervical cell carcinoma demonstrates markedly enlarged lymph node at left pelvic sidewall. This is consistent with pelvic lymph node metastasis, which is indicative of stage IIIB disease. Cystic consistency is not unusual for metastatic cervical carcinoma. Primary tumor is well depicted as hypoattenuating circumscribed mass. Cyst is present in anteriorly located left ovary.
Tables
HPV Alpha Group |
Types |
Evidence for Cervical Cancer Causation |
1 |
16 |
Most carcinogenic HPV type, known to cause cancer at several sites |
18,31,33,35,39,45,51,52,56,58, 59 |
Sufficient evidence |
|
2A |
68 |
Limited evidence in humans and strong mechanistic evidence |
2B |
26,53,66,67,70,73,82 |
Limited evidence in humans |
30,34,69,85,97 |
Classified by phylogenetic analogy to HPV types with sufficient or limited evidence in humans |
|
3 |
6,11 |
Inadequate epidemiological evidence and absence of carcinogenic potential in mechanistic studies |
HPV = human papillomavirus. |
||
TNM Stage |
FIGO Stage |
|
TX |
- |
Primary tumor cannot be assessed |
T0 |
- |
No evidence of primary tumor |
Tis |
0 |
Carcinoma in situ |
T1 |
I |
Cervical carcinoma confined to uterus (extension to corpus should be disregarded) |
T1a |
IA |
Invasive carcinoma diagnosed only by microscopy. All macroscopically visible lesions—even with superficial invasion—are T1b/1B. Stromal invasion with a maximal depth of 5.0 mm measured from the base of the epithelium and a horizontal spread of 7.0 mm or less. Vascular space involvement, venous or lymphatic, does not affect classification. |
T1a1 |
IA1 |
Measured stromal invasion 3 mm or less in depth and 7 mm or less in lateral spread |
T1a2 |
IA2 |
Measured stromal invasion more than 3 mm but not more than 5 mm with a horizontal spread 7 mm or less |
T1b |
IB |
Clinically visible lesion confined to the cervix or microscopic lesion greater than IA2 |
T1b1 |
IB1 |
Clinically visible lesion 4 cm or less in greatest dimension |
|
IB2 |
Clinically visible lesion more than 4 cm |
T2 |
II |
Cervical carcinoma extends beyond the cervix but not to the pelvic sidewall or to the lower third of vagina |
T2a |
IIA |
Tumor without parametrial invasion |
T2b |
IIB |
Tumor with parametrial invasion |
T3 |
III |
Tumor extends to the pelvic wall and/or involves the lower third of the vagina and/or causes hydronephrosis or nonfunctioning kidney |
T3a |
IIIA |
Tumor involves lower third of vagina; no extension to pelvic sidewall |
T3b |
IIIB |
Tumor extends to pelvic sidewall and/or causes hydronephrosis or nonfunctioning kidney |
- |
IV |
Cervical carcinoma has extended beyond the true pelvis or has involved (biopsy proven) the bladder mucosa or rectal mucosa. Bullous edema does not qualify as a criteria for stage IV disease. |
T4 |
IVA |
Spread to mucosa of adjacent organs (bladder, rectum, or both) |
M1 |
IVB |
Distant metastasis |
Stage |
Tumor |
Node |
Metastasis |
0 |
Tis |
N0 |
M0 |
IA1 |
T1a1 |
N0 |
M0 |
IA2 |
T1a2 |
N0 |
M0 |
IB1 |
T1b1 |
N0 |
M0 |
IIA |
T2a |
N0 |
M0 |
IIB |
T2b |
N0 |
M0 |
IIIA |
T3a |
N0 |
M0 |
IIIB |
T1 |
N1 |
M0 |
- |
T2 |
N1 |
M0 |
- |
T3a |
N1 |
M0 |
- |
T3b |
Any N |
M0 |
IVA |
T4 |
Any N |
M0 |
IVB |
Any T |
Any N |
M1 |
Patient Status |
Recommended Screening Method |
Comments |
< 21 years old |
No screening |
Sexual history is not a consideration |
21-29 years old |
Cytology alone every 3 years |
|
30-65 years old |
Preferred: HPV and cytology co-testing every 5 years Acceptable: Cytology alone every 3 years |
|
>65 years old |
Screening can be discontinued after either three consecutive negative cytology tests or two negative cytology and HPV tests within 10 years, provided the most recent test was within 5 years |
Women with a history of cervical intraepithelial neoplasia (CIN) 2, CIN 3, or adenocarcinoma in situ should continue routine age-based screening for at least 20 years |
After total hysterectomy |
No screening necessary |
Applies to women without a cervix and without a history of CIN 2, CIN 3, adenocarcinoma in situ, or cancer in the past 20 years |
After HPV vaccination |
Follow the same age-specific recommendations as unvaccinated women |
