In the United States, an estimated 12,710 new cases of invasive cervical cancer are diagnosed annually, and there are 4290 deaths from the disease. In contrast, with more than 529,000 new cases diagnosed annually and a >50% mortality rate, cervical cancer is the second most common cause of cancer-related morbidity and mortality among women in developing countries. This dichotomy is largely the result of a 75% decrease in the incidence of cervical cancer in developed countries following the implementation of population-based screening programs and treatment of preinvasive disease. The average age at diagnosis of patients with cervical cancer is 51 years. However, the disease can occur in the second decade of life and during pregnancy, and nearly 20% of cervical cancers are diagnosed in women age 65 or older. More than 95% of patients with early cancer of the cervix can be cured.
The major epidemiologic risk factors for cervical cancer are the same as those for CIN and were discussed earlier. HPV is central to the development of cervical neoplasia. HPV DNA is found in 99.7% of all cervical carcinomas. HPV-16 is the most prevalent HPV type in squamous cell carcinoma and adenocarcinoma, followed by HPV-18 and HPV-45. Other associated risk factors are tobacco use, immunosuppression, infection with HIV or a history of other STIs, high parity, and oral contraceptive use.
HPV is epitheliotropic. Once the epithelium is acutely infected with HPV, 1 of 3 clinical scenarios ensues:
Asymptomatic latent infection;
Active infection in which HPV undergoes vegetative replication but not integration into the genome (eg, leading to condyloma or CIN I); or
Neoplastic transformation following integration of oncogenic HPV DNA into the human genome.
The virus infects a subset of primitive basal cells in the epithelium where it will undergo replication. The infected cell then enters the proliferating epithelial component. Active infection, in which HPV undergoes replication but remains episomal, is characterized by minimal viral oncogene expression. However, integration of HPV into the human genome is associated with cell immortalization, allowing for malignant transformation. This involves an upregulation of the viral oncogenes E6 and E7. These oncoproteins interfere with cell-cycle control in the human host cell. E6 and E7 have the ability to complex with the tumor suppressor genes p53 and Rb, respectively. The disabling of these 2 major tumor suppressor genes is thought to be central to host cell immortalization and transformation induced by HPV and the observed increased genetic instability.
Incipient cancer of the cervix is generally a slowly developing process. Most cervical cancers probably begin as a high-grade dysplastic change (see previous section) or CIS with gradual progression over a period of several years. At least 90% of carcinomas of the cervix develop from the intraepithelial layers, almost always within 1 cm of the squamocolumnar junction of the cervix either on the portio vaginalis of the cervix or slightly higher in the endocervical canal.
Early stromal invasion (stage IA1) up to a depth of 3 mm below the basement membrane is a localized process, provided there is no pathologic evidence of lymphovascular space involvement. Penetration of the stroma beyond this point carries an increased risk of lymphatic metastasis (Table 48–2). When the lymphatics are involved, tumor cells are carried to the regional pelvic lymph nodes (parametrial, hypogastric, obturator, external iliac, and sacral) (Fig. 48–6). The more pleomorphic or extensive the local disease, the greater is the likelihood of lymph node involvement. As the tumor grows, it also spreads by direct extension to the parametria.
Table 48–2. Risk of Any Lymph Node Metastasis for Patients with Microscopic Squamous Cell Carcinoma of the Cervix. ||Download (.pdf)
Table 48–2. Risk of Any Lymph Node Metastasis for Patients with Microscopic Squamous Cell Carcinoma of the Cervix.
|Depth of Tumor Invasion||Risk of Lymph Node Metastasis|
|FIGO stage IA1|
|Early stromal invasion (<1 mm)||3/1543 (0.2%)|
|Microinvasion (1–3 mm)||5/809 (0.6%)|
|FIGO stage IA2|
|Microscopic 3–5 mm invasion||14/214 (6.5%)|
Lymphatic spread of carcinoma of the cervix.
Squamous cell carcinoma clinically confined to the cervix involves the regional pelvic lymph nodes in 15–20% of cases. When the cancer involves the parametrium (stage IIB), tumor cells can be found in the pelvic lymph nodes in 30–40% of cases and in the para-aortic nodes in approximately 15–30% of cases. The more advanced the local disease, the greater is the likelihood of distant metastases. The para-aortic nodes are involved in approximately 45% of patients with stage IVA disease.
Ovarian involvement is rare, occurring in approximately 0.5% of squamous cell carcinomas and 1.7% of adenocarcinomas. The liver and lungs are the most common sites of blood-borne metastasis, but the tumor may involve the brain, bones, bowels, adrenal glands, spleen, or pancreas.
When cancer of the cervix is untreated or fails to respond to treatment, death occurs in 95% of patients within 2 years after the onset of symptoms. Death can occur from uremia, pulmonary embolism, or hemorrhage from direct extension of tumor into blood vessels. Life-threatening sepsis from complications of pyelonephritis or vesicovaginal and rectovaginal fistulas is possible. Large bowel obstruction from direct extension of tumor into the rectosigmoid can be the terminal event. Pain from perineural extension is a significant management problem of advanced disease.
Approximately 70–75% of cervical carcinomas are squamous cell; the remainder are composed of various types of adenocarcinomas (20–25%), adenosquamous carcinomas (3–5%), and undifferentiated carcinomas.
Cervical squamous cell carcinomas have been classified according to the predominant cell type: large cell nonkeratinizing, large cell keratinizing, and small cell carcinomas. The large cell nonkeratinizing variety accounts for the majority of tumors.
Verrucous Squamous Carcinoma
Verrucous squamous carcinoma, which has been associated with HPV-6, is a rare subtype of well-differentiated squamous carcinoma. It is a slow-growing, locally invasive neoplasm. Histologically, this tumor is composed of well-differentiated squamous cells with frondlike papillae and little apparent stromal invasion, but it is potentially lethal. Radical resection is the mainstay of therapy.
Papillary Squamous Carcinoma
Papillary squamous carcinoma of the cervix is characterized by highly dysplastic squamous cells forming papillary fronds with thin fibrovascular cores. The gross appearance of this lesion may be warty or fungating.
Adenocarcinoma of the cervix is derived from the glandular elements of the cervix. The incidence of adenocarcinomas, including the mucinous, endometrioid, clear cell, and serous types, has been rising over the last several decades, especially in women younger than 35 years of age. Part of this increase may be a result of an increasing prevalence of HPV infection, and part may be a result of improvements in screening and prevention of squamous preinvasive disease, thus leading to a histologic shift toward adenocarcinoma. When the initial growth of adenocarcinoma of the cervix is within the endocervical canal and the ectocervix appears normal, this lesion might not be diagnosed until it is advanced and ulcerative. Cervical adenocarcinoma is subdivided into endocervical type (usual type; minimal deviation adenocarcinoma [adenoma malignum] and well-differentiated villoglandular adenocarcinoma), endometrioid type, clear cell type, papillary serous type, intestinal type, mesonephric type, and mixed type. The clear cell type may be related to in utero exposure to DES. It has a prognosis comparable to that of other adenocarcinomas of the cervix.
Minimal Deviation Adenocarcinoma (Adenoma Malignum)
Adenoma malignum, or minimal deviation adenocarcinoma, is an extremely well-differentiated adenocarcinoma that may be difficult to recognize as a malignant process. It represents approximately 1% of adenocarcinomas of the cervix and has been associated with Peutz-Jeghers syndrome. It occurs mainly in the fifth and sixth decades of life. Diagnosis is often delayed because of frequently normal cervical cytology smears. Punch biopsies are often nondiagnostic, requiring conization for further evaluation.
Another uncommon variant of adenocarcinoma is adenoid cystic carcinoma. This lesion is considered more aggressive than most cervical adenocarcinomas and occurs more commonly in black women of high parity in their sixth and seventh decades of life. It should not be confused with adenoid basal carcinomas, which have an indolent growth pattern.
Adenosquamous carcinomas contain an admixture of malignant squamous and glandular cells; subtypes include the mature type, signet-ring type (mucoepidermoid carcinoma), and glassy cell type. Glassy cell carcinoma is a poorly differentiated form of adenosquamous carcinoma and is considered to have an extremely aggressive course. It accounts for approximately 1–2% of cervical cancers. Synchronous adenocarcinomas and squamous cell carcinomas that invade each other are called collision tumors.
Approximately one-third of small cell carcinomas of the cervix stain positive for neuroendocrine markers (neuron-specific enolase, chromogranin, synaptophysin). These tumors need to be distinguished from small cell type of squamous tumors. They have a high frequency of lymphovascular space invasion, lymph node metastases, recurrence, and poor survival. Neuroendocrine carcinomas are not limited to the small-sized tumor cells. Poorly differentiated large cell carcinomas may express neuroendocrine differentiation by immunohistochemistry. Carcinoid tumors, arising from the argyrophil cells of the endocervical epithelium, are malignant but have rarely been associated with the carcinoid syndrome. Because of their propensity for early systemic spread, systemic chemotherapy is an integral part of the treatment of neuroendocrine tumors of the cervix.
Direct extension of metastatic tumors to the cervix includes those originating from the endometrium, rectum, and bladder. Lymphatic or vascular metastases occur less often but are associated with endometrial, ovarian, gastric, breast, colon, kidney, and pancreas carcinomas. Sarcomas, lymphomas, choriocarcinomas, and melanomas are encountered rarely in the cervix.
Until now, prevention of morbidity and death from cervical cancer largely involved recognition and treatment of preinvasive and early invasive disease. Over 60% of women who develop cervical cancer in developed countries either never have been screened or have not been screened in the preceding 5 years. Risk factors must be recognized, and screening, treatment intervention, and patient education must be modified.
Universal cytologic screening of all women age 21 years or older must be continued on a regular basis until better, more sensitive and specific means of screening are found and outreach into underserved areas is improved. Women with preinvasive cervical neoplasia should be treated and followed up closely (Fig. 48–5). It is important to remember that cervical cytology smears are of limited value in detecting frankly invasive disease, with some studies finding false-negative rates up to 50%. Sexual abstinence is an effective but impractical prophylactic measure. Education of young women and men about risk factors and the necessity for regular screening, as well as information about the association of HIV infection and smoking with the development of cervical cancers, is crucial.
The role of HPV vaccination has been discussed earlier.
Abnormal vaginal bleeding is the most common symptom of invasive cancer and may take the form of a blood-stained leukorrheal discharge, scant spotting, or frank bleeding. Leukorrhea, usually sanguineous or purulent, odorous, and nonpruritic, is frequently present. A history of postcoital bleeding may be elicited on specific questioning.
Pelvic pain, often unilateral and radiating to the hip or thigh, is a manifestation of advanced disease, as is the involuntary loss of urine or feces through the vagina, a sign of fistula formation. Weakness, weight loss, and anemia are characteristic of the late stages of the disease, although acute blood loss and anemia may occur in a bulky or ulcerating stage I lesion.
Physical examination findings include a grossly normal-appearing cervix with preclinical disease. As the local disease progresses, physical signs appear. Infiltrative cancer produces enlargement, irregularity, and a firm consistency of the cervix and eventually of the adjacent parametria. The growth pattern can be endophytic, leading to a barrel-shaped enlargement of the cervix, or exophytic, where the lesion generally appears as a friable, bleeding, cauliflowerlike lesion of the portio vaginalis. Ulceration may be the primary manifestation of invasive carcinoma; in the early stages, the change often is superficial, so that it may resemble an ectropion or chronic cervicitis. With further progression of the disease, the ulcer becomes deeper and necrotic, with indurated edges and a friable, bleeding surface. The adjacent vaginal fornices may become involved next. Eventually, extensive parametrial involvement by the infiltrative process may produce a nodular thickening of the uterosacral and cardinal ligaments with resultant loss of mobility and fixation of the cervix.
Because of the failure of malignant cells to desquamate and the obscuring effect of inflammatory cells, it is not uncommon for an invasive carcinoma of the cervix to exist despite a negative cytologic smear. Any suspicious lesion of the cervix should be sampled by adequate biopsy, regardless of cytologic examination result. Biopsy of any Schiller-positive areas or of any ulcerative, granular, nodular, or papillary lesion provides the diagnosis in most cases. Colposcopically directed biopsies with endocervical sampling or conization of the cervix may be required when reports of suspicious or probable exfoliated carcinoma cells are made by the pathologist and a visible or palpable lesion of the cervix is not evident. Colposcopic warning signs of early invasive cancer in a field of CIN include capillaries that are markedly irregular, appearing as commas, corkscrews, and spaghetti-shaped vessels with great variation in caliber and abrupt changes in direction, often causing acute angles. Ulcerations or a markedly irregular appearance of the cervix with a waxy, yellowish surface and numerous bizarre, atypical blood vessels are common. Bleeding may occur also after slight irritation.
In the setting of a biopsy revealing CIS, where invasion cannot be ruled out, or in the setting of a negative colposcopy in the face of a significantly abnormal cervical cytology smear, conization of the cervix should be performed to determine the presence or absence of invasion. If a cervical biopsy shows microinvasive cancer (<3 mm of invasion), a cone biopsy is necessary to rule out deeper invasion. The conization specimen should be properly marked for the pathologist (eg, with a pin or small suture), so that the area of involvement can be specifically localized in relation to the circumference and margins of the cervix. Conization for a lesion grossly suggestive of invasive cancer is not indicated, as it only delays the initiation of appropriate therapy and predisposes the patient to serious pelvic infections and bleeding. The diagnosis of such a lesion can almost always be confirmed by simple cervical biopsy.
Chest radiographs are indicated in all patients with cervical cancer and an intravenous pyelogram (IVP) or computed tomography (CT) urogram should be performed to determine if there is any ureteral obstruction producing hydroureter and hydronephrosis. Magnetic resonance imaging (MRI), CT scan, lymphangiography, or positron emission tomography (PET) scanning may demonstrate involvement of the pelvic or periaortic lymph nodes or other sites of metastases. The sensitivities of CT, MRI, and PET for lymph node metastases in cervical cancer are approximately 45%, 60%, and 80%, respectively. Integrated PET CT appears to have a slightly higher sensitivity for detecting nodal metastases than PET alone. Although the latter imaging studies are not used to assign disease stage in the International Federation of Gynecology and Obstetrics (FIGO) classification, they may be of value for planning treatment, particularly the extent of the radiation therapy field or scope of surgery.
It is important to estimate the extent of the disease not only for prognostic purposes, but also for treatment planning. Clinical staging also affords a means of comparing methods of therapy for various stages of the disease worldwide. The classification adopted by FIGO is the most widely used staging system (Table 48–3). Cervical cancer is staged by clinical examination and evaluation of the bladder, ureters, and rectum. If the lesion is clearly confined to the cervix by office examination, only chest radiography and evaluation of the ureters by IVP or CT scan with intravenous contrast are necessary to assign the stage. If it is not possible to evaluate the extent of local disease in the office, examination under anesthesia with cystoscopy and proctoscopy may be necessary. Although CT scan, MRI, lymphangiography, and PET scan may offer information helpful for treatment planning, these findings do not change the FIGO stage of disease. The FIGO stage of disease is also not changed by surgicopathologic findings of metastatic disease at the time of radical hysterectomy or lymphadenectomy.
Table 48–3. 2009 International Federation of Gynecology and Obstetrics (FIGO) Staging of Cervical Cancer. ||Download (.pdf)
Table 48–3. 2009 International Federation of Gynecology and Obstetrics (FIGO) Staging of Cervical Cancer.
|Stage 0||Carcinoma in situ|
|Stage I||Cervical carcinoma confined to the cervix (extension to the corpus should be disregarded)|
|Stage IA1||Invasive cervical cancer diagnosed by microscopy only|
|Stage IA1||Stromal invasion no deeper than 3 mm, no wider than 7 mm in horizontal spread|
|Stage IA2||Stromal invasion >3, but no more than 5 mm and no wider than 7 mm in horizontal spread|
|Stage IB||Clinically visible lesion confined to the cervix or microscopic disease greater than stage IA|
|Stage IB1||Clinically visible lesion not >4 cm|
|Stage IB2||Clinically visible lesion >4 cm|
|Stage II||Tumor extends beyond uterus but not to pelvic sidewall or lower third of vagina|
|Stage IIA||Vaginal involvement without parametrial involvement|
|Stage IIA1||Clinically visible lesion not >4 cm|
|Stage IIA2||Clinically visible lesion >4 cm|
|Stage IIB||Parametrial involvement|
|Stage III||Tumor extends to pelvic sidewall and/or causes hydronephrosis and/or extends to lower third of vagina|
|Stage IIIA||Involvement of lower third of vagina with no extension to sidewall|
|Stage IIIB||Extension to pelvic sidewall and/or hydronephrosis|
|Stage IV||Extension beyond the true pelvis or into mucosa of rectum or bladder|
|Stage IVA2||Extension into adjacent organs|
|Stage IVB||Distant metastases|
A variety of lesions of the cervix can be confused with cancer. Entities that must sometimes be ruled out include cervical ectropion, acute or chronic cervicitis, condyloma acuminata, cervical tuberculosis, ulceration secondary to STD (syphilis, granuloma inguinale, lymphogranuloma venereum, chancroid), abortion of a cervical pregnancy, metastatic choriocarcinoma or other cancers, and rare lesions such as those of actinomycosis or schistosomiasis. Histopathologic examination is usually definitive.
The complications of cervical cancer, for the most part, are those related to tumor size or invasion, necrosis of the tumor, infection, and metastatic disease. The natural history of the disease was outlined earlier. There are also problems pertaining to treatment of the disease (eg, radical surgery or radiation therapy; see next section, Treatment).
Invasive carcinoma of the cervix spreads primarily by direct extension and lymphatic dissemination. The therapy of patients with cervical cancer needs to address not only the primary tumor site, but also the adjacent tissues and lymph nodes. This is generally accomplished by either radical hysterectomy and pelvic lymphadenectomy, radiation with concomitant chemotherapy, or a combination thereof.
Treatment of Early-Stage Disease (Stage Ia2 to Iia2)
Patients with early-stage cervical cancer may be treated either with radical hysterectomy and pelvic lymphadenectomy or with primary radiation with concomitant chemotherapy. The overall 5-year cure rates for surgery and for radiation therapy in operable patients are approximately equal. The advantages of surgery are that the ovaries may be left intact and be transposed out of the radiation field if adjuvant postoperative therapy appears necessary, that the extent of disease can be determined surgicopathologically, and that grossly metastatic lymph nodes can be resected. Furthermore, surgery may be more appropriate in sexually active women with early-stage disease as radiation causes vaginal stenosis and atrophy. Adjuvant radiation with or without concomitant chemotherapy is administered to selected patients at increased risk for recurrence following radical hysterectomy.
Radical Hysterectomy & Therapeutic Lymphadenectomy
Radical hysterectomy (techniques initially described by Wertheim, Meigs, and Okabayashi) with pelvic lymphadenectomy is the surgical procedure for invasive cancer limited to the cervix and upper vagina (stages I and II). The operation is technically difficult and should be performed only by those experienced in radical pelvic surgery. Surgery involves dissection of the ureters from the paracervical structures so that the ligaments supporting the uterus and upper vagina can be removed. When the operation is done vaginally, a deep Schuchardt (paravaginal) incision is required for exposure. Five different types of hysterectomy have been described based on the extent of parametrial dissection and vaginal tissue removed (Table 48–4). Typically, a type I hysterectomy is indicated for patients with stage IA1 disease. An alternative treatment is cervical conization in the young patient wishing to preserve fertility. Stage IA2 to IIA2 can be treated with a type II (modified radical) or type III (radical) hysterectomy. It is rarely necessary to remove as much vaginal tissue as was initially recommended. As long as complete tumor clearance can be provided, a modified radical hysterectomy appears to provide therapeutic outcomes comparable to a radical hysterectomy for stage IB and IIA disease, but with shorter operating time and lower urologic morbidity. Full pelvic lymphadenectomy is indicated at the time of radical hysterectomy, followed by para-aortic lymphadenectomy for tumors larger than 2 cm or those with suspicious pelvic lymph nodes. Resection of all grossly involved lymph nodes provides a distinct survival advantage. Microscopic evaluation of the lymph nodes allows for tailoring of the postoperative radiation field, if indicated.
Table 48–4. Types of Hysterectomy Based on Radicality. ||Download (.pdf)
Table 48–4. Types of Hysterectomy Based on Radicality.
|Type of Hysterectomy||Principles of Procedure|
|Type I||Extrafascial hysterectomy with removal of all cervical tissue without dissecting into the cervix itself.|
|Type II||The uterine artery is ligated where it crosses over the ureter. The uterosacral and cardinal ligaments are divided midway toward their attachment to sacrum and pelvic sidewall. The upper third of the vagina is resected.|
|Type III||The uterine artery is ligated at its origin from the superior vesical or internal iliac artery. Uterosacral and cardinal ligaments are resected at their attachments to the sacrum and pelvic sidewall. The upper half of the vagina is resected.|
|Type IV||The ureter is completely dissected from the vesicouterine ligament, the superior vesical artery is sacrificed, and three-fourths of the vagina is resected.|
|Type V||Involves the additional resection of a portion of the bladder or the distal ureter with ureteral reimplantation into the bladder.|
Adjuvant Postoperative Radiation with or Without Concomitant Chemotherapy
Postoperative adjuvant radiation therapy with concomitant chemotherapy is indicated in women with localized cervical cancer at high risk for recurrent disease, such as positive lymph nodes, positive or close resection margins, or microscopic parametrial involvement. In this setting, adjuvant radiation with platinum-based chemotherapy is superior to adjuvant radiation alone, with an improvement in the 4-year progression-free interval from 63% to 80%. Women with intermediate-risk factors for recurrent disease, such as large tumor size, deep cervical stromal invasion, and lymphovascular space invasion, also benefit from postoperative adjuvant radiation. These patients have an improved 2-year recurrence-free survival of 88% with adjuvant radiation versus 79% without adjuvant therapy. Whether the addition of chemotherapy to the adjuvant radiation further improves outcomes for women with intermediate-risk factors is currently under investigation.
Primary Radiation with Concomitant Chemotherapy
For the treatment of early cervical cancer (stages IA to IIA), primary therapy with definitive radiation or radical surgery followed by tailored radiation if indicated by the surgical findings produces comparable outcomes. The choice of treatment depends on the tumor size, the general condition of the patient, and patient preferences. Surgery is often preferred for young patients in the hope of preserving ovarian function. If it is likely that the patient will need postoperative radiation therapy, transposition of the ovaries to a location outside the radiation field can be performed. The main argument for primary chemoradiation exists in patients with larger tumors, due to the added morbidity of triple-modality therapy (see later section Special Situations; bulky stage IB2 and IIA2 cervical cancer). For primary radiation of cervical cancer, external-beam radiation is used in combination with intracavitary irradiation (see Chapter 52). At least 5 controlled trials have demonstrated the superiority of radiation with concomitant platinum-based chemotherapy over radiation alone. This has led to the adoption of radiation plus concomitant chemotherapy as the standard of care whenever radiation therapy is given for the treatment of cervical cancer over a broad spectrum of disease stages.
Treatment of Locally Advanced Disease (Stage IIB to Iva)
Patients with locally advanced cervical cancer are best treated with primary radiation (external beam plus brachytherapy; see Chapter 52) with concomitant chemotherapy. Extended-field radiation should be considered in the presence of para-aortic lymph node metastases documented at surgical staging or by imaging, especially when biopsy confirmed and in the absence of other systemic metastases. The benefit of cisplatin-based combined-modality therapy over radiation alone for advanced disease has been demonstrated in at least 3 randomized controlled trials, which found a 30–50% reduction in the risk of death from cervical cancer for patients treated with chemoradiation compared to those treated with radiation alone. This difference is most significant for patients with stage II disease (and bulky IB disease) in whom, in 1 study, chemoradiation, compared to radiation alone, improved 5-year survival rates from 58% to 77%. For patients with more advanced disease, there is still significant benefit, but it appears to be less pronounced. The optimal drug regimen is not known. Many experts recommend weekly cisplatin concomitantly with radiation. A recent study suggested the superiority of weekly combination cisplatin/gemcitabine during chemoradiation. However, the experimental group also received 2 additional cycles of adjuvant cisplatin/gemcitabine after brachytherapy and toxicity was significant. It is unclear what proportion of the improvement in outcome can be attributed to the multiagent chemoradiotherapy versus the adjuvant chemotherapy. This question is currently being investigated by the Gynecologic Cancer Intergroup.
Treatment of Disseminated Primary (Stage Ivb) & Persistent or Recurrent Disease
The use of chemotherapeutic agents in the treatment of cervical carcinoma has been discouraging. This is partly because most patients who may be candidates for this type of treatment either present with disseminated disease or have cancer that has already failed to respond to radical surgery or radiation therapy. In this setting, chemotherapy is generally palliative and not curative. Modest activity in recurrent or disseminated cervical cancer has been observed with single-agent cisplatin, ifosfamide, paclitaxel, and vinorelbine. If the patient can tolerate it, multiagent chemotherapy is preferred as it is associated with significantly higher response rates and longer progression-free survival. There is also a small overall survival advantage to multiagent chemotherapy with cisplatin and topotecan. Combination therapy using paclitaxel and platinum offers very similar outcomes, with response rate and median survival time of 36% and 9.7 months, compared to 27% and 9.6 months, respectively, for cisplatin and topotecan. Other acceptable combination regimens include cisplatin/vinorelbine and cisplatin/gemcitabine. Surgical resection of lung metastases is an alternative to palliative chemotherapy for highly selected patients with isolated, potentially resectable pulmonary metastases. Palliative radiation therapy may be indicated, especially for the control of symptoms, such as pain or hemorrhage. If a patient develops a palpable mass in the left supraclavicular region, it can be palliated with radiation therapy with concomitant chemotherapy, with or without resection.
Total Pelvic Exenteration for Isolated Central Pelvic Recurrence of Disease
Patients who develop a central recurrence of cervical cancer after primary therapy with radiation or after surgery followed by radiation may be candidates for this extensive, potentially curative surgical procedure if a complete evaluation fails to reveal evidence of metastatic disease. In a small proportion of patients with cancer of the cervix treated initially with radiation, a small recurrence of the cancer may be noted centrally within the cervix. A radical hysterectomy may be an alternative to total pelvic exenteration in this selected subgroup of patients. Surgery is the only potentially curative method of treating cancers that persist or recur centrally following adequate radiation therapy. In such instances, pelvic exenteration is often necessary to make certain that all of the cancer has been removed.
Pelvic exenteration is one of the most formidable of all gynecologic operations and requires removal of the bladder, rectum, and vagina, along with the uterus if hysterectomy has not yet been performed. This is followed by the reconstructive phase of the procedure. Urinary diversion needs to be provided, necessitating the creation of either a continent ileocolonic pouch or a noncontinent ileal conduit. In either case, a stoma is created in the anterior abdominal wall. If extensive rectal resection was required, a sigmoid colostomy serves for the passage of feces. If a low rectal anastomosis could be accomplished, a temporary diverting colostomy is recommended for all patients who have received prior radiation. The vagina can be reconstructed using various myocutaneous flaps, such as vertical rectus abdominis or gracilis myocutaneous flaps. Depending on the location of the lesion, an anterior (preservation of the rectosigmoid) or posterior (preservation of the bladder) exenteration is at times an alternative.
Because of the high surgical morbidity and mortality rates, stringent criteria are necessary to justify these procedures. Pelvic exenteration should be reserved primarily for problems that cannot be effectively managed in any other manner. In essence, this means (1) a biopsy-proven persistence or recurrence of cervical cancer following an adequate course of radiation therapy or radical surgery in which the recurrent or persistent tumor occupies the central portion of the pelvis (without metastases) and is completely removable; and (2) a patient who is able to cope with the urinary and fecal stomas in the abdomen created by the operation. Both psychological and physical preparation of the patient for this operation and its aftermath are of vital importance. Because of the extreme difficulties encountered in making an accurate assessment preoperatively, only about half of the patients explored for a total pelvic exenteration will intraoperatively be confirmed to have resectable, nonmetastatic disease. Favorable prognostic factors in addition to an isolated central pelvic recurrence with no side wall fixation are a long disease-free interval and size of the recurrence < 3 cm in diameter. The 5-year survival rate following pelvic exenteration for recurrent cervical cancer averages 30–40%.
Comprehensive care of a patient with cancer involves, in addition to antitumor therapy, good symptom relief and personal and family support. The palliative care for patients with progressive cervical cancer poses many challenges. The emphasis should be to facilitate comfort, dignity, autonomy, and personal rehabilitation and development, especially in the face of an incurable disease.
Most patients with progressive cervical cancer eventually develop symptoms related principally to the site and extent of the malignant disease. Ulceration of the cervix and adjacent vagina produces a foul-smelling discharge. Tissue necrosis and slough may initiate life-threatening hemorrhage. If the bladder or rectum is involved in the tissue breakdown, fistulas result in incontinence of urine and feces. Pain caused by involvement of the lumbosacral plexus, soft tissues of the pelvis, or bone is frequently encountered in advanced disease. Ureteral compression leading to hydronephrosis and, if bilateral, to renal failure and uremia is a common terminal event. The comfort and well-being of the patient can be considerably enhanced even though cure cannot be effected. A foul, purulent discharge may be ameliorated by astringent douches and antimicrobial vaginal creams or suppositories. Hemorrhage from the vagina often can be controlled by packing the area with gauze impregnated with a hemostatic agent; occasionally, emergent radiation or hypogastric artery embolization is indicated.
Current management of severe pain combines the use of a long-acting narcotic such as morphine or a transdermal fentanyl patch with short-acting narcotics for breakthrough pain and nonsteroidal anti-inflammatory agents. Anxiolytics and antidepressants may be of considerable value. For patients with significant pain who are no longer responding to oral medications, a subcutaneous or intravenous morphine drip can be started. In patients with lower back or extremity pain, a peridural catheter can be placed and connected to a subcutaneous pump with a reservoir for continuous morphine instillation. This method gives pain relief without the sedating effects of oral and parenteral narcotics.
Radiation therapy may be very helpful in the relief of pain caused by bony metastases and in the treatment of lesions that recur following primary surgical treatment of cervical cancer. In general, if initial therapy was accomplished by adequate radiation therapy, retreatment is contraindicated because it does little good and carries the potential of massive radiation necrosis.
The definitive diagnosis of microinvasive carcinoma of the cervix can only be made by conization. These patients may be treated by simple abdominal or vaginal hysterectomy. For a young woman desiring to maintain fertility, conization only is an acceptable treatment modality for microinvasive carcinoma with a depth of invasion of 3 mm or less, if the conization margins are negative, and if there is no evidence of lymphovascular space invasion. If conization margin and endocervical sampling are positive, the risk of residual disease is as high as 33%. In this case, repeat conization should be performed if uterine preservation is the goal. FIGO staging is not influenced by the presence of lymphovascular space invasion, which occurs in close to 10% of patients with stage IA1 disease. These patients have a small but significant risk for lymph node metastases to parametrial and pelvic lymph nodes. This subgroup of patients should therefore be treated like patients with stage IA2 disease.
Over the past 2 decades, radical trachelectomy has evolved as an alternative to radical hysterectomy in carefully selected young women with early-stage (IA2 or small IB1) cervical cancer and no evidence of lymph node metastases who wish to preserve fertility. A preoperative MRI is critical for treatment planning as it allows for measurement of the distance between the upper margin of the lesion and the isthmus. The radical trachelectomy can be performed transvaginally or abdominally via open or robotic approach; ideally the cervix is amputated 1 cm above the tumor to optimize oncologic outcome and 1 cm below the isthmus to maintain some cervical function for future pregnancies. An open or minimally invasive therapeutic lymphadenectomy is performed, and following radical resection of the cervix, a cerclage is placed. Experience with this technique is growing, and the oncologic outcome, with recurrence rates <5% and mortality rates of 2–3%, is comparable in carefully selected patients to radical hysterectomy. A review of pregnancy outcomes in women who underwent radical trachelectomy revealed that 40% of women conceived following radical trachelectomy. Of those women who do conceive, 16–20% have a first-trimester abortion, close to 10% have a second-trimester pregnancy loss, 25% have a preterm delivery, and 42% deliver a live born infant at term. The majority of successful pregnancy outcomes have occurred with a cerclage in place.
The management of patients with stage IB2 and bulky IIA2 disease is a matter of considerable debate. Proposed management strategies include the following.
Primary Radiation Therapy with Concomitant Chemotherapy & the Option of a Subsequent Adjuvant Extrafascial Hysterectomy
Radiation therapy is usually recommended for patients with bulky cervical cancers with the addition of concomitant chemotherapy. Many of these tumors, however, contain hypoxic central areas that do not respond well to radiation, as is reflected in a 15–35% pelvic failure rate. This provides the rationale for the performance of an adjuvant hysterectomy following radiation, which is associated with a significant reduction in pelvic recurrences to 2–5%. However, the impact of adjuvant hysterectomy on extrapelvic recurrences and survival is less well established.
Primary Radical Hysterectomy & Therapeutic Lymphadenectomy, Followed by Tailored Radiation with Concomitant Chemotherapy When Indicated by Pathologic Findings
The potential benefits of this approach include the removal of the large primary tumor, complete surgical staging with the opportunity to resect any grossly involved lymph nodes, and the preservation of ovarian function as ovarian transposition can be performed if adjuvant radiation therapy is likely. If postoperative radiation becomes necessary, the radiation field can be tailored to the surgicopathologic findings. The resection of macroscopically involved lymph nodes has a therapeutic benefit because it improves survival to that of patients with microscopic lymph node metastases only. A primary surgical approach should be taken in patients with acute or chronic pelvic inflammatory disease, an undiagnosed coexistent adnexal mass, or anatomic alterations that make radiation therapy difficult.
Neoadjuvant Chemotherapy Followed by Radical Hysterectomy and Lymphadenectomy & Subsequent Chemoradiation When Indicated by Pathologic Findings
Neoadjuvant chemotherapy, frequently 3 cycles of platinum-based combination therapy followed by radical hysterectomy and lymphadenectomy, has been proposed as a treatment strategy for these patients. Neoadjuvant chemotherapy is reported to improve the resectability of bulky lesions, pelvic disease control, and possibly long-term survival. Although this is a provocative treatment strategy, in most studies, patients ultimately received multimodality treatment with chemotherapy, radical surgery, and radiation, and it remains unclear whether the use of neoadjuvant chemotherapy followed by surgery gives superior long-term results in the era of modern chemoradiotherapy. This question is currently being studied in phase III trials by the European Organization for the Research and Treatment of Cancer.
Carcinoma of the Cervix during Pregnancy
Invasive carcinoma of the cervix in pregnancy is found more frequently in areas where routine prenatal cytologic examination is done. Abnormal cervical cytology in pregnancy calls for immediate colposcopic evaluation and any other diagnostic modalities necessary to exclude invasive cancer (see section on preinvasive disease).
Invasive cervical cancer complicates approximately 0.05% of pregnancies. As is the case with nonpregnant patients, the principal symptom is bleeding, but the diagnosis is frequently missed because the bleeding is assumed to be related to the pregnancy rather than to cancer. The possibility of cancer must be kept in mind. The diagnosis and management of invasive cervical cancer during pregnancy present the patient and the physician with many challenges. Pregnancy does not appear to affect the prognosis for women with cervical cancer, and the fetus is not affected by the maternal disease, but may suffer morbidity from its treatment (eg, preterm delivery).
If the pregnancy is early and the disease is stage I to IIA, radical hysterectomy and therapeutic lymphadenectomy can be performed with the fetus left in situ, unless the patient is unwilling to terminate the pregnancy. Women at a gestational age closer to fetal viability or who are unwilling to lose the baby may decide to continue the pregnancy after careful discussion regarding the maternal risks. With early-stage disease (≤stage IB1/IIA1), the literature supports expectant management with careful serial examinations to exclude disease progression as a reasonable choice. With more advanced disease (≥ stage IB2/IIA2), neoadjuvant chemotherapy may offer an opportunity to delay definitive therapy until fetal maturity while reducing maternal risks potentially associated with treatment delay. Delivery in patients with cervical dysplasia and CIS may be via the vaginal route. Patients with invasive cervical cancer should be delivered by caesarean section to avoid potential cervical hemorrhage and dissemination of tumor cells during vaginal delivery. A caesarean radical hysterectomy with therapeutic lymphadenectomy is the procedure of choice for patients with stages IA2–IIA disease as soon as fetal maturity is established.
As in the nonpregnant patient, radiation with concomitant chemotherapy is used for the treatment of more advanced disease. Irradiation may be carried out with the expectation of spontaneous abortion. In selected cases with locally advanced disease in which the patient declines pregnancy termination, consideration may be given to neoadjuvant chemotherapy in an effort to prevent disease progression during the time needed to achieve fetal maturity. Delivery should be by caesarean section. A lymphadenectomy can be performed at the same time. Postpartum the patient should receive chemoradiation following guidelines established for the nonpregnant patient.
Carcinoma of the Cervical Stump
About 2% of all cervical cancers occur in the cervical stump. Early-stage cervical cancer noted on a cervical stump (left in situ following supracervical hysterectomy for an unrelated indication) should be treated with radical trachelectomy and therapeutic lymphadenectomy in the medically fit patient. Surgery is preferred over chemoradiation in this setting as the delivery of an adequate radiation dose may be difficult in a patient with a short cervical stump. However, radiation with concomitant chemotherapy is the preferred treatment modality for patients with more advanced disease.
Cervical Cancer Incidentally Diagnosed after Simple Hysterectomy
Women who are found to have microinvasive disease after a simple hysterectomy do not require any additional therapy. Patients with invasive disease who do not have gross parametrial disease are candidates for a radical parametrectomy, upper vaginectomy, and lymphadenectomy. This approach may be particularly desirable for young women in whom ovarian function can be preserved or for any surgically fit women with enlarged lymph nodes that should be resected prior to chemoradiation. Indications for chemoradiation follow the same guidelines as outlined earlier. Chemoradiation may be associated with less morbidity and comparable oncologic outcomes.
The operative mortality rate in radical hysterectomy with lymphadenectomy has been reduced to <1%. The most common complication is prolonged bladder dysfunction. Approximately 75% of patients have adequate recovery of bladder function within 1–2 weeks after radical hysterectomy, and most patients will have satisfactory voiding function by 3 weeks. Serious complications include fistula formation; ureterovaginal fistula is the most common type (1–2%), followed by vesicovaginal and rectovaginal fistulas. Modified radical hysterectomy, as compared to radical hysterectomy, is associated with a shorter operating time, a more rapid return of bladder function, and fewer fistulas. Other complications are urinary tract infections, lymphocysts and lymphedema, wound sepsis, dehiscence, thromboembolic disease, ileus, postoperative hemorrhage, and intestinal obstruction.
The surgical mortality rate from pelvic exenteration has been reduced from approximately 25% to <5%, but as many as 50% of patients experience major morbidity. Complications include intraoperative and postoperative hemorrhage, infectious morbidity, urinary fistulas or obstruction, urinary pouch dysfunction, pyelonephritis, bowel obstruction or intestinal leaks and fistulas, stomal retraction, electrolyte disturbances, and other less common occurrences.
Radiation Therapy with Concomitant Chemotherapy
Approximately 35% of patients with invasive cervical cancer will have recurrent or persistent disease following therapy. Approximately 50% of deaths from cervical cancer occur in the first year after treatment, another 25% in the second year, and 15% in the third year. This explains the generally accepted schedule of posttreatment surveillance in asymptomatic patients with more frequent visits initially. Symptomatic patients should be evaluated with appropriate examinations immediately when symptoms occur. The most common signs and symptoms of recurrent malignant disease are a palpable tumor in the pelvis or abdomen, ulceration of the cervix or vagina, pain in the pelvis, back, groin, and lower extremity, unilateral lower extremity edema, vaginal bleeding or discharge, supraclavicular lymphadenopathy, ascites, unexplained weight loss, progressive ureteral obstruction, and cough (especially with hemoptysis or chest pain).
The Society of Gynecologic Oncologists has recently developed risk-stratified recommendations for the posttreatment follow-up of patients with cervical cancer. These are summarized in Table 48–5.
Table 48–5. Cervical Cancer Surveillance Recommendations. ||Download (.pdf)
Table 48–5. Cervical Cancer Surveillance Recommendations.
|0–12 Months||12–24 Months||24–36 Months||3–5 Years||>5 Years|
|Review of symptoms and physical exam|
|Low risk (early stage, treated with surgery alone, no adjuvant therapy)||Every 6 mo||Every 6 mo||Every 6 mo*||Every 6 mo*||Every 6 mo*|
|High risk (advanced stage, treated with primary chemo/RT or surgery plus adjuvant therapy)||Every 3 mo||Every 3 mo||Every 3 mo||Every 3 mo||Every 3 mo*|
|Routine radiographic imaging (CXR, PET/CT, MRI)||Insufficient data to support routine use||Insufficient data to support routine use||Insufficient data to support routine use||Insufficient data to support routine use||Insufficient data to support routine use|
|Recurrence suspected||CT and/or PET scan||CT and/or PET scan||CT and/or PET scan||CT and/or PET scan||CT and/or PET scan|
The major prognostic factors affecting survival are stage, lymph node status, tumor volume, depth of cervical stromal invasion, lymphovascular space invasion, and to a lesser extent, histologic type and grade. After stage of disease, lymph node status is the most important prognostic factor. For example, following radical surgery, patients with stage IB or IIA disease have a 5-year survival of 88–96% with negative lymph nodes, compared to 64–73% in the presence of lymph node metastases.
Table 48–6 summarizes survival rates by stage of disease. These are based on the FIGO Annual Report on the Results of Treatment in Gynecological Cancer, in which results of treatment for each stage of cervical cancer are reported by more than 100 participating institutions worldwide. The results are equated in terms of 5-year cure rates, or those patients who are living and show no evidence of cervical cancer 5 years after beginning therapy.
Table 48–6. Survival of Patients with Cervical Cancer Based on International Federation of Gynecology and Obstetrics (FIGO) Stage. ||Download (.pdf)
Table 48–6. Survival of Patients with Cervical Cancer Based on International Federation of Gynecology and Obstetrics (FIGO) Stage.
|Stage||Number of Patients (%)||1 Year||2 Years||5 Years|
Recurrences following radiation therapy are not often centrally located and thus amenable to exenteration procedures. Only approximately 25% of recurrences are localized to the central portion of the pelvis. The most common site of recurrence is the pelvic side wall.
Anderson B, LaPolla J, Turner D, et al. Ovarian transposition in cervical cancer. Gynecol Oncol
Ault KA. Vaccines for the prevention of human papillomavirus and associated gynecologic diseases: a review. Obstet Gynecol Surv
2006;61(6 Suppl 1):S26–S31.
Averette HE, Nguyen HN, Donato DM, et al. Radical hysterectomy for invasive cervical cancer: a 25-year prospective experience with the Miami technique. Cancer
Benedet JL, Bender H, Jones H 3rd, et al. FIGO staging classifications and clinical practice guidelines in the management of gynecologic cancers. FIGO Committee on Gynecologic Oncology. Int J Gynaecol Obstet
Benedet JL, Odicino F, Maisonneuve P, et al. FIGO annual report: carcinoma of the cervix uteri. Int J Gynaecol Obstet
2003; 83(Suppl 1):41–47.
Chemoradiotherapy for Cervical Cancer Meta-analysis Collaboration (CCCMAC). Reducing uncertainties about the effects of chemoradiotherapy for cervical cancer: individual patient data meta-analysis. Cochrane Database Syst Rev
Cosin JA, Fowler JM, Chen MD, et al. Pretreatment surgical staging of patients with cervical carcinoma: the case for lymph node debulking. Cancer
Dargent D, Martin X, Sacchetoni A, et al. Laparoscopic vaginal radical trachelectomy: a treatment to preserve the fertility of cervical carcinoma patients. Cancer
Dueñas-González A, Zarbá JJ, Patel F, et al. Phase III, open-label, randomized study comparing concurrent gemcitabine
and radiation followed by adjuvant gemcitabine
versus concurrent cisplatin
and radiation in patients with stage IIB to IVA carcinoma of the cervix. J Clin Oncol
Eifel PJ, Thoms WW Jr, Smith TL, et al. The relationship between brachytherapy dose and outcome in patients with bulky endocervical tumors treated with radiation alone. Int J Radiat Oncol Biol Phys
Feeney DD, Moore DH, Look KY, et al. The fate of the ovaries after radical hysterectomy and ovarian transposition. Gynecol Oncol
FIGO Committee on Gynecologic Oncology. Revised FIGO staging for carcinoma of the vulva, cervix, and endometrium. Int J Gynecol Obstet
Gallion HH, van Nagell JR Jr, Donaldson ES, et al. Combined radiation therapy and extrafascial hysterectomy in the treatment of stage IB barrel-shaped cervical cancer. Cancer
Hacker NF, Wain GV, Nicklin JL. Resection of bulky positive lymph nodes in patients with cervical carcinoma. Int J Gynaecol Cancer
, Hellman K, Pettersson BF, et al. Carcinoma of the cervical stump: fifty years of experience. Oncol Rep
Hopkins MP, Lavin JP. Cervical cancer in pregnancy. Gynecol Oncol
Hricak H, Gatsonis C, Chi DS, et al. Role of imaging in pretreatment evaluation of early invasive cervical cancer: results of the intergroup study American College of Radiology Imaging Network 6651-Gynecologic Oncology Group 183. J Clin Oncol
Jemal A, Bray F, Center MM, et al. Global cancer statistics. CA Cancer J Clin
Jolley JA, Battista L, Wing DA. Management of pregnancy after radical trachelectomy: case reports and systematic review of the literature. Am J Perinatol
Keys HM, Bundy BN, Stehman FB, et al. Cisplatin
, radiation, and adjuvant hysterectomy compared with radiation and adjuvant hysterectomy for bulky stage IB cervical carcinoma. N Engl J Med
Landoni F, Maneo A, Cormio G, et al. Class II versus class III radical hysterectomy in stage IB–IIA cervical cancer: a prospective randomized study. Gynecol Oncol
Landoni F, Maneo A, Colombo A, et al. Randomised study of radical surgery versus radio-therapy for stage IB–IIA cervical cancer. Lancet
Lazo PA. The molecular genetics of cervical carcinoma. Br J Cancer
Lee YN, Wang KL, Lin MH, et al. Radical hysterectomy with pelvic lymph node dissection for treatment of cervical cancer: a clinical review of 954 cases. Gynecol Oncol
Long HJ 3rd, Bundy BN, Grendys EC
Jr, et al. Randomized phase III trial of cisplatin
with or without topotecan
in carcinoma of the uterine cervix: a Gynecologic Oncology Group study. J Clin Oncol
Metcalf KS, Johnson N, Calvert S, Peel KR. Site specific lymph node metastasis in carcinoma of the cervix: is there a sentinel node? Int J Gynecol Cancer
Monk BJ, Sill MW, McMeekin DS, et al. Phase III trial of four cisplatin-containing doublet combinations in stage IVB, recurrent, or persistent cervical carcinoma: a Gynecologic Oncology Group study. J Clin Oncol
Moore DH, Blessing JA, McQuellon RP, et al. Phase III study of cisplatin
with or without paclitaxel
in stage IVB, recurrent, or persistent squamous cell carcinoma of the cervix: a Gynecologic Oncology Group study. J Clin Oncol
Morris M, Eifel PJ, Lu J, et al. Pelvic radiation with concurrent chemotherapy compared with pelvic and para-aortic radiation for high-risk cervical cancer. N Engl J Med
Omura GA. Chemotherapy for stage IVB or recurrent cancer of the uterine cervix. J Natl Cancer Inst Monogr
Omura GA, Blessing JA, Vaccarello L, et al. Randomized trial of cisplatin
plus mitolactol versus cisplatin
in advanced squamous carcinoma of the cervix: a Gynecologic Oncology Group study. J Clin Oncol
Parkin DM, Pisani P, Ferlay J. Global cancer statistics. CA Cancer J Clin
Perez CA, Grigsby PW, Camel HM, et al. Irradiation alone or combined with surgery in stage IB, IIA, and IIB carcinoma of uterine cervix: update of a nonrandomized comparison. Int J Radiat Oncol Biol Phys
Peters WA III, Liu PY, Barrett RJ 2nd, et al. Concurrent chemotherapy and pelvic radiation therapy compared with pelvic radiation therapy alone as adjuvant therapy after radical surgery in high-risk early-stage cancer of the cervix. J Clin Oncol
Piver MS, Rutledge F, Smith JP. Five classes of extended hysterectomy for women with cervical cancer. Obstet Gynecol
Plante M, Renaud MC, François H, et al. Vaginal radical trachelectomy: An oncologically safe fertility-preserving surgery. An updated series of 72 cases and review of the literature. Gynecol Oncol
Plante M, Renaud MC, Hoskins IA, et al. Vaginal radical trachelectomy: a valuable fertility-preserving option in the management of early-stage cervical cancer. A series of 50 pregnancies and review of the literature. Gynecol Oncol
Roman LD, Felix JC, Muderspach LI, et al. Risk of residual invasive disease in women with microinvasive squamous cancer in a conization specimen. Obstet Gynecol
Rose PG, Bundy BN, Watkins EB, et al. Concurrent cisplatin-based radiotherapy and chemotherapy for locally advanced cervical cancer. N Engl J Med
Rotman M, Sedlis A, Piedmonte MR, et al. A phase III randomized trial of postoperative pelvic irradiation in stage IB cervical carcinoma with poor prognostic features: follow-up of a gynecologic oncology group study. Int J Radiat Oncol Biol Phys
Salani R, Backes FJ, Fung MF, et al. Posttreatment surveillance and diagnosis of recurrence in women with gynecologic malignancies: Society of Gynecologic Oncologists recommendations. Am J Obstet Gynecol
Sardi JE, Giaroli A, Sananes C, et al. Long-term follow-up of the first randomized trial using neoadjuvant chemotherapy in stage IB squamous carcinoma of the cervix: the final results. Gynecol Oncol
Sasieni PD, Cuzick J, Lynch-Farmery E. Estimating the efficacy of screening by auditing smear histories of women with and without cervical cancer. The National Coordinating Network for Cervical Screening Working Group. Br J Cancer
Sedlis A, Bundy BN, Rotman MZ, et al. A randomized trial of pelvic radiation therapy versus no further therapy in selected patients with stage IB carcinoma of the cervix after radical hysterectomy and pelvic lymphadenectomy: a Gynecologic Oncology Group study. Gynecol Oncol
Sood AK, Sorosky JI, Mayr N, et al. Cervical cancer diagnosed shortly after pregnancy: prognostic variables and delivery routes. Obstet Gynecol
Sutton GP, Bundy BN, Delgado G, et al. Ovarian metastases in stage IB carcinoma of the cervix: a Gynecologic Oncology Group study. Am J Obstet Gynecol
Tewari K, Cappuccini F, Gambino A, et al. Neoadjuvant chemotherapy in the treatment of locally advanced cervical carcinoma in pregnancy: a report of two cases and review of issues specific to the management of cervical carcinoma in pregnancy including planned delay of therapy. Cancer
Vizcaino AP, Moreno V, Bosch FX, et al. International trends in the incidence of cervical cancer: I. Adenocarcinoma and adenosquamous cell carcinomas. Int J Cancer
Walboomers JM, Jacobs MV, Manos MM, et al. Human papillomavirus is a necessary cause of invasive cervical cancer worldwide. J Pathol
Whitney CW, Sause W, Bundy BN, et al. Randomized comparison of fluorouracil
as an adjunct to radiation therapy in stage IIB–IVA carcinoma of the cervix with negative para-aortic lymph nodes: a Gynecologic Oncology Group and Southwest Oncology Group study. J Clin Oncol
Wright JD, NathavithArana R, Lewin SN, et al. Fertility-conserving surgery for young women with stage IA1 cervical cancer: safety and access. Obstet Gynecol